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Opioid-Induced Hyperalgesia and Inflammaging in the Management of Spine Pain: The Case for Genetically Directed Dopamine Homeostasis

  • International Journal of Spine Surgery
  • August 2025,
  • 19
  • (4)
  • 459-484;
  • DOI: https://doi.org/10.14444/8756

Abstract

Background The management of spine-related pain with narcotics, both before and after surgery, poses major challenges, including drug diversion, limited effectiveness, and worsening of pain symptoms over time. Chronic opioid use is associated with hypodopaminergia-induced hyperalgesia, whereby dopamine depletion increases pain sensitivity. Patients with inherently low dopaminergic function are particularly predisposed to hyperalgesia and reduced pain tolerance.

Methods An alternative therapeutic strategy centers on genetically guided pro-dopamine regulation, which aims to transmodulate dopaminergic signaling to mitigate hyperalgesia. Early identification of predisposition through genetic testing, combined with pharmacogenetic and pharmacogenomic monitoring, is proposed to optimize treatment approaches.

Results Pro-dopamine regulators have demonstrated promising results across 43 clinical studies, showing potential to reduce stress, craving, and relapse rates, while improving emotional well-being and attenuating pain sensitivity. These findings suggest that pro-dopamine regulation may serve as a viable frontline therapy for managing chronic pain and associated Reward Deficiency Syndrome behaviors, offering a significant reduction in the adverse effects commonly observed with chronic opioid therapy.

Conclusions Given the limitations of dopaminergic blockade through chronic opioid agonist therapy, there is a critical need to reevaluate current pain management practices. The induction of dopamine homeostasis via pro-dopamine regulation represents a novel and potentially transformative strategy. Spine surgeons, pain specialists, and addiction medicine practitioners are urged to consider this approach as a promising alternative for improving long-term outcomes in patients suffering from chronic pain.

Introduction

In 2020, the United States experienced an average of 44 deaths daily due to prescription opioid overdoses, resulting in more than 16,000 fatalities that year alone.1 Nearly a quarter (24%) of all overdose deaths that year were related to prescription opioids, indicating a 16% increase in prescription opioid-related morbidity from 2019 to 2020. Postsurgical pain management often marks patients’ initial exposure to opioids, posing a documented risk for chronic opioid dependence among opioid-naïve individuals. Alarmingly, around 70% of those using prescription opioids acquire them through diversion, often via legitimate prescriptions of friends and family.2 Many surgeons, including spine and orthopedic specialists, who rank as the third-highest opioid prescribers, administer opioids to control postoperative pain. Miscalculations in assessing postoperative pain can lead to excessive opioid prescriptions after surgery, inadvertently contributing to the surplus of unused pills that can be diverted (Figure 1).3

Flowchart illustrating the progression of opioid addiction, starting from an initial postoperative opioid prescription for postsurgical pain management that may result in chronic pain and opioid medication use. The sequence begins with the management of chronic pain and progresses through stages of increased tolerance, leading to the need for higher doses. This escalation often results in physical dependence, followed by withdrawal symptoms. To avoid withdrawal, continued use occurs, which may lead to psychological dependence and, ultimately, full addiction. The flowchart also highlights various treatment options available at the stage of addiction, including detoxification, medication-assisted treatment, cognitive behavioral therapy, and support groups. The key stages and treatment options are visually emphasized with distinct colors to differentiate them within the progression of opioid addiction.
Figure 1

Flowchart illustrating the progression of opioid addiction, starting from an initial postoperative opioid prescription for postsurgical pain management that may result in chronic pain and opioid medication use. The sequence begins with the management of chronic pain and progresses through stages of increased tolerance, leading to the need for higher doses. This escalation often results in physical dependence, followed by withdrawal symptoms. To avoid withdrawal, continued use occurs, which may lead to psychological dependence and, ultimately, full addiction. The flowchart also highlights various treatment options available at the stage of addiction, including detoxification, medication-assisted treatment, cognitive behavioral therapy, and support groups. The key stages and treatment options are visually emphasized with distinct colors to differentiate them within the progression of opioid addiction.

This shift in medical practice has been influenced in part by information from pharmaceutical companies that downplayed the addiction risks of certain opioid pain relievers.4 The American Pain Society introduced the concept of pain as the “fifth vital sign,” advocating for its evaluation and treatment on par with traditional vital signs like temperature, blood pressure, respiratory rate, and heart rate.2 This concept gained further traction in 2001 with the endorsement by The Joint Commission, which placed pain management practices under closer scrutiny.5 Consequently, the highly addictive potential of these drugs only became widely understood after significant misuse, abuse, and diversion had already occurred.

Patients undergoing spine surgery are particularly vulnerable to addiction due to several factors. The extended life expectancy and the proliferation of minimally invasive spine surgery techniques have increased the number of annual spine surgeries in the United States to nearly 1 million. Many patients are prescribed opioids before consulting a spine surgeon, making them opioid-experienced and heightening the risk of misuse, abuse, and dependency.6 Additionally, substantial postoperative opioid needs are common7 because uncontrolled postoperative pain following spinal surgery is common and underscores the need for effective pain management strategies.8 A 2020 study by Yang et al revealed that 57% of patients experienced inadequate pain control within the first 24 hours after surgery.9 This inadequate pain control was defined by a mean numeric rating scale score of greater than 4. The study utilized data from the Canadian Spine Outcomes and Research Network to develop a predictive model. The authors identified key risk factors such as younger age, female sex, preoperative opioid use, higher depression scores, fusion surgery, and procedures involving 3 or more motion segments. Patients classified in the highest risk category had an 85% likelihood of experiencing poor pain control postoperatively. This study highlights the critical need for tailored pain management approaches, including preoperative interventions such as opioid deprescribing, psychotherapy, and genetic testing to potentially mitigate these risks and improve patient outcomes.

Despite identifying specific predictors influencing opioid overuse patterns, such as prior opioid use, surgical type, patient age, body mass index, depression or anxiety diagnoses, hospital stay length, and discharge pain scores,10 there is a notable absence of precise pharmacogenetic parameters in interventional and surgical pain management protocols. The traditional nonopioid methods of postoperative pain control for spine patients do not include genetic testing or therapies aimed at dopamine (DA) homeostasis. Instead, these strategies emphasize a multimodal approach that incorporates nonopioid medications such as nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and gabapentinoids as well as ketamine and lidocaine infusions. Regional and neuraxial techniques, like spinal or epidural anesthesia, and behavioral interventions, including cognitive behavioral therapy and patient education, are also employed (Table 1). The focus is primarily on optimizing pain relief through pharmacologic and nonpharmacologic methods, without mention of precision medicine techniques such as genetic testing for pain sensitivity or interventions aimed at modulating DA-related pathways.11

View this table:
Table 1

Key nonopioid pain management strategies for surgical patients.

