• However, it was discovered that its use in low doses follows alternate pharmacodynamic pathways with various effects. When used in doses of 1 to 5 mg it acts as a glial modulator with a neuroprotective effect via inhibition of microglial activation. It binds to Toll-like receptor 4 and acts as an antagonist, therefore inhibiting the downstream cellular signaling pathways that ultimately lead to pro-inflammatory cytokines, therefore reducing inflammatory response.


  • Its other mode of action involves transient opioid receptor blockade ensuing from low-dose use which upregulates opioid signaling resulting in increased levels of endogenous opioid production, known as opioid rebound effect


  • Low dose naltrexone has gained popularity as an off-label treatment of several autoimmune diseases including multiple sclerosis and inflammatory bowel disease, as well as chronic pain disorders including fibromyalgia, complex regional pain syndrome, and diabetic neuropathy. 


  • Low-dose naltrexone (LDN) may also have utility in improving mood disorders and the potential to enhance the quality of life. This article will therefore propose the potential off-label use of LDN in management of nonmalignant pain in the palliative medicine setting.



The following is taken from NaltrexLow website

What is NaltrexLow™ (LDN) Used For?

  •  * LDN is being used as an immune system modifier, providing relief to patients with autoimmune and inflammatory diseases, viral diseases and central nervous system disorders.

  •  ** It is also being used to treat pain disorders. Since 2002, over 80 leading universities have performed studies or published their experiences with using LDN for over 50 medical conditions that are caused by a dysregulated immune system; from multiple sclerosis, Crohn’s, rheumatoid arthritis, lupus, thyroid disorders, fibromyalgia, psoriasis, to cancer and HIV - NaltrexLow™ offers hope for a brighter future.

NaltrexLow™ Questions & Answers

1. How does NaltrexLow™ - LDN work?

  • Endorphins (feel-good molecules) are produced in most cells in the body and are important regulators of cell growth and the immune system. Disorders of the immune system can occur when endorphins are at unusually low levels.

  • Low dose naltrexone is a drug that binds to the body’s natural opiate ( endorphin) receptors for a short time. The body, feeling starved of natural endorphins (opiates), is now tricked to significantly increase its production of endorphins. Once the low-dose naltrexone stops blocking the opiate receptors (usually in 2- 3 hours), the body is then able to benefit from the hugely increased levels of endorphins circulating in the bloodstream. This is known as “the rebound effect”.

  • The benefits of the rebound effect can only be utilized by taking a low dose of regular naltrexone. Taking a high dose of naltrexone or using a slow-release formulation will continue to block the opioid receptors and no benefit can be achieved from the elevated endorphin levels.

  • Individuals vary in their metabolic speed and this will result in variations of the speed at which LDN is eliminated from the body, as well as the length of the rebound effect. A single daily dose of between 3 mg and 4.5 mg works well for most people, however some people benefit from building up their dose slowly or taking even two doses daily.

  • To watch a short video explaining how LDN works, click here.

2. How quickly does NaltrexLow™ - LDN work?

  • Some patients experience a very fast response to LDN; immediately or within days of taking it. In many cases, the response becomes evident after about two weeks of use. In some cases, especially those of long standing chronic conditions, it has taken up to two months for benefit to accrue. LDN doesn’t work for everyone, however it is a very safe drug - so it is reasonable to wait up to 2 - 3 months to assess the intensity of its effect.


3. When should I take NaltrexLow™ - LDN?

  • Although many people take LDN in the evening or before sleep, scientific studies have shown that it is equally effective if taken during the day. This is important for those people who sometimes experience sleep disturbances as result of LDN.

4. Which medications must be avoided when using NaltrexLow™ (LDN)?

  • LDN should not be combined with any opiate-based drugs, as LDN can cancel their effects. Many painkillers are opiate-based. Drugs such as Imodium® are also opiate-based and LDN may neutralize its effect.

5. What are the side effects of NaltrexLow™ (LDN)?

  • Side effects from LDN are unusual. Sleep disturbances sometimes happen during the first few days of use, if taken at night. This can be avoided by taking it earlier in the day. Vivid dreams are reported more frequently. Low dose naltrexone is considered safe and non-toxic.

6. Can I use NaltrexLow™ (LDN) while pregnant or breastfeeding?

  • The use of any medicinal product during pregnancy or breastfeeding should be discussed with your physician.


