Critique of the CDC’s Draft Guidelines on the Use of Opioid Analgesics for Chronic Pain Endnotes

(Note: The endnotes which provide the references for this critique have been collected into this final part of this document.)

1. Deborah Dowell, Tamara M. Haegerich, Roger Chou. CDC Guideline for Prescribing Opioids for Chronic Pain—United States, 2016. http://static1.squarespace.com/static/54d50ceee4b05797b34869cf/t/566f4391df40f39ea7ef24f7/145013236970

2. Institute of Medicine of the National Academies. Clinical Practice Guidelines We Can Trust: Standards for Developing Trustworthy Clinical Practice Guidelines (CPGs). http://iom.nationalacademies.org/~/media/Files/Report%20Files/2011/Clinical-Practice-Guidelines-We-Can-Trust/Clinical%20Practice%20Guidelines%202011%20Insert.pdf

3. Richard N. Shiffman. Recognizing Trustworthy Guidelines: The New IOM Standards. p. 6. (Ellipses in original) http://www.cdc.gov/od/science/quality/docs/trustworthy_gls.pdf

4. Public Law 110-275, July 15, 2008, Section 304. https://www.gpo.gov/fdsys/pkg/PLAW-110publ275/pdf/PLAW-110publ275.pdf

5. Jill Eden, Laura Levit, Alfred Berg, and Sally Morton, Editors; Committee on Standards for Systematic Reviews of Comparative Effectiveness Research; Board on Health Care Services; Institute of Medicine. Finding What Works in Health Care: Standards for Systematic Reviews. The National Academies Press, Washington, D.C.: 2011, p. 18. http://www.nap.edu/read/13059/chapter/5#85

6. Richard N. Shiffman. Recognizing Trustworthy Guidelines: The New IOM Standards. p. 34. http://www.cdc.gov/od/science/quality/docs/trustworthy_gls.pdf

7. Institute of Medicine of the National Academies. Clinical Practice Guidelines We Can Trust: Standards for Developing Trustworthy Clinical Practice Guidelines (CPGs), p. 2. http://iom.nationalacademies.org/~/media/Files/Report%20Files/2011/Clinical-Practice-Guidelines-We-Can-Trust/Clinical%20Practice%20Guidelines%202011%20Insert.pdf

8. Richard N. Shiffman. Recognizing Trustworthy Guidelines: The New IOM Standards. p. 34. http://www.cdc.gov/od/science/quality/docs/trustworthy_gls.pdf

9. Jill Eden, Laura Levit, Alfred Berg, and Sally Morton, Editors; Committee on Standards for Systematic Reviews of Comparative Effectiveness Research; Board on Health Care Services; Institute of Medicine. Finding What Works in Health Care: Standards for Systematic Reviews. The National Academies Press, Washington, D.C.: 2011, pp. 84-85. http://www.nap.edu/read/13059/chapter/5#85

10. CDC Guideline for Prescribing Opioids for Chronic Pain–United States, 2016. Online Appendix 2: Contextual Evidence Review, p. 2. www.regulations.gov/contentStreamer?documentId=CDC-2015-0112-0004&disposition=attachment&contentType=pdf

11. 21 U.S. Code § 360bbb–8b – Use of clinical investigation data from outside the United States. https://www.law.cornell.edu/uscode/text/21/360bbb%E2%80%938b

12. CDC Guideline for Prescribing Opioids for Chronic Pain – United States, 2016. Online Appendix 2: Contextual Evidence Review, pp. 2, 4, 10, 11, 13. www.regulations.gov/contentStreamer?documentId=CDC-2015-0112-0004&disposition=attachment&contentType=pdf

13. CDC Guideline for Prescribing Opioids for Chronic Pain–United States, 2016. Online Appendix 2: Contextual Evidence Review, p. 1. www.regulations.gov/contentStreamer?documentId=CDC-2015-0112-0004&disposition=attachment&contentType=pdf

14. CDC Guideline for Prescribing Opioids for Chronic Pain – United States, 2016. Online Appendix 2: Contextual Evidence Review, p. 2. www.regulations.gov/contentStreamer?documentId=CDC-2015-0112-0004&disposition=attachment&contentType=pdf

15. Richard N. Shiffman. Recognizing Trustworthy Guidelines: The New IOM Standards. p. 24 http://www.cdc.gov/od/science/quality/docs/trustworthy_gls.pdf

16. Justin Kung, Ram R. Miller, Philip A. Mackowiak. Failure of clinical practice guidelines to meet Institute of Medicine Standards: Two more decades of little, if any, progress. Archives of Internal Medicine, November 26, 2012;172(21):1628-1633. http://archinte.jamanetwork.com/article.aspx?articleid=1384245

17. Pat Anson. CDC maintains secrecy over opioid guidelines. Pain News Network, September 18, 2015.

18. Jason Chaffetz, Elijah E. Cummings, Jim Jordan, Matt Cartwright, Mark Meadows, Gerald E. Connolly. House of Representatives Committee on Oversight and Government Reform letter to Thomas Frieden, M.D., Director, Centers for Disease Control, December 18, 2015. https://oversight.house.gov/wp-content/uploads/2015/12/2015-12-18-JC-EEC-Jordan-Meadows-Cartwright-Connolly-to-Frieden-CDC-FACA-due-Jan.-5.pdf

19. Peter Pitts. At the CDC. Morning Consult, September 24, 2015. http://morningconsult.com/opinions/opioids-and-sunshine-at-the-cdc/

20. Jane Ballantyne, MD. COPE Faculty. http://www.coperems.org/cope-faculty/ accessed December 29, 2015. See also http://www.supportprop.org/board-of-directors/ accessed December 15, 2015.

21. http://www.supportprop.org/advocacy/ accessed December 23, 2015

22 http://www.supportprop.org/about-prop/ accessed December 15, 2015

23. http://www.phoenixhouse.org/about/ accessed December 15, 2015

24. Roger Chou, Gilbert J. Fanciullo, Perry G. Fine, Jeremy A. Adler, Jane C. Ballantyne, Pamela Davies, Marilee I. Donovan, David A. Fishbain, Kathy M. Foley, Jeffrey Fudin, Aaron M. Gilson, Alexander Kelter, Alexander Mauskop, Patrick G. O’Connor, Steven D. Passik, Gavril W. Pasternak, Russell K. Portenoy, Ben A. Rich, Richard G. Roberts, Knox H. Todd, Christine Miaskowski, for the American Pain Society–American Academy of Pain Medicine Opioids Guidelines Panel. Opioid treatment guidelines: Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. The Journal of Pain, February 2009;10(2):113-130. http://health.utah.gov/prescription/pdf/guidelines/ASP.AAPMguidelines.pdf

25. Jane Ballantyne, Randi Beck, Andrew Bertagnolli, Marie Boudreaux, Hannah Burdge, Mary Catlin, Roger Chou, Gary Franklin, Rivka Klaff, Andrew Kolodny, Erin Krebs, Tony Mariano, Deborah Nelson, Roger Rosenblatt, Grant Scull, Michelle Seelig, Mark Stephens, Mark Sullivan, David Tauben, Claire Trescott, Michael Von Korff. The National Summit for Opioid Safety. Principles for more selective and cautious opioid prescribing. Seattle Washington, October 31-November 1, 2012. http://depts.washington.edu/anesth/education/forms/pain/Principles_opioidPrescribing.pdf

26. Jane C. Ballantyne, Jianren Mao. Opioid therapy for chronic pain. New England Journal of Medicine, November 13, 2003;349:1943-1953. http://www.nejm.org/doi/full/10.1056/nejmra025411

27. Barry Meier. Pendulum swings against wide use of painkillers. The New York Times, Herald-Tribune, April 9, 2012. http://health.heraldtribune.com/2012/04/09/pendulum-swings-against-wide-use-of-painkillers/

28. Jane C. Ballantyne, Mark D. Sullivan, Andrew Kolodny. Opioid dependence vs addiction: A distinction without a difference? Archives of Internal Medicine, September 24, 2012;172(17):1342-1343. http://www.thblack.com/links/RSD/ArchIntMed2012_172_1342_DependVSAdict.pdf

29. Jane C. Ballantyne. “Safe and effective when used as directed”: The case of chronic use of opioid analgesics. Journal of Medical Toxicology, December 2012;8(4):417-423. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3550253/

30. Jane C. Ballantyne. What Is the Evidence for the Effectiveness of Opioid Analgesics for Chronic Pain From Clinical and Administrative Data, p. 11. http://www.fda.gov/downloads/Drugs/NewsEvents/UCM307844.pdf

31. Press Release. Cohen Milstein Sellers & Toll PLLC Announces the Investigation of Insys Therapeutics, Inc. June 5, 2014 8:00am EDT. http://www.reuters.com/article/dc-cohen-milstein-idUSnBw055260a+100+BSW20140605

32. Jessica M. Karmasek. Cohen Milstein law firm strengthening relationships with state AGs, earning millions. LegalNewsline.Com, April 21, 2015. http://legalnewsline.com/stories/510550711-cohen-milstein-law-firm-strengthening-relationships-with-state-ags-earning-millions

33. Eric Lipton. Lawyers create big paydays by coaxing attorneys general to sue. New York Times, New York edition, December 19, 2014, p. A1. http://www.nytimes.com/2014/12/19/us/politics/lawyers-create-big-paydays-by-coaxing-attorneys-general-to-sue-.html?_r=1

34. C.J. Ballantyne. Opioid controls: regulate to educate. Pain Medicine. April 2010;11(4):480-481. http://onlinelibrary.wiley.com/doi/10.1111/j.1526-4637.2010.00822.x/abstract

