{"publication_id":"3b9d2db0-4fb0-44d4-bab5-5c3b2794f100","traces":[{"claim_id":"claim_1","claim":"This paper synthesizes evidence on Low dose naltrexone inflammation across 39 accepted source papers and 1510 high-confidence extracted claims. 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. 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. 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. 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.","citation_support":[],"candidate_sources":[{"study":"Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial","year":2022,"doi":"10.1016/j.bjane.2022.08.003","url":"https://doi.org/10.1016/j.bjane.2022.08.003","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Paula 2022","excerpt":"INTRODUCTION: Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management. OBJECTIVE: The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia. METHODS: This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review","year":2023,"doi":"10.1093/pm/pnad074","url":"https://doi.org/10.1093/pm/pnad074","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Rupp 2023","excerpt":"BACKGROUND: At low doses, naltrexone (LDN) has been shown to modulate inflammation through the interruption of microglial cell activation within the central nervous system. One of the most likely contributors to centralized pain is changes in microglial cell processing. Therefore, it has been postulated that LDN can be used to manage patients with pain resulting from central sensitization due to this relationship. This scoping review aims to synthesize the relevant study data for LDN as a novel treatment strategy for various centralized pain conditions. METHODS: A comprehensive literature search was conducted in PubMed, Embase, and Google Scholar, guided by the Scale for Assessment of Narrative Review Articles (SANRA) criteria. RESULTS: Forty-seven studies related to centralized pain conditions were identified. Many of the studies were case reports/series and narrative reviews, but a few randomized control trials have been conducted. Overall, the body of evidence revealed improvement in patient-reported pain severity and in outcomes related to hyperalgesia, physical function, quality of life, and sleep.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone: What is the Evidence? A Narrative Review","year":2026,"doi":"10.1007/s12325-026-03612-5","url":"https://doi.org/10.1007/s12325-026-03612-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Gouda 2026","excerpt":"Naltrexone is prescribed off-label at low doses, typically 0.5-6.0 mg, for a variety of therapeutic indications. This review evaluates the clinical evidence for low-dose naltrexone (LDN). A literature search was conducted in February 2026 across PubMed, Embase and CINAHL for studies published from 1989 to 2026. Title and abstract searches for \"low dose naltrexone\" identified peer-reviewed English-language studies using doses of ≤ 12.5 mg in humans. A total of 105 studies were reviewed, including 15 randomised controlled trials (RCTs) in chronic pain, autoimmune and neuroimmune disorders, gastrointestinal disease, dermatological conditions, post-infectious syndromes, mental health and oncology. Across these fields, early positive findings from uncontrolled studies were rarely replicated in placebo-controlled trials. Most available evidence consists of case reports and small feasibility studies that are prone to publication bias and rely heavily on subjective outcomes. LDN is generally safe, inexpensive and well tolerated, with most studies using a daily dose of 4.5 mg. Although these features contribute to its appeal, current evidence does not support routine clinical use.","source_id":"source_3","support_kind":"candidate_source_row"},{"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","year":2023,"doi":"10.1016/j.heliyon.2023.e15638","url":"https://doi.org/10.1016/j.heliyon.2023.e15638","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Partridge 2023","excerpt":"BACKGROUND: Low dose naltrexone (LDN) is used off-label by many individuals with fibromyalgia to help manage their pain. There is no current systematic literature review summarising the evidence to support this use of LDN. The objectives of this study were to evaluate if patients with fibromyalgia prescribed LDN have reduced pain scores and greater quality of life compared with those allocated to placebo in randomized controlled trials. Secondly to determine if changes in inflammatory markers and brain structure and function are observed among patients with fibromyalgia taking LDN. METHODS: Systematic literature searches were conducted in MEDLINE , Embase Classic + Embase, APA PsychInfo, and The Cochrane Library from inception to May 2022. Reference lists from the selected papers were cross-checked with database search results. RESULTS: Three studies met our inclusion criteria for the assessment of efficacy, and two studies on potential LDN mechanisms. Results indicated some evidence to suggest LDN reduces pain and increases quality of life.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series","year":2023,"doi":"10.2147/JPR.S389957","url":"https://doi.org/10.2147/JPR.S389957","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"McKenzie-Brown 2023","excerpt":"PURPOSE: Low-dose naltrexone (LDN) has increased in popularity as a non-opioid medication that may decrease chronic pain symptoms. LDN is most commonly used to treat fibromyalgia, complex regional pain syndrome (CRPS), and painful diabetic neuropathy. Other studies suggest that LDN provides general symptom reduction in inflammatory conditions such as Crohn's disease and multiple sclerosis. We reviewed our experience with patients to whom we have prescribed LDN to see what types of painful conditions were most responsive to LDN in our patient population. PATIENTS AND METHODS: Charts from patients who came to the Pain Center between 2014 and 2021 were reviewed. RESULTS: Of the n = 137 patients who were prescribed LDN, 44% had no evidence of ever filling the prescription, and 4.4% of the responses were not charted. Of the remaining who took LDN (n = 70), 64% had some relief and were designated as 'Responders'. The most common pain diagnosis was neuropathic pain which, when added to the diagnosis of complex regional pain syndrome, accounted for 51% of responders to LDN.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_2","claim":"This paper synthesizes evidence on Low dose naltrexone inflammation across 39 accepted source papers and 1510 high-confidence extracted claims.","citation_support":[],"candidate_sources":[{"study":"Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial","year":2022,"doi":"10.1016/j.bjane.2022.08.003","url":"https://doi.org/10.1016/j.bjane.2022.08.003","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Paula 2022","excerpt":"INTRODUCTION: Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management. OBJECTIVE: The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia. METHODS: This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review","year":2023,"doi":"10.1093/pm/pnad074","url":"https://doi.org/10.1093/pm/pnad074","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Rupp 2023","excerpt":"BACKGROUND: At low doses, naltrexone (LDN) has been shown to modulate inflammation through the interruption of microglial cell activation within the central nervous system. One of the most likely contributors to centralized pain is changes in microglial cell processing. Therefore, it has been postulated that LDN can be used to manage patients with pain resulting from central sensitization due to this relationship. This scoping review aims to synthesize the relevant study data for LDN as a novel treatment strategy for various centralized pain conditions. METHODS: A comprehensive literature search was conducted in PubMed, Embase, and Google Scholar, guided by the Scale for Assessment of Narrative Review Articles (SANRA) criteria. RESULTS: Forty-seven studies related to centralized pain conditions were identified. Many of the studies were case reports/series and narrative reviews, but a few randomized control trials have been conducted. Overall, the body of evidence revealed improvement in patient-reported pain severity and in outcomes related to hyperalgesia, physical function, quality of life, and sleep.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone: What is the Evidence? A Narrative Review","year":2026,"doi":"10.1007/s12325-026-03612-5","url":"https://doi.org/10.1007/s12325-026-03612-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Gouda 2026","excerpt":"Naltrexone is prescribed off-label at low doses, typically 0.5-6.0 mg, for a variety of therapeutic indications. This review evaluates the clinical evidence for low-dose naltrexone (LDN). A literature search was conducted in February 2026 across PubMed, Embase and CINAHL for studies published from 1989 to 2026. Title and abstract searches for \"low dose naltrexone\" identified peer-reviewed English-language studies using doses of ≤ 12.5 mg in humans. A total of 105 studies were reviewed, including 15 randomised controlled trials (RCTs) in chronic pain, autoimmune and neuroimmune disorders, gastrointestinal disease, dermatological conditions, post-infectious syndromes, mental health and oncology. Across these fields, early positive findings from uncontrolled studies were rarely replicated in placebo-controlled trials. Most available evidence consists of case reports and small feasibility studies that are prone to publication bias and rely heavily on subjective outcomes. LDN is generally safe, inexpensive and well tolerated, with most studies using a daily dose of 4.5 mg. Although these features contribute to its appeal, current evidence does not support routine clinical use.","source_id":"source_3","support_kind":"candidate_source_row"},{"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","year":2023,"doi":"10.1016/j.heliyon.2023.e15638","url":"https://doi.org/10.1016/j.heliyon.2023.e15638","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Partridge 2023","excerpt":"BACKGROUND: Low dose naltrexone (LDN) is used off-label by many individuals with fibromyalgia to help manage their pain. There is no current systematic literature review summarising the evidence to support this use of LDN. The objectives of this study were to evaluate if patients with fibromyalgia prescribed LDN have reduced pain scores and greater quality of life compared with those allocated to placebo in randomized controlled trials. Secondly to determine if changes in inflammatory markers and brain structure and function are observed among patients with fibromyalgia taking LDN. METHODS: Systematic literature searches were conducted in MEDLINE , Embase Classic + Embase, APA PsychInfo, and The Cochrane Library from inception to May 2022. Reference lists from the selected papers were cross-checked with database search results. RESULTS: Three studies met our inclusion criteria for the assessment of efficacy, and two studies on potential LDN mechanisms. Results indicated some evidence to suggest LDN reduces pain and increases quality of life.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series","year":2023,"doi":"10.2147/JPR.S389957","url":"https://doi.org/10.2147/JPR.S389957","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"McKenzie-Brown 2023","excerpt":"PURPOSE: Low-dose naltrexone (LDN) has increased in popularity as a non-opioid medication that may decrease chronic pain symptoms. LDN is most commonly used to treat fibromyalgia, complex regional pain syndrome (CRPS), and painful diabetic neuropathy. Other studies suggest that LDN provides general symptom reduction in inflammatory conditions such as Crohn's disease and multiple sclerosis. We reviewed our experience with patients to whom we have prescribed LDN to see what types of painful conditions were most responsive to LDN in our patient population. PATIENTS AND METHODS: Charts from patients who came to the Pain Center between 2014 and 2021 were reviewed. RESULTS: Of the n = 137 patients who were prescribed LDN, 44% had no evidence of ever filling the prescription, and 4.4% of the responses were not charted. Of the remaining who took LDN (n = 70), 64% had some relief and were designated as 'Responders'. The most common pain diagnosis was neuropathic pain which, when added to the diagnosis of complex regional pain syndrome, accounted for 51% of responders to LDN.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_3","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.","citation_support":[],"candidate_sources":[{"study":"Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial","year":2022,"doi":"10.1016/j.bjane.2022.08.003","url":"https://doi.org/10.1016/j.bjane.2022.08.003","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Paula 2022","excerpt":"INTRODUCTION: Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management. OBJECTIVE: The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia. METHODS: This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review","year":2023,"doi":"10.1093/pm/pnad074","url":"https://doi.org/10.1093/pm/pnad074","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Rupp 2023","excerpt":"BACKGROUND: At low doses, naltrexone (LDN) has been shown to modulate inflammation through the interruption of microglial cell activation within the central nervous system. One of the most likely contributors to centralized pain is changes in microglial cell processing. Therefore, it has been postulated that LDN can be used to manage patients with pain resulting from central sensitization due to this relationship. This scoping review aims to synthesize the relevant study data for LDN as a novel treatment strategy for various centralized pain conditions. METHODS: A comprehensive literature search was conducted in PubMed, Embase, and Google Scholar, guided by the Scale for Assessment of Narrative Review Articles (SANRA) criteria. RESULTS: Forty-seven studies related to centralized pain conditions were identified. Many of the studies were case reports/series and narrative reviews, but a few randomized control trials have been conducted. Overall, the body of evidence revealed improvement in patient-reported pain severity and in outcomes related to hyperalgesia, physical function, quality of life, and sleep.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone: What is the Evidence? A Narrative Review","year":2026,"doi":"10.1007/s12325-026-03612-5","url":"https://doi.org/10.1007/s12325-026-03612-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Gouda 2026","excerpt":"Naltrexone is prescribed off-label at low doses, typically 0.5-6.0 mg, for a variety of therapeutic indications. This review evaluates the clinical evidence for low-dose naltrexone (LDN). A literature search was conducted in February 2026 across PubMed, Embase and CINAHL for studies published from 1989 to 2026. Title and abstract searches for \"low dose naltrexone\" identified peer-reviewed English-language studies using doses of ≤ 12.5 mg in humans. A total of 105 studies were reviewed, including 15 randomised controlled trials (RCTs) in chronic pain, autoimmune and neuroimmune disorders, gastrointestinal disease, dermatological conditions, post-infectious syndromes, mental health and oncology. Across these fields, early positive findings from uncontrolled studies were rarely replicated in placebo-controlled trials. Most available evidence consists of case reports and small feasibility studies that are prone to publication bias and rely heavily on subjective outcomes. LDN is generally safe, inexpensive and well tolerated, with most studies using a daily dose of 4.5 mg. Although these features contribute to its appeal, current evidence does not support routine clinical use.","source_id":"source_3","support_kind":"candidate_source_row"},{"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","year":2023,"doi":"10.1016/j.heliyon.2023.e15638","url":"https://doi.org/10.1016/j.heliyon.2023.e15638","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Partridge 2023","excerpt":"BACKGROUND: Low dose naltrexone (LDN) is used off-label by many individuals with fibromyalgia to help manage their pain. There is no current systematic literature review summarising the evidence to support this use of LDN. The objectives of this study were to evaluate if patients with fibromyalgia prescribed LDN have reduced pain scores and greater quality of life compared with those allocated to placebo in randomized controlled trials. Secondly to determine if changes in inflammatory markers and brain structure and function are observed among patients with fibromyalgia taking LDN. METHODS: Systematic literature searches were conducted in MEDLINE , Embase Classic + Embase, APA PsychInfo, and The Cochrane Library from inception to May 2022. Reference lists from the selected papers were cross-checked with database search results. RESULTS: Three studies met our inclusion criteria for the assessment of efficacy, and two studies on potential LDN mechanisms. Results indicated some evidence to suggest LDN reduces pain and increases quality of life.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series","year":2023,"doi":"10.2147/JPR.S389957","url":"https://doi.org/10.2147/JPR.S389957","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"McKenzie-Brown 2023","excerpt":"PURPOSE: Low-dose naltrexone (LDN) has increased in popularity as a non-opioid medication that may decrease chronic pain symptoms. LDN is most commonly used to treat fibromyalgia, complex regional pain syndrome (CRPS), and painful diabetic neuropathy. Other studies suggest that LDN provides general symptom reduction in inflammatory conditions such as Crohn's disease and multiple sclerosis. We reviewed our experience with patients to whom we have prescribed LDN to see what types of painful conditions were most responsive to LDN in our patient population. PATIENTS AND METHODS: Charts from patients who came to the Pain Center between 2014 and 2021 were reviewed. RESULTS: Of the n = 137 patients who were prescribed LDN, 44% had no evidence of ever filling the prescription, and 4.4% of the responses were not charted. Of the remaining who took LDN (n = 70), 64% had some relief and were designated as 'Responders'. The most common pain diagnosis was neuropathic pain which, when added to the diagnosis of complex regional pain syndrome, accounted for 51% of responders to LDN.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_4","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.","citation_support":[],"candidate_sources":[{"study":"Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial","year":2022,"doi":"10.1016/j.bjane.2022.08.003","url":"https://doi.org/10.1016/j.bjane.2022.08.003","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Paula 2022","excerpt":"INTRODUCTION: Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management. OBJECTIVE: The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia. METHODS: This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review","year":2023,"doi":"10.1093/pm/pnad074","url":"https://doi.org/10.1093/pm/pnad074","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Rupp 2023","excerpt":"BACKGROUND: At low doses, naltrexone (LDN) has been shown to modulate inflammation through the interruption of microglial cell activation within the central nervous system. One of the most likely contributors to centralized pain is changes in microglial cell processing. Therefore, it has been postulated that LDN can be used to manage patients with pain resulting from central sensitization due to this relationship. This scoping review aims to synthesize the relevant study data for LDN as a novel treatment strategy for various centralized pain conditions. METHODS: A comprehensive literature search was conducted in PubMed, Embase, and Google Scholar, guided by the Scale for Assessment of Narrative Review Articles (SANRA) criteria. RESULTS: Forty-seven studies related to centralized pain conditions were identified. Many of the studies were case reports/series and narrative reviews, but a few randomized control trials have been conducted. Overall, the body of evidence revealed improvement in patient-reported pain severity and in outcomes related to hyperalgesia, physical function, quality of life, and sleep.