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In the last few years, CBD oil has been touted as a wonder cure, providing relief for a range of symptoms and medical conditions, from anxiety to pain. Many people suffering from chronic pain wonder whether CBD oil can truly produce the promised results. The short answer is that it can for many people. The more you learn about CBD oil for pain, the clearer it becomes that this natural substance offers relief, but it is not a miracle.

Top Picks for CBD Oil for Pain

To save you time in your search for a CBD oil for pain management, we gathered some of the best products in the industry. All of these products have certificates of analysis and come from reputable companies.

Problems with Traditional Pain Medications

Although there are many pharmaceutical medications to relieve pain, they all come with their own set of issues. CBD oil offers the same — or better — relief from the pain without the challenges. Here are just a few of the problems with traditional pain medications you will not need to worry about with CBD.

The biggest problem for many is the risk of dependency on traditional pain medications. Some prescription pain medications are more addictive than others, but many carry a risk of dependency. You only need to look at the current opioid epidemic to see this risk.

In addition to the risk of dependency, most prescription pain medications come with potential side effects that are common. Some common side effects of pain medications include constipation, drowsiness, clouded thinking, nausea, and slowed breathing. By contrast, those who take CBD rarely experience side effects. If they do, those effects are minor.

There is also the fact that most prescription medications will include a long list of ingredients which are necessary to create the consistency, to time the dose, and more. While this makes sense, it is bad news for those with allergies. It means that people with certain allergies are unable to take traditional pain medications. Furthermore, they may need to always read the ingredient list in search of a change in the formula that could lead to an allergic reaction.

By contrast, it is simple to find CBD oils that have minimal ingredients. Many only have the CBD extract and a carrier oil. This means that unless you are allergic to CBD itself, it should be much easier to find a CBD oil that does not produce an allergic reaction than finding a prescription medication that does.

Of course, this advantage only applies to those with allergies, but it is an important consideration.

What Is CBD Oil?

CBD oil contains CBD or cannabidiol. Cannabidiol is one of the more than 100 cannabinoids that naturally occur in the cannabis plant. CBD is non-psychoactive and comes from cannabis or hemp.

Other Uses of Hemp

In addition to being grown to produce CBD, hemp plants are also grown for the plant itself. Hemp is popular for fabric, rope, and other applications due to its strength. The hemp plant also grows quickly.

People Have Used CBD and Cannabis for Generations

The use of CBD oil, or the marijuana plant, is not new. In 2015, National Geographic published an article that detailed some of our ancient history of cannabis use. The writers outlined how archaeologists had found charred cannabis seeds in Siberian burial mounds that were probably from 3000 B.C. Chinese medicine has also been using cannabis for thousands of years. Our founding fathers grew hemp on their plantations.

Full-Spectrum vs. Isolate CBD Oil

When you start looking at CBD oils, you will notice that some say “full-spectrum,” “isolate,” or “THC-free.” These labels identify whether CBD is the only cannabinoid in the oil or if it contains others, as well. There are pros and cons of each option, depending on your preference.

THC Is Psychoactive

Most full-spectrum CBD oils will also contain low quantities of THC. THC, or tetrahydrocannabinol, is a psychoactive cannabinoid. In other words, THC produces the high associated with smoking marijuana. It will also show up on drug tests. As such, those who need their mind to be 100 percent clear or who need to pass drug tests should avoid CBD oils that contain THC. Look for a product labeled THC-free or an isolate.

The Entourage Effect

CBD oils that do contain THC will only have it in small quantities, typically under 0.03 percent. This is the legal limit for THC quantities in hemp products. Most people will not get high from this small quantity, but you may notice some changes to your mental state or hints of the psychoactive effects.

The main reason to opt for a CBD oil with THC in it is for the entourage effect. The entourage effect is the way that CBD and THC interact with each other to enhance the results. In other words, most people who take a CBD oil that contains THC will experience greater pain relief than those who take CBD oil without THC.

How Does CBD Relieve Pain?

For centuries, people have used cannabis to relieve pain, but we have only begun to understand how CBD offers this relief in recent years. From back pain to arthritis pain, CBD can provide relief.

Interactions with the Endocannabinoid System

The pain relief comes down to the way that CBD interacts with the endocannabinoid system. The CBD in cannabis attaches itself to your receptors. A cannabinoid receptor has many purposes, including managing pain. By contrast, THC attaches to CB1 receptors, where it creates the high associated with marijuana.

Essentially, CBD activates the body’s CB2 receptors. In doing so, it activates many pathways responsible for easing pain.

CB2 receptors are part of the immune system, which is why they are important for inflammation and pain. The CB1 receptors are in the brain, linked to appetite, memory, thinking, mood, and coordination.

Interactions with Glycerin Receptors

Some recent research suggests that CBD may also provide pain relief via interactions with glycerin receptors. These are in the spinal cord and brain and are part of the central nervous system. Many, but not all, people with chronic pain will experience disabling of these receptors due to inflammatory factors. When those receptors are disabled, this can increase the pain. CBD may reduce pain by re-enabling the receptors. This explanation for CBD’s pain-reduction properties still requires more research.

Pain-Relieving Benefits of CBD Oil

For those with chronic or temporary pain, CBD oil can provide plenty of benefits that focus on reducing your pain, whether you deal with multiple sclerosis, joint pain, or another type of pain.

Some conditions, like fibromyalgia, lead to chronic pain due to central nervous system dysfunctions. Some experts believe that the reduction in pain threshold, known as hypersensitivity, from fibromyalgia may be related to an endocannabinoid system deficiency. This same hypersensitivity to pain can also cause changes in moods and sleeping problems. However, CBD will reduce this sensitivity via its interactions with the endocannabinoid system. As a bonus, the treatment also improves the quality of sleep.

When you take CBD, you should notice your muscles begin to relax. Relaxed muscles will make it easier to move, something that is especially important for anyone with chronic pain who wants to engage in daily activities. It is especially important if you suffer from chronic pain and want to increase your mobility, build up muscle, or exercise. Those with chronic pain may find exercising is less painful if they take CBD oil before.

For those dealing with neuropathic pain, CBD can provide relief. This is due to CBD’s targeting of nervous system neurons that transmit pain signals. As a result, those who deal with neuropathic pain will experience an easing of their symptoms when taking CBD oil.

The anti-inflammatory properties of CBD also make it a great choice for reducing pain. It is common to experience tissue damage and severe pain due to chronic inflammation. CBD can reduce both short and long-term inflammation. This reduction in inflammation will reduce your related pain. It will also improve your everyday functionality since muscles, joints, or limbs will no longer be too inflamed to function properly.

Benefits Associated with Using CBD Oil for Pain Relief

In addition to the pain-related benefits of CBD oil, there are some additional advantages associated with this natural compound.

Depending on your type of chronic pain, you may experience a fear of being touched due to the additional pain that contact causes. That fear of being touched due to pain can spiral out of control and affect your daily life, even once you control your pain.

By reducing your pain, you will no longer have to worry as much about the pain associated with being touched. This should reduce your fear of someone accidentally brushing against you. You will also notice a reduction in this type of fear, due to the relaxation and anxiety-reducing benefits of CBD.

It is very common for those who cannot get a good night’s rest to experience more pain. The body needs sleep to complete natural healing and alleviate some of the pain associated with conditions like fibromyalgia and rheumatoid arthritis. Unfortunately, chronic pain makes it hard to fall asleep at night since it is nearly impossible to relax.

CBD helps you fall asleep and get that soothing rest by relieving the pain. After all, it is much easier to fall asleep when you are pain-free than if you are in pain. You are also less likely to wake up in the middle of the night from pain.

Additionally, CBD’s neuroprotective properties make it easier to fall asleep and stay asleep. The relaxation benefit of CBD helps you get a good night’s rest, so your body can take time to heal.

It is common for those experiencing chronic pain to also suffer from depression. If you cannot move around without experiencing pain, it makes it hard to remain positive as you go through your daily life.

In addition to relieving pain, CBD can also have a direct impact on depression. That is because cannabidiol triggers the release of mood-boosting chemicals such as serotonin. It also numbs the brain receptors that can worsen depression. The result can be feeling pain-free and happier with life. Studies have already supported CBD’s antidepressant-like effects.

CBD can also help you feel less anxious. It should be unsurprising that if you experience less pain, one of the main sources of anxiety in your life will reduce. In addition to this, CBD can help with an overall reduction in anxiety. You would not want to take advantage of this effect with cannabis since THC can sometimes increase anxiety or trigger paranoia.

By contrast, CBD will help relax your nerves. CBD can help create a general feeling of relaxation. It can also help you overcome situations that would potentially induce anxiety. This can also provide potential benefits for those with PTSD who experience anxiety as well as pain from the trauma.

These antianxiety properties of CBD are not limited to adults. One study from 2016 found potential in CBD oil for treating anxiety in children. The potential of cannabidiol for anxiety relief is so impressive that one study said there is “considerable potential” for using it to treat anxiety disorders.

Research Showing CBD Oil’s Pain-Relieving Abilities

Experts still need to conduct more research into CBD, as the gray legal area with cannabis held previous studies back. Even so, there is already plenty of promising research demonstrating that CBD can reduce pain, including both human studies and animal studies.

CBD for Arthritis Pain — December 2017

A study published in Pain in 2017 looked at the ability of CBD to prevent joint neuropathy and the pain associated with osteoarthritis. The researchers found evidence to support both of these functions of cannabidiol. They concluded that these abilities of CBD were due to its nerve-protective properties and anti-inflammatory properties on the joints.

CBD for Arthritis Pain — July 2016

Another study exploring CBD for arthritis pain, this study from the European Journal of Pain found that topically applied CBD relieved pain-related behaviors in rats with arthritis.

Cannabinoids for Hard-to-Manage Pain — February 2008

One study explored the effects of cannabinoids on treating pain in those with conditions that are hard to manage. This study, published in Therapeutics and Clinical Risk Management, showed that cannabinoids could reduce the pain of patients with conditions or pain that is hard to manage. Many patients in the study had cancer or multiple sclerosis, both of which are notorious for their challenging-to-treat pain.

This study focused on pain related to cancer. It gave patients an oral spray that combined CBD and THC, along with opioids. The study found that using the extract in addition to the opioids provided improved relief from pain compared to just the opioids.

There was another study in 2013 with a similar premise and similar findings, also using a THC-CBD oral spray. The two studies featured many of the same researchers.

Cannabis for Fibromyalgia — April 2011

A study from 2011 looked at the use of cannabis to treat the pain associated with fibromyalgia. This study found that patients experienced relief from pain, and most only had mild side effects. Those few side effects felt included drowsiness, dizziness, and dry mouth. For the study’s participants, those mild side effects were worth it for the relief provided.

CBD for Migraines — 2017

In 2017, a study looked at CBD and THC for treating migraines. The study had participants take either just THC or mostly CBD with a little THC. Patients who received both CBD and THC saw a drop in pain that was slightly more than that from a tricyclic antidepressant, amitriptyline, commonly prescribed for pain.

CBD for Chronic Pain — November 2018 Review

One review in 2018 looked at past studies on the effectiveness of CBD at treating chronic pain. The studies it examined took place as early as 1975 and as late as March 2018. The studies look at multiple types of pain, including fibromyalgia, cancer pain, and neuropathic pain. The review concluded that CBD could assist with overall pain management without negative effects.

The Legality of CBD Oil

Unfortunately, there is not a clear-cut answer to whether CBD oil is legal. The short answer is that it should be legal in your jurisdiction, but it is more complicated than this.

The Drug Enforcement Administration’s Stance

In 2015, the Drug Enforcement Administration (DEA) eased the requirements for clinical trials on CBD that are FDA-approved. Cannabis is still a Schedule I controlled substance, but the DEA loosened its restriction on the quantities of CBD allowed for use in studies.

The Agriculture Improvement Act of 2018 — The Farm Bill

The Farm Bill in 2018 made it CBD legal, as long as it comes from hemp. For CBD to be legal under the Farm Bill, it cannot have more than 0.3 percent THC, a figure that depends on the dry weight.

If CBD comes from cannabis instead of hemp, then it is not legal. Cannabis is still a Schedule I drug and illegal due to the Controlled Substances Act.

Importantly, for the CBD to be legal, it must not only meet the requirement of having 0.3 percent or less THC, but it must also be grown in accordance with the law. That means that a licensed producer who follows federal regulations must have grown the hemp in question.

FDA-Approved Prescription Medications with CBD

The FDA has already approved a medication that contains CBD. Epidiolex treats forms of epilepsy that are rare and severe. The FDA approval of this medication shows that the organization has a willingness to consider CBD in medicines, at least in certain situations.

State Laws

State laws also play a role in whether CBD is legal. Most states allow for hemp oil CBD since it is legal at the federal level. States with medical marijuana will also allow cannabis-based CBD if you have a medical cannabis license. Those with recreational marijuana typically allow cannabis-based CBD as long as you are of age.

The best way to stay within the law is to check the CBD regulations in your jurisdiction before buying or using any product. That said, it is rare for anyone to be prosecuted for using CBD products, although it could theoretically happen.

CBD Oil Is Safe

Before taking any supplement or medication, you should always research whether it is safe, and CBD is no exception. Research into cannabidiol is still relatively new. So far, CBD appears to be completely safe. Even the National Institute on Drug Abuse indicates that CBD is a safe drug and does not seem to have any addictive properties.

FDA Regulation

The caveat is that while CBD is safe, the FDA does not currently regulate products containing it. This means that the organization does not supervise CBD oil or hold CBD oil manufacturers to any standards. Instead, the FDA treats CBD oil as a supplement, with the lack of restrictions that come with it.

This may change in the future. In December 2018, an FDA statement announced the Agriculture Improvement Act of 2018. The same statement also indicated that the FDA treats products with cannabis or CBD, just like other FDA-regulated products. This may indicate that the FDA will begin regulating CBD products instead of treating them like supplements without regulation.

Most Manufacturers Offer Independent Lab Testing

Because the FDA does not regulate CBD oil, most manufacturers of CBD products, including oil, take steps to provide customers with confidence in their products. In addition to the common claims of “high-quality” or “organic” products, the most-respected manufacturers offer independent lab results on their products.

Companies will have a third-party lab test their products for purities and things such as heavy metals. They then publish these results on their website. This way, customers can have confidence in the products they buy, even if they are not FDA-regulated.

Potential Side Effects

There are minimal potential side effects associated with CBD oil for pain, especially compared to pharmaceutical pain medications. The largest risk is drowsiness, which is why you should not operate heavy machinery or drive when taking CBD oil. You may also experience changes in weight or appetite or diarrhea when taking CBD.

Potential Medication Interactions

There is one main caveat to the safety of CBD oil — it can interact with certain medications. Because of this, you should always discuss taking CBD with your doctor or pharmacist before you start taking it. Some of the common medications that CBD can interact with include clozapine, ondansetron, progesterone, testosterone, omeprazole, diazepam, ibuprofen, ketamine, warfarin, codeine, tramadol, alprazolam, morphine, and benzodiazepines. That list is far from conclusive. If you absolutely cannot talk to your doctor before taking CBD, at least look online to confirm it does not interact with any of your current medications.

Other Potential Interactions

There is also some indication that certain supplements and herbs may enhance the drowsiness from CBD. These include skullcap, sage, melatonin, catnip, calamus, Jamaican dogwood, and St. John’s wort, among others. The same source, MedlinePlus, indicates that taking CBD when eating a meal with high-fat content can increase your body’s absorption of cannabidiol, increasing your potential reaction.

How to Use CBD Oil for Pain

If you appreciate the idea of taking CBD oil for pain, then you will find yourself with many ways to incorporate it into your daily life. You can take CBD oil directly, mix it into something else, or purchase products that contain CBD oil.

Your decision of which method to use will likely depend on your personal preference, convenience, and the bioavailability of the CBD. Bioavailability refers to the amount that your body can effectively use, and it depends on the method chosen. For example, vaping CBD has a bioavailability of 40 percent, while oral CBD may have a bioavailability of just 6 percent.

Oils and Tinctures

Oils and tinctures are among the most common methods of taking CBD oil for pain or other health benefits. You take these orally, typically by placing a few drops of the substance under your tongue. Both the time for the effects to begin and the duration of the effects of CBD are moderate with this method.

Topical Treatments

If you want to target the pain relief from CBD on a specific part of your body, you may want to consider topical treatments. These are lotions and salves that include CBD, sometimes with additional ingredients to moisturize or soothe the skin. A study from the European Journal of Pain found that applying topical CBD reduces pain from arthritis.

Vaping

Vaping CBD oil lets you inhale it via a vape pen. This will deliver the cannabidiol directly into your system for quick absorption. However, since the effects begin sooner, they also start to wear off sooner than other methods. In addition to the nearly immediate relief associated with vaping CBD oil, many patients appreciate that various flavors are available.

CBD Capsules

You can also easily find capsules or soft gels containing CBD oil. These offer convenience via their pre-dosed nature. They will take a little longer to start working because the capsule must first travel through the digestive system.

CBD Gummies and Other Edibles

The final popular option is to eat CBD edibles, such as gummies. These are pre-dosed like capsules, offering convenience. However, they have the benefit of tasting better. Think of it as taking a chewable vitamin instead of the one you swallow. Gummies and edibles must pass through the digestive system before they can start working, but the effects should be among the longest lasting of any method.

Dosing for CBD Oil

There is no official recommendation on how much CBD oil you should take. This will depend on your level of pain, your weight, your genetics, your metabolism, and more. Experts agree that you should always start with a smaller dose and work your way up to a larger one if it does not provide relief. If you take too much CBD, you increase your risk of side effects. Most will suggest starting with an amount of CBD between 10 and 25 milligrams per day, then increase if necessary.

Choosing Your CBD Oil

If you suffer from chronic pain and want to try CBD oil, then you will have plenty of options available. How do you choose which one to try? Keep the following factors in mind.

Lab Testing

As mentioned, you should always opt for a CBD oil that has undergone independent lab testing. You want to be able to look at the lab results or a certificate of analysis to confirm potency and safety.

The Hemp

Look at where the hemp was grown and then check the regulations for growing hemp in that country. If the hemp was grown in the U.S., for example, you know it follows U.S. laws.

Potency

The potency will be an important decision for you. If you are new to using CBD, find a product with a low dose. If you find you need higher doses to experience relief, find an oil with a higher potency, so you do not need to take as much of it. Don’t forget to consider whether you want a THC-free product.

The Company

Do not forget to consider the reputation of the company manufacturing and selling the CBD oil. Read reviews and look for complaints against the company, so you know which ones to avoid.

Conclusion

Those who suffer from chronic pain may experience relief from CBD. Cannabidiol is non-psychoactive and comes from the cannabis plant. Numerous studies have shown that taking CBD can help provide pain relief from a range of conditions, including fibromyalgia, arthritis, and cancer. CBD is legal in most areas due to its lack of THC, and you should have no problem finding a CBD oil to help you with pain relief.

Taking CBD oil for pain bears minimal side effects, with the most common one being drowsiness. It is safe to use and available in various forms and doses depending on your needs. Start with a small dose when you begin using CBD oil and work your way up to a higher dose if you do not experience relief. In addition to pain relief, taking CBD should help with inflammation, anxiety, and depression.

Abdominal pain is one of the most common concerns that pregnant women express to their obstetricians. They wonder if their pain is something normal or if it is something to be worried about. They do not want to raise the alarm to their doctor if the problem is normal and should be expected during a typical pregnancy. In most instances, abdominal pain that is not severe is nothing most pregnant women need to worry about. However, there are exceptions to that rule. In all cases, a pregnant woman should always err on the side of caution and involve her doctor if she is worried about the problem.

What Causes Pregnancy Pain?

The overall changes to a pregnant woman’s body often lead to many pains. First, there is the weight gain, which can cause aches, including in the abdominal cavity. Second, some hormones naturally relax the joints all around the woman’s body in slow preparation for birth. Third, a pregnant woman may also notice pain that comes along with digestive changes, including heartburn and constipation. Finally, when labor is coming within the next few weeks, the body also changes more, which can lead to pregnancy pain all around the body.

What Is Normal Pregnancy Pain?

One common complaint of pregnancy pain is when the round ligaments around the abdomen stretch unexpectedly. It can happen with sudden movements, and it can happen one time and not happen again when a pregnant woman makes a repetitive motion. It can come as sharp pain across the abdomen, or it may come as a dull ache that is little more than annoying.

Another possible, and normal, pregnancy pain is back pain. It is due to the increased pressure the abdomen puts on the lower back, especially at the later stages of pregnancy when the baby reaches his or her full-term weight. The hormones going through the woman’s body relax the joints and ligaments specifically around the pelvis, which includes the area across the lower back. It can lead to constant back pain around the end of pregnancy.

Normal pregnancy pain also includes the pain that comes when labor begins. It is when the cervix opens enough to allow the baby to pass through and be delivered. This type of pain can be dull at first and slowly progress into a sharper pain, or it can be an overwhelming pain from the onset. It can also appear as abdominal pain, or it can show up as back pain. Some women have some combination of both abdominal and back pain during labor, and this often depends on the direction the baby is facing.

Are Braxton-Hicks Contractions Something to Worry About?

Many women face Braxton-Hicks contractions, especially during the second half of pregnancy. These are considered trial contractions for the woman’s body. It is the uterus trying to contract to make sure that everything goes well during labor and delivery. These contractions are considered benign by obstetricians, but they can be difficult to discern from traditional contractions. The differences between Braxton-Hicks contractions and those that are connected to labor include:

Managing Pregnancy Pain

For the most part, pregnant women find coping with pregnancy pain easier by staying active and listening to their bodies. The body gives off signals when it is getting overused or overwhelmed. Pregnant women need to listen to these signals and take it easy when their body indicates that it has had enough. Going into pregnancy and being inactive is likely going to increase the pain a woman goes through. Instead, go for regular walks, keep up with any exercise that the doctor says is safe, and rest when the body shows it needs to.

Another way of managing pain is making sure to remain hydrated. Dehydration can increase the pain a pregnant woman feels, and it can also cause an increase in pain that a pregnant woman goes through. Simply making sure to consume at least 100 ounces of water per day can be all she needs to do since the need for water is higher during pregnancy. If the pain is extreme or if it interferes with the ability for a normal daily routine, the woman needs to speak with her doctor about it.

What Is Serious Pregnancy Pain?

Pregnancy pain is difficult to discern at times. The same symptom could point to a urinary tract infection or a miscarriage in progress. The best way to know for sure if the issue is serious is to get a doctor’s advice on the specific type and location of the pain. Here are some general guidelines as to when the pain is serious and needs immediate attention.

Symptoms of Preterm Labor to Be on the Lookout For

Early labor happens to pregnant women between 37 weeks gestation and 39 weeks gestation. However, that is not considered preterm labor. Preterm labor is when a mother goes into labor before 37 weeks gestation. It means the baby has not fully developed and could be more susceptible to ailments or struggles at birth.

A baby born before 23 weeks is often considered too early to be viable. It means the baby likely passes away during or shortly after birth, so knowing the signs of preterm labor is crucial. If caught early enough, sometimes preterm labor can be stopped or stalled, buying the baby more time inside the womb to finish developing.

For pregnant women, any pain that is sharp, unexpected, and does not go away right away needs to be checked out by an obstetrician. It could be any number of things, including problems with the placenta, internal bleeding, or the baby struggling.

Cramping that feels similar to menstrual cramps is another sign pregnant women need to be wary of. Mild cramping can happen because of dehydration or being sick, but with hydration, the cramps should subside. If they do not, it could point to preterm labor.

Bleeding or watery discharge are also signs of preterm labor. These are serious signs of a problem that should never be ignored. It could point to the imminent delivery of the baby or that the baby is in danger. The sooner the pregnant woman can get to a hospital for an exam, the better.

Conclusion

Understanding the normal pregnancy pains, women can feel more in control over their pregnancy. It can be difficult to decide if there is a reason for concern, so hopefully, this gives pregnant women a sense of empowerment over whether they need to worry. When in doubt, a call to the doctor’s office is always the best option. It can be what needs to happen to save a woman and child from danger.


    RABDOMIOLISIS

    DEFINICION

    La rabdomiolisis es un síndrome causado por injuria en el músculo
    esquelético y la resultante liberación del contenido de las células
    musculares (mioglobina, potasio, fosfato, etc.) dentro del plasma.

    CAUSAS TOXICAS

    La rabdomiolisis se ha asociado con una variedad de toxinas y drogas.
    Estas pueden ya sea causar un efecto directo tóxico en los músculos
    (envenenamiento metabólico) o indirectamente predisponer a
    rabdomiolisis.

    Efecto Tóxico Directo:   Amatoxinas
                             Monóxido de carbono
                             Colchicina
                             Etilénglicol
                             Mordedura de ofidios

    Efectos Indirectos:      Excesiva hiperactividad muscular o rigidez
                             (distonía)
                             Convulsiones prolongadas
                             Hipertermia
                             Compresión muscular por inmovilidad
                             prolongada (coma)

    CAUSAS NO TOXICAS

    Coma o inmovilidad prolongada de cualquier causa
    Lesión muscular directa
    Actividad muscular excesiva
         Actividades deportivas de resistencia
         Convulsiones
    Inmunológicas
         Dermatomiositis
         Polimiositis
    Lesión muscular isquémica
         Lesión por aplastamiento
         Oclusión vascular
    Metabólicas
         Hipocalemia
         Hipofosfatemia
    Infecciones virales
         Coxakie
         Influenza

    CUADRO CLINICO

    La presentación clínica es extremadamente variable. En pacientes
    concientes, la principal queja puede ser sensibilidad muscular, 

    rigidez y calambres, acompañado por debilidad y pérdida de la función.
    Sin embargo, la mialgia puede estar ausente o ser mínima inicialmente
    (luego del ingreso). En pacientes comatosos, el hallazgo de
    endurecimiento de los brazos o piernas pueden sugerir rabdomiolisis.
    Los cambios en la piel debidos a lesión isquémica tisular
    (decolorarión, ampollas) pueden estar presentes en el área afectada.
    El examen físico puede revelar un edema muscular muscular duro que
    puede empeorar luego de la rehidratación parenteral. Cuando el edema
    muscular es severo puede resultar en un síndrome compartamental, con
    ausencia de pulsos.

    La orina oscura (roja o café) es una manifestación clásica de
    rabdomiolisis. Signos de deshidratación (debido a secuestro de fluídos
    en los músculos dañados) puede estar presente junto con oliguria. En
    la rabdomiolisis debido a envenenamiento severo los hallazgos
    musculares pueden ser pasados por alto si es que los hallazgos
    indicativos de la enfermedad subyacente (ejm: agitación extrema,
    convulsiones, hipertermia) dominan el cuadro clínico. Los signos
    relacionados con complicaciones de rabdomiolisis (ejemplo
    Hipercalemia, falla renal aguda, acidosis metabólica, coagulación
    intravascular diseminada y, raramente falla respiratoria) pueden
    igualmente constituir los principales hallazgos clínicos.

    INVESTIGACIONES RELEVANTES

    Una actividad sérica de la creatinfosfoquinasa mayor a cinco veces su
    valor normal (en ausencia de enfermedad cardíaca o cerebral) es el
    indicador más sensitivo de rabdomiolisis.

    La mioglobinemia puede resultar de la salida del contenido del miosito
    hacia el plasma. Cuando la destrucción muscular es aguda puede ocurrir
    una mioglobinuria extensa y causar  visibles cambios en la coloración
    de la orina (rojo-café). Una reacción positiva de Ortotoluidina 
    (Hematest), en ausencia de glóbulos rojos en la orina confirman la
    presencia de mioglobinuria.

    Los hallazgos de laboratorio que se pueden encontrar son:
    Hiperpotasemia, hipocalcemia, hiperfosfatemia, hiperuricemia,
    elevación sérica de úrea y creatinina, elevación de la TGO y HDL. La
    creatinina puede estar desproporcionalmente elevada en relación a la

    insuficiencia renal, debido a la liberación de creatinina preformada
    desde los músculos dañados.

    TRATAMIENTO

    El principal objetivo del tratamiento es mantener las funciones
    vitales:

     Diazepam en caso de excesiva actividad muscular (ejemplo
    agresividad, convulsiones), iniciar el tratamiento con diazepam (5-10
    mg intravenoso lento,  hasta un máximo de 30 mg).

     Líquidos se debe administrar cristaloides a fin de mantener una
    diuresis adecuada (>3-4 mls/hr).

     Furosemida/manitol

    Diuréticos: la furosemida o manitol pueden ser utilizados cuando la
    administración de líquidos por sí sola es inadecuada.

     Bicarbonato de sodio La alcalinización urinaria ha sido propuesta
    para prevenir la nefrotoxicidad por la mioglobina, sin embargo su
    efectividad no ha sido demostrada en forma concluyente.

     Sales de calcio

    La hipocalcemia es un hallazgo común en la rabdomiolisis,  raramente
    sintomática cuando se presenta por sí sola,  por lo que no necesita
    tratamiento.

     Hemodiálisis La diálisis está indicada sí existe falla renal aguda
    y/o se produzcan complicaciones con riesgo vital (ejemplo
    hipercalemia).
     Fasciotomía Está indicada raramente y puede asociarse con serias
    complicaciones.

    EVOLUCION CLINICA Y MONITOREO
    Monitoreo de los signos vitales

    Diuresis

    Rítmo cardíaco

    Sodio, potasio, calcio séricos

    Hematocrito/hemoglobina

    Gasometría arterial

    Creatinfosfoquinasa

    Creatinina y urea sérica

    ASAT (TGO), HDL

    Hemotest (reacción ortotoluidina):

    Si el hemotest es positivo, se debe descartar hematuria con un examen
    microscópico de orina.

    Recuento plaquetario, nivel de fibrinógeno, TP y TTP sirven para
    detectar trombocitopenia o coagulación intravascular diseminada.

    COMPLICACIONES POTENCIALES / SECUELAS
    La debilidad muscular prolongada es el hallazgo más frecuente en la
    rabdomiolisis. La neuropatía periférica con déficit neurológico
    permanente puede resultar por isquemia neuronal luego de un síndrome
    compartamental. La falla renal aguda secundaria a la rabdomiolisis
    tiene un buen pronóstico cuando se instaura tratamiento en forma
    temprana.

    AUTOR (ES) REVISADO POR:

    Autor:         Dr. T. Della Puppa, Centro Antiveleni, Milano, Italy.

    Revisado por:  Sao paulo 9/94, Cardiff 3/95, Berlin 10/95: A. Wong, T
                   Meredith, V. Danel.

    Traductores:   Miguel Brito, Daniela Pasqualatto y Javier Mallet
                   (Brazil, October 1999)
    

Summary for UKPID

 

   OPIOID ANALGESIC

    Kathryn Pughe, BSc (Hons) MRPharmS

 

    National Poisons Information Service (Newcastle Centre)

    Regional Drug & Therapeutics Centre

    Wolfson Building

    Claremont Place

    Newcastle upon Tyne

    NE1 4LP

    UK



    This monograph has been produced by staff of a National Poisons

    Information Service Centre in the United Kingdom.  The work was

    commissioned and funded by the UK Departments of Health, and was

    designed as a source of detailed information for use by poisons

    information centres.

 

    Peer review group: Directors of the UK National Poisons Information

    Service.



    PRODUCT DETAILS

 

    Name

 

         Generic             Alfentanil hydrochloride

         Proprietary         Rapifen,

                             Rapifen Intensive Care

 

    Chemical Group/Family

 

         Opioid analgesic

         BNF 4.7.2

 

    Reference Number

 

         CAS 71195-58-9 alfentanil

         CAS 69049-06-5 alfentanil HCl, anhydrous

         CAS 70879-28-6 alfentanil HCl, monohydrate

 

         Product licence

         0242/0091 (Rapifen)

         0242/0137 (Rapifen Intensive Care)

 

    Manufacturer/Supplier

 

         Janssen-Cilag Ltd

         PO Box 79

         Saunderton

         High Wycombe

         Bucks

         HP14 4HJ

 

         Tel  01494 567567

         Fax  01494 567568

 

    Presentation

 

         Rapifen

         Clear, colourless injection alfentanil HCl 0.5 mg/ml

         2 ml and 10 ml ampoules, packs of 10

 

         Rapifen Intensive Care

         Clear, colourless injection alfentanil HCl 5 mg/ml

         1 ml ampoules, packs of 10

 

    Physico-Chemical Properties

 

    Chemical structure

         C21H32N6O3HCl.H2O

         N-[1-[2-(4-Ethyl-5-oxo-2-tetrazolin-1-yl)ethyl]-4-

         (methoxymethyl)-4-piperidyl]propionanilide hydrochloride

         monohydrate

 

    Physical state at room temperature

         White crystalline powder

 

    Molecular weight (free base)

         471.0 (416.5)

 

    pKa (>N-)

         6.5

 

    Solubility

         in alcohol               1 in 5

         in water                 1 in 7

 

    Name

 

         Generic        Buprenorphine

         Proprietary    Temgesic

 

    Chemical Group / Family

 

         Opioid analgesics

         BNF 4.7.2

 

    Reference Number

 

         CAS 52485-79-7 buprenorphine

         CAS 53152-21-9 buprenorphine HCl

 

         Product licence numbers

         0063/0007 (0.3 mg inj)

         0063/0008 (0.2 mg tabs)

         0063/0009 (0.4 mg tabs)

 

    Manufacturer/Supplier

 

         Reckitt & Colman Products Ltd.,

         Dansom Lane,

         Hull

         HU8 7DS

 

         Tel: 01482 326151

         Fax: 01482 582526

 

    Presentation

 

         Temgesic Sublingual

         White 200 mcg tabs marked with a 2 and a sword symbol in blister

         pack of 5x10

         White 400 mcg tabs marked with a 4 and a sword symbol in blister

         pack of 5x10

 

         Temgesic Injection

         Colourless injection 300 mcg/ml,

         1 ml ampoules, packs of 5

 

    Physico-Chemical Properties

 

    Chemical structure

         C29H41NO4.HCl

         N-Cyclopropylmethyl-7-[1-(S)-hydroxy-1,2,2-trimethylpropyl]- 

         endoethano-6,7,8,14-tetrahydro-nororipavine

 

    Physical state at room temperature

         white odourless powder

 

    Molecular weight (free base)

         468

 

    pKa

         8.42, 9.92

 

    Solubility

         in alcohol     1 in 24

 

    Name

 

         Generic             Codeine phosphate

                             Compound prep -

                             Co-codamol, Co-codaprin

 

         Proprietary         Compound preparations -

                             Aspav, Codafen Continus, Galcodine,

                             Kaodene, Kapake, Migraleve, Panadeine,

                             Paracodol, Parake, Solpadol, Terpoin,

                             Tylex

 

                             Also in various OTC products

 

         Synonym / street    Schoolboy

 

    Chemical Group/Family

 

         Opioid analgesics

         BNF 4.7.2

 

    Reference Number

 

         CAS 52-28-8 (Codeine PO4 - anhydrous)

         CAS 41444-62-6 (Codeine PO4 - hemihydrate)

         CAS 5913-76-8 (Codeine PO4 - sesquihydrate)

 

    Manufacturer/Supplier

 

         Generic

 

    Presentation

 

         15 mg round white tabs in containers of 100

         30 mg round white tabs in containers of 100 or 500

         60 mg round white tabs in containers of 100

         25 mg/5 ml syrup bottles of 100 ml and 500 ml

         60 mg/ml inj in boxes of 10 amps

         15 mg/5 ml linctus bottles of 100 ml and 1L

         3 mg/5 ml paediatric linctus bottles of 100 ml and 1L

 

    Physico-Chemical Properties

 

    Chemical structure

         C18H21NO3.H3PO4.´H2O

         7,8-Didehydro-4,5alpha-epoxy-3-methoxy-N-methylmorphinan-

         6alpha-ol phosphate hemihydrate

 

    Physical state at room temperature

         fine, white, needle-shaped crystals or a white crystalline powder

 

    Molecular weight (free base)

         299.4

 

    pKa

         8.2

 

    Solubility

         in alcohol     1 in 325

         in water       1 in 4

 

    Name

 

         Generic             Dextromoramide tartrate

         Proprietary         Palfium

         Synonym / street    Peach palf

 

    Chemical Group / Family

 

         Opioid analgesics

         BNF 4.7.2

 

    Reference Number

 

         CAS 2922-44-3

 

         Product licence numbers

         0075/5015R (5 mg tabs)

         0075/0035R (10 mg tabs)

         0075/5014R (10 mg suppositories)

 

    Manufacturer/Supplier

 

         Boehringer Mannheim UK

         (Pharmaceuticals) Ltd,

         Simpson Parkway,

         Kirkton Campus,

         Livingston,

         West Lothian

         EH54 7BH

 

         Tel  01506 412512

         Fax  01506 411395

 

    Presentation

 

         Palfium

         White scored 5 mg tabs in blister packs of 60

         Peach scored 10 mg tabs in blister packs of 60

         Light cream 10 mg suppositories in packs of 10

 

    Physico-Chemical Properties

 

    Chemical structure

         C25H32N2O2.C4H6O6

         (d)-1-(3-Methyl-4-morpholino-2,2-diphenylbutyryl)- 

         pyrrolidine tartrate

 

    Physical state at room temperature

         white, amorphous or crystalline powder

 

    Molecular weight (free base)

         542.6 (392.5)

 

    pKa

         7.1

 

    Solubility

 

         in alcohol          1 in 85

         in water            1 in 25

 

    Name

 

         Generic        Dextropropoxyphene hydrochloride

         Proprietary    Doloxene

                        Compound preparations - 

                        Cosalgesic, Distalgesic, Doloxene Compound

 

    Chemical Group / Family

 

         Opioid analgesics

         BNF 4.7.2

 

    Reference Number

 

         CAS 1639-60-7

 

         Product licence number

         0006/5068

 

    Manufacturer/Supplier

 

         Eli Lilly & Co Ltd

         Dextra Court,

         Chapel Hill,

         Basingstoke,

         Hampshire,

         RG21 5SY

 

         Tel  01256 315000

         Fax  01256 315569

 

         Compound preparations available from APS, Berk, Cox, Dista,

         Norton, Sterwin

 

    Presentation

 

         Doloxene

         Opaque pink 65 mg caps marked Lilly H64 in blister packs of 10 x

         10

 

         Doloxene compound

         Light grey opaque cap, red opaque body marked H91 in blister

         packs of 100

 

    Physico-Chemical Properties

 

    Chemical structure

         C22H29NO2.HCl

         (d)-(1S,2R)-1-Benzyl-3-dimethylamino-2-methyl-1-phenylpropyl 

         proprionate hydrochloride

 

    Physical state at room temperature

         white to slightly yellow odourless powder

 

    Molecular weight (free base)

         375.9 (339.5)

 

    pKa (amino)

         6.3

 

    Solubility

         in alcohol     1 in 1.5

         in water       1 in 0.3

 

    Name

 

         Generic             Diamorphine hydrochloride

         Proprietary         Diagesil

         Synonym / street    Heroin; Boy; Brown sugar; Black tar; Chinese;

                             Chinese rock; Crap; Dana; Dujie; Elephant;

                             H;Harry; Horse; Joy powder; Junk; Mexican

                             brown;Noise; Persia; Poor man's speedball;

                             Rock; Rock'n roll; Rufus; Smack; Speedball;

                             Stuff; TNT; White elephant; White junk; White

                             stuff.

