In vitro results suggest that methadone undergoes hepatic
N-demethylation by cytochrome P450 enzymes, principally CYP3A4, CYP2B6,
CYP2C19, and to a lesser extent by CYP2C9 and 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 CYP
inhibitors may reduce metabolism and potentiate methadone's effects. Although
antiretroviral drugs such as efavirenz, nelfinavir, nevirapine, ritonavir,
lopinavir+ritonavir combination are known to inhibit CYPs, they are shown to
reduce the plasma levels of methadone, possibly due to their CYP induction
activity. 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 Partial
As with other mu-agonists, patients maintained on
methadone may experience withdrawal symptoms when given opioid antagonists,
mixed agonist/antagonists, and partial agonists. Examples of such agents are
naloxone, naltrexone, pentazocine, nalbuphine, butorphanol, and buprenorphine.
Abacavir, amprenavir, efavirenz, nelfinavir, nevirapine,
ritonavir, lopinavir+ritonavir combination
Coadministration of these antiretroviral agents resulted
in increased clearance or decreased plasma levels of methadone.
Methadone-maintained patients beginning treatment with these antiretroviral
drugs should be monitored for evidence of withdrawal effects and methadone dose
should be adjusted accordingly.
Didanosine And Stavudine
Experimental evidence demonstrated that methadone
decreased the area under the concentration-time curve (AUC) and peak levels for
didanosine and stavudine, with a more significant decrease for didanosine.
Methadone disposition was not substantially altered.
Experimental evidence demonstrated that methadone
increased the AUC of zidovudine which could result in toxic effects.
Cytochrome P450 Inducers
Methadone-maintained patients beginning treatment with
CYP3A4 inducers should be monitored for evidence of withdrawal effects and
methadone dose should be adjusted accordingly. 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 a marked reduction in serum methadone
levels and a 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 to 4 days) resulted in an approximately 50%
reduction in methadone exposure and withdrawal symptoms occurred concurrently.
Upon discontinuation of phenytoin, the incidence of withdrawal symptoms
decreased and methadone exposure increased to a level comparable to that prior
to phenytoin administration.
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 primarily
by 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, methadone-treated patients coadministered
strong inhibitors of CYP3A4, such as azole antifungal agents (e.g.,
ketoconazole) and macrolide antibiotics (e.g., erythromycin), with methadone
should be carefully monitored and dosage adjustment should be undertaken if
warranted. Some selective serotonin reuptake inhibitors (SSRIs) (e.g.,
sertraline, fluvoxamine) may increase methadone plasma levels upon
coadministration with methadone and result in increased opiate effects and/or
Repeat dose administration of oral voriconazole (400 mg
Q12h for 1 day, then 200 mg Q12h for 4 days) increased the Cmax and AUC of
(R)-methadone by 31% and 47%, respectively, in subjects receiving a methadone
maintenance dose (30 to 100 mg QD). The Cmax and AUC of (S)-methadone increased
by 65% and 103%, respectively. Increased plasma concentrations of methadone
have been associated with toxicity including QT prolongation. Frequent monitoring
for adverse events and toxicity related to methadone is recommended during
coadministration. Dose reduction of methadone may be needed.
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. However, if the use of methadone is
necessary in such patients, a sensitivity test should be performed in which
repeated small, incremental doses of methadone are administered over the course
of several hours while the patient's condition and vital signs are under careful
PBlood levels of desipramine have increased with
concurrent methadone administration.
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
Caution should also be exercised when treating methadone
patients concomitantly with drugs capable of inducing electrolyte disturbances
(hypomagnesemia, hypokalemia) that may prolong the QT interval. These drugs
include diuretics, laxatives, and, in rare cases, mineralocorticoid hormones.
Interactions With Alcohol And Drugs Of Abuse
Methadone may be expected to have additive effects when
used in conjunction with alcohol, other opioids or CNS depressants, or with
illicit drugs that cause central nervous system depression. Deaths have been
reported when methadone has been abused in conjunction with benzodiazepines.
Since methadone as used by tolerant patients at a
constant maintenance dosage does not act as a tranquilizer, patients will react
to life problems and stresses with the same symptoms of anxiety as do other
individuals. The physician should not confuse such symptoms with those of
narcotic abstinence and should not attempt to treat anxiety by increasing the
dose of methadone. The action of methadone in maintenance treatment is limited
to the control of narcotic withdrawal symptoms and is ineffective for relief of
Patients in methadone maintenance treatment for opioid
dependence who experience physical trauma, postoperative pain or other acute
pain cannot be expected to derive analgesia from their existing dose of
methadone. Such patients should be administered analgesics, including opioids,
in doses that would otherwise be indicated for non-methadone-treated patients
with similar painful conditions. 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 non-tolerant patients.
Physical dependence is manifested by withdrawal symptoms
after abrupt discontinuation of a drug or upon administration of an antagonist.
Physical dependence is expected during opioid agonist therapy of opioid
If a physically dependent patient abruptly discontinues
use of methadone, or the dose of methadone does not adequately “cover” the
patient, an opioid abstinence or withdrawal syndrome may develop and is characterized
by some or all of the following: restlessness, lacrimation, rhinorrhea,
yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms may also
develop, including irritability, anxiety, backache, joint pain, weakness,
abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased
blood pressure, respiratory rate, or heart rate.
Infants born to mothers physically dependent on opioids
may also be physically dependent and may exhibit respiratory difficulties and
withdrawal symptoms (see PRECAUTIONS : Pregnancy, Labor and Delivery).
In general, opioids should not be abruptly discontinued
(see DOSAGE AND ADMINISTRATION: For Medically Supervised Withdrawal
After a Period of Maintenance Treatment).
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
should be observed and the possibility of respiratory depression requires added