Phenotypic profiling and personalized approaches to pain management are from current clinical practice and do not explore genetic-based therapies or specific modulation of DA homeostasis as part of postoperative pain control. A dysfunction in the brain’s reward pathways may exist in the context of a neurogenetic condition marked by a lack of DA hemostasis. This reward deficiency syndrome (RDS), coined by Blum et al in 1995, arises from an imbalance or deficiency in the DA system and results in diminished pleasure and satisfaction (Figure 2). Consequently, individuals with RDS may pursue various risk behaviors to temporarily boost DA levels and compensate for their impaired reward response. These behaviors include substance abuse (alcohol, drugs, and nicotine), compulsive actions (gambling, overeating, and hypersexuality), and non–substance-related activities (excessive shopping and internet use). These are often efforts to self-medicate or artificially stimulate the brain’s reward system, but they can lead to addiction and other adverse effects.

Reward deficiency syndrome (RDS) is a neurogenetic condition characterized by a dysfunction in the brain’s reward pathways, primarily involving the neurotransmitter dopamine. This syndrome occurs when there is an imbalance or deficiency in the dopamine system, leading to reduced feelings of pleasure and satisfaction. As a result, individuals with RDS may engage in a range of risky behaviors as they seek out activities or substances that can temporarily enhance dopamine release and compensate for their deficient reward response. Associated risk behaviors with RDS include substance abuse, such as alcohol, drugs, and nicotine; compulsive behaviors like gambling, overeating, and hypersexuality; and even non–substance-related behaviors such as excessive shopping or internet use. These behaviors are often attempts to self-medicate or artificially stimulate the brain’s reward system, but they can lead to addiction and other negative outcomes. The concept of RDS underscores the importance of understanding genetic and neurobiological factors in the development of addictive and compulsive behaviors, highlighting the need for personalized treatment approaches that address the underlying dopamine deficiency rather than just the symptoms of addiction.
Figure 2

Reward deficiency syndrome (RDS) is a neurogenetic condition characterized by a dysfunction in the brain’s reward pathways, primarily involving the neurotransmitter dopamine. This syndrome occurs when there is an imbalance or deficiency in the dopamine system, leading to reduced feelings of pleasure and satisfaction. As a result, individuals with RDS may engage in a range of risky behaviors as they seek out activities or substances that can temporarily enhance dopamine release and compensate for their deficient reward response. Associated risk behaviors with RDS include substance abuse, such as alcohol, drugs, and nicotine; compulsive behaviors like gambling, overeating, and hypersexuality; and even non–substance-related behaviors such as excessive shopping or internet use. These behaviors are often attempts to self-medicate or artificially stimulate the brain’s reward system, but they can lead to addiction and other negative outcomes. The concept of RDS underscores the importance of understanding genetic and neurobiological factors in the development of addictive and compulsive behaviors, highlighting the need for personalized treatment approaches that address the underlying dopamine deficiency rather than just the symptoms of addiction.

Integrating genetic factors could be instrumental in preparing patients for postoperative pain and determining effective pain management strategies. Given that opioids are among the top 30 medications with significant pharmacogenetic implications, leveraging genetic information to guide pain management is promising but remains underutilized.12 A patient’s genetic profile related to opioid susceptibility and responsiveness could potentially replace traditional pain management methods, reducing opioid-related risks and identifying more effective treatments.13 Therefore, the authors of this perspective article advocate for the induction of novel concepts such as DA homeostasis via prodopamine regulation rather than the widespread application of dopaminergic blockade through chronic opioid agonist therapy using either methadone or buprinorphine.

Mesolimbic Systems in Pain Control

Tonic pain suppression involves several systems beyond those known to suppress phasic pain, including forebrain sites and regions rostral to the brainstem. Both psychostimulants and opioids decrease tonic pain while enhancing transmission in mesocorticolimbic dopaminergic neurons associated with natural rewards like sex and food (Figure 3). These neurons, originating from cell bodies in the nucleus accumbens (NAc) and ventral tegmental area (VTA), communicate with the prefrontal cortex via functional connectivity.14,15 Opioids indirectly activate these neurons, inducing DA release, which provides rewarding and analgesic effects.16 DA-depleting lesions in the ventral midbrain, which contain cell bodies for ascending forebrain projections, block morphine’s analgesic effects, underscoring the role of mesolimbic DA neurons in pain suppression.17

The flowchart illustrates the mesolimbic systems in pain control, highlighting the role of tonic pain suppression, which involves forebrain sites, regions rostral to the brainstem, and mesocorticolimbic dopaminergic neurons. These neurons originate in the nucleus accumbens (NAc) and ventral tegmental area (VTA), communicating with the prefrontal cortex. Opioids induce dopamine release, leading to rewarding and analgesic effects, while dopamine-depleting lesions block the analgesic effects of morphine.
Figure 3

The flowchart illustrates the mesolimbic systems in pain control, highlighting the role of tonic pain suppression, which involves forebrain sites, regions rostral to the brainstem, and mesocorticolimbic dopaminergic neurons. These neurons originate in the nucleus accumbens (NAc) and ventral tegmental area (VTA), communicating with the prefrontal cortex. Opioids induce dopamine release, leading to rewarding and analgesic effects, while dopamine-depleting lesions block the analgesic effects of morphine.

The Role of DA in Pain Management

Pain pathways primarily originate in the dorsal horn of the spinal cord and medulla, but additional neurological loci, particularly within the mesolimbic system (the brain’s reward center), play a crucial role in modulating pain sensitivity. Genetic polymorphisms significantly impact pain tolerance, suggesting that these variations could predispose individuals to different pain sensitivities. Identifying specific gene polymorphisms presents novel therapeutic targets for pain treatment. Individuals exhibit varied responses to medications and nutraceuticals in terms of efficacy and toxicity.18 Inherited differences in drug metabolism and genetic variants in drug targets, such as the DA D2 receptor, substantially influence the clinical effectiveness and safety of medications.

DA D2 Receptors and Chronic Pain

Early studies revealed biochemical commonalities between opioids and alcohol, particularly concerning DA condensation products. Tetrahydropapaveroline, a derivative of DA, is influenced by alcohol metabolism (Figure 4).19–22 Subcortical and cortical dopaminergic systems modulate pain signals, with DA D2 receptors playing an inhibitory role in persistent pain models.23 High D2 receptor availability correlates with low pain thresholds and enhanced pain modulation capacity, involving mu receptor interaction.24 Changes in the striatal dopaminergic system, observed in chronic pain conditions via positron emission tomography, show increased D2 receptor availability and altered D1/D2 ratios.23 Psychoactive drugs trigger DA surges in the NAc, differentially modulating mu receptor activity through D1 and D2 receptors.25

This flowchart illustrates the role of dopamine in pain management, where dopamine modulates pain sensitivity within the mesolimbic system. Genetic polymorphisms significantly affect pain tolerance, and identifying these polymorphisms presents potential therapeutic targets. Additionally, variations in drug response due to genetic factors, particularly involving dopamine D2 receptors, influence the effectiveness and safety of medications. The diagram also addresses the relationship between dopamine D2 receptors and chronic pain, emphasizing the inhibitory role of D2 receptors in persistent pain. High D2 receptor availability is associated with low pain thresholds and increased pain modulation capacity. Chronic pain conditions lead to changes in the striatal dopaminergic system, including altered D1/D2 receptor ratios, which affect the modulation of mu receptor activity by psychoactive drugs.
Figure 4

This flowchart illustrates the role of dopamine in pain management, where dopamine modulates pain sensitivity within the mesolimbic system. Genetic polymorphisms significantly affect pain tolerance, and identifying these polymorphisms presents potential therapeutic targets. Additionally, variations in drug response due to genetic factors, particularly involving dopamine D2 receptors, influence the effectiveness and safety of medications. The diagram also addresses the relationship between dopamine D2 receptors and chronic pain, emphasizing the inhibitory role of D2 receptors in persistent pain. High D2 receptor availability is associated with low pain thresholds and increased pain modulation capacity. Chronic pain conditions lead to changes in the striatal dopaminergic system, including altered D1/D2 receptor ratios, which affect the modulation of mu receptor activity by psychoactive drugs.

Stress, DA, Inflammation, and Chronic Pain Pathophysiology

The interplay between stress, endorphins, and the hypothalamic-pituitary-adrenal axis is well documented.15 Polymorphisms in the DA D2 receptor are associated with stress-coping mechanisms.26 Stress can exacerbate or induce pain, with stress exposure activating DA transmission in mesocorticolimbic neurons (Figure 5).27 Opioid mechanisms in the VTA mediate this effect, with stress causing met-enkephalin release in the VTA, providing natural analgesia.28 The gate control theory of pain suggests that sensory input is modulated before pain perception.29 Stress-induced analgesia involves substance P (SP) release in the VTA, activating DA neurons and augmenting DA release in the NAc, similar to opioids.30 Stress-induced inflammation and its detrimental impact on pain perception are well established. In a series of experiments, Altier et al suggested that the neuronal release of the tachykinin neuropeptide SP in the VTA might contribute similar to the stress-induced suppression of tonic pain.30,31 Their findings indicated that SP activation of midbrain DA neurons inhibited tonic pain in the formalin test, implicating DA in this process. Stress exposure induces analgesia by releasing SP in the VTA, which then activates mesocorticolimbic DA neurons. Notably, both opioids and SP share the psychopharmacological ability to enhance DA release in the NAc. Additionally, opioids, whether administered systemically or directly into the VTA, increase DA metabolism and extracellular levels of DA in the NAc.

This flowchart illustrates the interplay between stress, endorphins, and the hypothalamic-pituitary-adrenal (HPA) axis, emphasizing the role of polymorphisms in the dopamine D2 receptor and their association with stress-coping mechanisms. Stress can exacerbate or induce pain by activating dopamine transmission in mesocorticolimbic neurons, a process mediated by opioid mechanisms in the ventral tegmental area (VTA). Stress triggers the release of met-enkephalin in the VTA, providing natural analgesia. The figure also highlights the gate control theory of pain, where sensory input is modulated before pain perception, and stress-induced analgesia, involving the release of substance P in the VTA. This release activates dopamine neurons and increases dopamine release in the nucleus accumbens (NAc), similar to the action of opioids.
Figure 5

This flowchart illustrates the interplay between stress, endorphins, and the hypothalamic-pituitary-adrenal (HPA) axis, emphasizing the role of polymorphisms in the dopamine D2 receptor and their association with stress-coping mechanisms. Stress can exacerbate or induce pain by activating dopamine transmission in mesocorticolimbic neurons, a process mediated by opioid mechanisms in the ventral tegmental area (VTA). Stress triggers the release of met-enkephalin in the VTA, providing natural analgesia. The figure also highlights the gate control theory of pain, where sensory input is modulated before pain perception, and stress-induced analgesia, involving the release of substance P in the VTA. This release activates dopamine neurons and increases dopamine release in the nucleus accumbens (NAc), similar to the action of opioids.

Hyperalgesia Neuromechanisms

The misuse of prescription opioids and illicit substances such as heroin or fentanyl is at an all-time high. Data from the National Survey on Drug Use and Health revealed that 80% of new heroin users previously abused prescription opioids, indicating a link between prescription analgesic misuse and heroin use.32 Tolerance significantly reduces the analgesic efficacy of opioids in patients with substance use disorders. The prevalence of chronic pain among individuals undergoing methadone maintenance is approximately 80%, with 30% of these patients reporting illegal opioid use while in pain.33–36 Turk et al37 and Boscarino et al38 suggested that previous opioid exposure predicts current and lifetime opioid misuse in chronic pain patients.

Christie39 demonstrated that chronic administration of mu-opioid receptor (MOR) agonists decreases MOR function, contributing to morphine tolerance. Animal studies have shown that inflammatory pain induces MORs in dorsal root ganglion neurons, the spinal cord, and the locus coeruleus, leading to reduced antinociceptive effects of MOR agonists.16 This suggests that inflammatory pain may dysregulate MOR activity in the VTA DA pathway, modifying opioid-induced reinforcing properties and altering opioid intake patterns in animals with a history of opioid use.

Several neuroscientists have linked opioid abuse in the presence of pain to the mesolimbic pathways, especially dopaminergic tone.40–42 One potential mechanism for hyperalgesia involves chronic morphine reducing the rewarding and nociceptive properties of opioids due to decreased DA release in the NAc43 and increased tumor necrosis factor-alpha levels in the NAc.44 Importantly, l-tetrahydropalmatine alleviates mechanical hyperalgesia in chronic inflammatory and neuropathic pain models in mice, an effect blocked by a DA D1 receptor antagonist.44

Dias et al showed that increasing DA in the NAc with the DA reuptake inhibitor GBR12909 blocked prostaglandin E2-induced acute hyperalgesia, an effect prevented by a DA D2 receptor antagonist but not by a D1 receptor antagonist.45 Hoshino et al demonstrated the antihyperalgesic effects of intrathecal bupropion, a DA, and noradrenaline reuptake inhibitor, in a rat model of neuropathic pain.46 These findings highlight the significant contribution of the descending inhibitory pathways, involving noradrenaline and DA, to the maintenance of neuropathic pain.

Shou et al showed that repeated electroacupuncture at specific acupoints improved thermal hyperalgesia and increased D1 and D2 gene expression levels.47 Zhang et al found that in morphine-dependent rats, both the latency of pain-excitation neurons discharges and the inhibitory duration of pain-inhibition neurons discharges were altered.48 DA inhibited pain-excitation neurons and augmented pain-inhibition neurons, indicating that DA plays a role in modulating pain signal transmission in morphine-dependent rats. Zhu et al49 revealed that the DA D3 receptor regulates basal pain sensitivity in mice, aligning with Gardner’s group, which highlighted the importance of the D3 receptor in heroin and oxycodone reinforcement. Treister et al50 found significant associations between cold pain tolerance and DAT-1 and monoamine oxidase A (MAO-A) polymorphisms, suggesting that low dopaminergic activity correlates with high pain sensitivity.

