Medication Interactions with Methadone and Buprenorphine

Lily Idle on Twitter: "Drug interactions. Coming soon: Positive and  Negative editions.… "

Patients being treated for opioid use disorder with methadone or buprenorphine often need other medications to treat chronic and acute medical conditions. When our opioid treatment program patients fill other prescriptions at retail pharmacies, the pharmacist might not know that the patient is on methadone or buprenorphine. Due to privacy laws, OTPs don’t report patient data to state prescription monitoring programs. That puts the burden on opioid treatment providers to watch for potential drug interactions.

I take that burden seriously.

Methadone, for various reasons, is more likely to have drug interactions than buprenorphine. Buprenorphine’s various pharmacologic properties reduce the risk of drug interactions. It has a high affinity for the opioid receptor, which means it’s not easily displaced off the receptor. Also, buprenorphine has a ceiling effect, so fluctuations in blood levels are less likely to cause sedation than methadone. Drug interactions can still occur, but not with the frequency or severity as with methadone.

Many medications interact with methadone, too many for me to reliably remember. I use a smart phone app to supplement my aging memory with up-to-date data. And if I can use these smart phone apps, believe me…anyone can. I prefer the Medscape app, though it’s only one of many. Other providers like Epocrates or others. If you work at an opioid treatment program and make dose decisions, I strongly recommend you get one of these apps, because there’s no way to remember or keep up with all new data.                                                                                                                  

Here are some of the main ways methadone interacts with other medications.


Any sedative medication can have an increased sedative effect when it is administered to a patient on methadone, or any other opioid, for that matter. Sedatives affect that ancient part of our brain that tells us to breath while we sleep. Opioids also affect that brain center, so when opioids and other sedatives are mixed, patients can fall asleep and stop breathing, which is how overdose deaths occur.

By far, the most commonly consumed sedative that my patients use, by prescription or illicitly, are benzodiazepines. However, other sedatives are just as deadly, and alcohol is a sedative drug too. Recently we’ve had more patients prescribe gabapentin (Neurontin) or its mirror-image molecule, pregabalin (Lyrica). These medications are commonly prescribed by primary care providers for just about any complaint of pain, anxiety, or anything else. When misused, or when taken with methadone, it can lead to impairment and even overdose.

I’ve railed against the inappropriate use of benzodiazepines so many times that even I get tired of hearing myself, so I’ll refer to reader to past blog entries. But let me just say that many patients being treated for opioid use disorder with methadone have been harmed by also taking benzos, prescribed or not prescribed. It’s a hazard that should be avoided if possible.

Cardiac Effects: prolonged QT interval

Methadone can prolong the QT interval in the heart. In the interest of not getting overly technical, let’s just say that the QT interval has to do with how the beats are conducted through the electrical system of the heart. If the QT interval lengthens past a critical point, it puts the patient at risk for a potentially fatal heart rhythm.

Many opioids can cause this, but methadone is probably the most well-known. Other opioids, like tramadol and oxycodone, carry some risk of QT prolongation, but usually not to a clinically significant degree. Some sources say buprenorphine can theoretically cause QT prolongation, but most experts don’t feel it’s clinically significant. In fact, if a patient on methadone develops QT prolongation issues, that patient is often recommended to switch to buprenorphine.

While methadone alone infrequently causes clinically significant QT interval prolongation, other factors can increase patient risk. For example, some patients with certain types of underlying heart problems may already be prone to QT prolongation and starting methadone could make this situation worse.

Many other medications also can cause QT prolongation. When these medications are started in a patient on methadone, the combination can cause significant QT interval prolongation.

For a recent list, go here:

As you will see, many common medications are listed. Common antibiotics, like cipro and erythromycin, cause prolonged QT interval and these are often prescribed to our patients. Many commonly prescribed mental health medications can prolong the QT interval.

What should opioid treatment providers do when a patient on methadone gets a new prescription for a medication which could critically prolong the QT interval? I’ve searched the internet and can’t find exact evidence-based solutions. But that’s not uncommon. Physicians often need to weigh decisions of risks and benefits of medications and act based on this.

First, I inform patients if there might be a problem. Next, I decide if the risk presented by the medication is so high that I need to ask the prescriber to change it. Or, if the patient is young and healthy, I might decide to check an EKG to monitor the QT interval. Lowering the dose of methadone can help reduce the QT interval, but at the risk of de-stabilizing the patient, so that’s rarely the best course of action.

