Background

Pain

The Institute of Medicine reported in 2011 that common chronic pain conditions affect at least 116 million adults in the U. S.^1, Chronic pain may be related to cancer, or be what is termed chronic noncancer pain, which may be secondary to a wide range of conditions, such as migraines, low back pain, or fibromyalgia. Multiple therapeutic options exist to manage pain, including pharmacotherapies, behavioral modifications, and physical and occupational therapy, and complementary/alternative therapies. Nonetheless, the Institute of Medicine has reported that many individuals receive inadequate pain prevention, assessment, and treatment. Given that pain is an individual and subjective experience, assessing and predicting response to pain interventions, including pain medications, is challenging.

Management

A variety of medication classes are available to manage pain: nonopioid analgesics, including acetaminophen and nonsteroidal anti-inflammatory drugs, opioid analgesics, which target central nervous system pain perception, and classes of adjuvants, including antiepileptic drugs (e.g., gabapentin, pregabalin), antidepressants (e.g., tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors), and topical analgesics. The management of chronic pain has been driven, in part, by the World Health Organization’s analgesic ladder for pain management, which was developed to manage cancer-related pain but has been applied to other forms of pain. The ladder outlines a stepped approach to pain management, beginning with nonopioid analgesia and proceeding to a weak opioid (e.g., codeine), with or without an adjuvant for persisting pain, and subsequently to a strong opioid (e.g., fentanyl, morphine), with or without an adjuvant for persisting or worsening pain. Various opioids are available in short- and long-acting preparations and administered through different routes, including oral, intramuscular, subcutaneous, sublingual, and transdermal.

Pharmacologic Treatment

For acute pain management, particularly postoperative pain, systemic opioids and nonopioid analgesics remain a mainstay of therapy. However, there has been growing interest in using an alternative, nonsystemic treatments in addition to or as an alternative to systemic opioids. These options include neuraxial anesthesia, including intraoperative epidural or intrathecal opioid injection, which can provide pain relief for up to 24 hours postoperatively, and postoperative indwelling epidural anesthesia with opioids and local anesthetics, which may be controlled with a patient-controlled anesthesia pump. Postoperative peripheral nerve blocks may also be used.

While available pain management therapies are effective for many patients, there is a high degree of heterogeneity in pain response, particularly for chronic pain. In addition, many opioids are associated with a significant risk of adverse events, ranging from mild (e.g., constipation) to severe (e.g., respiratory depression), and are associated with risk of dependence, addiction, and abuse. Limitations in currently available pain management techniques have led to an interest in the use of pharmacogenetics to improve the targeting of therapies and prediction and avoidance of adverse events.

Genetics of Pain Management

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. Currently available genetic tests relevant to pain management assess single-nucleotide variants in single genes potentially relevant to pharmacokinetic or pharmacodynamic processes.

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 proposed for use in the management of pain. Genes identified as being relevant to pain management are summarized in Table 1.

Table 1. Genes Relevant to Pain Management

Gene	Locus	Gene Product Function
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
SLC6A4 (serotonin transporter gene)	17q11.2	Clears serotonin metabolites from synaptic spaces in the CNS
DRD1 (dopamine receptor gene)	5q35.2	G-protein-coupled receptors that have dopamine as their ligands
DRD2 (dopamine receptor gene)	11q23.2
DRD4 (dopamine receptor gene)	11p15.5
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-methyl-transferase gene)	22q11.21	Responsible for enzymatic metabolism of catecholamine neurotransmitters dopamine, epinephrine, and norepinephrine
MTHFR (methylenetetrahydrofolate reductase gene)	1p36.22	Converts folic acid to methylfolate, a precursor to norepinephrine, dopamine, and serotonin neurotransmitters
GABA A receptor gene	5q34	Ligand-gated chloride channel that responds to GABA, a major inhibitory neurotransmitter
OPRM1(μ-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
OPRK1 (κ-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		Hepatic enzymes responsible for the metabolism of a wide variety of medications, including analgesics
CYP2D6	22q13.2
CYP2C19	10q23.33
CYP2C9	10q23.33
CYP3A4	7q22.1
CYP2B6	19q13.2
CYP1A2	15q24.1

CNS: central nervous system; GABA: g-aminobutyric acid; UDP: uridine diphosphate glycosyltransferase.

Commercially Available Genetic Tests for Pain Management

Several test labs market panel 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 adverse events. Specific variants included in the panels are shown in Table 2.

