The following article is reprinted with permission from its author, Richard A. Lawhern, Ph.D. It was originally published here: http://face-facts.org/lawhern/warning-fda/
By Richard A. Lawhern, Ph.D.
“There is always a well-known solution to every human problem — neat, plausible, and wrong.”
– attributed to H.L. Mencken
On May 9-10, 2017, the US FDA held a workshop titled “Training Health Care Providers on Pain Management and Safe Use of Opioid Analgesics—Exploring the Path Forward.” I attended that Workshop in person to offer public comment on behalf of chronic pain patients. This paper is an expansion on the same theme.
“… If you are truly concerned with the safety of patients who are prescribed opioid analgesics, then your first duty may be to adjourn this conference with a public acknowledgment that you aren’t ready to train doctors because you have no viable or safe standard of medical care in which to train them. This is true because the March 2016 CDC Guidelines on prescription of opioids are fundamentally incomplete, desperately flawed, and actively dangerous to the lives and health of hundreds of thousands of people.” 1
When we survey the large body of contemporary popular and scholarly discourse concerning chronic pain and drug addiction, we ignore to our peril the idea famously offered by Mencken. This is perhaps nowhere more true than in the March 2016 CDC Guidelines on prescription of opioid analgesics to adults with long-term non-cancer pain. That document has prompted a hailstorm of sustained criticism from pain patients and medical professionals alike 2,3. In my view, the criticism is fully deserved.
Primary criticisms of the CDC Guidelines can be summarized as follows:
- Guidelines were developed by a core consultants working group which was hand-picked with an anti-opioid agenda in mind — and which met in secret until challenged by the Washington Legal Foundation 4 and Congress 5,6. The process of guideline development was dominated by addiction psychiatrists who had little training in pain management. None of the Board Certified pain management specialists in the group had practiced outside hospitals. Medical ethics consultants were never consulted.
- Even after Congress forced CDC to schedule public input to the Guidelines 6, dissenting voices of pain patients and pain management specialists among more than 4,700 comments were largely ignored.
- Writers of the guidelines drew strong conclusions from very weak medical evidence or unsupported opinion. Research referenced in support of the guidelines was manipulated to draw conclusions on opioid and non-opiod therapy that were unsupported by the medical evidence 1,7. Pertinent research was omitted from consideration, possibly because it contradicted conclusions of the CDC consultants. 8
- Although phrased as “voluntary” and directed to general practitioners, the guidelines became de facto restrictive standards even before the document was issued. A Congressional budget resolution bill in December 2015 made CDC guidelines mandatory for the US Department of Veterans Affairs. Multiple restrictive State laws have been modeled on the CDC conclusions. US HHS Centers for Medicare and Medicaid have proposed mandatory “soft audits” of insurance claims, delaying the filling of prescriptions until a doctor can verify them, where opioid dose levels exceed the limits proposed in the guidelines. The natural result of such audits will be to further restrict prescribing to people in agony.
To these generally understood weaknesses in the CDC guidelines, we must examine three additional observations which have not been as widely discussed in public sources.
