Some pain syndromes may be difficult to treat due to a poor response to opioids. This situation demands a range of alternative measures, including the use of adjuvant drugs with independent effects, such as antidepressants, sodium channel-blocking agents, steroids and anti-inflammatory drugs (NSAIDs); drugs that reduce opioid side effects; and drugs that enhance analgesia produced by opioids, such as N-methyl-D-aspartate (NMDA) antagonists, calcium channel antagonists, and clonidine. Other approaches, including opioid trials, neural blockade when necessary, and psychological interventions, also may be useful.