Benefit-Risk Analysis of Buprenorphine for Pain Management

Figures & data

Figure 1 Mechanism of Action of Buprenorphine at Opioid and NOP Receptors. At µ-opioid receptors, buprenorphine is a partial agonist with very high binding affinity, which results in potent analgesia, contributes to a ceiling effect on respiratory depression and euphoria, and reduces other adverse events commonly observed with opioid use owing to unique phosphorylation and signaling activity. Buprenorphine has antagonistic activity with high binding affinity at κ- and δ-opioid receptors, which may limit constipation, respiratory depression, dysphoria, and substance abuse. The agonistic activity and low binding affinity at the NOP receptor contribute to spinal analgesia and may limit the substance abuse potential and tolerance commonly observed with full µ-opioid receptor agonists.

Abbreviations: NOP, nociceptin; OR, opioid receptor.

Table 1 Buprenorphine Products

FDA-Approved Indication	Pain Management			Addiction Medicine
	Acute Pain	Chronic Pain		OUD		Opioid Dependence
Trade name	Buprenex	Belbuca	Butrans	Brixadi^a	Sublocade	Probuphine	Generic Subutex
Route of administration	Injection	Buccal	Transdermal	Injection	Injection	Implant	Sublingual
Available dose range	300 µg/mL	75, 150, 300, 450, 600, 750, or 900 µg	5, 7.5, 10, 15, or 20 µg/h	8, 16, 24, or 32 mg weekly; 64, 96, or 128 mg monthly	100 and 300 mg/month	74.2 mg/6 months	2 or 8 mg
Bioavailability	100%	46%-65%	15%	100%	100%	N/A	15%-30%

Notes: Combination products are not included. Please see package inserts for full indication, dosing, and REMS requirements for each product. ^aTentative FDA approval.

Abbreviations: FDA, US Food and Drug Administration; OUD, opioid use disorder; REMS, Risk Evaluation and Mitigation Strategies.

Figure 2 Pain Relief Induced by Intramuscular Morphine or Sublingual Buprenorphine Following Surgery. Pain scores were determined using a VAS after the administration of 0.4 mg SL buprenorphine or an injection of 10 mg/mL morphine. *p<0.05 for comparisons between groups at that time.

Notes: Data from Edge et al (1979).⁴¹ Abbreviations: h, hour(s); SL, sublingual; VAS, visual analog scale.

Figure 3 Efficacy of Transdermal Buprenorphine Compared With Conventional Opioids in Patients With Chronic Cancer Pain. Average pain intensity was measured on a numeric rating scale. Data are mean (SD). Data from Corli et al (2016).⁴⁵

Figure 4 Efficacy of Buprenorphine Buccal Film in Patients With Chronic Low Back Pain. Mean NRS scores during the titration and long-term treatment phases with buprenorphine buccal film in (A) de novo patients and (B) rollover patients.

Notes: Copyright ©2017. Dove Medical Press. Reproduced from Hale M, Urdaneta V, Kirby MT, Xiang Q, Rauck R. Long-term safety and analgesic efficacy of buprenorphine buccal film in patients with moderate-to-severe chronic pain requiring around-the-clock opioids. J Pain Res. 2017;10:233–240.⁵⁰Abbreviation: NRS, numerical rating scale.

Figure 5 Efficacy of the Transdermal and Buccal Film Formulations of Buprenorphine. Responder analysis of similar opioid-experienced chronic pain clinical trials. Comparisons are of efficacy data for transdermal buprenorphine (20 μg/h) and buprenorphine buccal film (150–900 μg/12h) with response defined as (A) ≥30% or (B) ≥50% reduction in pain intensity.

Notes: Copyright ©2019. Dove Medical Press. Adapted from Pergolizzi JV, Jr., Raffa RB. Safety and efficacy of the unique opioid buprenorphine for the treatment of chronic pain. J Pain Res. 2019;12:3299–3317.⁷

Figure 6 Effect of Buprenorphine Buccal Film and Oxycodone Hydrochloride on Minute Ventilation. Effect of each drug treatment on respiratory drive: mean minute ventilation over time. In the partial completer population (n=16), mean minute ventilation for BBF was not significantly different from placebo at any time point. *p<0.05, **p<0.01, ***p<0.001.

Notes: Reprinted by permission from Springer Nature, Adv Ther, Webster LR, Hansen E, Cater J, Smith T, Phase A. I placebo-controlled trial comparing the effects of buprenorphine buccal film and oral oxycodone hydrochloride administration on respiratory drive.  Copyright 2020;37(11):4685–4696.⁵⁴Abbreviations: BBF, buprenorphine buccal film; Oxy, oxycodone.

Figure 7 Adverse Events Reported in Clinical Trials of Buprenorphine Buccal Film Compared With Conventional Opioids for Chronic Pain. The percentage of patients who reported adverse events in clinical trials for buprenorphine buccal film²¹ compared with those reported for extended-release formulations of oxymorphone,⁸⁷ hydromorphone,⁸⁸ and oxycodone.⁶⁹

Notes: Copyright ©2019. Dove Medical Press. Adapted from Pergolizzi JV, Jr., Raffa RB. Safety and efficacy of the unique opioid buprenorphine for the treatment of chronic pain. J Pain Res. 2019;12:3299–3317.⁷

Edge WG, Cooper GM, Morgan M. Analgesic effects of sublingual buprenorphine. Anaesthesia. 1979;34(5):463–467. doi:10.1111/j.1365-2044.1979.tb06325.x

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 PubMed Web of Science ®Google Scholar

Hale M, Urdaneta V, Kirby MT, Xiang Q, Rauck R. Long-term safety and analgesic efficacy of buprenorphine buccal film in patients with moderate-to-severe chronic pain requiring around-the-clock opioids. J Pain Res. 2017;10:233–240. doi:10.2147/JPR.S120170

 PubMed Web of Science ®Google Scholar

Pergolizzi JV Jr., Raffa RB. Safety and efficacy of the unique opioid buprenorphine for the treatment of chronic pain. J Pain Res. 2019;12:3299–3317. doi:10.2147/JPR.S231948

 PubMed Web of Science ®Google Scholar

Webster LR, Hansen E, Cater J, Smith T, Phase A. I placebo-controlled trial comparing the effects of buprenorphine buccal film and oral oxycodone hydrochloride administration on respiratory drive. Adv Ther. 2020;37(11):4685–4696. doi:10.1007/s12325-020-01481-0

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