Low-dose Naltrexone Research Articles

Repurposing low-dose naltrexone for the prevention and treatment of immunothrombosis in COVID-19.

Coronavirus disease 2019 (COVID-19) is characterized by striking dysregulation of the immune system, with evidence of hyperinflammation, an impaired induction of interferons, and delayed adaptive immune responses. In addition to dysfunctional immune responses, thrombosis is a hallmark of severe COVID-19. Because traditional anticoagulation strategies are associated with increased bleeding, novel strategies that address both the immune and thrombotic dysfunction associated with COVID-19 would be of tremendous benefit. In this commentary, we discuss the unique properties of low dose naltrexone (LDN) which could be leveraged to reduce the immune-mediated thrombotic complications in COVID-19. Mechanistically, LDN can blunt innate immune responses and Toll-like receptor (TLR) signaling, reducing interleukin1 (IL-1), tumor necrosis factor-alpha (TNF-α), and interferon (IFN) levels. Because of the immune-mediated thrombotic mechanisms that underlie COVID-19, we hypothesize that the immune-modulating and known pharmacologic properties of LDN could be leveraged as a novel therapeutic strategy in COVID-19.

Topical Therapeutic Options in Corneal Neuropathic Pain.

Purpose of Review: Corneal neuropathic pain can be difficult to treat, particularly due to its lack of response to standard dry eye therapies. We describe a variety of topical therapeutic options that are available to treat corneal neuropathic pain with a significant or primary peripheral component. We also describe possible mechanisms of action for such topical therapies. Recent Findings: Topical corticosteroids and blood-derived tear preparations can be helpful. Newer therapies, including topical lacosamide and low-dose naltrexone are emerging therapeutic options that may also be considered. Summary: Corneal neuropathic pain with a significant peripheral component may be managed with a variety of topical therapeutic options.

EFFICACY OF LOW DOSE NALTREXONE IN PATIENTS WITH CROHN’S COLITIS AND ILEITIS

Abstract In a Phase 2 placebo-controlled trial, low dose naltrexone (LDN) improved inflammation of the gastrointestinal mucosa and improved clinical activity scores in patients with mild to moderate Crohn’s disease (CD). We present two patients with symptomatic CD with a rapid clinical and endoscopic response to LDN: 1) Crohn’s colitis with prolonged maintenance to LDN which had failed mesalamine with immunomodulator therapy; and 2) Crohn’s ileitis with prolonged remission with addition of LDN to biologic and immunomodulator therapy. CASE 1: A 43-year-old male with a 23-year history of Crohn’s colitis of mild-to-moderate severity was previously treated with 150 mg mercaptopurine and mesalamine. Despite this treatment he had left-sided abdominal cramping, urgency, and 8-12 loose bowel movements with bleeding. Colonoscopy showed severe rectal ulcerations and normal ileum (Figure 1A). He started 1 mg oral naltrexone daily which was increased to 4 mg daily over 1 mo and a tapering course of budesonide. Mesalamine was continued. Six mo later, he stated he had 2 to 3 semi-formed bowel movements daily without bleeding or urgency. He was maintained on mesalamine and LDN 4.5 mg daily for 3 years. Colonoscopy showed dramatic improvement of rectal ulcerations and 3 small erosions in the proximal ascending colon which were not present on the previous colonoscopy (Figure 1B). At the time of this colonoscopy he was doing well clinically with a plan to augment LDN therapy with a probiotic and an anti-inflammatory diet. This case demonstrates favorable clinical and endoscopic response to an LDN-based regimen that was rapid and durable, with a short exposure to steroid. CASE 2: A 42-year-old female with a history of severe CD of the colon and ileum starting at age 27. She required total colectomy and end ileostomy at age 36. Three years after surgery she developed recurrent ileal ulcerations and strictures leading to further ileal resection. Later that year, ileoscopy demonstrated ileal ulcers (Figure 2A) and she was started on infliximab and mercaptopurine. She was stable for 3 years but then developed higher ileostomy output and fatigue. Methotrexate was substituted for mercaptopurine which helped reduce symptoms for 2 years. With increasing ostomy output, infliximab dosing interval was reduced from 8 weeks to 5 weeks which led to less output and less fatigue. After a year, symptoms returned, and naltrexone was added with 1 mg increasing to 4.5 mg over 1 month. Within 4 months, her symptoms were in remission and ileoscopy showed flat scars where ulcers had been seen in the past (Figure 2B). Her disease remained in endoscopic remission for 3 years documented by two more ileoscopies. The patient maintained clinical response to the combination of infliximab (6 week intervals), methotrexate, and LDN. Owing to a change in insurance she was lost to follow up at this point. Figure 1. Rectal images before starting LDN for CD (A) and 3 years of maintenance therapy with LDN (B) Figure 2. Ileal ulcers seen after the second surgery (A) and scar tissue seen at the ulcer sites at the time the patient with on infliximab, methotrexate, and LDN (B)