Modern applications of Naltrexone

  • Naltrexone has been used in 50 mg doses for decades to help patients recover from addiction to alcohol, heroin, and other opiate drugs. However, more than 20 years ago it was discovered that very small doses of this drug—3 to 4.5 mg—have profound effects on the immune system.

  • Is safe, inexpensive, yet underused drug that is extremely beneficial for patients with any condition marked by immune system dysfunction.

  • LDN works by reducing proinflammatory cytokines and interleukins.

  • LND boosts levels of endorphins, peptides produced in the brain and adrenal glands, that are best known for relieving pain and enhancing sense of well-being—they're responsible for the "runner's high" brought on by strenuous exercise. But these natural peptides are also powerful modulators of the immune system.

  • When LDN is taken at bedtime, it attaches to opioid receptors and temporarily blocks endorphins from attaching. This signals the body to increase production of endorphins, which helps orchestrate the activity of stem cells, macrophages, natural killer cells, T and B cells, and other immune cells. As a result, LDN enhances the body's ability to fight disease.


  • Although LDN is gaining increasing recognition as a highly effective therapy for conditions ranging from autoimmune disorders and allergies to cancer and autism, it is largely ignored by conventional physicians.


  • Patients with multiple sclerosis, rheumatoid arthritis, lupus, Crohn's disease and other autoimmune disorders have seen reductions in flare-ups and intensity of symptoms. Those suffering with fibromyalgia and chronic fatigue report more energy and less pain. Individuals dealing with various types of cancer receive an invaluable immune boost from LDN.


  • Children with autism have also been helped. Furthermore, because of its broad immune-enhancing properties, LDN is an excellent preventive therapy that boosts immune function in older individuals.

  • LDN is safe, effective, and inexpensive. The only problem most patients encounter is finding a physician who knows about it and is willing to prescribe it.

Clinical Research 

Med Hypotheses. 2020 Jan 2;137:109546. doi: 10.1016/j.mehy.2019.109546. [Epub ahead of print]

Low-Dose Naltrexone reduces symptoms in Stiff-Person Syndrome.

Zappaterra M1, Shouse E2, Levine RL3.

Author information


Stiff-Person Syndrome (SPS) is a rare neurologic disorder characterized by severe and progressively worsening muscle stiffness and rigidity. SPS can be very painful due to unpredictable muscle spasms which can be triggered by various stimuli, such as noise, touch, or emotional experiences. There is thought to be an autoimmune component to the disorder.

We present the case of a 59-year-old woman diagnosed with SPS who appears to have experienced a dramatic reduction in her symptoms after being treated with Low-Dose Naltrexone (LDN). Prior to this treatment regimen, she had tried many treatments with only limited derived benefit. She was started on LDN and after 6 weeks, reported reductions in pain, anxiety, depression, agoraphobia, and muscle tightness. Upon multiple follow-ups, leading up to 12 months, she continually displayed reduced symptoms and improved quality of life.

We conclude that LDN may have some utility in treating and managing the symptoms of SPS. We hypothesize that this may be possible due to LDN operating via anti-inflammatory pathways as well as acting as an opioid antagonist. We assert that further research as it relates to LDN and SPS in addition to other chronic pain conditions is warranted.

Cureus. 2019 Mar 11;11(3):e4225. doi: 10.7759/cureus.4225.

Sjogren's Syndrome: Clinical Benefits of Low-dose Naltrexone Therapy.

Zashin S1.

Author information


Sjogren's Syndrome is a chronic autoimmune disorder that causes the inflammation of the lacrimal and salivary glands, resulting in dryness of the eyes and mouth. In addition, fatigue and musculoskeletal pain, often described as aching, is very common. Treatment directed toward alleviating the fatigue and pain associated with Sjogren's is currently very limited. This report describes a case of a 47-year-old female with suspected Sjogren's based on long-standing dry eyes, dry mouth, joint pain, fatigue, elevated measures of inflammation, and a positive rheumatoid factor. She failed standard therapy but improved clinically with low-dose naltrexone therapy.

Am J Hosp Palliat Care. 2019 Oct;36(10):907-912. doi: 10.1177/1049909119838974. Epub 2019 Mar 27.

Pharmacology Update: Low-Dose Naltrexone as a Possible Nonopioid Modality for Some Chronic, Nonmalignant Pain Syndromes.

Trofimovitch D1, Baumrucker SJ2.

