Chronic pain patients who are treated with opioid therapy represent a significant challenge to medical professionals. When pain recurs in the face of a previously effective opioid regimen, treatment options include dose escalation, opioid rotation, drug holidays, and the addition of adjuvants. Some experts advocate the use of N-methyl-D-aspartate receptor (NMDA-R) antagonists to combat tolerance. Recently, the use of an intravenous (i.v.) ketamine infusion to predict the response to a dextromethorphan (DX) treatment trial has been described. In this study, 56 opioid-exposed patients with recurrent pain were treated with a low-dose (0.1mg/kg) i.v. ketamine test followed by a DX treatment course. Using previously designated cutoff values for a positive response to ketamine (67% or more pain relief) and DX (50% or more pain relief), the sensitivity, specificity, positive predictive value, and negative predictive value for an i.v. ketamine infusion to predict subsequent response to DX treatment were 72%, 68%, 52%, and 85%, respectively. The observed agreement between analgesic responses was 78%, indicating a highly significant correlation (r=0.54, P=0.0001). Subgroup classification revealed no significant differences in the response to either ketamine or DX treatment based on pain classification (i.e., nociceptive, neuropathic, or mixed) or placebo response. In contrast, a weaker correlation between ketamine and DX response was found in subjects requiring high-dose rather than low-dose opioid therapy. A significant correlation also was noted between the development of side effects for the two NMDA-R antagonists. Based on these results, we conclude that an i.v. ketamine test may be a valuable tool in predicting subsequent response to DX treatment in opioid-exposed patients. with persistent pain.