Analgesic effect and plasma concentrations of codeine and morphine after two dose levels of codeine following oral surgery

Abstract

A double blind randomised cross over investigation was carried out in 25 male patients undergoing two oral surgical extractions, one for each lower wisdom tooth. The two extractions were performed about 6 weeks apart and were carried out under local anaesthesia. One hour after each extraction the patients randomly received 90 or 45 mg codeine. During the following 5 h the patients rated the intensity of their pain on a visual analogue scale. Blood was simultaneously sampled and assayed for codeine and its metabolite morphine. Mean pain intensity difference was just significantly higher after 90 mg codeine compared to 45 mg. The mean plasma concentrations of codeine and morphine were significantly higher after the 90 mg dose. However, for the two dose levels of codeine there was no obvious relationship between the difference in analgesic effect and the difference in the plasma concentration of codeine or morphine. The plasma concentrations of morphine were 2-3% of those of codeine and the levels were relatively low. Local formation of morphine from codeine within the human brain should therefore be investigated. Four patients were unable to demethylate codeine to a detectable plasma concentration of morphine after 90 mg codeine. In those patients the analgesic effect during the first hours was better after 90 mg codeine than after 45 mg. This suggests some analgesic effect of codeine itself.

Evidence for morphine-independent central nervous opioid effects after administration of codeine: Contribution of other codeine metabolites

“…Clinical effects of codeine not accounted for by plasma morphine had been observed in experimental studies after oral codeine doses of 100 mg, 9 170 mg, 10 and 50 mg 13 . In the clinical setting some effects of codeine apart from morphine formation 11 were reported after 90 mg oral codeine. To administer a dose in the range of the doses after which the effects aimed for in this study had been observed, subjects first received codeine as an oral solution (ct‐Arzneimittel, Berlin, Germany) at doses initially set at a base level of 80 mg codeine but later increased to 120 mg because of small miotic effects in the first subjects.…”

“…However, inhibition of CYP2D6 by quinidine did not always completely extinguish the analgesic effects of 100 mg codeine despite a very low plasma morphine concentration 9 . Subjects with nonfunctional CYP2D6 had side effects from 170 mg codeine, 10 and in 4 patients with an inability to O ‐demethylate codeine, an analgesic effect of 90 mg codeine after dental surgery was reported 11 . In addition, codeine was proposed to produce cognitive impairment independent of measurable blood morphine concentrations 12 .…”

“…The codeine effects reported as not being attributable to morphine formation consisted of a variety of opioid actions such as cognitive impairment, 12 sedation, dizziness, euphoria/dysphoria, headache, blurred vision, itching, flush, 10 or prolongation of gastrointestinal transit 13 . Analgesia has also been reported in this context, 11 but other investigators explicitly excluded it as a morphine‐independent effect after codeine administration 10 . Thus, because analgesic effects were uncertain to provide a basis to judge the contribution of codeine metabolites other than morphine to its effects and side effects such as sedation or headache often provide a weak data basis for exact quantification of opioid effects, we chose the pupil diameter as the target parameter for this study (for review, see reference 15).…”

Minor and Short-Acting Analgesics, Including Opioid Combination Products

“…22 Studies have demonstrated that only a small percentage of the total dose (3%) 23 is converted by CYP2D6 to morphine. A weak analgesic, codeine is similar in structure to morphine but has affinity for the µ-opioid receptor that is 300 times lower.…”

A review of the efficacy and safety of opioid analgesics post‐craniotomy*

“…The efficacy of codeine is further confounded by large interindividual and interethnic differences in demethylation capacity. Variable expression of the enzymes involved in the biotransformation of drugs can lead to substantial differences in the production rate and plasma concentration of metabolites, and hence, the efficacy of a pro‐drug (Quilding et al ., 1993; Williams et al ., 2002). The enzyme that catalyzes the demethylation of codeine to morphine is cytochrome P‐450 CYP2D6.…”