Methadone Drug Interactions

Mixing methadone with other drugs can be life-threatening.

Methadone is commonly used in the treatment of opioid use disorder (OUD) but may also be used to treat severe pain. Many people who are prescribed methadone may also have co-occurring physical or mental health disorders.

When methadone is mixed with other opioids or similar drugs, like benzodiazepines, it can cause increased levels of methadone in the blood and a life-threatening overdose. Other drug classes, including anticonvulsants and antivirals, may cause methadone withdrawal symptoms.

If you are on methadone maintenance, always consult with your healthcare provider about all medications you are taking.

Metabolism Of Methadone

Methadone is an opioid agonist that activates receptors in the central nervous system (CNS) to relieve pain and reduce cravings.

It is metabolized in the liver, mainly through the enzyme (protein) cytochrome P450 3A4 (also known as CYP3A4). Drug interactions that involve this protein are associated with an increased risk of adverse effects.

It is important to understand other medications that can cause serious adverse effects if combined with methadone. Serious drug interactions can cause methadone to work ineffectively or may increase its effects, which can cause an opioid overdose.

Drug Interactions

A drug interaction can cause the levels of methadone to increase in the body (and increase the risk of respiratory depression) or decrease methadone levels (and increase the risk of opioid withdrawal).

Respiratory Depression

Respiratory depression is a life-threatening condition and the main cause of opioid toxicity, which can cause hypotension (low blood pressure), slow breathing, and loss of consciousness.

Opioid Withdrawal Syndrome 

When methadone is taken with drugs that increase its metabolism, it can trigger methadone withdrawal symptoms. Methadone withdrawal is a result of opioid dependence and occurs because of chemical changes in the brain.

Drug classes that may cause drug interactions with methadone include:

Central Nervous System (CNS) Depressants 

CNS depressants are drugs that include opiate analgesics (painkillers), benzodiazepines, and barbiturates. Like methadone, these drugs slow brain activity and, in high doses, can cause respiratory depression.

CNS depressant drugs include:

  • oxycodone
  • tramadol
  • alprazolam
  • diazepam
  • phenobarbital

Although most opioids will increase methadone levels in the body, Suboxone (buprenorphine/naloxone) is an opioid that contains an opioid antagonist, naloxone, which blocks the effects of opioids.

Naltrexone (Vivitrol) is also an opioid antagonist used in the treatment of opioid addiction. Both of these medications can cause immediate withdrawal symptoms if combined with other opioid medications.


Antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants, can cause adverse reactions if taken with methadone.

Antidepressants may cause inhibition of the protein CYP3A4, which can slow metabolism and increase the sedative effects of methadone.

Antidepressant drugs include:

  • fluoxetine
  • fluvoxamine
  • sertraline
  • desipramine


Antifungals, which are sometimes available over-the-counter, and antibiotics are used to treat infections. Both of these may raise methadone concentrations in the blood, which can lead to increased drowsiness and respiratory depression.

Antifungal and antibiotic drugs include:

  • fluconazole
  • ketoconazole
  • rifampin
  • erythromycin
  • itraconazole


Anticonvulsants, including carbamazepine and phenytoin, are prescription medications most commonly used in the treatment of seizures.

Anticonvulsants are inducers of methadone metabolism, which can cause reduced levels of methadone in your body and cause the onset of opioid withdrawal symptoms.


Viral infections, like human immunodeficiency virus (HIV) and hepatitis C, are treated with antiviral medications. HIV antiviral medications can interact with methadone and either increase or decrease methadone metabolism, depending on the drug.

Nelfinavir, abacavir, nevirapine, and ritonavir are HIV antivirals that can reduce methadone levels in the blood and may cause withdrawal syndrome. However, the antiviral saquinavir may increase methadone levels in the body.

Methadone Warnings

Methadone treatment, along with therapy, can effectively help someone maintain long-term recovery. It can also be a beneficial treatment for severe or chronic pain. However, methadone is also a controlled substance that carries a risk of abuse, dependence, and health effects.

In addition, methadone can cause severe side-effects when you first start taking it, as your body adjusts to the medication. Nausea, drowsiness, dizziness, and constipation may decrease after the first few doses of methadone.

You may experience breathing problems, which can be worsened with asthma or lung disease. Your prescribing doctor will review your medical history and determine if there are any conditions that may increase the risk of dangerous reactions.

Methadone Addiction Treatment

If you think you may be struggling with methadone abuse or dependence and want to stop, help is available. After completing a medical detox program, Northeast Addictions Treatment Center can provide you with comprehensive outpatient services that are tailored to fit your needs.

If you would like to learn more about our treatment programs, please contact us today.

Written by
Northeast Addition Editorial Team

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This page does not provide medical advice.

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