It is especially difficult to treat a disease for which no solid reason behind it can be found. Could it be possible that everyone who has pain out of proportion to the cause, loss of function of a limb and autonomic changes to their limb have their condition for the same basic reason? Science has yet to figure that out.
It has been suggested that RSD is purely an abnormality of the sympathetic nervous system, yet there is evidence that the actual pathophysiology of RSD is a hypersensitivity to one or more neurotransmitters. There could also be a release of a pain substance, such as substance P or a disturbance of the body’s normal opioid metabolism. The inflammatory response may be exaggerated. There could even be spinal involvement in this disease.
Although it was once considered absolute that the sympathetic nervous system was the underlying cause of RSD, it is now believed that the cause is not due to an increase in sympathetic tone. More likely, the cause is due to an increase in catecholamine sensitivity because of denervation of the sympathetic nervous system. This goes along with an increase in the number or sensitivity of the peripheral axonal adrenoceptors to make for pain hypersensitivity.
Other pathophysiological mechanisms that have been thought of regarding RSD include neurogenic inflammation with neuropeptide release by pain-receiving afferent nerves and sympathetic efferent nerves. Substance P may be involved as might calcitonin gene-related peptide and neuropeptide Y. Each of them induces an inflammatory response and cause skin erythema, edema, and increased pain in the affected area. Nerve inflammation at the site of the injury plus neuromediator accumulation or deterioration probably causes RSD. Unfortunately, no single neurotransmitter or modulator has been found to be responsible for all the symptoms found in this disorder.
Functional MRI studies have been done that suggest RSD could be a systemic condition rather than a set of similar symptoms. It appears to involve cognitive, motor and nociceptive aspects of the nervous system. When an affected arm was pricked with a pin, it was found to be painful. This was associated with significant activation of the contralateral S1 cortex, bilateral S2 cortex and the insula of the brain. Associative aspects of the somatosensory cortex on both sides were activated.
In contrast to the previously thought increase in sympathetic activity of the autonomic nervous system, there appears to be a reduction in sympathetic nerve outflow. It now appears that the central nervous system has a bigger role in causing and perpetuating the disease.
Some researchers have discovered that the N-methyl-D-aspartate or NDMA receptor has a big involvement in the sensitization process of the central nervous system (CNS). Levels of glutamate in the CNS further wind up and sensitize the nervous system, particularly centrally. What this means is that RSD may not be local at all but may be a CNS disease with the potential to affect the whole body. NDMA also has receptors in the peripheral nervous system, which may play a role in the disease.
In short, the pathophysiology of RSD has not yet been identified but there are a great many possibilities.
Although RSD and CRPS are now well-accepted diagnoses, the conditions remain relatively uncommon. Unfortunately, this means that many primary care physicians, surgeons, and other medical professionals who are seeing a patient with these puzzling and unusual symptoms may not recognize the condition, having never personally seen it before. This can often result in delayed diagnosis and unneeded stress for sufferers who feel that their reports of severe pain are being ignored or not being believed.