35. Jane C. Ballantyne, Miles Belgrade, Russ Carlisle, Roger Chou, Edward C. Covington, Robert W. Day, Richard A. Deyo, Irfan Dhalla, Thomas A. Farley, Gary M. Franklin, Stephen G. Gelfand, Stuart Gitlow, Roland W. Gray, Erik Gunderson, W. Michael Hooten, David Juurlink, Andrew Kolodny, Thomas R. Kosten, Kurt Kroenke, Eric B. Larson, Petros Levounis, Elinore F. McCance-Katz, Lewis Nelson, Rosemary Orr, William Phillips, Charles Reznikoff, Roger Rosenblatt, Nirav R. Shah, Harris Silver, Kurt C. Stange, Jon Streltzer, Mark Sullivan, Barbara J. Turner, Judith Turner, Michael Von Korff, Sidney M. Wolfe, Art Van Zee. Letter, Dockets Management Branch, Food and Drug Administration, July 25, 2012. http://paindr.com/wp-content/uploads/2012/08/2012-07-25_FDA-letter-from-physicians-for-responsible-opioid-prescribing.pdf I have written a separate commentary (available upon request) regarding the ethical breaches that these demands represent, and the FDA’s scientific rebuffs were withering: (1) The FDA repudiated the spurious distinction between “cancer” and “noncancer pain:” “It is FDA’s view that a patient without cancer, like a patient with cancer, may suffer from chronic pain, and PROP has not provided scientific support for why labeling should recommend different treatment for such patients. In addition, FDA knows of no physiological or pharmacological basis upon which to differentiate the treatment of chronic pain in a cancer setting or patient from the treatment of chronic pain in the absence of cancer, and comments to the Petition docket reflect similar concerns. FDA therefore declines to make a distinction between cancer and non-cancer chronic pain in opioid labeling.” (2) The FDA rejected PROP’s unscientific dose ceiling: “For the reasons discussed in further detail below, the scientific literature does not support establishing a maximum recommended daily dose of 100 mg MED [morphine equivalent dose]. Further, creating a maximum dose of 100 mg MED, or another dose ceiling, could imply a superior opioid safety profile under that set threshold, when there are no data to support such a conclusion. The Agency therefore denies PROP’s request that opioid labeling specify a maximum daily dose.” (3) It rejected PROP’s duration demands, noting that the evidence PROP used “did not suggest that chronic opioid therapy causes addiction, or vice versa. Both addiction and chronic opioid therapy were measured at one-point in time, so it is unknown which happened first: addiction or chronic opioid therapy.” “The cited literature does not identify a duration threshold beyond which the risk of addiction outweighs the benefits of opioid treatment. PROP has selected a 90-day limit, but provides no evidence that addiction (however it is defined) increases significantly after 90 days of use such that it would support a labeling change.” (4) While granting PROP’s request to remove “moderate pain” from opioids labeling, the FDA refused to restrict them to “severe pain,” using the PROP letter as the occasion to actually liberalize opioid labeling. The new labeling substitutes language that “underscores that patients in pain should be assessed not only by their rating on a categorical pain intensity scale, but also based on a more thoughtful determination that their pain—however it may be defined—is severe enough to require daily, around-the-clock, long-term opioid treatment, and for which alternative treatment options are inadequate. This framework better enables prescribers to make decisions based on a patient’s individual needs…[and] allows prescribers to make an assessment of pain relative to a patient’s ability to perform daily activities or enjoy a reasonable quality of life, not only on where a patient’s pain falls on an intensity scale.“ (Janet Woodcock. Letter, Andrew Kolodny, MD, President, Physicians for Responsible Opioid Prescribing, September 10, 2013. http://paindr.com/wp-content/uploads/2013/09/FDA_CDER_Response_to_Physicians_for_Responsible_Opioid_Prescribing_Partial_Petition_Approval_and_Denial.pdf)

36. Jane C. Ballantyne, Naomi S. Shin. Efficacy of Opioids for Chronic Pain: A Review of the Evidence. Clinical Journal of Pain, July-August 2008;24(6):469–478. http://chroniccare.rehab.washington.edu/chronicpain/resources/efficacyofopioidsforchronicpain.pdf

37. Lewis Nelson, M.D.

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39. Jeanmarie Perrone, M.D.

40. Jeanmarie Perrone, Lewis S. Nelson. Medication reconciliation for controlled substances—an “ideal” prescription-drug monitoring program. The New England Journal of Medicine, June 21, 2012;366:2341-2343. http://www.nejm.org/doi/full/10.1056/NEJMp1204493

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43. Erin E. Krebs. Unintended consequences: Current state of prescription opioid use and misuse in the US. April 14, 2012, p. 15. www.janussc.org/janus/docs/Janus-Opioid-Conference-Summit-Keynote-04142012.pptx A less sensational, but more easily grasped, way of expressing the same information is some degree of overdose in 3 of every 100 people treated for 20 years.

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89. Interview with Judy Woodruff. How should U.S. regulate powerful painkillers? PBS NewsHour, January 6, 2015. http://www.pbs.org/newshour/bb/u-s-regulate-powerful-painkillers/ See also: Dr. Andrew Kolodny on Combating Drug Abuse. C-Span, October 25, 2051, at 00:23:04. http://www.c-span.org/video/?328904-4/washington-journal-dr-andrew-kolodny-drug-abuse-us

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91. Presumably, then, physicians must also overprescribe cocaine (“Coke,” “Crack”), cathinones (“Bath Salts”), ethanol (alcohol), ketamine (“K,” “Special K,” “Vitamin K,” “Lady K,” “Jet,” “Super Acid,” “Bump,” “Special LA Coke,” “KitKat,” “Cat Valium”), methamphetamines (“Chalk,” “Chrissy,” “Crank,” “Crystal,” “Glass,” “Go,” “Hydro,” “Ice,” “Meth,” “Rock Candy,” “Speed,” “Whiz”), 3,4-methylenedioxymethamphetamine (“Ecstasy,” “MDMA,” “Molly”), phencyclidine (“Amp,” “Angel Dust,” “Animal Tranquilizer,” “Dips,” “Dust,” “Elephant,” “Embalming Fluid,” “Formaldehyde,” “Fry,” “Hog,” “Ozone,” “PCP,” “Peace Pill,” “Rocket Fuel,” “Sernyl,” “Sernylan,” “Super Kools,” “Tictac,” “Tranq,” “Water,” “Wet”), tobacco, toluene (toluol, methylbenzene, methyl benzol, and phenylmethane), alpha-pyrrolidinopentiophenone (“alpha-PVP,” “Flakka”), and (outside of “medical marijuana” states) marijuana (“Cannabis, “Pot,” “Reefer,” “Buds,” “Grass,” “Weed,” “Dope,” “Ganja,” “Herb,” “Boom,” “Gangster,” “Mary Jane,” “MJ,” “Sinsemilla,” “Shit,” “Joint,” “Hash,” “Hash Oil,” “Blow,” “Blunt,” “Green,” “Kilobricks,” “Thai Sticks”).

92. http://feduprally.org/study-opioid-overprescription-a-problem-for-all-doctors/ accessed December 23, 2015. Note that this study used to support this claim actually showed only that opioids are prescribed exactly the same way other medications are, rather than by outlying physicians (“pill mills”): Jonathan H. Chen, Keith Humphreys, Nigam H. Shah, Anna Lembke. Distribution of opioids by different types of Medicare prescribers. Journal of the American Medical Association Internal Medicine, December 14, 2015. http://archinte.jamanetwork.com/article.aspx?articleid=2474400 Neither the study design nor the Medicare database is capable of showing whether opioids are over- or under- or appropriately prescribed.

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99. In NM, a state with unusually high rates of addiction, from 1990 through 2005, the rates of unintentional overdose deaths related to heroin were 2.4 times as high as those related to prescription opioids, even though deaths that could not be definitively attributed to heroin were categorized as “opioid-related” due to morphine. (Nina G. Shah, Sarah L. Lathrop, R. Ross Reichard, Michael G. Landen. Unintentional drug overdose death trends in New Mexico, USA, 1990–2005: Combinations of heroin, cocaine, prescription opioids and alcohol. Addiction, 2007;103:126–136. http://www.ihra.net/files/2010/08/23/Shah_-_Unintentional_Drug_Overdose.pdf)

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102.Other data supports declining use, as well: Richard C. Dart, Hilary L. Surratt, Theodore J. Cicero, Mark W. Parrino, S. Geoff Severtson, Becki Bucher-Bartelson, Jody L. Green. Trends in opioid analgesic abuse and mortality in the United States. New England Journal of Medicine, January 15, 2015;372:241-248. http://www.nejm.org/doi/full/10.1056/NEJMsa1406143#t=articleResults Monitoring the Future Study: Trends in Prevalence of Various Drugs for 8th Graders, 10th Graders, and 12th Graders; 2012 – 2015 (in percent) http://www.drugabuse.gov/trends-statistics/monitoring-future/monitoring-future-study-trends-in-

103.Andrew Kolodny, David T. Courtwright, Catherine S. Hwang, Peter Kreiner, John L. Eadie, Thomas W. Clark, G. Caleb Alexander. The prescription opioid and heroin crisis: A public health approach to an epidemic of addiction. Annual Review of Public Health, March 2015;36:559-574. http://www.annualreviews.org/doi/full/10.1146/annurev-publhealth-031914-122957

104.Florence Yates Hann. The Story Of Chanticleer Adapted from the French of Edmond Rostand. Frederick A. Stokes Company, 1913, pp. 62-63. http://babel.hathitrust.org/cgi/pt?id=hvd.hnt6k8;view=1up;seq=93 Originally, Edmond Rostand. Chantecler: pièce en quatre actes, en vers, January 1, 1910, Fasquelle https://play.google.com/books/reader?id=tvGRAAAAIAAJ&printsec=frontcover&output=reader&hl=en&pg=GBS.PA65

105.David Juurlink, M.D., Ph.D.

106.http://www.supportprop.org/board-of-directors/ accessed December 15, 2015.

107.David Juurlink. Canada’s opioid crisis is fueled by doctors. Huffpost Canada Politics, September 7, 2014, updated November 7, 2014. http://www.huffingtonpost.ca/david-juurlink/opioid-crisis-doctors_b_5775274.html

108.Dr. Deborah Dowell. CDC Workshop: Drivers of Rx Drug Overdoses. National Rx & Heroin Drug Abuse Summit, http://nationalrxdrugabusesummit.org/biographies/dr-deborah-dowell/

109.Centers for Disease Control and Prevention, National Center for Injury Prevention and Control, Division of Unintentional Injury Prevention. When the Prescription Becomes the Problem. http://www.cdc.gov/drugoverdose/media/

110.Deborah Dowell, Hillary V. Kunins, Thomas A. Farley. Opioid analgesics—risky drugs, not risky patients. Journal of the American Medical Association, June 5, 2013;309(21):2219-2220. https://jama.jamanetwork.com/article.aspx?articleid=1686609 For an opposing perspective, see: Ronald T. Libby. Treating doctors as drug dealers: The DEA’s war on prescription painkillers. Policy Analysis, June 16, 2005;(545):1-27. http://object.cato.org/sites/cato.org/files/pubs/pdf/pa545.pdf

111.Li-Tzy Wu, George E Woody, Chongming Yang, Paolo Mannelli, Dan G Blazer. Substance Abuse and Rehabilitation, May 3, 2011;2:77–88. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3114372/#__ffn_sectitle “Heroin users reported a short mean interval from first use to onset of abuse (1.5 years) or dependence (2.0 years)…; the corresponding mean estimates for PO [prescription opioid] abuse and dependence among NMPOUs [nonmedical prescription opioid users] were 2.6 and 2.9 years, respectively….”

