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 CYP 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 methadones 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 Agonists
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 anti-retroviral agents resulted in increased
clearance or decreased plasma levels of methadone. Phenadone-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 AUC and peak levels for didanosine and stavudine, with a more
significant decrease for didanosine. Phenadone disposition was not substantially
Zidovudine - Experimental evidence demonstrated that methadone increased the
area under the concentration-time curve (AUC) of zidovudine which could result
in toxic effects.
Cytochrome P450 Inducers
Phenadone-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:
Rifampin - 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.
Phenytoin - 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. Johns 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 toxicity.
Voriconazole - Repeat dose administration of oral voriconazole (400mg
Q12h for 1 day, then 200mg 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 patients condition and vital signs are
under careful observation.
Desipramine - Blood levels of desipramine have increased with concurrent
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 methadone 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
Phenadone 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.
Anxiety - Since methadone as used by tolerant patients at a constant
maintenance dosage does not act as a tranquilizer, patients who are maintained
on this drug 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 general anxiety.
Acute Pain - Maintenance patients on a stable dose of methadone 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
Risk of Relapse in Patients on Phenadone Maintenance Treatment of Opioid Addiction
Abrupt opioid discontinuation can lead to development of opioid withdrawal
of these symptoms have 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 opioid therapy.
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.
Phenadone 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, Addisons 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.