Archive for 29/03/2010

Factors Contributing to Increased Deaths and Efforts to Prevent Them
March 2009


Dr Lewis is one of the world’s leading experts in drug testing. His speaking manner combines what T. S. Eliot might have termed a lugubrious drollery with a profound grasp on his subject. It is easy to be light-hearted about ‘piss tests’ but it is also deadly serious if your own job, drivers licence or liberty depend upon such a result.

We were reminded first up what urine testing can NEVER determine with any accuracy: (1) the dose, (2) the time it was taken or (3) the pharmacological effect of any substance being tested.

The most common drug assays they perform are for methadone and metabolites, cannabinoids, opiates, cocaine, benzodiazepines and amphetamines. Barbiturates often omitted these days since their illicit use seems to have ceased for all practical purposes. The term ‘amphetamine type substances’ (ATS) is now superseding ‘sympathomimetic amines’.

This group includes dexamphetamine, methylamphetamine, ecstasy (MDMA), methylenedioxyamphetamine (MDA), and other ‘designer’ drugs such as paramethoxyamphetamine (PMA) and their metabolites, but also ephedrine, pseudoephedrine. One needs to know the particular immunoassay ‘kit’ being used to be sure what exactly is detected and at what level.

Laboratories are asked to perform tests both in a clinical setting as well as for forensic, workplace or medico-legal reasons. For clinical purposes a cost effective and fast turn-around time approach is used. This starts with an inexpensive immunoassay which is very sensitive for most of the drugs being tested for, but generally not specific. Hence a negative batch of tests can yield a fast, efficient response to the clinician. Positive immunoassay results for any of the drug groups (or negative for methadone) may indicate further testing, typically using GCMS (gas chromatography/mass spectrometry), which is considered the ‘gold standard’.

Although thin layer chromatography (TLC) is not commonly used nowadays, Dr Lewis says it still has a place: it presents information on a large range of drugs to view at a single glance, and is inexpensive. Because the TLC depends upon the human factor of recognising patterns, it is subjective and unless the spot patterns correspond to known medication, confirmatory testing by mass spectrometry is usually conducted. Although it is not used for medico legal work, it still has a place in clinical settings, as an adjunct to mass spectrometry in presumptively identifying a wide range of therapeutic substances not amenable to immunoassay.

In particular cases there will need to be specific tests done, especially for suspected drug use which may not be detected by the usual immunoassays. These include tests for doctors, nurses or other health care workers on conditional registration due to drug use. Such drugs include pethidine, tramadol and the short acting anaesthetic propofol. Abuse of these drugs outside the medical setting is exceptional.

Note that buprenorphine is also hard to detect by simple methods. Although there is an immunoassay for the drug, toxicologists must be aware of possible false positives from a number of unrelated therapeutic substances. However, like methadone, when the dose is taken under supervision such testing is less important than, say, in England where much treatment is unsupervised and testing for the prescribed medication can be crucial in determining compliance and overall stability.

Dr Lewis then detailed the limitations and strengths of modern immunoassays in determining a class of drug but only in two cases can they detect specific metabolites, EDDP (for methadone) and 6-mono acetyl morphine (heroin). The value of a negative test was pointed out. We were reminded that testing was almost pointless in hospital casualty cases: for overdoses, the results are usually not available until either the patient is dead or else recovered.

Also, medications are used so routinely and such patients may have injuries necessitating local anaesthetics, dressings, iodine, etc in the course of their treatment in the casualty ward that results are close to meaningless.

Specifically, Dr Lewis said that positive opiate and ATS immunoassays should be taken with caution as there are many causes of false positives. These include poppy seeds, cough mixtures, decongestants and common analgesics. Dr Lewis told us that his own urine remained positive for ‘opiates’ for nine days after a dose of the cough suppressant pholcodine. The main value of these screening tests is when the result is negative. Note that ‘opiate’ immunoassays do not detect the ‘opioids’ methadone, buprenorphine, pethidine and others. Oxycodone has only a very weak response to “opiate” immunoassays.

