Miscellaneous Methadone Facts : Emergency Medicine News

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Miscellaneous Methadone Facts

Roberts, James R. MD

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Emergency Medicine News 31(3):p 9-11, March 2009. | DOI: 10.1097/01.EEM.0000347243.16787.df

    Learning Objectives: After reading this article, the physician should be able to:

    1. Discuss the criteria required for a physician to be allowed to dispense methadone.
    2. Describe the pharmacokinetics of methadone.
    3. Explain the issues involved with long-term methadone maintenance.

    Release Date: March 2009

    Emergency physicians occasionally see patients taking methadone as maintenance therapy to combat heroin or other opioid addictions. The vagaries of methadone maintenance are somewhat of a mystery to clinicians not involved in addiction medicine, and few of us are cognizant of the finer points of interventions for opioid addiction or methadone programs.

    Opioid addicts don't fare well in the emergency medical system. Many nurses and physicians dislike them from the get-go, have problems dealing objectively with their medical problems, and certainly eschew involvement in their addiction issues. Drug-seeking is the behavior most of us have come to expect, but many addicts, particularly those motivated enough to be in methadone maintenance, do not spend their day trying to score Percocet from the ED by feigning pain or other bizarre conditions. The daily denizen of the ED for most of us is the part-time drug-seeker who wants to get high or supplement his income by selling prescribed Dilaudid on the street.

    These addicts are a crafty bunch. They spin yarns and suck you in with all sorts of sob stories, excuses, promises, and requests for a cornucopia of analgesics, muscle relaxants, and sedatives. Few clinicians have mastered the art of dealing with the subterfuge of these individuals, except with outright confrontation or a hastily orchestrated ED egress with the help of a burly security guard.

    Well-managed methadone maintenance is, however, a different story. Narcotic addiction has to be a horrendous lifestyle and a truly miserable existence. Methadone promises to make life bearable for this sad segment of the population. While few emergency physicians ever dole out methadone, methadone maintenance patients do show up in the ED with legitimate medical complaints. In addition, patients on high-dose methadone can experience painful conditions or injuries requiring additional analgesia. It is not easy, but if one can put aside preconceived notions about addiction and begin a productive medical encounter, methadone maintenance presents a fascinating challenge to the EP.

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

    Batki SL, et al

    U.S. Department of Health and Human Services

    www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat5.chapter.82676

    This prodigious HHS publication is a compendium of various opioid addiction and treatment issues. Opioid dependence is best reviewed as a chronic relapsing medical condition with substantial health and societal complications. In 1990, the National Institutes of Health explicitly rejected the widely held notion that opioid addiction is self-induced or simply a failure of willpower. The concept that opioid addicts bring it all on themselves and can get clean if only they wanted to stop getting high is an omnipresent bias in the general population shared by many enlightened medical personnel. In fact, opioid addiction results in complex neurobiological changes in cellular and molecular systems, resulting from repeated exposure to short-acting opioids and a vicious cycle of intoxication and withdrawal. The course of opioid addiction is as predictable a disease as hypertension and diabetes, and addictive behavior is quite characteristic. Long-acting opioids such as methadone stabilized these abnormalities.

    Methadone maintenance programs, currently termed medication-assisted treatment (MAT) for opioid addiction, have staunch advocates and equally fervent opponents. The concept of supplying one narcotic free of charge to discourage the use of another, thus substituting one addiction for another, is a difficult concept for many to accept. Equally difficult to accept is the concept that heroin addicts simply cannot stop using heroin on their own. Heroin is so addictive and the issues surrounding its continued use so complex that it is clearly naive to believe that abstinence is the answer. Once addicted, just saying no to heroin is nearly impossible.

    Opioid addiction is a treatable but often not curable disorder. First tried in earnest in the United States in 1988 (see the classic study by Dole: JAMA 1988;260[20]:3025), methadone maintenance has emerged with the pharmacologic rationale that long-term methadone maintenance relieves withdrawal and blocks heroin euphoria. This results in an opportunity for the heroin addict to attain and maintain psychosocial stabilization in an attempt to get his life together free from the ravages of having to score heroin three times a day by whatever means possible. Many patients maintain their methadone treatment for many years, and the goal is not always to become methadone-free. There is, however, about a 70 percent to 80 percent first-time failure rate, and returning to daily opioid abuse is a common scenario.