Author information


Pain can have a devastating effect on the quality of life of patients in palliative medicine. Thus far, majority of research has been centered on opioid-based pain management, with a limited empirical evidence for the use of nonopioid medications in palliative care. However, opioid and nonopioid medications such as nonsteroidal anti-inflammatory drugs have their limitations in the clinical use due to risk of adverse effects, therefore, there is a need for more research to be directed to finding an alternative approach to pain management in comfort care setting. The purpose of this article is to discuss a potential new drug that would adequately alleviate pain and enhance quality of life without significant risks of adverse effects that would limit its use. 

Naltrexone is a reversible competitive antagonist at μ-opioid and κ-opioid receptors, which when used at standard doses of 50 to 150 mg was initially intended for use in opioid and alcohol use disorders.

 * However, it was discovered that its use in low doses follows alternate pharmacodynamic pathways with various effects. When used in doses of 1 to 5 mg it acts as a glial modulator with a neuroprotective effect via inhibition of microglial activation. It binds to Toll-like receptor 4 and acts as an antagonist, therefore inhibiting the downstream cellular signaling pathways that ultimately lead to pro-inflammatory cytokines, therefore reducing inflammatory response.


Its other mode of action involves transient opioid receptor blockade ensuing from low-dose use which upregulates opioid signaling resulting in increased levels of endogenous opioid production, known as opioid rebound effect


 ** Low dose naltrexone has gained popularity as an off-label treatment of several autoimmune diseases including multiple sclerosis and inflammatory bowel disease, as well as chronic pain disorders including fibromyalgia, complex regional pain syndrome, and diabetic neuropathy. Low-dose naltrexone (LDN) may also have utility in improving mood disorders and the potential to enhance the quality of life. This article will therefore propose the potential off-label use of LDN in management of nonmalignant pain in the palliative medicine setting.

Med Sci (Basel). 2018 Dec; 6(4): 82.

Published online 2018 Sep 21. doi: 10.3390/medsci6040082

Full pdf: Low-Dose Naltrexone (LDN)—Review of Therapeutic Utilization


Int Immunopharmacol. 2019 Aug 9;75:105785. doi: 10.1016/j.intimp.2019.105785. [Epub ahead of print]

Interaction of opioid growth factor (OGF) and opioid antagonist and their significance in cancer therapy.

Wang R1, Zhang Y2, Shan F3.


Endogenous opioids are neuro-peptides with multifunctional properties. Historically, opioids are used to mediate pain; however, excess opiate consumption can lead to addiction. One endogenous opioid, methionine enkephalin (MENK), was reported to modulate cell growth, MENK was identified as an opioid growth factor (OGF) that interacts with the OGF receptor (OGFr) and regulates cell proliferation. Further, opioid antagonists, including naltrexone and naloxone are widely used to reverse drug and alcohol overdoses. Naltrexone (NTX) acts on all opioid receptors, blocking the interaction between OGF and OGFr, and thus influencing cell growth. During the last decades, insights have been made concerning the interaction between OGF and OGFr, confirming that both opioids and opioid antagonists have an important role in balancing host homeostasis, host immunity and mediating cancer therapy. This review provides insight into the interactions between OGF and OGFr in the treatment of cancers.

Sr Care Pharm. 2019 Jan 1;34(1):43-46. doi: 10.4140/TCP.n.2019.43.

The Use of Low-Dose Naltrexone for Chronic Pain.

Bostick KMMcCarter AGNykamp D.


The use of low-dose naltrexone for the treatment of chronic pain is novel because it is a nonopioid alternative. Oral naltrexone in a dosage range from 1 mg to 4.5 mg is referred to as low-dose naltrexone. Low-dose naltrexone use is "off label" and has been used successfully to manage chronic pain, autoimmune disorders, and dermatologic conditions. Low-dose naltrexone could be a viable treatment option for chronic pain because other agents for chronic pain, such as nonsteroidal agents, have adverse effects of gastrointestinal bleeding, renal injury, and increase a patient's risk of myocardial infarction or stroke. Additionally, low-dose naltrexone has minimal adverse effects, no drug-drug interactions, and is relatively inexpensive compared with other options for chronic pain.

Cureus. 2019 Jan 23;11(1):e3943. doi: 10.7759/cureus.3943.

Low-dose Naltrexone: An Alternative Treatment for Erythrodermic Psoriasis.

Beltran Monasterio EP1.