We were then shown the plates used for thin layer chromatography and a list of 20 common drugs which can be definitively determined using this method (eg. morphine, codeine, oxazepam, pseudo-ephedrine, paracetamol and nicotine). GCMS was then described in response to a question from the floor.

In essence it appears that there are two properties of each substance which are identified in the method, causing a unique fingerprint from the two derived figures. It is more expensive than other methods, but more accurate and specific, being able to detect both the original base compound as well as ‘derivatised’ products.

Then we had a brief tutorial on the use of testing for alcohol consumption. Everyone knows about breath testing, but 5% of alcohol is excreted in the urine and there is a direct correlation between plasma and urine alcohol concentration of 1.3:1. However, due to the short half life of alcohol, such testing is only of any use within hours of the drug use. And, as with other drugs, a certain level could be associated with a small amount of drug used very recently, or equally, a large amount used quite some time before.

There are also unexpected false positives, including a case Dr Lewis described where urine from a diabetic in a rehabilitation facility had undergone fermentation (probably by yeasts) before being tested; the calculated blood alcohol concentration (0.34) would have been lethal. A less ‘gross’ error might not have been discovered, and this would have led to the automatic expulsion of the person from the rehab facility.

Tests for cannabis are of limited value since, for most, its use is not relevant to the treatment or supervision being given. Hence Dr Lewis only performs cannabis tests when specifically requested, such as in patients being treated for cannabis dependence, to assess progress.

We were then taken through some metabolic pathways. Heroin breaks down within minutes into 6-acetyl morphine, then to morphine. This then is broken down into morphine-6 or -3 glucuronide which are excreted. Codeine is largely conjugated into codeine-6 glucuronide, but importantly, a small proportion is transformed into morphine. A positive test for morphine can therefore sometimes occur due to codeine use (but not the other way around). A warning: most tests underestimate the amount of codeine in urine, as the metabolite codeine-6 glucuronide is hard to „bust“ into codeine, which can be detected.

It is important to know the relative amounts of morphine and codeine in a urine sample as the ratios affect correct interpretation as to what may or may not have been ingested.

Diazepam is broken down into another active metabolite, oxazepam. This can occur via two intermediaries, nordiazepam and temazepam. Most of the common sedatives and related drugs such as clobazam will show up as benzos on the initial immunoassay. However, specific confirmatory testing must be done when clobazam is used in therapeutic trials to test against ‘street’ benzos.

Stimulants were then covered including the new definition of ice in an age of global warming (ice-bergs and all!). Amphetamine was first synthesised by the Germans in 1887. It was heavily marketed in the US in the 1930s as ‘Benzedrine’. Methylamphetamine is easier to manufacture, especially if one has the base product pseudoephedrine. We were then told that the latest ‘craze’ for stimulants is purely based on stronger, highly purified drug being available in the form of ‘crystal meth’ or ‘ice’.

Methylamphetamine powder is a salt, „crystal“ a highly purified salt, and „base“ is an oil. Urine testing cannot distinguish between them as these are the same drug. While Dr Lewis’ lab has found 2005 was the year with highest mean amphetamine levels, in 2006 the maximum levels found each week continued to climb to being 5 fold the 2003 levels. While these are dramatic findings, it is hard to know their significance overall except to imply that some users are taking very large amounts of methylamphetamine, viz, “ice”.

Cannabis has many metabolites which are detected on screening, and confirmed with carboxy –THC on GCMS. It is very lipophilic, and gets stored in the fat cells of the body. Cannabinoid urine tests may be negative within a few hours of a single smoke; daily use may take many days, and heavy use a month or more. If a high level is found then it is easy to know that there is continuous use. Carboxy-THC: creatinine ratios can indicate increasing or decreasing use (see case vignettes below).