GeneSight Analgesic (Assurex Health) is a genetic panel test 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."^2, Results are provided with a color-coded report based on efficacy and tolerability, which displays those medications that should be used as directed, used with caution, or used with increased caution and more frequent monitoring. The company’s website does not specify testing methods. Publications describing other tests provided by the company specify that testing is conducted via single-nucleotide variants sequencing performed via a multiplex polymerase chain reaction.

Pain Medication DNA Insight (Pathway Genomics) 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 results report includes the genotype/single-nucleotide variants for each gene included, along with a description of the toxicity risk, the dose required, medication efficacy, or plasma concentration based on genotype results for a range of medications used for pain management, primarily opioids.^3, The testing method is not specified on the company’s website.

Millennium PGT^SM (Pain Management) (Millennium Health) is a genetic panel test intended to help physicians select pain medication. The panel analyzes 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.

Molecular Testing Labs™ Pain Management Panel (Molecular Testing Labs) is a panel designed to evaluate the metabolism of pain relievers.^4, The manufacturer’s website states the test evaluates “a number of relevant genes coding for the metabolism of a wide variety of pain relief drugs,” but the specific genes analyzed are not readily described.

Genelex offers several pharmacogenomic panels, one of which (the YouScript® Analgesic Panel) focuses on genes relevant to pain management.^5,

AltheaDx offers IDgenetix pain tests that analyze the genes and genetic variants involved in the metabolism of opioids, nonsteroidal anti-inflammatory drugs, and other pain drugs as well as variations in pharmacodynamic genes, such as the μ-opioid receptor gene (OPRM1).

Other laboratories, including CompanionDx, ARUP Laboratories, and AIBioTech, which markets the PersonaGene Genetic Panel, offer panels of CYP450 genes. Panels that are restricted to CYP450 genes are discussed in Cytochrome p450 Genotyping' (Policy #033 in the Medicine Section)..

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

Table 2. Genes Included in Commercially Available Genetic Panels for Pain Management

Gene	Potential Role in Pain Management
COMT	Val158Met variant associated with alterations in emotional processing and executive function. Other variants have been associated with pain sensitivity
MTHFR	Multiple variants identified, which are associated with a wide variety of clinical disorders
GABA	1519T>C GABA A 6 gene variant associated with methamphetamine dependence
OPRK1 (κ-opioid receptor)	Variants associated with the risk for opioid addiction
OPRM1 (μ-opioid receptor)	A118Gvariant (rs1799971) associated with reduced pain sensitivity and opioid requirements
VKORC1
UGT2B15	Tamoxifen, diclofenac, naloxone, carbamazepine, and benzodiazepines inhibit UGT2B7 potentially leading to opioid hyperalgesia
CYP genes	Hepatic enzymes responsible for the metabolism of a wide variety of medications, including analgesics
CYP2D6	CYP2D6 is primary metabolizer for multiple oral opioids; metabolizer phenotype associated with variability in opioid effects
CYP2C19
CYP3A4	Involved in metabolism of up to 60% of clinically used drugs
CYP1A2
CYP2C9
CYP2B6
CYP3A5

CYP: cytochrome; GABA: g-aminobutyric acid.

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. The GeneSight Analgesic panel, the Pathway Genomics Pain Medication DNA Insight panel, the Millennium PGT (Pain Management) panel, and YouScript Analgesic panel are available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

No genetic tests approved by the Food and Drug Administration for pain management were identified.

Related Policies

• Cytochrome P450 Genotype-Guided Treatment Strategy (Policy #033 in the Medicine Section)
• Genetic Testing for Diagnosis and Management of Mental Health Conditions (Policy #100 in the Pathology Section)

Commercially available genetic tests for pain management consist of panels of single-nucleotide variants (SNVs) or (less commonly) individual SNV testing. SNVs 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)
• γ-aminobutyric acid (GABA) A receptor gene
• OPRM1(μ-opioid receptor gene)
• OPRK1 (κ-opioid receptor gene)
• UGT2B15 (uridine diphosphate glycosyltransferase 2 family, member 15)
• Cytochrome p450 genes: CYP2D6, CYP2C19, CYP2C9, CYP3A4, CYP2B6, CYP1A2.

The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical policy updates starting in 2017 (see Table PG1). The Society’s nomenclature is recommended by the Human Variome Project, the Human Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table PG2 shows the recommended standard terminology¾“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”¾to describe variants identified that cause Mendelian disorders.

