Skip to main content

Advertisement

SpringerLink
Log in

Cebranopadol for the Treatment of Chronic Pain

  • Chronic Pain Medicine (O Viswanath, Section Editor)
  • Published:
Current Pain and Headache Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Regardless of the etiology, if pain persists chronically, it can detrimentally impact multiple aspects of a patient’s well-being. Both physical and psychological effects are significant in many chronic pain patients. In this regard, psychological consequences can alter a patient’s quality of life, functionality, and social functioning. Opioids have been the long-established gold standard for acute pain treatment in settings such as the postoperative period. An alternative to opioids in pain management has been highly sought after. Through a non-selective mechanism, cebranopadol is a first-in-class oral drug which combines agonism of the mu and nociceptin opioid peptide (NOP) receptors to provide improved analgesia, while reducing the occurrence of many typically opioid side effects. This manuscript is a narrative review of the possible use of cebranopadol in pain management.

Recent Findings

In pre-clinical studies, cebranopadol was similar to morphine in its pain control efficacy. In a phase IIa trial, cebranopadol was superior to placebo in reducing pain. In a randomized clinical trial, cebranopadol was superior to morphine. Another study concluded that cebranopadol had a lower misuse potential when compared to hydromorphone.

Summary

In summary, cebranopadol offers new opportunities in treating chronic moderate to severe pain, while also countering risks of addiction. Additional studies are warranted to further evaluate the safety and efficacy of cebranopadol. In this regard, cebranopadol could prove to be a promising alternative to current pain treatment options.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Data Availability

All data presented in this manuscript is publically available on indexing websites such as PubMed.

References

  1. Loeser JD, Melzack R. Pain: an overview. The Lancet. 1999;353(9164):1607–9.

    Article  CAS  Google Scholar 

  2. Cohen SP, Vase L, Hooten WM. Chronic pain: an update on burden, best practices, and new advances. The Lancet. 2021;397(10289):2082–97.

    Article  Google Scholar 

  3. Glare P, Aubrey KR, Myles PS. Transition from acute to chronic pain after surgery. The Lancet. 2019;393(10180):1537–46.

    Article  Google Scholar 

  4. Rodrigue D, Winkelmann J, Price M, Kalandranis E, Klempner L, Kapoor-Hintzen N. Opioid misuse: an organizational response while managing cancer-related pain. Clin J Oncol Nurs. 2020;24(2):170–6.

    Article  PubMed  Google Scholar 

  5. Anderson DJ, Cao DY, Zhou J, McDonald M, Razzak AN, Hasoon J, et al. Opioids in urology: how well are we preventing opioid dependence and how can we do better? Health Psychol Res. 2022 Sep 15 [cited 2023 Jun 30];10(3). Available from: https://healthpsychologyresearch.openmedicalpublishing.org/article/38243-opioids-in-urology-how-well-are-we-preventing-opioid-dependence-and-how-can-we-do-better.

  6. Virgen CG, Kelkar N, Tran A, Rosa CM, Cruz-Topete D, Amatya S, et al. Pharmacological management of cancer pain: novel therapeutics. Biomed Pharmacother Biomedecine Pharmacother. 2022;156: 113871.

    Article  CAS  Google Scholar 

  7. Gress K, Charipova K, Jung JW, Kaye AD, Paladini A, Varrassi G, et al. A comprehensive review of partial opioid agonists for the treatment of chronic pain. Best Pract Res Clin Anaesthesiol. 2020;34(3):449–61.

    Article  PubMed  Google Scholar 

  8. Berardino K, Carroll AH, Ricotti R, Popovsky D, Civilette MD, Urits I, et al. The ramifications of opioid utilization and outcomes of alternative pain control strategies for total knee arthroplasties. Orthop Rev. 2022 Aug 30 [cited 2023 Jun 30];14(3). Available from: https://orthopedicreviews.openmedicalpublishing.org/article/37496-the-ramifications-of-opioid-utilization-and-outcomes-of-alternative-pain-control-strategies-for-total-knee-arthroplasties.

