On June 11, 2019, two FDA advisory committees will meet outside Washington DC. One is focused on Drug Safety and Risk Management and the other on Anesthetic and Analgesic Drug Products. Their declared agenda begins as follows:
“FDA is seeking public input on the clinical utility and safety concerns associated with the higher range of opioid analgesic dosing (both in terms of higher strength products and higher daily doses) in the outpatient setting. FDA is interested in better understanding current clinical use and situations that may warrant use of higher doses of opioid analgesics. We are also interested in discussing the magnitude and frequency of harms associated with higher doses of opioid analgesics relative to lower doses, as well as optimal strategies for managing these risks while ensuring access to appropriate pain management for patients.
“FDA frequently hears from patients and healthcare providers that higher dose opioid analgesics continue to be a unique and necessary part of effective pain management for some patients. FDA is also cognizant of serious safety concerns associated with both higher strengths and higher daily doses of opioid analgesics, both in patients and in others who may access these drugs. Higher strength products may be more harmful in cases of accidental exposure and overdose and may also be more sought out for misuse and abuse. Along with a number of other factors, a higher daily opioid dose is associated with greater risk of overdose. Concerns have also been raised that higher dose opioid regimens may carry a higher risk of addiction, although robust evidence for a causal relationship is lacking. [Link ]
As a patient advocate I frequently interact with government agencies on the kinds of issues summarized above. I have offered the following (slightly edited) insights to the Committees, with references from medical journals. I beg pardon from readers who aren’t regularly exposed to “doctor speak”. Doctors and regulators were the original targeted audience.
- Published data demonstrate a very wide range of minimum effective dose levels in individual pain patients, due to genetic polymorphism in liver enzymes which govern opioid metabolism. There is no one size fits all patient or therapy plan. Literally millions of US citizens benefit from high-dose opioid therapy with no evidence of addiction or mortality risk. To further restrict availability of high dose opioids in an already profoundly hostile regulatory environment would be both misdirected and abusive of patients.
- Published CDC data demonstrate no consistent relationship between overall rates of opioid prescribing by doctors versus overdose-related mortality from all sources. The contribution of medically prescribed opioids to mortality is so small that it gets lost in the noise of illegal street drugs. To the limited extent that there are any trend lines in the mortality data, they suggest that since 2016, mortality is marginally lower in US States where rates of opioid prescribing have remained highest. Prior to 2016, trend lines were flat, with very low correlation. There is no observable cause and effect relationship between overall rates of prescribing versus rates of overdose death.
- Models employed by HHS/CMS to identify potentially at-risk “over-utilizers” of opioids have been shown to have limited predictive value. Over half of all high-dose Medicare patients identified as having elevated risk of substance abuse are not diagnosed within 18 months. More than half of all overdose-related deaths in one US State occurred in people who had no current prescription. Rates of overdose mortality in people over age 55 – many of them Medicare patients — are the lowest of any age group, while mortality in people under 25 is six times higher.
- Studies of the impact of high-dose opioid analgesics on overdose mortality reveal an average rate of overdose-related mortality at 0.25% per year (2.5 deaths per 1000). This is comparable to mortality observed in medications for atrial fibrillation following stroke. While mortality rates rise with dose, there is no distinct “upward knee” threshold in mortality versus dose.
- Also of concern is an historical but unsupported bias against co-prescription of opioids and benzodiazepine drugs. Under-treated anxiety and depression are factors in elevated risk of patient mortality. Yet there are no published observational trials in live patients, to demonstrate actual risk of respiratory depression; all evidence is inferential, drawn from cause of death assignments that are confounded by non-uniform standards among county medical examiners.
Under the principle of “first do no harm”, I urge the Advisory Committees to refrain from recommending further restrictive measures on prescribing. You are dealing with patient populations so small that direct safety improvements cannot be measured. But the indirect effect of such restrictions will reliably be to further poison the regulatory environment for all pain patients and to encourage the departure of medical professionals from pain management.
Cease, halt, and desist.
Patients who are managed on high dose opioid therapy may share their stories and concerns at [link ]
Author Note: Richard A Lawhern, PhD is a technically trained non-physician patient advocate and healthcare writer, with 22 years experience in moderating social media support groups and over 70 published papers and addresses. He is a frequent contributor at National Pain Report.