On Biodelivery and Norbuprenorphine

Over the past few months, I’ve read a few posts at the forum that are worth sharing.  I’ve been torn whether to share them with the general buprenorphine community, or only with doctors who prescribe the medication.  I’ve decided that since the ideas came from a layperson community, I’m not opening the floodgates to irresponsible behavior by repeating what I’ve read.  Feel free to comment if you believe I’ve made the wrong decision.

But first, a word of warning to persons taking buprenorphine:   Do NOT take steps to deliberately alter drug delivery beyond the things that your doctor approves of, such as avoiding drinking liquids right after dosing, or placing the film against your cheek instead of under the tongue—a useful step particularly for someone with dentures.  Do NOT try to increase the effects of buprenorphine by taking substances that block metabolism of the drug.  Such actions risk turning a lifesaving medication into just one more drug of abuse, putting you back into the miserable condition where you existed before buprenorphine treatment!

Bioavailability has become a significant issue for differentiating buprenorphine products.  Late-generation products have increased bioavailability— from 25% with Suboxone Film to 40% and 50% in Zubsolv and Bunavail, respectively.  One result of higher bio-availability is that lower doses of buprenorphine are needed to create identical buprenorphine blood levels.  A second result is lower blood levels of buprenorphine’s primary metabolite, norbuprenorphine, resulting in less constipation during buprenorphine treatment.

Some buprenorphine patients have learned about bioavailability, and have used the forum to describe their efforts to maximize delivery of buprenorphine to the bloodstream.  Over the past few weeks two discussions popped up that relate to different aspects of the same general issue.   And while similar discussions have come and gone over the years, there seems to be a growing sophistication to the discussions.

One recent discussion focused around the use of grapefruit juice to boost the actions of buprenorphine by delaying drug metabolism at CYP3A4, a cytochrome enzyme found in the liver.  Several writers described feeling a boost in mu-receptor activity when they dosed their buprenorphine after drinking grapefruit juice, a side effect that I considered unlikely given the ‘ceiling effect’ of buprenorphine and the rather limited impact of delaying metabolism in a medication that already has a long half-life.  But I realized, during the discussion, that grapefruit juice may be doing far more than reducing the breakdown of sublingually-absorbed buprenorphine.

When a person takes a buprenorphine product, 50% (Bunavail) to 75% (Suboxone Film) of the buprenorphine is swallowed, absorbed at the intestine, and converted to norbuprenorphine at the liver via ‘first pass metabolism.’  But blocking CYP3A4 may allow swallowed buprenorphine to escape first pass metabolism, causing swallowed buprenorphine appear in the inferior vena cava as buprenorphine rather than norbuprenorphine.  In such a case, blood levels of buprenorphine would increase not by the small factor expected from delayed metabolism of a long-half-life drug, but instead by a very large amount—doubling or even tripling the blood levels of buprenorphine.

I have not researched the issue, so I don’t know whether the effects of grapefruit juice on CYP3A4 are strong enough to eliminate or reduce the second-pass effect on swallowed buprenorphine.   But the topic is worth a look—a hint to some aspiring grad student out there!

In another discussion, a patient wrote that he is about to be kicked out of treatment because his doctor doesn’t think he is taking the buprenorphine that he is prescribed.  The patient wrote that he is not only taking the medication, he is INJECTING the medication, ‘so there should be even more buprenorphine in his system than normal.’

Lost on the patient, besides the general  folly of injecting non-sterile, non-IV-grade substances, is that many doctors measure levels of norbuprenorphine to make sure that their patients didn’t just ‘dose’ on the day of their appointments.  I suspect that this patient delivers far less buprenorphine to his liver by dosing intravenously, resulting in very little production of norbuprenorphine.

Why does he inject, by the way?  Like most people who inject buprenorphine, he says he doesn’t really know the answer to that question.  He says that injecting is a means of drug delivery that he has become used to, and that he is hesitant to give up. He is used to getting everything that he can out of heroin…. and he wants to get everything he can now, out of buprenorphine.  He says he doesn’t experience any ‘high’ when he injects buprenorphine.  I explained to him that by behaving so foolishly, he opens the door to huge risks – including the risk of losing access to buprenorphine.

Hope everyone had a nice Thanksgiving.