112.D. Paonek, D. Dowell, D. Heller. Preventing misuse of prescription opioid drugs. City Health Information, December 2011;30(4):23-30. http://www.nyc.gov/html/doh/downloads/pdf/chi/chi30-4.pdf

113.Thomas R. Frieden. Preventing prescription drug overdose: New challenges, new opportunities. National Rx Drug Abuse Summit, Operation UNITE, Atlanta, GA, April 8, 2015. http://www.slideshare.net/OPUNITE/wed-frieden-webversionrxod-unite-apr-8-videoexternal

114.Tamara M. Haegerich, Leonard J. Paulozzi, Brian J. Manns, Christopher M. Jones. What we know, and don’t know, about the impact of state policy and systems-level interventions on prescription drug overdose. Drug and Alcohol Dependence, December 1, 2014;145:34-47. http://www.drugandalcoholdependence.com/article/S0376-8716%2814%2901846-8/pdf

115.Jeanmarie Perrone, Matthew J. Bair, and David Tauben. Peer Review Plan for CDC Opioid Prescribing Guidelines for Chronic Pain. http://www.cdc.gov/injury/pdfs/fundedprograms/peer-review-plan-for-cdc-opioid-prescribing-guidelines-for-chronic-pain.pdf

116.Department of Emergency Medicine Leadership & Faculty: Jeanmarie Perrone, MD. http://www.med.upenn.edu/apps/faculty/index.php/g321/p1870

117.Jeanmarie Perrone. To curb prescription opioid abuse, physicians need to get with the program. MD, August 17, 2012, http://www.hcplive.com/journals/pain-management/2012/august-2012/To-Curb-Prescription-Opioid-Abuse-Physicians-Need-to-Get-with-the-Program

118.http://www.ncbi.nlm.nih.gov/pubmed?term=Matthew%20Bair

119.Matthew J. Bair. Barriers and Facilitators to Chronic Pain Self-Management: A Qualitative Study of Primary Care Patients with Comorbid Musculoskeletal Pain and Depression, p. 38. http://www.hsrd.research.va.gov/for_researchers/cyber_seminars/archives/sopm-011410.pdf

120.Matthew J. Bair. Barriers and Facilitators to Chronic Pain Self-Management: A Qualitative Study of Primary Care Patients with Comorbid Musculoskeletal Pain and Depression, p. 40. http://www.hsrd.research.va.gov/for_researchers/cyber_seminars/archives/sopm-011410.pdf

121.National Institutes of Health Interagency Pain Research Coordinating Committee. National Pain Strategy: A Comprehensive Population Health-Level Strategy for Pain (Draft) https://web.archive.org/web/20150706070945/http://iprcc.nih.gov/docs/DraftHHSNationalPainStrategy.pdf

122.David J. Tauben M.D. http://www.uwmedicine.org/Pages/bio.aspx?bioid=28139&redirect

123.Agency Medical Directors’ Group. Interagency Guideline on Prescribing Opioids for Pain, 3rd edition, June 2015, http://www.agencymeddirectors.wa.gov/Files/2015AMDGOpioidGuideline.pdf

124.This would only be true if the tapering were performed too quickly.

125.Richard C. Dart, Hilary L. Surratt, Theodore J. Cicero, Mark W. Parrino, S. Geoff Severtson, Becki Bucher-Bartelson, Jody L. Green. Trends in opioid analgesic abuse and mortality in the United States. New England Journal of Medicine, January 15, 2015;372:241-248. http://www.nejm.org/doi/full/10.1056/NEJMsa1406143#t=articleResults In a study of heroin users, 94% responded to open-ended questions by saying that they used it because prescription opioids were much more expensive and difficult to obtain: Theodore J. Cicero, Matthew S. Ellis, Hilary L. Surratt, Steven P. Kurtz. The changing face of heroin use in the United States: A retrospective analysis of the past 50 years. Journal of the American Medical Association Psychiatry, July 2014;71(7):821-826. http://archpsyc.jamanetwork.com/article.aspx?articleid=1874575

126.Richard N. Shiffman. Recognizing Trustworthy Guidelines: The New IOM Standards. p. 12. http://www.cdc.gov/od/science/quality/docs/trustworthy_gls.pdf

127.Richard N. Shiffman. Recognizing Trustworthy Guidelines: The New IOM Standards. p. 22. (emphasis in original) http://www.cdc.gov/od/science/quality/docs/trustworthy_gls.pdf

128.Institute of Medicine of the National Academies. Clinical Practice Guidelines We Can Trust: Standards for Developing Trustworthy Clinical Practice Guidelines (CPGs), p. 1. http://iom.nationalacademies.org/~/media/Files/Report%20Files/2011/Clinical-Practice-Guidelines-We-Can-Trust/Clinical%20Practice%20Guidelines%202011%20Insert.pdf

129.Richard N. Shiffman. Recognizing Trustworthy Guidelines: The New IOM Standards. p. 8. http://www.cdc.gov/od/science/quality/docs/trustworthy_gls.pdf

130.Richard N. Shiffman. Recognizing Trustworthy Guidelines: The New IOM Standards. p. 11. http://www.cdc.gov/od/science/quality/docs/trustworthy_gls.pdf

131.Richard N. Shiffman. Recognizing Trustworthy Guidelines: The New IOM Standards. p. 13. http://www.cdc.gov/od/science/quality/docs/trustworthy_gls.pdf

132.Allan D. Sniderman, Curt D. Furberg. Why Guideline-Making Requires Reform. The Journal of the American Medical Association, January 28, 2009;301(4):429-431. http://jama.jamanetwork.com/article.aspx?articleid=183265

133.Tom Frieden. Johns Hopkins Bloomberg School of Public Health Convocation–May 19, 2015. Transcript. www.jhsph.edu/alumni/_docs/tom-frieden-convocation-speech-2015.doc

134.IBD Editorials. Budget ‘Cuts’ Aren’t Why CDC Fumbled Ebola. http://news.investors.com/ibd-editorials/101314-721520-cdc-failures-on-ebola-are-not-from-phantom-budget-cuts.htm

135.Centers for Disease Control and Prevention Budget Request Summary—Fiscal Year 2014. http://assets.bizjournals.com/atlanta/pdf/cdc%20budget%20req%20sum%202014.pdf

136.Centers for Disease Control and Prevention. CDC Grand Rounds: Prescription Drug Overdoses—a U.S. Epidemic. Journal of the American Medical Association, 2012;307(8):774-776. http://jama.jamanetwork.com/article.aspx?articleid=1356004

137.Matthew Perrone. Painkiller politics: Effort to curb prescribing under fire. AP: The Big Story, December 18, 2015. http://bigstory.ap.org/article/765439c771b649a7b6940fda87595735/effort-curb-painkiller-prescribing-faces-stiff-opposition

138.The Wizard of Oz. The Wizard of Oz, 1939. http://www.wendyswizardofoz.com/printablescript.htm

139.Terrence Shaneyfelt. In guidelines we cannot trust: Comment on “Failure of clinical practice guidelines to meet Institute of Medicine Standards” Archives of Internal Medicine, November 26, 2012;172(21):1633-1634. http://archinte.jamanetwork.com/article.aspx?articleid=1384244

140.Mark Curnutte. Who fueled the opioid explosion? Pharmaceutical and medical organizations may be responsible for the dual public health crisis–painkiller and heroin addiction. Cincinnati.com http://local.cincinnati.com/community/pages/painday3/

141.“The term “dangerous drug” means a controlled substance, as defined in section 802 of title 21.” 42 USC 5117aa-21: Definitions. http://uscode.house.gov/view.xhtml?req=%28dangerous+drug%29&f=treesort&fq=true&num=90&hl=true&edition=prelim&granuleId=USC-prelim-title42-section5117aa-21 “'[D]angerous drug’ means a narcotic drug, a controlled substance, or a controlled substance analog (as defined in section 102 of the Comprehensive Drug Abuse Prevention and Control Act of 1970 (21 U.S.C. 802))” 46 U.S. Code § 2101 – General definitions. https://www.law.cornell.edu/uscode/text/46/2101 A search of state laws (December 21, 2015) showed that AZ follows these definitions, but CA, GA, NM, NV, OH, OK, and TX define “dangerous drug” to mean any substance that requires a prescription (This definition appears to modeled after the 1952 Prescription Drug Amendment to the Federal Food, Drug, and Cosmetic Act, for which see: Edward B. Williams. Federal law of prescription drugs. Notre Dame Law Review, May 1, 1952;27(3):377-404. http://scholarship.law.nd.edu/cgi/viewcontent.cgi?article=3744&context=ndlr.).

142.Report of the International Narcotics Control Board for 2004 (E/INCB/2004/1), p. 31. http://www.incb.org/documents/Publications/AnnualReports/AR2004/AR_04_English.pdf As commonly observed by others, people view pharmaceuticals as safer and more predictable than nonpharmaceutical drugs.

143.Counterfeit Drugs. Institute for Effective Diagnosis. http://effectivediagnosis.org/counterfeit-drugs/ accessed December 23, 2015

144.Michael M. Vanyukov, Ralph E. Tarter, Galina P. Kirillova, Levent Kirisci, Maureen D. Reynolds, Mary Jeanne Kreek, Kevin P. Conway, Brion S. Maher, William G. Iacono, Laura Bierut, Michael C. Neale, Duncan B. Clark, Ty A. Ridenour. Common liability to addiction and “gateway hypothesis”: Theoretical, empirical and evolutionary perspective. Drug and Alcohol Dependence, 2012;123(Suppl 1):S3–17. http://www.drugandalcoholdependence.com/article/S0376-8716%2811%2900555-2/fulltext

145.Gillian Mohney. Heroin-related deaths quadruple as drug epidemic continues to impact U.S. ABC News, July 7, 2015. http://abcnews.go.com/Health/heroin-related-deaths-quadruple-drug-epidemic-continues-impact/story?id=32285495 In contrast, according to the CDC’s own National Institute on Drug Abuse, most heroin injectors did not use prescription opioids before heroin: Nearly half of young people who inject heroin surveyed in three recent studies reported abusing prescription opioids before starting to use heroin.” (National Institute on Drug Abuse. Drug Facts: Heroin. http://www.drugabuse.gov/publications/drugfacts/heroin accessed December 29, 2015)

146.United Nations Office on Drugs and Crime. The non-medical use of prescription drugs: Policy direction issues. September 2011, p. 29. http://www.unodc.org/docs/youthnet/Final_Prescription_Drugs_Paper.pdf

147.Steven J Baumrucker. Opioid Safe Prescribing: Intro to the TN Guidelines, p. 12. http://www.ouramazingworld.org/uploads/4/3/8/6/43860587/baumrucker_tennessee_chronic_pain_guidelines_and_the_effects_of_repealing_the_intractable_pain_act.pdf

148.For oxycodone in 2002.

149.Joranson DE, Gilson AM. Drug crime is a source of abused pain medications in the United States. Journal of Pain and Symptom Management, 2005;30(4):299-301. http://www.painpolicy.wisc.edu/sites/www.painpolicy.wisc.edu/files/05jpsm.pdf

150.They did not report the percentage of hydrocodone that was diverted, but noted that more than twice as many units of hydrocodone were diverted than the other six studied opioid analgesics combined.

151.John Glover. The Importance of On-Dose Technologies in the Fight Against Misuse, Abuse and Illegal Diversion of Opioids: A White Paper. http://capsugel.com/media/library/the_importance_of_on_dose_technologies_in_the_fight_against_misuse_abuse_and_illegal_diversion_of_opioids.pdf

152.Steve Wood. Combating pharmaceutical counterfeiting and diversion. Pharmaceutical Online, November 19, 2014. http://www.pharmaceuticalonline.com/doc/combating-pharmaceutical-counterfeiting-and-diversion-0001

153.David De Jean. Serialization To solve pharma counterfeiting, a $70 billion issue. Pharmaceutical Online, November 13, 2014. http://www.pharmaceuticalonline.com/doc/serialization-to-solve-pharma-counterfeiting-a-billion-issue-0001

154.The National Center on Addiction and Substance Abuse at Columbia University. Under the Counter: The Diversion and Abuse of Controlled Prescription Drugs in the U.S., July 2005, pp. iii, 63-71. http://www.casacolumbia.org/download/file/fid/1202

155.Olaf H. Drummer. Postmortem toxicology of drugs of abuse. Forensic Science International, June 10, 2004;142(2–3):101–113. http://www.fsijournal.org/article/S0379-0738%2804%2900103-3/abstract?cc=y=

156.National Highway Traffic Safety Administration. Drugs and Human Performance Fact Sheets: Morphine (and Heroin). http://www.nhtsa.gov/PEOPLE/injury/research/job185drugs/morphine.htm accessed December 25, 2015

157.Nina G. Shah, Sarah L. Lathrop, R. Ross Reichard, Michael G. Landen. Unintentional drug overdose death trends in New Mexico, USA, 1990–2005: Combinations of heroin, cocaine, prescription opioids and alcohol. Addiction, 2007;103:126–136. http://www.ihra.net/files/2010/08/23/Shah_-_Unintentional_Drug_Overdose.pdf

158.Center for Health Statistics. Overdose deaths related to non-pharmaceutical fentanyl on the rise in New Jersey. CHS Briefs, December 2006. http://www.state.nj.us/health/chs/oisp/documents/fentanyl_06.pdf

159.Source intentionally omitted.

160.J.C. Torpey. Fake oxycodone pills contain fentanyl: Did fake Tennessee pills come from Alberta? Inquisitr, May 14, 2015. http://www.inquisitr.com/2090488/fake-oxycodone-pills-contain-fentanyl-did-fake-tennessee-pills-come-from-alberta/

161.Heroin-fentanyl mix plaguing many states: Two McKees Rocks men arrested in bust. Pittsburgh Post-Gazette, January 31, 2014. http://www.post-gazette.com/local/crime/2014/01/31/Two-McKees-Rocks-men-arrested-in-heroin-bust/stories/201401310142

162.T.S. Jones, L. Krzywicki, J Maginnis, N.L Jones, R. Weiskopf, M. Reid, C. Schmidt, J. Fiedler, J.M. Topolski, M. Graham, R. Psara, M. Case, S. McCune, S.M. Marcus, V.W. Weedn, K. Hempstead, S.J. Klein, G. Roseborough, S Alles, K. Nalluswami, S. Kelly, T. Zobeck, T. McCormick, D. Peters, M. Wilson, E. Regula, K. Hoffman, D. Lentine. Nonpharmaceutical fentanyl-related deaths—multiple states, April 2005—March 2007. Morbidity and Mortality Weekly Report, July 25, 2008;57(29):793-796. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5729a1.htm

163.Northern Border. USBorderPatrol.com http://www.usborderpatrol.com/Border_Patrol1920.htm accessed December 23, 2015

164.Julian Sher. OxyContin smuggling from Canada rises sharply. The Globe and Mail, November 14, 2011, last updated September 6, 2012. http://www.theglobeandmail.com/life/health-and-fitness/oxycontin-smuggling-from-canada-rises-sharply/article547508/

165.Robert G. Carlson, Ramzi W. Nahhas, Raminta Daniulaityte, Silvia S. Martins, Linna Li, Russel Falck. Latent class analysis of non-opioid dependent illegal pharmaceutical opioid users in Ohio. Drug and Alcohol Dependence, 2014;134:259–266. http://www.drugandalcoholdependence.com/article/S0376-8716%2813%2900415-8/pdf

166.Theodore J. Cicero, Matthew S. Ellis, Hilary L. Surratt, Steven P. Kurt. Factors influencing the selection of hydrocodone and oxycodone as primary opioids in substance abusers seeking treatment in the United States. Pain, 2013;154:2639–2648. http://cicero.wustl.edu/skip/publications/documents/Factorsinfluencingtheselectionofhydrocodoneandoxycodoneasprimaryopioidsinsubstanceabuserssee.pdf

167.Report of the International Narcotics Control Board for 2004 (E/INCB/2004/1), p. iii. http://www.incb.org/documents/Publications/AnnualReports/AR2004/AR_04_English.pdf

168.Bob Roehr. Controversial Tom Frieden named to lead CDC. Windy City Times, May 18, 2009. http://www.windycitymediagroup.com/gay/lesbian/news/ARTICLE.php?AID=21192

169.Manny Alvarez. Dr. Manny: CDC director Dr. Tom Frieden should resign. Dr Manny’s Notes, October 13, 2014. http://www.foxnews.com/health/2014/10/13/dr-manny-cdc-director-dr-thomas-frieden-should-resign.html

170.Ford Vox. Why CDC chief must go. CNNOpinion, October 16, 2014. http://www.cnn.com/2014/10/16/opinion/vox-frieden-should-resign/

171.Thomas Barrabi. Who Is Tom Frieden? CDC director faces calls for resignation amid Ebola missteps. International Business Times, October 16, 2014. http://www.ibtimes.com/who-tom-frieden-cdc-director-faces-calls-resignation-amid-ebola-missteps-1706175

172.Sean Piccoli. Ex-FEMA Chief Michael Brown: CDC’s Frieden should resign. Newsmax, October 17, 2014. http://www.newsmax.com/Newsmax-Tv/cdc-tom-frieden-michael-brown-fema/2014/10/17/id/601484/

173.Gary M. Franklin. Opioids for chronic noncancer pain: A position paper of the American Academy of Neurology. Neurology, September 30, 2014;83(14):1277-1284. http://www.neurology.org/content/83/14/1277.longThe ideal approach would be to prespecify an MCID [minimum clinically important difference] in both pain and functional outcome on the order of a 20%–30% improvement, and perhaps to use a composite measure including both measures.” I have consistently used this approach (but requiring evidence for at least a 30% improvement) in my own clinical practice.

Critique of the CDC’s Draft Guidelines on the Use of Opioid Analgesics for Chronic Pain Part Five

 

(Note: The endnotes which provide the references for this critique have been collected into the final part of this document.)

The curve of increasing overdose deaths was unchanged following “5th vital sign.”

Rather than blaming prescribers, as the CDC and most of the contributors to its draft guidelines do, the International Narcotics Control Board declares that “diversions of narcotic drugs and psychotropic substances mostly occur when consignments pass from the wholesale level to the retail level.”[142] Criticizing preoccupations with physician prescriptions, others point to robberies, break ins, and pilferage of as much of 22.4%[148] of total U.S. pharmaceutical production,[149] based upon data from the Drug Enforcement Administration (DEA).[150] The unchecked flow of pain medications diverted from nonmedical sources will not be addressed if diversion control focuses only on prescribers and patients.”[149] Moreover, such figures are likely to seriously underestimate the diversion problem, because criminals have penetrated the legitimate supply chain to divert legitimate product to illegitimate uses and have introduced illegitimate product into the legitimate supply chain”[151] with near impunity, avoiding detection by simply replacing the diverted pharmaceuticals with counterfeits.[152, 153] The controlled substances of all sorts that are readily available on the Internet require a credit card, not a prescription,[154] but these “credit card painkillers” inflate statistics on “prescription painkillers.”

More often than not, laboratory tests reveal the presence of one or more substances in addition to the opioid, suggesting that the depressant effects of alcohol or other drugs on the central nervous system were additive with those of the pain reliever in causing death.”[38]

Furthermore, the assumption that the finding of a “prescription painkiller” is due to a pharmaceutical product is often false.

