A randomised placebo-controlled Phase III multicentre trial: low-dose intravenous immunoglobulin treatment for long-standing complex regional pain syndrome (LIPS trial)

Abstract

Background Complex regional pain syndrome (CRPS) is a rare, severe post-traumatic pain condition affecting distal limbs. Patients who do not spontaneously improve in 12 months are classed as having ‘long-standing CRPS’ and often cannot be effectively treated, leading to a poor prognosis. CRPS is associated with functional autoantibodies. Two small trials, including a randomised controlled trial, have suggested that low-dose intravenous immunoglobulin (IVIg) may be an effective treatment for some patients. Objective We hypothesised that low-dose IVIg is effective for reducing pain in long-standing CRPS. Methods A randomised, double blinded placebo-controlled multicentre trial in seven UK pain management centres. Patients were eligible if they had moderate or severe long-standing CRPS that they had experienced for up to 5 years. Participants were randomly allocated to receive 0.5 g/kg IVIg, the active intervention, or visually indistinguishable 0.1% albumin in saline placebo. Randomisation was initiated by study sites via an independent online randomisation system and was 1 : 1 with varying block sizes, stratified by study centre. Participants, investigators and assessors were blinded to group assignment. The study drug/placebo was infused intravenously at the study centres on day 1 and day 23 after randomisation. The primary outcome was the 24-hour average pain intensity between day 6 and day 42, on an 11-point (0–10) numeric rating scale, compared between the groups. Outcomes were analysed using a mixed-effects regression model that used 37 measurements of pain intensity (the primary outcome) per participant. All patients who received an infusion and provided any outcome were included in the intention-to-treat analysis. Results A total of 111 patients were recruited and assigned between 27 August 2013 and 28 October 2015. Three patients were excluded because they had been inappropriately randomised, five patients were withdrawn from the primary analysis because they provided no outcomes and 103 patients were analysed for the primary outcome. The average pain score in the IVIg group was 0.27 units (95% confidence interval –0.24 to 0.80 units) higher than in the placebo group. Therefore, there is no significant evidence of a treatment effect at the 5% level and there was no significant difference between groups. Six serious adverse events but no suspected unexpected serious adverse reactions were reported during the blinded and open-label phase. Conclusion and future work Low-dose immunoglobulin was not effective in relieving pain in patients with moderate to severe CRPS of 1–5 years’ duration. Better drug treatments for long-standing CRPS are urgently required. Trial registration Current Controlled Trials ISRCTN42179756. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership. Additional funding was obtained by the Pain Relief Foundation. Biotest UK Ltd provided the active study medication at no cost.

Safety of the 9-Valent Human Papillomavirus Vaccine

“…23,24 Reports suggestive of POTS (hallmark of which is orthostatic symptoms of unknown etiology), CRPS (a rare, poorly understood chronic pain condition), and other selected prespecified conditions were evaluated by using established diagnostic criteria. [25][26][27][28][29][30][31] Cause of death was determined from information documented in the autopsy report, death certificate, or medical records.…”

“…We identified 1 report of a possible case of CRPS 26 : a 13-year-old girl with history of anxiety who experienced perisacral pain that spread to her back and lower extremities the day after vaccination with 9vHPV. At the time of the report, she continued to experience severe pain and bilateral decreased range of motion and weakness in her lower extremities.…”

Systematic reviews do not (yet) represent the ‘gold standard’ of evidence: A position paper

“…While many pain conditions are relatively common, others are rare, making patient recruitment difficult. Systematic review of CRPS demonstrates that most studies involve very few patients, although at least two studies have recruited around 100 patients (Goebel et al, 2017;Mbizvo et al, 2015). Despite these modest numbers, this systematic review was able to make a relevant observation about the absence of a placebo effect in CRPS.…”

“…This depends on two main factors: the size of any likely treatment effect and the practicalities of recruiting patients with the disorder. Treatment effects in acute and chronic pain are known to vary between zero for intravenous immunoglobulins in complex regional pain syndrome (CRPS; Goebel et al, 2017) and 95% for oral opioids in cancer pain (Wiffen et al, 2017) and between these values (Moore, Derry et al, 2013Moore, Straube et al, 2013. While many pain conditions are relatively common, others are rare, making patient recruitment difficult.…”

Application of the IASP grading system for ‘nociplastic pain’ in chronic pain conditions: A field study

“…Further, the pain must have been reported for at least 3 months before inclusion and the average pain should be of at least moderate severity (numeric rating scale (NRS) ≥ 4/10). For the CP1 groups inand exclusion criteria were a confirmed diagnosis of FMS or CRPS based on documentation in patient records that followed established diagnostic criteria (Andreas Goebel et al, 2017;Finnerup et al, 2016;F. Wolfe et al, 1990;Frederick Wolfe et al, 2010) and freedom from specific rheumatological or systemic inflammatory or other major medical conditions.…”