Several observations from experimantal studies evidence the complexity of opioid responsiveness particularly as it pertains to neuropathic pain and the development of tolerance. It is difficult to extrapolate these findings to humans in pain. Contradictory findings may be explained by differences in the underlying mechanisms produced by different experimental procedures. These alterations may result in a reduction of the antinociceptive effects of opioids even before the treatment starts with a consequent rightward shift of the morphine dose-response curve. To complicate the situation, if a relationship between the mechanism of pain and opioid receptor subtypes exists, different pain mechanisms may result in different responsiveness to alternative opioids, based on the density or sensitivity of the receptor subtype involved. This may explain the loss of efficacy with increasing doses until treatment-limiting toxicity finally occur, or the development of opioidinduced hyperalgesia. Alternative opioids with high intrinsic efficacy may be more effective in conditions characterized by a rapid development of tolerance or sustained by a neuropathic pain mechanism, or both. Combination of opioids may also improve the response. Agents with NMDA antagonist properties selectively reduce slow temporal summation of electrically and thermally evoked second pain in a dose-dependent manner with a clear distiction from the effects of morphine, which did not change the size of the area of secondary hyperalgesia and did not affect wind-up-like pain. NMDA antagonists have shown to be promising agents in the different clinical situations, although the use of these agents requires expertise due to the development of possible adverse effects of the available NMDA antagonists, which may limit their routine use. According to these experimental observations, neuropathic pain and hyperalgesia as well as tolerance development in cancer pain patients may potentially be prevented or decreased by changing the clinical approach by opioids or by a repeated treatment with NMDA antagonists, so that any manipulation targeted to prevent NMDA receptor activation, its intracellular consequences, or calcium influx would inhibit the induction of tolerance and hyperalgesia. Data from basic research are of paramount importance to develop clinical models able to increase the possibilities to resolve difficult pain problems, previously considered intractable.