Naltrexone Abstracts 2

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ALSUntangled No. 8: Low dose naltrexone for ALS.
         (2011) Download

Bernard Bihari, MD: low-dose naltrexone for normalizing immune system function.
            (Bihari, 2013) Download

Low-dose naltrexone for disease prevention and quality of life.
            (Brown and Panksepp, 2009) Download
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 a 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.

Treatment of Complex Regional Pain Syndrome (CRPS) using low dose naltrexone (LDN).
            (Chopra and Cooper, 2013) Download
Complex Regional Pain Syndrome (CRPS) is a neuropathic pain syndrome, which involves glial activation and central sensitization in the central nervous system. Here, we describe positive outcomes of two CRPS patients, after they were treated with low-dose naltrexone (a glial attenuator), in combination with other CRPS therapies. Prominent CRPS symptoms remitted in these two patients, including dystonic spasms and fixed dystonia (respectively), following treatment with low-dose naltrexone (LDN). LDN, which is known to antagonize the Toll-like Receptor 4 pathway and attenuate activated microglia, was utilized in these patients after conventional CRPS pharmacotherapy failed to suppress their recalcitrant CRPS symptoms.

Low-dose naltrexone suppresses ovarian cancer and exhibits enhanced inhibition in combination with cisplatin.
         (Donahue et al., 2011) Download
Ovarian cancer is the leading cause of death from gynecological malignancies. Although initial therapeutic modalities are successful, 65% of these women relapse with only palliative treatments available thereafter. Endogenous opioids repress the proliferation of human ovarian cancer cells in vitro, and do so in a receptor-mediated manner. The present study examined whether modulation of opioid systems by the opioid antagonist naltrexone (NTX), alone or in combination with standard of care therapies (taxol/paclitaxel, cisplatin), alters human ovarian cancer cell proliferation in tissue culture and tumor progression in mice. Administration of NTX for six hours every two days, but not continuously, reduced DNA synthesis and cell replication from vehicle-treated controls in tissue culture. Moreover, brief exposure to NTX in combination with taxol or cisplatin had an enhanced anticancer action. Mice with established ovarian tumors and treated with a low dosage of NTX (LDN), which invokes a short period of opioid receptor blockade, repressed tumor progression in a non-toxic fashion by reducing DNA synthesis and angiogenesis but not altering cell survival. The combination of LDN with cisplatin, but not taxol, resulted in an additive inhibitory effect on tumorigenesis with enhanced depression of DNA synthesis and angiogenesis. LDN combined with cisplatin alleviated the toxicity (e.g. weight loss) associated with cisplatin. LDN treatment upregulated the expression of the opioid growth factor (OGF, chemical term ([Met(5)]-enkephalin) and its receptor, OGFr. Previous tissue culture studies have reported that OGF is the only opioid peptide with antiproliferative activity on ovarian cancer cells, with OGF action mediated by OGFr. Thus, the common denominator of intermittent opioid receptor blockade by short-term NTX or LDN on ovarian cancer proliferation and tumorigenesis recorded herein appears to be related to the OGF-OGFr axis. These preclinical data may offer a non-toxic and efficacious pathway-related treatment that can benefit patients with ovarian cancer.

A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis.
            (Gironi et al., 2008) Download
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.

Cancer Treatment Combining Lipoic Acid and Naltrexone, and, Lipoic Acid’s Use As An Effective Cure for Severe Liver Disease: An Interview With Burt Berkson, M.D., PhD.
         (Hamilton, 2010) Download