 

    Chemical Group / Family

 

         Opioid analgesics

         BNF 4.7.2

 

    Reference Number

 

         CAS 561-27-3 (diamorphine)

         CAS 1502-96-0 (diamorphine HCl)

 

         Product licence numbers

 

         5 mg inj       0039/5662

         10 mg inj      0039/5663

         30 mg inj      0039/5665

         100 mg inj     0039/0154

         500 mg inj     0039/0163

 

    Manufacturer/Supplier

 

         Generics -     Aurum, Berk, CP, Evans, Hillcross

 

         Evans Medical Ltd

         Evans House

         Regent Park

         Kingston Rd

         Leatherhead

         Surrey

         KT22 7PQ

 

         Tel  01372 364000

         Fax  01372 364190

 

    Presentation

 

         Round white scored 10 mg tabs in packs of 100 (Aurum)

         White / off-white powder for reconstitution, 5 mg, 10 mg, 30 mg,

         100 mg and 500 mg injections in boxes of 5 ampoules

 

    Physico-Chemical Properties

 

    Chemical structure

         C21H23NO5.HCl.H2O

         7,8-Dehydro-4,5-epoxy-N-methyl morphinan-3,6-diol diacetate

         hydrochloride

 

    Physical state at room temperature

         almost white crystalline powder

 

    Molecular weight (free base)

         423.9 (369.4)

 

    pKa

         7.6

 

    Solubility

         in alcohol          1 in 12

         in water            1 in 1.6

 

    Name

 

         Generic             Dihydrocodeine tartrate

         Proprietary         DF 118, DF 118 Forte, DHC Continus

                             Compound preparations -

                             Co-dydramol, Galake, Paramol, Remedeine,

                             Remedeine Forte

 

    Chemical Group / Family

 

         Opioid analgesics

         BNF 4.7.2

 

    Reference Number

 

         CAS 125-28-0 (dihydrocodeine)

         CAS 5965-13-9 (dihydrocodeine tartrate)

 

         Product licence numbers

         0337/0230 (DF118 Forte)

         0337/0196 (DF118 Inj)

         0337/0115 (60 mg tabs)

         0337/0140 (90 mg tabs)

         0337/0141 (120 mg tabs)

         0337/0197 (elixir)

         0530/0229 (30 mg tabs by Norton)

 

    Manufacturer/Supplier

 

         Napp, Aurum and generics

 

         Napp Laboratories Ltd

         Cambridge Science Park

         Milton Road

         Cambridge

         CB4 4GW

 

         Tel  01223 424444

         Fax  01223 424441

 

    Presentation

 

         Generics

         30 mg tabs bottles of 20, 100, 500

 

         Dihydrocodeine Elixir BP

         Brown syrup of 10 mg/5ml in bottles of 150 ml and 1 litre

 

         DF118 Injection

         Colourless solution of 50 mg/ml in boxes of 5 ampoules

 

         DF118 Forte Tablets

         Round, white 40 mg tabs marked with DF118 and Forte, in bottles

         of 100

 

         DHC Continus Tablets

         White capsule-shaped tablets

         60 mg tabs m/r, marked DHC 60 packs of 56

         90 mg tabs m/r, marked DHC 90 packs of 56

         120 mg tab m/r, marked DHC120 pack of 56

 

    Physico-Chemical Properties

 

    Chemical structure

         C18H23NO3.C4H6O6

         4,5-Epoxy-3-methoxy-17-methylmorphinan-6-ol tartrate

 

    Physical state at room temperature

         odourless white crystalline powder

 

    Molecular weight

         451.5

 

    pKa

         8.8

 

    Solubility

         in alcohol          sparingly

         in water            1 in 4.5

 

    Name

 

         Generic             Dipipanone hydrochloride

         Proprietary         Diconal (with 30 mg cyclizine)

         Synonym / street    Dike

 

    Chemical Group / Family

 

         Opioid analgesics

         BNF 4.7.2

 

    Reference Number

 

         CAS 467-83-4 (dipipanone)

         CAS 856-87-1 (dipipanone HCl)

 

         Product licence number

         0003/5027R

 

    Manufacturer/Supplier

 

         Glaxo Wellcome

         Stockley Park West

         Uxbridge

         Middlesex

         UB11 1BT

 

         Tel  0800 413524

         Fax  0181 990 4372

 

    Presentation

 

         Round pink 10 mg tabs, scored and marked WELLCOME F3A, in blister

         packs of 50

 

    Physico-Chemical Properties

 

    Chemical structure

         C24H31NO.HCl.H20

         4,4-Diphenyl-6-piperidino-3-hepanone hydrochloride

 

    Physical state at room temperature

         white crystalline powder

 

    Molecular weight (free base)

         404.0 (349.5)

 

    pKa (amine)

         8.5

 

    Solubility

         in alcohol          1 in 1.5

         in water            1 in 40

 

    Name

 

         Generic             Fentanyl citrate

         Proprietary         Durogesic, Sublimaze

         Synonym / street    China white

 

    Chemical Group / Family

 

         Opioid analgesics

         BNF 4.7.2

 

    Reference Number

 

         CAS

 

         Product licence numbers

         0242/0192 (Durogesic 25)

         0242/0193 (Durogesic 50)

         0242/0194 (Durogesic 75)

         0242/0195 (Durogesic 100)

         0242/5001R (Sublimaze)

 

    Manufacturer/Supplier

 

         Janssen-Cilag Ltd

         Saunderton

         High Wycombe

         Buckinghamshire

         HP14 4HJ

 

         Tel  01494 567444

         Fax  01494 567445

 

    Presentation

 

         Durogesic patches

         Transparent self-adhesive patches containing a reservoir of

         fentanyl.

         '25' patch, marked Durogesic 25 µg fentanyl/h in pink, in boxes

         of 5

         '50' patch, marked Durogesic 50 µg fentanyl/h in green, in boxes

         of 5

         '75' patch, marked Durogesic 75 µg fentanyl/h in blue, in boxes

         of 5

         '100' patch, marked Durogesic 100 µg fentanyl/h in grey, in boxes

         of 5

 

         Sublimaze injection

         Clear, colourless, aqueous injection

         0.05 mg/ml 2 ml ampoules in packs of 10

         0.05 mg/ml 10 ml ampoules in packs of 10

 

    Physico-Chemical Properties

 

    Chemical structure

         C22H28N2O.C6H8O7

         N-(1-Phenethyl-4-piperidyl)propionanilide dihydrogen citrate

 

    Physical state at room temperature

         white crystalline powder

 

    Molecular weight (free base)

         528.6 (336.5)

 

    pKa (amino)

         8.43

 

    Solubility

         in alcohol          1 in 140

         in water            1 in 40

 

    Name

 

         Generic             Meptazinol hydrochloride

         Proprietary         Meptid

 

    Chemical Group / Family

 

         Opioid analgesics

         BNF 4.7.2

 

    Reference Number

 

         CAS 54340-58-8 (meptazinol)

         CAS 59263-76-2 (meptazinol HCl)

         CAS 34154-59-1 (+/_ - meptazinol HCl)

 

         Product licence number

         10536/0007 (tablets)

         10536/0008 (injection)

 

    Manufacturer/Supplier

 

         Monmouth Pharmaceuticals Ltd

         3 & 4 Huxley Road

         Surrey Research Park

         Guildford

         Surrey

         GU2 5RE

 

         Tel  01483 565299

         Fax  01483 563658

 

    Presentation

 

         Oval, orange film-coated 200 mg tabs, marked MPL 023, in 5

         blister packs of 20

         Clear solution of 100 mg/ml for injection in 1 ml clear glass

         ampoules in packs of 10

 

    Physico-Chemical Properties

 

    Chemical structure

         C15H23NO.HCl

         3-(3-Ethyl-1-methyl-hexahydro-1H-azepin-3-yl)-phenol

         hydrochloride

 

    Physical state at room temperature

         white or creamy powder

 

    Molecular weight (free base)

         269.8 (233.3)

 

    pKa  (phenol)            8.7

         (amino)             11.9

 

    Solubility

         in alcohol          -

         in water            -

 

    Name

 

         Generic             Methadone hydrochloride

         Proprietary         Physeptone

         Synonym / street    Doll, dollies, dolophine

 

    Chemical Group / Family

 

         Opioid analgesics

         BNF 4.7.2

 

    Reference Number

 

         CAS 76-99-3 (methadone)

         CAS 297-88-1 (methadone, +/_)

         CAS 1095-90-5 (methadone HCl)

         CAS 125-56-4 (methadone HCl, +/_)

 

    Manufacturer/Supplier

 

         Generics- CP, Martindale

 

         Glaxo Wellcome

         Stockley Park West

         Uxbridge

         Middlesex

         UB11 1 BT

 

         Tel  0800 413524

         Fax  0181 990 4372

 

    Presentation

 

         Physeptone

         Round, white 5 mg tabs, scored and marked                        

         WELLCOME L4A in 5 blister strips of 10

         10 mg/ml inj in 1 ml ampoules in boxes of 5 and 100

 

         Generics

         Injections - 10 mg/ml in 1ml, 2 ml, 3.5 ml and 5 ml amps in boxes

         of 10

         Linctus BP in bottles of 500 ml

         Mixture 1 mg/ml in bottles of 30 ml, 50 ml, 100 ml and 500 ml

         (also sugar free versions)

 

    Physico-Chemical Properties

 

    Chemical structure

         C21H27NO.HCl

         6-Dimethylamino-4,4-diphenyl-3-heptanone hydrochloride

 

    Physical state at room temperature

         white or colourless crystalline powder

 

    Molecular weight (free base)

         345.9 (309.5)

 

    pKa (amino)

         8.3

 

    Solubility

         in alcohol          1 in 7

         in water            1 in 12

 

    Name

 

         Generic             Morphine

                             Combination products:

                             Kaolin & Morphine mixture,

                             Morphine & Atropine injection

         Proprietary         Cyclimorph, Morcap SR, MST,

                             MXL, Oramorph, Oramorph

                             SR , Sevredol

 

         Synonym / street    Cube juice, dreamer, hard stuff, hocus, M,

                             monkey, Miss Emma, morf, morpho

 

    Chemical Group / Family

 

         Opioid analgesics

         BNF 4.7.2

 

    Reference Number

 

         CAS 57-27-2 (anhydrous morphine)

         CAS 6009-81-0 (morphine monohydrate)

         CAS 52-26-6 (anhydrous morphine HCl)

         CAS 6055-06-7 (morphine HCl trihydrate)

         CAS 64-31-3 (anhydrous morphine SO4)

         CAS 6211-15-0 (morphine SO4 hydrate)

         CAS 302--31-8 (anhydrous morphine tartrate)

         CAS 6032-59-3 (morphine tartrate trihydrate)

 

         Product licence numbers

         0003/5022R (Cyclimorph 10)

         0003/5023R (Cyclimorph 15)

 

         Morcap SR

         20 mg 4515/0080

         50 mg 4515/0081

         100 mg 4515/0082

 

         MST Continus tablets

         10 mg 0337/0055; 15 mg 0337/0180;

         30 mg 0337/0059; 60 mg 0337/0087;

         100 mg 0337/0088; 2000 mg 0337/0149.

 

         MST Continus suspensions

         20 mg 0337/0165; 30 mg 0337/0166;

         60 mg 0337/0225; 100 mg 0337/0226;

         200 mg 0337/0227.

 

         MXL capsules

         0337/0259-0264 (marketing authorisation)

 

         Oramorph SR tablets

         10 mg 0015/0208; 30 mg 0015/0209;

         60 mg 0015/0210; 100 mg 0015/0211

 

         Oramorph solutions

         10 mg/5 ml 0015/0122; 20 mg/ml 0015/0125;

         10 mg/5 ml UDV 0015/0157;

         30 mg/5 ml UDV 0015/0158;

         100 mg/5 ml UDV 0015/0159

 

         Sevredol tablets

         10 mg 0337/0142; 20 mg 0337/0143;

         50 mg 0337/0265 (marketing authorisation)

 

    Manufacturer/Supplier

 

         Boehringer Ingelheim, Napp, IMS, Sanofi

         Winthrop, Wellcome.

         Generics - Evans, Martindale

 

         Napp Laboratories Ltd

         Cambridge Science Park

         Milton Road

         Cambridge

         CB4 4GW

 

         Tel: 01223 424444

         Fax: 01223 424441

 

    Presentation

 

         Cyclimorph inj - 1 ml amps in boxes of 5

         Morcap SR - transparent caps containing creamy-white / tan

         pellets in blister strips of 30 or 60.

         MST Continus tablets - blister packs of 60

         10 mg tabs golden brown; 15 mg tabs green;

         30 mg tabs dark purple; 60 mg tabs orange;

         100 mg tabs grey; 200 mg tabs teal green.

         MST Continus susp - cartons of 30 foil sachets containing pink

         granules.

         MXL caps - containers of 28 or 30 caps or blister strips of 28 or

         30.

         30 mg light blue marked MS OD30; 60 mg brown marked MS OD60; 90

         mg pink marked MS OD90;

         120 mg olive marked MS OD120;

         150 mg blue MS OD150; 200 mg  rust MS OD200.

         Oramorph SR tabs - blister pack of 10 or 60.

         10 mg greyish orange; 30 mg purple;

         60 mg orange; 100 mg grey.

         Oramorph oral solution - clear, colourless solution 10 mg/5 ml in

         bottles of 100 ml, 300 ml and 500 ml.

         Oramorph concentrate - clear, red solution in bottles of 30 ml

         and 120 ml with calibrated dropper.

         Oramorph unit dose vials - clear, colourless solution in 5 ml

         polyethylene vials, packs of 25 vials. Available as 10 mg/5 ml,

         30 mg/5 ml and 100 mg/5 ml.

         Sevredol - film coated, capsule shaped tablets in blister packs

         and containers of 56 and 112.

         10 mg blue marked IR 10; 20 mg pink marked IR 20;

         50 mg pale green marked IR 50.

 

    Physico-Chemical Properties

 

    Chemical structure

         C17H17NO3.H2O

         7,8-Didehydro-4,5-epoxy-3,6-dihydroxy-n-methylmorphinan

 

    Physical state at room temperature

         colourless white crystalline powder

 

    Molecular weight (anhydrous)

         303.4 (285.3)

 

    pKa

         tertiary amine      7.93

         phenolic hydrogen   9.63

 

    Solubility

         in alcohol          1 in 250

         in water            1 in 5000

 

    Name

 

         Generic             Nalbuphine hydrochloride

         Proprietary         Nubain

 

    Chemical Group / Family

 

         Opioid analgesics

         BNF 4.7.2

 

    Reference Number

 

         CAS 20594-83-6 (nalbuphine)

         CAS 23277-43-2 (nalbuphine HCl)

 

         Product licence number

         11173/0013

 

    Manufacturer/Supplier

 

         Du Pont Pharmaceuticals Ltd

         Avenue One

         Letchworth Garden City

         Herts

         SG6 2HU

 

         Tel  01462 488200

         Fax  01462 488319

 

    Presentation

 

         Clear, colourless solution of 10 mg/ml in 1 ml and 2 ml ampoules

         in boxes of 10

 

    Physico-Chemical Properties

 

    Chemical structure

         C21H27NO4.HCl

         (I)-(-)-(5R,6S,14S)-9a-(Cyclobutylmethyl)-4,5-epoxymorphinan-

         3,6alpha,14-triol hydrochloride

 

    Physical state at room temperature

         white to off-white powder

 

    Molecular weight (free base)

         393.9 (357.4)

 

    pKa

         8.71, 9.96

 

    Solubility

 

         in alcohol          soluble

         in water            soluble

 

    Name

 

         Generic             Oxycodone

         Proprietary         -

 

    Chemical Group/Family

 

         Opioid analgesics

         BNF 4.7.2

 

    Reference Number

 

         CAS 76-42-6 (oxycodone)

         CAS 124-90-3 (oxycodone HCl)

 

    Manufacturer/Supplier

 

         BCM Specials

 

    Presentation

 

         Only available in UK through above supplier as suppositories for

         use in palliative care

 

    Physico-Chemical Properties

 

    Chemical structure

         C18H21NO4,HCl

 

    Physical state at room temperature

         NIF

 

    Molecular weight (free base)

         351.8

 

    pKa

         NIF

 

    Solubility

 

         in alcohol          NIF

         in water            NIF

 

    Name

 

         Generic             Papaveretum

         Proprietary         Aspav (with aspirin)

 

    Chemical Group / Family

 

         Opioid analgesics

         BNF 4.7.2

 

    Reference Number

 

         CAS -NA

 

         Product licence

         0142/5597 (Aspav)

 

    Manufacturer/Supplier

 

         Martindale Pharmaceuticals

         Bampton road

         Harold Hill

         Romford

         Essex

         RM3 8UG

 

         Tel: 01708 386660

         Fax: 01708 384032

 

    Presentation

 

         Papaveretum inj

         7.7 mg/ml - 1 ml amps in boxes of 10

         15.4 mg/ml - 1 ml amps in boxes of 10

 

         Papaveretum with hyoscine inj

         15.4 mg/ml + hyoscine 400 mcg/ml - 1 ml amp in boxes of 10

 

         Aspav

         Round, white tablets containing 7.71 mg papaveretum + 500 mg

         aspirin, marked AP, in containers of 100

 

    Physico-Chemical Properties

 

    Chemical structure

         mixture of opium alkaloid hydrochlorides

         253 parts of morphine HCl

         23 parts of papaverine HCl

         20 parts of codeine HCl

 

    Physical state at room temperature

         yellowish-brown powder

 

    Molecular weight (free base)

         NA

 

    pKa

         NA

 

    Solubility

 

         in alcohol          NA

         in water            NA

 

    Name

 

         Generic             Pentazocine hydrochloride

         Proprietary         Fortral

                             Fortagesic ( with paracetamol)

 

    Chemical Group / Family

 

         Opioid analgesics

         BNF 4.7.2

 

    Reference Number

 

         CAS 359-83-1 (pentazocine)

         CAS 2276-52-0 (pentazocine HCl)

         CAS 64024-15-3 (pentazocine HCl)

 

         Product licence numbers

         11723/0028 (Fortagesic)

         11723/0033 (Fortral 25 mg tabs)

         11723/0090 (Pentazocine 25 mg tabs)

         11723/0088 (Pentazocine 50 mg caps)

         11723/0031 (Fortral injection)

         11723/0032 (Fortral suppositories)

 

    Manufacturer/Supplier

 

         Sanofi Winthrop Ltd (& Sterwin)

         One Onslow Street

         Guildford

         Surrey

         GU1 4YS

 

         Tel  01483 505515

         Fax  01483 35432

 

    Presentation

 

         Pentazocine

         Orange / grey 50 mg caps, marked PZN 50; Cox NP; PT50 G; yellow /

         grey ftl 50 in bottles of 100

         Round, white 25 mg tabs, marked PZN 25; Cox PZ; S 24; G PT 25 in

         bottles of 100

 

         Fortral

         Round, white 25 mg tabs, marked STERWIN / Fortral in bottles of

         100

 

         30 mg/ml inj 1 ml and 2 ml amps in boxes of 10

         50 mg supp in boxes of 20

 

         Fortagesic

         Round, white 15 mg tabs, marked FORTAGESIC in bottles of 100

 

    Physico-Chemical Properties

 

    Chemical structure

         C19H27NO.HCl

         1,2,3,4,5,6-Hexahydro-6,11-dimethyl-3-(3-methylbut-2-enyl)-2,6-

         methano-3-benzazocin-gamma-ol hydrochloride

 

    Physical state at room temperature

         white or cream crystalline powder

 

    Molecular weight (free base)

         321.9 (285.4)

 

    pKa

         8.7, 10.0

 

    Solubility

         in alcohol          1 in 16

         in water            1 in 30

 

    Name

 

         Generic             Pethidine hydrochloride

         Proprietary         Pamergan P100 (with promethazine)

         Synonym / street    Meperidine

 

    Chemical Group / Family

 

         Opioid analgesics

         BNF 4.7.2

 

    Reference Number

 

         CAS 57-42-1 (pethidine)

         CAS 50-13-5 (pethidine HCl)

 

         Product licence numbers

 

         Marketing authorisation number

         0156/0020R (Pamergan P100)

 

    Manufacturer/Supplier

 

         Generics - Martindale, Roche

 

         Martindale Pharmaceuticals

         Brampton Road

         Harold Hill

         Romford

         Essex

         RM3 8UG

 

         Tel  01708 386660

         Fax  01708 384032

 

    Presentation

 

         50 mg tabs in containers of 50

         50 mg/ml inj in boxes of 10

         100 mg/ml inj in boxes of 10

 

         Pamergan P100

         50 mg inj with promethazine 25 mg/ml - 2 ml ampoules in packs of

         10

 

    Physico-Chemical Properties

 

    Chemical structure

         C15H21NO2.HCl

         Ethyl 1-methyl-4-phenylpiperine-4-carboxylate hydrochloride

 

    Physical state at room temperature

         white colourless crystalline powder

 

    Molecular weight (free base)

         283.8 (247.3)

 

    pKa

         8.6

 

    Solubility

 

         in alcohol          1 in 20

         in water            >1 in 2

 

    Name

 

         Generic             Phenazocine hydrobromide

         Proprietary         Narphen

 

    Chemical Group / Family

 

         Opioid analgesics

         BNF 4.7.2

 

    Reference Number

 

         CAS 127-35-5 (phenazocine)

         CAS 1239-04-9 (phenazocine HBr)

 

         Product licence number

         0337/0198

 

    Manufacturer/Supplier

 

         Napp Laboratories Ltd

         Cambridge Science Park

         Milton Road

         Cambridge

         CB4 4GW

 

         Tel  01223 424444

         Fax  01223 424441

 

    Presentation

 

         Round white 5 mg tabs, marked N / 5 in containers of 100

 

    Physico-Chemical Properties

 

    Chemical structure

         C22H27NOHBr.´H2O

         1,2,3,4,5,6-Hexahydro-6,11-dimethyl-3-phenethyl-2,6-methaon-3-

         benzazocin-8-ol hydrobromide hemihydrate

 

    Physical state at room temperature

         white microcystalline powder

 

    Molecular weight (free base)

         411.4 (321.4)

 

    pKa (amino)

         8.5

 

    Solubility

         in alcohol          1 in 45

         in water            1 in 350

 

    Name

 

         Generic             Phenoperidine

         Proprietary         Operidine

 

    Chemical Group/Family

 

         Opioid analgesics

         BNF 4.7.2

 

    Reference Number

 

         CAS 562-26-5 (phenoperidine)

         CAS 3627-49-4 (phenoperidine HCl)

 

         Product licence number

         0242/5000R

 

    Manufacturer/Supplier

 

         Janssen-Cilag Ltd

         Saunderton

         High Wycombe

         Buckinghamshire

         HP14 4HJ

 

         Tel: 01494 567444

         Fax: 01494 567445

 

    Presentation

 

         Clear, colourless solution containing 1 mg/ml for inj in 2 ml

         amps in packs of 10 and 10 ml amps in packs of 5

 

    Physico-Chemical Properties

 

    Chemical structure

         C23H29NO3.HCl

         Ethyl 1-(3-hydroxy-3-phenylpropyl)-4-phenylpiperidine-4-

         carboxylate hydrochloride

 

    Physical state at room temperature

         white, crystalline powder

 

    Molecular weight (free base)

         403.9 (367.5)

 

    pKa

         8.01

 

    Solubility

 

         in alcohol          1 in 10

         in water            -

 

    Name

 

         Generic             Pholcodine

         Proprietary         Galenphol, Pavacol-D

                             Also in various OTC preps

 

    Chemical Group/Family

 

         Opioid analgesics

         BNF 4.7.2

 

    Reference Number

 

         CAS 509-67-1 (anhydrous pholcodine)

 

    Manufacturer/Supplier

 

         Generics - APS, Norton

 

         Galen Ltd

         Seagoe Industrial Estate

         Craigavon

         Northern Ireland

         BT63 5UA

 

         Tel 01762 334974

 

    Presentation

 

         Pholcodine linctus 5 mg/5 ml in bottles of 100 ml, 140 ml, 200

         ml, 300 ml, 2 L

         Pholcodine linctus strong 10 mg/5 ml in bottles of 100 ml, 2 L

         Pholcodine paediatric linctus 2 mg/5 ml in bottles of 90 ml, 2 L

 

    Physico-Chemical Properties

 

    Chemical structure

 

         C23H30N2O4.H2O

         3-O-(2-Morphinoethyl)morphine monohydrate

 

    Physical state at room temperature

         colourless crystalline powder

 

    Molecular weight (anhydrous)

         416.5 (398.5)

 

    pKa

         8.0, 9.3

 

    Solubility

         in alcohol          1 in 3

         in water            1 in 50

 

    Name

 

         Generic             Tramadol hydrochloride

         Proprietary         Tramake, Zydol, Zydol SR

 

    Chemical Group/Family

 

         Opioid analgesics

         BNF 4.7.2

 

    Reference Number

 

         CAS 27203-92-5 (tramadol)

         CAS 22204-88-2 (tramadol HCl)

         CAS 36282-47-0 (tramadol HCl)

 

         Product licence numbers

         08821/0005 (Zydol caps)

         08821/0004 (Zydol amps)

 

    Manufacturer/Supplier

 

         Searle

         PO Box 53

         Lane End Road

         High Wycombe

         Buckinghamshire

         HP12 4HL

 

         Tel: 01494 521124

         Fax: 01494 447872

 

    Presentation

 

         Zydol

         Green / yellow 50 mg caps - blister packs of 10, 100 and 140

         50 mg soluble tabs in packs of 20 and 100

         Colourless aqueous solution containing 100 mg in 2 ml amps in

         boxes of 5

 

         Zydol SR

         Round white 100 mg tabs, marked T1 in blister packs of 60 and 100

         Round orange 150 mg tabs, marked T2 in blister packs of 60

         Round orange 200 mg tabs, marked T3 in blister packs of 60

 

         Tramake

         Yellow / green 50 mg caps, marked TRAMAKE, in blister packs of

         100

 

    Physico-Chemical Properties

 

    Chemical structure

         C16H25NO2,HCl

         (+/-) - trans-2- Dimethyl-nomethyl-methoxyphenyl)cyclohexanol

         hydrochloride

 

    Physical state at room temperature

         NIF

 

    Molecular weight (free base)

         299.8

 

    pKa

         NIF

 

    Solubility

         in alcohol          NIF

         in water            NIF

 

    SUMMARY

 

    The effects in overdosage will be potentiated by simultaneous

    ingestion of alcohol and other psychotropic drugs.

 

    Progressive depression of the central nervous system leading to deep

    coma, cyanosis and marked reduction of the respiratory rate before

    respiratory arrest occurs.

 

    The pupils are usually pin-point in size and nausea and vomiting are

    common in less severe cases.

 

    Hypotension, tachycardia, hallucinations and rhabdomyolysis have been

    reported.

 

    Additional features in addicts:

    Overdosage in these cases may be due to ingestion, smoking (e.g.

    heroin) or intravenous or subcutaneous injection. Injection sites may

    therefore be present in some cases, particularly over the antecubital

    fossae, feet and groins.

 

    Beware of the risks of hepatitis B and HIV infection.

 

    Non-cardiogenic pulmonary oedema and rhabdomyolisis are particularly

    common after intravenous injection of opioid analgesics.

 

    Management

 

  1. Give naloxone (NARCAN) preferably intravenously if coma or

    respiratory depression are present. Adults: naloxone 800 mcg IV to

    start, then 400 mcg every 2 minutes until the patient improves

    (respiratory rate, consciousness, pupil size) or until 3.2 mg have

    been given. Children: 0.01 mg/kg body weight, increase up to 0.1 mg/kg

    if no response or sub-optimal response; Neonates: Initial doses of 10

    to 30 mcg/kg IV.

 

    Failure of a definite opioid overdose to respond to naloxone suggests

    that another CNS depressant drug or brain damage is present.

 

  1. Observe the patient carefully for recurrence of CNS and respiratory

    depression. The plasma half-life of naloxone is shorter than that of

    most opioid analgesics. Repeated doses of naloxone may be required.

    Intravenous infusions of naloxone have been recommended in situations

 

    where repeated doses have been necessary. Set up an infusion (5 x 400

    mcg ampoules naloxone = 2 mg in 500 ml 5% dextrose) at a rate equal to

    2/3 of the dose required to wake the patient per hour. Infusions are

    not substitutes for frequent review of the patients clinical state and

    administration of bolus doses of naloxone as required.

 

  1. Do not delay in establishing a clear airway, adequate ventilation

    and oxygenation if there is no response to naloxone.

 

  1. Assisted ventilation with positive end-expiratory pressure may be

    necessary if pulmonary oedema is a complication.

 

  1. Other supportive measures as indicated by the patient's progress.

 

    SUBSTANCE

 

    SUBSTANCE /PRODUCT NAME

 

    Alfentanil

    Buprenorphine

    Codeine

    Dextromoramide

    Dextropopoxyphene

    Diamorphine

    Dihydrocodeine

    Dipipanone

    Fentanyl

    Meptazinol

    Methadone

    Nalbuphine

    Opium

    Oxycodone

    Pentazocine

    Pethidine

    Phenazocine

    Phenoperidine

    Pholcodine

    Tramadol

 

    PROPERTIES

 

    USES

 

    Indications

 

    Opioid analgesics are mainly used for the relief of moderate to severe

    pain. They are also used in anaesthesia for premedication induction or

    maintenance. Morphine is generally the standard against which other

    opioids are compared and is considered by many to be the analgesic of

    choice for severe pain associated with terminal illness. Opioids with

    a quicker onset and shorter duration of action such as fentanyl are

    preferred for use in anaesthesia.

 

    Codeine and pholcodine are used for the suppression of cough; for

    intractable cough in terminal illness morphine or diamorphine may be

    used.

 

    Methadone is used in the treatment of opioid dependence.

 

    Therapeutic doses

 

    SUMMARY

 

    Opioids are subject to dosage variability based on the intended

    indication and the patient's ability to handle the drug. The goal of

    therapy for analgesia is to use the smallest effective dose. The

    following summarizes usual dosages.

 

    ALFENTANIL

 

    By iv infusion with assisted ventilation adult and child initially

    50 to 100 micrograms per kg over 10 mins or as a bolus followed by

    maintenance of 0.5 - 1 microgram/kg/min.

 

    Analgesia and suppression of respiratory activity during intensive 

    care, with assisted ventilation, initially 2 mg/hour (approx. 30

    microgram/kg/hour), adjusted according to response (usual range 0.5-10

    mg/hour); more rapid initial control may be obtained with an iv dose

    of 5 mg in divided portions over 10 minutes (slowing if hypotension or

    bradycardia occur); additional doses of 0.5-1 mg may be given by iv

    injection during short painful procedures.

 

    By iv injection, spontaneous respiration, adult, initially up to 500

    micrograms over 30 seconds; supplemental 250 micrograms. With assisted

    ventilation adult and child initially 30-50 micrograms/kg;

    supplemental 15 micrograms/kg

 

    BUPRENORPHINE

 

    Pain - by im or slow iv injection 300-600 micrograms every 6-8

    hours; child over 6 months 3-6 microgram/kg every 6-8 hours (max 9

    microgram/kg).

 

    By sublingual administration, initially 200-400 microgram every 8

    hours, increasing if necessary to 200-400 micrograms every 6-8 hours;

    child over 6 months, 16-25 kg, 100 micrograms; 25-37.5 kg, 100-200

    micrograms; 37.5-50 kg, 200-300 micrograms.

 

    Premedication - by sublingual administration 400 micrograms, by im

    injection 300 micrograms

 

    Peri-operative analgesia - by slow iv injection, 300-450 micrograms

 

    CODEINE

 

    Mild to moderate pain - 30 to 60 mg orally, every 4 hours when

    necessary, to a maximum of 240 mg daily. Child, 1-12 years, 3 mg/kg

    daily in divided doses

 

    By intramuscular injection 30-60 mg every 4 hours when necessary

 

    Diarrhoea - 30 mg 3-4 times daily (range 15-60 mg). Child not

    recommended.

 

    Cough - 5-10 ml 3-4 times daily; child 5-12 years, 2.5-5 ml 3-4

    times daily. Paediatric linctus, child 1-5 years 5 ml 3-4 times daily.

 

    DEXTROMORAMIDE

 

    Oral 5 mg increasing to 20 mg when required.

    Rectal 10 mg when required.

    Child not recommended.

 

    DEXTROPOPOXYPHENE

 

    65 mg every 6-8 hours when necessary

    65 mg dextropopoxyphene hydrochloride = 100 mg dextropopoxyphene

    napsylate

    Child not recommended

 

    DIAMORPHINE

 

    Acute pain by sc or im injection 5 mg repeated every 4 hrs if

    necessary (up to 10 mg for heavier well-muscled patients).

    By slow iv injection quarter to half corresponding im dose.

    Myocardial infarction, by slow iv injection (1 mg/minute), 5 mg

    followed by a further 2.5-5 mg if necessary; elderly or frail

    patients, reduce dose by half.

    Acute pulmonary oedema, by slow iv injection (1 mg/minute), 2.5-5

    mg.

    Chronic pain, oral, sc or im injection 5-10 mg regularly every 4

    hrs; increased according to needs.

    Child not recommended.

 

    DIHYDROCODEINE

 

    Oral 30 mg every 4-6 hrs when necessary.

    Child over 4 yrs 0.5-1 mg/kg every 4-6 hrs

    Deep sc or im injection up to 50 mg every 4-6 hrs if necessary.

    Child over 4 yrs 0.5-1 mg/kg every 4-6 hrs

 

    DIPIPANONE

 

    Diconal (dipipanone 10mg, cyclizine 30 mg) 1 tablet gradually

    increased to 3 tablets every 6 hours. Child not recommended.

 

    FENTANYL

 

    By iv injection, spontaneous respiration 50-200 micrograms, then 50

    micrograms as required; Child, 3-5 micrograms/kg then 1 microgram/kg

    as required.

    With assisted ventilation 0.3-3.5 mg, then 100-200 micrograms as

    required; Child, 15 micrograms/kg then 1-3 micrograms/kg as required.

    Patches - apply to skin on torso or upper arm and replace after 72

    hours. Child not recommended.

 

    MEPTAZINOL

 

    Oral 200 mg every 3-6 hrs as required. Child not recommended.

    By im injection 75-100 mg every 2-4 hrs if necessary, obstetric

    analgesia 100-150 mg according to patient's weight (2 mg/kg). Child

    not recommended.

    By slow iv injection 50-100mg every 2-4 hrs if necessary. Child not

    recommended.

 

    METHADONE

 

    Pain - oral, sc or im injection 5-10 mg every 6-8 hrs, adjusted

    according to response. Child not recommended.

    Opioid dependence - initially 10-20 mg daily, increased by 10-20 mg

    daily until no signs of withdrawal or intoxication; usual dose 40-60

    mg daily. Child not recommended.

    Cough in terminal disease - linctus, 2.5-5 ml every 4-6 hours,

    reduced to twice daily on prolonged use.

 

    MORPHINE

 

    Acute pain - by sc or im injection 10 mg every 4 hrs if necessary

    (15 mg for heavier well-muscled patients); Child, up to 1 month 150

    micrograms/kg, 1-12 months

    200 micrograms/kg, 1-5 years 2.5-5 mg/kg, 6-12 years 5-10 mg.

    By slow iv injection quarter to half corresponding im dose.

    Chronic pain - oral, sc or im injection 5-20 mg regularly every 4

    hrs; increased according to needs. Rectal, 15-30 mg regularly every 4

    hours. (NB. modified release preparations have different dosage

    schedules).

    Myocardial infarction, by slow iv injection (2 mg/minute), 10 mg

    followed by a further 5-10 mg if necessary. Elderly or frail patients

    reduce dose by half.

    Acute pulmonary oedema, by slow iv injection (2 mg/minute) 5-10 mg.

    Analgesia - by sc or im injection, up to 10 mg 1-1´ hours before

    operation; child, by im injection, 150 microgram/kg.

 

    NALBUPHINE

 

    Pain - by sc, im, or iv injection, 10-20 mg for 70 kg patient every

    3-6 hrs, adjusted according to response; Child up to 300 micrograms/kg

    repeated once or twice as necessary.

 

    Myocardial infarction - by slow iv injection, 10-20 mg repeated

    after 30 minutes if necessary.

 

    Premedication - by sc, im or iv injection, 100-200 micrograms/kg.

 

    Induction - by iv injection, 0.3-1 mg/kg over 10-15 minutes.

 

    Intra-operative analgesia, by iv injection, 250-500 micrograms/kg at

    30 minute intervals.

 

    OPIUM

 

    Parenteral: 5-20 mg by im or sc injection every 4-5 hours as needed

    Rectal: 1 suppository once or twice a day

 

    OXYCODONE

 

    Analgesia: 5 mg every 6 hours as needed, or 4.88 mg of the combined

    salt every 6 hours as needed. Children 6-12 years 0.61 mg of the

    combined salt every 6 hours as needed. Children 12 years or older 1.22

    mg of the combined salt every 6 hours as needed.

 

    OXYMORPHONE

 

    Parenteral

 

    Analgesia - initially 1-1.5 mg by sc or im injection every 4-6 hours

    as needed.

    Initial iv dose 0.5 mg, increased cautiously until satisfactory

    analgesia obtained.

    Labour - 0.5-1 mg by im injection

    Rectal: One 5 mg suppository every 4-6 hours as needed.

    Not for use in children under 12 years.

 

    PAPAVERETUM

 

    By sc, im or iv injection, 7.7-15.4 mg repeated every 4 hours if

    necessary; Elderly initially 7.7 mg; Child up to 1 month 115.5

    micrograms/kg, 1-12 months 115.5-154 micrograms/kg. 1-12 years 154-231

    micrograms/kg.

    In general the iv dose should be quarter to half the corresponding sc

    or im dose.

    Papaveretum and hyoscine injection - premedication, by sc or im

    injection, 0.5-1 ml.

 

    PENTAZOCINE

 

    Pain - oral 50mg every 3-4 hours (range 25-100 mg); Child 6-12 years

    25 mg.

    By sc, im or iv injection moderate pain 30mg, severe pain 45-60 mg

    every 3-4 hours when necessary; Child over 1 year, by sc or im

    injection, up to 1 mg/kg, by iv injection up to 500 microgram/kg.

    Suppositories 50 mg up to 4 times daily. Child not recommended.

 

    PETHIDINE

 

    Pain - oral 50-150 mg every 4 hours; Child 0.5-2 mg/kg.

    Sc or im injection, 25-100 mg repeated after 4 hours; Child im

    injection 0.5-2 mg/kg.

    Slow iv injection, 25-50 mg, repeated after 4 hours

    Obstetric analgesia - sc or im injection 50-100 mg, repeated 1-3

    hours later if necessary; max 400 mg in 24 hours.

    Premedication - by im injection, 25-100 mg 1 hour before operation;

    Child 0.5-2 mg/kg. Adjunct to nitrous oxide-oxygen, by slow iv

    injection, 10-25 mg repeated as required.

    Pamergan P100 - by im injection, for obstetric analgesia, 1-2 ml every

    4 hours if necessary; severe pain, 1-2 ml every 4-6 hours if

    necessary.

    Premedication - 2 ml by im injection 1-1´ hours before operation;

    Child, by im injection, 8-12 years 0.75 ml, 13-16 years 1 ml.

 

    PHENAZOCINE

 

    Severe pain - oral or sublingual, 5 mg every 4-6 hrs when necessary;

    single doses may be increased to 20 mg; Child not recommended.

 

    PHENOPERIDINE

 

    Analgesia during operation, enhancement of anaesthetics, by iv

    injection, with spontaneous respiration, up to 1 mg, then 500

    micrograms every 40-60 minutes as required; child 30-50 micrograms/kg.

    With assisted ventilation, 2-5 mg, then 1 mg as required; child 100-

    150 micrograms/kg.

 

    PHOLCODINE

 

    Dry or painful cough

 

    Pholcodine linctus - 5-10 ml 3-4 times daily; child 5-12 years 2.5-5

    ml.

    Pholcodine linctus, strong - 4 ml 3-4 times daily.

    Paediatric linctus - child 1-5 years 5 ml 3 times daily; 6-12 years

    5-10 ml.

 

    TRAMADOL

 

    Moderate to severe pain - oral 50-100 mg not more often than every 4

    hours; total of more than 400 mg daily not usually required; Child not

    recommended.

    By im or iv injection (over 2-3 minutes), or iv infusion, 50-100 mg

    every 4-6 hrs.

    Postoperative pain, 100 mg initially then 50 mg every 10-20 minutes

    if necessary during first hour to total max 250 mg (including initial

    dose) in first hour, then 50-100 mg every 4-6 hours; max 600 mg daily.

    Child not recommended.

 

    Modified release - 100 mg twice daily increased if necessary to

    150-200 mg twice daily; total of more than 400 mg daily not usually

    required; child not recommended.

 

    NALOXONE

 

    2 mg (adult) or 0.01 mg/kg body weight for children if coma or

    respiratory depression are present. Repeat the dose if there is no

    response within two minutes. Child, 0.01 mg/kg body weight for

    children if coma or respiratory depression are present. Repeat the

    dose if there is no response within two minutes.

 

    NALTREXONE

 

    To prevent relapse in detoxified formerly opioid dependent patients:

    25 mg initially then 50 mg daily; the total weekly dose may be divided

    and given on 3 days of the week for improved compliance. Child not

    recommended.

 

    Contraindications

 

    Known opiate sensitivity. Avoid in acute respiratory depression, acute

    alcoholism and where risk of paralytic ileus. Not indicated for acute

    abdomen. Avoid in raised intracranial pressure or head injury (in

    addition to interfering with respiration, affect pupillary responses

    vital for neurological assessment). Avoid injection in

    phaeochromocytoma (risk of pressor response to histamine release).

 

    Abuses

 

    Dependence can occur with most of the opioid analgesics; it is not

    generally a problem when they are used legitimately.

    All opiates, in particular diamorphine (heroin), have potential for

    abuse because of their euphoriant effect. Dependence can develop

    rapidly with repeated administration.

 

    EPIDEMIOLOGY

 

    EPIDEMIOLOGY OF POISONING

 

    In 1991 226 deaths (190 male, 36 female) were attributed to opiates

    and related narcotics. This represents 11.4% of deaths from poisoning

    by drugs, medicaments and biological substances. 144 deaths (130 male,

    14 female) were due to accidental poisoning, 32 (20 male, 12 female)

    to suicide and self-inflicted injury, 1 (female) to homicide and

    injury purposely inflicted by other persons, and 49 to injury

    undetermined whether accidentally or purposely inflicted (HMSO

    Mortality Statistics).