Mansikka et al51 provided evidence from D2 knockout mice that DA D2 receptors may attenuate referred hypersensitivity caused by sustained nociception. Wood52 noted that chronic stress reduces DA output in the NAc, contributing to long-term hyperalgesia. Verma et al53 demonstrated the predominant role of DA D2 receptors, compared to D1 receptors, in anti-nociception, suggesting an interlink between dopaminergic D2 and opioid systems. Matamales et al mapped a DA-dependent transcriptional activation marker in spiny projection neurons expressing D1 or D2 receptors in mice.54 This dynamic transmodulation is essential for updating goal-directed learning and reshaping volitional action. Challenge treatment with D1- and D2-class agonists in combination led to increased stereotypy and striosome-predominant gene expression, suggesting D1 to D2 receptor synergism underlies changes in basal ganglia activation and psychomotor stimulant sensitization.54

Opioid-Induced Hyperalgesia

The ongoing debate surrounding rebound hyperalgesia related to opioid dosage focuses on the phenomenon where long-term opioid use leads to an increased sensitivity to pain rather than its relief. Several studies have highlighted that chronic opioid therapy, particularly at higher doses, can paradoxically make patients more sensitive to pain—a condition known as opioid-induced hyperalgesia (OIH). This paradoxical effect is thought to occur because opioids, while initially effective at relieving pain, may alter the nervous system’s processing of pain over time. Specifically, chronic exposure to opioids can change the way pain signals are transmitted and perceived, potentially enhancing the body’s sensitivity to painful stimuli. As a result, patients on long-term opioid therapy often experience more pain, even at the same or higher doses of opioids, necessitating further increases in dosage that perpetuate the cycle of hyperalgesia. This phenomenon is often mislabeled as opioid tolerance. The debate on rebound hyperalgesia related to opioid dosage continues, with several studies highlighting this phenomenon.55–59

Genes, Opiate Addiction, and Transmodulation

Individuals exhibit variable responses to opioids, influenced by genetic, biochemical, and receptor interactions. Pharmacogenetic testing of candidate genes, such as PENK (Proenkephalin; naturally helps modulate pain, stress, and emotional responses) and mu receptors,60 could lead to personalized treatments, potentially improving clinical outcomes. Without precise gene-based prescreening and appropriate supplementation, treatment efficacy can be unpredictable. Documented information on genetic polymorphisms in enzymes, receptors, and transporters related to opioid pharmacokinetics and pharmacodynamics is extensive (Table 2).61 For instance, cytochrome P450 enzymes, uridine diphosphoglucuronosyltransferases, opioid receptors, and ABC transporters are key examples of pharmacogenetic targets. Genetically guided transmodulation using pro-dopamine regulators, like the precision neuro-nutrient KB220,62 combined with pharmaceutical opioid analgesics, might mitigate hypodopaminergia-induced hyperalgesia. Therefore, both pharmaceutical and nutraceutical industries are encouraged to incorporate genome-based formulations into ongoing research. To substantiate the rationale for each selected risk allele, we conducted an extensive literature review. Despite some controversy, the guiding principle for selecting these alleles was their collective impact on reducing dopaminergic function. Each allele is associated with a decrease in DA activity, contributing to a higher risk of addiction and related behaviors. Table 1 details the justification for each allele selection based on this principle.

View this table:
Table 2

Sampling of relevant gene and single nucleotide polymorphism (SNP).

Integration of Pharmacogenetics into Pain Management

It is well known that humans have varied responses to opioids. For instance, morphine sulfate may provide specific analgesic effects for some patients with postherpetic neuralgia, while it may not help others with the same condition. Such variability can occur with any pain condition and any analgesic agent, including opioids and anti-inflammatory drugs. These differences can be attributed to pharmacokinetic and pharmacodynamic factors, as well as other unknown variables. Historically, clinicians could not predict which patients would respond well or poorly to different opioids. However, recent sophisticated research has provided pharmacogenetic insights into the neurogenetic mechanisms of opioid-induced analgesia (Figure 6). These discoveries highlight the diverse genetics, biochemistry, and receptor interactions involved in opioid effects in humans. Specific candidate genes, including those for catechol-O-methyl-transferase, and potentially in the future melanocortin-1 receptor, guanosine triphosphate cyclohydrolase, and the MOR, have been extensively studied. Research has found associations between these genes and analgesic needs in both acute and chronic pain conditions, as well as pain sensitivity (Table 1).25,155–159

This diagram illustrates the role of dopamine in pain management, where dopamine modulates pain sensitivity within the mesolimbic system. Genetic polymorphisms significantly affect pain tolerance, and identifying these polymorphisms presents potential therapeutic targets. Additionally, variations in drug response due to genetic factors, particularly involving dopamine D2 receptors, influence the effectiveness and safety of medications. The diagram also addresses the relationship between dopamine D2 receptors and chronic pain, emphasizing the inhibitory role of D2 receptors in persistent pain. High D2 receptor availability is associated with low pain thresholds and increased pain modulation capacity. Chronic pain conditions lead to changes in the striatal dopaminergic system, including altered D1/D2 receptor ratios, which affect the modulation of mu receptor activity by psychoactive drugs.
Figure 6

This diagram illustrates the role of dopamine in pain management, where dopamine modulates pain sensitivity within the mesolimbic system. Genetic polymorphisms significantly affect pain tolerance, and identifying these polymorphisms presents potential therapeutic targets. Additionally, variations in drug response due to genetic factors, particularly involving dopamine D2 receptors, influence the effectiveness and safety of medications. The diagram also addresses the relationship between dopamine D2 receptors and chronic pain, emphasizing the inhibitory role of D2 receptors in persistent pain. High D2 receptor availability is associated with low pain thresholds and increased pain modulation capacity. Chronic pain conditions lead to changes in the striatal dopaminergic system, including altered D1/D2 receptor ratios, which affect the modulation of mu receptor activity by psychoactive drugs.

The Genetic Addiction Risk Score (GARS) can help predict patient responses to opioids, facilitating personalized opioid analgesic therapy (Figure 7).155 Candidate genes, such as catechol-O-methyl-transferase and MORs, have been linked to analgesic requirements and pain sensitivity.158–160 The GARS test measures risk polymorphisms across 10 reward genes (Figure 8). This test has heuristic value in predicting high genetic risk for opioid dependence by assessing variations within the Brain Reward Cascade. Variations in the Brain Reward Cascade, whether genetic or epigenetic, can predispose individuals to addictive behaviors and affect pain tolerance. The GARS test, the first to accurately predict vulnerability to pain, addiction, and other compulsive behaviors collectively defined by the RDS,161–165 is particularly relevant.

