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Clinical Trials for LDN

Updated: May 3, 2013


In Brief

Around the globe, there has been a quantum leap forward in the number of ongoing research studies on LDN. Here is a capsule look at a number of such projects.

Developments that are detailed below:

  • Two studies in Mali, Africa demonstrating LDN’s successful use in HIV/AIDS—published October 2011.
  • A study of LDN in the treatment of MS at the University of California, San Francisco, published February 2010.
  • A multi-institutional clinical trial of LDN for PPMS in Italy, which includes endorphin measurements, completed in fall 2007, published September 2008.
  • A Phase II placebo-controlled clinical trial of LDN for Crohn’s disease at Penn State.
  • A placebo-controlled pilot study at Penn State on the efficacy of LDN for children and adolescents with Crohn’s disease.
  • A clinical trial of LDN in the treatment of fibromyalgia at Stanford Medical Center, published February 2013.
  • A study by the MindBrain Consortium in Akron, Ohio of, especially, the affective changes in MS treated with LDN, begun late 2007.
  • An animal research study at Penn State of naltrexone in a model of a disease that mimics MS, under a small grant from the National MS Society.
  • Animal research on neurodegeneration at NIEHS, suggesting a protective role for naltrexone.

Recently Published Clinical Trials of LDN

[Note: all boldfacing, below, was so chosen by the editor.]

> LDN for the Treatment of Fibromyalgia—Stanford Medical Center

Background. A single-blind, small clinical trial of LDN for the treatment of fibromyalgia was begun at Stanford Medical Center in June 2007; principal Investigator Sean Mackey and sub-investigator Jarred Younger. The results were published as “Fibromyalgia Symptoms are Reduced by Low-Dose Naltrexone: a Pilot Study” in Pain Med. 2009 May-Jun;10(4):663-72. Younger reported:

The LDN trial on 10 individuals gave us encouraging results. The findings warranted a larger, double-blind trial [involving] individuals with fibromyalgia.

Stanford researchers have further extended their study of LDN for the pain of fibromyalgia.

Abstract

Arthritis & Rheumatism
Volume 65, Issue 2, pages 529–538, February 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

Jarred Younger, Noorulain Noor, Rebecca McCue, Sean Mackey [Stanford University]

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.

> LDN for Children With Moderate/Severe Crohn’s Disease—Penn State College of Medicine, Hershey, PA

Background. Dr. Jill P. Smith continues to demonstrate LDN’s efficacy in treating this inflammatory bowel disease in all of the many ages affected.

Abstract

J Clin Gastroenterol. 2012 Nov 21. [Epub ahead of print]

Safety and Tolerability of Low-dose Naltrexone Therapy in Children With Moderate to Severe Crohn's Disease: A Pilot Study.

Smith JP, Field D, Bingaman SI, Evans R, Mauger DT.

Departments of *Medicine †Pediatrics ‡Public Health Sciences, College of Medicine, Pennsylvania State University, Hershey, PA.

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.

PMID: 23188075 [PubMed - as supplied by publisher]

> Studies in Mali on LDN for HIV and AIDS

Background. Planning for this work dates back to 2003. With neurologist Dr. Jaquelyn McCandless and her colleague husband, Jack Zimmerman, as both “Expatriate Clinical Monitors” and major financial supporters, the support of Hussein Alfa Nafo, and with a local research team led by Dr. Abdel Kader Traore and other health officials at the University Hospital in Bamako, Mali in Africa, two separate studies of LDN use in HIV/AIDS have now been completed and published in a peer reviewed journal, the Journal of AIDS and HIV Research.

The studies were approved for only a 3mg LDN dosage (rather than an anticipated 4.5mg). In addition, careful attention was given to special counseling aimed at improving preventive health practices of local women and children. Skip’s Pharmacy of Boca Raton, Florida prepared the LDN and placebo capsules.

Summary. With the first study, the researchers found that LDN is both safe and free of side effects and that it appears to be efficacious in strengthening the immune system of HIV+ individuals. In this study’s patients, who all had HIV infection but whose CD4 levels were not yet low enough to warrant antiretroviral (ARV) drug therapy, the mean CD4 % count remained unchanged throughout the study. This is in contrast to the usual outcomes in all other similar groups in the past, who were untreated, whose CD4% continued to decline month after month inexorably. The researchers concluded that for HIV+ individuals “LDN might offer a simple, relatively safe, inexpensive and easily monitored treatment alternative.”

