Role of alendronate in therapy for posttraumatic complex regional pain syndrome type I of the lower extremity

Objective. To evaluate the effects of the antiresorptive agent alendronate at a daily oral dose of 40 mg in patients with posttraumatic complex regional pain syndrome type I (CRPS I) of the lower extremity. Methods. Forty patients were enrolled in this 8-week randomized, double-blind, placebo-controlled study of alendronate therapy for CRPS I, a condition associated with regional osteoclastic overactivity. An optional 8-week open extension of alendronate therapy (weeks 12–20) was available after a 4-week period without therapy. Clinical assessments included joint mobility, edema of the lower extremity, tolerance to pressure in the lower extremity, and levels of spontaneous pain. Urinary levels of type I collagen N-telopeptide (NTX) were assessed by enzyme-linked immunosorbent assay. Patients were examined at weeks 4, 8, 12, 16, 20, and 24. Statistical analysis included two-way factorial analysis of variance. Results. In contrast to placebo-treated patients (n 20), all of the alendronate-treated patients (n 19) exhibited a marked and sustained improvement in levels of spontaneous pain, pressure tolerance, and joint mobility, as well as a significant reduction in urinary levels of NTX at weeks 4 and 8. The improvement was maintained at week 12. Twelve patients from each treatment group volunteered for the 8-week open trial, and all of them had a positive response to alendronate. Conclusion. Our findings support the use of oral alendronate in posttraumatic CRPS I. By reducing local acceleration of bone remodeling, alendronate might relieve pain by effects on nociceptive primary afferents in bone, pain-associated changes in the spinal cord, and possibly also through a central mechanism. Reflex sympathetic dystrophy, which is now called complex regional pain syndrome type I (CRPS I) according to criteria of the International Association for the Study of Pain (IASP), is a clinical syndrome characterized by pain, allodynia, hyperalgesia, edema, abnormal vasomotor and sudomotor activity, movement disorders, joint stiffness, regional osteopenia, and dystrophic changes in soft tissue (1–7). For many patients, the pain and ensuing loss of function lead to permanent disability. The nature of the inciting event may be quite variable, including visceral lesions, but trauma of an extremity accounts for more than 50% of the cases (2–5,8). It is now believed that this syndrome is, at least in part, a disease of both the central and peripheral nervous systems (6,7). There is indeed experimental evidence that a sustained peripheral injury may change the expression of genes in dorsal root ganglia and central pain-projecting neurons of the dorsal horn, and it is thought that the resulting change in phenotype establishes and maintains sensitization (hyperalgesia and allodynia), neurogenic inflammation, and autonomic dysregulation (9,10). There is also clinical evidence of changes in the central representation of the somatosensory, sympathetic, and somatomotor systems (7). The natural history of CRPS I usually varies with its location. CRPS I of the upper extremity is reportedly associated with a relatively short-term morbidity. Yet, at