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12 Articles in Volume 21, Issue #2
Advanced Practice Matters with Theresa & Jeremy: MAT and the DATA Waiver Debate
Analgesics of the Future: The Potential of Vocacapsaicin Injections for Knee Pain
Authorities Update Opioid and Naloxone Prescribing Policies as Overdoses Soar
Autologous Adipose-Derived Biocellular (Stem Cell-Rich) Prolotherapy into Hoffa’s Fat Pad Improves Knee Osteoarthritis
Behavioral Medicine: How to Utilize Acceptance and Commitment Therapy in Primary Care
Case Report: How We Grew Our Pain Practice Amidst Pandemic, Opioid Crisis
Chronic Overlapping Pelvic Pain Disorders: Differential Diagnoses and Treatment
Fentanyl Transdermal Patch: Variability is Key When Prescribing
Optimizing Opioid Therapy with Pharmacogenetics
Research Insights: Advances in Shoulder Arthroplasty and Revision Surgery
Research Insights: How to Address Osteoarthritis Treatment Gaps in Women
Topical Anti-Inflammatories: Analgesic Options for Arthritis Beyond NSAIDs

Optimizing Opioid Therapy with Pharmacogenetics

New CPIC practice guideline discusses CYP2D6 genetic variations and their impact on patient metabolism. A look at prescribing considerations for codeine, tramadol, hydrocodone, and oxycodone.

The Clinical Pharmacogenetics Implementation Consortium (CPIC)* recently published a clinical practice guideline on the use of pharmacogenetic information for opioid therapy for pain control. This guideline includes recommendations for how CYP2D6 genetic test results can be used to optimize therapy for codeine, tramadol, and hydrocodone.

CYP2D6 is a member of the cytochrome P450 (CYP450) superfamily of enzymes, and is the major enzyme responsible for metabolizing codeine and tramadol to their active metabolites, morphine and (+)-O-desmethyltramadol (aka M1), respectively. However, the CYP2D6 gene is highly polymorphic, with genetic variants that can lead to very low (poor), normal, or accelerated (ultrarapid) metabolism of the codeine, tramadol and other drugs (see Table I).

The CPIC guideline recommends that CYP2D6 poor metabolizers avoid codeine and tramadol use. (Image: iStock)


CYP2D6 Ultrarapid Metabolizers and Poor Metabolizers: Codeine and Tramadol

The guideline recommends avoiding codeine or tramadol use in CYP2D6 ultrarapid metabolizers. Ultrarapid metabolism of codeine or tramadol can lead to high concentrations of the active metabolite, morphine or O-desmethyltramadol (also known as M1), which may increase the risk for toxicity. Indeed, the FDA labeling information for codeine and tramadol warns of life-threatening or fatal respiratory depression in CYP2D6 ultrarapid metabolizers even at label-recommended dosage (see Codeine, Prescribing Information, 2019; Ultram, Prescribing Information, 2019). This risk has prompted the contraindication of codeine and tramadol for children.1 There have been several neonatal fatalities in breastfeeding mothers who are CYP2D6 ultrarapid metabolizers and taking codeine for pain, prompting a warning not only in the FDA label but also from the American College of Obstetrics and Gynecology (ACOG).2

Of note, CYP2D6 genetic testing is available from many laboratories.

The CPIC guideline also recommends that CYP2D6 poor metabolizers should avoid codeine or tramadol use. Poor metabolism of codeine or tramadol is associated with minimal generation of the active metabolite and a muted analgesic response. Identification of CYP2D6 poor metabolizers allows the clinician to prescribe an alternative to codeine or tramadol that may be more effective.  


CYP2D6 Metabolism: Hydrocodone and Oxycodone

For hydrocodone, all CYP2D6 metabolizer types have similar recommendations. While hydrocodone is metabolized by CYP2D6 to a more potent metabolite, hydromorphone, the relative contributions of hydrocodone and hydromorphone to analgesia are not clear. As such, CPIC recommends that normal metabolizers, intermediate metabolizers, poor metabolizers, and ultrarapid metabolizers all use hydrocodone label recommended age- or weight-specific dosing. The only change in the guideline is for poor and intermediate metabolizers, in which the recommendation states: “If no response and opioid use is warranted, consider non-codeine and non-tramadol opioid.”

The guideline authors also conducted a literature review for oxycodone/CYP2D6, as well as COMT (catechol-o-methyltransferase) and OPRM1 (mu opioid receptor).  Data for oxycodone/CYP2D6 and COMT was conflicting and weak. For OPRM1, the authors acknowledged evidence for a small increase in postoperative morphine dose requirements, but concluded that the alteration in dose was so modest as to not be clinically actionable. As such, no clinical recommendations were made for the use of CYP2D6 genotype and oxycodone or COMT or OPRM1 genotypes with any opioid.  

