'Cold Case': Vascular dysregulation in the chronic Complex Regional Pain Syndrome

The aim of this thesis was to study the nature of the vascular alterations in patients with cold chronic Complex Regional Pain Syndrome. CRPS usually develops as a disproportionate consequence of trauma and is characterised by spontaneous pain, movement disorders and abnormal regulation of blood flow and sweating. We hypothesised that endothelial dysfunction may in part be responsible for the diminished blood flow in cold chronic CRPS. An improvement on endothelial level would therefore lead to an increased blood flow and a subsequent improvement in pain and activity. In the second chapter we studied the characteristics of 195 patients with potential CRPS that visited our out-patients clinic. We found that a subgroup of patients with a lower temperature in the affected extremity had a longer disease duration and higher pain scores. The results of immunohistochemical staining on skin sections (chapter 3) and the measurement of blister fluids (chapter 4) indicate that endothelial dysfunction may play a role in chronic CRPS. Five female patients were treated with the nitric oxide donor isosorbide dinitrate (ISDN). In this pilot study, described in chapter five, topical application of ISDN improved temperature and pain in most patients. Two randomized placebo-controlled trials were initiated, both including 24 chronic cold CRPS patients. In the first study, which is described in chapter six, ISDN ointment was used by patients with CRPS in one hand. In the second study (chapter 7) the phosphodiesterase inhibitor tadalafil was used to induce vasodilation in patients with CPRS in one foot. Although neither studies produced a significant improvement in temperature asymmetry and blood flow there was a significant reduction of pain in the tadalafil group. We concluded that tadalafil may be a promising new treatment for patients with chronic cold CRPS due to endothelial dysfunction, which deserves further investigation. In chapter 8 we discuss the mechanisms responsible for ischemia and pain in chronic cold CPRS. The diminished blood flow may be caused by either sympathetic dysfunction, hypersensitivity to circulating catecholamines or endothelial dysfunction. Pain in CRPS may be of neuropathic, inflammatory, nociceptive, functional nature or of mixed origin. This origin of the pain should be the basis of the symptomatic therapy. Future research should focus on developing easily applied methods for clinical use to differentiate between central and peripheral blood flow regulation disorders in individual patients

Long-Term Clinical Results of Percutaneous Cervical Nucleoplasty for Cervical Radicular Pain:A Retrospective Cohort Study

PURPOSE: Percutaneous cervical nucleoplasty (PCN) is a minimally invasive treatment for cervical radicular pain due to a disc herniation. Preliminary results show equivalent patient-reported outcomes of PCN as compared to conventional anterior cervical discectomy. However, there is a paucity of long-term outcome data. Therefore, the primary objective of this study is to investigate the long-term clinical results of PCN. PATIENTS AND METHODS: A retrospective analysis was conducted on patients who underwent PCN at a secondary referral center between 2010 and 2014. Before surgery and five days after surgery, numeric rating scales (NRS) for arm pain and neck pain and data on complications were collected. To determine long-term follow-up outcomes, patients were sent a questionnaire booklet containing the Core Outcome Measures Index-Neck (COMI-Neck), NRS for arm pain and neck pain, Likert-scales on patient satisfaction and questions regarding the incidence of reoperations and complications. RESULTS: The baseline characteristics were collected for 158 patients. At a median follow-up of 41.5 months (interquartile range (IQR) 27.0 to 57.5), data were available for 118 patients (74.7%). At short-term follow-up, patients that underwent PCN had a mean decrease of 3.0 on the NRS for arm pain (95% CI 2.5 to 3.6) compared to baseline, while at long-term follow-up, a mean decrease of 2.8 (95% CI 1.0 to 3.6) was observed. At the long-term follow-up, 67.8% of the patients were fully recovered from all symptoms and 93.3% remained satisfied with the PCN treatment results. The reoperation rate for recurrent disc herniation was 21.4% at long-term follow-up. CONCLUSION: PCN appears to be a safe and effective treatment at short-term and long-term follow-up of a specific selection of cervical herniated discs, with an acceptable long-term reoperation rate. These study results suggest a potential role of PCN as a less invasive treatment option for cervical radicular pain due to a soft disc herniation, before anterior cervical discectomy should be considered

Evidence for local inflammation in complex regional pain syndrome type 1.

