Billions Spent, Few Saved: Rethinking National Institutes of Health HEAL Initiative in Light of Dopaminergic Alternatives to the Opioid Trap

The Persistent Failure of Opioid Substitution Therapies

The ongoing opioid epidemic has underscored the critical need for innovative approaches in pain management that transcend symptomatic relief and instead target the underlying neurobiological dysfunctions. Traditional opioid replacement therapies—though positioned as harm-reduction strategies—often fall short of reestablishing healthy brain reward function and may inadvertently reinforce dependence by sustaining dysregulation within the mesolimbic dopamine system.1–5 Similarly, pharmacological treatments for cocaine use disorder remain largely ineffective. Recent proposals, such as cocaine-assisted treatment modeled after heroin-assisted paradigms, aim to reduce harm through medically supervised, controlled dosing regimens aligned with user preferences.6

NIH Heal Initiative: Ambition Without Impact

Parallel efforts by the National Institutes of Health (NIH) under the Helping to End Addiction Long-term (HEAL) Initiative have pursued strategies that combine controlled opioid administration7 with behavioral phenotyping, mindfulness-based therapies, and data harmonization protocols.7–10 These were intended to enable scalable, collaborative, and data-driven research into novel treatment frameworks.9 However, despite extensive investments, no meaningful reduction in opioid-related fatalities has been demonstrated.11 A 2024 article published in the New England Journal of Medicine represents a key milestone for the HEAL Initiative, summarizing findings from a research portfolio spanning 1265 funded grants. The initiative was designed to accelerate scientific solutions addressing both opioid and stimulant use disorders and to advance more effective treatments for chronic pain.

Since its launch in 2018, the NIH’s HEAL Initiative has reportedly invested over $3.2 billion in federal funding across more than 1800 research projects with the stated aim of accelerating scientific solutions to the opioid crisis and chronic pain. Yet, despite this extraordinary expenditure, the tangible outcomes—measured in terms of reduced overdose deaths, widespread clinical implementation of new therapies, or improved standards for pain care—remain elusive. Information about the HEAL Initiative’s financial allocations is publicly available only in a highly fragmented manner. The official NIH HEAL Initiative website provides a downloadable spreadsheet of awardees listing project titles, institutions, and research focus areas (https://heal.nih.gov/funding/awarded), but no funding amounts are disclosed per project or investigator. Instead, aggregate totals must be derived from press releases, program announcements, and third-party reporting.

For instance, a 2023 article in Frontiers in Pain Research noted that more than $3.2 billion has been distributed since the program’s inception.10 A separate press release from UC San Francisco (UCSF) reports that its researchers alone secured 10 HEAL grants totaling more than $40 million in 2024.12 This staggering allocation includes $29.4 million to Jeffrey C. Lotz, PhD, professor and vice chair of research in Orthopedic Surgery, to establish the Core Center for Patient-Centric Mechanistic Phenotyping in Chronic Low Back Pain (REACH)—an interdisciplinary consortium dedicated to classifying pain phenotypes and developing personalized, nonopioid treatments for chronic low back pain (cLBP). Another $7.56 million was awarded to Prasad Shirvalkar, MD, PhD, assistant professor of anesthesiology, to advance deep brain stimulation (DBS) implants for chronic pain, in collaboration with Edward Chang, MD, and Philip Starr, MD, from the UCSF Weill Institute for Neurosciences. Additional awards include $4.39 million to Sharmila Majumdar, PhD, for developing advanced deep-learning magnetic resonance imaging (MRI) technologies for faster reconstruction and better detection of spinal degeneration; $3.6 million (including $1.1 million for Phase I) to Aaron Fields, PhD, and Roland Krug, PhD, for pioneering MRI methods to identify endplate pathologies; and $2.62 million to James Sorensen, PhD, professor of psychiatry, across 5 separate grants, to evaluate early intervention strategies to prevent the transition from risky opioid use to opioid use disorder. Smaller yet significant awards include $500,000 to Michael McManus, PhD, and Lily Jan, PhD, to study ion channels critical to neural function and pain signaling.12 These UCSF awards are part of a larger $945 million nationwide funding wave distributed by the HEAL Initiative in 2024 alone, spanning approximately 375 projects.12 Since its inception in 2018, the initiative has funneled billions of taxpayer dollars into academic research projects targeting pain and addiction. However, despite these large sums, there is little evidence that these investments have produced scalable solutions, tangible breakthroughs, or clinically transformative therapies to reduce opioid dependence or effectively address chronic pain (Figure 1).

