Complex Regional Pain Syndrome Type 1 (CRPS-1) responds poorly to standard pain treatment. We evaluated if the N-methyl-D-aspartate receptor antagonist S(+)-ketamine improves pain in CRPS-1 patients. Sixty CRPS-1 patients (48 females) with severe pain participated in a double-blind randomized placebo-controlled parallel-group trial. Patients were given a 4.2-day intravenous infusion of low-dose ketamine (n=30) or placebo (n=30) using an individualized stepwise tailoring of dosage based on effect (pain relief) and side effects (nausea/vomiting/psychomimetic effects). The primary outcome of the study was the pain score (numerical rating score: 0-10) during the 12-week study period. The median (range) disease duration of the patients was 7.4 (0.1-31.9) years. At the end of infusion, the ketamine dose was 22.2+/-2.0 mg/h/70 kg. Pain scores over the 12-week study period in patients receiving ketamine were significantly lower than those in patients receiving placebo (P<0.001). The lowest pain score was at the end of week 1: ketamine 2.68+/-0.51, placebo 5.45+/-0.48. In week 12, significance in pain relief between groups was lost (P=0.07). Treatment did not cause functional improvement. Patients receiving ketamine more often experienced mild to moderate psychomimetic side effects during drug infusion (76% versus 18%, P<0.001). In conclusion, in a population of mostly chronic CRPS-1 patients with severe pain at baseline, a multiple day ketamine infusion resulted in significant pain relief without functional improvement. Treatment with ketamine was safe with psychomimetic side effects that were acceptable to most patients.

While buprenorphine's analgesic effect increased significantly, respiratory depression was similar in magnitude and timing for the two doses tested. We conclude that over the dose range tested buprenorphine displays ceiling in respiratory effect but none in analgesic effect.

Our data confirm a ceiling effect of buprenorphine but not fentanyl with respect to respiratory depression.

The study was registered at trialregister.nl under number NTR2716.

Although a contribution of sex in opioid efficacy has garnered much attention, the confirmation and direction of any such difference remain elusive. We performed a systematic review of the available literature on sex differences in μ and mixed μ/κ opioid effect on acute and experimental pain. Fifty unique studies (including three unpublished studies) were included in the analyses. Across the 25 clinical studies on μ-opioids there was no significant sex-analgesia association. Restricting the analysis to patient-controlled analgesia (PCA) studies (irrespective of the opioid) yielded greater analgesia in women (n=15, effect size 0.22, 95% c.i. 0.02-0.42, P=0.028). Further restricting the analysis to PCA morphine studies yielded an even greater effect in women (n=11, effect size=0.36, 95% c.i. 0.17-0.56, P=0.003). Meta-regression indicated that the longer the duration of PCA, the difference in effect between the sexes further increased. Across experimental pain studies on μ-opioids women had greater antinociception from opioids (n=11, effect size=0.35; 95% c.i. 0.01-0.69, P=0.047), which was predominantly due to 6 morphine studies. Female patients had greater μ/κ opioid analgesia (n=7, effect size 0.84; 95% c.i. 0.25-1.43, P=0.005), but no sex-analgesia association was present in experimental studies (n=7). Sex differences exist in morphine-induced analgesia in both experimental pain studies and clinical PCA studies, with greater morphine efficacy in women. The data on non-morphine μ and mixed μ/κ-opioids are less convincing and require further study.