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In human studies, low COMT (catechol-O-methyltransferase) activity has been associated with increased sensitivity to acute clinical preoperative or postoperative pain. We explored the association between the COMT genotype and three chronic pain conditions: migrainous headache, fibromyalgia, or chronic widespread pain and chronic musculoskeletal pain. Furthermore, we evaluated whether COMT genotype affects the efficacy of opioids in chronic pain. After a systematic literature review, we carried out meta-analyses on the three chronic pain conditions. The efficacy of opioids was evaluated using a systematic review only. The meta-analyses showed that fibromyalgia or chronic widespread pain is the only type of chronic pain that could be associated with the COMT single nucleotide polymorphism rs4680 (Val158Met). Met158, which results in the low-activity variant of COMT, is the risk allele. In chronic clinical pain, the effect of the COMT polymorphism depends on the pain condition. Low COMT activity is not associated with migrainous headache or chronic musculoskeletal pain conditions, but it may increase the risk for fibromyalgia or chronic widespread pain. Low COMT activity increases opioid receptors and enhances opioid analgesia and adverse effects in some cancer pains. Findings from animal studies that have utilized COMT inhibitors elucidate the mechanism behind these findings. In rodent pain models, COMT inhibitors are pronociceptive, except for neuropathic pain models, where nitecapone was found to be antiallodynic. The complex interplay between enhanced adrenergic and dopaminergic activity in different parts of the nociceptive system probably explains the complicated actions of low COMT activity.