Why is morphine not the ultimate analgesic and what can be done to improve it?

Although opioids are unsurpassed in the treatment of acute and cancer pain, their use in chronic noncancer pain is clearly limited. This review discusses some open and controversial issues such as the balance between pain relief and side effects, whether all types of pain can be treated with opioids, and current efforts to develop opioids with an improved efficacy-side effect ratio. Whereas respiratory depression or tolerance are usually not major issues in long-term opioid use, it seems questionable whether opioids can produce an analgesic response in certain types of pain when there is a major affective component to the pain or when learned pain behavior is the main problem. Efforts to improve opioids have traditionally aimed at enhancing the selectivity of opioid receptor ligands towards mu-, delta-, and kappa-receptors. Another major strategy has been the search for opioid analgesics acting at opioid receptors outside the central nervous system, with the prospect to avoid centrally mediated side effects.