Alcohol, Xanax, and More: 11 Methadone Interactions to Watch For

Methadone (Methadose) is an opioid medication. It’s prescribed for chronic pain when nonopioid alternatives don’t work. It also treats opioid use disorder (OUD).

Methadone is known for having many drug interactions. It can interact with other medications that have similar side effects. Other methadone interactions occur because of how the body metabolizes it (breaks it down).

Here, we’ll cover 11 methadone interactions to watch for. Some interactions are especially dangerous because they increase the risk of opioid overdose. These interactions should usually be avoided entirely. Other interactions may not be as serious.

Good to know: Due to the high risk of some of these interactions, it’s a good idea to provide both your prescriber and pharmacist with an up-to-date and complete medication list. This will help your healthcare team evaluate potential interactions and keep you safe.

1. Benzodiazepines, such as Xanax

Benzodiazepines are sedative medications, which means they slow down brain activity. They’re used for several health conditions, including anxiety and panic disorder. Examples include lorazepam (Ativan) and alprazolam (Xanax). 

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Benzodiazepines are known to cause drowsiness and dizziness. Opioids also cause these side effects. Combining benzodiazepines and opioids can lead to slowed breathing and overdose. In fact, some research shows that your risk of overdose is five times higher in the first 3 months of taking an opioid and benzodiazepine together versus taking an opioid alone. That’s why it’s best to avoid this combination in most cases. 

However, avoiding it entirely may not be possible for everyone. If your prescriber recommends a benzodiazepine, pay close attention to symptoms of an interaction. This includes excessive drowsiness, dizziness, and slowed breathing.

2. Alcohol

You should avoid alcohol completely if you take methadone. Taking alcohol with methadone increases your risk of an opioid overdose. In fact, it’s estimated that alcohol is involved in 20% of opioid overdoses.

There’s no amount of alcohol that’s safe to drink with methadone. It’s also important to note that methadone lasts several days in the body. So even if you stop methadone, it’s not safe to start drinking alcohol right away. Talk to your prescriber about if and when it would be safe to resume drinking alcohol.

3. Muscle relaxers, such as Soma

Muscle relaxers are a group of medications that treat muscle spasms. They can also cause drowsiness and dizziness as side effects. When combined with methadone, this increases your risk for excessive drowsiness and opioid overdose.

The risk of overdose may be higher with muscle relaxers that are most known for causing drowsiness. Examples include baclofen (Ozobax DS, Fleqsuvy) and carisoprodol (Soma). Other muscle relaxers, like methocarbamol (Robaxin), are less likely to cause severe drowsiness. These may be less risky when combined with opioids.

EXPERT PICKS: WHAT TO READ NEXT

• Methadone vs. Suboxone: Methadone and Suboxone are two first-choice medications for treating opioid use disorder. Learn about their differences and how to determine which medication is best for you.

• Avoiding alcohol: Don’t drink alcohol if you take opioids. Learn about the risks of this combination, including an increased chance of overdose.

• Methadone side effects: Drowsiness, dizziness, and more — learn what to watch for if you take methadone.

Still, it’s best to avoid taking muscle relaxers with methadone if possible. If your prescriber believes both are necessary, they may recommend a muscle relaxer that's less likely to cause drowsiness. And they’ll likely recommend taking it for the shortest amount of time needed. Taking the lowest dose possible also lowers your risk.

4. Other opioids, such as oxycodone

Taking too many opioids is dangerous. It increases your chances of experiencing drowsiness, nausea, and accidents or injuries. Large amounts of opioids can also slow your breathing and lead to overdose and death.

Examples of other opioids include tramadol (Qdolo, ConZip) and oxycodone (Roxicodone, OxyContin). There are also buprenorphine-containing medications, such as Suboxone (buprenorphine / naloxone). Like methadone, Suboxone is used to treat OUD. Your prescriber may recommend one over the other depending on your situation.

Although it’s safest to avoid combining methadone with other opioids, there may be situations where your prescriber recommends more than one opioid to treat your chronic pain. But make sure you follow their instructions for how to take your medications. Taking opioids exactly as your prescriber recommends can help minimize your risks.

If you’re taking methadone for OUD, let your prescriber know right away if you return to opioid use. They can help you find resources to get back on track in your recovery.

If you or someone you know struggles with substance use, help is available. Call SAMHSA’s National Helpline at 1-800-662-4357 to learn about resources in your area.

5. Sleep medications, such as diphenhydramine

There are many prescription and over-the-counter (OTC) medications that treat insomnia (trouble sleeping). Prescription options include “Z-drugs,” such as zolpidem (Ambien, Intermezzo, Edluar) and eszopiclone (Lunesta). OTC sleep medications include diphenhydramine (ZzzQuil) and doxylamine (Unisom).

As you’d expect, these medications cause drowsiness. They can also cause dizziness, and slowed breathing or overdose when combined with methadone. It’s best to avoid any sleep  medications if you take methadone.

If you have trouble sleeping, talk to your prescriber about what you can do to improve your sleep before taking any medications.

6. Antibiotics, antifungals, and antivirals

Some antibiotics, antifungals, and antivirals (collectively known as antimicrobials) can interact with methadone. They do this by affecting certain proteins in your liver called CYP enzymes. These enzymes are responsible for metabolizing methadone.

