Where’s the Buprenorphine asked Mr. Obvious? Thanks, CDC!

A quick note tonight, hopefully with a longer post to follow this weekend…
I’ve been frustrated by the people behind the Wisconsin PDMP, or Prescription Drug Monitoring Program, for their mistakes related to buprenorphine. Whoever came up with the numbers made a rookie error when calculating the equivalent morphine dose of patients taking buprenorphine products. The error is easy to notice by anyone who works with the drug, but apparently difficult to grasp by anyone with the power to correct the database figures.
Those people include, by the way, the folks at Brandeis University who give the numbers to Wisconsin, and the people at the CDC who give them to Brandeis. I’ve written to all of them; the bright folks at the CDC skimmed my explanation of their error and responded with a form-email that provides a link to where I can get ‘answers to my questions’.
Thanks, CDC!
In short, the people doing the calculation take a low dose of buprenorphine– say 200 micrograms– and extrapolate out in a straight line to 16 mg, ignoring the ceiling effect of partial agonists like buprenorphine. The calculation causes the PDMP to display a graph showing that people on buprenorphine are on the equivalent of 1200 mg of morphine. Any physician who sees that data (and all WI physicians are required by law to use the PDMP effective April 1) will think that the buprenorphine patient needing post-op pain is on THAT dose of opioids. Talk about an April Fool’s joke– nothing like hypoxia in the recovery room to brighten everyone’s mood! Don’t worry though– in their email they pointed out the disclaimer in fine print that the site shouldn’t actually be used to compare or convert opioid doses.
Then why make the calculation and show the graph, asks Mr. Obvious?!
This is getting longer than I intended… Another annoying State tidbit is the series of letters to Wisconsin physicians warning about the severe risk of harm from prescribing benzodiazepines to patients on buprenorphine. I’ve written to those folks as well, pointing out that combinations of benzodiazepines with opioid agonists are much, much, much more dangerous than with buprenorphine. I’ve explained how somehow, sometime long ago, the phrase ‘buprenorphine can only cause death in adults if given to someone without opioid tolerance AND combined with a second respiratory depressant, to which the person also lacks tolerance’ (a true statement) was changed to ‘buprenorphine is dangerous when combined with benzodiazepines’ (mostly ‘fake news’).
I haven’t written as many letters over this second issue because I’m no big fan of benzodiazepines. But both issues annoy me greatly, maybe because the errors of logic in both cases are SO obvious. Even for government work!!
Speaking of government work, the Milwaukee County Common Council released figures about the surge in overdose deaths, including a breakdown by ethnicity, age, county region, and drugs found at autopsy. Mr. Obvious has a question for the people writing to doctors to tell them about the SEVERE risks from buprenorphine: ‘What drug is NOT on the list of the 8 most-common drugs found in toxicology tests of overdose patients?’ A hint: It starts with a ‘B’!

17 thoughts on “Where’s the Buprenorphine asked Mr. Obvious? Thanks, CDC!”

  1. I ?YOU…FOR ADVOCACY AND UNDERSTANDING. I PRAY THAT ONE DAY ALL PRESCRIBING PHYSICIANS WILL CARE ENOUGH TO EDUCATE THEMSELVES. HOWEVER I AM PESSIMISTIC.

    1. It pays sometimes to be pessimistic I have ran across so many uneducated misinformed doctors that I cannot count them. In West Tennessee where I live, having to go to an emergency room while on suboxone is a recipe for abuse from the entire er staff and doctor.

  2. so how much stronger is zubsolv 8.1 mg x 1 a day than morphine then? also my doctor was not going to treat me cause i have been taking klonopin .05 x 2 daily for 9 years and .05x 3 daily for one year. \i tell you they are generic and barely work anyhow. so he wants me to just stop, but shrink said today you cant just abrupty stop taking them. so im down to 2 and hope the zubsolv doctor will let me take them.

