In vitro results indicate that methadone undergoes
hepatic N-demethylation by cytochrome P450 enzymes, principally CYP3A4, and to
a lesser extent CYP2D6. Coadministration of methadone with inducers of these
enzymes may result in a more rapid metabolism and potential for decreased
effects of methadone, whereas administration with inhibitors may reduce
metabolism and potentiate methadone's effects. Therefore, drugs administered
concomitantly with methadone should be evaluated for interaction potential;
clinicians are advised to evaluate individual response to drug therapy.
Opioid antagonists, mixed agonist/antagonists, and
As with other μ-agonists, patients maintained on
methadone may experience withdrawal symptoms when given these agents. Examples
of such agents are naloxone, naltrexone, pentazocine, nalbuphine, butorphanol,
Based on the known metabolism of methadone, nevirapine
may decrease plasma concentrations of methadone by increasing its hepatic
metabolism. Opioid withdrawal syndrome has been reported in patients treated
with nevirapine and methadone concomitantly. Methadone-maintained patients
beginning nevirapine therapy should be monitored for evidence of withdrawal and
methadone dose should be adjusted accordingly.
Coadministration of efavirenz in HIV-infected
methadone-maintenance patients has resulted in decreased methadone plasma
concentrations of methadone associated with signs of opiod withdrawal, and necessitating
increases in methadone dose.
Ritonavir and Ritonavir/Lopinavir
Reduced plasma methadone levels have been observed after
administration of ritonavir alone or ritonavir/lopinavir combination.
Withdrawal symptoms were however, inconsistently observed. Caution is warranted
when administering methadone to patients receiving ritonavir-containing
regimens in addition to other drugs known to decrease methadone plasma levels.
Experimental evidence suggests that methadone increases
the area under the concentration-time curve (AUC) of zidovudine with possible
Didanosine and Stavudine
Experimental evidence suggests that methadone decreased
the AUC and peak levels for didanosine and stavudine, with a more significant
decrease for didanosine. Methadone disposition was not substantially altered.
Cytochrome P450 Inducers
The following drug interactions were reported following
coadministration of methadone with inducers of cytochrome P450 enzymes.
In patients well-stabilized on methadone, concomitant
administration of rifampin resulted in marked reduction in serum methadone
levels and concurrent appearance of withdrawal symptoms.
In a pharmacokinetic study with patients on methadone
maintenance therapy, phenytoin administration (250 mg b.i.d initially for 1 day
followed by 300 mg QD for 3-4 days) resulted in ~50% reduction in methadone
exposure and concurrently withdrawal symptoms occurred. Upon discontinuation of
phenytoin, the incidence of withdrawal symptoms decreased and the methadone
exposure increased and was comparable to pre-phenytoin dose scenario.
St. John's Wort, Phenobarbital, Carbamazepine
Administration of methadone along with other CYP3A4
inducers may result in withdrawal symptoms
Cytochrome P450 inhibitors
Since the metabolism of methadone is mediated by the
CYP3A4 isozyme, coadministration of drugs that inhibit CYP3A4 activity may
cause decreased clearance of methadone. The expected clinical results would be
increased or prolonged opioid effects. Thus patients coadministered with
inhibitors of CYP3A4 such as azole antifungal agents (e.g., ketoconazole),
macrolide antibiotics (e.g., erythromycin), while receiving methadone should be
carefully monitored and dosage adjustment made if warranted. Some selective
serotonin reuptake inhibitors (SSRI's) (i.e., sertraline, fluvoxamine) upon coadministration
may increase methadone plasma levels and result in increased opiate effects or toxicity.
Monoamine Oxidase (MAO) Inhibitors
Therapeutic doses of meperidine have precipitated severe
reactions in patients concurrently receiving monoamine oxidase inhibitors or
those who have received such agents within 14 days. Similar reactions thus far
have not been reported with methadone; but if the use of methadone is necessary
in such patients, a sensitivity test should be performed in which repeated
small incremental doses are administered over the course of several hours while
the patient's condition and vital signs are under careful observation.
