Spinal cord stimulation (SCS) may provide pain relief in approximately 60%-70% of well selected patients with pain caused by peripheral nerve injury. We have previously demonstrated that intrathecal (IT) administration of small doses of certain drugs, both in experimental animals and in patients, significantly enhances the pain-relieving effect of SCS. The alpha2-adrenoceptor agonist, clonidine, is extensively used as an adjunct to spinal morphine and is suggested to be particularly effective for neuropathic pain, but its clinical use is limited by side effects such as sedation and hypotension. In this study, we investigated the dose-response characteristics of IT clonidine, and whether a subeffective dose of clonidine could enhance the effect of SCS in nerve-injured rats with tactile hypersensitivity (allodynia). Results showed that clonidine, in doses of 1-20 microg, reduced the hypersensitivity in a dose-dependent manner. In rats in which SCS per se failed to suppress tactile hypersensitivity, the combination of SCS and a subeffective dose of clonidine appeared to be highly synergistic and markedly attenuated the hypersensitivity. These results suggest that small doses of IT clonidine may be combined with SCS in neuropathic pain patients who do not obtain satisfactory relief with SCS alone.