The second study, a randomized clinical trial of patients with markedly reduced CD4 levels, compared those who were given both ARV and LDN to a control group given ARV and placebo. It was found that the ARV+LDN group showed a significantly higher increase in CD4 count by 6 months of treatment and it was concluded that “further exploration of LDN as part of an HIV+ treatment regimen is warranted.”

Abstracts

1) Journal of AIDS and HIV Research Vol. 3(10), pp. 180-188, October 2011

Single cohort study of the effect of low dose naltrexone on the evolution of immunological, virological and clinical state of HIV+ adults in Mali

Abdel K. TRAORE, Oumar THIERO, Sounkalo DAO, Fadia F. C. KOUNDE, Ousmane FAYE, Mamadou CISSE, Jaquelyn B. McCANDLESS, Jack M. ZIMMERMAN, Karim COULIBALY, Ayouba DIARRA, Mamadou S. KEITA, Souleymane DIALLO, Ibrahima G. TRAORE and Ousmane KOITA

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.


2) Journal of AIDS and HIV Research Vol. 3(10), pp. 189-198, October 2011

Impact of low dose naltrexone (LDN) on antiretroviral therapy (ART) treated HIV+ adults in Mali: A single blind randomized clinical trial

Abdel K. TRAORE, Oumar THIERO, Sounkalo DAO, Fadia F. C. KOUNDE, Ousmane FAYE, Mamadou CISSE, Jaquelyn B. McCANDLESS, Jack M. ZIMMERMAN, Karim COULIBALY, Ayouba DIARRA, Mamadou S. KEITA, Souleymane DIALLO, Ibrahima G. TRAORE and Ousmane KOITA

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 antiretroviral (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.

[Editor’s Note: These long awaited scientific studies on Low Dose Naltrexone for HIV+ individuals not only have helped bring the late Dr. Bihari’s dream of a Developing Nations Project much closer to realization but also have clearly demonstrated LDN’s unique ability to strengthen the immune system. If responsible health care authorities around the globe pay proper attention to these findings, it is still possible to prevent the further deterioration of tens of millions of people who are presently HIV+.]


> LDN for Crohn’s Disease—Penn State College of Medicine, Hershey, PA

Background. Dr. Jill P. Smith’s original article, "Low-Dose Naltrexone Therapy Improves Active Crohn’s Disease," was published in the Jan 11, 2007 online edition of the American Journal of Gastroenterology (2007;102:1–9) [print edition Apr '07]. This was the first clinical study of LDN published by a US medical journal. Dr. Smith, Professor of Gastroenterology at Pennsylvania State University's College of Medicine, found that two-thirds of the patients in her pilot study went into remission and fully 89% of the group responded to LDN treatment to some degree. She concluded that “LDN therapy appears effective and safe in subjects with active Crohn’s disease.” That open-label Penn State trial demonstrated the efficacy of LDN in a small group of patients. As a result, Dr. Smith received an NIH grant that permitted the more definitive Phase II placebo-controlled clinical trial.

Phase II. Dr. Smith and her colleagues have now published the results of their Phase II study of 40 adults with Crohn’s disease, “Therapy with the Opioid Antagonist Naltrexone Promotes Mucosal Healing in Active Crohn’s Disease: A Randomized Placebo-Controlled Trial”, in the online journal Digestive Diseases and Sciences, March 8, 2011.

The 4.5mg daily dose of naltrexone proved to have very positive results, with significant improvements in the Crohn’s Disease Activity Index scores and with substantial healing demonstrated by endoscopy.

Abstract

Dig Dis Sci. 2011 Mar 8. [Epub ahead of print]

Therapy with the Opioid Antagonist Naltrexone Promotes Mucosal Healing in Active Crohn's Disease: A Randomized Placebo-Controlled Trial.

Smith JP, Bingaman SI, Ruggiero F, Mauger DT, Mukherjee A, McGovern CO, Zagon IS.