Antimicrobials that block certain CYP enzymes can increase methadone levels. This makes side effects like drowsiness and slowed breathing more likely. Examples include:

• Macrolide antibiotics, such as erythromycin (Ery-Tab) and azithromycin (Z-pack)

• Azole antifungals, such as fluconazole (Diflucan) and ketoconazole (Nizoral)

• Protease inhibitor antivirals, such as lopinavir / ritonavir (Kaletra) and darunavir (Prezista)

On the other hand, antimicrobials that activate CYP enzymes can decrease methadone levels. This can make methadone less effective, or possibly cause opioid withdrawal symptoms. Rifampin (Rifadin) is one antibiotic that may decrease methadone levels.

If you’ve been prescribed one of these medication types, ask your healthcare team to check for a methadone interaction. There may be treatment options that don’t interact with methadone.

7. St John’s wort

St John’s wort is an herbal supplement that’s marketed to treat depression. It activates your CYP enzymes, increasing how quickly methadone is metabolized. This can lower methadone levels and can make it less effective. It can also lead to opioid withdrawal symptoms, such as irritability, nausea and vomiting, and diarrhea.

Talk to your prescriber if you’re taking this supplement or are interested in starting it. They can talk to you about other treatment options. Or, they can discuss symptoms of an interaction to watch for.

8. Some seizure medications, such as gabapentin

Certain seizure medications can activate CYP enzymes, leading to decreased methadone levels. This can make methadone less effective and increase your risk of opioid withdrawal. Examples of seizure medications that may interact with methadone include carbamazepine (Tegretol), phenytoin (Dilantin, Phenytek), and phenobarbital. 

Seizure medications can also interact with methadone by increasing the risk of side effects. For example, taking methadone with gabapentin (Neurontin), topiramate (Topamax), and levetiracetam (Keppra) can increase your risk of drowsiness and dizziness.

Additionally, methadone can increase the risk of seizures in people with a seizure disorder (epilepsy). So make sure your prescriber has your full medical history if you’re prescribed methadone. This will help them keep you safe while taking methadone.

9. Medications that prolong the QT interval, such as quetiapine

Methadone increases your risk of a condition called long QT syndrome. This is when your heart takes longer than normal to reset in between beats. Although rare, it can lead to a life-threatening arrhythmia (abnormal heart rhythm) called torsades de pointes.

Methadone can interact with other medications that also increase your risk of long QT syndrome. Examples include:

• Some antidepressants, such as amitriptyline

• Macrolide antibiotics, such as azithromycin

• Fluoroquinolone antibiotics, such as ciprofloxacin (Cipro)

• Antiarrhythmic medications, such as amiodarone (Pacerone)

• Some nausea medications, such as ondansetron (Zofran)

• Some migraine medications, such as sumatriptan (Imitrex, Tosymra)

While long QT syndrome is rare, taking multiple medications that increase your risk makes it more likely to occur. That’s why it’s best to give your prescriber a list of the medications you take before starting methadone. This will help them check for interactions.

10. Medications that increase serotonin, such as Lexapro

Methadone increases a brain chemical called serotonin. Taking it with other medications that have the same effect increases your risk for serotonin syndrome. Symptoms include sweating, shivering, and a fast heartbeat. In severe cases, it can cause seizures, hallucinations, and loss of consciousness. 

Medications and supplements that increase serotonin include:

• Selective serotonin reuptake inhibitors (SSRIs) like escitalopram (Lexapro) and paroxetine (Paxil)

• Serotonin and norepinephrine reuptake inhibitors (SNRIs) like duloxetine (Cymbalta) and venlafaxine (Effexor XR)

• Other opioids, such as tramadol

• Monoamine oxidase inhibitors (MAOIs), such as selegiline (Zelapar, Emsam) 

• Triptans, such as sumatriptan

• Stimulant medications, such as Adderall (mixed amphetamine salts)

These aren't the only medications that increase serotonin. So ask your healthcare team to check your medication list for possible methadone interactions that can lead to serotonin syndrome. Although it’s rare, your risk is higher if you take several medications that increase serotonin at once.

11. Naltrexone

Naltrexone (Vivitrol) is an opioid antagonist medication that treats alcohol use disorder and OUD. It works by blocking the effects of opioids and alcohol. It’s available as an oral tablet and intramuscular injection.

Although both naltrexone and methadone can treat OUD, they aren’t used together. In fact, naltrexone can block the effects of methadone and cause opioid withdrawal symptoms. So if you need naltrexone, you may need to wait at least 7 to 10 days after your last dose of methadone before starting it. Your prescriber will help you determine when it’s safe to start naltrexone.

Good to know: Naloxone (Narcan, Zimhi) or nalmefene (Opvee, Zurnai) are also opioid antagonists. But they’re used in a different way than naltrexone. Naloxone and nalmefene are used to quickly reverse the effects of an opioid overdose. These are life-saving medications. It’s a good idea to keep one of them with you at all times if you or a loved one takes methadone or another opioid. You can obtain naloxone nasal spray over the counter, but nalmefene is prescription only.

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Written by:

Alex Evans, PharmD, MBA

Alex Evans, PharmD, MBA, has been a pharmacist for 12 years. His first job was floating in a community chain pharmacy.

Edited by:

Amy B. Gragnolati, PharmD, BCPS

Amy Gragnolati, PharmD, BCPS, is a pharmacy editor for GoodRx. Amy currently holds her pharmacist license in Georgia and California.

Reviewed by:

Bailey E. Eason, PharmD, MS, BCPS

Bailey Eason has been licensed for 6 years and has held licenses in three states (North Carolina, Virginia, and Illinois). She has held positions as a health-system pharmacy administration resident, operating room pharmacy manager, pharmacy manager of clinical operations: surgery, neurology and controlled substances, and most recently as program director  of drug diversion for a large academic health system.

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