Therapeutic Uses and Efficacy of Low-Dose Naltrexone: A Scoping Review

Abstract

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. Search results yielded 2,399 articles; 995 did not meet inclusion criteria, 1,166 were excluded after screening by title, and 142 were excluded after screening by abstract. Ultimately, 68 articles were included after a full-text review. The articles selected presented clinical examples of LDN efficacy for a variety of medical conditions. These articles also helped to illuminate the current gaps in research, pointing to the need for larger clinical trials and proper dosing studies.

Introduction and background

Alternative treatments to opioids are of increasing importance and relevance for managing chronic pain [1]. Despite over 50 million Americans experiencing chronic pain each year, there are still minimal efficacious, inexpensive, and non-addictive treatment options [2]. Naltrexone, a mu-opioid receptor antagonist, is an FDA-approved medication primarily used at a 50 mg dose for the treatment of opioid and alcohol use disorder. In recent years, interest has grown in low-dose naltrexone (LDN), typically administered at 1 mg to 6 mg, for its potential anti-inflammatory and analgesic effects beyond its established role in addiction treatment. Research suggests that LDN may act as a glial cell modulator by antagonizing toll-like receptor 4, leading to anti-inflammatory and immunomodulatory effects [3]. Naltrexone at low doses, known as LDN, is becoming increasingly used and studied for its efficacy against various pain-related or painful conditions, certain cancers, and immune dysregulation disorders. Low-dose naltrexone is also inexpensive and is generally well tolerated with minimal side effects [3].

The efficacy of LDN has been most commonly reported in preclinical and clinical studies examining the treatment of fibromyalgia, multiple sclerosis, complex regional pain syndrome (CRPS), various gastrointestinal conditions (including Crohn’s disease), dermatological conditions (such as Hailey-Hailey disease), and certain cancers [4]. However, studies continue to emerge that analyze the effect of LDN against a variety of conditions, even extending beyond chronic painful and autoimmune conditions. The clinical use of LDN remains off-label, with no standardized, regulatory-approved treatment protocols.

This scoping review sought to establish a basis of the current knowledge of LDN based on current studies available and identify the gaps in current research. This review focused on the studies completed in the last 15 years and specifically focused on which medical conditions have been studied against LDN and what the efficacy was amongst these various conditions.

Review

Methods

The protocol used for this review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) Checklist [5]. Inclusion criteria required the article to be original research, published in English, conducted on human subjects, published in the last 15 years, had full text available, and included treatment with LDN in an off-label capacity (i.e. not for the treatment of alcohol or opioid use disorder). PubMed and Excerpta Medica database (Embase) were used to select the articles. The search terms and automation tools are summarized in Table 1.

The initial search resulted in 797 PubMed results and 1,602 Embase results. Zotero (Corporation for Digital Scholarship, Vienna, VA) was used to manage all article results, and any duplicates between the databases were removed from the initial search. Following the removal of duplicates with Zotero as well as the use of automation tools for initial screening, 1,404 articles were included for further screening. These articles were then screened by title, eliminating articles that did not align with the subject matter of this scope, which yielded 238 results. The articles were then screened by abstract, further eliminating studies that did not observe LDN efficacy or treatment, which yielded 96 articles. These 96 articles were given a full-text review and assessed for eligibility. Following a full-text review, 68 articles were included in the final selection. The selection process resulting in the final 68 articles is summarized in Figure 1. Additionally, the 68 final articles are summarized in Table 2, which emphasizes the purpose of the research study, the LDN protocol used, and the conclusion gathered from the study.

Results

The final articles selected, 68 in total, ranged greatly in terms of the medical condition(s) studied. To summarize, the included medical conditions and number of studies are listed in Table 3.

