Low-dose naltrexone for disease prevention and quality of life

Summary

The use of low-dose naltrexone (LDN) for the treatment and prophylaxis of various bodily disorders is discussed. Accumulating evidence suggests that LDN can promote health supporting immune-modulation which may reduce various oncogenic and inflammatory autoimmune processes. Since LDN can upregulate endogenous opioid activity, it may also have a role in promoting stress resilience, exercise, social bonding,and emotional well-being, as well as amelioration of psychiatric problems such as autism and depression. It is proposed that LDN can be used effectively as a buffer for a large variety of bodily and mental ailments through its ability to beneficially modulate both the immune system and the brain neurochemistries that regulate positive affect.

Introduction

Preventive medicine has excelled in reducing the risk factors of high cholesterol with various statins, and accruing cardiac damage with baby aspirin blood thinners. There is considerable controversy about general health sustaining effects of adequate vitamins, minerals, herbals and specific purified nutritionals, but there is relatively little medical research on discrete biochemical supplements to facilitate general health and well-being. In this essay we introduce low-dose naltrexone (LDN) as a potential way to strengthen brain and bodily resources to facilitate emotional homeostas is and also provide background prophylaxis against and potential treatment of various cancers and auto immune disorders–-an idea that has already been extensively discussed on the web (e.g., www.Lowdosenaltrexone.org).

Naltrexone, an orally effective, long-lasting opiate receptor antagonist, was approved by the FDA for treating alcohol and opiate addiction in 1984, but its general patent expired the following year. It is a non-selective antagonist, with robust effects on pleaure promoting mu opioid receptors (MOR) and delta opioid receptors (DOR) <1>, with less antagonism of aversion-mediating kappa opioid receptors (KOR) <2> but substantial effect on the more recently discover edorphanin FQ or nociceptin opioid family <3>. The benefits of high dose naltrexone in narcotic addiction are explained by blockade of all pleasure producing effects of opioids, and similar mechanisms may explain the ability of naltrexone to reduce binging on alcohol.

Here we will consider the potential benefits of low-dose nalrexone (LDN) as a way to strengthen both brain and bodily resources to promote psychological well-being as well as bodily health, especially along the dimension of reduced likelihood of cancers and autoimmune problems. Intermediate levels of LDN (at 0.25mg/kg given every other day) were initially found to have some benefits in the treatment of a subset of autistic children <4,5>. One of the clinical impressions was an increased social initiative and cheerfulness, especially on the non-medication days, as if a rebound effect of positive social chemistries (e.g.,opioids) was occurring. There is now increasing data that would suggest that a temporary blockade of opioid receptors with LDN may lead to an upregulation of mood enhancing endogenous opioids, and hence perhaps dopamine activity, which may further promote positive frames of mind. As importantly, endogenous opioids have robust immune modulatory properties, which may be harnessed through LDN to facilitate body resources to retard and combat oncogenic and autoimmune processes and reduce the impact of allostatic load on the body.

Mult Scler. 2008 Sep;14(8):1076-83.

A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis.

Gironi M, Martinelli-Boneschi F, Sacerdote P, Solaro C, Zaffaroni M, Cavarretta R, Moiola L, Bucello S, Radaelli M, Pilato V, Rodegher M, Cursi M, Franchi S, Martinelli V, Nemni R, Comi G, Martino G.

Institute of Experimental Neurology (INSPE) and Department of Neurology, San Raffaele Scientific Institute, Via Olgettina 58, Milan, Italy.

Abstract

A sixth month phase II multicenter-pilot trial with a low dose of the opiate antagonist Naltrexone (LDN) has been carried out in 40 patients with primary progressive multiple sclerosis (PPMS). The primary end points were safety and tolerability. Secondary outcomes were efficacy on spasticity, pain, fatigue, depression, and quality of life. Clinical and biochemical evaluations were serially performed. Protein concentration of beta-endorphins (BE) and mRNA levels and allelic variants of the mu-opiod receptor gene (OPRM1) were analyzed. Five dropouts and two major adverse events occurred. The remaining adverse events did not interfere with daily living. Neurological disability progressed in only one patient. A significant reduction of spasticity was measured at the end of the trial. BE concentration increased during the trial, but no association was found between OPRM1 variants and improvement of spasticity. Our data clearly indicate that LDN is safe and well tolerated in patients with PPMS.

Pain Med. 2009 May-Jun;10(4):663-72. Epub 2009 Apr 22.

Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study.

Younger J, Mackey S.