 

    Codeine is a constituent of many over-the-counter analgesics commonly

    taken in overdosage, but its effects are usually (but not always)

    overshadowed by those of salicylate or paracetamol. Self-poisonings

    with combined preparations of dextropopoxyphene and paracetamol are

 

    now much less common than previously, although still pose potentially

    serious problems.

 

    Poisoning with morphine, heroin and methadone is usually the result of

    accidental iv overdosage by drug addicts due to the unpredictable

    potency of 'street' drugs. There are therefore likely to be marked

    differences in the incidence of this type of opioid poisoning, with a

    much larger problem expected in selected quarters of large cities than

    in rural areas. Dextromoramide and dipipanone are now rarely

    encountered (Proudfoot 1993).

 

    ADVERSE EFFECTS AND INTERACTIONS

 

    ADVERSE EFFECTS

 

    Opioid analgesics share many side-effects, although qualitative and

    quantitative differences exist. The most common effects include nausea

    and vomiting (particularly in the initial stages), constipation,

    drowsiness and confusion. Larger doses produce respiratory depression

    and hypotension, with circulatory failure and deepening coma.

 

    Other adverse effects include difficulty with micturition, ureteric or

    biliary spasm, dry mouth, sweating, headache, facial flushing,

    vertigo, bradycardia, tachycardia, palpitations, postural hypotension,

    hypothermia, hallucinations, dysphoria, mood changes, dependence,

    miosis, decreased libido or potency, rashes, urticaria, and pruritis.

 

    Nystagmus was reported in a woman who received tetracaine and

    preservative-free morphine intrathecally. Naloxone reversal was

    successful (Ueyama et al, 1992).

 

    Paradoxical pain responses have been reported with high-dose

    therapeutic use of nalbuphine and buprenorphine with naloxone.

 

    A case of seizures following pethidine administration has been

    reported in a child (Kyff & Rice, 1990).

 

    A case of jerking movements progressing to seizures and

    unconsciousness was reported in a 60-year-old man given 25 mcg/kg

    alfentanil over 30 seconds (Strong & Matson, 1989).

 

    Myoclonic activity has been reported in two patients on high-dose

    spinal opioid therapy for pain (Parkinson et al, 1990).

 

    High-dose pethidine has been reported to cause muscle twitching

    (Morisy & Platt, 1986).

 

    A trauma victim given high doses of nalbuphine (up to 300 mg/day)

    experienced nightmares and extreme pain.

 

    INTERACTIONS

 

    Alcohol - enhanced sedative and hypotensive effect

 

    Anti-Arrhythmics - delayed absorption of mexiletine

 

    Antibacterials

    rifampicin accelerates metabolism of methadone (reduced effect);

    erythromycin increases plasma concentration of alfentanil

    ciprofloxacin - manufacturer advises avoid premedication with opioid

    analgesics (reduced plasma ciprofloxacin concentration)

 

    Anticoagulants - dextropopoxyphene enhances effects of warfarin and

    nicoumalone

 

    Antidepressants - CNS excitation or depression (hypertension or

    hypotension) with MAOIs (including moclobemide) and pethidine, and

    possibly other opioids

 

    Antiepileptics -    carbamazepine - effect enhanced by

                        dextropopoxyphene

                        carbamazepine - decreases effect of tramadol

 

    Antipsychotics - enhanced sedative and hypotensive effect

 

    Antivirals - plasma concentration of zidovudine possibly increased by

    methadone

 

    Anxiolytics & Hypnotics - enhanced sedative effect

 

    Cisapride - possible antagonism of gastro-intestinal effect

 

    Dopaminergics - hyperpyrexia and CNS toxicity with selegilene

 

    Metoclopramide & Domperidone - antagonism of gastro-intestinal effects

 

    Ulcer-Healing Drugs - cimetidine inhibits metabolism of opioid

    analgesics notably pethidine (increased plasma concentration)

 

    MECHANISM OF ACTION / TOXICITY

 

    Opioid analgesics possess some of the properties of naturally

    occurring opioid peptides, including encephalins, endorphins and

    dynorphins.

    Pharmacologically the opioid analgesics are broadly similar,

    qualitative and quantitative differences may be dependent on their

    interaction with opioid receptors.

    There are several types of opioid receptor, distributed in distinct

    patterns through the central and peripheral nervous systems. The three

    main types in the CNS have been designated µ (mu), (kappa) and

    (delta).

 

    µ - analgesia (mainly supraspinal sites), respiratory depression,

    miosis, reduced gastro-intestinal motility and euphoria; µ1

    (supraspinal analgesia) and µ2 (respiratory depression and

    gastro-intestinal activity) subtypes have been postulated.

    kappa - analgesia (mainly in the spinal cord), less intense miosis and

    respiratory depression, dysphoria and psychomimetic effects

    delta - probably analgesia, selective for encephalins

    Other receptors include (sigma) and (epsilon). The psychomimetic

    effects of agonist-antagonists such as pentazocine that are poorly

    antagonised by naloxone have been thought to be mediated by sigma

    receptors.

 

    Opioid analgesics act at one or more of these receptors as full

    agonists, partial agonists, or antagonists. Opioid analgesics have

    differing affinities for particular receptors and different degrees of

    activation once bound.

 

    A weak or partial agonist, is a partial agonist at one receptor site

    and has some antagonist activity at other receptors.

 

    Opioid antagonists are those drugs that bind but do not activate

    opioid receptor sites. Naloxone, an opioid receptor antagonist, acts

    at µ, kappa and delta receptor sites.

 

    FEATURES OF POISONING

 

    Acute Effects

 

    Ingestion

 

    Summary

 

    Opioid overdosage may result in central nervous system and respiratory

    depression with hypoxia, hypotension, shock, gastric hypomotility with

    ileus, and noncardiogenic pulmonary oedema.

 

    Opioid overdose may result in central nervous system depression.

    Decreased mental status is one of the most prominent symptoms in a

    narcotic overdose, which may progress to coma. Lethargy and coma

    associated with pinpoint pupils occur frequently. Pupils may be

    dilated in the presence of severe acidosis, hypoxia, or respiratory

    depression. Prolonged coma may result due to delayed gastric emptying.

    Seizures, myoclonic reactions, and spongiform encephalopathy have been

    reported in abusers of opioids.

 

    Respiratory depression and apnea are characteristic effects of opioid

    overdose and when severe may result in severe hypoxia, leading to

    hypotension and shock, pulmonary edema, and respiratory arrest (Wilkes

    et al, 1981; Jaffe & Martin, 1990).

 

    Delayed onset respiratory depression has been described 3, 6, 9, 14

    and 24 hours following oral methadone ingestions (Wilen et al, 1975;

    Sey et al, 1971; Geller et al, 1994). Prolonged toxicity of 24 to 48

 

    hours duration including respiratory depression may occur in

    individuals overdosing with methadone (Sey et al, 1971; Romac et al,

    1986; Gayle et al, 1991). Respiratory depression that was NOT

    reversible by naloxone 10 mg was reported in a 61-year-old woman who

    ingested 50 meptazinol 200 mg tablets (Davison et al 1987).

 

    Hypotension, cardiac arrhythmias, pulmonary hypertension and cyanosis

    have been reported following overdose. Hypotension and shock may

    occur, especially in the presence of prolonged and severe hypoxia

    (Miller et al, 1980; Whipple et al, 1994; Lawrenson et al, 1993).

 

    Atrial fibrillation has been reported following abuse of crude heroin

    in an adult male patient (Lawrenson et al, 1993). Pentazocine overdose

    has been associated with ventricular dysrhythmias (Stahl & Kasser,

    1983). Bradycardia may develop in patients with severe respiratory

    depression (Sey et al, 1971).

 

    Increased pulmonary artery pressure, pulmonary wedge pressure, LVEDP,

    arterial pressure, and pulmonary vascular resistance may be noted

    following overdosage of butorphanol.

 

    Hypothermia has been reported following overdoses of opiates.

    Hypomotility with ileus may occur following overdose.

 

    Acute tubular necrosis secondary to rhabdomyolysis and myoglobinuria,

    glomerulonephritis, glomerulosclerosis, renal amyloidosis and renal

    failure have been reported in heroin abusers. Rhabdomyolysis has been

    reported following heroin abuse or seizures associated with opioid

    overdose (Blain et al 1985).

 

    Hypoglycaemia has been reported following a heroin overdose. ACTH

    inhibition may occur with therapeutic and toxic opioid doses.

    Haemolysis has occurred in some patients following administration of

    high doses of fentanyl. Seborrhoea may be seen following MPTP (a

    derivative of pethidine) overdose.

 

    Inhalation

 

    Inhalation of opioids may result from drug abuse by persons crushing

    and 'snorting' tablets. Clinical effects and treatment are based on

    the oral route of exposure.

    Airway obstruction and bronchospasm have been associated casually with

    inhalation of heroin heated over metal foil. Eosinophils have been

    detected in the peripheral blood and/or respiratory secretions in

    these patients. More investigation is needed to determine the factors

    and the mechanisms involved.

 

    Hughes & Calverley (1988) report three cases of severe acute asthma

    following inhalation of heroin vapor. Fatal respiratory arrest

    occurred in two of these patients.

 

    Delayed onset respiratory depression has been described 4 hours

    following intranasal heroin use (Steinberg & Karlinger, 1968).

 

    Dermal

 

         - NIF

 

    Ocular

 

         - NIF

 

    Other Routes

 

    Bronchospasm and wheezing have been reported in both intravenous and

    inhalational abusers of heroin. Respiratory arrest occurred in 3

    patients after epidural infusion of fentanyl and bupivicaine. Each

    patient responded dramatically to naloxone (Weightman, 1991).

 

    If pulmonary oedema occurs it is generally abrupt in onset (immediate-

    2 hours) following intravenous heroin overdose (Duberstein & Kaufman,

    1971). An adult male who injected heroin once into his right brachial

    plexus area presented in a coma with acute pulmonary edema, flaccid

    paralysis of the ipsilateral arm and leg, and severe edema of the arm.

    Severe brachial plexitis was present, which the authors speculated was

    a hypersensitivity response (Stamboulis et al, 1988).

 

    Fever may occur several hours after injection of aqueous mixtures of

    pentazocine and tripelennamine tablets.

 

    Chronic Effects

 

    Ingestion

 

    Respiratory depression leading to respiratory arrest, pulmonary

    oedema, hypoxia, bronchospasm, acute asthma, bullous pulmonary damage

    and pneumonitis have occurred with therapeutic use and abuse of

    opioids.

 

    Coma, seizures, myoclonic reactions and spongiform encephalopathy have

    been reported in abusers of opioids. Grand mal seizures have been

    reported with doses of fentanyl.

    Seizures may occur with chronic use or abuse of pethidine and are

    often proceeded by myoclonus, are of limited duration, respond to

    conventional treatment, and resolve following a discontinuation of

    pethidine. Other signs of nervous system stimulation may continue for

    7 days. 48 of 67 patients demonstrated agitation, tremors, myoclonus,

    or seizures following chronic pain therapy with pethidine. A

    Parkinson-like syndrome has been seen in abusers of pethidine

    analogues.

 

    PAIN

 

    High doses of opioids or combination opioid agonists/antagonists have

    been reported to cause a paradoxical pain reaction which resolves upon

    cessation of the drug.

 

    Severe respiratory depression and pain were reported after

    administration of a high dose of buprenorphine. These signs were

    alleviated after naloxone administration.

 

    PERIPHERAL NEUROPATHY

 

    HEROIN: De Gans et al (1985) report 7 patients who developed

    rhabdomyolysis and neuropathy of a peripheral nerve or nerve plexus

    after heroin abuse without evidence of muscle or nerve compression.

 

    Hypomotility with ileus may occur with chronic abuse, or in patients

    on methadone maintenance. Constipation is common. Tolerance does not

    develop.

 

    Naltrexone may cause dose-related increases in liver enzymes when used

    chronically.

 

    Morphine has been found to stimulate prolactin release. Opioids such

    as morphine are implicated in causing hypoglycaemia.

 

    Morphine and some other opioids have a histamine releasing effect

    which may be responsible for urticaria and pruritis. Urticarial rash

    has been reported during therapeutic use of codeine.

 

    Inhalation

 

    SPONGIFORM LEUCOENCEPHALOPATHY

 

    Spongiform leucoencephalopathy was reported in two patients who were

    regular heroin smokers. Both had neurological signs (cerebellar

    ataxia, bilateral pyramidal signs, dysarthria); CT scan and autopsy

    showed extensive white-matter spongiosis and vacuolization.

    "Chinesing," or inhaling preheated heroin, has been associated with

    severe neurological illness and postmortem findings of spongiform

    encephalopathy.

 

    Dermal

 

         - NIF

 

    Ocular

 

         - NIF

 

    Other routes

 

    iv injection

 

    Pain and irritation may occur on injection as morphine and some other

    opioids have a histamine releasing effect

 

    iv and intranasal

 

    PARKINSON'S SYNDROME

 

    A syndrome closely resembling moderate to severe idiopathic

    Parkinson's Disease has been described in intravenous and intranasal

    drug users following use of a derivative of pethidine, 1-methyl-4-

    phenyl-1,2,3,6-tetrahydropyridine (MPTP). Symptoms may partially

    respond to levodopa and/or bromocriptine and usually slowly resolve

    over 18 months or longer. If recovery does not occur following an

    acute phase, a chronic and permanent parkinsonian syndrome is

    observed. Prolonged industrial exposure to MPTP has also resulted in

    Parkinsonism.

 

    AT RISK GROUPS

 

    Elderly

 

    Plasma half -lives of opiates are usually longer in older age groups

    due to reduced clearance. Adverse effects are likely to occur at lower

    doses than in younger adults

 

    Pregnancy

 

    Buprenorphine

 

    There are no studies on the use of buprenorphine in human pregnancy.

    Animal studies indicate that buprenorphine is not teratogenic in rats

    or rabbits (Heel et al 1979), but caused delayed parturition in the

    rat (Evans et al 1989).

 

    Codeine

 

    Despite the fact that codeine has been extensively used, there are

    very few data available on the effects of codeine in either animal or

    human pregnancy.

 

    Retrospective studies involving first trimester use of codeine have

    shown conflicting evidence of possible teratogenic effects. A wide

    range of anomalies have been associated with its use, including CVS

    defects, cleft lip and palate, musculoskeletal defects, dislocated hip

    and inguinal hernia (Saxen 1975a; Bracken & Holford 1981; Rothman et

    al 1979; Zeitler & Rothman 1985; Bracken 1986). Other studies

    involving over 1200 pregnancies found no significant increase in

    either major or minor malformations, or any pattern of defects (Saxen

    1975b; Heinonen et al 1977; Jick et al 1981; Aselton et al 1985).

 

    Although the retrospective studies imply an association of codeine use

    with fetal malformations, the inherent bias and methods of data

    collection do not permit a causal relationship to be established. It

    would seem that occasional therapeutic use of codeine in pregnancy is

    not likely to cause fetal damage.

 

    Like other narcotic analgesics, codeine use near term or during

    delivery can produce respiratory depression in the neonate which can

    be alleviated by naloxone (Bonica 1967).

 

    Neonatal withdrawal symptoms eg. tremor, jitteriness, diarrhoea and

    poor feeding may be seen following either short term (prior to or

    during delivery) or long term use of codeine by the mother (van

    Leeuwen et al 1965; Mangurten & Benawra 1980).

 

    Codeine overdose in pregnancy

 

    Data from the UK TIS on a small number of pregnancies (16) in which

    the mother overdosed with codeine phosphate either alone or as a

    combined analgesic preparation does not suggest an increased fetal

    risk above the background rate in the absence of severe maternal

    toxicity.

 

    Dextropropoxyphene

 

    There are very few published data on the effects of dextropropoxyphene

    in human pregnancy. There are a small number of anecdotal case reports

    of malformations allegedly associated with its use, but with no

    recurrent pattern of malformations or syndrome of defects. From the

    data presented a causal relationship seems unlikely (Boelter, 1980;

    Golden et al 1982).

 

    The Boston Collaborative Perinatal Project identified 2914 women who

    had taken propoxyphene at sometime during their pregnancy, 686 were

    first trimester exposures. There was no increase in either major or

    minor malformations and no syndrome of defects was detected (Heinonen

    et al 1977). Similarly, in another cohort of over 100 pregnancies, all

    first trimester exposures, no increase in fetal toxicity was reported

    (Jick et al 1981).

 

    Transient neonatal toxicity i.e. withdrawal symptoms have been

    reported in the infants of mothers who were on long term therapy with

    dextropropoxyphene (Tyson, 1974; Klein et al 1975; Quillian & Dunn,

    1976 and Ente & Mehra 1978). Irritability, hyperactivity, tremors and

    high-pitched cries are the most common features observed.

 

    Overdoses

 

    Follow-up data from the NTIS on over 400 cases of paracetamol overdose

    (including 40 taking coproxamol) during pregnancy shows no increase in

    the incidence of either spontaneous abortions or malformations in the

    absence of severe maternal toxicity.

    There were over 130 first trimester exposures.

 

    Diamorphine (heroin)

 

    No convincing evidence for an increase in abnormalities has been

    presented in humans but the numbers of mother/child pairs are too

    small to exclude an increase in abnormalities. All investigations are

    hampered by numerous confounding factors.

 

    There is conformity in numerous reports of an increased frequency of

    growth retardation including reduced head circumference, and in

    perinatal mortality. Retardations in development of the babies is

    reported and in some studies may predominantly be due to inadequacies

    in postnatal care.

 

    In a high proportion of newborns from heroin using mothers, withdrawal

    symptoms are seen lasting a few days or weeks but may persist for

    several months, though only a low percentage of the infants require

    therapy.

 

    Methadone

 

    The data available relate to use of heroin and methadone in pregnancy,

    and provide no convincing evidence for an increased risk of

    malformations. However, the number of mother-child pairs is small.

 

    The most consistent findings are; IUGR, decreased head circumference,

    and increased perinatal mortality. It is not clear whether the

    retardation in postnatal development are directly related to drug

    exposure in utero or to deficiencies in postnatal care. A high

    proportion of the babies have neonatal withdrawal symptoms which may

    last from several days -months.

 

    In some pregnancies substitution of methadone for heroin seems to

    reduce pregnancy risks . However the withdrawal symptoms in the

    neonate are often more severe and persistent. Higher risk of SIDS

    (Sudden Infant Death Syndrome).

 

    If exposure is to continue throughout pregnancy, it would be important

    to ensure adequate maternal nutrition and monitor fetal growth. Access

    to good paediatric care would be essential.

 

    Morphine

 

    No evidence linking the therapeutic use of morphine with abnormalities

    (Heinonen et al 1977). Case reports have associated use of morphine in

    the first trimester with malformations, but other drugs were also

    taken so it is difficult to establish a causal relationship.

 

    Neonatal respiratory depression may occur at birth if morphine is used

    during labour. Neonatal withdrawal effects may be seen in the infants

    of addicted mothers 12 to 72 hours after birth. Infants may be

    dehydrated, irritable, and experience tremors and cry continually.

 

    Naloxone

 

    There is little data available on the use of naloxone during human

    pregnancy. Animal studies do not indicate any teratogenic effects.

 

    Few adverse neonatal effects have been seen when naloxone has been

    used to antagonise respiratory depression following maternal analgesic

    use. There have been case reports of naloxone induced fetal asphyxia

    (Goodlin 1981) and fits in the neonate of an opiate addict (Gibbs et

    al 1989).

 

    Pentazocine

 

    There are few data available on the effects of pentazocine in human

    pregnancy. Animal studies in rats and rabbits showed no evidence of

    adverse effects on fertility, length of gestation, litter size or

    fetal development.

 

    Pentazocine crosses the human placenta, and has been associated with

    enhanced uterine activity but no adverse fetal effects (Filler &

    Filler 1966). Neonatal withdrawal effects may occur if pentazocine is

    used near term.

 

    Tramadol

 

    There are no published data on the outcome of human pregnancy after

    tramadol exposure in the first trimester. Tramadol has been used

    during labour with no significant adverse effects on the

    fetus/neonate.

    Animal studies have not demonstrated any increase in fetal

    malformation.

    Searle have outcome data from 9 pregnancies:

 

    3 premature deliveries - no malformations

         (2x 1st trimester and 1x1-3 trimester exposures)

    1 neonatal opiate withdrawal - no malformations (1-3 trimester

    exposure)

    1 neonatal convulsions - no malformations (exposed at 38/40)

    2 Caesarean deliveries - no malformations

    (1 for fetal distress - exposed just prior to delivery, 1 for uterine

    rupture - exposed at 5/40)

    1 maternal and fetal death (malaria infection) - 3rd trimester

    exposure

    1 spontaneous abortion at 7/40, exposed at 4-5/40

    1 ETOP (spina bifida) - exposed at 15/40 - therefore not causally

    related to tramadol

 

    Children

 

    Plasma half-lives of opiates are usually longer in children due to

    reduced clearance.

 

    Others

 

    Addicts

 

    Addicts develop tolerance to high doses which would be fatal to a new

    user.

    Addicts experience withdrawal symptoms on discontinuation of drug.

 

    Renal impairment

 

    Patients with renal impairment have increased systemic effects.

 

    Hepatic dysfunction

 

    Some patients with hepatic dysfunction are especially sensitive to

    opioids and experience prolonged sedation and respiratory depression,

    whereas many patients with liver impairment are able to tolerate

    opioids normally.

 

    MANAGEMENT

 

    Decontamination

 

    If patient is unconscious or has respiratory depression, attend to

    this first - see supportive care (airway and naloxone).

 

    Opiates delay gastric emptying and may be slow release (MST). Slow

    release preparations have a slower onset of action and increased

    duration of action than immediate release preparations. In overdose,

    onset of symptoms may be delayed, but last longer, thus continued

    observation and supportive care will be indicated.

 

    Gastric lavage carries the risk of gut perforation and aspiration.

    Endotracheal intubation is mandatory in unconscious patients or those

    with poor gag reflexes.

 

    Activated charcoal may be a safer option, however, lavage may be

    justified if performed soon after ingestion for very large overdoses,

    especially in the presence of alcohol as activated charcoal is less

    effective in these circumstances.

 

    Induction of emesis is not recommended because of the potential for

    CNS depression and seizures.

 

    For the asymptomatic body packer whole bowel irrigation may be a

    relatively safe and effective means of rapid decontamination (see case

    data).

 

    Prevention Of Absorption

 

    Activated charcoal is effective for reducing the absorption of opiates

    for up to 4 hours post ingestion (Proudfoot suggests up to 6 hours) as

    opiates delay gastric emptying. The dose should be at least 10 times 

 

    the quantity of drug taken. Doses of 50-100 g (adults) or

    25-50 g (children) should be aimed for. Lactulose (20 ml) should be

    given to prevent constipation.

    Patients who vomit, or who have reduced levels of consciousness can be

    treated via a nasogastric tube protecting the airway if necessary.

 

    Supportive care

 

    Support respiratory and cardiovascular function.

 

    If the patient is unconscious or has respiratory depression:

    Ensure clear airway

 

    ADULTS: give naloxone 800 mcg IV to start, then 400 mcg every 2

    minutes until the patient improves (respiratory rate, consciousness,

    pupil size) or until 3.2 mg have been given.

 

    CHILDREN: 0.01 mg/kg body weight if coma or respiratory depression are

    present. Repeat the dose if there is no response within two minutes. A

    larger dose of 0.1 mg/kg may be used if no improvement is seen, or

    response is sub-optimal.

 

    NEONATES: Initial doses of 10 to 30 mcg/kg IV are recommended.

 

    Failure of a definite opioid overdose to respond to naloxone suggests

    that another CNS depressant drug or brain damage is present.

    Observe the patient carefully for recurrence of CNS and respiratory

    depression. The plasma half-life of naloxone is shorter than that of

    most opioid analgesics. Relapse may occur after 20 minutes. Repeated

    doses of naloxone may be required.

 

    Intravenous infusions of naloxone have been recommended in situations

    where repeated doses have been necessary. Set up an infusion (5 x 400

    mcg ampoules naloxone = 2 mg in 500 ml 5% dextrose) at a rate equal to

    2/3 of the dose required to wake the patient per hour.

    Infusions are not substitutes for frequent review of the patients

    clinical state and administration of bolus doses of naloxone as

    required.

 

    Do not delay in establishing a clear airway, adequate ventilation and

    oxygenation if there is no response to naloxone.

    If pulmonary oedema is a complication maintain ventilation and

    oxygenation with close arterial blood gas monitoring. Assisted

    ventilation with positive expiratory pressure may be necessary.

 

    SEIZURES

 

    Administer diazepam IV bolus (DOSE: ADULT: 5 to 10 mg initially which

    may be repeated every 15 minutes PRN up to 30 mg. CHILD: 0.25 to 0.4

    mg/kg/dose up to 10 mg/dose). If seizures cannot be controlled or

    recur, administer phenytoin or phenobarbitone.

 

    HYPOTENSION: Administer IV fluids and place in Trendelenburg position.

    If unresponsive to these measures, administer dopamine (2 to 5

    mcg/kg/min) (first choice) or norepinephrine (0.1 to 0.2 mcg/kg/min)

    and titrate according to response.

 

    PARKINSON'S SYNDROME

 

    A syndrome closely resembling moderate to severe idiopathic

    Parkinson's Disease has been described in intravenous and intranasal

    drug users following use of a derivative of pethidine,

    1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Symptoms may

    partially respond to levodopa and/or bromocriptine and usually slowly

    resolve over 18 months or longer.

 

    Other supportive measures as indicated by the patient's progress.

 

    Monitoring

 

    Plasma opioid levels are not clinically useful.

    Treatment is based more on clinical presentation than on specific

    laboratory data.

    Monitor arterial blood gases, pulmonary function, and chest x-ray for

    patients with significant exposure.

 

    Patients with intravenous overdose requiring naloxone reversal should

    be monitored for 4 hours after the last dose of naloxone to observe

    for evidence of pulmonary edema.

    Patients with oral opioid overdose should be monitored for 6 hours and

    admitted if signs or symptoms develop. Patients with overdose of

    methadone or other long acting opioids require admission as clinical

    effects may be delayed.

 

    Antidotes

 

    NALOXONE

 

    A pure opioid antagonist, may be used for the complete or partial

    reversal of opioid depression, including mild to severe respiratory

    depression induced by natural and synthetic opioids, the

    agonist/antagonists nalbuphine and pentazocine, or dextropropoxyphene.

    It may also be used for the diagnosis of suspected acute opioid

    overdose.

 

    Adverse effects

 

    Abrupt reversal of narcotic depression may result in nausea, vomiting,

    sweating, tachycardia, increased blood pressure, tremulousness,

    seizures and cardiac arrest.

    Acute withdrawal effects may be precipitated in large opioid

    overdoses, or in patients physically opioid dependent.

    In postoperative patients, larger than necessary dosage of naloxone

    may result in significant reversal of analgesia and excitement. 

 

    Hypotension, hypertension, ventricular tachycardia and fibrillation,

    and pulmonary oedema have been associated with postoperative use of

    naloxone.

 

    Hoffman et al (1991) recommend administering naloxone only to altered

    mental status patients with bradypnoea (respirations of 12 or less) in

    questionable opiate overdoses.

 

    DOSE

 

    Adults

 

    Opioid overdose: 0.8-2 mg by iv injection repeated at intervals of

    2-3 minutes up to a maximum of 10 mg if respiratory function does not

    improve (question diagnosis).

    Can also be given by sc or im injection if no iv access.

    Post-operative use: 100-200 mcg iv is usually sufficient, a full 2

    minutes should be allowed to elapse between each 100 mcg increment.

    The dose should be titrated for each patient to obtain optimum

    respiratory response while maintaining adequate analgesia.

 

    Children: Initial iv dose 10mcg/kg, a subsequent dose of 100 mcg/kg

    may be given according to response.

 

    Neonates: Infants born to mothers given analgesics in labour, initial

    iv, im or sc dose of 10 mcg/kg, repeated after 2-3 minutes according

    to response. Alternatively, a single dose of 200 mcg (approx. 60

    mcg/kg) may be given im at birth.

 

    Observe the patient carefully for recurrence of CNS and respiratory

    depression. The plasma half-life of naloxone is shorter than that of

    most opioid analgesics, particularly dextropropoxyphene,

    dihydrocodeine and methadone. Relapse may occur after 20 minutes.

    Repeated doses of naloxone may be required.

 

    Intravenous infusions of naloxone have been recommended in situations

    where repeated doses have been necessary. Set up an infusion (5 x 400

    mcg ampoules naloxone = 2 mg in 500 ml 5% dextrose) at a rate of 2/3

    of the dose required to wake the patient per hour.

    Infusions are not substitutes for frequent review of the patients

    clinical state and administration of bolus doses of naloxone as

    required.

 

    Alternative routes

 

    Subcutaneous or intramuscular routes may be effective if iv route is

    not feasible (onset of action slower). Naloxone can also be given

    intralingually or intrathecally in the absence of intravenous access.

 

    CASE DATA

 

    CODEINE

 

    A 3-month-old preterm infant received codeine 6.6 mg/kg within 24

    hours, well above the recommended dose of 1 to 2 mg/kg. The infant

    developed apnea and presented at the hospital with pinpoint pupils and

    was semi-comatose. Effects were reversed with IV naloxone (Wilkes et

    al, 1981).

 

    A 30 year old woman was admitted after having ingested 100 compound

    aspirin / codeine tablets (30 g aspirin and 800 mg codeine) and an

    unknown amount of diazepam. She was drowsy but responded to verbal

    commands, had pinpoint pupils, and was sweating and hyperventilating

    with a pulse rate of 115/min and blood pressure of 120/80 mm Hg.

    Arterial blood gas analysis showed a mixed respiratory alkalosis and

    metabolic acidosis pH 7.4, carbon dioxide tension 3.1 kPa, oxygen

    tension 13.6 kPa and bicarbonate 15 mmol/l. Immediately after

    administration of naloxone (0.8 mg iv) the pupils dilated and she

    became fully conscious. Plasma salicylate and codeine concentrations

    were 1006 mg/l and 650 mcg/l respectively. Plasma urea, sodium and

    potassium concentrations were normal. Diazepam and nordiazepam

    concentrations were 0.38 mg/l and 0.84 mg/l respectively. Forced

    alkaline diuresis was performed; 21 hours post admission the plasma

    salicylate concentration measured 462 mg/l. On 3 occasions during

    forced alkaline diuresis her conscious level deteriorated such that

    she responded only to painful stimuli and pinpoint pupils. These

    effects were reversed by naloxone, with a further 4 mg being

    administered in total. The authors also report a second case (Leslie

    et al 1986).

 

    DEXTROPROPOXYPHENE

 

    Young & Lawson (1980) reviewed 82 patients admitted with acute

    Distalgesic(R) poisoning. On admission 20 patients had grade 4 and 2

    had grade 3 coma; 12 had respiratory arrest, 4 severe convulsions, 3

    aspiration pneumonia, 1 cardiac arrest and 3 patients died. All of the

    complication were considered directly attributable to

    dextropropoxyphene and were treated with naloxone and assisted

    ventilation where appropriate. 23 patients had one or more of these

    complications.

 

    A 14 day old infant weighing 4.43 kg was admitted to hospital after

    his 2 yr old brother was discovered feeding him Distalgesic(R) 2 hours

    previously. One hour after ingestion the infant became pale, drowsy

    and unresponsive with shallow respirations. On arrival at hospital he

    was pale, mottled and limp. The pupils were markedly constricted and

    he was practically apnoeic with only occasional shallow gasps.

    Naloxone 0.1 mg im resulted in complete recovery after only 20-30s.

    Four further episodes of apnoea occurred, responding to naloxone each

    time. The infant was discharged home after 4 days.

 

    FENTANYL

 

    A 36 year old male became intoxicated from fentanyl by heating and

    inhaling the contents from a fentanyl patch. He collapsed after 1

    inhalation with a respiratory rate of 6/min, heart rate of 120 bpm and

    an unobtainable blood pressure. He responded to naloxone injection 2

    mg iv and was discharged a few hours later with stable vital signs and

    mental status (Marquardt and Tharratt, 1994). The patient died

    following a subsequent inhalation session.

 

    HEROIN

 

    A 31-year-old male ingested 28 heroin-containing packets in an attempt

    to clear US Customs. The patient received a total of 31 litres of

    whole bowel irrigation, with polyethylene glycol electrolyte lavage

    solution, over the course of 52 hours, which resulted in the

    successful recovery of all packets. The procedure was well tolerated

    except for one episode of hypoglycemia. Lab data remained within

    normal limits and the patient denied abdominal cramping throughout the

    procedure (Betzelos & Mueller, 1991). A review article of the

    literature on opioid body-packers is available (Stewart et al, 1990).

 

    Utecht et al (1992) present a series of 14 patients, nine of whom

    swallowed heroin-containing packets and five of whom inserted them

    rectally. Thirteen had evidence of packets on KUB. Bisacodyl

    suppositories were used to evacuate packets from the rectum. No

    patient received ipecac or gastric lavage.

 

    MEPTAZINOL

 

    Respiratory depression that was NOT reversible by naloxone 10 mg was

    reported in a 61-year-old woman who ingested 50 meptazinol 200 mg

    tablets (Davison et al, 1987).

 

    RHABDOMYOLYSIS

 

    Blain et al (1985) report 3 cases of opiate overdose were the patients

    developed acute muscle damage with elevated serum aspartate

    aminotransferase and creatine kinase activities, increased serum

    myoglobin concentrations, raised plasma creatinine concentrations,

    hypocalcaemia and hyperphosphataemia. The abnormalities gradually

    resolved over 7-10 days, but recovery was complicated due to the

    development of acute renal failure (requiring haemodialysis) in one

    patient. Plasma drug concentrations, shortly after admission, in the

    patients taking dihydrocodeine and morphine were grossly elevated (184

    and 60 mcg/l respectively). Clinical evidence of myopathy was minimal

    in all three patients and muscle biopsy of one patient was normal at 7

    days.

 

    Author

 

    Kathryn Pughe, BSc (Hons) MRPharmS

 

    National Poisons Information Service (Newcastle Centre)

    Regional Drug & Therapeutics Centre

    Wolfson Building

    Claremont Place

    Newcastle upon Tyne

    NE1 4LP

    UK

 

    This monograph was produced by the staff of the Newcastle Centre of

    the National Poisons Information Service in the United Kingdom. The

    work was commissioned and funded by the UK Departments of Health, and

    was designed as a source of detailed information for use by poisons

    information centres.

 

    Peer review was undertaken by the Directors of the UK National Poisons

    Information Service.

 

    Last updated June 1997

 

    REFERENCES

 

    JOURNALS

 

  1.   Aselton P, Jick H, Milunsky A, Hunter JR, Stergachis A. First

         trimester drug use and congenital disorders. Obstet Gynecol 1985;

         65: 451-455.

 

  1.   Beattie JO, Chen CP, MacDonald TH. Neonatal Distalgesic

         poisoning. Lancet 1981; : 49.

 

  1.   BetzelosS, Mueller P. Whole bowel irrigation in a heroin body-

         packer (Abstract). Vet Hum Toxicol 1991; 33: 353.

 

  1.   Blain PG, Lane RJM, Bateman DN, Rawlins MD. Opiate-induced

         rhabdomyolysis. Human Toxicol 1985; 4: 71-74.

 

  1.   Boelter W. Proposed fetal propoxyphene Darvon syndrome. Clin Res

         1980; 28: 115a.

 

  1.   Bracken MB. Drug use in pregnancy and congenital heart disease in

         offspring. N Engl J Med 1986; 314: 1120.

 

  1.   Bracken MB, Holford TR. Exposure to prescribed drugs in pregnancy

         and association with congenital malformations. Obstet Gynaecol

         1981; 58: 336-344.

 

  1.   Davison AG et al. Meptazinol overdose producing near fatal

         respiratory depression. Human Toxicol 1987; 6:(4) 331.

 

  1.   De Gans J, Stam J, Van Wijngaarden GK. Rhabdomyolysis and

         concomitant neurological lesions after intravenous heroin abuse.

         J Neurol Neurosurg Psychiatry 1985; 48: 1057-1059.

 

  1. Ente G, Mehra MC. Neonatal drug withdrawal from propoxyphene

         hydrochloride. N Y State J Med 1978; 78: 2084-2085.

 

  1. Evans RG, Olley JE, Rice GE, Abrahams JM. Effects of subacute

         opioid administration during late pregnancy in the rat on the

         initiation, duration and outcome of parturition and maternal

         levels of oxytocin and arginine vasopressin. Clin Exp Pharmacol

         Physiol 1989; 16: 169-178.

 

  1. Filler WW, Filler NW. Effect of a potent non-narcotic analgesic

         agent (pentazocine) on uterine contractility and fetal heart

         rate. Obstet Gynaecol 1966; 28: 224-232.

 

  1. Gibbs J, Newson T, Williams J et al. Naloxone hazard in infant of

         opioid abuser (letter). Lancet 1989; 2: 159-160.

 

  1. Golden NL, King KC, Sokol RJ. Propoxyphene and acetaminophen.

         Clin Pediatr 1982; 21: 752-754.

 

  1. Goodlin RC. Naloxone and its possible relationship to fetal

         endorphin levels and fetal distress. Am J Obstet Gynaecol 1981;

         139: 16-19.

 

  1. Heel RC, Brogden RN, Speight TM et al. Buprenorphine: a review of

         its pharmacological properties and therapeutic efficacy. Drugs

         1979; 17: 81-110.

 

  1. Hoffman JR, Schriger DL, Luo JS. The empiric use of naloxone in

         patients with altered mental status: A reappraisal. Ann Emerg Med

         1991; 20: 246-252.

 

  1. Hughes S, Calverley PMA. Heroin inhalation and asthma. Br Med J

         1988; 297: 1511-1512.

 

  1. Jick H, Holmes LB, Hunter JR, Madsen S, Stergachis A. First

         trimester drug use and congenital disorders. JAMA 1981; 246: 343-

         346.

 

  1. Klein RB, Blatman S, Little GA. Probable neonatal propoxyphene

         withdrawal: A case report. Pediatrics 1975; 55: 882-884.

 

  1. Kyff JV, Rice TL. Meperidine-associated seizures in a child

         (letter). Clin Pharm 1990; 9: 337-338.

 

  1. Leslie PJ, Dyson EH, Proudfoot AT. Opiate toxicity after

         self-poisoning with aspirin and codeine. Br Med J 1986; 292: 96.

 

  1. Mangurten HH, Benawra R. Neonatal codeine withdrawal in infants

         of non-addicted mothers. Pediatrics 1980; 65: 159-160.

 

  1. Marquardt KA, Tharratt RS. Inhalation abuse of fentanyl patch.

         Clin Toxicol 1994; 32(1): 75-78.

 

  1. Morisy L, Platt D. Hazards of high-dose-meperidine (letter). JAMA

         1986; 255: 467-468.

 

  1. Parkinson SK, Bailey SL, Little WL et al. Myoclonic seizure

         activity with chronic high-dose spinal opioid administration.

         Anesthesiology 1990; 72: 743-745.

 

  1. Quillian WW, Dunn CA. Neonatal drug withdrawal from propoxyphene.

         JAMA 1976; 235: 2128.

 

  1. Rothman KJ, Fyler DC, Goldblatt A, Kreidberg MR. Exogenous

         hormones and other drug exposures of children with congenital

         heart disease. Am J Epidemiol 1979; 109: 433-439.

 

  1. Saxén I. Associations between oral clefts and drugs taken during

         pregnancy. Int J Epidemiol 1975a; 4: 37-44.

 

  1. Saxén I. Epidemiology of cleft lip and palate. Br J Prevent Soc

         Med 1975b; 29: 103-110.

 

  1. Stamboulis E, Psimaras A, Malliara-Loulakaki S. Brachial and

         lumbar plexitis as a reaction to heroin. Drug Alcohol Depend

         1988; 22: 205-207.

 

  1. Stewart A, Heaton ND, Hogbin B. Body packing - a case report and

         review of the literature. Postgrad Med J 1990; 66: 659-661.

 

  1. Strong WE, Matson M. Probable seizure after alfentanil. Anesth

         Analg 1989; 68: 692-693.

 

  1. Tyson HK. Neonatal withdrawal symptoms associated with maternal

         use of propoxyphene hydrochloride (DAVON). J Pediatr 1974; 85:

         684-685.

 

  1. Ueyama H, Nishimura M, Tashiro C. Naloxone reversal of nystagmus

         associated with intrathecal morphin administration (letter).

         Anesthesiology 1992; 76: 153.

 

  1. Utecht MJ, Stone AF, McCarron MM. Heroin body packers. J Emerg

         Med 1993; 11: 33-40.

 

  1. Van Leeuwen G, Guthrie R, Strange F. Narcotic withdrawal reaction

         in a newborn infant due to codeine. Pediatrics 1965; 36: 635-636.

 

  1. Wilkes TCR, Davies DP, Dar MF. Apnea in a 3 month old baby

         prescribed compound linctus containing codeine. Lancet 1981; 1:

         1166-1167.

 

  1. Young RJ, Lawson AAH. Distalgesic poisoning - cause for concern.

         Br Med J 1980; 1: 1045-1047.

