Methadone Drug Interactions: What to Know

Methadone is a medicine that has helped many individuals to overcome an opioid use disorder. As with most drugs, combining it with certain prescription or over the counter medications may cause interactions. Learn more about methadone drug interactions below. 

Key Facts

• Methadone can have pharmacokinetic and pharmacodynamic interactions.
• There are high risk drugs to avoid taking when on methadone.
• Specific drugs can alter methadone levels, leading to adverse effects.
• There are steps you can take to ensure safety while taking methadone.

What Are Methadone Drug Interactions?

If you are taking more than one drug, you should always be aware of potential drug interactions. An interaction occurs when one drug either increases or decreases the effects of another drug.

The interaction can lead to problems with the absorption, metabolism and the way the body distributes and excretes the medicine. In some cases, these interactions can have life threatening outcomes.

Methadone is a prescription medication that is often used in a medication assisted treatment (MAT) program. In this article, we will discuss how it works and the potential interactions to watch for when using methadone.

How Methadone Works and How Drug Interactions Happen

Methadone is a long acting full opioid agonist used to treat opioid use disorder and in some cases, chronic pain.

As you start taking it, the amount of the drug builds up in the body over days. Changes in dose, whether large or small, can affect metabolism and other bodily functions.

Two types of interactions may occur: pharmacodynamic or pharmacokinetic.

Pharmacodynamic Interactions

Pharmacodynamic interactions can occur when you take other central nervous system (CNS) depressants along with methadone. Symptoms that may appear include excessive sedation, respiratory depression, overdose or death.

As well, other medicines can add to methadone’s effect on the heart’s QT interval, or the time it takes your heart to contract and recover.

Pharmacokinetic Interactions

Pharmacokinetic interactions can alter liver enzyme activity, particularly CYP3A4, CYP2B6 and CYP2D6. These enzymes alter absorption and elimination, thus raising or lowering methadone levels.

These changes in the amount of methadone in your body can trigger withdrawal, cravings or even cause toxicity.

High Risk Methadone Drug Interactions: What to Avoid

Methadone is an opioid and acts as a central nervous system (CNS) depressant. If you are taking other drugs that produce similar results, you could face dangerous drug interactions.

Sedatives and CNS depressants

CNS drugs include benzodiazepines, such as Xanax, Ativan and Klonopin. Other CNS depressants include alcohol, sleep medications or “Z-drugs”, barbiturates, gabapentin and muscle relaxers, like carisoprodol and cyclobenzaprine.

Combining any of these drugs with methadone greatly increases the risk of serious respiratory depression or even overdose.

Many methadone programs strictly control the use of benzodiazepines to avoid these risks. If you are currently taking a benzodiazepine, your program may require you to taper your medication slowly and under medical supervision.

To reduce your chances of adverse consequences, never mix alcohol, extra sedatives or sleep medications on top of methadone.

If you misuse or mix medicines, keep naloxone in the home and teach your friends or family how to administer it in case of a drug interaction or overdose.

Other opioids, Opioid Blockers, and Pain Medicines

Taking more than one opioid with your methadone prescription increases your chances of serious harm.

There are risks associated with stacking short-acting opioids. Meaning, if you use oxycodone, hydrocodone, morphine, heroin or fentanyl on top of methadone, you have a much higher overdose risk.

Additionally, partial agonists and antagonists, like buprenorphine, naloxone and naltrexone, can precipitate withdrawal or block the methadone, especially when switching between MAT medications. 

To ensure safer pain management strategies while on methadone, work with your provider to develop a pain management regimen.

This should include the use of safer interventions such as acetaminophen and NSAIDs, if appropriate, local/regional anesthesia, physical therapy or non-pharmacologic pain management measures. 

Medications That Affect Heart Rhythm and the QT Interval

The QT interval refers to the time it takes for your heart to contract and recover, or in simpler terms, your heart rhythm. Methadone can prolong your QT interval.

Further, adding other QT-prolonging drugs raises your risk for developing torsades de pointes and sudden cardiac death, especially at higher methadone doses.

Examples of QT interval prolonging drugs include certain antipsychotics, like quetiapine, haloperidol and ziprasidone.

Also, antidepressants like citalopram and escitalopram and antiarrhythmics like amiodarone and sotalol are known to impact the heart rhythm.

