Skip to main content


Log in

Tapentadol, Buprenorphine, and Levorphanol for the Treatment of Neuropathic Pain: a Systematic Review

  • Neuropathic Pain (A Abd-Elsayed, Section Editor)
  • Published:
Current Pain and Headache Reports Aims and scope Submit manuscript


Purpose of Review

The objective of this systematic review is to present the available evidence for the utilization of the atypical opioids tapentadol, buprenorphine, and levorphanol for the treatment of neuropathic pain.

Recent Findings

In total, 1619 articles were retrieved of which 10 studies were included. Of 5 included studies pertaining to tapentadol, 4 studies show tapentadol monotherapy to be effective for the treatment of diabetic peripheral neuropathy or chronic, radiating low back pain. Of the 3 studies included for buprenorphine, only one was a randomized controlled trial found not to have a statistically significant reduction in pain with TD buprenorphine likely due to very high withdrawal rates during the trial. Only 2 case reports were included from the available literature for levorphanol providing low-quality anecdotal evidence.


The role of tapentadol, buprenorphine, and levorphanol for neuropathic pain conditions requires robust research including randomized controlled trials to evaluate their efficacy and safety.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data Availability

Not applicable.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. van Hecke O, Austin SK, Khan RA, Smith BH, Torrance N. Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain. 2014;155(4):654–62.

    Article  PubMed  Google Scholar 

  2. IASP Terminology [Internet]. International Association for the Study of Pain Available from: Accessed 3/9/19.

  3. Gierthmühlen J, Baron R. Neuropathic pain. Semin Neurol. 2016;36(5):462–8.

    Article  PubMed  Google Scholar 

  4. Cruccu G, Truini A. A review of neuropathic pain: from guidelines to clinical practice. Pain Ther. 2017;6(Suppl 1):35–42.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Dworkin RH, O’Connor AB, Backonja M, Farrar JT, Finnerup NB, Jensen TS, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain. 2007;132(3):237–51.

    Article  CAS  PubMed  Google Scholar 

  7. Maher DP, Chen L, Mao J. Intravenous ketamine infusions for neuropathic pain management: a promising therapy in need of optimization. Anesth Analg. 2017;124(2):661–74.

    Article  CAS  PubMed  Google Scholar 

  8. Miotto K, Cho AK, Khalil MA, Blanco K, Sasaki JD, Rawson R. Trends in tramadol: pharmacology, metabolism, and misuse. Anesth Analg. 2017;124(1):44–51.

    Article  CAS  PubMed  Google Scholar 

  9. Pergolizzi JV, LeQuang JA, Taylor R, Ossipov MH, Colucci D, Raffa RB. Designing safer analgesics: a focus on μ-opioid receptor pathways. Expert Opin Drug Discovery. 2018;13(10):965–72.

    Article  CAS  Google Scholar 

  10. Dart RC, Cicero TJ, Surratt HL, Rosenblum A, Bartelson BB, Adams EH. Assessment of the abuse of tapentadol immediate release: the first 24 months. J Opioid Manag. 2012;8(6):395–402.

    Article  PubMed  Google Scholar 

  11. Aiyer R, Gulati A, Gungor S, Bhatia A, Mehta N. Treatment of chronic pain with various buprenorphine formulations: a systematic review of clinical studies. Anesth Analg. 2018;127(2):529–38 An important review of buprenorphine for the treatment of chronic pain.

    Article  CAS  PubMed  Google Scholar 

  12. Duehmke RM, Derry S, Wiffen PJ, Bell RF, Aldington D, Moore RA. Tramadol for neuropathic pain in adults. Cochrane Database Syst Rev. 2017;6:CD003726.

    PubMed  Google Scholar 

  13. McNicol ED, Ferguson MC, Schumann R. Methadone for neuropathic pain in adults. Cochrane Database Syst Rev. 2017;5:CD012499.

    PubMed  Google Scholar 

  14. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzche PC, Ioannidis JPA, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62(10):e1–34.

    Article  PubMed  Google Scholar 

  15. Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898.

    Article  PubMed  Google Scholar 

  16. Sterne JAC, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomized studies of interventions. BMJ. 2016;355:i4919.

    PubMed  PubMed Central  Google Scholar 

  17. Baron R, Likar R, Martin-Mola E, Blanco FJ, Kennes L, Muller M, et al. Effectiveness of tapentadol prolonged release (PR) compared with oxycodone/naloxone PR for the management of severe chronic low back pain with a neuropathic component: a randomized, controlled, open-label, phase 3b/4 study. Pain Pract. 2016;16(5):580–99.

    Article  PubMed  Google Scholar 

  18. Baron R, Jansen J-P, Binder A, Pombo-Suarez M, Kennes L, Muller M, et al. Tolerability, safety, and quality of life with tapentadol prolonged release (pr) compared with oxycodone/naloxone pr in patients with severe chronic low back pain with a neuropathic component: a randomized, controlled, open-label, phase 3b/4 trial. Pain Pract. 2016;16(5):600–19.

