Drug-Drug Interactions of Methadone

2015

Antiretroviral drugs

Methadone is often used for opioid replacement therapy in intravenous drug abusers. The incidence of HIV infection is significantly higher in this population than in the general public, and interactions with drugs used for the treatment of AIDS are therefore important.

Methadone is predominantly metabolized by CYP3A4. Antiretroviral therapy with a non-nucleoside reverse transcriptase inhibitor (for example efavirenz, abacavir, and nevirapine) and/or a protease inhibitor (for example amprenavir) will induce the metabolism of methadone. This therapeutic combination is becoming increasingly common in HIV-positive substance misusers. Two studies have explicitly shown a significant reduction of methadone concentration by 28-87%. In the first study, 11 patients taking methadone maintenance therapy were given efavirenz and had a mean increase in methadone dosage requirement of 22%. In the second study, five methadone-maintained opioid-dependent individuals were given a combination of abacavir and amprenavir; the methadone concentration fell to 35% of the original concentration within 14 days.

In a prospective study of 54 patients taking antiretroviral drugs who also took methadone and a further 154 patients who did not take methadone there were similar clinical, virological, and immunological outcomes after 12 months. These results support the usefulness of methadone in the management of intravenous drug users with HIV infection.

Protease inhibitors

In an in vitro study of the effects of the HIV-1 protease inhibitors, ritonavir, indinavir, and saquinavir, which are metabolized by the liver CYP3A4, all three protease inhibitors inhibited methadone demethylation and buprenor-phine dealkylation in rank order of potency ritonavir > indinavir > saquinavir. Clinical studies are required to establish the further relevance of these observations.

Zidovudine

The metabolism of the antiviral nucleoside zidovudine to the inactive glucuronide form in vitro was inhibited by methadone. The concentration of methadone required for 50% inhibition was over 8 ng/ml, a supratherapeutic concentration, thus raising questions about the clinical significance of the effect. However, in eight recently detoxified heroin addicts, acute methadone treatment increased the AUC of oral zidovudine by 41% and of intravenous zidovudine by 19%, following the start of oral methadone (50 mg/day). These effects resulted primarily from inhibition of zidovudine glucuro-nidation, but also from reduced renal clearance of zidovudine, and methadone concentrations remained in the target range throughout. It is recommended that increased toxicity surveillance, and possibly reduction in zidovudine dose, are indicated when the two drugs are co-administered.

Cimetidine

Cimetidine increases the effects of methadone, probably by inhibition of methadone metabolism.

Drugs that affect CYP3A

In a randomized four-way crossover study in healthy subjects, the effects of intravenous and oral methadone were measured after pre-treatment with rifampicin (hepatic/ intestinal CYP3A induction), troleandomycin (hepatic/ intestinal CYP3A inhibition), grapefruit juice (selective intestinal CYP3A inhibition), or nothing. Intestinal and hepatic CYP3A activity affected methadone N-demethylation only slightly and had no significant effects on methadone concentrations, clearance, or clinical effects. There was a significant correlation between methadone oral availability and intestinal availability, since only rifampicin altered oral methadone availability. This suggests a role of intestinal metabolism and in first-pass extraction of methadone. This study used a single, relatively low dose of methadone (15 micrograms) rather than a therapeutic dose at steady state (80-100 micro-grams/day), when tolerance will be taken into consideration.

Enzyme inducers

Enzyme-inducing drugs, such as carbamazepine, phenobarbital, phenytoin, and rifampicin, enhance the metabolism of methadone, leading to lower serum methadone concentrations.

Fluconazole

In a randomized, double-blind, placebo-controlled trial, oral fluconazole increased the serum methadone AUC by 35%. Although renal clearance was not significantly affected, mean serum methadone peak and trough concentrations rose significantly, while renal clearance was not significantly altered.

Grapefruit juice

In an unblinded study, the effect of grapefruit juice on the steady-state pharmacokinetics of methadone was evaluated for 5 days in eight patients taking methadone (mean dose 107, range 63-150, micrograms/day). Grapefruit juice was associated with a modest increase in methadone availability that would not normally enhance its adverse effects. Only 6-8 glasses of grapefruit juice per day can lead to inhibition of hepatic CYP3A. Further studies need to be done to clarify to what extent intestinal and/or hepatic metabolic activities play a part in methadone availability and the subsequent risk of overdosage in individuals taking high maintenance doses of methadone. Since the therapeutic effect of methadone is mainly mediated by the R-enantiomer, monitoring plasma concentrations of R-methadone could be recommended, but it is an imprecise indicator of therapeutic activity.

Phenytoin

Phenytoin enhances the metabolism of methadone.

Rifampicin

Enzyme-inducing drugs, such as rifampicin, enhance the metabolism of methadone, leading to lower serum methadone concentrations. This interaction is thought to have caused acute methadone withdrawal symptoms in two patients with AIDS.

Selective serotonin re-uptake inhibitors

Fluvoxamine

Fluvoxamine increases the effects of methadone, probably by inhibition of methadone metabolism.

Paroxetine

Paroxetine 20 mg/day, a selective CYP2D6 inhibitor, was given for 12 days to 10 patients on methadone maintenance. Eight were genotyped as CYP2D6 homozygous extensive metabolizers and two as poor metabolizers. Paroxetine increased the steady-state concentrations of R-methadone and S-methadone, especially in the extensive metabolizers.