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Figure 1

This timeline illustrates the progression of the National Institutes of Health (NIH) Helping to End Addiction Long-term (HEAL) Initiative from its launch in 2018 through projected milestones in 2025. Key phases are highlighted, including early goals to accelerate opioid and pain research (2018), initial funding rounds (2019), and the surpassing of $1 billion in cumulative investment by 2020. By 2023, more than $3.2 billion had been invested across 1800+ projects, with notable funding such as the $343.7 million HEALing Communities Study and exploratory research on deep brain stimulation for chronic pain. In 2024, $945 million was allocated nationwide, including $40 million across 10 grants to UC San Francisco for imaging, phenotyping, and opioid intervention research. By 2025, only 4 publications—mainly from BACPAC’s COMEBACK and BACKHOME studies—had emerged with limited evidence of scalable clinical breakthroughs. Despite significant taxpayer investment, the initiative’s return on investment, transparency, and translational impact remain under scrutiny.

In the UCSF REACH case, a key site within the NIH’s Back Pain Consortium (BACPAC), 4 articles were published in 20259,13–15 on the 2 leading large-scale, complementary studies—comeBACK and BACKHOME—aimed at advancing the mechanistic phenotyping of cLBP. The comeBACK study is a longitudinal, in-person cohort of 450 adults with cLBP, designed for deep clinical phenotyping, while the BACKHOME study represents the largest prospective remote registry of its kind, engaging approximately 3000 adults across the US. Together, these studies capture a broad spectrum of biopsychosocial variables—clinical, behavioral, and contextual—with the goal of defining distinct cLBP subtypes and treatment-relevant phenotypes. This work will facilitate the development of patient-centered outcome measures, improve pain management strategies, and enable precision-medicine approaches in chronic pain care. Additionally, under the NIH HEAL Initiative umbrella, Lotz’s group contributed to the RE-JOIN Consortium, which developed a standardized data framework for human joint pain studies, particularly of the knee and temporomandibular joints. Through a robust harmonization of data elements across projects and institutions, RE-JOIN’s infrastructure is anticipated to facilitate future integration of clinical and preclinical pain data.

Dr. Prasad Shirvalkar’s team worked on advancing deep brain stimulation (DBS) as a therapeutic modality for chronic pain under the NIH HEAL Initiative, publishing 3 articles since 2023.16–18 His team’s research has focused on identifying neural biomarkers of spontaneous pain using long-term brain recordings, particularly in the orbitofrontal and anterior cingulate cortices. His work has helped establish foundational principles for using closed-loop DBS—systems that adapt stimulation in real time based on brain activity—offering a promising alternative to traditional open-loop approaches. By integrating stereoelectroencephalography and rigorous statistical methods, Shirvalkar’s team has developed a patient-specific, data-driven workflow for targeting effective DBS sites. These innovations aim to deliver more personalized, durable relief for patients suffering from intractable chronic pain. The $7.99 million awarded to Drs. Sharmila Majumdar, PhD, Aaron Fields, PhD, and Roland Krug, PhD produced 1 article thus far since 2023, with Dr. Majumdar as a co-author to the BACPAC study but none thus far—as of the time of the writing of this article—on the funded research on deep-learning MRI technologies.19

Despite the NIH HEAL Initiative’s well-intentioned goal of fostering personalized, neurobiologically informed solutions for chronic pain and opioid misuse, the disproportionate size of many individual awards—such as the $29.4 million allocated to a single pain classification center—highlights a troubling disconnect between investment and impact. While these efforts have contributed to exploratory research and theoretical frameworks, they have yet to yield meaningful clinical breakthroughs or widespread improvements in patient care. This is further corroborated by the published research listed in the latest annual report listed on the HEAL website (https://heal.nih.gov/research/publications). Thus far, the 1265 HEAL-funded grant projects have resulted in the publication of 217 studies on a wide range of topics, ranging from translating research into practice through real-world interventions in emergency departments and justice settings to developing new prevention strategies such as technology-enabled behavioral tools and housing-first models. Special focus is placed on improving outcomes for infants and children exposed to opioids, with studies on neonatal care protocols and neurodevelopmental tracking. The initiative also explores novel therapies—such as extended-release formulations and anti-craving medications—and leads pain-management advances through the Back Pain Consortium (BACPAC), which has published 16 articles to date on imaging, biomechanics, and integrative rehabilitation models. Additional work includes validating new molecular pain targets and broader reflections on the HEAL Initiative’s strategic direction (Table 1). However, only 1 article addressed novel therapeutic options for opioid use disorder and overdose,20 and another focused on translating data into action to prevent overdose.21

