Pharmacogenetic Testing for Pain Management

Last Reviewed: July 18, 2019

BCBSND contracts with eviCore for its Laboratory Management Program.  eviCore is an independent company providing specific medical policy and precertification services to BCBSND. Effective 1-1-2020, Lab Management (molecular and genomic testing) is delegated to eviCore.

Description

Genetic factors may contribute to a range of aspects of pain and pain control, including predisposition to conditions that lead to pain, pain perception, and the development of comorbid conditions that may affect pain perception. The currently available genetic tests relevant to pain management assess) SNPs in single genes potentially relevant to pharmacokinetic or pharmacodynamic processes. These genetic associations may be relevant for several clinical purposes:

  • Drug selection or avoidance:
    • To identify individuals likely or not likely to respond to a specific medication.
    • To identify individuals at high risk of adverse drug reactions.
    • To identify individuals at high risk of opioid addiction or abuse.
  • Dose optimization:
    • Identify individuals who are likely to require higher or lower doses of a drug.
    • Estimate the dose and dosing frequency.

Genesrelated to these clinicalscenariosinclude, broadly speaking, those involved in neurotransmitter uptake, clearance, and reception; opioid reception; and hepatic drug metabolism. Panels of genetic tests have been developed and have been proposed for use in the management of pain. Genes that have been identified as being relevant to pain management and that are included in currently available panels are summarized in Table 1.

Table 1: Genes Relevant to Pain Management

Gene Locus Gene Product Function Potential Role in Pain Management
5HT2C (serotonin receptor gene) Xq23 1 of 6 subtypes of serotonin receptor, which is involved in release of dopamine and norepinephrine  
5HT2A (serotonin receptor gene) 13q14-21 Another serotonin receptor subtype Polymorphisms (ie, 102T/C) have been associated with variation in pain threshold
SLC6A4 (serotonin transporter gene) 17q11.2 Clears serotonin metabolites from synaptic spaces in the CNS  
DRD1 (dopamine receptor gene) 5q35.2    
DRD2 (dopamine receptor gene) 11q23.2    
DRD4 (dopamine receptor gene) 11p15.5 G-protein-coupled receptors that have dopamine as their ligands DRD4 VNTR have been associated with presence of pain-related disorders (fibromyalgia, TMJ syndrome, migraine)
DAT1 or SLC6A3 (dopamine transporter gene) 5p15.33 Mediates dopamine reuptake from synaptic spaces in the CNS  
DBH (dopamine beta-hydroxylase gene) 9q34.2 Catalyzes the hydroxylase of dopamine to norepinephrine; active primarily in adrenal medulla and postganglionic synaptic neurons  
COMT (catechol O-methyltransferase gene) 22q11.21 Responsible for enzymatic metabolism of catecholamine neurotransmitters dopamine, epinephrine, and norepinephrine Val158Met polymorphism has been associated with alterations in emotional processing and executive function.

Other polymorphisms have been associated with pain sensitivity
MTHFR (methylenetetrahydrofolate reductase gene) 1p36.22 Converts folic acid to methylfolate, a precursor to norepinephrine, dopamine, and serotonin neurotransmitters Multiple polymorphisms have been identified, which are associated with a wide variety of clinical disorders
GABA A receptor gene 5q34 Ligand-gated chloride channel that responds to GABA, a major inhibitory neurotransmitter  
OPRM1 (m-opioid receptors gene) 6q25.2 G-protein coupled receptor that is primary site of action for commonly used opioids, including morphine, heroin, fentanyl, and methadone A118G polymorphism (rs1799971) has been associated with reduced pain sensitivity and opioid requirements
OPRK1 (k-opioid receptor gene) 8q11.23 Binds the natural ligand dynorphin and synthetic ligands  
UGT2B15 (uridine diphosphate glycosyltransferase 2 family, member 15) 4q13.2 Member of UDP family involved in the glycosylation and elimination of potentially toxic compounds  
Cytochrome p450 genes CYP2D6 22q13.2   CYP2D6 is primary metabolizer for multiple oral opioids; metabolizer phenotype has been associated with variability in opioid effects
CYP2C19
CYP2C9		 10q23.33
10q23.33		 Hepatic enzymes responsible for the metabolism of a wide variety of medications, including analgesics  
CYP3A4 CYP3A4 7q22.1   Involved in metabolism of up to 60% of clinically used drugs
CYP2B6 19q13.2    
CYP1A2 15q24.1    

