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We welcome guest blogger Dr. Stephen E. Nadeau, Senior Research Advisor, Alliance for the Treatment of Intractable Pain. Dr. Nadeau agreed to share his response to The Oregon Pain Guidance Clinical Advisory Group, Tapering Workgroup*. For more context, the Advisory group recently posted a set of guidelines for tapering opioid doses in patients with chronic nonmalignant pain who have been receiving long-term treatment with opioid analgesics. These recommendations were specifically designed to be utilized by clinicians throughout the state of Oregon and are available HERE. Of note, opioid tapering or abrupt cessation of opioids was covered on paindr.com in a previous post, If you are forced to stop opioids.



*The Workgroup and contributors include Jane Ballantyne, Roger Chou, Paul Coelho, Ruben Halperin, Andrew Kolodny, Anna Lembke, Jim Shames, Mark Stephens, and David Tauben.



Thank you, Dr. Nadeau, for your patient advocacy and response letter as it appears below.

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Ballantyne and colleagues, in their recent article, “Tapering – Guidance and Tools” (https://www.oregonpainguidance.org/guideline/tapering/), make the implicit assumption that tapering of opioid regimens in patients with chronic nonmalignant pain is a desirable thing – this, despite the evidence that the cost of chronic pain to American society, based upon health care expenditures and cost of lost productivity, is $560-635 billion/year (1); the evidence from randomized controlled trials employing designs that replicate good clinical practice that opioids are highly effective in the treatment of nonmalignant pain (2-6); the evidence that this beneficial effect can be sustained for years (7-9); and the evidence that the annual case fatality rate associated with chronic opioid treatment of pain is 0.08% with dosage of <200 mg morphine equivalent/day (MMED) (10), 0.25%/year with dosage of >100 MMED (11), and 0.5%/year with dosage >400 MMED (10). The latter two case-fatality rates are quite comparable to the risks of fatal bleeding associated with use of rivaroxaban (0.2%/year) and warfarin (0.5%/year) in the prophylaxis of stroke due to atrial fibrillation (12). Given the extreme impact of chronic pain on a patient’s life, this small risk is likely to be acceptable to nearly all. Ballantyne et al. state “it is widely recognized that prolonged continuous high dose opioid pain treatment is neither effective nor safe for the majority of patients.” “Widely misperceived” would be more accurate, as these claims are not supported by scientific evidence.



The authors also seem to suggest that, because the CDC recommended an upper limit of 90 MMED (13), doses above this level must be fraught with unacceptable risk. This CDC recommendation ignores the case-fatality data presented above and it further makes the assumption that “one dose fits all.” Data from randomized controlled trials that have adequately titrated opioid dosage suggest 13-fold variability in dose requirements (2, 4), variability that can be attributed to differences in pain intensity, genetic differences in hepatic metabolism (14), and genetic differences in central nervous system nociceptive signal transduction (15).



The authors seem to further justify their tapering recommendations with the statement that “overdose rates continue to be high compared to historical standard.” No question, but it is critical to ask, “Why is this?” Despite draconian reductions in prescription opioid dosage, mortality from prescription opioids has remained static at about 17,000/year since 2012. However, deaths from illicit opioids, overwhelmingly heroin and illicit fentanyl in variable combinations, have risen from 7,000 in 2011 to approximately 30,000 in 2017 (CDC data). Richard Lawhern, PhD, has shown, using state by state data on CDC websites readily available to all, that the correlation between number of opioid prescriptions/100 persons and mortality rate is 0.05. The very idea that constraining prescription opioids in the clinic is somehow going to solve the still- growing crisis in the streets begs credulity.



I welcome the authors’ emphasis on balancing the risks of opioid treatment of chronic pain against its benefits. However, a judicious weighing of this balance must also take into account the overwhelming impact of chronic, inadequately-controlled pain on people’s lives. This reality must be fully appreciated, along with inter-individual variability in dose requirements, the modest risks of chronic opioid therapy, even in substantial dosage, and the patient’s vital input on the adequacy of pain control.



The most essential strategies for addressing the opioid overdose crisis and the CDC-manufactured chronic pain crisis are:



1) revise the CDC 2016 Guidelines so that they accurately reflect the scientific data;

2) release physicians to pursue unfettered good clinical practice in their management of patients in pain;

3) markedly enhance training of physicians in the management of chronic pain, including robust training in medical school and residencies and continuing education workshops (online courses will not suffice);

4) markedly increase the national resources dedicated to treatment of the opioid use disorder crisis in the streets (16).

As always, comments are welcomed with enthusiasm!

Stephen E. Nadeau, MD is a Professor of Neurology at the University of Florida College of Medicine and Associate Chief of Staff for Research at the Malcom Randall VA Medical Center in Gainesville, FL. He is a neurologist and a cognitive neuroscientist. He has devoted much of his clinical career since 1982 to the care of patients with chronic nonmalignant pain.





Disclaimer:

The contents of this manuscript do not represent the views of the United States Department of Veterans Affairs, the United States Government, or the University of Florida.

References

1. Institute of Medicine. Relieving Pain in America: a Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: National Academies Press; 2011.

2. Hale ME, Ahdieh H, Ma T, Rauck R, Oxymorphone ER Study Group 1. Efficacy and safety of OPANA ER (oxymorphone extended release) for relief of moderate to severe low back pain in opioid-experienced patients: a 12-week, randomized, double-blind, placebo-controlled study. Journal of Pain. 2007;8:175-84.

3. Hale ME, Dvergsten C, Gimbel J. Efficacy and safety of oxymorphone extended release in chronic low back pain: results of a randomized, double-blind, placebo- and active-controlled phase III study. Journal of Pain. 2005;6:21-8.

4. Katz N, Rauck R, Ahdieh H, Gerritsen van der Hoop R, Kerwin R, Podolsky G. A 12-week, randomized, placebo-controlled trial assessing the safety and efficacy of oxymorphone extended release for opioid-naive patients with chronic low back pain. Current Medical Research and Opinion. 2007;23:117-28.

5. Rauck RL, Nalamachu S, Wild JE, Walker GW, Robinson CY, Davis CS, et al. Single-entity hydrocodone extended-release capsules in opioid-tolerant subjects with moderate-to-severe chronic low back pain: a randomized double-blind, placebo-controlled study. Pain Medicine. 2014;15:975-85.

6. Katz N, Kopecky EA, O’Connor M, Brown RH, Fleming AB. A phase 3, multicenter, randomized, double-blind, placebo-controlled, safety, tolerability, and efficacy study of Xtampza ER in patients with moderate-to-severe chronic low back pain. Pain. 2015;156:2458-67.

7. Milligan K, Lanteri-Minet M, Borchert K, Helmers H, Donald R, Kress H-G, et al. Evaluation of long-term efficacy and safety of transdermal fentanyl in the treatment of chronic noncancer pain. Journal of Pain. 2001;2:197-204.

8. Mystakidou K, Parpa E, Tsilika E, Mavromati A, Smyrniotis V, Georgaki S, et al. Long-term management of noncancer pain with transdermal therapeutic system-fentanyl. Journal of Pain. 2003;4:298-306.

9. Roth SH, Fleischmann RM, Burch FX, Dietz F, Bockow B, Rapoport RJ, et al. Around-the-clock, controlled-release oxycodone therapy for osteoarthritis-related pain. Archives of Internal Medicine. 2000;160:853-60.

10. Gomes T, Juurlink DN, Dhalla IA, Mailis-Gagnon A, Paterson JM, Mamdani MM. Trends in opioid use and dosing among socio-economically disadvantaged patients. Open Medicine. 2011;5:13-22.

11. Bohnert ASB, Valenstein M, Bair MJ, Ganoczy D, McCarthy JF, Ilgen MA, et al. Association between opioid prescribing patterns and opioid overdose-related deaths. Journal of the American Medical Association. 2011;305:1315-21.

12. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. New England Journal of Medicine. 2011;365:883-91.

13. Dowell D, Haegerich T, Chou R. CDC Guideline for prescribing opioids for chronic pain — United States, 2016. Morbidity and Mortality Weekly Report. 2016;65:1-49.

14. Agarwal D, Udoji MA, Trescot A. Genetic testing for opioid pain management. Pain Therapy. 2017;6:93-105.

15. Galvan A, Skorpen F, Klepstad P, Knudsen A, Fladvad T, Falvella FS, et al. Multiple loci modulate opioid therapy response for cancer pain. Clinical Cancer Research. 2011;17:4581-97.

16. Winkelman TNA, Chang VW, Binswanger IA. Health, polysubstance use, and criminal justice involvement among adults with varying levels of opioid use. JAMA Network Open. 2018. DOI: 10.1001/jamanetworkopen.2018.0558

17. Richard A Lawhern, Ph.D. and John Alan Tucker, Ph.D. “Analysis of US Opioid Mortality and ER Visit Data”, May 15, 2018, available at http://face-facts.org/atip/analysis-of-cdc-wonder-rx-and-er-data-v1-4-may-2018-2/

