The Complexity of Pain Care

Does the HEAL Initiative Research Plan Misunderstand the Complexity of Pain Care? – By Richard A. Lawhern, PhD and Stephen E. Nadeau, MD – May 3, 2019

This informative article carefully, and with published scientific evidence, explains why pain care with prescribed opioids is not the cause of the “opioid crisis”:

With relatively little public fanfare, the US National Institutes of Health (NIH) launched an integrated set of research initiatives, called Helping to End Addiction Long-term (HEAL), one year ago to “provide scientific solutions to the opioid crisis.”

Funding for this initiative was put into place for FY2019 at $502 million, of which approximately $170 million is focused on the discovery of biological markers to characterize acute and chronic pain as well as the development of non-opioid therapies.   

The federal government’s declaration of a public emergency around opioids in 2017 served as the impetus for HEAL, but the initiative touches only tangentially on the causes of the crisis.

One major component, for example, is the illicit use of heroin admixed with fentanyl, costing tens of thousands of lives a year. These deaths are born out of a series of complex factors, including

• the growth of hard pockets of poverty,
• hopelessness, and desperation;
• failure to provide adequate care for the mental illness that looms large in most every addict’s life;
• the enormous profitability of opioid sales (whether licit or illicit); and variously ill-conceived and mistimed public policy efforts.3

The 2016 CDC Guideline on Prescribing Opioids for Chronic Pain follows in this vein. Because the guideline did not remotely target the causes of the growing crisis, it could not have been expected to impact it — a prediction now confirmed by the ever-increasing tide of opioid-related deaths. The guideline succeeded only in creating a second crisis: a collapse of treatment for those living daily in moderate to severe chronic pain.

While the HEAL initiative contains a great deal of bold and scientifically inspired thinking, its rationale is contaminated with the unscientific precepts of the 2016 CDC guideline.

CDC assumptions were not based on good science and have been repudiated in multiple public and US agency forums, including the American Medical Association.

In fact, the CDC and FDA themselves recently issued major “clarifications” on the guideline and how rapid opioid discontinuation or tapers can actually be harmful to patients. See PPM’s editorial on this subject.

In the following sections, the authors offer their perspective and cautionary notes intended to support reconsideration of key directives within NIH’s HEAL Initiative Research Plan for the management of acute or chronic pain

The HEAL Initiative Research Plan: A Look at the Pain-Focused Elements

Enhancing Pain Management

The section of the HEAL initiative on enhancing pain management begins with the following assertion:

“Many of the 50 million Americans with chronic pain are prescribed opioid medications to manage their pain, yet there is limited evidence to suggest that long-term use of opioids is effective for patients with chronic pain.”

As pointed out in multiple published papers, authors of the guideline interpreted the paucity of long-term trials for opioid pain relievers as an indication that such therapies have not been shown to be effective. But under this criterion, none of the major categories of pain therapy considered in the guideline could have been proven effective.

Length of trials for both non-pharmacologic therapies and non-opioid analgesics have generally been limited to 90 days or less, and dropouts are frequent among chronic pain patients treated with placebo.

Further, the medical community now has multiple studies indicating that the annual case fatality rate attributable to prescription opioid dosage in excess of 100 MMED is on the order of 0.25%,8-10 a risk that most patients with moderate to severe chronic pain would likely deem acceptable

Deaths from prescription opioids have remained static since 2012.

Deaths from heroin and fentanyl have increased from 7,500 in 2012 to nearly 30,000 in 2017.

Furthermore, the demographics of opioid mortality clearly implicate two distinct populations: individuals over age 54 who are prescribed opioids two to three times as often as younger adults; and individuals aged 15 to 24.

Opioid overdose-related mortality in seniors is the lowest of any age group but overdose mortality in youth has skyrocketed over a period of 17 years to levels six times higher than in seniors.

This body of data is not reflected in the HEAL strategy rationale.

As noted by Nora D. Volkow, MD, director of the National Institute on Drug Abuse (NIDA):

“Unlike tolerance and physical dependence, addiction is not a predictable result of opioid prescribing.

Addiction occurs in only a small percentage of persons who are exposed to opioids — even among those with pre-existing vulnerabilities.”

Mental health receives relatively little attention in the HEAL document and socioeconomic factors are mentioned only in very narrow contexts. This is quite startling given that a major facet of the opioid crisis is almost entirely a street-drug crisis.

Street drug abuse commonly starts with non-medical use of diverted opioid tablets. However, multiple studies make clear that the risk of long-term opioid use in patients prescribed opioids for post-surgical pain is miniscule.

In a US 2018 study reported in the British Medical Journal, investigators examined outcomes among more than 586,000 patients prescribed opioids for the first time after surgery. Less than 1% continued renewing their prescriptions longer than 13 weeks; 0.6% were later diagnosed with opioid use disorder (OUD) during follow-up periods averaging 2.6 years.

Finally, a 2016 study reported in JAMA tracked long-term opioid prescription renewals in non-surgical patients and compared prescription rates to 642,000 patients who underwent one of 11 common types of surgery. Opioid prescriptions were defined as “chronic” when 10 or more scripts were written in 1 year or when a prescription was renewed continuously for more than 120 days. In this study, the rate for chronic prescriptions of opioid analgesics among millions of non-surgical patients was estimated at 0.136%.

Biological Underpinnings of Chronic Pain

It is well-accepted medical practice to titrate dosage to the desired level (eg, with antihypertensive medications, anticonvulsants, antidepressants, and innumerable other drug classes). This same approach seems to be a logical response to polymorphic variability in opioid metabolism but is not mentioned in the HEAL strategy.

“The Acute to Chronic Pain Signatures Program” is one research opportunity described in the HEAL plan.

…the Signatures program assumes that acute pain frequently evolves into chronic pain, whereas there is robust scientific evidence (some cited herein) that this is not the case.

There is no doubt that  post-operative pain may be improved. However, it is likely that in many if not most cases of those living in moderate to severe chronic pain, the pain evolved in the absence of an acute incident.

Establishing the Best Pain Management Strategies for Acute and Chronic Pain Conditions

In this section of the HEAL research plan, clinical trials on pain management effectiveness are discussed.

First, there needs to be a major emphasis on the development of innovative trial designs that will test opioids as they are optimally used in current clinical practice, and in particular, to accommodate adequate dose titration and the high incidence of idiosyncratic side effects

Of the nearly 100 published randomized controlled trials of opioids for chronic pain, only a handful come close to meeting these standards, all of them employing enriched enrollment randomized withdrawal (EERW) designs (see for instance, References 19-23).

Second, it is essential that non-opioid therapies be vetted through comparative effectiveness trials. It is highly unlikely that non-pharmacological and non-opioid drug treatments will be able to replace opioids in the near term for adequate treatment of moderate to severe chronic pain, although they may enable opioid dosage reduction

Overall Observations

The initiative’s short-term goals (ie, 3 to 5 years) focus on approaches and strategies while actionable results are not foreseen for 5 or more years.

In the meantime, the two opioid crises—the heroin and fentanyl crisis in the streets and the CDC 2016 manufactured crisis impacting patients living in moderate to severe chronic pain—will continue unabated.

More direct and immediate measures to combat these frontline problems need to be taken now, very likely through multiple agencies beyond the NIH.