CNS: central nervous system; CYP: cytochrome; GABA: y-aminobutyric acid; TMJ temporomandibular joint; UG: uridine diphosphate glycosyltransferase; VNTR: varying number of tandem repeats.

Commercially Available Genetic Tests for Pain Management

Several test labs market panels of tests or individual tests designed to address one or more aspects of pain management, including but not limited to drug selection, drug dosing, or prediction of AEs. Specific polymorphisms included in the panels are shown in Table 2.

  • GeneSight Analgesic (Assurex Health, Mason, OH) is a genetic panel test that is intended to analyze “how patients’ genes can affect their metabolism and possible response to FDA [U.S. Food and Drug Administration]-approved opioids, NSAIDs and muscle relaxants commonly used to treat chronic pain.” Results are provided with a color-coded report based on efficacy and tolerability, which displays which medications should be used as directed, used with caution, or used with increased caution and more frequent monitoring. The company’s website does not specify the testing methods. Publications describing other tests provided by the company specify that testing is conducted via SNP sequencing performed via multiplex polymerase chain reaction.
  • Proove Biosciences (Irvine, CA) offers several genetic panelsthat address pain control. The Proove® Opioid Risk Panel is a panel of 12 genes that is intended to predict opioid abuse and failure of opioid therapy. Genetic testing results are provided with along with an overall 2 “Dependence Risk Index.” The company also marketsthe Proove® Pain Perception panel, which is a panel test for SNPs in several genes related to pain perception, including COMT and at least 3 other genes. Results are provided with a report which stratifies patients’ pain sensitivity based on COMT haplotype. Genetic testing for these panelsis conducted by sequencing of target regions with reverse-transcription polymerase chain reaction.
  • Pain Medication DNA Insight™ (Pathway Genomics, San Diego, CA) is a panel test intended to identify genetic variants that affect how an individual will respond to the analgesic effects of certain types of pain medications. The result report includes the genotype/SNP for each gene included, along with a description of the toxicity risk, dose required, medication efficacy, or plasma concentration based on genotype results for a range of medications used for pain management, primarily opioids. The testing method is notspecified on the company’s website.
  • Millennium PGT (Pain Management) (Millennium Health, San Diego, CA) is a genetic panel test intended to help physicians select pain medication. The panel includes analysis of 11 genes related to pain management; results are provided with a proprietary “Millennium Analysis of Patient Phenotype” report that provides decision support for medications that may be affected by the patient’s genotype.

Other laboratories, including CompanionDx (Houston, TX), and AIBioTech (Richmond, VA), which markets the PersonaGene Genetic Panel, offer panels of CYP450 genes. Panels that are restricted to CYP450 genes are beyond the scope of this policy and are discussed in Policy No. 2.04.38 (Cytochrome p450 Testing).

In addition to the available panel tests, several labs offer genetic testing for individual genes that are included in some of the panels, including MTFHR, CYP450 genes, and OPRM1 (see Table 2).