Then there was a discussion about laboratory ‘cut-offs’ which are essential for legal purposes, but less meaningful for clinical purposes, except to reduce the numbers of false positives. Cut-offs are also necessarily somewhat arbitrary, like the drink driving limits – and can vary from place to place or from time to time. Currently 50ng/ml is used for immunoassays of cannabinoids, and 15 ng/ml for the specific GCMS for carboxy-THC (plus or minus a figure for lab uncertainty; this means an actual cut off of around 18-19 ng/ml). Dr Lewis believes there is a case for higher cut-offs to be used for cannabinoids, to identify substantial cannabis use, rather than low level or more importantly residual drug from previous heavy use.

Some case vignettes in the second half illustrated common problems. Three patients with positive immunoassay for opiates claimed only to have taken codeine-based analgesics. One had codeine and morphine on GCMS, and this could be explained by metabolism of codeine to morphine, or other sources or morphine such as poppy seeds, morphine sulphate etc. Another had urine positive for morphine, and negative for codeine: this could occur if there was extensive metabolism of codeine to morphine (for example by cytochrome CYP2D6 ultrarapid metabolisers) and especially if the laboratory test underestimated the amount of codeine (see above). In the last case, urine was positive for morphine and monoacetyl-morphine: the latter can only come from heroin use.

In a case of roadside drug testing, a woman justified her positive salivary cannabis test by saying „I never smoke pot, but my partner smokes it all the time“. Dr Lewis explained that this test does not pick up metabolites of THC, only the parent drug, and is not very sensitive, missing a large proportion of cannabis users (as reported by the European ROSITA study). Thus passive smoking could not cause a positive test. A man on methadone, who had not had a positive urine test for many years, blamed his positive urine cannabinoid test on his partner, who ‘smoked 30 cones each day’. A positive immunoassay test result is unlikely to be a result of passive inhalation. It is more likely be a false positive due to other medication, cross contamination or else laboratory error.

Dr Lewis described the benefits of using carboxy-THC:creatinine levels to help allow for variation in urine concentrations due to level of hydration. Cases were shown from the Drug Court, where declining THC:creatinine ratios were consistent with ongoing abstinence; in another case a spike in ration of THC:creatinine led to punitive action, but might have been explained by the person going to the gym, and mobilising cannabinoids stored in fat cells. Another case from the Drug Court showed how the sequence of appearance or disappearance of diazepam metabolites (nordiazepam, oxazepam and temazepam) could be used to make inferences about recent diazepam use. In this case, as in almost every example discussed, Dr Lewis was able to give examples of exceptions, where other causes than the most obvious might account for the result. So urine tests should never be interpreted uncritically by untrained people.

In another case, a worker was suspended for producing „dilute urine“ (wrongly described as a „false negative urine test“) because of low creatinine urine (1.4 mmol/L), and allegedly told he would need to produce two urine tests with creatinine higher than 5 mmol/L. However, this worker’s serum creatinine was low owing to lean body build, while urea, electrolytes, specific gravity, osmolality were consistent with physiological urine. THC:creatinine ratios might help adjust for hydration (some people deliberately drink lots of water to dilute their urine) but could also discriminate against people with naturally low creatinine. A urine creatinine level as low as 0.9 mmol/L is physiologically achievable. Below this suggests the likelihood, and below 0.5 mmol/L the near certainty, of external interference with the sample, usually meaning dilution after urination.

Methadone maintenance is somewhat of a mystery to clinicians not involved in addiction medicine, and opioid addicts don’t fare well in the emergency medical system. Many nurses and physicians have trouble dealing with them objectively and don’t want to be involved. Well-managed methadone maintenance is, however, a different story. Few EPs dole out methadone, but maintenance patients show up in the ED with legitimate complaints. Patients on high-dose methadone can experience painful conditions or injuries requiring additional analgesia. It’s not easy, but if one can put aside preconceived notions about addiction, methadone maintenance presents a fascinating challenge to the EP.

