Beyond Dopamine: Precision Pain Medicine Requires Phenotyping and Team Science, Not Just New Targets

To the Editor—

Lewandrowski and colleagues raise important concerns about National Institutes of Health Helping to End Addiction Long-term (NIH HEAL) Initiative returns and propose dopaminergic repletion as an alternative in their recent perspective titled “Billions Spent, Few Saved.”¹ However, before declaring HEAL a failure, consider that this initiative represents the first-ever dedicated federal investment in pain research, and that even this required sharing funding with addiction. Cancer research has received dedicated NIH funding since 1971 and Alzheimer disease since 1984; chronic pain had no comparable investment until 2018.² We are asking for 7 years of funding to solve what other fields have had decades to address.

The authors’ analysis of pain research reveals a problem that their solution does not address. We test mechanism-based interventions in mechanistically heterogeneous populations, then express surprise when average effects disappoint. Consider “chronic low back pain,” the BACPAC (Back Pain Consortium) Research Program focus they critique. This category encompasses disc pathology, facet inflammation, muscle dysfunction, central sensitization, psychological distress, and potentially reward deficiency, each requiring different treatments.^3,4 However, trials enroll patients by diagnosis, not mechanism.

The dopaminergic hypothesis has merit in the context of pain. The GARS test represents a genuine advance.⁵ However, reward deficiency is one phenotype, not the phenotype. Without comprehensive phenotyping to identify which patients have hypodopaminergic states vs peripheral nociception, central sensitization, or inflammatory mechanisms, dopaminergic nutraceuticals risk the same fate as other pain interventions: modest average effects in heterogeneous populations, followed by premature abandonment.

Lewandrowski et al frame their proposal as an alternative to HEAL investments. I argue for integration. HEAL-funded infrastructure (eg, common data elements)⁶ provides the foundation for testing whether dopaminergic approaches work and in whom. Critically, this integration requires team science. Precision pain medicine demands expertise spanning fields and techniques (eg, clinical medicine, neuroscience, [epi]genetics, neuroimaging, sensory physiology, and psychology); thus, no single laboratory or discipline can phenotype comprehensively. HEAL’s investment in multisite collaborative networks makes such integration possible.

What has been missing is the final step: using phenotyping to guide treatment selection in prospective trials with prespecified subgroup analyses.⁷ For example, the dopaminergic hypothesis deserves rigorous evaluation in GARS-stratified patients, alongside peripheral, central, inflammatory, and psychological frameworks.

Abandoning pain phenotyping now would squander the first serious investment in this field and dismantle the collaborative infrastructure required for progress. Precision pain medicine is achievable. However, precision requires both phenotyping and team science to implement it. There are no shortcuts.