New Research Directions
The workshop participants identified several critical needs in our basic understanding of RSD/CRPS, as well as potential directions for basic and clinical research on new treatment strategies. These needs were in the areas of 1) diagnostic criteria, 2) epidemiology, 3) RSD/CRPS model systems, 4) disease mechanisms, 5) integration between basic research and clinical research, and 6) therapy:
A consensus definition of RSD/CRPS with standardized diagnostic criteria. There is practical agreement among neurologists, anesthesiologists and others about the minimal clinical criteria (signs and symptoms) that define RSD/CRPS. However, without a universally accepted definition and diagnostic criteria and a further validation and extension of the present clinical criteria, it is difficult to accurately identify RSD/CRPS patients, select patients for clinical trials, validate experimental human and animal model systems for research, and last-but-not-least to formulate testable hypotheses. The participants suggested that an expert meeting to specifically define the clinical and diagnostic criteria, based on what is known, should be a high priority for the field. Once determined, these consensus criteria should be disseminated to the medical, research and advocacy communities, in particular to those groups involved in the epidemiological studies, design of appropriate models for symptoms in RSD/CRPS, research on underlying mechanisms and the design of RSD/CRPS therapies tested in prospective clinical trials.
Epidemiological studies of RSD/CRPS using well-defined diagnostic criteria. Epidemiological studies to identify characteristics of patients at high risk for developing RSD/CRPS, to better define the relationship between certain clinical signs and disease onset, progression and distribution on the body, and to find out the incidence of patients with RSD/CRPS were considered a high priority. Patients with RSD/CRPS exhibit different combinations of symptoms. Does the individual RSD/CRPS patient progress through the three stages of the disorder as described in the literature. Most patients do not seem to go through different stages, although this has not been thoroughly investigated. Currently the symptomatic variability among RSD/CRPS patients makes it difficult to draw firm conclusions about mechanisms of the disorder based on clinical profiles, and could contribute to unclear findings in clinical trials. Strict patient selection based on defined clinical criteria could help to resolve this problem. Epidemiological studies may also help to clarify the anecdotal evidence regarding different incidence rates between women and men and the differences in the disease state between children and adults with RSD/CRPS. Finally, epidemiological studies may serve to work out prospective studies in order to find predictors for the development of RSD/CRPS.
Validate the existing models of CRPS and generate new models that recapitulate the unique features of RSD/CRPS. Appropriate experimental systems in which to study RSD/CRPS are required to advance the field; current model systems do not accurately reflect all of the symptoms experienced by patients, such as the potential gender disparity. We have models to study mechanisms operating in CRPS II (which may develop after trauma with nerve lesion); however, as noted by Dr. Gary Bennett, we almost totally lack animal models to study mechanisms operating in RSD/CRPS. Further, there are few simple in vivo or in vitro experimental model systems available to study potential RSD/CRPS disease mechanisms or to predict the efficacy of potential therapeutics.
Define disease mechanisms that give rise to RSD/CRPS in susceptible individuals. Several theories about disease mechanisms were presented at the workshop, but most questions addressing mechanisms clearly remain open. The participants felt that further research efforts focused on determining underlying mechanisms that cause RSD/CRPS are absolutely necessary to make progress in the design of a more appropriate (mechanism-based) diagnostic classification of RSD/CRPS patients and in the design of better therapeutic strategies. In the past, research efforts relevant to RSD/CRPS have generally focused on one component of the syndrome, such as pain, or blood flow, or bone/joint changes, but very little or not at all on central nervous system components related to the sensory, motor and sympathetic systems. Because RSD/CRPS affects multiple body systems, it is important to investigate the interactions between these peripheral and central components.
Integrate research on animal and human models with clinical research on patients. The workshop participants found it essential (and attractive) that research on animal and human models and clinical investigations of RSD/CRPS should be closely aligned. Thus research on mechanisms performed on different models must be interactive with clinical research. Any model, even the human one, is only an approximation to the clinical situation. Research on mechanisms in the models should concentrate on symptoms but not on syndromes.
New RSD/CRPS therapies tested in prospective clinical trials. To date, there are no clinical trials on the efficacy of various treatments of RSD/CRPS available that used evidence-based-medicine criteria (Dr. David Borsook). The participants presented preliminary anecdotal evidence for therapeutic approaches, such as long-term sympathetic and/or spinal cord blockade and physical therapy that could be tested in controlled, prospective clinical trials. Trials designed to treat patients at risk for developing RSD/CRPS (e.g., those undergoing knee-replacement surgery) would help to standardize the patient populations and may contribute to more reliable clinical results. As suggested by Dr. Howard Fields, a collaborative, multi-disciplinary, multi-site translational research program on RSD/CRPS may help to facilitate the development and testing of new therapies for this disorder.
In summary, there was a consensus amongst the participants of the workshop that future research on the mechanisms of RSD/CRPS must be much better integrated with the observation on the human patients, i.e. with the clinic. Design of both animal and human models must be more closely integrated with each other and with the clinic in order to focus the scientific questions, the formulation of hypotheses and the experimental approaches. Only such an interdisciplinary and multidisciplinary approach has a realistic chance of uncovering the pathophysiology and improving treatment of RSD/CRPS. Such an approach should be optimal to use and focus the different methodological techniques that are available to reach these aims. The best way to achieve this overall aim is to create research programs in association with the clinic in which the RSD/CRPS patients are diagnosed and treated.