The previously cited New England Journal of Medicine HEALing Communities Study—a multistate demonstration project—received $343.7 million in a single round of funding.12 However, to determine the actual cost of individual studies or interventions, users must manually search the NIH RePORTER database (https://reporter.nih.gov), where grant-level dollar amounts are stored—assuming the project number or principal investigator’s name is known. This process is time-consuming, nontransparent, and largely inaccessible to the general public or policymakers seeking a comprehensive audit of outcomes per dollar spent.

Disconnect Between Research Investment and Real-World Outcomes

Moreover, there is little evidence that this immense investment has meaningfully translated into scalable, transformative interventions. Most outputs from HEAL-funded projects have remained in the form of early-stage pilot studies, academic publications, and preclinical research without real-world uptake. Unlike the rapid development pipelines seen in other public health emergencies (eg, COVID-19 vaccine development), the HEAL Initiative appears hampered by academic inertia, redundancy, and a lack of translational focus. Despite the magnitude of taxpayer funding, the HEAL Initiative provides a sobering case study in government inefficiency. Billions of dollars have been awarded, yet with no central repository of financial data tied to measurable clinical outcomes, no framework for disinvestment from ineffective programs, and no clear roadmap for systemic change, the public remains largely in the dark. The opacity surrounding funding allocation and the absence of clearly defined success metrics raise serious questions about the return on investment for one of the most ambitious public health research efforts in recent memory.

Toward a Neurobiological Paradigm

In light of the limited clinical impact of existing HEAL-funded interventions, alternative, neurobiologically targeted strategies warrant serious consideration. Recent work published in the International Journal of Spine Surgery on opioid-induced hyperalgesia and inflammaging provides rich mechanistic and policy insight that reinforces key pillars of this argument.22 Specifically, the article established a foundational link between chronic opioid exposure and dopaminergic suppression, contributing to heightened pain sensitivity through neuroinflammatory cascades and impaired reward processing. Emerging evidence indicates that chronic pain and addiction are not merely comorbid but share overlapping neurobiological pathways—particularly dysfunction within the brain’s dopaminergic reward system, a condition known as reward deficiency syndrome (RDS).23 In this context, nutraceuticals24—dietary formulations combining dopamine precursors and enkephalinase inhibitors—offer a promising restorative approach aimed at normalizing dopamine function and reducing both pain and addictive cravings.25 When paired with genetic screening tools such as the Genetic Addiction Risk Severity test, this strategy supports a precision medicine model for mitigating postoperative pain and addiction risk in genetically vulnerable patients. Furthermore, the IJSS article strengthens the conceptual groundwork for positioning “reward system repair”—via dopaminergic repletion—as a central tenet of next-generation enhanced recovery after surgery (ERAS) protocols (ERAS 2.0), particularly in genetically predisposed patients.

Pain and Reward: A Shared Neurobiological Substrate

Chronic pain and addiction are no longer viewed as separate clinical phenomena but rather as overlapping expressions of a common neurobiological vulnerability centered in the brain’s reward circuitry (Figure 2).26 The mesolimbic dopamine system27—particularly projections from the ventral tegmental area28 to the nucleus accumbens29—is critical not only for processing reward and motivation but also for modulating the emotional and cognitive dimensions of pain. In both chronic pain and opioid use disorder, this system becomes dysregulated, resulting in blunted responsiveness to natural rewards and increased sensitivity to stress and discomfort.30–35

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Figure 2

The shared neurocircuitry of pain and addiction is highlighted in the dopaminergic axis as the overlapping neurobiological pathways involved in chronic pain and addiction, centered around the mesolimbic dopaminergic system. Key structures include the ventral tegmental area (VTA), which projects to the nucleus accumbens—a core region implicated in both reward processing and pain modulation. Disruptions in this circuitry, such as dopaminergic hypofunction, contribute to reward deficiency syndrome, predisposing individuals to heightened pain sensitivity, opioid craving, and vulnerability to addiction, underscoring the rationale for neurobiologically targeted interventions, such as dopaminergic nutraceuticals, in managing pain and reducing opioid dependence.

