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Opioid-induced constipation: rationale for the role of norbuprenorphine in buprenorphine-treated individuals

Authors Webster L, Camilleri M, Finn A

Received 21 November 2015

Accepted for publication 21 March 2016

Published 14 June 2016 Volume 2016:7 Pages 81—86


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Professor Li-Tzy Wu

Video abstract presented Lynn R Webster.

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Lynn R Webster,1 Michael Camilleri,2 Andrew Finn3

1PRA Health Sciences, Salt Lake City, UT, 2Mayo Clinic Rochester, MN, 3BioDelivery Sciences, Inc., Raleigh, NC, USA

Abstract: Buprenorphine and buprenorphine–naloxone fixed combinations are effective for managing patients with opioid dependence, but constipation is one of the most common side effects. Evidence indicates that the rate of constipation is lower when patients are switched from sublingual buprenorphine–naloxone tablets or films to a bilayered bioerodible mucoadhesive buccal film formulation, and while the bilayered buccal film promotes unidirectional drug flow across the buccal mucosa, the mechanism for the reduced constipation is unclear. Pharmacokinetic simulations indicate that chronic dosing of sublingually administered buprenorphine may expose patients to higher concentrations of norbuprenorphine than buprenorphine, while chronic dosing of the buccal formulation results in higher buprenorphine concentrations than norbuprenorphine. Because norbuprenorphine is a potent full agonist at mu-opioid receptors, the differences in norbuprenorphine exposure may explain the observed differences in treatment-emergent constipation between the sublingual formulation and the buccal film formulation of buprenorphine–naloxone. To facilitate the understanding and management of opioid-dependent patients at risk of developing opioid-induced constipation, the clinical profiles of these formulations of buprenorphine and buprenorphine-naloxone are summarized, and the incidence of treatment-emergent constipation in clinical trials is reviewed. These data are used to propose a potential role for exposure to norbuprenorphine, an active metabolite of buprenorphine, in the pathophysiology of opioid-induced constipation.

Keywords: opioid, safety, buccal, sublingual, dependence, maintenance

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