Conclusions:
LTOT is often the only available choice for patients with chronic pain
who are unable to recover function despite various interventions and
will likely remain so for the foreseeable future. Re-conceptualization
of opioids as a complex relief medication and LTOT as therapeutic
induction of functionally adaptive opioid dependence enables us to
consider LTOT dependence as a tool to facilitate functional
rehabilitation with provider and patient collaboration around the
decision to initiate LTOT. However, if LTOT is initiated, it should be
done so with the clear plan for ongoing reassessment and duration of
therapy no longer than ~ 2 years. Having a planned
maximal duration of therapy can help avoid the development of OICP, but
OICP may manifest before that period. The diagnosis of OICP can address
the stigma of addiction associated with the use of the term
“dependence” and facilitate engagement with an individual patient with
chronic pain who is not doing well on LTOT. OICP is a difficult
iatrogenic problem and any temptation to blame the patient should be
avoided. LTOT reevaluation based on the concept of adaptive versus
maladaptive opioid dependence can also demystify the opaque process of
LTOT revaluation. We hope these concepts and principles offered her
would lead to more fruitful collaborations between patients, providers,
researchers, payors, and policy makers. There is a need for further
research on the conceptualization of effective LTOT as therapeutic
induction of physiological opioid dependence.
Acknowledgement: The concepts in this manuscript was initially
developed by Ajay Manhapra and refined further through discussion
between the authors. Ajay Manhapra prepared the first draft of the
manuscript and all authors revised subsequent versions of the
manuscript.
Conflict of Interest statements: The authors have no conflict
of interest to report.
Funding information: Support for Dr. MacLean is provided by VA
Clinical Science Research and Development Career Development Award
(1IK2CX002286). No other funding was involved in the preparation of this
manuscript.
Data availability statement: No primary data was used.
References
1. Sullivan MD, Ballantyne JC. Questioning the Right to Pain Relief and
Its Role in the Opioid Epidemic. Mayo Clin Proc.2023;98(8):1216-1224.
2. Ballantyne JC, Sullivan MD, Kolodny A. Opioid Dependence vs
Addiction: A Distinction Without a Difference? Archives of
internal medicine. 2012;172(17):1342-1343.
3. Ballantyne JC, Stannard C. New addiction criteria: diagnostic
challenges persist in treating pain with opioids. Pain. 2013;1.
4. Manhapra A, Arias AJ, Ballantyne JC. The conundrum of opioid tapering
in long-term opioid therapy for chronic pain: A commentary.Substance Abuse. 2017:1-10.
5. Mojtabai R. National trends in long-term use of prescription opioids.Pharmacoepidemiol Drug Saf. 2018;27(5):526-534.
6. Krebs EE, Clothier B, Nugent S, et al. The evaluating prescription
opioid changes in veterans (EPOCH) study: Design, survey response, and
baseline characteristics. PLoS One. 2020;15(4):e0230751.
7. Shah D, Zhao X, Wei W, et al. 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):819-832.
8. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids
for Chronic Pain - United States, 2016. MMWR Recomm Rep.2016;65(1):1-49.
9. Chou R, Hartung D, Turner J, 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.Rockville, MD: Agency for Healthcare Research and Quality (US); 2020.
10. Dowell D, Ragan KR, Jones CM, Baldwin GT, Chou R. CDC Clinical
Practice Guideline for Prescribing Opioids for Pain - United States,
2022. MMWR Recomm Rep. 2022;71(3):1-95.
11. Jones CMP, Day RO, Koes BW, et al. Opioid analgesia for acute low
back pain and neck pain (the OPAL trial): a randomised
placebo-controlled trial. Lancet. 2023;402(10398):304-312.
12. Pathan SA, Mitra B, Cameron PA. Titrated doses are optimal for
opioids in pain trials - Authors’ reply. Lancet.2016;388(10048):961-962.
13. Pathan SA, Mitra B, Straney LD, et al. Delivering safe and effective
analgesia for management of renal colic in the emergency department: a
double-blind, multigroup, randomised controlled trial. Lancet.2016;387(10032):1999-2007.
14. Gordon KS, Manhapra A, Crystal S, et al. 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 and alcohol dependence. 2020;216:108291.