Low-dose naltreoxone for the treatment of irritable bowel syndrome: a pilot study
            (Kariv et al., 2006) Download
Preclinical studies have shown that a very low dose of naltreoxone hydrochloride (NTX), an opiate antagonist, can block excitatory opioid receptors without affecting inhibitory opioid receptors, resulting in analgesic potency without side effects. The present study assessed the efficacy and safety of PTI-901 (low-dose NTX) treatment in Irritable bowel syndrome (IBS) patients. Forty-two IBS patients participated in an open-label study. Participants received 0.5 mg PTI-901/day for 4 weeks and were evaluated during baseline, during treatment, and at 4-week follow-up. Patients recorded degree of abdominal pain, stool urgency, consistency, and frequency. Primary outcomes were number of pain-free days and overall symptom relief, evaluated by a global assessment score. Data were analyzed per protocol. Global assessment improved in 76% of 42 patients. During treatment, the mean weekly number of pain-free days increased from 0.5+/-1 to 1.25+/-2.14 (P=0.011). There were no significant adverse reactions. PTI-901 improves pain and overall feeling, and is well tolerated by IBS patients. A large, randomized, double-blind, placebo-controlled study is justified.

Long-term remission of adenoid cystic tongue carcinoma with low dose naltrexone and vitamin d3 - a case report.
            (Khan, 2014) Download
Naltrexone (ReVia(R)) is a long-acting oral pure opiate antagonist which is approved for the treatment of alcohol addiction as a 50mg per day tablet. The mechanism of action is complete opiate blockade, which removes the pleasure sensation derived from drinking alcohol (created by endorphins). Low Dose Naltrexone ("LDN") in the range of 3-4.5 mg per day has been shown to have the opposite effect - brief opiate receptor blockade with resulting upregulation of endogenous opiate production. Through the work of Bihari and Zagon, it has been determined that the level of the endogenous opiate methionine-enkephalin is increased by LDN. Met-enkephalin is involved in regulating cell proliferation and can inhibit cancer cell growth in multiple cell lines. Increased met-enkepahlin levels created by LDN thus have the potential to inhibit cancer growth in humans. Phase II human trials of met-enkephalin, case reports published by Berkson and Rubin, and the clinical experience of Bihari confirmed the potential role of LDN in treating pancreatic and other cancers. However, large scale trials are lacking and are unlikely to be funded given the current non-proprietary status of naltrexone. A case report is presented of successful treatment of adenoid cystic carcinoma as further evidence of LDN's potential as a unique non-toxic cancer therapy.

Low dose naltrexone (LDN) enhances maturation of bone marrow dendritic cells (BMDCs).
            (Meng et al., 2013) Download
It has been demonstrated previously that immune cell activation and proliferation were sensitive to the effects of naltrexone, a non-peptidic delta-opioid receptor selective antagonist and opioid receptors on BMDCs have been detected [1]. However, there is little prior data published on naltrexone and DCs. Therefore, we hypothesized that LDN could exert modulating effect on BMDCs. In present study, we studied influence of LDN on both phenotypic and functional maturation of BMDCs. Changes of BMDC post-treatment with LDN were evaluated using conventional light microscope and transmission electron microscopy (TEM); flow cytometry(FCM); cytochemistry; acid phosphatase activity(ACP) test; FITC-dextran bio-assay; mixed lymphocytes and enzyme-linked immunosorbent assay (ELISA). We have found that LDN enhances maturation of BMDCs as evidenced by 1) up-regulating the expression of MHC II, CD40, CD83, CD80 and CD86 molecules on BMDCs; 2) down-regulating the rates of pinocytosis and phagocytosis accompanied by the results of decreased ACP, and FITC-dextran bio-assay; 3) mounting potential of BMDCs to drive T cell; and 4) inducing secretion of higher levels of IL-12 and TNF-alpha. It is therefore concluded that LDN can efficiently promote the maturation of BMDCs via precise modulation inside and outside BMDCs. Our study has provided meaningful mode of action on the role of LDN in immunoregulation, and rationale on future application of LDN for enhancing host immunity in cancer therapy and potent use in the design of DC-based vaccines for a number of diseases.