EFFICACY OF LOW DOSE NALTREXONE IN PATIENTS WITH CROHN’S COLITIS AND ILEITIS

In a Phase 2 placebo-controlled trial, low dose naltrexone (LDN) improved inflammation of the gastrointestinal mucosa and improved clinical activity scores in patients with mild to moderate Crohn’s disease (CD). We present two patients with symptomatic CD with a rapid clinical and endoscopic response to LDN: 1) Crohn’s colitis with prolonged maintenance to LDN which had failed mesalamine with immunomodulator therapy; and 2) Crohn’s ileitis with prolonged remission with addition of LDN to biologic and immunomodulator therapy.

Effects of low-dose naltrexone on quality of life in high-grade glioma patients: a placebo-controlled, double-blind randomized trial.

At diagnosis and throughout the disease course, patients with high-grade glioma (HGG) experience a diminished quality of life (QOL) and increased fatigue. Naltrexone, an orally semisynthetic opiate antagonist, is FDA-approved for the treatment of heroin/alcohol addiction, and low-dose naltrexone (LDN) has been observed to improve QOL and lower fatigue in other neurological illnesses, such as multiple sclerosis. LDN is believed to function as a partial agonist and can lead to shifts in neurochemicals that reduce fatigue. Based on this, we sought to study whether LDN has an impact on QOL and fatigue in patients with HGG. In a placebo-controlled, double-blind study, we randomized 110 HGG patients to receive placebo (N = 56) or LDN 4.5mg orally at night (N = 54). Subjects received LDN or placebo at day 1 of concurrent radiation and temozolomide therapy and continued for 16weeks. Change from baseline in patient-reported outcomes of QOL (Functional Assessment of Cancer Therapy-Brain) and fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue) was assessed. Demographics were WHO grade IV (85%), male (56%), KPS 90-100 (51%), grossly resected (55%), and mean age of 56years. QOL and fatigue changes between baseline and post concurrent chemotherapy and radiation therapy were not significantly different between patients receiving LDN or placebo. The adverse event profiles for LDN and placebo were similar and attributed to concomitant use of temozolomide. LDN has no effect on QOL and fatigue in HGG patients during concurrent chemotherapy and radiation therapy. United States National Library of Medicine Clinical Trials.gov NCT01303835, Date 2/25/2011.

Study protocol for a randomised, double-blinded, placebo-controlled phase III trial examining the add-on efficacy, cost–utility and neurobiological effects of low-dose naltrexone (LDN) in patients with fibromyalgia (INNOVA study)

IntroductionThere is evidence that low-dose naltrexone (LDN; <5.0 mg/day) reduces pain and improves the quality of life of people with fibromyalgia syndrome (FMS). However, no randomised controlled trials with long-term...

Aticaprant (Clinically Developed Kappa-Opioid Receptor Antagonist) Combined With Naltrexone Prevents Alcohol "Relapse" Drinking.

