Efficacy and Tolerability of Co-Administering Full µ-Opioid Receptor Agonists with Buprenorphine and Mixed Opioid Agonists

We read with great interest the paper by van Niel, J. Schneider and Tzschentke [1] titled “Efficacy of Full μ-Opioid Receptor Agonists is not Impaired by Concomitant Buprenorphine or Mixed Opioid Agonists/Antagonists – Preclinical and Clinical Evidence”. The authors describe overall evidence on analgesic effects of buprenorphine, pentazocine or nalbuphine in co-administration with opioid analgesics, under various clinical pain conditions. They contradict the consensus that these compounds diminish μ-opioid (MOP) receptor analgesia when co-administered with a full MOP receptor agonist and may potentially provoke opioid withdrawal [1].

We would like to commend van Niel, J. Schneider and Tzschentke for their insightful and comprehensive study on this specific topic. We believe such an investigation is critically needed; and their conclusions may have far-reaching clinical impact.

As concluded by van Niel, J. Schneider and Tzschentke, buprenorphine, which clinically behaves as a full MOP receptor agonist, can be co-administered safely with full opioid agonists without precipitating withdrawal. However, in the FDA-approved package insert (FDA-PI) of buprenorphine, there is a statement claiming “Because of the partial agonist properties of buprenorphine, sublingual tablets may precipitate opioid withdrawal signs and symptoms in individuals physically dependent on full opioid agonists, if administered sublingually or parenterally before the agonist effects of other opioids have subsided” [2]. This may be an example of ill-founded information, which may be included into textbooks and official labels, impacting physicians in practice. As a matter of fact, the term “opioid withdrawal” has been mentioned over 20 times in the buprenorphine FDA-PI. Yet, both the preclinical and clinical data reviewed by van Niel et al. clearly demonstrate that buprenorphine can be combined with a full MOP agonist without precipitating opioid withdrawal. Further, many physicians prescribe buprenorphine patches for moderate to severe persistent pain, together with an immediate-release opioid analgesic, such as morphine or hydrocodone, for breakthrough pain, without encountering withdrawal symptoms.

We wonder, therefore, if the withdrawal symptoms listed in the FDA-PI were an exaggerated untoward effect, rather than true opioid withdrawal symptoms. Thus, we re-visited the clinical trial adverse events data referenced for Buprenorphine in the FDA-PI. To our surprise, the percentage of withdrawal symptoms was significantly lower in subjects taking buprenorphine (18.4%,19/103) than in those taking placebo (37.4%, 40/107) [2]. How then, is it possible that the placebo group reported more opioid withdrawal symptoms than the buprenorphine group? These data beg for additional questions as to the validity of the reported “opioid withdrawal symptoms” in reported trials. We wonder whether buprenorphine actually provokes any opioid withdrawal at all?

Opioid receptors were first identified in the brain and spinal cord four decades ago and there continues to be an evolving understanding of opioid pharmacology and physiology. Many experts believe we are only in our early stages of clearly understanding different opioid agents at a true molecular level. In this regard, van Niel et al. did not mention or review any data on butorphanol, another mixed opioid agnist/antagonist, which is widely prescribed in clinical practice. We wonder, therefore, if there are similar data concerning butorphanol when used in combination with other full opioid agonist(s). In our clinical practices, we have not encountered any withdrawal problems in patients who used butorphanol for headaches, while being prescribed other opioid(s) for severe chronic pain states.

In summary, the present investigation provides an excellent review and summary of both preclinical and clinical data in the combined usage of full-opioid agonist partial or mixed opioid agonist. We believe that at a minimum, the “withdrawal warning” in the FDA-PI should be updated to reflect our improved body of literature. Inaccurate statements as described not only deter trials of potentially combinational synergistic therapy, but also lead to confusion and to erroneous conclusions. There are both obvious medical and legal ramifications from these type of faulty conclusions, e. g. unsubstantiated assertions. Describing an alleged dangerous opioid withdrawal symptom, referenced in the “warning” in the described PIs and others, can increase litigation and reflect scientific falsehood which can confuse physicians in their attempt to provide the best care to their patients.

• References

• 1 van Niel J.C.G., Schneider J., Tzschentke T.M. 2016. Efficacy of Full μ-Opioid Receptor Agonists is not Impaired by Concomitant Buprenorphine or Mixed Opioid Agonists/Antagonists–Preclinical and Clinical Evidence. Drug Research
• 2 TYA Pharmaceuticals . 2016 , March 14). Buprenorphine Hydrochloride (TYA Pharmaceuticals): FDA Package Insert, Page 3. Retrieved August 24, 2016, from http://medlibrary.org/lib/rx/meds/buprenorphine-hydrochloride-11/page/3/