BACKGROUND: The pathophysiology of complex regional pain syndrome type 1 (CRPS 1) is still a matter of debate. Peripheral afferent, efferent and central mechanisms are supposed. Based on clinical signs and symptoms (e.g. oedema, local temperature changes and chronic pain) local inflammation is suspected. AIM: To determine the involvement of neuropetides, cytokines and eicosanoids as locally formed mediators of inflammation. METHODS: In this study, nine patients with proven CRPS 1 were included. Disease activity and impairment was determined by means of a Visual Analogue Scale, the McGill Pain Questionnaire, the difference in volume and temperature between involved and uninvolved extremities, and the reduction in active range of motion of the involved extremity. Venous blood was sampled from and suction blisters made on the involved and uninvolved extremities for measurement of cytokines interleukin (IL)-6, II-1beta and tumour necrosis factor-alpha (TNF-alpha), the neuropetides NPY and CRGP, and prostaglandin E2RESULTS: The patients included in this study did have a moderate to serious disease activity and impairment. In plasma, no changes of mediators of inflammation were observed. In blister fluid, however, significantly higher levels of IL-6 and TNF-alpha in the involved extremity were observed in comparison with the uninvolved extremity. CONCLUSIONS: This is the first time that involvement of mediators of inflammation in CRPS 1 has been so clearly and directly demonstrated. This observation opens new approaches for the succesful use and development of immunosuppressives in CRPS 1

Effect of tadalafil on blood flow, pain, and function in chronic cold Complex Regional Pain Syndrome: a randomized controlled trial

Background. This double-blind, randomized, controlled trial investigated the effect of the phosphodiesterase-5 inhibitor tadalafil on the microcirculation in patients with cold Complex Regional Pain Syndrome (CRPS) in one lower extremity. Methods. Twenty-four patients received 20 mg tadalafil or placebo daily for 12 weeks. The patients also participated in a physical therapy program. The primary outcome measure was temperature difference between the CRPS side and the contralateral side, determined by measuring the skin temperature with videothermography. Secondary outcomes were: pain measured on a Visual Analogue Scale, muscle force measured with a MicroFet 2 dynamometer, and level of activity measured with an Activity Monitor (AM) and walking tests. Results. At the end of the study period, the temperature asymmetry was not significantly reduced in the tadalafil group compared with the placebo group, but there was a significant and clinically relevant reduction of pain in the tadalafil group. Muscle force improved in both treatment groups and the AM revealed small, non-significant improvements in time spent standing, walking, and the number of short walking periods. Conclusion. Tadalafil may be a promising new treatment for patients that have chronic cold CRPS due to endothelial dysfunction, and deserves further investigation. Trial Registration. The registration number in the Dutch Trial Register is ISRCTN60226869

Diagnosing complex regional pain syndrome using an electronic nose, a pilot study

Objective: Complex regional pain syndrome (CRPS)is a complication after surgery or trauma and is characterized by a continuing regional pain in a distal extremity. The pain is disproportionate in severity and duration in relation to the preceding trauma. Currently, the diagnosis is based on the patients’signs and symptoms. There is no objective clinically applicable test available to confirm the diagnosis of CRPS, however this could contribute to a more reliable and valid diagnosis. Since the treatment of CRPS differs from that of other types of pain this could thereby lead to earlier and (more) appropriate treatment and possibly to lower medical costs. The Aeonose™ is a diagnostic test device which detects volatile organic profiles in exhaled air. Exhaled breath analysis using an electronic nose has been successfully applied to differentiate between sick and healthy persons for various indications. This study was a feasibility study in which we investigated whether the Aeonose™ is able to

Cost-Effectiveness of Radiofrequency Denervation for Patients With Chronic Low Back Pain:The MINT Randomized Clinical Trials

