During my Interventional Pain Medicine fellowship, one of my attending physicians suggested I speak about opioids’ influence on the immune system for my Grand Rounds lecture for the Anesthesiology department. Thus began my in-depth and continuing study of these drugs’ interaction with the human body — it is, I assure you, mostly adverse. Specifically, I began studying the differential pharmacodynamics of buprenorphine with respect to other opiates. At the time, at least according to many studies in animals, buprenorphine was neutral, as compared to the very suppressive immune effect of the full opioid agonists (i.e., virtually every other opioid on the market, although there may be some lesser effect on the part of Tramadol, likely due to its serotonergic effect). I also had the opportunity to work some with an Addiction physicians in my area and learned more about buprenorphine medication-assisted therapy (MAT) and his experience using it for pain. Specifically, he was able to comment on use of buprenorphine to avoid opioid-induced hyperalgesia (OIH).

At one point during my fellowship, I was presented with yet another patient almost begging for more opiate. I was told by my attending to “increase the opiate by ten percent every six months.” I distinctly noted to myself: but when does that end? Does it stop at 60 mg daily morphine equivalent (ME)? 600? 6,000? 60,000? Does one just continue to increase the opiate until…until what? It didn’t make sense to me to “give in” to tolerance, to placate it, to succumb to it. It made more sense to me to stop at some point, rather than allow the development of tolerance to drive an increase in dose. I thought that the patient had to learn to live with some pain at some point, and could not continually chase the ever-elusive “I shall have no pain” paradigm. 

When I finished the fellowship, I began prescribing buprenorphine to certain patient populations — e.g., those at greater risk for infection (immune suppressed or already battling infection), patients with cancer or a history of cancer, and patients who had history of addiction or family history of addiction (to any drug). (Colorado, where I was practicing, allows a doctor to prescribe buprenorphine “off-label” for pain without a license for addiction MAT.) At that time, buprenorphine was not on the market as Butrans or Belbuca, and I didn’t know of other pain physicians prescribing it for chronic pain. Now, I believe more pain physicians have begun prescribing buprenorphine, albeit rarely by off label. 

I should note, I have never been a high opioid prescriber (I didn’t ascribe to my attendings’ and many physicians’ practice of abetting tolerance by increasing drug dosages). My patients were on relatively low levels of full agonist opioids or they were naïve. I have not been deterred by convention; I’ve been inclined to think that, if anything, I was sparing the patient a worse toxin — I thus let patients cut the generic buprenorphine 2 mg tablet into quarters for the less naïve patient, or the Suboxone 2mg/0.5mg film into tiny pieces (1/8 to 1/16) and take it BID to TID as primary opioid (if any opioid was needed after prescribing non-opioid analgesics) for chronic pain. 

In my practice, I observed a number of important things about buprenorphine’s effects in the chronic pain population:

1. It does not seem to promote OIH at all. In fact, some patients are able to tell me that the full agonists aggravate their pain — and that increasing the dose actually worsens it. I also believe this effect is far more common than reported, and generally occurs in all patients.
2. It has less cognitive suppression. My patients report that they “think better” (as in more clearly), and have better memory on buprenorphine.
3. It may indeed turn out to be the only opioid with evidence of functional outcome in chronic pain patients. Over years, my patients say they still experience pain control with the drug — that is, its effects do not diminish. My patients also report that they achieve more active lifestyles with the drug than without it, and are more active on buprenorphine than they were on full-opioid agonists. They cite less pain and better cognition, too.
4. It causes less constipation. In fact, not even my addiction patients (who are on higher doses than 2 mg of buprenorphine per my “line” of opiate dose that constitutes addiction) seem to need to take gastrointestinal prophylaxis drugs.
5. It has lesser risk for addiction. I did have two chronic pain patients over this near-decade develop florid addictive behavior, but one had evidence of addiction to the full agonist opioids, and both had existing significant psychiatric risk for addiction (PTSD, among other psychiatric diseases). This represented a far lower rate of addiction among my patients than I had seen even with the weak, full-agonist Tramadol. Virtually all my Tramadol patients showed addiction. (Based on my observations, I now believe Tramadol should be Schedule II.)
6. My patients have better mood. They show less anxiety and depression on buprenorphine than they had on full agonists. This led me to realize that these patients’ difficult behavior is somewhat iatrogenic, i.e., due to the full agonist opiate. (2)
7. Putting a pain patient on buprenorphine – or even suggesting the drug instead of full agonists – seems to be a litmus test for opioid addiction. That is, patients unwilling to try buprenorphine often “fail” it in favor of full agonists, the most common being oxycodone.
8. I had very few true “failures” of the drug. This was less than in clinical studies with Belbuca, due to my weaning patients off the full agonist first (and thus avoiding any precipitated withdrawal symptoms). In fact, I believe only two patients over this period developed adverse effects from the drug – headache – serious enough to discontinue it from a physiologic perspective. All other cases seem to have been related to addiction: e.g., a patient would say, “It doesn’t treat my pain as well, I need (insert patient’s favorite full agonist).” Claims like this don’t hold much water given buprenorphine’s better neuropathic pain coverage.
9. Buprenorphine is a potent analgesic. It is tightly bound to the μ-opioid receptor; consistent partial activation gives at least as strong a response in the neuron as an on-again/off-again response of a full agonist. Indeed, it is approximately 30 times more potent than morphine.
10. Buprenorphine is better at treating neuralgic pain than other opiates, including methadone, Tramadol, and Tapentadol.

Thankfully, many of the effects of these drugs have now been explained by neuroscientists (e.g., the exemplary work of Linda Watkins, PhD). For example, the action of these drugs on glial cells via activation of TLR4 is now better understood. I believe Dr. Watkins’ work with rodents explains what I have observed for the many years in my human chronic pain patients. Namely, I saw intimately the full agonists’ predilection for so many adverse outcomes: OIH, respiratory depression, constipation, sedation, imbalance, tolerance, dependence, addiction, and even mood disorder. I saw the improvement of mood and function as I transitioned patients from full agonists to buprenorphine.

And the difference with buprenorphine? Buprenorphine does not activate the TLR4 at clinical dosages and therefore does not cause neuroinflammation and may improve the endogenous opioid balance.

For a fairly complete review article on buprenorphine (not including its differential mood effects), see: “12 Reasons to Consider Buprenorphine as a Frontline Analgesic for the Management of Pain” by Mellar Davis, MD.

Patricia L. Little, MD is currently an assistant professor in the University of Tennessee’s Department of Anesthesiology. Conflict of Interest: Dr. Little is a speaker for BDSI, the maker of Belbuca.

This article was kindly edited by Steve Boggs, MD, MBA, Interim Chair, Department of Anesthesiology, University of Tennessee, Health Sciences Center.

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