Skip to main content
SpringerLink
Log in

Complex Persistent Opioid Dependence—an Opioid-induced Chronic Pain Syndrome

  • Palliative and Supportive Care (J Hardy, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

Long-term opioid therapy (LTOT) for chronic cancer and non-cancer pain is commonly ineffective in providing its stated goal of improving function through good control of pain. Opioid tapering (slow dose reduction and/or discontinuation), the logical solution, also appears to be ineffective among many patients on LTOT as it often leads to even worse pain control and function, leaving the patients and providers managing LTOT in a clinical conundrum with little treatment choices. Complex persistent opioid dependence (CPOD) was recently offered as a heuristic to explain this clinical conundrum exemplified by the ineffectiveness of both LTOT and opioid tapering. This manuscript provides a detailed description of the neurobehavioral underpinnings of CPOD, explaining how long-term opioid use can lead to more pain even while experiencing relief with each opioid dose. CPOD is characterized by the allostatic opponent mechanisms of neuroadaptations related to the progression of opioid dependence and tolerance involving nociceptive/anti-nociceptive brain systems causing opioid-induced hyperalgesia and reward/anti-reward systems causing hyperkatefia or suffering that induces pain experience through the cognitive/emotional component of pain mechanisms. “Opioid Induced Chronic Pain syndrome” (OICP) is offered as an alternate clinical diagnostic term instead of CPOD that has several limitations as a diagnosis term including poor patient acceptance due to stigma towards addiction and clinical confounding with opioid use disorder, a related but separate clinical entity. OICP with LTOT is conceptualized as a recoverable iatrogenic problem that can be managed by pain providers. Broad guidance on management of OICP is also provided.

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

References and Recommended Reading

  1. Mojtabai R. National trends in long-term use of prescription opioids. Pharmacoepidemiol Drug Saf. 2018;27(5):526–34. https://doi.org/10.1002/pds.4278.

    Article  PubMed  Google Scholar 

  2. Shah D, Zhao X, Wei W, Gandhi K, Dwibedi N, Webster L, Sambamoorthi U. A longitudinal study of the association of opioid use with change in pain interference and functional limitations in a nationally representative cohort of adults with osteoarthritis in the United States. Adv Ther. 2020;37(2):819–32. https://doi.org/10.1007/s12325-019-01200-4.

    Article  CAS  PubMed  Google Scholar 

  3. Krebs EE, Clothier B, Nugent S, Jensen AC, Martinson BC, Goldsmith ES, Donaldson MT, Frank JW, Rutks I, Noorbaloochi S. The evaluating prescription opioid changes in veterans (EPOCH) study: design, survey response, and baseline characteristics. PLoS One. 2020;15(4):e0230751. https://doi.org/10.1371/journal.pone.0230751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Chou R, et al. Opioid treatments for chronic pain [Internet]- Comparative Effectiveness Review, No. 229. Avilable at https://www.ncbi.nlm.nih.gov/books/NBK556253/?report=classic. 2020, Rockville, MD: Agency for Healthcare Research and Quality (US).

  5. Serrie A, Lange B, Steup A. Tapentadol prolonged-release for moderate-to-severe chronic osteoarthritis knee pain: a double-blind, randomized, placebo- and oxycodone controlled release-controlled study. Curr Med Res Opin. 2017;33(8):1423–32. https://doi.org/10.1080/03007995.2017.1335189.

    Article  CAS  PubMed  Google Scholar 

  6. Borchgrevink PC. Long-term low-dose transdermal buprenorphine therapy for chronic noncancer pain. Scand J Pain. 2010;1(3):120–1. https://doi.org/10.1016/j.sjpain.2010.05.034.

    Article  PubMed  Google Scholar 

  7. Krebs EE, Gravely A, Nugent S, Jensen AC, DeRonne B, Goldsmith ES, Kroenke K, Bair MJ, Noorbaloochi S. Effect of opioid vs nonopioid medications on pain-related function in patients with chronic back pain or hip or knee osteoarthritis pain: the SPACE randomized clinical trial. JAMA. 2018;319(9):872–82. https://doi.org/10.1001/jama.2018.0899.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Quinlan J, Willson H, Grange K. Hopes and fears before opioid tapering: a quantitative and qualitative study of patients with chronic pain and long-term opioids. Br J Pain. 2021;15(2):120–8. https://doi.org/10.1177/2049463720974053.

