Candy McCabe

Intravenous immunoglobulin treatment of the complex regional pain syndrome: a randomized trial.

BACKGROUNDnTreatment of long-standing complex regional pain syndrome (CRPS) is empirical and often of limited efficacy. Preliminary data suggest that the immune system is involved in sustaining this condition and that treatment with low-dose intravenous immunoglobulin (IVIG) may substantially reduce pain in some patients.nnnOBJECTIVEnTo evaluate the efficacy of IVIG in patients with longstanding CRPS under randomized, controlled conditions.nnnDESIGNnA randomized, double-blind, placebo-controlled crossover trial. (National Research Registry number: N0263177713; International Standard Randomised Controlled Trial Number Registry: 63918259)nnnSETTINGnUniversity College London Hospitals Pain Management Centre.nnnPATIENTSnPersons who had pain intensity greater than 4 on an 11-point (0 to 10) numerical rating scale and had CRPS for 6 to 30 months that was refractory to standard treatment.nnnINTERVENTIONnIVIG, 0.5 g/kg, and normal saline in separate treatments, divided by a washout period of at least 28 days.nnnMEASUREMENTSnThe primary outcome was pain intensity 6 to 19 days after the initial treatment and the crossover treatment.nnnRESULTSn13 eligible participants were randomly assigned between November 2005 and May 2008; 12 completed the trial. The average pain intensity was 1.55 units lower after IVIG treatment than after saline (95% CI, 1.29 to 1.82; P < 0.001). In 3 patients, pain intensity after IVIG was less than after saline by 50% or more. No serious adverse reactions were reported.nnnLIMITATIONnThe trial was small, and recruitment bias and chance variation could have influenced results and their interpretation.nnnCONCLUSIONnIVIG, 0.5 g/kg, can reduce pain in refractory CRPS. Studies are required to determine the best immunoglobulin dose, the duration of effect, and when repeated treatments are needed.nnnPRIMARY FUNDING SOURCEnAssociation of Anaesthetists of Great Britain and Ireland, University College London Hospitals Charity, and CSL-Behring.

Using graded motor imagery for complex regional pain syndrome in clinical practice: Failure to improve pain

There is good evidence from studies conducted in a single‐centre research setting for the efficacy of graded motor imagery (GMI) treatment, a complex physiotherapy intervention, to reduce pain in long‐standing complex regional pain syndrome (CRPS). However, whether GMI is effective in clinical practice is not established.

Mirror Visual Feedback Therapy. A Practical Approach

Mirror visual feedback (MVF) was first proposed as a therapy to relieve amputee phantom limb pain in the early 1990s. It is increasingly used to treat a range of other chronic pain conditions. The evidence base to date is limited. Much of the literature consists of pilot projects or case study designs although larger randomized controlled trails are now emerging. However, the described protocols for MVF are inadequate to adapt to clinical practice. In addition, the therapist sees a heterogeneous population whose characteristics may fall outside those of the tight inclusion/exclusion criteria of research studies. This article provides the theoretical background to MVF and a detailed description of applying this therapy in clinical practice.

Clinical evidence of parietal cortex dysfunction and correlation with extent of allodynia in CRPS type 1

Unusual symptoms such as digit misidentification and neglect‐like phenomena have been reported in complex regional pain syndrome (CRPS), which we hypothesized could be explained by parietal lobe dysfunction.

What outcome measures are commonly used for Complex Regional Pain Syndrome clinical trials? A systematic review of the literature

Complex Regional Pain Syndrome (CRPS) is a chronic pain condition, often triggered by trauma to a limb and characterized by sensory, motor, autonomic and trophic changes within the affected limb. Due to the multi‐faceted nature of the condition there are a wide range of potential health outcome measures for use within CRPS related clinical trials. This aim of this systematic literature review was to identify which patient or health professional questionnaire format outcome measures have been used in CRPS specific clinical trials, and which of these have been developed specifically for use in CRPS populations. Information gained from this review will inform an international consortium project to define a Core Outcome measurement set for CRPS Clinical trials.

