Sixty-seven studies (n=3,991) were included in the review: 28 RCTs, 27 non-randomised trials and 12 case series/reports. Thirty-five studies were in patients with cancer pain. Other studies included patients with chronic pain,, presumed substance abuse, HIV/AIDS, pre-surgical patients, or healthy volunteers.
Sedation (2 studies).
One study found no benefit of epidural versus oral opioid administration. The second reported moderate improvements in symptoms of sedation associated with the administration of donepezil.
Nausea and vomiting (7 RCTs and 3 case studies).
Methylnaltrexone reduce nausea and vomiting without reversing opioid analgesia. Co-administration of dopamine antagonists with opioids may help prevent nausea and vomiting. Ondansetron at doses of 8 to 16 mg demonstrated efficacy in controlling emesis. Cyclizine reduced the incidence of vomiting, with a less marked effect on nausea alone. Scopolamine patches behind the ear may benefit patients with worsened nausea while ambulatory.
Delirium (1 case series and 1 case report).
Both studies reported a reversal of delirium with treatment (rehydration, discontinuation of benzodiazepines and antihistamines, opioid rotation, addition of haloperidol or risperidone).
Myoclonus (12 case reports/series).
The majority of these related to morphine-induced myoclonus. Benzodiazepines (including diazepam, clonazepam and midazolam) have been successfully used for this indication. Alternatives included dantrolene, local anaesthetics and opioid rotation.
Pruritis (3 RCTs and 2 case reports).
Intravenous ondansetron and propofol were shown to be efficacious in the randomised studies. Intradermal co-administration of naloxone with morphine was not proven to reduce itching.
Respiratory depression (10 RCTs and 2 case studies).
Naloxone and nalmefene both reduced or reversed respiratory depression without compromising analgesia in RCTs. Case studies suggested that naloxone might be effective when administered intravenously or intralingually. Studies of psysostigmine to reverse respiratory depression had conflicting results. Other studies suggested that verapamil did not affect morphine-induced respiratory depression whereas ketoprofen reduced it, and ketamine reduced fentanyl-induced hypoventilation without preventing a decrease in blood oxygenation.
Constipation (17 studies).
Polyethylene glycol and senna might be as equally effective as lactulose, but more cost-effective. The Ayurvedic medication Misrakasneham might be as effective as senna and more acceptable to patients. Methylnaltrexone, naloxone and ADL 8-2698 demonstrated a dose-dependent reversal of constipation.
Opioid rotation (7 uncontrolled studies). One study showed that rotation from morphine to subcutaneous oxycodone improved mental state, nausea and vomiting. Studies generally suggested that multiple rotations might be required, various side-effects might be reduced, and that lower than putative equi-analgesic doses might be required once successful rotation has been accomplished.