Is Intravenous Immunoglobulin Therapy for Chronic Pain Conditions an Underused Treatment Option?
Cite as: Thalla N, Newton K, Elmofty D. Is intravenous immunoglobulin therapy for chronic pain conditions an underused treatment option?. ASRA Pain Medicine News 2022;47. https://doi.org/10.52211/asra020122.008.
Current treatment options for chronic pain are limited, given its overwhelming burden in the United States.1 Despite advancements in the knowledge of pain mediation and its underlying pathophysiology, management options remain limited and unsatisfactory in patients with chronic pain conditions. However, it has led to our understanding of the immune system’s role in both the pathogenesis and sustenance of chronic pain and opened doors to further treatment options.
Recent studies have evaluated intravenous immunoglobulin G therapy for conditions that tend to be refractory to conventional pain treatment options, including fibromyalgia, painful diabetic neuropathy, complex regional pain syndrome, post-polio syndrome, and small fiber neuropathy.
Research findings during the past 20 years suggest that the immune system can directly affect pain signaling pathways in both the central and peripheral nervous systems.2 Study reports have well described that inflammatory mediators such as cytokines and chemokines are released by immune-mediated cells following an injury, and they are often attributed to inflammatory pain. However, immune cells such as the central nervous system’s glial cells have shown direct activity and response in several different nociceptive and neuropathic pain states.3 Once activated, immune-mediated cells have a key role in both central and peripheral sensitization.
In the central nervous system, specifically the spinal cord, the key players are the microglial cells, whereas mast cells and activated macrophages are among the key components for the peripheral nervous system.1,4 The cells release mediators with two opposing phenotypes: algesic and analgesic.5 An imbalance between mediator production and dysregulated proliferation of those cells in response to an initial insult can directly damage neurons and alter cellular channel regulation and ion balance, leading to sensitization and ultimately development of chronic pain states.5
Intravenous immunoglobulin G (IVIG) therapy was proposed as an analgesic modality in chronic pain states because of its synergistic role in cytokine reduction and alteration of expression and suppression of immune cell proliferation.6 IVIG therapy has historically been used for autoimmune diseases such as Guillain-Barre syndrome, but it has also been shown to be effective in treating chronic pain in animal models.6,7 Recent studies have evaluated its use for conditions that tend to be refractory to conventional pain treatment options, including fibromyalgia, painful diabetic neuropathy (PDN), complex regional pain syndrome (CRPS), post-polio syndrome (PPS), and small fiber neuropathy.6 Many physicians may not be familiar with the pathophysiology of immune modulation and chronic pain and therefore may not consider IVIG as a treatment option for those types of conditions.
Research on the pathophysiology of fibromyalgia suggests that inflammatory-mediated cytokines are elevated in the skin and serum of affected patients.8,9 Findings from other studies have also suggested that a significant subgroup of fibromyalgia patients may develop a component of autoimmune demyelination similar to the process that occurs with chronic inflammatory demyelinating polyneuropathy.10 A small study involving 15 patients demonstrated positive results in pain relief, tenderness, and muscle strength among patients who received IVIG therapy.10 Similarly, another small study of seven patients with an overlapping diagnosis of fibromyalgia and small fiber neuropathy found that nerve fiber densities on skin biopsy improved after six months of IVIG therapy.11
PDN is a chronic and difficult-to-treat pain condition for which various modalities have been explored, including IVIG. A randomized controlled trial evaluated the effectiveness of IVIG in 23 patients with refractory PDN in two treatment arms, IVIG versus saline. IVIG was given for five consecutive days; 7 of the 11 patients in the treatment group met the primary endpoint of 50% pain reduction, compared to none in the placebo group, and the results were sustained for up to eight weeks after the final infusion.11,12
CRPS has been challenging to understand, but a growing body of evidence is showing that immune mediation may be a key culprit.13 Two major studies have been conducted involving IVIG and CRPS. The first was a randomized crossover study with 13 patients that compared IVIG to saline.14 When researchers measured patients’ numeric pain rating scale scores at 6 and 19 days following the infusion, IVIG displayed a significant clinical benefit with an average decline of 1.5 in pain scores compared to placebo. A larger, double-blinded, randomized controlled trial involved 111 patients with moderate to severe CRPS who were divided into two treatment arms: IVIG 0.5 mg/kg versus saline.8 The subjects received two infusions and were assessed at 6 and 42 days after study initiation, but no significant benefit for IVIG was achieved. Further studies are needed to optimize IVIG therapy for CRPS, including clearly defining the number, strength, and doses of infusions.