Under the best of circumstances, drug testing after death is fraught with pitfalls.[155] “Identifying risk factors among opioid overdose decedents has been difficult due, in part, to the widely varying methods employed by state death investigators to collect mortality data and to report on drug involvement in overdose.”[46] Even in life, drug testing is complicated, for example, by the fact that heroin (and codeine) are rapidly converted to morphine in the body.[156] This is important, if for no other reason than that morphine, but not heroin, might be a “prescription painkiller.” Even though heroin is more commonly abused than morphine, the default assumption is to blame a prescription opioid: The finding of a morphine blood concentration in a decedent is classified as a morphine-caused death if the differentiation between heroin- and morphine-caused death is not definitive.”[157] Even when the drug is correctly identified, the practice of automatically attributing death to a drug found in the blood[157] is invalid, because no concentration of a drug of abuse can be interpreted in isolation without a thorough examination of the relevant circumstances and after the conduct of a post-mortem to eliminate or corroborate relevant factors that could impact on the drug concentration and the possible effect of a substance on the body.[155]

…the exact number of deaths remains unknown for several reasons: 1) lack of standardized national definitions among death investigators to interpret postmortem toxicology findings, 2) state-level variations in determining the manner of death (e.g., suicide vs accident vs undetermined), and 3) poorly defined toxicology categories used to classify deaths in the ICD-10.”[46]

Failure to distinguish between counterfeit and pharmaceutical versions of a drug also inflates the apparent rates of “prescription” drug abuse and overdoses. For example, fentanyl is a “prescription painkiller,” but not necessarily a pharmaceutical.[158] It is easily manufactured. One kitchen chemist provides detailed instructions for what he claims to be a greater than 80% overall yield of more than 99.5% pure fentanyl, which he cuts 1:100 with milk sugar and sells as “white heroin.”[159] Counterfeit “Percocet” (oxycodone), that is actually nonpharmaceutical fentanyl, is widely available,[160] and heroin laced with fentanyl is commonplace.[161, 162] Since illicit fentanyl tests the same as legitimate fentanyl, and since heroin rapidly converts into morphine,[99] without additional information, heroin and illicit fentanyl inflate statistics on “prescription painkillers.

Even if the product is a pharmaceutical, until the recent rescheduling of hydrocodone combination products, people could “get a doctor’s DEA number, call up a pharmacy, pretend to be the doctor, and get themselves a hydrocodone prescription with five refills on it.”[95] Likewise, a pharmaceutical opioid may never have been intended to fill a prescription in the United States. Considering the status of our border,[163] smuggling of pharmaceutical controlled substances from Canada, for example, is big, highly profitable,[154] and easy. These factors also inflate statistics on “prescription painkillers.”

Adding to the complication, one study found that one-in-six nondependent “nonmedical” users of pharmaceutical opioids reported exclusively using them to self-medicate pain.[165] Another study of 2262 opioid dependent substance abusers whose primary drug was a prescription opioid analgesic found, “Although getting high was the desire of nearly all users of both oxycodone and hydrocodone, 50–60% also indicated that the management of pain was an important factor.”[166]

The CDC‘s obsession with prescriptions also puts it at odds with the International Narcotics Control Board, which declares that “focus on supply…does not and cannot have a long-term effect.”[167]

Even before he began his tenure as Director of the CDC, Tom Frieden was criticized by those who knew him as “a vindictive man” with a “an authoritarian my-way-or-the-highway approach and an unabashed secretiveness undignified of a public servant.”[168] The secretiveness[17, 18] and the forced outcomes in the opioid analgesic guidelines developed under him are extensions of this pattern.

Unfortunately, Frieden’s incompetent Ebola leadership[169, 170, 171, 172] is not the only reason for him to go. His blatant biases, his presumptuous disregard for the opinions of those who are internationally-recognized experts in addiction and abuse, his indifference toward facts, and his heavy-handed violations of the public trust have made it impossible to have confidence in guidelines produced by the CDC, so long as it remains under his politicized control.

There is a better approach, such as the open and comprehensive National Pain Strategy.[121] Instead of applying generic restrictions prescriptions of opioid analgesics for chronic pain, we ought to be prescribing them to those patients who clearly demonstrate significant functional improvements because of them,[173] while we maximize alternative therapies. Whether the number of such patients will be many or few, patients and their physicians deserve guidelines that they can trust.

Until January 13, 2016, you may comment upon these guidelines by Internet (http://www.regulations.gov) or by mail (National Center for Injury Prevention and Control, Centers for Disease Control and Prevention, 4770 Buford Highway NE., Mailstop F-63, Atlanta, GA 30341, Attn: Docket CDC-2015-0112).

(See Endnotes)

Critique of the CDC’s Draft Guidelines on the Use of Opioid Analgesics for Chronic Pain Part Four

(Note: The endnotes which provide the references for this critique have been collected into the final part of this document.)

The CDC, itself, has published standards requiring a balanced “guideline development group”[126] and a broad base of reviewers[15] comprising “a full spectrum of relevant stakeholders.”[127; emphasis in original] However, out of twenty-five contributors and reviewers: Seven have highly questionable credentials. Another ten are overtly hostile toward opioid analgesics, while there is indirect evidence for such hostility in three more (thirteen total). Only five have both credentials and points-of-view that are distinct from the public positions of the CDC’s director, Tom Frieden, but one of those five has a financial tie to the CDC, creating a conflict of interests. Two are from the CDC’s Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, which is promoting a social media campaign against prescription opioids, one of the two is “Team Lead” for its “Prescription Drug Overdose Team,” and neither is an independent voice from Tom Frieden. Two are medical advisors to ARPO. One is chief medical officer of Phoenix House. Five are officials of PROP, an agency of Phoenix House, and at least two others are members of it. One is a “committee member” of FED Up!, a political action organization that is sponsored by PROP, Phoenix House, and ARPO. Eight are signatories to the logically, scientifically, and ethically questionable PROP letter demanding that the FDA limit opioid analgesics for “non-cancer pain” to low doses for “severe pain” for a maximum of ninety days. At least nine are responsible for the PROP guidelines or a modification of it, or else have a public position in favor of it. At least eight were authors of other guidelines. Two of three authors and two of three outside reviewers already had public positions that opioid analgesics are harmful or without benefits. At least five contributors have significant financial conflicts of interests, and the activities or declared positions of nineteen create significant intellectual conflicts of interest.

Furthermore, if authoring guidelines counts as participation in an “advisory board” (as I believe it does), at least fifteen of the twenty-five appointments violate the IOM’s Standard 2.3: “Members of the GDG [Guideline Development Group] should divest themselves of financial investments they or their family members have in, and not participate in marketing activities or advisory boards of, entities whose interests could be affected by CPG [Clinical Practice Guideline] recommendations.”[128] Certainly, the interests of PROP, Phoenix House, ARPO, and FED Up!, the American Association of Family Practitioners, and even funding for the CDC’s Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, “could be affected by” the CDC’s clinical practice guidelines.

Worse, by the definition published by the CDC, itself, the activities of least fifteen (and arguably eighteen) of the twenty-four represent “Intellectual COI [conflicts of interests]: academic activities that create the potential for an attachment to a specific point of view that could unduly affect an individual’s judgment about a specific recommendation….”[129]

By the standards published by the CDC, “Members with COIs [conflicts of interests] should be a minority,[130] but they are the majority of this group. Those same standards note that mere disclosure of conflicts of interest, whether they be financial or intellectual, can actually promote biased advice, because of the phenomena of “Strategic exaggeration” (the “Tendency to provide more biased advice to counteract anticipated discounting”) and “Moral licensing” (“The often unconscious feeling that biased advice is justifiable because the advisee has been warned.”).[131]

Surely the CDC is aware that “what is to be decided is often already decided with the selection of the deciders.”[132] The agency that is vested in its #RxProblem campaign against opioid analgesics[109] clearly chose people with prejudged opinions against opioid analgesics for the same reason that it chose to conduct a one-sided (harms) review of the literature on opioid analgesicsto force the outcome, and provide them a chance to get through it what the FDA refused to give them.[35]

Under Frieden, the CDC ignored the IOM’s requirement[7] that guidelines be based upon a systematic review of the world literature, as well as the standards it has published, requiring “thorough and unbiased review of existing knowledge.”[15] Instead, the CDC only conducted systematic reviews for harms. For benefits, the CDC substituted “rapid reviews,limited to U.S. studies, and incongruously focused on “overdose, cardiovascular events, motor vehicle crashes, and fractures,” and then excluded the information from its strength of evidence analysis.[13] In other words, the CDC’s literature review was designed to find no benefits, but to thoroughly document harms. While the CDC posts that guidelines that are not based upon a thorough and systemic review of the scientific evidence are neither trustworthy nor should be included in the National Guidelines Clearinghouse,[8] it claims that its own guideline irregularities were justified by the need to “streamline.”[13] Streamline for what? Why did this streamlining specifically leave them “informed neitherby a systematic review of evidence” nor by “an assessment of the benefits and harms of alternative care options, so that they do not even so much as qualify as “clinical practice guidelines,” under the IOM’s definition.[2; emphasis in original]

The man who preaches “the importance of practicing interventional epidemiology” through political activism, who advocates science with a political agenda,[133] who poses with a congressman to campaign against opioid analgesics,[109] whose appointment and tenure solely depend upon the President of the United States, whose budget is political,[134, 135] and under whom the CDC targets physician prescribing, conducts its #RxProblemcampaign,[109] openly advocates enforcement as the solution to opioids,[136] and speaks approvingly of Washington State moving “aggressively” to curb opioid prescribing,[85] expects us to believe that the guidelines developed under him were apolitical.[137] If the guidelines were not political, then why, of the twenty five selected to have roles in these guidelines, were at least nineteen politically tainted? Sixteen contributors are known to engage in, or to advocate, political processes to impose upon others their own views about prescribing opioid analgesics, one of whom implies that opioid analgesic prescriptions should be prohibited, and two more at least have close ties with those in the political camp. Of the sixteen that are unambiguously politically active, six are members of the board of directors of an organization which its own president describes as a lobbying group,[20] of which three have leadership roles in two other political action organizations. No politics, indeed. Pay no attention to that man behind the curtain.”[138]

The question, in the letter from the House of Representatives Committee on Oversight and Government Reform, regarding the “efforts by the CDC to ensure that the composition of the ‘Core Expert Group’ was balanced in terms of points of view,”[18] can be answered by noting that at least ten of the contributors are active in campaigns against the use of opioid analgesics for chronic pain, that two are under CDC Director Tom Frieden, in the CDC‘s own Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, and that at least eleven (and arguably thirteen) are members of the same incestuously interlocking network. If Guideline panel membership is the main determinant of the trustworthiness of guidelines,”[139] these guidelines cannot be trusted.