Alcohol relapse is the treatment target for medications development for alcohol dependence. Aticaprant, a selective and short-acting kappa-opioid receptor (KOR) antagonist, has recently been under development for new clinical implications (depression or anhedonia). Recent studies have also found that aticaprant reduces alcohol intake and prevents stress- triggered alcohol seeking in rodents via a KOR-mediated mechanism. Here, we further investigated whether aticaprant alone or in combination with naltrexone (mu-opioid receptor [MOR] antagonist) altered alcohol relapse-like drinking using a mouse alcohol deprivation effect (ADE) paradigm to mimic the relapse episodes in human alcoholics. A long-acting and selective KOR antagonist nor-BNI was used as a reference compound for the effects of the KOR antagonism on the ADE. After 3-week intermittent-access alcohol drinking (two-bottle choice, 24-h access every other day), male and female mice displayed excessive alcohol intake and then pronounced ADE after 1-week abstinence. Aticaprant alone decreased alcohol ADE in a dose- dependent manner (1–3 mg/kg) in both males and females. Aticaprant at a lower dose (0.3 mg/kg) than the effective one (3 mg/kg) combined with a low dose of naltrexone (1 mg/kg) reduced the ADE in both sexes, and the combination was effective after a multi-dosing regimen (5 daily injections during the abstinence) without development of tolerance, suggesting synergistic effects of the combination. In contrast, nor-BNI alone or with naltrexone had no effect on the ADE in either sex. Our present study suggests that a combination of clinically developed, short-acting KOR antagonist aticaprant with low-dose naltrexone has therapeutic potential in alcohol “relapse” treatment.

A Systematic Literature Review on the Clinical Efficacy of Low Dose Naltrexone and its Effect on Putative Pathophysiological Mechanisms Among Patients Diagnosed with Fibromyalgia

A Systematic Literature Review on the Clinical Efficacy of Low Dose Naltrexone and its Effect on Putative Pathophysiological Mechanisms Among Patients Diagnosed with Fibromyalgia

Timing of treatment with an endogenous opioid alters immune response and spinal cord pathology in female mice with experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is a progressive disease of the central nervous system (CNS) that primarily affects women during the second or third decade of life. The mechanism is hypothesized to involve unregulated peripheral inflammation resulting in blood-brain barrier damage, and eventual axonal damage and demyelination. Based on this understanding, the animal model of MS, experimental autoimmune encephalomyelitis (EAE), often is utilized to study lymphocyte activation. Therapeutic paradigms of exogenous opioid growth factor (OGF) or low-dose naltrexone (LDN) treatment can modulate EAE, but little is reported regarding OGF or LDN effects on peripheral inflammation, microglia activation, and/or macrophage proliferation. Moreover, little is known about differential responses to LDN or OGF relative to the duration and timing of treatment. Utilizing a female mouse model of EAE, two treatment regimens were established to investigate differences between prophylactic treatment and traditional therapy initiated at the time of disease presentation. Prophylactic OGF or LDN treatment delayed the onset of behavior, suppressed neutrophil replication, and curtailed lymphocyte proliferation which ultimately improved behavioral outcome. Traditional therapy with OGF or LDN reversed behavioral deficits, restored OGF and IL-17 serum levels, and inhibited microglial activation within 8days. Reduced serum OGF levels in untreated EAE mice correlated with increased microglia activation within lumbar spinal cords. Both treatment regimens of OGF or LDN reduced activated microglia, whereas only prophylactic treatment prevented CNS macrophage aggregation. These data demonstrate that the timing of LDN or OGF treatment initiation alters outcomes and can prevent or reverse behavioral deficits, cytokine activation, and spinal cord pathology.

Low-dose naltrexone for the treatment of fibromyalgia: protocol for a double-blind, randomized, placebo-controlled trial