In the conclusions column of Table 2, 62 studies reported at least some degree of efficacy in at least one or more participants when using LDN as treatment. What was an indication of treatment effectiveness varied with the type of medical condition being observed, with some studies reporting treatment efficacy as a decrease in overall pain and other studies considering treatment efficacy as an improvement in symptoms specific to the studied medical condition. Treatment efficacy ranged from mild symptom or pain relief to complete symptom clearance or disease remission. For example, Bolton et al. reported that treatment with LDN showed a range of responses, from life-changing to a reduction in some symptoms [10]. The type of study also varied amongst the 68 studies. Thirty-two of the 68 studies were case reports or case series that focused on small populations of patients treated with LDN in a clinical setting. Due to their limited sample sizes, these studies provided restricted data, which influenced the scope of conclusions that could be drawn regarding LDN’s overall effectiveness but still contributed valuable insights to the broader body of research. With the exclusion of case reports and series, the remaining 36 studies included randomized trials, as well as prospective, retrospective, observational, and pilot studies. These 36 studies included larger populations and were able to provide more overall data regarding treatment with LDN. Vrooman et al. [67] looked at a large set of clinical data following LDN treatment for a variety of medical conditions. The results of this study were similar to those of numerous other studies; however, this study was able to extrapolate from a larger data set. This study reported substantial benefits in terms of pain reduction, improved cognitive function, and, occasionally, primary condition regression amongst several conditions following LDN treatment. Similarly, Driver et al. [20] observed LDN treatment against several conditions and reported that 65% of patients perceived benefit in terms of their pain symptoms in addition to other symptoms (e.g., fatigue, brain fog, sleep). Many of the articles reported similar conclusions following treatment with LDN. As apparent in the LDN protocol portion of Table 2, the majority of studies reported LDN usage between 1 to 6 mg, with 4.5 mg being the most commonly utilized dosage across all studies.

Of the 68 articles selected, six articles reported LDN as an ineffective treatment against the medical condition being studied. Beaudette-Zlatanova et al. studied both osteoarthritis and inflammatory arthritis, and the study concluded that there were too few patients enrolled to rule out modest benefits or to assess inflammatory or neuropathic pain [7]. Bested et al. looked at LDN efficacy against fibromyalgia and concluded that LDN had no clinically relevant analgesic efficacy [9]. Due Bruun et al. also studied LDN against fibromyalgia and concluded that LDN was not superior to placebo treatment but might improve memory impairment associated with fibromyalgia [21]. Idrisoglu et al. looked at LDN treatment for amyotrophic lateral sclerosis and found that while safe, LDN was ineffective when combined with riluzole [25]. Peter et al. studied high-grade glioma patients, reporting that LDN did not significantly impact QOL or fatigue but indicated a subset of patients with high levels of baseline fatigue had some benefit [46]. Raknes and Småbrekke investigated multiple sclerosis and aimed to determine whether prescribing LDN led to a reduction in the dispensing of other multiple sclerosis medications. They concluded that there was no change in non-LDN multiple sclerosis treatments prescribed [50]. With the exception of these six studies, the remaining 62 studies reported LDN to have some degree of efficacy against the studied disease state, reporting effects ranging from mild symptom relief to total disease remission. Of the studies reporting treatment efficacy, authors reported efficacy against fibromyalgia [12, 20, 27, 37, 45, 56, 70, 71], multiple sclerosis [15, 17, 27, 32, 55], and rheumatoid arthritis [51], contrasting with some of the previously mentioned studies that did not find LDN efficacious against these disease states. No other studies included in this review reported on amyotrophic lateral sclerosis, high-grade glioma, or osteoarthritis.

