After 7 days

After 28 days

After 6 months

After 12 months

Figure 15.5. Here the results of the NMDA receptor antagonist memantine on acute phantom limb pain are shown in amputees who participated in a doubleblind randomized study with either memantine or placebo. Note the significantly lower incidence of phantom limb pain at the 12-month follow-up in the memantine condition.

results. Pharmacologic interventions include a host of agents and although tricyclic antidepressants and sodium channel blockers have been indicated as treatments of choice for neuropathic pain (see Sindrup and Jensen, 1999 for a review), there are few controlled studies for phantom limb pain. Controlled studies have been performed for opioids (Huse et al., 2001a), calcitonin (Jaeger and Maier, 1992), keta-mine (Nikolajsen et al., 1996) and gabapentin (Bone et al., 2002) all of which were found to effectively reduce phantom limb pain. Memantine, an NMDA receptor antagonist like ketamine, was, however, not effective in three studies (Nikolajsen et al., 2000b; Maier et al., 2003; Wiech et al., 2004). Antidepressants yielded no pain relief (Robinson et al., 2004). We found positive effects of both opioids (Huse et al., 2001a) and memantine (Koeppe et al., 2003) on both chronic phantom limb pain and cortical reorganization suggesting that more work is necessary to determine under which circumstances which phar-macologic agents can effectively reverse the mal-adaptive plastic changes that are a consequence of amputation and chronic pain.

15.4 Conclusions and summary

The empiric evidence discussed above suggests that neuroplastic changes in the central nervous system play an important role in the development and maintenance of chronic pain. It is so far not clear to what extent changes in the spinal cord, the brain stem or the thalamus contribute to the changes in cortical reorganization and to what extent cortical reorganization affects the lower levels. Longitudinal studies and controlled outcome studies would also be needed to elucidate in greater detail the efficacy and mechanisms of feedback-based interventions designed to alter cortical pain memories.

Functional reorganization in both the somatosensory and the motor system was observed in neuropathic and musculoskeletal pain. In chronic low back pain and fibromyalgia patients the amount of reorganizational change increases with chronicity, in phantom limb pain and other neuropathic pain syndromes cortical reorganization is correlated with the amount of pain. A complicating factor is that in chronic pain syndromes lack of use of an affected body part may contribute to the central changes that are observed. These central alterations may be viewed as pain memories that alter the processing of both painful and non-painful input to the somatosensory system as well as its effects on the motor system. Cortical plasticity related to chronic pain can be modified by behavioral interventions that provide feedback to the brain areas that were altered by somatosensory pain memories or by pharmacologic agents that prevent or reverse maladaptive memory formation. Future research needs to focus on emotional changes that contribute to and interact with the sensory and motor changes described here.

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