Table PG1. Nomenclature to Report on Variants Found in DNA

Previous	Updated	Definition
Mutation	Disease-associated variant	Disease-associated change in the DNA sequence
	Variant	Change in the DNA sequence
	Familial variant	Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives

Table PG2. ACMG-AMP Standards and Guidelines for Variant Classification

Variant Classification	Definition
Pathogenic	Disease-causing change in the DNA sequence
Likely pathogenic	Likely disease-causing change in the DNA sequence
Variant of uncertain significance	Change in DNA sequence with uncertain effects on disease
Likely benign	Likely benign change in the DNA sequence
Benign	Benign change in the DNA sequence

ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.

Genetic Counseling

Experts recommend formal genetic counseling for patients who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and understanding risk factors can be difficult for some patients; genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing; further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Medicare Coverage:
There is no National Coverage Determination (NCD) for Pharmacogenetic Testing for Pain Management. In the absence of an NCD, coverage decisions are left to the discretion of Local Medicare Carriers. Novitas Solutions, Inc, the Local Medicare Carrier for jurisdiction JL, has not issued a determination for this service. Therefore, Medicare Advantage Products will follow the Horizon BCBSNJ Medical Policy for Pharmacogenetic Testing for Pain Management.

[RATIONALE: This policy was created in 2015 and has been updated regularly with searches of the MEDLINE database. The most recent literature update was performed through October 15, 2019.

The primary goal of pharmacogenomics testing and personalized medicine is to achieve better clinical outcomes compared with the standard of care. Drug response varies greatly between individuals, and genetic factors are known to play a role. However, in most cases, the genetic variation only explains a modest portion of the variance in the individual response because clinical outcomes are also affected by a wide variety of factors including alternate pathways of metabolism and patient- and disease-related factors that may affect absorption, distribution, and elimination of the drug. Therefore, assessment of clinical utility cannot be made by a chain of evidence from clinical validity data alone. In such cases, evidence evaluation requires studies that directly demonstrate that the pharmacogenomic test alters clinical outcomes; it is not sufficient to demonstrate that the test predicts a disorder or a phenotype.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function - including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Testing-guided treatment for Managing Acute and Chronic Pain

Clinical Context and Therapy Purpose

The purpose of pharmacogenetic testing-guided treatment for the management of acute and chronic pain is to:

• Select appropriate pain medications or avoid the use of inappropriate pain medications
  • To identify individuals likely or unlikely 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.
• Optimize the dose selection or frequency by:
  • Identifying individuals who are likely to require higher or lower doses of a drug.

The following PICOs were used to select literature to inform this policy.

Patients

The relevant population of interest are patients with chronic and acute pain, including conditions such as cancer, migraines, low back pain, and fibromyalgia.

Interventions

Testing for individual genes is available for most, or all, or the genes listed in Table 2, as well as for a wider range of genes. Because of a large number of potential genes, panel testing is available from a number of genetic companies. These panels include a variable number of genes that broadly test potential response to four relevant medication classes: opioids, nonsteroidal anti-inflammatory drugs, muscle relaxants, and opioid dependency.

Comparators

The following practice is currently being used to treat chronic and acute pain: standard pain management without genetic testing. Patients with chronic and acute pain are likely to be managed by a wide variety of specialties such as chiropractors, primary care physicians, physiatrists (rehabilitation physicians), neurologists, rheumatologists, orthopedic surgeons, oncologists, pain management specialists, physical therapists, and acupuncturists. Most patients are likely to be tested in an outpatient setting. Referral for genetic counseling is important for the explanation of the genetic disease, heritability, genetic risk, test performance, and possible outcomes.

Outcomes

Specific outcomes in each of these categories are listed in Table 3.

Table 3. Outcomes of Interest for Individuals with Chronic or Acute Pain

Outcomes	Details
Morbid events	Opioid addiction, adverse events
Health status measures	Pain relief, functional status
Medication use	No. of unsuccessful medication trials, no. of medications needed, dose of medication, dose frequency

The potential beneficial outcomes of primary interest would be improvements in pain, functioning, and quality of life.

The potential harmful outcomes are those resulting from a false test result. False-positive or -negative test results can lead to the initiation of unnecessary treatment and adverse events from that treatment or under-treatment.

Outcomes in the first three months are relevant because the interest is in whether a genetic testing-guided treatment strategy for managing acute and chronic pain results in better pain control, reduces adverse events, or avoids treatment failure. Genetic testing may be used for pain management planning before a procedure associated with acute pain or to evaluate an individual with difficulty managing chronic pain.