  9. Vos T, Abajobir AA, Abate KH, Abbafati C, Abbas KM, Abd-Allah F, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet. 2017;390(10100):1211–59.

    Article  Google Scholar 

  10. Merskey H, Bogduk N. Pain terms: a list with definitions and notes on usage. Recommended by the IASP Subcommittee on Taxonomy. Pain. 1979;6(3):249.

    Google Scholar 

  11. Mills SEE, Nicolson KP, Smith BH. Chronic pain: a review of its epidemiology and associated factors in population-based studies. Br J Anaesth. 2019;123(2):e273–83.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Fayaz A, Croft P, Langford RM, Donaldson LJ, Jones GT. Prevalence of chronic pain in the UK: a systematic review and meta-analysis of population studies. BMJ Open. 2016;6(6):e010364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Greenspan JD, Craft RM, LeResche L, Arendt-Nielsen L, Berkley KJ, Fillingim RB, et al. Studying sex and gender differences in pain and analgesia: a consensus report. Pain. 2007;132(Supplement 1):S26-45.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Haliloglu S, Carlioglu A, Akdeniz D, Karaaslan Y, Kosar A. Fibromyalgia in patients with other rheumatic diseases: prevalence and relationship with disease activity. Rheumatol Int. 2014;34(9):1275–80.

    Article  CAS  PubMed  Google Scholar 

  15. Rodriguez-Raecke R, Niemeier A, Ihle K, Ruether W, May A. Brain gray matter decrease in chronic pain is the consequence and not the cause of pain. J Neurosci. 2009;29(44):13746–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gaskin DJ, Richard P. The economic costs of pain in the United States. J Pain. 2012;13(8):715–24.

    Article  PubMed  Google Scholar 

  17. Nahin RL. Estimates of pain prevalence and severity in adults: United States, 2012. J Pain. 2015;16(8):769–80.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Institute of Medicine (US) Committee on Advancing Pain Research, Care, and Education. Relieving pain in America: a blueprint for transforming prevention, care, education, and research. Washington, D.C.: National Academies Press; 2011 [cited 2022 Dec 21]. Available from: http://www.nap.edu/catalog/13172.

  19. Crofford LJ. Adverse effects of chronic opioid therapy for chronic musculoskeletal pain. Nat Rev Rheumatol. 2010;6(4):191–7.

    Article  CAS  PubMed  Google Scholar 

  20. Painter JT, Crofford LJ. Chronic opioid use in fibromyalgia syndrome: a clinical review. J Clin Rheumatol. 2013;19(2):72–7.

    Article  PubMed  Google Scholar 

  21. Kalso E, Edwards JE, Moore AR, McQuay HJ. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain. 2004;112(3):372–80.

    Article  CAS  PubMed  Google Scholar 

  22. Elman I, Borsook D, Lukas SE. Food intake and reward mechanisms in patients with schizophrenia: implications for metabolic disturbances and treatment with second-generation antipsychotic agents. Neuropsychopharmacology. 2006;31(10):2091–120.

    Article  CAS  PubMed  Google Scholar 

  23. Wise RA, Koob GF. The development and maintenance of drug addiction. Neuropsychopharmacology. 2014;39(2):254–62.

    Article  PubMed  Google Scholar 

  24. Elman I, Borsook D. Common brain mechanisms of chronic pain and addiction. Neuron. 2016;89(1):11–36.

    Article  CAS  PubMed  Google Scholar 

  25. Koob G, Le Moal M. Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology. 2001;24(2):97–129.

    Article  CAS  PubMed  Google Scholar 

  26. Mercadante S, Portenoy RK. Opioid poorly-responsive cancer pain. J Pain Symptom Manag. 2001;21(3):255–64.

  27. Cahill CM, Walwyn W, Taylor AMW, Pradhan AAA, Evans CJ. Allostatic mechanisms of opioid tolerance beyond desensitization and downregulation. Trends Pharmacol Sci. 2016;37(11):963–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Volkow ND, McLellan AT. Opioid abuse in chronic pain — misconceptions and mitigation strategies. Longo DL, editor. N Engl J Med. 2016;374(13):1253–63.

