Chronic pain affects 20% of the world population. The chronic pain drugs market is currently valued at $62 billion, with opioids leading the revenue contribution at 27%. Opioid analgesics have been the more effective class of drugs for chronic pain patients.  Most chronic pain patients on opioid drugs experience one or more adverse reactions or side effects. While most drugs cause adverse reactions in patients, complications from opioids range from therapeutic failure to overdose and death. Many individuals who receive prescription opioids transition to synthetic or illicit drugs. In 2016, there were 42,249 deaths in the US related to opioid misuse. Thus, being able to characterize the factors that predict a patient’s response to an opioid analgesic- i.e. the associations between genetics and opioid response, will help better target prescriptions. One tool for such an approach is pharmacogenetic testing (PGx testing), or a genetic test that assesses a patient’s risk of an adverse reaction or likelihood of responding to a drug therapy. PGx test results can potentially inform drug selection and dosing.

Can physicians use genetic variability in opioid response to customize prescriptions for patients? If so, is PGx testing being used today?

Associations between genetics and opioid response

Researchers classify genetic variations associated with opioid therapy into (a) pharmacokinetics or metabolism of drugs, (b) pharmacodynamics or physiological effects of drugs, or (c) addiction risk. Variations in opioid drug metabolism or pharmacokinetics is by far the most well studied.  Many drugs and most opioids undergo metabolism with the help of cytochrome P450 (CYP) enzymes, before entering systemic circulation.  Of which, enzyme CYP2D6 plays a crucial role in the metabolism and conversion of codeine into morphine.  The genetic factors or polymorphisms that influence the activity or function of CYP2D6 can cause substantial variability in the metabolism opioids.
Patients fall into four different groups based on the functionality of CYP2D6 against codeine.  These four groups include:

(a) ultra-rapid metabolizers (UM) or patients who produce extreme amounts of morphine,
(b) extensive metabolizers or patients who produce normal amounts of morphine,
(c) intermediate metabolizers or patients who produce reduced amounts of morphine, and
(d) poor metabolizers (PM) or patients who produce insufficient amounts of morphine.

Poor and ultra-rapid metabolizers exhibit extremities in this response. For example, with codeine, there can be up to 30 fold difference in serum morphine concentrations between the PM and UM individuals.  The prescribed average opioid dosage can not give enough relief to a poor metabolizer.  While the average dosage can cause serious consequences including respiratory or central nervous system depression, and increased risk of addiction for an ultra metabolizer. Hence, knowledge of the CYP2D6 function i.e. the underlying genotype can indeed be used to inform therapy or dosage. Clear Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines exist for codeine prescription, while studies on genetic variation in other opioid-CYP2D6 pairs remain inconclusive.

Is pharmacogenetic testing for codeine being used today?

Primary care physicians (PCP) are the key decision makers for both diagnosing chronic pain and prescribing opioids. Understanding the use and implementation of PGx testing from their perspective is crucial in evaluating the utility of such tests in opioid prescription.  Five internists who manage multiple patients on opioids at the University of California, San Francisco (UCSF), said they had observed a large variance in response to opioids in their patients. However, none of them used PGx testing to guide their decision-making process for opioid prescription or had ever used it in the past. The reasons were many:

Insurance and reimbursement were frequent topics related to PGx testing. Dr. Molly Heublein, a primary care specialist in women’s health primary care at UCSF Medical Center mentioned insurance being the biggest barrier. She said, “the biggest holdup is insurance and reimbursement, if insurance will not pay for it, it will not happen.”  To get insurers to improve coverage, laboratory scientists need to show benefits of using PGx testing in the form of improved patient outcomes. This is lacking for most opioids. Dr. Era Kryzhanovskaya, an assistant clinical professor at UCSF, shared similar concerns. She said, “I haven’t ordered a pharmacogenetic test for opioids yet. The field is super nascent; there are also issues with the coverage of the test, the cost of the test, and [interpretability] of the test”. If the cost and coverage were not the barriers, she said she would consider using the test, except, questions of trusting the laboratory test, and her ability to interpret the tests continue to linger.

A potential solution is to get hospitals to invest in PGx testing with the goal of saving in the long term. Apart from the coverage for PGx testing, it is also the formulary process that could be a big hurdle. Medical cost coverage is distinct from drug coverage. Insurers have formularies, or approved drugs they agree to cover. Getting drug coverage for patients who switch to a more preferred opioid option after PGx testing could thus be problematic.

None of the five physicians had strong opinions on PGx testing. Dr. Ida Sim, a primary care physician, informatics researcher, and entrepreneur at UCSF, talked about practical limitations of using genetic testing for codeine prescription. She said, “it is often easier and cheaper to prescribe Tylenol 3 and see if the patient is responding to the drug in a week. It is practical issues like that; practicing clinicians will tell you it will not make my life any easier, it will not save cost, we will find out anyway; it is better to use the money and send them to a pain psychologist.”

Since cost is a major theme, would physicians be more willing to use PGx testing if it was free? Dr. Sim replied that it would depend on the sensitivity and specificity of the tests, as one might expect. She said she is more interested in the genetic variance in response to different non-steroidal anti-inflammatory drugs (NSAIDs).  Physicians use NSAIDs before prescribing opioids.

Most physicians avoid prescribing opioids due to the large variance in response. Will physicians use PGx testing if insurers covered the costs, and if researchers identified more targets?  Dr. Kryzhanovskaya said, “potentially,  especially on those for whom opioids are already prescribed;  the jury’s still out on how much the results will influence practice.”

There is scientific consensus on the genetic variability in opioid response, but there are huge gaps in identifying precise SNPs that affect response and metabolism of commonly used opioids. Most clinicians do not use codeine-CYP2D6 PGx tests, although it is available.  Will genetic testing inform opioid prescription process tomorrow even if insurance and reimbursement weren’t a limiting factor? Perhaps. As of today, internists think the specificity of testing and implementation, and the field is too nascent.

Sai Ganesan, PhD is a science communication fellow at Biotech Connection Bay Area. She’s also a postdoctoral scholar at University of California, San Francisco

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