Pharmacogenetic Testing for Pain Management

POLICY NUMBER

A.2.04.131

DESCRIPTION

While multiple pharmacologic therapies are available for the management of acute and chronic pain, there is a high degree of heterogeneity in pain response, particularly in the management of chronic pain, and in adverse events. Testing for genetic variants that are relevant to pharmacokinetics or pharmacodynamics of analgesics may assist in selecting and dosing drugs affected by these genetic variants.

Pain

During 2021, an estimated 20.9% (51.6 million) of U.S. adults experienced chronic pain and 6.9% (17.1 million) had high-impact chronic pain (ie, chronic pain that limits daily activities). 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, 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.

Pharmacologic Treatment

A variety of medication classes are available to manage pain: nonopioid analgesics, including acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), opioid analgesics, which target central nervous system pain perception, and classes of adjuvants, including antiepileptic drugs (eg, gabapentin, pregabalin), antidepressants (eg, 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 stepwise approach to pain management, beginning with nonopioid analgesia and proceeding to a weak opioid (eg, codeine), with or without an adjuvant for persisting pain, and subsequently to a strong opioid (eg, 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, intravenous, intramuscular, subcutaneous, sublingual, and transdermal.

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 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 pharmacologic 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 (eg, constipation) to severe (eg, respiratory depression), and a risk of dependence, addiction, and abuse. Limitations in currently available pain management techniques have led to 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 (SNVs) 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 the table below.

Genes Relevant to Pain Management

CNS: central nervous system; CYP: cytochrome P450; GABA: g-aminobutyric acid; UDP: uridine diphosphate glycosyltransferase.

Opioid Use Disorder Risk

Opioid use disorder (OUD) is a chronic disorder in which individuals have a pattern of opioid misuse. Currently, the standard of care for OUD risk prediction includes structured clinician interviews. Pharmacogenetic testing has recently become commercially available in the United States to assess the risk of developing opioid use disorders in individuals with a need for pharmacologic management of acute pain.

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 (CLIA). The OmeCare OmePainMeds panel, the Millennium PGT (Pain Management) panel, and YouScript Analgesic panel are available under the auspices of the CLIA. Laboratories that offer laboratory-developed tests must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of these tests.

No genetic tests approved by the FDA for pain management were identified.

Of note, in February 2020, the FDA expressed "concerns with firms offering genetic tests making claims about how to use the genetic test results to manage medication treatment that are not supported by recommendations in the FDA-approved drug labeling or other scientific evidence." Due to these concerns, the FDA announced a collaboration between the FDA’s Center for Devices and Radiological Health and Center for Drug Evaluation and Research intended to provide the agency’s view of the state of the current science in pharmacogenetics. This collaborative effort includes a web resource that describes "some of the gene-drug interactions for which the FDA believes there is sufficient scientific evidence to support the described associations between certain genetic variants, or genetic variant-inferred phenotypes, and altered drug metabolism, and in certain cases, differential therapeutic effects, including differences in risks of adverse events."

In December 2023, AvertD™ (AutoGenomics, Inc.) received approval from the FDA for their premarket approval application (PMA) (PMA Number: P230032; Product Code: QZH). The device "is a prescription, qualitative genotyping test used to detect and identify 15 genetic polymorphisms in genomic DNA isolated from buccal samples collected from individuals 18 years of age and older. The test may be used as part of a clinical evaluation and risk assessment to identify patients who may be at elevated risk for developing opioid use disorder (OUD). The test is indicated for use only in patients prior to receiving a first prescription of oral opioids for 4-30 days for acute pain, such as in patients scheduled to undergo a planned surgical procedure and who consent to having the test performed." Of note, in October 2022, the FDA voted strongly against AvertD in an Advisory Committee Meeting. The Advisory Committee panel described mitigation strategies to address the risks of the device, including:

• "Presentation of the device results along a continuum rather than as a binary result.

• Strong and plain language that makes clear the test is not intended to be used alone but instead with other tools to evaluate risk.

• Clear labeling that opioid sparing techniques should be used in all patients regardless of the results of the test.

• Additional studies to better understand test performance in subpopulations that were not included in the clinical study population."

Related medical policies –

• Cytochrome P450 Genotype-Guided Treatment Strategy

• Genetic Testing for Diagnosis and Management of Mental Health Conditions

POLICY

Genetic testing for pain management is considered investigational for all indications (see Policy Guidelines section).