This composition, like the one-sided literature review, perfectly reflects CDC Director, Tom Frieden‘s own agenda. Frieden says opioid analgesics should be “reserved for situations like severe cancer pain.”[140] Does Frieden think that pain in patients with cancer is a different kind than it is in those without cancer? Or does he, like PROP (but quite unlike the FDA)[35]—stand logic and ethics on their heads, by saying that pain which will be suffered for the rest of people’s lives should be treated for those people and pains that are expected be short-lived, but not for those people and those pains that are expected to last for years? Apparently so, because Frieden misleadingly refers to opioid analgesics by their legal classification[141] as “dangerous drugs,”[113] sensationally–but falsely[111]claiming that “just a few doses may lead to a lifelong struggle with addiction” and the “risk of injection drug use including heroin.”[113] In the later, Frieden disregards: (1) the FDA’s counter to PROP,[35] (2) the International Narcotics Control Board‘s opinion that pharmaceuticals are substitutes for illicit drugs with similar effects,[142] and (3) the Institute for Effective Diagnosis‘ observation that “prescription drugs are now being substituted for illegal drugs,because of a preference for the standardization, purity, and sanitation represented by drugs manufactured under the supervision of the Food and Drug Administration (FDA).[143] Tom Frieden treats the logically incoherent and scientifically untenable “gateway hypothesis”[144] as fact, connects the startling rise” in heroin use with prescriptions for opioid analgesics[145] by decree, and announces that people are primed for heroin use because they were addicted to an opioid painkiller.”[145] Frieden’s propaganda against prescriptions also puts him at odds with the United Nations Office on Drugs and Crime, which flatly states, Health-care professionals should not be blamed for the problem as a whole.”[146]

CDC Director Dr. Thomas Frieden and Congressman Hal Rogers

(Continued)

Critique of the CDC’s Draft Guidelines on the Use of Opioid Analgesics for Chronic Pain Part Three

 

(Note: The endnotes which provide the references for this critique have been collected into the final part of this document.)

The CDC’s peer review panel includes PROP’s vice-president for state regulatory affairs,[28] who is one of the authors of a guideline partially sponsored, and largely authored, by that organization[25] and is the sole author of another guideline.[80] He is chair of the Washington State Agency Medical Directors Group,[81] which sets standards for opioid prescribing.[82] He calls accidental opioid overdoses “one of the worst manmade epidemics in history,” for which he believes regulation is the solution.[83] He promotes “public advocacy” and “professional advocacy” to restrict opioid analgesics,[84] advocates “aggressively” curbing opioid prescribing[85] and credits the PROP guidelines[25] with reducing mortality from opioid overdoses,[45] even though similar reductions were seen elsewhere, prior to the existence of these guidelines[46, 47]. He is one of the seven contributors to the CDC’s guidelines who is also a signatory to the logically, scientifically, and ethically questionable PROP letter to the FDA, demanding that opioid analgesics for “non-cancer pain” be limited to low doses for severe pain” for a maximum of ninety days.[35]

The CDC’s Stakeholder Review Group[86] includes the co-founder and executive director of PROP.[87] Along with at least two of the core experts from PROP, he equates physical dependence (unpleasant physical symptoms upon abrupt discontinuation) with addiction (compulsive use in spite of evidence of harm).[28] Perhaps, then, physical dependence should be understood in place of The increased prevalence of opioid addiction,” which he says, in a paper of which he is first author, is caused by overprescribing of OPRs [opioid pain relievers].”[88] He is a “committee member” of FED Up! Coalition,[89 which is a “legislation and advocacy” group claiming thatthe root cause of the problem is overprescribing,”[90, 91] that all physicians overprescribe,[92] that “action from the federal government” can “bring this public health crisis to an end”[93] (FED Up! sponsorship by his own Phoenix House, PROP, and ARPO[94] unambiguously positions them as political organizations, as well.). He promotes “public advocacy” and “professional advocacy” to restrict opioid analgesics[84] and says the effects that hydrocodone and oxycodone produce are indistinguishable from heroin.[89] In case of doubt as to his intent, he told the FDA, “what we’re really talking about are heroin

pills,”[95] and he is one of five medical advisors to Advocates for the Reform of Prescription Opioids (ARPO),[96] which claims that “legally prescribed opioid narcotics are pharmaceutical-grade heroin produced in a laboratory.”[97] ARPO is another advocacy group “with the goal of ending the epidemic of death and addiction caused by prescription opioid drugs”[98, 99] through regulation. He is another of the seven contributors to the CDC’s guidelines who is a signatory to the logically, scientifically, and ethically questionable PROP letter demanding that the FDA limit opioid analgesics for “non-cancer pain” to low doses for severe pain” for a maximum of ninety days.[35] He, too, was one of the authors of the guideline partially sponsored, and largely authored, by PROP.[25] Hypocritically presuming to tell everyone else what to do, as the chief medical officer of Phoenix House,[100] he cannot keep his own House in order: Its more than one-hundred thirty “drug and alcohol addiction treatment” programs[23] have come under fire for “emphasizing business considerations,” “’rampant’ drug use,” altering medical records, “insufficient, inadequately trained or abusive staff; dirty premises; and lax security, with residents coming and going as they wished,” “insufficient clinical and mental health services, strip searches conducted without consent, and failure to file incident reports.”[101] He is also first author of a review that presented data showing an approximately 30% decline in the number of new opioid users over the same interval that opioid prescriptions increased approximately 250%,[102] as proving “the increased prevalence of opioid addiction caused by overprescribing of OPRs [opioid pain relievers].”[103] Not only is dishonest representation of data an ethical breach, but his claiming that temporal sequence proves causation puts him in the scientific company of the barnyard rooster of a well-known fable.[104]

Another[105] of the Stakeholder Review Group[23] is a member of the boards of the political advocacy organizations, PROP[106] and ARPO.[96] As a member of ARPO’s board, he apparently endorses its position that “legally prescribed opioid narcotics are pharmaceutical-grade heroin produced in a laboratory.”[97] Noting thatoverdose deaths have risen and addiction rates and demand for treatment have skyrocketed,” he claims, “This happened because doctors began prescribing opioids more liberally for patients with chronic pain.”[107] (Apparently, other possibilities are not even worthy of mention and dismissal.). He is one of the seven contributors to the CDC’s guidelines who also is a signatory to the to the to logically, scientifically, and ethically questionable PROP letter demanding that the FDA limit opioid analgesics for “non-cancer pain” to low doses for severe pain” for a maximum of ninety days.[35]

In keeping with the CDC’s focus on harms, to the exclusion of benefits, the first author of its draft guidelines[1] is its own “Team Lead for the Prescription Drug Overdose Team,”[106] from its Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, which is behind the “#RxProblem” social media campaign.[106] She is featured as a speaker for a National Rx Drug Abuse & Heroin Summit,[108] believes that opioids are simply “risky drugs,”[109] falsely[110] claims that the most important risk factor for addiction and overdose is any prescription of any duration for opioid analgesics,[111] and helped author New York City’s opioid prescribing guidelines.”[112] Of course, having a boss who claims that “just a few doses” can lead to addiction, “injection drug use,” and heroin[113] also poses a significant financial conflict of interests to an author of the opioid guidelines written for him.

Apparently, one was not enough, because the second author was also from the CDC’s Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control.[1] She is first author of a paper that, like the review for these guidelines, focuses on harm from opioid analgesics and ignores benefits,[114] claiming that there is “a critical need” for information “about policies and practices that will improve prescribing,” where “policies” are political solutions and “improve,” in context, means “reduce.” Apart from her own biases, writing opioid guidelines for a boss with reckless antagonism toward opioid analgesics poses a significant financial conflict of interests.

The third author[1] of this guideline was an author of a guideline partially sponsored, and largely authored, by PROP[25] and was first author of another opioid prescribing guideline.[24] He is one of the seven contributors to the CDC’s guidelines who is also a signatory to the logically, scientifically, and ethically questionable PROP letter demanding that the FDA limit opioid analgesics for “non-cancer pain” to low doses for “severe pain” for a maximum of ninety days.[35]

The CDC guidelines had three outside reviewers.[115] One of these is director of a division of medical toxicology in a department of emergency medicine,[116] whose objectivity and credibility may be judged by her published blame of “all doctors” for “causing the problem” of opioid overdoses,[117] and by a paper she coauthored with one of the core experts from PROP. In that paper, they equated opioid prescribers with illegal “drug cartels and street dealers,”[40] implying that the prescribing of opioid analgesics should be prohibited, as well. Another outside reviewer’s[115] focus is on the mental health of patients with chronic pain, the sexism and racism of those treating it,[118] and such scientifically rigorous “pain self-management” research as “Positive thinking”[119] and “Positive attitude and using positive thinking/affirmations.”[120] The other outside reviewer[115] was a “Professional Education and Training” member for the National Institutes of Health Interagency Pain Research Coordinating Committee’s draft National Pain Strategy,[121] is one of the authors of the guideline partially sponsored, and largely authored, by PROP,[25] is a board member of that organization, and was co-chair of the Washington State Agency Medical Directors’ Group opioid treatment guideline,[122] the preface of which declares that “preventing the next group of Washington residents from developing chronic disability due to unnecessary, ineffective, and potentially harmful COAT [chronic opioid analgesic therapy] is a key objective of this guideline.”[123] Clearly, this group of three fails the test of IOM standard 7.1: “External reviewers should comprise a full spectrum of relevant stakeholders, including scientific and clinical experts, organizations (e.g., health care, specialty societies), agencies (e.g., federal government), patients, and representatives of the public,”[7] (published with emphasis on the CDC’s own site: “a full spectrum of relevant stakeholders.”[124; emphasis in original])

The CDC’s choice of a toxicology-emergency medicine[115] outside reviewer for its guidelines on opioid analgesics for chronic pain is, by itself, a telling preoccupation with harms and disregard for either chronic pain or the benefits of opioid analgesics, especially when she has already announced that opioid overdoses are to be blamed on “all doctors.”[117] Its choice of an outside reviewer whose work in chronic pain has been limited to mental health, such scientifically nebulous treatments as positive thinking,[119] positive attitudes, and positive affirmations,[120] and to sexism and racism in opioid therapy,[119] demonstrates its own disregard for scientific rigor and its politicization of chronic pain. Its choice of a co-chair of an existing guideline and member of an advocacy group opposing opioid analgesics demonstrates its own prejudices, especially when the guideline over which that person co-chaired describes chronic opioid analgesic therapy as “unnecessary, ineffective, and potentially harmful.”[123]

The president, the vice-president, and the executive director and co-founder of PROP and chief medical officer of Phoenix House (members of the CDC guidelines’ Core Expert Group, peer review group, and Stakeholder Review Group, respectively) actually equate physical dependence following medical opioid therapy with addiction.[28] While they note that sudden nonavailability of opioids, tolerance, and attempts to taper[124] can trigger cravings and addictive behaviors, the predictable consequences[125] of medically abandoning patients who have used opioid analgesics for any length of time would benefit the “business considerations” of the Phoenix House chain,[110] for which PROP is a front.[22]

(Continued)

Critique of the CDC’s Draft Guidelines on the Use of Opioid Analgesics for Chronic Pain Part Two

 

(Note: The endnotes which provide the references for this critique have been collected into the final part of this document.)