The Genetic Addiction Risk Score (GARS) test evaluates an individual’s predisposition to addictive behaviors by analyzing specific genetic variants associated with neurotransmitter systems involved in the brain’s reward pathways, including dopamine, serotonin, and endorphins. The test identifies risk alleles—gene variants linked to a higher likelihood of developing addiction—and assigns a score based on their presence. Each gene variant can contribute 0, 1, or 2 points to the total score, depending on the number of risk alleles detected. The total GARS represents the cumulative genetic predisposition, with higher scores indicating a stronger genetic risk for addiction. Scores are interpreted as low, moderate, or high risk, guiding clinical decisions and personalized treatment strategies. Although the GARS test assesses risk, it does not diagnose addiction; the results should be considered alongside other clinical assessments and environmental factors.
Figure 7

The Genetic Addiction Risk Score (GARS) test evaluates an individual’s predisposition to addictive behaviors by analyzing specific genetic variants associated with neurotransmitter systems involved in the brain’s reward pathways, including dopamine, serotonin, and endorphins. The test identifies risk alleles—gene variants linked to a higher likelihood of developing addiction—and assigns a score based on their presence. Each gene variant can contribute 0, 1, or 2 points to the total score, depending on the number of risk alleles detected. The total GARS represents the cumulative genetic predisposition, with higher scores indicating a stronger genetic risk for addiction. Scores are interpreted as low, moderate, or high risk, guiding clinical decisions and personalized treatment strategies. Although the GARS test assesses risk, it does not diagnose addiction; the results should be considered alongside other clinical assessments and environmental factors.

The Genetic Addiction Risk Score (GARS) test evaluates 10–12 specific genetic variants that are closely associated with the brain’s reward pathways and the risk of addictive behaviors. These genetic variants collectively contribute to an individual’s predisposition to addictive behaviors by affecting the brain’s reward circuitry. The GARS test assesses the presence and combination of these variants to provide a genetic risk score that can be used to guide personalized interventions and prevention strategies. These genetic variants are found in key neurotransmitter systems, including dopamine, serotonin, and endorphins, which play crucial roles in regulating mood, motivation, and pleasure. The following are some of the key genetic variants tested in the GARS assessment: 1. DRD2 (Dopamine Receptor D2): Variants in this gene are linked to reduced dopamine receptor density, leading to decreased reward sensitivity and an increased risk of substance abuse and other addictive behaviors. 2. DAT1 (Dopamine Transporter): This gene regulates dopamine reuptake in the brain. Certain polymorphisms can result in altered dopamine availability, contributing to impulsivity and the propensity for addiction. 3. ANKK1 (Ankyrin Repeat and Kinase Domain Containing 1): Often associated with the DRD2 gene, variations in ANKK1 influence dopamine receptor signaling and have been linked to higher risks of addiction and compulsive behaviors. 4. COMT (Catechol-O-Methyltransferase): This enzyme is involved in the breakdown of dopamine. Variants in the COMT gene can affect dopamine levels in the prefrontal cortex, impacting decision-making and increasing susceptibility to addictive behaviors. 5. MAOA (Monoamine Oxidase A): This gene encodes an enzyme that breaks down neurotransmitters like dopamine and serotonin. Certain variants can lead to imbalances in these neurotransmitters, contributing to impulsivity and addiction risk. 6. OPRM1 (Opioid Receptor Mu 1): Variants in this gene affect the opioid system, influencing pain perception and the rewarding effects of substances like alcohol and opioids, thereby increasing the likelihood of addiction. 7. BDNF (Brain-Derived Neurotrophic Factor): This gene is involved in neuroplasticity. Variants in BDNF can affect the brain's ability to adapt to new experiences, potentially increasing vulnerability to addictive behaviors. 8. 5HTTLPR (Serotonin Transporter Gene): Polymorphisms in this gene affect serotonin transport and are linked to mood disorders and increased risk-taking behaviors, which can contribute to addiction. 9. GABRB3 (Gamma-Aminobutyric Acid Receptor Subunit Beta-3): Variants in this gene influence the GABAergic system, which is critical for inhibitory signaling in the brain. Dysregulation here can lead to anxiety and susceptibility to substance abuse. 10. TH (Tyrosine Hydroxylase): This gene is involved in the synthesis of dopamine. Variants in TH can influence dopamine production, affecting reward processing and increasing addiction risk. 11. SLC6A3 (Solute Carrier Family 6 Member 3): This gene encodes the dopamine transporter protein, and its variants can affect dopamine reuptake, contributing to altered dopamine signaling and an increased risk of addictive behaviors. 12. CHRNA4 (Cholinergic Receptor Nicotinic Alpha 4 Subunit): Variants in this gene are associated with nicotine dependence and other substance use disorders due to its role in acetylcholine receptor function in the brain.
Figure 8

The Genetic Addiction Risk Score (GARS) test evaluates 10–12 specific genetic variants that are closely associated with the brain’s reward pathways and the risk of addictive behaviors. These genetic variants collectively contribute to an individual’s predisposition to addictive behaviors by affecting the brain’s reward circuitry. The GARS test assesses the presence and combination of these variants to provide a genetic risk score that can be used to guide personalized interventions and prevention strategies. These genetic variants are found in key neurotransmitter systems, including dopamine, serotonin, and endorphins, which play crucial roles in regulating mood, motivation, and pleasure. The following are some of the key genetic variants tested in the GARS assessment: 1. DRD2 (Dopamine Receptor D2): Variants in this gene are linked to reduced dopamine receptor density, leading to decreased reward sensitivity and an increased risk of substance abuse and other addictive behaviors. 2. DAT1 (Dopamine Transporter): This gene regulates dopamine reuptake in the brain. Certain polymorphisms can result in altered dopamine availability, contributing to impulsivity and the propensity for addiction. 3. ANKK1 (Ankyrin Repeat and Kinase Domain Containing 1): Often associated with the DRD2 gene, variations in ANKK1 influence dopamine receptor signaling and have been linked to higher risks of addiction and compulsive behaviors. 4. COMT (Catechol-O-Methyltransferase): This enzyme is involved in the breakdown of dopamine. Variants in the COMT gene can affect dopamine levels in the prefrontal cortex, impacting decision-making and increasing susceptibility to addictive behaviors. 5. MAOA (Monoamine Oxidase A): This gene encodes an enzyme that breaks down neurotransmitters like dopamine and serotonin. Certain variants can lead to imbalances in these neurotransmitters, contributing to impulsivity and addiction risk. 6. OPRM1 (Opioid Receptor Mu 1): Variants in this gene affect the opioid system, influencing pain perception and the rewarding effects of substances like alcohol and opioids, thereby increasing the likelihood of addiction. 7. BDNF (Brain-Derived Neurotrophic Factor): This gene is involved in neuroplasticity. Variants in BDNF can affect the brain's ability to adapt to new experiences, potentially increasing vulnerability to addictive behaviors. 8. 5HTTLPR (Serotonin Transporter Gene): Polymorphisms in this gene affect serotonin transport and are linked to mood disorders and increased risk-taking behaviors, which can contribute to addiction. 9. GABRB3 (Gamma-Aminobutyric Acid Receptor Subunit Beta-3): Variants in this gene influence the GABAergic system, which is critical for inhibitory signaling in the brain. Dysregulation here can lead to anxiety and susceptibility to substance abuse. 10. TH (Tyrosine Hydroxylase): This gene is involved in the synthesis of dopamine. Variants in TH can influence dopamine production, affecting reward processing and increasing addiction risk. 11. SLC6A3 (Solute Carrier Family 6 Member 3): This gene encodes the dopamine transporter protein, and its variants can affect dopamine reuptake, contributing to altered dopamine signaling and an increased risk of addictive behaviors. 12. CHRNA4 (Cholinergic Receptor Nicotinic Alpha 4 Subunit): Variants in this gene are associated with nicotine dependence and other substance use disorders due to its role in acetylcholine receptor function in the brain.