    Article  PubMed  Google Scholar 

  9. Schneider MDPJP, Kirsh PKL. Defining clinical issues around tolerance, hyperalgesia, and addiction: a quantitative and qualitative outcome study of long-term opioid dosing in a chronic pain practice. J Opioid Manag. 2010;6(6):385–95. https://doi.org/10.5055/jom.2010.0036.

    Article  PubMed  Google Scholar 

  10. Frank JW, Levy C, Matlock DD, Calcaterra SL, Mueller SR, Koester S, Binswanger IA. Patients’ perspectives on tapering of chronic opioid therapy: a qualitative study. Pain Med. 2016;17(10):1838–47. https://doi.org/10.1093/pm/pnw078.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Larochelle MR, Liebschutz JM, Zhang F, Ross-Degnan D, Wharam JF. Opioid prescribing after nonfatal overdose and association with repeated overdose: a cohort study. Ann Intern Med. 2016;164(1):1–9. https://doi.org/10.7326/M15-0038.

    Article  PubMed  Google Scholar 

  12. Manhapra A, Arias AJ, Ballantyne JC. The conundrum of opioid tapering in long-term opioid therapy for chronic pain: a commentary. Subst Abus 2017;1-10. https://doi.org/10.1080/08897077.2017.1381663.

  13. FDA, FDA identifies harm reported from sudden discontinuation of opioid pain medicines and requires label changes to guide prescribers on gradual, individualized tapering accessed at https://www.fda.gov/drugs/drug-safety-and-availability/fda-identifies-harm-reported-sudden-discontinuation-opioid-pain-medicines-and-requires-label-changes. 2019.

  14. Harden P, Ahmed S, Ang K, Wiedemer N. Clinical implications of tapering chronic opioids in a veteran population. Pain Med. 2015;16(10):1975–81. https://doi.org/10.1111/pme.12812.

    Article  PubMed  Google Scholar 

  15. McPherson S, Lederhos Smith C, Dobscha SK, Morasco BJ, Demidenko MI, Meath THA, Lovejoy TI. Changes in pain intensity after discontinuation of long-term opioid therapy for chronic noncancer pain. Pain. 2018;159(10):2097–104. https://doi.org/10.1097/j.pain.0000000000001315.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Darnall BD, Ziadni MS, Stieg RL, Mackey IG, Kao MC, Flood P. Patient-centered prescription opioid tapering in community outpatients with chronic pain. JAMA Intern Med. 2018;178(5):707–8. https://doi.org/10.1001/jamainternmed.2017.8709.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Frank JW, Lovejoy TI, Becker WC, Morasco BJ, Koenig CJ, Hoffecker L, Dischinger HR, Dobscha SK, Krebs EE. Patient outcomes in dose reduction or discontinuation of long-term opioid therapy: a systematic review. Ann Intern Med. 2017;167(3):181–91. https://doi.org/10.7326/M17-0598.

    Article  PubMed  Google Scholar 

  18. Mackey K, Anderson J, Bourne D, Chen E, Peterson K. Benefits and harms of long-term opioid dose reduction or discontinuation in patients with chronic pain: a rapid review. J Gen Intern Med. 2020;35(Suppl 3):935–44. https://doi.org/10.1007/s11606-020-06253-8.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Ljungvall H, et al. “My life is under control with these medications”: an interpretative phenomenological analysis of managing chronic pain with opioids. BMC Musculoskelet Disord. 2020;21(1):61. https://doi.org/10.1186/s12891-020-3055-5.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Behar E, et al. “Chasing the pain relief, not the high”: experiences managing pain after opioid reductions among patients with HIV and a history of substance use. PLoS One. 2020;15(3):e0230408. https://doi.org/10.1371/journal.pone.0230408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Benintendi A, Kosakowski S, Lagisetty P, Larochelle M, Bohnert ASB, Bazzi AR. “I felt like I had a scarlet letter”: recurring experiences of structural stigma surrounding opioid tapers among patients with chronic, non-cancer pain. Drug Alcohol Depend. 2021;222:108664. https://doi.org/10.1016/j.drugalcdep.2021.108664.

