The safety of buprenorphine when not combined with a benzodiazepine has been twisted to suggest buprenorphine is uniquely dangerous when combined with benzodiazepines, which is not true.

I’ve heard more and more from insurers, regulators, and well-meaning agencies about the dangers of combining buprenorphine and benzodiazepines.   Some insurers protest paying for buprenorphine if patients are taking benzodiazepines.  Medicaid recently sent a letter that described a ‘severe risk’ of using benzodiazepines in patients on buprenorphine.  And the state drug database contains a graph for each patient of the morphine-equivalent narcotic dose over time, and shades the data in red if benzodiazepines are also prescribed.


Readers of my blog know I’m no big fan of benzodiazepines (read this for example).  But in an era of ‘fake news’, I’m even less of a fan of incorrect statements by doctors.   The drug database also ignores the ceiling effect of buprenorphine, and extrapolates the morphine equivalency of low doses of buprenorphine as if the dose response ‘curve’ was a straight line.  That ridiculous calculation leads the graph of opioid use to show buprenorphine patients as taking the equivalence of 900 mg of morphine per day.  The harm is minor I suppose by limitations on access to the database, but the error leads to misperceptions among doctors, and could potentially lead to mistakes in treatment decisions.

Benzodiazepines are respiratory depressants, especially when added to opioids.  The combination is dangerous when patients take doses of either class of drug that are higher than their tolerance levels.  The ceiling effect of buprenorphine eliminates that risk in patients who are stable on addiction-level doses of the drug, i.e. doses above the ceiling threshold.  A patient taking a maximal amount of buprenorphine CANNOT take a dose of buprenorphine that will cause respiratory depression.  Note the word ‘maximal’, not ‘maximum’.   By maximal, I mean a dose above about 8 mg per day, beyond which further doses will have no increase in mu receptor activity.

It is very difficult, and rare, to die from buprenorphine.  A person who lacks tolerance to opioids can die from buprenorphine, but deaths in that case are rare unless a second respiratory depressant is added– usually a benzodiazepine.  The high safety of buprenorphine, except when combined with a benzodiazepine, has been twisted in comments about the drug (and in the minds of regulators) to buprenorphine being uniquely dangerous when combined with benzodiazepines, which is not true.  Benzodiazepines are much, much more dangerous when combined with opioid agonists.  That risk is almost completely mitigated by buprenorphine, providing the person is tolerant to buprenorphine.

Buprenorphine rarely causes overdose unless combined with benzodiazepines in patients who are not tolerant to opioids.  Valid questions over benzo use should not be confounded by fears over buprenorphine.
Below, I will paste a letter I recently sent to one insurer who refused to cover buprenorphine in a patient on benzodiazepines.  Comments, of course, are welcome– and encouraged.


XXX XXXX is treated with Suboxone for opioid dependence, and with a combination of medication for depression and anxiety that includes clonazepam and a shorter-acting benzodiazepine, currently lorazepam.    He has a history of (a significant anxiety disorder that I won’t disclose here).
The issue of benzodiazepine use in combination with opioids is complex, but fairly predictable in people who use benzodiazepines correctly (e.g. at regular intervals, rather than taking a month’s supply in three days and then going without for several weeks).

I am experienced in the use of medications that have respiratory depressant properties.  I am Board Certified in Anesthesiology and also in Psychiatry, and I worked as an anesthesiologist for over ten years before training in psychiatry.  I also have a PhD in neurochemistry, and I teach the section on opioids at the Medical College of Wisconsin.  I will take some time to explain the interaction of benzodiazepines and buprenorphine—so I hope you will read my comments and take them seriously.

Buprenorphine has been known to be a very safe medication for the past 3 decades.  Review of the pharmacology literature will show that deaths from buprenorphine are rare. While over 30,000 Americans die from overdose each year, only about 40 of those deaths occur in people who have buprenorphine detected in the bloodstream.  Of those 40 deaths, almost all were from opioid agonists, with buprenorphine NOT acting as a contributor to the death—and in most cases the death would have been prevented had MORE buprenorphine been present in the bloodstream.

The few deaths attributable to buprenorphine each year in adults require 1. An absent or low opioid tolerance, AND 2. the presence of second respiratory depressant that the person also lacks tolerance to.  Because of the ceiling effect, which caps the CO2 response-shift from mu-receptor activation,  deaths from buprenorphine alone are rare in adults.   Death is possible in adults naïve to opioids–  but only if a second respiratory depressant is present.

