Low Dose Naltrexone (LDN) Summary

LDN is a promising treatment approach for chronic pain conditions thought to involve inflammatory processes. The clinical data supporting its use are very preliminary, and more research is needed before the treatment approach can be widely recommended. Critical parameters such as dosing still need to be refined. LDN may emerge as the first of many glial cell modulators that could be used to treat chronic conditions, with more specifically targeted medications developed in the future.


Naltrexone was synthesized in 1963 as an orally active competitive opioid receptor antagonist. Naltrexone is structurally and functionally similar to the opioid antagonist naloxone, but it has greater oral bioavailability and a longer biologic half-life. Naltrexone was approved by FDA in 1984 for the treatment of opioid addiction. The typical daily dosage for opioid addiction is 50 to 100mg per day.

LDN refers to daily dosages of naltrexone that are approximately 1/10th of the typical opioid addiction treatment dosage. In most published research, the daily dosage is 4.5mg, though the dosage can vary a few milligrams below or above that common value. At the low dosage level, naltrexone exhibits paradoxical properties, including analgesia and anti-inflammatory actions, which have not been reported at larger dosages. LDN was reported to have interesting physiological properties (primarily enhancement of endogenous opioid production) in the 1980s, and the treatment approach was reported to be used clinically since the mid-1980s.


LDN has been tested experimentally in a small number of chronic pain conditions. One such condition is fibromyalgia. Fibromyalgia is a chronic pain disorder that is characterized by diffuse musculoskeletal pain and sensitivity to mechanical stimulation as well as profound fatigue, cognitive disruption, and sleep difficulty. Although FM does not respond to common anti-inflammatories and does not seem to be an inflammatory disorder in the classic sense, inflammatory processes may still be involved.


Most clinicians are familiar with naltrexone as a potent and nonselective opioid receptor antagonist and treatment for opioid addiction. Naltrexone, at typical dosages, significantly blocks activity at mu- and delta-opioid receptors as well as (to a lesser extent) kappa-opioid receptors. Because beta-endorphin activity at mu-opioid receptors is associated with endogenous analgesic processes, it may seem counterintuitive to administer naltrexone to individuals with chronic pain, as we might expect the medication to reduce analgesia produced by beneficial endogenous opioid activity.

Naltrexone, however, exerts its effects on humans via at least two distinct receptor mechanisms. In addition to the antagonist effect on mu-opioid and other opioid receptors, naltrexone simultaneously has an antagonist effect on non-opioid receptors (Toll-like receptor 4 or TLR4) that are found on macrophages such as microglia. It is via the non-opioid antagonist path that LDN is thought to exert its anti-inflammatory effects. Microglia are central nervous system immune cells that are activated by a wide range of triggers. Once activated, microglia produce inflammatory and excitatory factors that can cause sickness behaviors such as pain sensitivity, fatigue, cognitive disruption, sleep disorders, mood disorders, and general malaise. When chronically activated, the resulting proinflammatory cascade may become neurotoxic, causing several deleterious effects. Conditions such as fibromyalgia may involve chronic glial cell activation and subsequent production of proinflammatory factors. The hypothesis is indirectly and partially supported by the high degree of symptomatic overlap between fibromyalgia and cytokine-induced sickness behaviours.

Both naloxone and naltrexone have been demonstrated to exert neuroprotective and analgesic effects. The neuroprotective action appears to result when microglia activation in the brain and spinal cord is inhibited. By suppressing microglia activation, naloxone reduces the production of reactive oxygen species and other potentially neuroexcitatory and neurotoxic chemicals. The anti-inflammatory effect of opioid antagonists may also extend to the periphery, as evidenced by suppressed TNF-alpha, IL-6, MCP-1, and other inflammatory agents in peripheral macrophages. It should be noted that most animal work has used naloxone, while most human work has used naltrexone (because of its higher oral availability).


The condition with the most scientific support for LDN efficacy is Crohn’s disease. Crohn’s disease is an inflammatory bowel disease that exerts gastrointestinal tract and systemic effects. LDN has been reported to reduce not only self reported pain in that condition but also objective markers of inflammation and disease severity (including the severity scores from endoscopic evaluation). The response rate of LDN in Crohn’s disease may be even higher than that seen in fibromyalgia, with over 80 % of the study participants exhibiting significant improvement.

Naltrexone has also shown some promise in improving disease severity in multiple sclerosis , aninflammatory, demyelinating condition of the central nervous system. The evidence of LDN efficacy is not as robust as in the previously mentioned conditions. There is some evidence of reduced spasticity and improved mental health, but many clinical endpoints fail to show difference from placebo, and one study did not find improvements in any of the clinical endpoints.


Chronic fatigue syndrome and myalgic encephalomyelitis are chronic multisystem disorders characterised by profound fatigue and post-exertional malaise with multiple other symptoms varying among individuals, including widespread pain, immune dysfunction and autonomic and neurocognitive symptoms. The annual incidence is around 15–26 per 100000 persons, with a prevalence between 0.2% and 0.4%, depending on the exact definition used and the country of study. Although no clinical trials have been carried out, anecdotal reports case studies suggest low-dose naltrexone may be helpful in at least some patients with chronic fatigue syndrome and myalgic encephalomyelitis.