School of Medicine, Department of Anesthesia, Division of Pain Management, Stanford University, 780 Welch Road, Suite 208, Palo Alto, CA 94304-1573, USA. jarred.younger@stanford.edu

Abstract

OBJECTIVE: Fibromyalgia is a chronic pain disorder that is characterized by diffuse musculoskeletal pain and sensitivity to mechanical stimulation. In this pilot clinical trial, we tested the effectiveness of low-dose naltrexone in treating the symptoms of fibromyalgia. DESIGN: Participants completed a single-blind, crossover trial with the following time line: baseline (2 weeks), placebo (2 weeks), drug (8 weeks), and washout (2 weeks). PATIENTS: Ten women meeting criteria for fibromyalgia and not taking an opioid medication. INTERVENTIONS: Naltrexone, in addition to antagonizing opioid receptors on neurons, also inhibits microglia activity in the central nervous system. At low doses (4.5 mg), naltrexone may inhibit the activity of microglia and reverse central and peripheral inflammation. OUTCOME MEASURES: Participants completed reports of symptom severity everyday, using a handheld computer. In addition, participants visited the lab every 2 weeks for tests of mechanical, heat, and cold pain sensitivity. RESULTS: Low-dose naltrexone reduced fibromyalgia symptoms in the entire cohort, with a greater than 30% reduction of symptoms over placebo. In addition, laboratory visits showed that mechanical and heat pain thresholds were improved by the drug. Side effects (including insomnia and vivid dreams) were rare, and described as minor and transient. Baseline erythrocyte sedimentation rate predicted over 80% of the variance in drug response. Individuals with higher sedimentation rates (indicating general inflammatory processes) had the greatest reduction of symptoms in response to low-dose naltrexone. CONCLUSIONS: We conclude that low-dose naltrexone may be an effective, highly tolerable, and inexpensive treatment for fibromyalgia.

Integr Cancer Ther. 2009 Dec;8(4):416-22.

Revisiting the ALA/N (alpha-lipoic acid/low-dose naltrexone) protocol for people with metastatic and nonmetastatic pancreatic cancer: a report of 3 new cases.

Berkson BM, Rubin DM, Berkson AJ.

The Integrative Medical Center of New Mexico, Las Cruces, NM, USA.

Abstract

The authors, in a previous article, described the long-term survival of a man with pancreatic cancer and metastases to the liver, treated with intravenous alpha-lipoic acid and oral low-dose naltrexone (ALA/N) without any adverse effects. He is alive and well 78 months after initial presentation. Three additional pancreatic cancer case studies are presented in this article. At the time of this writing, the first patient, GB, is alive and well 39 months after presenting with adenocarcinoma of the pancreas with metastases to the liver. The second patient, JK, who presented to the clinic with the same diagnosis was treated with the ALA/N protocol and after 5 months of therapy, PET scan demonstrated no evidence of disease. The third patient, RC, in addition to his pancreatic cancer with liver and retroperitoneal metastases, has a history of B-cell lymphoma and prostate adenocarcinoma. After 4 months of the ALA/N protocol his PET scan demonstrated no signs of cancer. In this article, the authors discuss the poly activity of ALA: as an agent that reduces oxidative stress, its ability to stabilize NF(k)B, its ability to stimulate pro-oxidant apoptosic activity, and its discriminative ability to discourage the proliferation of malignant cells. In addition, the ability of lowdose naltrexone to modulate an endogenous immune response is discussed. This is the second article published on the ALA/N protocol and the authors believe the protocol warrants clinical trial.

Am J Gastroenterol. 2007 Apr;102(4):820-8. Epub 2007 Jan 11.

Low-dose naltrexone therapy improves active Crohn's disease.

Smith JP, Stock H, Bingaman S, Mauger D, Rogosnitzky M, Zagon IS.

Department of Medicine, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.

Abstract

OBJECTIVES: Endogenous opioids and opioid antagonists have been shown to play a role in healing and repair of tissues. In an open-labeled pilot prospective trial, the safety and efficacy of low-dose naltrexone (LDN), an opioid antagonist, were tested in patients with active Crohn's disease. METHODS: Eligible subjects with histologically and endoscopically confirmed active Crohn's disease activity index (CDAI) score of 220-450 were enrolled in a study using 4.5 mg naltrexone/day. Infliximab was not allowed for a minimum of 8 wk prior to study initiation. Other therapy for Crohn's disease that was at a stable dose for 4 wk prior to enrollment was continued at the same doses. Patients completed the inflammatory bowel disease questionnaire (IBDQ) and the short-form (SF-36) quality of life surveys and CDAI scores were assessed pretreatment, every 4 wk on therapy and 4 wk after completion of the study drug. Drug was administered by mouth each evening for a 12-wk period. RESULTS: Seventeen patients with a mean CDAI score of 356 +/- 27 were enrolled. CDAI scores decreased significantly (P= 0.01) with LDN, and remained lower than baseline 4 wk after completing therapy. Eighty-nine percent of patients exhibited a response to therapy and 67% achieved a remission (P < 0.001). Improvement was recorded in both quality of life surveys with LDN compared with baseline. No laboratory abnormalities were noted. The most common side effect was sleep disturbances, occurring in seven patients. CONCLUSIONS: LDN therapy appears effective and safe in subjects with active Crohn's disease. Further studies are needed to explore the use of this compound.

