Treatment with low-dose intravenous immunoglobulin (IVIg) is no more effective than placebo in patients with complex regional pain syndrome (CRPS), new research suggests.
The randomized controlled trial of more than 100 adult patients with CRPS showed that those who received two infusions of IVIg at 0.5 g/kg of body weight for 6 weeks did not have a significantly greater reduction in pain than those who received matching placebo.
Pain interference and quality of life (QOL) scores also did not differ significantly between the two treatment groups.
“After our earlier small studies, we were very surprised to see that this didn’t work,” lead author, Andreas Goebel, MD, PhD, Pain Research Institute, Institute of Translational Medicine, University of Liverpool, United Kingdom, told Medscape Medical News.
“The take-away message for clinicians is mainly that in a well-conducted trial, this intervention was not effective, unfortunately,” said Dr Goebel.
The findings were published online October 3 in Annals of Internal Medicine.
Rare Condition
CRPS “is a rare chronic pain condition (population prevalence, less than 1 in 2000) arising after trauma to distal limbs,” write the investigators.
“Most patients improve spontaneously; however, the 15% who still have symptoms 1 years after onset have a quality of life among the worst of patients with any medical condition, and their prognosis is poor,” they add.
“We currently have very little that we can offer these patients, as far as interventions to reduce their pain,” said Dr Goebel. “In fact, there is no evidence-based drug treatments that can reduce pain in patients with this persistent condition, having it for more than a year.”
“After a chance observation,” the researchers conducted an observational and a small randomized study showing that low-dose IVIg significantly reduced pain scores in patients with this condition, spurring them to confirm efficacy in a larger population.
Between August 2013 and October 2015, 111 patients were enrolled at seven pain management centers in the United States for the phase 3 LIPS (Low-Dose Immunoglobulin in Longstanding Complex Regional Pain Syndrome) trial.
The participants, all of whom had moderate-to-severe CRPS for 1 to 5 years, were randomly assigned to receive IVIg at 0.5 g/kg of body weight at baseline and at day 22 (n = 55; 63% women; mean age, 44 years) or “visually indistinguishable placebo of 0.1% albumin in saline” (n = 56; 75% women; mean age, 41 years).
The primary outcome was 24-hour average pain intensity on an 11-point numeric rating scale, which was self-recorded daily on paper diaries for 6 weeks.
Results showed that the active treatment group had a mean average pain intensity score of 7.2 points (standard deviation [SD], 1.3) vs 6.9 points (SD, 1.5) for the placebo group.
The adjusted mean difference between the group was 0.27 (95% confidence interval, –0.25 to 0.80; P = 0.3), “which excluded the prespecified, clinically important difference of –1.2,” note the investigators.
In addition, 68% of the IVIg group and 66% of the placebo group had lower pain scores, and 1 and 3 group members, respectively, had 30% pain reduction, while only 1 member of the placebo group had 50% pain reduction.
Alternatives Needed
Secondary outcomes were pain interference scores on the Brief Pain Inventory (BPI) and scores on the 5-level Euro-QOL 5-dimensional questionnaire (EQ-5D-5L).
At baseline, both treatment groups had a mean score of about 7.3 on the BPI at baseline. After 6 weeks, the pain interference scores decreased to 7.24 (SD, 1.54) and 6.89 (SD, 2.08) for those receiving low-dose IVIg and placebo, respectively, which was not significantly different.
The mean baseline score on the EQ-5D-5L was about 0.33 for both groups. At 6 weeks, the scores were a nonsignificantly different 0.41 (SD, 0.27) and 0.37 (SD, 0.29) for each group, respectively.
In this blinded phase, 1 patient in each treatment group had a serious adverse event (SAE). The patient receiving IVIg had severe headaches and the patient receiving placebo had severe headaches and vomiting.
In an optional 6-week open extension phase, 4 patients receiving low-dose IVIg had an SAE.
“Our results do not extend to treatment with full-dose IVIg, such as a 2-g/kg infusion,” note the investigators. They add that using albumin as the placebo may have also “confounded treatment effects because of its possible activity in immune-mediated disorders.”
Still, “alternative analgesic technologies are needed to allow treatment of this often-devastating condition,” they write.
“I think the results were definitive for low-dose treatment,” added Dr Goebel. “I think we could still look at high-dose treatment, but I don’t have any experience with that.”
All Hope Gone?
In an accompanying editorial with a title that asks: “Is Hope Gone?”, Frank Birklein, MD, University of Mainz, Germany, and Claudia Sommer, MD, University of Würzburg, Germany, note that although these study results were not positive, the pursuit of immunomodulatory therapy for patients with CRPS is not wrong.
“As a frequently used expression states, the absence of evidence should not be equated with evidence of absence,” they write.
Reasons for the trial’s failure of effectiveness may include the low dose used, “whereas neurologic autoimmune diseases usually are treated with doses 4 times higher,” and that animal models have suggested that “immune mediators may sensitize not only peripheral nociceptors but also nociceptive neurons in the dorsal horn of the spinal cord, beyond the blood-brain barrier,” note the editorialists.
“We congratulate Goebel and colleagues for the tremendous effort they devoted to the current trial, but the possible pitfalls we discuss…should prevent us from prematurely closing the book on immunomodulatory treatment of CRPS.”
That said, based on the current results, “IVIg is not our first choice of an agent to investigate in future trials,” they conclude.
The study was supported by the United Kingdom Clinical Research Collaboration-registered King’s Clinical Trials Unit at King’s Health Partners, which is partly funded by the National Institute for Health Research (NIHR) Biomedical Research Center for Mental Health, Maudsley National Health Service Foundation Trust, and King’s college London; and by the NIHR Evaluation, Trials, and Studies Coordinating Center. It was also supported by grants from the Efficacy and Mechanism Evaluation Program, the Pain Relief Foundation Liverpool, and a Medical Research Council and NIHR partnership. Biotest United provided the active medication at no cost. Dr Goebel reports receiving grants and nonfinancial support from Biotest during the study and personal fees from Biotest and Assome Therapeutics outside the study. A full list of disclosures for the other study authors is in the original article.
Ann Intern Med. Published online October 3, 2017. Full article, Editorial
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