Does cytochrome 2D6 genotype affect the analgesic efficacy of codeine after ambulatory surgery? Prospective trial in 987 adults.

Background: Paracetamol-codeine combination tablet is widely used in pain management after day surgery. For safety reasons, its use has decreased in recent years. Codeine is a prodrug metabolised in the liver by the cytochrome P450 2D6 (CYP2D6) enzyme to morphine that produces the analgesic effect of codeine. CYP2D6 is highly polymorphic, and based on genotypes, individuals can be divided into four categories: poor-, intermediate-, normal- and ultrarapid metabolisers. Differences in morphine and its metabolite concentrations have been described between different CYP2D6 genotypes following codeine administration. The aim of the study was to investigate the possible effect of CYP2D6 genotype on codeine efficacy and adverse effects in a large cohort of adult patients undergoing ambulatory surgery.

Methods: A total of 987 patients scheduled for ambulatory surgery were included in the analyses. Operation types or anaesthesia methods were not limited in the study protocol. All study patients received a fixed dose of paracetamol (1000 mg) and codeine (60 mg) orally for premedication. A blood sample was drawn to identify the genotype of CYP2D6. At home, the first-line analgesic was paracetamol-codeine combination of 1-2 tablets at 1-3 times per day. Data on the efficacy and side effects of codeine were collected on the day of surgery and the following two postoperative days.

Results: Of the studied patients, 37 (3.7%) were poor CYP2D6 metabolisers, 264 (27%) were intermediate, 623 (63%) were normal and 63 (6.4%) were ultrarapid metabolisers. Activity scores ranged from 0 to 4. CYP2D6 genotype was not associated in a statistically significant manner with postoperative pain, opioid consumption or the adverse effects of codeine, except for constipation at home. Poor CYP2D6 metabolisers reported significantly less severe constipation compared with normal metabolisers (p = .009, OR 0.40, 95% Cl 0.20-0.80).

Conclusion: CYP2D6 genotype appears to be of minor importance for the analgesic efficacy of oral paracetamol-codeine combination therapy after ambulatory surgery in adult patients undergoing similar types of surgery as in the present study but it may affect the risk of constipation.