Drugs and Human Performance FACT SHEETS -Methadone

Source: Methadone is a synthetic narcotic analgesic and is a schedule II controlled substance. Methadone is available by prescription as oral solutions (1-2 mg/mL strength), tablets (5-10 mg), dispersible tablets (40 mg), or injectable solutions (10 mg/mL).

Drug Class: Narcotic analgesic.

Medical and Recreational Uses: Methadone is an analgesic prescribed for the relief of moderate to severe pain, and is used in detoxification treatment of opioid dependence and maintenance in narcotic addiction. Compared to morphine, methadone has a much longer duration of action, suppressing opiate withdrawal symptoms and remaining efficacious for an extended period of time with repeated administration. Recreationally, methadone is abused for its sedative and analgesic effects.

Potency, Purity and Dose: Available as the racemic mixture, (R)- or l -methadone is

8-50 times more potent than the (S)- or d-isomer. For relief of severe acute pain the usual adult dose is 2.5-10 mg every 3-4 hours. For methadone maintenance the daily dose is generally 60-80 mg, but can vary from 30-120 mg. For detoxification treatment an initial oral dose of 15-20 mg is administered, with an additional dose if withdrawal symptoms are not suppressed; a stabilizing dose of 40 mg in single or divided dosages is prescribed for 2-3 weeks, then the dose is gradually decreased. Concurrent use of other prescription medication is common.

Route of Administration: Oral ingestion, intravenous, intramuscular or subcutaneous injection.

Pharmacodynamics: Methadone is a long acting m opioid receptor agonist with potent central analgesic, sedative, and antitussive actions. Methadone inhibits ascending pain pathways, alters perception of and response to pain (dissociative effect), and produces generalized CNS depression. Respiratory depression also occurs due to complete blockade of respiratory centers to pCO 2. (S)-Methadone lacks significant respiratory depressive action and addiction liability.

Pharmacokinetics: When administered orally, methadone is rapidly absorbed from the gastrointestinal tract and can be detected in the blood within 30 minutes. Oral bioavailability varies from 41-99% and plasma protein binding is 60-90%. After repeated administration there is gradual accumulation in tissues. As for most lipid soluble drugs, a large between and within subject variability is observed. The half-life of (R,S)-methadone is 15-60 hours, and 10-40 hours for (R)-methadone. Methadone undergoes extensive biotransformation in the liver primarily to two inactive metabolites,

2-ethylidene-1.5-dimethyl-3.3diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline (EMDP), through N-demethylation and cyclization. These are eliminated by the kidney and excreted through the bile. In total, nine metabolites have been identified including two minor active metabolites, methadol and normethadol.

Molecular Interactions / Receptor Chemistry: Methadone is metabolized to EDDP via the cytochrome P450 CYP3A4 isoform. Potential inhibitors of this isoform could decrease the rate of methadone elimination if administered concurrently, while potential inducers could increase the rate of elimination. Methadone itself inhibits cytochrome P450 2D6 isoform.

Blood to Plasma Concentration Ratio: 0.75 and 0.77 reported.

Interpretation of Blood Concentrations: Methadone can be detected in plasma within 30 minutes following oral ingestion, reaching a peak concentration at ~4 hours. Mean EDDP concentration are ~15% that of methadone. There is often a large overlap between reported therapeutic (0.03-0.56 mg/L) and fatal concentrations (0.06-3.1 mg/L). Peak serum concentrations following a single oral dose of 15 mg were 0.075 mg/L, 0.86 mg/L for 100 mg, and 0.83 mg/L for 120 mg ; all at 4 hours. Chronic oral administration of 100-200 mg to tolerant subjects produced average peak plasma concentrations of 0.83 mg/L at 4 hours, decreasing to 0.46 mg/L at 24 hours. Peak plasma methadone concentrations of 0.034 mg/L were obtained at 50 minutes following intramuscular injection of 10 mg, while intravenous administration of 10 mg produced concentrations of 0.096 mg/L at 34 minutes. Concentrations greater than 0.10 mg/L are required for prevention of opiate withdrawal symptoms. In cancer patients treated for pain relief and sedation, methadone concentrations were 0.35 ± 0.18 mg/L.

Interpretation of Urine Test Results: The percentage of a dose excreted in the urine as unchanged methadone and EDDP will vary with the pH of the urine. Urinary excretion of unchanged parent drug is 5-50% and EDDP 3-25%. It may be possible to use excretion data to monitor individuals’ compliance in a methadone program after establishing their intraindividual variation in excretion patterns through long-term monitoring.

Effects:

Psychological: Drowsiness, sedation, dizziness, lightheadedness, mood swings (euphoria to dysphoria), depressed reflexes, altered sensory perception, stupor, and coma.

Physiological: Strong analgesia, headache, dry mouth, facial flushing, nausea, constipation, respiratory depression, muscle flaccidity, pupil constriction, and decreased heart rate.

Duration of Effects: Onset of analgesia occurs 10-20 minutes following parenteral administration and 30-60 minutes after oral administration. Oral administration results in a delay in onset, lower peak concentration and longer duration of action. Following single oral doses effects may last 6-8 hours, increasing to 22-48 hours in cases of chronic administration.

Side Effect Profile: Sedation, alteration in cognitive and sensory efficiency, respiratory depression, nausea, vomiting, headache, constipation, urinary retention, sweating, sleep disorders, and concentration disorders. Infrequent side effects include urticaria, hypersensitivity reaction, shock, and pulmonary edema. Overdose can include slow, shallow breathing, respiratory depression, clammy skin, convulsions, extreme somnolence, apnea, circulatory collapse, cardiac arrest, coma, and possible death.

Tolerance, Dependence and Withdrawal Effects: Upon repeated administration, tolerance may develop to the nauseant, miotic, sedative, respiratory depressant, and cardiovascular effects of methadone. Tolerance develops more slowly to methadone than to morphine in some patients. Methadone can produce physiological and psychological drug dependence of the morphine type, and has the potential for being abused. Withdrawal symptoms are similar to those of other opioids but are less severe, slower in onset, and last longer. Symptoms include watery eyes, runny nose, nausea, loss of appetite, diarrhea, cramps, muscle aches, dysphoria, restlessness, irritability, anxiety, pupillary dilation, piloerection, tremors, chills, sweating, increased sensitivity to pain, insomnia, and tachycardia.

Drug Interactions: There is additive CNS depressive effects with concurrent use of sedatives, hypnotics, tranquilizers, other narcotic analgesics, tricyclic antidepressants, alcohol and other CNS depressant drugs, resulting in exaggerated respiratory depression and sedation. Methadone can potentiate the deleterious effects of alcohol. Pentazocine, nalbuphine, butorphanol and buprenorphine are partial agonists and will behave as antagonists in the presence of methadone, resulting in the precipitation of withdrawal symptoms. Rifampin reduces blood concentrations of methadone and may lead to withdrawal. Blood levels of desipramine have increased with concurrent methadone therapy.

Performance Effects: In general, laboratory studies have shown that non-tolerant individuals receiving single doses of methadone have produced dose-dependent reductions in reaction time, visual acuity, information processing, and sedation. Significant psychomotor impairments are seldom evident when tolerant subjects have been tested, including performance deficits in reaction time, attention, and peripheral vision. In the majority of experimental clinical trials, psychophysical performance tests have yielded the same results for methadone substitution patients as for control groups. However, variable results have been observed. Attention and perception tasks have been impaired in methadone maintenance patients, but sociodemographic factors may have played a role. In patients receiving 35-85 mg methadone daily, significant impairment was measured on attention, perception and learning tasks but there was no reaction time deficit. In patients receiving a daily average of 63 mg methadone, significant impairment in distance perception, attention span and time perception was observed. No significant adverse effects were measured with addicts stabilized for at least 1 year on daily oral doses of methadone.