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone: What is the Evidence? A Narrative Review","year":2026,"doi":"10.1007/s12325-026-03612-5","url":"https://doi.org/10.1007/s12325-026-03612-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Gouda 2026","excerpt":"Naltrexone is prescribed off-label at low doses, typically 0.5-6.0 mg, for a variety of therapeutic indications. This review evaluates the clinical evidence for low-dose naltrexone (LDN). A literature search was conducted in February 2026 across PubMed, Embase and CINAHL for studies published from 1989 to 2026. Title and abstract searches for \"low dose naltrexone\" identified peer-reviewed English-language studies using doses of ≤ 12.5 mg in humans. A total of 105 studies were reviewed, including 15 randomised controlled trials (RCTs) in chronic pain, autoimmune and neuroimmune disorders, gastrointestinal disease, dermatological conditions, post-infectious syndromes, mental health and oncology. Across these fields, early positive findings from uncontrolled studies were rarely replicated in placebo-controlled trials. Most available evidence consists of case reports and small feasibility studies that are prone to publication bias and rely heavily on subjective outcomes. LDN is generally safe, inexpensive and well tolerated, with most studies using a daily dose of 4.5 mg. Although these features contribute to its appeal, current evidence does not support routine clinical use.","source_id":"source_3","support_kind":"candidate_source_row"},{"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","year":2023,"doi":"10.1016/j.heliyon.2023.e15638","url":"https://doi.org/10.1016/j.heliyon.2023.e15638","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Partridge 2023","excerpt":"BACKGROUND: Low dose naltrexone (LDN) is used off-label by many individuals with fibromyalgia to help manage their pain. There is no current systematic literature review summarising the evidence to support this use of LDN. The objectives of this study were to evaluate if patients with fibromyalgia prescribed LDN have reduced pain scores and greater quality of life compared with those allocated to placebo in randomized controlled trials. Secondly to determine if changes in inflammatory markers and brain structure and function are observed among patients with fibromyalgia taking LDN. METHODS: Systematic literature searches were conducted in MEDLINE , Embase Classic + Embase, APA PsychInfo, and The Cochrane Library from inception to May 2022. Reference lists from the selected papers were cross-checked with database search results. RESULTS: Three studies met our inclusion criteria for the assessment of efficacy, and two studies on potential LDN mechanisms. Results indicated some evidence to suggest LDN reduces pain and increases quality of life.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series","year":2023,"doi":"10.2147/JPR.S389957","url":"https://doi.org/10.2147/JPR.S389957","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"McKenzie-Brown 2023","excerpt":"PURPOSE: Low-dose naltrexone (LDN) has increased in popularity as a non-opioid medication that may decrease chronic pain symptoms. LDN is most commonly used to treat fibromyalgia, complex regional pain syndrome (CRPS), and painful diabetic neuropathy. Other studies suggest that LDN provides general symptom reduction in inflammatory conditions such as Crohn's disease and multiple sclerosis. We reviewed our experience with patients to whom we have prescribed LDN to see what types of painful conditions were most responsive to LDN in our patient population. PATIENTS AND METHODS: Charts from patients who came to the Pain Center between 2014 and 2021 were reviewed. RESULTS: Of the n = 137 patients who were prescribed LDN, 44% had no evidence of ever filling the prescription, and 4.4% of the responses were not charted. Of the remaining who took LDN (n = 70), 64% had some relief and were designated as 'Responders'. The most common pain diagnosis was neuropathic pain which, when added to the diagnosis of complex regional pain syndrome, accounted for 51% of responders to LDN.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_5","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.","citation_support":[],"candidate_sources":[{"study":"Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial","year":2022,"doi":"10.1016/j.bjane.2022.08.003","url":"https://doi.org/10.1016/j.bjane.2022.08.003","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Paula 2022","excerpt":"INTRODUCTION: Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management. OBJECTIVE: The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia. METHODS: This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review","year":2023,"doi":"10.1093/pm/pnad074","url":"https://doi.org/10.1093/pm/pnad074","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Rupp 2023","excerpt":"BACKGROUND: At low doses, naltrexone (LDN) has been shown to modulate inflammation through the interruption of microglial cell activation within the central nervous system. One of the most likely contributors to centralized pain is changes in microglial cell processing. Therefore, it has been postulated that LDN can be used to manage patients with pain resulting from central sensitization due to this relationship. This scoping review aims to synthesize the relevant study data for LDN as a novel treatment strategy for various centralized pain conditions. METHODS: A comprehensive literature search was conducted in PubMed, Embase, and Google Scholar, guided by the Scale for Assessment of Narrative Review Articles (SANRA) criteria. RESULTS: Forty-seven studies related to centralized pain conditions were identified. Many of the studies were case reports/series and narrative reviews, but a few randomized control trials have been conducted. Overall, the body of evidence revealed improvement in patient-reported pain severity and in outcomes related to hyperalgesia, physical function, quality of life, and sleep.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone: What is the Evidence? A Narrative Review","year":2026,"doi":"10.1007/s12325-026-03612-5","url":"https://doi.org/10.1007/s12325-026-03612-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Gouda 2026","excerpt":"Naltrexone is prescribed off-label at low doses, typically 0.5-6.0 mg, for a variety of therapeutic indications. This review evaluates the clinical evidence for low-dose naltrexone (LDN). A literature search was conducted in February 2026 across PubMed, Embase and CINAHL for studies published from 1989 to 2026. Title and abstract searches for \"low dose naltrexone\" identified peer-reviewed English-language studies using doses of ≤ 12.5 mg in humans. A total of 105 studies were reviewed, including 15 randomised controlled trials (RCTs) in chronic pain, autoimmune and neuroimmune disorders, gastrointestinal disease, dermatological conditions, post-infectious syndromes, mental health and oncology. Across these fields, early positive findings from uncontrolled studies were rarely replicated in placebo-controlled trials. Most available evidence consists of case reports and small feasibility studies that are prone to publication bias and rely heavily on subjective outcomes. LDN is generally safe, inexpensive and well tolerated, with most studies using a daily dose of 4.5 mg. Although these features contribute to its appeal, current evidence does not support routine clinical use.","source_id":"source_3","support_kind":"candidate_source_row"},{"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","year":2023,"doi":"10.1016/j.heliyon.2023.e15638","url":"https://doi.org/10.1016/j.heliyon.2023.e15638","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Partridge 2023","excerpt":"BACKGROUND: Low dose naltrexone (LDN) is used off-label by many individuals with fibromyalgia to help manage their pain. There is no current systematic literature review summarising the evidence to support this use of LDN. The objectives of this study were to evaluate if patients with fibromyalgia prescribed LDN have reduced pain scores and greater quality of life compared with those allocated to placebo in randomized controlled trials. Secondly to determine if changes in inflammatory markers and brain structure and function are observed among patients with fibromyalgia taking LDN. METHODS: Systematic literature searches were conducted in MEDLINE , Embase Classic + Embase, APA PsychInfo, and The Cochrane Library from inception to May 2022. Reference lists from the selected papers were cross-checked with database search results. RESULTS: Three studies met our inclusion criteria for the assessment of efficacy, and two studies on potential LDN mechanisms. Results indicated some evidence to suggest LDN reduces pain and increases quality of life.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series","year":2023,"doi":"10.2147/JPR.S389957","url":"https://doi.org/10.2147/JPR.S389957","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"McKenzie-Brown 2023","excerpt":"PURPOSE: Low-dose naltrexone (LDN) has increased in popularity as a non-opioid medication that may decrease chronic pain symptoms. LDN is most commonly used to treat fibromyalgia, complex regional pain syndrome (CRPS), and painful diabetic neuropathy. Other studies suggest that LDN provides general symptom reduction in inflammatory conditions such as Crohn's disease and multiple sclerosis. We reviewed our experience with patients to whom we have prescribed LDN to see what types of painful conditions were most responsive to LDN in our patient population. PATIENTS AND METHODS: Charts from patients who came to the Pain Center between 2014 and 2021 were reviewed. RESULTS: Of the n = 137 patients who were prescribed LDN, 44% had no evidence of ever filling the prescription, and 4.4% of the responses were not charted. Of the remaining who took LDN (n = 70), 64% had some relief and were designated as 'Responders'. The most common pain diagnosis was neuropathic pain which, when added to the diagnosis of complex regional pain syndrome, accounted for 51% of responders to LDN.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_6","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.","citation_support":[],"candidate_sources":[{"study":"Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial","year":2022,"doi":"10.1016/j.bjane.2022.08.003","url":"https://doi.org/10.1016/j.bjane.2022.08.003","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Paula 2022","excerpt":"INTRODUCTION: Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management. OBJECTIVE: The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia. METHODS: This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review","year":2023,"doi":"10.1093/pm/pnad074","url":"https://doi.org/10.1093/pm/pnad074","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Rupp 2023","excerpt":"BACKGROUND: At low doses, naltrexone (LDN) has been shown to modulate inflammation through the interruption of microglial cell activation within the central nervous system. One of the most likely contributors to centralized pain is changes in microglial cell processing. Therefore, it has been postulated that LDN can be used to manage patients with pain resulting from central sensitization due to this relationship. This scoping review aims to synthesize the relevant study data for LDN as a novel treatment strategy for various centralized pain conditions. METHODS: A comprehensive literature search was conducted in PubMed, Embase, and Google Scholar, guided by the Scale for Assessment of Narrative Review Articles (SANRA) criteria. RESULTS: Forty-seven studies related to centralized pain conditions were identified. Many of the studies were case reports/series and narrative reviews, but a few randomized control trials have been conducted. Overall, the body of evidence revealed improvement in patient-reported pain severity and in outcomes related to hyperalgesia, physical function, quality of life, and sleep.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone: What is the Evidence? A Narrative Review","year":2026,"doi":"10.1007/s12325-026-03612-5","url":"https://doi.org/10.1007/s12325-026-03612-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Gouda 2026","excerpt":"Naltrexone is prescribed off-label at low doses, typically 0.5-6.0 mg, for a variety of therapeutic indications. This review evaluates the clinical evidence for low-dose naltrexone (LDN). A literature search was conducted in February 2026 across PubMed, Embase and CINAHL for studies published from 1989 to 2026. Title and abstract searches for \"low dose naltrexone\" identified peer-reviewed English-language studies using doses of ≤ 12.5 mg in humans. A total of 105 studies were reviewed, including 15 randomised controlled trials (RCTs) in chronic pain, autoimmune and neuroimmune disorders, gastrointestinal disease, dermatological conditions, post-infectious syndromes, mental health and oncology. Across these fields, early positive findings from uncontrolled studies were rarely replicated in placebo-controlled trials. Most available evidence consists of case reports and small feasibility studies that are prone to publication bias and rely heavily on subjective outcomes. LDN is generally safe, inexpensive and well tolerated, with most studies using a daily dose of 4.5 mg. Although these features contribute to its appeal, current evidence does not support routine clinical use.","source_id":"source_3","support_kind":"candidate_source_row"},{"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","year":2023,"doi":"10.1016/j.heliyon.2023.e15638","url":"https://doi.org/10.1016/j.heliyon.2023.e15638","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Partridge 2023","excerpt":"BACKGROUND: Low dose naltrexone (LDN) is used off-label by many individuals with fibromyalgia to help manage their pain. There is no current systematic literature review summarising the evidence to support this use of LDN. The objectives of this study were to evaluate if patients with fibromyalgia prescribed LDN have reduced pain scores and greater quality of life compared with those allocated to placebo in randomized controlled trials. Secondly to determine if changes in inflammatory markers and brain structure and function are observed among patients with fibromyalgia taking LDN. METHODS: Systematic literature searches were conducted in MEDLINE , Embase Classic + Embase, APA PsychInfo, and The Cochrane Library from inception to May 2022. Reference lists from the selected papers were cross-checked with database search results. RESULTS: Three studies met our inclusion criteria for the assessment of efficacy, and two studies on potential LDN mechanisms. Results indicated some evidence to suggest LDN reduces pain and increases quality of life.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series","year":2023,"doi":"10.2147/JPR.S389957","url":"https://doi.org/10.2147/JPR.S389957","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"McKenzie-Brown 2023","excerpt":"PURPOSE: Low-dose naltrexone (LDN) has increased in popularity as a non-opioid medication that may decrease chronic pain symptoms. LDN is most commonly used to treat fibromyalgia, complex regional pain syndrome (CRPS), and painful diabetic neuropathy. Other studies suggest that LDN provides general symptom reduction in inflammatory conditions such as Crohn's disease and multiple sclerosis. We reviewed our experience with patients to whom we have prescribed LDN to see what types of painful conditions were most responsive to LDN in our patient population. PATIENTS AND METHODS: Charts from patients who came to the Pain Center between 2014 and 2021 were reviewed. RESULTS: Of the n = 137 patients who were prescribed LDN, 44% had no evidence of ever filling the prescription, and 4.4% of the responses were not charted. Of the remaining who took LDN (n = 70), 64% had some relief and were designated as 'Responders'. The most common pain diagnosis was neuropathic pain which, when added to the diagnosis of complex regional pain syndrome, accounted for 51% of responders to LDN.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_7","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.","citation_support":[],"candidate_sources":[{"study":"Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial","year":2022,"doi":"10.1016/j.bjane.2022.08.003","url":"https://doi.org/10.1016/j.bjane.2022.08.003","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Paula 2022","excerpt":"INTRODUCTION: Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management. OBJECTIVE: The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia. METHODS: This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review","year":2023,"doi":"10.1093/pm/pnad074","url":"https://doi.org/10.1093/pm/pnad074","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Rupp 2023","excerpt":"BACKGROUND: At low doses, naltrexone (LDN) has been shown to modulate inflammation through the interruption of microglial cell activation within the central nervous system. One of the most likely contributors to centralized pain is changes in microglial cell processing. Therefore, it has been postulated that LDN can be used to manage patients with pain resulting from central sensitization due to this relationship. This scoping review aims to synthesize the relevant study data for LDN as a novel treatment strategy for various centralized pain conditions. METHODS: A comprehensive literature search was conducted in PubMed, Embase, and Google Scholar, guided by the Scale for Assessment of Narrative Review Articles (SANRA) criteria. RESULTS: Forty-seven studies related to centralized pain conditions were identified. Many of the studies were case reports/series and narrative reviews, but a few randomized control trials have been conducted. Overall, the body of evidence revealed improvement in patient-reported pain severity and in outcomes related to hyperalgesia, physical function, quality of life, and sleep.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone: What is the Evidence? A Narrative Review","year":2026,"doi":"10.1007/s12325-026-03612-5","url":"https://doi.org/10.1007/s12325-026-03612-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Gouda 2026","excerpt":"Naltrexone is prescribed off-label at low doses, typically 0.5-6.0 mg, for a variety of therapeutic indications. This review evaluates the clinical evidence for low-dose naltrexone (LDN). A literature search was conducted in February 2026 across PubMed, Embase and CINAHL for studies published from 1989 to 2026. Title and abstract searches for \"low dose naltrexone\" identified peer-reviewed English-language studies using doses of ≤ 12.5 mg in humans. A total of 105 studies were reviewed, including 15 randomised controlled trials (RCTs) in chronic pain, autoimmune and neuroimmune disorders, gastrointestinal disease, dermatological conditions, post-infectious syndromes, mental health and oncology. Across these fields, early positive findings from uncontrolled studies were rarely replicated in placebo-controlled trials. Most available evidence consists of case reports and small feasibility studies that are prone to publication bias and rely heavily on subjective outcomes. LDN is generally safe, inexpensive and well tolerated, with most studies using a daily dose of 4.5 mg. Although these features contribute to its appeal, current evidence does not support routine clinical use.","source_id":"source_3","support_kind":"candidate_source_row"},{"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","year":2023,"doi":"10.1016/j.heliyon.2023.e15638","url":"https://doi.org/10.1016/j.heliyon.2023.e15638","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Partridge 2023","excerpt":"BACKGROUND: Low dose naltrexone (LDN) is used off-label by many individuals with fibromyalgia to help manage their pain. There is no current systematic literature review summarising the evidence to support this use of LDN. The objectives of this study were to evaluate if patients with fibromyalgia prescribed LDN have reduced pain scores and greater quality of life compared with those allocated to placebo in randomized controlled trials. Secondly to determine if changes in inflammatory markers and brain structure and function are observed among patients with fibromyalgia taking LDN. METHODS: Systematic literature searches were conducted in MEDLINE , Embase Classic + Embase, APA PsychInfo, and The Cochrane Library from inception to May 2022. Reference lists from the selected papers were cross-checked with database search results. RESULTS: Three studies met our inclusion criteria for the assessment of efficacy, and two studies on potential LDN mechanisms. Results indicated some evidence to suggest LDN reduces pain and increases quality of life.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series","year":2023,"doi":"10.2147/JPR.S389957","url":"https://doi.org/10.2147/JPR.S389957","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"McKenzie-Brown 2023","excerpt":"PURPOSE: Low-dose naltrexone (LDN) has increased in popularity as a non-opioid medication that may decrease chronic pain symptoms. LDN is most commonly used to treat fibromyalgia, complex regional pain syndrome (CRPS), and painful diabetic neuropathy. Other studies suggest that LDN provides general symptom reduction in inflammatory conditions such as Crohn's disease and multiple sclerosis. We reviewed our experience with patients to whom we have prescribed LDN to see what types of painful conditions were most responsive to LDN in our patient population. PATIENTS AND METHODS: Charts from patients who came to the Pain Center between 2014 and 2021 were reviewed. RESULTS: Of the n = 137 patients who were prescribed LDN, 44% had no evidence of ever filling the prescription, and 4.4% of the responses were not charted. Of the remaining who took LDN (n = 70), 64% had some relief and were designated as 'Responders'. The most common pain diagnosis was neuropathic pain which, when added to the diagnosis of complex regional pain syndrome, accounted for 51% of responders to LDN.