Neuropathic pain is difficult to treat in clinical practice, and the underlying mechanisms are insufficiently elucidated. Previous studies have demonstrated that the neuronal Fc-gamma-receptor type I (FcγRI) of the dorsal root ganglion (DRG) mediates antigen-specific pain. However, the mechanisms of neuronal FcγRI in neuropathic pain remain to be explored. Here, it is found that the activation of FcγRI-related signals in primary neurons induces neuropathic pain in a rat model. This work first reveals that sciatic nerve injury persistently activates neuronal FcγRI-related signaling in the DRG, and conditional knockout (CKO) of the FcγRI-encoding gene Fcgr1 in rat DRG neurons significantly alleviates neuropathic pain after nerve injury. C-reactive protein (CRP) is increased in the DRG after nerve injury, and CRP protein of the DRG evokes pain by activating neuronal FcγRI-related signals. Furthermore, microinjection of naive IgG into the DRG alleviates neuropathic pain by suppressing the activation of neuronal FcγRI. These results indicate that the activation of neuronal CRP/FcγRI-related signaling plays an important role in the development of neuropathic pain in chronic constriction injury (CCI) rats. The findings may provide novel insights into the neuroimmune responses after peripheral nerve injury and suggest potential therapeutic targets for neuropathic pain.

Immunoglobulins (IG) are widely used for the treatment of a variety of immune-mediated diseases. The exact mechanism of action remains unknown, but IG modulate the expression and function of Fc receptors, interfere with complement activation and production of cytokines, neutralize pathogenic autoantibodies, and affect the activation and effector functions of B and T lymphocytes. Immunoglobulins are usually delivered intravenously, and are effective in ameliorating motor symptoms, and/or preventing disease progression in immune-mediated neuropathies, including Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy.

The aim of this systematic review and meta-analysis was to study the potential of IG for the treatment of painful peripheral neuropathy (PPN). The outcome of interest was the percentage of patients with PPN who achieved pain relief following IG administration.

We performed a systematic literature search on March 17, 2022, in the PubMed database without any publication date restrictions. We also looked for unpublished or ongoing trials in clinicaltrials.org. Pain reduction following IG treatment had to be within the aims (primary or secondary).

The aforementioned literature search strategy revealed five studies (two open-label, three randomized placebo-controlled) eligible to be included. The pooled estimate of the percentage of patients with PPN who received immunoglobulins and reported pain relief was found to be 65% (95% CI 58-71%). The likelihood of achieving pain relief with immunoglobulin treatment was 2.9 times higher (95% CI 1.6-5.2) compared to placebo (p = 0.0003).

The use of IG for the treatment of pain due to peripheral neuropathy has a potential therapeutic benefit. Further studies across patients with different types of painful peripheral neuropathy are needed to better characterize this effect. Registration number on PROSPERO: CRD42022319614.

Fibromyalgia syndrome (FMS) is the most common chronic widespread pain condition in rheumatology. Until recently, no clear pathophysiological mechanism for fibromyalgia had been established, resulting in management challenges. Recent research has indicated that serum immunoglobulin Gs (IgGs) may play a role in FMS. We undertook a research prioritisation exercise to identify the most pertinent research approaches that may lead to clinically implementable outputs.

Research priority setting was conducted in five phases: situation analysis; design; expert group consultation; interim recommendations; consultation and revision. A dialogue model was used, and an international multi-stakeholder expert group was invited. Clinical, patient, industry, funder, and scientific expertise was represented throughout. Recommendation-consensus was determined via a voluntary closed eSurvey. Reporting guideline for priority setting of health research were employed to support implementation and maximise impact.

Arising from the expert group consultation (n = 29 participants), 39 interim recommendations were defined. A response rate of 81.5% was achieved in the consensus survey. Six recommendations were identified as high priority- and 15 as medium level priority. The recommendations range from aspects of fibromyalgia features that should be considered in future autoantibody research, to specific immunological investigations, suggestions for trial design in FMS, and therapeutic interventions that should be assessed in trials.

By applying the principles of strategic priority setting we directed research towards that which is implementable, thereby expediating the benefit to the FMS patient population. These recommendations are intended for patients, international professionals and grant-giving bodies concerned with research into causes and management of patients with fibromyalgia syndrome.

The efficacy and safety of high-dose intravenous immunoglobulin (IVIG) in treatment-resistant diabetic painful polyneuropathy (DPN) were assessed.

This was a randomized, double-blind, placebo-controlled, multicenter trial (EudraCT 2010-023883-42).

This trial was conducted at eight sites in Italy with a neurology specialist level of care.

Twenty-six diabetic patients with DPN who reported baseline severity of pain >60 units (mm) on a VAS scale at enrollment and were resistant to antidepressants and antiepileptic drugs were enrolled; 23 were randomized (11 in the IVIG arm and 12 in the placebo arm). All patients completed the study and were evaluated. All patients were Caucasian, 15 were male, and 21 had a diagnosis of type II diabetes.

IVIG (0.4 g/kg/d) or placebo was given for five consecutive days. Pain intensity (visual analog scale, Neuropathic Pain Symptom Inventory) and quality of life (36-Item Short-Form Health Survey, Clinical/Patient Global Impression of Change questionnaires) assessments were performed at visits: baseline, start of therapy (one week later), end of therapy (five days later), and follow-up (four and eight weeks later).

The study achieved its prespecified primary end point of ≥50% pain reduction at four weeks after IVIG, achieved in seven of 11 patients (63.6%) in the IVIG group vs zero of 12 in the placebo group (P = 0.0013). Only two adverse events were reported during the study: one patient in the treatment arm reported a mild "dermatitis psoriasiform," whereas one patient from the placebo group reported a mild "influenza."

Treatment with IVIG at the dose given was efficacious and safe for patients with DPN resistant to standard therapies.

Objectives Complex regional pain syndrome (CRPS) is a rare chronic pain condition for which no curative treatment exists. Patients in tertiary centres are often required to make decisions about treatment options. This study was conducted to explore how prior attendance of a pain management program might alter patients' decision making processes. Methods This qualitative study uses focus groups to gather patient views on an immunosuppressant drug treatment (mycophenolate) for the management of CRPS. Participants were allocated to one of three focus groups based on their treatment journey; Group 1 (n=3) were involved in a recent mycophenolate drug trial; Group 2 (n=5) were neither involved in the trial nor attended a Pain Management Programme (PMP); Group 3 (n=6) were not involved in the trial but had attended a PMP. Outcomes were considered within the framework of Leventhal's Common Sense Model (CSM) in relation to the decision making process. Results Thematic analysis identified differing themes for each group. Group 1: (1) Medication as a positive form of treatment, (2) The trial/drug and (3) Pacing. Group 2: (1) Medication as form of treatment, (2) Other forms of support/treatment and (3) Side effects of mycophenolate. Group 3: (1) Varied view of medication, (2) Consideration of other forms of support and (3) Side effects. Conclusions Attendance on a PMP might provide patients with skills to better manage uncertainty when faced with various treatment options. Leventhal's model goes some way to explaining this. The specific importance of, and benefit from understanding pacing when commencing an effective drug treatment for chronic pain became apparent.

Complex regional pain syndrome (CRPS) is a devastating posttraumatic neuroinflammatory condition with both autoinflammatory and autoimmune features, characterized by unrelenting severe pain and disability, with the majority of affected patients being unable to function socially or vocationally. Remission is more likely in children than adults, and if treatment is started early. Once established, there are no universally effective treatments, and these are desperately needed. A single limb is often involved, but there can be multi-limb spread, and systemic autonomic manifestations. We describe a case of long-standing CRPS with multi-limb spread and systemic autonomic features, controlled only with very high dose oral corticosteroids, which led to several complications. Multiple other treatment modalities failed or were insufficient to control the CRPS and allow tapering of the corticosteroids, but the patient had a dramatic response to hyperbaric oxygen therapy (HBOT), allowing a reduction in prednisone dose to just over the physiologic range. When symptoms started to increase several months later, a second course of HBOT treatments allowed reduction in prednisone dose into the physiologic range while still controlling CRPS symptoms. This case is unique in that it shows that HBOT can be effective in long-standing CRPS, both initially, and for subsequent flares, and adds to the evidence supporting HBOT as a potential treatment for this condition. Graphical Abstract HBOT effect on prednisone dose for symptom control.

In the last two decades, motor cortex stimulation has been recognized as a valuable alternative to pharmacological therapy for the treatment of neuropathic pain. Although this technique started to be used in clinical studies, the debate about the optimal settings that enhance its effectiveness without inducing tissue damage is still open. To this purpose, computational approaches applied to realistic human models aimed to assess the current density distribution within the cortex can be a powerful tool to provide a basic understanding of that technique and could help the design of clinical experimental protocols. This study aims to evaluate, by computational techniques, the current density distributions induced in the brain by a realistic electrode array for cortical stimulation. The simulation outcomes, summarized by specific metrics quantifying the efficacy of the stimulation (i.e., the effective volume and the effective depth of penetration) over two cortical targets, were evaluated by varying the interelectrode distance, the stimulus characteristics (amplitude and frequency), and the anatomical human model. The results suggest that all these parameters somehow affect the current density distributions and have to be therefore taken into account during the planning of effective electrical cortical stimulation strategies. In particular, our calculations show that (1) the most effective interelectrode distance equals 2 cm; (2) increasing voltage amplitudes increases the effective volume; (3) increasing frequencies allow enlarging the effective volume; and (4) the effective depth of penetration is strictly linked to both the anatomy of the subject and the electrode placement.