Low Dose Naltrexone: Side Effects and Efficacy in Gastrointestinal Disorders.
            (Ploesser et al., 2010) Download
Use of low dose naltrexone has been advocated for a variety of medical problems. Only a few articles published in peer review journals have documented side effects of low dose naltrexone. The purpose of this study was to determine the frequency of adverse effects of low dose naltrexone in patients who have been treated for a variety of gastrointestinal disorders. The secondary purpose was to determine global efficacy in a retrospective survey. Patients (206) form a single gastroenterologist's clinical practice who had been prescribed naltrexone were mailed a survey to evaluate the side effects and efficacy of naltrexone. Patients had either irritable bowel syndrome without evidence for small intestinal bacterial overgrowth, chronic idiopathic constipation, or inflammatory bowel disease. Patients with diarrhea were given 2.5 mg daily, constipation 2.5 mg twice daily, and inflammatory bowel disease 4.5 mg daily. In the patients who returned the survey, 47/121 (38.8%) had no side effects. Of the 74/121 (61.2%) patients who had side effects, 58 had one or more neurological complaints, and 32 had one or more gastrointestinal side effects. In the patients with side effects, 24/74 (32.4%) had short lived symptoms. Low dose naltrexone was terminated owing to side effects in 20/74 patients (27.0%). In 13 patients with idiopathic irritable bowel syndrome, 2 were markedly worse. In 85 patients with irritable bowel syndrome-small intestinal bacterial overgrowth, 15 were markedly improved, 32 were moderately worse, and 1 was markedly worse. In 12 patients with chronic constipation, 7 were markedly improved, 1 was moderately improved, 1 was mildly improved, and 4 were unchanged. Low dose naltrexone frequently has side effects but in most is tolerable. It appears to be helpful for a member of patients with gastrointestinal disorders.

Adverse effects of high doses of intravenous alpha lipoic Acid on liver mitochondria.
            (Vigil et al., 2014) Download
Alpha lipoic acid (ALA, thioctic acid), among other actions, is an essential coenzyme in the conversion of pyruvate to acetyl co-enzyme A. Therefore, it is necessary for the production of energy for aerobic organisms. Scientists have found that it can be used medically to help regenerate liver tissue, reverse the complications of diabetes mellitus, slow or stop the growth of cancer cells, and chelate heavy metals, among other actions. In this article, the authors describe the cellular mitochondrial damage from excessively high doses of this beneficial agent.

Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels.
            (Younger et al., 2013) Download
OBJECTIVE: To determine whether low dosages (4.5 mg/day) of naltrexone reduce fibromyalgia severity as compared with the nonspecific effects of placebo. In this replication and extension study of a previous clinical trial, we tested the impact of low-dose naltrexone on daily self-reported pain. Secondary outcomes included general satisfaction with life, positive mood, sleep quality, and fatigue. METHODS: Thirty-one women with fibromyalgia participated in the randomized, double-blind, placebo-controlled, counterbalanced, crossover study. During the active drug phase, participants received 4.5 mg of oral naltrexone daily. An intensive longitudinal design was used to measure daily levels of pain. RESULTS: When contrasting the condition end points, we observed a significantly greater reduction of baseline pain in those taking low-dose naltrexone than in those taking placebo (28.8% reduction versus 18.0% reduction; P = 0.016). Low-dose naltrexone was also associated with improved general satisfaction with life (P = 0.045) and with improved mood (P = 0.039), but not improved fatigue or sleep. Thirty-two percent of participants met the criteria for response (defined as a significant reduction in pain plus a significant reduction in either fatigue or sleep problems) during low-dose naltrexone therapy, as contrasted with an 11% response rate during placebo therapy (P = 0.05). Low-dose naltrexone was rated equally tolerable as placebo, and no serious side effects were reported. CONCLUSION: The preliminary evidence continues to show that low-dose naltrexone has a specific and clinically beneficial impact on fibromyalgia pain. The medication is widely available, inexpensive, safe, and well-tolerated. Parallel-group randomized controlled trials are needed to fully determine the efficacy of the medication.

