The spinal mechanisms of action of opioids under normal conditions are reasonably well understood. The spinal effects of opioids can be enhanced or reduced depending on pathology and activity in other segmental and nonsegmental pathways. This plasticity will be considered in relation to the control of different pain states using opioids. The complex and contradictory findings on the supraspinal actions of opioids are explicable in terms of heterogeneous descending pathways to different spinal targets using multiple transmitters and receptors – therefore opioids can both increase and decrease activity in descending pathways. These pathways could exhibit considerable plasticity. There is increasing evidence that delta opioid receptor agonists have the potential to replace morphine as major analgesics with reduced side-effect profiles. The concept of preemptive analgesia, based on preventing the induction of some of the negative plastic influences on opioid controls and the detrimental effects of pain, is sound, but experimental verification in the clinical setting is difficult. For example, a delayed compensatory upregulation of inhibitory systems, particularly in inflammation, may counter persistent painful inputs. Combination therapy with opioids may be beneficial in many pain states where either negative influences are blocked or inhibitory controls are enhanced. Finally, developmental aspects of these systems are discussed in connection with the treatment of pain in young children, where inhibitory systems in the spinal cord are immature.