Low-Dose Intravenous Immunoglobulin Treatment for Long-Standing Complex Regional Pain Syndrome: A Randomized Trial

Complex regional pain syndrome (CRPS) is a rare chronic pain condition (population prevalence, less than 1 in 2000) arising after trauma to distal limbs (1, 2). The diagnosis is clinical, based on the assessment of sensory, motor, and autonomic abnormalities in the affected limb (3). Most patients improve spontaneously; however, the 15% who still have symptoms 1 year after onset have a quality of life among the worst of patients with any medical condition, and their prognosis is poor (4, 5). Treatment with analgesic drugs, such as antidepressants, or with anticonvulsants rarely is effective (6). Recommended therapy is multidisciplinary care; however, many patients will not achieve pain relief (7). After a chance observation, we conducted a prospective open study and a small randomized crossover trial in which low-dose intravenous immunoglobulin (IVIg) substantially reduced pain in this patient group. In both studies, 25% of patients had profound pain relief of greater than 50% (8, 9). The phase 3 LIPS (Low-Dose Immunoglobulin in Long-Standing Complex Regional Pain Syndrome) randomized controlled trial (RCT) was conducted to confirm the efficacy of repeated-dose treatment with low-dose IVIg compared with placebo in a large group of patients with long-standing CRPS. The primary outcome was pain intensity measured daily for 6 weeks after infusion and was compared between the IVIg and placebo groups. Methods Design Overview In this parallel-group trial, patients with CRPS were randomly assigned in 1:1 allocation to receive either 2 infusions of IVIg, 0.5 g/kg of body weight, or placebo. All patients were offered an open-label extension of 2 IVIg infusions. Providers, researchers, and outcome assessors were blinded to treatment assignment. The East of England Welwyn committee gave ethics approval (reference: 12/EE/0164). Patients were provided with informational leaflets about the trial, and those interested in participating provided written informed consent. The study protocol has been published (10) and is available in Supplement 1. Supplement 1. Study Protocol Setting and Participants The study recruited patients from 7 secondary and tertiary care pain treatment centers in the United Kingdom; potential participants were identified from the internal databases of these study centers or were referred to the centers as new patients. To enhance recruitment, the study was promoted regularly throughout the United Kingdom in pain medicine journals, through letters to each specialist pain clinic, on social network sites, and within CRPS patient organizations. Eligible participants were nonpregnant adults with moderate or severe CRPS (on the basis of the Budapest research criteria [3]). The CRPS severity cutoff was concealed and determined by a mean pain intensity score of 5 points or higher on an 11-point (0- to 10-point) numeric rating scale (NRS) recorded in the first 7 daily pain diary entries during screening, with no single entry below 4 points. A pain intensity score of 4 points is considered a cut point between mild and moderate pain (11). The Budapest research criteria, used by all the recruitment centers, require the presence of at least 1 regional sign in at least 2 of the following 4 diagnostic categories: sensory abnormalities, such as allodynia; swelling or sweating; color or temperature changes; and motor or trophic changes. The criteria also require the report of symptoms in all 4 categories. Patients with CRPS type I (without nerve injury) or II (with nerve injury) were eligible to participate. Eligible patients had CRPS for 1 to 5 years and no other pain that, in the study physicians opinion, might interfere with their personal assessment of CRPS pain changes. Before enrollment, patients received tricyclic antidepressants, gabapentinoids, and mild and strong opioids, as well as specialized pain physiotherapy, unless these treatments were refused or contraindicated. Patients with an implanted spinal cord stimulator were eligible if they met pain intensity criteria with the stimulator turned on. Participants continued their usual exercise and medication regimens. Further details regarding inclusion and exclusion criteria are provided in the study protocol (Supplement 1) (10). After giving consent and being screened for eligibility, suitable patients completed a screening diary for 7 days, then were contacted by telephone to ascertain their diary values; those who met the pain eligibility criteria were randomly assigned to a study group 10 to 21 days after screening (that is, on day 0). Randomization and Interventions Participants were individually randomly assigned (1:1) to receive IVIg or placebo by site staff via an independent online system, using block randomization with randomly varying block sizes, stratified by study center. The intervention was blinded by preparation of the IVIg (0.5 g/kg) or placebo solution (0.1% albumin in normal