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_8","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.","citation_support":[],"candidate_sources":[{"study":"Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial","year":2022,"doi":"10.1016/j.bjane.2022.08.003","url":"https://doi.org/10.1016/j.bjane.2022.08.003","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Paula 2022","excerpt":"INTRODUCTION: Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management. OBJECTIVE: The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia. METHODS: This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review","year":2023,"doi":"10.1093/pm/pnad074","url":"https://doi.org/10.1093/pm/pnad074","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Rupp 2023","excerpt":"BACKGROUND: At low doses, naltrexone (LDN) has been shown to modulate inflammation through the interruption of microglial cell activation within the central nervous system. One of the most likely contributors to centralized pain is changes in microglial cell processing. Therefore, it has been postulated that LDN can be used to manage patients with pain resulting from central sensitization due to this relationship. This scoping review aims to synthesize the relevant study data for LDN as a novel treatment strategy for various centralized pain conditions. METHODS: A comprehensive literature search was conducted in PubMed, Embase, and Google Scholar, guided by the Scale for Assessment of Narrative Review Articles (SANRA) criteria. RESULTS: Forty-seven studies related to centralized pain conditions were identified. Many of the studies were case reports/series and narrative reviews, but a few randomized control trials have been conducted. Overall, the body of evidence revealed improvement in patient-reported pain severity and in outcomes related to hyperalgesia, physical function, quality of life, and sleep.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone: What is the Evidence? A Narrative Review","year":2026,"doi":"10.1007/s12325-026-03612-5","url":"https://doi.org/10.1007/s12325-026-03612-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Gouda 2026","excerpt":"Naltrexone is prescribed off-label at low doses, typically 0.5-6.0 mg, for a variety of therapeutic indications. This review evaluates the clinical evidence for low-dose naltrexone (LDN). A literature search was conducted in February 2026 across PubMed, Embase and CINAHL for studies published from 1989 to 2026. Title and abstract searches for \"low dose naltrexone\" identified peer-reviewed English-language studies using doses of ≤ 12.5 mg in humans. A total of 105 studies were reviewed, including 15 randomised controlled trials (RCTs) in chronic pain, autoimmune and neuroimmune disorders, gastrointestinal disease, dermatological conditions, post-infectious syndromes, mental health and oncology. Across these fields, early positive findings from uncontrolled studies were rarely replicated in placebo-controlled trials. Most available evidence consists of case reports and small feasibility studies that are prone to publication bias and rely heavily on subjective outcomes. LDN is generally safe, inexpensive and well tolerated, with most studies using a daily dose of 4.5 mg. Although these features contribute to its appeal, current evidence does not support routine clinical use.","source_id":"source_3","support_kind":"candidate_source_row"},{"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","year":2023,"doi":"10.1016/j.heliyon.2023.e15638","url":"https://doi.org/10.1016/j.heliyon.2023.e15638","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Partridge 2023","excerpt":"BACKGROUND: Low dose naltrexone (LDN) is used off-label by many individuals with fibromyalgia to help manage their pain. There is no current systematic literature review summarising the evidence to support this use of LDN. The objectives of this study were to evaluate if patients with fibromyalgia prescribed LDN have reduced pain scores and greater quality of life compared with those allocated to placebo in randomized controlled trials. Secondly to determine if changes in inflammatory markers and brain structure and function are observed among patients with fibromyalgia taking LDN. METHODS: Systematic literature searches were conducted in MEDLINE , Embase Classic + Embase, APA PsychInfo, and The Cochrane Library from inception to May 2022. Reference lists from the selected papers were cross-checked with database search results. RESULTS: Three studies met our inclusion criteria for the assessment of efficacy, and two studies on potential LDN mechanisms. Results indicated some evidence to suggest LDN reduces pain and increases quality of life.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series","year":2023,"doi":"10.2147/JPR.S389957","url":"https://doi.org/10.2147/JPR.S389957","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"McKenzie-Brown 2023","excerpt":"PURPOSE: Low-dose naltrexone (LDN) has increased in popularity as a non-opioid medication that may decrease chronic pain symptoms. LDN is most commonly used to treat fibromyalgia, complex regional pain syndrome (CRPS), and painful diabetic neuropathy. Other studies suggest that LDN provides general symptom reduction in inflammatory conditions such as Crohn's disease and multiple sclerosis. We reviewed our experience with patients to whom we have prescribed LDN to see what types of painful conditions were most responsive to LDN in our patient population. PATIENTS AND METHODS: Charts from patients who came to the Pain Center between 2014 and 2021 were reviewed. RESULTS: Of the n = 137 patients who were prescribed LDN, 44% had no evidence of ever filling the prescription, and 4.4% of the responses were not charted. Of the remaining who took LDN (n = 70), 64% had some relief and were designated as 'Responders'. The most common pain diagnosis was neuropathic pain which, when added to the diagnosis of complex regional pain syndrome, accounted for 51% of responders to LDN.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_9","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.","citation_support":[{"source_id":"source_2","study":"Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review","doi":"10.1093/pm/pnad074","url":"https://doi.org/10.1093/pm/pnad074","support_kind":"cited_as_match","cited_as":"Rupp 2023","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review","excerpt":"BACKGROUND: At low doses, naltrexone (LDN) has been shown to modulate inflammation through the interruption of microglial cell activation within the central nervous system. One of the most likely contributors to centralized pain is changes in microglial cell processing. Therefore, it has been postulated that LDN can be used to manage patients with pain resulting from central sensitization due to this relationship. This scoping review aims to synthesize the relevant study data for LDN as a novel treatment strategy for various centralized pain conditions. METHODS: A comprehensive literature search was conducted in PubMed, Embase, and Google Scholar, guided by the Scale for Assessment of Narrative Review Articles (SANRA) criteria. RESULTS: Forty-seven studies related to centralized pain conditions were identified. Many of the studies were case reports/series and narrative reviews, but a few randomized control trials have been conducted. Overall, the body of evidence revealed improvement in patient-reported pain severity and in outcomes related to hyperalgesia, physical function, quality of life, and sleep."},{"source_id":"source_3","study":"Low-Dose Naltrexone: What is the Evidence? A Narrative Review","doi":"10.1007/s12325-026-03612-5","url":"https://doi.org/10.1007/s12325-026-03612-5","support_kind":"cited_as_match","cited_as":"Gouda 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review","excerpt":"Naltrexone is prescribed off-label at low doses, typically 0.5-6.0 mg, for a variety of therapeutic indications. This review evaluates the clinical evidence for low-dose naltrexone (LDN). A literature search was conducted in February 2026 across PubMed, Embase and CINAHL for studies published from 1989 to 2026. Title and abstract searches for \"low dose naltrexone\" identified peer-reviewed English-language studies using doses of ≤ 12.5 mg in humans. A total of 105 studies were reviewed, including 15 randomised controlled trials (RCTs) in chronic pain, autoimmune and neuroimmune disorders, gastrointestinal disease, dermatological conditions, post-infectious syndromes, mental health and oncology. Across these fields, early positive findings from uncontrolled studies were rarely replicated in placebo-controlled trials. Most available evidence consists of case reports and small feasibility studies that are prone to publication bias and rely heavily on subjective outcomes. LDN is generally safe, inexpensive and well tolerated, with most studies using a daily dose of 4.5 mg. Although these features contribute to its appeal, current evidence does not support routine clinical use."},{"source_id":"source_31","study":"Therapeutic Uses and Efficacy of Low-Dose Naltrexone: A Scoping Review","doi":"10.7759/cureus.81086","url":"https://doi.org/10.7759/cureus.81086","support_kind":"cited_as_match","cited_as":"Leiber 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review","excerpt":"Low-dose naltrexone (LDN) has been suggested as a novel treatment option for several conditions and is of increasing interest due to its potential ability to address certain medical conditions that lack effective treatments or frequently rely on the use of opioids as treatment. This article will synthesize evidence and assess the scope of literature that examines low-dose naltrexone's efficacy against painful and other relevant medical conditions. A scoping review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. Resources utilized for the review included PubMed and Excerpta Medica database (Embase). Articles included were required to be original research, published in English, conducted on human subjects, published in the last 15 years, have full text available, and include treatment with naltrexone in an off-label capacity (i.e., not for the treatment of alcohol or opioid use disorder). Zotero (Corporation for Digital Scholarship, Vienna, VA), a reference management software, was used to review all search results with this criterion."}],"candidate_sources":[]},{"claim_id":"claim_10","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.","citation_support":[{"source_id":"source_6","study":"Low-dose naltrexone as an adjunctive treatment for major depressive disorder: findings from a randomized, double-blind, placebo-controlled hybrid parallel-arm study","doi":"10.3389/fphar.2026.1767654","url":"https://doi.org/10.3389/fphar.2026.1767654","support_kind":"cited_as_match","cited_as":"Moloney 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"INTRODUCTION: Major depressive disorder (MDD) is a leading cause of global disability. Current treatments are limited by poor efficacy in approximately one-third of patients. Neuroinflammation may be an underlying mechanism of MDD and represents a novel target for pharmacological therapy. This study aimed to investigate the effects of a putative centrally acting anti-inflammatory agent, low-dose naltrexone (LDN), in MDD. METHODS: Patients with MDD experiencing moderate depressive symptoms and receiving antidepressant treatment were randomized to receive 12 weeks of LDN (up to 4.5 mg per day) or 12 weeks of inactive placebo. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale (MADRS) at 12 weeks, analyzed using a linear mixed-effects model adjusted for baseline. RESULTS: Thirty-seven patients were randomized. At 12 weeks, MADRS scores (M ± SD) were reduced by 10.5 ± 5.6 in the LDN group and 9.8 ± 5.9 placebo group; with no difference between groups (p = 0.97). LDN did not affect high-sensitivity C-reactive protein (hsCRP) levels or exploratory measures of depression, behavioral activation, quality of life, sickness symptoms and mood."},{"source_id":"source_7","study":"Efficacy and safety of low-dose naltrexone for the management of fibromyalgia: a systematic review and meta-analysis of randomized controlled trials with trial sequential analysis","doi":"10.3344/kjp.24202","url":"https://doi.org/10.3344/kjp.24202","support_kind":"cited_as_match","cited_as":"Vatvani 2024","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review","excerpt":"BACKGROUND: Fibromyalgia is characterized by the presence of chronic widespread pain that may impair patient's quality of life. Currently, the use of naltrexone as a therapeutic agent for fibromyalgia is not supported by enough evidence, especially from randomized controlled trials (RCTs). This study aims to analyze the efficacy and safety of low-dose naltrexone (LDN) for the management of fibromyalgia. METHODS: A comprehensive search was conducted on the Scopus, Medline, ClinicalTrials.gov, and Cochrane Library databases up until May 20th, 2024. This review incorporates RCTs that examine the comparison between LDN and placebo in fibromyalgia patients. We employed random-effect models to analyze the odds ratio and mean difference (MD) for presentation of the outcomes. RESULTS: A total of 4 RCTs with 222 fibromyalgia patients were incorporated. The results of our meta-analysis showed a significant reduction in pain scores (MD: -0.86, 95% confidence interval [CI]: -1.20, -0.51, P < 0.001, I 2 = 33%) and higher increment in pressure pain threshold (MD: 0.17, 95% CI: 0.08, 0.25, P < 0.001, I 2 = 0%) among fibromyalgia patients who received LDN than those who only received a placebo."},{"source_id":"source_13","study":"No change in the consumption of thyroid hormones after starting low dose naltrexone (LDN): a quasi-experimental before-after study","doi":"10.1186/s12902-020-00630-4","url":"https://doi.org/10.1186/s12902-020-00630-4","support_kind":"cited_as_match","cited_as":"Raknes 2020","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"BACKGROUND: Low dose naltrexone (LDN) is reported to have beneficial effects in several autoimmune diseases. The purpose of this study was to examine whether starting LDN was followed by changes in the dispensing of thyroid hormones to patients with hypothyroidism. METHODS: We performed a quasi-experimental before-after study based on the Norwegian Prescription Database. Study participants were identified by using reimbursement codes for hypothyroidism. Cumulative dispensed Defined Daily Doses and the number of users of triiodothyronine (T3) and levothyroxine (LT4) 1 year before and after the first LDN prescription was compared in three groups based on LDN exposure. RESULTS: We identified 898 patients that met the inclusion criteria. There was no association between starting LDN and the subsequent dispensing of thyroid hormones. If anything, there was a tendency towards increasing LT4 consumption with increasing LDN exposure. CONCLUSION: The results of this study do not support claims of efficacy of LDN in hypothyroidism."},{"source_id":"source_16","study":"Low-dose naltrexone for the treatment of fibromyalgia: protocol for a double-blind, randomized, placebo-controlled trial","doi":"10.1186/s13063-021-05776-7","url":"https://doi.org/10.1186/s13063-021-05776-7","support_kind":"cited_as_match","cited_as":"Bruun 2021","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","excerpt":"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."},{"source_id":"source_20","study":"Low-dose naltrexone for treatment of pain in patients with fibromyalgia: a randomized, double-blind, placebo-controlled, crossover study","doi":"10.1097/PR9.0000000000001080","url":"https://doi.org/10.1097/PR9.0000000000001080","support_kind":"cited_as_match","cited_as":"Bested 2023","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review","excerpt":"INTRODUCTION: Fibromyalgia (FM) is a chronic fluctuating, nociplastic pain condition. Naltrexone is a µ-opioid-receptor antagonist; preliminary studies have indicated a pain-relieving effect of low-dose naltrexone (LDN) in patients with FM. The impetus for studying LDN is the assumption of analgesic efficacy and thus reduction of adverse effects seen from conventional pharmacotherapy. OBJECTIVES: First , to examine if LDN is associated with analgesic efficacy compared with control in the treatment of patients with FM. Second , to ascertain the analgesic efficacy of LDN in an experimental pain model in patients with FM evaluating the competence of the descending inhibitory pathways compared with controls. Third, to examine the pharmacokinetics of LDN. METHODS: The study used a randomized, double-blind, placebo-controlled, crossover design and had a 3-phase setup. The first phase included baseline assessment and a treatment period (days -3 to 21), the second phase a washout period (days 22-32), and the third phase a baseline assessment followed by a treatment period (days 33-56). Treatment was with either LDN 4.5 mg or an inactive placebo given orally once daily."},{"source_id":"source_36","study":"The Effect of Low-Dose Naltrexone on Medication in Inflammatory Bowel Disease: A Quasi Experimental Before-and-After Prescription Database Study","doi":"10.1093/ecco-jcc/jjy008","url":"https://doi.org/10.1093/ecco-jcc/jjy008","support_kind":"cited_as_match","cited_as":"Raknes 2018","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"BACKGROUND AND AIMS: Low-dose naltrexone [LDN] is a controversial off-label treatment used by many Crohn's disease [CD] and ulcerative colitis [UC] patients. A small number of preliminary studies indicate that LDN might be beneficial in CD, but evidence is too scarce to demonstrate efficacy. We sought to examine whether initiation of LDN therapy by patients with inflammatory bowel disease [IBD] was followed by changes in dispensing of relevant medication. METHODS: We performed a quasi-experimental before-and-after study following a sudden increase in LDN use in the Norwegian population in 2013. IBD patients were identified from among all the patients who had at least one LDN prescription recorded in the Norwegian Prescription Database [NorPD] in 2013. Drug dispensing 2 years before and after the first LDN prescription was compared. RESULTS: We identified 582 IBD patients who had received LDN. Of the 256 patients who became persistent LDN users, there were reductions in the number of users for [i] all examined drugs [-12%], [ii] intestinal anti-inflammatory agents [-17%], [iii] other immunosuppressants [-29%], [iv] intestinal corticosteroids [-32%] and [v] aminosalicylates [-17%]."}],"candidate_sources":[]},{"claim_id":"claim_11","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.","citation_support":[],"candidate_sources":[{"study":"Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial","year":2022,"doi":"10.1016/j.bjane.2022.08.003","url":"https://doi.org/10.1016/j.bjane.2022.08.003","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Paula 2022","excerpt":"INTRODUCTION: Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management. OBJECTIVE: The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia. METHODS: This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review","year":2023,"doi":"10.1093/pm/pnad074","url":"https://doi.org/10.1093/pm/pnad074","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Rupp 2023","excerpt":"BACKGROUND: At low doses, naltrexone (LDN) has been shown to modulate inflammation through the interruption of microglial cell activation within the central nervous system. One of the most likely contributors to centralized pain is changes in microglial cell processing. Therefore, it has been postulated that LDN can be used to manage patients with pain resulting from central sensitization due to this relationship. This scoping review aims to synthesize the relevant study data for LDN as a novel treatment strategy for various centralized pain conditions. METHODS: A comprehensive literature search was conducted in PubMed, Embase, and Google Scholar, guided by the Scale for Assessment of Narrative Review Articles (SANRA) criteria. RESULTS: Forty-seven studies related to centralized pain conditions were identified. Many of the studies were case reports/series and narrative reviews, but a few randomized control trials have been conducted. Overall, the body of evidence revealed improvement in patient-reported pain severity and in outcomes related to hyperalgesia, physical function, quality of life, and sleep.