Most autoimmune diseases are associated with pathological pain development. Autoimmune diseases with pathological pain include complex regional pain syndrome, rheumatoid arthritis, and Guillian-Barré syndrome to name a few. The present Review explores research linking the immune system to the development of pathological pain in autoimmune diseases. Pathological pain has been linked to T-cell activation and the release of cytokines from activated microglia in the dorsal horn of the spinal cord. New research on the role of autoantibodies in autoimmunity has generated insights into potential mechanisms of pain associated with autoimmune disease. Autoantibodies may act through various mechanisms in autoimmune disorders. These include the alteration of neuronal excitability via specific antigens such as the voltage-gated potassium channel complexes or by mediating bone destruction in rheumatoid arthritis. Although more research must be done to understand better the role of autoantibodies in autoimmune disease related pain, this may be a promising area of research for new analgesic therapeutic targets. © 2016 Wiley Periodicals, Inc.

Human immunoglobulin G (IgG) concentrates are immune-modulating, anti-inflammatory plasma-derived products. Clinical studies in recent years have suggested that IgG attenuates neuropathic pain. In this study, effects of sulphonated IgG on the development and maintenance of a mechanical allodynia-like response were examined in mice with neuropathic pain induced by a partial sciatic nerve ligation (PSL). When sulphonated IgG (400 or 1,000 mg/kg/day, i.p.) was administered for 5 days, from 1 day before surgery to post-operative day (POD) 3, the development of a mechanical allodynia-like response was attenuated. On the other hand, sulphonated IgG had little effect on the maintenance of a mechanical allodynia-like response when administered for 5 days, from POD 11 to POD 15, at which time a mechanical allodynia-like response had already been developed. To explore the mechanism of sulphonated IgG, the mRNA expression of inflammatory cytokines was evaluated in the injured sciatic nerve. Sulphonated IgG (1,000 mg/kg/day, i.p.) that was administered for 3 days, from 1 day before surgery to POD 1, significantly attenuated the up-regulation of tumor necrosis factor-α and monocyte chemotactic protein-1 mRNAs on POD 1. These results suggest that prophylactic treatment with sulphonated IgG attenuates the development of mechanical allodynia-like response by inhibition of inflammatory cytokine expression in mice with PSL.

Although fibromyalgia and complex regional pain syndrome (CRPS) have distinct clinical phenotypes, they do share many other features. Pain, allodynia and dysaesthesia occur in each condition and seem to exist on a similar spectrum. Fibromyalgia and CRPS can both be triggered by specific traumatic events, although fibromyalgia is most commonly associated with psychological trauma and CRPS is most often associated with physical trauma, which is frequently deemed routine or minor by the patient. Fibromyalgia and CRPS also seem to share many pathophysiological mechanisms, among which the most important are those involving central effects. Nonetheless, peripheral effects, such as neurogenic neuroinflammation, are also important contributors to the clinical features of each of these disorders. This Review highlights the differing degrees to which neurogenic neuroinflammation might contribute to the multifactorial pathogenesis of both fibromyalgia and CRPS, and discusses the evidence suggesting that this mechanism is an important link between the two disorders, and could offer novel therapeutic targets.

Eosinophilic granulomatosis with polyangiitis (EGPA), previously called Churg-Strauss syndrome, frequently affects the peripheral nervous system. We conducted a multicenter, double-blind, three-arm treatment period, randomized, pre-post trial to assess the efficacy of intravenous immunoglobulin (IVIg) administration for residual peripheral neuropathy in patients with EGPA that is in remission, indicated by laboratory indices. Twenty-three patients were randomly assigned into three groups, in which the timing of IVIg and placebo administration was different. Each group received one course of intervention and two courses of placebo at 2-week intervals. Treatment effects were assessed every 2 weeks for 8 weeks. The primary outcome measure, the amount of change in the manual muscle testing sum score 2 weeks after IVIg administration, significantly increased (p = 0.002). The results over time suggested that this effect continued until the last assessment was done 8 weeks later. The number of muscles with manual muscle testing scores of three or less (p = 0.004) and the neuropathic pain scores represented by the visual analogue scale (p = 0.005) also improved significantly 2 weeks after IVIg administration. This study indicates that IVIg treatment for EGPA patients with residual peripheral neuropathy should be considered even when laboratory indices suggest remission of the disease.