Figure. Clients line…

Most  have treated methadone maintenance therapy (MMT) clients in the ED, and have dealt with withdrawal, missed appointments, and overdose. I have visited a few methadone clinics, and the whole concept is fascinating, giving great insight into a government-sponsored medical entity.

Treatment Improvement Protocol Series 43: Medication-Assisted Treatment for Opioid Addiction in Opioid Treatment Program

This massive document summarizes the consensus of the U.S. Health and Human Services on MMT, which is administered through the Substance Abuse and Mental Health Services Administration and the Center for Substance Abuse Treatment, branches of HHS. This 14-chapter document has everything you want to know about MMT.

Edit by Exilope:

Initial Screening: Anyone can walk into an MMT clinic and request treatment. Initial screening exams and interviews determine the applicant’s eligibility and the process includes an assessment of their readiness to accept treatment. Ongoing, if not daily interventions, are required to keep the patient in the system and off the opioid. The addiction severity index collects basic information, and it can be used to track progress. Much of the information is supplied by the addict, and truthfulness on their part is paramount for success.

Comment: I suspect most people don’t walk in off the street thinking about MMT for the first time. All potential clients likely consider it many times or talk about it with fellow addicts. They are often prompted to try MMT by those who have been through the process, some more than one time. One would assume that an opioid addict who shows up at the clinic has hit rock bottom or finally has accepted they have an addiction they cannot control. Many are in overt withdrawal. They are ready to sign up.

First impressions are lasting ones. The HHS recommends a plethora of warm and fuzzy approaches to help the addict adjust and feel supported. A nonconfrontational and nonaccusatory attitude is stressed. Unlike the ED, MMT clinics want to be in the business of dispensing methadone. Clinics are usually prepared to provide immediate information, if not methadone treatment, on the first day.

A variety of preprinted documents are handed out that describe the services, rules, and expectations of the program. Policies are in place to deal with disruptive and violent clients and pregnant women. Clinics also try to identify treatment barriers and offer financial assistance and psychiatric crisis intervention. Many patients also have underlying psychiatric disorders, legal difficulties, child care issues, and transportation and family concerns. Cultural, ethical, and spiritual factors also complicate MMT. Those patients who seem in crisis can be referred for inpatient medical facility or psychiatric care. The correlation between opioid addiction and the risk of suicide is well known, and initial screening and periodic assessment helps determine that ongoing risk.

Admission Issues: A significant delay between the first contact, initial screening, and methadone treatment, especially failure to quickly address withdrawal, adversely affects the number of applicants who enter the program. It’s difficult to deal with an opioid addict in withdrawal; his patience wears thin, and he wants treatment now. Recognizing the realities of crowding and limited resources, MMT clinics can provide an interim maintenance program without formal screening or actual admission to the site. By federal regulation, medication can be administered for up to 120 days with only minimal screening procedures.

Violent or threatening patients can be turned down, but I have been amazed at how understanding and supportive some of the staff are; it’s similar to the mentality emergency physicians use to treat those who are not the nicest people. MMT, like emergency medicine, is a service industry, and the customers often possess the mentality of the McDonald’s client. They want it now, they want it their way, and they don’t want to pay much for it. Frustrated clients who elope are, however, a loss for everyone. Programs are not free, and cash and insurance are accepted, but often the down-and-out addict qualifies for local aid.

Information, Collection, and Dissemination: During the first few visits, a substance abuse history is obtained, and treatment options are discussed. Consent to treat is elicited, and addicts must sign a bevy of documents that provide further information on the multifaceted MMT process. Patients must be 18 or have parental approval. Otherwise, the services are confidential even to family members. Confidential information is not given to any inquiry except the court. The specifics of the individual’s opioid addiction, including recent pattern changes and binges, are gathered. Other drugs such as benzodiazepines and alcohol are often confounding issues, and the patient’s daily pattern of opioid abuse is determined, essentially by his own admission.