Table 2: Genes Included in Genetic Panels for Pain Management

Gene Commercially Available Test Panels
  Proove Narcotic Risk (Proove Biosciences) Proove Pain Perception (Proove Biosciences) GeneSightRx Analgesic (AssureRx Health) Pain Medication DNA Insight (Pathway Genomics) Millennium PGT (Pain Management (Millennium Health)
SLC6A4 (5-HTT; serotonin transporter) X        
5HT2C (serotonin receptor)          
5HT2A (serotonin receptor) X        
DRD1 (dopamine receptor) X X      
DRD2 (dopamine receptor) X X      
DRD4 (dopamine receptor) X      
DAT1 (dopamine transporter) X        
DA beta-hydroxylase X X      
COMT (catechol O-methyltransferase) X X     X
MTHFR X     X X
GABA X        
OPRK1 (k-opioid receptor) X X      
OPRM1 (m-opioid receptor) X   X X X
VKORC1         X
UGT2B15         X
CYP genes          
CYP2D6     X X X
CYP2C19     X X X
CYP3A4     X   X
CYP1A2     X    
CYP2C9     X X X
CYP2B6       X X
CYP3A5         X

CNS: central nervous system; CYP: cytochrome; GABA: y-aminobutyric acid; TMJ temporomandibular joint; UG: uridine diphosphate glycosyltransferase; VNTR: varying number of tandem repeats.

Commercially Available Genetic Tests for Pain Management

Several test labs market panels of tests or individual tests designed to address one or more aspects of pain management, including but not limited to drug selection, drug dosing, or prediction of AEs. Specific polymorphisms included in the panels are shown in Table 2.

  • GeneSight Analgesic (Assurex Health, Mason, OH) is a genetic panel test that is intended to analyze “how patients’ genes can affect their metabolism and possible response to FDA [U.S. Food and Drug Administration]-approved opioids, NSAIDs and muscle relaxants commonly used to treat chronic pain.” Results are provided with a color-coded report based on efficacy and tolerability, which displays which medications should be used as directed, used with caution, or used with increased caution and more frequent monitoring. The company’s website does not specify the testing methods. Publications describing other tests provided by the company specify that testing is conducted via SNP sequencing performed via multiplex polymerase chain reaction.
  • Proove Biosciences (Irvine, CA) offers several genetic panelsthat address pain control. The Proove® Opioid Risk Panel is a panel of 12 genes that is intended to predict opioid abuse and failure of opioid therapy. Genetic testing results are provided with along with an overall 2 “Dependence Risk Index.” The company also marketsthe Proove® Pain Perception panel, which is a panel test for SNPs in several genes related to pain perception, including COMT and at least 3 other genes. Results are provided with a report which stratifies patients’ pain sensitivity based on COMT haplotype. Genetic testing for these panelsis conducted by sequencing of target regions with reverse-transcription polymerase chain reaction.
  • Pain Medication DNA Insight™ (Pathway Genomics, San Diego, CA) is a panel test intended to identify genetic variants that affect how an individual will respond to the analgesic effects of certain types of pain medications. The result report includes the genotype/SNP for each gene included, along with a description of the toxicity risk, dose required, medication efficacy, or plasma concentration based on genotype results for a range of medications used for pain management, primarily opioids. The testing method is notspecified on the company’s website.
  • Millennium PGT (Pain Management) (Millennium Health, San Diego, CA) is a genetic panel test intended to help physicians select pain medication. The panel includes analysis of 11 genes related to pain management; results are provided with a proprietary “Millennium Analysis of Patient Phenotype” report that provides decision support for medications that may be affected by the patient’s genotype.

Other laboratories, including CompanionDx (Houston, TX), and AIBioTech (Richmond, VA), which markets the PersonaGene Genetic Panel, offer panels of CYP450 genes. Panels that are restricted to CYP450 genes are beyond the scope of this policy and are discussed in Policy No. 2.04.38 (Cytochrome p450 Testing).

In addition to the available panel tests, several labs offer genetic testing for individual genes that are included in some of the panels, s, including MTFHR, CYP450 genes, and OPRM1 (see Table 2).

Table 2: Genes Included in Genetic Panels for Pain Management

Gene Commercially Available Test Panels
  Proove Narcotic Risk (Proove Biosciences) Proove Pain Perception (Proove Biosciences) GeneSightRx Analgesic (AssureRx Health) Pain Medication DNA Insight (Pathway Genomics) Millennium PGT (Pain Management (Millennium Health)
SLC6A4 (5-HTT; serotonin transporter) X        
5HT2C (serotonin receptor)          
5HT2A (serotonin receptor) X        
DRD1 (dopamine receptor) X X      
DRD2 (dopamine receptor) X X      
DRD4 (dopamine receptor) X      
DAT1 (dopamine transporter) X        
DA beta-hydroxylase X X      
COMT (catechol O-methyltransferase) X X     X
MTHFR X     X X
GABA X        
OPRK1 (k-opioid receptor) X X      
OPRM1 (m-opioid receptor) X   X X X
VKORC1         X
UGT2B15         X
CYP genes          
CYP2D6     X X X
CYP2C19     X X X
CYP3A4     X   X
CYP1A2     X    
CYP2C9     X X X
CYP2B6       X X
CYP3A5         X

Regulatory Status

No FDA-approved genetic tests for pain management were identified. The Proove Narcotic Risk and Pain Perception panel, the GeneSight Analgesic panel, the Pathway Genomics Pain Medication DNA Insight panel, and the Millennium PGT (Pain Management) panel are laboratory-developed tests that are not subject to FDA approval. Clinical laboratories may develop and validate testsin-house (“home-brew”) and market them as a laboratory service; such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act.

Policy/Criteria

Genetic testing for pain management is considered investigational for all indications.

Members must consult their applicable benefit plans or contact a Member Services representative for specific coverage information.

Billing and Coding

Commercially available genetic tests for pain management consist of panels of single nucleotide polymorphisms(SNPs) or (less commonly) individual SNP testing. SNPsthat have been implicated in pain management include the following (see also Table 1):

  • 5HT2C (serotonin receptor gene)
  • 5HT2A (serotonin receptor gene)
  • SLC6A4 (serotonin transporter gene)
  • DRD1 (dopamine receptor gene)
  • DRD2 (dopamine receptor gene)
  • DRD4 (dopamine receptor gene)
  • DAT1 or SLC6A3 (dopamine transporter gene)
  • DBH (dopamine beta-hydroxylase gene)
  • COMT (catechol O-methyltransferase gene)
  • MTHFR (methylenetetrahydrofolate reductase gene)
  • Y-aminobutyric acid (GABA) A receptor gene
  • OPRM1 (µ-opioid receptor gene)
  • OPRK1 (K-opioid receptor gene)
  • UGT2B15 (uridine diphosphate glycosyltransferase 2 family, member 15)
  • Cytochrome p450 genes: CYP2D6, CYP2C19, CYP2C9, CYP3A4, CYP2B6, CYP1A2

This policy does not address testing for congenital insensitivity to pain.

The following tests have been codified in CPT:
There is specific CPT coding for this testing: 81225: CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *4, *8, *17)

81226: CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *4, *5, *6, *9, *10, *17, *19, *29, *35, *41, *1XN, *2XN, *4XN) 81227: CYP2C9 (cytochrome P450, family 2,subfamily C, polypeptide 9) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *5, *6)

81291: MTHFR (5, 10-methylenetetrahydrofolate reductase) (eg, hereditary hypercoagulability) gene analysis, common variants(eg, 677T, 1298C)

Code 81401 includes CYP3A4 testing:
81401: Molecular pathology procedure, Level 2 (eg, 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat) includes –

CYP3A4 (cytochrome P450, family 3, subfamily A, polypeptide 4) (eg, drug metabolism), common variants (eg,*2, *3, *4, *5, *6)

There is no specific CPT code for pain management testing panels. If there are CPT codes for the component tests in the panel and there is no algorithmic analysis used, the individual CPT codes may be reported. The unlisted molecular pathology code 81479 would be reported once for the balance of the panel.

