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Does the HEAL Initiative Research Plan Misunderstand the Complexity of Pain Care?

May 1, 2019
A critique of NIH's strategic vision for pain management, including why more short-term goals are needed to address the current opioid crisis - both in the streets and in HCP offices.

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.”1 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. (Editor's Note: In October 2019, the NIH awarded $945 million in research funds towards the HEAL Initiative).

There is much to welcome in this initiative. Understanding of the mechanisms underlying pain, addiction, and pain treatment could be significantly advanced if the initiative is sustained. A major qualification, however, is that there has been vast research on these subjects for the past 50 years without the yielding of any major breakthroughs and little change in treatment. For instance, in 1969, clinicians used opioids and amitriptyline for pain and methadone for addiction; today, they primarily use opioids, duloxetine, gabapentin, and pregabalin for pain, and methadone and buprenorphine for addiction. Chronic pain is still not well managed and its estimated costs in medical care and lost productivity are on the order of $600 billion annually.2 The scientific challenge to move this field forward is enormous and the authors are not convinced that HEAL offers a full or time-effective solution.

Source: 123RFEnding the opioid crisis requires a strategy around both short- and long-term goals.

At the Real Root of the Opioid Crisis

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 Pain4 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.1

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.”1 Although this claim is repeated frequently in US public conversations on opioid regulation, it is regrettably an artifact of the 2016 CDC guideline. 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.5 A very small number of trials have employed adequately titrated opioids and excluded the many patients who cannot tolerate particular opioids. These trials, despite their limitations and relatively short duration, suggest that opioids may be highly effective for moderate to severe chronic pain.6,7

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. This risk might be substantially reduced by a better understanding of the causes of inadvertent opioid overdose, something not considered in the HEAL initiative, and by better training of medical professionals in pain management.

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 2017.11 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.12 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.13

Data from the 2015 National Survey on Drug Use and Health (NSDUH) tells us that heroin and fentanyl use is at least as much a mental health and socioeconomic problem as it is one of addiction.14,15 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,16 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. This threshold estimate likely represents a maximum because the diagnoses were frequently made by general practitioners lacking training in opioid addiction. It is quite plausible that many of those so labeled actually had chronic pain.

Finally, a 2016 study reported in JAMA17 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%. For four of 11 surgical procedures, the same rate of prescriptions occurred after surgery as before. For the seven remaining procedures, long-term opioid prescription renewals rose only marginally: to 0.174% for cesarean delivery and up to 0.69% for total knee replacement. In this study, it is again plausible that much of these increases reflected the emergence of chronic pain rather than misuse of prescribed opioids.

Biological Underpinnings of Chronic Pain

In the HEAL research plan section on biological underpinnings of chronic pain, NIH states: “Chronic pain is complex, diverse, and difficult to manage, and current treatments, such as opioids, are not effective for many individuals,” citing a paper by Morrone, et al, on opioid resistance.18 The reference provided actually speaks to the presumed ineffectiveness of opioids in only one context: genetic polymorphic variability of opioid metabolism. Unlike the CDC guideline, Morrone, et al, acknowledged in their paper the wide range of individualized opioid metabolism. However, the HEAL plan appears to over-generalize. 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 program focuses on the use of “neuroimaging, -omics, sensory testing, and psychosocial assessments” after an acute pain event to help form “a comprehensive data set to help predict which patients will recover and which patients will develop long-lasting chronic pain.” This signature prediction approach is meant to identify risk and “ prevent the occurrence of lasting pain, thereby reducing reliance on opioids.”

The authors welcome further research on the mechanisms of pain and its treatment. However, 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. The mechanisms underlying non-post-operative chronic pain and its persistence remain very poorly understood.

Discovery and Pre-Clinical Development of Non-Addictive Treatments for Pain

A second research opportunity put forward by the HEAL team focuses on discovering and validating “novel targets for safe and effective pain treatment.”1NIH is ready to support “multi-site validation studies and multidisciplinary tools to reveal novel targets for the treatment of pain, encompassing all levels of the pain-processing pathway from a basic biology perspective.” The authors welcome this type of research aimed at increasing opportunities to identify and make available “small molecules, natural products, biologics, and devices that engage targets for the treatment of pain.”

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. NIH writes: Evidence for optimal pain management in many clinical situations is often insufficient. The HEAL Pain Management Effectiveness Research Network (ERN) will provide infrastructure to conduct Phase 3 clinical trials designed to evaluate the effectiveness of pharmacologic and nonpharmacologic therapies for a broad array of acute and chronic pain conditions.”1

The authors recommend adding two steps to this strategic vision. 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). Although EERW designs constitute a major advance, they still suffer a number of shortcomings, most of which can likely be overcome.

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. Care must be taken to carefully document the characteristics of “usual therapy” in such trials, particularly if such therapy is continued in parallel with non-opioid therapies among the trial population.24

Overall Observations

Overall, there is much to applaud in the HEAL initiative and the boldness of NIH’s vision is most welcome. However, any adequately informed scientist making a realistic assessment of this ambitious research program would have to conclude that the benefits are not likely to be reaped for many years. 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.

 

Last updated on: October 9, 2019
Continue Reading:
Too Little, Too Late: US Government Backtracks on Opioid Discontinuation
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