The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain.
            (Younger et al., 2014) Download
Low-dose naltrexone (LDN) has been demonstrated to reduce symptom severity in conditions such as fibromyalgia, Crohn's disease, multiple sclerosis, and complex regional pain syndrome. We review the evidence that LDN may operate as a novel anti-inflammatory agent in the central nervous system, via action on microglial cells. These effects may be unique to low dosages of naltrexone and appear to be entirely independent from naltrexone's better-known activity on opioid receptors. As a daily oral therapy, LDN is inexpensive and well-tolerated. Despite initial promise of efficacy, the use of LDN for chronic disorders is still highly experimental. Published trials have low sample sizes, and few replications have been performed. We cover the typical usage of LDN in clinical trials, caveats to using the medication, and recommendations for future research and clinical work. LDN may represent one of the first glial cell modulators to be used for the management of chronic pain disorders.

 

 


References

(2011), ‘ALSUntangled No. 8: Low dose naltrexone for ALS.’, Amyotroph Lateral Scler, 12 (1), 76-78. PubMedID: 21174518
Bihari, B (2013), ‘Bernard Bihari, MD: low-dose naltrexone for normalizing immune system function.’, Altern Ther Health Med, 19 (2), 56-65. PubMedID: 23594453
Brown, N and J Panksepp (2009), ‘Low-dose naltrexone for disease prevention and quality of life.’, Med Hypotheses, 72 (3), 333-37. PubMedID: 19041189
Chopra, P and MS Cooper (2013), ‘Treatment of Complex Regional Pain Syndrome (CRPS) using low dose naltrexone (LDN).’, J Neuroimmune Pharmacol, 8 (3), 470-76. PubMedID: 23546884
Donahue, RN, PJ McLaughlin, and IS Zagon (2011), ‘Low-dose naltrexone suppresses ovarian cancer and exhibits enhanced inhibition in combination with cisplatin.’, Exp Biol Med (Maywood), 236 (7), 883-95. PubMedID: 21685240
Gironi, M, et al. (2008), ‘A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis.’, Mult Scler, 14 (8), 1076-83. PubMedID: 18728058
Hamilton, K. R. (2010). Cancer Treatment Combining Lipoic Acid and Naltrexone, and, Lipoic Acid’s Use As An Effective Cure for Severe Liver Disease: An Interview With Burt Berkson, M.D., PhD. Retrieved from http://www.prescription2000.com/Interview-Transcripts/2010-01-22-burt-berkson-lipoic-acid-naltrexone-transcript.html
Kariv, R, et al. (2006), ‘Low-dose naltreoxone for the treatment of irritable bowel syndrome: a pilot study.’, Dig Dis Sci, 51 (12), 2128-33. PubMedID: 17080248
Khan, A (2014), ‘Long-term remission of adenoid cystic tongue carcinoma with low dose naltrexone and vitamin d3 - a case report.’, Oral Health Dent Manag, 13 (3), 721-24. PubMedID: 25284545
Meng, J, et al. (2013), ‘Low dose naltrexone (LDN) enhances maturation of bone marrow dendritic cells (BMDCs).’, Int Immunopharmacol, 17 (4), 1084-89. PubMedID: 24455776
Ploesser, J, LB Md Weinstock, and E Pharmd Thomas (2010), ‘Low Dose Naltrexone: Side Effects and Efficacy in Gastrointestinal Disorders.’, Int J Pharm Compd, 14 (2), 171-73. PubMedID: 23965429
Vigil, M, BM Berkson, and AP Garcia (2014), ‘Adverse effects of high doses of intravenous alpha lipoic Acid on liver mitochondria.’, Glob Adv Health Med, 3 (1), 25-27. PubMedID: 24753992
Younger, J, et al. (2013), ‘Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels.’, Arthritis Rheum, 65 (2), 529-38. PubMedID: 23359310
Younger, J, L Parkitny, and D McLain (2014), ‘The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain.’, Clin Rheumatol, 33 (4), 451-59. PubMedID: 24526250