Warning to the FDA: Beware of “Simple” Solutions

Warning to the FDA: Beware of “Simple” Solutions in Chronic Pain and Addiction – Face Facts – by Richard Lawhern –  May 2017

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  

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

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
• 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
• Although phrased as “voluntary” and directed to general practitioners, the guidelines became de facto restrictive standards
  Multiple restrictive State laws have been modeled on the CDC conclusions.
  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.
• 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,
• 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

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

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.

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

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.

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.