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone: What is the Evidence? A Narrative Review","year":2026,"doi":"10.1007/s12325-026-03612-5","url":"https://doi.org/10.1007/s12325-026-03612-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Gouda 2026","excerpt":"Naltrexone is prescribed off-label at low doses, typically 0.5-6.0 mg, for a variety of therapeutic indications. This review evaluates the clinical evidence for low-dose naltrexone (LDN). A literature search was conducted in February 2026 across PubMed, Embase and CINAHL for studies published from 1989 to 2026. Title and abstract searches for \"low dose naltrexone\" identified peer-reviewed English-language studies using doses of ≤ 12.5 mg in humans. A total of 105 studies were reviewed, including 15 randomised controlled trials (RCTs) in chronic pain, autoimmune and neuroimmune disorders, gastrointestinal disease, dermatological conditions, post-infectious syndromes, mental health and oncology. Across these fields, early positive findings from uncontrolled studies were rarely replicated in placebo-controlled trials. Most available evidence consists of case reports and small feasibility studies that are prone to publication bias and rely heavily on subjective outcomes. LDN is generally safe, inexpensive and well tolerated, with most studies using a daily dose of 4.5 mg. Although these features contribute to its appeal, current evidence does not support routine clinical use.","source_id":"source_3","support_kind":"candidate_source_row"},{"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","year":2023,"doi":"10.1016/j.heliyon.2023.e15638","url":"https://doi.org/10.1016/j.heliyon.2023.e15638","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Partridge 2023","excerpt":"BACKGROUND: Low dose naltrexone (LDN) is used off-label by many individuals with fibromyalgia to help manage their pain. There is no current systematic literature review summarising the evidence to support this use of LDN. The objectives of this study were to evaluate if patients with fibromyalgia prescribed LDN have reduced pain scores and greater quality of life compared with those allocated to placebo in randomized controlled trials. Secondly to determine if changes in inflammatory markers and brain structure and function are observed among patients with fibromyalgia taking LDN. METHODS: Systematic literature searches were conducted in MEDLINE , Embase Classic + Embase, APA PsychInfo, and The Cochrane Library from inception to May 2022. Reference lists from the selected papers were cross-checked with database search results. RESULTS: Three studies met our inclusion criteria for the assessment of efficacy, and two studies on potential LDN mechanisms. Results indicated some evidence to suggest LDN reduces pain and increases quality of life.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series","year":2023,"doi":"10.2147/JPR.S389957","url":"https://doi.org/10.2147/JPR.S389957","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"McKenzie-Brown 2023","excerpt":"PURPOSE: Low-dose naltrexone (LDN) has increased in popularity as a non-opioid medication that may decrease chronic pain symptoms. LDN is most commonly used to treat fibromyalgia, complex regional pain syndrome (CRPS), and painful diabetic neuropathy. Other studies suggest that LDN provides general symptom reduction in inflammatory conditions such as Crohn's disease and multiple sclerosis. We reviewed our experience with patients to whom we have prescribed LDN to see what types of painful conditions were most responsive to LDN in our patient population. PATIENTS AND METHODS: Charts from patients who came to the Pain Center between 2014 and 2021 were reviewed. RESULTS: Of the n = 137 patients who were prescribed LDN, 44% had no evidence of ever filling the prescription, and 4.4% of the responses were not charted. Of the remaining who took LDN (n = 70), 64% had some relief and were designated as 'Responders'. The most common pain diagnosis was neuropathic pain which, when added to the diagnosis of complex regional pain syndrome, accounted for 51% of responders to LDN.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_12","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.","citation_support":[],"candidate_sources":[{"study":"Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial","year":2022,"doi":"10.1016/j.bjane.2022.08.003","url":"https://doi.org/10.1016/j.bjane.2022.08.003","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Paula 2022","excerpt":"INTRODUCTION: Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management. OBJECTIVE: The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia. METHODS: This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review","year":2023,"doi":"10.1093/pm/pnad074","url":"https://doi.org/10.1093/pm/pnad074","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Rupp 2023","excerpt":"BACKGROUND: At low doses, naltrexone (LDN) has been shown to modulate inflammation through the interruption of microglial cell activation within the central nervous system. One of the most likely contributors to centralized pain is changes in microglial cell processing. Therefore, it has been postulated that LDN can be used to manage patients with pain resulting from central sensitization due to this relationship. This scoping review aims to synthesize the relevant study data for LDN as a novel treatment strategy for various centralized pain conditions. METHODS: A comprehensive literature search was conducted in PubMed, Embase, and Google Scholar, guided by the Scale for Assessment of Narrative Review Articles (SANRA) criteria. RESULTS: Forty-seven studies related to centralized pain conditions were identified. Many of the studies were case reports/series and narrative reviews, but a few randomized control trials have been conducted. Overall, the body of evidence revealed improvement in patient-reported pain severity and in outcomes related to hyperalgesia, physical function, quality of life, and sleep.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone: What is the Evidence? A Narrative Review","year":2026,"doi":"10.1007/s12325-026-03612-5","url":"https://doi.org/10.1007/s12325-026-03612-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Gouda 2026","excerpt":"Naltrexone is prescribed off-label at low doses, typically 0.5-6.0 mg, for a variety of therapeutic indications. This review evaluates the clinical evidence for low-dose naltrexone (LDN). A literature search was conducted in February 2026 across PubMed, Embase and CINAHL for studies published from 1989 to 2026. Title and abstract searches for \"low dose naltrexone\" identified peer-reviewed English-language studies using doses of ≤ 12.5 mg in humans. A total of 105 studies were reviewed, including 15 randomised controlled trials (RCTs) in chronic pain, autoimmune and neuroimmune disorders, gastrointestinal disease, dermatological conditions, post-infectious syndromes, mental health and oncology. Across these fields, early positive findings from uncontrolled studies were rarely replicated in placebo-controlled trials. Most available evidence consists of case reports and small feasibility studies that are prone to publication bias and rely heavily on subjective outcomes. LDN is generally safe, inexpensive and well tolerated, with most studies using a daily dose of 4.5 mg. Although these features contribute to its appeal, current evidence does not support routine clinical use.","source_id":"source_3","support_kind":"candidate_source_row"},{"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","year":2023,"doi":"10.1016/j.heliyon.2023.e15638","url":"https://doi.org/10.1016/j.heliyon.2023.e15638","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Partridge 2023","excerpt":"BACKGROUND: Low dose naltrexone (LDN) is used off-label by many individuals with fibromyalgia to help manage their pain. There is no current systematic literature review summarising the evidence to support this use of LDN. The objectives of this study were to evaluate if patients with fibromyalgia prescribed LDN have reduced pain scores and greater quality of life compared with those allocated to placebo in randomized controlled trials. Secondly to determine if changes in inflammatory markers and brain structure and function are observed among patients with fibromyalgia taking LDN. METHODS: Systematic literature searches were conducted in MEDLINE , Embase Classic + Embase, APA PsychInfo, and The Cochrane Library from inception to May 2022. Reference lists from the selected papers were cross-checked with database search results. RESULTS: Three studies met our inclusion criteria for the assessment of efficacy, and two studies on potential LDN mechanisms. Results indicated some evidence to suggest LDN reduces pain and increases quality of life.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series","year":2023,"doi":"10.2147/JPR.S389957","url":"https://doi.org/10.2147/JPR.S389957","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"McKenzie-Brown 2023","excerpt":"PURPOSE: Low-dose naltrexone (LDN) has increased in popularity as a non-opioid medication that may decrease chronic pain symptoms. LDN is most commonly used to treat fibromyalgia, complex regional pain syndrome (CRPS), and painful diabetic neuropathy. Other studies suggest that LDN provides general symptom reduction in inflammatory conditions such as Crohn's disease and multiple sclerosis. We reviewed our experience with patients to whom we have prescribed LDN to see what types of painful conditions were most responsive to LDN in our patient population. PATIENTS AND METHODS: Charts from patients who came to the Pain Center between 2014 and 2021 were reviewed. RESULTS: Of the n = 137 patients who were prescribed LDN, 44% had no evidence of ever filling the prescription, and 4.4% of the responses were not charted. Of the remaining who took LDN (n = 70), 64% had some relief and were designated as 'Responders'. The most common pain diagnosis was neuropathic pain which, when added to the diagnosis of complex regional pain syndrome, accounted for 51% of responders to LDN.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_13","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.","citation_support":[],"candidate_sources":[{"study":"Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial","year":2022,"doi":"10.1016/j.bjane.2022.08.003","url":"https://doi.org/10.1016/j.bjane.2022.08.003","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Paula 2022","excerpt":"INTRODUCTION: Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management. OBJECTIVE: The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia. METHODS: This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review","year":2023,"doi":"10.1093/pm/pnad074","url":"https://doi.org/10.1093/pm/pnad074","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Rupp 2023","excerpt":"BACKGROUND: At low doses, naltrexone (LDN) has been shown to modulate inflammation through the interruption of microglial cell activation within the central nervous system. One of the most likely contributors to centralized pain is changes in microglial cell processing. Therefore, it has been postulated that LDN can be used to manage patients with pain resulting from central sensitization due to this relationship. This scoping review aims to synthesize the relevant study data for LDN as a novel treatment strategy for various centralized pain conditions. METHODS: A comprehensive literature search was conducted in PubMed, Embase, and Google Scholar, guided by the Scale for Assessment of Narrative Review Articles (SANRA) criteria. RESULTS: Forty-seven studies related to centralized pain conditions were identified. Many of the studies were case reports/series and narrative reviews, but a few randomized control trials have been conducted. Overall, the body of evidence revealed improvement in patient-reported pain severity and in outcomes related to hyperalgesia, physical function, quality of life, and sleep.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone: What is the Evidence? A Narrative Review","year":2026,"doi":"10.1007/s12325-026-03612-5","url":"https://doi.org/10.1007/s12325-026-03612-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Gouda 2026","excerpt":"Naltrexone is prescribed off-label at low doses, typically 0.5-6.0 mg, for a variety of therapeutic indications. This review evaluates the clinical evidence for low-dose naltrexone (LDN). A literature search was conducted in February 2026 across PubMed, Embase and CINAHL for studies published from 1989 to 2026. Title and abstract searches for \"low dose naltrexone\" identified peer-reviewed English-language studies using doses of ≤ 12.5 mg in humans. A total of 105 studies were reviewed, including 15 randomised controlled trials (RCTs) in chronic pain, autoimmune and neuroimmune disorders, gastrointestinal disease, dermatological conditions, post-infectious syndromes, mental health and oncology. Across these fields, early positive findings from uncontrolled studies were rarely replicated in placebo-controlled trials. Most available evidence consists of case reports and small feasibility studies that are prone to publication bias and rely heavily on subjective outcomes. LDN is generally safe, inexpensive and well tolerated, with most studies using a daily dose of 4.5 mg. Although these features contribute to its appeal, current evidence does not support routine clinical use.","source_id":"source_3","support_kind":"candidate_source_row"},{"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","year":2023,"doi":"10.1016/j.heliyon.2023.e15638","url":"https://doi.org/10.1016/j.heliyon.2023.e15638","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Partridge 2023","excerpt":"BACKGROUND: Low dose naltrexone (LDN) is used off-label by many individuals with fibromyalgia to help manage their pain. There is no current systematic literature review summarising the evidence to support this use of LDN. The objectives of this study were to evaluate if patients with fibromyalgia prescribed LDN have reduced pain scores and greater quality of life compared with those allocated to placebo in randomized controlled trials. Secondly to determine if changes in inflammatory markers and brain structure and function are observed among patients with fibromyalgia taking LDN. METHODS: Systematic literature searches were conducted in MEDLINE , Embase Classic + Embase, APA PsychInfo, and The Cochrane Library from inception to May 2022. Reference lists from the selected papers were cross-checked with database search results. RESULTS: Three studies met our inclusion criteria for the assessment of efficacy, and two studies on potential LDN mechanisms. Results indicated some evidence to suggest LDN reduces pain and increases quality of life.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series","year":2023,"doi":"10.2147/JPR.S389957","url":"https://doi.org/10.2147/JPR.S389957","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"McKenzie-Brown 2023","excerpt":"PURPOSE: Low-dose naltrexone (LDN) has increased in popularity as a non-opioid medication that may decrease chronic pain symptoms. LDN is most commonly used to treat fibromyalgia, complex regional pain syndrome (CRPS), and painful diabetic neuropathy. Other studies suggest that LDN provides general symptom reduction in inflammatory conditions such as Crohn's disease and multiple sclerosis. We reviewed our experience with patients to whom we have prescribed LDN to see what types of painful conditions were most responsive to LDN in our patient population. PATIENTS AND METHODS: Charts from patients who came to the Pain Center between 2014 and 2021 were reviewed. RESULTS: Of the n = 137 patients who were prescribed LDN, 44% had no evidence of ever filling the prescription, and 4.4% of the responses were not charted. Of the remaining who took LDN (n = 70), 64% had some relief and were designated as 'Responders'. The most common pain diagnosis was neuropathic pain which, when added to the diagnosis of complex regional pain syndrome, accounted for 51% of responders to LDN.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_14","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.","citation_support":[],"candidate_sources":[{"study":"Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial","year":2022,"doi":"10.1016/j.bjane.2022.08.003","url":"https://doi.org/10.1016/j.bjane.2022.08.003","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Paula 2022","excerpt":"INTRODUCTION: Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management. OBJECTIVE: The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia. METHODS: This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review","year":2023,"doi":"10.1093/pm/pnad074","url":"https://doi.org/10.1093/pm/pnad074","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Rupp 2023","excerpt":"BACKGROUND: At low doses, naltrexone (LDN) has been shown to modulate inflammation through the interruption of microglial cell activation within the central nervous system. One of the most likely contributors to centralized pain is changes in microglial cell processing. Therefore, it has been postulated that LDN can be used to manage patients with pain resulting from central sensitization due to this relationship. This scoping review aims to synthesize the relevant study data for LDN as a novel treatment strategy for various centralized pain conditions. METHODS: A comprehensive literature search was conducted in PubMed, Embase, and Google Scholar, guided by the Scale for Assessment of Narrative Review Articles (SANRA) criteria. RESULTS: Forty-seven studies related to centralized pain conditions were identified. Many of the studies were case reports/series and narrative reviews, but a few randomized control trials have been conducted. Overall, the body of evidence revealed improvement in patient-reported pain severity and in outcomes related to hyperalgesia, physical function, quality of life, and sleep.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone: What is the Evidence? A Narrative Review","year":2026,"doi":"10.1007/s12325-026-03612-5","url":"https://doi.org/10.1007/s12325-026-03612-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Gouda 2026","excerpt":"Naltrexone is prescribed off-label at low doses, typically 0.5-6.0 mg, for a variety of therapeutic indications. This review evaluates the clinical evidence for low-dose naltrexone (LDN). A literature search was conducted in February 2026 across PubMed, Embase and CINAHL for studies published from 1989 to 2026. Title and abstract searches for \"low dose naltrexone\" identified peer-reviewed English-language studies using doses of ≤ 12.5 mg in humans. A total of 105 studies were reviewed, including 15 randomised controlled trials (RCTs) in chronic pain, autoimmune and neuroimmune disorders, gastrointestinal disease, dermatological conditions, post-infectious syndromes, mental health and oncology. Across these fields, early positive findings from uncontrolled studies were rarely replicated in placebo-controlled trials. Most available evidence consists of case reports and small feasibility studies that are prone to publication bias and rely heavily on subjective outcomes. LDN is generally safe, inexpensive and well tolerated, with most studies using a daily dose of 4.5 mg. Although these features contribute to its appeal, current evidence does not support routine clinical use.","source_id":"source_3","support_kind":"candidate_source_row"},{"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","year":2023,"doi":"10.1016/j.heliyon.2023.e15638","url":"https://doi.org/10.1016/j.heliyon.2023.e15638","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Partridge 2023","excerpt":"BACKGROUND: Low dose naltrexone (LDN) is used off-label by many individuals with fibromyalgia to help manage their pain. There is no current systematic literature review summarising the evidence to support this use of LDN. The objectives of this study were to evaluate if patients with fibromyalgia prescribed LDN have reduced pain scores and greater quality of life compared with those allocated to placebo in randomized controlled trials. Secondly to determine if changes in inflammatory markers and brain structure and function are observed among patients with fibromyalgia taking LDN. METHODS: Systematic literature searches were conducted in MEDLINE , Embase Classic + Embase, APA PsychInfo, and The Cochrane Library from inception to May 2022. Reference lists from the selected papers were cross-checked with database search results. RESULTS: Three studies met our inclusion criteria for the assessment of efficacy, and two studies on potential LDN mechanisms. Results indicated some evidence to suggest LDN reduces pain and increases quality of life.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series","year":2023,"doi":"10.2147/JPR.S389957","url":"https://doi.org/10.2147/JPR.S389957","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"McKenzie-Brown 2023","excerpt":"PURPOSE: Low-dose naltrexone (LDN) has increased in popularity as a non-opioid medication that may decrease chronic pain symptoms. LDN is most commonly used to treat fibromyalgia, complex regional pain syndrome (CRPS), and painful diabetic neuropathy. Other studies suggest that LDN provides general symptom reduction in inflammatory conditions such as Crohn's disease and multiple sclerosis. We reviewed our experience with patients to whom we have prescribed LDN to see what types of painful conditions were most responsive to LDN in our patient population. PATIENTS AND METHODS: Charts from patients who came to the Pain Center between 2014 and 2021 were reviewed. RESULTS: Of the n = 137 patients who were prescribed LDN, 44% had no evidence of ever filling the prescription, and 4.4% of the responses were not charted. Of the remaining who took LDN (n = 70), 64% had some relief and were designated as 'Responders'. The most common pain diagnosis was neuropathic pain which, when added to the diagnosis of complex regional pain syndrome, accounted for 51% of responders to LDN.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_15","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.","citation_support":[],"candidate_sources":[{"study":"Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial","year":2022,"doi":"10.1016/j.bjane.2022.08.003","url":"https://doi.org/10.1016/j.bjane.2022.08.003","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Paula 2022","excerpt":"INTRODUCTION: Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management. OBJECTIVE: The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia. METHODS: This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review","year":2023,"doi":"10.1093/pm/pnad074","url":"https://doi.org/10.1093/pm/pnad074","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Rupp 2023","excerpt":"BACKGROUND: At low doses, naltrexone (LDN) has been shown to modulate inflammation through the interruption of microglial cell activation within the central nervous system. One of the most likely contributors to centralized pain is changes in microglial cell processing. Therefore, it has been postulated that LDN can be used to manage patients with pain resulting from central sensitization due to this relationship. This scoping review aims to synthesize the relevant study data for LDN as a novel treatment strategy for various centralized pain conditions. METHODS: A comprehensive literature search was conducted in PubMed, Embase, and Google Scholar, guided by the Scale for Assessment of Narrative Review Articles (SANRA) criteria. RESULTS: Forty-seven studies related to centralized pain conditions were identified. Many of the studies were case reports/series and narrative reviews, but a few randomized control trials have been conducted. Overall, the body of evidence revealed improvement in patient-reported pain severity and in outcomes related to hyperalgesia, physical function, quality of life, and sleep.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone: What is the Evidence? A Narrative Review","year":2026,"doi":"10.1007/s12325-026-03612-5","url":"https://doi.org/10.1007/s12325-026-03612-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Gouda 2026","excerpt":"Naltrexone is prescribed off-label at low doses, typically 0.5-6.0 mg, for a variety of therapeutic indications. This review evaluates the clinical evidence for low-dose naltrexone (LDN). A literature search was conducted in February 2026 across PubMed, Embase and CINAHL for studies published from 1989 to 2026. Title and abstract searches for \"low dose naltrexone\" identified peer-reviewed English-language studies using doses of ≤ 12.5 mg in humans. A total of 105 studies were reviewed, including 15 randomised controlled trials (RCTs) in chronic pain, autoimmune and neuroimmune disorders, gastrointestinal disease, dermatological conditions, post-infectious syndromes, mental health and oncology. Across these fields, early positive findings from uncontrolled studies were rarely replicated in placebo-controlled trials. Most available evidence consists of case reports and small feasibility studies that are prone to publication bias and rely heavily on subjective outcomes. LDN is generally safe, inexpensive and well tolerated, with most studies using a daily dose of 4.5 mg. Although these features contribute to its appeal, current evidence does not support routine clinical use.","source_id":"source_3","support_kind":"candidate_source_row"},{"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","year":2023,"doi":"10.1016/j.heliyon.2023.e15638","url":"https://doi.org/10.1016/j.heliyon.2023.e15638","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Partridge 2023","excerpt":"BACKGROUND: Low dose naltrexone (LDN) is used off-label by many individuals with fibromyalgia to help manage their pain. There is no current systematic literature review summarising the evidence to support this use of LDN. The objectives of this study were to evaluate if patients with fibromyalgia prescribed LDN have reduced pain scores and greater quality of life compared with those allocated to placebo in randomized controlled trials. Secondly to determine if changes in inflammatory markers and brain structure and function are observed among patients with fibromyalgia taking LDN. METHODS: Systematic literature searches were conducted in MEDLINE , Embase Classic + Embase, APA PsychInfo, and The Cochrane Library from inception to May 2022. Reference lists from the selected papers were cross-checked with database search results. RESULTS: Three studies met our inclusion criteria for the assessment of efficacy, and two studies on potential LDN mechanisms. Results indicated some evidence to suggest LDN reduces pain and increases quality of life.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series","year":2023,"doi":"10.2147/JPR.S389957","url":"https://doi.org/10.2147/JPR.S389957","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"McKenzie-Brown 2023","excerpt":"PURPOSE: Low-dose naltrexone (LDN) has increased in popularity as a non-opioid medication that may decrease chronic pain symptoms. LDN is most commonly used to treat fibromyalgia, complex regional pain syndrome (CRPS), and painful diabetic neuropathy. Other studies suggest that LDN provides general symptom reduction in inflammatory conditions such as Crohn's disease and multiple sclerosis. We reviewed our experience with patients to whom we have prescribed LDN to see what types of painful conditions were most responsive to LDN in our patient population. PATIENTS AND METHODS: Charts from patients who came to the Pain Center between 2014 and 2021 were reviewed. RESULTS: Of the n = 137 patients who were prescribed LDN, 44% had no evidence of ever filling the prescription, and 4.4% of the responses were not charted. Of the remaining who took LDN (n = 70), 64% had some relief and were designated as 'Responders'. The most common pain diagnosis was neuropathic pain which, when added to the diagnosis of complex regional pain syndrome, accounted for 51% of responders to LDN.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_16","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.","citation_support":[],"candidate_sources":[{"study":"Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial","year":2022,"doi":"10.1016/j.bjane.2022.08.003","url":"https://doi.org/10.1016/j.bjane.2022.08.003","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Paula 2022","excerpt":"INTRODUCTION: Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management. OBJECTIVE: The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia. METHODS: This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review","year":2023,"doi":"10.1093/pm/pnad074","url":"https://doi.org/10.1093/pm/pnad074","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Rupp 2023","excerpt":"BACKGROUND: At low doses, naltrexone (LDN) has been shown to modulate inflammation through the interruption of microglial cell activation within the central nervous system. One of the most likely contributors to centralized pain is changes in microglial cell processing. Therefore, it has been postulated that LDN can be used to manage patients with pain resulting from central sensitization due to this relationship. This scoping review aims to synthesize the relevant study data for LDN as a novel treatment strategy for various centralized pain conditions. METHODS: A comprehensive literature search was conducted in PubMed, Embase, and Google Scholar, guided by the Scale for Assessment of Narrative Review Articles (SANRA) criteria. RESULTS: Forty-seven studies related to centralized pain conditions were identified. Many of the studies were case reports/series and narrative reviews, but a few randomized control trials have been conducted. Overall, the body of evidence revealed improvement in patient-reported pain severity and in outcomes related to hyperalgesia, physical function, quality of life, and sleep.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone: What is the Evidence? A Narrative Review","year":2026,"doi":"10.1007/s12325-026-03612-5","url":"https://doi.org/10.1007/s12325-026-03612-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Gouda 2026","excerpt":"Naltrexone is prescribed off-label at low doses, typically 0.5-6.0 mg, for a variety of therapeutic indications. This review evaluates the clinical evidence for low-dose naltrexone (LDN). A literature search was conducted in February 2026 across PubMed, Embase and CINAHL for studies published from 1989 to 2026. Title and abstract searches for \"low dose naltrexone\" identified peer-reviewed English-language studies using doses of ≤ 12.5 mg in humans. A total of 105 studies were reviewed, including 15 randomised controlled trials (RCTs) in chronic pain, autoimmune and neuroimmune disorders, gastrointestinal disease, dermatological conditions, post-infectious syndromes, mental health and oncology. Across these fields, early positive findings from uncontrolled studies were rarely replicated in placebo-controlled trials. Most available evidence consists of case reports and small feasibility studies that are prone to publication bias and rely heavily on subjective outcomes. LDN is generally safe, inexpensive and well tolerated, with most studies using a daily dose of 4.5 mg. Although these features contribute to its appeal, current evidence does not support routine clinical use.","source_id":"source_3","support_kind":"candidate_source_row"},{"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","year":2023,"doi":"10.1016/j.heliyon.2023.e15638","url":"https://doi.org/10.1016/j.heliyon.2023.e15638","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Partridge 2023","excerpt":"BACKGROUND: Low dose naltrexone (LDN) is used off-label by many individuals with fibromyalgia to help manage their pain. There is no current systematic literature review summarising the evidence to support this use of LDN. The objectives of this study were to evaluate if patients with fibromyalgia prescribed LDN have reduced pain scores and greater quality of life compared with those allocated to placebo in randomized controlled trials. Secondly to determine if changes in inflammatory markers and brain structure and function are observed among patients with fibromyalgia taking LDN. METHODS: Systematic literature searches were conducted in MEDLINE , Embase Classic + Embase, APA PsychInfo, and The Cochrane Library from inception to May 2022. Reference lists from the selected papers were cross-checked with database search results. RESULTS: Three studies met our inclusion criteria for the assessment of efficacy, and two studies on potential LDN mechanisms. Results indicated some evidence to suggest LDN reduces pain and increases quality of life.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series","year":2023,"doi":"10.2147/JPR.S389957","url":"https://doi.org/10.2147/JPR.S389957","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"McKenzie-Brown 2023","excerpt":"PURPOSE: Low-dose naltrexone (LDN) has increased in popularity as a non-opioid medication that may decrease chronic pain symptoms. LDN is most commonly used to treat fibromyalgia, complex regional pain syndrome (CRPS), and painful diabetic neuropathy. Other studies suggest that LDN provides general symptom reduction in inflammatory conditions such as Crohn's disease and multiple sclerosis. We reviewed our experience with patients to whom we have prescribed LDN to see what types of painful conditions were most responsive to LDN in our patient population. PATIENTS AND METHODS: Charts from patients who came to the Pain Center between 2014 and 2021 were reviewed. RESULTS: Of the n = 137 patients who were prescribed LDN, 44% had no evidence of ever filling the prescription, and 4.4% of the responses were not charted. Of the remaining who took LDN (n = 70), 64% had some relief and were designated as 'Responders'. The most common pain diagnosis was neuropathic pain which, when added to the diagnosis of complex regional pain syndrome, accounted for 51% of responders to LDN.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_17","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.","citation_support":[],"candidate_sources":[{"study":"Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial","year":2022,"doi":"10.1016/j.bjane.2022.08.003","url":"https://doi.org/10.1016/j.bjane.2022.08.003","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Paula 2022","excerpt":"INTRODUCTION: Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management. OBJECTIVE: The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia. METHODS: This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review","year":2023,"doi":"10.1093/pm/pnad074","url":"https://doi.org/10.1093/pm/pnad074","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Rupp 2023","excerpt":"BACKGROUND: At low doses, naltrexone (LDN) has been shown to modulate inflammation through the interruption of microglial cell activation within the central nervous system. One of the most likely contributors to centralized pain is changes in microglial cell processing. Therefore, it has been postulated that LDN can be used to manage patients with pain resulting from central sensitization due to this relationship. This scoping review aims to synthesize the relevant study data for LDN as a novel treatment strategy for various centralized pain conditions. METHODS: A comprehensive literature search was conducted in PubMed, Embase, and Google Scholar, guided by the Scale for Assessment of Narrative Review Articles (SANRA) criteria. RESULTS: Forty-seven studies related to centralized pain conditions were identified. Many of the studies were case reports/series and narrative reviews, but a few randomized control trials have been conducted. Overall, the body of evidence revealed improvement in patient-reported pain severity and in outcomes related to hyperalgesia, physical function, quality of life, and sleep.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone: What is the Evidence? A Narrative Review","year":2026,"doi":"10.1007/s12325-026-03612-5","url":"https://doi.org/10.1007/s12325-026-03612-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Gouda 2026","excerpt":"Naltrexone is prescribed off-label at low doses, typically 0.5-6.0 mg, for a variety of therapeutic indications. This review evaluates the clinical evidence for low-dose naltrexone (LDN). A literature search was conducted in February 2026 across PubMed, Embase and CINAHL for studies published from 1989 to 2026. Title and abstract searches for \"low dose naltrexone\" identified peer-reviewed English-language studies using doses of ≤ 12.5 mg in humans. A total of 105 studies were reviewed, including 15 randomised controlled trials (RCTs) in chronic pain, autoimmune and neuroimmune disorders, gastrointestinal disease, dermatological conditions, post-infectious syndromes, mental health and oncology. Across these fields, early positive findings from uncontrolled studies were rarely replicated in placebo-controlled trials. Most available evidence consists of case reports and small feasibility studies that are prone to publication bias and rely heavily on subjective outcomes. LDN is generally safe, inexpensive and well tolerated, with most studies using a daily dose of 4.5 mg. Although these features contribute to its appeal, current evidence does not support routine clinical use.","source_id":"source_3","support_kind":"candidate_source_row"},{"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","year":2023,"doi":"10.1016/j.heliyon.2023.e15638","url":"https://doi.org/10.1016/j.heliyon.2023.e15638","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Partridge 2023","excerpt":"BACKGROUND: Low dose naltrexone (LDN) is used off-label by many individuals with fibromyalgia to help manage their pain. There is no current systematic literature review summarising the evidence to support this use of LDN. The objectives of this study were to evaluate if patients with fibromyalgia prescribed LDN have reduced pain scores and greater quality of life compared with those allocated to placebo in randomized controlled trials. Secondly to determine if changes in inflammatory markers and brain structure and function are observed among patients with fibromyalgia taking LDN. METHODS: Systematic literature searches were conducted in MEDLINE , Embase Classic + Embase, APA PsychInfo, and The Cochrane Library from inception to May 2022. Reference lists from the selected papers were cross-checked with database search results. RESULTS: Three studies met our inclusion criteria for the assessment of efficacy, and two studies on potential LDN mechanisms. Results indicated some evidence to suggest LDN reduces pain and increases quality of life.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series","year":2023,"doi":"10.2147/JPR.S389957","url":"https://doi.org/10.2147/JPR.S389957","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"McKenzie-Brown 2023","excerpt":"PURPOSE: Low-dose naltrexone (LDN) has increased in popularity as a non-opioid medication that may decrease chronic pain symptoms. LDN is most commonly used to treat fibromyalgia, complex regional pain syndrome (CRPS), and painful diabetic neuropathy. Other studies suggest that LDN provides general symptom reduction in inflammatory conditions such as Crohn's disease and multiple sclerosis. We reviewed our experience with patients to whom we have prescribed LDN to see what types of painful conditions were most responsive to LDN in our patient population. PATIENTS AND METHODS: Charts from patients who came to the Pain Center between 2014 and 2021 were reviewed. RESULTS: Of the n = 137 patients who were prescribed LDN, 44% had no evidence of ever filling the prescription, and 4.4% of the responses were not charted. Of the remaining who took LDN (n = 70), 64% had some relief and were designated as 'Responders'. The most common pain diagnosis was neuropathic pain which, when added to the diagnosis of complex regional pain syndrome, accounted for 51% of responders to LDN.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_18","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.","citation_support":[],"candidate_sources":[{"study":"Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial","year":2022,"doi":"10.1016/j.bjane.2022.08.003","url":"https://doi.org/10.1016/j.bjane.2022.08.003","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Paula 2022","excerpt":"INTRODUCTION: Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management. OBJECTIVE: The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia. METHODS: This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review","year":2023,"doi":"10.1093/pm/pnad074","url":"https://doi.org/10.1093/pm/pnad074","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Rupp 2023","excerpt":"BACKGROUND: At low doses, naltrexone (LDN) has been shown to modulate inflammation through the interruption of microglial cell activation within the central nervous system. One of the most likely contributors to centralized pain is changes in microglial cell processing. Therefore, it has been postulated that LDN can be used to manage patients with pain resulting from central sensitization due to this relationship. This scoping review aims to synthesize the relevant study data for LDN as a novel treatment strategy for various centralized pain conditions. METHODS: A comprehensive literature search was conducted in PubMed, Embase, and Google Scholar, guided by the Scale for Assessment of Narrative Review Articles (SANRA) criteria. RESULTS: Forty-seven studies related to centralized pain conditions were identified. Many of the studies were case reports/series and narrative reviews, but a few randomized control trials have been conducted. Overall, the body of evidence revealed improvement in patient-reported pain severity and in outcomes related to hyperalgesia, physical function, quality of life, and sleep.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone: What is the Evidence? A Narrative Review","year":2026,"doi":"10.1007/s12325-026-03612-5","url":"https://doi.org/10.1007/s12325-026-03612-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Gouda 2026","excerpt":"Naltrexone is prescribed off-label at low doses, typically 0.5-6.0 mg, for a variety of therapeutic indications. This review evaluates the clinical evidence for low-dose naltrexone (LDN). A literature search was conducted in February 2026 across PubMed, Embase and CINAHL for studies published from 1989 to 2026. Title and abstract searches for \"low dose naltrexone\" identified peer-reviewed English-language studies using doses of ≤ 12.5 mg in humans. A total of 105 studies were reviewed, including 15 randomised controlled trials (RCTs) in chronic pain, autoimmune and neuroimmune disorders, gastrointestinal disease, dermatological conditions, post-infectious syndromes, mental health and oncology. Across these fields, early positive findings from uncontrolled studies were rarely replicated in placebo-controlled trials. Most available evidence consists of case reports and small feasibility studies that are prone to publication bias and rely heavily on subjective outcomes. LDN is generally safe, inexpensive and well tolerated, with most studies using a daily dose of 4.5 mg. Although these features contribute to its appeal, current evidence does not support routine clinical use.","source_id":"source_3","support_kind":"candidate_source_row"},{"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","year":2023,"doi":"10.1016/j.heliyon.2023.e15638","url":"https://doi.org/10.1016/j.heliyon.2023.e15638","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Partridge 2023","excerpt":"BACKGROUND: Low dose naltrexone (LDN) is used off-label by many individuals with fibromyalgia to help manage their pain. There is no current systematic literature review summarising the evidence to support this use of LDN. The objectives of this study were to evaluate if patients with fibromyalgia prescribed LDN have reduced pain scores and greater quality of life compared with those allocated to placebo in randomized controlled trials. Secondly to determine if changes in inflammatory markers and brain structure and function are observed among patients with fibromyalgia taking LDN. METHODS: Systematic literature searches were conducted in MEDLINE , Embase Classic + Embase, APA PsychInfo, and The Cochrane Library from inception to May 2022. Reference lists from the selected papers were cross-checked with database search results. RESULTS: Three studies met our inclusion criteria for the assessment of efficacy, and two studies on potential LDN mechanisms. Results indicated some evidence to suggest LDN reduces pain and increases quality of life.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series","year":2023,"doi":"10.2147/JPR.S389957","url":"https://doi.org/10.2147/JPR.S389957","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"McKenzie-Brown 2023","excerpt":"PURPOSE: Low-dose naltrexone (LDN) has increased in popularity as a non-opioid medication that may decrease chronic pain symptoms. LDN is most commonly used to treat fibromyalgia, complex regional pain syndrome (CRPS), and painful diabetic neuropathy. Other studies suggest that LDN provides general symptom reduction in inflammatory conditions such as Crohn's disease and multiple sclerosis. We reviewed our experience with patients to whom we have prescribed LDN to see what types of painful conditions were most responsive to LDN in our patient population. PATIENTS AND METHODS: Charts from patients who came to the Pain Center between 2014 and 2021 were reviewed. RESULTS: Of the n = 137 patients who were prescribed LDN, 44% had no evidence of ever filling the prescription, and 4.4% of the responses were not charted. Of the remaining who took LDN (n = 70), 64% had some relief and were designated as 'Responders'. The most common pain diagnosis was neuropathic pain which, when added to the diagnosis of complex regional pain syndrome, accounted for 51% of responders to LDN.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_19","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.","citation_support":[],"candidate_sources":[{"study":"Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial","year":2022,"doi":"10.1016/j.bjane.2022.08.003","url":"https://doi.org/10.1016/j.bjane.2022.08.003","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Paula 2022","excerpt":"INTRODUCTION: Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management. OBJECTIVE: The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia. METHODS: This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review","year":2023,"doi":"10.1093/pm/pnad074","url":"https://doi.org/10.1093/pm/pnad074","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Rupp 2023","excerpt":"BACKGROUND: At low doses, naltrexone (LDN) has been shown to modulate inflammation through the interruption of microglial cell activation within the central nervous system. One of the most likely contributors to centralized pain is changes in microglial cell processing. Therefore, it has been postulated that LDN can be used to manage patients with pain resulting from central sensitization due to this relationship. This scoping review aims to synthesize the relevant study data for LDN as a novel treatment strategy for various centralized pain conditions. METHODS: A comprehensive literature search was conducted in PubMed, Embase, and Google Scholar, guided by the Scale for Assessment of Narrative Review Articles (SANRA) criteria. RESULTS: Forty-seven studies related to centralized pain conditions were identified. Many of the studies were case reports/series and narrative reviews, but a few randomized control trials have been conducted. Overall, the body of evidence revealed improvement in patient-reported pain severity and in outcomes related to hyperalgesia, physical function, quality of life, and sleep.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone: What is the Evidence? A Narrative Review","year":2026,"doi":"10.1007/s12325-026-03612-5","url":"https://doi.org/10.1007/s12325-026-03612-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Gouda 2026","excerpt":"Naltrexone is prescribed off-label at low doses, typically 0.5-6.0 mg, for a variety of therapeutic indications. This review evaluates the clinical evidence for low-dose naltrexone (LDN). A literature search was conducted in February 2026 across PubMed, Embase and CINAHL for studies published from 1989 to 2026. Title and abstract searches for \"low dose naltrexone\" identified peer-reviewed English-language studies using doses of ≤ 12.5 mg in humans. A total of 105 studies were reviewed, including 15 randomised controlled trials (RCTs) in chronic pain, autoimmune and neuroimmune disorders, gastrointestinal disease, dermatological conditions, post-infectious syndromes, mental health and oncology. Across these fields, early positive findings from uncontrolled studies were rarely replicated in placebo-controlled trials. Most available evidence consists of case reports and small feasibility studies that are prone to publication bias and rely heavily on subjective outcomes. LDN is generally safe, inexpensive and well tolerated, with most studies using a daily dose of 4.5 mg. Although these features contribute to its appeal, current evidence does not support routine clinical use.","source_id":"source_3","support_kind":"candidate_source_row"},{"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","year":2023,"doi":"10.1016/j.heliyon.2023.e15638","url":"https://doi.org/10.1016/j.heliyon.2023.e15638","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Partridge 2023","excerpt":"BACKGROUND: Low dose naltrexone (LDN) is used off-label by many individuals with fibromyalgia to help manage their pain. There is no current systematic literature review summarising the evidence to support this use of LDN. The objectives of this study were to evaluate if patients with fibromyalgia prescribed LDN have reduced pain scores and greater quality of life compared with those allocated to placebo in randomized controlled trials. Secondly to determine if changes in inflammatory markers and brain structure and function are observed among patients with fibromyalgia taking LDN. METHODS: Systematic literature searches were conducted in MEDLINE , Embase Classic + Embase, APA PsychInfo, and The Cochrane Library from inception to May 2022. Reference lists from the selected papers were cross-checked with database search results. RESULTS: Three studies met our inclusion criteria for the assessment of efficacy, and two studies on potential LDN mechanisms. Results indicated some evidence to suggest LDN reduces pain and increases quality of life.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series","year":2023,"doi":"10.2147/JPR.S389957","url":"https://doi.org/10.2147/JPR.S389957","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"McKenzie-Brown 2023","excerpt":"PURPOSE: Low-dose naltrexone (LDN) has increased in popularity as a non-opioid medication that may decrease chronic pain symptoms. LDN is most commonly used to treat fibromyalgia, complex regional pain syndrome (CRPS), and painful diabetic neuropathy. Other studies suggest that LDN provides general symptom reduction in inflammatory conditions such as Crohn's disease and multiple sclerosis. We reviewed our experience with patients to whom we have prescribed LDN to see what types of painful conditions were most responsive to LDN in our patient population. PATIENTS AND METHODS: Charts from patients who came to the Pain Center between 2014 and 2021 were reviewed. RESULTS: Of the n = 137 patients who were prescribed LDN, 44% had no evidence of ever filling the prescription, and 4.4% of the responses were not charted. Of the remaining who took LDN (n = 70), 64% had some relief and were designated as 'Responders'. The most common pain diagnosis was neuropathic pain which, when added to the diagnosis of complex regional pain syndrome, accounted for 51% of responders to LDN.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_20","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.","citation_support":[{"source_id":"source_1","study":"Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial","doi":"10.1016/j.bjane.2022.08.003","url":"https://doi.org/10.1016/j.bjane.2022.08.003","support_kind":"cited_as_match","cited_as":"Paula 2022","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"INTRODUCTION: Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management. OBJECTIVE: The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia. METHODS: This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA)."},{"source_id":"source_2","study":"Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review","doi":"10.1093/pm/pnad074","url":"https://doi.org/10.1093/pm/pnad074","support_kind":"cited_as_match","cited_as":"Rupp 2023","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review","excerpt":"BACKGROUND: At low doses, naltrexone (LDN) has been shown to modulate inflammation through the interruption of microglial cell activation within the central nervous system. One of the most likely contributors to centralized pain is changes in microglial cell processing. Therefore, it has been postulated that LDN can be used to manage patients with pain resulting from central sensitization due to this relationship. This scoping review aims to synthesize the relevant study data for LDN as a novel treatment strategy for various centralized pain conditions. METHODS: A comprehensive literature search was conducted in PubMed, Embase, and Google Scholar, guided by the Scale for Assessment of Narrative Review Articles (SANRA) criteria. RESULTS: Forty-seven studies related to centralized pain conditions were identified. Many of the studies were case reports/series and narrative reviews, but a few randomized control trials have been conducted. Overall, the body of evidence revealed improvement in patient-reported pain severity and in outcomes related to hyperalgesia, physical function, quality of life, and sleep."},{"source_id":"source_3","study":"Low-Dose Naltrexone: What is the Evidence? A Narrative Review","doi":"10.1007/s12325-026-03612-5","url":"https://doi.org/10.1007/s12325-026-03612-5","support_kind":"cited_as_match","cited_as":"Gouda 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review","excerpt":"Naltrexone is prescribed off-label at low doses, typically 0.5-6.0 mg, for a variety of therapeutic indications. This review evaluates the clinical evidence for low-dose naltrexone (LDN). A literature search was conducted in February 2026 across PubMed, Embase and CINAHL for studies published from 1989 to 2026. Title and abstract searches for \"low dose naltrexone\" identified peer-reviewed English-language studies using doses of ≤ 12.5 mg in humans. A total of 105 studies were reviewed, including 15 randomised controlled trials (RCTs) in chronic pain, autoimmune and neuroimmune disorders, gastrointestinal disease, dermatological conditions, post-infectious syndromes, mental health and oncology. Across these fields, early positive findings from uncontrolled studies were rarely replicated in placebo-controlled trials. Most available evidence consists of case reports and small feasibility studies that are prone to publication bias and rely heavily on subjective outcomes. LDN is generally safe, inexpensive and well tolerated, with most studies using a daily dose of 4.5 mg. Although these features contribute to its appeal, current evidence does not support routine clinical use."},{"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","doi":"10.1016/j.heliyon.2023.e15638","url":"https://doi.org/10.1016/j.heliyon.2023.e15638","support_kind":"cited_as_match","cited_as":"Partridge 2023","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review","excerpt":"BACKGROUND: Low dose naltrexone (LDN) is used off-label by many individuals with fibromyalgia to help manage their pain. There is no current systematic literature review summarising the evidence to support this use of LDN. The objectives of this study were to evaluate if patients with fibromyalgia prescribed LDN have reduced pain scores and greater quality of life compared with those allocated to placebo in randomized controlled trials. Secondly to determine if changes in inflammatory markers and brain structure and function are observed among patients with fibromyalgia taking LDN. METHODS: Systematic literature searches were conducted in MEDLINE , Embase Classic + Embase, APA PsychInfo, and The Cochrane Library from inception to May 2022. Reference lists from the selected papers were cross-checked with database search results. RESULTS: Three studies met our inclusion criteria for the assessment of efficacy, and two studies on potential LDN mechanisms. Results indicated some evidence to suggest LDN reduces pain and increases quality of life."},{"source_id":"source_5","study":"Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series","doi":"10.2147/JPR.S389957","url":"https://doi.org/10.2147/JPR.S389957","support_kind":"cited_as_match","cited_as":"McKenzie-Brown 2023","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"PURPOSE: Low-dose naltrexone (LDN) has increased in popularity as a non-opioid medication that may decrease chronic pain symptoms. LDN is most commonly used to treat fibromyalgia, complex regional pain syndrome (CRPS), and painful diabetic neuropathy. Other studies suggest that LDN provides general symptom reduction in inflammatory conditions such as Crohn's disease and multiple sclerosis. We reviewed our experience with patients to whom we have prescribed LDN to see what types of painful conditions were most responsive to LDN in our patient population. PATIENTS AND METHODS: Charts from patients who came to the Pain Center between 2014 and 2021 were reviewed. RESULTS: Of the n = 137 patients who were prescribed LDN, 44% had no evidence of ever filling the prescription, and 4.4% of the responses were not charted. Of the remaining who took LDN (n = 70), 64% had some relief and were designated as 'Responders'. The most common pain diagnosis was neuropathic pain which, when added to the diagnosis of complex regional pain syndrome, accounted for 51% of responders to LDN."},{"source_id":"source_6","study":"Low-dose naltrexone as an adjunctive treatment for major depressive disorder: findings from a randomized, double-blind, placebo-controlled hybrid parallel-arm study","doi":"10.3389/fphar.2026.1767654","url":"https://doi.org/10.3389/fphar.2026.1767654","support_kind":"cited_as_match","cited_as":"Moloney 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"INTRODUCTION: Major depressive disorder (MDD) is a leading cause of global disability. Current treatments are limited by poor efficacy in approximately one-third of patients. Neuroinflammation may be an underlying mechanism of MDD and represents a novel target for pharmacological therapy. This study aimed to investigate the effects of a putative centrally acting anti-inflammatory agent, low-dose naltrexone (LDN), in MDD. METHODS: Patients with MDD experiencing moderate depressive symptoms and receiving antidepressant treatment were randomized to receive 12 weeks of LDN (up to 4.5 mg per day) or 12 weeks of inactive placebo. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale (MADRS) at 12 weeks, analyzed using a linear mixed-effects model adjusted for baseline. RESULTS: Thirty-seven patients were randomized. At 12 weeks, MADRS scores (M ± SD) were reduced by 10.5 ± 5.6 in the LDN group and 9.8 ± 5.9 placebo group; with no difference between groups (p = 0.97). LDN did not affect high-sensitivity C-reactive protein (hsCRP) levels or exploratory measures of depression, behavioral activation, quality of life, sickness symptoms and mood."},{"source_id":"source_7","study":"Efficacy and safety of low-dose naltrexone for the management of fibromyalgia: a systematic review and meta-analysis of randomized controlled trials with trial sequential analysis","doi":"10.3344/kjp.24202","url":"https://doi.org/10.3344/kjp.24202","support_kind":"cited_as_match","cited_as":"Vatvani 2024","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review","excerpt":"BACKGROUND: Fibromyalgia is characterized by the presence of chronic widespread pain that may impair patient's quality of life. Currently, the use of naltrexone as a therapeutic agent for fibromyalgia is not supported by enough evidence, especially from randomized controlled trials (RCTs). This study aims to analyze the efficacy and safety of low-dose naltrexone (LDN) for the management of fibromyalgia. METHODS: A comprehensive search was conducted on the Scopus, Medline, ClinicalTrials.gov, and Cochrane Library databases up until May 20th, 2024. This review incorporates RCTs that examine the comparison between LDN and placebo in fibromyalgia patients. We employed random-effect models to analyze the odds ratio and mean difference (MD) for presentation of the outcomes. RESULTS: A total of 4 RCTs with 222 fibromyalgia patients were incorporated. The results of our meta-analysis showed a significant reduction in pain scores (MD: -0.86, 95% confidence interval [CI]: -1.20, -0.51, P < 0.001, I 2 = 33%) and higher increment in pressure pain threshold (MD: 0.17, 95% CI: 0.08, 0.25, P < 0.001, I 2 = 0%) among fibromyalgia patients who received LDN than those who only received a placebo."},{"source_id":"source_36","study":"The Effect of Low-Dose Naltrexone on Medication in Inflammatory Bowel Disease: A Quasi Experimental Before-and-After Prescription Database Study","doi":"10.1093/ecco-jcc/jjy008","url":"https://doi.org/10.1093/ecco-jcc/jjy008","support_kind":"cited_as_match","cited_as":"Raknes 2018","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"BACKGROUND AND AIMS: Low-dose naltrexone [LDN] is a controversial off-label treatment used by many Crohn's disease [CD] and ulcerative colitis [UC] patients. A small number of preliminary studies indicate that LDN might be beneficial in CD, but evidence is too scarce to demonstrate efficacy. We sought to examine whether initiation of LDN therapy by patients with inflammatory bowel disease [IBD] was followed by changes in dispensing of relevant medication. METHODS: We performed a quasi-experimental before-and-after study following a sudden increase in LDN use in the Norwegian population in 2013. IBD patients were identified from among all the patients who had at least one LDN prescription recorded in the Norwegian Prescription Database [NorPD] in 2013. Drug dispensing 2 years before and after the first LDN prescription was compared. RESULTS: We identified 582 IBD patients who had received LDN. Of the 256 patients who became persistent LDN users, there were reductions in the number of users for [i] all examined drugs [-12%], [ii] intestinal anti-inflammatory agents [-17%], [iii] other immunosuppressants [-29%], [iv] intestinal corticosteroids [-32%] and [v] aminosalicylates [-17%]."}],"candidate_sources":[]},{"claim_id":"claim_21","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.","citation_support":[],"candidate_sources":[{"study":"Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial","year":2022,"doi":"10.1016/j.bjane.2022.08.003","url":"https://doi.org/10.1016/j.bjane.2022.08.003","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Paula 2022","excerpt":"INTRODUCTION: Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management. OBJECTIVE: The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia. METHODS: This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review","year":2023,"doi":"10.1093/pm/pnad074","url":"https://doi.org/10.1093/pm/pnad074","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Rupp 2023","excerpt":"BACKGROUND: At low doses, naltrexone (LDN) has been shown to modulate inflammation through the interruption of microglial cell activation within the central nervous system. One of the most likely contributors to centralized pain is changes in microglial cell processing. Therefore, it has been postulated that LDN can be used to manage patients with pain resulting from central sensitization due to this relationship. This scoping review aims to synthesize the relevant study data for LDN as a novel treatment strategy for various centralized pain conditions. METHODS: A comprehensive literature search was conducted in PubMed, Embase, and Google Scholar, guided by the Scale for Assessment of Narrative Review Articles (SANRA) criteria. RESULTS: Forty-seven studies related to centralized pain conditions were identified. Many of the studies were case reports/series and narrative reviews, but a few randomized control trials have been conducted. Overall, the body of evidence revealed improvement in patient-reported pain severity and in outcomes related to hyperalgesia, physical function, quality of life, and sleep.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone: What is the Evidence? A Narrative Review","year":2026,"doi":"10.1007/s12325-026-03612-5","url":"https://doi.org/10.1007/s12325-026-03612-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Gouda 2026","excerpt":"Naltrexone is prescribed off-label at low doses, typically 0.5-6.0 mg, for a variety of therapeutic indications. This review evaluates the clinical evidence for low-dose naltrexone (LDN). A literature search was conducted in February 2026 across PubMed, Embase and CINAHL for studies published from 1989 to 2026. Title and abstract searches for \"low dose naltrexone\" identified peer-reviewed English-language studies using doses of ≤ 12.5 mg in humans. A total of 105 studies were reviewed, including 15 randomised controlled trials (RCTs) in chronic pain, autoimmune and neuroimmune disorders, gastrointestinal disease, dermatological conditions, post-infectious syndromes, mental health and oncology. Across these fields, early positive findings from uncontrolled studies were rarely replicated in placebo-controlled trials. Most available evidence consists of case reports and small feasibility studies that are prone to publication bias and rely heavily on subjective outcomes. LDN is generally safe, inexpensive and well tolerated, with most studies using a daily dose of 4.5 mg. Although these features contribute to its appeal, current evidence does not support routine clinical use.","source_id":"source_3","support_kind":"candidate_source_row"},{"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","year":2023,"doi":"10.1016/j.heliyon.2023.e15638","url":"https://doi.org/10.1016/j.heliyon.2023.e15638","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Partridge 2023","excerpt":"BACKGROUND: Low dose naltrexone (LDN) is used off-label by many individuals with fibromyalgia to help manage their pain. There is no current systematic literature review summarising the evidence to support this use of LDN. The objectives of this study were to evaluate if patients with fibromyalgia prescribed LDN have reduced pain scores and greater quality of life compared with those allocated to placebo in randomized controlled trials. Secondly to determine if changes in inflammatory markers and brain structure and function are observed among patients with fibromyalgia taking LDN. METHODS: Systematic literature searches were conducted in MEDLINE , Embase Classic + Embase, APA PsychInfo, and The Cochrane Library from inception to May 2022. Reference lists from the selected papers were cross-checked with database search results. RESULTS: Three studies met our inclusion criteria for the assessment of efficacy, and two studies on potential LDN mechanisms. Results indicated some evidence to suggest LDN reduces pain and increases quality of life.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series","year":2023,"doi":"10.2147/JPR.S389957","url":"https://doi.org/10.2147/JPR.S389957","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"McKenzie-Brown 2023","excerpt":"PURPOSE: Low-dose naltrexone (LDN) has increased in popularity as a non-opioid medication that may decrease chronic pain symptoms. LDN is most commonly used to treat fibromyalgia, complex regional pain syndrome (CRPS), and painful diabetic neuropathy. Other studies suggest that LDN provides general symptom reduction in inflammatory conditions such as Crohn's disease and multiple sclerosis. We reviewed our experience with patients to whom we have prescribed LDN to see what types of painful conditions were most responsive to LDN in our patient population. PATIENTS AND METHODS: Charts from patients who came to the Pain Center between 2014 and 2021 were reviewed. RESULTS: Of the n = 137 patients who were prescribed LDN, 44% had no evidence of ever filling the prescription, and 4.4% of the responses were not charted. Of the remaining who took LDN (n = 70), 64% had some relief and were designated as 'Responders'. The most common pain diagnosis was neuropathic pain which, when added to the diagnosis of complex regional pain syndrome, accounted for 51% of responders to LDN.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_22","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.","citation_support":[{"source_id":"source_11","study":"Pilot RCT comparing low-dose naltrexone, gabapentin and placebo to reduce pain among people with HIV with alcohol problems","doi":"10.1371/journal.pone.0297948","url":"https://doi.org/10.1371/journal.pone.0297948","support_kind":"cited_as_match","cited_as":"Tsui 2024","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","excerpt":"BACKGROUND: To estimate the effects on pain of two medications (low-dose naltrexone and gabapentin) compared to placebo among people with HIV (PWH) with heavy alcohol use and chronic pain. METHODS: We conducted a pilot, randomized, double-blinded, 3-arm study of PWH with chronic pain and past-year heavy alcohol use in 2021. Participants were recruited in St. Petersburg, Russia, and randomized to receive daily low-dose naltrexone (4.5mg), gabapentin (up to 1800mg), or placebo. The two primary outcomes were change in self-reported pain severity and pain interference measured with the Brief Pain Inventory from baseline to 8 weeks. RESULTS: Participants (N = 45, 15 in each arm) had the following baseline characteristics: 64% male; age 41 years (SD±7); mean 2 (SD±4) heavy drinking days in the past month and mean pain severity and interference were 3.2 (SD±1) and 3.0 (SD±2), respectively. Pain severity decreased for all three arms. Mean differences in change in pain severity for gabapentin vs. placebo, and naltrexone vs. placebo were -0.27 (95% confidence interval [CI] -1.76, 1.23; p = 0.73) and 0.88 (95% CI -0.7, 2.46; p = 0.55), respectively."}],"candidate_sources":[]},{"claim_id":"claim_23","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).","citation_support":[{"source_id":"source_1","study":"Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial","doi":"10.1016/j.bjane.2022.08.003","url":"https://doi.org/10.1016/j.bjane.2022.08.003","support_kind":"cited_as_match","cited_as":"Paula 2022","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"INTRODUCTION: Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management. OBJECTIVE: The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia. METHODS: This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA)."},{"source_id":"source_2","study":"Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review","doi":"10.1093/pm/pnad074","url":"https://doi.org/10.1093/pm/pnad074","support_kind":"cited_as_match","cited_as":"Rupp 2023","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review","excerpt":"BACKGROUND: At low doses, naltrexone (LDN) has been shown to modulate inflammation through the interruption of microglial cell activation within the central nervous system. One of the most likely contributors to centralized pain is changes in microglial cell processing. Therefore, it has been postulated that LDN can be used to manage patients with pain resulting from central sensitization due to this relationship. This scoping review aims to synthesize the relevant study data for LDN as a novel treatment strategy for various centralized pain conditions. METHODS: A comprehensive literature search was conducted in PubMed, Embase, and Google Scholar, guided by the Scale for Assessment of Narrative Review Articles (SANRA) criteria. RESULTS: Forty-seven studies related to centralized pain conditions were identified. Many of the studies were case reports/series and narrative reviews, but a few randomized control trials have been conducted. Overall, the body of evidence revealed improvement in patient-reported pain severity and in outcomes related to hyperalgesia, physical function, quality of life, and sleep."},{"source_id":"source_11","study":"Pilot RCT comparing low-dose naltrexone, gabapentin and placebo to reduce pain among people with HIV with alcohol problems","doi":"10.1371/journal.pone.0297948","url":"https://doi.org/10.1371/journal.pone.0297948","support_kind":"cited_as_match","cited_as":"Tsui 2024","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","excerpt":"BACKGROUND: To estimate the effects on pain of two medications (low-dose naltrexone and gabapentin) compared to placebo among people with HIV (PWH) with heavy alcohol use and chronic pain. METHODS: We conducted a pilot, randomized, double-blinded, 3-arm study of PWH with chronic pain and past-year heavy alcohol use in 2021. Participants were recruited in St. Petersburg, Russia, and randomized to receive daily low-dose naltrexone (4.5mg), gabapentin (up to 1800mg), or placebo. The two primary outcomes were change in self-reported pain severity and pain interference measured with the Brief Pain Inventory from baseline to 8 weeks. RESULTS: Participants (N = 45, 15 in each arm) had the following baseline characteristics: 64% male; age 41 years (SD±7); mean 2 (SD±4) heavy drinking days in the past month and mean pain severity and interference were 3.2 (SD±1) and 3.0 (SD±2), respectively. Pain severity decreased for all three arms. Mean differences in change in pain severity for gabapentin vs. placebo, and naltrexone vs. placebo were -0.27 (95% confidence interval [CI] -1.76, 1.23; p = 0.73) and 0.88 (95% CI -0.7, 2.46; p = 0.55), respectively."}],"candidate_sources":[]},{"claim_id":"claim_24","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).","citation_support":[{"source_id":"source_21","study":"A randomized, double-blind, placebo-controlled, hybrid parallel-arm study of low-dose naltrexone as an adjunctive anti-inflammatory treatment for major depressive disorder","doi":"10.1186/s13063-022-06738-3","url":"https://doi.org/10.1186/s13063-022-06738-3","support_kind":"cited_as_match","cited_as":"Plank 2022","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"BACKGROUND: Major depressive disorder (MDD) is a leading cause of disability worldwide. The current treatments are ineffective in approximately one-third of patients, resulting in a large economic burden and reduced quality of life for a significant proportion of the global population. There is considerable evidence that increased inflammation may distinguish a sub-type of MDD, and there are no validated diagnostic tools or treatments for neuroinflammation in MDD patients. The current study aims to explore the potential role of low-dose naltrexone (LDN), a drug with purported anti-inflammatory properties in the central nervous system, as an adjunctive treatment in patients with MDD. METHODS/DESIGN: This double-blind placebo-controlled hybrid parallel arm study enables the exploration of peripheral and central inflammatory markers with LDN as an approach to investigate inflammation as a pathophysiological contributor to MDD."},{"source_id":"source_31","study":"Therapeutic Uses and Efficacy of Low-Dose Naltrexone: A Scoping Review","doi":"10.7759/cureus.81086","url":"https://doi.org/10.7759/cureus.81086","support_kind":"cited_as_match","cited_as":"Leiber 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review","excerpt":"Low-dose naltrexone (LDN) has been suggested as a novel treatment option for several conditions and is of increasing interest due to its potential ability to address certain medical conditions that lack effective treatments or frequently rely on the use of opioids as treatment. This article will synthesize evidence and assess the scope of literature that examines low-dose naltrexone's efficacy against painful and other relevant medical conditions. A scoping review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. Resources utilized for the review included PubMed and Excerpta Medica database (Embase). Articles included were required to be original research, published in English, conducted on human subjects, published in the last 15 years, have full text available, and include treatment with naltrexone in an off-label capacity (i.e., not for the treatment of alcohol or opioid use disorder). Zotero (Corporation for Digital Scholarship, Vienna, VA), a reference management software, was used to review all search results with this criterion."},{"source_id":"source_35","study":"Is low-dose naltrexone effective in chronic pain management?","doi":"10.12788/jfp.0654","url":"https://doi.org/10.12788/jfp.0654","support_kind":"cited_as_match","cited_as":"Radi 2023","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review","excerpt":"YES. Low-dose naltrexone is as effective as amitriptyline in the treatment of painful diabetic neuropathy and has a superior safety profile (strength of recommendation [SOR], B; single randomized controlled trial [RCT]). Low-dose naltrexone significantly reduced pain by 32% in inflammatory conditions and 44% in neuropathic conditions (SOR, B; single retrospective cohort study). Doses as low as 5.4 mg were found to reduce pain in 95% of patients with fibromyalgia (SOR, B; single prospective dose-response study)."}],"candidate_sources":[]},{"claim_id":"claim_25","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).","citation_support":[{"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","doi":"10.1016/j.heliyon.2023.e15638","url":"https://doi.org/10.1016/j.heliyon.2023.e15638","support_kind":"cited_as_match","cited_as":"Partridge 2023","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review","excerpt":"BACKGROUND: Low dose naltrexone (LDN) is used off-label by many individuals with fibromyalgia to help manage their pain. There is no current systematic literature review summarising the evidence to support this use of LDN. The objectives of this study were to evaluate if patients with fibromyalgia prescribed LDN have reduced pain scores and greater quality of life compared with those allocated to placebo in randomized controlled trials. Secondly to determine if changes in inflammatory markers and brain structure and function are observed among patients with fibromyalgia taking LDN. METHODS: Systematic literature searches were conducted in MEDLINE , Embase Classic + Embase, APA PsychInfo, and The Cochrane Library from inception to May 2022. Reference lists from the selected papers were cross-checked with database search results. RESULTS: Three studies met our inclusion criteria for the assessment of efficacy, and two studies on potential LDN mechanisms. Results indicated some evidence to suggest LDN reduces pain and increases quality of life."},{"source_id":"source_30","study":"Low-Dose Naltrexone in Chronic Pain Management: Mechanisms, Evidence, and Clinical Implications","doi":"10.3390/jpm16030151","url":"https://doi.org/10.3390/jpm16030151","support_kind":"cited_as_match","cited_as":"McKenzie 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"Chronic pain imposes a substantial burden on global health and remains challenging to manage, despite ongoing advances in pharmacologic and interventional therapies. Recognition of chronic pain as a condition driven by central sensitization and neuroimmune dysregulation has prompted interest in therapies that target these mechanisms rather than peripheral nociception alone. Low-dose naltrexone (LDN), administered at doses substantially lower than those used for opioid or alcohol use disorders, has emerged as a repurposed treatment with potential analgesic and anti-inflammatory properties. This review summarizes the pharmacologic characteristics of LDN, with emphasis on its proposed mechanisms involving transient opioid receptor blockade, modulation of microglial activation, Toll-like receptor signaling, and central neuroimmune pathways. Available clinical evidence evaluating LDN across a range of chronic pain conditions, such as fibromyalgia, neuropathic pain syndromes, inflammatory and autoimmune disorders, headache disorders, and other centralized pain states, is critically reviewed."}],"candidate_sources":[]},{"claim_id":"claim_26","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.","citation_support":[{"source_id":"source_1","study":"Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial","doi":"10.1016/j.bjane.2022.08.003","url":"https://doi.org/10.1016/j.bjane.2022.08.003","support_kind":"cited_as_match","cited_as":"Paula 2022","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"INTRODUCTION: Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management. OBJECTIVE: The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia. METHODS: This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA)."},{"source_id":"source_2","study":"Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review","doi":"10.1093/pm/pnad074","url":"https://doi.org/10.1093/pm/pnad074","support_kind":"cited_as_match","cited_as":"Rupp 2023","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review","excerpt":"BACKGROUND: At low doses, naltrexone (LDN) has been shown to modulate inflammation through the interruption of microglial cell activation within the central nervous system. One of the most likely contributors to centralized pain is changes in microglial cell processing. Therefore, it has been postulated that LDN can be used to manage patients with pain resulting from central sensitization due to this relationship. This scoping review aims to synthesize the relevant study data for LDN as a novel treatment strategy for various centralized pain conditions. METHODS: A comprehensive literature search was conducted in PubMed, Embase, and Google Scholar, guided by the Scale for Assessment of Narrative Review Articles (SANRA) criteria. RESULTS: Forty-seven studies related to centralized pain conditions were identified. Many of the studies were case reports/series and narrative reviews, but a few randomized control trials have been conducted. Overall, the body of evidence revealed improvement in patient-reported pain severity and in outcomes related to hyperalgesia, physical function, quality of life, and sleep."},{"source_id":"source_3","study":"Low-Dose Naltrexone: What is the Evidence? A Narrative Review","doi":"10.1007/s12325-026-03612-5","url":"https://doi.org/10.1007/s12325-026-03612-5","support_kind":"cited_as_match","cited_as":"Gouda 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review","excerpt":"Naltrexone is prescribed off-label at low doses, typically 0.5-6.0 mg, for a variety of therapeutic indications. This review evaluates the clinical evidence for low-dose naltrexone (LDN). A literature search was conducted in February 2026 across PubMed, Embase and CINAHL for studies published from 1989 to 2026. Title and abstract searches for \"low dose naltrexone\" identified peer-reviewed English-language studies using doses of ≤ 12.5 mg in humans. A total of 105 studies were reviewed, including 15 randomised controlled trials (RCTs) in chronic pain, autoimmune and neuroimmune disorders, gastrointestinal disease, dermatological conditions, post-infectious syndromes, mental health and oncology. Across these fields, early positive findings from uncontrolled studies were rarely replicated in placebo-controlled trials. Most available evidence consists of case reports and small feasibility studies that are prone to publication bias and rely heavily on subjective outcomes. LDN is generally safe, inexpensive and well tolerated, with most studies using a daily dose of 4.5 mg. Although these features contribute to its appeal, current evidence does not support routine clinical use."},{"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","doi":"10.1016/j.heliyon.2023.e15638","url":"https://doi.org/10.1016/j.heliyon.2023.e15638","support_kind":"cited_as_match","cited_as":"Partridge 2023","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review","excerpt":"BACKGROUND: Low dose naltrexone (LDN) is used off-label by many individuals with fibromyalgia to help manage their pain. There is no current systematic literature review summarising the evidence to support this use of LDN. The objectives of this study were to evaluate if patients with fibromyalgia prescribed LDN have reduced pain scores and greater quality of life compared with those allocated to placebo in randomized controlled trials. Secondly to determine if changes in inflammatory markers and brain structure and function are observed among patients with fibromyalgia taking LDN. METHODS: Systematic literature searches were conducted in MEDLINE , Embase Classic + Embase, APA PsychInfo, and The Cochrane Library from inception to May 2022. Reference lists from the selected papers were cross-checked with database search results. RESULTS: Three studies met our inclusion criteria for the assessment of efficacy, and two studies on potential LDN mechanisms. Results indicated some evidence to suggest LDN reduces pain and increases quality of life."