Forty-one RCTs (n=6,019) were included, of which 30 had a placebo control. Thirty-one trials were double-blind and in 30 of these the double-blinding was considered adequate.
The methodological quality was high in 87% of the trials, and randomisation was considered adequate in 17 of the 41 trials.
The average drop-out rate in the opioid groups was 33%, of which 21% was due to side-effects and 15% due to inadequate pain relief (some patients dropped out for both reasons). The average drop-out rate in the control groups was 38%, of which 10% was due to side-effects and 30% due to inadequate pain relief.
Opioids versus placebo (30 trials included; 28 contributed data to the analysis).
Opioids were significantly more effective than placebo for pain relief (SMD -0.60, 95% CI: -0.69, -0.50). Sensitivity analyses with type of opioids, study design and study quality showed no change in the evidence. There was statistically significant heterogeneity (I2=48%).
For functional outcomes, there was a statistically significant difference in favour of opioids (SMD -0.31, 95% CI: -0.41, -0.22). Opioids were significantly more effective than placebo, except for long-acting morphine, patients with mixed pain and low-quality studies. There was statistically significant heterogeneity (I2=63%).
Opioids versus other drugs (8 trials).
There was no statistically significant difference in pain relief between opioids and other analgesics (SMD -0.05, 95% CI: -0.32, 0.21). Sensitivity analyses showed no change with study quality and type of comparator. However, the strong opioids were significantly more effective than other drugs (SMD -0.34, 95% CI: -0.67, -0.01). Further data from one trial showed that codeine plus acetaminophen was superior to acetaminophen alone at 7 days of follow-up, but not afterwards.
For functional outcomes, non-opioid analgesics were significantly more effective than opioids (SMD 0.16, 95% CI: 0.03, 0.30); however, this was heavily influenced by one trial which compared diclofenac with a weak opioid (dextropropoxyphene).
Side-effects and other complications.
Six side-effects occurred significantly more common in opioid than placebo groups: constipation (RD 16%, 95% CI: 10, 22), nausea (RD 15%, 95% CI: 11, 19), dizziness or vertigo (RD 8%, 95% CI: 5, 12), vomiting (RD 5%, 95% CI: 2, 7), somnolence or drowsiness 9% (95% CI: 5, 13)and dry skin, itching or pruritus (RD 4%, 95% CI: 1, 6). There was no statistically significant difference between the opioid and control groups in the rate of other side-effects, such as diarrhoea, appetite loss, abdominal pain, dry mouth, headache, fatigue, blurred vision or accommodation disturbance, sleeplessness or insomnia, confusion and sweating.
Compared with other analgesics, three side-effects were significantly more common with opioids: nausea (RD 14%, 95% CI: 4, 25), constipation (RD 9%, 95% CI: 1, 17), and somnolence or drowsiness (RD 6%, 95% CI: 0, 11). Diarrhoea occurred less frequently with opioids than with other analgesics (RD -2%, 95% CI: -3, 0). There was no statistically significant difference between the opioid and control groups in the rate of other side-effects.
One trial reported that 8.7% of patients taking morphine developed drug cravings compared with 4.3% in the placebo group. Two trials found that patients with opioids reported better sexual function than placebo, though most trials did not ask about sexual dysfunction.