“Clinicians need pharmaceu tical options with greater safety profiles for treating pain, but the [investment and private sector interest] in such therapies is not there.”

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Opioid prescribing rates have fallen steadily since 2010,1  with a 45% decline between 2015 and 2019.2  This drop is attributable, in part, to legal and policy responses to the multifactorial opioid-related drug poisoning crises—crises that continue with ever-increasing morbidity and mortality.3  In fact, legal and policy responses have sometimes failed to account for the complexity of the crises—creating additional harms by incentivizing not only opioid prescribing avoidance but avoidance of patients associated with opioids altogether. People with chronic pain, substance use disorder, or both have long been stigmatized and marginalized in healthcare institutions and by healthcare providers for myriad reasons, including fears of criminal prosecution4  and other legal entanglements involving controlled-substances prescribing.5  The response to the overdose crisis has left these patients, who number in the tens of millions,6,7  with fewer providers willing to care for them and those remaining willing providers with fewer therapies in their arsenal. The promise of new drugs with lower abuse profiles could both replenish that arsenal of therapeutic options and improve access to care by decreasing physician avoidance.

In this issue, Maher et al.8  review clinical development programs for pain therapeutics from 2000 to 2020, building on research from Hwang et al.,9  who identified that much of the recent research and development in pain therapeutics comes from reformulations of existing drugs, primarily opioids. The current article takes a larger dataset, characterizing compounds in development as either having high or low abuse potential. They found that development of medications with high abuse potential declined after 2010 and that medications with low abuse potential were increasingly studied over the same time period. However, the authors note that the probability of trial success remained higher among medications with high abuse potential.

Clinicians need pharmaceutical options with greater safety profiles for treating pain, but private sector interest and investment in such therapies is not there. This is not surprising—the private, for-profit sector has little incentive to invest in high-risk research and development of novel mechanisms of action, so private sector–driven research and development ultimately perpetuates the status quo. Companies look for quick paths to market and high-revenue potential. The current incentive structure strongly favors the development of abuse-deterrent formulations that increase healthcare costs while providing little in the way of patient benefit.10  As the authors note, these products have not fared well in the marketplace.

The problems with research and development in this sector have not evolved substantially in the past several years, yet the authors’ proposed solutions focus on the interests of the private sector in drug development. By centering their analysis on the private sector through “forecasting financial performance and valuation of [pain medication development] programs,” the analysis fails to account for other potentially more promising public sector financing mechanisms to facilitate important new drug development. Public sector and nonprofit contributions are especially useful when the final product may be less lucrative or the path to success is less certain, as it is here. For instance, early-stage research and development funding is essential to the development of new antibiotics, particularly those with novel mechanisms of action.11 

Greater investment in research and development must be undertaken from National Institutes of Health, National Institute of Drug Abuse, and other public/nonprofit stakeholders in this area. In fact, much of transformative drug development is facilitated by investigator-initiated study protocols12  that often depend on federal and private foundation funding sources.13  In the context of pain treatment, incentives focused on opioid reformulation have largely failed to provide patient benefit and have created additional difficulties while generating limited revenues for the manufacturer. Many pharmaceutical companies have ceased opioid manufacturing and distribution altogether, sometimes as part of a legal settlement.14  The many civil, administrative, and criminal legal remedies for manufacturers’ roles in the overdose crisis may have further chilled their interest in ongoing investment in new therapies.

These findings point to the need for more substantive reforms at the federal level. Federal research focused on basic scientific principles, including the biology and mechanisms of pain, is needed. The National Institutes of Health and other research sponsors must allocate funding toward the development of safer analgesics, nonpharmacologic pain management strategies, and more comprehensive long-term clinical studies,15  including patient outcomes after both initiation and discontinuation of existing pharmacotherapies.16  Expanding support for the National Institutes of Health Helping to End Addiction Long-term (HEAL) Initiative is one way to achieve this goal. Supporting research and development from small- and medium-size companies, in the form of tax credits or public–private partnerships, must be prioritized.

Changes are also warranted in public and private financing models to encourage and reward interdisciplinary pain treatment programs—programs that are highly effective in enhancing well-being and function but are poorly reimbursed and somewhat complex to administer. They are therefore currently scarce in a system that continues to financially reward fragmented and intervention-heavy care.17  Investment in cross-disciplinary training for providers in pain management, substance use disorder treatment, and psychiatry is needed, as well as in trauma-informed care. Innovative, noninvasive biotechnology also holds promise, such as virtual reality devices for both acute and chronic pain. 18  To change the trajectory of pain management research, concerted action by key private and public stakeholders across multimodal treatment domains is the best path forward.

Dr. Dineen Gillespie (under the name Kelly K. Dineen) coauthored two amici briefs to the U.S. Supreme Court in support of the petitioner, in the case of Ruan v United States (oral arguments heard March 1, 2022). Dr. Sinha is a cosigner of the briefs.

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