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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.”

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