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Try out PMC Labs and tell us what you think. Learn More. Drug interactions are a leading cause of morbidity and mortality. Methadone and buprenorphine are frequently prescribed for the treatment of opioid addiction. Patients needing treatment with these medications often have co-occurring medical and mental illnesses that require medication treatment. The abuse of illicit substances is also common in opioid-addicted individuals. These clinical realities place patients being treated with methadone and buprenorphine at risk for potentially toxic drug interactions.
A substantial literature has accumulated on drug interactions between either methadone or buprenorphine with other medications when ingested concomitantly by humans. This review summarizes current literature in this area. The World Health Organization reports that drug interactions are a leading cause of morbidity and mortality.
Furthermore, there has been a dramatic increase in deaths related to methadone use, both for the treatment of pain and illicit use, in the United States in recent years. Drug interactions have been implicated in many of these deaths. Interactions between cocaine, alcohol, and other substances will also be summarized. Drug interactions can occur through several mechanisms. One or more mechanisms may be involved in the expression of a clinically ificant drug interaction. The primary mechanisms of drug interactions include effects of drugs on hepatic metabolism of pharmaceuticals including effects on cytochrome P CYP enzymes or effects on glucuronidation, medication effects on the function of the drug transporter, P-glycoprotein, and effects on absorption of drugs.
For example, some drugs when taken in combination exhibit synergism that can increase drug effects resulting in toxicity. The opioid medications, methadone and buprenorphine are extensively metabolized by human liver. Specifically CYP3A4 plays a ificant role in the metabolism of methadone, and buprenorphine. Perhaps the best studied mechanism for drug interactions is seen with medications that inhibit the function of hepatic metabolic enzymes.
Laboratory assays are well-developed and provide insights on the inhibitory effect of a specific compound on major liver CYP enzymes, particularly CYP3A4. With buprenorphine, a CYP3A4 substrate, systemic exposure increase is noted following concomitant administration with ketoconazole, a strong CYP3A4 inhibitor. Drug interactions with other CYP3A4 inhibitors, listed in the Table 1below may cause an increase in systemic levels or pharmacodynamic effects of buprenorphine.
Although assays that can reliably show induction of CYP enzymes exist, these assays are unable to predict drug interactions when the compounds inhibit some CYP enzymes while inducing other CYP enzymes. In such situations, we often learn of inducing properties of a drug through clinical observations.
For example, HIV antiretroviral ARV medications such as ritonavir, nelfinavir, and nevirapine, are known to inhibit CYP3A4; however, they are shown to reduce the plasma levels of methadone, possibly due to induction of other CYP enzymes involved in its metabolic clearance. Glucuronidation can also be a late step in the metabolism of drugs which undergo a series of metabolic steps with intermediates produced as a result of metabolism by CYP enzymes.
Glucuronidation renders a metabolite water soluble so that it can then be excreted. An example of a clinically ificant drug interaction mediated by inhibition of glucuronidation is that of the effect of methadone on zidovudine elimination. Methadone can inhibit zidovudine glucuronidation resulting in increased concentrations that, in some cases, may produce zidovudine toxicity. Some drug interactions occur as a result of the production of a pharmacologically active metabolite as in the case of simultaneous cocaine and alcohol consumption which in the formation of cocaethylene, a cocaine-like compound that can contribute to toxicities associated with the abuse of these substances.
This has been observed when methadone-maintained patients were administered the ARV medication, stavudine, resulting in sub-therapeutic stavudine concentrations. Pharmacodynamic interactions can result when two or more drugs with the capability of producing similar pharmacological effects in an individual are ingested in the same time frame resulting in ificant adverse effects. For example, when buprenorphine and benzodiazepines e. It can be difficult to determine what mechanism s are responsible for adverse drug interactions.
Controlled studies in humans that include simultaneous administration of medications and measurement of plasma drug concentrations are important to understanding the pharmacokinetic and pharmacodynamic drug interactions important in the treatment of common medical and mental disorders. In the following sections, important drug interactions that have been described will be briefly reviewed. The majority of injection drug users are addicted to heroin or opium.
There are several medical treatments available for opioid dependent patients. These include medical withdrawal from opioids and maintenance treatment with methadone or buprenorphine. Medical withdrawal from opioids has been shown to have a high relapse rate. US FDA-approved therapies for opioid maintenance therapy include methadone, l-acetyl-methadol not currently manufactured in the U. This population represents a ificant risk for personal harm and harm to others should they relapse to opioid use and continue high risk injection drug use and sexual practices. For that reason, much research has been devoted to determining the presence of clinically ificant drug interactions between opioids and ARV medications.
Some methadone-maintained patients with HIV disease who were started on AZT therapy for HIV infection were noted to develop symptoms that appeared to be consistent with opioid withdrawal including muscle and t pain, dysphoria, insomnia, and depression. The of this study led to another question: did interactions between methadone and AZT characterize interactions between AZT and other opioid therapies? To test this question, another study was conducted in which the interaction of AZT with either buprenorphine, LAAM, or naltrexone was examined.