Additional studies of similar caliber have demonstrated efficacious results with IVIG for postherpetic neuralgia and PPS. In one, IVIG demonstrated a significant reduction in pain scores over placebo when used for PPS.15 IVIG was administered at a dose of 0.4 mg/kg for five consecutive days, and patients reported higher quality-of-life measures at two-month follow-up visits. Case reports and case series have also shown the treatment to be efficacious in a variety of less common neuropathic conditions.16 None of the studies reported severe adverse reactions with IVIG treatment.6,7,8,12,15
Providers and patients should consider several factors before deciding whether to pursue IVIG, including cost of care: a 2 mg/kg treatment in the United States may cost up to $8,500.6 Large, randomized controlled trials with a diverse group of study subjects are needed to make a more conclusive determination regarding IVIG’s role in treating certain chronic pain syndromes. However, given the potentially promising results from available studies, additional research should be considered focusing on the intersection of immunology and chronic pain.
Nirguna Thalla, MD, MBA, is a resident in the department of Rehabilitation Medicine at MedStar Georgetown University and in the department of Physical Medicine and Rehabilitation at MedStar National Rehabilitation Hospital in Washington, DC.
Keith Newton, MD, is a resident at the University of Central Florida College of Medicine and HCA Healthcare in Orlando, FL.
Dalia Elmofty, MD, is an associate professor and associate program director of the pain fellowship at the University of Chicago Medicine in Chicago, IL.
- Kohrt BA, Griffith JL, Patel V. Chronic pain and mental health: integrated solutions for global problems. Pain. 2018;159(Suppl 1):S85–90. https://doi.org/10.1097/j.pain.0000000000001296
- Totsch SK, Sorge RE. Immune system involvement in specific pain conditions. Mol Pain. 2017;13:1744806917724559. https://doi.org/10.1177/1744806917724559
- Marchand F, Perretti M, McMahon SB. Role of the immune system in chronic pain. Nat Rev Neurosci. 2005;6(7):521–32. https://doi.org/10.1038/nrn1700
- Tamburin S, Borg K, Caro XJ, et al. Immunoglobulin g for the treatment of chronic pain: report of an expert workshop. Pain Med. 2014;15(7):1072–82. https://doi.org/10.1111/pme.12319
- Xu M, Bennett DLH, Querol LA, et al. Pain and the immune system: emerging concepts of IgG-mediated autoimmune pain and immunotherapies. J Neurol Neurosurg Psychiatry. 2020;91(2):177–88. https://doi.org/10.1136/jnnp-2018-318556
- Chang MC, Park D. Effectiveness of intravenous immunoglobulin for management of neuropathic pain: a narrative review. J Pain Res. 2020;13:2879–84. https://doi.org/10.2147/JPR.S273475
- Goebel A. Cellular and behavioural models to predict responses to immunoglobulin G treatment in complex regional pain syndrome. Clin Exp Immunol. 2014;178(Suppl 1):136–7. https://doi.org/10.1111/cei.12543
- Goebel A, Bisla J, Carganillo R, et al. A randomised placebo-controlled phase III multicentre trial: low-dose intravenous immunoglobulin treatment for long-standing complex regional pain syndrome (LIPS trial). Southampton (UK): NIHR Journals Library; November 2017. https://doi.org/10.3310/eme04050
- Salemi S, Rethage J, Wollina U, et al. Detection of interleukin 1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha in skin of patients with fibromyalgia. J Rheumatol. 2003;30(1):146–50. https://pubmed.ncbi.nlm.nih.gov/12508404
- Caro XJ, Winter EF, Dumas AJ. A subset of fibromyalgia patients have findings suggestive of chronic inflammatory demyelinating polyneuropathy and appear to respond to IVIg. Rheumatology (Oxford). 2008;47(2):208–11. https://doi.org/10.1093/rheumatology/kem345
- Metyas S, Chen C, Quismorio A, Abdo N, Kamel K. Improvement of nerve fiber density in fibromyalgia patients treated with IVIg. Curr Rheumatol Rev. 2020;16(4):280–4. https://doi.org/10.2174/1573397115666191106120622
- Jann S, Fazio R, Cocito D, et al. High-dose intravenous immunoglobulin is effective in painful diabetic polyneuropathy resistant to conventional treatments. Results of a double-blind, randomized, placebo-controlled, multicenter trial. Pain Med. 2020;21(3):576–85. https://doi.org/10.1093/pm/pnz331
- Stanton-Hicks MD. CRPS: what's in a name? Taxonomy, epidemiology, neurologic, immune and autoimmune considerations. Reg Anesth Pain Med. 2019;44(3):376–87. https://doi.org/10.1136/rapm-2018-100064
- Goebel A, Baranowski A, Maurer K, Ghiai A, McCabe C, Ambler G. Intravenous immunoglobulin treatment of the complex regional pain syndrome: a randomized trial. Ann Intern Med. 2010;152(3):152–8. https://doi.org/10.7326/0003-4819-152-3-201002020-00006
- Bertolasi L, Frasson E, Turri M, et al. A randomized controlled trial of IV immunoglobulin in patients with postpolio syndrome. J Neurol Sci. 2013;330(1-2):94–9. https://doi.org/10.1016/j.jns.2013.04.016