  29. Faculty of Pain Medicine. Opioids Aware: a resource for patients and healthcare professionals to support prescribing of opioid medicines for pain. [cited 2022 Dec 21]. Opioids Aware. Available from: https://www.fpm.ac.uk/opioids-aware.

  30. Guy GP, Zhang K, Bohm MK, Losby J, Lewis B, Young R, et al. Vital signs: changes in opioid prescribing in the United States, 2006–2015. MMWR Morb Mortal Wkly Rep. 2017;66(26):697–704.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Nicholson B. Differential diagnosis: nociceptive and neuropathic pain. Am J Manag Care. 2006;12(9 Suppl):S256-262.

    PubMed  Google Scholar 

  32. Yoon SY, Oh J. Neuropathic cancer pain: prevalence, pathophysiology, and management. Korean J Intern Med. 2018;33(6):1058–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bennett MI, Rayment C, Hjermstad M, Aass N, Caraceni A, Kaasa S. Prevalence and aetiology of neuropathic pain in cancer patients: a systematic review. Pain. 2012;153(2):359–65.

    Article  PubMed  Google Scholar 

  34. Boland EG, Mulvey MR, Bennett MI. Classification of neuropathic pain in cancer patients. Curr Opin Support Palliat Care. 2015;9(2):112–5.

    Article  PubMed  Google Scholar 

  35. Fallon MT. Neuropathic pain in cancer. Br J Anaesth. 2013;111(1):105–11.

    Article  CAS  PubMed  Google Scholar 

  36. Lema MJ, Foley KM, Hausheer FH. Types and epidemiology of cancer-related neuropathic pain: the intersection of cancer pain and neuropathic pain. Oncologist. 2010;15(S2):3–8.

    Article  PubMed  Google Scholar 

  37. Sisignano M, Baron R, Scholich K, Geisslinger G. Mechanism-based treatment for chemotherapy-induced peripheral neuropathic pain. Nat Rev Neurol. 2014;10(12):694–707.

    Article  CAS  PubMed  Google Scholar 

  38. Park SB, Goldstein D, Krishnan AV, Lin CSY, Friedlander ML, Cassidy J, et al. Chemotherapy-induced peripheral neurotoxicity: a critical analysis: CIPN: A Critical Analysis. CA Cancer J Clin. 2013;63(6):419–37.

    Article  PubMed  Google Scholar 

  39. Griffith KA, Zhu S, Johantgen M, Kessler MD, Renn C, Beutler AS, et al. Oxaliplatin-induced peripheral neuropathy and identification of unique severity groups in colorectal cancer. J Pain Symptom Manage. 2017;54(5):701-706.e1.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Pachman DR, Qin R, Seisler DK, Smith EML, Beutler AS, Ta LE, et al. Clinical course of oxaliplatin-induced neuropathy: results from the randomized phase III trial N08CB (Alliance). J Clin Oncol. 2015;33(30):3416–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ventzel L, Jensen AB, Jensen AR, Jensen TS, Finnerup NB. Chemotherapy-induced pain and neuropathy: a prospective study in patients treated with adjuvant oxaliplatin or docetaxel. Pain. 2016;157(3):560–8.

    Article  CAS  PubMed  Google Scholar 

  42. Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, Griffin JW, et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology. 2008;70(18):1630–5.

    Article  CAS  PubMed  Google Scholar 

  43. Ballantyne JC, Kalso E, Stannard C. WHO analgesic ladder: a good concept gone astray. BMJ. 2016;6: i20.

    Article  Google Scholar 

  44. 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 

  45. Hershman DL, Lacchetti C, Dworkin RH, Lavoie Smith EM, Bleeker J, Cavaletti G, et al. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2014;32(18):1941–67.

    Article  CAS  PubMed  Google Scholar 

  46. Atkinson TJ, Crowley H. Analgesics of the future: cebranopadol as an opioid alternative. Pract Pain Manag. 2020;20(3).