BackgroundLow-dose naltrexone (LDN) is used widely as an off-label treatment for pain despite limited evidence for its effectiveness. A few small trials with a high risk of bias have investigated the effect of LDN on pain associated with fibromyalgia in women, but larger and more methodologically robust studies are needed. The primary aim of this randomized controlled trial is to investigate if 12 weeks of LDN treatment is superior to placebo in reducing the average pain intensity during the last 7 days in women with fibromyalgia.MethodsA single-center, permuted block randomized, double-blind, placebo-controlled, parallel-group trial will be performed in Denmark. Randomization comprises 100 women aged 18–64 years diagnosed with fibromyalgia who will be treated with either LDN or placebo for 12 weeks including a 4-week titration phase. The primary outcome is change in average pain intensity (during the last 7 days) from baseline to 12 weeks. Secondary outcomes are other fibromyalgia-related symptoms, i.e., tenderness, fatigue, sleep disturbance, stiffness, memory problems, depression, anxiety and measures of global assessment, physical function, impact of fibromyalgia, pain distribution, and health-related quality of life. Intention-to-treat analysis will be performed, and the number of responders with a more than 15%, 30%, and 50% improvement of pain after 12 weeks will be calculated for the LDN and placebo groups. Exploratory outcomes include measures of pain sensitivity, muscle performance, and biomarkers.DiscussionThis study will contribute with high-level evidence on the efficacy of low-dose naltrexone for the treatment of pain in women with fibromyalgia. Secondary outcomes include both disease-specific and generic components investigating whether LDN influences other symptoms than pain. Explorative outcomes are included to provide greater insight into the mechanism of action of LDN and possibly a better understanding of the underlying pathology in fibromyalgia.Trial registrationEudraCT 2019-000702-30. Registered on 12 July 2019. ClinicalTrials.gov NCT04270877. Registered on 17 February 2020

Effect of Low-Dose Naltrexone on Egyptian Children with Intractable Epilepsy: A Case Series Study.

Epilepsy is a chronic neurological disorder affecting 50 million patients worldwide, in need of continuous treatment, while 30% of them are refractory to treatment. Despite multiple antiepileptic drugs are available for the treatment of epilepsy, still refractory epilepsy especially in children represents a social burden in developing countries. Low-dose naltrexone (LDN) has been proposed as an immune modulator in multiple diseases and proved benefit especially in diseases with immune dysregulation. The purpose of this study is to demonstrate the effect of LDN in the treatment of children with intractable epilepsy and discuss its potential role in epileptogenesis process.

Metronomic chemotherapy for advanced diffuse hepatocellular carcinoma in a dog

Primary liver tumors represent 0.6% to 1.3% of neoplasms in dogs. Hepatocellular carcinoma (HCC) is the most common liver tumor. It is divided into three morphological groups: massive, nodular and diffuse. The presumptive diagnosis is made through imaging tests, such as ultrasound, although confirmation is made by histopathology. Surgery remains the treatment of choice for massive tumors, but there is no standard treatment for nodular and diffuse forms. This study aimed to report a case of prolonged survival in a dog with diffuse HCC, treated with metronomic chemotherapy and palliative care including non-steroidal anti-inflammatory and low-dose naltrexone.

Darier and Hailey‐Hailey disease: update 2021

The autosomal-dominant genodermatoses Darier disease and Hailey-Hailey disease present special challenges to dermatologists. Despite their similar pathogenesis featuring impaired adhesion of suprabasal keratinocytes as a result of defective ATPases in epidermal calcium channels, the two diseases differ considerably in clinical presentation and therapeutic options. Darier disease is characterized by reddish brown, keratotic papules in seborrheic and intertriginous areas, which may coalesce into extensive lesions. Individuals affected with Hailey-Hailey disease primarily develop intertriginous papulovesicles and small blisters, which often evolve into erythematous plaques with erosions and painful fissures. Quality of life is significantly reduced because of complaints (itch, burning sensation, pain), body malodor and chronicity. Therapeutic options remain limited. Antiseptics and intermittent topical corticosteroids are a cornerstone of therapy, and systemic anti-infective treatment is often required in cases of superinfection. Ablative surgical interventions such as dermabrasion and CO2 laser surgery can lead to long-term remissions in intertriginous Hailey-Hailey disease, while temporary relief may also be achieved by intralesional injections of botulinum toxin. Of the systemic medications available for Darier disease, acitretin, which is approved for this purpose, has the best supporting evidence. The efficacy of immunosuppressants and immune modulators is inconsistent. Low-dose naltrexone produces more satisfactory results in Hailey-Hailey than Darier disease. The present CME article summarizes current knowledge of the two dermatoses, taking recent developments into account.

