Annotation of CPIC Guideline for alfentanil, buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, levomethadone, morphine, naltrexone, remifentanil, sufentanil, tramadol and COMT, OPRM1

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Summary

There are currently no recommendations for dosing of alfentanil, buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, levomethadone, naltrexone, remifentanil, sufentanil or tramadol based on OPRM1 or COMT genotypes.

No recommendation

Annotation

The authors of the CPIC® guideline for opioids and CYP2D6, OPRM1 and COMT evaluated the available evidence for therapeutic dose recommendations for alfentanil, buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, levomethadone, naltrexone, remifentanil, sufentanil and tramadol based on OPRM1 or COMT genotypes.

Although they found evidence to suggest that the rs1799971 G allele in OPRM1 is associated with increased morphine dose requirements, the alteration in dose is so small that it is not clinically actionable. There was insufficient evidence to provide any other recommendations for other opioids and OPRM1 variants. Similarly, there was mixed evidence about the association between variants in COMT and opioid dose or response.

December 2020

The CPIC guideline for opioids and CYP2D6, OPRM1 and COMT genotypes has been published in Clinical Pharmacology and Therapeutics. This is an update to the CPIC guideline for codeine and CYP2D6.
These guidelines are applicable to:
- adult patients
- pediatric patients
Excerpts from the guideline:
- "OPRM1 variants inconsistently have been shown to alter post-operative dose requirements for some opioids. There is evidence for a small increase in post-operative morphine dose requirements (approximately 10%) in some clinical studies in patients carrying at least one copy of the OPRM1 rs1799971 G allele, though the alteration in morphine dose is so modest as to not be clinically actionable."
- "There is also insufficient evidence at this time to conclude altered analgesic response to other opioids in relation to rs1799971, or other OPRM1 variants."
- "For the most highly studied COMT variant, rs4680, there is no evidence to support an association of this variant with opioid adverse events, and there is mixed evidence for an association between COMT rs4680 genotype and analgesia or opioid dose requirements."
- "For all other COMT variants, there is mixed evidence for an association between COMT genotype and analgesia, opioid dose requirements or adverse events."
Download and read:
- Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6, OPRM1, and COMT genotype and select opioid therapy
- Guideline supplement

Guideline Supplemental Table S7: Morphine therapy recommendations based on OPRM1 genotype

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Genotype	Implications	Recommendations	Classification of recommendation^a	Considerations
rs1799971 G	The rs1799971 G allele is associated with small but statistically significant decreases in analgesia and/or increases in morphine requirements in some studies. However, this does not appear to translate into clinically actionable dose alterations.	No recommendation	No recommendation	Most publications focus on morphine for postoperative pain. Many factors contribute to variability in postoperative morphine response including age, psychological status, tolerance, surgery type and duration, genetics and presurgical pain and opioid use. Due to the marginal difference in dose between genotypes and numerous other factors affecting this outcome, the safest recommendation is to “start low and go slow.”
Other variants	No effect or insufficient evidence for morphine adverse events, opioid dose requirements, or analgesia	No recommendation	No recommendation

Guideline Supplemental Table S8: Fentanyl therapy recommendations based on OPRM1 genotype

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Genotype	Implications	Recommendations	Classification of recommendation^a	Considerations
rs1799971 G	No effect for fentanyl adverse events and analgesia. Mixed evidence for an association between OPRM1 rs1799971 and fentanyl dose requirements.	No recommendation	No recommendation	Many factors contribute to variability in fentanyl response including age, psychological status, tolerance, surgery type and duration, genetics and presurgical pain and opioid use.
Other variants	No effect or insufficient evidence for fentanyl adverse events, opioid dose requirements, or analgesia	No recommendation	No recommendation

Guideline Supplemental Table S9: Other opioids (alfentanil, buprenorphine, codeine, hydrocodone, hydromorphone, levomethadone, methadone, naltrexone, oxycodone, remifentanil, sufentanil and tramadol) therapy recommendations based on OPRM1 genotype

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Genotype	Implications	Recommendations	Classification of recommendation^a	Considerations
rs1799971 G	No effect or insufficient evidence for adverse events, opioid dose requirements, analgesia, or change in opioid dependence/withdrawal therapy	No recommendation	No recommendation	Many factors contribute to variability in postoperative opioid response including age, psychological status, tolerance, surgery type and duration, genetics and presurgical pain and opioid use.
Other variants	No effect or insufficient evidence for opioid adverse events, opioid dose requirements, analgesia, or change in opioid dependence/withdrawal therapy	No recommendation	No recommendation	Many factors contribute to variability in postoperative opioid response including age, psychological status, tolerance, surgery type and duration, genetics and presurgical pain and opioid use.

Guideline Supplemental Table S10: Opioid therapy recommendations based on COMT genotype

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Genotype	Implications	Recommendations	Classification of recommendation^a	Considerations
rs4680 A	No effect for opioid adverse events. Insufficient evidence for an association between COMT rs4680 genotype, analgesia and opioid dose requirements.	No recommendation	No recommendation	Many factors contribute to variability in opioid response including other gene variants, age, psychological status, indication and duration of opioid use. Mixed evidence indicates both supporting and non-supporting evidence for an association with neither direction dominating.
Other variants	Insufficient evidence for an association between COMT genotype, analgesia, opioid dose requirements and adverse events	No recommendation	No recommendation	Many other factors contribute to variability in opioid response including other gene variants, age, psychological status, indication and duration of opioid use.

^a Rating scheme described in the Strength of Recommendations section in the guideline supplement

PharmGKB ID

PA166227941