SUPPLEMENTAL INFORMATION

Practice Guidelines and Position Statements

Clinical Pharmacogenetics Implementation Consortium
In 2012, the Clinical Pharmacogenetics Implementation Consortium issued guidelines a the management of codeine therapy in the context of CYP2D6 genotype, which were updated in 2014 to reflect U.S. Food and Drug Administration (FDA) labeling about codeine in children status post tonsillectomy with or without adenoidectomy and to include other opioids metabolized by CYP2D6.54,55 These guidelines did not specifically recommend CYP2D6 genotyping in particular patients, although they did provide the following codeine therapy recommendations based on CYP2D6 phenotype (see Table 8).

Table 8. CPIC Guideline for Codeine Therapy Based on CYP2D6 Phenotype (Adapted from Crews et al55)

CYP2D6 Phenotype Implications for Codeine Metabolism Recommendations for Codeine Therapy Classification of Recommendations for Codeine Therapy Considerations for Alternative Opiods
Ultrarapid metabolizer Increased formation of morphine after codeine administration, leading to higher risk of toxicity Avoid codeine use due to potential for toxicity Strong Alternatives not affected by this CYP2D6 phenotype include morphine and nonopioid analgesics. Tramadol and, to lesser extent, hydrocodone and oxycodone not good alternatives because their metabolism is affected by CYP2D6 activity
Extensive metabolizer Normal morphine formation Use labelrecommended age or weight-specific dosing Strong  
Intermediate metabolizer Reduced morphine formation Use labelrecommended age or weight-specific dosing. If no response, consider alternative analgesics (eg, morphine or a nonopioid). Moderate Monitor tramadol use for response
Poor metabolizer Poor metabolizer Avoid codeine use due to lack of efficacy Strong Alternatives not affected by this CYP2D6 phenotype include morphine and nonopioid analgesics. Tramadol and, to a lesser extent, hydrocodone and oxycodone not good alternatives because their metabolism is affected by CYP2D6 activity; these agents should be avoided.

American Academy of Neurology
In 2014, the American Academy of Neurology published a position paper on the use of opioids for chronic noncancer pain.56 Regarding pharmacogenetic testing, the guidelines stated that genotyping to determine whether response to opioid therapy can or should be more individualized is an emerging issue that will “require critical original research to determine effectiveness and appropriateness of use.”