saline) in bottles of identical appearance. Upon notification, nonblinded dispensing site pharmacists removed the bottle label indicating the trial group before dispensing the agents. All other study site staff, the trial manager or site monitor, the statistician, and the chief investigator remained blinded to the patients treatment assignments until database lock. No participants required emergency unblinding. Blinded infusions were scheduled on days 1 and 22 after randomization. A predetermined time window around the infusion days provided flexibility (first infusion, up to 5 working days; second infusion, day 221 day). The primary outcome period, days 6 to 42 after randomization, remained fixed and was thus independent of the actual infusion dates. Patients who completed the blinded phase were offered open-label IVIg on days 43 and 64 after randomization. The dosages prescribed were within normal, weight-determined clinical limits (0.5 g/kg) for low-dose treatment. Outcomes and Follow-up The primary outcome measure was the average 24-hour pain intensity score on an 11-point NRS, with 0 designating no pain and 10 pain as bad as you can imagine. This outcome was measured daily from days 6 to 42, with this interval prespecified to exclude the period of early, unspecific, temporary pain increases, such as headaches (8). Secondary outcomes were pain interference, measured with the interference subscale of the Brief Pain Inventory (11-point NRS from 0 to 10 points), with higher scores indicating more interference (12), and quality of life (measured by the 5-level EuroQol 5-dimensional questionnaire [EQ-5D-5L]), where higher scores indicate a better quality of life (13). All other outcomes were exploratory. Paper diaries documenting the participants average 24-hour pain intensity were self-administered from days 1 to 42 after randomization (an example diary is provided in Supplement 2). Patients who decided to have 2 open infusions after the blinded phase completed additional 24-hour diaries until day 84, then completed weekly pain diaries for 9 more weeks. The other patients completed weekly diaries for 3 weeks. Site staff contacted participants twice after each infusion to confirm their adherence to keeping the pain diaries and to document any adverse events. Supplement 2. Web Appendix At screening and day 43, patients completed questionnaires assessing their multidimensional pain experience. Multidimensional assessment tools were used, including those for pain interference, quality of life, and other factors, in line with consensus recommendations for pain trials (14); details are provided in Supplement 2 and the study protocol (Supplement 1) (10). At these 2 time points, we also measured skin temperature of both the CRPS-affected and contralateral limbs (see protocol in Supplement 1). At the screening visit, blood was drawn for safety analysis (full blood count and assessment of serum immunoglobulin, creatinine, urea, and electrolyte levels) and, if applicable, pregnancy tests were administered to determine each patients eligibility. Reasons for withdrawal from randomly assigned treatment were reported at days 22 and 43 after randomization. Patients recorded adverse events and reactions in their diaries, and these notes were transcribed on days 22 and 43 after randomization. In addition, study nurses queried patients for adverse events by asking open-ended questions during scheduled telephone calls on days 2 and 5 after each infusion. A study physician rated the severity and causality of each event on categorical scales. Adverse events related to open-label infusions, reported from 43 to 85 days after randomization, were tabulated separately. Serious adverse events were monitored for 21 days after the final dose of IVIg (or placebo) or until resolution. Statistical Analysis The sample size was based on the following assumptions from a pilot study (8): 122 participants were needed to detect a clinically meaningful difference, on a group level (15), in a pain score of 1.2 points on the NRS, determined by using a 2-sample t test assuming 5% statistical significance, 85% power, and a common SD of 2.2 (as in the previous study). Assuming 10% loss to follow-up and 5% nonadherence increased this number to 152 participants. We intended to collect 37 measurements of pain intensity (the primary outcome) per participant and to analyze the outcome by using a mixed-effects regression model. Therefore, the sample size was reduced on the basis of these extra measurements. From the pilot study (8), the correlation between a patients measures was assumed to be 0.7; hence, the multiplying factor was [1 + (371)0.7]/37= 0.71. Therefore, the total sample size required was calculated as 1520.71= 108 participants (54 participants per study group). All statistical analyses were conducted by using Stata, version 14 (StataCorp). The primary outcome was analyzed by using a random intercept mixed model (Stata: mixed) to establish any difference in pain scores between the IVIg and placebo gro

