Introduction

Substance use disorders (SUDs) affect a significant portion of the surgical population. Addiction is now understood as a chronic, relapsing disorder with strong genetic underpinnings—accounting for approximately 40–60% of individual vulnerability.

Genetic influences not only determine the risk of addiction but also affect perioperative analgesic needs, opioid responsiveness, and withdrawal potential.

For anesthesiologists, these factors present important perioperative challenges. Tailored care requires the integration of genetics, pharmacology, and regional anesthesia techniques to deliver safe and effective management.

Reference

• Volkow ND, Koob GF, McLellan AT. Neurobiologic advances from the brain disease model of addiction. N Engl J Med. 2016;374(4):363–371.

Basic Science

Genetic and Molecular Biology of Addiction

Key genetic variations influence addiction risk and perioperative drug response:

• DRD2 (Dopamine D2 receptor)
• A1 allele linked to higher addiction risk
• Associated with lower pain threshold
• OPRM1 (Mu-opioid receptor)
• A118G polymorphism reduces opioid efficacy
• CYP2D6 (Cytochrome P450 enzyme)
• Responsible for metabolism of codeine, tramadol, oxycodone
• Phenotypes range from poor to ultra-rapid metabolizers
• CYP2B6 (Cytochrome P450 enzyme)
• Influences methadone clearance
• Genetic variation may prolong QT interval
• GABRA2 (GABA-A receptor subunit)
• Modulates alcohol sensitivity
• Alters benzodiazepine response

• Noble EP. D2 dopamine receptor gene in psychiatric and neurologic disorders and its phenotypes. Am J Med Genet B Neuropsychiatr Genet. 2003;116B(1):103–125.
• Bond C, LaForge KS, Tian M, et al. SNP in the human mu-opioid receptor gene alters beta-endorphin binding and activity. Proc Natl Acad Sci USA. 1998;95(16):9608–9613.
• Crews KR, Gaedigk A, Dunnenberger HM, et al. CPIC guidelines for codeine therapy based on CYP2D6 genotype. Clin Pharmacol Ther. 2012;91(2):321–326.
• Eap CB, Buclin T, Baumann P. Interindividual variability of methadone pharmacokinetics. Clin Pharmacokinet.2002;41(14):1153–1193.
• Edenberg HJ, Dick DM, Xuei X, et al. GABRA2 variants and alcohol dependence. Am J Hum Genet.2004;74(4):705–714.

Neuropharmacology and Tolerance Pathophysiology

Chronic substance use alters brain circuitry, receptor expression, and pain processing:

• Opioids
• Chronic exposure upregulates NMDA receptors
• Contributes to opioid-induced hyperalgesia
• Stimulants
• Induce sympathetic overactivity
• Increase cardiovascular risk perioperatively
• Alcohol and Benzodiazepines
• Downregulate GABA receptors
• Cause tolerance to sedation and increase withdrawal risk

References

• Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology.2006;104(3):570–587.
• Vearrier D, Osterhoudt KC. Stimulant toxicity and the sympathetic nervous system. Clin Perinatol. 2014;41(1):93–106.
• Koob GF, Volkow ND. Neurobiology of addiction: neurocircuitry analysis. Lancet Psychiatry. 2016;3(8):760–773.

Perioperative Integration

Preoperative Evaluation

• Obtain a detailed history of substance use, including last use and withdrawal symptoms
• Review current treatment, including methadone, buprenorphine, or naltrexone
• Investigate pharmacogenetic factors such as CYP2D6 and OPRM1
• Screen for psychiatric comorbidities
• Coordinate care with addiction medicine services
• Evaluate early the role of regional anesthesia in the perioperative plan

• McCance-Katz EF, Sullivan LE, Nallani S. Drug interactions among opioids and prescribed medications. Am J Addict. 2010;19(1):4–16.

Intraoperative Management

Benefits of Regional Anesthesia in SUD Patients

• Provides opioid-sparing analgesia, particularly useful in opioid-tolerant or OPRM1-variant patients
• Reduces withdrawal risk in those on methadone or buprenorphine
• Promotes hemodynamic stability in stimulant users
• Fits well within multimodal strategies, improving recovery and reducing delirium risk

• Koppert W, Sittl R, Scheuber K, et al. Modulation of remifentanil-induced hyperalgesia by S(+)-ketamine and clonidine. Anesthesiology. 2003;99(1):152–159.
• Alford DP, Compton P, Samet JH. Acute pain management in patients on buprenorphine or methadone. Ann Intern Med. 2006;144(2):127–134.
• Bhananker SM, Posner KL, Cheney FW, et al. Injury and liability associated with regional anesthesia: a closed claims analysis. Anesthesiology. 2006;105(4):841–846.
• Mariano ER, Schatman ME. A new paradigm for regional analgesia in the U.S. Reg Anesth Pain Med.2019;44(3):285–288.

Regional Techniques

• Upper limb: supraclavicular, infraclavicular blocks
• Lower limb: femoral, adductor canal, popliteal blocks
• Thoracic: erector spinae plane (ESP), paravertebral blocks
• Abdominal: transversus abdominis plane (TAP), quadratus lumborum (QL) blocks
• Pelvic/Perineal: spinal, epidural, pudendal blocks

• Memtsoudis SG, Cozowicz C, Zubizarreta N, et al. Peripheral nerve blocks in joint arthroplasty. Best Pract Res Clin Anaesthesiol. 2019;33(1):67–77.

Postoperative Management

• Employ continuous nerve catheters (e.g., adductor canal, ESP) to prolong analgesia
• Use multimodal strategies with acetaminophen, NSAIDs, ketamine, or dexmedetomidine
• Tailor opioid prescribing based on pharmacogenetic considerations (CYP2D6, OPRM1 status)

• Smith HS. Perioperative pain management in the opioid-tolerant patient. Clin J Pain. 2011;27(2):174–180.

Risk Mitigation and Guidelines

• Follow ASA practice guidelines for acute pain and perioperative substance use
• Modify ERAS protocols to account for patients on MAT or with active SUD
• Incorporate pharmacogenomic insights, including CYP2D6 and OPRM1 variants, into clinical decision-making

• American Society of Anesthesiologists. Practice guidelines for acute pain management. Anesthesiology.2012;116(2):248–273.
• Ljungqvist O, Scott M, Fearon KC. Enhanced Recovery After Surgery: a review. JAMA Surg. 2017;152(3):292–298.

Conclusion

A precision-medicine approach to anesthesia for patients with substance use disorders is essential.

• Genetic polymorphisms in CYP450 enzymes and opioid or dopamine receptors influence analgesic efficacy and risk of complications.
• Regional anesthesia provides a cornerstone of opioid-sparing, individualized care.
• Careful perioperative planning reduces withdrawal risk, enhances hemodynamic stability, and improves recovery.