}],"candidate_sources":[]},{"claim_id":"claim_27","claim":"| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |","citation_support":[],"candidate_sources":[{"study":"Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial","year":2022,"doi":"10.1016/j.bjane.2022.08.003","url":"https://doi.org/10.1016/j.bjane.2022.08.003","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Paula 2022","excerpt":"INTRODUCTION: Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management. OBJECTIVE: The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia. METHODS: This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review","year":2023,"doi":"10.1093/pm/pnad074","url":"https://doi.org/10.1093/pm/pnad074","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Rupp 2023","excerpt":"BACKGROUND: At low doses, naltrexone (LDN) has been shown to modulate inflammation through the interruption of microglial cell activation within the central nervous system. One of the most likely contributors to centralized pain is changes in microglial cell processing. Therefore, it has been postulated that LDN can be used to manage patients with pain resulting from central sensitization due to this relationship. This scoping review aims to synthesize the relevant study data for LDN as a novel treatment strategy for various centralized pain conditions. METHODS: A comprehensive literature search was conducted in PubMed, Embase, and Google Scholar, guided by the Scale for Assessment of Narrative Review Articles (SANRA) criteria. RESULTS: Forty-seven studies related to centralized pain conditions were identified. Many of the studies were case reports/series and narrative reviews, but a few randomized control trials have been conducted. Overall, the body of evidence revealed improvement in patient-reported pain severity and in outcomes related to hyperalgesia, physical function, quality of life, and sleep.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone: What is the Evidence? A Narrative Review","year":2026,"doi":"10.1007/s12325-026-03612-5","url":"https://doi.org/10.1007/s12325-026-03612-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Gouda 2026","excerpt":"Naltrexone is prescribed off-label at low doses, typically 0.5-6.0 mg, for a variety of therapeutic indications. This review evaluates the clinical evidence for low-dose naltrexone (LDN). A literature search was conducted in February 2026 across PubMed, Embase and CINAHL for studies published from 1989 to 2026. Title and abstract searches for \"low dose naltrexone\" identified peer-reviewed English-language studies using doses of ≤ 12.5 mg in humans. A total of 105 studies were reviewed, including 15 randomised controlled trials (RCTs) in chronic pain, autoimmune and neuroimmune disorders, gastrointestinal disease, dermatological conditions, post-infectious syndromes, mental health and oncology. Across these fields, early positive findings from uncontrolled studies were rarely replicated in placebo-controlled trials. Most available evidence consists of case reports and small feasibility studies that are prone to publication bias and rely heavily on subjective outcomes. LDN is generally safe, inexpensive and well tolerated, with most studies using a daily dose of 4.5 mg. Although these features contribute to its appeal, current evidence does not support routine clinical use.","source_id":"source_3","support_kind":"candidate_source_row"},{"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","year":2023,"doi":"10.1016/j.heliyon.2023.e15638","url":"https://doi.org/10.1016/j.heliyon.2023.e15638","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Partridge 2023","excerpt":"BACKGROUND: Low dose naltrexone (LDN) is used off-label by many individuals with fibromyalgia to help manage their pain. There is no current systematic literature review summarising the evidence to support this use of LDN. The objectives of this study were to evaluate if patients with fibromyalgia prescribed LDN have reduced pain scores and greater quality of life compared with those allocated to placebo in randomized controlled trials. Secondly to determine if changes in inflammatory markers and brain structure and function are observed among patients with fibromyalgia taking LDN. METHODS: Systematic literature searches were conducted in MEDLINE , Embase Classic + Embase, APA PsychInfo, and The Cochrane Library from inception to May 2022. Reference lists from the selected papers were cross-checked with database search results. RESULTS: Three studies met our inclusion criteria for the assessment of efficacy, and two studies on potential LDN mechanisms. Results indicated some evidence to suggest LDN reduces pain and increases quality of life.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series","year":2023,"doi":"10.2147/JPR.S389957","url":"https://doi.org/10.2147/JPR.S389957","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"McKenzie-Brown 2023","excerpt":"PURPOSE: Low-dose naltrexone (LDN) has increased in popularity as a non-opioid medication that may decrease chronic pain symptoms. LDN is most commonly used to treat fibromyalgia, complex regional pain syndrome (CRPS), and painful diabetic neuropathy. Other studies suggest that LDN provides general symptom reduction in inflammatory conditions such as Crohn's disease and multiple sclerosis. We reviewed our experience with patients to whom we have prescribed LDN to see what types of painful conditions were most responsive to LDN in our patient population. PATIENTS AND METHODS: Charts from patients who came to the Pain Center between 2014 and 2021 were reviewed. RESULTS: Of the n = 137 patients who were prescribed LDN, 44% had no evidence of ever filling the prescription, and 4.4% of the responses were not charted. Of the remaining who took LDN (n = 70), 64% had some relief and were designated as 'Responders'. The most common pain diagnosis was neuropathic pain which, when added to the diagnosis of complex regional pain syndrome, accounted for 51% of responders to LDN.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_28","claim":"Dosing and pharmacokinetics context: 35 sources; significant source statistic in 12/35 sources; receipt-level direction coded null.","citation_support":[],"candidate_sources":[{"study":"Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial","year":2022,"doi":"10.1016/j.bjane.2022.08.003","url":"https://doi.org/10.1016/j.bjane.2022.08.003","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Paula 2022","excerpt":"INTRODUCTION: Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management. OBJECTIVE: The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia. METHODS: This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review","year":2023,"doi":"10.1093/pm/pnad074","url":"https://doi.org/10.1093/pm/pnad074","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Rupp 2023","excerpt":"BACKGROUND: At low doses, naltrexone (LDN) has been shown to modulate inflammation through the interruption of microglial cell activation within the central nervous system. One of the most likely contributors to centralized pain is changes in microglial cell processing. Therefore, it has been postulated that LDN can be used to manage patients with pain resulting from central sensitization due to this relationship. This scoping review aims to synthesize the relevant study data for LDN as a novel treatment strategy for various centralized pain conditions. METHODS: A comprehensive literature search was conducted in PubMed, Embase, and Google Scholar, guided by the Scale for Assessment of Narrative Review Articles (SANRA) criteria. RESULTS: Forty-seven studies related to centralized pain conditions were identified. Many of the studies were case reports/series and narrative reviews, but a few randomized control trials have been conducted. Overall, the body of evidence revealed improvement in patient-reported pain severity and in outcomes related to hyperalgesia, physical function, quality of life, and sleep.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone: What is the Evidence? A Narrative Review","year":2026,"doi":"10.1007/s12325-026-03612-5","url":"https://doi.org/10.1007/s12325-026-03612-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Gouda 2026","excerpt":"Naltrexone is prescribed off-label at low doses, typically 0.5-6.0 mg, for a variety of therapeutic indications. This review evaluates the clinical evidence for low-dose naltrexone (LDN). A literature search was conducted in February 2026 across PubMed, Embase and CINAHL for studies published from 1989 to 2026. Title and abstract searches for \"low dose naltrexone\" identified peer-reviewed English-language studies using doses of ≤ 12.5 mg in humans. A total of 105 studies were reviewed, including 15 randomised controlled trials (RCTs) in chronic pain, autoimmune and neuroimmune disorders, gastrointestinal disease, dermatological conditions, post-infectious syndromes, mental health and oncology. Across these fields, early positive findings from uncontrolled studies were rarely replicated in placebo-controlled trials. Most available evidence consists of case reports and small feasibility studies that are prone to publication bias and rely heavily on subjective outcomes. LDN is generally safe, inexpensive and well tolerated, with most studies using a daily dose of 4.5 mg. Although these features contribute to its appeal, current evidence does not support routine clinical use.","source_id":"source_3","support_kind":"candidate_source_row"},{"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","year":2023,"doi":"10.1016/j.heliyon.2023.e15638","url":"https://doi.org/10.1016/j.heliyon.2023.e15638","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Partridge 2023","excerpt":"BACKGROUND: Low dose naltrexone (LDN) is used off-label by many individuals with fibromyalgia to help manage their pain. There is no current systematic literature review summarising the evidence to support this use of LDN. The objectives of this study were to evaluate if patients with fibromyalgia prescribed LDN have reduced pain scores and greater quality of life compared with those allocated to placebo in randomized controlled trials. Secondly to determine if changes in inflammatory markers and brain structure and function are observed among patients with fibromyalgia taking LDN. METHODS: Systematic literature searches were conducted in MEDLINE , Embase Classic + Embase, APA PsychInfo, and The Cochrane Library from inception to May 2022. Reference lists from the selected papers were cross-checked with database search results. RESULTS: Three studies met our inclusion criteria for the assessment of efficacy, and two studies on potential LDN mechanisms. Results indicated some evidence to suggest LDN reduces pain and increases quality of life.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series","year":2023,"doi":"10.2147/JPR.S389957","url":"https://doi.org/10.2147/JPR.S389957","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"McKenzie-Brown 2023","excerpt":"PURPOSE: Low-dose naltrexone (LDN) has increased in popularity as a non-opioid medication that may decrease chronic pain symptoms. LDN is most commonly used to treat fibromyalgia, complex regional pain syndrome (CRPS), and painful diabetic neuropathy. Other studies suggest that LDN provides general symptom reduction in inflammatory conditions such as Crohn's disease and multiple sclerosis. We reviewed our experience with patients to whom we have prescribed LDN to see what types of painful conditions were most responsive to LDN in our patient population. PATIENTS AND METHODS: Charts from patients who came to the Pain Center between 2014 and 2021 were reviewed. RESULTS: Of the n = 137 patients who were prescribed LDN, 44% had no evidence of ever filling the prescription, and 4.4% of the responses were not charted. Of the remaining who took LDN (n = 70), 64% had some relief and were designated as 'Responders'. The most common pain diagnosis was neuropathic pain which, when added to the diagnosis of complex regional pain syndrome, accounted for 51% of responders to LDN.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_29","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.","citation_support":[{"source_id":"source_11","study":"Pilot RCT comparing low-dose naltrexone, gabapentin and placebo to reduce pain among people with HIV with alcohol problems","doi":"10.1371/journal.pone.0297948","url":"https://doi.org/10.1371/journal.pone.0297948","support_kind":"cited_as_match","cited_as":"Tsui 2024","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","excerpt":"BACKGROUND: To estimate the effects on pain of two medications (low-dose naltrexone and gabapentin) compared to placebo among people with HIV (PWH) with heavy alcohol use and chronic pain. METHODS: We conducted a pilot, randomized, double-blinded, 3-arm study of PWH with chronic pain and past-year heavy alcohol use in 2021. Participants were recruited in St. Petersburg, Russia, and randomized to receive daily low-dose naltrexone (4.5mg), gabapentin (up to 1800mg), or placebo. The two primary outcomes were change in self-reported pain severity and pain interference measured with the Brief Pain Inventory from baseline to 8 weeks. RESULTS: Participants (N = 45, 15 in each arm) had the following baseline characteristics: 64% male; age 41 years (SD±7); mean 2 (SD±4) heavy drinking days in the past month and mean pain severity and interference were 3.2 (SD±1) and 3.0 (SD±2), respectively. Pain severity decreased for all three arms. Mean differences in change in pain severity for gabapentin vs. placebo, and naltrexone vs. placebo were -0.27 (95% confidence interval [CI] -1.76, 1.23; p = 0.73) and 0.88 (95% CI -0.7, 2.46; p = 0.55), respectively."},{"source_id":"source_16","study":"Low-dose naltrexone for the treatment of fibromyalgia: protocol for a double-blind, randomized, placebo-controlled trial","doi":"10.1186/s13063-021-05776-7","url":"https://doi.org/10.1186/s13063-021-05776-7","support_kind":"cited_as_match","cited_as":"Bruun 2021","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","excerpt":"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."},{"source_id":"source_19","study":"Low-dose naltrexone for post-COVID fatigue syndrome: a study protocol for a double-blind, randomised trial in British Columbia","doi":"10.1136/bmjopen-2024-085272","url":"https://doi.org/10.1136/bmjopen-2024-085272","support_kind":"cited_as_match","cited_as":"Naik 2024","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","excerpt":"INTRODUCTION: A significant proportion of individuals suffering from post COVID-19 condition (PCC, also known as long COVID) can present with persistent, disabling fatigue similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-viral fatigue syndromes. There remains no clear pharmacological therapy for patients with this subtype of PCC, which can be referred to as post-COVID fatigue syndrome (PCFS). A low dose of the opioid antagonist naltrexone (ie, low-dose naltrexone (LDN)) has emerged as an off-label treatment for treating fatigue and other symptoms in PCC. However, only small, non-controlled studies have assessed LDN in PCC, so randomised trials are urgently required. METHODS AND ANALYSIS: A prospective, randomised, double-blind, parallel arm, placebo-controlled phase II trial will be performed to assess the efficacy of LDN for improving fatigue in PCFS. The trial will be decentralised and open to eligible individuals throughout the Canadian province of British Columbia (BC). Participants will be recruited through the province-wide Post-COVID-19 Interdisciplinary Clinical Care Network (PC-ICCN) and research volunteer platform (REACH BC)."}],"candidate_sources":[]},{"claim_id":"claim_30","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.","citation_support":[],"candidate_sources":[{"study":"Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial","year":2022,"doi":"10.1016/j.bjane.2022.08.003","url":"https://doi.org/10.1016/j.bjane.2022.08.003","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Paula 2022","excerpt":"INTRODUCTION: Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management. OBJECTIVE: The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia. METHODS: This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA).","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review","year":2023,"doi":"10.1093/pm/pnad074","url":"https://doi.org/10.1093/pm/pnad074","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Rupp 2023","excerpt":"BACKGROUND: At low doses, naltrexone (LDN) has been shown to modulate inflammation through the interruption of microglial cell activation within the central nervous system. One of the most likely contributors to centralized pain is changes in microglial cell processing. Therefore, it has been postulated that LDN can be used to manage patients with pain resulting from central sensitization due to this relationship. This scoping review aims to synthesize the relevant study data for LDN as a novel treatment strategy for various centralized pain conditions. METHODS: A comprehensive literature search was conducted in PubMed, Embase, and Google Scholar, guided by the Scale for Assessment of Narrative Review Articles (SANRA) criteria. RESULTS: Forty-seven studies related to centralized pain conditions were identified. Many of the studies were case reports/series and narrative reviews, but a few randomized control trials have been conducted. Overall, the body of evidence revealed improvement in patient-reported pain severity and in outcomes related to hyperalgesia, physical function, quality of life, and sleep.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone: What is the Evidence? A Narrative Review","year":2026,"doi":"10.1007/s12325-026-03612-5","url":"https://doi.org/10.1007/s12325-026-03612-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Gouda 2026","excerpt":"Naltrexone is prescribed off-label at low doses, typically 0.5-6.0 mg, for a variety of therapeutic indications. This review evaluates the clinical evidence for low-dose naltrexone (LDN). A literature search was conducted in February 2026 across PubMed, Embase and CINAHL for studies published from 1989 to 2026. Title and abstract searches for \"low dose naltrexone\" identified peer-reviewed English-language studies using doses of ≤ 12.5 mg in humans. A total of 105 studies were reviewed, including 15 randomised controlled trials (RCTs) in chronic pain, autoimmune and neuroimmune disorders, gastrointestinal disease, dermatological conditions, post-infectious syndromes, mental health and oncology. Across these fields, early positive findings from uncontrolled studies were rarely replicated in placebo-controlled trials. Most available evidence consists of case reports and small feasibility studies that are prone to publication bias and rely heavily on subjective outcomes. LDN is generally safe, inexpensive and well tolerated, with most studies using a daily dose of 4.5 mg. Although these features contribute to its appeal, current evidence does not support routine clinical use.","source_id":"source_3","support_kind":"candidate_source_row"},{"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","year":2023,"doi":"10.1016/j.heliyon.2023.e15638","url":"https://doi.org/10.1016/j.heliyon.2023.e15638","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Partridge 2023","excerpt":"BACKGROUND: Low dose naltrexone (LDN) is used off-label by many individuals with fibromyalgia to help manage their pain. There is no current systematic literature review summarising the evidence to support this use of LDN. The objectives of this study were to evaluate if patients with fibromyalgia prescribed LDN have reduced pain scores and greater quality of life compared with those allocated to placebo in randomized controlled trials. Secondly to determine if changes in inflammatory markers and brain structure and function are observed among patients with fibromyalgia taking LDN. METHODS: Systematic literature searches were conducted in MEDLINE , Embase Classic + Embase, APA PsychInfo, and The Cochrane Library from inception to May 2022. Reference lists from the selected papers were cross-checked with database search results. RESULTS: Three studies met our inclusion criteria for the assessment of efficacy, and two studies on potential LDN mechanisms. Results indicated some evidence to suggest LDN reduces pain and increases quality of life.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series","year":2023,"doi":"10.2147/JPR.S389957","url":"https://doi.org/10.2147/JPR.S389957","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"McKenzie-Brown 2023","excerpt":"PURPOSE: Low-dose naltrexone (LDN) has increased in popularity as a non-opioid medication that may decrease chronic pain symptoms. LDN is most commonly used to treat fibromyalgia, complex regional pain syndrome (CRPS), and painful diabetic neuropathy. Other studies suggest that LDN provides general symptom reduction in inflammatory conditions such as Crohn's disease and multiple sclerosis. We reviewed our experience with patients to whom we have prescribed LDN to see what types of painful conditions were most responsive to LDN in our patient population. PATIENTS AND METHODS: Charts from patients who came to the Pain Center between 2014 and 2021 were reviewed. RESULTS: Of the n = 137 patients who were prescribed LDN, 44% had no evidence of ever filling the prescription, and 4.4% of the responses were not charted. Of the remaining who took LDN (n = 70), 64% had some relief and were designated as 'Responders'. The most common pain diagnosis was neuropathic pain which, when added to the diagnosis of complex regional pain syndrome, accounted for 51% of responders to LDN.","source_id":"source_5","support_kind":"candidate_source_row"}]}]}