Department of Medicine, The Pennsylvania State University, College of Medicine, GI Medicine H-045, 500 University Drive, Hershey, PA, 17033, USA, jsmith2@psu.edu.

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.


> LDN for MS—University of California, San Francisco

Bruce Cree, MD and co-researchers at the Multiple Sclerosis Center at UCSF published their study “Pilot Trial 0f Low Dose Naltrexone and Quality of Life in MS” in the online Annals of Neurology on 19 Feb 2010.

The study began in early 2007. Some 80 patients with MS were involved in this double-blind, “randomized, placebo-controlled, crossover-design study of the effects of low dose naltrexone on quality of life as measured by the multiple sclerosis quality of life inventory.” Each subject received either LDN or a placebo for 8 weeks, followed by one week without either, and then a further 8 weeks on the the alternate capsule. A substantial contribution toward the study was made by the voluntary LDN for MS Research Fund.

The results were published in February 2010 in the Annals of Neurology (full pre-publication text available here):

Pilot trial of low dose naltrexone and quality of life in MS
Bruce A.C. Cree, Elena Kornyeyeva, Douglas S. Goodin
Multiple Sclerosis Center at UCSF

Abstract

Objective:
To evaluate the efficacy of 4.5 mg nightly naltrexone on the quality of life of multiple sclerosis patients.

Methods:
This single center, double-masked, placebo-controlled, crossover studied evaluated the efficacy of eight weeks of treatment with 4.5 mg nightly naltrexone (Low dose naltrexone or LDN) on self reported quality of life of MS patients.

Results:
80 subjects with clinically definite multiple sclerosis were enrolled and 60 subjects completed the trial. 10 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 SF-36 (P=.04), a 6 point improvement on the Mental Health Inventory (P<.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=.05).

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


Figure 2: SF-36, PCS=physical component summary scale score, range 13.6 - 61.9 baseline 34.9. MCS=mental component summary scale score, range 15.6 – 70.0, baseline 44.2.



Figure 3: PES=pain effects scale, range 6 – 30, baseline 16.1. MHI=mental health inventory, range 0 – 100, baseline 63.5


> LDN for MS—Milan, Italy

A long-awaited pilot study of low dose naltrexone therapy in multiple sclerosis was run by the Milan neurological researcher, Dr. Maira Gironi and colleagues. Several northern Italian hospitals began enrolling patients for the study during the first week of December 2006. Dr. Gironi reports that the 6 months of LDN treatment was completed in August 2007. Importantly, Dr. Gironi’s research team in Milan has long been a locus for significant research on endorphins in relation to illness, and this study has been tracking accurate assessments of the patients’ beta-endorphin levels in response to their LDN treatment.

The subjects were 40 patients affected with Primary Progressive MS. PPMS is an uncommon form of multiple sclerosis that progresses inexorably and for which neurologists have never had an approved treatment to offer.

Results were published in September 2008:

Multiple Sclerosis. 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; Fondazione Don Carlo Gnocchi, IRCCS, 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.

[Editor’s Note: That only one patient showed any progression of PPMS during the six-month period of this trial is extraordinary, as is the occurrence of a statistically significant reduction in spasticity. Two major adverse events were reported but were unassociated with MS or with LDN: one patient had previously unrecognized polycystic kidney disease and the other was diagnosed with metastatic lung cancer.]


Clinical Trials in Progress or Awaiting Publication

> Trial of LDN for Glioma Now Recruiting Participants—Duke University

This study began in May 2011 and has an estimated primary completion date in March 2013. Katherine B Peters, MD, PhD, a neuro-oncologist at Duke University, is the principal investigator. This placebo-controlled, randomized clinical trial will involve 72 patients, all of whom have high-grade malignant glioma. They will receive, in addition to standard chemoradiation, either placebo or LDN. The primary outcome will determine the effects of LDN on quality of life measures; however, also measured will be differences in both functional capacity and in neurocognitive function. The study is funded with a $50,000 grant from the Brain Tumor Fund for the Carolinas. For further information, please contact Sarah Woodring at 919-684-2527. Further details about the trial can be found here.

> LDN for MS—Akron, Ohio

In May 2007, the MindBrain Consortium and the Department of Psychiatry of Summa Hospital System of Akron, