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Carisoprodol (and Meprobamate)
Gamma-Hydroxybutyrate (GHB, GBL,
Lysergic acid diethylamide (LSD)
Methamphetamine (and Amphetamine)
Morphine (and Heroin)
Zolpidem (and Zaleplon, Zopiclone)
Biographical Sketches of Lead
Authors and Main Contributors
Methadone hydrochloride is a white crystalline powder or colorless
crystals. Available primarily in tablet or liquid form.
Dolophine® Hydrochloride, Methadose®, Methadone Hydrochloride
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
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
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.
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
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.