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.
Genes related to these clinical scenarios include, 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 panels that 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 markets the 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 panels is 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 not specified 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 Companion Dx (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).
I
n 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) | GeneSight Rx
Analgesic
(Assure Rx
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 panels that 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 markets the 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 panels is 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 not specified 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 Companion Dx (Houston, TX), and AI Bio Tech (Richmond, VA), which markets the Persona Gene 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) | GeneSight Rx
Analgesic
(Assure Rx
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 tests in-house (home-brew) and market them as a laboratory service; such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act.