IVIG Improves Symptoms in Refractory Complex Regional Pain Syndrome
By Pam Harrison
Medscape Medical News
February 9, 2010 — Low-dose intravenous immunoglobulin (IVIG) reduces pain and improves autonomic limb symptoms in patients with long-standing, refractory complex regional pain syndrome (CRPS), a small but randomized study of long-standing, refractory CRPS patients shows.
Published in the February issue of the Annals of Internal Medicine, researchers under lead study author Andreas Goebel, MD, PhD, from University of Liverpool, United Kingdom, found "clear evidence" for a treatment effect, with an average decrease of 1.55 units in pain scores vs saline after IVIG infusion during the subsequent 14 days, with no serious adverse events (P < .001).
For 3 of the 13 initially randomized participants, pain intensity was 50% lower or better after IVIG treatment compared with saline controls.
"We can't treat these patients very well with standard therapy, and the reduction in pain scores we saw with IVIG is an indication of very strong pain relief," Dr. Goebel told Medscape Neurology. "Most importantly, 3 patients had over 50% pain relief and 2 had over 30% relief.”
Pain Intensity
For the study, 13 participants with a pain intensity greater than 4 on an 11-point numerical rating scale and with CRPS for 6 to 30 months refractory to standard treatment were randomly assigned to active therapy or saline followed by the alternative infusion, each infusion given for 2 consecutive days. Twelve patients completed the trial.
"We required all patients to have tried acetaminophen, nonsteroidal anti-inflammatory drugs, opioids, tricyclic antidepressants, gabapentin or pregabalin, and physiotherapy with an unsatisfactory outcome," the study authors note. Patients received standard medical therapy during the study but no new analgesic drugs were allowed.
... the reduction in pain scores we saw with IVIG is an indication of very strong pain relief.
Patients randomized to active therapy received a total immunoglobulin dose of 0.5 g/kg — a lower dose than that commonly used for other conditions, investigators observe, because preliminary findings indicated that this dose was still effective in CRPS but had minimal adverse events. As the study authors report, 5 patients or 42% of the cohort achieved median pain scores that were at least 2 points lower after IVIG treatment than with saline.
Interestingly, 1 patient reported a median pain score that was 2 points lower after saline administration than after IVIG. "Ongoing pain relief after the first infusion required delay of the second infusion in 4 patients (3 patients after IVIG and 1 patient after saline)," the investigators add. Two patients who received IVIG as the second infusion reported "much improved" or "very much improved" pain 28 days after the second infusion, 1 patient for 2 weeks and the other for 3 weeks.
Of the 11 patients with limb-symptom measurements for each treatment period, 1 patient reported some improvement after both active and placebo infusion, whereas 3 patients reported no improvement after either infusion. The remaining 7 patients reported an improvement after IVIG infusion but not after saline (P = .016).
Serendipitous Observation
The idea of using IVIG as a treatment for CRPS arose from a serendipitous observation a number of years ago, Dr. Goebel notes, when a patient with chronic pain who required IVIG treatment for an unrelated condition reported significant pain relief after the infusion.
"We know now that there are immune problems in CRPS, but we did not know this at the time," he observes. Subsequent to that observation, researchers have reported that CRPS at least in part appears to be mediated by pathogenic autoantibodies on the surface of neurons.
By infusing IVIG, these autoantibodies could be neutralized, if not entirely eliminated. The study authors also point out that in long-standing CRPS only a few medical interventions are effective, but all are cumbersome to administer and associated with serious adverse reactions; to date, no drug treatment has been found to provide viable pain relief.
"To our knowledge, we have shown for the first time that low-dose IVIG reduces pain in patients with long-standing, refractory CRPS, with few adverse reactions," the investigators conclude. IVIG may "emerge as an effective and safe novel clinical treatment option for otherwise refractory disease, [although] confirmatory trials are required."
Autoantibody Implicated
A leading researcher in CRPS, Franz Blaes, MD, from the University of Giessen, Hessen, Germany, told Medscape Neurology that in 2004 he and his colleagues identified autoantibody on the surface of nerve cells and that these autoantibodies had been implicated in CRPS.
“A lot of autoimmune diseases respond to IVIG, so we started to treat chronic CRPS patients with IVIG to see if it worked,” he told Medscape Neurology. Although researchers are not entirely sure how IVIG functions in autoimmune disease, given in high doses, it may downregulate some immune cell function by reacting with these autoantibodies and neutralizing them.
it looks more like an inflammatory disease...
As Dr. Blaes also explained, at least in the acute phase of CRPS, "it looks more like an inflammatory disease — there is a lot of edema, the limb is hot and swollen, and levels of autoantibodies are higher in the acute states."
Thinking that IVIG may well be more effective in acute CRPS when autoantibody levels are high, Dr. Blaes and colleagues are currently investigating whether IVIG may be even more effective in patients with early-stage CRPS, and acute-phase CRPS patients are currently being enrolled in a prospective, randomized, placebo-controlled, crossover study.
The study was supported by the Association of Anaesthetists of Great Britain and Ireland, the University College London Hospitals Trustees, and CSL-Behring. Dr. Goebel and Dr. Blaes have disclosed no relevant financial relationships.
