Opioids combined with antidepressants or antiepileptic drugs for cancer pain: Systematic review and meta-analysis

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Combining antidepressant or antiepileptic drugs with opioids has resulted in increased pain relief when used for neuropathic pain in non-cancer conditions. However, evidence to support their effectiveness in cancer pain is lacking.


To determine if there is additional benefit when opioids are combined with antidepressant or antiepileptic drugs for cancer pain.


Systematic review and meta-analysis. Randomised control trials comparing opioid analgesia in combination with antidepressant or antiepileptic drugs versus opioid monotherapy were sought. Data on pain and adverse events were extracted. Data were pooled using DerSimonian–Laird random-effects meta-analyses, and heterogeneity was assessed.


Seven randomised controlled trials that randomised 605 patients were included in the review. Patients’ pain was described as neuropathic cancer pain, cancer bone pain and non-specific cancer pain. Four randomised controlled trials were included in the meta-analysis in which opioid in combination with either gabapentin or pregabalin was compared with opioid monotherapy. The pooled standardised mean difference was 0.16 (95% confidence interval, −0.19, 0.51) showing no significant difference in pain relief between the groups. Adverse events were more frequent in the combination arms. Data on amitriptyline, fluvoxamine and phenytoin were inconclusive.


Combining opioid analgesia with gabapentinoids did not significantly improve pain relief in patients with tumour-related cancer pain compared with opioid monotherapy. Due to the heterogeneity of patient samples, benefit in patients with definite neuropathic cancer pain cannot be excluded. Clinicians should balance the small likelihood of benefit in patients with tumour-related cancer pain against the increased risk of adverse effects of combination therapy.

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