Modulation of Pain Sensitization in Complex Regional Pain Syndrome

BACKGROUND Chronic pain represents a major challenge worldwide, with significant clinical, social and economic implications. Complex regional pain syndrome (CRPS) is a chronic pain condition that usually, but not exclusively, develops in response to acute trauma or surgery. It is characterized by pain disproportionate to the preceding trauma, in addition to sensory abnormalities and autonomic disturbances, trophic changes and impaired motor function. Reports indicate that the incidence of CRPS is 26.2/100.000 life-years, with a 3.5:1 female male ratio, and with a mean age at diagnosis 52.7y. The condition is complex and is probably the result of multimodal pathogenesis, that has a significant impact on daily functioning and quality of life (QoL). In addition, few cases resolve completely within 12 months of onset, has a large impact on work ability and some develop chronic pain and disability. The socioeconomic consequences are therefore substantial and an increased focus on CRPS diagnosis and treatment is needed. Because of the complexity of the condition, treatment is difficult and include physiotherapy, education, spinal cord stimulation (SCS) and medical treatment. Primary treatment involves medical treatment which might include important adverse effects such as fatigue, insomnia, anxiety and weight gain, to name a few. Regardless, results vary significantly. One explanation is the multimodality of pain that involves both peripheral nerves, the spinal cord and higher brain centers, modulated by immune cells, interneurons, descending pathways, cognitive and psychosocial factors. Changes in pain sensitization has been proposed to be a driving factor in CRPS and is the result of distorted somatosensory signaling in the central nervous system. Pain normally reflects damaging peripheral input, acting as an important protective function, however, this concept might get distorted so that pain no longer represent peripheral noxious stimuli but rather functional changes of the central nervous system. The pain in these situations arises spontaneously, can be elicited by normally innocuous stimuli (allodynia), is exaggerated and prolonged in response to noxious stimuli (hyperalgesia), and spreads beyond the site of injury (secondary hyperalgesia). Testing some of the underlying mechanisms provides the means to directly evaluate these pain symptoms suggested to be among the primary complaints in CPRS. Accordingly, a range of sensory changes has been suggested including thermal and mechanical hyperalgesia and hypoesthesia. A study found hyperalgesia to blunt pressure in patients with CRPS and with peripheral nerve injury, which has been confirmed by others, suggesting an importance of deep somatic structures such as muscles and bones. Another study showed changes in thermal sensitivity with both heat and cold hyperalgesia in the acute phase of CRPS and a modulation of thermal detection thresholds as the CRPS progressed. In addition, a study reported changes in endogenous pain modulation, implying a shift towards facilitation, whereas others found limited change. These differential results alongside heterogeneous mechanisms associated with diverse clinical features complicates treatment significantly which might only affect a small portion of patients. It is crucial to establish whether patients can be identified and distinguished to facilitate optimal decisions and effects of treatment strategies. This project applies a psychophysical method, based on conventional quantitative sensory testing (QST), to quantify somatosensory function in CRPS patients, to provide a mechanisms-based approach to diagnosis and treatment. Recently QST has been used to complement traditional neurological testing, with greater precision and reliability when assessing somatosensory aberrations and its clinical value is well recognized. Nevertheless, because of a lack of standardization and a paucity in normative data, the application of QST in clinical settings remains scarce. The current project applies QST methodology developed at the Spine center of Southern Denmark, Lillebaelt Hospital, specifically designed to meet clinical demands and will be part of a novel initiative to implement and standardize QST in clinical practice in Denmark. The methodology might prove valuable in a range of different pathologies such as headache, fibromyalgia and diabetic neuropathy. In addition, the current project will combine QST measurement with functional measurements and patient reported outcomes on depression, anxiety and sleep using a national database on pain in collaboration with Pain Center South, University Hospital Odense. The modulation of QST, their interaction and time course together with functional measurements and PRO-data might be a powerful combination for the diagnosis of patients, monitoring and prediction of therapy success. A therapy often used as an adjunct to medication is transcutaneous electrical nerve stimulation (TENS) which is an inexpensive, noninvasive and safe treatment for pain. Electrical stimulation is delivered to peripheral sensory nerves using surface electrodes and has been shown to have a beneficial effect on centralized pain, showing normalized hyperalgesia post intervention. Nevertheless, the beneficial effects remain controversial as more high-quality studies are needed. In addition, pain is complex and depends on contextual, social, psychological and biological factors not necessarily attributed to a specific pathology. These are rarely considered concurrently. The current project will evaluate the effect of TENS, in respect to patients psychological, functional and somatosensory profile, adding valuable information to the existing body of literature.

The aim of the current project is three-fold; 1) to test the feasibility and validity of standardized quantitative sensory testing for CRPS in clinical practice, 2) to evaluate changes in sensitization and 3) to evaluate the effectiveness of transcutaneous electrical nerve stimulation (TENS) and identify subgroups that benefit the most.

The investigators hypothesize that quantitative sensory testing is feasible in a clinical setting and will in combination with functional measurements and PRO-data be a valuable tool for the diagnosis of patients and for the monitoring and prediction of therapy success.

TRIAL DESIGN The project will utilize quantitative methods and strong randomized controlled research designs. The project will consist of two parts; 1) Evaluation of CRPS patient compared to healthy controls, and validation of method. Participants will be assessed at baseline prior to treatment with QST (mechanical stimulation, pain thresholds, cold/heat sensitivity) as outcome measure to identify somatosensory profiles of CRPS patients compared to normative data. 2) Evaluation of treatment with TENS compared to treatment as usual. Patients will be randomly allocated to either a TENS intervention group (TENS) or a treatment as usual group (MED) and will be assessed at baseline, re-test pre TENS, post intervention and 3 month post intervention. Outcomes include QST and patient reported outcomes (pain, quality of life, depression, anxiety, sleep, a.m.). Subsequent analysis of data is planned, to evaluate its ability to predict therapeutic outcomes of TENS.

RECRUITMENT AND SAMPLE SIZE Patients will be recruited from the clinic for CRPS and neuropathic pain, Hospital of South West Jutland, (SVS), University Hospital of Southern Denmark. The clinic functions as a specialized CRPS clinic in the Region of Southern Denmark. Healthy controls will be recruited amongst staff at SVS and partners, relatives or friends.