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The use of spinal opioids for intractable pain is limited by development of tolerance and opioid resistance of some types of pain.The literature regarding clinical experience with spinal mu opioid agonists for chronic and cancer pain was reviewed. Experimental use of intrathecal non-mu opioid agonists and non-opioid agonists and antagonists was also reviewed.Intrathecal mu agonists, particularly morphine, are effective for most patients with cancer pain, though in some patients rapid tolerance or marked resistance develop. Varied results are seen among chronic pain patients. Delta opioid agonists and a variety of non-opioid agonist analgesics are effective in standard analgesic testing paradigms, and some agents are effective in clinical trials. NMDA and NK-1 receptor antagonists are effective in models that produce sensitization of spinal dorsal horn neurons.A number of new agents appear to have promise as intrathecal drugs for patients with intractable chronic and cancer pain.