    Article  PubMed  Google Scholar 

  19. Baron R, Martin-Mola E, Müller M, Dubois C, Falke D, Steigerwald I. Effectiveness and safety of tapentadol prolonged release (PR) versus a combination of tapentadol PR and pregabalin for the management of severe, chronic low back pain with a neuropathic component: a randomized, double-blind, phase 3b study. Pain Pract. 2015;15(5):455–70.

    Article  PubMed  Google Scholar 

  20. Biondi D, Xiang J, Benson C, Etropolski M, Moskovitz B, Rauschkolb C. Tapentadol immediate release versus oxycodone immediate release for treatment of acute low back pain. Pain Phys. 2013;16(3):E237–46.

    Article  Google Scholar 

  21. Schwartz S, Etropolski M, Shapiro DY, Okamoto A, Lange R, Haeussler J, et al. Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: results of a randomized-withdrawal, placebo-controlled trial. Curr Med Res Opin. 2011;27(1):151–62.

    Article  CAS  PubMed  Google Scholar 

  22. Vinik A, Shapiro D, Rauschkolb-Loffler C, Lange B, Karcher K, Pennett D, et al. Efficacy and tolerability of tapentadol extended release (ER) in patients with chronic, painful diabetic peripheral neuropathy (DPN): results of a phase 3, randomized-withdrawal, placebo-controlled study. J Pain. 2012;13(4 SUPPL. 1):S72.

    Article  Google Scholar 

  23. Simpson RW, Wlodarczyk JH. Transdermal buprenorphine relieves neuropathic pain: a randomized, double-blind, parallel-group, placebo-controlled trial in diabetic peripheral neuropathic pain. Diabetes Care. 2016;39(9):1493–500.

    Article  CAS  PubMed  Google Scholar 

  24. Canneti A, Luzi M, Di Marco P, Cannata F, Pasqualitto F, Spinoglio A, et al. Safety and efficacy of transdermal buprenorphine and transdermal fentanyl in the treatment of neuropathic pain in AIDS patients. Minerva Anestesiol. 2013;79(8):871–83.

    CAS  PubMed  Google Scholar 

  25. Penza P, Campanella A, Martini A, Melli G, Lombardi R, Camozzi F, et al. Short- and intermediate-term efficacy of buprenorphine TDS in chronic painful neuropathies. J Peripher Nerv Syst. 2008;13(4):283–8.

    Article  CAS  PubMed  Google Scholar 

  26. Rowbotham MC, Twilling L, Davies PS, Reisner L, Taylor K, Mohr D. Oral opioid therapy for chronic peripheral and central neuropathic pain. N Engl J Med. 2003;348(13):1223–32.

    Article  CAS  PubMed  Google Scholar 

  27. Reddy A, Ng A, Mallipeddi T, Bruera E. Levorphanol for treatment of intractable neuropathic pain in cancer patients. J Palliat Med. 2018;21(3):399–402.

    Article  PubMed  Google Scholar 

  28. Hartrick CT. Tapentadol immediate-release for acute pain. Expert Rev Neurother. 2010;10(6):861–9.

    Article  CAS  PubMed  Google Scholar 

  29. Anderson P. FDA approves tapentadol ER for diabetic neuropathy [Internet]. Medscape. Available from: Accessed 3/16/19.

  30. Gandley A. FDA approves tapentadol for chronic pain [Internet]. Medscape. Available from: Accessed 3/16/19.

  31. Pierce DM, Shipstone E. Pharmacology update: tapentadol for neuropathic pain. Am J Hosp Palliat Care. 2012;29(8):663–6.

    Article  PubMed  Google Scholar 

  32. Zannikos PN, Smit JW, Stahlberg H-J, Wenge B, Hillewaert VM, Etropolski MS. Pharmacokinetic evaluation of tapentadol extended-release tablets in healthy subjects. J Opioid Manag. 2013;9(4):291–300.

    Article  PubMed  Google Scholar 

  33. Kögel B, De Vry J, Tzschentke TM, Christoph T. The antinociceptive and antihyperalgesic effect of tapentadol is partially retained in OPRM1 (μ-opioid receptor) knockout mice. Neurosci Lett. 2011;491(2):104–7 This animal study provides evidence that the noradrenaline reuptake inhibitor mechanism has an analgesic effect in neuropathic pain models.

    Article  PubMed  CAS  Google Scholar 

  34. Brown SM, Holtzman M, Kim T, Kharasch ED. Buprenorphine metabolites, buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide, are biologically active. Anesthesiology. 2011;115(6):1251–60.

    Article  CAS  PubMed  Google Scholar 

  35. Wang Y, Cipriano A, Munera C, Harris SC. Dose-dependent flux of buprenorphine following transdermal administration in healthy subjects. J Clin Pharmacol. 2016;56(10):1263–71.