- The strong emphasis of the CDC guidelines was on reducing opioid addiction, not pain management. However, published evidence suggests that the most reliable risk factors in addiction are status as an adolescent, a history of family trauma, and/or prolonged unemployment. None of these factors is addressed by restriction of opioid analgesics needed by pain patients. 9
- While it may seem plausible that higher sustained doses of opioid analgesics might be associated with higher risk of addiction, the guidelines reference no literature supporting a particular threshold over others. The proposed maximum 90 Morphine Milligram Equivalent Daily Dose (MMED) is essentially arbitrary and is poorly supported by the limited evidence available 10. This maximum is being forced upon patients who have been stable on higher doses for years, despite the absence of any criteria for such action in the Guidelines. 11
- The Guidelines are dangerously silent on a fundamental issue which should shape both prescription opioid practice standards and physician education. Opioid pain relievers do not create their effects directly in the brain. Drugs must first be metabolized by enzymes into their component chemical parts. However, there are substantial genetic variations in the ability of individuals to accomplish this metabolism. Multiple gene alleles play a role. 12
Drawing from long-established medical literature, it is known that:
“Cytochrome P450 enzymes are essential for the metabolism of many medications. Although this class has more than 50 enzymes, six of them metabolize 90 percent of drugs, with the two most significant enzymes being CYP3A4 and CYP2D6. Genetic variability (polymorphism) in these enzymes may influence a patient’s response to commonly prescribed drug classes, including beta blockers and antidepressants. Cytochrome P450 enzymes can be inhibited or induced by drugs, resulting in clinically significant drug-drug interactions that may cause unanticipated adverse reactions or therapeutic failures…” 13
Some patients “hyper-metabolize” or ‘poorly metabolize’ one or more commonly used opioid analgesics. For example, in patients with faults in the CYP2D6 allele who hyper-metabolize, the medication Codeine gets split rapidly by the enzymatic system into the prodrug morphine — at much higher levels than the original dose of codeine. Lethal blood levels can occur from doses that would be innocuous in a person with normal metabolism. This prompted the FDA to ban Codeine and Tramadol for children 14 — although genomic testing was ignored in favor of denying these alternatives to all children.
Enzyme faults, drug interactions, gastric bypass, Crohn’s disease, gastroparesis, late stage diabetes, etc. can also cause poor metabolism (p-glycoproteins, CYP3A4, CYP2B6, CYP2D6, OPMR, COMT, MTHFR) and patients with these issues will often require significantly higher doses to generate therapeutic levels of analgesics. 12,13,14,15 Underlying disease progression also needs to be considered in dose increase over time.
There are potentially millions of pain patients in the US who both need and respond well to opioid doses exceeding 400 MMED. There are case reports of patients doing well on megadoses exceeding 2500 MMED 15,16. Based on the preponderance of this evidence, it should be apparent that there can be no one-size-fits-all “maximum dose” or “addiction risk threshold” in the prescription of opioid analgesics. Guidelines should not state such a maximum. Dose must be tailored to each individual and informed by genomic testing when therapy fails. Prescription guidelines need to be explicit in directing that for patients who have been on stable doses and who have sustained improved function and quality of life over time, there is no scientific rationale for arbitrary withdrawal or tapering down from even “high” dose levels. To the contrary, such tapering may contribute to iatrogenic suicide.
From postings by tens of thousands of chronic pain patients in social media, it is clear that the existing CDC opioid guidelines have directly resulted in an exodus of physicians out of pain management practice. Patients are being summarily discharged or unilaterally tapered down from opioid dose levels that have safely controlled pain and promoted function for many years. Suicides have occurred and more should be anticipated as ever more patients are plunged into agony, disability, and depression by denial of care. 17,18
Given the substantial body of published medical and popular literature which contradicts the CDC de facto standard to which the FDA proposes to train doctors, the only ethically and scientifically sound direction for present FDA training efforts must be to publicly acknowledge that the CDC opioid guidelines must first be withdrawn and rewritten to correct their many errors and omissions. On the second time around, ethics consultants should be included in the writing group. Pain management specialists active in community practice should lead the effort. Pain patients or advocates must be voting members of the group.
This time, the CDC and FDA need to develop a practice guideline that is truly “patient centered,” rather than being a knee-jerk response to political pressure to “do something” even if that something is clearly the wrong thing. 19
About the Author: Richard A (“Red”) Lawhern, Ph.D. is a non-physician writer, research analyst, patient advocate, and website moderator for chronic pain patients, families, and physicians. His wife and daughter are chronic pain patients. His 20 years of experience has produced articles and critical commentaries at the US Trigeminal Neuralgia Association, Ben’s Friends online communities for patients with rare disorders, US National Institutes for Neurologic Disorder and Stroke, Wikipedia, WebMD, Mad in America, Pain News Network, National Pain Report, the American Council on Science and Health, the Global Summit for Diagnostic Alternatives of the Society for Humanistic Psychology, Psychiatric News and Psychology Today.