Blood levels of desipramine have increased with
concurrent methadone therapy.
Potentially Arrhythmogenic Agents
Extreme caution is necessary when any drug known to have
the potential to prolong the QT interval is prescribed in conjunction with
methadone. Pharmacodynamic interactions may occur with concomitant use of
methadone and potentially arrhythmogenic agents such as class I and III
antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium
channel blockers. Caution should also be exercised when prescribing concomitant
drugs capable of inducing electrolyte disturbances that may prolong the QT
interval (hypomagnesemia, hypokalemia). These include diuretics, laxatives, and
in rare cases mineralocorticoid hormones.
Interactions with other CNS Depressants
Patients receiving other opioid analgesics, general
anesthetics, phenothiazines, other tranquilizers, sedatives, hypnotics, or
other CNS depressants (including alcohol) concomitantly with methadone may experience
respiratory depression, hypotension, profound sedation, or coma.
Use with Mixed Agonist/Antagonist Opioid Analgesics
Agonist/antagonist analgesics (i.e., pentazocine,
nalbuphine, butorphanol, or buprenorphine) should not be administered to
patients who have received or are receiving a course of therapy with a pure
opioid agonist, such as Methadone Hydrochloride Injection. In this situation,
mixed agonist/antagonist analgesics may reduce the analgesic effect of
Methadone Hydrochloride Injection and/or may precipitate withdrawal symptoms.
Methadone, used by tolerant patients at a constant
maintenance dosage, is not a tranquilizer. Patients who are maintained on this
drug will react to life problems and stresses as do other individuals. Anxiety
in a patient on methadone should not be confused with narcotic abstinence and
should not prompt treatment by increasing the dosage of methadone. The action
of methadone in maintenance treatment is limited to the control of symptoms of
opioid dependence or pain. Methadone is ineffective for relief of general anxiety.
Maintenance patients on a stable dose of methadone who
experience physical trauma, postoperative pain or other causes of acute pain cannot
be expected to derive analgesia from their stable dose of methadone regimens.
Such patients should be given analgesics, including opioids, that would be indicated
in other patients experiencing similar nociceptive stimulation. Due to the
opioid tolerance induced by methadone, when opioids are required for management
of acute pain in methadone patients, somewhat higher and/or more frequent doses
will often be required than would be the case for other, non-tolerant patients.
Risk Of Relapse In Patients On Methadone Maintenance
Treatment Of Opioid Addiction
Abrupt opioid discontinuation can lead to development of
opioid withdrawal symptoms (see PRECAUTIONS). Presentation of these
symptoms has been associated with an increased risk of susceptible patients to
relapse to illicit drug use and should be considered when assessing the risks
and benefit of methadone use.
Tolerance And Physical Dependence
Tolerance is the need for increasing doses of opioids to
maintain a defined effect such as analgesia (in the absence of disease
progression or other external factors). Physical dependence is manifested by withdrawal
symptoms after abrupt discontinuation of a drug or upon administration of an
antagonist. Physical dependence and/or tolerance are not unusual during chronic
If methadone is abruptly discontinued in a physically
dependent patient, an abstinence syndrome may occur. The opioid abstinence or
withdrawal syndrome is characterized by some or all of the following: restlessness,
lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis.
Other symptoms also may develop, including: irritability, anxiety, backache,
joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting,
diarrhea, or increased blood pressure, respiratory rate, or heart rate.
In general, chronically administered methadone should not
be abruptly discontinued.
Methadone should be given with caution and the initial
dose reduced in certain patients, such as the elderly and debilitated and those
with severe impairment of hepatic or renal function, hypothyroidism, Addison's
disease, prostatic hypertrophy, or urethral stricture. The usual precautions
appropriate to the use of parenteral opioids should be observed and the
possibility of respiratory depression should always be kept in mind.