Treating Chronic Pain and Anxiety – a Modest Proposal

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Richard A Lawhern, PhD Stephen E. Nadeau, MD


Introduction: the CDC guidelines of 2016 and 2022 strongly proscribed the co-prescription of opioids and benzodiazepines, implicitly suggesting that the combination was associated with high risk. This position now strongly influences health provider organizations, clinicians, pharmacies, health insurance companies, and boards of medicine. We have previously comprehensively reviewed the generally high-quality published studies, all employing a retrospective cohort design. These studies suggest that, to the extent that the combination increases mortality risk, the magnitude of the increase is small and it likely reflects a conflation of mortality risk related to the underlying conditions and the risks associated with simultaneous use of drugs of both classes. We here recapitulate the results of our prior analyses, contrast them with CDC positions, and introduce the results of additional studies, some only recently published and some of which we had previously been unaware.

Methods: Analytic review of the scientific literature.

Results and Discussion: Studies previously analyzed by us focused exclusively on risks associated with co-prescription. The results of further studies, reviewed here, suggest that, while there are small populations in whom co-prescription, or even solely prescription of benzodiazepines, may be risky, risks of morbid outcomes in clinic populations in general are dominated by the impact of psychiatric disease and opioids make a very small and indirect contribution. A recently published study has demonstrated the very high mortality risk associated with tapering and discontinuing benzodiazepines. Our modest proposal bears on the importance of applying a deeper understanding of published papers and the de facto meaning of the cited risk factors for death.

Conclusion: There has been substantial misconstrual of association with causation. Opioids and benzodiazepines have emerged as, at worst, very minor contributors to mortality and may often be better viewed as markers of the disorders that actually cause excess deaths: psychiatric disease and undertreatment of physical pain.

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LAWHERN, Richard A; NADEAU, Stephen E.. Treating Chronic Pain and Anxiety – a Modest Proposal. Medical Research Archives, [S.l.], v. 12, n. 6, june 2024. ISSN 2375-1924. Available at: <>. Date accessed: 22 july 2024. doi:
Research Articles


1. Nadeau SE, Wu JK, and Lawhern RA. Opioids and chronic pain: an analytical review of the clinical evidence. Front. Pain Res. Pharmacologi-cal Treatment of Pain. 2021;2:721357
accessed May 24, 2024

2. Oliva EM, Bowe T, and Tavakoli S, et al, Devel¬opment and applications of the Veteran 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. Doi:10.1037/ser0000099

3. Dowell D, Ragan KR, Jones CM, Baldwin GT, Chou R, CDC Clinical Practice Guideline for Pre¬scribing Opioids for Pain — United States, 2022” MMWR Morb Mortal Wkly Rep. 2022;71(3):1-95. Doi:10.15585/mmwr.rr7103a1

4. Sun EC, Dixit A, Humphreys K, Darnall BD, Baker LC, Mackey S. Association between concurrent use of prescription opioids and benzodiazepines and overdose: retrospective analysis. BMJ. 2017;356:J760. Doi:10.1136/bmj.j760

5. Peppin JF. The marginalization of patients on chronic opioid therapy. Pain Physician. 2009;12:493–8. Doi:10.36076/ppj.2009/12/493

6. Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert ASB. Benzodiazepine prescribing patterns and deaths from drug overdose among US veterans receiving opioid analgesics: case-cohort study. BMJ. 2015;350:h2698. Doi: 10.1136/bmj.h2698

7. Xu KY, Hartz SM, Borodovsky JT, Bierut LJ, Grucza RA. Association between benzodiaze-pine use with or without opioid use and all-cause mortality in the United States, 1999-2015. JAMA Netw Open. 2020;3:e2028577. Doi: 10.1001/jamanetworkopen.2020.28557

8. Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisi KM, Marshall S. Cohort study of the im-pact of high-dose opioid analgesics on overdose mortality. Pain Med. 2016;17:85–98. Doi: 10.1111/pme.12907

9. Zedler B, Xie L, Wang L, Joyce A, Vick C, Brigham J, et al. Development of a risk index of serious prescription opioid-induced respiratory depression or overdose in Veterans' Health administration patients. Pain Med. 2015;16:1566–79. Doi: 10.1111/pme.12777

10. Banks S, Kerns R. Explaining high rates of de-pression in chronic pain: a diathesis-stress frame¬work. Psychol Bul. 1996;119:95–110. Doi:10.1037/0033-2909.119.1.95

11. Mitchell AJ, Vaze A, Rao S. Clinical diagnosis of depression in primary care: a meta-analysis. Lancet. 2009;374:609–19. Doi:10.1016/S0140-6736(09)60879-5

12. Braden JB, Russo J, Fan MY, Edlund MJ, Martin BC, DeVries A, et al. Emergency department vis¬its among recipients of chronic opioid therapy. Arch Intern Med. 2010;170:1425–32. Doi:10.1001/archinternmed.2010.273