Study Selection Criteria

For the evaluation of clinical validity of pharmacogenetic tests for pain management, methodologically credible studies were selected using the following principles:

For the evaluation of the clinical validity of the tests, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)
• Included a suitable reference standard
• Patient/sample clinical characteristics were described
• Patient/sample selection criteria were described
• Included a validation cohort separate from the development cohort.

Multiple observational studies of genetic testing for pain management have been published that include genome-wide association studies, which correlate specific genetic variants with pain medication requirements or measures of pain control, and case-control and cohort studies, which report differences in pain medication requirements or measures of pain control for different genotypes with mixed findings. Therefore, trials are important to validate such hypotheses. However, only one prospective cohort study using historical controls and one non-randomized cluster trial have assessed genotype-guided management of pain; they are summarized in Tables 4 and 5 and discussed next.

Senagore et al (2017) reported on the results of a prospective cohort study of 63 consecutive patients undergoing open or laparoscopic colorectal and major ventral hernia surgery.^6, The authors compared the findings with a historical cohort of 47 patients who underwent similar surgeries but were managed with standard enhanced recovery protocol. Results showed that the overall benefit of analgesia score was statistically significantly lower in patients in whom the analgesia protocol was initiated based on results of genotype testing vs the historical control on postoperative day one and day five (all p<0.05). The need for narcotic-equivalent analgesics was also statistically significantly lower in the genotype tested group vs historical controls.

Smith et al (2019) reported a prospective non-blinded pragmatic trial of 375 patients whose pain treatment was guided by CYP2D6 inhibitors (both gene variants and drug inhibitors) at 4 primary care clinics or standard of care pain management at 3 clinics without assessment of CYP2D6 inhibitors.^7, Based on genotyping alone, 10% of the CYP2D6-guided group were considered intermediate or poor metabolizers (IM/PM). The percentage of patients who were considered IM or PM increased to 35% after drug interactions were considered. In the CYP2D6-guided IM/PM group, there was a more frequent change to a nonopioid therapy. The reduction in pain was statistically significant, though modest, compared to the standard of care group (see Table 5)

Table 4. Summary of Key Nonrandomized Trials

Study	Study Type	Country	Dates	Participants	Treatment1	Treatment2	Follow- Up
Senagore et al (2017)6,	Prospective cohort	U.S.	2015-2016	Patients undergoing open or laparoscopic colorectal and major ventral hernia surgery (n=110)	Pharmacogenetic testing-guideda standard enhanced recovery protocol (n=63)	Historical group managed with standard enhanced recovery protocol (n=47)	5 d
Smith et al (2019)7,	Non-randomized cluster trial	U.S.	2015-2017	Patients from 7 primary care clinics who had uncontrolled pain or for whom a change in medication was being considered, mean pain was 6.55 out of 10 (N=375)	Testing for CYP2D6 variants and assessment of CYP2D6 inhibitors to guide therapy (n=235)	Treatment based on standard of care. (n=135)	3 mo

^a NeuroIDgenetix pain panel analyzes 9 genes, including CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, ABCB1, COMT, and OPRM1.

Table 5. Summary of Key Nonrandomized Trials

Study
Senagore et al (2017)6,	OBASa	OBAS Pain Subscore	Postoperative Opioid Use,bmg
n	97	96	96
Pharmacogenetic	Day 1: 3.8 Day 5: 3.0	Day 1: 1.8 Day 5: 1.2	104.5 (122.1)
Control	Day 1: 5.4 Day 5: 4.5	Day 1: 2.3 Day 5: 2.0	222.1 (221.1)
p	0.01	0.04	0.018
Smith et al (2019)7,	Change in pain intensity mean (SD)
	IM/PM
Treatment based on CYPD26 inhibitors (n	-1.01 (1.59)
Standard of care (n=16)	-0.40 (1.20)
p	0.016

OBAS: Overall Benefit of Analgesia Score.

^a The primary outcome measure was OBAS, which assesses the combined impact on analgesia, patient satisfaction, and the impact of drug-associated side effects. The lower the score, the better is overall analgesia.

^b Measured in narcotic equivalent analgesics.

Table 6. Relevance Limitations

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Follow-Upe
Senagore et al (2017)6,		1. Not clearly defined. It is unclear if the intensity of the protocols was similar across the 2 groups	1. Not clearly defined	5. Clinical significant difference was not prespecified 6. Clinical significant difference not supported	1. Insufficient duration for benefit 2. Insufficient duration for harms
Smith et al (2019)7,		4. Intervention included both pharmacogenetic and drug inhibitors		4. Medications were assessed by the electronic health record and did not include possible changes in over-the-counter medications. 5. Clinically significant difference was not prespecified

The study limitations stated in this table are those notable in the current review; this is not a comprehensive limitations assessment.