This dysregulation is described by the RDS framework,36–40 which posits that individuals with genetically or epigenetically impaired dopaminergic signaling are more prone to compulsive reward-seeking behaviors, substance misuse, and heightened pain perception. In the context of surgery or trauma, patients with RDS may experience amplified pain and exhibit greater vulnerability to opioid craving and dependency.

Neuroadaptations further exacerbate this cycle. Chronic opioid use leads to D2 receptor downregulation,41–46 impaired dopamine synthesis, and glial activation—a key driver of neuroinflammation. These changes suppress endogenous reward pathways, reinforcing a hypodopaminergic state that sustains both pain and addictive behaviors.47 Understanding this shared substrate underscores the need for interventions that restore dopaminergic balance, rather than merely suppressing symptoms with opioids or their substitutes.

Dopamine-Targeted Nutraceuticals: Mechanism and Clinical Promise

Nutraceuticals are a class of nutrigenomic compounds designed to support and restore optimal brain function by targeting neurotransmitter systems, particularly dopamine.48 Unlike conventional pharmacological treatments, nutraceuticals aim to rebalance the brain’s reward circuitry without addictive potential. One of the most well-studied examples is KB220Z, a patented pro-dopamine regulator (PDR) composed of amino acid precursors,49 enkephalinase inhibitors,50 and adaptogenic compounds. Several other branded or proprietary formulations have emerged that aim to modulate dopaminergic tone through amino acid precursors, enkephalinase inhibitors, and adaptogenic compounds. While these formulations vary in composition, delivery method, and regulatory oversight, they share a common goal: supporting dopamine homeostasis as a therapeutic strategy in pain, addiction, and mood disorders.

• Synaptamine️ is a patented variant of KB220, formulated with a similar profile of amino acid precursors and enkephalinase inhibitors. It has been marketed as a pro-dopamine compound designed to enhance reward system signaling in individuals with RDS.51,52 Like KB220Z, Synaptamine is supported by early-stage studies using 53quantitative electroencephalogram and neuroimaging modalities51 to assess its impact on reward circuitry function.

• NutriDyn is a well-established provider of clinical-grade nutraceuticals, offering a range of amino acid and neurotransmitter support formulas. While not specifically branded as PDRs, several NutriDyn products include key precursors such as L-tyrosine, DL-phenylalanine, and vitamin B6, which support dopamine synthesis and catecholamine metabolism. These formulations are often incorporated into personalized protocols aimed at improving mood, cognitive function, and stress resilience. Although not targeted explicitly at RDS, NutriDyn’s evidence-informed blends are increasingly used adjunctively in chronic pain and recovery settings where dopaminergic tone may be impaired.

• PDR blends54 are increasingly offered by integrative physicians and licensed compounding pharmacies. These formulations typically include key dopamine precursors such as L-tyrosine and DL-phenylalanine, as well as adaptogenic herbs like Rhodiola rosea to support stress resilience and neurotransmitter balance. While not standardized across providers, these PDR blends are often customized based on genetic profiles, symptom presentation, or neurochemical testing.

• Custom amino acid therapy protocols developed by companies like NeuroScience, Inc., offer a tiered approach to neurotransmitter precursor balancing, often using urinary neurotransmitter testing as a guide.55 These protocols target multiple neurotransmitter systems, including dopamine, serotonin, and GABA, and are used in clinical settings ranging from chronic pain and fatigue to mood dysregulation. The NeuroScience Inc. products that include amino acid precursors to dopamine (such as L-tyrosine, DL-phenylalanine, L-DOPA, and L-methionine/SAMe), according to specification sheets and the product guide, include AdreCor, AdreCor with Licorice Root, and AdreCor with SAMe—each contains L-tyrosine (precursor to dopamine) and L-methionine (for SAMe, a catecholamine synthesis cofactor); AttenTrex—provides L-tyrosine along with cofactors supportive of catecholamine production; Balance D—includes N-acetyl-L-tyrosine and Mucuna cochinchinensis (99% LDOPA), direct dopamine precursor; ExcitaPlus—contains high levels of L-tyrosine, L-methionine, and L-DOPA from Mucuna extract; and Focus DL—contains DL-phenylalanine (which converts downstream to dopamine).