The opioid guideline is an update of the codeine guideline published in 2014. Other published CPIC guidelines for pain medications include NSAIDs/CYP2C9,3 and tricyclic antidepressants/CYP2D6/CYP2C19.4

See also, testing and monitoring pharmacogenomics in behavioral and mental health as a comorbidity with chronic pain.


In Practice: Key Questions for Clinical Pharmacists and Pain Management Prescribers

The author of this review consulted with PPM Co Editor-at-Large Jeffrey Fudin, PharmD, DAIPM, FCCP, FASHP, to get a handle on what the CPIC prescribing updates mean for clinical pharmacists working in the pain management field.

Why is this guideline important for a pain provider to know about?

Dr. Fudin: As we all know, patients differ dramatically in their response to certain pain medications. A patient’s genetic makeup may be one factor leading to patient-to-patient variability. Pharmacogenetic testing is a tool the pain provider can employ to help optimize their patient’s therapy. For example, CYP2D6 UM (ultrarapid metabolizer) genotype may lead to some patients having toxic, life-threatening side effects if placed on codeine or tramadol.  This updated clinical guideline gives clear recommendations on what the pain provider should do based on CYP2D6 genetic test results.

For patients who are CYP2D6 poor metabolizers and ultrarapid metabolizers, the guideline recommends that codeine and tramadol be avoided and that alternate pain medications be considered.

It's important ot recognize that the guideline was developed by clinicians who treat pain as well as pharmacogenetic researchers,* and is based on a comprehensive review of the literature.

Is there guidance on which patients should receive a CYP2D6 genetic test?

Dr. Fudin:  No. CPIC guidelines provide recommendations on how to optimize therapy when genetic test results are available. They do not include who or when to test. This decision should be based on clinical judgment.

If a patient has COMT and OPRM1 results, should you disregard? 

Dr. Fudin: The CPIC guideline does not include standard clinical practice recommendations for COMT and OPRM1 due to lack of evidence. However, the data can still be useful when included in clinical decision-making for specific cases.  As an example, a patient who is an intermediate metabolizer at CYP2D6 could be considered for tramadol therapy, based on the guideline. However if the patient also has reduced activity at both COMT and OPRM1, I would also consider other non-opioid therapy because of the potential for ineffective analgesic response. I have found COMT information helpful for prescribing antidepressants for patients with pain and comorbid depression.5

What about drug-drug interactions and how they may play a role in response to opioids?

Dr. Fudin: As you probably know, CYP2D6 activity can be modified by drug-drug-interactions. As an example, paroxetine is known to have very strong CYP2D6 inhibitor activity. As such, even if a patient is genetically a normal metabolizer, if he/she is taking paroxetine, and codeine/tramadol is being considered for pain, you may want to either replace the paroxetine with another antidepressant that is not affected by CYP2D6 such as citalopram and avoid codeine/tramadol.

Are there other genes that should be considered when prescribing opioids?

Dr. Fudin: There are other genes that have association with opioid response at least in some studies,6 for example, UGT2B7 and ABCB1. However, these genes have less evidence to support clinical utility compared to COMT and OPRM1.


*About the Clinical Pharmacogenetics Implementation Consortium (CPIC)

Of note, CPIC is an NIH-funded organization with a membership of hundreds of clinicians, scientists, researchers and others knowledgeable about pharmacogenetics with the purpose of facilitating use of pharmacogenetic test results for improving patient care. CPIC guidelines provide a rigorous review of the scientific literature by experts and provide evidence-based actionable recommendations to clinicians through the publication of pragmatic guidelines that improve patient care. 

Several examples of health systems and other institutions that rely on CPIC guidelines for patient care include the Mayo Clinic, Cleveland Clinic, St. Jude’s Children’s Research Hospital, Boston Children’s Hospital, and Northshore University Health System.

The updated guideline discussed herein, Guideline for Opioids and CYP2D6, OPRM1, and COMT, hasbeen endorsed or supported by many other organizations including the American Society of Health Systems Pharmacists (ASHP), the American Society for Clinical Pharmacology and Therapeutics (ASCPT), and the College of American Pathologists (CAP).



Disclosure: Dr. Del Tredici discloses being an employee of, as well as a stockholder/shareholder, with Acadia Pharmaceuticals.

This article is being published in advance of the PPM March/April 2021 issue.


Last updated on: May 26, 2021
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