Author information


This clinical case demonstrates the benefits of patient treatment with low-dose naltrexone (LDN) used in erythrodermic psoriasis. A patient with a confirmed history of psoriasis by histopathology was treated with 4.5 mg of LDN during six months follow-up after an erythrodermic psoriasis flare-up. The patient showed significant improvement in her flare-up and psoriasis remission after only three months of 4.5 mg of LDN on a daily basis. Low-dose naltrexone (LDN) has proven to be a great ally in treating erythrodermic psoriasis flare-ups as an alternative treatment with less collateral side effects.

Dermatol Ther. 2019 Apr 8:e12892. doi: 10.1111/dth.12892. [Epub ahead of print]

Use of low-dose naltrexone in the treatment of severe Hailey-Hailey disease: One case report.

Garayar Cantero M1, Canseco Martín M1, Aguado García Á1, Manchado López P1.

Author information


Hailey-Hailey disease (HHD) or chronic benign familial pemphigus is an autosomal dominant genodermatosis with complete penetrance characterized by painful vesicles, erosions, and macerated intertriginous skin. We present a 66-year-old woman with a personal 35-year history of pruritic recurrent vesicles and erosions in both axillae and inguinal folds. HHD was confirmed by cutaneous biopsy. Past treatments had failed, including topical corticosteroids, antibiotics and oral doxycycline, minocycline, dapsone, and acitretin. Phototherapy and intralesional injection of toxin botulinum A was performed in the axillae. The patient was started on naltrexone 6.25 mg nightly. Six weeks later, complete clearing was observed. At typical doses, naltrexone blocks μ and δ opiod receptors, thereby blocking the union of β-endorphins at those sites. Paradoxically, at low doses, the partial binding to those receptors leads to a homeostatic increase of opioid receptors and an upregulation of endogenous opioids. Low-dose naltrexone (LDN) may also exert an anti-inflammatory action through its antagonist effect on toll-like receptor 4 found on macrophages. We consider that LDN is an effective and safe alternative for the HHD, representing an important progress in the management of this disease with limited therapeutic options.

Life Sci. 2019 May 1;224:232-240. doi: 10.1016/j.lfs.2019.03.069. Epub 2019 Mar 28.

Systemic administration of low-dose naltrexone increases bone mass due to blockade of opioid growth factor receptor signaling in mice osteoblasts.

Tanaka K1, Kondo H2, Hamamura K2, Togari A2.

Author information



Opioid receptor blockers such as naloxone and naltrexone have been suggested to have a bone mass-increasing effect. However, the mechanisms at play have not been clarified. We examined the effects of naltrexone on osteoblasts and determined the expression of opioid growth factor receptor (OGFR) in osteoblasts. Naltrexone blocks the OGFR and other canonical opioid receptors. Thus, we designed experiments to clarify the effects of naltrexone on bone tissue by examining the physiological role of OGFR signaling in osteoblasts and the changes in bone structure after naltrexone systemic administration in mice.


We used mouse osteoblast-like cell line MC3T3-E1 for in vitro experiments. We cultured MC3T3-E1 cells in the presence of the OGFR agonist met-enkephalin (met-enk). Then, we measured cell proliferation activity and analyzed the expression levels of cell proliferation-related genes. For our in vivo experiments, we administered naltrexone intraperitoneally to mice daily for 28 days and administered the animals in the control group equivalent volumes of saline. After sacrificing the mice, we performed micro-computed tomography and bone morphology analyses.


Met-enk suppressed cell proliferation in MC3T3-E1 cells. Moreover, Low dose naltrexone administration significantly increased their femoral bone mass, bone formation ratio, and osteoblast number/bone surface values when comparing the values for the same variables in the control group.


Our results suggest that naltrexone increases bone mass due to osteoblast number increments caused by the OGFR signaling block. Opioid receptor blockers have potential as therapeutic agents for osteoporosis as well as opioid antagonists.

Cureus. 2018 Jul 5;10(7):e2924. doi: 10.7759/cureus.2924.

Low Dose Naltrexone and Lung Cancer: A Case Report and Discussion.

Miskoff JA1, Chaudhri M1.

Author information


Low dose naltrexone (LDN) has been promising as a complementary medication for patients with a broad range of medical disorders. Although not a proven cure, evidence from clinical trials supports LDN as being a valuable adjunct for disorders in which the immune system plays a centralized role. Additionally, clinical trials have proposed a unique mechanism(s) allowing LDN to affect tumors including non-small cell lung cancer (NSCLC) at the cellular level by augmenting the immune system. We present a case of a 50-year-old male with a prolonged survival and a past medical history of prostate and lung cancer.