    Article  PubMed  Google Scholar 

  22. Agnoli A, Xing G, Tancredi DJ, Magnan E, Jerant A, Fenton JJ. Association of dose tapering with overdose or mental health crisis among patients prescribed long-term opioids. JAMA. 2021;326(5):411–9. https://doi.org/10.1001/jama.2021.11013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gordon KS, Manhapra A, Crystal S, Dziura J, Edelman EJ, Skanderson M, Kerns RD, Justice AC, Tate J, Becker WC. All-cause mortality among males living with and without HIV initiating long-term opioid therapy, and its association with opioid dose, opioid interruption and other factors. Drug Alcohol Depend. 2020;216:108291. https://doi.org/10.1016/j.drugalcdep.2020.108291.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Oliva EM, Bowe T, Manhapra A, Kertesz S, Hah JM, Henderson P, Robinson A, Paik M, Sandbrink F, Gordon AJ, Trafton JA. Associations between stopping prescriptions for opioids, length of opioid treatment, and overdose or suicide deaths in US veterans: observational evaluation. Bmj. 2020;368:m283. https://doi.org/10.1136/bmj.m283.

    Article  PubMed  PubMed Central  Google Scholar 

  25. DiBenedetto DJ, Wawrzyniak KM, Finkelman M, Kulich RJ, Chen L, Schatman ME, Stone MT, Mao J. Relationships between opioid dosing, pain severity, and disability in a community-based chronic pain population: an exploratory retrospective analysis. Pain Med. 2019;20(11):2155–65. https://doi.org/10.1093/pm/pny240.

    Article  PubMed  Google Scholar 

  26. Ballantyne JC, Sullivan MD, Kolodny A. Opioid dependence vs addiction: a distinction without a difference? Arch Intern Med. 2012;172(17):1342–3. https://doi.org/10.1001/archinternmed.2012.3212.

    Article  PubMed  Google Scholar 

  27. Vowles KE, McEntee ML, Julnes PS, Frohe T, Ney JP, van der Goes DN. Rates of opioid misuse, abuse, and addiction in chronic pain: a systematic review and data synthesis. Pain. 2015;156(4):569–76. https://doi.org/10.1097/01.j.pain.0000460357.01998.f1.

    Article  PubMed  Google Scholar 

  28. Ditre JW, Zale EL, LaRowe LR. A reciprocal model of pain and substance use: transdiagnostic considerations, clinical implications, and future directions. Annu Rev Clin Psychol. 2019;15:503–28. https://doi.org/10.1146/annurev-clinpsy-050718-095440.

    Article  PubMed  Google Scholar 

  29. Manhapra A, Becker WC. Pain and addiction: an integrative therapeutic approach. Med Clin North Am. 2018;102(4):745–63. https://doi.org/10.1016/j.mcna.2018.02.013.

    Article  PubMed  Google Scholar 

  30. Navratilova E, Porreca F. Reward and motivation in pain and pain relief. Nat Neurosci. 2014;17(10):1304–12. https://doi.org/10.1038/nn.3811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Galaro JK, Celnik P, Chib VS. Motor cortex excitability reflects the subjective value of reward and mediates its effects on incentive-motivated performance. J Neurosci. 2019;39(7):1236–48. https://doi.org/10.1523/JNEUROSCI.1254-18.2018.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Haleem DJ, Nawaz S. Inhibition of reinforcing, hyperalgesic, and motor effects of morphine by buspirone in rats. J Pain. 2017;18(1):19–28. https://doi.org/10.1016/j.jpain.2016.10.001.

    Article  CAS  PubMed  Google Scholar 

  33. Colloca L, Lopiano L, Lanotte M, Benedetti F. Overt versus covert treatment for pain, anxiety, and Parkinson’s disease. Lancet Neurol. 2004;3(11):679–84. https://doi.org/10.1016/s1474-4422(04)00908-1.

    Article  PubMed  Google Scholar 

  34. Colloca L. The placebo effect in pain therapies. Annu Rev Pharmacol Toxicol. 2019;59:191–211. https://doi.org/10.1146/annurev-pharmtox-010818-021542.