  1. Institute of Medicine, Committee on Advancing Pain Research Care and Education. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington (DC): National Academies Press; 2011.
  2. GeneSight. “GeneSight Analgesic”. http://genesight.com/clinicians/genesight-tests/analgesic/. Accessed October 13, 2015.
  3. Biosciences P. Patient FAQ. 2014; https://proove.com/?page_id=1125. Accessed December 15, 2014.
  4. Biosciences P. Proove Opioid Response. 2015; https://proove.com/proove-opioid-response/. Accessed October 13, 2015.
  5. Biosciences P. Proove Non Opioid Response. 2015; https://proove.com/proove-non-opioid-response/. Accessed October 13, 2015.
  6. Carma Nabavi PG. Personal Communication. 2014.
  7. Labs MT. Pain Management Panel. http://moleculartestinglabs.com/pain-drug-interaction-panel-clinician. Accessed October 13, 2015.
  8. Genelex. Clinically Actionable Pharmacogenetic Tests. n.d.; http://genelex.com/pharmacogenetic-tests/. Accessed October 14, 2015.
  9. Klepstad P, Fladvad T, Skorpen F, et al. Influence from genetic variability on opioid use for cancer pain: a European genetic association study of 2294 cancer pain patients. Pain. May 2011;152(5):1139-1145. PMID 21398039
  10. Scarpi E, Calistri D, Klepstad P, et al. Clinical and genetic factors related to cancer-induced bone pain and bone pain relief. Oncologist. Dec 2014;19(12):1276-1283. PMID 25342315
  11. Lotsch J, von Hentig N, Freynhagen R, et al. Cross-sectional analysis of the influence of currently known pharmacogenetic modulators on opioid therapy in outpatient pain centers. Pharmacogenet Genomics. Jun 2009;19 (6):429-436. PMID 19514130
  12. Blanco F, Muriel C, Labrador J, et al. Influence of UGT2B7, CYP3A4, and OPRM1 Gene Polymorphisms on Transdermal Buprenorphine Pain Control in Patients with Critical Lower Limb Ischemia Awaiting Revascularization. Pain Pract. Sep 2016;16(7):842-849. PMID 26407542
  13. Jannetto PJ, Bratanow NC. Utilization of pharmacogenomics and therapeutic drug monitoring for opioid pain management. Pharmacogenomics. Jul 2009;10(7):1157-1167. PMID 19604091
  14. Lassen D, Damkier P, Brosen K. The pharmacogenetics of tramadol. Clin Pharmacokinet. Aug 2015;54(8):825-836. PMID 25910878
  15. Kirchheiner J, Keulen JT, Bauer S, et al. Effects of the CYP2D6 gene duplication on the pharmacokinetics and pharmacodynamics of tramadol. J Clin Psychopharmacol. Feb 2008;28(1):78-83. PMID 18204346
  16. Wang G, Zhang H, He F, et al. Effect of the CYP2D6*10 C188T polymorphism on postoperative tramadol analgesia in a Chinese population. Eur J Clin Pharmacol. Nov 2006;62(11):927-931. PMID 16960721
  17. Kirchheiner J, Schmidt H, Tzvetkov M, et al. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J. Aug 2007;7(4):257-265. PMID 16819548
  18. Baber M, Chaudhry S, Kelly L, et al. The pharmacogenetics of codeine pain relief in the postpartum period. Pharmacogenomics J. Oct 2015;15(5):430-435. PMID 25752520
  19. Camorcia M, Capogna G, Stirparo S, et al. Effect of mu-opioid receptor A118G polymorphism on the ED50 of epidural sufentanil for labor analgesia. Int J Obstet Anesth. Jan 2012;21(1):40-44. PMID 22153130
  20. Chou WY, Yang LC, Lu HF, et al. Association of mu-opioid receptor gene polymorphism (A118G) with variations in morphine consumption for analgesia after total knee arthroplasty. Acta Anaesthesiol Scand. Aug 2006;50(7):787-792. PMID 16879459
  21. Fukuda K, Hayashida M, Ide S, et al. Association between OPRM1 gene polymorphisms and fentanyl sensitivity in patients undergoing painful cosmetic surgery. Pain. Dec 15 2009;147(1-3):194-201. PMID 19783098