The opioid withdrawal history and the energy required to maintain the addiction is sought. Many patients are in withdrawal when they come to the clinic, making historical information open to exaggeration, but many downplay their use (like the alcohol history obtained in the ED). Some withhold a history of other addictions, perhaps thinking they might supplement the methadone if needed. Blood tests for specific drugs are not required nor usually performed to quantify use. A serum drug level is of no value in this scenario. Questioning the history can intimidate the prospective client and set up an adversarial relationship at the beginning. Again, unlike the ED, MMT clinics put a lot of trust in the truthfulness of the addict.

Medical Assessment: The aim of medical assessment is to determine the safety of methadone use. The drug is often dispensed on the first visit because of withdrawal. It is generally required that someone be addicted for one year before admission. There appears to be some flexibility in this criterium, especially for prisoners, pregnant women, or those previously treated. There may be uncertainty about past narcotic use, but generally a broad definition is accepted for opioid addiction, and one need not administer Narcan to test for withdrawal.

Generally, the staff obtains a medical history that documents drug-related diseases such as hepatitis, AIDS, tuberculosis, or STDs. Within 14 days of admission, a basic physical examination is performed, including blood tests for HIV, syphilis, and hepatitis. Federal regulations do not require a full panel of laboratory tests; that appears to be a state issue. Patients usually are tested randomly by a urine screen immunoassay test for additional drug abuse at least eight times each year per SAMHSA. Because methadone does not yield a positive opioid result unless specifically tested, a positive opioid screen usually means exogenous drugs.

Multiple Substance Abuse: It is common knowledge that opioid addicts often abuse other substances, especially alcohol, amphetamines, benzodiazepines, prescription opioids, cocaine, sedatives, and marijuana. CNS depressants are particularly dangerous when combined with opioids. Patients generally are asked to report other substances they used in the past. The accuracy of this form depends, of course, on patient honesty. Alcohol is a favorite of most, and heroin addicts particularly like to add cocaine for additional euphoria. Benzodiazepines are commonly used to boost methadone and enhance the high. Patients also self-medicate because of withdrawal symptoms or because they are anxious, depressed, or lonely.

MMT clients all know using an exogenous substance can kill them and defeat the purpose of MMT. Using exogenous drugs negatively affects attendance rates and cooperation with other programs. Interestingly, patients are not frequently discharged from MMT because they abuse other substances. The main goal is to retain the patient in MMT, allowing for human frailty, lack of self-control, and poor judgment. MMT clients are given multiple chances despite violating explicit rules and regulations.

Drug Testing: Clients are randomly tested for other drugs, usually with an immunoassay urine screen. This is not a perfect system because it only identifies those using other substances frequently and only detects drugs that show up on a urine screen. Of course, it has to be your urine, and there is always someone around who wants to give a clean sample for the right price.

Periodic drug testing provides objective evidence of treatment success and monitors patient progress. Typical urine testing evaluates for commonly abused substances with a qualitative immunoassay technique that has cutoff concentrations. Testing drug levels in the blood is not helpful because tolerance, time of use, and the need to send the test to a reference lab does not allow for meaningful interpretation of data. Most drugs remain in the system and are excreted in the urine for two to four days following use. Measuring methadone serum levels during treatment has minimal value and is not done routinely, but this may be used to identify a rapid or slow metabolizer. Obviously, urine tests are not quantitative; they merely give positive or negative results.

Urine collection may be monitored to avoid contamination or substitution. There are no firm and fast rules for the method of testing, and direct observation is not mandatory. The most common test is an enzyme-multiplied immunoassay technique (EMIT), which uses antibodies to specific drugs or metabolites. Oxycodone is often not identified with this test; nor are clonazepam, Seroquel, hallucinogens, fentanyl, Demerol, dextromethorphan, propoxyphene, and a variety of street drugs. On-site dipstick urine testing is common, but some clinics will confirm the initial clinic screen via a reference laboratory. Many clinics test patients at intake to prove they used opioids recently. The continued use of heroin or other opioids may prompt an increase in the methadone dose because it’s common to supplement during withdrawal.