 

  1. Zeitler S, Rothman KJ. Congenital heart disease in relation to

         maternal use of benedictin and other drugs in early pregnancy. N

         Engl J Med 1985; 313: 347-352.

 

    BOOKS

 

  1.   ABPI Compendium of Data Sheets and Summaries of Product

         Characteristics. Datapharm Publications Ltd. 1996-97.

 

  1.   AHFS Drug Information. McEvoy GK (Ed.) 1996.

 

  1.   Bonica JJ. Principles and practice of obstetric analgesia and

         anaesthesia. Philadelphia: F A Davis and Co. 1967: 245

 

  1.   Briggs GG, Freeman RK and Yaffe SJ. Drugs in Pregnancy and

         Lactation, 4th Edition. Williams & Wilkins, 1994.

 

  1.   British National Formulary, Number 33 (March 1997). British

         Medical Association and The Royal Pharmaceutical Society Of Great

         Britain, 1997.

 

  1.   Dollery C (Ed). Therapeutic Drugs. Churchill Livingstone, 1991.

 

  1.   Ellenhorn MJ. Ellenhorn's Medical Toxicology: Diagnosis and

         Treatment of Human Poisoning. 2nd Edition. Williams & Wilkins,

         1997.

 

  1.   Heinonen OP, Slone D and Shapiro S. Birth Defects and Drugs in

         Pregnancy. Littleton: Publishing Sciences Group, 1977: 322-34.

 

  1.   Martindale The Extra Pharmacopeia 31st Edition, Reynolds JEF

         (Ed.). The Royal Pharmaceutical Society Of Great Britain, 1996.

 

  1. Mortality Statistics. Series DH2 No.18. Office of Population

         Censuses & Surveys. London: HMSO, 1993.

 

  1. Proudfoot AT. Acute Poisoning, Diagnosis & Management. 2nd

         Edition. Butterworth-Heinemann Ltd, 1993.

 

    CD-ROMs / Databases

 

  1.   Poisindex System(R) Micromedex Inc, Denver Colorado, Edition

         expires 31/3/97.

 

  1.   Reprotox System(R), Micromedex inc., Denver Colorado, Edition

         Expires 31/3/97.

 

  1.   TOXBASE, National Poisons Information Service, 1997.

 

    Unpublished reports etc.

 

  1.   Data collated by the National Teratology Information Service

         (NTIS).

 

  1.   Data collated by the European Network of Teratology Information

         Services (ENTIS).

    



See Also:

        Opioids (Group PIM G023)











CLOSTRIDIUM BOTULINUM

International Programme on Chemical Safety

Poisons Information Monograph 858

Bacteria

1. NAME

1.1 Scientific name

1.2 Family

1.3 Common names and synonyms

2. SUMMARY

2.1 Main risks and target organs

2.2 Summary of clinical effects

2.3 Diagnosis

2.4 First Aid Measures and Management Principles

2.5 Poisonous parts

2.6 Main Toxins

3. CHARACTERISTICS

3.1 Description of the bacterium

3.1.1 Special identification features

3.1.2 Habitat

3.1.3 Distribution

3.2 Poisonous parts

3.3 The Toxin

3.3.1 Name(s)

3.3.2 Description, chemical structure, stability

3.3.3 Other physicochemical characteristics

3.4 Other Chemical Contents of the bacteria

4. USES/CIRCUMSTANCES OF POISONING

4.1 Uses

4.1.1 Uses

4.1.2 Description

4.2 High risk circumstances

4.3 High risk geographical areas

5. ROUTES OF EXPOSURE

5.1 Oral

5.2 Inhalation

5.3 Dermal

5.4 Eye

5.5 Parenteral

5.6 Others

6. KINETICS

6.1 Absorption by route of exposure

6.2 Distribution by routes of exposure

6.3 Biological half-life by routes of exposure

6.4 Metabolism

6.5 Elimination and excretion

7. TOXINOLOGY

7.1 Mode of action

7.2 Toxicity

7.2.1 Human data

7.2.1.1 Adults

7.2.1.2 Children

7.2.2 Relevant animal data

7.2.3 Relevant in vitro data

7.3 Carcinogenicity

7.4 Teratogenicity

7.5 Mutagenicity

7.6 Interactions

8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

8.1 Material sampling plan

8.1.1 Sampling and specimen collection

8.1.1.1 Toxicological analyses

8.1.1.2 Biomedical analyses

8.1.1.3 Arterial blood gas analysis

8.1.1.4 Haematological analyses

8.1.1.5 Other (unspecified) analyses

8.1.2 Storage of laboratory samples and specimens

8.1.2.1 Toxicological analyses

8.1.2.2 Biomedical analyses

8.1.2.3 Arterial blood gas analysis

8.1.2.4 Haematological analyses

8.1.2.5 Other (unspecified) analyses

8.1.3 Transport of laboratory samples and specimens

8.1.3.1 Toxicological analyses

8.1.3.2 Biomedical analyses

8.1.3.3 Arterial blood gas analysis

8.1.3.4 Haematological analyses

8.1.3.5 Other (unspecified) analyses

8.2 Toxicological analyses and their interpretation

8.2.1 Tests on toxic ingredient(s) of material

8.2.1.1 Simple Qualitative Test(s)

8.2.1.2 Advanced Qualitative Confirmation Test(s)

8.2.1.3 Simple Quantitative Method(s)

8.2.1.4 Advanced Quantitative Method(s)

8.2.2 Tests for biological specimens

8.2.2.1 Simple Qualitative Test(s)

8.2.2.2 Advanced Qualitative Confirmation Test(s)

8.2.2.3 Simple Quantitative Method(s)

8.2.2.4 Advanced Quantitative Method(s)

8.2.2.5 Other Dedicated Method(s)

8.2.3 Interpretation of toxicological analyses

8.3 Biomedical investigations and their interpretation

8.3.1 Biochemical analysis

8.3.1.1 Blood, plasma or serum

8.3.1.2 Urine

8.3.1.3 Other fluids

8.3.2 Arterial blood gas analyses

8.3.3 Haematological analyses

8.3.4 Interpretation of biomedical investigations

8.4 Other biomedical (diagnostic) investigations and their interpretation

8.5 Overall interpretation of all toxicological analyses and toxicological investigations

8.6 References

9. CLINICAL EFFECTS

9.1 Acute poisoning

9.1.1 Ingestion

9.1.2 Inhalation

9.1.3 Skin exposure

9.1.4 Eye contact

9.1.5 Parenteral exposure

9.1.6 Other

9.2 CHRONIC POISONING

9.2.1 Ingestion

9.2.2 Inhalation

9.2.3 Skin exposure

9.2.4 Eye contact

9.2.5 Parenteral exposure

9.2.6 Other

9.3 Course, prognosis, cause of death

9.4 Systematic description of clinical effects

9.4.1 Cardiovascular

9.4.2 Respiratory

9.4.3 Neurological

9.4.3.1 CNS

9.4.3.2 Peripheral nervous system

9.4.3.3 Autonomic nervous system

9.4.3.4 Skeletal and smooth muscle

9.4.4 Gastrointestinal

9.4.5 Hepatic

9.4.6 Urinary

9.4.6.1 Renal

9.4.6.2 Other

9.4.7 Endocrine and reproductive systems

9.4.8 Dermatological

9.4.9 Eye, ear, nose, throat: local effects

9.4.10 Haematological

9.4.11 Immunological

9.4.12 Metabolic

9.4.12.1 Acid base disturbances

9.4.12.2 Fluid and electrolyte disturbances

9.4.12.3 Others

9.4.13 Allergic reactions

9.4.14 Other clinical effects

9.4.15 Special risks

9.5 Other

9.6 Summary

10. MANAGEMENT

10.1 General principles

10.2 Life supportive procedures and symptomatic/specific treatment

10.3 Decontamination

10.4 Enhanced elimination

10.5 Antidote/antitoxin treatment

10.5.1 Adults

10.5.2 Children

10.6 Management discussion

11. ILLUSTRATIVE CASES

11.1 Case reports from literature

12. ADDITIONAL INFORMATION

12.1 Specific preventive measures

12.2 OTHER

13. REFERENCES

14. AUTHOR(S), REVIEWER(S) DATA (INCLUDING EACH UPDATING), COMPLETE ADDRESSES

 

1. NAME

1.1 Scientific name

Clostridium botulinum

1.2 Family

1.3 Common names and synonyms

Botulinum toxin;

Toxinum botulinum;

Botulinum A toxin haemagglutinin complex;

Dysport® (botulinum toxin type A) (Ipsen, UK);

Oculinum® (botulinum toxin type A) (Allergan Pharmaceuticals, USA);

Botox® (botulinum toxin type A) (Allergan Pharmaceuticals, USA);

Myobloc (botulinum toxin type B) (Elan Pharmaceuticals, USA)

Jad kielbasiany (Polish);

2. SUMMARY

2.1 Main risks and target organs

Botulism is characterised by symmetrical, descending, flaccid paralysis of motor and autonomic nerves usually beginning with cranial nerves. It occurs when neuromuscular transmission is interrupted by a protein neurotoxin produced by the spore-forming, obligate anaerobic bacterium Clostridium botulinum. Paralysis begins with the cranial nerves, then affects the upper extremities, the respiratory muscles, and, finally, the lower extremities in a proximal-to-distal pattern. In severe cases, extensive respiratory muscle paralysis leads to ventilatory failure and death unless supportive care is provided.

2.2 Summary of clinical effects

There are five clinical categories of botulism: 1) foodborne botulism; 2) wound botulism; 3) infant botulism; 4) adult infectious botulism; 5) inadvertent, following botulinum toxin injection.

Foodborne botulism

Onset generally occurs 18 to 36 hours after exposure (range, 6 hours to 8 days). Initial symptoms can include nausea, vomiting, abdominal cramps or diarrhoea. After the onset of neurologic symptoms, constipation is typical. Dry mouth, blurred vision, and diplopia are usually the earliest neurologic symptoms. They are followed by dysphonia, dysarthria, dysphagia, and peripheral muscle weakness. Symmetric descending paralysis is characteristic of botulism.

Wound botulism

This can be defined as clinical evidence of botulism following lesions, with a resultant infected wound and no history suggestive of foodborne illness. Except for the gastrointestinal symptoms, the clinical manifestations are similar to those seen in foodborne botulism. However, the incubation period is much longer (4 to 14 days), as time is required for the incubation of spores, growth of Clostridium, and release of toxins.

Infant botulism

This is caused by the absorption of toxin produced by Clostridium botulinum that colonize the intestinal tracts of infants under one year of age. It is often associated with ingestion of honey and the first clinical sign is usually constipation. After a few weeks, progressive weakness and poor feeding are observed. Tthe weakness is symmetrical and descending. It evolves over hours or several days. The infant is afebrile and has a weak cry, has either absent or diminished spontaneous movements, decreased sucking, floppy head and decreased motor response to stimuli. The autonomic nervous system manifestations include dry mucous membranes, urinary retention, diminished gastro-intestinal motility, fluctuation of heart rate, and changes in skin colour. Duration of hospitalisation may last from a few days to six months.

Adult infectious botulism

It occurs as a result of intestinal colonization with Clostridium botulinum and in vivo toxin production in a manner similar to that of infant botulism. These patients often have a history of abdominal surgery, achlorhydria, Crohn's disease or recent antibiotic treatment. The disease may simulate a Guillain-Barré Syndrome.

Inadvertendt botulism

This has been reported in patients who have been treated with intramuscular injections of botulinum toxin. Marked clinical weakness is observed as well as electrophysiologic abnormalities.

2.3 Diagnosis

Foodborne botulism

This should be suspected in a patient with acute onset of gastro-intestinal symptoms associated with autonomic (dry mouth, difficulty focusing eyes) and cranial nerves dysfunction (ptosis, diplopia, dysarthria, dysphagia). A history of home-prepared or home-preserved food (often, inadequately pasteurized vegetables) and similar symptoms in people who have shared the same food increases likelihood of the diagnosis. The initial diagnosis should be made on the basis of history and physical findings. Confirmatory tests may take days to be performed. Serum, stools and suspected food should be tested for the presence of botulism. The mouse inoculation test is still the most reliable method. Stool specimens should be cultured for C. botulinum as a confirmatory test. Isolation of C. botulinum organism devoid of toxin from the suspected food has little significance.

Wound botulism

Specimens of wound exudate, a tissue sample, or a swab sample should be obtained for anaerobic culture in addition to a serum toxin assay. A stool specimen should be obtained in order to exclude food or intestinal colonization as sources of toxin.

Infant botulism

This should be suspected in an infant with constipation, poor feeding, diminished sucking and crying ability, neck and peripheral muscle weakness, or ventilatory distress. Stool cultures for C. botulinum and testing for the presence of toxin in the stool should be performed in such patients.

Adult infectious botulism

This is a rare disease and should be suspected in patients with some abnormality of the gastro-intestinal tract who develop cranial nerve autonomic dysfunction, and muscular weakness. Stool cultures for C. botulinum and testing for the presence of toxin should be performed. Endogenous antibody production to botulinum toxin has been described.

Inadvertent botulism

This may be suspected in patients with recent history of botulin A toxin injection, especially into big muscles for systemic effect, or perhaps, in a suicide attempt.

2.4 First Aid Measures and Management Principles

Foodborne botulism

Emptying the stomach by gastric lavage or induction of vomiting with syrup of ipecac could be considered if the suspected food ingestion was recent (within 1 hour). It should not be attempted if neurological symptoms are already present.

Administer activated charcoal and a cathartic (such as sorbitol) but not magnesium salts since magnesium may potentiate neuromuscular block. Maintain airway and assist ventilation if required.

Obtain arterial blood gases. Monitor respiration closely since respiratory arrest can occur abruptly.

Administer Trivalent ABE antitoxin (7500 IU of type A, 5500 IU of type B, and 8500 IU of type E antitoxins) per patient. First test for serum sensitivity by injecting 0.1 mL of a 1:10 dilution of antitoxin in saline intradermally. Monitor for any reaction for 15 minutes before administering a full dose. If a reaction occurs the dose and rate of infusion must be reduced and the reaction must be treated. A single dose of antitoxin is usually sufficient.

Wound botulism

Because of the slow recovery period, trivalent antitoxin administration may need to be repeated.

Infant botulism

Equine botulinum antitoxin is not used in infant botulism because of the potential risk of anaphylaxis, serum sickness, or the sensitization of the infant to horse antigen. A human-derived antitoxin product (immune globulin) is being evaluated in a controlled trial in California (USA) for use in infants. For information on the Infant Botulism Prevention Programme contact the California Department of Health Services at (510) 540-2646 (24 hours).

Adult infectious botulism

Trivalent antitoxin may need to be readministered after the first dose because of the prolonged evolution.

2.5 Poisonous parts

Botulism is caused by a group of anaerobic spore-forming organisms called Clostridium botulinum. This is classified as a single species but consists of at least three genetically distinguishable groups of organisms that have been recognized as toxic for humans. They share the ability to produce neurotoxins with similar pharmacological activities but diverse serologic properties. The toxin types are classified as A, B, C, D, E, F and G. Human botulism has been described with the strains of Clostridium botulinum that produce toxin types A, B and E. Less frequently, cases involving type F toxin produced by C. baratii and type E toxin produced by C. butyricum have been published

2.6 Main Toxins

Although the seven neurotoxins (A, B, C, D, E, F and G) are genetically distinct, they possess similar molecular weights and have a common subunit structure. The complete amino acid sequences of the various serotypes are becoming known. Regions of sequence homology among the serotypes and between botulinum toxins and tetanus toxin, suggest that they all employ similar mechanisms of action.

The toxins are synthesized as single chain polypeptides with a molecular mass of approximately 150 kDa. In this form, the toxin molecules have relatively little potency as neuromuscular agents. Neurotoxin activation requires a two-step modification in the tertiary structure of the protein.

3 CHARACTERISTICS

3.1 Description of the bacterium

3.1.1 Special identification features

Clostridium botulinum is a gram positive, obligate anaerobic, spore-forming, rod-shaped bacterium.

3.1.2 Habitat

Clostridium botulinum organisms are commonly found in soils and marine sediments throughout the world.

3.1.3 Distribution

  1. botulinum may be found in any region of the world. Since it is found in the soil, it may contaminate vegetables cultivated in or on the soil. It will also colonize the gastro-intestinal tract of fishes, birds and mammals.

3.2 Poisonous parts

All clostridial neurotoxins are synthesized as a single inactive polypeptide chain of 150 kDa without a leader sequence and hence are presumably released from the cell by bacterial lysis (Schiavo et al, 1995).

The organisms that can produce botulinum neurotoxin are diverse. Even though they were shown to have different phenotypic characteristics, all organisms capable of producing botulinum neurotoxin become classified as Clostridium botulinum (Prevot, 1953).

These are the characteristic of clostridia capable of producing botulinum neurotoxin:

 

C. BOTULINUM GROUP

 

I

II

III

IV*

C. baritii

C. butyricum

Toxin type

A, B, F

B, E, F

C, D

G

F

E

Growth temperature (°C)

Optimum

35 – 40

18 – 25

40

37

30 – 37

30 – 45

Minimum

12

3.3

15

 

 

10

* C. argentinense has been proposed for this group (Hatheway, 1995).

3.3 The Toxin

3.3.1 Name(s)

Human botulism is primarily caused by Clostridium botulinum that produce toxin type A, B and E. Type F toxin produced by Clostridium baratii and type E toxin produced by Clostridium butyricum have also been implicated in human botulism.

Strains of C. botulinum that produce type C or type D toxin for the most part cause botulism only in non-human species (Shapiro et al, 1998).

3.3.2 Description, chemical structure, stability

All clostridial neurotoxins are synthesized as a single inactive polypeptide chain of 150 kDa without a leader sequence and hence are presumably released from the cell by bacterial lysis. Bacterial or tissue protease cleaves these toxins within an exposed highly protease-sensitive loop and generates the active di-chain neurotoxins composed of a heavy chain (H, 100 kDa) and a light chain (L, 50 kDa) joined by disulphide bonds, that is associated with one atom of zinc. This interchain S-S bond plays a critical role in cell penetration, and its cleavage by reduction abolishes toxicity (Schiavo et al, 1995).

The heavy chain can be divided functionally into an amino terminal domain (Hn) and a carboxyl terminal domain (Hc) (Halpern & Neale, 1995).

The light chain (amino acids 1-448) acts as a zinc endopeptidase, with proteolytic activity concentrated at the N-terminal end. The heavy chain (amino acids 449-1280) provides cholinergic specificity and promotes light chain translocation across the endosomal membrane of the neurotransmitter.

If the disulphide bond that links the two chains is broken before the toxin is internalised in the cell, the light chain cannot enter the axon terminal membrane, and there is a virtually complete loss of toxicity (Brin, 1997) (see 7,1 Mode of action).

3.3.3 Other physicochemical characteristics

The toxin in the complex is rather stable, especially under acidic conditions (pH 3,5 to 6,5), but the complex dissociates under slightly alkaline conditions and the biological activity is readily inactivated in this state. The neurotoxin can be separated from the non-toxic components and purified by ion-exchange chromatography (Midura, 1996). Although botulinum spores are relatively heat resistant the toxin itself is heat sensitive. Heating it at 80° C for 30 minutes or 100° C for 10 minutes destroys the active toxin (Slovis & Jones, 1998).

3.4 Other Chemical Contents of the bacteria

  1. botulinum spores produced by all strains are highly heat resistant. Toxins produced by some C. botulinum bacteria are non-proteolytic, which means that affected food may look and smell normal (Cherington, 1998).

4. USES/CIRCUMSTANCES OF POISONING

4.1 Uses

4.1.1 Uses

Neurotoxin: Pharmaceutical for human use: agent acting on the nervous system; Other

Bacterium: Warfare/Anti riot agent: biological warfare agent

4.1.2 Description

Botulin toxin A is used in the treatment of spastic muscular conditions such as torticollis, cervical and upper limb dystonia, childhood strabismus, apraxia of eye-lid opening, hemifacial spasm, writer’s cramp, spasticity in cerebral palsy in children etc, but also in the treatment of hyperhidrosis (Munchau & Bhatia, 2000).

4.2 High risk circumstances

There are 5 clinical categories of botulism of which the foodborne type is the most common. Canned or bottled food, particularly homemade, may contain botulinum (Cherington, 1998; Slovis & Jones, 1998).

Foodborne botulism

·

Home-prepared and home-preserved foods (often inadequately pasteurized vegetables, despite the name coming from the Latin botulus =sausage) are the most frequent cause of poisoning. The particular foods involved vary according to geographical and cultural peculiarities:

·

Strong-smelling preserved bean curd in China (Ying & Shuyan, 1986)

·

Canned vegetables in U.S.A (MacDonald et al, 1986

·

Meat from marine animals or fish/fish eggs fermented in traditional ways in Canada (Hauschild & Gauvreau, 1985)

·

Preserved ham in Portugal (Lecour et al, 1988) and France (Roblot et al, 1994)

·

Home-made sauce; baked potatoes sealed in aluminum foil; cheese sauce; sautéed onions held under a layer of butter; garlic in oil; traditionally prepared salted or fermented fish

The vehicles for botulism change with time even in the same country. For example, in USA, new sources have been described in recent years (Shapiro et al, 1998; Townes et al, 1996). This influences the type of toxin involved (Hatheway, 1995; Hauschild, 1992). Cases recorded in 38 countries between 1951 and 1989 show that 72 % of the outbreaks and 48 % of the cases were reported from Poland. Of the 2622 outbreaks in which the toxin type was determined, 34 % were type A, 52 % type B, and 12 % type E. Two incidents of type F foodborne botulism were reported during this period.

Wound botulism

A review of 40 cases of wound botulism published in the literature (Mechem & Walter, 1994) showed that most of these cases involved puncture wounds, open fractures, lacerations, crush injuries, shotgun wounds, drug abuse (abscesses), and surgical incisions. In some cases, no site of inoculation could be found. In the 13 cases where the toxin was isolated, 11 had type A, one had type B and the type of the toxin was not mentioned in one case. The use of Mexican black tar heroin was responsible for a cluster of cases in California (Anderson et al, 1997; Maselli et al, 1997).

Infant botulism

In most cases, the source of ingestion is unknown but in 15 % of cases, ingestion of honey is suspected (Shapiro et al, 1998).

The toxin type in infant botulism is generally either A or B, and the organisms are group I C. botulinum. Two cases have been reported in USA involving strain C. baratii that produce a neurotoxin similar to type F and two cases have been reported in Italy caused by strains C. butyricum that produce type E neurotoxin (Hatheway, 1995).

Adult infectious botulism

Two patients with clinical signs and symptoms of botulism yielded C. botulinum type A in their stool cultures for as long as 119 and 130 days after onset of illness (Hatheway, 1995).

Factors associated with this form of botulism were bowel surgery, Crohn's disease, or previous contaminated food exposure without illness.

Inadvertent botulism

This is a more recent form of botulism caused by the use of the toxin to treat dystonic and other movement disorders (Cherington, 1998; Bhatia et al 1999). In patients with torticollis treated with botulinum A toxin injected into the neck muscles dysphagia may develop from toxin penetrating the nearby pharyngeal muscles. The penetration of the toxin to distant muscles or generalized weakness due to systemic distribution of the toxin is rare (Bakheit et al, 1997; Bhatia et al, 1999).

4.3 High risk geographical areas

Out of 449 outbreaks with 930 cases reported in literature reviews (Hatheway, 1995), 72 % of the outbreaks and 48 % of the cases occurred in Poland.

Clostridial spores are resistant to heat and may survive the home-preserving process at temperatures below 120 °C. At high altitude boiling food prior to canning may not provide a high enough temperature to destroy the spores (Cherington, 1998).

Traditional food preparation and preservation is a major factor in the production of foodborne botulism (Hauschild, 1992). Non-acidic foods need to be pasteurized twice, at 24h intervals, to kill the bacteria generated from the surviving spores (Cherington, 1998).

5 ROUTES OF EXPOSURE

5.1 Oral

Foodborne botulism

This is caused by ingestion of food contaminated by a preformed neurotoxin of the bacterium Clostridium botulinum. Home-preserved foods containing fish, vegetables, or potatoes are often involved in outbreaks of botulism. High acid content foods are rarely involved. C. botulinum spores are heat-resistant but the toxin is heat-labile. Boiling food to ensure thorough heating of the interior should destroy the toxin (Cherington, 1998).

Infant botulism

This is a result of colonization of the intestinal tract after ingestion of spores of C. botulinum. The infant intestinal tract often lacks both the protective bacterial flora and the clostridium-inhibiting bile acids found in normal adult intestinal tract. Honey was found to be the vehicle of the spores in 26 cases (Arnon, 1992). Most cases occur before the age of 6 months. Microbiologic surveys of honey products have reported the presence of clostridial spores in up to 25 % of products. For this reason, honey should not be given to children during the first year of life (Cherington, 1998; Hatheway, 1995; Shapiro et al, 1998).

Adult infectious botulism

In most cases, the responsible food could not be identified. One adult appeared to develop botulism 47 days after exposure to a food that caused botulism in four other family members (Hatheway, 1995).

5.2 Inhalation

Studies in monkeys indicate that, if aerosolised, botulinum toxin also can be absorbed through the lung (Shapiro et al, 1998).

Three cases of botulism in laboratory workers have been ascribed to inhalation of the toxin (Cherington, 1998).

Recent concern about the use of C. botulinum neurotoxin aerosol in a terrorist attack has drawn attention to the potential risk to public health and the need for preventive measures to be developed (Steffen et al, 1997). This prompted the development of a heptavalent (type A-G) equine botulinum immune globulin (BIG) containing purified F(ab)2 by the United States army (Middlebrook & Brown, 1995).

5.3 Dermal

Neither the spores nor the neurotoxins are able to penetrate intact skin. However damaged skin may be affected (Slovis & Jones 1998)

5.4 Eye

No data available.

5.5 Parenteral

Wound botulism

The first case of wound botulism was published in 1951. The case occurred in 1943 and involved an adolescent girl who had sustained an open fracture of her left leg and right ankle following a fall from a building (Mechem & Walter, 1994). At the time of that review, a total of 40 cases had been reported in the English-language literature.

Inadvertent botulism

Several cases have been reported following intramuscular administration of the toxin for therapeutic purposes (Cherington, 1998; Bhatia et al 1999).

5.6 Others

No information available.

6 KINETICS

6.1 Absorption by route of exposure

No data available

6.2 Distribution by routes of exposure

Botulinum toxins are absorbed from the intestinal tract or the infected wound site and are carried via the lymphatic system, and from the intestinal tract by the bloodstream to the neuromuscular endings. Toxin types differ in their affinity for nerve tissue, with type A having the greatest affinity (Midura, 1996). The toxin must enter the nerve ending to exert its effect. Binding of toxin to both peripheral and central nerves is selective and saturable. Pharmacologic and morphologic data suggest that internalisation is via a receptor-mediated endocytotic/lysosomal vesicle pathway. The process is independent of Ca++ concentration, is partially dependent on nerve stimulation, and is energy dependent (Brin, 1997).

6.3 Biological half-life by routes of exposure

No data available.

6.4 Metabolism

No data available.

6.5 Elimination and excretion

No data available.

7 TOXINOLOGY

7.1 Mode of action

Botulinum neurotoxin reaches nerve terminals at the neuromuscular junction, where it binds to the neuronal membrane, moves into the cytoplasm of the axon terminal, and acts to block excitatory synaptic transmission, leading to flaccid paralysis (Halpern & Neale, 1995). There are three steps involved in toxin mediated paralysis: 1) internalisation 2) disulphide reduction and translocation 3) inhibition of the neurotransmitter release (Brin, 1997). The toxin must enter the nerve ending to exert its effect. Binding of toxin to both peripheral and central nerves is selective and saturable. The C-terminal half of the heavy chain determines cholinergic specificity and is responsible for binding, while the light chain is the intracellular toxic moiety. If the disulphide bond that links the two chains is broken before the toxin is internalised by the cell, the light chain cannot enter and there is virtually complete loss of toxicity (Brin, 1997).

The toxin blocks the release of acetylcholine but not its synthesis or storage. Botulinum toxin is a zinc endopeptidase specific for protein components of the neuroexocytosis apparatus. It cleaves synaptobrevin, a membrane protein of synaptic vesicles. The types A, C and E act on proteins of the presynaptic membrane. Types A and E cleave SNAP-25 while serotype C cleaves syntaxin (Schiavo et al, 1995; Montecucco et al, 1996).

7.2 Toxicity

7.2.1 Human data

7.2.1.1 Adults

Comprehensive reviews of the epidemiology, clinical features and management principles have been published in recent years (Hauschild, 1992; Hatheway, 1995; Cherington, 1998; Shapiro et al, 1998; CDC, 1998).

Foodborne botulism

New food items were involved in outbreaks like home-made sauce, baked potatoes sealed in aluminium foil, cheese sauce, sautéed onions held under a layer of butter, garlic in oil, and traditionally prepared salted or fermented fish. The use of modern plastic containers introduced a new risk factor in the ingestion of traditional food in the arctic regions (Hauschild, 1992; Proulx et al, 1997).

A recent comparison of the severity of botulism by toxin type found that endotracheal intubation was required for 67 % of type A patients, 52 % of type B, and 39 % of type E (Woodruff et al, 1992). Severity scores for classification of botulism have been proposed (Roblot et al, 1994).

Wound botulism

This has also been reviewed from the published literature and from a cluster of cases related to the use of black tar heroin (Burningham et al, 1994; Crawford, 1994; Maselli et al, 1997; Anderson et al, 1997).

Adult infectious botulism

This has also been described with greater frequency in recent years (Hatheway, 1995; Shapiro et al, 1998; Cherington, 1998). It is generally associated with abdominal surgery, gastro-intestinal diseases or asymptomatic exposure to contaminated food. It may be hypothesised that the use of anti H2 histamine medication in these patients may favour the intestinal colonization by C. botulinum since the toxin complex is stable under acidic conditions but dissociates under slightly alkaline conditions.

7.2.1.2 Children

Infant botulism has also been the subject of comprehensive review (Midura, 1996; Glatman-Freedman, 1996; Pickett et al, 1976; Long, 1984; Arnon, 1992; Wiggington & Thill, 1983). The ingestion of honey has been implicated in many cases but the source of contamination is frequently unknown. It occurs among children less than one year of age and mostly in the first six months of life. It has a wide spectrum of severity. Some infants manifest with only mild symptoms and may go unrecognised while other cases present as sudden infant death syndrome. Hospitalisation averages approximately five weeks, but may last up to six months. Infant botulism has been reported from countries all over the world except Africa. Most cases were reported in the United States. The toxin types involved in these cases were A and B in approximately the same proportion.

7.2.2 Relevant animal data

The parenteral median LD50 of botulinum toxin in monkeys and mice is 0.4ng/kg (Gill 1982).

Botulism also occurs in animals. The clinical features are essentially the same as in humans The toxin involved in these cases was either C or D (Hatheway, 1995). A detailed review of the subject has been published (Smith & Sugiyama, 1988).

Animal models were used to evaluate the efficacy of the antitoxins (Middlebrook & Brown, 1995). Guinea pigs were given 20 IU human botulinum immune globulin per kilogram either 4 hours before or 4 to 8 hours after an oral challenge of type A toxin, and all survived with no clinical signs.

Guinea pigs treated with 1 IU/kg trivalent botulism antitoxin were completely protected from subcutaneous toxin challenge, although protection decreased when antibody was given post challenge.

Supportive care improves the efficacy of botulinum antibody

therapy in monkeys.

Infant botulism

Using a mouse model system of intestinal colonization it was demonstrated that the intestinal microflora of adult animals ordinarily prevents colonisation of the intestines by C. botulinum (Moberg & Sugiyama, 1979). The infective dose of spores for infant mice was much smaller than that of their antibiotic-treated adult counterparts; the 50 % infective dose for normal infant mice was only 700 spores (Midura, 1996). In one experiment 10 spores were sufficient to infect an infant mouse (Sugiyama & Mills, 1978).

7.2.3 Relevant in vitro data

Detailed reviews of the chemistry, pharmacology, toxicity, immunology and mechanism of action of botulinum neurotoxins have been published in recent years (Halpern & Neale, 1995; Middlebrook & Brown, 1995; Schiavo et al, 1995; Montecucco et al, 1996; Brin, 1997; Coffield et al, 1997). The nucleotide sequence for all seven toxin types has been elucidated (Shapiro et al, 1998).

7.3 Carcinogenicity

No data available.

7.4 Teratogenicity

There is no evidence to date that the fetus is at risk of neonatal botulism when the mother is affected by botulism (Cherington, 1998). There are a few case reports in the literature where the mother acquired botulism during pregnancy. In no case there was there evidence of transport of the toxin across the placental barrier.

7.5 Mutagenicity

No data available.

7.6 Interactions

Aminoglycoside antibiotics potentiate the neuromuscular blockade induced by botulinum toxins both in the human experience of infant botulism and the mouse model (Wang, 1984). Cathartic agents containing magnesium should be avoided because of the theoretical concern that increased magnesium levels may enhance the action of botulinum toxin (Shapiro et al, 1998).

8 TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

8.1 Material sampling plan

8.1.1 Sampling and specimen collection

Specimens of serum, faeces, vomitus and gastric contents, together with implicated foods should be collected for testing for toxin and the presence of C. botulinum (Shapiro et al, 1998).

In wound botulism wound exudate, debrided tissue, or a swab sample should be obtained for anaerobic culture. Serum should also be collected for serum toxin assay and a stool specimen should be collected to exclude foodborne botulism. In infant botulism, stools should be collected for culture and toxin identification.

Serum should be collected before antitoxin is given, otherwise there may be a false negative result. If possible at least 3ml of serum should be collected, although as little as 0.5ml may be sufficient. A larger volume, ideally 10-15ml, will allow specific identification of the botulinum toxin involved and repeat testing if necessary (CDC, 1998)

8.1.1.1 Toxicological analyses

The mouse innoculation test is still the most reliable method. The type of toxin, particularly A, B, and E can be detected by injecting the specific antitoxin in combination with the patient’s serum into the mouse (Griffin et al, 1997).

8.1.1.2 Biomedical analyses

The differential diagnosis of botulism with other neurological diseases may require rapid repetitive electromyography, lumbar puncture, edrophonium chloride testing, magnetic resonance imaging or computed tomography of the brain (Shapiro et al, 1998; Cherington, 1998).

8.1.1.3 Arterial blood gas analysis

8.1.1.4 Haematological analyses

8.1.1.5 Other (unspecified) analyses

8.1.2 Storage of laboratory samples and specimens

8.1.2.1 Toxicological analyses

All specimens except those from wounds should be refrigerated, preferably not frozen, and examined as soon as possible. Wound specimens should be placed in anaerobic transport devices and sent to the laboratory without refrigeration (CDC, 1998).

Food should be left in its original container if possible or placed in a labelled, unbreakable, sterile container.

8.1.2.2 Biomedical analyses

8.1.2.3 Arterial blood gas analysis

8.1.2.4 Haematological analyses

8.1.2.5 Other (unspecified) analyses

8.1.3 Transport of laboratory samples and specimens

8.1.3.1 Toxicological analyses

Samples should be conveyed to the laboratory as quickly as possible. The samples should be packed in sterile, leakproof containers. If they have to be sent a long distance then the samples should be placed in insulated shipping containers with refrigerant. If a delay of several days is likely then serum and stool samples should be frozen and packed in dry ice. Packaging should be adequately labelled to indicate that the contents are a biological hazard (CDC, 1998).

8.1.3.2 Biomedical analyses

8.1.3.3 Arterial blood gas analysis

8.1.3.4 Haematological analyses

8.1.3.5 Other (unspecified) analyses

8.2 Toxicological analyses and their interpretation

8.2.1 Tests on toxic ingredient(s) of material

8.2.1.1 Simple Qualitative Test(s)

8.2.1.2 Advanced Qualitative Confirmation Test(s)

8.2.1.3 Simple Quantitative Method(s)

8.2.1.4 Advanced Quantitative Method(s)

8.2.2 Tests for biological specimens

8.2.2.1 Simple Qualitative Test(s)

8.2.2.2 Advanced Qualitative Confirmation Test(s)

8.2.2.3 Simple Quantitative Method(s)

8.2.2.4 Advanced Quantitative Method(s)

8.2.2.5 Other Dedicated Method(s)

8.2.3 Interpretation of toxicological analyses

8.3 Biomedical investigations and their interpretation

8.3.1 Biochemical analysis

8.3.1.1 Blood, plasma or serum

8.3.1.2 Urine

8.3.1.3 Other fluids

CSF is normally clear, although a slightly elevated protein level is sometimes seen (Hughes et al, 1981).

8.3.2 Arterial blood gas analyses

8.3.3 Haematological analyses

8.3.4 Interpretation of biomedical investigations

8.4 Other biomedical (diagnostic) investigations and their interpretation

Electromyography, including single fibre electromyography (SFEMG) may be useful in differential diagnostics.

8.5 Overall interpretation of all toxicological analyses and toxicological investigations

8.6 References

9 CLINICAL EFFECTS

9.1 Acute poisoning

9.1.1 Ingestion

Foodborne botulism

The initial symptoms may occur 18 to 36 hours post ingestion. They may be gastro-intestinal especially in type E and include nausea, vomiting, abdominal cramps or diarrhoea. Constipation will predominate after the onset of neurological symptoms. The initial symptoms are dry mouth, blurring of vision and diplopia. These may be followed by ptosis, ophthalmoplegia, dysarthria, and dysphagia. These abnormalities of the cranial nerve are followed by a symmetrical descending pattern of weakness and paralysis. After the cranial nerves, the toxin affects the upper extremities, the respiratory muscles and, finally the lower extremities. If patients show signs of progression, they should be closely monitored for respiratory difficulties.

In severe cases, respiratory muscle paralysis may lead to ventilatory failure and death unless supportive care is provided (Shapiro et al, 1998). Ventilatory support may be required for long periods of time in severe cases (2 to 8 weeks). This increases the risk of medical complications. The recovery of autonomic function takes longer than that of neuromuscular transmission. Fatality rates are higher for older patients (greater than 60 years) and those who were index patients (the first or only patient in an outbreak), but antitoxin is effective in preventing progression of disease and in shortening the duration of ventilatory failure (Tacket, 1984).

Infant botulism

Infant botulism occurs in children of less than one year of age and mostly during the first 6 months of life. The clinical symptoms vary greatly from case to case. Constipation is frequently the first symptom, defined as 3 or more days without defecation. Progressive weakness and poor feeding follow after a few weeks. The weakness is symmetrical and descending as in foodborne botulism. It evolves over hours to several days. Other symptoms include lethargy, difficulty in sucking and swallowing, weak cry, hypotonia, pooled oral secretions and loss of head control.

Neurologic symptoms may include ptosis, ophthalmoplegia, weak gag reflex, dilated and sluggish pupils, dry mouth and neurogenic bladder.

The severity of the clinical picture varies from a mild intoxication to a fatal illness. However, prognosis is good with proper supportive treatment.

Adult infectious botulism

The clinical features of adult infectious botulism are similar to those of foodborne botulism except for the initial gastrointestinal symptomatology. The interval between bowel surgery or food exposure and the onset of clinical features may be one or more months. The clinical severity in reported cases has been quite variable.

9.1.2 Inhalation

Studies in monkeys indicate that, if aerosolised, botulinum toxin also can be absorbed through the lung (Shapiro et al, 1998).

9.1.3 Skin exposure

Neither C. botulinum spores nor its neurotoxins can be absorbed through intact skin, however damaged skin may be affected (Slovis & Jones 1998).

9.1.4 Eye contact

No data available.

9.1.5 Parenteral exposure

Wound botulism

Out of 40 published cases in the literature (Mechem & Walter, 1994) 78 % had a clear history of wounds, including abrasions, avulsions, lacerations, puncture wounds and abscesses. In other patients, the site of inoculation was obscure.

9.1.6 Other

9.2 CHRONIC POISONING

9.2.1 Ingestion

Strictly speaking there is no such thing as chronic poisoning by botulism. In the cases of adult infectious botulism and infant botulism, the clinical picture may last several days or weeks. However, it is probably caused by a single exposure.

9.2.2 Inhalation

No data available.

9.2.3 Skin exposure

No data available.

9.2.4 Eye contact

No data available.

9.2.5 Parenteral exposure

No data available.

9.2.6 Other

9.3 Course, prognosis, cause of death

Foodborne botulism

The symmetrical descending paralysis, when it occurs, usually appears 18 to 36 hours after exposure and generally lasts for 2 to 8 weeks. However, in severe cases, ventilatory support may be required for up to 7 months (Shapiro et al, 1998).

The prognosis is dependent on the quality of the supportive treatment. If adequate ventilation is maintained, the prognosis is good. If, however, ventilatory support is required for a long period of time (weeks to months) risks of medical complications (respiratory infections, ARDS) increase significantly. The improvement of critical care in recent years has reduced mortality from 50% to 9% (Cherington, 1998).

The cause of death in the first days following ingestion is respiratory failure due to a lack of adequate ventilatory support. In cases requiring long term ventilatory support, death is generally caused by medical complications.