2. Stephen A. Martin, MD, EdM; Ruth A. Potee, MD, DABAM; and Andrew Lazris, MD, “Neat, Plausible, and Generally Wrong: A Response to the CDC Recommendations for Chronic Opioid Use” ↩
3. Bob Tedeschi, “A ‘civil war’ over painkillers rips apart the medical community — and leaves patients in fear” STAT News, January 17, 2017.↩
4. Pat Anson, “Law Firm Wants Transparency in Medicare Opioid Policy,” Pain News Network, May 24, 2017. ↩
5. Rich Samp, “CDC Bows To Demands For Transparency And Public Input On Draft Opioid-Prescribing Guidelines”Forbes, December 15, 2015. ↩
6. Congress of the United States, House of Representatives Committee on Government Reform, Letter to Thomas Frieden, MD, Director CDC, December 18, 2015↩
7. Baraa O. Tayeb, MD Ana E. Barreiro, MPH Ylisabyth S. Bradshaw, DO, MS Kenneth K. H. Chui, PhD, Daniel B. Carr, AM, MD, DABPM, FFPMANZCA (Hon) “Durations of Opioid, Nonopioid Drug, and Behavioral Clinical Trials for Chronic Pain: Adequate or Inadequate?” Pain Med. 2016 Nov; 17(11):2036-2046↩
8. Noble M, Treadwell JR, Tregear SJ, Coates VH, Wiffen PJ, Akafomo C, Schoelles KM, Chou R, “Opioids for Long Term Treatment of Non-Cancer Pain”, Journal of Pain and Symptom Management, Vol 35, No. 2, February 2008, Updated December 2010. ↩
9. Maia Szlavavitz, “Opioid Addiction Is a Huge Problem, but Pain Prescriptions Are Not the Cause – Cracking down on highly effective pain medications will make patients suffer for no good reason,” Scientific American, May 10, 2016. ↩
10. Richard A. Lawhern, Ph.D. “Tracking Down the ‘Research’ Behind the CDC’s Opioid Prescribing Guidelines, National Pain Report, August 10, 2016. ↩
11. Pat Anson, “Survey Finds CDC Opioid Guidelines Harming Patients,” Pain News Network, March 15,2017. ↩
12. Steven H. Richeimer, MD and John J. Lee, MD “Genetic Testing in Pain Medicine—The Future Is Coming,” Practical Pain Management, October 17, 2016. ↩
13. Tom Lynch, PharmD and Amy Price MD, “The Effect of Cytochrome P450 Metabolism on Drug Response, Interactions, and Adverse Events,” American Family Physician, August 1, 2007. ↩
14. US Food and Drug Administration, “Information for Healthcare Professionals: Use of Codeine Products in Nursing Mothers,” August 14, 2013.↩
15. Jennifer Schneider, MD; Alfred Anderson, MD; and Forest Tennant MD, Dr PH, “Patients Who Require Ultra-High Opioid Doses,” Practical Pain Management, September 2009.↩
16. Forrest Tennant, MD, Dr PH, “Ultra-High Dose Opioid Therapy; Uncommon and Declining, but Still Needed.” Practical Pain Management, October 28, 2014, ↩
17. Observations of the author from postings to over 30 Facebook groups among aggregate memberships exceeding 20,000 pain patients, family members, and medical professionals.↩
18. Stefan G. Kurtesz, MD, MSc, “Turning the Tide or Riptide? The Changing Opioid Epidemic,” Journal of Substance Abuse, Vol 38, Issue 1, ↩
19. Editors, PAiNWeek, “What if Prescribing Guidelines Were Patient Centered? – Rethinking Public Policy for Better Patient Outcomes and Expanding CDC Guidelines*,” April 11, 2017, ↩
* The introduction by PAINWeek is linked to an article by the author on National Pain Report titled “How Would Opioid Prescription Guidelines Read if Pain Patients Wrote Them?” The same article was re-published in The Journal of Medicine of the National College of Physicians, titled “The CDC’s Fictitious Opioid Epidemic, Part II.”