    Article  CAS  PubMed  Google Scholar 

  35. Shurman J, Koob GF, Gutstein HB. Opioids, pain, the brain, and hyperkatifeia: a framework for the rational use of opioids for pain. Pain Med. 2010;11(7):1092–8. https://doi.org/10.1111/j.1526-4637.2010.00881.x.

    Article  PubMed  Google Scholar 

  36. Solomon RL, Corbit JD. An opponent process theory of motivation temporal dynmaics of affect. Psychol Rev. 1974;81:119–45.

    Article  CAS  PubMed  Google Scholar 

  37. Solomon RL. Recent experiments testing an opponent-process theory of acquired motivation. Acta Neurobiol Exp (Wars). 1980;40(1):271–89.

    CAS  Google Scholar 

  38. Solomon RL, Corbit JD. An opponent-process theory of motivation. Am Econ Rev. 1978;68(6):12–24.

    Google Scholar 

  39. Le Moal M, Koob GF. Drug addiction: pathways to the disease and pathophysiological perspectives. Eur Neuropsychopharmacol. 2007;17(6-7):377–93. https://doi.org/10.1016/j.euroneuro.2006.10.006.

    Article  CAS  PubMed  Google Scholar 

  40. Ballantyne JC, Koob GF. Allostasis theory in opioid tolerance. Pain. 2021;162(9):2315–9. https://doi.org/10.1097/j.pain.0000000000002280.

    Article  PubMed  Google Scholar 

  41. Koob GF, Le Moal M. Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology. 2001;24(2):97–129. https://doi.org/10.1016/s0893-133x(00)00195-0.

    Article  CAS  PubMed  Google Scholar 

  42. Koob GF. Drug addiction: hyperkatifeia/negative reinforcement as a framework for medications development. Pharmacol Rev. 2021;73(1):163–201. https://doi.org/10.1124/pharmrev.120.000083.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Leknes S, Brooks JCW, Wiech K, Tracey I. Pain relief as an opponent process: a psychophysical investigation. Eur J Neurosci. 2008;28(4):794–801. https://doi.org/10.1111/j.1460-9568.2008.06380.x.

    Article  PubMed  Google Scholar 

  44. Seymour B, O'Doherty JP, Koltzenburg M, Wiech K, Frackowiak R, Friston K, Dolan R. Opponent appetitive-aversive neural processes underlie predictive learning of pain relief. Nat Neurosci. 2005;8(9):1234–40. https://doi.org/10.1038/nn1527.

    Article  CAS  PubMed  Google Scholar 

  45. Compton P, Athanasos P, Elashoff D. Withdrawal hyperalgesia after acute opioid physical dependence in nonaddicted humans: a preliminary study. J Pain. 2003;4(9):511–9. https://doi.org/10.1016/j.jpain.2003.08.003.

    Article  PubMed  Google Scholar 

  46. Vanderah TW, Ossipov MH, Lai J, Malan PT, Porreca F. Mechanisms of opioid-induced pain and antinociceptive tolerance: descending facilitation and spinal dynorphin. Pain. 2001;92(1-2):5–9. https://doi.org/10.1016/s0304-3959(01)00311-6.

    Article  CAS  PubMed  Google Scholar 

  47. Allbutt C. On the abuse of hypodermic injections of morphia. Practitioner. 1870;5:327–31.

    Google Scholar 

  48. Andrews HL. The effect of opiates on the pain threshold in post-addicts. J Clin Invest. 1943;22(4):511–6. https://doi.org/10.1172/JCI101420.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Simons LE, Elman I, Borsook D. Psychological processing in chronic pain: a neural systems approach. Neurosci Biobehav Rev. 2014;39:61–78. https://doi.org/10.1016/j.neubiorev.2013.12.006.

    Article  PubMed  Google Scholar 

  50. Chu LF, Angst MS, Clark D. Opioid-induced hyperalgesia in humans: molecular mechanisms and clinical considerations. Clin J Pain. 2008;24(6):479–96. https://doi.org/10.1097/AJP.0b013e31816b2f43.

