Background     Buprenorphine is an opioid agonist/antagonist that is used sublingually for opioid misuse disorder (see Fast Fact #221).  In 2010, the Food and Drug Administration approved a buprenorphine transdermal system (the ‘Butrans®’ patch) for analgesic use in the United States. This Fast Fact reviews the use of buprenorphine patch for pain, with applications in different patient populations.  

Pharmacology     Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappa- and delta-opioid receptors. It is metabolized mainly in the liver via Phase I biotransformation of buprenorphine to its active metabolite nor-buprenorphine (1). Nor-buprenorphine exhibits high affinity for μ (mu), δ (delta), and κ (kappa) opioid receptors. Compared to usual opioids, nor-buprenorphine is less lipophilic and less likely to cross the blood brain barrier. Based on these pharmacological properties, buprenorphine provides analgesia with decreased incidence of sedation, euphoria, and respiratory depression compared to other opioids (1).  A ceiling effect for pain relief, previously identified in animals and humans, has not been found at the lower doses used for analgesia. In transdermal doses up to 70 mcg/hr, buprenorphine does not antagonize the effect of other opioids used for breakthrough pain (2).

Equianalgesic Ratios     Buprenorphine is effective parenterally for post-operative pain; 0.3 mg is equianalgesic to 10 mg IV morphine.   A trial of sublingual buprenorphine for pain (an off-label use in the U.S.) found that 0.4 mg is as effective for acute pain as 5 mg IV morphine (3). The transdermal buprenorphine to oral morphine equianalgesic ratio has been reported to be between 1:70 to 1:115 (e.g., 100 mg of oral morphine/24 hours ≈ 0.87-1.42 mg transdermal buprenorphine/24hr ≈ 36-59 mcg/hr transdermal buprenorphine).  The transdermal buprenorphine:fentanyl ratio is reported to be 0.8 mcg buprenorphine to 0.6 mcg fentanyl (4) (e.g., 20 mcg/hour of transdermal buprenorphine is approximately equivalent to 12 mcg/hour of transdermal fentanyl). 

Using the Low-Dose Buprenorphine Patch    The U.S. formulation of the buprenorphine transdermal patch is available in strengths of 5, 10, and 20 mcg/hour, and is worn for seven days at a time.  The patch has been studied in opioid naïve patients (16), but the 20 mcg/hour patch is not intended for initial use.  The safety and efficacy of transdermal buprenorphine has not been fully established in children. In children >13 years of age, the dosing is felt to be equivalent to adults.  Buprenorphine reaches a steady state level 48 hours after application of the first patch, and, with a terminal half-life of 26 hours, levels decline slowly after patch removal. Withdrawal symptoms tend to be milder than with other long-acting opioids (5). Use of more than one patch at a time is not recommended due to risk of QT prolongation, with a mean QTc prolongation of 9.2 ms at a dose of 40 mcg/hour (6).  Hence, the buprenorphine patch, is usually not a practical analgesic option for patients with relatively high opioid requirements (>80 mg/day of oral morphine daily equivalents).  Note: in Europe doses between 70-210 mcg/hour have been used for cancer pain with a different patch system (7). 

Initiating the Low-Dose Buprenorphine Patch (Manufacturer’s Recommendations) ⁽⁶⁾

Baseline Daily Oral Morphine Equivalent	Starting Patch Dose
<30 mg	5 mcg/hour
30-80 mg	10 mcg/hour
>80 mg/day	Usage not recommended

Clinical Applications    The buprenorphine patch has shown to be non-inferior to other opioids in studies of chronic lower back pain, osteoarthritis, and cancer pain (8).   Because of its kappa antagonism, it has theoretical advantages in the treatment of neuropathic pain, though evidence for this is limited to case reports (9, 10).  It has also been shown experimentally to have antihyperalgesic effects (11).  Other advantages of buprenorphine include a decreased risk of respiratory depression and a lack of accumulation in renal failure, including in hemodialysis patients (12).  Some studies have reported less constipation, nausea, and sedation with buprenorphine (13,14). In a trial comparing transdermal buprenorphine in patients over 65 with younger patients, older patients had equivalent analgesia without any differences in accumulation of buprenorphine or its metabolites (15). 