PLoS One. 2018 Oct 4;13(10):e0204830. doi: 10.1371/journal.pone.0204830. eCollection 2018.

The effect of naltrexone as a carboplatin chemotherapy-associated drug on the immune response, quality of life and survival of dogs with mammary carcinoma.

Machado MC1, da Costa-Neto JM1, Portela RD2, D'Assis MJMH1, Martins-Filho OA3, Barrouin-Melo SM1, Borges NF4, Silva FL5, Estrela-Lima A1.

Author information


The objective of this study was to evaluate the effect of low-dose naltrexone (LDN) as a carboplatin chemotherapy-associated drug in female dogs with mammary carcinoma in benign mixed tumors (MC-BMT) after mastectomy and to assess its association with quality of life and survival rates. Sixty female dogs were included in this study, all of which had histopathological diagnosis of MC-BMT and were divided into three groups: G1 (control), consisting of animals submitted only to mastectomy with or without regional metastasis; G2, composed of treated animals that did not present with metastasis; and G3, treated dogs that presented with metastasis. G2 and G3 were also subdivided according to the treatment administered: chemotherapy alone (MC-BMT(-) C/MC-BMT(+) C) or LDN and chemotherapy (MC-BMT(-) C+LDN/MC-BMT(+) C+LDN). All animals were subjected to clinical evaluation, mastectomy, peripheral blood lymphocyte immunophenotyping, beta-endorphin and met-enkephalin quantification, and evaluation of survival rates and quality of life scores. The results showed higher serum concentrations of beta-endorphin and met-enkephalin, fewer chemotherapy-related side effects, and better quality of life and survival rates in the LDN-treated groups than in LDN-untreated groups (P < 0.05). Evaluation of clinical and pathological parameters indicated a significant association between the use of LDN and both prolonged survival and enhanced quality of life. These results indicate that LDN is a viable chemotherapy-associated treatment in female dogs with MC-BMT, maintaining their quality of life and prolonging survival rates.

Biomedicines. 2017 Apr 18;5(2). pii: E16. doi: 10.3390/biomedicines5020016.

Reduced Pro-Inflammatory Cytokines after Eight Weeks of Low-Dose Naltrexone for Fibromyalgia.

Parkitny L1, Younger J2.

Author information


Fibromyalgia (FM) is a complex, multi-symptom condition that predominantly affects women. The majority of those affected are unlikely to gain significant symptomatic control from the few treatments that are approved for FM. In this 10-week, single-blind, crossover trial we tested the immune effects of eight weeks of oral administration of low-dose naltrexone (LDN). We enrolled eight women with an average age of 46 years, symptom severity of 62 out of 100, and symptom duration of 14 years. We found that LDN was associated with reduced plasma concentrations of interleukin (IL)-1β, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p40, IL-12p70, IL-15, IL-17A, IL-27, interferon (IFN)-α, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, and granulocyte-colony stimulating factor (G-CSF). We also found a 15% reduction of FM-associated pain and an 18% reduction in overall symptoms. The findings of this pilot trial suggest that LDN treatment in fibromyalgia is associated with a reduction of several key pro-inflammatory cytokines and symptoms. The potential role of LDN as an atypical anti-inflammatory medication should be explored further.

Genes Brain Behav. 2017 Apr;16(4):449-461. doi: 10.1111/gbb.12362. Epub 2017 Jan 17.

Hypothalamic-specific proopiomelanocortin deficiency reduces alcohol drinking in male and female mice.

Zhou Y1, Rubinstein M2, Low MJ3, Kreek MJ1.

