Research Trials of LDN

• 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.

• Mounting evidence indicates that microglial activation contributes to neuronal damage in neurodegenerative diseases. Recent studies show that in response to certain environmental toxins and endogenous proteins, microglia can enter an over activated state and release reactive oxygen species (ROS) that cause neurotoxicity. Pattern recognition receptors expressed on the microglial surface seem to be one of the primary, common pathways by which diverse toxin signals are transduced into ROS production. Over activated microglia can be detected using imaging techniques and therefore this knowledge offers an opportunity not only for early diagnosis but, importantly, for the development of targeted anti-inflammatory therapies that might slow or halt the progression of neurodegenerative disease.

• 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-opioid 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.

• 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 every day, 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.

• OBJECTIVE
• To evaluate the efficacy of 4.5mg nightly naltrexone on the quality of life of multiple sclerosis (MS) patients.
 

• METHODS
• This single-center, double-masked, placebo-controlled, crossover study evaluated the efficacy of 8 weeks of treatment with 4.5mg nightly naltrexone (low-dose naltrexone, LDN) on self-reported quality of life of MS patients.
 

• RESULTS
• Eighty subjects with clinically definite MS were enrolled, and 60 subjects completed the trial. Ten withdrew before completing the first trial period: 8 for personal reasons, 1 for a non-MS-related adverse event, and 1 for perceived benefit. Database management errors occurred in 4 other subjects, and quality of life surveys were incomplete in 6 subjects for unknown reasons. The high rate of subject dropout and data management errors substantially reduced the trial's statistical power. LDN was well tolerated, and serious adverse events did not occur. LDN was associated with significant improvement on the following mental health quality of life measures: a 3.3-point improvement on the Mental Component Summary score of the Short Form-36 General Health Survey (p = 0.04), a 6-point improvement on the Mental Health Inventory (p < 0.01), a 1.6-point improvement on the Pain Effects Scale (p =.04), and a 2.4-point improvement on the Perceived Deficits Questionnaire (p = 0.05).
 

• INTERPRETATION
• LDN significantly improved mental health quality of life indices. Further studies with LDN in MS are warranted.

• BACKGROUND
• Endogenous opioid peptides have been shown to play a role in the development and/or perpetuation of inflammation. We hypothesize that the endogenous opioid system is involved in inflammatory bowel disease, and antagonism of the opioid-opioid receptor will lead to reversal of inflammation.
 

• AIMS
• A randomized double-blind placebo-controlled study was designed to test the efficacy and safety of an opioid antagonist for 12 weeks in adults with active Crohn's disease.
 

• METHODS
• Forty subjects with active Crohn's disease were enrolled in the study. Randomized patients received daily oral administration of 4.5-mg naltrexone or placebo. Providers and patients were masked to treatment assignment. The primary outcome was the proportion of subjects in each arm with a 70-point decline in Crohn's Disease Activity Index score (CDAI). The secondary outcome included mucosal healing based upon colonoscopy appearance and histology.
 

• RESULTS
• Eighty-eight percent of those treated with naltrexone had at least a 70-point decline in CDAI scores compared to 40% of placebo-treated patients (p = 0.009). After 12 weeks, 78% of subjects treated with naltrexone exhibited an endoscopic response as indicated by a 5-point decline in the Crohn's disease endoscopy index severity score (CDEIS) from baseline compared to 28% response in placebo-treated controls (p = 0.008), and 33% achieved remission with a CDEIS score <6, whereas only 8% of those on placebo showed the same change. Fatigue was the only side effect reported that was significantly greater in subjects receiving placebo.
 

• CONCLUSIONS
• Naltrexone improves clinical and inflammatory activity of subjects with moderate to severe Crohn's disease compared to placebo-treated controls. Strategies to alter the endogenous opioid system provide promise for the treatment of Crohn's disease.