    MAT patients can function in society, but heroin addicts cannot. The reduced criminal activity associated with MAT versus heroin use is well recognized. There are no serious side effects associated with continued methadone use except perhaps for constipation, some drowsiness, and decreased sexual interest and performance. Women stabilized on methadone generally have uneventful pregnancies, something that cannot be said for heroin-addicted mothers. Although these newborns can experience opioid withdrawal, it is usually treated easily. There is no recognized cognitive impairment of children exposed to methadone in utero.

    While methadone is effective, rather large doses must be used, and attempting to maintain patients on lower doses can be one reason why treatment failures occur. Daily methadone doses of less than 60 mg are usually inadequate for most patients. While 5 mg to 10 mg of methadone may blunt the pain of cancer, it does little to thwart the craving for heroin. The current purity of street heroin is one reason high doses of methadone may be required. Of course, higher doses of street heroin also can increase the risk of toxicity if patients try to override methadone with elicit heroin use.

    MAT is under strict regulation by the U.S. Department of Health and Human Services, the Substance and Mental Health Services Administration (SAMSHA), and the Center for Substance Abuse Treatment (CSAT). One can Google these organizations, as well as “methadone” and the “Federal Register” to get oodles of information on all aspects of MAT.

    The pharmacology of methadone is well known, and kinetics are generally similar across the population. A subset of patients, likely impossible to prospectively identify or quantify, exhibit a wide range of metabolic clearance rates that may require serum level testing or trial and error to ferret out. The safety profile of methadone has been termed by these governmental organizations as “excellent when these drugs are taken as directed by the manufacturer.” There are a few diverse factors affecting the pharmacologic effect of methadone, most of which cannot be quantified, tested, or anticipated. Metabolism varies, sometimes significantly so, based on genetics, chronic diseases, drug interactions, and individual response. There are fast as well as slow metabolizers.

    Most take methadone once a day; some require twice-a-day dosing. Available in liquid, diskette, IM, and powder, most MAT centers use the liquid and witnessed swallowing to avoid diversion. Because methadone is metabolized in the liver by the CPY450 enzyme system, both the health of the liver and the use of drugs that inhibit or induce enzyme activity theoretically result in changes in methadone kinetics. The true clinical relevance of many proposed drug interactions is unclear. Little real data are available, and many theoretical discussions are put forth, but trial and error with dosing and occasionally serum blood level testing help sort out the vagaries. As might be intuited, more than half of heroin addicts entering a methadone maintenance clinic have some type of chronic liver disease, usually from alcohol or hepatitis.

    Tobacco smoking, chronic ethanol use, phenytoin, rifampin, barbiturates, and carbamazepine may decrease methadone levels by inducing the CYP450 enzyme activity (especially CYP3A4, but perhaps up to five isoforms). Interestingly, methadone can initially enhance its own hepatic clearance. Antibiotics (but not azithromycin), antifungals, amitriptyline, and cimetidine (and perhaps some SSRIs) inhibit CYP3A4, and can theoretically elevate serum methadone levels. The true clinical consequence of such drug interactions are vague and difficult to quantify. Of course, concomitant alcohol, benzodiazepines, and other opioids potentiate methadone's clinical effects.

    While some patients attempt at withdrawal from MAT after a year or two, it is not uncommon for many patients to remain in treatment for five to 10 years or even a lifetime. Early termination increases illicit drug use, not only heroin but cocaine and alcohol. Even while patients are maintained on methadone, 20 to 50 percent will use cocaine or alcohol or other street or prescription drugs.

    Recent legislation allows patients to take methadone home in a two- to four-week supply after demonstrating good behavior for a year or two, but initially all dosing is daily, with a single take-home dose for holidays. Diversion of take-home methadone remains a significant issue for many methadone maintenance programs.

    Individuals using heroin experience a brief intense high that lasts for three to six hours, remain in a comfort zone for a few hours, and then begin withdrawal at eight to 12 hours. Withdrawal is called “being sick” in the heroin community, and such patients are so sick that they cannot avoid using heroin again, and so need to use heroin two or three times a day. The benefit of methadone is that it maintains the patient in the comfort zone throughout the day.

    It may take four to five half-lives of methadone to obtain this comfort level, and dosing regimens are challenging to achieve. The maximum dosing per federal guidelines is 30 mg to 40 mg per day to start. The half-life of methadone is about 24 to 36 hours, and it generally takes four to five half-lives of any given medication to maintain a steady serum concentration. Because of a long half-life, serum levels from any given dose may increase daily, even without an increase in dose.