The fact that death from buprenorphine can only occur in the presence of benzodiazepines has been misinterpreted at times, in warnings about opioids, as the idea that benzodiazepines and buprenorphine are uniquely dangerous when combined.   Understand that patients tolerant to buprenorphine have a partial-pressure of carbon dioxide equal to 40 mm mercury (the normal level).  Because of the ceiling effect, additional doses or amounts of buprenorphine cannot shift the carbon dioxide response curve.  For that reason, patients who have been maintained on buprenorphine doses above the ‘ceiling threshold’ for over a couple weeks have no respiratory depression from the drug.  Such patients have similar respiratory responses to benzodiazepines as those of normal patients.

Mr XXXX is fully tolerant to the cap effect of buprenorphine, so he is not at risk of respiratory depression from the drug.  Frankly, he is in a much safer position than other patients contemplating benzodiazepines, because if he used opioid agonists their effects on respiratory function would be blocked.

I am not a big fan of benzodiazepines, and for that reason have tried to taper Mr. XXXX off of them in the past.  But when we have attempted to taper them, the insomnia and anxiety symptoms become more severe, causing him to isolate from others and miss work.  I am fearful- for good reason—that attempts to reduce benzodiazepines at this point would result in another significant depressive episode, resulting in hospital admission.  My goal has been to avoid any further increase in his dosage—something we have been able to do over the past two years.

Understand that the risk of respiratory depression comes down to tolerance, for both opioids and benzodiazepines.  Mr. XXXX uses the same amount of each medication every 24 hours, and does not stockpile medications or use medications impulsively.  His tolerance to BOTH medications, along with the cap on opioid effects intrinsic to buprenorphine, provides a significant margin of safety.


Krista · February 8, 2017 at 7:57 pm

Thanks so much for all the great info! You make it so easy to understand how the medication works on your body and brain! So happy I found your blog!!! I have been on suboxone for 2 1/2 years and I have also always had extremely bad anxiety and am on klonopin d/t that. I do not and would not abuse my benzo, have always used just as prescribed, even in active addiction! I’m thankful that I have a doctor who understands, as you, that some people need that medication to function normally!! I’m also so thankful that I finally woke up and sought help with this amazing med, it has literally saved my life and continues to do so to this day!!! Absolutely NO desire or thoughts to use and haven’t since becoming stable on this medication!!!! Thanks for your knowledge and support, I really appreciate it ??

Christopher · March 29, 2017 at 1:10 pm

I’m Chris, I was on Roxycodone form a bad car accident that broke my arm, hand, ribs and sliped my disc. It was extremely painful. This was in 2006 and my doctor gave me 240 30mg a month of Roxys. That’s 6 a day. At the time I had no tolerance to opiates and it made me nauseous all the time. After 2 years I had a strong tolerance and starting to need more to stop the pain. Sometimes I would take 300mg at once just to feel better. In.2010 a law came out that you can only get 180 a month. That’s when I starting abusing it. Two years later in 2012 the doctor stoped giving them to me so I was buying it on the street. That became way to expensive. That’s when I starting using heroin. The heroin epidemic is the governments fault because they put severe restrictions on opiates and no doctors wanted to prescribe in turn made it hard to get and made it very expensive to buy on the street. That’s why the opiate problems are so bad. In 2013 I found a Sub doctor and starting taking suboxone. I’ve been on 8mg a day and it saved my life. I’ve been on it for almost 4 years and I don’t even think about using anything. I’m also on Klonopin 1mg once a day and it works wounders for anxiety, depression and feeling of well being. You can take both together if you use it as prescribed. If you need to be on.a benzodiazepine stay away from Valium and xanax. Klonopin is safer because it has a slow onset. Plus it last longer. Just don’t abuse both meds and you will be fine. I saw on one of these posts that the ceiling effect on Suboxone 4mg. That’s wrong information. The ceiling effect of subs is 32mg. If you have a tolerance to subs no matter how much you take will not get you high. Subs are light years over methadone and if you want to get off oxycodone, heroin, ext. Subs are the best drug to use. I’ve been mixing Klonopin with suboxone for 4 years and I feel better then ever. Bottom line is don’t abuse your meds and you will be fine.