Development of a complex intervention for people with chronic pain after knee replacement: the STAR care pathway

BackgroundApproximately 20% of people who have total knee replacement experience chronic pain afterwards, but there is little evidence about effective interventions for managing this type of pain. This article describes the systematic development and refinement of a complex intervention for people with chronic pain after knee replacement. The intervention is a care pathway involving an assessment clinic and onward referral, with telephone follow-up as required. In the design of this multistage study, we chose to focus on ensuring that the intervention was deliverable, implementable and acceptable.MethodsIn line with the UK Medical Research Council’s recommendations for comprehensive development of complex interventions, multiple phases of work were undertaken. Following on from initial development work to design the intervention, the draft intervention content was refined through consensus questionnaires with 22 health professionals and discussion at meetings with 18 healthcare professionals. Testing of intervention delivery and acceptability to patients was undertaken by two health professionals delivering the assessment clinic to ten patients. Views about future implementation within the context of a randomised trial were evaluated through a questionnaire based on the Normalisation Measure Development (NoMAD) instrument with ten health professional stakeholders.ResultsConsensus work with health professionals ensured the components of the intervention were appropriate and informed a number of substantive changes to improve the intervention. Testing of intervention delivery identified a number of logistical issues that were then addressed in the development of a comprehensive intervention training manual. Engagement with stakeholders indicated that the intervention could be successfully implemented in a clinical setting for evaluation in a randomised trial.ConclusionsThis work has informed the development and refinement of a complex intervention for people with chronic pain after knee replacement. The next stage is to evaluate the clinical and cost-effectiveness of the STAR care pathway in a multicentre randomised trial.

Maintained physical activity and physiotherapy in the management of distal upper limb pain - a protocol for a randomised controlled trial (the arm pain trial)

BackgroundDistal upper limb pain (pain affecting the elbow, forearm, wrist, or hand) can be non-specific, or can arise from specific musculoskeletal disorders. It is clinically important and costly, the best approach to clinical management is unclear. Physiotherapy is the standard treatment and, while awaiting treatment, advice is often given to rest and avoid strenuous activities, but there is no evidence base to support these strategies. This paper describes the protocol of a randomised controlled trial to determine, among patients awaiting physiotherapy for distal arm pain, (a) whether advice to remain active and maintain usual activities results in a long-term reduction in arm pain and disability, compared with advice to rest; and (b) whether immediate physiotherapy results in a long-term reduction in arm pain and disability, compared with physiotherapy delivered after a seven week waiting list period.Methods/DesignBetween January 2012 and January 2014, new referrals to 14 out-patient physiotherapy departments were screened for potential eligibility. Eligible and consenting patients were randomly allocated to one of the following three groups in equal numbers: 1) advice to remain active, 2) advice to rest, 3) immediate physiotherapy. Patients were and followed up at 6, 13, and 26xa0weeks post-randomisation by self-complete postal questionnaire and, at six weeks, patients who had not received physiotherapy were offered it at this time. The primary outcome is the proportion of patients free of disability at 26xa0weeks, as determined by the modified DASH (Disabilities of the Arm, Shoulder and Hand) questionnaire.We hypothesise (a) that advice to maintain usual activities while awaiting physiotherapy will be superior than advice to rest the arm; and (b) that fast-track physiotherapy will be superior to normal (waiting list) physiotherapy. These hypotheses will be examined using an intention-to-treat analysis.DiscussionResults from this trial will contribute to the evidence base underpinning the clinical management of patients with distal upper limb pain, and in particular, will provide guidance on whether they should be advised to rest the arm or remain active within the limits imposed by their symptoms.Trial registrationRegistered on http://www.controlled-trials.com (reference number: ISRCTN79085082).

