Pharmacogenomic considerations in opioid analgesia

Figures & data

Figure 1 CYP metabolism involved in opioid clearance.

Table 1 Codeine therapy recommendations based on CYP2D6 phenotype

Phenotype	Implications for codeine metabolism	Recommendations for codeine therapy	Classification of recommendation for codeine therapy
Ultrapid metabolized (CYP2D6 activity score > 2)	Increased morphine formation Higher risk of morphine toxicity	Avoid codeine use (potential for toxicity) Consider alternative such as morphine or a non-opioid Consider avoiding tramadol	Strong
Extensive metabolizer (CYP2D6 activity score = 1–2)	Normal morphine formation	15–60 mg every 4th as needed for pain (label recommendation)	Strong
Intermediate metabolizer (CYP2D6 activity score = 0.5)	Reduced morphine formation	Start at 15–60 mg every 4th as needed for pain If no response, consider alternative analgesics Monitor tramadol use for response	Moderate
Poor metabolizer (CYP2D6 activity score = 0)	Greatly reduced morphine formation Insufficient pain relief	Avoid codeine use (lack of efficacy) Consider alternative such as morphine or a non-opioid. Consider avoiding tramadol	Strong

Adapted from the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideliness for Codeine Therapy in the Context of Cytochrome P450 2D6 (CYP2D6) Genotype.⁸

Figure 2 Concentrations of tramadol and enantiomers in different CYP2D6 genotypes. Adapted with permission from Macmillan Publishers Ltd: Stamer et al. Clin Pharmacol Ther. 2007; 82:41–47.⁶⁴

Abbreviations: PM, poor metabolizers; HZ/IM, heterozygous individual/intermediate metabolizer; EM, extensive metabolizer; UM, ultra rapid metabolizer. *P < 0.001 (Kruskal-Wallis test).

Table 2 OPRM1 genotype and fentanyl requirement

Subjects [n]	Study cohort	Route of administration	Measured outcomes	Observed associations in G118 carriers
223 [124]	Nulliparous women in early labor	Spinal (up–down sequential and randomized doses)	ED50 (median effective dose providing 60 minutes of early labor analgesia)	Analgesia requested at later stage (greater cervical dilatation) Lower spinal fentanyl dose (ED50)
147 [125]	Nulliparous women in early labor	Spinal (25 mcg)	Duration of effective analgesia in early labor	No difference in duration of analgesia
280 [137]	Healthy Japanese, orodental surgery	Preop IV test (2 mcg/kg) Postop IV PCA (40 mcg/10 minutes)	Cold-pressor test before vs after IV dose 24-hour postop IV PCA consumption	Pre-IV test: increased sensitivity Post-IV test: reduced analgesic effect Reduced fentanyl sensitivity in women vs men No difference in VAS scores and 24-hae postop fentanyl consumption
189 [139]	Han Chinese, laparoscopic abdominal surgery	Preop IV (5 mcg/kg) Intraop IV (1 mcg/kg/30 minutes) Postop IV (1 mcg/kg)	Postop pain scores (15, 30, 45, 60 minutes) Time to awakening Respiratory depression PaCO2	Higher pain scores (at 15 and 30 minutes) Shorter time for awakening Lower PaCO2
174 [136]	Han Chinese, hysterectomy	Preextubation (1 mcg/kg) Postop IV PCA (continuous 5 mcg/hour, bolus 20 mcg/5 minutes)	Preop electrical pain threshold 24-hour postop VAS scores 24-hour postop IV PCA consumption	No difference in pain threshold Lower electrical pain tolerance threshold (gene-dose-dependent effect) No difference of initial postop or averaged 24-hour pain scores Higher consumption of postop fentanyl Trend for lower incidence PONV

Abbreviations: IV, intravenous; PCA, patient-controlled analgesia; VAS, visual analog scale; PONV, postoperative nausea and vomiting.

CrewsKRGaedigkADunnenbergerHMClinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotypeClin Pharmacol Ther20129132132622205192

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StamerUMMusshoffFKobilayMMadeaBHoeftAStuberFConcentrations of tramadol and O-desmethyl-tramadol enantiomers in different CYP2D6 genotypesClin Pharmacol Ther200782414717361124

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