    Article  PubMed  Google Scholar 

  51. Celerier E, et al. Progressive enhancement of delayed hyperalgesia induced by repeated heroin administration: a sensitization process. J Neurosci. 2001;21(11):4074–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology. 2006;104(3):570–87. https://doi.org/10.1097/00000542-200603000-00025.

    Article  CAS  PubMed  Google Scholar 

  53. Carcoba LM, Contreras AE, Cepeda-Benito A, Meagher MW. Negative affect heightens opiate withdrawal-induced hyperalgesia in heroin dependent individuals. J Addict Dis. 2011;30(3):258–70. https://doi.org/10.1080/10550887.2011.581985.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Koob GF, Powell P, White A. Addiction as a Coping response: hyperkatifeia, deaths of despair, and COVID-19. Am J Psychiatry. 2020;177(11):1031–7. https://doi.org/10.1176/appi.ajp.2020.20091375.

    Article  PubMed  Google Scholar 

  55. Ballantyne JC, Sullivan MD, Koob GF. Refractory dependence on opioid analgesics. Pain. 2019;160(12):2655–60. https://doi.org/10.1097/j.pain.0000000000001680.

    Article  CAS  PubMed  Google Scholar 

  56. Koob GF. Neurobiology of opioid addiction: opponent process, hyperkatifeia, and negative reinforcement. Biol Psychiatry. 2020;87(1):44–53. https://doi.org/10.1016/j.biopsych.2019.05.023.

    Article  CAS  PubMed  Google Scholar 

  57. Manhapra A, Sullivan MD, Ballantyne JC, MacLean RR, Becker WC. Complex persistent opioid dependence with long-term opioids: a gray area that needs definition, better understanding, treatment guidance, and policy changes. J Gen Intern Med. 2020;35(Suppl 3):964–71. https://doi.org/10.1007/s11606-020-06251-w.

    Article  PubMed  PubMed Central  Google Scholar 

  58. IHS. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38(1):1–211. https://doi.org/10.1177/0333102417738202.

    Article  Google Scholar 

  59. Massey TH, Robertson NP. Medication-overuse headache: causes, consequences and management. J Neurol. 2021;268(9):3505–7. https://doi.org/10.1007/s00415-021-10720-5.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Gatzounis R, den Hollander M, Meulders A. Optimizing long-term outcomes of exposure for chronic primary pain from the lens of learning theory. J Pain. 2021. https://doi.org/10.1016/j.jpain.2021.04.012.

  61. Louw A, Diener I, Butler DS, Puentedura EJ. The effect of neuroscience education on pain, disability, anxiety, and stress in chronic musculoskeletal pain. Arch Phys Med Rehabil. 2011;92(12):2041–56. https://doi.org/10.1016/j.apmr.2011.07.198.

    Article  PubMed  Google Scholar 

  62. Ashar YK, Gordon A, Schubiner H, Uipi C, Knight K, Anderson Z, Carlisle J, Polisky L, Geuter S, Flood TF, Kragel PA, Dimidjian S, Lumley MA, Wager TD. Effect of pain reprocessing therapy vs placebo and usual care for patients with chronic back pain: a randomized clinical trial. JAMA Psychiatry. 2021;79:13–23. https://doi.org/10.1001/jamapsychiatry.2021.2669.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pain Medicine, Hampton VA Medical Center, 100 Emancipation Drive, Hampton, VA, 23667, USA

    Ajay Manhapra MD

  2. New England Mental Illness Research Education and Clinical Center (MIRECC), West Haven, CT, USA

    Ajay Manhapra MD

  3. Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA

    Ajay Manhapra MD

  4. Departments of Physical Medicine and Rehabilitation and Psychiatry, Eastern Virginia Medical School, Norfolk, VA, USA

    Ajay Manhapra MD

Authors
  1. Ajay Manhapra MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ajay Manhapra MD.

Ethics declarations

Conflict of Interest

The authors declare no competing interest.

Human and Animal Rights and Informed Consent

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

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 Palliative and Supportive Care

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Manhapra, A. Complex Persistent Opioid Dependence—an Opioid-induced Chronic Pain Syndrome. Curr. Treat. Options in Oncol. 23, 921–935 (2022). https://doi.org/10.1007/s11864-022-00985-x

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11864-022-00985-x

Keywords

Search

Navigation