  22. Ginosar Y, Birnbach DJ, Shirov TT, et al. Duration of analgesia and pruritus following intrathecal fentanyl for labour analgesia: no significant effect of A118G mu-opioid receptor polymorphism, but a marked effect of ethnically distinct hospital populations. Br J Anaesth. Sep 2013;111(3):433-444. PMID 23592691
  23. Ginosar Y, Davidson EM, Meroz Y, et al. Mu-opioid receptor (A118G) single-nucleotide polymorphism affects alfentanil, requirements for extracorporeal shock wave lithotripsy: a pharmacokinetic-pharmacodynamic study. Br J Anaesth. Sep 2009;103(3):420-427. PMID 19605407
  24. Hayashida M, Nagashima M, Satoh Y, et al. Analgesic requirements after major abdominal surgery are associated with OPRM1 gene polymorphism genotype and haplotype. Pharmacogenomics. Nov 2008;9(11):1605-1616. PMID 19018716
  25. Kim KM, Kim HS, Lim SH, et al. Effects of genetic polymorphisms of OPRM1, ABCB1, CYP3A4/5 on postoperative fentanyl consumption in Korean gynecologic patients. Int J Clin Pharmacol Ther. May 2013;51(5):383-392. PMID 23557865
  26. Kolesnikov Y, Gabovits B, Levin A, et al. Combined catechol-O-methyltransferase and mu-opioid receptor gene polymorphisms affect morphine postoperative analgesia and central side effects. Anesth Analg. Feb 2011;112(2):448-453. PMID 21127283
  27. Landau R, Kern C, Columb MO, et al. Genetic variability of the mu-opioid receptor influences intrathecal fentanyl analgesia requirements in laboring women. Pain. Sep 30 2008;139(1):5-14. PMID 18403122
  28. Zhang W, Chang YZ, Kan QC, et al. Association of human micro-opioid receptor gene polymorphism A118G with fentanyl analgesia consumption in Chinese gynaecological patients. Anaesthesia. Feb 2010;65(2):130-135. PMID 20003118
  29. Cajanus K, Kaunisto MA, Tallgren M, et al. How much oxycodone is needed for adequate analgesia after breast cancer surgery: effect of the OPRM1 118A>G polymorphism. J Pain. Dec 2014;15(12):1248-1256. PMID 25239082
  30. Liu J, Hu D, Jiang Y, et al. Association between single nucleotide polymorphisms in the OPRM1 gene and intraoperative remifentanil consumption in northern Chinese women. Pharmacology. 2014;94(5-6):273-279. PMID 25500932
  31. Xu GH, Gao M, Sheng QY, et al. Opioid receptor A118G polymorphism does not affect the consumption of sufentanil and ropivacaine by patient-controlled epidural analgesia after cesarean section. Ther Drug Monit. Feb 2015;37(1):53-PMID 24977380
  32. Bialecka M, Jurewicz A, Machoy-Mokrzynska A, et al. Effect of interleukin 6 -174G>C gene polymorphism on opioid requirements after total hip replacement. J Anesth. Aug 2016;30(4):562-567. PMID 27048515
  33. Zwisler ST, Enggaard TP, Mikkelsen S, et al. Impact of the CYP2D6 genotype on post-operative intravenous oxycodone analgesia. Acta Anaesthesiol Scand. Feb 2010;54(2):232-240. PMID 19719813
  34. Liao Q, Chen DJ, Zhang F, et al. Effect of CYP3A4*18B polymorphisms and interactions with OPRM1 A118G on postoperative fentanyl requirements in patients undergoing radical gastrectomy. Mol Med Rep. Mar 2013;7(3):901-908. PMID 23313934
  35. Zhang W, Yuan JJ, Kan QC, et al. Influence of CYP3A5*3 polymorphism and interaction between CYP3A5*3 and CYP3A4*1G polymorphisms on post-operative fentanyl analgesia in Chinese patients undergoing gynaecological surgery. Eur J Anaesthesiol. Apr 2011;28(4):245-250. PMID 21513075
  36. Madadi P, Ross CJ, Hayden MR, et al. Pharmacogenetics of neonatal opioid toxicity following maternal use of codeine during breastfeeding: a case-control study. Clin Pharmacol Ther. Jan 2009;85(1):31-35. PMID 18719619
  37. Aoki J, Hayashida M, Tagami M, et al. Association between 5-hydroxytryptamine 2A receptor gene polymorphism and postoperative analgesic requirements after major abdominal surgery. Neurosci Lett. Jul 19 2010;479(1):40-43. PMID 20478362
