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.
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:
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.
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.
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 |
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.
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.
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):
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.”