  47. Ziemichod W, Kotlinska J, Gibula-Tarlowska E, Karkoszka N, Kedzierska E. Cebranopadol as a novel promising agent for the treatment of pain. Molecules. 2022;27(13):3987.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Shen Q, Deng Y, Ciccocioppo R, Cannella N. Cebranopadol, a mixed opioid agonist, reduces cocaine self-administration through nociceptin opioid and mu opioid receptors. Front Psychiatry. 2017;13(8):234.

    Article  Google Scholar 

  49. Göhler K, Sokolowska M, Schoedel KA, Nemeth R, Kleideiter E, Szeto I, et al. Assessment of the abuse potential of cebranopadol in nondependent recreational opioid users: a phase 1 randomized controlled study. J Clin Psychopharmacol. 2019;39(1):46–56.

    Article  PubMed  Google Scholar 

  50. Cox BM, Christie MJ, Devi L, Toll L, Traynor JR. Challenges for opioid receptor nomenclature: IUPHAR Review 9: challenges for opioid receptor nomenclature. Br J Pharmacol. 2015;172(2):317–23.

    Article  CAS  PubMed  Google Scholar 

  51. Reinscheid RK, Nothacker HP, Bourson A, Ardati A, Henningsen RA, Bunzow JR, et al. Orphanin FQ: a neuropeptide that activates an opioidlike G protein-coupled receptor. Science. 1995;270(5237):792–4.

    Article  CAS  PubMed  Google Scholar 

  52. Schröder W, Lambert DG, Ko MC, Koch T. Functional plasticity of the N/OFQ-NOP receptor system determines analgesic properties of NOP receptor agonists: the N/OFQ-NOP receptor system in analgesia. Br J Pharmacol. 2014;171(16):3777–800.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Linz K, Christoph T, Tzschentke TM, Koch T, Schiene K, Gautrois M, et al. Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist. J Pharmacol Exp Ther. 2014;349(3):535–48.

    Article  PubMed  Google Scholar 

  54. Lambert DG, Bird MF, Rowbotham DJ. Cebranopadol: a first in-class example of a nociceptin/orphanin FQ receptor and opioid receptor agonist. Br J Anaesth. 2015;114(3):364–6.

    Article  CAS  PubMed  Google Scholar 

  55. Kleideiter E, Piana C, Wang S, Nemeth R, Gautrois M. Clinical pharmacokinetic characteristics of cebranopadol, a novel first-in-class analgesic. Clin Pharmacokinet. 2018;57(1):31–50.

    Article  CAS  PubMed  Google Scholar 

  56. Wiesenfeld-Hallin Z, Xu XJ, Hughes J, Horwell DC, Hökfelt T. PD134308, a selective antagonist of cholecystokinin type B receptor, enhances the analgesic effect of morphine and synergistically interacts with intrathecal galanin to depress spinal nociceptive reflexes. Proc Natl Acad Sci. 1990;87(18):7105–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Lambert DG. The nociceptin/orphanin FQ receptor: a target with broad therapeutic potential. Nat Rev Drug Discov. 2008;7(8):694–710.

    Article  CAS  PubMed  Google Scholar 

  58. Sałat K, Furgała A, Sałat R. Evaluation of cebranopadol, a dually acting nociceptin/orphanin FQ and opioid receptor agonist in mouse models of acute, tonic, and chemotherapy-induced neuropathic pain. Inflammopharmacology. 2018;26(2):361–74.

    Article  PubMed  Google Scholar 

  59. Eddy NB, Leimbach D. Synthetic analgesics. II. Dithienylbutenyl- and dithienylbutylamines. J Pharmacol Exp Ther. 1953;107(3):385–93.

  60. Sałat K, Podkowa A, Kowalczyk P, Kulig K, Dziubina A, Filipek B, et al. Anticonvulsant active inhibitor of GABA transporter subtype 1, tiagabine, with activity in mouse models of anxiety, pain and depression. Pharmacol Rep PR. 2015;67(3):465–72.

    Article  PubMed  Google Scholar 

  61. Sałat K, Kulig K, Gajda J, Więckowski K, Filipek B, Malawska B. Evaluation of anxiolytic-like, anticonvulsant, antidepressant-like and antinociceptive properties of new 2-substituted 4-hydroxybutanamides with affinity for GABA transporters in mice. Pharmacol Biochem Behav. 2013;110:145–53.