Opioid treatment programs vary widely in their abilities to get and interpret ECGs. Thankfully, I’m trained in Internal Medicine and feel comfortable getting my ECG calipers to calculate the QT interval and yes, of course I correct for heart rate too.

Here are two examples of how I handled potential QT situations.

The first patient was young and healthy, and dosing with methadone at 95mg per day. He was started on ciprofloxacin for two weeks for an infection. The other prescriber had done a culture of the infectious situation and cipro was one of few antibiotics that the bacteria was sensitive to, so antibiotic choices were limited. I decided to check an ECG after my patient had been taking cipro for a few days, and the QT was fine. He was able to remain on the cipro until the infection cleared, with no problems

The second patient was older, nearly 50, with several chronic medical conditions including severe mental health diagnoses. A new psychiatrist changed his medication and started him on ziprasidone (Geodon), a medication infamous for causing QT prolongation. My patient was dosing at 115mg per day, and extremely fearful about any dose change. I did an ECG as soon as I knew he was on Geodon, and his QT interval was significantly lengthened. I called his new psychiatrist and explained the problem and she immediately switched him to a lower-risk medication. A repeat ECG done a few days after the switch showed his QT was back to normal, and he did well on this second medication, with good resolution of his mental health symptoms.

Drug affected methadone metabolism by the Cytochrome P450 System

Other drugs and substances affect methadone blood concentrations by influencing the rate of methadone metabolism. Methadone is an active opioid, while its first metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (called EDDP for short), is not pharmacologically active. That metabolic process is done in the liver via the cytochrome P450 (CYP450 for short) system. Many other medications affect this system.

Some medications that affect the CYP 450 system slow methadone metabolism and are called inhibitors. They can increase methadone blood levels and the opioid effect it has. Conversely, medications called inducers speed metabolism of methadone into its inactive metabolite, and thus can reduce methadone’s blood level and effect.

Of course, rising or falling methadone blood levels affects patient stability.

To add to the complexity, there are different types of cytochrome P450 enzymes. Several are involved with methadone metabolism, named CYP 3A4, CYP 2D6, CYP2B6, and CYP 2C29. And each enzyme’s activity is further determined by what genes we’ve inherited. Other medications that are metabolized by CYP3A4 are thought to be particularly prone to affect methadone metabolism and regarded with more caution.

So…it’s complicated. But as if that complication weren’tt enough, some scientists now say that though in the past we thought methadone was mainly metabolized by CYP 3A4, that’s old data, and now, we should be looking at drugs metabolized by CYP 2B6. In fact, in a recent article I read, “It has now been unequivocally established that CYP2B6, not CYP3A4, is the principle determinant of methadone metabolism, clearance, elimination, and plasma concentrations in humans.”  [1]

Also, some medications act as inhibitors of inducers of methadone in a test tube but not in real life.

What’s a doctor to do?

Again, I’ve searched the internet for evidence-based recommendations. Should we increase the patient’s methadone dose if he’s started on a medication that induces methadone’s metabolism? Or should we wait to see if the patient has symptoms before we change the dose? Conversely, should we decrease a patient’s methadone dose if she is started on a medication that inhibits methadone’s metabolism, in case her blood levels are going to rise? Or should we just prohibit the use of any medication that can affect methadone blood levels?

That last option, though it would make my life easier, isn’t possible. For example, nearly all mental health medications interact with methadone in some way or another. There’s no way for a patient to get treatment without using medications with the potential to affect methadone metabolism.

Same as with the QT interval problem, the degree of risk must be assessed for each patient. The degree of risk varies with patient medical history, and the known risk of the inducers or inhibitors. For example, patients newly started on phenytoin nearly always have a clinically significant drop in methadone blood level. For those patients, I’ll make sure I have an order in place to increase their methadone dose with any symptoms of opioid withdrawal.

Most other cases aren’t so clear-cut. I’ll inform patients of potential risks and ask that they communicate with us regularly.

Almost all medications that treat HIV influence methadone metabolism, making it essential for the opioid treatment provider to communicate directly with the provider prescribing HIV medications.

In fact, good communication is essential with other prescribers and I try to cultivate a cooperative attitude with them, so far as it is possible with me.

Our opioid treatment program patients, particularly as they age, will be prescribed medication with possible interactions with their methadone. For their safety, each OTP must have a system in place that: 1. Gets patients to report new prescriptions as soon as possible 2. Gets that information to the program medical provider in order to make decisions about safety and monitoring 3. Informs patients of potential risks 4.  Arranges follow up meeting with medical providers when appropriate 5. Opioid treatment providers must collaborate with other prescribers when necessary

Each OTP needs a system that works for their facility, and methods can differ widely between OTPs. It doesn’t matter how we get the job done, just that it gets done.

Our patients’ safety depends upon this.

  1. Kharasch, “Current Concepts in methadone metabolism and Transport,” Clinical Pharmacology in Drug Devopement, 2019

10 responses to this post.

  1. Posted by Christopher Dover on June 20, 2021 at 7:31 pm

    Could someone advise please if Effexor (venlefaxine) metabolites methadone too quickly.?
    The best I ever felt was on methadone for 12 months, but I had to switch back to Subs because whilst on methadone and Effexor together I was waking flat and depressed anticipating my next dose of M. I’ve read a couple of methadone & Effexor patients say the same thing….


  2. Posted by on June 20, 2021 at 7:33 pm

    Hi Dr Janaburson,

    Could you say please if Effexor (venlefaxine) metabolites methadone too quickly.? The best I ever felt was on methadone for 12 months, but I had to switch back to Subs because whilst on methadone and Effexor together I was waking flat and depressed anticipating my next dose of M. I’ve read a couple of methadone & Effexor patients say the same thing….  Regards  Chris 

    Sent from myMail for iOS

    Sunday, 20 June 2021, 11:55 pm +1000 from : >janaburson posted: ” > > > > >Patients being treated for opioid use disorder with methadone or buprenorphine often need other medications to treat chronic and acute medical conditions. When our opioid treatment program patients fill other prescriptions at retail pharmacies, the p” >


    • The only interaction I’ve found is that both methadone and venlafaxine can prolong the QT interval of the heart, not that venlafaxine changes the metabolism of methadone


  3. Posted by Rebecca Glover, RPh. on June 21, 2021 at 4:10 pm

    I am astounded that OTP’s aren’t required to report to state PMPs due to privacy issues? If that is indeed the case why is any controlled substance prescription required to be reported? I guess I don’t understand why it is a violation of privacy to report OTP methadone but not a privacy issue to report methadone that is taken for pain.


    • You ask a great question! The reason is the stigma associated with diagnoses of substance use disorders. Patients on opioids for acute or chronic pain are often viewed with sympathy, while people with opioid use disorder are often judged harshly. Even medical professionals do this. For example, a local provider once told me that if any of his patients came to see me to get on methadone or buprenorphine, I should tell them NOT to come back and see him because he would kick them out of his practice. It’s hard for patients on methadone for opioid use disorder to get primary care providers. They often tell such patients, “I’m not equipped to handle your medical needs,” when what they really mean is “I don’t want your kind in my waiting room. Take your dirty habit elsewhere!”
      I’ve had patients on buprenorphine products be treated harshly at community pharmacies, and stigma is even worse with methadone.


  4. Posted by Jerry R McKee on June 21, 2021 at 5:47 pm

    Thanks for commenting on the potential DDI issues with methadone and the protections of 42CFR which may, in fact, sometimes lead to patient harm. Where you are clearly very meticulous in guarding against these potential harmful DDIs, what about the potential harm for the patient that shows up in the urgent care center and does not disclose that they are on methadone and receives a prescription for a quinalone? I believe that in this case the privacy laws are an impediment to patient safety.


  5. Posted by Alan Wartenberg MD on July 12, 2021 at 7:06 pm

    One of the things I tried to do, with some success, is have a safety discussion with my patients (particularly on methadone) that they need to strongly consider telling their pharmacist that they are on methadone. I go over the safety reasons in terms of DDI’s and that most, if not all pharmacies have drug interaction programs on their computers to alert unaware physicians/prescribers that there may be a problem, as well as informing the patient.

    We all know that many patients are reluctant to tell either their doctors or their pharmacists about methadone, and for understandable reasons. I also gave them a letter that explained their treatment and encouraged either the pharmacist or prescriber to contact me or our counseling/nursing staff.

    What we found was that patients who did this very rarely had a problem with anger or disdain from the provider, and the fact that they voluntarily offered this information had significant effects in lowering stigma. I think we should all consider doing this, and I also think it would be a great study.


  6. Posted by Betsy Ragone on August 17, 2021 at 11:26 pm

    Hi Jana, it’s Betsy Ragone from Michaels VOICE (hoping you remember me from several years ago). I have a favor. I have a zoom meeting every Tuesdays at 630pm. It’s for families (right now all parents) there is an ongoing divide about MAT. Is it possible you can talk to my group. On some Tuesday in as September or October about MAT and your opinion, thoughts, experience.

    My phone number is 704-301-7165

    Sent from my iPhone



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