Author information


Opioid receptor antagonist naltrexone reduces alcohol consumption and relapse in both humans and rodents. This study investigated whether hypothalamic proopiomelanocortin (POMC) neurons (producing beta-endorphin and melanocortins) play a role in alcohol drinking behaviors. Both male and female mice with targeted deletion of two neuronal Pomc enhancers nPE1 and nPE2 (nPE-/-), resulting in hypothalamic-specific POMC deficiency, were studied in short-access (4-h/day) drinking-in-the-dark (DID, alcohol in one bottle, intermittent access (IA, 24-h cycles of alcohol access every other day, alcohol vs. water in a two-bottle choice) and alcohol deprivation effect (ADE) models. Wild-type nPE+/+ exposed to 1-week DID rapidly established stable alcohol drinking behavior with more intake in females, whereas nPE-/- mice of both sexes had less intake and less preference. Although nPE-/- showed less saccharin intake and preference than nPE+/+, there was no genotype difference in sucrose intake or preference in the DID paradigm. After 3-week IA, nPE+/+ gradually escalated to high alcohol intake and preference, with more intake in females, whereas nPE-/- showed less escalation. Pharmacological blockade of mu-opioid receptors with naltrexone reduced intake in nPE+/+ in a dose-dependent manner, but had blunted effects in nPE-/- of both sexes. When alcohol was presented again after 1-week abstinence from IA, nPE+/+ of both sexes displayed significant increases in alcohol intake (ADE or relapse-like drinking), with more pronounced ADE in females, whereas nPE-/- did not show ADE in either sex. Our results suggest that neuronal POMC is involved in modulation of alcohol 'binge' drinking, escalation and 'relapse', probably via hypothalamic-mediated mechanisms, with sex differences.

Exp Biol Med (Maywood). 2017 Jan 1:1535370217724791. doi: 10.1177/1535370217724791. [Epub ahead of print]

Serum [Met5]-enkephalin levels are reduced in multiple sclerosis and restored by low-dosenaltrexone.

Ludwig MD1, Zagon IS1, McLaughlin PJ1.

Author information


Low-dose naltrexone is a widely used off-label therapeutic prescribed for a variety of immune-related disorders. The mechanism underlying low-dose naltrexone's efficacy for fatigue, Crohn's disease, fibromyalgia, and multiple sclerosis is, in part, intermittent blockade of opioid receptors followed by upregulation of endogenous opioids. Short, intermittent blockade by naltrexone specifically blocks the opioid growth factor receptor resulting in biofeedback events that increase production of the endogenous opioid growth factor (OGF) (chemically termed [Met5]-enkephalin) facilitating interactions between opioid growth factor and opioid growth factor receptor that ultimately, result in inhibited cell proliferation.

Preclinical studies have reported that enkephalin levels are deficient in animal models of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Our hypothesis is that serum enkephalin levels are diminished in humans with multiple sclerosis and experimental autoimmune encephalomyelitis mice, and that change in serum opioid growth factor levels may serve as a reasonable candidate biomarker for the onset of experimental autoimmune encephalomyelitis and response to therapy. To address this, we designed a two-part study to measure endogenous opioids in multiple sclerosis patients, and to investigate the temporal pattern of decline in serum enkephalin concentrations in mice with chronic progressive experimental autoimmune encephalomyelitis and treated with low-dosenaltrexone. For comparison, we investigated whether low-dose naltrexone exposure in normal mice also resulted in altered enkephalin levels. In both animal models, we monitored tactile and heat sensitivity, as well as differential white blood cell counts as indicators of inflammation.

Serum [Met5]-enkephalin levels were lower in humans with multiple sclerosis relative to non-multiple sclerosis patients, and low-dosenaltrexone restored their levels. In experimental autoimmune encephalomyelitis mice, [Met5]-enkephalin levels were depressed prior to the appearance of clinical disease, and were restored with low-dose naltrexone treatment. Low-dose naltrexone therapy had no effect on serum [Met5]-enkephalin or β-endorphin in normal mice. Thus, [Met5]-enkephalin (i.e. opioid growth factor) may be a reasonable candidate biomarker for multiple sclerosis, and may signal new pathways for treatment of autoimmune disorders. Impact statement This report presents human and animal data identifying a novel biomarker for the onset and progression of multiple sclerosis (MS). Humans diagnosed with MS have reduced serum levels of OGF (i.e. [Met5]-enkephalin) relative to non-MS neurologic patients, and low-dose naltrexone (LDN) therapy restored their enkephalin levels. Serum OGF levels were reduced in mice immunized with MOG35-55 prior to any clinical behavioral sign of experimental autoimmune encephalomyelitis, and LDN therapy restored their serum OGF levels. β-endorphin concentrations were not altered by LDN in humans or mice. Thus, blood levels of OGF may serve as a new, selective biomarker for the progression of MS, as well as response to therapy.

Mult Scler J Exp Transl Clin. 2016 Sep 29;2:2055217316672242. doi: 10.1177/2055217316672242. eCollection 2016 Jan-Dec.

Long-term treatment with low dose naltrexone maintains stable health in patients with multiple sclerosis.

Ludwig MD1, Turel AP2, Zagon IS1, McLaughlin PJ1.

Author information



A retrospective study was conducted on patients at Penn State Hershey Medical Center diagnosed with relapsing-remitting multiple sclerosis between 2006 and 2015.


Laboratory and clinical data collected over this 10-year period were reviewed. Two cohorts of patients were established based on their relapsing-remitting multiple sclerosis therapy at the time of their first visit to Penn State. One group of patients (n = 23) was initially prescribed low dose naltrexone at the time first seen at Hershey. This group was offered low dose naltrexone because of symptoms of fatigue or refusal to take an available disease-modifying therapy. The second group of patients (n = 31) was treated with the glatiramer acetate (Copaxone) and offered low dose naltrexone as an adjunct therapy to their disease-modifying therapy.


Patient data from visits after 1-50 months post-diagnosis were evaluated in a retrospective manner. Data obtained from patient charts included clinical laboratory values from standard blood tests, timed 25-foot walking trials, and changes in magnetic resonance imaging reports. Statistical analyses between the groups and for each patient over time indicated no significant differences in clinical laboratory values, timed walking, or changes in magnetic resonance imaging.


These data suggest that the apparently non-toxic, inexpensive, biotherapeutic is safe and if taken alone did not result in an exacerbation of disease symptoms.

Int J Oncol. 2016 Aug;49(2):793-802. doi: 10.3892/ijo.2016.3567. Epub 2016 Jun 7.

Naltrexone at low doses upregulates a unique gene expression not seen with normal doses: Implications for its use in cancer therapy.

Liu WM1, Scott KA1, Dennis JL1, Kaminska E1, Levett AJ1, Dalgleish AG1.

Author information


It has been reported that lower doses of the opioid antagonist naltrexone are able to reduce tumour growth by interfering with cell signalling as well as by modifying the immune system. We have evaluated the gene expression profile of a cancer cell line after treatment with low-dosenaltrexone (LDN), and assessed the effect that adapting treatment schedules with LDN may have on enhancing efficacy. LDN had a selective impact on genes involved with cell cycle regulation and immune modulation. Similarly, the pro-apoptotic genes BAD and BIK1 were increased only after LDN. Continuous treatment with LDN had little effect on growth in different cell lines; however, altering the treatment schedule to include a phase of culture in the absence of drug following an initial round of LDN treatment, resulted in enhanced cell killing.

Furthermore, cells pre-treated with LDN were more sensitive to the cytotoxic effects of a number of common chemotherapy agents. For example, priming HCT116 with LDN before treatment with oxaliplatin significantly increased cell killing to 49±7.0 vs. 14±2.4% in cultures where priming was not used. Interestingly, priming with NTX before oxaliplatin resulted in just 32±1.8% cell killing. Our data support further the idea that LDN possesses anticancer activity, which can be improved by modifying the treatment schedule.

Neuropeptides. 2016 Oct;59:39-45. doi: 10.1016/j.npep.2016.06.003. Epub 2016 Jun 22.

Evaluation of therapeutic effect of low dose naltrexone in experimentally-induced Crohn's disease in rats.

Tawfik DI1, Osman AS2, Tolba HM3, Khattab A3, Abdel-Salam LO4, Kamel MM5.

Author information



Crohn's disease is a relapsing inflammatory condition afflicting the digestive tract. Drugs used for treatment of Crohn's disease may be associated with serious side effects. Endogenous opioid peptides modulate inflammatory cytokine production. Opioid antagonists have been shown to play a role in healing and repair of tissues. This work was designed to detect the possible beneficial effects of opioid antagonist naltrexone in indomethacin-induced Crohn's disease in rats.


Enteritis was induced in male albino rats by two subcutaneous injection of indomethacin in a dose of 7.5mg/kg 24h apart started on day one. Salfasalazine, naltrexone and their combination were administered orally from day one of induction of enteritis to day 10. Disease activity index, serum levels of C-reactive protein and tumor necrosis factor-α, macroscopic and microscopic pathological scores and in vitro motility studies were evaluated.


Induction of enteritis resulted in significant increase of disease activity index, significant elevation of serum levels of C-reactive protein and tumor necrosis factor-α, significant deterioration of pathological scores and significant increase in the mean contractility response of the isolated ileal segments compared with normal untreated rats. Treatment with sulfasalazine, low dose of natrexone or their combination resulted in significant improvement of all measured parameters compared with enteritis group.


