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Written by

Professor Robert B Raffa Professor Robert B Raffa is professor of pharmacology, Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, Pennsylvania, US

Dr Joseph V Pergolizzi Jr Dr Joseph V Pergolizzi Jr is an adjunct assistant professor, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, US

Buprenorphine: a review of pharmacology

Published 18 May 2016

Buprenorphine is a complex molecule associated with a number of myths about its pharmacology and mechanism of action, write Professor Robert Raffa and Dr Joseph Pergolizzi

Key learning points

  • Buprenorphine has a multimechanistic pharmacological profile.
  • Buprenorphine is a centrally acting analgesic. It does not have a local anaesthetic action, and does not inhibit cyclo-oxygenase isozymes (COX-1 or COX-2).
  • Buprenorphine is successfully used for managing a variety of pain types.

Buprenorphine was first synthesised in the late 1960s;1 at the time, studies lacked methodological standards that would be considered fundamental today and investigators had to interpret their data based on limited pharmacological knowledge. Given these circumstances, it is not surprising that myths about buprenorphine arose. What is surprising, however, is that some persist despite clear evidence to the contrary.

Buprenorphine is successfully used for managing a variety of pain types, including nociceptive, musculoskeletal, neuropathic and cancer pains.2

Buprenorphine is a semi-synthetic opioid, derived from thebaine, and buprenorphine and morphine have similar molecular structures.3 But the molecules are sufficiently different that each has its own unique pharmacology and clinical attributes.3 Buprenorphine is a centrally acting analgesic.3 It does not have a local anaesthetic action and does not inhibit cyclo-oxygenase isozymes (COX-1 or COX-2).3

Binding at opioid receptors

The literature on buprenorphine’s binding profile at opioid receptors is extensive. However, while buprenorphine is consistently regarded as an agonist at mu-opioid receptors, the literature is inconsistent with regard to buprenorphine’s affinity to delta-opioid and kappa-opioid receptors, where it is variably said to be an agonist, antagonist or even inverse agonist at these receptors.2,3

Buprenorphine is often referred to as a partial agonist, that is, it demonstrates less intrinsic effect in assays than that of a full agonist, morphine.4,5 However, it is possible for the same compound, and this is true of both morphine and buprenorphine, to be a partial agonist in some laboratory tests, and be a full agonist in the clinical setting.2,4

Buprenorphine’s intrinsic activity on second-messenger transduction mechanisms has also been compared with morphine in a variety of cell lines, and the key feature of its antinociceptive efficacy has been assessed in standard preclinical models of acute and nociceptive pain.2,6,7

Despite it’s characterisation as a partial agonist in vitro, in a review, buprenorphine was shown to produce the same level of analgesic effect as the full agonists morphine, fentanyl, sufentanil and oxycodone, indicating that the designation of buprenorphine as a partial agonist cannot be generalised to analgesia.2

Switching to buprenorphine

In managing pain, clinicians may consider switching a patient from one opioid to another opioid (opioid rotation). There is a myth that opioid rotation is not possible with buprenorphine, because, being a partial mu-agonist, it should precipitate withdrawal when administered to a patient who is taking a full agonist opioid, thus having an antagonistic effect on other opioids. This myth likely originated from projections from some test-tube and animal studies, over-interpretation of radioligand binding data, and misunderstanding about fundamental pharmacologic principles, particularly as related to the difference between intrinsic activity and clinical efficacy. We have discussed these elsewhere.4

It is certainly true that a molecule with a higher affinity (for example, buprenorphine) will displace a molecule of lower affinity (other opioids). However, there is no evidence that buprenorphine needs to occupy all of the mu-opioid receptor population to produce analgesia (that is, that there is no receptor reserve). In fact there is evidence to the contrary.2,8 Further, complete displacement of a full agonist by a partial agonist does not result in complete reversal of the full agonist effect. Instead, the effect – necessarily from fundamental principles5 – plateaus at the same level observed when the partial agonist is given alone. Full reversal can only be produced by an antagonist,5 which buprenorphine is not.

To counter the myth that buprenorphine has an antagonist effect on other opioids, Kögel et al administered morphine, oxycodone or hydromorphone to animals that were pretreated with buprenorphine.9 They demonstrated that the analgesic effects were not blocked, but were additive with that of buprenorphine.9 The same was true when buprenorphine was administered after the other opioids. That is, the combination of buprenorphine with other opioids produced greater effect, not less.9

Respiratory depression

Buprenorphine is multimechanistic. Its mechanism of action includes at least the opioid receptors, the ORL-1 (nociceptin) receptor and likely another (non-opioid) component.8,10,11 In contrast to other opioids, buprenorphine has been demonstrated to have a dose-ceiling effect with respect to respiratory depression, but not on analgesia.12 This finding may be due to its different receptor binding profile compared with other opioids.

Conclusion

It is important to address myths about buprenorphine because the drug has distinct attributes not shared by most of the other opioids.12 The extent to which these attributes might be important to a particular patient is a clinical decision; however, the decision should be informed by pharmacology and unbiased clinical evaluation, not by preconceived notions or myths.

  • Professor Robert B Raffa is professor of pharmacology, Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, Pennsylvania, US and Dr Joseph V Pergolizzi Jr is an adjunct assistant professor, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, US

References

  1. Budd K, Raffa RB. Introduction. In: Budd K, Raffa RB (editors). Buprenorphine – the unique opioid analgesic. Stuttgart, Thieme, 2005.
  2. Raffa RB, Haidery M, et al. Journal of Clinical Pharmacy and Therapeutics 2014;39(6):577–583.
  3. Cowan A, Friderichs E, et al. 1 Basic Pharmacology of Buprenorphine. In: Budd K, Raffa RB (editors). Buprenorphine – the unique opioid analgesic. Stuttgart, Thieme, 2005.
  4. Raffa RB, Pergolizzi JV Jr. Practical Pain Management 2013;13(8):33–39.
  5. Rang HP, Dale MM, et al. Chapter 2 How Drugs Act: General Principles. In: Rang HP, Dale MM, et al (editors). Rang and Dale’s Pharmacology. 7th edition. Edinburgh, Elsevier Churchill Livingstone, 2012.
  6. Traynor JR. Reviews in Analgesia 2004;8(1):11–22.
  7. Pergolizzi J, Aloisi AM, et al. Pain Practice 2010;10(5):428–450.
  8. Raffa RB, Ding Z. Acute Pain 2007;9(3):145–152.
  9. Kögel B, Christoph T, et al. European Journal of Pain 2005;9(5):599–611.
  10. Tallarida RJ, Cowan A, et al. Drug & Alcohol Dependence 2010;109(1–3):126–129.
  11. Ding Z, Raffa RB. British Journal of Pharmacology 2009;157(5):831–843.
  12. Davis MP. Journal of Supportive Oncology 2012;10(6):209–219.

Date of preparation: May 2016; MINT/PAEU-16003