    Article  PubMed  Google Scholar 

  62. Sałat K, Cios A, Wyska E, Sałat R, Mogilski S, Filipek B, et al. Antiallodynic and antihyperalgesic activity of 3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-dihydrofuran-2-one compared to pregabalin in chemotherapy-induced neuropathic pain in mice. Pharmacol Biochem Behav. 2014;122:173–81.

    Article  PubMed  Google Scholar 

  63. Andrea Scholz, MD, John Bothmer, PhD, Maurits Kok, MSc, Kornelia Hoschen, MSc, and Stephen Daniels, DO. Cebranopadol: a novel, first-in-class, strong analgesic: results from a randomized phase IIa clinical trial in postoperative acute pain. Pain Physician. 2018;21(3):E-193-E206.

  64. Eerdekens MH, Kapanadze S, Koch ED, Kralidis G, Volkers G, Ahmedzai SH, et al. Cancer-related chronic pain: investigation of the novel analgesic drug candidate cebranopadol in a randomized, double-blind, noninferiority trial. Eur J Pain Lond Engl. 2019;23(3):577–88.

    Article  CAS  Google Scholar 

  65. Christoph A, Eerdekens MH, Kok M, Volkers G, Freynhagen R. Cebranopadol, a novel first-in-class analgesic drug candidate: first experience in patients with chronic low back pain in a randomized clinical trial. Pain. 2017;158(9):1813–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Dahan A, Boom M, Sarton E, Hay J, Groeneveld GJ, Neukirchen M, et al. Respiratory effects of the nociceptin/orphanin FQ peptide and opioid receptor agonist, cebranopadol, in healthy human volunteers. Anesthesiology. 2017;126(4):697–707.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Fruit St, Boston, MA, 02114, USA

    Amber N. Edinoff

  2. Louisiana Addiction Research Center, Shreveport, LA, 71103, USA

    Amber N. Edinoff, Elyse M. Cornett & Alan D. Kaye

  3. School of Osteopathic Medicine, University of the Incarnate Word, San Antonio, TX, 78235, USA

    Chelsi J. Flanagan

  4. School of Medicine, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, 71103, USA

    Logan T. Roberts & Ross M. Dies

  5. Department of Neurology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, 71103, USA

    Saurabh Kataria

  6. University of Arizona College of Medicine-Phoenix, Phoenix, AZ, 85004, USA

    Eric D. Jackson & Danielle M. Wenger

  7. Department of Anesthesiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, 71103, USA

    Audrey J. DeWitt, Elyse M. Cornett & Alan D. Kaye

  8. Department of Pharmacy Practice, Thomas J. Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, CA, 95211, USA

    Adam M. Kaye

Authors
  1. Amber N. Edinoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chelsi J. Flanagan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Logan T. Roberts
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ross M. Dies
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Saurabh Kataria
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eric D. Jackson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Audrey J. DeWitt
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Danielle M. Wenger
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Elyse M. Cornett
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Adam M. Kaye
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Alan D. Kaye
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.N.E. and A.D.K. were responsible for the conceptualization of the manuscript. A.N.E., C.J.F., L.T.R., R.M.D., and S.K. were responsible for the writing of the original manuscript. A.N.E., E.D.J., A.J.D., D.M.W., E.M.C., A.M.K., and A.D.K. were involved in all revisions of the manuscript. All authors consent to the publication of this manuscript.

Corresponding author

Correspondence to Amber N. Edinoff.

Ethics declarations

Conflict of Interest

The authors have no conflict of interest to declare.

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. This narrative review did not require consent from subjects or review by an institutional review board.

Additional information

Publisher's Note

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Edinoff, A.N., Flanagan, C.J., Roberts, L.T. et al. Cebranopadol for the Treatment of Chronic Pain. Curr Pain Headache Rep 27, 615–622 (2023). https://doi.org/10.1007/s11916-023-01148-9

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11916-023-01148-9

Keywords

Search

Navigation