    Jeffrey Junig MD PhD · March 29, 2017 at 6:28 pm

    I agree with most of your comments, but not the comment about ceiling effect. The ceiling effect is easier to describe with a graph, and for anyone interested I show the graph on my youtube channel (go to the suboxdoc channel). The reason people feel stable on buprenorphine is because above the ceiling threshold, there is no change in opioid effect as blood level changes. The vast majority of patients will feel stable all day after one dose of 16 mg (and often a dose as low as 4 mg per day). So if 16 mg is enough to keep someone above that threshold for the ENTIRE DAY, then the dose that REACHES that threshold is obviously much lower. And again, many of my patients get to that point with a dose of only 4 mg per day. For those people, the ceiling theshold appears to occur at about a dose of 2 mg. To explain in another way– at a dose of 2 mg, they get an opioid effect equal to the effect of 40 mg of methadone. If they just took 2 mg each morning, they would get that effect a couple hours after dosing, but then they would have cravings and withdrawal all day and night, as the blood level dropped and the opioid effect dropped.
    But instead, they take a dose of 4 mg. Because the ceiling threshold occurs at 2 mg of buprenorphine, they still get an opioid effect only equal to 40 mg of methadone. But as they go through the day, their blood level never drops below the level caused by a 2 mg dose. Maybe by the end of 24 hours the blood level is finally down to that level– to the level created by a 2 mg dose– and they are still feeling an opioid effect equal to 40 mg methadone. Then they take the next day’s dose of 4 mg, and 2 hours later their blood level is higher…. but they still feel exactly the same, because the entire time their opioid receptors were stimulated to the exact same degree.
    On the other stuff– the benzo/bupe issue– I agree for the most part about safety. It essentially comes down to tolerance. Buprenorphine is very safe, because people become tolerant to the maximal opioid effect of the medication. Benzos are less safe because higher doses will result in greater effects. But as the comment said, the same daily dose or constant blood level will not add much risk, as tolerance will develop to that blood level.
    As for the causes of the opioid epidemic, there are many places to put the blame. I don’t think you ever should have been put on that much oxycodone in the first place– and in the future it will be very difficult for doctors to treat pain in that same way. Another cause of the heroin problem though was when the formulation was changed for Oxycontin. Suddenly all of the people crushing and snorting the drug couldn’t crush it anymore, so instead, they moved to heroin. Heroin is absorbed through mucous membranes more slowly than heroin, so in order to get the same effect as snorting oxycodone, addicts started injecting heroin. The cost of oxycodone also went up at that time, just as cheap heroin was pouring into the country, mainly from Mexico. Not to sound like Trump, but the flood of heroin was ignored, and never treated like the crisis that it was. Think about it…. a couple hundred thousand young people died over the past 8 years, and we had a total of one comment from the President, in March of 2016. Much too little, much too late. I wonder… how and why could such a huge problem be ignored for so long? And I have no answer to that question. Obviously, ignoring the problem never hurt Obama’s popularity– but it should have. Reagan was strongly criticized for ‘ignoring’ AIDS in the 1980’s by the media, and the opioid problem makes that crisis look small.

Lisa N · November 24, 2017 at 10:48 am

I feel this article is very accurate concerning the combined use of benzo’s and buprenorphine…. I routinely combine the two in low doses as I have found that opiate dependence is not an isolated disorder and some individuals with opiate dependence also have severe underlying anxiety that only a benzo can help. With proper monitoring, people do very well on both and their level of function improves, not declines, as is thought to be the case.

Scared · December 20, 2018 at 5:04 pm

What if you are on 1mg subutex daily, would it be unsafe to start taking xanax? Since you arent taking enough to reach the ceiling effect? What dose of xanax should I start with? Im very afraid to die every single day and thus I really need the xanax but am too afraid to start it. Im paralyzed by fear and unable to even walk outside of going to the bathroom, since I think my body cant handel it, any advice on dosage/safety would be appreciated, thanks.

    Jeffrey Junig MD PhD · December 31, 2018 at 1:22 pm

    I’m hesitant to suggest that anybody do something that could be dangerous. But many doctors have patients on both buprenorphine and benzodiazepines. If there is something unusual about your situation – for example if you are over 60 yrs old, or weigh less than 120 pounds, or have severe respiratory disease, then you should be more careful than others when taking respiratory depressants. You should also always ask your own doctor about his/her recommendations.
    But when a person is on a steady dose of buprenorphine, tolerance develops, reducing the respiratory effects of the drug. Overdoses from combinations of Xanax and buprenorphine generally occur in people who do not have tolerance to either drug. If you are taking buprenorphine at any dose for more than a few weeks, the risk of adding a benzo is very small. If you’re concerned, start with 0.25 mg of Xanax.
    I don’t like using benzos like Xanax for anxiety though, because tolerance develops to the Xanax, and then anxiety becomes worse when it wears off. Patients tend to gradually increase the dose of Xanax, and then they become stuck on that as well.

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