While formal comparative trials are limited, these formulations represent a growing category of dopamine-targeted nutraceuticals positioned at the intersection of functional medicine, psychiatry, and chronic pain care. They are engineered to modulate dopaminergic tone, enhance neuroplasticity, and reduce neuroinflammation (Figure 3).56 Further research is warranted to clarify their relative efficacy, ideal use cases, and potential for integration into perioperative or long-term recovery pathways.

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Figure 3

The mechanistic pathways and clinical promise of nutraceuticals in pain and addiction recovery are outlined in this flowchart. The proposed mechanisms of action and clinical benefits of nutraceuticals containing amino acid precursors, enkephalinase inhibitors, and adaptogens. The mechanistic pathways include dopaminergic modulation (via upregulation of D2 receptor density and sensitivity), enhanced brain-derived neurotrophic factor (BDNF) expression supporting neuroplasticity, and anti-inflammatory effects through attenuation of glial cell activation. These effects collectively aim to normalize reward circuitry and enhance dopamine release. The anticipated clinical outcomes include reduced drug-seeking behavior, improved stress resilience, increased activation of reward areas, diminished opioid cravings, and improved mood and pain control.

The proposed mechanisms of action include balanced regulation of dopamine receptor density and sensitivity, particularly D2 receptors, which are often downregulated in chronic opioid users.24 Nutraceuticals may also stimulate brain-derived neurotrophic factor expression,57,58 promoting synaptic repair and improved neural connectivity.49 Additionally, several compounds exhibit anti-inflammatory properties59 by attenuating glial cell activation, a key contributor to central sensitization and chronic pain.

Evidence supporting nutraceutical efficacy is growing.60–69 Animal studies have demonstrated enhanced dopamine release, reduced drug-seeking behavior, and improved stress resilience. Electroencephalography53 and functional MRI studies in humans24 have shown increased activation in reward-related brain regions following KB220Z administration, suggesting normalization of reward circuitry function. Early clinical trials and case series have reported reduced opioid cravings, improved mood, and better pain control in patients with reward deficiency traits. While further randomized controlled trials are needed, these findings highlight the potential of nutraceuticals as safe, nonopioid tools for restoring brain homeostasis in the context of pain and addiction.

The Gars Test and Personalized Dopaminergic Recovery

The GARS test is a DNA-based assay developed to identify inherited polymorphisms in genes involved in the brain’s reward circuitry, particularly those regulating dopamine synthesis, receptor density, transport, and metabolism.70 By evaluating variations in genes such as DRD2,71 DAT1,72 COMT,73 and OPRM1, GARS provides a genetic risk score that reflects an individual’s predisposition to RDS—a condition associated with heightened vulnerability to addiction, compulsive behaviors, and altered pain sensitivity.74,75

In the context of spine surgery and postoperative pain management, GARS testing can serve as a valuable tool to stratify patients who may be at increased risk for opioid dependence or suboptimal recovery due to underlying dopaminergic imbalance. For such individuals, targeted use of nutraceuticals—including dopamine-precursor compounds like KB220Z—may offer a personalized approach to restoring neurochemical balance, reducing opioid cravings, and enhancing analgesic response.76

This strategy aligns with the broader goals of precision medicine, which emphasize the customization of health care based on individual genetic, biological, and environmental profiles.77 By integrating GARS testing into preoperative assessment protocols, clinicians can proactively identify high-risk patients and implement nonopioid, neurorestorative interventions aimed at both pain prevention and addiction mitigation, bridging 2 traditionally siloed aspects of perioperative care.78

Clinical Applications in Pain and Spine Surgery

The integration of nutraceuticals into clinical practice offers a promising adjunct to current strategies in spine, neuro-, and orthopedic surgery at low risk to patients. By enhancing dopaminergic tone and restoring balance within the brain’s reward system, nutraceuticals can play a pivotal role in augmenting prehabilitation efforts—priming the neurochemical environment to better tolerate surgical stress, reduce pain perception, and support neuroplastic recovery.79

Dr Stephen DeFelice coined the term “nutraceutical” from “nutrition” and “pharmaceutical” in 1989.79 The integration of nutraceuticals into clinical practice offers a promising adjunct to current strategies in spine, neuro-, and orthopedic surgery at low risk to patients. By enhancing dopaminergic tone and restoring balance within the brain’s reward system, nutraceuticals can play a pivotal role in augmenting prehabilitation efforts—priming the neurochemical environment to better tolerate surgical stress, reduce pain perception, and support neuroplastic recovery.80

In the postoperative setting, nutraceuticals may help reduce opioid requirements by enhancing endogenous pain modulation and dampening craving in patients with RDS. For individuals with chronic pain—particularly those with prolonged opioid exposure or a genetic predisposition to addiction—these compounds offer sustained support for long-term recovery by promoting both analgesia and emotional regulation. Their mechanism of action is best described through the metaphor of being “food for neurons”—providing the neurochemical building blocks needed to restore dopaminergic balance, support synaptic health, and facilitate the repair of disrupted reward circuitry.