Evaluation of pain clinic patients using the GARS test and the Addiction Severity Index (ASI—Media Version V)166 demonstrated that GARS of 4 or more alleles predicted drug addiction risk severity, while scores of 7 or more alleles predicted alcohol addiction risk severity (Figure 8). In a recent clinical trial, Reverse Transcription Polymerase Chain Reaction (RT-PCR) for single nucleotide polymorphism genotyping and multiplex PCR/capillary electrophoresis for fragment analysis was employed, examining the role of 11 alleles in a 10-reward gene panel, which reflects brain reward circuitry activity in 121 chronic opioid users.167 The cohort consisted of 55 men and 66 women, with average ages of 54 and 53 years, respectively, and included Caucasians, African Americans, Hispanics, and Asians. Inclusion criteria required that the morphine milligram equivalent was 30 to 600 mg/day for men and 20 to 180 mg/day for women, for chronic pain treatment over 12 months. Ninety-six percent of participants had 4 or more risk alleles, and 73% had 7 or more, indicating high predictive risk for opioid and alcohol dependence. These findings suggest that chronic opioid users in pain clinics possess a high genetic risk for addiction. Early genetic risk identification with the GARS test at treatment entry may help prevent iatrogenic opioid dependence. Since pain sensitivity is thought to be influenced by the mesolimbic projection system, where genetic polymorphisms can affect an individual’s susceptibility to pain and tolerance levels, identifying these genetic predispositions allows health care providers to customize pain management strategies. This approach minimizes the risk of addiction and improves overall treatment efficacy. By incorporating pharmacogenetic information into clinical practice, opioid treatment and rotation strategies can be optimized, thereby enhancing pain management outcomes.

Neuronutrient Targets

Individuals exhibit varying responses to medications and specific nutraceuticals, both in terms of toxicity and treatment efficacy.18 These differences can be attributed to inherited variations in the metabolism and disposition of drugs and nutrients, as well as genetic polymorphisms in drug and neuronutrient targets, such as the DA D2 receptor. These genetic differences can significantly impact the clinical effectiveness and toxicity of medications and nutraceuticals.168 Accurate gene-based prescreening and subsequent supplementation are crucial for predictable efficacy (Figure 9). The nutraceutical industry, like the pharmaceutical industry, can undertake ongoing research and incorporate genome-based formulations as discussed here. Genetic polymorphisms in genes coding for enzymes, receptors, and transporters related to opioid disposition (pharmacokinetics) and pharmacology (pharmacodynamics) are well documented.169 Examples include pharmacogenetics of various enzymes, such as cytochrome P450s and uridine diphosphoglucuronosyltransferases, opioid receptors, and the ABC family of transporters. Combining the prodopamine regulator, the precision nutraceuticals (KB220), with pharmaceutical opioid analgesic agents could help mitigate hyperalgesia induced by hypodopaminergia.170 This approach leverages genetically guided transmodulation of addiction risk polymorphisms, as illustrated in (Figure 10).

This figure represents the results of a Genetic Addiction Risk Score (GARS) test, which assesses an individual’s genetic predisposition to addiction-related behaviors by analyzing specific single nucleotide polymorphisms (SNPs) and variable number tandem repeats in key genes associated with the brain’s reward pathways. This patient’s total risk allele count is 11 out of a possible 21 for men (22 for women), indicating an elevated risk for addictive behaviors. The GARS test revealed the following genetic variants and risk alleles: 1. DRD3 (rs6280): Risk allele C – Patient has 1 risk allele. 2. DRD4 (rs1800955): Risk allele C/T – Patient has 1 risk allele. 3. OPRM1 (rs1799971): Risk allele C – Patient has 2 risk alleles. 4. DRD1 (rs4532): Risk allele C/T – Patient has 1 risk allele. 5. DRD2 (rs1800497): Risk allele G – Patient has 1 risk allele. 6. COMT (rs4680): Risk allele A/G – Patient has 2 risk alleles. 7. DAT1 (rs28363170): Risk allele A/A – Patient has 1 risk allele. 8. DRD4 (rs761010487): Risk allele A/A – Patient has 1 risk allele. 9. HTTLPR (rs4795541): Risk allele S/S – Patient has 1 risk allele. 10. MAOA (rs768062321): Risk allele 4R – Patient has 0 risk alleles. 11. GABRB3 (rs764926719): Risk allele 181/185 – Patient has 1 risk allele. Interpretation: The presence of 11 risk alleles out of a possible 21 indicates an elevated genetic risk for drug addiction. Additionally, with 7 or more risk alleles, the patient also shows a heightened risk for alcoholism. These results from the GARS test provide valuable insights into the individual’s genetic predisposition to addictive behaviors, which can inform personalized treatment and preventive strategies.
Figure 9

This figure represents the results of a Genetic Addiction Risk Score (GARS) test, which assesses an individual’s genetic predisposition to addiction-related behaviors by analyzing specific single nucleotide polymorphisms (SNPs) and variable number tandem repeats in key genes associated with the brain’s reward pathways. This patient’s total risk allele count is 11 out of a possible 21 for men (22 for women), indicating an elevated risk for addictive behaviors. The GARS test revealed the following genetic variants and risk alleles: 1. DRD3 (rs6280): Risk allele C – Patient has 1 risk allele. 2. DRD4 (rs1800955): Risk allele C/T – Patient has 1 risk allele. 3. OPRM1 (rs1799971): Risk allele C – Patient has 2 risk alleles. 4. DRD1 (rs4532): Risk allele C/T – Patient has 1 risk allele. 5. DRD2 (rs1800497): Risk allele G – Patient has 1 risk allele. 6. COMT (rs4680): Risk allele A/G – Patient has 2 risk alleles. 7. DAT1 (rs28363170): Risk allele A/A – Patient has 1 risk allele. 8. DRD4 (rs761010487): Risk allele A/A – Patient has 1 risk allele. 9. HTTLPR (rs4795541): Risk allele S/S – Patient has 1 risk allele. 10. MAOA (rs768062321): Risk allele 4R – Patient has 0 risk alleles. 11. GABRB3 (rs764926719): Risk allele 181/185 – Patient has 1 risk allele. Interpretation: The presence of 11 risk alleles out of a possible 21 indicates an elevated genetic risk for drug addiction. Additionally, with 7 or more risk alleles, the patient also shows a heightened risk for alcoholism. These results from the GARS test provide valuable insights into the individual’s genetic predisposition to addictive behaviors, which can inform personalized treatment and preventive strategies.