Effects on Driving: The drug manufacturer cautions that methadone may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, and that the sedative effects of the drug may be enhanced by concurrent use of other CNS depressants, including alcohol. In healthy, non-methadone using volunteers, single doses of methadone will impair driving ability. Numerous European studies of long-term methadone maintenance patients have shown that appropriately administered methadone does not cause significant psychomotor or cognitive impairment when administered regularly and when the subject abstains from all other drugs. However, in the majority of cases, patients did not exhibit stable abstinence from drug use and had an increased occurrence of simultaneous psychiatric/neurotic disorders or personality disturbances which, by themselves, could be a reason to doubt their driving ability. In Germany, the Joint Advisory Council for Traffic Medicine at the Federal Ministry of Transport, Building and Housing and the Federal Ministry for Health issued the following recommendation: Heroin addicts treated with methadone are generally not fit to drive; however, these patients may be considered fit to drive if they show a period of methadone substitution for more than a year; stable psychosocial integration; no evidence of the consumption of additional psychotropic substances; evidence of a subject’s readiness to feel responsible for himself/herself; therapy compliance; and no evidence of serious personality defects.

DEC Category: Narcotic Analgesic.

DEC Profile: Horizontal gaze nystagmus not present; vertical gaze nystagmus not present; lack of convergence not present; pupil size constricted; little to no reaction to light; pulse rate down; blood pressure down; body temperature down. Other characteristic indicators may include muscle tone flaccidity, droopy eyelids, drowsiness, depressed reflexes, and dry mouth.

Panel’s Assessment of Driving Risks: Moderate to severely impairing in naïve or non-tolerant individuals, causing dose-dependent reductions in reaction time, visual acuity and information processing. Significant psychomotor impairment is not expected in tolerant individuals. Driving ability and driving fitness are nevertheless often limited because of consumption of additional psychotropic substances and psychopathological findings.

References and Recommended Reading:

Baselt RC. Drug effects on psychomotor performance. Biomedical Publications, Foster City, CA; pp 241-243;2001.

Berghaus G, Staak M, Glazinski R, Höher K, Joó S, Friedel B. Complementary empirical study on the driver fitness of methadone substitution patients. In: Alcohol, Drugs and Traffic Safety, T92, Verlag TÜV Rheinland GmbH Köln 1993; 120-26.

Chesher GB. Understanding the opioid analgesics and their effect on driving performance. Alcohol, Drugs & Driving 1989;5:111-38.

Felder C, Uehlinger C, Baumann P, Powell K, Eap CB. Oral and intravenous methadone use: some clinical and pharmacokinetic aspects. Drug & Alcohol Dependence 1999;55:137-43.

Friedel B, Berghaus G. Methadone and driving. In: Alcohol, Drugs and Traffic Safety T95. Proceedings of the 13th International Conference on Alcohol, Drugs and Traffic Safety, Adelaide, August 1995, 307-10.

Gordon AM, Friel P, Logan BK. Methadone findings in drivers and post mortem cases in Washington state. Presented at the Society of Forensic Toxicologist annual meeting, New Orleans LA, 2001.

Gordon NB, Appel PW. Functional potential of the methadone-maintained person. Alcohol, Drugs & Driving 1995;11:31-7.

Hauri-Bionda R, Bar W, Friedrich-Koch A. Driving fitness/driving capacity of patients treated with methadone. Schweiz Med Wochenschr 1998;128(41):1538-47.

Inturrisi CE, Verebely K. The levels of methadone in plasma in methadone maintenance. Clin Pharmac Ther 1972;13:633-7.

Joó S. Methadone substitution and driver ability: Research findings and conclusions from a discussion of experts. J Traffic Med 1994;22:101-3.

Physicians’ Desk Reference, Medical Economics Company, Montvale, NJ, 2002.