15. Solomon DH, Rassen JA, Glynn RJ, et al. The comparative safety of
opioids for nonmalignant pain in older adults. Archives of
internal medicine. 2010;170(22):1979-1986.
16. Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Prescription of
Long-Acting Opioids and Mortality in Patients With Chronic Noncancer
Pain. JAMA. 2016;315(22):2415-2423.
17. Tolle T, Fitzcharles MA, Hauser W. Is opioid therapy for chronic
non-cancer pain associated with a greater risk of all-cause mortality
compared to non-opioid analgesics? A systematic review of propensity
score matched observational studies. Eur J Pain.2021;25(6):1195-1208.
18. Campbell G, Nielsen S, Larance B, et al. Pharmaceutical Opioid Use
and Dependence among People Living with Chronic Pain: Associations
Observed within the Pain and Opioids in Treatment (POINT) Cohort.Pain Medicine. 2015;16(9):1745-1758.
19. Hasin DS, Shmulewitz D, Stohl M, et al. Diagnosing Prescription
Opioid Use Disorder in Patients Using Prescribed Opioids for Chronic
Pain. The American journal of psychiatry. 2022:appiajp21070721.
20. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing
Opioids for Chronic Pain — United States, 2016. MMWR
Recommendations and Reports. 2016;65(1):1-49.
21. Frank JW, Levy C, Matlock DD, et al. Patients’ Perspectives on
Tapering of Chronic Opioid Therapy: A Qualitative Study. Pain
medicine (Malden, Mass). 2016;17(10):1838-1847.
22. Henry SG, Paterniti DA, Feng B, et al. Patients’ Experience With
Opioid Tapering: A Conceptual Model With Recommendations for Clinicians.The journal of pain : official journal of the American Pain
Society. 2019;20(2):181-191.
23. McNeilage AG, Avery NS, Holliday S, Glare PA, Ashton-James CE. A
qualitative trajectory analysis of patients’ experiences tapering
opioids for chronic pain. Pain. 2022;163(2):e246-e260.
24. 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.
25. Frank JW, Lovejoy TI, Becker WC, et al. Patient Outcomes in Dose
Reduction or Discontinuation of Long-Term Opioid Therapy: A Systematic
Review. Ann Intern Med. 2017;167(3):181-191.
26. 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):935-944.
27. Mark TL, Parish W. Opioid medication discontinuation and risk of
adverse opioid-related health care events. Journal of substance
abuse treatment. 2019;103:58-63.
28. Mazurenko O, Blackburn J, Zhang P, et al. Recent tapering from
long-term opioid therapy and odds of opioid-related hospital use.Pharmacoepidemiol Drug Saf. 2022.
29. Oliva EM, Bowe T, Manhapra A, et al. Associations between stopping
prescriptions for opioids, length of opioid treatment, and overdose or
suicide deaths in US veterans: observational evaluation. Bmj.2020;368:m283.
30. Perez HR, Buonora M, Cunningham CO, Heo M, Starrels JL. Opioid Taper
Is Associated with Subsequent Termination of Care: a Retrospective
Cohort Study. J Gen Intern Med. 2020;35(1):36-42.
31. Fenton JJ, Magnan E, Tseregounis IE, Xing G, Agnoli AL, Tancredi DJ.
Long-term Risk of Overdose or Mental Health Crisis After Opioid Dose
Tapering. JAMA Netw Open. 2022;5(6):e2216726.
32. Glanz JM, Binswanger IA, Shetterly SM, Narwaney KJ, Xu S.
Association Between Opioid Dose Variability and Opioid Overdose Among
Adults Prescribed Long-term Opioid Therapy. JAMA Netw Open.2019;2(4):e192613.
33. Hallvik SE, El Ibrahimi S, Johnston K, et al. Patient outcomes after
opioid dose reduction among patients with chronic opioid therapy.Pain. 2022;163(1):83-90.
34. Hayes CJ, Krebs EE, Li C, Brown J, Hudson T, Martin BC. Association
between discontinuing chronic opioid therapy and newly diagnosed
substance use disorders, accidents, self-inflicted injuries and drug
overdoses within the prescribers’ health care system: a retrospective
cohort study. Addiction. 2022;117(4):946-968.
35. James JR, Scott JM, Klein JW, et al. Mortality After Discontinuation
of Primary Care-Based Chronic Opioid Therapy for Pain: a Retrospective
Cohort Study. J Gen Intern Med. 2019;34(12):2749-2755.