Cost     The average wholesale price for a month’s supply of four 10 mcg patches is $336.

Summary     The buprenorphine patch is a reasonable analgesic option in patients with low opioid requirements, especially patients with chronic kidney disease and/or patients who are older, frailer, or at heightened risk of intolerable side effects from other opioids.  

References

1. Johnson RE, Fudula PJ, Payne R.  Buprenorphine:  considerations for pain management.  J Pain Symptom Manage. 2005; 29:297-326.
2. Mercadante S, Villari P, Ferrera P, et al. Safety and effectiveness of intravenous morphine for episodic breakthrough pain in patients receiving transdermal buprenorphine.  J Pain Symptom Manage. 2006;32:175-9.  
3. Jalili M, Fathi M, Moradi-Lakeh M, Zehtabchi S.  Sublingual Buprenorphine in Acute Pain Management: A Double-Blind Randomized Clinical Trial.  Ann Emerg Med. 2012; 59:276-80. PMID 22115823.
4. Mercadante S, Casuccio A, Tirelli W, Giarratano A.  Equipotent doses to switch from high doses of opioids to transdermalbuprenorphine.  Support Care Cancer. 2009; 17: 715-8.
5. Jasinski DR, Pevnick JS, Griffith JD. Human pharmacology and abuse potential of the analgesic buprenorphine: a potentialagent for treating narcotic addiction.  Arch Gen Psychiatry. 1978;35: 501-16.
6. Purdue Pharma. Available at: http://www.purduepharma.com/pi/prescription/ButransPI.pdf. Accessed February 23, 2012.Mercadante S, Ferrera P, Villari P.  Is there a ceiling effect of transdermal buprenorphine? Preliminary data in cancer patients.  Support Care Cancer. 2007;15: 441-4.  
7. Pergolizzi JV Jr, Mercadante S, Echaburu AV, et al.  The role of transdermal buprenorphine in the treatment of cancer pain: an expert panel consensus.  Curr Med Res Opin. 2009; 25:1517-28.
8. Rodriguez-Lopez M. Transdermal buprenorphine in the management of neuropathic pain. Rev Soc Esp Dolor. 2004;11(Suppl V):11-21.
9. Penza P, Campanella A, Martini A, et al.  Short- and intermediate-term efficacy of buprenorphine  TDS in chronic painful neuropathies.  J Peripher Nerv Syst. 2008;13: 283-288.  
10. Koppert W, Ihmsen H, Körber N, et al. Different profiles of buprenorphine-induced hyperalgesia and antihyperalgesia in a human pain model.  Pain. 2005;118: 15-22.  
11. Pergolizzi J, Aloisi AM, Dahan A, et al.  Current knowledge of buprenorphine and its unique pharmacological profile.  Pain Pract.2010;10: 428-50. 
12. Likar R, Vadlau EM, Breschan C, Kager I, Korak-Leiter M, Ziervogel G.  Comparable analgesic efficacy of transdermal buprenorphine in patients over and under 65 years of age.  Clin J Pain. 2008;24:536-43.
13. Bach V, Kamp-Jensen M, Jensen NH, et al. Buprenorphine and sustained release morphine – effect and side-effects in chronic use. The Pain Clinic. 1991;4:87–93.
14. R. Likar, H. Kayser and R. Sittl. Long-term management of chronic pain with transdermal buprenorphine: a multicenter, open-label, follow-up study in patients from three short-term clinical trials. Clin Ther. 2006; 28: 943–52.
15. Steiner D, Sitar S, Wen W, et al. Efficacy and safety of the seven-day buprenorphine transdermal system in opioid-naïve patients with moderate to severe chronic low back pain: an enriched, randomized, double-blind, placebo-controlled study. J Pain Symptom Manage. 2011;42:903-917.

Conflicts of Interest Statement:   The authors have no relevant conflicts of interest to disclose.   

Authors’ Affiliation: University of Pittsburgh Medical Center, Pittsburgh, PA.

Version History:  First published July 2013. Re-copy-edited in September 2015 with pricing information updated and pediatric information added. Further updates in October 2020 by Dr. Kelvin Lou.