Paradoxical Effects of the Opioid Antagonist Naltrexone on Morphine Analgesia, Tolerance, and Reward in Rats

Abstract

Opioid agonists such as morphine have been found to exert excitatory and inhibitory receptor-mediated effects at low and high doses, respectively. Ultra-low doses of opioid antagonists (naloxone and naltrexone), which selectively inhibit the excitatory effects, have been reported to augment systemic morphine analgesia and inhibit the development of tolerance/physical dependence. This study investigated the site of action of the paradoxical effects of naltrexone and the generality of this effect. The potential of ultra-low doses of naltrexone to influence morphine-induced analgesia was investigated in tests of nociception. Administration of intrathecal (0.05 and 0.1 ng) or systemic (10 ng/kg i.p.) naltrexone augmented the antinociception produced by an acute submaximal dose of intrathecal (5 μg) or systemic (7.5 mg/kg i.p.) morphine in the tail-flick test. Chronic intrathecal (0.005 and 0.05 ng) or systemic (10 ng/kg) naltrexone combined with morphine (15 μg i.t.; 15 mg/kg i.p.) over a 7-day period inhibited the decline in morphine antinociception and prevented the loss of morphine potency. In animals rendered tolerant to intrathecal (15 μg) or systemic (15 mg/kg) morphine, administration of naltrexone (0.05 ng i.t.; 10 and 50 ng/kg i.p.) significantly restored the antinociceptive effect and potency of morphine. Thus, in ultra-low doses, naltrexone paradoxically enhances morphine analgesia and inhibits or reverses tolerance through a spinal action. The potential of naltrexone to influence morphine-induced reward was also investigated using a place preference paradigm. Systemic administration of ultra-low doses of naltrexone (16.7, 20.0, and 25.0 ng/kg) with morphine (1.0 mg/kg) extended the duration of the morphine-induced conditioned place preference. These effects of naltrexone on morphine-induced reward may have implications for chronic treatment with agonist-antagonist combinations.

Br J Pharmacol. 2007 Jul;151(6):877-87. Epub 2007 May 14.

Augmentation of spinal morphine analgesia and inhibition of tolerance by low doses of mu- and delta-opioid receptor antagonists.

Abul-Husn NS, Sutak M, Milne B, Jhamandas K.

Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.

Abstract

BACKGROUND AND PURPOSE: Ultralow doses of naltrexone, a non-selective opioid antagonist, have previously been found to augment acute morphine analgesia and block the development of tolerance to this effect. Since morphine tolerance is dependent on the activity of micro and delta receptors, the present study investigated the effects of ultralow doses of antagonists selective for these receptor types on morphine analgesia and tolerance in tests of thermal and mechanical nociception. EXPERIMENTAL APPROACH: Effects of intrathecal administration of mu-receptor antagonists, CTOP (0.01 ng) or CTAP (0.001 ng), or a delta-receptor antagonist, naltrindole (0.01 ng), on spinal morphine analgesia and tolerance were evaluated using the tail-flick and paw-pressure tests in rats. KEY RESULTS: Both micro and delta antagonists augmented analgesia produced by a sub-maximal (5 microg) or maximal (15 microg) dose of morphine. Administration of the antagonists with morphine (15 microg) for 5 days inhibited the progressive decline of analgesia and prevented the loss of morphine potency. In animals exhibiting tolerance to morphine, administration of the antagonists with morphine produced a recovery of the analgesic response and restored morphine potency. CONCLUSIONS AND IMPLICATIONS: Combining ultralow doses of micro- or delta-receptor antagonists with spinal morphine augmented the acute analgesic effects, inhibited the induction of chronic tolerance and reversed established tolerance. The remarkably similar effects of micro- and delta-opioid receptor antagonists on morphine analgesia and tolerance are interpreted in terms of blockade of the latent excitatory effects of the agonist that limit expression of its full activity.