Infant botulism

The course of the disease is extremely variable. Some are the fulminant type and difficult to differentiate from the Sudden Infant Death Syndrome (Midura, 1996). When the onset of illness is sufficiently gradual to permit hospitalisation, the prognosis is excellent.

Wound botulism

The prognosis for patients with wound botulism is favourable, assuming adequate ventilatory support is maintained (Mechem & Walter, 1994). The case-fatality rate for wound botulism is approximately 15 % (Shapiro et al, 1998).

9.4 Systematic description of clinical effects

9.4.1 Cardiovascular

Autonomic nervous system instability may induce tachycardia and hypertension. Orthostatic hypotension may also occur (Cherington 1998, Shapiro et al 1998).

9.4.2 Respiratory

Respiratory depression is caused by respiratory muscle paralysis. It may lead to ventilatory failure and death.

9.4.3 Neurological

9.4.3.1 CNS

Paralysis of cranial nerves causes blurred vision, diplopia, dysphonia, dysarthria and dysphagia.

9.4.3.2 Peripheral nervous system

Following paralysis of the cranial nerves, a symmetrical descending paralysis will occur. It will affect the upper extremities, then the respiratory muscles, and, finally, the lower extremities in a proximal to distal manner.

9.4.3.3 Autonomic nervous system

Botulinum toxin causes a blockade of the autonomic cholinergic junctions resulting in dry mouth, blurred vision, orthostatic hypotension, constipation and urinary retention.

9.4.3.4 Skeletal and smooth muscle

Therapeutic use of botulinum toxin by direct injection of the drug produces a variety of histological changes (Montecucco et al, 1996). However, this has not been studied in cases of poisoning.

A case of gallbladder dysfunction induced by botulin A toxin has been described (Schnider P et al, 1993) as well as necrotising fasciitis as complication of botulinum toxin treatment (Latimer et al, 1998).

9.4.4 Gastrointestinal

Gastrointestinal symptoms may be observed 18 to 36 hours after ingestion in foodborne botulism. They include nausea, vomiting, abdominal cramps, and, occasionally, diarrhoea. In a later phase, after the onset of neurological symptoms and signs, constipation may occur. Gastric dilatation and paralytic ileus have been described (Adorjan et al, 1998).

Constipation is also frequently observed in infant botulism.

9.4.5 Hepatic

The liver is not affected by botulinum toxins.

9.4.6 Urinary

9.4.6.1 Renal

No direct effect.

9.4.6.2 Other

Neurogenic bladder may occur in the various forms of

botulism.

9.4.7 Endocrine and reproductive systems

No direct effect.

9.4.8 Dermatological

No direct effect.

9.4.9 Eye, ear, nose, throat: local effects

Blurred vision, dysphagia, dry mouth, diplopia, dysarthria, ptosis, extraocular muscle weakness, reduced gag reflex, tongue weakness, fixed or dilated pupils, nystagmus may all be observed following the toxin induced blockade of cranial nerves and autonomic nervous system.

9.4.10 Haematological

No data available.

9.4.11 Immunological

Severe allergic reactions may occur following administration of the equine antitoxin.

9.4.12 Metabolic

9.4.12.1 Acid base disturbances

Respiratory acidosis may occur if the ventilation is not

properly supported.

9.4.12.2 Fluid and electrolyte disturbances

No data available.

9.4.12.3 Others

No data available.

9.4.13 Allergic reactions

None with the botulinum toxin but allergic reactions may occur with the administration of the equine antitoxin.

9.4.14 Other clinical effects

No data available.

9.4.15 Special risks

Foodborne botulism

Home-canned and home-preserved food, uncured ham or sausages. Traditional food made with fish or sea-mammals.

Infant botulism

Ingestion of honey has implicated in some cases. Intestinal colonisation in adults has been associated with bowel surgery and chronic inflammatory disease of the intestine.

Inadvertent botulism

The therapeutic use of botulinum toxin needs special caution in patients with disturbed neuro-muscular transmission (myasthenia, Lambert-Eaton syndrome) and in patients concomitantly treated with aminoglycosides (Borodic, 1998; Wang et al, 1984).

A case report indicates that necrotising fasciitis can be a complication of botulinum toxin injection (Latimer et al, 1998).

9.5 Other

No data available.

9.6 Summary

10 MANAGEMENT

10.1 General principles

Supportive treatment, especially adequate mechanical ventilation, is of prime importance in the management of severe botulism. Surgical debridement and antimicrobial treatment are also required in wound botulism. Antitoxin administration is the only specific pharmacological treatment available.

10.2 Life supportive procedures and symptomatic/specific treatment

Adequate mechanical ventilation is required following respiratory muscle paralysis caused by botulinum toxin. This may be required for a period of weeks or even months, especially in infant botulism. Special care should be taken in order to prevent secondary infections.

10.3 Decontamination

Foodborne botulism

The efficacy of gastric decontamination in preventing botulism has not been studied. Since the features of foodborne botulism do not appear for several hours it is unlikely that gastric decontamination would be useful in an already symptomatic patient. In the case of recent ingestion (<1 hour) of possibly contaminated food emptying the stomach by induction of vomiting with syrup of ipecac, or by gastric lavage could be considered. Administer activated charcoal and a cathartic (such as sorbitol). Cathartic agents containing magnesium salts should be avoided because of the theoretical concern that increased magnesium levels may enhance the action of botulinum toxin (Shapiro, 1998).

Wound botulism

Surgical debridement should be performed.

10.4 Enhanced elimination

There is no way to increase the elimination of the toxin.

10.5 Antidote/antitoxin treatment

10.5.1 Adults

Foodborne botulism

One vial (7500 international units of type A, 5500 international units of type B and 8500 international units of type E antitoxins) equine antitoxin should be administered by infusion (Shapiro, 1998). Because of the risk of an allergic reaction to the equine serum, the patient should be asked about past history of asthma, hay fever or allergic reactions when in contact with horses.

Epinephrine chlorhydrate solution (1:1000) 1 mL should be available for immediate administration if required.

Sensitivity test:

An ocular or cutaneous sensitivity test should be performed prior to administration of the equine antitoxin.

Cutaneous test:

0.1 mL of the antitoxin serum diluted 1:100 in normal saline is administered by subcutaneous injection. If there is a positive history of allergies, this dose should be reduced to 0.05 mL of a 1:1000 dilution by subcutaneous injection. The interpretation of the result is done after 5 to 30 minutes. It is considered positive if a papule with a hyperemic areola occurs. The size of the papule and of the hyperemic zone give an indication of the level of sensitivity of the patient and the risk of an adverse effect to the administration of the antitoxin.

N.B. A negative cutaneous sensitivity test does not entirely exclude the possibility of a serum reaction.

Except in young children, an ocular test is easier to perform and produces less non-specific reactions. A drop of antitoxin serum diluted to 1:10 in a solution of normal saline is instilled in one eye. A control solution containing only normal saline is instilled in the other eye. Tears and conjunctivitis represent a positive reaction.

Serum reactions to equine antitoxin serums:

Anaphylactic reaction: Immediately administer 0.5 mL of a solution of epinephrine chlorhydrate 1:1000 SC or IM.

Fever

This may occur 20 to 60 minutes after the administration of the antitoxin. It is characterised by shivering, slight dyspnea and fever.

Serum sickness

This may occur up to 2 weeks after the administration of the antitoxin. The signs and symptoms are the following: fever, skin rash, oedema, swelling of the glands, articular pains. Urticarial reaction may respond to the administration of epinephrine. More severe cases may require the administration of cortisone.

Use of the equine antitoxin in a sensitive person.

Desensitisation protocol:

-0.05 mL of a 1:20 dilution solution SC

-0.1 mL of a 1:10 dilution solution SC

-0.3 mL of a 1:10 dilution solution SC

-0.1 mL of a non diluted solution

-0.2 mL of a non diluted solution SC

-0.5 mL of a non diluted solution SC

-Administration of the remaining therapeutic doses IM (Canadian Pharmacists Association, 1999)

Wound botulism

The treatment is similar to foodborne botulism.

Infant botulism

The use of equine antitoxin therapy is not recommended in children (Shapiro et al, 1998). However, the safety and efficacy of a human-derived antitoxin product (human botulism immune globulin) is being investigated in California (USA) for use in infants. For information on the Infant Botulism Prevention Programme contact the California Department of Health Services at (510) 540-2646 (24 hours).

Adult infectious botulism

The antitoxin protocol is the same as in foodborne poisoning. However, additional doses of antitoxin may be required. Care should be taken since sensitivity to equine serum may have been developed since the first administration.

10.5.2 Children

The protocol for the administration of the trivalent antitoxin is similar to the one used in adults.

10.6 Management discussion

11. ILLUSTRATIVE CASES

11.1 Case reports from literature

Wound botulism

A 27 year old heroin user was admitted with a 2 day history of muscle weakness. On examination he was afebrile and fully responsive but unable to keep his head upright. He deteriorated over the next few days, developing symmetrical flaccid paresis of the neck muscles, dysphagia, dysarthria, dry mouth, eyelid ptosis, mydriasis, diplopia, and urinary retention. He was unable to sit unsupported and had proximal paresis of all limbs with preserved deep tendon reflexes.

This patient usually administered heroin by subcutaneous or intramuscular injection and was noted to have several skin wounds. Wound botulism was suspected and he was treated with an intravenous dose of 500mL of trivalent equine botulism antitoxin (Botulism Antitoxin Behring, Chiron Behring, Germany) followed by 250ml six hours later. He was also given intravenous benzylpenicillin 20 megaunits daily, and surgical wound debridement was carried out. He developed respiratory failure and had to be mechanically ventilated for 16 days.

Electrophysiological investigations on day 26 revealed low compound muscle action potentials in the right arm and leg. Standard needle electromyography of the affected muscles showed brief low-amplitude irregular potentials. The diagnosis of wound botulism was confirmed in a mouse bioassay with serum drawn on day 3, just before administration of antitoxin (Jensenius et al, 2000).

Foodborne botulism

Six cases of botulism were described in Hungary. The first incident involved five members of the same family. The illness was moderately severe in three patients and mild in two patients. One of the patients had cirrhosis of the liver, and her condition became critical because of the repeated bleeding from oesophageal varices. A separate case involved a patient with sporadic illness. This patient developed severe gastric dilatation and paralysis of the bowels causing ileus at the start of the illness. In both sets of cases the diagnosis was confirmed by toxin tests in addition to the symptoms and food history. The symptoms regressed slowly, in about three weeks, in all patients. There were no deaths (Adorjan T et al, 1998).

12 ADDITIONAL INFORMATION

12.1 Specific preventive measures

  1. botulinum produces heat-resistant spores. Some strains will not survive above 80C, but others can only be destroyed by heating above boiling point. The thermal resistance of spores increases in foods with a higher pH and a lower salt content (CDC, 1998).

The growth of C. botulinum is inhibited by high temperature, acidification, dehydration, salination, certain food preservatives e.g. nitrite, ascorbates, polyphosphates, and competing microorganisms such as Lactobacillus spp (CDC, 1998). Nitrite and nitrate food preservatives have their own inherent problems (WHO working group, 1977).

Botulinum toxin is heat labile and can be inactivated by heating to 80C (CDC, 1998).

The prevention of foodborne botulism is achieved by processing food in such a way as to kill spores, and/or inhibit bacterial growth, and/or denature preformed toxin. Since many cases of botulism are associated with home-preserved food, public education about the need for adequate heating, appropriate storage etc is important.

Since honey has been identified as a food source of infant botulism this food should not be given to infants under the age of one year.

12.2 OTHER

13 REFERENCES

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Anderson MW, Sharma K, Feeney CM (1997) Wound botulism associated with black tar heroin. Acad Emerg Med, 4:805-809.

Arnon SS (1992) Infant botulism, p. 1095-1102. In Feigen RD and Cherry JD (eds), Textbook of pediatric infectious disease, 3rd ed. Saunders, Philadelphia.

Bakheit AM, Ward CD, McLellan DL (1997) Generalised botulism-like syndrome after intramuscular injections of botulinum toxin type A: a report of two cases. Journal of Neurology, Neurosurgery & Psychiatry; 62(2): 198

Bhatia KP, Munchau A, Thompson PD, Houser M, Chauhan VS, Hutchinson M, Shapira AH, Marsden CD (1999) Generalised muscular weakness after botulinum toxin injections for dystonia: a report of three cases. Journal of Neurology, Neurosurgery & Psychiatry; 67(1):90-3

Borodic G (1998) Myasthenic crisis after botulinum toxin. Lancet; 352(9143): 1832

Brin MF (1997) Botulinum toxin: chemistry, pharmacology, toxicity and immunology. Muscle Nerve, Suppl 6: S146-S168.

Burningham MD, Walter FG, Mechem C, Haber J, Ekins BR (1994) Wound botulism. Ann Emerg Med, 24(6): 1184-1187.

Canadian Pharmacists Association (1999) Compendium of products and pharmaceutical specialities (1999). p. 132-133.

CDC (Centers for Disease Control and Prevention) (1998), Botulism in the United States, 1899-1996. Handbook for Epidemiologists, Clinicians, and Laboratory Workers, Atlanta GA. Centers for Disease Controls and Prevention.

Cherington M (1998) Clinical spectrum of botulism. Muscle Nerve, 21: 701-710.

Coffield JA, Bakry N, Zhang RD, Carlson J, Gomella LG, Simpson LL (1997) In vitro characterization of botulinum toxin types A, C and D action on human tissues: combined electrophysiologic, pharmacological and molecular biologic approaches. J Pharmacol Exp Ther, 280: 1489-1498.

Ferrari ND, Weisse ME (1995) Botulism. Adv Pediatr Infect Dis, 10: 81-91.

Gill DM (1982) Bacterial toxins: a table of lethal amounts. Microbiol Rev; 46: 86-94

Glatman-Freedman A (1996) Infant botulism. Pediatric Rev, 17(5): 185-186.

Griffin PM, Hatheway CL, Rosenbaum RB, Sokolow R (1997) Endogenous antibody production to botulinum toxin in an adult with intestinal colonization botulism and underlying Crohn's Disease. J Infect Dis, 175: 633-637.

Halpern JL, Neale EA (1995) Neurospecific binding, internalization, and retrograde axonal transport. Curr Top Microbiol Immunol, 195: 221-241.

Hatheway CL (1995) Botulism: The present status of the disease. Curr Top Microbiol Immunol, 195: 55-75.

Hatheway CL, Snyder JD, Seals JE, Edell TA, Lewis GE Jr. (1984) Antitoxin levels in botulism patients treated with trivalent equine botulism antitoxin to toxin types A, B, and E. J Inf Diseases, 150(3): 407-412.

Hauschild AHW (1992) Epidemiology of human foodborne botulism. In. Hauschild AHW, Dodds KL (eds) Clostridium botulinum: ecology and control in foods. Dekker, New York.

Hauschild AHW, Gauvreau L (1985) Food-borne botulism in Canada, 1971-84. Can Med Assoc J. 133:1141-1146.

Hibbs RG, Weber JT, Corwin A, Allos BM, El Rehim MSA, El Sharkawy S, Sarn JE, McKee KT Jr (1996) Experience with the use of an investigational F(ab')2 heptavalent botulism immune globulin of equine origin during an outbreak of type E botulism in Egypt. Clin Infect Dis, 23: 337-340.

Hughes JM, Blumenthal JR, Merson MH, Lombard GL, Dowell VR, Gangarosa EJ (1981). Clinical features of types A and B food-borne botulism. Annals of Internal Medicine; 95(4): 442-5

Hurst DL, Marsh WW (1993) Early severe infantile botulism. J Pediatr, 122: 909-911.

Jensenius M, Løzstad RZ, Dhaenens G, Rørvik LM (2000) A heroin user with a wobbly head. Lancet; 365(9236): 1160

Kozaki S, Kamata Y, Nishiki TI, Kakinuma H, Maruyama H, Takahashi H, Karasawa T, Yamakawa K, Nakamura S (1998) Characterization of clostridium botulinum type B neurotoxin associated with infant botulism in Japan. Infect Immun, Oct: 4811-4816.

Latimer PR, Hodgkins PR, Vakalis AN, Butler RE, Evans AR, Zaki GA, Quelle (1998) Necrotising fasciitis as a complication of botulinum toxin injection. Eye; 12 (Pt 1): 51-3

Lecour H, Ramos MH, Almeida B, Barbosa R (1988) Food-borne botulism – a review of 13 outbreaks. Arch Intern Med, 148: 578-580.

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Mechem CC & Walter FG (1994) Wound botulism. Vet Human Toxicol, 36(3): 233-237.

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Proulx JF, Milor-Roy V, Austin J (1997) Quatre éclosions de botulisme dans la région de la Baie d'Ungava, au Nunavik, Québec. Relevé des maladies transmissibles au Canada, 23-4: 30-32.

Roblot P, Roblot F, Fauchère JL, Devilleger A, Maréchaud R, Breux JP, Grollier G, Becq-Giraudon B (1994) Retrospective study of 108 cases of botulism in Poitiers, France. J Med Microbiol, 40: 379-384.

Schiavo G, Rossetto O, Tonello F, Montecucco C (1995) Intracellular targets and metalloprotease activity of tetanus and botulism neurotoxins. Curr Top Microbiol Immunol, 195: 257-274.

Schnider P, Brichta A, Schmied M, Auff E (1993) Gallbladder dysfunction induced by botulinum A toxin. Lancet, 342(8874):811-2

Shapiro RL, Hatheway C, Swerdlow DL (1998) Botulism in the United States: a clinical and epidemiologic review. Ann Intern Med, 129(3): 221-228.

Shapiro RL, Hatheway C, Becher J, Swerdlow DL (1997) Botulism surveillance and emergency response. JAMA, 278(5): 433-435.

Slovis CM, Jones ID. Botulism and food poisoning (1998) In Clinical management of poisoning and drug overdose. Eds Haddon, Shannon and Winchester. 3rd ed. p399-406, Saunders and Co, Philadelphia.

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Wigginton JM, Thill P (1983) Infant botulism. Clin Pediatr, 32:669-674.

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Woodruff BA, Griffin PM, McCroskey LM, Smart JF, Wainwright RB, Bryant RG, et al. (1992) Clinical and laboratory comparison of botulism from toxin types A, B, and E in the United States, 1975-1988. J Infect Dis, 166:1281-1286.

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14 AUTHOR(S), REVIEWER(S) DATA (INCLUDING EACH

UPDATING), COMPLETE ADDRESSES

Author:

Albert J Nantel, Scientific Adviser, Centre de Toxicologie du Québec

 

August, 1999

Reviewer:

Janusz Szajewski, MD

 

Warsaw Poisons Centre

 

Telephone +48 22 839 0677

 

Facsimile +48 22 839 0677

 

e-mail szajewsk@waw.pdi.net

Reviewed at INTOX 12, Erfurt, Germany, November 2000.

Reviewers: M. Balali-Mood, B. Groszek, W. Temple, N. Langford

Edited by J.Tempowski (IPCS), February 2002 (ipcsintox@who.int)






Codeine

1. NAME

  1.1 Substance

  1.2 Group

  1.3 Synonyms

  1.4 Identification numbers

      1.4.1 CAS number

      1.4.2 Other numbers

  1.5 Brand names, Trade names

  1.6 Manufacturers, Importers

  1.7 Presentation, Formulation

2. SUMMARY

  2.1 Main risks and target organs

  2.2 Summary of clinical effects

  2.3 Diagnosis

  2.4 First aid measures and management principles

3. PHYSICO-CHEMICAL PROPERTIES

  3.1 Origin of the substance

  3.2 Chemical structure

  3.3 Physical Properties

      3.3.1 Properties of the substance

        3.3.1.1 Colour

        3.3.1.2 State/Form

        3.3.1.3 Description

      3.3.2 Properties of the locally available formulation

  3.4 Other characteristics

      3.4.1 Shelf-life of the substance

      3.4.2 Shelf-life of the locally available formulation

      3.4.3 Storage conditions

      3.4.4 Bioavailability

      3.4.5 Specific properties and composition

4. USES

  4.1 Indications

      4.1.1 Indications

      4.1.2 Description

  4.2 Therapeutic dosage

      4.2.1 Adults

      4.2.2 Children

  4.3 Contraindications

5. ROUTES OF ENTRY

  5.1 Oral

  5.2 Inhalation

  5.3 Dermal

  5.4 Eye

  5.5 Parenteral

  5.6 Other

6. KINETICS

  6.1 Absorption by route of exposure

  6.2 Distribution by route of exposure

  6.3 Biological half-life by route of exposure

  6.4 Metabolism

  6.5 Elimination and excretion

7. PHARMACOLOGY AND TOXICOLOGY

  7.1 Mode of action

      7.1.1 Toxicodynamics

      7.1.2 Pharmacodynamics

  7.2 Toxicity

      7.2.1 Human data

        7.2.1.1 Adults

        7.2.1.2 Children

      7.2.2 Relevant animal data

      7.2.3 Relevant in vitro data

  7.3 Carcinogenicity

  7.4 Teratogenicity

  7.5 Mutagenicity

  7.6 Interactions

  7.7 Main adverse effects

8. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS

  8.1 Sample

      8.1.1 Collection

      8.1.2 Storage

      8.1.3 Transport

  8.2 Toxicological analytical methods

      8.2.1 Test for active ingredient

      8.2.2 Test for biological sample

  8.3 Other laboratory analyses

      8.3.1 Haemotological investigations

      8.3.2 Biochemical investigations

      8.3.3 Arterial blood gas analysis

      8.3.4 Other relevant biomedical analyses

  8.4 Interpretation

  8.5 References

9. CLINICAL EFFECTS

  9.1 Acute poisoning

      9.1.1 Ingestion

      9.1.2 Inhalation

      9.1.3 Skin exposure

      9.1.4 Eye contact

      9.1.5 Parenteral exposure

      9.1.6 Other

  9.2 Chronic poisoning

      9.2.1 Ingestion

      9.2.2 Inhalation

      9.2.3 Skin exposure

      9.2.4 Eye contact

      9.2.5 Parenteral exposure

      9.2.6 Other

  9.3 Course, prognosis, cause of death

  9.4 Systematic description of clinical effects

      9.4.1 Cardiovascular

      9.4.2 Respiratory

      9.4.3 Neurological

        9.4.3.1 Central nervous system(CNS)

        9.4.3.2 Peripheral nervous system

        9.4.3.3 Autonomic nervous system

        9.4.3.4 Skeletal and smooth muscle

      9.4.4 Gastrointestinal

      9.4.5 Hepatic

      9.4.6 Urinary

        9.4.6.1 Renal

        9.4.6.2 Others

      9.4.7 Endocrine and reproductive systems

      9.4.8 Dermatological

      9.4.9 Eye, ears, nose, throat: local effects

      9 4.10 Hematological

      9.4.11 Immunological

      9.4.12 Metabolic

        9.4.12.1 Acid-base disturbances

        9.4.12.2 Fluid and electrolyte disturbances

        9.4.12.3 Others

      9.4.13 Allergic reactions

      9.4.14 Other clinical effects

      9.4.15 Special risks

  9.5 Other

10. MANAGEMENT

  10.1 General principles

  10.2 Relevant laboratory analyses

      10.2.1 Sample collection

      10.2.2 Biomedical analysis

      10.2.3 Toxicological analysis

      10.2.4 Other investigations

  10.3 Life supportive procedures and symptomatic/specific treatment

  10.4 Decontamination

  10.5 Elimination

  10.6 Antidote treatment

      10.6.1 Adults

      10.6.2 Children

  10.7 Management discussion

11. ILLUSTRATIVE CASES

  11.1 Case reports from literature

  11.2 Internally extracted data on cases

  11.3 Internal cases

12. ADDITIONAL INFORMATION

  12.1 Availability of antidotes

  12.2 Specific preventive measures

  12.3 Other

13. REFERENCES

14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)

 

  1. NAME 

 

       1.1 Substance

 

           Codeine   (USAN)

 

           (Fleeger, 1993)

 

       1.2 Group

 

           ATC classification index

 

           Cough and cold preparations(R05)/Antitussives excl. 

           combinations with expectorants (R05D)/Opium alkaloids and 

           derivatives (R05DA) 

 

           (WHO, 1992)

 

       1.3 Synonyms

 

           Codeinum; codeina; methylmorphine; morphine 3-methylether;

           morphine monomethyl ether.

 

       1.4 Identification numbers

 

           1.4.1 CAS number 

 

                 Codeine base (anhydrous)           76-57-3

                 Codeine base (monohydrate)         6059-47-8

                 Codeine hydrochloride              1422-07-7

                 Codeine phosphate (anhydrous)      52-28-8

                 Codeine phosphate (hemihydrate)    41444-62-6

                 Codeine phosphate (sesquihydrate)  5913-76-8

                 Codeine sulfate (anhydrous)        1420-53-7

                 Codeine sulfate (trihydrate)       6854-40-6

 

           1.4.2 Other numbers

 

                 RTECS

 

                 Codeine base (anhydrous)     QD0893000

 

       1.5 Brand names, Trade names

 

           Monocomponent products

 

           Actacode (Sigma, Australia)

           Codate (USV, Australia)

           Codinfos (Spain)

           Codelix (Drug Houses Australia, Australia)

           Codicept (Sanol, Germany)

           Codicompren (Cascan, Germany)

           Codipertussin (Fink, Germany and Switzerland)

           Codlin (Nelson, Australia)

           Codyl (Boehringer Ingelheim, Germany)

 

           Galcodine (Galen, UK)

           Paveral (Desbergers, Canada)

           Perduretas Codeina (Medea, Spain)

           Solcodein (Inibsa, Spain)

           Tricodein (Zyma, Germany; Solco, Switzerland)       

           Fosfato de codeina; Dipirona con codeina; Espasmo Cibalena; 

           Trigésico con codeina 

           (Squibb, Uruguay)

 

           Other numerous combination products containing codeine or its 

           salts are available. 

 

           (To be completed by each Centre using local data).

 

       1.6 Manufacturers, Importers

 

           Ciba Geigy, Gramon, Farmaco Uruguayo, Coro, Roussel Fisher, 

           and many others. 

 

           (To be completed by each Centre using local data).

 

       1.7 Presentation, Formulation

 

           Various formulations are available, e.g. codeine syrup

           5 mg/ml; codeine phosphate syrup 5 mg/ml; codeine tablets 15, 

           30 and 60 mg; codeine phosphate injection 15, 30 and 60 mg/ml 

           (Reynolds, 1989, McEvoy, 1989). 

 

           (To be completed by each Centre using local data).

 

  1. SUMMARY

 

       2.1 Main risks and target organs

 

           Respiratory depression is the main risk.  The characteristic 

           triad of opiate poisoning is coma, pin-point pupils and 

           respiratory depression which are found in severe codeine 

           poisoning. 

 

           Most fatalities occur after intravenous administration in 

           drug abusers who have taken codeine in association with other 

           depressant drugs or alcohol. 

 

           Deaths can also occur after oral overdosage.

     

       2.2 Summary of clinical effects

 

           Toxic doses of codeine produce unconsciousness, pinpoint 

           pupils,  slow and shallow respiration, cyanosis, weak pulse, 

           hypotension and in some cases pulmonary oedema, spasticity 

           and twitching of the muscles.  The main and most dangerous 

           effect is respiratory depression.  Death from respiratory 

           failure may occur within 2 to 4 hours after oral dose. 

           Convulsions may occur, especially in children.  

 

           Hallucinations, trembling, uncontrolled muscle movements, 

           mental depression and skin rash may be observed. 

     

           Chronic ingestion or injection leads to addiction.  In this 

           case pinpoint pupils and changes in mood may be  observed (or 

           no evident signs of use). 

 

           The withdrawal syndrome is characterized by yawning, 

           lacrimation, pilomotor reactions, severe gastrointestinal 

           disturbances  with cramps, vomiting, diarrhoea  or 

           constipation, sweating, fever, chills, increase respiratory 

           rate, insomnia, tremor,  mydriasis and myalgia. 

 

       2.3 Diagnosis

 

           Coma, pin-point pupils and respiratory depression is the 

           typical clinical triad of opiate poisoning.  In codeine 

           poisoning, skin rash with urticaria are often associated. 

 

           Urine and blood should be collected for biomedical and 

           toxicological analyses. 

 

       2.4 First aid measures and management principles

 

           In case of severe, acute poisoning, establish clear airway, 

           provide artificial ventilation, oxygen and monitor 

           haemodynamic status. 

 

           In the fully conscious patient, consider gastric lavage if 

           patient seen within one or two hours after ingestion. 

           Activated charcoal should be given afterwards. The use of a 

           cathartic is no longer recommended. 

     

           The recommended antidote is naloxone, given 0.4 mg 

           intravenously and repeated as necessary every two to three 

           minutes, until recovery. 

 

           Intravenous fluids, vasopressors and other supportive 

           measures as needed in shock.  

 

           Maintain body warmth. 

         

  1. PHYSICO-CHEMICAL PROPERTIES

 

       3.1 Origin of the substance

 

           Codeine is obtained either naturally, from opium (extracted 

           from Papaver somnifera) or by methylation of morphine. 

 

           It is a phenanthrenic alkaloid and constitutes 0.5% of raw 

           opium. 

 

       3.2 Chemical structure

 

           Molecular formula

 

           C18H21NO

 

           Molecular weight 

 

           Codeine base (anhydrous)    299.36

           Codeine base (monohydrate)  317.4

 

           Structural names

         

           7,8-Didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol. 

 

           (5alpha,6alpha)-7,8-Didehydro-4,5-epoxy-3-methoxy-17-

           methylmorphinan-6-ol. 

           

       3.3 Physical Properties

 

           3.3.1 Properties of the substance

 

                 3.3.1.1 Colour

 

                         Codeine base

 

                         Colourless (crystals) or white (powder)

 

                 3.3.1.2 State/Form

 

                         Codeine base

 

                         Crystals or a crystalline powder

 

                 3.3.1.3 Description

 

                         Codeine base

 

                         Odourless 

                         Bitter taste 

                         Melting point is 154°C to 158°C 

                         Effloresces slowly in dry air 

                         Affected by light 

                         Soluble 1 in 120 of water in 15 of boiling 

                         water, in 2 of alcohol, in 0.5 of chloroform, 

                         in 50 of ether.   

                         Soluble in aryl-alcohol and methyl alcohol. 

                         Very soluble in dilute acids, slightly soluble 

                         in a excess of potassium hydroxide solution. 

                         pH of more than 9 in a 0.5% solution of codeine 

                         in water. pKa 8.2 (Casarett & Doull, 1980). 

 

           3.3.2 Properties of the locally available formulation 

 

                 To be completed by each Centre using local data.

 

       3.4 Other characteristics 

 

           3.4.1 Shelf-life of the substance

 

                 No data available.

                 

           3.4.2 Shelf-life of the locally available formulation

            

                 Codeine formulations are generally considered to be 

                 stable. 

 

           3.4.3 Storage conditions

     

                 Store in airtight containers, protected from light.

                         

           3.4.4 Bioavailability

 

                 To be completed by each Centre using local data.

 

           3.4.5 Specific properties and composition

 

                 Codeine is commercially available as water soluble 

                 hydrochloride, sulfate or phosphate and is administered 

                 orally in the form of linctuses for the relief of 

                 coughs, and as tablets for the relief of pain.  Codeine 

                 phosphate is also given parenterally for the relief of 

                 pain. 

 

                 Codeine, usually as the phosphate, is often 

                 administered by mouth together with acetylsalicylic 

                 acid or paracetamol. 

 

                 The equivalence of the analgesic effects is 120 mg of 

                 codeine corresponds to 10 mg of morphine. and 30 mg of 

                 codeine to 325 to 600 mg of aspirin (Gilman et al., 

                 1990). 

 

                 Codeine is less potent than morphine as an analgesic. 

 

                 (To be completed by each Centre using local data). 

 

  1. USES 

 

       4.1 Indications 

 

           4.1.1 Indications 

 

                 Analgesic for relief of moderate pain, and an 

                 antitussive (principal uses). 

 

                 Antidiarrhoeal. 

 

                 Used frequently in  association with other analgesics 

                 or antihistamines, sedatives and stimulants in some 

                 pharmaceutical preparations. (This represents a higher 

 

                 risk of poisoning and fatality [Ellenhorn & Barceloux, 

                 1988]). 

 

                 Codeine is used as a drug of abuse, and it may produce 

                 dependence and withdrawal syndromes. 

     

           4.1.2 Description 

 

                 Not relevant. 

 

       4.2 Therapeutic dosage 

         

           4.2.1 Adults 

 

                 Analgesic 

 

                 Codeine and its salts (sulfate or phosphate) are 

                 administered in doses of 15 to 60 mg, four to six times 

                 a day. (Note: Orally, a dose of 30 mg of codeine is 

                 equivalent to 325 to 600 mg of aspirin [Gilman et al., 

                 1990]). 

 

                 The maximum daily dose for the relief of pain is 360 mg 

                 (Reynolds, 1993). 

 

                 Antitussive 

 

                 15 mg to 30 mg of codeine phosphate 3 to 4 times a day 

                 (Reynolds, 1993).  Not more than 120 mg/day is 

                 recommended. 

                

                 Parenteral 

 

                 A dose of 120 mg of codeine given subcutaneously 

                 produces analgesia equivalent to that resulting from 10 

                 mg of morphine. 

 

                 Doses given by intramuscular or subcutaneous routes are 

                 similar to those given orally (Reynolds, 1993). 

                

           4.2.2 Children 

            

                 Analgesic 

 

                 0.5 mg/kg body weight (codeine phosphate) divided into 

                 four to six doses a day (Reynolds, 1993). 

                 

                 Antitussive 

 

                 The dose should not exceed 0.25 mg/kg/day divided into 

                 three or four doses. 

 

                 5 to 12 years 

 

                 7.5 to 15 mg (codeine phosphate) three to four times a 

                 day (Reynolds, 1993). 

 

                 1 to 5 years 

 

                 3 mg (codeine phosphate)  three to four times a day 

                 (Reynolds, 1993). 

 

                 Under one year 

 

                 Not generally recommended, but 1 mg/kg by mouth or 

                 intramuscular injection as a single dose presented a 

                 relatively small risk of respiratory depression and the 

                 patient should be observed closely (Reynolds, 1993). 

 

       4.3 Contraindications 

 

           Codeine is contraindicated during pregnancy. 

 

           Paediatric and geriatric patients may be more susceptible to 

           the effects of codeine, especially to respiratory depression.  

           Lower doses may be required for this kind of patient, as well 

           as for those who suffer from some type of respiratory 

           insufficiency. 

 

           When prescribing for infants, prematurity should be taken 

           into account. Administration of cough suppressants containing  

           codeine should be avoided in children less than 12 months 

           (Reynolds, 1982). 

 

  1. ROUTES OF ENTRY

 

       5.1 Oral   

 

           This is the most common route of entry.

 

       5.2 Inhalation 

 

           No data available.

 

       5.3 Dermal

 

           No data available.

 

       5.4 Eye 

 

           No data available.

 

       5.5 Parenteral 

 

           Intramuscular administration of the phosphate derivative is 

           sometimes indicated. 

 

           The intravenous route may be used by drug abusers.

 

       5.6 Other

 

           No data available.

 

  1. KINETICS

 

       6.1 Absorption by route of exposure 

 

           Codeine and its salts are well absorbed from the 

           gastrointestinal tract.  After ingestion, the peak plasma 

           level is attained in one hour (Reynolds, 1989). 

           Bioavailability is about 50% (Moffat, 1986)

      

           Codeine, in contrast to morphine, is two-thirds as effective 

           orally as parenterally, both as an analgesic and as a 

           respiratory depressant. It has therefore a highly oral-

           parenteral potency ratio (due to lower first-pass metabolism 

           in the liver) (Goodman & Gilman, 1985). 

 

       6.2 Distribution by route of exposure 

 

           The volume of distribution is 3.5 L/kg (Baselt & Cravey, 

           1989; Moffat, 1986) after oral administration and 2.6 L/kg 

           after intramuscular injection (Vivian, 1979).  

 

           Protein binding of codeine is about 25% in human serum 

           (Reynolds, 1989). Moffat (1986) states that plasma protein 

           binding is about 7 to 25%. 

     

       6.3 Biological half-life by route of exposure 

 

           The half-life of codeine in plasma is 2.5 to 4 hours (Gilman 

           et al.,1985; Reynolds, 1989). 

 

       6.4 Metabolism 

 

           Codeine is metabolized mainly in the liver where it undergoes 

           0-demethylation to form morphine, N-demethylation to form 

           norcodeine , and partial conjugation to form glucuronides and 

           sulphates of both the unchanged drug and its metabolites 

           (Moffat, 1986). 

 

           The rate of metabolism of codeine is 30 mg/hour (Nomof et 

           al., 1977). 

 

       6.5 Elimination and excretion 

 

           Total systemic clearance of codeine from the plasma is 10 to 

           15 mL/min/kg (Moffat, 1986). 

 

           Eighty six per cent of the drug is excreted within 24 hours, 

           (Gilman et al., 1985; Moffat, 1986) mainly in urine as 

           norcodeine and free and conjugated morphine.  Negligible 

 

           amounts of codeine and its metabolites are found in faeces 

           (McEvoy, 1989).  

 

           Of the 86% excreted after an oral dose 40 to 70% is free or 

           conjugated codeine, 5 to 15% free or conjugated morphine, 10 

           to 20% is free or conjugated norcodeine; unchanged drug 

           accounts for  6 to 8% of the dose excreted in urine within 24 

           hours but this can increase to 10% if the urinary pH is 

           decreased. (Moffat, 1986). 

 

           After intramuscular administration, 15 to 20% is excreted 

           unchanged in acid urine within 24 hours (Moffat, 1986). 

         

           Codeine passes into the breast milk in very small amounts, 

           probably insignificant, which is compatible with breast-

           feeding (Committee on Drugs, AAP, 1983), and small amounts 

           are excreted in the bile (Moffat, 1986). 

     

  1. PHARMACOLOGY AND TOXICOLOGY 

 

       7.1 Mode of action 

 

           7.1.1 Toxicodynamics 

 

                 Codeine is a mu receptor agonist. Overdose produces CNS 

                 depression, respiratory depression, pinpoint pupils and 

                 coma, but to a lesser degree than morphine. 

            

                 In overdose, codeine may cause pulmonary oedema within 

                 2 or 3 hours (Sklar & Timms, 1977). 

 

           7.1.2 Pharmacodynamics 

 

                 Codeine binds with stereospecific receptors at many 

                 sites within the CNS to alter processes affecting both 

                 the perception of pain and the emotional response to 

                 pain.  Precise sites and mechanisms of  action have not 

                 been fully determined.  It has been proposed that there 

                 are multiple subtypes of opioid receptors, each 

                 mediating various therapeutic and/or side effects of 

                 opioid drugs.  Codeine has a very low affinity for 

                 opioid receptors and the analgesic effect of codeine 

                 may be due to its conversion to morphine (Gilman et 

                 al., 1985). 

 

                 The actions of an opioid analgesic may therefore depend  

                 upon its binding affinity for each type of receptor and 

                 whether it acts as a full agonist or a partial agonist 

                 or is inactive at each type of receptor.  At least two 

                 of these types of receptors (mu and kappa) mediate 

                 analgesia.  Codeine probably produces its effects via 

                 agonist actions at the mu receptors. 

 

       7.2 Toxicity 

 

           7.2.1 Human data 

 

                 7.2.1.1 Adults 

 

                         The adult lethal dose is 0.5 to 1.0 g (Gosselin 

                         et al., 1984).  This dose may cause convulsions 

                         and unconsciousness, and death from respiratory 

                         failure may result within 4 hours.  Moffat 

                         (1986) estimated the minimum lethal adult dose 

                         at 800 mg. 

            

                         Serum concentrations over 5 mg/L were detected 

                         in an adult who had self-administered 900 mg of 

                         codeine intravenously; he regained 

                         consciousness only after 3 days when serum 

                         levels reached 1.3 mg/L (Huffman & Ferguson, 

                         1975). 

 

                         Drug concentrations in codeine fatalities are 

                         approximately 2.8 mg/L in blood and 103.8 mg/L 

                         in urine (Baselt & Cravey, 1989). 

 

                         The development of tolerance increases the 

                         potentially toxic doses.  In volunteer studies 

                         individuals could tolerate up to 240 mg by 

                         mouth, 4 times daily (Reynolds, 1982). 

                      

                 7.2.1.2 Children 

 

                         Doses over 5 mg/kg may cause serious 

                         respiratory depression. 

 

                         Children may display signs of toxicity at 

                         1/20 th of the minimum lethal dose of 800 mg 

                         (Moffat, 1986). 

 

                         A cough syrup which contained 10 mg of 

                         codeine/5 mL, produced severe poisoning after 

                         two 5 mL doses in a prematurely born 3 month 

                         old baby (Wilkes et al., 1981). 