A narrative review of therapies for scalp dermatomyositis

Cutaneous involvement of the scalp is a common manifestation of dermatomyositis (DM), occurring in up to 82% of adults with DM. Scalp DM predominantly affects women and is characterized by dermatitis, alopecia, pruritus, and/or burning. While cutaneous DM negatively impacts quality-of-life, scalp symptoms in particular are often severe, debilitating, and recalcitrant to standard DM therapies. Currently, there is a paucity of guidelines to inform management of scalp symptoms in patients with cutaneous DM. In this narrative review, we summarize the treatments utilized to manage scalp DM and highlight potential areas for future research. We identified eight studies that reported on 27 treatments focused on cutaneous DM and described outcomes on scalp symptoms. A majority of the treatments were standard therapies for cutaneous DM and resulted in no or minimal improvement in scalp symptoms. Five therapies did result in complete resolution of scalp symptoms and were recommended as potential areas of future research. These included low-dose naltrexone and platelet-rich plasma, as well as two frequent and one less common therapy for cutaneous DM respectively: intravenous immunoglobulin, rituximab, and apremilast. Though the literature was not systematically assessed in this review, these findings illustrate not only that strategies for refractory scalp DM are lacking, but also that those demonstrating potential efficacy are limited by low levels of evidence. Additional studies, especially randomized controlled trials, are needed to better inform management of scalp DM.

Low-Dose Naltrexone Co-Treatment in the Prevention of Opioid-Induced Hyperalgesia.

Opioid-induced hyperalgesia (OIH) is characterized by a heightened sensitivity to pain that occurs in patients following opioid use. Prescription of opioids is currently the standard form of pain management for both neuropathic and nociceptive pain, due to the relief that patients typically report following their use. Opioids, which aim to provide analgesic effects, can paradoxically cause increasing degrees of pain among the users. The increased nociception can be either due to the underlying pain for which the opioid was initially prescribed, or other unrelated pain. As a result, those who are initially prescribed opioids for chronic pain relief may instead be left with no overall relief, and experience additional algesia. While OIH can be treated through the reduction of opioid use, antagonistic treatment can also be utilized. In an attempt to reduce OIH in patients, low doses of the opioid antagonist naltrexone can be given concurrently. This review will analyze the current role and effectiveness of the use of naltrexone in managing OIH in opioid users as described in clinical and non-clinical studies. Additionally, it seeks to characterize the underlying mechanisms that enable opioid antagonist naltrexone to reduce OIH while still allowing opioids to act as an analgesic. The authors find that OIH is a prevalent condition, and in order to effectively combat it, clinicians and patients can benefit from an extended study on how naltrexone can be utilized as a treatment alongside opioids prescribed for pain management.

Immunometabolic Modulatory Role of Naltrexone in BV-2 Microglia Cells.

Background: Naltrexone is an opioid receptor antagonist commonly used to treat opioid and alcohol dependence. The use of low dose naltrexone (LDN) was found to have anti-inflammatory properties for treatment of diseases such as fibromyalgia, Crohn’s disease, multiple sclerosis and regional pain syndromes. Related to its anti-neuroinflammatory properties, the mechanism of action is possibly mediated via Toll-like receptor 4 antagonism, which is widely expressed on microglial cells. The aim of the present study was to assess the immunometabolic effects of naltrexone on microglia cells in in vitro conditions. Methods: All experiments were performed in the BV-2 microglial cell line. The cells were treated with naltrexone at 100 μM concentrations corresponding to low dose for 24 h. Cell viability was assessed for every drug dose. To induce additional activation, the cells were pretreated with LPS and IFN-γ. Immunofluorescence was used to analyse the classical microglial activation markers iNOS and CD206, while Seahorse was used for real-time cellular metabolic assessments. mTOR activity measured over the expression of a major direct downstream target S6K was assessed using western blot. Results: LDN induced a shift from highly activated pro-inflammatory phenotype (iNOShighCD206low) to quiescent anti-inflammatory M2 phenotype (iNOSlowCD206high) in BV-2 microglia cells. Changes in the inflammatory profile were accompanied by cellular metabolic switching based on the transition from high glycolysis to mitochondrial oxidative phosphorylation (OXPHOS). LDN-treated cells were able to maintain a metabolically suppressive phenotype by supporting OXPHOS with high oxygen consumption, and also maintain a lower energetic state due to lower lactate production. The metabolic shift induced by transition from glycolysis to mitochondrial oxidative metabolism was more prominent in cells pretreated with immunometabolic modulators such as LPS and IFN-γ. In a dose-dependent manner, naltrexone also modulated mTOR/S6K expression, which underlies the cell metabolic phenotype regulating microglia immune properties and adaptation. Conclusion: By modulating the phenotypic features by metabolic switching of activated microglia, naltrexone was found to be an effective and powerful tool for immunometabolic reprogramming and could be a promising novel treatment for various neuroinflammatory conditions.