The COMT (catechol-O-methyltransferase) gene plays a critical role in the metabolism of dopamine and norepinephrine, 2 key neurotransmitters involved in the brain’s reward pathways. This gene, located on chromosome 22 at q11.2, produces an enzyme that degrades dopamine in the synapse, thus regulating its levels in the brain. The specific genetic variant of interest, rs4680, involves a single nucleotide polymorphism where either guanine (G) or adenine (A) is present at this position. The presence of the G allele results in the amino acid valine (Val) at codon 158, leading to the production of an enzyme variant that metabolizes dopamine at up to 4 times the rate of the Met variant (where adenine is present, resulting in methionine at codon 158). This accelerated breakdown of dopamine, known as hypodopaminergia, is associated with a higher risk of both substance-related (eg, alcohol, nicotine, and opioids) and non–substance-related (eg, attention deficit hyperactivity disorder, anxiety, and OCD) reward deficiency behaviors. To mitigate the clinical impacts of this genetic variant, neuroceuticals are recommended to help support dopamine levels. These neuroceuticals aim to compensate for the increased dopamine metabolism in individuals with the Val variant, potentially reducing the risk of associated addictive and behavioral disorders. For individuals with the G/G genotype at rs4680 (double Val carriers), the following supplements are advised to enhance dopamine synthesis and availability: 1. L-Phenylalanine: An amino acid precursor to tyrosine, which is a building block for dopamine. 2. L-Tyrosine: A direct precursor to dopamine, aiding in its synthesis. 3. N-Acetyl-Cysteine (NAC): Supports glutathione production, which can help protect dopamine neurons from oxidative stress. 4. Rhodiola Root: An adaptogenic herb known to support neurotransmitter function and combat stress-induced dopamine depletion. OCD, obsessive-compulsive disorder.
Figure 10

The COMT (catechol-O-methyltransferase) gene plays a critical role in the metabolism of dopamine and norepinephrine, 2 key neurotransmitters involved in the brain’s reward pathways. This gene, located on chromosome 22 at q11.2, produces an enzyme that degrades dopamine in the synapse, thus regulating its levels in the brain. The specific genetic variant of interest, rs4680, involves a single nucleotide polymorphism where either guanine (G) or adenine (A) is present at this position. The presence of the G allele results in the amino acid valine (Val) at codon 158, leading to the production of an enzyme variant that metabolizes dopamine at up to 4 times the rate of the Met variant (where adenine is present, resulting in methionine at codon 158). This accelerated breakdown of dopamine, known as hypodopaminergia, is associated with a higher risk of both substance-related (eg, alcohol, nicotine, and opioids) and non–substance-related (eg, attention deficit hyperactivity disorder, anxiety, and OCD) reward deficiency behaviors. To mitigate the clinical impacts of this genetic variant, neuroceuticals are recommended to help support dopamine levels. These neuroceuticals aim to compensate for the increased dopamine metabolism in individuals with the Val variant, potentially reducing the risk of associated addictive and behavioral disorders. For individuals with the G/G genotype at rs4680 (double Val carriers), the following supplements are advised to enhance dopamine synthesis and availability: 1. L-Phenylalanine: An amino acid precursor to tyrosine, which is a building block for dopamine. 2. L-Tyrosine: A direct precursor to dopamine, aiding in its synthesis. 3. N-Acetyl-Cysteine (NAC): Supports glutathione production, which can help protect dopamine neurons from oxidative stress. 4. Rhodiola Root: An adaptogenic herb known to support neurotransmitter function and combat stress-induced dopamine depletion. OCD, obsessive-compulsive disorder.

Reward Deficiency, Hyperalgesia, and Inflammaging

There is overwhelming evidence that DA plays a crucial role in behavioral and substance addictions, as well as in pain mechanisms, particularly hyperalgesia. Despite this, there is still debate on how best to modulate DA clinically to treat and prevent chronic morphine-induced hyperalgesia. A prudent approach may involve long-term dopaminergic upregulation during chronic opioid treatment with various pharmaceutical opioid analgesics. This strategy aims to enhance brain reward functional connectivity and volume, thereby addressing reward deficiency and stress-induced antireward states, characterized by increased pain sensitivity and reduced pain tolerance.

Ingredients in nutraceuticals such as KB220 variants are designed to support this dopaminergic upregulation (Figure 9). For instance, D-phenylalanine is a known inhibitor of enkephalinase171 and has anti-inflammatory properties.172 Rhodiola rosea acts as a catabolic inhibitor of both catechol-O-methyl-transferase and MAO-A,173 while N-acetyl-cysteine (NAC) aids in glutaminergic repair.174 Chromium175 and L-tryptophan176 enhance serotonergic function, and Nicotinamide Adenine Dinucleotide (NADH),177 CoQ10,178 and pyridoxine-6-phosphate179 serve as catalysts for improved DA synthesis. These substances play roles in mitigating inflammation-induced aging by targeting various pathways associated with inflammation, neurotransmitter function, and oxidative stress:

  1. D-phenylalanine: This amino acid inhibits enkephalinase, an enzyme that breaks down enkephalins, which are natural peptides that help regulate pain and inflammation. By preventing the degradation of enkephalins, D-phenylalanine helps maintain their anti-inflammatory effects, thus reducing chronic inflammation, which is a key contributor to aging.171

  2. R rosea: This adaptogen acts as an inhibitor of the enzymes catechol-O-methyl-transferase and MAO-A. These enzymes are involved in the breakdown of neurotransmitters like DA and serotonin. By inhibiting these enzymes, R rosea helps maintain higher levels of these neurotransmitters, which can reduce stress and inflammation, both of which accelerate aging.173

  3. NAC: NAC is a precursor to glutathione, 1 of the body’s most important antioxidants. It aids in glutaminergic repair, which is crucial for maintaining the balance of the neurotransmitter glutamate. By boosting glutathione levels, NAC helps combat oxidative stress and inflammation, thereby protecting cells from damage and slowing down the aging process.174

  4. Chromium and L-tryptophan: These substances enhance serotonergic function. Serotonin plays a role in mood regulation and has anti-inflammatory properties. Improved serotonergic function can help reduce chronic inflammation, which is associated with accelerated aging and various age-related diseases.175,176

  5. NADH, CoQ10, and pyridoxine-6-phosphate: These substances are catalysts for improved DA synthesis. DA is essential for numerous physiological functions, including mood regulation and neuroprotection. Adequate DA levels help manage stress and reduce inflammation. Additionally, CoQ10 is a powerful antioxidant that supports mitochondrial function, protecting cells from oxidative damage and aging.177–179

Discussion

Pain control after spinal surgery remains problematic particularly when it comes to practical strategies to reduce opioid consumption. A 2022 systematic review by Geisler et al180 investigated the effectiveness of various analgesic treatments for patients undergoing 1- or 2-level spinal fusion surgery, a common procedure with significant postoperative pain challenges. The study aimed to determine which postoperative pain management strategies are most effective in reducing opioid consumption and improving pain control in the immediate postoperative period. The review included 44 randomized controlled trials (RCTs) with a total of 2983 participants. The primary outcome was opioid consumption within the first 24 hours after surgery. Five key analgesic interventions were identified, such as NSAIDs, epidural analgesia, ketamine infusion, local infiltration analgesia, and intrathecal morphine.