13. Dunn KM, Saunders KW, Rutter CM, Banta-Green CJ, Merrill JO, Sullivan MD, et al. Opioid prescriptions for chronic pain and overdose. Ann Intern Med. 2010;152:85–92. Doi:10.7326/0003-4819-152-2-201001190-00006

14. Craven MA, Bland R. Depression in primary care: current and future challenges. Can J Psy-chiatry. 2013;58:442–8. Doi:10.1177/070674371305800802

15. Braden JB, Sullivan MD, Ray GT, Saunders K, Merrill J, Silverberg MJ, et al. Trends in long-term opioid therapy for noncancer pain among people with a history of depression. Gen Hosp Psychiatry. 2009;31:564–70. Doi:10.1016/j.genhosppsych.2009.07.003

16. Quinn PD, Hur K, Chang Z, Krebs EE, Bair MJ, Scott EL, et al. Incident and long-term opioid therapy among patients with psychiatric condi-tions and medications: a national study of com-mercial health care claims. Pain. 2017;158:140–8. Doi:10.1097/j.pain.0000000000000730

17. Elrashidi MY, Philpot LM, Ramar P, Leasure WB, Ebbert JO. Depression and anxiety among pa-tients on chronic opioid therapy. Health Serv Res Manag Epidemiol. 2018;5:1–7. Doi:10.1177/2333392818771243

18. Grant BF, Stinson FS, Dawson DA, Chou P, Dufour MC, Compton W, et al. Prevalence and co-oc¬currence of substance use disorders and inde¬pendent mood and anxiety disorders. Arch Gen Psychiatry. 2004;61:8070816. Doi:10.1001/archpsyc.61.8.807

19. Han B, Compton WM, Bianco C, Crane E, Lee JD, Jones CM. Prescription opioid use, misuse, and use disorders in U.S. adults: 2015 national sur¬vey on drug use and health. Ann Intern Med. 2017;167:293–301. Doi:10.7326/M17-0865

20. Grattan A, Sullivan MD, Saunders KW, Camp-bell CJ, Von Korff MR. Depression and prescrip-tion opioid misuse among chronic opioid therapy recipients with no history of substance abuse. Ann Fam Med. 2012;10:304–11. Doi:10.1370/afm.1371

21. Bohnert ASB, Logan JE, Ganoczy D, Dowell D. A detailed exploration into the association of prescribed opioid dosage and overdose deathes among patients with chronic pain. Med Care. 2016;54:435-41. Doi:10.1097/MLR.0000000000000505

22. Nadeau SE, Lawhern RA. The two opioid crises – problems, causes, and potential solutions: an an¬alytic review”, Med Res Arch, 2023;11(12). Doi:10.18103/mra.v 11i12.4846

23. Lötsch J, Skarke, C, Liefhold J, Geisslinger G. Genetic Predictors of the Clinical Response to Opioid Analgesics. Clinical utility and future per¬spectives. Clin Pharmacokinet. 2004;43(4):983-1013. Doi: 10.2165/00003088-200443140-00003

24. Agrawal D, Udoji MA, and Trescot A. Genetic Testing for Opioid Pain Management: A Primer. Pain Ther. 2017;6:93-105. Doi:10.1007/s40122-017-0069-2.

25. Nadeau, SE, Del Rocco N, and Wu S, “Opioid trials: time for a new approach? Enriched enroll¬ment, randomized gradual withdrawal designs.” Pain Manag. 2022;12(3):243-247. Doi:10.2217/pmt-2021-0112

26. Nadeau SE, Lawhern RA. Management of chronic non-cancer pain: a framework. Pain Manag. 2022;12(6):751-777. Doi:10.2217/pmt-2022-0017

27. Lawhern, RA Doctors diagnosing addiction – are the blind leading the blind? Med Res Arch. 2023,11(11):4726. Doi:10.18103/mra-v11i11.4726

28. Nadeau SE, Lawhern RA. The two opioid crises. Problems, causes, and potential solutions: an an¬alytic review. Med Res Arch. 2023;11(12). Doi:10.18103/mra.v 11i12.4846

29. Fishbain DA, Cole B, Lewis J, Rosomoff HL, Roso¬mof RS. What percentage of chronic nonmalig¬nant pain patients exposed to chronic opioid an¬algesic therapy develop abuse/addiction and/or aberrant drug-related behaviors? A structured evidence-based review.” Pain Med. 2008;9:445-59. Doi: 10.1111/j.1526-4637.2007.00370.

30. Weissman DE, Haddox JD. Opioid pseudoad-diction—an iatrogenic syndrome. Pain. 1989;36:363-6.

31. Bohnert ASB, Valenstein M, Bair MJ, Ganoczy D, McCarthy JF, Ilgen MA, et al. Association be-tween opioid prescribing patterns and opioid overdose-related deaths. JAMA. 2011;305:1315-21. Doi:10.1001/jama.2011.370

32. Maust DT, Petzold K, Strominger J, Kim M, Boh-nert ASB. Benzodiazepine discontinuation and mortality among patients receiving long-term benzodiazepine therapy. JAMA Netw Open. 2023;6(12):e2348557. Doi: jamanetworkopen.2023.48557