Given their low-risk profile and nonaddictive mechanism of action, nutraceuticals merit serious consideration for integration into spine and orthopedic surgery protocols, particularly in ERAS pathways. They may also serve as a valuable adjunct in chronic pain clinics and addiction recovery programs, where restoring dopaminergic balance is a critical therapeutic goal.

A strong call to action is warranted for the development of well-designed clinical trials that evaluate the efficacy of nutraceuticals in surgical populations. This includes prospective studies assessing outcomes such as opioid consumption, pain scores, functional recovery, and neurocognitive resilience in both opioid-naïve and high-risk patients. The time is ripe for a neurobiologically informed shift in pain management — one that moves beyond symptomatic relief to address the root of dysfunction in the reward system. This approach directly supports our framing of nutraceutical formulations not merely as an adjunctive analgesic, but as a neurorestorative therapy aimed at reversing opioid-induced dysfunction in the mesolimbic system.

Differentiating Peripheral and Central Pain Modulation Strategies

While local anesthetic agents like Exparel (liposomal bupivacaine) offer targeted peripheral nociceptive blockade, they do not address the central dopaminergic dysregulation commonly seen in chronic pain or opioid-exposed patients. In contrast, nutraceuticals acting on the central reward circuitry thereby aiming to restore dopaminergic tone, reduce craving, and enhance emotional and cognitive dimensions of recovery. These 2 modalities are not competing but complementary, and their combined use may provide a more robust, multilayered analgesic strategy aligned with ERAS 2.0 as they apply to spine surgery (Table 2).81–84 By addressing both nociceptive and affective components of pain, this integrated approach holds promise for reducing opioid consumption and promoting more complete recovery.

Layered Analgesia Within ERAS: Exparel️ and Nutraceuticals

Local anesthetics such as liposomal bupivacaine (Exparel️) offer effective peripheral nociceptive blockade for immediate postoperative pain and are a validated part of ERAS protocols.85 In contrast, dopaminergic nutraceuticals target central mood, craving, and reward modulation, addressing the neuropsychological dimensions of pain and recovery. Used together, these agents may form a complementary strategy: Exparel for acute surgical pain and nutraceuticals for central sensitization, motivation, perioperative, postoperative, and long-term opioid reduction. This layered approach reflects the evolving understanding that effective pain care requires both peripheral interruption and central recalibration.

Access, Regulatory Status, and Consent

Given the growing clinical interest in nutraceuticals, it is essential to clarify their regulatory classification and practical considerations to avoid legal or ethical ambiguity. These nutraceuticals are typically categorized as a dietary supplement under the Dietary Supplement Health and Education Act, and US Food and Drug Administration (FDA) approval for the treatment of pain, opioid dependence, or any medical condition is not required. However, dietary supplements must comply with labeling, manufacturing, and safety requirements under the Dietary Supplement Health and Education Act, and they cannot claim to treat, cure, or prevent diseases unless undergoing FDA drug approval. Supplements can be used off-label (eg, as adjuncts in clinical care) with appropriate patient consent, particularly in integrative or functional medicine settings. As such, any clinical application—particularly in perioperative or postoperative pain management—should be framed as an adjunctive intervention in off-label application. Hence, the FDA’s Expanded Access (Compassionate Use) program does not apply to nutraceuticals, as that pathway applies exclusively to investigational drugs, biologics, and devices under formal investigational new drug application or investigational device exemption protocols.

To ensure transparency and mitigate medicolegal risk, clinicians are advised to obtain documented informed consent when recommending or prescribing nutraceuticals. This consent should outline the supplement’s nonpharmaceutical status, its proposed neurorestorative mechanism of action, the current level of clinical evidence, and its intended role within a broader, multimodal treatment plan.