    At three to five days (give or take a few days), the rate of increase of methadone blood concentrations levels off with constant dosing, and a steady serum level is achieved. Patients may experience withdrawal before the steady state is achieved, however, so some early manipulation of the dosing based on the clinician's experience is acceptable and actually prudent to avoid supplemental heroin use, withdrawal, or elopement from the program. The opioid addict knows a lot about drugs, usually has ready access, and simply cannot always resist supplementing his habit during the induction phase. Using minimal methadone doses to start can be counterproductive.

    Addicts may exaggerate their street drug use to get more methadone right off the bat fearing withdrawal if they don't get enough. Induction is a tricky time for the nascent methadone patient. The patient must be squeaky clean, motivated, totally honest with the prescriber, adhere assiduously to dosing regimens, and eschew the drugs, alcohol, and other bad habits on which he has become dependent. MAT patients are told to avoid all medications, even over-the-counter drugs and herbal medicines, but this may fall on deaf ears during induction. Self-medication for methadone-inspired GI upset with cimetidine, for example, can decrease methadone clearance.

    Doses are increased slowly, usually by 5 mg to 10 mg every three to five days, but there is wide individual variation. The paramount goal is to keep the new recruit out of withdrawal and in the program. Although it often requires 80 mg to 120 mg of methadone to maintain an addict in remission, there is no absolute maximum dose. Doses of 150 mg to 200 mg are not unusual, and up to an amazing 500 mg to 700 mg a day have been reported as necessary to be effective in reducing heroin use. (Mt Sinai J Med 2000;67[5–6]404.) The proper dose of methadone is “enough.” Peak or trough serum levels can help manage withdrawal and dosing.

    Opiate-positive urine tests (a sign of heroin use because methadone does not register as an opiate) decreases dramatically as the dose of methadone is raised. One study found that methadone doses as high as 100 mg a day demonstrated 87 percent continued heroin use. This decreased to three percent with a mean dose of 211 mg a day (range 120–780 mg a day!). (Mt Sinai J Med 2000;67[5–6]404.) Small doses of methadone simply don't work in most patients. It can be tricky to maintain the desired response while juggling the dose to safety and effectiveness. Medical evaluation of objective signs and subjective symptoms are the most sensitive and reliable methods of dose titration. (J Psychoactive Drugs 1999;31[2]:95.)

    Methadone exists in both L-isomer and D-isomer, and the L-methadone has up to 50 times more analgesic properties than the D-isomer and much more potential to produce respiratory depression. Methadone is about 90% protein-bound, and cannot be dialyzed. The high potency of street heroin in today's market has caused methadone programs to increase their dosing regimens accordingly. Methadone levels are not significantly altered by two to four alcoholic drinks per day, and methadone kinetics are relatively normal in patients with mild to moderate liver impairment.

    Methadone deaths are rare in individuals who have access to methadone dispensed through treatment programs, but the table identifies some risk scenarios that have been identified by SAMHSA. Most deaths occur within the first few weeks, and although attributed to “toxic effects of methadone” by the unenlightened medical examiner, sudden deaths often remain largely unexplained. Fentanyl, a popular street drug, for example, will not be found in most autopsies. Death and methadone in the serum (note that methadone isomers are never quantified) does not necessarily identify methadone as a lethal culprit.

    Psychotherapeutic Benefits of Opioid Agonist Therapy

    Tenore PL

    J Addict Dis

    2008;27(3):49

    Opium has been used for centuries, even as early as 3400 BC when poppy cultivation yielded opium to treat anxiety and depression and induce euphoria. Hippocrates prescribed opium for a variety of conditions, and it was widely used as a successful treatment for refractory depression in the 19th century. With the development of nonopioid medications to treat depression and anxiety and with the omnipresent problems surrounding opioid addiction (especially after the Vietnam War), opioids have been legally available only for treating pain.

    Methadone works on the pleasure-reward centers of the brain, at mesolimbic dopaminergic neurons in the obscure limbic system, by generating a variety of effects similar to pituitary endorphins that bind the mu opioid receptors throughout the CNS. Dopamine is released in the CNS, translating into pleasure, reward, and euphoria. Lack of dopamine (akin to lower endorphin levels) leads to anhedonia (inability to experience pleasure) and depressive symptoms. Many antidepressants act by increasing dopamine levels, and dopamine is good for the psyche.