Some antibiotics, such as macrolides and fluoroquinolones, may also contribute to adverse cardiovascular effects.

Prescription and OTC Medicines That Change Methadone Levels

Prescription and non-prescription medicines can increase or decrease methadone levels. It is essential to know how the drugs will interact with methadone before taking them.

Drugs That Raise Methadone Levels (CYP Inhibitors)

CYP3A4/CYP2B6/CYP2D6 inhibitors can increase serum methadone levels, causing more sedation and overdose risk even at the same dose.

Examples of these drugs include azole antifungals such as fluconazole and ketoconazole and macrolide antibiotics such as clarithromycin and erythromycin.

Others include selective serotonin reuptake inhibitors (SSRIs) and selective serotonin norepinephrine inhibitors (SNRIs), which are antidepressants like fluoxetine, paroxetine and sertraline.

Furthermore, HIV protease inhibitors like cimetidine and grapefruit juice may also cause an increase in methadone levels.

Drugs That Lower Methadone Levels (CYP Inducers)

Enzyme inducing medications speed up methadone breakdown, resulting in withdrawal symptoms and cravings and can put you at risk for relapse. Work with your doctor to adjust doses as needed to avoid these risks.

Examples of medicines that decrease methadone levels include rifampin and other tuberculosis drugs.

Antiepileptics, such as carbamazepine, phenytoin and phenobarbital, as well as some antiretrovirals, like efavirenz and nevirapine, may contribute to lower levels.

OTC Medicines, Supplements, and Substances to Always Mention

Other medicines may change the way methadone is absorbed or metabolized in your system include sedating antihistamines, such as diphenhydramine and doxylamine.

Cough syrups containing codeine, dextromethorphan or alcohol, and particular gastrointestinal or urinary agents that alter pH or absorption, can also complicate methadone treatment.

Herbal products labeled as “natural” for mood or sleep, like St. John’s wort, kava, kratom, CBD, and THC products, may affect liver enzymes, leading to CNS depression and potentially altering drug testing results.

How to Stay Safe on Methadone When You Take Other Medications

The more your doctor knows about your health and the medicines you take, the better care you will receive. Being open and honest with your providers is key to staying safe when you take methadone and other medications.

How Your Treatment Team Checks for Interactions and Keeps You Safe

The first time you meet, give your provider a complete list of your medications and be honest about other substances you are using.

Your doctor will review your medical history and may obtain a baseline ECG or labs to assess your cardiac health, ensuring you are given the correct dose of methadone and to manage any QT-prolonging medicines that you are taking.

They may even enroll you in a prescription monitoring program.

Your doctor will conduct regular dose reviews, obtain urine drug screens and communicate with your other providers. It is critical to check with your doctor regarding clinic policies about benzodiazepines and other controlled substances.

To increase your safety, use only one pharmacy when possible. Also, sign releases so providers can discuss your care.

Never forget to contact your MAT clinic or provider before surgery, after an emergency department visit or when making significant changes to your medications.

Warning Signs of a Serious Methadone Interaction and When to Get Help

Taking methadone can put you at risk for overdose and respiratory depression.

Signs to watch for include extreme sleepiness, nodding off during conversations, slowed or noisy breathing, blue lips or fingertips or difficulty waking.

You should have naloxone available when taking methadone. If any of these symptoms develop,you must call 911 immediately and administer naloxone as soon as possible. 

If you quit taking methadone abruptly, you may experience withdrawal symptoms. This may also occur if you are taking inducers or blockers that prevent methadone from working correctly.

Signs of withdrawal include sweating, goosebumps, a runny nose, stomach cramps, anxiety, and intense cravings. You may also feel a strong desire to return to opioid use.

You should also watch for symptoms of a pounding heart, fainting, severe dizziness, fever, confusion, muscle stiffness, shaking or jerking movements.

These are red flags that you are having a cardiac or serotonin emergency, related to methadone use, and need immediate help.

Find Treatment Near You

To learn more about methadone or its potential drug interactions, reach out to a local treatment center today. Qualified staff can answer your questions and direct you to the right provider.

You can also use the Rehab.com treatment directory and filter by location, level of care, insurance, or special programs or call the confidential helpline 800-985-8516 ( Sponsored Helpline )  to find a treatment program to meet your needs.