    Article  CAS  PubMed  Google Scholar 

  36. Kuhlman JJ, Lalani S, Magluilo J, Levine B, Darwin WD. Human pharmacokinetics of intravenous, sublingual, and buccal buprenorphine. J Anal Toxicol. 1996;20(6):369–78.

    Article  CAS  PubMed  Google Scholar 

  37. Lim SCB, Schug S, Krishnarajah J. The pharmacokinetics and local tolerability of a novel sublingual formulation of buprenorphine. Pain Med. 2019;20(1):143–52.

    Article  PubMed  Google Scholar 

  38. Kumar R, Saadabadi A. Buprenorphine. [Updated 2018 Oct 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2018.

    Google Scholar 

  39. Buccal buprenorphine approved for patients with chronic pain [Internet]. Formulary Watch. Available from: Accessed 3/23/19.

  40. Waknine Y. FDA approves 7-day buprenorphine pain patch [Internet]. Medscape. Available from: Accessed 3/23/19.

  41. Commissioner O of the. Press Announcements - FDA approves first once-monthly buprenorphine injection, a medication-assisted treatment option for opioid use disorder [Internet]. Available from: Accessed 3/23/19.

  42. Press Announcements - FDA approves first buprenorphine implant for treatment of opioid dependence [Internet]. Available from: Accessed 3/23/19.

  43. Rosenthal RN, Goradia VV. Advances in the delivery of buprenorphine for opioid dependence. Drug Des Devel Ther. 2017;11:2493–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Andrilla CHA, Moore TE, Patterson DG. Overcoming barriers to prescribing buprenorphine for the treatment of opioid use disorder: recommendations from rural physicians. J Rural Health. 2019;35(1):113–21.

    Article  PubMed  Google Scholar 

  45. Wen Z-H, Chang Y-C, Wong C-S. Implications of intrathecal pertussis toxin animal model on the cellular mechanisms of neuropathic pain syndrome. Acta Anaesthesiol Sin. 2003;41(4):187–96.

    PubMed  Google Scholar 

  46. Womer DE, DeLapp NW, Shannon HE. Intrathecal pertussis toxin produces hyperalgesia and allodynia in mice. Pain. 1997;70(2–3):223–8.

    Article  CAS  PubMed  Google Scholar 

  47. Wheeler-Aceto H, Cowan A. Buprenorphine and morphine cause antinociception by different transduction mechanisms. Eur J Pharmacol. 1991;195(3):411–3.

    Article  CAS  PubMed  Google Scholar 

  48. Gudin J, Fudin J, Nalamachu S. Levorphanol use: past, present and future. Postgrad Med. 2016;128(1):46–53.

    Article  PubMed  Google Scholar 

  49. Prommer E. Levorphanol: the forgotten opioid. Support Care Cancer. 2007;15(3):259–64.

    Article  PubMed  Google Scholar 

  50. Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10(9):895–926.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Inquimbert P, Moll M, Latremoliere A, Tong CK, Whang J, Sheehan GF, et al. NMDA receptor activation underlies the loss of spinal dorsal horn neurons and the transition to persistent pain after peripheral nerve injury. Cell Rep. 2018;23(9):2678–89 This study demonstrates in a mouse model evidence that NMDA receptor activation plays a role in the transition from acute to chronic neuropathic pain states.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lutfy K, Cowan A. Buprenorphine: a unique drug with complex pharmacology. Curr Neuropharmacol. 2004;2(4):395–402.

    Article  CAS  PubMed  Google Scholar 

  53. Wiffen PJ, Derry S, Moore RA, Stannard C, Aldington D, Cole P, et al. Buprenorphine for neuropathic pain in adults. Cochrane Database Syst Rev. 2015;9:CD011603.

    Google Scholar 

  54. Bouhassira D, Attal N, Fermanian J, Alchaar H, Gautron M, Masquelier E, et al. Development and validation of the Neuropathic Pain Symptom Inventory. Pain. 2004;108(3):248–57.

    Article  PubMed  Google Scholar 

  55. Attal N, Lanteri-Minet M, Laurent B, Fermanian J, Bouhassira D. The specific disease burden of neuropathic pain: results of a French nationwide survey. Pain. 2011;152(12):2836–43.

    Article  PubMed  Google Scholar 

Download references

Code Availability

Not applicable.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Samantha C. Erosa.

Ethics declarations

Conflict of Interest

Dr. Samantha Erosa and Dr. Paul Haffey have no conflicts of interest to report nor was any financial support received by any of the authors, either directly or indirectly, for this publication.

Dr. Amitabh Gulati is a consultant for Medtronic, Flowonix, and AIS. Dr. Neel Mehta is a consultant for Biodelivery Sciences, Nevro, Salix Pharmaceuticals, and Sollis Therapeutics.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Neuropathic Pain

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Erosa, S.C., Haffey, P.R., Mehta, N. et al. Tapentadol, Buprenorphine, and Levorphanol for the Treatment of Neuropathic Pain: a Systematic Review. Curr Pain Headache Rep 25, 18 (2021).

Download citation

  • Accepted:

  • Published:

  • DOI: