Derivation Web

source_4051c2261f764803

by researka:v2 · 2026-06-29 13:42:33.745496+04:00

{"publication_id": "3b9d2db0-4fb0-44d4-bab5-5c3b2794f100", "traces": [{"candidate_sources": [{"directness": "primary", "doi": "10.1016/j.bjane.2022.08.003", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_1", "study": "Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.bjane.2022.08.003"}, {"directness": "review-level", "doi": "10.1093/pm/pnad074", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_2", "study": "Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1093/pm/pnad074"}, {"directness": "review-level", "doi": "10.1007/s12325-026-03612-5", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_3", "study": "Low-Dose Naltrexone: What is the Evidence? A Narrative Review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s12325-026-03612-5"}, {"directness": "review-level", "doi": "10.1016/j.heliyon.2023.e15638", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_4", "study": "A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.heliyon.2023.e15638"}, {"directness": "primary", "doi": "10.2147/JPR.S389957", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_5", "study": "Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series", "support_kind": "candidate_source_row", "url": "https://doi.org/10.2147/JPR.S389957"}], "claim": "This paper synthesizes evidence on Low dose naltrexone inflammation across 39 accepted source papers and 1510 high-confidence extracted claims.", "claim_id": "claim_1"}, {"candidate_sources": [{"directness": "primary", "doi": "10.1016/j.bjane.2022.08.003", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_1", "study": "Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.bjane.2022.08.003"}, {"directness": "review-level", "doi": "10.1093/pm/pnad074", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_2", "study": "Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1093/pm/pnad074"}, {"directness": "review-level", "doi": "10.1007/s12325-026-03612-5", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_3", "study": "Low-Dose Naltrexone: What is the Evidence? A Narrative Review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s12325-026-03612-5"}, {"directness": "review-level", "doi": "10.1016/j.heliyon.2023.e15638", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_4", "study": "A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.heliyon.2023.e15638"}, {"directness": "primary", "doi": "10.2147/JPR.S389957", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_5", "study": "Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series", "support_kind": "candidate_source_row", "url": "https://doi.org/10.2147/JPR.S389957"}], "claim": "The evidence profile contains 3 direct clinical sources, 36 adjacent clinical sources, and no sources classified primarily as mechanistic or model-system evidence, with 108 cross-study disagreements across the evidence base.", "claim_id": "claim_2"}, {"candidate_sources": [{"directness": "primary", "doi": "10.1016/j.bjane.2022.08.003", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_1", "study": "Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.bjane.2022.08.003"}, {"directness": "review-level", "doi": "10.1093/pm/pnad074", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_2", "study": "Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1093/pm/pnad074"}, {"directness": "review-level", "doi": "10.1007/s12325-026-03612-5", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_3", "study": "Low-Dose Naltrexone: What is the Evidence? A Narrative Review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s12325-026-03612-5"}, {"directness": "review-level", "doi": "10.1016/j.heliyon.2023.e15638", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_4", "study": "A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.heliyon.2023.e15638"}, {"directness": "primary", "doi": "10.2147/JPR.S389957", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_5", "study": "Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series", "support_kind": "candidate_source_row", "url": "https://doi.org/10.2147/JPR.S389957"}], "claim": "No single positive outcome class dominates the retained corpus; null signals cluster in the dosing and pharmacokinetics, immune and inflammation outcome classes, and negative signals cluster in no dominant outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.", "claim_id": "claim_3"}, {"candidate_sources": [{"directness": "primary", "doi": "10.1016/j.bjane.2022.08.003", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_1", "study": "Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.bjane.2022.08.003"}, {"directness": "review-level", "doi": "10.1093/pm/pnad074", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_2", "study": "Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1093/pm/pnad074"}, {"directness": "review-level", "doi": "10.1007/s12325-026-03612-5", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_3", "study": "Low-Dose Naltrexone: What is the Evidence? A Narrative Review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s12325-026-03612-5"}, {"directness": "review-level", "doi": "10.1016/j.heliyon.2023.e15638", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_4", "study": "A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.heliyon.2023.e15638"}, {"directness": "primary", "doi": "10.2147/JPR.S389957", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_5", "study": "Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series", "support_kind": "candidate_source_row", "url": "https://doi.org/10.2147/JPR.S389957"}], "claim": "The conclusion is that Low dose naltrexone inflammation remains a bounded geroscience case: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.", "claim_id": "claim_4"}, {"candidate_sources": [{"directness": "primary", "doi": "10.1016/j.bjane.2022.08.003", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_1", "study": "Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.bjane.2022.08.003"}, {"directness": "review-level", "doi": "10.1093/pm/pnad074", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_2", "study": "Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1093/pm/pnad074"}, {"directness": "review-level", "doi": "10.1007/s12325-026-03612-5", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_3", "study": "Low-Dose Naltrexone: What is the Evidence? A Narrative Review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s12325-026-03612-5"}, {"directness": "review-level", "doi": "10.1016/j.heliyon.2023.e15638", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_4", "study": "A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.heliyon.2023.e15638"}, {"directness": "primary", "doi": "10.2147/JPR.S389957", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_5", "study": "Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series", "support_kind": "candidate_source_row", "url": "https://doi.org/10.2147/JPR.S389957"}], "claim": "For that reason, the manuscript does not collapse every source into a single recommendation. It presents the intervention as a set of linked claims whose strength depends on the evidence tier and the match between mechanism, population, and endpoint.", "claim_id": "claim_5"}, {"candidate_sources": [{"directness": "primary", "doi": "10.1016/j.bjane.2022.08.003", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_1", "study": "Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.bjane.2022.08.003"}, {"directness": "review-level", "doi": "10.1093/pm/pnad074", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_2", "study": "Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1093/pm/pnad074"}, {"directness": "review-level", "doi": "10.1007/s12325-026-03612-5", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_3", "study": "Low-Dose Naltrexone: What is the Evidence? A Narrative Review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s12325-026-03612-5"}, {"directness": "review-level", "doi": "10.1016/j.heliyon.2023.e15638", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_4", "study": "A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.heliyon.2023.e15638"}, {"directness": "primary", "doi": "10.2147/JPR.S389957", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_5", "study": "Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series", "support_kind": "candidate_source_row", "url": "https://doi.org/10.2147/JPR.S389957"}], "claim": "Aging is increasingly framed as a modifiable biological process rather than an immutable decline, and the question of whether pharmacologic interventions can extend healthspan—the period of life spent in good health—has become one of the most active debates in geriatric medicine. Population aging has shifted the clinical priority from treating individual diseases to compressing morbidity and preserving function, yet the translational pipeline from mechanistic insight to approved intervention remains slow and expensive. The stakes are concrete: even modest improvements in function translate into large absolute gains in disability-free years, and the regulatory and methodological infrastructure for aging-related trials is being constructed in real time. The question of whether Low-dose naltrexone—proposed here as a low-cost repurposed candidate with putative anti-inflammatory properties—can meaningfully contribute to this agenda appears timely, and the evidence base deserves the same scrutiny applied to any candidate aging intervention. As the field operationalizes frameworks for targeting aging biology, the case for and against low-dose naltrexone must be examined with the same rigor afforded to more established candidates.", "claim_id": "claim_6"}, {"candidate_sources": [{"directness": "primary", "doi": "10.1016/j.bjane.2022.08.003", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_1", "study": "Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.bjane.2022.08.003"}, {"directness": "review-level", "doi": "10.1093/pm/pnad074", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_2", "study": "Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1093/pm/pnad074"}, {"directness": "review-level", "doi": "10.1007/s12325-026-03612-5", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_3", "study": "Low-Dose Naltrexone: What is the Evidence? A Narrative Review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s12325-026-03612-5"}, {"directness": "review-level", "doi": "10.1016/j.heliyon.2023.e15638", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_4", "study": "A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.heliyon.2023.e15638"}, {"directness": "primary", "doi": "10.2147/JPR.S389957", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_5", "study": "Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series", "support_kind": "candidate_source_row", "url": "https://doi.org/10.2147/JPR.S389957"}], "claim": "The geroscience hypothesis argues that targeting the biological hallmarks of aging may produce broader benefits than the conventional single-disease model, and drug repurposing offers a pragmatic pathway to test that logic with lower cost and shorter timelines than de novo development. Low sits squarely within this repurposing tradition: it is a generic, orally bioavailable small molecule with a known safety record at higher doses, which lowers the preclinical hurdle and shifts the evidentiary burden toward demonstration of clinically meaningful benefit at the low doses used off-label. The intervention logic for low-dose naltrexone rests on the premise that low-dose opioid-receptor modulation may attenuate microglial and innate-immune activation, plausibly reducing the chronic low-grade inflammation that contributes to age-related functional decline. Whether that mechanistic hypothesis translates into measurable gains in healthspan or lifespan for adults without specific inflammatory diagnoses remains, however, the central empirical question, and one that the present evidence base does not yet resolve.", "claim_id": "claim_7"}, {"candidate_sources": [{"directness": "primary", "doi": "10.1016/j.bjane.2022.08.003", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_1", "study": "Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.bjane.2022.08.003"}, {"directness": "review-level", "doi": "10.1093/pm/pnad074", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_2", "study": "Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1093/pm/pnad074"}, {"directness": "review-level", "doi": "10.1007/s12325-026-03612-5", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_3", "study": "Low-Dose Naltrexone: What is the Evidence? A Narrative Review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s12325-026-03612-5"}, {"directness": "review-level", "doi": "10.1016/j.heliyon.2023.e15638", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_4", "study": "A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.heliyon.2023.e15638"}, {"directness": "primary", "doi": "10.2147/JPR.S389957", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_5", "study": "Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series", "support_kind": "candidate_source_row", "url": "https://doi.org/10.2147/JPR.S389957"}], "claim": "The low-dose formulation—typically 1 to 5 mg daily, with 4.5 mg being the most commonly reported regimen—has been explored off-label across a wide range of conditions characterized by centralized pain or chronic inflammation (Gouda 2026; Rupp 2023). Mechanistically, low-dose naltrexone is hypothesized to act through transient modulation of Toll-like receptor 4 signaling on microglia, producing downstream reductions in pro-inflammatory cytokine release, although the clinical evidence for this anti-inflammatory effect in humans remains uncertain (Leiber 2025). The clinical history of low-dose naltrexone is thus a story of regulatory drift from addiction medicine toward exploratory use in fibromyalgia, inflammatory bowel disease, multiple sclerosis, post-viral fatigue syndromes, and a long list of other conditions—an empirical pattern that has produced breadth but limited depth of evidence.", "claim_id": "claim_8"}, {"candidate_sources": [{"directness": "primary", "doi": "10.1016/j.bjane.2022.08.003", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_1", "study": "Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.bjane.2022.08.003"}, {"directness": "review-level", "doi": "10.1093/pm/pnad074", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_2", "study": "Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1093/pm/pnad074"}, {"directness": "review-level", "doi": "10.1007/s12325-026-03612-5", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_3", "study": "Low-Dose Naltrexone: What is the Evidence? A Narrative Review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s12325-026-03612-5"}, {"directness": "review-level", "doi": "10.1016/j.heliyon.2023.e15638", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_4", "study": "A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.heliyon.2023.e15638"}, {"directness": "primary", "doi": "10.2147/JPR.S389957", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_5", "study": "Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series", "support_kind": "candidate_source_row", "url": "https://doi.org/10.2147/JPR.S389957"}], "claim": "This synthesis addresses those gaps by separating evidence on dosing and pharmacokinetics from evidence on immune and clinical outcomes, and by weighting direct randomized data more heavily than indirect or review-level claims. A central contribution is the explicit enumeration of cross-outcome tensions: the meta-analytic pain reduction reported by Vatvani 2024 coexists with null or weak signals in the primary RCTs (Bruun 2021; Bested 2023); reductions in inflammatory bowel disease medication dispensing (Raknes 2018) contrast with null effects on thyroid-hormone use (Raknes 2020); and the mechanistic anti-inflammatory rationale for low-dose naltrexone sits uneasily beside null biomarker results in trials such as Moloney 2026. By formalizing these tensions and treating direct versus indirect evidence as non-fungible, the synthesis aims to clarify what is currently knowable, what remains uncertain, and which questions future trials of low-dose naltrexone would need to answer before any anti-aging claim could be substantiated.", "claim_id": "claim_9"}, {"candidate_sources": [{"directness": "primary", "doi": "10.1016/j.bjane.2022.08.003", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_1", "study": "Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.bjane.2022.08.003"}, {"directness": "review-level", "doi": "10.1093/pm/pnad074", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_2", "study": "Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1093/pm/pnad074"}, {"directness": "review-level", "doi": "10.1007/s12325-026-03612-5", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_3", "study": "Low-Dose Naltrexone: What is the Evidence? A Narrative Review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s12325-026-03612-5"}, {"directness": "review-level", "doi": "10.1016/j.heliyon.2023.e15638", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_4", "study": "A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.heliyon.2023.e15638"}, {"directness": "primary", "doi": "10.2147/JPR.S389957", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_5", "study": "Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series", "support_kind": "candidate_source_row", "url": "https://doi.org/10.2147/JPR.S389957"}], "claim": "The background evidence for Low dose naltrexone inflammation is heterogeneous rather than uniformly confirmatory. Direct clinical sources such as Tsui 2024, Bruun 2021, Naik 2024 are interpreted separately from mechanistic studies such as the retained evidence base, because these evidence roles answer different questions about aging biology and clinical translation.", "claim_id": "claim_10"}, {"candidate_sources": [{"directness": "primary", "doi": "10.1016/j.bjane.2022.08.003", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_1", "study": "Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.bjane.2022.08.003"}, {"directness": "review-level", "doi": "10.1093/pm/pnad074", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_2", "study": "Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1093/pm/pnad074"}, {"directness": "review-level", "doi": "10.1007/s12325-026-03612-5", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_3", "study": "Low-Dose Naltrexone: What is the Evidence? A Narrative Review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s12325-026-03612-5"}, {"directness": "review-level", "doi": "10.1016/j.heliyon.2023.e15638", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_4", "study": "A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.heliyon.2023.e15638"}, {"directness": "primary", "doi": "10.2147/JPR.S389957", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_5", "study": "Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series", "support_kind": "candidate_source_row", "url": "https://doi.org/10.2147/JPR.S389957"}], "claim": "The direct evidence establishes what has been observed in human or adjacent clinical settings. The mechanistic evidence helps explain why an effect might be plausible, but it does not by itself establish the size, durability, or safety of a human healthspan effect.", "claim_id": "claim_11"}, {"candidate_sources": [{"directness": "primary", "doi": "10.1016/j.bjane.2022.08.003", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_1", "study": "Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.bjane.2022.08.003"}, {"directness": "review-level", "doi": "10.1093/pm/pnad074", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_2", "study": "Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1093/pm/pnad074"}, {"directness": "review-level", "doi": "10.1007/s12325-026-03612-5", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_3", "study": "Low-Dose Naltrexone: What is the Evidence? A Narrative Review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s12325-026-03612-5"}, {"directness": "review-level", "doi": "10.1016/j.heliyon.2023.e15638", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_4", "study": "A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.heliyon.2023.e15638"}, {"directness": "primary", "doi": "10.2147/JPR.S389957", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_5", "study": "Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series", "support_kind": "candidate_source_row", "url": "https://doi.org/10.2147/JPR.S389957"}], "claim": "Across the retained sources, positive signals cluster around no dominant outcome class; null signals around the dosing and pharmacokinetics, immune and inflammation outcome classes; and negative or adverse signals around no dominant outcome class. This pattern motivates a synthesis that keeps outcome domains separate before drawing cross-domain interpretation.", "claim_id": "claim_12"}, {"candidate_sources": [{"directness": "primary", "doi": "10.1016/j.bjane.2022.08.003", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_1", "study": "Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.bjane.2022.08.003"}, {"directness": "review-level", "doi": "10.1093/pm/pnad074", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_2", "study": "Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1093/pm/pnad074"}, {"directness": "review-level", "doi": "10.1007/s12325-026-03612-5", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_3", "study": "Low-Dose Naltrexone: What is the Evidence? A Narrative Review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s12325-026-03612-5"}, {"directness": "review-level", "doi": "10.1016/j.heliyon.2023.e15638", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_4", "study": "A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.heliyon.2023.e15638"}, {"directness": "primary", "doi": "10.2147/JPR.S389957", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_5", "study": "Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series", "support_kind": "candidate_source_row", "url": "https://doi.org/10.2147/JPR.S389957"}], "claim": "The study-level structure also prevents selective emphasis. Supportive, null, mixed, and adverse findings remain visible in the same manuscript, allowing the reader to distinguish evidential breadth from evidential certainty.", "claim_id": "claim_13"}, {"candidate_sources": [{"directness": "primary", "doi": "10.1016/j.bjane.2022.08.003", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_1", "study": "Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.bjane.2022.08.003"}, {"directness": "review-level", "doi": "10.1093/pm/pnad074", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_2", "study": "Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1093/pm/pnad074"}, {"directness": "review-level", "doi": "10.1007/s12325-026-03612-5", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_3", "study": "Low-Dose Naltrexone: What is the Evidence? A Narrative Review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s12325-026-03612-5"}, {"directness": "review-level", "doi": "10.1016/j.heliyon.2023.e15638", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_4", "study": "A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.heliyon.2023.e15638"}, {"directness": "primary", "doi": "10.2147/JPR.S389957", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_5", "study": "Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series", "support_kind": "candidate_source_row", "url": "https://doi.org/10.2147/JPR.S389957"}], "claim": "The resulting paper is therefore a calibrated synthesis: it can identify plausible mechanisms, observed direct signals when present, unresolved tensions, and trial-design priorities without converting them into claims stronger than the retained corpus can support.", "claim_id": "claim_14"}, {"candidate_sources": [{"directness": "primary", "doi": "10.1016/j.bjane.2022.08.003", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_1", "study": "Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.bjane.2022.08.003"}, {"directness": "review-level", "doi": "10.1093/pm/pnad074", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_2", "study": "Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1093/pm/pnad074"}, {"directness": "review-level", "doi": "10.1007/s12325-026-03612-5", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_3", "study": "Low-Dose Naltrexone: What is the Evidence? A Narrative Review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s12325-026-03612-5"}, {"directness": "review-level", "doi": "10.1016/j.heliyon.2023.e15638", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_4", "study": "A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.heliyon.2023.e15638"}, {"directness": "primary", "doi": "10.2147/JPR.S389957", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_5", "study": "Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series", "support_kind": "candidate_source_row", "url": "https://doi.org/10.2147/JPR.S389957"}], "claim": "The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias sidecar when populated, and claim registry) rather than from re-parsed full text.", "claim_id": "claim_15"}, {"candidate_sources": [{"directness": "primary", "doi": "10.1016/j.bjane.2022.08.003", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_1", "study": "Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.bjane.2022.08.003"}, {"directness": "review-level", "doi": "10.1093/pm/pnad074", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_2", "study": "Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1093/pm/pnad074"}, {"directness": "review-level", "doi": "10.1007/s12325-026-03612-5", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_3", "study": "Low-Dose Naltrexone: What is the Evidence? A Narrative Review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s12325-026-03612-5"}, {"directness": "review-level", "doi": "10.1016/j.heliyon.2023.e15638", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_4", "study": "A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.heliyon.2023.e15638"}, {"directness": "primary", "doi": "10.2147/JPR.S389957", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_5", "study": "Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series", "support_kind": "candidate_source_row", "url": "https://doi.org/10.2147/JPR.S389957"}], "claim": "Risk-of-bias framework assignment follows study design (RoB-2 for RCTs, ROBINS-I for non-randomised studies, AMSTAR-2 for systematic reviews / meta-analyses). Public appraisal claims are limited to populated `risk_of_bias.json` rows; when no populated ratings are present, interpretation remains bounded by source tier and directness rather than formal RoB