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The pathophysiology of many chronic pain syndromes involves both a neuropathic and a nociceptive component. Such chronic pain conditions, the so-called mixed pain syndromes, require both a careful assessment and a multimodal therapeutic approach. Mixed pain syndromes are very common and include a large proportion of low back pain, cancer pain, chronic postoperative pain, as well as most forms of osteoarthritis. A multimodal treatment approach may involve synchronous use of 2 or more agents with different mechanisms of action or the use of a single agent that works on multiple pain mechanisms. Since drug combinations create the possibility of drug-drug interactions, consideration should be given to drugs that are not metabolized through the P450 enzyme system. Any analgesic regimen that involves the use of an opioid should include principles of safe prescribing, including stratification of risk for opioid misuse.