 

           7.2.2 Relevant animal data 

 

                 Codeine 

 

                 LD50 (oral) rat           427 mg/kg 

                 LD50 (intravenous) rat     75 mg/kg 

                 LD50 (subcutaneous) rat   229 mg/kg

 

                 Codeine phosphate

 

                 LD50 (oral) rat           266 mg/kg

                 LD50 (intravenous) rat     54 mg/kg

 

                 LD50 (subcutaneous) rat   365 mg/kg

                 LD50 (intramuscular) rat  208 mg/kg

            

                 (Sax & Lewis, 1989)

 

           7.2.3 Relevant in vitro data

 

                 No relevant data available.

 

       7.3 Carcinogenicity

 

           No data available.

 

       7.4 Teratogenicity    

 

           Briggs et al. (1986) examined the results of five studies 

           covering the maternal use of codeine during the first 

           trimester of pregnancy. While there was no evidence found to 

           suggest a relationship to large categories of major or minor 

           malformations, possible associations were found with 

           respiratory malformations, hydrocephaly, pyloric stenosis, 

           cardiac and circulatory system defects, cleft lip and palate, 

           umbilical hernia and inguinal hernia, dislocated hip and 

           other musculoskeletal defects. The association of codeine and 

           respiratory and heart malformation was statistically 

           significant.  Data on inguinal hernias, circulatory system 

           defects, cleft lip and palate, dislocated hips and 

           musculoskeletal defects and alimentary tract defects were 

           inconclusive .  But all the data serves as a  clear warning 

           that indiscriminate use of codeine represents a risk to the 

           foetus. 

 

       7.5 Mutagenicity 

          

           No data available. 

 

       7.6 Interactions 

 

           Incompatible with bromides, iodides and salts of heavy 

           metals. 

 

           Codeine phosphate for injection has been reported to be 

           physically or chemically incompatible with solutions 

           containing amylobarbital, aminophylline, ammonium chloride, 

           thiazides, sodium bicarbonate, pentobarbitone, thiopentone 

           and sodium heparin (McEvoy, 1989).      

     

           Antidiarrhoeal opioids given concurrently with codeine may 

           result in increased constipation, paralytic ileus, as well as 

           an increased risk of respiratory depression (Shee & Pounder, 

           1980).  Given together with antihypertensive drugs codeine 

           may potentiate hypotension and increase the risk of 

           orthostatic hypotension. 

 

           Concurrent use with other analgesic opioids may result in 

           additive CNS depression, respiratory depression, and 

           hypotensive effects. 

            

           Atropine or antimuscarinic agents administered with codeine 

           may produce constipation, ileus, urinary retention. 

 

           With monoamine oxidase inhibitors fatal reactions may occur. 

           Symptoms and signs include excitation, sweating, hypertension 

           or hypotension, severe respiratory depression, seizures, 

           hyperpyrexia and coma. 

 

           Neuromuscular blocking agents may also increase the 

           depressant effects. 

 

           Codeine may antagonize the effects of metoclopramide on 

           gastrointestinal motility. 

 

           Naloxone antagonizes the analgesic effects and may 

           precipitate withdrawal symptoms in dependent patients.  The 

           dosage of the antagonist should be carefully titrated when 

           used to treat codeine overdose in patients who are dependent 

           (USP,1985). 

 

       7.7 Main adverse effects 

 

           In acute asthma attack, codeine depresses the respiratory 

           centre and increases airway resistance. 

 

           Cardiac arrhythmias and seizures may be induced or 

           exacerbated. 

 

           Codeine abuse or dependency may produce emotional instability 

           or suicidal tendencies. 

 

           Codeine may cause biliary tract spasms in case of 

           cholelithiasis disease or gallstones. 

 

           In head trauma or raised intracranial pressure,  the risk of 

           respiratory depression and further elevation of cerebrospinal 

           fluid pressure is increased by codeine, which also causes 

           sedation and pupillary changes (misleading diagnosis on the 

           clinical course  of cerebral trauma). 

 

           Codeine may cause urinary retention in patients with 

           prostatic hypertrophy, obstruction, or urethral strictures. 

 

           Administration of codeine should be cautious in case of renal 

           function impairment as codeine is excreted primarily by the 

           kidneys. 

 

           Caution is also advised in administration to very young, ill 

           or debilitated patients who may be more sensitive to the 

           depressant effects, especially on the respiratory system. 

 

  1. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS

 

       8.1 Sample

 

           8.1.1 Collection

 

           8.1.2 Storage

 

           8.1.3 Transport

 

       8.2 Toxicological analytical methods

 

           8.2.1 Test for active ingredient

 

           8.2.2 Test for biological sample

 

       8.3 Other laboratory analyses

 

           8.3.1 Haemotological investigations

 

           8.3.2 Biochemical investigations

 

           8.3.3 Arterial blood gas analysis

 

           8.3.4 Other relevant biomedical analyses

 

       8.4 Interpretation

 

       8.5 References

    

  1. CLINICAL EFFECTS 

 

       9.1 Acute poisoning 

 

           9.1.1 Ingestion 

           

                 Toxic doses of codeine will cause unconsciousness, 

                 pinpoint pupils, slow shallow respiration, cyanosis, 

                 hypotension, spasms of gastrointestinal and biliary 

                 tracts, and in some cases pulmonary oedema, spasticity, 

                 twitching of the muscles and convulsions. Death from 

                 respiratory failure may occur within 4 hours after 

                 large overdose. 

 

                 Initial signs of overdose are cold and clammy skin, 

                 skin rash, confusion, nervousness or restlessness, 

                 dizziness, low blood pressure, respiratory distress, 

                 bradycardia, weakness and miosis. 

 

           9.1.2 Inhalation 

 

                 No data available. 

 

           9.1.3 Skin exposure 

 

                 No data available. 

 

           9.1.4 Eye contact 

 

                 No data available. 

 

           9.1.5 Parenteral exposure 

 

                 In case of overdose, the symptoms are basically the 

                 same as by ingestion but will develop more rapidly. 

     

           9.1.6 Other 

 

                 No data available. 

 

       9.2 Chronic poisoning 

 

           9.2.1 Ingestion 

 

                 Clinical findings in case of chronic use or addiction 

                 of codeine may not be evident. Pinpoint pupils and 

                 rapid changes in the mood may be observed (Dreisbach, 

                 1987). 

 

                 Symptoms of withdrawal may be cramps, vomiting, 

                 diarrhoea or constipation, sweating, fever, chills, 

                 increase in respiratory rate, insomnia, tremor and 

                 mydriasis.  A narcotic antagonist such as nalorphine or 

                 naloxone may precipitate the withdrawal reaction.  

         

           9.2.2 Inhalation 

 

                 No data available. 

 

           9.2.3 Skin exposure 

 

                 No data available. 

         

           9.2.4 Eye contact 

 

                 No data available. 

 

           9.2.5 Parenteral exposure 

 

                 Chronic intravenous use is seen in addicts and causes 

                 similar symptoms as oral but with an increased risk of 

                 life threatening situations. 

 

           9.2.6 Other 

 

                 No data available. 

         

       9.3 Course, prognosis, cause of death 

 

           Within one hour of a large oral overdose the patient will 

           suffer increasing CNS depression, miosis, and a fall in body 

           temperature with hypotension.  This may progress to coma with 

           respiratory depression within 4 hours.  

 

           Intravenous injection may cause these effects more rapidly. 

            

           Death from codeine overdose is relatively rare. An 

           association with alcohol or other CNS depressants increases 

           the risk of fatalities.  

 

           Death is due to respiratory arrest, which may occur within 4 

           hours after a toxic oral dose or subcutaneous administration, 

           or immediately after intravenous overdose 

            

       9.4 Systematic description of clinical effects 

 

           9.4.1 Cardiovascular 

 

                 Palpitations, hypotension. 

 

           9.4.2 Respiratory 

 

                 Depression of the respiratory centre and increased 

                 airway resistance leads to acute respiratory failure, 

                 which may be enhanced by acute pulmonary oedema. 

 

           9.4.3 Neurological 

 

                 9.4.3.1 Central nervous system(CNS) 

 

                         Codeine causes less euphoria and sedation than 

                         morphine, but CNS depression and coma occur in 

                         case of overdose.  Codeine has a weaker 

                         depressive effect than other opiates to the 

                         cortex and medullary centres, but is more 

                         stimulating to the spinal cord.  It may induce 

                         unusual excitation and convulsions, especially 

                         in children (Reynolds, 1989). 

      

                 9.4.3.2 Peripheral nervous system 

 

                         No data available. 

 

                 9.4.3.3 Autonomic nervous system 

 

                         No data available. 

 

                 9.4.3.4 Skeletal and smooth muscle 

 

                         No data available. 

      

           9.4.4 Gastrointestinal 

                

                 Spasm and ileus occur especially when codeine is 

                 administered with spasmolytics. 

            

           9.4.5 Hepatic 

 

                 Codeine may cause biliary tract spasm. 

 

                 Increases in intrabiliary pressure may be observed 

                 after administration of 10 to 20 mg of codeine 

                 (Reynolds, 1982). 

 

           9.4.6 Urinary 

 

                 9.4.6.1 Renal 

 

                         No data available. 

 

                 9.4.6.2 Others 

 

                         Urinary retention may occur. 

 

           9.4.7 Endocrine and reproductive systems 

 

                 No data available. 

 

           9.4.8 Dermatological 

 

                 Rash, itching or swelling of face may occur. 

 

           9.4.9 Eye, ears, nose, throat: local effects 

 

                 Miosis is a characteristic symptom in the overdosed 

                 patient and in the chronic drug abuser. 

 

           9 4.10 Hematological 

 

                  No data available. 

 

           9.4.11 Immunological 

 

                  No data available. 

 

           9.4.12 Metabolic 

 

                  9.4.12.1 Acid-base disturbances 

 

                           No specific effect. 

 

                  9.4.12.2 Fluid and electrolyte disturbances 

 

                           No specific effect. 

 

                  9.4.12.3 Others 

 

                           No data available. 

 

           9.4.13 Allergic reactions 

 

                  Rashes, bronchospasm and/or anaphylactic reaction have 

                  been reported after codeine overdose (Reynolds, 1993). 



           9.4.14 Other clinical effects 

 

                  No data available. 

 

           9.4.15 Special risks 

 

                  Pregnancy 

 

                  A possible association between cardiac and respiratory 

                  malformations and codeine was reported (Reynolds, 

                  1989; Briggs et al., 1986).Data on inguinal hernias, 

                  circulatory system defects, cleft lip and palate, 

                  dislocated hips and musculoskeletal defects and 

                  alimentary tract defects were inconclusive (Briggs et 

                  al, 1986).  But all the data serves a clear warning 

                  that indiscriminate use of codeine does represent a 

                  risk to the foetus. 

     

                  Codeine crosses the placenta and regular use during 

                  pregnancy may result in addiction of the foetus 

                  leading to withdrawal syndrome in the newborn 

                  (irritability, excessive crying, tremors, hyperactive 

                  reflexes, fever, vomiting, diarrhoea, yawning).  

 

                  It may also produce respiratory depression in the 

                  newborn whose mother has received codeine during 

                  labour (Briggs et al., 1986). 

 

                  Breast feeding 

 

                  It is excreted in the breast milk in small amounts 

                  that are probably insignificant, and is compatible 

                  with breast feeding, after therapeutic doses 

                  (Committee on Drugs, AAP, 1983). 

                

                  Other 

 

                  Patients with hypothyroidism are at higher risk of 

                  respiratory depression. 

            

       9.5 Other 

 

           No data available. 

 

  1. MANAGEMENT 

 

        10.1 General principles

 

             Respiratory depression should be treated through either 

             artificial ventilation and/or artificial ventilation and 

             intravenous naloxone. Cardio-circulatory function should be 

             monitored. 

 

             In case of ingestion, and in the conscious or intubated 

             patient, gastric aspiration and lavage should be considered 

             (provided the patient is seen early after the ingestion) 

             and activated charcoal should be administered in order to 

             reduce absorption. 

 

             In the drug user, codeine is rarely taken alone, therefore 

             symptomatology of overdose may not be clear-cut.  It is 

             usually modified or enhanced by the other drugs. 

 

        10.2 Relevant laboratory analyses 

 

             10.2.1 Sample collection 

 

                    Blood and urine. 

 

             10.2.2 Biomedical analysis 

 

                    Routine blood, arterial gases and urinalysis are 

                    required. 

 

             10.2.3 Toxicological analysis 

 

             10.2.4 Other investigations 

 

                    Nothing specific. 

 

        10.3 Life supportive procedures and symptomatic/specific 

             treatment 

         

             Administration of the antidote naloxone may be required.  

 

             Establish and maintain adequate ventilation: endotracheal 

             intubation and assisted ventilation are needed in the 

             severely poisoned patient. 

            

             Administration of intravenous fluids, vasopressors and 

             other supportive measures may be required.  

 

             Maintain body warmth and fluid balance. 

 

             Monitor continuously: arterial blood gases (PaO2, PaCO2), 

             pH, respiration, blood pressure and consciousness. 

                                   

        10.4 Decontamination

 

             In fully conscious patients gastric lavage followed by 

             charcoal should be considered if the patient is seen within 

             1 or 2 hours after the ingestion. 

 

        10.5 Elimination

 

             Dialysis is not indicated. 

 

        10.6 Antidote treatment

 

             10.6.1 Adults

 

                    Naloxone is a specific opioid antagonist.

 

                    The effect of naloxone may be of shorter duration 

                    than that of the narcotic analgesic. (Reynolds, 

                    1989). 

 

                    Since naloxone is a competitive antagonist of opiate 

                    poisoning, there can be no absolute guidelines on 

                    dosage. Naloxone should be given intravenously, in 

                    successive doses of 0.4 to 2.0 mg, until the desired 

                    response has been obtained. 

 

                    An alternative approach, which may be appropriate 

                    for opiate addicts, is to give naloxone (0.8 to 1.2 

  1. mg) intramuscularly, before waking the patient with 

                    an intravenous dose of 0.4 to 0.8 mg. Adequate 

                    ventilatory support must be given. The patient then 

                    has a "depot" of antidote in case he/she departs 

                    soon after the initial treatment (as many addicts 

                    do). (Meredith et al., 1993) 

 

                    If an effective increase in pulmonary ventilation is 

                    not achieved after the first dose, it may be 

                    repeated every 2 or 3 minutes until respiration 

                    returns to normal and the patient responds to 

                    stimuli. 

 

                    In an individual physically dependent on narcotics 

                    (e.g. codeine), the administration of the usual dose 

                    of narcotic antagonist may precipitate an acute 

                    withdrawal syndrome (Barnhart, 1987). This may 

                    require administration of intravenous diazepam. 

 

                    In case of renal failure, it is not necessary to 

                    reduce the dose of naloxone. 

 

                    Naloxone also has a longer action than either 

                    nalorphine or levorphan neither of which should be 

                    used as antidotes, unless naloxone is not available. 

              

             10.6.2 Children 

 

                    In children the usual initial dose is 10 mcg/kg body 

                    weight given intravenously, followed, if necessary, 

                    by a larger dose of 100 mcg/kg.  

 

                    In newborns of addicted mothers the injection of 

                    naloxone may precipitate acute severe withdrawal 

                    syndrome. 

                

        10.7 Management discussion 

 

             Naloxone is the most effective antidote as yet, but it may 

             not be available in some countries.  Levallorphan 

             (tartrate) or nalorphine (hydrochloride or hydrobromide) 

             antagonize the respiratory depression produced by narcotics 

             but may also have agonist effects and induce side-effects. 

            

             Naloxone is of diagnostic value in coma of unknown origin, 

             where narcotic overdose is suspected. 

 

             If the antidote is not available, the treatment relies on 

             the life-supportive measures, especially in maintaining 

             proper ventilation. 

 

  1. ILLUSTRATIVE CASES 

 

        11.1 Case reports from literature 

 

             Case 1 

 

             A 31 month old baby was transferred to the hospital after 

             having ingested 6.6 mg/kg of codeine.  On arrival he had 

             collapsed, and was cold and semi-comatose with pinpoint 

             pupils and Sheynes-stokes breathing.  He was treated with 

             intravenous naloxone and was discharged after two days 

             without sequelae (Wilkes, et al, 1981). 

 

             Case 2 

            

             An evaluation of codeine intoxication in 430 children, 

             reported the following symptoms in decreasing order of 

             frequency: sedation, rash, miosis, vomiting, itching, 

             ataxia, and swelling of the skin (oedema).  Respiratory 

             failure occurred in eight children, two of whom died; all 

             eight had taken 5 mg/kg body weight or more. 

 

        11.2 Internally extracted data on cases 

 

             Only a few uneventful cases have been registered, and  

             mostly involved children receiving cough medication. 

 

        11.3 Internal cases 

 

             To be completed by each Centre using local data. 

 

  1. ADDITIONAL INFORMATION 

 

        12.1 Availability of antidotes 

 

             To be completed by the Centre. 

 

        12.2 Specific preventive measures 

 

             Caution is advised in administration of codeine to small 

             children, the elderly or very ill patients, who may be more 

             sensitive to the effects, especially to the respiratory 

             depression. 

 

             Caution is advised when administered with other medication 

             and during pregnancy and lactation. 

            

        12.3 Other 

 

             No data available. 

 

  1. REFERENCES 

 

        Barnhart ER, ed. (1987) Physician's Desk Reference, 41st ed.  

        New Jersey,  Medical Economics Company Inc. 

          

        Baselt RC & Cravey RH (1989) Disposition of toxic drugs and 

        chemicals in man, 3rd Ed. Year Book Medical Publishers Inc, pp 

        214-218. 

 

        Briggs GG, Freeman RK, Sumner JY (1986) Drugs in pregnancy and 

        lactation, 2nd ed. Williams & Wilkins pp 102-103c. 

 

        Casaret & Doull's (1980) Toxicology, 2nd Ed. Macmillan 

        Publishing Co, Inc New York; 663, 678-691. 

 

        Committee on Drugs - American Academy of Pediatrics (1983) The 

        transfer of drugs and other chemicals into human breast milk. 

        Pediatrics; 72: 375-383. 

 

        Dreisbach (1987) Handbook of poisoning, prevention. Appleton 

        Lange Norwalk, Connecticut, pp 324, 325-341. 

 

        Ellenhorn MJ & Barceloux DG (1988)  Medical toxicology, 

        diagnosis and treatment of human poisoning.  New York,  

        Elsevier. 

 

        Fleeger CA, ed. (1993) USAN 1994: USAN and the USP dictionary of 

        drug names. Rockville, MD, United States Pharmacopeial 

        Convention, Inc., p 171. 

 

        Gosselin RE, Hodge HC, Smith RP (1984) Clinical toxicology of 

        commercial products. William and Wilkins. 

 

        Gilman AG, Rall TW, Nies AS & Taylor P, eds. (1990) Goodman and  

        Gilman's the pharmacological basis of therapeutics, 8th ed. New 

        York, Pergamon Press, pp 497-500. 

 

        Gilman AG, Goodman LS, Rall TW & Murad F eds. (1985)  Goodman & 

        Gilman's the pharmacological basis of therapeutics. 7th ed. New 

        York, Macmillan Publishing Company. 

 

        Goodman et Gilman (1987) Editorial Medica Panamericana. pp 506, 

        527-553. 

 

        Huffman DH & Ferguson RL (1975) Acute codeine overdose: 

        correspondence between clinical course and codeine metabolism. 

        John Hopkins Med J, 136:183-186. 

        

        McEvoy GK, ed. (1989) American hospital formulary service, drug 

        information, Bethesda, American Society of Hospital Pharmacists. 

 

        Meredith TJ, Jacobsen D, Haines JA, & Berger JC eds. (1993) 

        Naloxone, flumazenil and dantrolene as antidotes. Cambridge, 

        Cambridge University Press, p 20. 

 

        Moffat AC, ed. (1986) Clarke's isolation and identification of 

        drugs in pharmaceuticals, body fluids, and post-mortem material. 

        2nd ed. London, The Pharmaceutical Press, pp 490-491. 

 

        Nomoff N, Elliott HW, & Parker KD (1977) Actions and metabolism 

        of codeine (methylmorphine) administration by continuous 

        intravenous infusion to humans.  11(5): 517-29. 

        

        Reynolds JEF, ed. (1982) Martindale, the extra pharmacopoeia, 

        28th ed. London, The Pharmaceutical Press, pp  1004, 1006-1031, 

 

        Reynolds JEF, ed. (1989) Martindale, the extra pharmacopoeia, 

        29th ed. London, The Pharmaceutical Press. pp 1297-1299 

 

        Reynolds JEF, ed. (1993) Martindale, the extra pharmacopoeia, 

        30th ed. London, The Pharmaceutical Press. pp 1069-1071. 

 

        Sax NI & Lewis RJ sr (1989) Dangerous properties of industrial 

        materials, 7th ed. New York, Van Nostrand Reinhold, p 944-945. 

 

        Shee E  & Pounder RE (1980) Loperamide, diphenoxylate and 

        codeine phosphate in chronic diarrhoea. Br Med J, 280: 524. 

 

        Sklar J & Timms RM (1977) Codeine-induced pulmonary edema. 

        Chest, 72(2): 230-231. 

 

        United States Pharmacopeia, 21st rev. The National formulary 

        16th ed. (1985) Rockville MD, United States Pharmacopeial 

        Convention,  pp 571-578. 

 

        Von Muhlendahl KE, Krienke EG, Scherf-Rahne B, & Baukloh G  

        (1976) Codeine intoxication in childhood. Lancet, 2:303-305. 

 

        Vivian D (1979) Three deaths due to hydrocodone in a resin 

        complex cough medicine. Drug Intell Clin Pharmacol, 13:445-446. 

 

        Wilkes TCR, Davies DP, & Dar MR (1981) Apnoea in a 3-month old 

        baby prescribed compound linctus containing codeine, letter. 

        Lancet 1: 1166-1167. 

 

  1. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE 

        ADDRESS(ES) 

 

        Author      Dr M.S. Perrugia Paolino

                    CIAT 7 piso

                    Hospital de Clinicas

                    Av. Italia s/n

                    Montevideo

                    Uruguay

 

                    Tel   598-2-470300

                    Fax   598-2-470300

 

        Date        February 1990

 

        Peer        Newcastle, United Kingdom, January 1991

        Review      Cardiff, United Kingdom, February 1994

                    Berlin, Germany, October 1995




  

 

   INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY




    ENVIRONMENTAL HEALTH CRITERIA 121




    ALDICARB










    This report contains the collective views of an international group of

    experts and does not necessarily represent the decisions or the stated

    policy of the United Nations Environment Programme, the International

    Labour Organisation, or the World Health Organization.

 

    Published under the joint sponsorship of

    the United Nations Environment Programme,

    the International Labour Organisation,

    and the World Health Organization

 

    First draft prepared by Dr. J. Risher and Dr. H. Choudhury,

    US Environmental Protection Agency,

    Cincinnati, Ohio, USA

 

    World Health Orgnization

    Geneva, 1991



         The International Programme on Chemical Safety (IPCS) is a

    joint venture of the United Nations Environment Programme, the

    International Labour Organisation, and the World Health

    Organization. The main objective of the IPCS is to carry out and

    disseminate evaluations of the effects of chemicals on human health

    and the quality of the environment. Supporting activities include

    the development of epidemiological, experimental laboratory, and

    risk-assessment methods that could produce internationally

    comparable results, and the development of manpower in the field of

    toxicology. Other activities carried out by the IPCS include the

    development of know-how for coping with chemical accidents,

    coordination of laboratory testing and epidemiological studies, and

    promotion of research on the mechanisms of the biological action of

    chemicals.

 

    WHO Library Cataloguing in Publication Data

 

    Aldicarb.

 

        (Environmental health criteria ; 121)

 

        1.Aldicarb - adverse effects 2.Aldicarb - toxicity 3.Environmental

        exposure 4.Environmental pollutants       I.Series

 

        ISBN 92 4 157121 7        (NLM Classification: WA 240)

        ISSN 0250-863X

 

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    names of proprietary products are distinguished by initial capital

    letters.



    CONTENTS

 

    ENVIRONMENTAL HEALTH CRITERIA FOR ALDICARB

 

  1. SUMMARY

 

         1.1. Identity, properties, and analytical methods

         1.2. Uses, sources, and levels of exposure

         1.3. Kinetics and metabolism

         1.4. Studies on experimental animals

         1.5. Effects on humans

 

  1. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL

         METHODS

 

         2.1. Identity

         2.2. Physical and chemical properties

         2.3. Conversion factors

         2.4. Analytical methods

 

  1. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

 

         3.1. Natural occurrence

         3.2. Anthropogenic sources

              3.2.1. Production levels, processes, and uses

                        3.2.1.1World production figures

                        3.2.1.2Manufacturing processes

 

  1. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

 

         4.1. Transport and distribution between media

              4.1.1. Air

              4.1.2. Water and soil

              4.1.3. Vegetation and wildlife

         4.2. Biotransformation

         4.3. Interaction with other physical, chemical or biological

              factors

              4.3.1. Soil microorganisms

 

  1. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

 

         5.1. Environmental levels

              5.1.1. Air

              5.1.2. Water

              5.1.3. Food and feed

         5.2. General population exposure

         5.3. Occupational exposure during manufacture, formulation

              or use

 

  1. KINETICS AND METABOLISM

 

         6.1. Absorption

         6.2. Distribution

         6.3. Metabolic transformation

         6.4. Elimination and excretion in expired air, faeces, and

              urine

 

  1. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS

 

         7.1. Single exposure

         7.2. Short-term exposure

         7.3. Skin and eye irritation; sensitization

         7.4. Long-term exposure

         7.5. Reproduction, embryotoxicity, and teratogenicity

         7.6. Mutagenicity and related end-points

         7.7. Carcinogenicity

         7.8. Other special studies

         7.9. Factors modifying toxicity; toxicity of metabolites

         7.10. Mechanisms of toxicity - mode of action

 

  1. EFFECTS ON HUMANS

 

         8.1. General population exposure

              8.1.1. Acute toxicity; poisoning incidents

              8.1.2. Human studies

              8.1.3. Epidemiological studies

         8.2. Occupational exposure

              8.2.1. Acute toxicity; poisoning incidents

              8.2.2. Effects of short- and long-term exposure;

                        epidemiological studies

 

  1. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

 

         9.1. Microorganisms

         9.2. Aquatic organisms

         9.3. Terrestrial organisms

         9.4. Population and ecosystem effects

 

  1. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE

         ENVIRONMENT

 

         10.1. Evaluation of human health risks

              10.1.1. Exposure levels

                        10.1.1.1  General population

                        10.1.1.2  Occupational exposure

              10.1.2. Toxic effects

              10.1.3. Risk evaluation

         10.2. Evaluation of effects on the environment

 

  1. CONCLUSIONS AND RECOMMENDATIONS

 

         11.1. Conclusions

              11.1.1. General population

              11.1.2. Occupational exposure

              11.1.3. Environmental effects

         11.2. Recommendations

 

  1. FURTHER RESEARCH

 

  1. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

 

         REFERENCES

 

         RESUME

 

         EVALUATION DES RISQUES POUR LA SANTE HUMAINE ET DES EFFETS

         SUR L'ENVIRONNEMENT

 

         CONCLUSIONS ET RECOMMENDATIONS

 

         RECHERCHES A EFFECTUER

 

         RESUMEN

 

         EVALUACION DE LOS RIESGOS PARA LA SALUD HUMANA Y DE LOS

         EFFECTOS EN EL MEDIO AMBIENTE

 

         CONCLUSIONES Y RECOMENDACIONES

 

         OTRAS INVESTIGACIONES

 

    WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR ALDICARB

 

    Members 

 

    Dr I. Boyer, The Mitre Corporation, McLean, Virginia, USA

 

    Dr G. Burin, Health Effects Division, Office of Pesticide

         Programs, US Environmental Protection Agency, Washington, DC, USA

         (Joint Rapporteur)

 

    Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood

         Experimental Station, Abbots Ripton, Huntingdon, United Kingdom

         (Vice Chairman)

 

    Professor W. J. Hayes, Jr., School of Medicine, Vanderbilt

         University, Nashville, Tennessee, USA (Chairman)

 

    Professor F. Kaloyanova, Institute of Hygiene and

         Occupational Health, Medical Academy, Sofia, Bulgaria

 

    Dr S. K. Kashyap, National Institute of Occupational

         Health, Indian Council of Medical Research, Meghani Nagar,

         Ahmedabad, India

 

    Dr H. P. Misra, University Center for Toxicology, Virginia

         Polytechnic Institute and State University, Blacksburg, Virginia,

         USA

 

    Mr D. Renshaw, Department of Health, Hannibal House,

         London, United Kingdom

 

    Dr J. Withey, Environmental & Occupational Toxicology

         Division, Environmental Health Center, Tunney's Pasture, Ottawa,

         Ontario, Canada

 

    Dr Shou-zheng Xue, School of Public Health, Shanghai

         Medical University, Shanghai, China

 

    Representatives of other organizations

 

    Dr L. Hodges, International Group of National Associations

         of Manufacturers of Agrochemical Products (GIFAP), Brussels,

         Belgium

 

    Dr J. M. Charles, International Group of National

         Associations of Manufacturers of Agrochemical Products (GIFAP),

         Brussels, Belgium

 

    Secretariat

 

    Dr B. H. Chen, International Programme on Chemical Safety,

         World Health Organization, Geneva, Switzerland (Secretary)

 

    Dr H. Choudhury, Environmental Criteria and Assessment

         Office, US Environmental Protection Agency, Cincinnati, Ohio, USA

         (Joint Rapporteur)

 

    Dr P. G. Jenkins, International Programme on Chemical

         Safety, World Health Organization, Geneva, Switzerland

 

    NOTE TO READERS OF THE CRITERIA MONOGRAPHS

 

         Every effort has been made to present information in the criteria

    documents as accurately as possible without unduly delaying their

    publication. In the interest of all users of the environmental health

    criteria monographs, readers are kindly requested to communicate any

    errors that may have occurred to the Manager of the International

    Programme on Chemical Safety, World Health Organization, Geneva,

    Switzerland, in order that they may be included in corrigenda, which

    will appear in subsequent volumes.

 

                                   *  * *

 

         A detailed data profile and a legal file can be obtained from the

    International Register of Potentially Toxic Chemicals, Palais des

    Nations, 1211 Geneva 10, Switzerland (Telephone No. 7988400 or

    7985850).

 

    ENVIRONMENTAL HEALTH CRITERIA FOR ALDICARB

 

         A WHO Task Group on Environmental Health Criteria for Aldicarb

    met in Cincinnati, USA, from 6 to 10 August 1990. Dr C. DeRosa opened

    the meeting on behalf of the US Environmental Protection Agency. Dr

    B.H. Chen of the International Programme on Chemical Safety (IPCS)

    welcomed the participants on behalf of the Manager, IPCS, and the

    three IPCS cooperating organizations (UNEP/ILO/ WHO). The Task Group

    reviewed and revised the draft criteria monograph and made an

    evaluation of the risks for human health and the environment from

    exposure to aldicarb.

 

         The first draft of this monograph was prepared by Dr J. Risher

    and Dr H. Choudhury of the US Environmental Protection Agency. The

    second draft was prepared by Dr H. Choudhury incorporating comments

    received following the circulation of the first draft to the IPCS

    Contact Points for Environmental Health Criteria documents. During the

    Task Group meeting all the participants contributed to review the

    large amount of information submitted by Rhône-Poulenc, and undertook

    a substantial revision of the second draft. Dr B.H. Chen and Dr P.G.

    Jenkins, both members of the IPCS Central Unit, were responsible for

    the overall scientific content and technical editing, respectively.

 

         The efforts of all who helped in the preparation and finalization

    of the document are gratefully acknowledged. The Secretariat wishes to

    thank Dr S. Dobson and Dr G. Burin for the significant contributions

    and revisions of the draft document during the meeting.

 

         Financial support for the meeting was provided by the US

    Environmental Protection Agency, Cincinnati, USA.

 

    ABBREVIATIONS



         ADI       acceptable daily intake

 

         ai        active ingredient

 

         CHO       Chinese hamster ovary

 

         FAD       flavin adenine dinucleotide

 

         FPD       flame photometric detector

 

         GC        gas chromatography

 

         GPC       gel permeation chromatography

 

         HPLC      high-performance liquid chromatography

 

         LC        liquid chromatography

 

         MATC      maximum acceptable toxic concentration

 

         MS        mass spectroscopy

 

         NADPH     reduced nicotinamide adenine dinucleotide phosphate

 

         NOEL      no-observed-effect level

 

         TLC       thin-layer chromatography

 

         UV        ultraviolet

 

  1. SUMMARY

 

    1.1  Identity, properties, and analytical methods

 

         Aldicarb is a carbamate ester. It is a white crystal-line solid,

    moderately soluble in water, and susceptible to oxidation and

    hydrolytic reactions.

 

         Several different analytical methods, including thin-layer

    chromatography, gas chromatography (electron capture, flame

    ionization, etc.), and liquid chromatography, are available. The

    currently preferred method for analysing aldicarb and its major

    decomposition products is high-performance liquid chromatography with

    post-column derivatization and fluorescence detectors.

 

    1.2  Uses, sources, and levels of exposure

 

         Aldicarb is a systemic pesticide that is applied to the soil to

    control certain insects, mites, and nematodes.  The soil application

    includes a wide range of crops, such as bananas, cotton, coffee,

    maize, onions, citrus fruits, beans (dried), pecans, potatoes,

    peanuts, soybeans, sugar beets, sugar cane, sweet potatoes, sorghum,

    tobacco, as well as ornamental plants and tree nurseries. Exposure of

    the general population to aldicarb and its toxic metabolites (the

    sulfoxide and sulfone) occurs mainly through food. The ingestion of

    contaminated food has led to poisoning incidents from aldicarb and its

    toxic metabolites (the sulfoxide and sulfone).

 

         Due to the high acute toxicity of aldicarb, both inhalation and

    skin contact under occupational exposure conditions may be dangerous

    for workers if preventive measures are inadequate. There have been a

    few incidents of accidental exposure of workers due to improper use or

    lack of protective measures.

 

         Aldicarb is oxidized fairly rapidly to the sulfoxide, 48%

    conversion of parent compound to sulfoxide occurring within 7 days

    after application to certain types of soils. It is oxidized much more

    slowly to the sulfone. Hydrolysis of the carbamate ester group, which

    inactivates the pesticide, is ph dependent, half-lives in distilled

    water varying from a few minutes at a pH of > 12 to 560 days at a pH

    of 6.0. Half-lives in surface soils are approximately 0.5 to 3 months

    and in the saturated zone from 0.4 to 36 months Aldicarb hydrolyses

    somewhat more slowly than either the sulfoxide or the sulfone.

    Laboratory measurement of the biotic and abiotic breakdown of aldicarb

    have yielded very variable results and have led to extrapolations

    radically different from field observation. Field data on the

    breakdown products of aldicarb furnish more reliable estimates of its

    fate.

 

         Sandy soils with low organic matter content allow the greatest

    leaching, particularly where the water table is high. Drainage

    aquifers and local shallow wells have been contaminated with aldicarb

    sulfoxide and sulfone; levels have generally ranged between 1 and

    50µg/litre, although an occasional level of approximately 500 µg/litre

    has been recorded.

 

         As aldicarb is systemic in plants, residues may occur in foods.

    Residue levels greater than 1 mg/kg have been reported in raw

    potatoes. In the USA, where the tolerance limit for potatoes is 1

    mg/kg, residue levels of up to 0.82 mg/kg have been reported from

    controlled field trials using application rates recommended by the

    manufacturer. An upper 95th percentile level of 0.43 mg/kg has been

    estimated from field trial data, and upper 95th percentile levels of

    up to 0.0677 mg/kg in raw potatoes have been determined from a

    market-basket survey.

 

    1.3  Kinetics and metabolism

 

         Aldicarb is efficiently absorbed from the gastrointestinal tract

    and, to a lesser extent, through the skin. It could be readily

    absorbed by the respiratory tract if dust were present. It distributes

    to all tissues, including those of the developing rat fetus. It is

    metabolically transformed to the sulfoxide and the sulfone (both of

    which are toxic), and is detoxified by hydrolysis to oximes and

    nitriles. The excretion of aldicarb and its metabolites is rapid and

    primarily via the urine. A minor part is also subject to biliary

    elimination and, consequently, to enterohepatic recycling. Aldicarb

    does not accumulate in the body as a result of long-term exposure. The

    inhibition of cholinesterase activity in vitro by aldicarb is

    spontaneously reversible, the half-life being 30-40 min.

 

    1.4  Studies on experimental animals

 

         Aldicarb is a potent inhibitor of cholinesterases and has a high

    acute toxicity. Recovery from its cholinergic effects is spontaneous

    and complete within 6 h, unless death intervenes. There is no

    substantial evidence to indicate that aldicarb is teratogenic,

    mutagenic, carcinogenic, or immunotoxic.

 

         Birds and small mammals have been killed as a result of ingesting

    aldicarb granules not fully incorporated into the soil as recommended.

    In laboratory tests, aldicarb is acutely toxic to aquatic organisms.

    There is no indication, however, that effects would occur in the

    field.

 

    1.5  Effects on humans

 

         The inhibition of acetylcholinesterase at the nervous synapse and

    myoneural junction is the only recognized effect of aldicarb in humans

    and is similar to the action of organophosphates. The carbamyolated

    enzyme is unstable, and spontaneous reactivation is relatively rapid

    compared with that of a phosphorylated enzyme. Non-fatal poisoning in

    man is rapidly reversible. Recovery is aided by the administration of

    atropine.

 

  1. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL METHODS

 

    2.1  Identity

 

         Common name:   Aldicarb

 

         Chemical structure:

 

                          CH3           O

                          '             "

                   CH3S - C - CH = N - OCNHCH3

                          '

                          CH3

 

         Molecular formula:  C7H14N2O2S

 

         Synonyms and        Aldicarb (English); Aldicarbe (French);

         common trade        Carbanolate; ENT 27 093; 2-methyl-2-

         names:              (methylthio)propanal

                             O-[(methylamino)-carbonyl]oxime (C.A.);

                             2-methyl-2-(methylthio)propionaldehyde

                             O-methyl-carbamoyloxime (IUPAC);

                             NCI-CO8640; OMS-771; Propanal,

                             2-methyl-2-(methylthio)-,

                             O-((methylamino)carbonyl)oxime; Temic;

                             Temik; Temik G; Temik M; Temik LD; Sentry;

                             Temik 5G; Temik 10G; Temik 15G; Temik 150G;

                             Union Carbide UC 21 149.

 

         CAS registry

         number              116-06-3

 

         RTECS no.           UE2275000.

 

    2.2  Physical and chemical properties

 

         Some physical and chemical properties of aldicarb are given in

    Table 1.

 

         Aldicarb, for which the IUPAC name is

    2-methyl-2-(methylthio)propionaldehyde O-methylcarbamoyloxime, is an

    oxime carbamate insecticide that was introduced in 1965 by the Union

    Carbide Corporation under the code number UC 21 149 and the trade name

    Temik (Worthing & Walker, 1987).

 

         Takusagawa & Jacobson (1977) reported that the molecular

    structure of the aldicarb crystal, as determined by single-crystal

    X-ray diffraction techniques, consists of an orthorhombic unit cell

    with eight molecules per cell. The C-O single bond length in the

    carbamate group was reported to be significantly greater than in

    carboxylic acid esters. This supports the theory that interaction with

    acetylcholinesterase involves disruption of this bond.

 

         Aldicarb has two geometrical isomers as shown below:

 

    

 

         The commercial product is a mixture of these two isomers. It is

    not certain which isomer is the more active.

 

    2.3  Conversion factors

 

    In air at 25 °C and 101.3 kPa (760 mmHg): 

 

                   1 ppm (v/v) = 7.78 mg/m3

 

                   1 mg/m3 = 0.129 ppm (v/v).

 

    2.4  Analytical methods

 

         The methods for analysing aldicarb include thin-layer

    chromatography (Knaak et al., 1966a,b; Metcalf et al., 1966), liquid

    chromatography (LC) (Wright et al., 1982), ultraviolet detection

    (Sparacino et al., 1973), post-column derivatization and fluorometric

    detection (Moye et al., 1977; Krause, 1979), and gas chromatography

    (GC) with various detectors. These include the Hall detector (Galoux

    et al., 1979), mass spectrometry (Muszkat & Aharonson, 1983), flame

    ionization detection (Knaak et al., 1966a,b), and esterification and

    electron capture detection (Moye, 1975). A multiple residue method

    exists for detecting N-methylcarbamate insecticide in grapes and

    potatoes. It involves separation by reverse phase liquid

    chromatography and detection by a post-column fluorometric technique

    (AOAC, 1990).