LDN Protects Bone Property Deterioration at Different Hierarchical Levels in T2DM Mice Bone.

Type 2 diabetes mellitus (T2DM) commonly affects bone quality at different hierarchical levels and leads to an increase in the risk of bone fracture. Earlier, some anti-diabetic drugs showed positive effects on bone mechanical properties. Recently, we have investigated that low-dose naltrexone (LDN), a TLR4 antagonist treatment, improves glucose tolerance in high-fat diet (HFD)-induced T2DM mice and also gives protection against HFD-induced weight gain. However, effects on bone are still unknown. In this study, the effects of LDN on the bone properties at different hierarchical levels in T2DM mice bone were investigated. In order to investigate these, four different groups of bone (divided based on diet and treatment) were considered in this present study. These are (a) normal control diet treated with saline water, (b) normal control diet treated with LDN, (c) HFD treated with saline water, and (d) HFD treated with LDN. Bone properties were measured in terms of fracture toughness, nano-Young’s modulus, hardness, mineral crystal size, bone composition, and bulk mineral to matrix ratio. Results indicated that fracture toughness, nano-Young’s modulus, and hardness were decreased in T2DM bone as compared to normal bone, and interestingly, treatment with the LDN increases these material properties in T2DM mice bone. Similarly, as compared to the normal bone, decrease in the mineral crystal size and bulk mineral-to-matrix ratio was observed in the T2DM bone, whereas LDN treatment protects these alterations in the T2DM mice bone. The bone size (bone geometry) was increased in the case of HFD-induced T2DM bone; however, LDN cannot protect to increase the bone size in the T2DM mice bone. In conclusion, LDN can be used to control the T2DM-affected bone properties at different hierarchical levels.

Potential Therapeutic Benefit of Low Dose Naltrexone in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Role of Transient Receptor Potential Melastatin 3 Ion Channels in Pathophysiology and Treatment

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating multi-systemic chronic condition of unknown aetiology classified as an immune dysfunction syndrome and neurological disorder. The discovery of the widely expressed Transient Receptor Potential Melastatin 3 (TRPM3) as a nociceptor channel substantially targeted by certain opioid receptors, and its implication in calcium (Ca2+)-dependent Natural Killer (NK) cell immune functions has raised the possibility that TRPM3 may be pharmacologically targeted to treat characteristic symptoms of ME/CFS. Naltrexone hydrochloride (NTX) acts as an antagonist to the mu (μ)-opioid receptor thus negating its inhibitory function on TRPM3. Based on the benefits reported by patients on their symptoms, low dose NTX (LDN, 3.0–5.0 mg/day) treatment seems to offer some potential benefit suggesting that its effect may be targeted towards the pathomechanism of ME/CFS. As there is no literature confirming the efficacy of LDN for ME/CFS patients in vitro, this study investigates the potential therapeutic effect of LDN in ME/CFS patients. TRPM3 ion channel activity was measured after modulation with Pregnenolone sulfate (PregS) and ononetin in NK cells on 9 ME/CFS patients taking LDN and 9 age- and sex-matched healthy controls using whole-cell patch-clamp technique. We report that ME/CFS patients taking LDN have restored TRPM3-like ionic currents in NK cells. Small ionic currents with a typical TRPM3-like outward rectification were measured after application of PregS, a TRPM3-agonist, in NK cells from patients taking LDN. Additionally, PregS-evoked ionic currents through TRPM3 were significantly modulated by ononetin, a TRPM3-antagonist, in NK cells from ME/CFS patients taking LDN. These data support the hypothesis that LDN may have potential as a treatment for ME/CFS by characterising the underlying regulatory mechanisms of LDN treatment involving TRPM3 and opioid receptors in NK cells. Finally, this study may serve for the repurpose of marketed drugs, as well as support the approval of prospective randomized clinical studies on the role and dose of NTX in treating ME/CFS patients.