    1. The calculation requires some assumptions. First, I’ll assume you are talking about oral morphine– which is less potent than injected morphine. I’ll assume that the amount of Zubsolv absorbed is 40% (which is what studies show. Bunavail has a 50% absorption, and Suboxone Film has a 30% absorption).
      Zubsolv doesn’t come as 8 mg; it comes in doses of 5.7 mg buprenorphine. 0.5 mg of IV buprenorphine = about 1.5 mg of Suboxone = about 40 mg of oral morphine = about 1.2 mg Zubsolv. In other words, about 1/4 of a standard, 5.7 mg dose of Zubsolv is equal to 40 mg of morphine.
      That is ABOUT the maximum amount of opioid effect that is possible from buprenorphine. My logic for that? People debate the dose of buprenorphine where the ‘ceiling effect’ occurs– i.e. where further increases in dose do not result in greater opioid effect– but from my experience with patients, I consider a dose of 4 mg of Suboxone to be the amount where people feel ‘level’ throughout the day. This gets complicated– but if 4 mg of Suboxone is enough buprenorphine to STAY above the ceiling threshold, than it takes considerably less buprenorphine to simply REACH that ceiling dose. My assumption for this calculation is that a dose of 1-2 mg of Suboxone film will reach a blood level where further dose increases do not increase opioid stimulation, where the dose/response curve flattens out.
      So that suggests that once you get to 1 mg of Suboxone film, i.e. about 300 micrograms of IV buprenorphine, there is little or no increase in opioid effect at higher buprenorphine doses. In other words, the maximum effect of Zubsolv, Suboxone, or any other buprenorphine medication is equal to about 40 mg of oral morphine.
      There are so many variables in this calculation that no number will be absolutely accurate. But clearly, taking the potency at low dose and extrapolating it far past the maximum effect of buprenorphine is far from accurate. Even if my assumptions are off in certain patients by, say, 100%, you still get a maximal opioid effect of 80-100 mg. Compare that number to the potency of 900-1200 mg of morphine cited in the CDC and state database numbers!
      I assume the clonazepam dose you are taking is 0.5 mg, not 0.05 (which would be a trace amount). Generic or not, clonazepam will cause tolerance over time, so ANY dose, brand or generic, will ‘barely work’ after a year. That’s the main problem with benzos; just like with opioids, there is NO way to make the effect last more than a few months, unless the dose is continually increased.
      Once a person is tolerant to buprenorphine, the risk from adding a benzo is very low. Likewise, once a person is tolerant to a benzo, the risk of adding buprenorphine is very low. About 40 people on buprenorphine drugs die each year, compared to 30,000 overdose deaths in people NOT on buprenorphine.

    2. thank you for your answer ; i guess i understand that one fourth of a 5. zubsolv is about 40 mgs of morphine. so is the whole thing equal to more or did you just say it has a level off. i was taking an 8.6 zubsolv it does exist, one a day. but now take 2 5.7x 2 a day. god i sure hope im not in an accident or something, it means regular opiates wont work? as you can see new to this . sober 5 months taking zubsolv and no other opiates just the benzos. i came to a treatment center after 5 yrs in pain management, i was in an accident 10 yrs ago and my spine is messed up. i tried everything before taking pain medicine

  3. impressive stuff. is thereason why those numbers seems to be calculated like this is becouse they simply take buprenorphine binding affinty at base level and multiply it from there up in a linear fashion? receptor occupancy IS equivalent to those doses of morphine, but bupe partial-agonism and its peculiar mixed agonism/antagonism obviusly limit most of its opiate properties at levels well below those converted morphine dosages..

    1. Good point, contrasting ‘receptor occupancy’ vs. opiate ‘properties’. I haven’t worked with binding data since grad school… we used a Scatchard plot to graph the relationship between bound/unbound ligand vs. the concentration of the ligand. The amount of receptor occupancy is referred to as ‘saturation’ (usually provided as a percentage). I believe that receptor occupancy vs. drug concentration would only be a straight line if graphed logarithmically, but I could be wrong about that? But your point is similar to mine. The PDMP and other sources point out the ‘morphine equivalency’– so they are clearly referring to opioid properties, not to receptor occupancy. And by ignoring the ‘peculiar’ properties of buprenorphine, they get it completely wrong.

      1. Oh yes, excuse my english, as its clearly not my first language. what i meant is that it looks like they simply assume buprenorphine binding affinity is 50 times that of morphine, and they keep the calculation linear as doses escalate, wich obviusly doesnt work for buprenorphine, as its mixed partial-agonism/antagonism limits the effects it has at much lower equivalent dosages, or you really would need to give people on 16mg of buprenorphine over a gram of morphine, something i never heard of and never seen happen. any doses over 8mg of buprenorphine, even at the higher end of the scale (24mg and up) i usually have seen it being adequately covered with anything beetween 120 and 160mg of oral morphine. i would love to hear about cases requiring much higer dosages after a switch to a full agonist, becouse honestly this is what i would had imagined happening, as i always assumed buprenorphine extremely high binding affinty makes it somewhat as a potent narcotic as fentanyl. what makes the difference is the physiological response, in this case, limited by its partial-agonism, but receptor stimulation and saturation are achieved quite easily with buprenoprhine at doses of few hundreds micrograms, so i always imagined people on “high doses” (like those in maintenance therapies) requiring huge amounts of full agonists during a switch. apparently, im wrong, and i would like to understand more of WHY this is the case. surely, its not ONLY becouse buprenorphine its a partial-agonist at the Mu, right? i mean, among other things, its metabolite its a full agonist… i also realize this is probably not the right place for this discussion, so excuse my long winded post, and thanks for sharing your experiences!

