Abstract: We included 15 studies including 721 participants with cancer pain due to diverse types of malignancy. All studies were performed on adults; there were no studies on children. The included studies were of adequate methodological quality, but all except for one were judged to be at a high risk of bias because of small study size, and six because of methods used to deal with missing data or high withdrawal rates. Three studies used a parallel group design; the remainder were cross-over trials in which there was an adequate washout period, but only one reported results for treatment periods separately. Twelve studies used codeine as a single agent and three combined it with paracetamol. Ten studies included a placebo arm, and 14 included one or more of 16 different active drug comparators or compared different routes of administration. Most studies investigated the effect of a single dose of medication, while five used treatment periods of one, seven or 21 days. Most studies used codeine at doses of 30 mg to 120 mg. There were insufficient data for any pooled analysis. Only two studies reported our preferred responder outcome of 'participants with at least 50% reduction in pain' and two reported 'participants with no worse than mild pain'. Eleven studies reported treatment group mean measures of pain intensity or pain relief; overall for these outcome measures, codeine or codeine plus paracetamol was numerically superior to placebo and equivalent to the active comparators. Adverse event reporting was poor: only two studies reported the number of participants with any adverse event specified by treatment group and only one reported the number of participants with any serious adverse event. In multiple-dose studies nausea, vomiting and constipation were common, with somnolence and dizziness frequent in the 21-day study. Withdrawal from the studies, where reported, was less than 10% except in two studies. There were three deaths, in all cases due to the underlying cancer. We identified only a small amount of data in studies that were both randomised and double-blind. Studies were small, of short duration, and most had significant shortcomings in reporting. The available evidence indicates that codeine is more effective against cancer pain than placebo, but with increased risk of nausea, vomiting, and constipation. Uncertainty remains as to the magnitude and time-course of the analgesic effect and the safety and tolerability in longer-term use. There were no data for children.

Plain-language summary: In this review we set out to estimate how well codeine worked, how many people had side effects, and how severe those side effects were - for example, whether they were so severe that participants stopped taking their oral codeine. We included 15 studies with 721 participants. The studies we found had methodological shortcomings: they were small and of short duration. They also reported results in different ways, so that it was not possible to combine results. In seven of the eight studies that compared codeine with placebo, codeine was better than placebo. In studies that compared codeine with another drug, the results were similar. Codeine at doses of 30 mg to 120 mg, alone or in combination with paracetamol, does seem to provide a good level of pain relief for some people with cancer pain. We cannot be certain about how many people will get this benefit, and we do not know whether, or by how much, adding paracetamol increases its effect. Codeine increases nausea, vomiting, and constipation, and may cause drowsiness or dizziness if used for more than a week. Some people will stop taking codeine because of the side effects. More trials comparing codeine with other treatments and using patient-centred outcomes are needed. The role of codeine in mild cancer pain, in addition to moderate to severe cancer pain, should be investigated.