Discussion

While the majority of the studies in this review reported treatment efficacy with LDN, the results varied significantly across the studies. Some studies reported complete disease remission, while others only noted mild symptom relief in a small percentage of participants. One explanation for the variability in treatment efficacy across various studies may be due to LDN dosage and protocol. The most common dosage amount across all studies was 4.5 mg of naltrexone taken once per day; however, there was some variation in effective dosages, with the majority ranging between 1 mg to 6 mg. Some studies used titration, gradually increasing the dosage until reaching 4.5 mg or an alternate effective dosage amount [6, 15, 31, 34]. For example, Marcus et al. utilized titration, starting at 0.1 mg LDN per day with increases by 0.1 mg on every third day with a 6 mg maximum [34]. Contrastingly, several other studies started their patients on a 4.5 mg dosage without initial titration [13, 16, 26, 28]. Observing the studies reporting ineffective treatment with LDN, none reported the use of titration when describing their dosage protocol [7, 9, 21, 25, 46, 50]. Marcus et al. reported a significant variation in effective doses amongst its participants [34]. This study also reported that multiple patients were able to achieve an effective dose on a titration schedule, even after prior unsuccessful attempts with fixed or variable doses of LDN. Further studies may be needed to determine proper dosing strategies, which was echoed by several authors. Additionally, previous studies ruling out LDN as an effective treatment for certain disease states might warrant reevaluation if titration was not utilized.

While most studies kept the dosage of naltrexone between 1 mg to 6 mg, some studies utilized higher dosages, which were both well-tolerated and effective [10, 20, 42, 44, 58]. Patel et al. reported treatment success with the usage of naltrexone between 12.5 and 50 mg without adverse effects [44]. This study concluded that the most utilized dosage of 4.5 mg naltrexone previously put forth by other publications may not be sufficient. While this article focused on higher dosages used for the treatment of Hailey-Hailey disease, further studies may be needed to explore the potential usage of naltrexone at slightly higher dosages than what was studied in the past. The information presented by several articles indicates that proper dosing studies need to be performed to investigate the true therapeutic range of LDN [27, 34].

Most studies described LDN as well-tolerated with minor adverse effects. The most commonly seen adverse effects noted across studies appeared to be vivid dreams, insomnia, nausea, and headache [19, 42, 48, 64, 70]. These side effects typically could be described as minor or transient [70] and were described as relatively rare and usually tolerable amongst the reported cases. These side effects do not appear to be a deterrent or concern for future utilization of LDN.

While the data presented across 62 of the 68 studies indicated some degree of treatment efficacy with LDN, it is worth noting apparent trends amongst the studies and which studies provided novel information about LDN. Amongst these articles, many focused on dermatological conditions. This included Hailey-Hailey disorder, Darier disease, alopecia and lichen planopilaris, psoriasis, and prurigo/acne excoriée. In these studies, LDN resulted in clearance of the lesions, vesicles, or erythema [6, 23]. Another feature among some dermatological-based studies was decreased pruritis [23, 65]. Similarly, pruritic symptoms were treated effectively in two non-dermatological studies, one related to pruritis in amyopathic dermatomyositis [33], and one related to pruritis in systemic sclerosis [22]. Other major areas of focus included gastrointestinal disorders. This included studies looking at mesenteric panniculitis and inflammatory bowel disease (both Crohn’s and ulcerative colitis). Successful treatment with LDN presented as decreased stools and abdominal pain [13] or total disease remission [30].

Another area of focus that a few studies explored was psychiatric illness. This included major depressive disorder (MDD) and excoriation disease. The effect of LDN on MDD was some benefit for MDD relapse on dopaminergic agents [39]. In excoriation disorder, LDN resulted in decreased compulsion [66]. Other studies cited comorbid depression improving when using LDN to treat other conditions. Ibrahim et al. reported concurrent improvement in depression while treating Hailey-Hailey disorder with LDN [24]. Other studies using LDN for fibromyalgia found improvement in comorbid depression [45,56].