Retaining Patients in MMT: The longer the patient stays in MMT, the less likely he will revert to using opioids. Staying in MMT for more than a year is associated with constructive lifestyles changes, decreased criminal behavior, and less transmission of infectious diseases. Older patients and those not in the criminal justice system tend to stay in the program longer. Those who have tried it before and failed are better candidates for retention the next time around.

But the key to MMT success, as this HHS publication notes, is: Adequate individualized medication dosages are probably the most important factor in patient retention because they contribute to patient comfort and satisfaction by reducing withdrawal symptoms and craving. The serum half-life of methadone is stated to be 24 to 36 hours, but in reality there is an extremely wide range (13-58 hours). Excessive methadone use occurs when daily visits and individual dose adjustment are not made.

Take-Home Medication: Methadone is usually dispensed daily in a liquid form, and ingestion is witnessed. This keeps patients from diverting tablets. Methadone diversion is a huge problem in this country, but that methadone is usually not obtained from clinics. A single take-home dose is common on Sundays and holidays. After six months to a year, compliant and reliable patients can take home one to four weeks of methadone, but initially, doses are only dispensed daily at the clinic. The requirement to show up every day can be problematic.

Figure. Christine Ad…

Dosing Schedule: A dose of 30 mg to 40 mg of methadone is the upper limit for the initial dose, per regulation. Initial dosing should be followed by increases over subsequent days until withdrawal symptoms are suppressed. A steady state of a dose is not reached for three to five, sometime seven days after a dosage change. The goal is to reach 80 mg to 120 mg methadone per day, a level that has been proven to improve compliance to the program. Using smaller doses or failing to increase the dose when withdrawal is still present is ineffectual and counterproductive. Withdrawal often prompts exogenous drug use or elopement.

The actual schedule is not set in stone, but daily dose increases of 5 mg to 10 mg a day for the first five to seven days to reach 60 mg a day are common. The 60 mg per day dose is maintained under daily observation to reach a steady state. The first week or two of MMT are the most dangerous for the patient and the time during which most fatalities occur. With daily observation and individual dose adjustments, induction is safe and effective as long as the patient is truthful and abstains from other drugs.

The quoted serum half-life of methadone can be misleading, and provides only a rough estimate to forecast dosing requirements and effectiveness. Methadone is eliminated more quickly from the blood and the effects wear off sooner until sufficient levels are obtained to saturate tissues, especially the liver. Smokers have increased clearance, and significant liver damage slows clearance. The optimal dose can only be determined by observing the individual daily, debriefing him on how he feels, and altering dosages in a safe, effective manner.

There is no uniformly suitable dose range or limit for all patients. Some require 400 mg to 700 mg a day while others do well on 80 mg to 120 mg a day. During induction, clinical observation and patient symptoms are the best indicators of whether a dose is too small or large. When this protocol is followed, methadone induction is safe and effective.

Comment: There are eight MMT clinics in Philadelphia, usually for heroin addiction, but more frequently for prescription opioid addiction. Most opioid addicts know the concepts of MMT well, and visit various clinics off and on throughout their addiction. The rules of MMT are straightforward, and each state is allowed some latitude on various issues. Some addicts have learned to work or abuse the system, but MMT is a godsend, if not a true lifeline, for many opioid addicts.

Addiction to hydrocodone, hydromorphone, and oxycodone is likely more widespread than street heroin. There is little difference between the prescription pill addict and the hardcore street heroin user on everyday issues or potential benefit from MMT. The well-to-do business man, the bored housewife, the professional athlete, or the Hollywood celebrity seem to prefer pills over the needle. Some physicians readily prescribe a slew of addicting medications, prescriptions are stolen or altered, and anyone can buy a few Percocet at the local high school. The Internet provides drugs as well as directions on use and how to beat drug tests and avoid overdose. Of course, heroin can be smoked and snorted as well, but there is less of a stigma involved with popping a pill than buying a bag of heroin on a lonely street corner.