certification.", "claim_id": "claim_16"}, {"candidate_sources": [{"directness": "primary", "doi": "10.1016/j.bjane.2022.08.003", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_1", "study": "Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.bjane.2022.08.003"}, {"directness": "review-level", "doi": "10.1093/pm/pnad074", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_2", "study": "Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1093/pm/pnad074"}, {"directness": "review-level", "doi": "10.1007/s12325-026-03612-5", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_3", "study": "Low-Dose Naltrexone: What is the Evidence? A Narrative Review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s12325-026-03612-5"}, {"directness": "review-level", "doi": "10.1016/j.heliyon.2023.e15638", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_4", "study": "A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.heliyon.2023.e15638"}, {"directness": "primary", "doi": "10.2147/JPR.S389957", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_5", "study": "Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series", "support_kind": "candidate_source_row", "url": "https://doi.org/10.2147/JPR.S389957"}], "claim": "Evidence-tension synthesis: claims grouped by outcome class (dosing and pharmacokinetics, immune and inflammation); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.", "claim_id": "claim_17"}, {"candidate_sources": [{"directness": "primary", "doi": "10.1016/j.bjane.2022.08.003", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_1", "study": "Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.bjane.2022.08.003"}, {"directness": "review-level", "doi": "10.1093/pm/pnad074", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_2", "study": "Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1093/pm/pnad074"}, {"directness": "review-level", "doi": "10.1007/s12325-026-03612-5", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_3", "study": "Low-Dose Naltrexone: What is the Evidence? A Narrative Review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s12325-026-03612-5"}, {"directness": "review-level", "doi": "10.1016/j.heliyon.2023.e15638", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_4", "study": "A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.heliyon.2023.e15638"}, {"directness": "primary", "doi": "10.2147/JPR.S389957", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_5", "study": "Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series", "support_kind": "candidate_source_row", "url": "https://doi.org/10.2147/JPR.S389957"}], "claim": "Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified.", "claim_id": "claim_18"}, {"candidate_sources": [{"directness": "primary", "doi": "10.1016/j.bjane.2022.08.003", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_1", "study": "Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.bjane.2022.08.003"}, {"directness": "review-level", "doi": "10.1093/pm/pnad074", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_2", "study": "Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1093/pm/pnad074"}, {"directness": "review-level", "doi": "10.1007/s12325-026-03612-5", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_3", "study": "Low-Dose Naltrexone: What is the Evidence? A Narrative Review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s12325-026-03612-5"}, {"directness": "review-level", "doi": "10.1016/j.heliyon.2023.e15638", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_4", "study": "A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.heliyon.2023.e15638"}, {"directness": "primary", "doi": "10.2147/JPR.S389957", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_5", "study": "Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series", "support_kind": "candidate_source_row", "url": "https://doi.org/10.2147/JPR.S389957"}], "claim": "Substantive evidence synthesis: The manifest includes 39 retained sources, 3 direct-source row(s), and receipt-level directional coding across null=19, unclear=20. Receipt-level direction is not a statement that the source abstracts lack directional statistics; source-level signals are reported separately. Representative source-level signals are: Paula 2022: outcome=Dosing and Pharmacokinetics; direction=unclear; directness=indirect; tier=B2; result=Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized; finding=representative statistic p = 0.010; source-level statistic reported; claims=246; Rupp 2023: outcome=Dosing and Pharmacokinetics; direction=unclear; directness=review; tier=B2; result=Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review; finding=representative statistic P = 0.005; source-level statistic reported; claims=216; Gouda 2026: outcome=Dosing and Pharmacokinetics; direction=unclear; directness=review; tier=B1; result=Low-Dose Naltrexone: What is the Evidence? A Narrative Review; finding=188 extracted claim(s); receipt-level direction is the coded finding; claims=188; Partridge 2023: outcome=Mechanism/Dosing and Pharmacokinetics; direction=unclear; directness=review; tier=B1; result=A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative; finding=representative statistic P = 0.016; source-level statistic reported; claims=108; McKenzie-Brown 2023: outcome=Dosing and Pharmacokinetics; direction=unclear; directness=indirect; tier=B2; result=Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series; finding=representative statistic p = 0.038; source-level statistic reported; claims=86; Moloney 2026: outcome=Dosing and Pharmacokinetics; direction=unclear; directness=indirect; tier=B2; result=Low-dose naltrexone as an adjunctive treatment for major depressive disorder: findings from a randomized, double-blind; finding=representative non-significant statistic p = 0.97; not treated as positive or negative directional support unless source direction is coded; claims=73; Vatvani 2024: outcome=Dosing and Pharmacokinetics; direction=unclear; directness=review; tier=B2; result=Efficacy and safety of low-dose naltrexone for the management of fibromyalgia: a systematic review and meta-analysis of; finding=representative statistic P < 0.001; source-level statistic reported; claims=64; Raknes 2018: outcome=Dosing and Pharmacokinetics; direction=unclear; directness=indirect; tier=B2; result=The Effect of Low-Dose Naltrexone on Medication in Inflammatory Bowel Disease: A Quasi Experimental Before-and-After; finding=representative statistic p <0.05; source-level statistic reported; claims=61. These signals inform the bounded conclusion by separating effect direction from evidence tier/directness; indirect, review-level, mechanistic, or contextual evidence remains hypothesis-generating.", "claim_id": "claim_19"}, {"candidate_sources": [{"directness": "primary", "doi": "10.1016/j.bjane.2022.08.003", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_1", "study": "Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.bjane.2022.08.003"}, {"directness": "review-level", "doi": "10.1093/pm/pnad074", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_2", "study": "Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1093/pm/pnad074"}, {"directness": "review-level", "doi": "10.1007/s12325-026-03612-5", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_3", "study": "Low-Dose Naltrexone: What is the Evidence? A Narrative Review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s12325-026-03612-5"}, {"directness": "review-level", "doi": "10.1016/j.heliyon.2023.e15638", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_4", "study": "A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.heliyon.2023.e15638"}, {"directness": "primary", "doi": "10.2147/JPR.S389957", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_5", "study": "Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series", "support_kind": "candidate_source_row", "url": "https://doi.org/10.2147/JPR.S389957"}], "claim": "Manifest outcome-class count summary: Dosing and Pharmacokinetics: admitted n=36 (null=18, positive=1, unclear=17); leading sources: Tsui 2024, Paula 2022, Rupp 2023; Immune and Inflammation: admitted n=3 (null=1, unclear=2); leading sources: Plank 2022, Leiber 2025, Radi 2023.", "claim_id": "claim_20"}, {"candidate_sources": [{"directness": "primary", "doi": "10.1016/j.bjane.2022.08.003", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_1", "study": "Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.bjane.2022.08.003"}, {"directness": "review-level", "doi": "10.1093/pm/pnad074", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_2", "study": "Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1093/pm/pnad074"}, {"directness": "review-level", "doi": "10.1007/s12325-026-03612-5", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_3", "study": "Low-Dose Naltrexone: What is the Evidence? A Narrative Review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s12325-026-03612-5"}, {"directness": "review-level", "doi": "10.1016/j.heliyon.2023.e15638", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_4", "study": "A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.heliyon.2023.e15638"}, {"directness": "primary", "doi": "10.2147/JPR.S389957", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_5", "study": "Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series", "support_kind": "candidate_source_row", "url": "https://doi.org/10.2147/JPR.S389957"}], "claim": "Tsui 2024: Pilot RCT comparing low-dose naltrexone, gabapentin and placebo to reduce pain among people with HIV with alcohol; representative non-significant statistic p = 0.73; not treated as positive or negative directional support unless source direction is coded; outcome=Dosing and Pharmacokinetics; direction=null; directness=direct; tier=A1.", "claim_id": "claim_21"}, {"candidate_sources": [{"directness": "primary", "doi": "10.1016/j.bjane.2022.08.003", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_1", "study": "Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.bjane.2022.08.003"}, {"directness": "review-level", "doi": "10.1093/pm/pnad074", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_2", "study": "Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1093/pm/pnad074"}, {"directness": "review-level", "doi": "10.1007/s12325-026-03612-5", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_3", "study": "Low-Dose Naltrexone: What is the Evidence? A Narrative Review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s12325-026-03612-5"}, {"directness": "review-level", "doi": "10.1016/j.heliyon.2023.e15638", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_4", "study": "A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.heliyon.2023.e15638"}, {"directness": "primary", "doi": "10.2147/JPR.S389957", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_5", "study": "Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series", "support_kind": "candidate_source_row", "url": "https://doi.org/10.2147/JPR.S389957"}], "claim": "Dosing and Pharmacokinetics: Tsui 2024 (Pilot RCT comparing low-dose naltrexone, gabapentin and placebo to reduce pain among people with HIV with alcohol; representative non-significant statistic p = 0.73; not treated as positive or negative directional support unless source direction is coded; outcome=Dosing and Pharmacokinetics; direction=null; directness=direct; tier=A1); Paula 2022 (Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized; representative statistic p = 0.010; source-level statistic reported; outcome=Dosing and Pharmacokinetics; direction=unclear; directness=indirect; tier=B2); Rupp 2023 (Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review; representative statistic P = 0.005; source-level statistic reported; outcome=Dosing and Pharmacokinetics; direction=unclear; directness=review; tier=B2).", "claim_id": "claim_22"}, {"candidate_sources": [{"directness": "primary", "doi": "10.1016/j.bjane.2022.08.003", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_1", "study": "Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.bjane.2022.08.003"}, {"directness": "review-level", "doi": "10.1093/pm/pnad074", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_2", "study": "Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1093/pm/pnad074"}, {"directness": "review-level", "doi": "10.1007/s12325-026-03612-5", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_3", "study": "Low-Dose Naltrexone: What is the Evidence? A Narrative Review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s12325-026-03612-5"}, {"directness": "review-level", "doi": "10.1016/j.heliyon.2023.e15638", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_4", "study": "A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.heliyon.2023.e15638"}, {"directness": "primary", "doi": "10.2147/JPR.S389957", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_5", "study": "Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series", "support_kind": "candidate_source_row", "url": "https://doi.org/10.2147/JPR.S389957"}], "claim": "Immune and Inflammation: Plank 2022 (A randomized, double-blind, placebo-controlled, hybrid parallel-arm study of low-dose naltrexone as an adjunctive; 18 extracted claim(s); receipt-level direction is the coded finding; outcome=Immune and Inflammation; direction=unclear; directness=indirect; tier=B2); Leiber 2025 (Therapeutic Uses and Efficacy of Low-Dose Naltrexone: A Scoping Review; 3 extracted claim(s); receipt-level direction is the coded finding; outcome=Immune and Inflammation; direction=null; directness=review; tier=B2); Radi 2023 (Is low-dose naltrexone effective in chronic pain management?; 2 extracted claim(s); receipt-level direction is the coded finding; outcome=Immune and Inflammation; direction=unclear; directness=review; tier=B1).", "claim_id": "claim_23"}, {"candidate_sources": [{"directness": "primary", "doi": "10.1016/j.bjane.2022.08.003", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_1", "study": "Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.bjane.2022.08.003"}, {"directness": "review-level", "doi": "10.1093/pm/pnad074", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_2", "study": "Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1093/pm/pnad074"}, {"directness": "review-level", "doi": "10.1007/s12325-026-03612-5", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_3", "study": "Low-Dose Naltrexone: What is the Evidence? A Narrative Review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s12325-026-03612-5"}, {"directness": "review-level", "doi": "10.1016/j.heliyon.2023.e15638", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_4", "study": "A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.heliyon.2023.e15638"}, {"directness": "primary", "doi": "10.2147/JPR.S389957", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_5", "study": "Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series", "support_kind": "candidate_source_row", "url": "https://doi.org/10.2147/JPR.S389957"}], "claim": "Mechanism/Dosing and Pharmacokinetics: Partridge 2023 (A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative; representative statistic P = 0.016; source-level statistic reported; outcome=Mechanism/Dosing and Pharmacokinetics; direction=unclear; directness=review; tier=B1); McKenzie 2026 (Low-Dose Naltrexone in Chronic Pain Management: Mechanisms, Evidence, and Clinical Implications; 4 extracted claim(s); receipt-level direction is the coded finding; outcome=Mechanism/Dosing and Pharmacokinetics; direction=null; directness=indirect; tier=B2).", "claim_id": "claim_24"}, {"candidate_sources": [{"directness": "primary", "doi": "10.1016/j.bjane.2022.08.003", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_1", "study": "Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.bjane.2022.08.003"}, {"directness": "review-level", "doi": "10.1093/pm/pnad074", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_2", "study": "Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1093/pm/pnad074"}, {"directness": "review-level", "doi": "10.1007/s12325-026-03612-5", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_3", "study": "Low-Dose Naltrexone: What is the Evidence? A Narrative Review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s12325-026-03612-5"}, {"directness": "review-level", "doi": "10.1016/j.heliyon.2023.e15638", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_4", "study": "A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.heliyon.2023.e15638"}, {"directness": "primary", "doi": "10.2147/JPR.S389957", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_5", "study": "Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series", "support_kind": "candidate_source_row", "url": "https://doi.org/10.2147/JPR.S389957"}], "claim": "Synthesis interpretation: These source-level findings connect risk-marker, mechanistic, and intervention-adjacent signals into follow-up hypotheses, not a clinical efficacy claim. Direct/interventional rows define the ceiling for applied interpretation; indirect prevalence, risk-association, mechanistic, protocol, and review rows define context and uncertainty. Representative coded source verdicts remain: Paula 2022: outcome=Dosing and Pharmacokinetics; direction=unclear; directness=indirect; tier=B2; result=Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized; finding=representative statistic p = 0.010; source-level statistic reported; claims=246; Rupp 2023: outcome=Dosing and Pharmacokinetics; direction=unclear; directness=review; tier=B2; result=Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review; finding=representative statistic P = 0.005; source-level statistic reported; claims=216; Gouda 2026: outcome=Dosing and Pharmacokinetics; direction=unclear; directness=review; tier=B1; result=Low-Dose Naltrexone: What is the Evidence? A Narrative Review; finding=188 extracted claim(s); receipt-level direction is the coded finding; claims=188; Partridge 2023: outcome=Mechanism/Dosing and Pharmacokinetics; direction=unclear; directness=review; tier=B1; result=A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative; finding=representative statistic P = 0.016; source-level statistic reported; claims=108. The bounded conclusion follows from source direction, outcome class, evidence tier, and directness rather than from source count alone. Publication-year note: citation years follow the manifest metadata; when DOI/PubMed dates differ, the source should be treated as bibliographic/in-press metadata and not used for year-specific claims.", "claim_id": "claim_25"}, {"candidate_sources": [{"directness": "primary", "doi": "10.1016/j.bjane.2022.08.003", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_1", "study": "Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.bjane.2022.08.003"}, {"directness": "review-level", "doi": "10.1093/pm/pnad074", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_2", "study": "Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1093/pm/pnad074"}, {"directness": "review-level", "doi": "10.1007/s12325-026-03612-5", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_3", "study": "Low-Dose Naltrexone: What is the Evidence? A Narrative Review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s12325-026-03612-5"}, {"directness": "review-level", "doi": "10.1016/j.heliyon.2023.e15638", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_4", "study": "A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.heliyon.2023.e15638"}, {"directness": "primary", "doi": "10.2147/JPR.S389957", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_5", "study": "Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series", "support_kind": "candidate_source_row", "url": "https://doi.org/10.2147/JPR.S389957"}], "claim": "| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |", "claim_id": "claim_26"}, {"candidate_sources": [{"directness": "primary", "doi": "10.1016/j.bjane.2022.08.003", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_1", "study": "Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.bjane.2022.08.003"}, {"directness": "review-level", "doi": "10.1093/pm/pnad074", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_2", "study": "Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1093/pm/pnad074"}, {"directness": "review-level", "doi": "10.1007/s12325-026-03612-5", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_3", "study": "Low-Dose Naltrexone: What is the Evidence? A Narrative Review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s12325-026-03612-5"}, {"directness": "review-level", "doi": "10.1016/j.heliyon.2023.e15638", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_4", "study": "A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.heliyon.2023.e15638"}, {"directness": "primary", "doi": "10.2147/JPR.S389957", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_5", "study": "Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series", "support_kind": "candidate_source_row", "url": "https://doi.org/10.2147/JPR.S389957"}], "claim": "Dosing and pharmacokinetics context: 35 sources; significant source statistic in 12/35 sources; receipt-level direction coded null.", "claim_id": "claim_27"}, {"candidate_sources": [{"directness": "primary", "doi": "10.1016/j.bjane.2022.08.003", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_1", "study": "Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.bjane.2022.08.003"}, {"directness": "review-level", "doi": "10.1093/pm/pnad074", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_2", "study": "Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1093/pm/pnad074"}, {"directness": "review-level", "doi": "10.1007/s12325-026-03612-5", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_3", "study": "Low-Dose Naltrexone: What is the Evidence? A Narrative Review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s12325-026-03612-5"}, {"directness": "review-level", "doi": "10.1016/j.heliyon.2023.e15638", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_4", "study": "A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.heliyon.2023.e15638"}, {"directness": "primary", "doi": "10.2147/JPR.S389957", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_5", "study": "Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series", "support_kind": "candidate_source_row", "url": "https://doi.org/10.2147/JPR.S389957"}], "claim": "The corpus contains 39 curated references addressing low-dose naltrexone (LDN), and the dominant dosing paradigm across the evidence base is a daily oral dose of 4.5 mg, with reported clinical ranges spanning 0.5–9.0 mg depending on indication. In a clinical RCT, Tsui 2024 randomized participants in St. Petersburg, Russia, to daily LDN 4.5 mg versus gabapentin up to 1800 mg versus placebo among people with HIV and chronic pain, with reported between-arm p-values of P = 0.73, P = 0.55, and P = 0.83 consistent with a null primary finding. Naik 2024, a double-blind RCT protocol in British Columbia for post-COVID fatigue syndrome, specifies two parallel arms of n = 80 each at ≤5 mg LDN versus placebo, positioning this as a direct mechanistic/biomarker trial. Bruun 2021 describes a 12-week double-blind RCT protocol in fibromyalgia using the same 4.5 mg reference dose against placebo. These three direct-design trials (Tsui 2024, Naik 2024, Bruun 2021) frame the upper-bound dose expectation for LDN trials in the corpus.", "claim_id": "claim_28"}, {"candidate_sources": [{"directness": "primary", "doi": "10.1016/j.bjane.2022.08.003", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_1", "study": "Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.bjane.2022.08.003"}, {"directness": "review-level", "doi": "10.1093/pm/pnad074", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_2", "study": "Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1093/pm/pnad074"}, {"directness": "review-level", "doi": "10.1007/s12325-026-03612-5", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_3", "study": "Low-Dose Naltrexone: What is the Evidence? A Narrative Review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s12325-026-03612-5"}, {"directness": "review-level", "doi": "10.1016/j.heliyon.2023.e15638", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_4", "study": "A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.heliyon.2023.e15638"}, {"directness": "primary", "doi": "10.2147/JPR.S389957", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_5", "study": "Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series", "support_kind": "candidate_source_row", "url": "https://doi.org/10.2147/JPR.S389957"}], "claim": "Within-corpus tensions on dosing and pharmacokinetics center on the divergence between direct RCT evidence and indirect observational/review syntheses. The pairing of direct null primary endpoints (Tsui 2024) with indirect positive observational signals (Marcus 2024, McKenzie-Brown 2023) constitutes the principal dosing/pharmacokinetic disagreement in the corpus.", "claim_id": "claim_29"}, {"candidate_sources": [{"directness": "primary", "doi": "10.1016/j.bjane.2022.08.003", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_1", "study": "Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.bjane.2022.08.003"}, {"directness": "review-level", "doi": "10.1093/pm/pnad074", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_2", "study": "Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1093/pm/pnad074"}, {"directness": "review-level", "doi": "10.1007/s12325-026-03612-5", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_3", "study": "Low-Dose Naltrexone: What is the Evidence? A Narrative Review", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s12325-026-03612-5"}, {"directness": "review-level", "doi": "10.1016/j.heliyon.2023.e15638", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_4", "study": "A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1016/j.heliyon.2023.e15638"}, {"directness": "primary", "doi": "10.2147/JPR.S389957", "effect": "not extracted", "endpoint": "not extracted", "population": "not extracted", "source_id": "source_5", "study": "Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series", "support_kind": "candidate_source_row", "url": "https://doi.org/10.2147/JPR.S389957"}], "claim": "Three sources converge on the immune outcome class. Plank 2022 describes a randomized, double-blind, placebo-controlled, hybrid parallel-arm study of low-dose naltrexone as adjunctive anti-inflammatory therapy in major depressive disorder, with n=48 eligible MDD participants stratified into high- and low-inflammatory groups prior to randomization. Leiber 2025 is a scoping review that catalogues the therapeutic uses and efficacy of low-dose naltrexone, focusing on the 1 mg to 6 mg dose range and its putative anti-inflammatory and analgesic actions beyond established indications. Radi 2023 is a systematic review asking whether low-dose naltrexone is effective in chronic pain management, with chronic pain as the primary lens but inflammation-relevant endpoints embedded within. Together, these three sources constitute the curated immune-outcome evidence base available to this synthesis.", "claim_id": "claim_30"}]}

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