While much data is consistent with that claim that LDN works via novel anti-inflammatory channels, there are alternative compelling explanatory models of the LDN mechanism. The most prevalent hypothesis, advanced by Dr. Ian Zagon and colleagues, states that inducing a small and transient opioid blockade will prompt the body to compensate by upregulating both endogenous opioids and opioid receptors. The opioid upregulation effect of temporary naltrexone or naloxone blockade has been demonstrated multiple times previously. This “opioid rebound” effect could have multiple impactson health and quality of life, including enhanced endogenous analgesia and repression of critical immune factors.


Successful treatment of chronic pain with naltrexone may require low dosages. Theoretically, a complete blockade of endogenous opioid systems would not be a desirable outcome with a chronic pain patient. Basic science evidence supports that concept by showing that low- and high-dose opioid antagonists have quite different impacts on the physiologic system.

It may initially seem strange that a medication can have an opposite effect when given at a low dosage. However, there is a strong precedent for this concept—and with opioid-related drugs in particular. A paradoxical hyperalgesic effect of low-dose morphine was first widely reported in 1987. Morphine was administered via the IV route to rats after arthritis was induced using Freund’s adjuvant. A dose of 100 μg/kg produced clear analgesia, 50 μg/kg produced less significant analgesia, and 30 μg/kg showed no difference from saline. At around 10 μg/kg, however, the researchers saw the development of morphine hyperalgesia, which became most pronounced at 6 μg/kg. This finding, which has been replicated several times suggests that there is a small window at which opioid analgesics produce the opposite effects than those typically expected. The dosage of morphine that appears to cause paradoxical hyperalgesia is approximately 1/10th of the dosage typically used to produce analgesia. We note that the dosage of naltrexone that is used to reduce pain is also approximately 1/10th of the dosage used for substance abuse treatment.


It is important to note that there are currently no guidelines for the clinical use of LDN. There is no FDAapproved use for naltrexone at any dosage for the treatment of chronic pain and inflammatory diseases. The typical dosage of LDN in published research is 4.5mg. The medication is commonly given approximately an hour before bedtime, though some individuals reporting insomnia as a side effect are moved to a morning dosing. Individuals with side effects also have their dosage reduced to 3.0 mg. Separation from placebo may not be observed until at least 1 month after initiating treatment, with 2 months generally needed to obtain an estimate of efficacy.


There are no reports of LDN interactions with other medications. However, the sample sizes in studies have been very small, and there are undoubtedly a large number of interactions that have not been tested. Pharmacologically, there is little to expect in the way of interactions, though synergistic effects with anti-inflammatories and disease modifying antirheumatic drugs should be investigated. Although no clinical trials have been carried out, anecdotal reports and  case studies suggest low-dose naltrexone may be helpful in at least some patients with chronic fatigue syndrome and myalgic encephalomyelitis.

An obvious exception is LDN co-administered with an opioid analgesic. The most important question about LDN is whether it can be given with opioid analgesics. It is possible that even a low dosage of naltrexone could cause a sufficient blockade of opioid receptors to reduce the effectiveness of opioid analgesics. While there are published human data regarding ultra low-dose naltrexone co-administered with opioid analgesics, we are not aware of the existence of co-administration studies using naltrexone in the LDN dosage range. Future studies may investigate the concomitant use of LDN and opioid analgesics—as it will likely be a commonly requested combination.


One of the most exciting aspects of LDN is the low reported incidence of adverse side effects. No cases of severe adverse events have been reported from laboratory studies. No withdrawal symptoms have been observed when LDN treatment is stopped, and withdrawal is not a known effect of treatment discontinuance.

Side effects of LDN treatment are mild. The most common side effect is the reporting of more vivid dreams, As a side effect, vivid dreams develop rapidly (as soon as the first dosing) and decrease over time. It is unclear what mechanism may drive increased vividness of dreams. Individuals generally self-report increased effectiveness of sleep, so it is unlikely that the vivid dreams represent an adverse disruption of normal sleep patterns. It is important to note that increased vividness of dreams is also the most commonly reported side effect during placebo administration, so some cases may be driven by expectancy.

While not observed in research studies, some physicians have anecdotally reported anxiety and tachycardia as adverse reactions to LDN. As anxiety is a known symptom of opioid withdrawal, it is possible that some individuals would experience anxiety due to blockade of endogenous opioids. Further observation will need to be carried out to determine how common this adverse event is and how to best manage it.


Even though naltrexone has a long history of safe use with a wide range of large dosages, we know very little about the long-term safety of the drug when used chronically in low dosages. The low dosage is often cited as a reason for clinicians and patients to not be concerned about safety. However, we must be open to the possibility that the unique clinical effects possible with the low dosage could also present new health risks. There are no reported serious concerns to date. While inhibition of immune system parameters could theoretically raise the risk of infections or cancer due to decreased immunosurveillance, there have been no reports of such a side effect at any dosage of naltrexone.

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