OBJECTIVES: To evaluate the cost-effectiveness of radiofrequency denervation when added to a standardized exercise program for patients with chronic low back pain. METHODS: An economic evaluation was conducted alongside 3 pragmatic multicenter, nonblinded randomized clinical trials (RCTs) in The Netherlands with a follow up of 52 weeks. Eligible participants were included between January 1, 2013, and October 24, 2014, and had chronic low back pain; a positive diagnostic block at the facet joints (n = 251), sacroiliac (SI) joints (n = 228), or a combination of facet joints, SI joints, and intervertebral discs (n = 202); and were unresponsive to initial conservative care. Quality-adjusted life-years (QALYs) and societal costs were measured using self-reported questionnaires. Missing data were imputed using multiple imputation. Bootstrapping was used to estimate statistical uncertainty. RESULTS: After 52 weeks, no difference in costs between groups was found in the facet joint or combination RCT. The total costs were significantly higher for the intervention group in the SI joint RCT. The maximum probability of radiofrequency denervation being cost-effective when added to a standardized exercise program ranged from 0.10 in the facet joint RCT to 0.17 in the SI joint RCT irrespective of the ceiling ratio, and 0.65 at a ceiling ratio of €30 000 per QALY in the combination RCT. CONCLUSIONS: Although equivocal among patients with symptoms in a combination of the facet joints, SI joints, and intervertebral discs, evidence suggests that radiofrequency denervation combined with a standardized exercise program cannot be considered cost-effective from a societal perspective for patients with chronic low back pain originating from either facet or SI joints in a Dutch healthcare setting

Effect of radiofrequency denervation on pain intensity among patients with chronic lowback pain the mint randomized clinical trials

IMPORTANCE Radiofrequency denervation is a commonly used treatment for chronic low back pain, but high-quality evidence for its effectiveness is lacking. OBJECTIVE To evaluate the effectiveness of radiofrequency denervation added to a standardized exercise program for patients with chronic low back pain. DESIGN, SETTING, AND PARTICIPANTS Three pragmatic multicenter, nonblinded randomized clinical trials on the effectiveness of minimal interventional treatments for participants with chronic low back pain (Mint study) were conducted in 16 multidisciplinary pain clinics in the Netherlands. Eligible participants were included between January 1, 2013, and October 24, 2014, and had chronic low back pain, a positive diagnostic block at the facet joints (facet joint trial, 251 participants), sacroiliac joints (sacroiliac joint trial, 228 participants), or a combination of facet joints, sacroiliac joints, or intervertebral disks (combination trial, 202 participants) and were unresponsive to conservative care. INTERVENTIONS All participants received a 3-month standardized exercise program and psychological support if needed. Participants in the intervention group received radiofrequency denervation as well. This is usually a 1-Time procedure, but the maximum number of treatments in the trial was 3. MAIN OUTCOMES AND MEASURES The primary outcomewas pain intensity (numeric rating scale, 0-10; whereby 0 indicated no pain and 10 indicated worst pain imaginable) measured 3 months after the intervention. The prespecified minimal clinically important difference was defined as 2 points or more. Final follow-up was at 12 months, ending October 2015. RESULTS Among 681 participants who were randomized (mean age, 52.2 years; 421 wom

Gut-directed hypnotherapy in children with irritable bowel syndrome or functional abdominal pain (syndrome): A randomized controlled trial on self exercises at home using CD versus individual therapy by qualified therapists

Background: Irritable bowel syndrome (IBS) and functional abdominal pain (syndrome) (FAP(S)) are common pediatric disorders, characterized by chronic or recurrent abdominal pain. Treatment is challenging, especially in children with persisting symptoms. Gut-directed hypnotherapy (HT) performed by a therapist has been shown to be effective in these children, but is still unavailable to many children due to costs, a lack of qualified child-hypnotherapists and because it requires a significant investment of time by child and parent(s). Home-based hypnotherapy by means of exercises on CD has been shown effective as well, and has potential benefits, such as lower costs and less time investment. The aim of this randomized controlled trial (RCT) is to compare cost-effectiveness of individual HT performed by a qualified therapist with HT by means of CD recorded self-exercises at home in children with IBS or FAP(S).Methods/Design: 260 children, aged 8-18 years with IBS or FAP(S) according to Rome III criteria are included in this currently conducted RCT with a follow-up period of one year. Children are randomized to either 6 sessions of individual HT given by a qualified therapist over a 3-month period or HT through self-exercises at home with CD for 3 months.The primary outcome is the proportion of patients in which treatment is successful at the end of treatment and after one year follow-up. Treatment success is defined as at least 50% reduction in both abdominal pain frequency and intensity scores. Secondary outcomes include adequate relief, cost-effectiveness an