Clinical and cost-effectiveness of the STAR care pathway compared to usual care for patients with chronic pain after total knee replacement: Study protocol for a UK randomised controlled trial

BackgroundApproximately 20% of patients experience chronic pain after total knee replacement. There is little evidence for effective interventions for the management of this pain, and current healthcare provision is patchy and inconsistent. Given the complexity of this condition, multimodal and individualised interventions matched to pain characteristics are needed. We have undertaken a comprehensive programme of work to develop a care pathway for patients with chronic pain after total knee replacement. This protocol describes the design of a randomised controlled trial to evaluate the clinical- and cost-effectiveness of a complex intervention care pathway compared with usual care.MethodsThis is a pragmatic two-armed, open, multi-centred randomised controlled trial conducted within secondary care in the UK. Patients will be screened at 2 months after total knee replacement and 381 patients with chronic pain at 3 months postoperatively will be recruited. Recruitment processes will be optimised through qualitative research during a 6-month internal pilot phase. Patients are randomised using a 2:1 intervention:control allocation ratio. All participants receive usual care as provided by their hospital. The intervention comprises an assessment clinic appointment at 3 months postoperatively with an Extended Scope Practitioner and up to six telephone follow-up calls over 12 months. In the assessment clinic, a standardised protocol is followed to identify potential underlying causes for the chronic pain and enable appropriate onward referrals to existing services for targeted and individualised treatment. Outcomes are assessed by questionnaires at 6 and 12 months after randomisation. The co-primary outcomes are pain severity and pain interference assessed using the Brief Pain Inventory at 12 months after randomisation. Secondary outcomes relate to resource use, function, neuropathic pain, mental well-being, use of pain medications, satisfaction with pain relief, pain frequency, capability, health-related quality of life and bodily pain. After trial completion, up to 30 patients in the intervention group will be interviewed about their experiences of the care pathway.DiscussionIf shown to be clinically and cost-effective, this care pathway intervention could improve the management of chronic pain after total knee replacement.Trial registrationISRCTN registry (ISRCTN92545361), prospectively registered on 30 August 2016.

Digital behaviour change interventions to facilitate physical activity in osteoarthritis: A systematic review

Background Digital behaviour change interventions (DBCIs) might offer an opportunity to support people with osteoarthritis (OA) to self-manage and monitor their levels of physical activity (PA). Objectives To determine the effectiveness of DBCIs for increasing physical activity in people with OA; to identify theory and techniques used; to examine outcome measures for physical activity; to document how uptake and usage is reported. Methods Electronic databases were searched up to July 2017. Interventions for adults with OA, which aimed to increase levels of physical activity, delivered via a digital platform, were included. Results Nine studies met the inclusion criteria. Six reported significant increases in physical activity. Interventions were mostly based on Social Cognitive Theory. Numerous behaviour change techniques (BCTs) were used. Most common physical activity outcomes measures were; self-reported aerobic exercise and self-reported strengthening exercises. Two studies used wearable activity monitors. A wide variety of methods were employed to report uptake and usage of DBCIs. Conclusions Existing DBCIs can have a short-term positive effect on levels of physical activity in this population, but it remains unclear how effective they might be, over a longer period of time. It is vital to document and evaluate how individual components influence the outcome and effectiveness of an intervention. Future interventions should identify BCTs used in the development stages, and use valid measures of both physical activity, and intervention usage, so that results are transparent and comparable.