We now know the names of the seventeen members of the Core Expert Group.[18, 19] Among these core experts is the president of Physicians for Responsible Opioid Prescribing (PROP), which her own biographical sketch calls “an advocacy group that lobbies government agencies concerning regulation for medical use of opioids.”[20] PROP is a political advocacy[21] program of Phoenix House[22] Foundation, Inc., which, in turn, runs more than one-hundred thirty “drug and alcohol addiction treatment” programs.[23] She is an author of at least two other guidelines on the use of opioid analgesics for chronic pain,[24, 25] including guidelines which were not only partially sponsored by PROP, but largely authored by persons associated with it.[25] In the past, she recognized that opioid therapy “can relieve pain and improve mood and level of functioning in many” of those “patients with chronic pain not associated with terminal disease,”[26] but her current position has been characterized as a “former believer turned crusading reformer.[27] She, along with another core expert from PROP and with one of the stakeholder reviewers from PROP, equates physical dependence (unpleasant physical symptoms upon abrupt discontinuation) with addiction (compulsive use in spite of evidence of harm).[28] She shares the CDC’s[13] and other of its “core experts’” peculiar concern with fractures due to opioid analgesics.[29, 30] She has received personal income from a pharmaceutical company as an “Expert Panel/Advisory” for an opioid analgesic,[24] and her pain unit was the recipient of a $1.5 million dollar educational and research grant for another pharmaceutical company’s opioid analgesic. She is a paid consultant to Cohen Milstein Sellers & Toll,[19] which brings lawsuits against pharmaceutical companies for their opioid marketing,[31, 32] has been criticized for accepting cases from states’ attorney generals to whose campaigns it had contributed,[32] as well as for other ethically suspect practices,[32, 33] and which stands to gain, in the form of more cases from states’ attorney generals and enhanced lawsuits against pharmaceutical companies, from guidelines for opioid analgesics. She advocates education by regulation and more opioid controls.[34] She is one among seven contributors to the CDC’s guidelines who is also a signatory to a letter, on PROP stationary, demanding that the FDA discriminate against “non-cancer pain” according to the degree of pain and the dose and duration of therapy. In particular, that letter demands that opioid-therapy of “non-cancer pain” be limited to low doses for severe pain” for a maximum of ninety days, because there are no long-term efficacy and safety studies.[35] Of course, not only have such studies never been done, but they can never be done, as she, herself, has recognized.[36] (Apart from the insurmountable ethical and logistical barriers to conducting long-term studies comparing opioid analgesics to “dummy” treatments in patients with “severe” pain, who would ever pay the multiple billions of dollars to conduct such studies? Certainly not the anti-opioid activists who insist that they are necessary.)

Another of the core experts[37] who contributed to the CDC guidelines gave the Food and Drug Administration (FDA) this advice for opioid analgesics: “We need to think about how we would construct a REMS [risk evaluation and mitigation strategy] if we were going to be marketing heroin.”[38] Lest his implication be missed, he is also coauthor, with one of the CDC guidelines outside reviewers,[39] of a paper equating prescribers with illegal drug cartels and street dealers,”[40] thus implying that the prescribing of opioid analgesics should be prohibited. He is also a signatory of the logically, scientifically, and ethically questionable PROP letter to the FDA demanding that opioid analgesics for “non-cancer pain” be limited to low doses forsevere pain” for a maximum of ninety days.[35]

Another core expert[40] shares the CDC’s,[13] and some of its other core experts, peculiar preoccupation with fractures associated with opioid analgesics.[34, 41] As a member of the Washington State Interagency Guideline on Opioid Dosing Panel[41] and a signatory to PROP’s logically, scientifically, and ethically questionable letter to the FDA demanding that opioid analgesics for “non-cancer pain” be limited to low doses for severe pain” for a maximum of ninety days,[35] he clearly has predefined views on the use opioid analgesics for chronic pain. He is among the seven contributors to the CDC guideline who is also an author of a guideline partially sponsored, and largely authored, by PROP[25]. He along with at least one other core expert from PROP and one stakeholder reviewers from PROP, equates physical dependence (unpleasant physical symptoms upon abrupt discontinuation) with addiction (compulsive use in spite of evidence of harm).[28]

While not as overtly hostile to opioid analgesics as most of the other authors of those PROP guidelines[25], another core expert[42] seems biased against them. Interestingly, she multiplied 0.00148 overdoses per person per year of opioid treatment by one hundred-thousand, in order to graph as much larger numbers and to present them as overdoses per one hundred-thousand person-years[43]—a minuscule unit that sounds huge.

Yet another core expert[44] is an author, along with two other core experts, of a paper crediting the guidelines partially sponsored by PROP, and largely authored by persons associated with it,[25] as having reduced mortality from opioid overdoses 50%[45] (Maybe so, but similar reductions have been seen elsewhere, prior to the existence of those guidelines.[46, 47]). She is among the seven contributors to the CDC’s guidelines who is also a signatory to the logically, scientifically, and ethically questionable PROP letter which demanded that the FDA limit opioid analgesics for “non-cancer pain” to low doses for severe pain” for a maximum of ninety days.[35]

One core expert[48] was an unspecified “leader”[49] in developing Ohio’s Emergency and Acute Care Facility Opioids and Other Controlled Substances Prescribing Guidelines (Emergency Guidelines).[50] However, the development that she led was merely a modification, based uponfeedback from Ohio emergency departments,[51] of the same guidelines[25] that have previously been noted as partially sponsored by PROP and largely authored by persons associated with it.

Another core expert‘s[52] bias may be seen from the fact that she is the first author of a paper (whose senior author is a PROP member and signatory to the PROP letter to the FDA[53]) illogically condemning physicians for not performing “risk reduction strategies”[54] for which she had already published that there is “lack of evidence”[55] to justify their use.

The only connection that I can find between one core expert[56] and opioid analgesics is his conclusion that opioid prescriptions for those 65 and older have increased[57]which reveals nothing about how—or whether—they ought to be prescribed. Tellingly, however, he has a history of manifest hostility toward the pharmaceutical industry, as an expert witness,[58] as co-creator of a database to be used against pharmaceutical companies,[59] and as author of many of articles attacking the pharmaceutical industry.[58]

Yet another’s[60] relevant experience seems to be limited to having chaired a position statement on prescription drug abuse. It said little more than that the American College of Physicians was against such abuse, perhaps because, ironically, it was authored by a lawyer and two other non-physicians.[61]

Another core expert’s[62] interest in opioids seems to be limited to naloxone treatment of overdoses[63] and to social, sexual, and racial “disparities” in overdose deaths[64]—as if we should be ensuring social, sexual, and racial equality in overdose deaths, too.

So far as I can tell, another core expert‘s[65] expertise is solely based upon being unspecified “staff” for the Oklahoma Injury Prevention Advisory Committee, from the Oklahoma State Department of Health, Prevention & Preparedness Administration.[66] One would expect the CDC to supply its own “staff” and not to rely upon them for its “Core Expert Group.”

Another[67] was an author of Arizona’s guidelines, which were developed by the department for which she is Deputy Medical Director.[68] These appear to be independent of the PROP guidelines[25].

One core expert[69] was a member of the steering committee[70] that developed the Tennessee Clinical Practice Guidelines For Management of Chronic Pain.[71] It is clearly independent of the PROP guidelines[25] and is noteworthy for requiring documentation in the medical record that the patient was “counseled that the goal of chronic opioid therapy is to increase function and reduce pain, not to eliminate pain.”[71]

Another core expert[72] who offers an alternative to CDC Director Tom Frieden’s views chaired the American Association of Family Practitioners’ (AAFP) guidelines, which stress that the AAFP opposes any actions that limit patient access to physician-prescribed drugs.”[73] Rather than targeting prescribers, as do Frieden and almost all of the other contributors, he promotes Project Lazarus, which he says successfully reduced “overdose deaths down to basically zero,”[74] while broadening “awareness of the extent and seriousness” of chronic pain.[75]

Another[76] core expert whose views may be an alternative to Frieden’s is an author for a paper which finds that the increase in deaths from prescription opioids was primarily due to just one drug, methadone.[46] It also showed not only that “Opioid drugs…can be used safely with only 0.64% of opioid prescriptions associated with a fatality,” but that the rate declined “dramatically” from 2002 through 2010.[46] This occurred prior to the guidelines to which three other core experts credit[45] reductions in overdose deaths. However, she has been partially funded by the CDC,[47] and so has a financial conflict of interests in helping to develop CDC guidelines.

In spite of the widespread preoccupation with overdoses from “prescription painkillers,” another of the core experts[77] has shown that overdose deaths from prescribed opioids are actually rare[78] and that nonmedical opioid overdoses are strongly correlated with pain and apparent self-medication.[79]

(Continued)

Critique of the CDC’s Draft Guidelines on the Use of Opioid Analgesics for Chronic Pain Part One

 

(Note: The endnotes which provide the references for this critique have been collected into the final part of this document.)

The recently released Centers for Disease Control and Prevention (CDC) draft guidelines for the use of opioid analgesics[1] make a mockery of the National Academy’s Institute of Medicine’s (IOM) standards for clinical guidelines.[2] In addition, not only do they violate the standards posted by the CDC, according to which the guidelines these guidelines should be excluded from the National Guidelines Clearinghouse,[3] but they do not even so much as meet the IOM’s definition for “clinical practice guidelines.”[2]

Such strong charges must be backed by arguments from strong evidence, which unfortunately means that these comments will not be brief.