36. 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):411-419.
37. Binswanger IA, Glanz JM, Faul M, et al. The Association between
Opioid Discontinuation and Heroin Use: A Nested Case-Control Study.Drug and alcohol dependence. 2020;217:108248.
38. Coffin PO, Rowe C, Oman N, et al. Illicit opioid use following
changes in opioids prescribed for chronic non-cancer pain. PLoS
One. 2020;15(5):e0232538.
39. DiPrete BL, Ranapurwala SI, Maierhofer CN, et al. Association of
Opioid Dose Reduction With Opioid Overdose and Opioid Use Disorder Among
Patients Receiving High-Dose, Long-term Opioid Therapy in North
Carolina. JAMA Netw Open. 2022;5(4):e229191.
40. Groenewald CB, Murray CB, Battaglia M, Scaini S, Quinn PD.
Prevalence of Pain Management Techniques Among Adults With Chronic Pain
in the United States, 2019. JAMA Netw Open. 2022;5(2):e2146697.
41. Kertesz SG. Turning the tide or riptide? The changing opioid
epidemic. Substance abuse : official publication of the
Association for Medical Education and Research in Substance Abuse.2017;38(1):3-8.
42. Change in Per Capita Opioid Prescriptions Filled at Retail
Pharmacies, 2008–2009 to 2017–2018.
43. Dowell D, Haegerich T, Chou R. No Shortcuts to Safer Opioid
Prescribing. The New England journal of medicine.2019;380(24):2285-2287.
44. Kertesz SG, Manhapra A. The drive to taper opioids: mind the
evidence, and the ethics. Spinal Cord Ser Cases. 2018;4:64.
45. Manhapra A. Complex Persistent Opioid Dependence-an Opioid-induced
Chronic Pain Syndrome. Curr Treat Options Oncol. 2022.
46. Ballantyne JC, Sullivan MD. Intensity of Chronic Pain–The Wrong
Metric? The New England journal of medicine.2015;373(22):2098-2099.
47. Fordyce WE, Roberts AH, Sternbach RA. The behavioral management of
chronic pain: a response to critics. Pain. 1985;22(2):113-125.
48. Oertel BG, Preibisch C, Wallenhorst T, et al. Differential opioid
action on sensory and affective cerebral pain processing. Clin
Pharmacol Ther. 2008;83(4):577-588.
49. LaGraize SC, Borzan J, Peng YB, Fuchs PN. Selective regulation of
pain affect following activation of the opioid anterior cingulate cortex
system. Exp Neurol. 2006;197(1):22-30.
50. Price DD, Von der Gruen A, Miller J, Rafii A, Price C. A
psychophysical analysis of morphine analgesia. Pain.1985;22(3):261-269.
51. Porreca F, Navratilova E. Reward, motivation, and emotion of pain
and its relief. Pain. 2017;158 Suppl 1:S43-S49.
52. Manhapra A, Arias AJ, Ballantyne JC. The conundrum of opioid
tapering in long-term opioid therapy for chronic pain: A commentary.Substance abuse : official publication of the Association for
Medical Education and Research in Substance Abuse. 2017:1-10.
53. Navratilova E, Porreca F. Reward and motivation in pain and pain
relief. Nature neuroscience. 2014;17(10):1304-1312.
54. Martel MO, Edwards RR, Jamison RN. The relative contribution of pain
and psychological factors to opioid misuse: A 6-month observational
study. Am Psychol. 2020;75(6):772-783.
55. Gilam G, Sturgeon JA, You DS, Wasan AD, Darnall BD, Mackey SC.
Negative Affect-Related Factors Have the Strongest Association with
Prescription Opioid Misuse in a Cross-Sectional Cohort of Patients with
Chronic Pain. Pain medicine (Malden, Mass). 2020;21(2):e127-e138.
56. Carpenter RW, Lane SP, Bruehl S, Trull TJ. Concurrent and lagged
associations of prescription opioid use with pain and negative affect in
the daily lives of chronic pain patients. J Consult Clin Psychol.2019;87(10):872-886.