Use of methadone in opioid withdrawal

A widely used technique for opioid detoxification, pioneered by Isbell and Vogel, involves the substitution of methadone for the illicit opioid, followed by a gradual reduction in the amount of methadone taken.

Methadone maintenance treatment was established in 1964 in New York City by Vincent Dole and Marie Nyswander. In the initial studies, subjects who were heavily addicted to heroin were evaluated and stabilized on daily methadone doses as inpatients before transfer to an outpatient clinic for continued treatment. With further experience, it was feasible to drop the inpatient phase.

Methadone is used to substitute for a variety of opioid drugs. It is well absorbed after oral ingestion, with peak blood concentrations after about 4 hours. Steady-state concentrations are reached after about 5 days. By virtue of its long duration of action (the half-life with regular dosing is about 22 hours), methadone suppresses opioid withdrawal symptoms for 24-36 hours. In the early stages of treatment patients may report problems such as drowsiness, insomnia, nausea, euphoria, difficulty in micturition, and excessive sweating. With the exception of chronic constipation and excessive sweating, these effects do not generally persist.

Methadone maintenance treatment is considered to be a medically safe treatment with relatively few and minimal adverse effects. However, the danger of serious adverse effects and death with the increasing use of methadone as maintenance therapy in drug addicts has been highlighted. It must be emphasized that a daily maintenance dose of 50-100 mg is toxic in a non-tolerant adult and as little as 10 mg can be fatal in a child. There is an increasing number of reports of the deaths of children of mothers on maintenance therapy from inadvertent ingestion.

British studies have shown that, using methadone, about 80% of inpatients, but only 17% of outpatients, were successfully withdrawn. However, the technique is not without problems, one being that the methadone reduces but does not eliminate withdrawal symptoms. The withdrawal response has been described as being akin to a mild case of influenza, objectively mild but subjectively severe. The fear of withdrawal symptoms expressed by those dependent on drugs should not be underestimated: these factors are associated with the subsequent severity of withdrawal symptoms, and they are more closely related to symptom severity than drug dosage. Methadone substitution can result in a protracted withdrawal response, with patients still experiencing significantly more symptoms than controls 2 weeks after withdrawal.

In a study of methadone withdrawal, patients who were withdrawn over 10 days had a withdrawal syndrome that began to increase in severity from day 3, with peak severity of symptoms on day 13; in those who were withdrawn over 21 days, symptoms began to increase about day 10 with a peak on day 20 and abated thereafter, although some patients did not recover fully until 40 days after starting withdrawal. Thus, the duration of the withdrawal syndrome is much the same for both treatments in terms of symptom severity. It is possible that an exponential rather than linear reduction in dosage may improve the withdrawal response. These results may be of clinical significance, in that patients may feel it important that they recover from withdrawal as quickly as possible, in order to participate fully in other aspects of drug withdrawal programs. However, although there was no difference between the 10-day and 21-day programs regarding completion rates for detoxification (70 and 79% respectively), the dropout rates after detoxification were significantly different. During the 10 days after the last dose of methadone, the dropout rate in the 21-day group was 18% compared with 30% in the 10-day group. These results may also have financial implications in respect of the number of subjects who can be admitted to treatment programs.

In some treatment programs, total abstinence is not considered to be a practical objective and treatment may involve the use of drugs such as methadone as maintenance therapy with the expectation of reducing illicit drug consumption. Well-organized methadone maintenance treatment can reduce the intake of illicit opioids in many injecting drug users.

Outcome studies of methadone maintenance treatment have reported favorable results. High rates of patient retention, reduced criminality, and improved social rehabilitation are reported. Despite its proved effectiveness, it remains a controversial approach among substance abuse treatment providers, public officials, policy makers, the medical profession, and the public at large. Nevertheless, almost every nation with a significant narcotic addiction problem has established a methadone maintenance treatment program.

For patients entering treatment from an institution where they have been drug-free, initial daily methadone doses should be no more than 20 mg. Otherwise initial daily doses of 30-40 mg should be sufficient to obtain the necessary balance between withdrawal and narcotic symptoms. Thereafter, stabilization is achieved by gradually increasing the dose. When methadone is given in adequate oral doses (usually 60 mg/day or more), a single dose in a stabilized patient lasts 24-36 hours, without creating euphoria and sedation. Tolerance to methadone seems to remain steady, and patients can be maintained on the same dose, in some cases for more than 20 years. The methadone dose must be determined individually, owing to individual variability in pharmacokinetics and pharmacodynamics. Maintenance of appropriate methadone blood concentrations is recommended.

Tolerance to the narcotic properties of methadone develops within 4-6 weeks, but tolerance to the auto-nomic effects (for example constipation and sweating) develops more slowly.

The major adverse effects during treatment occur during the initial stabilization phase. In addition to constipation and sweating, the most frequently reported adverse effects are transient skin rash, weight gain, and fluid retention. Since the main metabolic pathway of methadone is CYP3A4, numerous drug interactions can be expected. Drugs that interact with methadone are listed in the table in the posts on opioids.

Selections from the book: “Meyler’s Side Effects of Psychiatric Drugs” (2009)