Low-Dose Naltrexone Use for Patients with Chronic Regional Pain Syndrome: A Systematic Literature Review

Complex regional pain syndrome is a rare, neuropathic disorder that affects fewer than 200,000 individuals in the United States annually. Current treatments often focus on pain management and fall short of relieving symptoms of pain and dystonia in patients. The goal of this systematic qualitative review is to evaluate the evidence for the use of low-dose naltrexone in the treatment of chronic pain syndromes. This is a systematic review. PubMed, Embase, and Web of Science were searched for articles containing the keywords "low-dose naltrexone" AND ("pain" OR "chronic pain" OR "fibromyalgia" OR "complex regional pain syndrome" OR "neuropathic pain" OR "nociceptive pain") between 1950 and July 17, 2020. A total of 30 publications were systematically reviewed. Exclusion criteria were articles that were unavailable in English, focused on acute pain only, and evaluated only animal models. Case studies were included for the purposes of our qualitative review. Out of 29 articles, we reviewed 11 prospective studies, 10 case studies, 3 systematic reviews, 2 retrospective studies, 2 simulation models, and one combination study. Articles focused on chronic pain syndromes as well as painful rheumatologic disorders and neurological disorders. We found that low-dose naltrexone treatment was positively associated with symptom relief in patients experiencing chronic pain, dystonia, and sleep disturbances. Due to the limited number of available articles focusing on the treatment of complex regional pain syndrome with low-dose naltrexone, the majority of studies analyzed focused on other chronic pain syndromes. There is a need for additional prospective and interventional studies addressing the use of low-dose naltrexone in the treatment of complex regional pain syndrome symptoms.

Complex Regional Pain Syndrome: A Comprehensive Review.

Complex regional pain syndrome (CRPS) is a chronic pain condition often involving hyperalgesia and allodynia of the extremities. CRPS is divided into CRPS-I and CRPS-II. Type I occurs when there is no confirmed nerve injury. Type II is when there is known associated nerve injury. Female gender is a risk factor for developing CRPS. Other risk factors include fibromyalgia and rheumatoid arthritis. Unfortunately, the pathogenesis of CRPS is not yet clarified. Some studies have demonstrated different potential pathways. Neuropathic inflammation, specifically activation of peripheral nociceptors of C-fibers, has been shown to play a critical role in developing CRPS. The autonomic nervous system (ANS) is involved. Depending on whether it is acute or chronic CRPS, norepinephrine levels are either decreased or increased, respectively. Some studies have suggested the importance of genetics in developing CRPS. More consideration is being given to the role of psychological factors. Some association between a history of depression and/or post-traumatic stress disorder (PTSD) and the diagnosis of CRPS has been demonstrated. Treatment modalities available range from physical therapy, pharmacotherapy, and interventional techniques. Physical and occupational therapies include mirror therapy and graded motor imagery. Medical management with non-steroidal anti-inflammatory drugs (NSAIDs) has not shown significant improvement. There have been supporting findings in the use of short-course steroids, bisphosphonates, gabapentin, and ketamine. Antioxidant treatment has also shown some promise. Other pharmacotherapies include low-dose naltrexone and Botulinum toxin A (BTX-A). Sympathetic blocks are routinely used, even if their short- and long-term effects are not clear. Finally, spinal cord stimulation (SCS) has been used for decades. In conclusion, CRPS is a multifactorial condition that still requires further studying to better understand its pathogenesis, epidemiology, genetic involvement, psychological implications, and treatment options. Future studies are warranted to better understand this syndrome. This will provide an opportunity for better prevention, diagnosis, and treatment of CRPS.