    Interestingly, the number of endorphin receptors increases in depression, yet with no matching increase in endorphin levels and a resultant low dopamine milieu. Opiates act as endorphins to saturate the endorphin receptors to restore well-being and mitigate depression. Very favorable antidepressant effects can be attributed to methadone and other opiates. Methadone is, in fact, a highly effective antidepressant medication, possibly explaining the incessant quest for Percocet, Dilaudid, morphine, and of course, heroin. Simply stated, methadone exerts potent positive therapeutic effects on mood. This is the proposed mechanism of the “opium cure” for depression.

    In addition to the endorphin-dopamine psychotherapeutic mechanisms of opioids, methadone has favorable effects on serotonin, catecholamines, corticosteroids, glutamate and the NMDA system, all essential to mood regulation. Methadone actually possesses selective serotonin reuptake inhibitor (SSRI) properties, and raises brain serotonin levels. Methadone may have been the first Prozac, and acts like TCAs and MAO inhibitors. The SSRI effect of methadone has been linked to its antidepressant effect, and many MAT depressed patients are concomitantly treated with SSRIs. Dually diagnosed patients do well with higher doses of methadone and SSRI supplementation. Synthetic opioids, such as Demerol, Tramadol, dextromethorphan, and propoxyphene also have SSRI effects. None of these drugs should be used in patients taking MAO inhibitors.

    NMDA receptors are located throughout the brain, and are stimulated by the brain's major excitatory neurotransmitter, glutamate. NMDA receptors account for modulation of learning, memory, excitation, and pain regulation as well as playing a major role in mood regulation. NMDA receptors stimulation makes you feel depressed via an antiserotonin effect. Methadone is an NMDA antagonist; the drug blocks NMDA-mediated depression. Methadone causes a marked decrease in NMDA receptor activity, even more so than morphine. It is this characteristic of methadone that makes it attractive to patients with depression and drug addiction. In fact, populations maintained on methadone have a higher retention rate when they have a dual diagnosis of a psychiatric condition and drug abuse. Higher doses of methadone, however, may be required to stabilize dually diagnosed patients.

    To reiterate, the best methadone dose is one that stops heroin use and helps stabilize psychiatric disease. Methadone has been shown to exert beneficial psychiatric effects, but SSRIs also are often used in patients with dual diagnosis disorders.

    Rationale for Methadone Maintenance to Treat Opioid Addiction

    Methadone treatment not only blunts heroin craving and prevents withdrawal, but is partly corrective, normalizing neurological and endocrinologic processes in patients whose endogenous ligand-receptor function has been deranged by long-term use of powerful narcotic drugs. Why some persons who are exposed to narcotics are more susceptible than others to this derangement and whether long-term addicts can recover normal function without maintenance therapy are questions for the future.

    At present, the most that can be said is that there seems to be a specific neurological basis for the compulsive use of heroin by addicts and that methadone taken in optimal doses can correct the disorder. Some of these positive effects in patients with opioid addiction and psychiatric disease, such as depression, can be related to the SSRI-TCA-MAOI-like effects of methadone on the CNS, and methadone clearly increases CNS serotonin levels.

    Source: Tenore PL. J Addict Dis 2008;27(3):49.

    Potential Adverse Effects from Methadone Prescribed by Methadone Maintenance Treatment (MMT) Programs

    MMT is extremely safe when administered following standard guidelines. Death and morbidity may be erroneously attributed to methadone by simple temporal relationships. Serum methadone levels cannot be interpreted scientifically in the tolerant addict. A plethora of unidentified variables (such as cardiomyopathy/arrhythmia), other potent synergistic drugs that cannot be measured (such as fentanyl), and comorbidity also contribute to side effects.

    • ▪ The accumulation of methadone to toxic levels during the start of opioid treatment or pain management caused by an overestimation of tolerance and methadone's long and often variable half-life.
    • ▪ The misuse of diverted methadone by individuals with little or no opioid tolerance who may have taken excessive doses in an attempt to achieve euphoric effects.
    • ▪ The synergistic effects of methadone in combination with other central nervous system depressants (alcohol, benzodiazepines, or other prescription opioids) among individuals with little or no tolerance.

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