Neuropathic pain conditions are clinically challenging for practitioners and patients. Pharmacotherapies may help to reduce pain intensity in some patients, but this relief can be insufficient for many and nonexistent in others. A newly-reported study found remarkably favorable results for intravenous immunoglobulin as an adjunct to standard therapies for neuropathic pain; however, small trials demonstrating large clinical effect sizes need to be considered very cautiously.
Severe pain is associated with many peripheral nervous system diseases and its successful treatment is an area of unmet need and ongoing research. Stefano Jann, MD — Department of Neurology, Niguarda Hospital, Milan, Italy — and colleagues conducted an open-label pilot study to assess the potential benefits of adjunctive intravenous immunoglobulin (IVIg) in patients with painful polyneuropathy that was resistant to conventional therapies [Jann et al. 2012].
Subjects completing the study included 19 outpatients of both sexes, mean age 66.5±7.5 years, who had been suffering from recalcitrant neuropathic conditions for at least 6 months and up to a maximum of 5 years. At baseline, all subjects reported severe levels of pain on a visual analog scale (VAS, 0mm-100mm).
Most subjects (12) suffered pain due to diabetic neuropathy, 2 had chemotherapy-induced neuropathy, 2 had HIV-related neuropathy, and 3 had idiopathic polyneuropathy. Current pharmacotherapies, to which subjects were variously refractory, included pregabalin, oxcarbazepine, duloxetine, and/or oxycodone.
Subjects were randomly allocated either to receive adjuvant IVIg (highly purified, unmodified human immunoglobulin, 2 g/kg) in addition to their regular therapy or to continue with their current pharmacotherapy (control group). Neither the researchers nor subjects were blinded to group allocation.
Writing in the October edition of Pain Medicine, the researchers report the mean value of pain intensity (VAS) in the IVIg group (N=8) dropped from 88mm at baseline to 49mm after the first week, and to 29mm at roughly 4 and 8 weeks (see graph). Meanwhile, mean VAS scores in the control group (N=9) only slightly changed, from 85mm to 78mm after 1 week and remained generally at that level during the rest of the 8 week study (*P<0.01 for all IVIg vs Control group differences).
Almost 100% of patients in both groups reported medium-to-strong pain at baseline on the Short Form McGill Pain Questionnaire. After 4–8 weeks, pain was reduced to moderate-to-light levels in 90% of patients in the IVIg group, whereas no improvement was reported in the control group (P<0.01). In quality of life measures — assessed via Short Form 36, Clinical Global Impression of Change, and Patient Global Impression of Change questionnaires — patients’ scores in the IVIg group at all followup points were more significantly favorable than those of the control group (P<0.01).
The researchers conclude that their data demonstrate a strongly beneficial effect of IVIg on neuropathic pain intensity and quality of life in patients previously resistant to conventional treatments. At the same time, however, they duly note that there were many methodological limitations of this study and they are working to develop a multicenter, double-blind, placebo-controlled trial.
COMMENTARY: We rarely report on such small-scale studies as this one by Jann et al., because the outcome effect sizes, no matter how large and statistically significant, cannot be trusted as being reliably definitive or valid. It is low-quality evidence that, at best, suggests a hypothesis worthy of further testing.
Benefits of IVIg therapy as demonstrated in this study were not an entirely new discovery. For example, a systematic review by Goebel  similarly found evidence from randomized controlled trials that IVIg at various doses is effective for reducing pain in complex regional pain syndrome and other chronic pain conditions. Earlier, a small study demonstrated IVIg as helpful for painful sensory neuropathy associated with Sjögren’s syndrome [Morozumi et al 2009], and there have been other small trials of a similar nature.
The hypothesis that IVIg therapy may provide markedly significant pain relief and improved quality of life in patients with recalcitrant neuropathies appears to be important for consideration in larger-scale research investigations. For example, in the Jann et al. study…
- The mean VAS score in the IVIg group at 2 months had declined to about 29mm, which is a mild level of pain, and the mean change from baseline was 59mm, representing a quite large and clinically significant effect size of about 3.96 (Cohen’s d; calculated by us from study data, using PTCalcs available here).
- Whereas, the mean pain score in the control group at 2 months was still a high 78mm, representing a mean change from baseline of only 6.7mm and an effect size of 0.63 (Cohen’s d). Although this was a moderate-sized effect it is clinically unimportant, which is not surprising since these patients were continuing on previously inadequate therapies.
Would such large, beneficial effects of IVIg therapy persist in high-quality clinical trials?
This might be questionable. A recently reported analysis in the October 24/31, 2012 edition of JAMA (Journal of the American Medical Association) found that, when treatment effects are remarkably large, they usually emerge from small studies [Pereira et al. 2012]. When additional trials of better quality are performed, the effect sizes become typically much smaller; in fact, well-validated large effects are uncommon. However, in many cases the authors note, adequate subsequent research may never be performed to definitively confirm or refute the earlier findings.
In an accompanying editorial in JAMA, Andrew Oxman, MD — of the Global Health Unit, Norwegian Knowledge Centre for the Health Services, Oslo, Norway — states, “The implications of all this for clinicians, patients, policy makers, and researchers is a reminder to be humble, uncertain, and collaborative” [Oxman 2012].
Oxman suggests that, although a range of effective interventions for any medical condition may be available, some with large effects, most have only modest effects and the true clinical benefits often are uncertain — which should be a humbling thought. Acknowledging such uncertainty is essential for reducing important doubts via well-designed clinical investigations. Along with that, collaboration is critical for identifying and agreeing to priorities and making sure not to waste scarce resources for research on unimportant hypotheses or for poorly designed studies.
So, it could be important that IVIg is further investigated for neuropathic pain conditions that have been resistant to other therapies, but only if trials are adequately designed and conducted for providing more definitive and valid results.
> Goebel A. Immunoglobulin responsive chronic pain. J Clin Immunol. 2010;30(Suppl 1):S103-S108 [abstract].
> Jann S, Francia A, Fruguglietti ME, et al. Efficacy and Safety of Intravenous Immunoglobulin as Adjuvant Treatment for Refractory Neuropathic Pain. Results of an Open-Label, Multicenter Study. Pain Medicine. 2012;13:1334–1341 [abstract].
> Morozumi S, Kawagashira Y, Iijima M, et al. Intravenous immunoglobulin treatment for painful sensor neuropathy associated with Sjögren’s syndrome. J Neurol Sci. 2009;279(1-2):57-61 [abstract].
> Oxman AD. Improving the Health of Patients and Populations Requires Humility, Uncertainty, and Collaboration. JAMA. 2012;308(16):1691-1692 [abstract].
> Pereira TV, Horwitz RI, Ioannidis JPA. Empirical Evaluation of Very Large Treatment Effects of Medical Interventions. JAMA. 2012;308(16):1676-1684 [abstract].
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