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Purpose Although autonomic features are part of the diagnostic criteria for complex regional pain syndrome (CRPS), the role of the autonomic nervous system in CRPS pathophysiology has been downplayed in recent years. The purpose of this review is to redress this imbalance. Methods We focus in this review on the contribution of the autonomic nervous system to CRPS pathophysiology. In particular, we discuss regional sympathetic and systemic autonomic disturbances in CRPS and the mechanisms which may underlie them, and consider links between these mechanisms, immune disturbances and pain. Results The focused literature research revealed that immune reactions, alterations in receptor populations (e.g., upregulation of adrenoceptors and reduced cutaneous nerve fiber density) and central changes in autonomic drive seem to contribute to regional and systemic disturbances in sympathetic activity and to sympathetically maintained pain in CRPS. Conclusions We conclude that alterations in the sympathetic nervous system contribute to CRPS pathology. Understanding these alterations may be an important step towards providing appropriate treatments for CRPS.

The aim of this study was to determine whether upregulated cutaneous expression of α1-adrenoceptors (α1-AR) is a source of pain in patients with complex regional pain syndrome (CRPS). Immunohistochemistry was used to identify α1-AR on nerve fibres and other targets in the affected and contralateral skin of 90 patients, and in skin samples from 38 pain-free controls. The distribution of α1-AR was compared between patients and controls, and among subgroups of patients defined by CRPS duration, limb temperature asymmetry, and diagnostic subtype (CRPS I vs CRPS II). In addition, α1-AR expression was investigated in relation to pain and pinprick hyperalgesia evoked by intradermal injection of the α1-AR agonist phenylephrine. Expression of α1-AR on nerve bundles in the CRPS-affected limb was greater in patients who reported prolonged pain and pinprick hyperalgesia around the phenylephrine injection site than in patients with transient pain after the injection. In addition, α1-AR expression in nerve bundles was greater in patients with CRPS II than CRPS I, and was greater in acute than more long-standing CRPS. Although less clearly associated with the nociceptive effects of phenylephrine, α1-AR expression was greater on dermal nerve fibres in the painful than contralateral limb. Together, these findings are consistent with nociceptive involvement of cutaneous α1-AR in CRPS. This involvement may be greater in acute than chronic CRPS, and in CRPS II than CRPS I.

Sensory disturbances often spread beyond the site of injury in complex regional pain syndrome (CRPS) but whether this applies equally to CRPS I and II, or changes across the course of the disease, is unknown. Establishing this is important, because different symptom profiles in CRPS I and II, or in acute vs chronic CRPS, might infer different pathophysiology and treatment approaches. To explore these questions, sensory disturbances were assessed in the limbs and forehead of 71 patients with CRPS I and 33 patients with CRPS II. Pain had persisted up to 12 months in 32 patients, for 13 to 36 months in 29 patients, and for longer than this in 43 patients. Patients with CRPS I were more likely to be female, and pain was more likely to be present in an additional limb, than patients with CRPS II. Conversely, pain was more likely to be associated with sensory deficits and allodynia in patients with CRPS II than CRPS I. Nevertheless, heightened sensitivity, allodynia, and/or hyperalgesia to mechanical and thermal stimuli were detected in a hemisensory distribution ipsilateral to the affected limb in both forms of CRPS. Some of these hemisensory disturbances strengthened with chronicity of pain. These findings suggest that heightened excitability of nociceptive pathways in CRPS spreads to hemisensory convergence points in the brainstem or higher brain centres, possibly in association with compromised pain controls. The similarity of symptom profiles in chronic CRPS I and II implies shared mechanisms despite different triggers.

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Objective: Findings regarding small nerve fiber damage in complex regional pain syndrome type I (CRPS-I) are not uniform, and studies have not included a matched healthy control group. The aim was to assess intraepidermal nerve fiber density (IENFD) in relation to thermal sensitivity of the same skin areas in CRPS-I patients and a gender- and age-matched healthy control group. Methods: IENFD was investigated in skin biopsies from the CRPS-affected and contralateral limbs of eight CRPS-I patients and from an equivalent site in eight gender- and age-matched healthy controls (HCs). Thermal thresholds (cold/warm detection, cold- and heat-pain detection) were assessed on the affected limb, the matching contralateral limb, and on the equivalent limbs of HCs, and participants rated the intensity of cold/heat and pain to static thermal stimuli (5 °C and 40 °C). Results: IENFD was significantly lower in both the affected and contralateral limbs of CRPS-I patients than HCs, but IENFD did not differ between the affected and contralateral limbs of patients. The heat pain threshold was lower in the affected CRPS-I limb than in HCs, but all other thermal thresholds were similar in both groups. CRPS-I patients rated the cold stimulus as colder and more painful in the affected limb, and the warm stimulus as hotter, bilaterally, than the HCs. Conclusions: CRPS-I may be associated with bilateral small fiber damage, and perhaps small fiber neuropathy and bilateral disturbances in thermo-sensory perception. These disturbances could stem from a systemic response to injury or might increase the risk of developing CRPS-I after physical trauma.

Background Ambiguous visual stimuli increase limb pain in patients with complex regional pain syndrome (CRPS), possibly due to afferent sensory feedback conflicts. Conflicting sensory stimuli can also generate unpleasant sensations in healthy people such as during motion sickness. We wanted to investigate the mechanisms underlying the link between sensory conflicts and pain in CRPS using optokinetic stimulation (OKS) – a method known to induce motion sickness. Methods Twenty-one CRPS patients underwent OKS and rated symptoms of motion sickness. Patients also rated limb pain and pain-related distress before, during and after OKS. In addition, pressure-pain and sharpness sensations were investigated on both sides of the forehead and in the affected and contralateral limb before and after OKS. Results Limb pain and forehead hyperalgesia to pressure increased in parallel in response to OKS. In a subgroup of nauseated patients who withdrew early from OKS, hyperalgesia to pressure in the ipsilateral forehead persisted longer than in the remaining participants. Sharpness sensations remained constant at all sites. Conclusions Sensory conflicts may facilitate pain in CRPS by activating the mechanisms of general facilitation of nociception and, during more severe sensory conflicts, also a facilitatory mechanism that operates mainly ipsilateral to the affected limb.