Code Description CPT

0078U Pain management (opioid-use disorder) genotyping panel, 16 common variants (ie, ABCB1, COMT, DAT1, DBH, DOR, DRD1, DRD2, DRD4, GABA, GAL, HTR2A, HTTLPR, MTHFR, MUOR, OPRK1, OPRM1), buccal swab or other germline tissue sample, algorithm reported as positive or negative risk of opioid-use disorder (new code effective 10/1/18)

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)

81479 Unlisted molecular pathology procedure

Pharmacogenetic Testing for Pain Management


When it comes to treating pain, there are a lot of different choices. These include things like over-the-counter remedies like acetaminophen and ibuprofen, medications that are rubbed onto the skin, and prescription drugs known as opioids. Antidepressants and antiseizure medications are also sometimes used to help with pain. Managing acute (sudden and intense) and chronic (long lasting) pain can be challenging.  Each person not only has a different response to pain, but they may also have a different response to pain medication. In short, what works for one person may not work for another. A person’s genetics may affect pain perception and how the body processes medications. Genetic tests have been developed to try to find out how a person might respond to drugs to treat pain. These genetic tests are investigational (unproven). There is not enough medical evidence in published studies to show whether these genetic tests will improve overall health results.

Note:   The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a service may be covered. 

Policy Coverage Criteria 

Service Investigational
Genetic testing for pain management

Genetic testing for pain management is considered investigational for all indications.
This policy does not address testing for congenital insensitivity to pain.
This policy is not intended to address testing that is limited to cytochrome P450 genotyping, which is addressed in a separate medical policy, (see Related Policies).
Commercially-available genetic tests for pain management consist 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)
* *-aminobutyric acid (GABA) A receptor gene
* OPRM1 (µ-opioid receptor gene)
* OPRK1 (*-opioid receptor gene)
* UGT2B15 (uridine diphosphate glycosyltransferase 2 family, member 15)
* Cytochrome p450 genes: CYP2D6, CYP2C19, CYP2C9, CYP3A4, CYP2B6, CYP1A2

 Evidence Review 


While multiple pharmacologic therapies are available for the management of acute and chronic pain, there is a lot of variability in the person’s response to pain, particularly in the management of chronic pain, and in the presence of adverse events (AEs). This has prompted interest in better targeting pain therapies through the use of pharmacogenetic testing of genes relevant to analgesic pharmacokinetics or pharmacodynamics. A number of panels of genetic tests for genes that have shown some association with the pharmacokinetics or pharmacodynamics of analgesic medications have been developed to aid in the management of pain.


Pain is a universal human experience and an important contributor to outpatient and inpatient medical visits. The Institute of Medicine (IOM) reported in 2011 that common chronic pain conditions affect at least 116 million adults in the United States.
 Chronic pain may be due to cancer or chronic noncancer conditions. These noncancer conditions may include 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 IOM 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.

Pain Management

A variety of medication classes are available to manage pain. These include non-opioid analgesics such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), and opioid analgesics which target central nervous system pain perception. Adjuvant medications such as antiepileptic drugs (eg, gabapentin, pregabalin), antidepressants (eg, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors), and topical analgesics have also been used. The management of chronic pain has been driven, in part, by the World Health Organization’s analgesic ladder for pain management, which was developed for the management of cancer-related pain but has been applied to the management of other forms of pain. The ladder outlines a stepped approach to pain management, beginning with non-opioid analgesia and proceeding to a weak opioid (eg, codeine), with or without an adjuvant for persisting pain. If these fail to control pain, the next step is 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 variety of routes, including oral, intramuscular, subcutaneous, sublingual, and transdermal.

Pharmacologic Treatment

For acute pain management, particularly postoperative pain, systemic opioids and non-opioid analgesics remain the mainstay of therapy. However, there has been growing interest in using alternative, nonsystemic treatments in addition to or instead of systemic opioids. These options include neuraxial anesthesia, a type of regional anesthesia including epidural or intrathecal opioid injection. This type of anesthesia may be managed by 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 great deal of variability in pain response, particularly in the management of chronic pain. In addition, many opioids have a significant risk of adverse events (AEs), ranging from mild (eg, constipation) to severe (eg, respiratory depression) and are associated with 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 in order to predict and avoid AEs.

Genetics of Pain Management

Genetic factors may influence many 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 look at single-nucleotide variants (SNVs) in single genes potentially related to pharmacokinetic or pharmacodynamic processes. 

Broadly speaking, genes related to these clinical scenarios include 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 identified as being relevant to pain management and that are included in currently available panels are summarized in Table 1.

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 variants 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 11 genes that is intended to predict opioid abuse and failure of opioid therapy. Genetic testing results are provided along with an overall “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.

In addition, Proove offers panels designed to predict good and poor responders to opioid therapies and non-opioid pain therapies. These are the Proove® Opioid Response