Sympathetic nerve blocks, pragmatic trials, and responder analysis.

S INCE the American Civil War, clinicians and neuroscientists have been mystified by patterns of persistent pain and cutaneous hypersensitivity after injuries to the limbs that are accompanied by remarkable neurovascular, sudomotor, motor, and trophic changes. These syndromes traditionally were labeled as reflex sympathetic dystrophy or causalgia, according to the absence or presence of identifiable injury to major nerve trunks. The designations reflex sympathetic dystrophy and causalgia were replaced in most part with the terms complex regional pain syndrome (CRPS) types 1 and 2, respectively, by an international consensus group in 1994, and revised to improve diagnostic specificity. The roles of the sympathetic nervous system in initiation or maintenance of this syndrome are matters of controversy, and the revised diagnostic criteria deemphasized the sympathetic nervous system as the primary pathophysiology and specific treatment target. Surgical interruption of sympathetic nervous system activity to treat pain was commonly used in the early and mid-twentieth century. Lumbar and cervicothoracic ganglia sympathetic blockade with local anesthetics have been performed for the diagnosis and management of reflex sympathetic dystrophy or CRPS since the 1940s. Clinicians and researchers have long noted that in some cases, local anesthetic sympathetic or somatic blocks and intravenous infusions of local anesthetics can produce prolonged interruption of pain that far exceeds the duration of known drug actions. Explanations are lacking for this remarkably prolonged interruption of pain by brief pharmacologic interventions. In this issue of ANESTHESIOLOGY, van Eijs et al. evaluated predictors of pain alleviation in response to a single sympathetic blockade in 49 adults with CRPS in a prospective observational study during the course of standard clinical care. Among patients who had no improvement with a structured course of rehabilitative treatment and medical management, pain relief of 50% occurred for 2–48 h in 5 patients and as long as 7 days in another 10. There were no identifiable predictors for favorable analgesic response, although the presence of allodynia or hypoesthesia was a negative predictor of a favorable response. Despite widespread use of sympathetic blocks in pain clinics, there are very few controlled clinical trials on sympathetic interruption by a range of approaches, including paravertebral local anesthetic injection, intravenous regional administration of a range of drugs, systemic adrenergic receptor antagonists, neurolytic blocks, or surgery. Although a few trials have shown significant differences in some outcome measures between active and control interventions, systematic reviews have concluded that overall the evidence for therapeutic benefit for temporary or neuroablative sympathetic interruption for CRPS is weak. In designing clinical trials, there are trade-offs between an emphasis on methodologic rigor for testing mechanistic hypotheses and an emphasis on clinical realism in assessing therapeutic benefit under conditions that reflect everyday clinical practice. Trials that emphasize mechanism have been called “explanatory,” and trials that emphasize benefit under real-world conditions have been called “pragmatic.” Pragmatic trials commonly are used in comparative effectiveness research, often with randomized comparison of subjects to two or more treatment regimens. Our previous study using a small dose comparison of lumbar sympathetic lidocaine to intravenous lidocaine and the Price et al., study are examples of explanatory trials; the designs were made deliberately different from usual clinical practice to better control for confounding factors and test mechanistic hypotheses.