Two studies reviewed LDN efficacy against chronic fatigue syndrome, reporting a majority of study participants had a positive treatment response with improved alertness and cognitive function [10,48]. Post-acute sequelae COVID-19 shares similar symptoms with chronic fatigue syndrome. Newer studies and ongoing trials for LDN are focusing specifically on post-acute sequelae of COVID-19 due to its high prevalence, which is seen globally in 43% of individuals who have previously had acute COVID-19 [11]. 3 studies were included in this review that looked at post-acute sequelae of COVID-19. These studies reported decreased fatigue, normalized sleep patterns, and a better functional status when treating post-acute sequelae COVID-19 with LDN [11,26,43]. All three studies looking at post-acute sequelae of COVID-19 concluded that further studies with larger, randomized, and controlled trials are warranted to further explore LDN efficacy and could possibly investigate which subpopulations may benefit from treatment.

The remaining studies focused mostly on chronic pain disorders and autoimmune conditions. These articles highlighted successful clinical uses for these conditions. This included fibromyalgia, multiple sclerosis, chronic pain syndrome, chronic regional pain syndrome, stiff-person syndrome, Sjogren’s syndrome, neuropathic pain, burning mouth syndrome, and rheumatoid and seropositive arthritis. Several of these articles mentioned successful LDN treatment that resulted in the discontinuation of other medications; this even included opioids in some instances [49, 51, 52]. Isman et al. focused on fibromyalgia, multiple sclerosis, and chronic pain syndrome and encouraged future studies to continue to investigate LDN as an off-label, non-opioid analgesic for pain, anti-inflammation, and disease modification [27]. These data help contribute to the current knowledge of LDN usage for treating chronic pain disorders and autoimmune disorders. These studies also provide compelling evidence that might prompt further research and clinical usage of LDN and contribute to the mounting amounts of evidence for these conditions. Additionally, many clinical trials are ongoing and may provide some more insight into LDN upon publication. Notably, ongoing clinical trials, such as LDN for pain management in HIV patients (NCT05537935)[74], LDN for post-COVID fatigue (NCT05430152) [75], LDN for diabetic neuropathy (NCT04678895) [76], and LDN for vasculitis (NCT03482479) [77], are investigating LDN’s efficacy across various conditions, providing valuable data to further refine its therapeutic potential.

This scoping review is limited in that it was only reviewed on PubMed and Embase. This review may have also excluded relevant research when reviewing articles by title and abstract only. This review also may have excluded relevant data by limiting the database search to the last 15 years. Scoping reviews typically do not conduct a formal risk of bias assessment. However, it is still important to acknowledge potential limitations and biases within the included studies. Many studies, particularly case reports and small-scale trials, had limited sample sizes, restricting the generalizability of their findings. Additionally, some studies lacked control groups, increasing the risk of confounding variables influencing the results. The potential for publication bias is also present, as studies reporting positive outcomes may have been more likely to be published than those reporting null or negative results. Among the randomized trials, variations in study design, follow-up duration, and outcome measures further contributed to inconsistencies in reported efficacy. The lack of standardized dosing protocols across studies introduces another element of bias, potentially affecting the comparability of findings.

Conclusions

These articles provide a compelling argument for future clinical usage and observation of LDN while also helping to establish areas where there is still room for further research and understanding. The wide range of medical conditions studied across all articles indicates both the multidisciplinary interest in and relevance of LDN. This also indicates that there may be room for further research on LDN efficacy against several medical conditions that have yet to be explored. The majority of articles presented real clinical evidence of successful LDN treatment against the studied medical conditions. While these articles provided compelling clinical examples, large, randomized, and controlled clinical trials are still lacking in the current literature on LDN. Ongoing clinical trials may provide more insight into LDN upon publication. Due to the absence of standardized treatment guidelines for LDN, these articles present a variety of dosage protocols. While further studies would be needed to determine proper dosing strategies, including dosage amount, frequencies, and duration, these articles provide examples of efficacious dosages of LDN that may aid in the assigning of protocols for future LDN use. Low-dose naltrexone was reported to be efficacious in many studies and generally well-tolerated, though some adverse effects were noted. Low-dose naltrexone could be a safe and cost-effective treatment option for a variety of medical conditions, even extending beyond chronic pain conditions or inflammatory conditions, as these articles highlighted.