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 follow-ups have been carried out. The INNOVA study will evaluate the add-on efficacy, safety, cost–utility and neurobiological effects of LDN for reducing pain in patients with FMS, with a 1-year follow-up.Methods and analysisA single-site, prospective, randomised, double-blinded, placebo-controlled, parallel design phase III trial will be performed. Eligibility criteria include being adult, having a diagnosis of FMS and experiencing pain of 4 or higher on a 10-point numerical rating scale. Participants will be randomised to a LDN intervention group (4.5 mg/day) or to a placebo control group. Clinical assessments will be performed at baseline (T0), 3 months (T1), 6 months (T2) and 12 months (T3). The primary endpoint will be pain intensity. A sample size of 60 patients per study arm (120 in total), as calculated prior to recruitment for sufficient power, will be monitored between January 2022 and August 2024. Assessment will also include daily ecological momentary evaluations of FMS-related symptoms (eg, pain intensity, fatigue and sleep disturbance), and side effects via ecological momentary assessment through the Pain Monitor app during the first 3 months. Costs and quality-adjusted life years will be also calculated. Half of the participants in each arm will be scanned with MRI at T0 and T1 for changes in brain metabolites related to neuroinflammation and central sensitisation. Inflammatory biomarkers in serum will also be measured.Ethics and disseminationThis study has been approved by the Ethics Committee of the Fundació Sant Joan de Déu. The results will be actively disseminated through peer-reviewed journals, conference presentations, social media and community engagement activities.Trial registration numberNCT04739995.

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

Background Low-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. Methods A 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. Discussion This 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 registration EudraCT 2019-000702-30. Registered on 12 July 2019. ClinicalTrials.gov NCT04270877. Registered on 17 February 2020

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.

Prurigo excoriée treated with low dose naltrexone

A 53-year-old woman presented with a 25-year history of acne excoriée and prurigo excoriée. Her symptoms began in 1988 coinciding with her husband’s death from a brain tumour when she was 27. The pruritus affected her quality of life and disturbed her sleep. She had scarring on her face and body resulting from persistent scratching. The pruritus proved refractory to treatment despite a multi-modal treatment approach including multiple topicals, phototherapy and systemic agents such as isotretinoin, antibiotics, anxiolytic agents and neuromodulators. She was extremely frustrated that various treatments had been ineffective at controlling the itch-scratch cycle. She was commenced on low dose naltrexone (LDN), 3 mg nocte, and she became itch free within a few weeks. She reports that the LDN has had a beneficial impact on her quality of life.

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

BACKGROUND: 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. OBJECTIVE: 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. STUDY DESIGN: This is a systematic review. METHODS: 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. RESULTS: 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. LIMITATIONS: 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. CONCLUSIONS: 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. KEY WORDS: Complex regional pain syndrome, reflex sympathetic dystrophy, low-dose naltrexone, chronic pain, opioid antagonist