^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.

^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.

^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.

^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.

^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms..

Study	Allocationa	Blindingb	Selective  Reportingc	Data  Completenessd	Powere	Statisticalf
Senagore et al (2017)6,	1. Participants not randomly allocated 2. Allocation not concealed 3. Allocation concealment unclear 4. Inadequate control for selection bias	1. Not blinded to treatment assignment 2. Not blinded outcome assessment 3. Outcome assessed by treating physician		1. High loss to follow-up or missing data; 13 (20%) of 63 patients excluded from analysis	1. Power calculations not reported 2. Power not calculated for primary outcome 3. Power not based on clinically important difference	3. Confidence intervals and/or p values not reported
Smith et al (2019)7,	1. Participants not randomly allocated 2. Allocation not concealed 3. Allocation concealment unclear 4. Inadequate control for selection bias	1. Not blinded to treatment assignment 2. Not blinded outcome assessment 3. Outcome assessed by treating physician

^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.

^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physicians.

^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.

^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).

^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important differences.

^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

For individuals who have a need for pharmacologic pain management who receive pharmacogenetic testing to target therapy, the evidence includes a prospective cohort study with historical controls that assessed genotype-guided management of postoperative pain and a pragmatic cluster trial that evaluated chronic pain control when treatment was guided by a combination of pharmacogenetic and drug inhibition of CYP2D6. The relevant outcomes are symptoms, health status measures, medication use, and treatment-related morbidity. The prospective cohort study reported on the use of genetic panel test results to guide the selection of analgesics in a postoperative setting and reported statistically significant improvement in total scores of a composite endpoint that measured analgesia, patient satisfaction, and the impact of drug-associated side effects vs historical controls. However, methodologic limitations precluded assessment of the effects on outcomes. The prospective cluster trial evaluated a combination of pharmacogenetic and drug inhibition of CYP2D6, finding a statistically significant but modest improvement in chronic pain control in the intermediate and poor metabolizers. The effect of pharmacogenetic testing alone cannot be determined from this trial. The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION

Practice Guidelines and Position Statements

American Academy of Neurology

The American Academy of Neurology (2014) published a position paper on the use of opioids for chronic noncancer pain.^8, Regarding pharmacogenetic testing, the guidelines stated that genotyping to determine whether the 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.”

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this policy are listed in Table 8.

Table 8. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT03534063	Implementing Genomics in Practice (IGNITE): CYP2D6 Genotype-Guided Pain Management in Patients Undergoing Arthroplasty Surgery	260	Mar 2020
NCT03498014	Comparison of Standard Opioid Prescription Versus Prescription Guided by Pharmacogenetic Analysis in Patients With Non-cancerous Chronic Pain.	80	Apr 2020
NCT03772535	Using Pharmacogenetics to Structure Individual Pain Management Protocols for Joint Replacement Patients	50	Dec 2020
NCT01140724	Predicting Perioperative Opioid Adverse Effects and Personalizing Analgesia in Children	1200	Apr 2021
Unpublished
NCT02081872a	Utility of PharmacoGenomics for Reducing Adverse Drug Effects	297,000	Jul 2017 (unknown)

NCT: national clinical trial.

^a Denotes industry-sponsored or cosponsored trial.]
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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Pharmacogenetic Testing for Pain Management
Pain Management, Pharmacogenetic Testing for
GeneSightRx Analgesic Panel
Proove Opioid Risk Panel
Proove Pain Perception Panel
Pain Medication DNA Insight Panel
Millennium PGT Panel
YouScript Analgesic Panel

References:
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 9, 2019.

3. Carma Nabavi PG. Personal Communication. 2014.

4. Labs MT. Pain Management Panel. http://moleculartestinglabs.com/pain-drug-interaction-panel-clinician. Accessed October 9, 2019.

5. Genelex. Clinically Actionable Pharmacogenetic Tests. n.d.; http://genelex.com/pharmacogenetic-tests/. Accessed October 9, 2019.

6. 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.

7. Smith DM, Weitzel KW, Elsey AR et al. CYP2D6-guided opioid therapy improves pain control in CYP2D6 intermediate and poor metabolizers: a pragmatic clinical trial. Genet. Med., 2019 Jan 24;21(8). PMID 30670877.

8. 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.

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

81225
81226
81227
81291
81401
81479
0070U
0071U
0072U
0073U
0074U
0075U
0076U
0078U