  38. Aoki Y, Nishizawa D, Kasai S, et al. Association between the variable number of tandem repeat polymorphism in the third exon of the dopamine D4 receptor gene and sensitivity to analgesics and pain in patients undergoing painful cosmetic surgery. Neurosci Lett. May 10 2013;542:1-4. PMID 23458670
  39. Jensen KB, Lonsdorf TB, Schalling M, et al. Increased sensitivity to thermal pain following a single opiate dose is influenced by the COMT val(158)met polymorphism. PLoS One. 2009;4(6):e6016. PMID 19547755
  40. Rakvag TT, Klepstad P, Baar C, et al. The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients. Pain. Jul 2005;116(1-2):73-78. PMID 15927391
  41. Kim H, Lee H, Rowan J, et al. Genetic polymorphisms in monoamine neurotransmitter systems show only weak association with acute post-surgical pain in humans. Mol Pain. 2006;2:24. PMID 16848906
  42. Kosek E, Jensen KB, Lonsdorf TB, et al. Genetic variation in the serotonin transporter gene (5-HTTLPR, rs25531) influences the analgesic response to the short acting opioid Remifentanil in humans. Mol Pain. 2009;5:37. PMID 19570226
  43. Prows CA, Zhang X, Huth MM, et al. Codeine-related adverse drug reactions in children following tonsillectomy: a prospective study. Laryngoscope. May 2014;124(5):1242-1250. PMID 24122716
  44. Candiotti KA, Birnbach DJ, Lubarsky DA, et al. The impact of pharmacogenomics on postoperative nausea and vomiting: do CYP2D6 allele copy number and polymorphisms affect the success or failure of ondansetron prophylaxis? Anesthesiology. Mar 2005;102(3):543-549. PMID 15731591
  45. Zhang W, Yuan JJ, Kan QC, et al. Study of the OPRM1 A118G genetic polymorphism associated with postoperative nausea and vomiting induced by fentanyl intravenous analgesia. Minerva Anestesiol. Jan 2011;77(1):33-39. PMID 21150856
  46. Tsai FF, Fan SZ, Yang YM, et al. Human opioid mu-receptor A118G polymorphism may protect against central pruritus by epidural morphine for post-cesarean analgesia. Acta Anaesthesiol Scand. Nov 2010;54(10):1265-1269. PMID 21039348
  47. Haerian BS, Haerian MS. OPRM1 rs1799971 polymorphism and opioid dependence: evidence from a meta-analysis. Pharmacogenomics. May 2013;14(7):813-824. PMID 23651028
  48. Coller JK, Beardsley J, Bignold J, et al. Lack of association between the A118G polymorphism of the mu opioid receptor gene (OPRM1) and opioid dependence: A meta-analysis. Pharmgenomics Pers Med. 2009;2:9-19. PMID 23226031
  49. Glatt SJ, Bousman C, Wang RS, et al. Evaluation of OPRM1 variants in heroin dependence by family-based association testing and meta-analysis. Drug Alcohol Depend. Oct 8 2007;90(2-3):159-165. PMID 17416470
  50. Arias A, Feinn R, Kranzler HR. Association of an Asn40Asp (A118G) polymorphism in the mu-opioid receptor gene with substance dependence: a meta-analysis. Drug Alcohol Depend. Jul 27 2006;83(3):262-268. PMID 16387451
  51. Patriquin MA, Bauer IE, Soares JC, et al. Addiction pharmacogenetics: a systematic review of the genetic variation of the dopaminergic system. Psychiatr Genet. Oct 2015;25(5):181-193. PMID 26146874
  52. Gammal RS, Crews KR, Haidar CE, et al. Pharmacogenetics for safe codeine use in sickle cell disease. Pediatrics. Jul 2016;138(1). PMID 27335380
  53. Senagore AJ, Champagne BJ, Dosokey E, et al. Pharmacogenetics-guided analgesics in major abdominal surgery: Further benefits within an enhanced recovery protocol. Am J Surg. Mar 2017;213(3):467-472. PMID 27955884
  54. Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther. Feb 2012;91(2):321-326. PMID 22205192
  55. Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin Pharmacol Ther. Apr 2014;95(4):376-382. PMID 24458010
  56. Franklin GM. Opioids for chronic noncancer pain: a position paper of the American Academy of Neurology. Neurology. Sep 30 2014;83(14):1277-1284. PMID 25267983