• To implement an immuno-regulatory approach for reducing or preventing the onset of AIDS symptoms in HIV+ individuals a single prospective cohort study was conducted to evaluate the effect of low-dose naltrexone (LDN) on HIV infected, asymptomatic, otherwise untreated Mali adults with CD4 levels between 350 and 600 cell/mm3.We measured changes in CD4 count, CD4%, BMI, hemoglobin, viral load, interferon alpha, and standard chemistry panel five times over a nine-month period. Linear regression mixed models were used with maximum likelihood as the estimation method for repeated measures on subjects. Of 55 subjects followed, 71% completed the full program without indications of clinical AIDS symptoms, side effects or enough loss of CD4 count to warrant initiation of ART medication. The decrease of CD4 count was marginally significant over the full testing period (p=.066) and became significant as the cohort aged (37.73 cells/mm3 with p=0.027 and 52.94 cells/mm3 with p=0.003, respectively, at six and nine months). In contrast, the estimated mean CD4% did not show significant decrease over the entire study (p=0.842). No other covariates were associated significantly with the results. These findings support the therapeutic potential of LDN in treating HIV+ in its early stages and suggest further studies are indicated.

• To implement an immuno-regulatory approach for reducing or preventing the onset of AIDS symptoms in HIV+ individuals we conducted a single blind nine-month randomized clinical trial to evaluate the impact of low-dose naltrexone (LDN) on asymptomatic HIV+ Mali adults undergoing antiretro virial (ART) treatment with CD4 counts below 350 cell/mm3.We measured differences between groups in CD4 count, CD4%, hemoglobin, viral load, interferon alpha, and standard chemistry panel five times during the clinical period. The random mixed model and restricted maximum likelihood method for estimating slopes for repeated measures on subjects were used to predict CD4 counts and CD4%. The improvement in CD4 count in the treatment group (51 subjects) was significantly greater than the control group (49 subjects) at 6 months (p = 0.041) and marginally at 9 months (p = 0.067). Improvement in CD4% in the treatment group also was observed throughout the clinical period but these increases were not significant relative to the control group. Since, for this period of time, the combination of LDN + ART appears to be more effective in increasing CD4 count, and since LDN is inexpensive, easy to administer and without side effects, further exploration of LDN together with ARV treatment is recommended.

• 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.

• BACKGROUND
• There is an unmet need for safe and effective medicines to treat children with Crohn's disease. Recently, investigations have shown an association between endogenous opioid peptides and inflammatory cells.
 

• AIMS
• The aims of this study were to evaluate the safety and tolerability of an opioid antagonist, naltrexone, in children with moderate to severe Crohn's disease.
 

• METHODS
• A pilot clinical trial was conducted in children with moderate to severe Crohn's disease. Fourteen subjects with a mean age of 12.3 years (range, 8 to 17 y) were enrolled. Children were randomized to placebo or naltrexone (0.1 mg/kg) orally for 8 weeks followed by open-labeled treatment with 8 additional weeks of naltrexone. Safety and toxicity were monitored by physical examinations and blood chemistries. Clinical activity was assessed by the Pediatric Crohn's Disease Activity Index (PCDAI) and Quality of life was monitored by the Impact III survey.
 

• RESULTS
• Oral naltrexone was well tolerated without any serious adverse events in children with moderate to severe Crohn's disease. PCDAI scores significantly decreased from pretreatment values (34.2±3.3) with an 8-week course of naltrexone therapy (21.7±3.9) (P=0.005). Twenty-five percent of those treated with naltrexone were considered in remission (score ≤10) and 67% had improved with mild disease activity (decrease in PCDAI score by at least 10 points) at the end of the study. Systemic and social quality of life improved with naltrexone treatment (P=0.035).
 

• CONCLUSIONS
• Naltrexone therapy seems safe with limited toxicity when given to children with Crohn's disease and may reduce disease activity.

• Dr. Ian Zagon and his team from Pennsylvania State University presented 3 papers on the effects of LDN in animal models of MS. Experimental autoimmune encephalomyelitis (EAE) is a disorder induced in animals that serves as a model of MS in humans.
• 1) Opioid growth factor and low dose naltrexone inhibit immunological responses associated with experimental autoimmune encephalomyelitis.
• The first phase of EAE is characterized by the production of pro-inflammatory cytokines, inflammation, and the recruitment of activated T-lymphocytes and antibodies to the site of inflammation, the central nervous system. The immune system launches an aggressive response to the attack, which contributes to disease progression. In one experiment mice with induced EAE were treated with LDN and observed.
• Results
• Both LDN and opioid growth factor (OGF), a metenkephalin that rises in response to LDN, were shown to repress disease progression. Study data demonstrate that early in the induction of EAE, treatment with either OGF or LDN reduces the number of lymphocytes primed to target myelin/oligodendrocyte glycoprotein (MOG) the primary myelin antigen targeted in MS. This study also suggests the mechanism by which the disease process occurs in MS and shows that treatment with either OGF or LDN suppresses T cell proliferation. This, in turn, stops disease progression.