Under a mandate from the Medicare Improvements for Patients and Providers Act of 2008[4], the IOM, in conjunction with the Agency for Healthcare Research and Quality,[5] developed Standards for Systematic Reviews[6] and Standards for Developing Trustworthy Clinical Practice Guidelines (CPGs).[2]

As defined by the IOM, “Clinical practice guidelines are statements that include recommendations intended to optimize patient care that are informed by a systematic review of evidence and an assessment of the benefits and harms of alternative care options.”[2; emphasis in original]

According to the IOM’s Standard “4.1 CPG [clinical practice guidelines] developers should use systematic reviews that meet standards set by the IOM’s Committee on Standards for Systematic Reviews of Comparative Effectiveness Research.”[7]

The CDC’s own posting says that, “To be trustworthy, guidelines should…Be based on a systematic review of the existing evidence,” and declares that, “Guidelines that have not included a thorough SR [Systemic Review] of the relevant scientific evidence base should be excluded from the NGC [National Guidelines Clearinghouse].”[8] However, the CDC’s description of the review process that it used for its guidelines either fails to document compliance with, or actually documents violation of, most of the IOM’s standards[9] for systematic reviews. For example, “CDC excluded all studies outside the United States.”[10] Why? Even the Food and Drug Administration is legally required to “accept data from clinical investigations conducted outside of the United States.”[11] When data is limited,[12] arbitrarily restricting it further is inexcusable. By its own description, the only portion of CDC’s review that was systematic dealt exclusively with harms, and, astoundingly, its “benefits” analysis focused on “overdose, cardiovascular events, motor vehicle crashes, and fractures.”[13] “Search terms also focused on opioids and chronic pain and their relation to overdose, cardiovascular events, motor vehicle crashes, and fractures (for benefits and harms)….”[13] The CDC justified these separate, nonsystemic, “rapid reviews” of “overdose, cardiovascular events, motor vehicle crashes, and fractures,” for the “Benefits and harms of opioid therapy,” by the need to “streamline” development of prescribing guidelines,[13] but then excluded even them from its strength-of-evidence analysis: “Given the nature of the studies, the purpose that contextual evidence serves, and the short timeline for developing the guidelines, CDC did not conduct rigorous evidence grading of the findings from the rapid reviews”[14] These behaviors, which violate the standard published by the CDC, requiring a “thorough and unbiased review of existing knowledge,”[15] represent a clear pattern, as may be seen from the fact that a study of practice guidelines singled out the CDC “in particular” for compliance that was “substantially worse than that of other organizations” for IOM standards for “Data Collection Method Given” and “Quality of Evidence Rated.”[16]

Although, according to its own posting, standards “Require transparency,”[15] the CDC was secretive[17, 18] about the members responsible for both the review and the guidelines, as well as how they were selected.[18]

(continued)

Biases in Nissen and Wolksi’s Avandia Analysis?

Remember that Nissen and Wolski said that they used the Peto method,1 but, “The patron saint of meta-analysis, Richard Peto, who helped bring the approach back from what we used to dismiss as ‘unplanned pooling,’ stressed approaches that would avoid bias . . . .”2

This post considers whether Nissen and Wolski avoided bias in their meta-analysis1 of rosiglitazone (Avandia; GlaxoSmithKline).

“Bias” is a serious charge.  Is it justified?

Let us begin by consulting Steven Nissen, himself.  Dr. Nissen has blasted “Flaws, Bias, Misinterpretation and Fraud in Randomized Clinical Trials.”3  Some of his dishonorable mentions included:

  • Use of unblinded study designs
  • Ascertainment bias
  • Errors of omission (selective reporting of results)
  • Type I (particularly multiplicity) and Type II error

Let’s see how many of those applied to Nissen and Wolski’s own meta-analysis.1

To begin with, Nissen and Wolski were unblinded, meaning they knew what effects their choices of studies would have:  “. . . this was not a blinded effort and the results were obtained with full knowledge of the effect of various analytic decisions on the outcome by the analysts.”2  In fact, they included the DREAM (Diabetes REduction Assessment With ramipril And rosiglitazone Medication) study in their meta-analysis because it suggested an increase in acute myocardial infarctions (heart attacks).

. . . in his presentation at the July 2010 AC [advisory committee of the Food and Drug Administration] meeting, Nissen made it clear that it was DREAM, with its adverse trends on AMI [acute myocardial infarction] as well as other endpoints (especially CHF [congestive heart failure]), that provoked the meta-analysis.2

Interestingly, Nissen uses his own unblinded study1 to contrast with the unblinded RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes) study.3

  • Unblinded study?  Check one.

Nissen and Wolski1 selectively chose studies to include, from among those that met their inclusion criteria,4 with the full knowledge of the impact that these choices would have upon the outcome:  “Nonetheless, it must be recognized that there was potential bias in its development (or at least the analysis was done with knowledge of what would emerge) . . . .”2

  • Ascertainment bias?   Check another.

I devoted a whole post to Nissen and Wolski’s1 strange omissions, in Strange Omissions in Nissen’s Avandia Analysis, January 31, 2014.  Suffice it to say that

There were, in fact, studies available to Nissen and to the public, which met Nissen’s inclusion criteria, but which he failed to include in his meta-analysis.  Nissen’s meta-analysis was thus biased by its failure to have conducted a complete, thorough review of the medical literature for qualifying RCTs [randomized controlled trials].4

  • Errors of omission?  Check another one.

I devoted another whole post to Nissen and Wolski’s results depending upon the errors of multiple comparisons (multiplicity), in More Concerns With Nissen’s Avandia Analysis, January 29, 2014.  In brief, the more comparisons beyond one, the greater the bias toward finding a difference that does not really exist.  Nissen and Wolski reported eight.  Apparently, Dr. Nissen did not pay much attention to his own graph of the effect of multiple comparisons.

  • Errors due to multiplicity?  Check one more.

Interestingly, although Dr. Nissen makes much of pharmaceutical sponsorship as being sufficient to prove bias,5 his list did not mention bias from sponsorships.  However, he did claim that “Companies are directed to pay any honoraria, speaking or consulting fees directly to charity so that neither income nor tax deduction is received.”3  This claim is not what it appears to be.  As will be seen in an upcoming post, Dr. Nissen’s hypocrisy in this.  Apparently, he has never been supported by GlaxoSmithKline, but

“. . . Steven Nissen has acknowledged that his work is supported by many GlaxoSmithKline competitors including Pfizer, AstraZeneca, Sanofi-Aventis, Eli Lilly and the Japanese drug company called Takeda, which makes the diabetes drug Actos that competes directly with Avandia.”6

  • Sponsorship bias?   Add another.

While Dr. Nissen acknowledged limitations with the analysis, “his concern was mainly about the true magnitude of the risk, not whether or not the risk was present or absent.”2  Dr. Nissen did not mention it in his list,3 but it is bias, nonetheless.

  • Bias toward a particular outcome?   Add a very big one.

How important were these biases to the results?  Considering “the fragility of their findings,”7 even a small effect from bias would devastate Nissen and Wolski’s meta-analysis–without considering all of the other profound flaws in their study.

In commenting on the Nissen meta-analysis, Psaty and Furburg7 noted that the weaknesses of the study were substantial and that “a few events either way might have changed the findings for myocardial infarction or death from cardiovascular causes.  In this setting, the possibility that the findings were due to chance cannot be excluded.”1

Six different types of bias in just one study, four of which Dr. Nissen, himself, puts on a par with fraud, flaws, and misinterpretations.3

Maybe Dr. Nissen thinks that what is good for randomized controlled trials is too good for a meta-analysis1 that was merely based upon  randomized controlled trials.

Or, maybe he is just biased.

© 2014 Myron Shank, M.D., Ph.D.8

1 Nissen Steven E., Wolski Kathy.  Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.  The New England Journal of Medicine 2007; 356:2457-2471.

2 Temple Robert.  Memorandum to Janet Woodcock:  Data on Rosiglitazone, August 8, 2010.  http://www.fda.gov/downloads/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm226066.pdf

3 Steven Nissen.  Flaws, bias, misinterpretation and fraud
in randomized clinical trials.  http://spo.escardio.org/eslides/view.aspx?eevtid=48&fp=3132

4 Schachtman Nathan A.  Learning to embrace flawed evidence–the Avandia MDL’s Daubert opinion. Schachtman Law January 10th, 2011. http://schachtmanlaw.com/learning-to-embrace-flawed-evidence-the-avandia-mdls-daubert-opinion/

5 Sullivan Thomas.  Nissen relationships with industry:  CME, professional societies and red dresses.  Policy and Medicine March 18, 2010.  http://www.policymed.com/2010/03/nissen-relationships-with-industry-cme-professional-societies-and-red-dresses.html (The reader is strongly encouraged to read this revealing article about Steven Nissen’s character and credibility.)

6 Milloy Steven.  Junk science: diabetes drug scare or scam?  FoxNews.com June 10, 2007. http://www.foxnews.com/story/2007/06/10/junk-science-diabetes-drug-scare-or-scam/

7 Psaty Bruce M., Furberg Curt D. Rosiglitazone and cardiovascular risk.  New England Journal of Medicine 2007; 356:2522-2524.

8 I served:  in the speaker program for Takeda Pharmaceuticals America, Inc. and Eli Lilly and Company, Chicago, Illinois, August 7, 1999; as a consultant for Takeda Pharmaceuticals America, Inc. and Eli Lilly and Company, “Current Update and Discussion of the Glitazone Class of Oral Antidiabetics,” January 3, 2001; on Avandia Regional Advisory Panels in Cleveland, Ohio (February 4, 1999), Toledo, Ohio (September 15, 1999), San Juan, Puerto Rico (February 2000), and Beverly Hills, California (April 2000); as a preceptor for SmithKline Beechum, Lima, Ohio (June 23-25, 1999); and in a “Meet-the-Specialist,” SmithKline Beecham, Lima, Ohio, (2000). In 2000, SmithKline Beechum merged with GlaxoWellcome, to form GlaxoSmithKline.  Before it became impractical to continue prescribing rosiglitazone (Avandia, Avandamet, Avandaryl; GlaxoSmithKline), I prescribed both it and pioglitazone (ACTOS, ACTOSPlusMet, DuetAct; Takeda).