 

        Table 1. Some physical and chemical properties of aldicarba

                                                                                 

    Relative molecular mass:           190.3

 

    Form:                              colourless crystals (odourless or slight

                                       sulfurous smell)

 

    Melting point:                     100 °C

 

    Boiling point:                     unknown; decomposes above 100 °C

 

    Vapour pressure (25 °C):           13 mPa (1 x 10-4 mmHg)

 

    Relative density (25 °C):          1.195

 

    Solubility (20 °C):                6 g/litre of water; 40% in acetone;

                                       35% in chloroform; 10% in toluene

 

    Properties:                        heat sensitive, relatively unstable

                                       chemical; stable in acidic media but 

                                       decomposes rapidly in alkaline media;

                                       non-corrosive to metal; non-flammable;

                                       oxidizing agents rapidly convert it to

                                       the sulfoxide and slowly to the sulfone

 

    Impurities                         dimethylamine; 2-methyl-2-(methylthio)

                                       propionitrile; 2-methyl-2-(2-methyl-

                                       thiopropylenaminoxy) propinaldehyde

                                       O-  (methylcarbamoyl) oxime;

                                       2-methyl-2-(methylthio) propionaldehyde

                                       oxime

 

    Log octanol/water partition        1.359

    coefficient

                                                                                 

 

    a  From: Kuhr & Dorough (1976), Worthing & Walker (1987), and FAO/WHO (1980).

    

         Because of aldicarb's thermal lability, it degrades rapidly in

    the injection port or on the column during GC analysis. Thus, short

    columns have been used to facilitate more rapid analyses and prevent

    thermal degradation (Riva & Carisano, 1969). A major drawback to using

    GC methods is that aldicarb degrades to aldicarb nitrile during GC;

    this degradation may also occur in the environment (US EPA, 1984).

    During GC analysis by conventional-length columns, aldicarb nitrile

    interferes with aldicarb analysis, thus necessitating a time-consuming

    clean-up procedure. Furthermore, aldicarb nitrile cannot be detected

    by LC with UV detection since absorption does not occur in the UV

    range (US EPA, 1984). The post-column fluorometric technique used in

    LC requires hydrolysis of the analyte, with the formation of

    methylamine, which reacts with o-phthalaldehyde to form a

    fluorophore. Since aldicarb nitrile does not hydrolyse to form

    methylamine, it cannot be detected (Krause, 1985a).

 

         US EPA (1984) reported that high-performance liquid

    chromatography (HPLC) can be used to determine

    N-methyl-carbamoyloximes and N-methylcarbamates in drinking-water.

    With this method, the water sample is filtered and a 400-µl aliquot is

    injected into a reverse-phase HPLC column. Compounds are separated by

    using gradient elution chromatography. After elution from the column,

    the compounds are hydrolysed with sodium hydroxide. The methylamine

    formed during hydrolysis reacts with o-phthalaldehyde (OPA) to form

    a fluorescent derivative, which is detected with a fluorescence

    detector. The estimated detection limit for this method is 1.3 µg

    aldicarb/litre.

 

         Reding (1987) suggested that samples be kept chilled, acidified

    with hydrochloric acid to pH 3, and dechlorinated with sodium

    thiosulfate. Other procedures used were the same as those described in

    the previous paragraph.

 

         In a collaborative study, Krause (1985a,b) reported an LC

    multi-residue method for determining the residues of

    N-methylcarbamate insecticides in crops. The average recovery for 11

    carbamates (which included aldicarb and aldicarb sulfone) from 14

    crops was 99%, with a coefficient of variation of 8% (fortification

    levels of 0.03-1.8 mg/kg), and for aldicarb sulfoxide, a very polar

    metabolite, was 55% and 57% at levels of 0.95 and 1.0 mg/kg,

    respectively. Methanol and a mechanical ultrasonic homogenizer were

    used to extract the carbamates. Water-soluble plant co-extractives and

    non-polar plant lipid materials were removed from the carbamate

    residues by liquid-liquid partitioning. Additional crop co-extractives

    (carotenes, chlorophylls) were removed with a Nuchar S-N-silanized

    Celite column. The carbamate residues were then separated on a

    reverse-phase LC column, using acetonitrile-water gradient mobile

    phase. Eluted residues were detected by an in-line post-column

    fluorometric detection technique. Six laboratories participated in

 

    this collaborative study.  Each laboratory determined all the

    carbamates at two levels (0.05 and 0.5 mg/kg) in blind duplicate

    samples of grapes and potatoes. Repeatability coefficients of

    variation and reproducibility coefficients of variation for all

    carbamates in the two crops averaged 4.7 and 8.7%, respectively. The

    estimated limit of quantification was 0.01 mg/kg.

 

         Ting & Kho (1986) discussed a rapid analytical method using HPLC.

    They modified their previous method (Ting et al., 1984) by using a

    25-cm CH-Cyclohexyl column instead of the 15-cm C-18 column. This

    modification resulted in the separation of the interference peak found

    in watermelon co-extractives. The separation of the interference peak

    and the aldicarb sulfoxide peak was made possible by the additional 10

    cm in the length of the column and the higher polarity of the

    CH-Cyclohexyl. Acetonitrile and methanol were used in the extraction

    and derivatization procedure before the HPLC determination. Water

    melons fortified with aldicarb sulfoxide at 0.1, 0.2, and 0.4 mg/kg

    showed a mean recovery of 74-76%.

 

         Chaput (1988) described a simplified method for determining seven

    N-methylcarbamates (aldicarb, carbaryl, carbofuran, methiocarb,

    methomyl, oxamyl, and propoxur) and three related metabolites

    (aldicarb sulfoxide, aldicarb sulfone, and 3-hydroxy-carbofuran) in

    fruits and vegetables. Residues are extracted from crops with

    methanol, and co-extractives are then separated by gel permeation

    chromatography (GPC) or GPC with on-line Nuchar-Celite clean-up for

    crops with high chlorophyll and/or carotene content (e.g., cabbage and

    broccoli). Carbamates are separated on a reverse-phase liquid

    chromatography column, using a methanol-water gradient mobile phase.

    Separation is followed by post-column hydrolysis to yield methylamine

    and by the formation of a flurophore with o-phthalaldehyde and

    2-mercaptoethanol prior to fluorescence detection. Recovery data were

    obtained by fortifying five different crops (apples, broccoli,

    cabbages, cauliflower, and potatoes) at 0.05 and 0.5 mg/kg. Recoveries

    averaged 93% at both fortification levels, except in the case of the

    very polar aldicarb sulfoxide for which recoveries averaged around 52%

    at both levels. The coefficient of variation of the method at both

    levels was < 5% and the limit of detection, defined as five times the

    baseline noise, varied between 5 and 10 µg/kg, depending on the

    compound.

 

         The International Register of Potentially Toxic Chemicals (IRPTC,

    1989) reported a GLC-FPD method for aldicarb analysis in foodstuffs.

    The limit of quantification was 0.01-0.03 mg/kg with a recovery rate

    of 76-125%. In this method, the acetone/dichloromethane-extracted

    sample is evaporated to dryness and the residue is dissolved in a

    buffered solution of potassium permanganate in water in order to

    oxidize the thioether pesticide and its sulfoxide metabolite to the

    corresponding sulfone. Aldicarb sulfone is then extracted with

    dichloromethane and the extract is evaporated to dryness. The residue

    is dissolved in acetone and the solution is analysed by GC-FPD using

    a pyrex column filled with 5% ov-225 on chromosorb W-HP, 150-180 U

    (the column temperature is 175 °C and the carrier gas is nitrogen with

    a flow rate of 60 ml/min).

 

  1. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

 

    3.1  Natural occurrence

 

         Aldicarb is a synthetic insecticide; there are no natural sources

    of this ester.

 

    3.2  Anthropogenic sources

 

    3.2.1  Production levels, processes, and uses

 

         Aldicarb is a systemic pesticide used to control certain insects,

    mites, and nematodes. It is applied below the soil surface (either

    placed directly into the seed furrow or banded in the row) to be

    absorbed by the plant roots. Owing to the potential for dermal

    absorption of carbamate insecticides (Maibach et al., 1971), aldicarb

    is produced only in a granular form. The commercial formulation,

    Temik, is available as Temik 5G, Temik 10G, and Temik 15G, which

    contain 50, 100, and 150 g aldicarb/kg dry weight, respectively. The

    metabolite aldicarb sulfone is also used as a pesticide under the

    common name aldoxycarb. Aldicarb is usually applied to the soil in the

    form of Temik 5G, 10G, or 15G granules at rates of 0.56-5.6 kg ai/ha.

    Soil moisture is essential for its release from the granules, and

    uptake by plants is rapid. Plant protection can last up to 12 weeks

    (Worthing & Walker, 1987), but actual insecticidal activity may vary

    from 2 to 15 weeks, depending on the organism involved and on the

    application method (Hopkins & Taft, 1965; Cowan et al., 1966; Davis et

    al., 1966; Ridgway et al., 1966). The effective life of this

    insecticide will vary, depending on the type of soil, the soil

    moisture, the soil temperature, the rainfall and irrigation

    conditions, and the presence of soil micro-organisms.

 

         Aldicarb is approved for use on a variety of crops, which include

    bananas, cotton plants, citrus fruits, coffee, maize, onions, sugar

    beet, sugar cane, potatoes, sweet potatoes, peanuts, pecans, beans

    (dried), soybeans, and ornamental plants (FAO/WHO 1980; Berg, 1981).

    Its use in the home and garden has been proscribed by the

    manufacturer.

 

         Since aldicarb is used in a granular form, this reduces the

    handling hazards, as water is necessary for the active ingredient to

    be released. Respirators and protective clothing should, however, be

    used in certain field application settings (Lee & Ransdell, 1984).

 

    3.2.1.1  World production figures

 

         In the USA, a total of 725 tonnes was sold domestically for

    commercial use in 1974 (SRI, 1984).

 

         The US EPA (1985) estimated that aldicarb production from 1979 to

    1981 ranged from 1360 to 2130 tonnes/year. In 1988, the US EPA

    estimated that between 2359 and 2586 tonnes of aldicarb were applied

    annually in the USA (US EPA, 1988a). More recent world production

    figures are not available.

 

    3.2.1.2  Manufacturing processes

 

         Aldicarb is produced in solution by the reaction of methyl

    isocyanate with 2-methyl-2-(methylthio)propanal-doxime (Payne et al.,

    1966). During normal production, loss to the environment is not

    significant.

 

  1. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

 

    4.1  Transport and distribution between media

 

         The fate and transport of aldicarb and its decomposition products

    in various types of soil have been studied extensively under

    laboratory and field conditions. Owing to the physical properties of

    aldicarb such as its low vapour pressure, its commercial granular

    form, and its application beneath the surface of the soil, the vapour

    hazard of aldicarb is low. Thus the fate of aldicarb in the atmosphere

    has not received much attention. Similarly, its fate in surface water

    has not been extensively studied. However, the rates and mechanisms of

    the hydrolysis of aldicarb have been studied in the laboratory in some

    detail.

 

    4.1.1  Air

 

         No studies on the stability or migration of aldicarb in the air

    over or near treated fields have been reported.  Laboratory migration

    studies with radiolabelled aldicarb in various soil types showed a

    loss of the applied substrate. This loss could not be explained unless

    aldicarb or its decomposition products had been transferred to the

    vapour phase (Coppedge et al., 1977). When 34 mg of 14C-aldicarb

    granules was applied 38 mm below the surface of a column of soil

    contained in a 63 x 128 mm poly-propylene tube, about 43% of the

    radiolabel was collected in the atmosphere above the column.

    Additional experiments showed that the transfer of radioactivity to

    the surrounding atmosphere was inversely proportional to the depth of

    application in the soil.  When 14C- and 35S-labelled aldicarb were

    used separately in similar experiments, only the experiments in which

    the 14C-labelled compound was used led to a transfer of

    radioactivity to the surrounding atmosphere, thus showing that the

    volatile compound was a carbon-containing breakdown product rather

    than aldicarb per se.

 

         In a subsequent study with aldicarb using 14C at the

    S-methyl, N-methyl, and tertiary carbon, Richey et al. (1977)

    reported that 83% of the radiolabel was recovered as carbon dioxide

    from a column of soil. The rate of degradation depended on the

    characteristics of the soil, e.g., pH and humidity.

 

         Supak et al. (1977) reported that when aldicarb (1 mg/g) was

    applied to clay soil and placed in a volatilizer, its volatilization

    was very limited. The authors stated that the possibility of aldicarb

    causing an air contamination hazard when it is applied in the field is

    negligible since it is applied at a rate of only 1.1-3.4 kg/ha and is

    inserted to 5-10 cm below the soil surface.

 

    4.1.2  Water and soil

 

         There have been numerous studies on aldicarb, under field and

    laboratory conditions, to investigate its movement through soil and

    water, persistence, and degradation. While earlier studies suggested

    that aldicarb degraded readily in soil and did not leach, later

    identification of residues in wells indicated that persistence could

    be longer than predicted and that mobility was greater. Laboratory

    studies have given variable results and the only totally reliable data

    are from full-scale field studies.

 

         In one of the few studies conducted with natural water (Quraishi,

    1972), rain overflow and seepage water were collected from ditches

    near untreated fields, filtered, and then treated with aldicarb at a

    concentration of 100 mg/litre. Solutions were stored in ambient

    lighting at temperatures ranging from 16 to 20 °C. It took 46 weeks

    for the aldicarb concentration to decrease to 0.37 mg/litre.

 

         Following an extensive study under laboratory-controlled

    conditions, Given & Dierberg (1985) reported that the hydrolysis of

    aldicarb was dependent on pH. They found that the apparent first-order

    hydrolysis rate over the pH range 6-8 and at 20 °C was relatively slow

    (Table 2). Above pH 8 the increase in the hydrolysis rate showed a

    first-order dependence on hydroxide ion concentration. The authors

    stated that these studies probably represented a "worst-case"

    situation with respect to the persistence of aldicarb in water, since

    other means of aldicarb removal or decomposition (e.g.,

    volatilization, adsorption, leaching, and plant and microbial uptake)

    had been prevented.

 

         Hansen & Spiegel (1983) showed that aldicarb hydrolyses at much

    slower rates than aldicarb sulfoxide and aldicarb sulfone. Since

    aldicarb oxidizes fairly rapidly to the sulfoxide and at a slower rate

    to the sulfone, and subsequent hydrolysis of the oxidation products

    usually occurs, aldicarb does not persist in the aerobic environment.

 

         In his review, de Haan (1988) discussed leaching of aldicarb to

    surface water in the Netherlands. Some of the factors favourable to

    leaching are weak soil binding, high rainfall, irrigation practices,

    and low transformation rates of the oxidation products of aldicarb.

 

         Aharonson et al. (1987) reported that hydrolysis of aldicarb is

    one of the abiotic chemical reactions that is linked to the detection

    of the pesticide in the ground water. The hydrolysis half-life at pH

    7 and 15 °C has been estimated by these authors to be as long as

    50-500 weeks.

 

        Table 2. Apparent first-order rate constant (k), half-life (t´), and

    coefficient of variation of the regression line (r2) for aldicarb

    hydrolysis at 20 °C in pH-buffered distilled watera

                                                                        

 

    pH          Period k (day-1)b          t´b               r2

                (days)                         (days)

                                                                        

 

    3.95        89 5.3 x 10-3            131   0.86

 

    6.02        89 1.2 x 10-3            559   0.90

 

    7.96        89 2.1 x 10-3            324   0.62

 

    8.85        89 1.3 x 10-3             55 0.98

 

    9.85        15 1.2 x 10-1              6 1.00

                                                                         

 

    a  Adapted from Given & Dierberg (1985).

    b  Rates and resulting half-life values for pH 6-8 represent

       only estimates since the slopes of the log percentage

       remaining versus time regression lines were probably not

       significantly different from zero.

 

             The products of aldicarb hydrolysis at 15 °C under alkaline

    conditions (pH 12.9 and 13.4) are aldicarb oxime, methylamine, and

    carbonate (Lemley & Zhong, 1983). The half-lives of hydrolysis at

    these two pHs are 4.0 and 1.3 min, respectively. Other hydrolysis

    data, determined at pH 8.5 and 8.2, yielded rates with half-lives of

    43 and 69 days, respectively (Hansen & Spiegel, 1983; Krause, 1985a).

    Lemley et al. (1988) reported that at pH values of 5-8 the sorption of

    aldicarb, aldicarb sulfoxide, and aldicarb sulfone decreases as the

    temperature increases from 15 to 35 °C.

 

         Andrawes et al. (1967) applied the pesticide at the recommended

    rate of 3.4 kg/ha to potato fields and found that < 0.5% of the

    original dose remained at the end of a 90-day period. In fallow soil,

    decomposition of aldicarb to its sulfoxide and sulfone was rapid, >

    50% of the administered compound dissipating within 7 days after

    application. Peak concentrations of the aldicarb sulfoxide (8.24

    mg/kg) and aldicarb sulfone (0.8 mg/kg) were reached at day 14 after

    the application.

 

         Ou et al. (1986) investigated the degradation and metabolism of

    14C-aldicarb in soils under aerobic and anaerobic conditions. They

    found that under aerobic conditions, aldicarb rapidly disappeared and

    aldicarb sulfoxide was rapidly formed; the latter in turn was slowly

    oxidized to aldicarb sulfone. The sulfoxide was the principal

    metabolite in soils under strictly aerobic conditions. Although the

 

    parent compound aldicarb persisted considerably longer in anaerobic

    soils, anaerobic half-lives for total toxic residue (aldicarb,

    aldicarb sulfoxide, and aldicarb sulfone) in subsurface soils were

    significantly shorter than under aerobic conditions.

 

         A number of factors, including soil texture and type, soil

    organic content, soil moisture levels, time, and temperature, affect

    the rate of aldicarb degradations (Coppedge et al., 1967; Bull, 1968;

    Bull et al., 1970; Andrawes et al., 1971a; Suspak et al., 1977). Bull

    et al.  (1970) reported that soil pH had no significant effect on the

    breakdown of aldicarb, but Supak et al. (1977) noted an increase in

    the rate of degradation when the pH was lowered.

 

         Lightfoot & Thorne (1987) investigated the degradation of

    aldicarb, aldicarb sulfoxide, and aldicarb sulfone in the laboratory

    using distilled water, water extracted from soil, and water with soil

    particles (Table 3). Degradation of all three compounds was greatest

    in the uppermost "plough" layer of the soil profile and much higher in

    the presence of soil particulates. Even after sterilization of the

    soil, degradation was fast in this layer, indicating that the effect

    of particulate matter is not entirely microbial. Degradation continued

    in the saturated zone (ground water) at a slower rate (particularly

    for the sulfoxide and sulfone). A further series of experiments

    investigated the degradation of mixtures of aldicarb sulfoxide and

    sulfone in soil and water from the saturated zone of two soil types

    (Table 4). The half-life was longer in the acidic Harrellsville soil

    than the alkaline Livingston soil. As in the case of laboratory

    experiments, the presence of particulates considerably increased the

    rate of degradation of the carbamates. Investigation of many variables

    in the laboratory led the authors to conclude that pH, temperature,

    redox potential, and perhaps the presence of trace substances can all

    affect degradation rates. They believed that laboratory

    experimentation could not provide definitive results without the

    identification of critical variables and that field observation was a

    more reliable indicator of aldicarb degradation

 

        Table 3.  Degradation rates for aldicarb, aldicarb sulfoxide,

              and aldicarb sulfonea

                                                                                  

                                                  Half-life at 25 °C (days)b

 

                                       Aldicarb                 Total carbamatesc

                                                                                  

 

    Plough-layer soil

         sterilized                   2.5 (2.3-2.6) 10 (7-16)

         unsterilized                 1.0 (0.9-1.1) 44 (39-50)

 

    Soil water

         sterilized                  1679 (1056-4064) 1924 (1133-6370)

         unsterilized                 156 (143-176) 175 (158-195)

 

    Distilled water (no buffers)      671 (507-994) 697 (518-1064)

 

    Saturated zone soil and water

         sterilized                    15 (14-16) 16 (15-18)

         unsterilized                  37 (33-42) 123 (115-132)

                                                                                  

 

    a    From: Lightfoot & Thorne (1987).

    b    Values in parentheses represent 95% confidence intervals.

    c    Aldicarb, aldicarb sulfoxide, and aldicarb sulfone.

    pH measurements

         sterilized soil water: 6.6-7.0 for 238 days;

         4.8-5.0 at day 368 unsterilized soil water: 6.6-6.7 for 56

         days; 4.2-4.4 at day 238, 3.2 at day 368 distilled water:

         7.3-7.5 for 238 days, 6.2-6.8 at day 368 saturated zone soil

         and water: 4.1-4.5 throughout entire study.

    

         Coppedge et al. (1977) studied the movement and persistence of

    aldicarb in four different types of soil in laboratory and field

    settings using a radiolabelled substrate. Samples of clay, loam,

    "muck" (soil with high organic content), and sand were packed in

    polypropylene columns (63 x 128 mm), saturated with water, and

    maintained at 25 °C throughout the study. Radiolabelled aldicarb

    granules (34 mg) were applied to each column at a point 38 mm below

    the soil surface. Water was then applied to each soil column at a rate

    of 2.5 cm/week for the next 7 weeks. The water eluted through the

    columns was collected and analysed for radiolabel. At the end of the

    7-week period, the soil was removed in layers 25 mm thick and analysed

    for residual radiolabel. The results of this study are shown in Tables

    5 and 6. The radiolabel (< 1%) in the loam and clay soils remained in

    the upper layers of the column, close to where it had been applied. In

    the sand, the residual radiolabel (2-3%) passed through to the lower

 

    parts of the column. A much higher percentage (5-6%)  of the

    radiolabel was retained in the muck soil column and was evenly

    distributed along the column. The radiolabel leached into the water

    eluted from the sand was 8-10 times greater than that from the other

    soil types. The nature of the decomposition products (ultimately shown

    to be carbon dioxide) resulted in some loss to the atmosphere

    surrounding the soils. The data in Table 6 indicate that most of the

    radioactivity retained in clay and loam soils represented aldicarb,

    sulfoxide whereas that in sand largely represented the parent

    compound. Greater leaching through sand decreased loss to the

    atmosphere by degradation to carbon dioxide.

 

         Coppedge et al. (1977) also studied the persistence  of aldicarb

    using field lysimeters. Aldicarb (34 mg), labelled with 35S, was

    added to columns (63 x 128 mm) containing Lufkin fine sandy loam soil

    at a point 76 mm below the surface. The contents were moistened with

    water and then buried in the same type of soil at a depth where the

    insecticide granules were 152 mm below the surface.  The experiment

    lasted for 7 weeks and rain was the only other source of moisture. The

    column recovered 3 days after the application yielded 71% of the

    radiolabel, while the column recovered at the end of 7 weeks yielded

    only 0.9%. This suggested an approximate half-life for the aldicarb of

    < 1 week, and the label distribution suggested an upward movement

    through volatilization of the decomposition products. The authors

    therefore concluded that there was little danger that aldicarb would

    move into the underground water supply in this type of soil.

 

         Bowman (1988) studied the mobility and persistence of aldicarb

    using field lysimeters containing cores (diameter, 15 cm; length, 70

  1. cm) of Plainfield sand. Half of the cores received only rainfall,

    while the remainder received rainfall plus simulated rainfall (50.8

  1. mm) on the second and eighth days after treatment, followed by

    simulated irrigation for the duration of the study. The results of

    this study indicated that under normal rainfall about 9% of the

    applied aldicarb leached out of the soil cores as sulfoxide or

    sulfone, whereas, in cores receiving supplementary watering, up to 64%

    of applied aldicarb appeared in the effluent principally as sulfoxide

    or sulfone.



        Table 4.  Degradation rates for aldicarb sulfoxide and aldicarb sulfone mixtures in groundwater degradation mechanism studiesa

                                                                                                                              

                                                      Sterilized (25 °C)                         Unsterilized (25 °C)

    Soil type and medium

                                               Half-lifeb                pHc              Half-lifeb                   pHc

                                                                                                                              

 

    Harrellsville, NC

         saturated zone soil and water                                                    137 (117-165) 5

 

    Harrellsville, NC (first set)

         saturated zone soil and water          378 (287-550) 4.3   1910 (1170-5180) 4.2

         coarse-filtered water                 1100 (760-1970) 4.6   > 2000 4.6

         fine-filtered water                 > 2000 4.6       > 2000 4.2

 

    Livingston, CA (original data)

         saturated zone soil and water                                                    8 (7-10) 7

 

    Livingston, CA

         saturated zone soil and water          1.3 (1.2-1.4) 9.0   7.5 (6.9-8.1) 8.4

         coarse-filtered water                 19 (17-22) 7.7     6.0 (5.7-6.3) 8.3

                                                                                                                              

 

    a    From: Lightfoot & Thorne (1987).

    b    Half-life (days) for carbamate residues.  Values in parentheses represent 95% confidence intervals.  Since the experiments

         were conducted for only 1 year, half-life estimates greater than about 600 days are not as reliable as other estimates. 

         Half-lives longer than about 2000 days could not be determined.

    c    Approximate average value during experiment.

 

    Table 5.  Distribution and persistence of 14C-aldicarb equivalents in soil columnsa,b

 

                                                                                                                                       

 

                                  Percentage of total dose in the various layers                        Percentage of total dose

 

    Soil type                                                           Total Unextractable In leached

                      0-25 c    25-50      50-75 75-100   100-128 extracted residue from     water d      Recovered        Lost

                                                                      from soil     soil

                                                                                                                                       

 

    Houston clay       0.4 0.1 0.1        T T 0.6 2.5           12.5 15.6 84.4

 

    Lufkin loam        1.2 0.3 0.1       0.1 T 1.7 3.0            3.9 8.6 91.4

 

    Coarse sand         T T 0.2       0.5 2.0 2.7 0.2           84.0 86.9 13.1

 

    Muck               8.7 5.3 8.5       5.6 4.8 32.9 7.1            3.5 43.5 56.5

 

                                                                                                                                  

 

    a    From: Coppedge et al. (1977).

    b    Results are the average from triplicate samples. Trace amounts (T) = < 0.1% of total dose.

    c    Layers are indicated by the distance (in mm) from the surface.

    d    Water that passed through the columns after the weekly addition of moisture.

 

    Table 6. 14C-labelled aldicarb and metabolites in water eluted through soil columnsa,b

                                                                                                                                   

 

                                                Percentage of total dose recovered at indicated days after treatment

 

    Soil type and compounds       3 10 16 23        29 35 41 47 53

 

                                                                                                                                   

 

    Clay

         aldicarb                                    0.5 0.2 T 0

         sulfoxide                                   3.2 1.9 0.4 0.2

     sulfone                                         0 T T 0

     other metabolites                               0.7 0.6 0.3 0.2

 

    Total                       0 3.2 4.4       2.7 0.8 0.7 0.4       0.3 0

    Accumulative total       0   3.2   7.6 10.3      11.1 11.8 12.2      12.5 12.5

 

    Sand

         aldicarb                                    7.3 31.5 5.0 5.4       2.3

         sulfoxide                                   0.9 2.6 1.6 2.0       2.1

         sulfone                                     0 0 0 0       0

          other metabolites                          0.2 1.9 0.4 0.5       1.1

 

    Total                       0 3.5 8.4      36.0 9.2 7.0   7.9 5.5 6.7

    Accumulative total       0   3.5 11.9      47.9 57.1 64.1      72.0 77.5 84.0

                                                                                                                                   

 

    Table 6 (contd). 14C-labelled aldicarb and metabolites in water eluted through soil columnsa,b

                                                                                                                                   

 

                                                Percentage of total dose recovered at indicated days after treatment

 

    Soil type and compounds       3 10 16 23        29 35 41 47 53

 

                                                                                                                                   

    Loam

         aldicarb                                    T T T       0

         sulfoxide                                   0.9 0.3 0.2 0.3 0.2       0.3

         sulfone                                     0 0 T T

         other metabolites                           0.2 T 0.2 T 0.1       0.2

 

    Total                        0 0.7 1.1     0.3 0.4 0.3 0.3       0.5 0.3

    Accumulative total        0 0.7       1.8 2.1 2.5       2.8 3.1 3.6 3.9

 

    Muck

         aldicarb                                              T

         sulfoxide                                             0.1

         sulfone                                               0

         other metabolites                                     0.2

 

    Total                        0 0.2 0.6     0.9 0.9 0.3 0.1       0.3 0.3

    Accumulative total        0 0.2       0.8 1.7 2.6       2.9 3.0 3.3 3.6

                                                                                                                                   

 

    a    From: Coppedge et al. (1977).

    b    Results are the average from triplicate samples. Trace amounts (T) = < 0.1% of total dose.  Where a "total" value is given

          without values for each component, the volume of samples was insufficient for individual analyses.

    

         Andrawes et al. (1971a) studied the fate of radio-labelled

    aldicarb ( S-methyl-14C-Temik) in potato fields. The initial soil

    concentration was 13.1 mg/kg, which fell to 25.6 and 9.5% of the

    applied amount after 7 and 90 days, respectively. Samples taken as

    early as 30 min after the application showed that 12.7% of the

    aldicarb had already been converted to aldicarb sufoxide. By day 7 it

    had increased to 48%. In fallow soil, aldicarb was applied as an

    acetone/water solution at the same level as that used in the planted

    field. The dissipation of 14C residues occurred at a relatively slow

    rate for the first 2 weeks and then at a faster rate. The breakdown

    products in both the fallow and planted fields were essentially the

    same.

 

         LaFrance et al. (1988) studied the adsorption characteristics of

    aldicarb on loamy sand and its mobility through a water-saturated

    column in the presence of dissolved organic matter. The results of

    these studies suggested that aldicarb does not undergo appreciable

    complexation with dissolved humic materials found in the interstitial

    water of the unsaturated zones. Thus the presence of dissolved humic

    substances in the soil interstitial water should not markedly affect

    the transport of the pesticide towards the water table.

 

         Woodham et al. (1973a) studied the lateral movement of aldicarb

    in sandy loam soil. They applied the granular commercial formulation

    of the pesticide (Temik 10G) to irrigated and non-irrigated fields at

    a rate of 16.8 kg/ha and placed it 15-20 cm to the side of cotton

    seedlings and 12.5-15 cm deep. Soil samples were collected throughout

    the growing season from a depth of 15 cm, from the bottom of a creek

    adjacent to a treated field, and from sites 0.40 and 1.61 km

    downstream. The aldicarb used in this study was found to have a short

    residence time. Levels in the treated field fell to 15% within one

    month. Only 8% remained after 47 days. No residues were found after 4

    months and no aldicarb was detected either between rows or in the bed

    of the creek that collected water drainage.  The authors concluded

    that aldicarb was translocated into crop plants and weeds but that

    there would be no carry-over of aldicarb or its metabolites from one

    growing season to another (Woodham et al., 1973b). The results of

    studies by Andrawes et al. (1971a) and Maitlen & Powell (1982) agree

    with the observations of Woodham and his colleagues. Gonzalez & Weaver

    (1986) failed to detect aldicarb or its breakdown products in run-off

    water from a field treated with aldicarb in California, USA.

 

         The method and timing of application can also affect the

    migration and degradation of aldicarb (Jones et al., 1986). Aldicarb

    was applied in-furrow during the planting of potatoes and as a

    top-dressing at crop emergence. At the end of the growing season the

    residues from the first application were found primarily in the top

    0.6 m of soil, and the residues from the emergence application were

    found primarily in the top 0.3 m of soil.

 

         In a three-year Wisconsin potato field study (sandy plain),

    Fathulla et al. (1988) monitored aldicarb residues in the saturated

    zone ground water under fluctuating conditions of temperature, pH, and

    total hardness. Soils were well drained sands, loamy sands or sandy

    loams (with 1 to 2% organic matter). The water table was high with a

    depth to the saturated zone of between 1.3 and 4.6 m. Sampling wells

    were bored to a maximum of 7.5 m for groundwater sampling. Rothschild

    et al. (1982) had found all residues of aldicarb (and its breakdown

    products) within the upper 1.5 m of the ground water in the same area

    in an earlier study. This is consistent with the views of both groups

    of authors that movement of aldicarb will occur in these aquifers. The

    report of Fathulla et al. (1988) indicated that detection and

    persistence of aldicarb in the ground water were dependent on

    alkalinity and temperature. Movement of aldicarb was lateral as well

    as vertical and the authors emphasized the importance of seasonal

    changes in water table depth and precipitation as factors influencing

    movement. Degradation by microorganisms in the upper layers of the

    soil and ground water was noted and identified as a major factor in

    the short-term fate of the aldicarb. Hegg et al. (1988) measured the

    movement and degradation of aldicarb in a loamy sand soil in South

    Carolina, USA, and found that it degraded at a rate corresponding to

    a half-life of 9 days with essentially no residues present 4 months

    after application. This was a faster loss of aldicarb from the soil

    than in comparable studies in neighbouring areas. Using the

    unsaturated plant root zone model (PRZM) with rainfall records from 15

    years, aldicarb residues were predicted to be limited to the upper 1.5

    m, regardless of year-to-year variations in rainfall.

 

         Pacenka et al. (1987) sampled both soil cores and ground water

    from sites on Long Island (New York, USA), where earlier surveys had

    suggested contamination of wells with aldicarb and its breakdown

    products (the sulfone and sulfoxide). Three study areas were chosen

    with shallow (3 m), medium (10 m), and deep (30 m) water tables. All

    were overlain with sandy soils. Soil cores, driven to the depth of the

    water table, were taken from a field where aldicarb had been applied

    to potatoes and from surrounding areas. Ground water was sampled from

    188 wells of varying depth and at different distances from the

    aldicarb source.  Results indicated that the residence time of

    aldicarb (including the sulfone and sulfoxide) in the soil depended on

    the depth of the water table and, hence, the overlying unsaturated

    zone. In the shallow and medium depth water table sites, all aldicarb

    residues had disappeared within 3 years of the last use of the

    compound. In deeper unsaturated layers, aldicarb residues were present

    at increasing concentrations in soil water from 10 m down to the water

    table at 30 m. The uppermost 10 m was free of residues. Analysis of

    the groundwater samples showed lateral movement of residues extending

    from 120 m to 270 m "downstream" of the source in a single year. It

    was calculated that the relatively shallow aquifer in the area (which

    lay over a deeper aquifer capped by an impervious layer of clay) would

 

    flush residues from the area completely within 100 years and lead to

    concentrations below the drinking-water guideline level (New York) of

    7 µg/litre being attained between 1987 and 2010 (depending on

    assumptions for dispersion and degradation). Pacenka et al. (1987)

    revised this figure downwards on the basis of their more extensive

    field observations, although no firm figure could be advanced.

 

         Studies in other geographical areas of the USA, including those

    showing some residues of aldicarb or the sulfoxide and sulfone in

    wells, have demonstrated a shorter residence time and more rapid

    degradation than in the Long Island study (Jones et al., 1986; Wyman

    et al., 1987; Jones, 1986, 1987). In these studies there was little

    lateral movement of the ground water in the saturated zone. Water

    table levels in these areas were generally high and much of the

    sampling of the ground water was in the top 4-5 m of the saturated

    zone. Much greater lateral movement of ground water in the Florida

    Ridge area at a shallower depth than similar movement in Long Island

    also shifted the aldicarb residues away from the treated area.

    However, degradation was sufficiently fast in these soils to reduce

    the chance of contamination of wells used for drinking-water. An

    impervious layer 6 m down would prevent deeper contamination in this

    area (Jones et al., 1987a).

 

         A review of well and groundwater monitoring of aldicarb residues

    throughout the USA has been published by Lorber et al. (1989, 1990),

    which indicates geographical areas at greatest risk of water

    contamination and local restrictions on the use of aldicarb.

 

    4.1.3  Vegetation and wildlife

 

         The uptake of aldicarb and its residues by food crops and plants

    has been reported in several studies (Andrawes et al., 1974; Maitlen

    & Powell, 1982). Residue levels in plants and crops grown in

    aldicarb-treated soil are given in Table 7. Of the many varieties and

    species of birds and mammals studied, only the oriole had aldicarb

    residues (0.07 mg aldicarb equivalents per kg) in its tissues (Woodham

    et al., 1973b).

 

         In a study by Iwata et al. (1977), aldicarb was applied to the

    soil in orange groves at rates of 2.8, 5.6, 11.2, and 22.4 kg ai/ha.

    Residues found on day 118 after application in the soil were 0.03,

    0.16, 0.20, and 0.42 mg/kg, respectively. On day 193, samples were

    taken from the pulp of oranges grown in soil that had been given the

    highest amount (22.4 kg ai/ha) of aldicarb. The residues in these

    samples ranged from 0.02-0.03 mg/kg.

 

         After aldicarb was applied to the leaves of young cotton plants

    under field conditions, it was not translocated to other parts of the

    plant to any great extent (Bull, 1968). Two weeks after application, 

 

    93% of the recovered radiolabel was found at the application site. The

    remainder was spread evenly throughout the plant, including the roots

    and fruit.

 

    4.2  Biotransformation

 

         In plants, aldicarb is metabolized by processes involving

    oxidation to the sulfoxide and sulfone, as well as by hydrolysis to

    the corresponding oximes and, ultimately, to the nitrile.

 

         There have been several studies on the metabolism of aldicarb by

    the cotton plant. Metcalf et al. (1966) found that aldicarb was

    completely converted within 4-9 days to the sulfoxide, which was then

    hydrolysed to the oxime. The subsequent oxidation of the sulfoxide to

    the sulfone occurred more slowly and was found to lead to

    bioaccumulation in aged residues (Coppedge et al., 1967).

 

         When aldicarb (10 µl of an aqueous solution containing 10µg

    aldicarb) was applied to the leaves of cotton plants, 7.1% of the

    administered dose was converted to the sulfoxide within 15 min. Two

    days later there was no residual aldicarb in or on the plant tissues,

    and the principal metabolite (78.4% of the initial dose) was the

    sulfoxide. After 8 days, 7.4% of the initial dose was found as the

    sulfone while the nitrile sulfoxide and an unidentified metabolite

    were the final products of decomposition (Bull, 1968).

 

    4.3  Interaction with other physical, chemical or biological factors

 

    4.3.1  Soil microorganisms

 

         Kuseske et al. (1974) studied the degradation of aldicarb under

    aerobic and anaerobic conditions and found that degradation was much

    slower under anaerobic conditions. Jones (1976) studied the metabolism

    of aldicarb by five common soil fungi. The potential for aldicarb

    detoxification by these fungi (in decreasing order) was as follows:

    Gliocladium catenulatum > Penicillium multicolor = Cunninghamella

    elegans > Rhizoctonia sp. > Trichoderma harzianum . The major

    organosoluble metabolites were identified as aldicarb sulfoxide, the

    oxime sulfoxide, the nitrile sulfoxide, and smaller amounts of the

    corresponding sulfones, indicating that the metabolic pathways were

    similar to those found in higher plants and animals.

 

         Spurr & Sousa (1966, 1974) tested the effects of aldicarb and its

    metabolites on pathogenic and saprophytic microorganisms and found

    that some of the microorganisms appeared to use aldicarb as a carbon

    source. The various bacteria and fungi used in these tests showed no

    growth inhibition when aldicarb was added at levels up to 20 times

    those usually used in field conditions.



        Table 7. Residues (in mg/kg) of aldicarb and its sulfoxide and sulfone metabolites found in various

    crops grown in aldicarb-treated soila,b

                                                                                                                                  

 

    Replicate           Potato Potato         Alfalfa Alfalfa Mint      Mustard Radish Radish

  1.                 leavesc       leaves       (transplanted) (seeded)       foliage greens tops     roots

                        (70)d          (408)     (456) (456)          (408) (408) (408)     (408)

                                                                                                                                   

 

    3.4 kg ai/ha application

 

         1               7.65 0.52           0.14 0.16 0.02       ND 0.08 ND

         2               7.93 0.15           ND 0.04 0.01       O.03 0.07 ND

         3               8.11 1.34           0.09 0.05 0.05       0.08 0.05 ND

         4               8.74 1.27           0.24 0.14 0.10

         5               9.60 1.03           0.13 0.24 0.06

 

    Average              8.41 0.66         0.12 0.13 0.05       0.04 0.07 ND

 

    15.0 kg ai/ha application

 

         1              19.30 0.69           0.89 0.89 0.64       ND 0.27 0.04

         2              14.90 1.10           0.34 1.47 0.92       0.26 0.27 0.05

         3              20.80 1.12           0.43 0.26 0.37       0.40 0.18 0.03

         4              19.40 0.50           0.76 0.61 0.23

         5              22.60 1.96           1.37 8.37 1.55

 

    Average             19.40 1.07           0.76 2.32 0.74       0.22 0.24 0.04

                                                                                                                                   

 

    a    From: Maitlen & Powell (1982).

    b    Residues in this table were determined by oxidizing the aldicarb, aldicarb sufoxide, and aldicarb sulfone and then

          determining them as one combined compound, aldicarb sulfone.  ND = none detected; the lower limit of reliable detection for

          these samples was < 5.0 ng/aliquot analysed or < 0.02 mg/kg.

    c    These samples are from the crop of 1979.  All others are from the crop of 1980.

    d    Figures in parentheses are the interval in days between treatment of soil and sampling of plants.