I am quite impressed with the understanding approach to MMT and the dedication of the clinic personnel. Methadone manufacturers stress that their product should be used only under strict HHS guidelines, and they actually reference the Federal Register code in the package insert. The dangers of inappropriate methadone use are well-reported in the literature, but it’s likely an underused drug for chronic pain control.

Society has written off many opioid addicts or would drop them in a heartbeat at any sign of deceit or additional drug use. Not so for MMT clinics; they bend over backwards to give everyone yet another chance. Using additional substances during MMT is very common. Klonopin, Xanax, Soma, and Seroquel are popular in my area to boost methadone’s high, and none show on a urine screen. It’s easy to buy any of these on the street, usually right outside the door of the clinic. It’s best to never underestimate the ingenuity or resourcefulness of an opioid addict so MMT works best in an environment of mutual trust and truthfulness. Lying to the counselor about past or present drug use or beating the drug test is tempting, but in the end, it can be a fatal error.

Buprenorphine interactions

Although there is significant confusion in the literature, buprenorphine is most commonly classified as a (partial) mu agonist/kappa antagonist. There is consensus that in the relatively ‘low doses’ used in clinical pain management, (5-100 mcg per hour), buprenorphine behaves like a ‚full‘ mu agonist. The partial agonist/antagonist effects seem only to become relevant for analgesia in very high doses used to treat opioid addiction (8-32 mg per day).

In patients on ‘analgesic doses’ of buprenorphine (eg transdermal), one can continue to use opioid analgesics for breakthrough pain in the usual way with good effect. The partial agonist/antagonist effect on supplemental opioid analgesia is not a major clinical issue. Other alternatives include sublingual buprenorphine or tramadol.

When treating acute pain after major surgery or trauma in patients on ‘high dose’ sublingual buprenorphine for addiction, continue the buprenorphine, using maximal multimodal analgesia including ketamine and neural blockade, supplemented with opioid PCA (using higher bolus doses) and monitoring the patient closely for adverse effects. In our experience, many patients undergoing major emergency surgery seem to do well with continuation of high dose sublingual buprenorphine and PCA fentanyl or morphine in appropriate doses. Conversion to standard opioids is complicated and often unnescessary.

Methadone interactions

Because methadone ‘saturates’ CYP450 (3A4) at low plasma levels (low hepatic clearance) compared with other opioids, it’s very ’susceptible‘ to;

  • The effects of a 30-fold variation in CYP450 enzyme activity between patients (fast, medium or slow methadone metabolisers), thus explaining the wide range of t1/2 (5-150 hours) and in part, highly variable clinical responses to methadone loading.
  • ‘Plasma accumulation‘, as the dose or frequency increases (the ’saturated‘ CYP450 can’t ‚burn off‘ the excess methadone):
  • Complex interactions with many drugs that share CYP450 for metabolism, particularly anticonvulsants, antidepressants, anti-microbial and antiretrovirals.

When prescribing methadone, always think about drug interactions at CYP450. Interactions are complex, with either induction (eg. phenytoin, rifamycins) or suppression (eg. fluvoxamine, fluoroquinalones, macrolides) of enzyme activity affecting methadone clearance, sometimes resulting in either withdrawal or accumulation respectively.

Methadone is highly-bound to plasma acute phase reactants (a1-acid glycoprotein), with the free methadone concentration decreasing when the level of phase reactants is raised (the free methadone is ‘mopped up’) such as in cancer or sepsis, leading to reduced analgesia or in rare cases withdrawal.

There are also substantial risks of over-sedation when methadone is combined with benzodiazepines, alcohol or THC.

Methadone, prolongs the QT interval in a dose dependent fashion (usually in doses greater than 200 mg per day) with case reports of Torsades de Pointes and VT. Check an ECG before commencing methadone, keep doses low and consider potential interaction with other drugs and conditions that prolong the QT interval.