  4. I have had at least three patients that I can readily recall who required conversion from buprenorphine to agonist only opioid. One was titrated in the hospital following extensive cancer surgery (my kudos the the surgical and anesthesia team at Indiana University Hospital for their knowledge and ability to appropriately manage a buprenorphine patient post op). The other two had acute pain uncontrolled by buprenorphine. Two were on a stable dosage of 8 mg Suboxone daily, one was on a stable dosage of 5.7 mg of Zubsolv daily. Control of withdrawal symptoms occurred at about 120mg oral morphine sulfate IR a day and 80mg of oxycodone IR a day. One patient did not get significantly better pain relief even after they had been titrated up to 160mg oral morphine sulfate.
    The bottom line is that, in my limited anecdotal clinical experience, 8 mg of suboxone requires at least 120 mg of oral morphine daily to control withdrawal symptoms, and these patients report inferior pain relief at this dosage. Transfer of patients from buprenorphine to agonist only opioids is of course complicated by the long half life of buprenorphine, and compliance issues and the perception of pain relief due to euphoric effects of agonist only opioids in addiction patients.
    Another frustration is that surgeons often under-dose buprenorphine patients when they ignore my post-op pain management advice. They frequently send patients home with four to eight norco or percocet a day. In addition, they fail to recognize the substantial risk of relapse when given opiates postoperatively, or just feel that is not their problem.
    I share your frustration with the emphasis on the danger of using buprenorphine and benzodiazapines together. It is certainly no more dangerous than using agonist only opiates and benzodiazapines together, and what doctor was not aware of the risk of combining opiates and benzodiazapines since their first class in pharmacology?
    In my experience, most patients will feel stable on 4 – 8 mg Suboxone a day. The exception I have found is that patients for whom alcohol was their drug of choice sometimes require considerably higher dosages of suboxone, even after years of treatment.

    1. Thank you for sharing your experiences. As you know, it is difficult to determine the equivalent dose of agonist to ‘match’ buprenorphine. You are describing the amounts needed to provide analgesia in PLACE of buprenorphine, so the doses you described would be higher than the tolerance of patients on buprenorphine (opioid analgesia requires the stimulation of opioid pathways to an extent greater than the person’s opioid tolerance). Complicating things further, buprenorphine stays around and blocks mu receptors for a LONG TIME. I’ve had patients stop buprenorphine for 2 weeks before a surgery, and even then their response to opioids suggests that the receptors are blocked (yes, it may just be that their limited response to agonists was caused by their higher tolerance. But when people are on buprenorphine they report the same thing even after significant doses of agonists– that the agonist did not ‘feel’ like an opioid. There was no high, no euphoria… suggesting that residual buprenorphine was limiting the effect of the agonist even after 2 weeks).
      When I use the data provided in the multiple opioid conversion calculators, or use the classic buprenorphine/morphine potency ratio of 40:1, I calculate a maximum buprenorphine effect of about 100 mg morphine. That number would be consistent with your observations, i.e. that 4-8 mg is enough buprenorphine in one dose to KEEP a patient above the ceiling threshold (if 4 mg is enough to KEEP someone above that threshold for 24 hours, than REACHING that threshold must occur at a dose significantly below 4 mg, right?). From multiple directions– from clinical experience and from calculations using known data– the maximum potency that any patient can get from buprenorphine is about equal to 100 mg morphine. Thus my frustration with the PDMP showing a value of 1200 mg!
      I share your frustration with the lack of knowledge or compassion by surgeons, when they grossly underdose our patients. I almost always now take over post-op pain control. As I’ve written elsewhere, I almost always keep the buprenorphine going, and treat pain with 15-20 mg of oxycodone every 3-4 hours. That almost always provides effective analgesia.

    2. I really appreciate the information that you are providing. I am a baby to the suboxone program, but have a law degree and research everything I can about this subject. I too was very concerned about them trying to take away my benzos when i started as I am 45 now and have been stable on 2 mg. of clonazepam since I was 17 for chronic insomnia, sleepwalking and night terrors. They started me out on zubsolv 5.7/1.4 twice a day. But luckily since I have been on this dosage so long they left me on it but I did tell the doctor I was taking 300mg. of morphine and 12-14 10mg. Percocet a day and that didn’t kill me thank God. Benzos have never been my d.o.c. thank God so I have never abused them, I take them at bed time. I am fortunate I guess they left me on it..Thank you for all your support and into. I appreciate you.

  5. I thought that since <1 mg. suboxone is used for pain management, that if you had to have emergency surgery, opioids would work post-op got pain.
    Am I wrong in this assumption?
    Best,

    1. Even 1 mg of buprenorphine will strongly block opioid agonists. Yes, agonists will work– but they will compete for the mu receptor with that 1 mg of buprenorphine, so higher than normal doses of agonist will be required. Moreover the subjective experience from agonists will be different with that buprenorphine on board; there will not be the normal euphoria and warm feeling from the agonist that people normally get when taking opioids. The person will experience pain relief dependent on dose, but not other opioid effects.

      1. Thank you for your reply. I’ve learned a lot reading everyone’s posts. It makes me realize how strong this drug actually is.
        I’m hoping that if I wean down to .25 before my surgery that I will have pain control on whatever they give me. I’m not looking for that euphoric feeling from it at all. Just don’t want to be in pain.
        Best,

  6. I agree, the Wisconsin PDMP leaves a lot to be desired. As a nurse, I don’t use the equivalent calculations, however, with the errors found in something that should be as easy as the refill history, the calculation errors don’t surprise me. I also think providers should have the ability to submit an alert that they believe others providers should be aware of.

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