    

 

  1. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

 

    5.1  Environmental levels

 

    5.1.1  Air

 

         Since aldicarb is applied in granular form to the soil surface,

    it reaches the atmosphere only by upward migration and by

    volatilization. Thus, it is not transported to the atmosphere to any

    great extent and so is not expected to contribute a significant health

    threat from this source. In a volatilization study (Supak et al.,

    1977), a special apparatus was designed to determine the volatility of

    aldicarb from the soil. The air eluted from the apparatus after it had

    passed over soil samples containing dispersed aldicarb was analysed by

    the method of Maitlen et al. (1970). This method allowed the

    quantitative analysis of aldicarb and its two oxidation products, the

    sulfoxide and sulfone, both of which are toxic. Nontoxic decomposition

    products, such as the sulfoxide and sulfone oximes, both of which

    interfere with the determination of aldicarb sulfone by this method,

    were removed by LC.  When aldicarb was mixed with soil to a

    concentration of 1 mg/kg, only 2µg of aldicarb volatilized over the

    first 9 days of the experiment and subsequent losses increased to a

    steady-state rate of approximately 1µg/day. According to the authors,

    this rate of volatilization was almost negligible and not high enough

    to cause a potential health hazard.

 

    5.1.2  Water

 

         Run-off to surface water and leaching to aquifers used as sources

    of water for human consumption have been investigated. Aldicarb

    residues have been found in drinking-water wells in New York

    (Wilkinson et al., 1983; Varma et al., 1983), Wisconsin (Rothschild et

    al., 1982), and Florida (Miller et al., 1985). The US EPA groundwater

    team reported that they had found groundwater residues in 22 states

    (US EPA, 1988b). In Canada, water samples taken from private wells

    showed contamination with aldicarb up to 6.0 µg/litre; ground water

    from Quebec (maximum of 28 µg/litre) and Ontario (maximum of 1.1

    µg/litre) also contained detectable levels (Hiebsch, 1988).

 

         Prince Edward Island, Canada, is wholly dependent upon ground

    water from a highly permeable sandstone aquifer for domestic,

    agricultural, and industrial use. Priddle et al.  (1989) reported that

    12% of monitored wells exceeded the Canadian drinking-water guideline

    of 9µg/litre for aldicarb. The maximum level detected was 15 µg/litre.

 

         Following extensive agricultural use of aldicarb and as a result

    of a combination of environmental and hydro-logical conditions on

    eastern Long Island, New York, in 1978 the insecticide

 

    and its metabolites had leached into groundwater aquifers that

    constitute the major source of drinking-water for local inhabitants.

    In December 1978, detectable levels of aldicarb were found in 20 of 31

    water sources; similar results were obtained in the following June.

    When both private and community wells located near potato farms were

    sampled in August 1979, analyses revealed detectable levels of

    aldicarb in potable water.  In March 1980, the Department of Health

    Services in Suffolk County, New York, undertook an extensive sampling

    programme that included nearly 8000 wells. Union Carbide performed the

    analyses, with the New York Department of Health serving as the

    quality control arm. Levels of aldicarb ranging from trace amounts to

    > 400 µg/litre were detected in 27% of the wells sampled. Baier &

    Moran (1981)  reported that of 7802 wells sampled, 5745 (73.6%) did

    not have detectable concentrations of aldicarb, 1025 (13.1%) had

    concentrations in excess of the 7 µg/litre guideline of the New York

    State Department of Health, and the remaining 1032 (13.3%) had trace

    amounts of this insecticide.

 

         Aldicarb has been found at levels of 1-50 µg/litre in the ground

    water of the USA (Cohen et al., 1986; de Hann, 1988).

 

         The contamination of the Long Island (New York) aquifer by

    aldicarb at levels of up to 500 µg/litre (in one well) was attributed

    by Marshall (1985) to a combination of circumstances (high rainfall,

    coarse sandy soil, low soil temperatures, and a shallow water table)

    that favoured leaching. There have been some predictions that this

    undesirable situation would persist for only a year or two, but also

    some suggestions that wells could remain contaminated for up to a

    century. Marshall (1985) also voiced concern that under anaerobic

    conditions in cool climates, such as those in northern regions, the

    breakdown of aldicarb and its residues would be a much slower process.

    Contamination would also be favoured by heavy usage of Temik.

 

         During 1982, aldicarb was identified in several wells in the

    state of Florida (Miller et al., 1985). The state Commission of

    Agriculture and Consumer Services subsequently banned the use of Temik

    on citrus crops in 1983. A University of Florida task force was

    appointed to sample the 10 largest drinking-water systems that

    obtained water from groundwater sources in 35 counties. Neither

    aldicarb nor its oxidative sulfoxide or sulfone metabolites were

    detected in any of the almost 400 samples collected.

 

         During the application season of 1984 (January to April), 2040

    tonnes of aldicarb was used on citrus fruits at a rate of 5.6 kg ai/ha

    in more than 30 counties in Florida. No residues were detected in

    samples taken from community water systems, but trace amounts of

    aldicarb, aldicarb sulfoxide, and aldicarb sulfone were found in the

 

    Calloosahatchee River from which Lee County draws its drinking-water.

    (However, no residues were found in finished drinking-water in Lee

    County). The authors stated that the persistence of aldicarb and its

    metabolites in shallow ground water may also contaminate

    drinking-water. The results of a monitoring study by the Union Carbide

    Corporation (UCC) showed that in shallow ground water aldicarb can

    move further from its application point than originally predicted.

 

    5.1.3  Food and feed

 

         Residues have been detected on a variety of crops for which

    aldicarb is used (see section 3.2.1). In the USA, aldicarb

    intoxication from eating contaminated watermelons has been reported in

    California (Jackson et al., 1986) and in Oregon (Green et al., 1987),

    and two episodes of poisoning from eating aldicarb-contaminated

    cucumbers have been reported in Nebraska (Goes et al., 1980).

    Store-bought cucumbers, grown hydroponically, were found to contain

    between 7 and 10 mg aldicarb/kg (Aaronson et al., 1980). It should be

    noted that aldicarb is not approved for use on these crops.

 

         Laski & Vannelli (1984) reported the results of a survey of

    potatoes grown in New York State in 1982. Fifty samples, each

    consisting of 9 kg, were collected after harvest from four areas. In

    each of these areas, except one (Long Island), aldicarb was applied at

    rates of 14 to 22 kg/ha at planting stage. Samples were analysed for

    aldicarb, aldicarb sulfoxide, and aldicarb sulfone by the method of

    Krause (1980). Over 50% (23 out of 43) of potato samples obtained from

    areas where aldicarb was applied were positive for aldicarb sulfoxide

    (trace to 0.48 mg/kg)  and/or sulfone (trace to 0.20 mg/kg), but

    aldicarb itself was not detected. No residues were found in any of the

    7 samples from Long Island. The maximum concentrations were detected

    in samples from the North Eastern location, where there is sandy soil.

    Potatoes with the maximum concentration (0.48 mg/kg) were found to

    contain two and a half times higher concentrations (1.2 mg/kg) when

    reanalysed by a more sensitive method (Union Carbide, 1983). The

    investigators suggested that soil type and climatic conditions

    influenced residues in the crops.

 

         When Krause (1985b) analysed aldicarb and its oxidative

    metabolites in "market basket" potatoes, he detected levels of

    aldicarb sulfone ranging from < 0.01 to 0.18 mg/kg and of aldicarb

    sulfoxide from < 0.01 to 0.61 mg/kg.  All 39 samples collected

    between 1980 and 1983 contained residues of aldicarb or its

    metabolites.

 

         Potato samples collected from farms in the north-central part of

    New York, where soil is of the wet muck type, contained lower aldicarb

    residues than did the rocky-sandy soil type found in the north-eastern

    part of the state, even though application rates were the same in both

    areas. These lower residue levels were the result of aldicarb

    decomposition associated with moisture. Cairns et al. (1984) described

    the persistence of aldicarb in fresh potatoes.

 

         Peterson & Gregorio (1988) reported upper 95 percentile residue

    levels of 0.0677 mg/kg in raw potatoes (tolerance = 1 mg/kg), 0.0658

    mg/kg in fresh bananas (tolerance = 0.3 mg/kg), and 0.0212 mg/kg in

    grapefruit (tolerance = 0.3 mg/kg) in a market basket survey conducted

    in the USA (national food survey). These authors also reported a

    maximum residue level of 0.82 mg/kg in raw potatoes obtained in

    controlled field trials, as well as upper 95 percentile residue levels

    as high as 0.43 mg/kg in raw potatoes, 0.12 mg/kg in bananas, and 0.17

    mg/kg in citrus products, estimated from the distribution of residue

    levels obtained in field trials.

 

    5.2  General population exposure

 

         The general population may be exposed to aldicarb and its

    residues primarily through the ingestion of food containing aldicarb

    and from contaminated water, as discussed in sections 5.1.2, 5.1.3.,

    and section 8. The largest documented episode of foodborne pesticide

    poisoning in North American history occurred in July 1985. This

    resulted from the consumption of Californian watermelons contaminated

    with up to 3.3 mg/kg of aldicarb sulfoxide (Ting & Kho, 1986).

 

         Hirsch et al. (1987) reported 140 cases of poisoning incidences

    in the Vancouver area of British Columbia, Canada. A review of the

    onset of symptoms and food consumed suggested illness associated with

    eating cucumbers contaminated with aldicarb. Analytical investigations

    confirmed that the cucumbers from one producer contained residues of

    total aldicarb up to 26 mg/kg.

 

         Petersen & Gregorio (1988) reported the results of a

    comprehensive analysis of aldicarb data from controlled field residue

    studies and provided estimates of the upper 95 percentile of residues

    in foods in the USA. The analysis showed that daily exposure at the

    upper 95 percentile consumption rate for aldicarb-treated commodities

    containing the estimated upper 95 percentile aldicarb residue levels

    would be approximately one-quarter of the daily exposure calculated by

    assuming that all of the aldicarb-treated commodities contained

    residues at the tolerance levels (e.g., 1.77 µg/kg per day versus 6.38

    µg/kg per day for the USA population). In addition, Petersen &

    Gregorio (1988) presented the results of a statistically designed 

 

    national food survey on the five commodities that were estimated to 

    be responsible for more than 90% of the dietary exposure to aldicarb 

    residues in the USA (bananas, white potatoes, sweet potatoes, oranges, 

    and grapefruit). Daily exposure to aldicarb at the 95 percentile 

    consumption rate for aldicarb-treated commodities containing the 

    95 percentile aldicarb residue levels, as estimated from the national 

    food survey, would be approximately 6% of the daily exposure calculated 

    by assuming aldicarb residue levels at the tolerance levels 

    (e.g. 0.40 µg/kg body weight per day versus 6.38 µg/kg per day for the 

    USA population).

 

         The highest daily exposure estimated from the results of the

    national food survey was 0.89 µg/kg per day for non-nursing infants

    and children (1-6 years of age).

 

         A US EPA survey indicated that the vast majority of wells

    contained levels of aldicarb residues less than 10 µg/litre and noted

    that heat treatment of water used in cooking would result in aldicarb

    residues no higher than 5 µg/litre (Cohen et al., 1986).

 

         Accidental leaks of several gases at a plant producing aldicarb

    in Institute, West Virginia, USA, required 135 people to be the

    hospitalized (Marshall, 1985).

 

    5.3  Occupational exposure during manufacture, formulation or use

 

         The dangers of inadequate safety precautions and improper dress

    and handling procedures are discussed in section 8. People involved in

    the manufacture and field application of aldicarb are potentially at

    higher risk than the general population (Doull et al., 1980) and

    should always take proper safety precautions.

 

  1. KINETICS AND METABOLISM

 

    6.1  Absorption

 

         A number of studies on various mammalian and non-mammalian

    species have shown that aldicarb, as well as its sulfoxide and sulfone

    metabolites, is absorbed readily and almost completely from the

    gastrointestinal tract (Knaak et al., 1966a,b; Andrawes et al., 1967;

    Dorough & Ivie, 1968; Dorough et al., 1970; Hicks et al., 1972; Cambon

    et al., 1979). Andrawes et al. (1967) reported that the uptake of

    aldicarb and aldicarb sulfoxide from the gastro-intestinal tract of

    the rat was rapid and efficient. They recovered 80-90% of the

    radiolabel in the urine during the first 24 h after administration.

    Their observation was substantiated by Knaak et al. (1966a,b), who

    also recovered > 90% of the administered oral dose in rats.

 

         Cambon et al. (1979) reported the rapid uptake of aldicarb in

    pregnant rats. The rats showed overt signs of depression of

    cholinesterase activity < 5 min after they were given single oral

    doses of aldicarb ranging from 0.001 to 0.10 mg/kg. At all dose

    levels, acetylcholin-esterase activity was significantly decreased in

    fetal blood, brain, and liver 1 h after dosing.

 

         Dorough et al. (1970) recovered 92% of the doses (0.006-0.52

    mg/kg per day) of aldicarb and aldicarb sulfone in the urine of

    lactating Holstein cows dosed during a 14-day period. Dorough & Ivie

    (1968) found that > 90% of a single dose of 0.1 mg/kg administered

    orally to lactating Jersey cows was absorbed and excreted in the

    urine. In laying hens, oral doses of aldicarb and aldicarb sulfone

    were administered in a 21-day short-term feeding study and in a single

    capsule dose study, respectively. In the short-term feeding study,

    80-85% of each daily dose was excreted in the faeces during the

    following 24 h, while 90% of the total dose consumed was excreted

    within one week after the cessation of aldicarb intake. In the single

    dose study, 90% of the single oral dose was excreted within 10 days

    (Hicks et al., 1972).

 

         Feldman & Maibach (1970) reported the relatively efficient dermal

    uptake of carbamate insecticides in man (73.9% of a dermally applied

    dose of carbaryl was absorbed over a period of 5 days compared with

    10% for five other representative pesticides). The percutaneous uptake

    of aldicarb in water or in toluene has also been demonstrated

    qualitatively in rabbits (Kuhr & Dorough, 1976; Martin & Worthing,

    1977) and in rats (Gaines, 1969).

 

    6.2  Distribution

 

         The rapid depression of acetylcholinesterase activity in fetal

    and maternal blood and tissues observed after the oral administration

    of aldicarb to pregnant rats demonstrated that aldicarb or its toxic

    metabolites (the sulfoxide and sulfone) are distributed to the tissues

    by the systemic circulation (Cambon et al., 1979, 1980). The

    quantitative distribution of radiolabelled aldicarb and its

    metabolites in the tissues of female rats, given a single oral dose of

    0.4 mg aldicarb/kg, is shown in Table 8 (Andrawes et al., 1967).

    Aldicarb and its residues appeared to be distributed among the various

    tissues examined with no tendency to be sequestered or accumulated in

    any one tissue, since animals killed from 5 to 11 days after dosing

    had no detectable radiolabelled residues.

 

         Aldicarb and its metabolites were found to be concentrated in the

    livers of cows fed 0.12, 0.6, or 1.2 mg aldicarb/kg diet for up to 14

    days (Dorough et al., 1970).  Levels of the radiolabel in muscle, fat,

    and bone were low or below the detection levels. In a previous study,

    Dorough & Ivie (1968) found that 3% of the radiolabel was excreted in

    the milk of a lactating cow after a single oral dose of 0.1 mg/kg.

 

         Hicks et al. (1972) conducted a study in which single oral doses

    (0.7 mg/kg) of aldicarb or a 1:1 molar ratio of aldicarb and aldicarb

    sulfone were administered to laying hens. The radiolabel equivalents

    were greatest in the liver and kidneys for the first 24 h, much lower

    levels being found in fat and muscle. In a second study,

    aldicarb/aldicarb sulfone was administered at 0.1, 1.0, or 20 mg/kg

    diet for 21 days. Distribution to the tissues after this multiple

    dosing regimen was similar to that after the single dose, the highest

    residue levels appearing in the liver and kidneys.

 

        Table 8. Total aldicarb equivalents (mg/kg) in tissues of rats treated

             orally with 35  S-aldicarba

                                                                                                

 

                                      Time period (days after dosing)b

 

                                Day 1              Day 2 Day 3             Day 4

                             W        D W         D W D       W D

                                                                                                

    Heart                   0.12 0.44 0.09     0.32 0.08 0.29 0.11     0.38

 

    Kidneys                 0.16 0.56 0.08     0.25 0.06 0.16 0.07     0.21

 

    Brain                   0.11 0.35 0.02     0.08 0.08 0.25 0.05     0.19

 

    Lungs                   0.15 0.60 0.02     0.48 0.04 0.14 0.06     1.19

 

    Spleen                  0.27 1.08 0.04     0.12 0.10 0.37 0.05     0.17

 

    Liver                   0.16 0.28 0.07     0.22 0.07 0.21 0.05     0.14

 

    Leg muscle              0.16 0.61 0.02     0.07 0.05 0.20 0.04     0.12

 

    Fat                     0.23 0.72 0.11     0.12 0.09 0.11 0.03     0.04

 

    Bone                    0.11 0.15 0.09     0.13 0.06 0.08 0.02     0.04

 

    Stomach                 0.19 0.64 0.07     0.26 0.08 0.29 0.06     0.19

 

    Stomach contents        0.18 0.94 0.14     1.05 0.10 0.65 0.03     0.09

 

    Small intestine         0.18 0.74 0.13     0.45 0.10 0.30 0.06     0.16

 

    Small intestine         0.25 1.20 0.19     1.03 0.08 0.49 0.06     0.24

         contents

                                                                                                 

 

    Table 8 cont'd. Total aldicarb equivalents (mg/kg) in tissues of rats treated

            orally with 35  S-aldicarba

                                                                                                

                                      Time period (days after dosing)b

 

                              Day 1               Day 2 Day 3             Day 4

                          W          D W        D W D       W D

                                                                                                

 

    Large intestine       0.15 0.66 0.12     0.54 0.08 0.27 0.13     0.30

 

    Large intestine       0.18 0.67 0.05     0.24 0.09 0.39 0.04     0.16

         contents

 

    Blood                 0.16 0.74 0.14     0.18 0.08 0.21 0.05     0.17

                                                                                                

 

    a     From: Andrawes et al. (1967).

    b     W = wet weight; D = dry weight.

    

 

    6.3  Metabolic transformation

 

         Carbamates undergo a limited number of in vivo reactions:

    oxidation, reduction, hydrolysis, and conjugation (Ryan, 1971). In

    animals, the enzymes involved in these processes are found in the

    microsomal fraction of the liver homogenate. In the case of aldicarb,

    both oxidation of the sulfur to the sulfoxide and sulfone and

    hydrolysis of the carbamate ester group are involved (Andrawes et al.,

    1967). Although the hydrolysis reaction destroys insecticidal

    activity, both the sulfoxide and sulfone are active anticholinesterase

    agents (Andrawes et al., 1967; Bull et al., 1967; NAS, 1977). The

    metabolic pathways for aldicarb in the rat are shown in Fig. 1

    (Wilkinson et al., 1983). The metabolism of aldicarb in animals

    usually results in the formation of the sulfoxide, sulfone, oxime

    sulfoxide, oxime sulfone, nitrile sulfoxide, nitrile sulfone, and at

    least five other metabolites (Knaak et al., 1966a,b; Dorough et al.,

    1970). Aldicarb metabolites formed by incubation with liver microsomal

    enzymes are similar to the metabolites formed in plants and insects

    (Oonnithan & Casida, 1967). The rapid conversion to the sulfoxide and

    sulfone has been demonstrated in plants (Metcalf et al., 1966;

    Coppedge et al., 1967) and animals (Andrawes et al., 1967; Dorough &

    Ivie, 1968).

 

         In vitro studies by Oonnithan & Casida (1967) showed that the

    first stage in the metabolism of aldicarb involves the microsomal

    reduced nicotinamide adenine dinucleotide phosphate (NADPH) system to

    form the sulfoxide, but that the subsequent oxidation to the sulfone

    derivative occurs only to a small extent. Andrawes et al. (1967)

    confirmed these findings and showed that in the presence of the NADPH

    cofactor the production of metabolites increases by a factor of 15.

    The same authors also demonstrated that the principal urinary

    metabolites in the rat consist of hydrolytic products with only a

    small amount of carbamate. In studies with pig liver enzymes, Hajjar

    & Hodgson (1982) concluded that, under aerobic conditions and in the

    presence of NADPH, the FAD-dependent monooxygenase is responsible for

    the observed oxidation of the thio-ether in the primary metabolic

    step. The same authors found that sulfoxidation is enhanced rather

    than inhibited by n-octylamine, a known inhibitor of cyto-chrome

    P-450-dependent oxygenation.

 

    6.4  Elimination and excretion in expired air, faeces, and urine

 

         Most studies on the elimination and excretion of aldicarb and its

    metabolites have used the radiolabelled compound. No kinetic

    coefficients have been reported, although studies in which rats (Knaak

    et al., 1966a,b; Andrawes et al., 1967; Dorough & Ivie, 1968; Marshall

    & Dorough, 1979), cows (Dorough & Ivie, 1968; Dorough et al., 1970),

    and chickens (Hicks et al., 1972) were used gave some information

    about the clearance rates, mechanisms, and routes of excretion. In all

    species, the principal excretion route for aldicarb and its

 

    metabolites (> 90%) is via the urine. A small amount of aldicarb and

    its metabolic products is excreted via the faeces (which is in part

    due to biliary excretion), or is exhaled as carbon dioxide.

 

         The total excretion of S-methyl-C14-, tert-butyl-C14-,

    and N-methyl-C14-labelled aldicarb by rats after oral dosing was

    investigated by Knaak et al. (1966a). Within 24 h, the total excretion

    of the S-methyl, tert-butyl, and N-methyl labels was

    approximately 90, 90, and 60%, respectively. For the S-methyl- and

    tert-butyl-labelled compounds, > 90% was excreted via the urine and

    only 1.1% of the radiolabel was excreted as carbon dioxide. In a study

    on rats dosed orally with aldicarb (labelled in a different position

    and with different radioisotopes), Andrawes et al. (1967) showed that

    > 80% of the applied dose (labelled with 14C) was excreted over 24

    days, while 6.6% was excreted in the faeces within 4 days.

 

         The biliary excretion of aldicarb and its metabolites was studied

    by Marshall & Dorough (1979) in rats with cannulated bile ducts. A

    single oral dose of 14C-thiomethyl aldicarb (0.1 mg/kg) in 0.2 ml of

    vegetable oil was given by intubation, and urine, bile, and faeces

    were collected over the next 72 h. Biliary excretion accounted for

    2.6, 9.5, 22.9, 28.1, and 28.6% of the administered dose at 3, 6, 12,

    24, and 48 h after dosing, respectively. More than 64% was excreted in

    the urine over the 48-h period, and < 1% was recovered from the

    faeces.

 

         In a study by Dorough & Ivie (1968), 83% of an oral dose of 0.1

    mg/kg given to a lactating cow was recovered in the urine within 24 h,

    this increasing to 90% over 22.5 days. Only 2.85% of the radiolabel

    was recovered in the faeces within 8 days after dosing. All samples of

    milk taken from 3 h to 22.5 days after dosing contained the radiolabel

    and accounted for 3.02% of the administered dose.

 

         Hicks et al. (1972) dosed laying hens with 35S-aldicarb or with

    a 1:1 molar ratio of 14C-aldicarb and 14C-aldicarb sulfone. The

    dose (0.7 mg/kg) was administered orally in a gelatin capsule. In both

    cases, the label was excreted rapidly; 75% of the radiolabel was

    recovered in the faeces within 24 h and > 80% was recovered within 48

  1. Repeated dosing, twice a day for 21 days, resulted in a similar

    pattern of excretion, 80-85% of the daily dose being excreted in the

    faeces within 24 h after the administration of each dose.

 

         

 

    

 

  1. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS

 

    7.1  Single exposure

 

         The acute oral and dermal toxicity of aldicarb has been studied

    in several species (Table 9). Oral LD50 values appear to be fairly

    consistent (0.3-0.9 mg/kg body weight in the rat) and not dependent on

    the carrier vehicle. Oral administration of the granular formulation

    of aldicarb gives LD50 values proportional to the active ingredient

    content (Carpenter & Smyth, 1965). The oral LD50 values for aldicarb

    sulfoxide and sulfone in rats are 0.88 mg/kg body weight and 25.0

    mg/kg body weight, respectively (Weil, 1968). Dermal LD50 values

    vary with the mode of application and the carrier vehicle used.

    Several acute dermal toxicity studies using different carrier vehicles

    have been reported. The dermal 24-h LD50 in rabbits for a single

    application of aldicarb in water was 32 mg/kg body weight (West &

    Carpenter, 1966).  However, when aldicarb was tested in propylene

    glycol, the observed dermal LD50 was 5 mg/kg body weight (Striegel

    & Carpenter, 1962). A dermal LD50 of 141 mg/kg body weight was

    reported in a 4-h exposure study on rabbits using dry Temik 10G

    formulation. On the basis of results of acute oral and dermal toxicity

    studies, aldicarb should be labelled as extremely hazardous (WHO,

    1990b).

 

         Carpenter & Smyth (1965) reported 100% mortality within 5 min

    when rats, mice, and guinea-pigs were exposed to aldicarb dust at a

    concentration of 200 mg/m3. The rats and mice were more sensitive

    than the guinea-pigs. Rats survived a dust concentration of 6.7

    mg/m3 for 15 min, but five out of six died after 30 min. All rats

    survived for 8 h when exposed to a saturated vapour concentration.

    Rats were also less sensitive to aerosol concentrations than to

    similar concentrations of the dust. Two of six rats survived an 8-h

    exposure to an aerosol concentration of 7.6 mg/m3. Weil & Carpenter

    (1970)  determined an LD50 of 0.44 mg/kg body weight in rats by the

    intraperitoneal route.



        Table 9.  Acute toxicity of aldicarb and its formulation products

                                                                                                         

 

    Compound       Route of Vehicle             Species LD50                  Reference

                   adminis                                     (mg/kg body

                   tration                                     weight)a

                                                                                                         

    Technical      oral                     rat 0.93 Martin & Worthing

    aldicarb                                                                       (1977)

 

                   oral           peanut oil     rat M: 0.8         Gaines (1969)

                                                                 F: 0.65

 

                   oral           corn oil     rat M: 0.09         Carpenter & Smyth

                                                                                   (1965)

 

                   oral           corn oil     rat F: 1.0         Weiden et al. (1965)

 

                   oral           not specified     mouse 0.3         Black et al. (1973)

 

                   skin           xylene     rat M: 3.0         Gaines (1969)

                                                                 F: 2.5

 

                   skin           not specified     rabbit 5.0         Weiden et al. (1965)

 

                   skin           propylene glycol    rabbit 5.0         Striegel & Carpenter

                                  (5%)                                             (1962)

 

    Temik 10G      oral not specified       rat 7.7 Weil (1973)

 

                   dermal         water     rat 400         Carpenter & Smyth

                   (4 h)                                                           (1965)

 

                   dermal         none     rat 200         Carpenter & Smyth

                                                                                   (1965)

 

                                                                                                         

 

    Table 9 cont'd.  Acute toxicity of aldicarb and its formulation products

                                                                                                         

 

    Compound       Route of ad-   Vehicle   Species LD50               Reference

                   ministration                                   (mg/kg body

                                                                  weight)a

                                                                                                         

 

                   dermal            none   rat 850       Weil (1973)

 

                   dermal            water (50%)   rabbit 32       West & Carpenter

                                                                                    (1966)

 

                   dermal            dimethyl   rabbit 12.5       West & Carpenter

                   (4 h)             phthalate                             (1966)

 

                   dermal            toluene (5%)   rabbit 3.5       West & Carpenter

                   (4 h)                                                            (1966)

                                                                                                         

 

    a    M = male; F = female.

    

 

         Trutter (1989a) investigated the clinical effects and the effect

    on plasma cholinesterase and erythrocyte acetylcholinesterase of a

    single feeding of aldicarb residues (about 83.4% sulfoxide and 16.6%

    sulfone). These residues were contained in a watermelon grown under

    experimental conditions, aldicarb having been applied to the soil at

    intervals beginning at the time of planting. Water-melon with a

    residue concentration of 4.9 mg/kg was fed to three male and three

    female cynomolgus monkeys at a dosage that provided a residue intake

    of 0.005 mg/kg body weight. Additional groups of three male and three

    female monkeys received untreated water-melon (20 g/kg body weight).

    The test monkeys received supplemental untreated water-melon so that

    their total intake of the fruit was the same as that of the controls.

    Cholinesterase activity was measured 16, 9, and 3 days before and

    immediately before the test. Peak inhibition of plasma cholinesterase

    (31-46%) occurred 1 h after treatment. It was only slightly less at 2

    h but was absent at 4 h after feeding. Observations continued at

    intervals for 24 h. No inhibition of erythrocyte cholinesterase and no

    clinical effects occurred (Trutter, 1989a).

 

         A similar study with identical numbers of cynomolgus monkeys was

    conducted using treated bananas. The total residue level (0.25-0.29

    mg/kg) in six bananas was less than that in the water-melon, and the

    average distribution of metabolites was different (91.8% sulfoxide and

    8.2% sulfone). The dosage of aldicarb metabolites for the test monkeys

    was 0.005 mg/kg body weight and the banana intake for both test and

    control animals was 20 g/kg body weight. Inhibition of cholinesterase

    was similar in male and female test monkeys, averaging 23% one hour

    after dosing, increasing to 33% by the second hour, and decreasing to

    24% by the fourth hour. No inhibition of erythrocyte cholinesterase

    and no clinical effects occurred (Trutter, 1989b).

 

    7.2  Short-term exposure

 

         Short-term studies have been conducted in several species with

    aldicarb and its principal metabolites (the sulfoxide and sulfone)

    both alone and in combination.

 

         In studies by Weil & Carpenter (1968b,c), male and female rats

    were fed daily doses of aldicarb sulfoxide (0, 0.125, 0.25, 0.5, and

    1.0 mg/kg body weight) or aldicarb sulfone (0, 0.2, 0.6, 1.8, 5.4, and

    16.2 mg/kg body weight) in the diet for 3 and 6 months.

    Acetylcholinesterase activities were depressed at the three highest

    levels of each compound, and this was accompanied by some growth

    retardation. No mortality or pathological effects (gross or

    microscopic) were observed. In an earlier study, Weil & Carpenter

    (1963) fed male and female rats daily with 0, 0.02, 0.10, or 0.50 mg

    aldicarb/kg for 93 days. Plasma cholinesterase activity was depressed

    in both males and females but erythrocyte cholinesterase activity was

    depressed only in males. Male and female rats fed doses of either 

 

    aldicarb sulfoxide or the sulfone (0.4, 1.0, 2.5, or 5.0 mg/kg body

    weight per day) for 7 days tolerated the lowest dose level of the

    sulfoxide with no effects on body or organ weight (Nycum & Carpenter,

    1970). There was no evidence of plasma, erythrocyte or brain

    cholinesterase inhibition at that dose level. However, these

    parameters were significantly affected at all higher dose levels. 

    Aldicarb sulfone caused a significant decrease in brain, plasma, and

    erythrocyte cholinesterase activity at the highest dose level in rats

    of both sexes. Reduction in brain cholinesterase activity also

    occurred at the two intermediate dose levels for the sulfone in female

    rats only.

 

         In a 13-week feeding study (NCI, 1979), there was 100% mortality

    in rats exposed to 100 or 320 mg aldicarb/kg and body weight loss at

    80 mg/kg in male rats.

 

         DePass et al. (1985) exposed 8-week-old male and female Wistar

    rats (10 of each sex per group) to a 1:1 mixture of aldicarb sulfoxide

    and aldicarb sulfone in their drinking-water for 29 days. Their study

    was based on a report by Wilkinson et al. (1983) that residues of

    aldicarb in drinking-water consist essentially of a 1:1 mixture of the

    sulfoxide and sulfone. The drinking-water levels were 0, 0.075, 0.30,

    1.20, 4.80, and 19.20 mg/litre (0-1.67 mg/kg body weight per day for

    males and 0-1.94 mg/kg body weight per day for females). The authors

    concluded that 4.8 mg/litre (470µg/kg body weight per day) was the

    no-observed-effect level (NOEL), based on erythrocyte

    acetylcholinesterase and plasma cholinesterase inhibition observed at

    the highest dose level.

 

         Short-term dermal studies were conducted in which Temik 10G (with

    10% ai) was applied with wetted gauze to the abraded skin of male

    albino rabbits for 6 h/day for 15 days (Carpenter & Smyth, 1966). Dose

    levels of 0.05, 0.10, and 0.20 g/kg body weight were applied daily,

    and weight gain, food consumption, organ weights, cholinesterase

    activity, and the histopathology of several tissues were examined.

    Only plasma cholinesterase activity levels and weight gain at dose

    levels of 0.1 and 0.2 g/kg per day were significantly altered.

 

         In a 2-year study on beagle dogs, aldicarb was administered in

    the diet at dose levels of 0, 0.025, 0.05, and 0.10 mg/kg body weight

    per day (Weil & Carpenter, 1966).  The same parameters as those

    monitored in the rat study conducted by these authors were

    investigated in this study, but none were significantly different from

    controls. The authors concluded that the NOEL for rats and dogs was at

    least 0.10 mg/kg body weight per day, since this was the highest level

    tested.

 

         In a study by Hamada (1988), male and female beagle dogs were fed

    for one year a diet containing 0, 1, 2, 5 or 10 mg technical aldicarb

    per kg to provide approximately 0, 0.025, 0.05, 0.13, or 0.25 mg/kg

    body weight per day. No dogs died during the study, and there were no

 

    effects on body weight, food and water consumption, organ weights, or

    on haematological, ophthalmological, histopathological, and gross

    pathological parameters. However, statistically significant increases,

    compared to controls, in the combined incidence of soft stools, mucoid

    stools, and diarrhoea were found in all groups treated with 0.05 mg/kg

    per day or more, as well as in females treated with 0.025 mg/kg per

    day. No statistically significant decrease in erythrocyte or brain

    cholinesterase was found in groups treated with 0.025 or 0.05 mg/kg

    body weight per day.  However, plasma cholinesterase was inhibited in

    male dogs treated with 0.05 mg/kg body weight per day or more

    throughout the observation period of this study (weeks  5-52). In

    addition, plasma cholinesterase was inhibited at the conclusion of the

    study (week 52) in male dogs treated with 0.025 mg/kg body weight per

    day. The author noted that plasma cholinesterase activity in the male

    dogs treated with 0.025 mg/kg body weight per day was subsequently

    determined to be within historical control values, and that the

    statistically significant increase in soft stools and related effects

    in females treated with 0.025 mg/kg body weight per day could be

    attributable to an unusually high incidence of mucoid stools in one

    dog during the last half of the experiment. The author concluded that

    the NOEL in this study was 1 mg/kg (0.025 mg/kg body weight per day).

 

         In a short-term study, Dorough et al. (1970) dosed lactating

    Holstein cows with Temik (10% ai) at 0.042 mg ai/kg body weight per

    day in their diet for 10 days and, in a second experiment, with a

    mixture of aldicarb and aldicarb sulfone (Temik equivalents of 0.006,

    0.027, and 0.052 mg/kg body weight per day) for a period of 14 days.

    Although no alteration in blood cholinesterase activity levels or

    other clinical effects were noted, aldicarb sulfoxide and sulfone were

    detected in tissues. Milk production, feed consumption, and amount of

    excreta were unaltered.

 

    7.3  Skin and eye irritation; sensitization

 

         Pozzani & Carpenter (1968) observed that aldicarb (0.7 mg/kg body

    weight) in saline injected intradermally into male guinea-pigs had no

    sensitizing properties.

 

         In male albino rabbits, application of aldicarb as a solution in

    propylene glycol on covered clipped skin did not produce any

    irritation. Instillation of 0.1 ml of a 25% suspension of aldicarb in

    propylene glycol or 1 mg of dry compound did not cause corneal

    irritation (Striegel & Carpenter, 1962).

 

         The administration of 25 mg of aldicarb (Temik 5G)  into the

    conjunctival sac of rabbits resulted in conjunctival irritation, which

    lasted for 24 h, in all the six test albino rabbits (Myers et al.,

    1983).

 

         In a study by Myers et al. (1982), the application of 500 mg

    Temik 5G, moistened in saline solution, did not produce primary skin

    irritation in rabbits. Similarly percutaneous administration to

    abraded skin did not cause focal skin irritation.

 

         Separate tests using aldicarb (75% wettable powder)  and

    technical aldicarb in saline resulted in no sensitization response in

    male albino guinea-pigs following intradermal injections (Pozzani &

    Carpenter, 1968).

 

    7.4  Long-term exposure

 

         In a study by Weil & Carpenter (1972), male and female rats were

    fed aldicarb (0.3 mg/kg body weight per day), aldicarb sulfoxide (0.3

    or 0.6 mg/kg body weight per day), aldicarb sulfone (0.6 or 2.4 mg/kg

    body weight/day), or a 1:1 mixture of the sulfoxide plus sulfone (0.6

    or 1.2 mg/kg body weight per day) for 2 years. No effects were

    observed at the low dose level with any of the treatments. At the high

    dose level (except in the case of the sulfone), there was increased

    mortality within the first 30 days and a reduction in plasma

    cholinesterase activity, as well as decreased weight gain in the

    males. The NOEL values determined for aldicarb, aldicarb sulfoxide,

    aldicarb sulfone, and a 1:1 aldicarb sulfoxide/aldicarb sulfone

    mixture were 0.3, 0.3, 2.4, and 0.6 mg/kg body weight per day,

    respectively.

 

         When male and female rats were fed diets containing aldicarb

    (0.005, 0.025, 0.05, or 0.1 mg/kg body weight per day) for 2 years,

    there were no effects on food consumption, mortality, lifespan,

    incidence of infection, liver and kidney weight, haematocrit,

    incidence of neoplasms and pathological lesions, or on plasma, brain,

    and erythrocyte cholinesterase levels (Weil & Carpenter, 1965).

 

    7.5  Reproduction, embryotoxicity, and teratogenicity

 

         Proctor et al. (1976) studied the effects of several methyl

    carbamate and organophosphate insecticides on teratogenicity and

    chicken embryo nicotinamide adenine dinucleotide (NAD) levels. Fertile

    White Leghorn eggs (45-55 g) were used for the test. After the eggs

    were incubated at 37 °C and 73% relative humidity for 4 or 5 days, 1

    mg of aldicarb in a 30-µl methoxytriglycol solution was injected into

    the yolk and the injection hole on the shell was then sealed with

    paraffin wax. On day 12 after injection, some of the embryos were

    removed and the NAD levels were examined. On day 19 after injection,

    the remaining embryos (at least 10) were examined. NAD levels were

    similar to those of controls. There were no terato-genic effects

    (straight legs, abnormal feathers, or wry neck) in any of the embryos

    exposed to aldicarb.

 

         In a study by Weil & Carpenter (1964), pregnant rats were fed

    with doses of 0, 0.04, 0.20, and 1.0 mg aldicarb per kg body weight

    per day. One group was fed throughout the pregnancy and until the pups

    were weaned, a second group was fed from the day of appearance of the

    vaginal plug until the 7th day of gestation, and a third group

    received aldicarb between days 5 and 15 of gestation.  Although the

    highest dose administered was near the reported LD50 for rats, no

    significant effects on fertility, viability of offspring, lactation or

    other parameters were observed.

 

         In a teratology study, Harlan-Wistar rats were fed aldicarb

    sulfone in their diets at dosages of 0.6, 2.4 or 9.6 mg/kg body weight

    per day, administered either during the first 20 days of gestation,

    during day 6 to day 15 of gestation, or during day 7 to day 9 of

    gestation. No treatment-related teratogenicity occurred as a result of

    any of the treatment regimes at any of the levels of exposure to the

    sulfone (Woodside et al., 1977).

 

         Groups of 16 pregnant Dutch Belted rabbits were given doses of 0,

    0.1, 0.25 or 0.50 mg aldicarb/kg body weight per day by gavage on days

    7-27 of gestation (IRDC, 1983). Fetuses were then removed by Caesarean

    section. One spontaneous abortion was reported in each group given

    0.25 or 0.50 mg/kg body weight per day. Although the number of viable

    fetuses and total implantation values were lower in all treatment

    groups than those in controls, they fell within historical control

    ranges and no significant differences were recorded.

 

         Developmental toxicity of aldicarb has been evaluated by Tyl &

    Neeper-Bradley (1988). Four groups of pregnant CD Sprague-Dawley rats,

    25 in each group, were administered aldicarb (0.125, 0.25 or 0.5 mg/kg

    body weight per day) in water solution by gavage from gestation days

    6 to 15. There were three treatment-related maternal deaths in the

    high-dose group on day 7 of gestation (second day of administration).

    Maternal toxicity at that dose level was indicated by reduced body

    weight and food consumption and cholinergic signs. Body weight and

    food consumption were also reduced in the rats given 0.25 mg/kg body

    weight per day. The NOEL for maternal toxicity was 0.125 mg/kg body

    weight per day. Litter weight was significantly reduced at 0.5 mg/kg

    body weight per day. Fetotoxicity was indicated by body weight

    reduction, increased skeletal variation, retarded ossification, and

    ecchymosis on the trunk. No embryotoxicity was observed. An increased

    incidence of dilation of the cerebral lateral ventricle was observed

    at the highest dose level. However, due to the very high baseline

    control value for such changes found in pooled historical review, this

    increase was not considered to be significant.