Genetic testing for acute pain management to assess the risk of developing opioid use disorder is considered investigational for all indications (see Policy Guidelines section).

POLICY EXCEPTIONS

None 

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

This policy does not address testing limited to cytochrome p450 genotyping, which is addressed in the  Cytochrome P450 Genotype-Guided Treatment Strategy medical policy. This policy also does not address testing for congenital insensitivity to pain.

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 the table in the policy Description):

• 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.

A commercially available genetic test (AvertD™, AutoGenomics, Inc.) to assess the risk of developing opioid use disorder consists of a panel that detects single nucleotide polymorphisms (SNPs) involved in the brain reward pathway. SNPs include the following:

• 5-HTR2A C>T (serotonin 2A receptor)

• COMT G>A (catechol-o-methyltransferase)

• DRD1 A>G (dopamine D1 receptor)

• DRD2 G>A (dopamine D2 receptor)

• DRD4 T>C (dopamine D4 receptor)

• DAT1 A>G (dopamine transporter)

• DBH C>T (dopamine beta hydroxylase)

• MTHFR C>T (methylene tetrahydrofolate reductase)

• OPRKI G>T (kappa Opioid Receptor)

• GABA C>A (gamma-Aminobutyric Acid [GABA])

• OPRM1 A>G (mu Opioid Receptor)

• MUOR G>A (mu Opioid Receptor)

• GAL T>C (galanin)

• DOR G>A (delta Opioid Receptor)

• ABCB1 C>T (ATP binding cassette transporter I [ABCB1]).

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting. 

POLICY HISTORY

04/09/2015: Approved by Medical Policy Advisory Committee.

08/04/2015: Code Reference section updated for ICD-10.

02/15/2016: Policy description updated regarding genetic tests for pain management. Policy statement unchanged. Policy guidelines updated regarding genetic counseling.

06/07/2016: Policy number A.2.04.131 added.

06/16/2017: Policy description updated regarding genes relevant to pain management and genetic tests for pain management. Policy statement unchanged. Policy Guidelines updated regarding standard terminology for variant classification.

06/26/2017: Code Reference section updated to revise code description for CPT code 81401.

12/21/2017: Code Reference section updated to add new 2018 CPT codes 81230 and 81231. Revised description for CPT code 81401 effective 01/01/2018.

01/25/2018: Code Reference section updated to add new 2018 CPT codes 0028U, 0029U, 0030U, 0031U, and 0032U.

10/01/2018: Code Reference section updated to add new CPT codes 0070U, 0071U, 0072U, 0073U, 0074U, 0075U, and 0076U.

01/09/2019: Policy description updated regarding genetic tests for pain management. Policy statement unchanged. Policy Guidelines updated regarding genetic counseling.

12/12/2019: Policy description updated regarding genes relevant to pain management. Policy statement unchanged. Policy Guidelines updated regarding cytochrome p450 genotyping. Code Reference section updated to remove deleted CPT code 0028U.

01/15/2021: Policy description updated regarding 2016 data and FDA concerns. Removed table regarding genes included in commercially available genetic panels for pain management. Policy statement unchanged. Policy Guidelines updated to remove genetics nomenclature and genetic counseling information.

12/16/2021: Code Reference section updated to add new CPT code 0290U, effective 01/01/2022.

01/27/2022: Policy description updated regarding tests. Policy statement unchanged.

09/13/2022: Code Reference section updated to add new CPT codes 0347U, 0348U, 0349U, and 0350U. Effective 10/01/2022.

05/01/2023: Policy description updated. Policy statement unchanged. Code Reference section updated to add CPT code 0078U.

12/18/2023: Policy description updated regarding chronic pain. Policy statement unchanged.

10/01/2024: Code Reference section updated to make note of deleted CPT code 0078U.

03/06/2025: Policy description updated regarding opioid use disorder risk and devices. Added policy statement that genetic testing for acute pain management to assess the risk of developing opioid use disorder is considered investigational for all indications (see Policy Guidelines section). Policy Guidelines updated regarding genetic tests used to assess the risk of developing opioid use disorder.

SOURCE(S)

Blue Cross and Blue Shield Association Policy # 2.04.131

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

Investigational Codes

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