• 2) Low-dose naltrexone (LDN) prevents development or delays onset and reduces severity of experimental autoimmune encephalomyelitis in mice.
• In Dr. Zagon's laboratory, mice were pre-treated with LDN before EAE was induced to show the effects of LDN on disease development and severity.
• Results
• Both LDN and OGF were shown to offer protection against the development of EAE and delay onset compared to untreated mice. In treated mice that developed EAE the disease was not as severe as EAE in untreated mice.
  

• 3) The complete blockade of opioid receptors with naltrexone exacerbates experimental autoimmune encephalomyelitis in a mouse model.
• Doctor Zagon explained that for naltrexone to reduce T cell activation and autoantibody production, naltrexone must be used intermittently.
• Results
• Dr. Zagon's team confirmed this premise in an experiment using high doses of naltrexone. In mice treated with high doses of naltrexone, EAE developed quickly and the disease was more severe. In mice with EAE, high doses of naltrexone exacerbated symptoms.
 

• CONCLUSIONS
• From his animal studies Dr. Zagon found that both LDN and OGF offer benefits in multiple sclerosis. Dr. Zagon is currently designing a human study in MS that he plans to conduct in the near future.
  
Research Trials that question LDN
  
  

• In December 2005, Pain Therapeutics, Inc announced the results of a study they conducted which concluded that naltrexone did not show benefit in the third month of treatment of irritable bowel syndrome, but did show benefit in the first two months. It should be noted here that they utilized naltrexone 0.5 mg in their study as opposed to normal dosing which is 1.75 mg to 4.5 mg every night.
• In 2004, Dr. Evers conducted a trial in Germany, evaluating LDN for Multiple Sclerosis and potentially implying that the drug may suppress the patient’s immune system instead of boost; however, it is important to note that the dose during the trial was given in the morning instead of at night, which may have led to the odd results.
  
Research Trials References
  
  

• Smith JP, Stock H, Bingaman S, et al. Low-dose naltrexone therapy improves active Crohn’s disease. Am J Gastroenterol. 2007 Apr;102(4):820-8.
• Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci. 2007 Jan;8(1):57-69.
• Gironi M, Martinelli-Boneschi F, Sacerdote P, et al. A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis. Mult Scler. 2008 Sep;14(8):1076-83.
• Younger J, Mackey S. Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. Pain Med. 2009 May-Jun;10(4):663-672.
• Cree BA, Komyeyeva E, Goodin DS. Pilot trial of low-dose naltrexone and quality of life in multiple sclerosis. Ann Neurol. 2010 Aug;68(2):145-150.
• Smith JP, Bingaman SI, Ruggiero F, et al. Therapy with the opioid antagonist naltrexone promotes mucosal healing in active Crohn’s disease: a randomized placebo controlled trial. Dig Dis Sci. 2011 Jul;56(7):2088-97.
• Traore AK, Thiero O, Dao S, et al. Single cohort study of the effect of low dose naltrexone on the evolution of immunological, virological, and clinical state of HIV+ adults in Mali. Journal of AIDS and HIV Research. 2011 Oct;3(10):180-188.
• Traore AK, Thiero O, Dao S, et al. Impact of low dose naltrexone (LDN) on antiretroviral therapy (ART) treated HIV+ adults in Mali: A single blind randomized clinical trial. Journal of AIDS and HIV Research. 2011 Oct:3(10):189-198.
• Younger J, Noor N, McCue R. 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. 2013 Feb;65(2):529-38.
• Smith JP, Field D, Bingaman SI, et al. Safety and tolerability of low-dose naltrexone therapy in children with moderate to severe Crohn’s disease: a pilot study. J Clin Gastroenterol. 2013 Apr;47(4):339-45.
•  Moore E. Low-dose naltrexone in multiple sclerosis. http://suite101.com/article/low-dose-naltrexone-in-multiple-sclerosis-a69916 (accessed 2013 Apr 30).