The current finding could provide new interesting opportunity for developing new therapeutic approaches for treatment of Crohn's disease. Use of naltrexone, especially in small dose, has little side effects making it of interest for treatment of Crohn's disease. Also, it provides the possibility of reduced doses of other drugs if it is used as combined therapy.

Pain. 2010 Sep;11(9):847-53. Epub 2010 Apr 24.

Hyperbaric oxygen treatment induces a 2-phase antinociceptive response of unusually long duration in mice

Chung E, Zelinski LM, Ohgami Y, Shirachi DY, Quock RM.

Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Pullman, Washington, USA.

Hyperbaric oxygen (HBO(2)) therapy is approved by the FDA for limited clinical indications but is reported to produce pain relief in several chronic pain conditions. However, there have been no studies to explain this apparent analgesic effect of HBO(2). Research conducted in our laboratory demonstrates that 4 daily 60-minute HBO(2) treatments at 3.5 absolute atmospheres induced an unparalleled antinociceptive response that consists of 1) an early phase that lasted at least 6 hours after the HBO(2) treatment before dissipating; and 2) a late phase that emerged about 18 hours after the early phase and lasted for up to 3 weeks. The early phase was sensitive to antagonism by acutely intracerebroventricular (i.c.v.)-administered opioid antagonist naltrexone and the nitric oxide synthase (NOS)-inhibitor L-NAME. The late phase was inhibited by treatment with i.c.v. naltrexone or L-NAME during the 4 daily HBO(2) treatments but was not antagonized by either naltrexone or L-NAME following acute pretreatment 2 weeks after HBO(2) treatment. These experimental results implicate a novel mechanism that is activated by HBO(2), resulting in an antinociceptive response of unusually long duration that is of potential interest in the clinical management of pain.

PERSPECTIVE: Hyperbaric oxygen treatment of mice can induce a 2-phase antinociceptive response of unusually long duration. Nitric oxide and opioid receptors appear to initiate or mediate both phases of the antinociceptive response. Further elucidation of the underlying mechanism may potentially identify molecular targets that cause long-lasting activation of endogenous analgesic systems.

Copyright 2010 American Pain Society. Published by Elsevier Inc. All rights reserved.


J Pain. 2009 Feb;10(2):167-72. Epub 2008 Oct 31.

A prolonged nitric oxide-dependent, opioid-mediated antinociceptive effect of hyperbaric oxygen in mice

Zelinski LM, Ohgami Y, Chung E, Shirachi DY, Quock RM.

Department of Pharmaceutical Sciences, College of Pharmacy, Pullman, Washington, USA.


Hyperbaric oxygen (HBO(2)) therapy is reported to cause pain relief in several conditions of chronic pain. A single 60-minute session of HBO(2) treatment produced a prolonged antinociceptive effect in mice that persisted for 90 minutes after cessation of treatment. The HBO(2)-induced antinociception was significantly attenuated by pretreatment before HBO(2) exposure with the opioid antagonist naltrexone, the nonspecific nitric oxide synthase (NOS)-inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME), and the selective neuronal NOS-inhibitor S-methyl-L-thiocitrulline (SMTC) but not the selective endothelial NOS-inhibitor N(5)-(1-iminoethyl)-L-ornithine (L-NIO). The antinociception was also significantly reduced by central pretreatment with a rabbit antiserum against dynorphin(1-13) but not by rabbit antisera against either beta-endorphin or methionine-enkephalin. The prolonged antinociceptive effect at 90 minutes after HBO(2)-induced treatment was also significantly attenuated by naltrexone but not L-NAME administered 60 minutes after HBO(2) treatment but before nociceptive testing. These findings indicate that the antinociception that persists for 90 minutes after HBO(2) exposure is mediated by nitric oxide (NO) and opioid mechanisms but that the NO involvement is critical during the HBO(2) treatment and not at the time of nociceptive testing. These results are consistent with the concept that HBO(2) may induce an NO-dependent release of opioid peptide to cause a long-acting antinociceptive effect. PERSPECTIVE: This article presents evidence of a persistent antinociceptive effect of hyperbaric oxygen treatment that is mediated by opioid and NO mechanisms. Further elucidation of the underlying mechanism could identify molecular targets to cause a longer-acting activation of endogenous pain-modulating systems.