The findings showed that NSAIDs and epidural analgesia significantly reduced opioid consumption in the first 24 hours after surgery. NSAIDs, which are typically avoided in spinal fusion due to concerns about their potential to impair bone healing, were found to be effective in reducing both opioid use and pain at rest within the first 6 hours postoperatively. Despite concerns about NSAIDs negatively affecting spinal fusion outcomes, their use in this context highlights their potential benefit in multimodal pain management to minimize opioid requirements. This approach is particularly relevant given the ongoing opioid crisis, as it suggests that NSAIDs could be safely incorporated into postoperative regimens to reduce reliance on opioids, provided that the potential risks are carefully managed. Epidural analgesia also showed a significant reduction in opioid use and pain scores, particularly in the first 24 hours. Intrathecal morphine was effective in reducing pain both at rest and during mobilization, especially in the first 6 and 24 hours postoperatively. Ketamine, while effective in reducing pain at rest after 24 hours, did not significantly reduce opioid consumption. While NSAIDs are often avoided in spinal fusion due to potential risks to bone healing, Geisler et al180 suggested that their use can significantly reduce opioid consumption and improve pain management in the immediate postoperative period. However, careful consideration of the risks and benefits is necessary, and further research is needed to establish the most effective pain management strategies for spinal fusion patients and the appropriate time for postoperative NSAID use.

The PROSPECT Working Group of the European Society of Regional Anaesthesia and Pain Therapy (ESRA)181 concurred with this approach in their recent guideline definition focusing on optimizing pain management for complex spine surgery, a procedure associated with intense postoperative pain. The ESRA review analyzed 31 RCTs and 4 systematic reviews published between 2008 and 2020. Key recommendations include the use of pre- or intraoperative paracetamol and NSAIDs or COX-2-specific inhibitors, continued postoperatively with opioids reserved for rescue analgesia. Additionally, intraoperative intravenous low-dose ketamine infusion and epidural analgesia using local anesthetics, with or without opioids, are recommended. The guideline emphasizes minimizing opioid use by prioritizing nonopioid analgesics.

The multivesicular liposome technology that encapsulates bupivacaine, prepared as an injectable suspension, preserves the drug’s molecular integrity and allows for controlled release over a desired period. It is 1 of the more innovative approaches to sustained and targeted drug delivery, enhancing therapeutic outcomes.182–184 Despite these findings, the ESRA review noted that the quality of evidence was generally low to very low, and there was considerable heterogeneity among the included studies. As such, the ESRA authors concluded that while certain analgesic interventions appear promising, the current literature does not allow for the identification of a “gold standard” for postoperative pain management in spinal fusion surgery. They emphasized the need for large-scale RCTs with a focus on individual responder analyses to better understand the clinical effectiveness of these interventions.

In this context, our hypothesis is illustrated in schematic models provided here that highlight the role of chronic opioid-induced hypodopaminergia, which is linked with increased hyperalgesia due to various neurochemical and neurogenetic impairments in the mesolimbic system. This model identifies disruptions in multiple neurotransmitter pathways, including serotonergic,185 endorphinergic,186 cannabinergic,187 opioidergic,188 glutaminergic,189 dopaminergic,190 and noradrenergic191 pathways. Understanding these neurochemical dysregulations and their connection to chronic OIH forms the foundation for the novel approach known as Precision Addiction Management (PAM).192 This approach aims to tailor treatment strategies based on individual neurogenetic profiles, thereby improving outcomes in managing addiction and associated pain disorders. By addressing the specific neurochemical imbalances and genetic factors contributing to hypodopaminergia and hyperalgesia, precision medicine offers a targeted and effective method for treating patients with opioid addiction and chronic pain.

To further refine treatment, phenotypes, such as hyperalgesia, can be assessed using the GARS. Achieving DA homeostasis through PAM involves customizing neuronutrient supplementation based on GARS test results (Figure 2). This personalized approach aims to increase functional connectivity and is complemented by behavioral interventions.193 These nutraceuticals, particularly in the KB220 variants, aim to achieve DA homeostasis through PAM. This approach involves customizing neuronutrient supplementation based on the GARS test results, allowing for a personalized treatment strategy. By tailoring supplementation to individual genetic profiles, this method helps enhance functional connectivity and manage inflammation more effectively, thereby reducing its impact on aging. Behavioral interventions complement these treatments, further supporting overall health and reducing the effects of chronic inflammation.

These considerations are in line with recent legislative changes, particularly the Nonopioids Prevent Addiction in the Nation Act. This Act, effective 1 January 2025, mandates that Medicare provide separate reimbursement for qualifying nonopioid options used in outpatient surgical procedures. This reimbursement policy, set at ASP + 6%, represents a significant shift in the health care policy framework, enabling spine surgeons to integrate nonopioid pain management strategies without financial disincentives. The inclusion of FDA-approved nonopioid medications and devices—specifically those that have demonstrated efficacy in reducing or replacing opioid use—provides a viable pathway to mitigate the risks associated with OIH. By leveraging these nonopioid alternatives, spine surgeons can align their practices with evolving standards that prioritize patient safety, reduce the potential for opioid dependency, and contribute to the broader effort to curb the opioid epidemic.

Conclusions

The use of opioids for treating spine pain presents significant challenges, including drug diversion, ineffectiveness, and exacerbation of pain through mechanisms like hypodopaminergia-induced hyperalgesia. This traditional approach can be counterproductive, causing more pain over time and predisposing patients with low dopaminergic function to low pain tolerance or hyperalgesia. An alternative approach involves the use of genetically directed prodopamine regulation, such as the KB220 variants, which aims to transmodulate dopaminergic signaling. This strategy has shown promise in clinical studies, suggesting that it can mitigate hyperalgesia and improve patient outcomes by enhancing brain reward functional connectivity and volume. Ingredients such as D-phenylalanine, R rosea, NAC, chromium, L-tryptophan, NADH, CoQ10, and pyridoxine-6-phosphate support dopaminergic upregulation and help manage inflammation-induced aging. These substances target various pathways associated with inflammation, neurotransmitter function, and oxidative stress, thereby reducing chronic inflammation and its impact on aging. To refine treatment, the GARS can assess phenotypes such as hyperalgesia, allowing for personalized neuronutrient supplementation and behavioral interventions. This comprehensive strategy, known as PAM, aims to achieve DA homeostasis, reduce stress, craving, and relapse and improve overall well-being. By addressing the specific neurochemical imbalances and genetic factors contributing to hypodopaminergia and hyperalgesia, precision medicine offers a targeted and effective method for treating patients with opioid addiction and chronic pain, potentially transforming pain management practices.

Footnotes

  • Funding The authors received no financial support for the research, authorship, and/or publication of this article.

  • Declaration of Conflicting Interests The authors report no conflicts of interest in this work.

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In this Issue

International Journal of Spine Surgery

Vol. 19, Issue 4

1 Aug 2025

Table of Contents Index by author

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Keywords

chronic pain, dopamine homeostasis, dopaminergic signaling, hyperalgesia, hypodopaminergia, opioid analgesics, precision, transmodulation