In fact, what was observed were non-clinically ificant decreases in AZT concentrations in patients treated with buprenorphine or LAAM; the opposite of that observed with methadone. These findings indicated that the observation for methadone was not representative of what would occur in the context of other opioids in combination with ARV therapies. To date, a of frequently utilized ARV therapies have been examined in combination with methadone and other opioid therapies. These drug interactions are summarized in Table 2. Selected important drug interactions are summarized below.
Interactions between methadone and several HIV therapies demonstrate the potential for adverse drug effects that can occur when absorption of a drug is altered. Methadone is a full mu opioid receptor agonist. A general effect of such drugs is to slow gastrointestinal mobility. Methadone has been associated with ificant decreases in HIV medications that are sensitive to the acidic environment of the stomach. Didanosine DDI or Videx in tablet formulation and stavudine d4T are two non-nucleoside reverse transcriptase inhibitors NRTIs that may produce sub-therapeutic plasma concentrations of methadone when administered to methadone-maintained individuals.
This formulation has been shown to be associated with therapeutic plasma concentrations in both methadone-maintained 23 and buprenorphine-maintained individuals. Adverse events related to inhibition of the clearance of opioid medications have the potential to produce opioid toxicity including altered cognition and decreased respiration.
Delavirdine is a non-nucleoside reverse transcriptase inhibitor that inhibits the function of CYP 3A4. Of equal concern are the drug interactions that result in diminished concentrations of opioid therapies. For example, co-administration of a medication that induces methadone metabolism could result in a reduction of plasma methadone concentrations in a methadone-maintained patient leading to the potential development of opiate withdrawal symptoms.
The onset of opiate withdrawal may be associated with abuse of opioids or other illicit substances and resumption of high risk behaviors related to drug abuse with risk for HIV transmission. This may be one reason that withdrawal does not occur even with induction of buprenorphine metabolism.
Further, buprenorphine is a partial mu opioid agonist with a high affinity for and slow dissociation from the mu opioid receptor which may protect buprenorphine-maintained individuals from opiate withdrawal. The use of ARV medications in those who also require opioid therapy for treatment of opioid addiction can be challenging with methadone.
However, to date, none of the adverse drug interactions that have been observed between methadone and ARVs have been observed in buprenorphine-maintained individuals. These findings may be useful to clinicians who must treat both HIV disease and opioid dependence in the same patient. What are the practical implications of drug interactions between opioid therapies and HIV medications? The necessary tapering of methadone to achieve buprenorphine induction could potentially destabilize the patient.
Rather, clinicians with such patients should be aware of major drug interactions that may occur between ARV and methadone and adjust medication doses accordingly. Tuberculosis can also occur independently and is seen more frequently in individuals addicted to heroin. Medications used to treat tuberculosis can have ificant interactions with methadone. The best known of these interactions is that of the effect of rifampin, a first-line agent used in combination with isoniazid for the treatment of tuberculosis infection, to induce methadone metabolism.
Some patients receiving buprenorphine also develop opiate withdrawal symptoms when treated with rifampin, however at this time, the final data is still pending. This same finding is likely to be true for buprenorphine-treated patients, although this has not yet been examined.
While rifabutin can also induce CYP 3A4, it appears not to produce the withdrawal symptoms rifampin does. This increasingly common infection also occurs in methadone-treated patients who will similarly require substitution of rifampin with rifabutin in this clinical circumstance. Isoniazid is a CYP 3A4 inhibitor, 41 but has not been associated with adverse events in opioid-maintained patients to date, perhaps because any effect to inhibit opioid metabolism is opposed by the concomitantly administered rifampin in patients with tuberculosis and receiving chronic opioid therapy.
These medications have a high rate of adverse symptoms and side effects associated with their use including depression, anxiety, malaise, myalgia, fatigue, and anemia ribavirin. To date, two studies have been reported in the literature and both have shown no ificant drug interactions between methadone and interferon. There are four antibiotic treatments, specifically antifungal and antibacterial therapies that cause potentially clinically ificant drug interactions with methadone as a result of inhibition of CYP 3A4 which can increase methadone concentrations.
Both the antifungal medications fluconazole 47 and voriconizole 48 are inhibitors of this enzyme and might increase methadone plasma concentrations when administered concomitantly. Similarly, ciprofloxacin inhibits CYP 3A4 and there has been a case report of life-threatening opioid toxicity when this medication was given to a methadone-maintained individual. Because buprenorphine is a substrate of CYP 3A4, its plasma concentrations would likely be increased in the presence of any of these antibiotics as well.
However, the ceiling effect for opioid agonist effects of buprenorphine could diminish any potential opioid toxicity. While exhaustive work examining drug interactions between opioids and medications commonly used to treat mental illness has not been undertaken, there are some findings that can be summarized in this review. Affective disorders, particularly major depression are common in opioid dependent patients. The serotonin reuptake inhibitors exert a variety of effects on the cytochrome P enzyme system.
Both fluoxetine and fluvoxamine have been examined in vitro for evidence of potential for drug interactions with methadone and buprenorphine. Both fluoxetine and fluvoxamine with fluvoxamine being more potent than fluoxetine inhibit CYP 3A4 and 2D6.
In vitro studies showed both antidepressants to be associated with decreased metabolism of methadone and buprenorphine.Methadone and adderall interaction
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Is it Dangerous to Mix Methadone with Other Drugs?