57. Goesling J, Henry MJ, Moser SE, et al. Symptoms of Depression Are
Associated With Opioid Use Regardless of Pain Severity and Physical
Functioning Among Treatment-Seeking Patients With Chronic Pain.The journal of pain : official journal of the American Pain
Society. 2015;16(9):844-851.
58. Colloca L, Lopiano L, Lanotte M, Benedetti F. Overt versus covert
treatment for pain, anxiety, and Parkinson’s disease. The Lancet
Neurology. 2004;3(11):679-684.
59. Colloca L. The Placebo Effect in Pain Therapies. Annual review
of pharmacology and toxicology. 2019;59:191-211.
60. Galaro JK, Celnik P, Chib VS. Motor Cortex Excitability Reflects the
Subjective Value of Reward and Mediates Its Effects on
Incentive-Motivated Performance. The Journal of neuroscience : the
official journal of the Society for Neuroscience. 2019;39(7):1236-1248.
61. Haleem DJ, Nawaz S. Inhibition of Reinforcing, Hyperalgesic, and
Motor Effects of Morphine by Buspirone in Rats. The journal of
pain : official journal of the American Pain Society. 2017;18(1):19-28.
62. Solomon RL, Corbit JD. An Opponent Process Theory of Motivation
Temporal Dynmaics of Affect. Psychol Rev. 1974.
63. Solomon RL. Recent experiments testing an opponent-process theory of
acquired motivation. Acta Neurobiol Exp (Wars).1980;40(1):271-289.
64. Solomon RL, Corbit JD. An opponent-process theory of motivation.The American Economic Review. 1978;68(6):12-24.
65. Ballantyne JC, Koob GF. Allostasis theory in opioid tolerance.Pain. 2021;162(9):2315-2319.
66. 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):964-971.
67. Heilig M, Egli M, Crabbe JC, Becker HC. Acute withdrawal, protracted
abstinence and negative affect in alcoholism: are they linked?Addiction biology. 2010;15(2):169-184.
68. Koob GF. Neurobiology of Opioid Addiction: Opponent Process,
Hyperkatifeia, and Negative Reinforcement. Biological psychiatry.2020;87(1):44-53.
69. Shurman J, Koob GF, Gutstein HB. Opioids, Pain, the Brain, and
Hyperkatifeia: A Framework for the Rational Use of Opioids for Pain.Pain Medicine. 2010;11(7):1092-1098.
70. Edmond SN, Snow JL, Pomeranz J, Van Cleve R, Becker WC. Arguments
for and against a new diagnostic entity for patients with chronic pain
on long-term opioid therapy for whom harms outweigh benefits. The
journal of pain : official journal of the American Pain Society. 2021.
71. Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative
systematic review. Anesthesiology. 2006;104(3):570-587.
72. Oliva EM, Bowe T, Tavakoli S, et al. Development and applications of
the Veterans Health Administration’s Stratification Tool for Opioid Risk
Mitigation (STORM) to improve opioid safety and prevent overdose and
suicide. Psychol Serv. 2017;14(1):34-49.
73. Fiellin DA, Friedland GH, Gourevitch MN. Opioid dependence:
rationale for and efficacy of existing and new treatments. Clin
Infect Dis. 2006;43 Suppl 4:S173-177.
74. Bullingham RE, McQuay HJ, Dwyer D, Allen MC, Moore RA. Sublingual
buprenorphine used postoperatively: clinical observations and
preliminary pharmacokinetic analysis. Br J Clin Pharmacol.1981;12(2):117-122.
75. Davis MP, Pasternak G, Behm B. Treating Chronic Pain: An Overview of
Clinical Studies Centered on the Buprenorphine Option. Drugs.2018;78(12):1211-1228.
76. Case AA, Kullgren J, Anwar S, Pedraza S, Davis MP. Treating Chronic
Pain with Buprenorphine-The Practical Guide. Curr Treat Options
Oncol. 2021;22(12):116.
77. Rhodin A, Gronbladh L, Nilsson LH, Gordh T. Methadone treatment of
chronic non-malignant pain and opioid dependence–a long-term
follow-up. Eur J Pain. 2006;10(3):271-278.
78. Neumann AM, Blondell RD, Jaanimagi U, et al. A preliminary study
comparing methadone and buprenorphine in patients with chronic pain and
coexistent opioid addiction. J Addict Dis. 2013;32(1):68-78.