Finally, patients should be informed that the monthly costs for nutraceuticals are typically out-of-pocket, as dietary supplements are not covered by insurance. This cost burden may impact adherence and access—particularly among vulnerable or fixed-income populations. To contextualize the financial impact, a recent longitudinal survey of 2990 older adults (with 2068 completing 5-year follow-up) found that 70.4% to 82.7% of participants used at least 1 dietary supplement during the study period. Of 160 identified formulations, 142 (88%) had price data available. The mean monthly cost per supplement ranged from $0.73 to $49.59, with DS users incurring an average monthly cost of $14.56 to $16.45 over the 5 years. This translated to a mean annual cost burden of $186 per user, highlighting the economic considerations associated with sustained supplement use in routine care. Integrating this therapy within an ethically grounded, personalized framework—including genetic risk stratification and shared decision-making—can help ensure responsible use while advancing research on nonopioid alternatives in pain care.

Integration and Clinical Study in Spine Surgery

For spine surgeons, dopaminergic repletion strategies can be integrated into existing perioperative workflows by embedding nutraceutical protocols within standard ERAS programs. Initiation could occur during the preoperative visit (typically 10–14 days before surgery), coupled with GARS testing to identify patients with genetic markers of RDS. For those at elevated risk, spine surgeons can prescribe a defined nutraceutical regimen continued through the postoperative period (eg, up to 4 weeks after discharge). This approach complements multimodal analgesia, reduces opioid reliance, and provides targeted neurochemical support during critical healing and recovery phases.

To rigorously evaluate effectiveness, spine surgeons should lead multicenter, randomized controlled trials within elective lumbar and cervical fusion populations—where opioid exposure is common and outcomes are measurable. Patients would be stratified by GARS status and randomized to receive either standard care or additional neuroceutical-supported care. Outcome metrics should include total morphine milligram equivalents used, pain scores (visual analog scale/numerical rating scale), length of stay, complication rates, time to ambulation, and validated quality-of-recovery metrics (eg, patient-reported outcomes measurement information system, Oswestry Disability Index, and Short Form-36). Secondary outcomes might include incidence of persistent opioid use at 90 days, craving intensity, and postoperative mood or cognitive recovery. Neuroimaging (eg, functional MRI) or electroencephalography may offer mechanistic insights into dopaminergic modulation. This research can be embedded in spine registries or ERAS pathways, enabling real-world validation and laying the groundwork for personalized, neurobiologically informed pain management in spine surgery—a big task ahead for those who want to lead the break with the old ways (Figure 4).86

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Figure 4

Integration pathway for nutraceuticals in perioperative spine care and ERAS 2.0. This flowchart outlines a proposed clinical framework for integrating nutraceuticals—such as KB220Z—into perioperative spine care through ERAS protocols. Beginning with the goal of restoring dopaminergic tone and reward system balance, the model includes preoperative Genetic Addiction Risk Severity (GARS) testing to identify patients at high risk for reward deficiency syndrome (RDS), followed by initiation of a nutraceutical protocol. Integration into ERAS programs continues through the postoperative phase with sustained nutraceutical support aimed at reducing opioid use and enhancing recovery. Mechanistic benefits include improved pain tolerance, neuroplasticity, emotional regulation, and analgesia. Parallel research tracks emphasize the need for clinical trials assessing outcomes such as opioid consumption, functional recovery, mood, and neuroimaging findings. ERAS = enhansed recovery after surgery; ERAS 2.0 = enhanced ERAS.

Call to Action

We advocate refining the current funding paradigm to emphasize clinician-led, outcome-driven innovation. Well-intentioned investments should ultimately translate into measurable clinical benefit. Building on the progress of national programs such as HEAL, we recommend realigning incentives so funding prioritizes implementation-ready solutions—those that demonstrably reduce opioid exposure and oipoid-related death and support dopaminergic restoration—rather than dispersing resources across siloed efforts.

Practically, funders can expand support for pragmatic, multi-site trials embedded in routine care pathways that pair layered, non-opioid analgesia with dopaminergic repletion, and tie continued funding to preregistered milestones—including total opioid use measured in morphine milligram equivalents (MMEs), pain and function (patient-reported outcomes), mood/craving, length of stay, readmissions, and 90-day persistent opioid use. These trials should be designed for real-world translation, using common data elements, rapid replication models, and integrated health-economic and equity analyses.

Therefore, we encourage a shift from funding that programs chase to funding that follows need—where scientific success is judged by relief of suffering, restoration of function, and durable reductions in opioid dependence. This approach complements ongoing federal efforts while accelerating what matters most: timely, scalable solutions at the point of care.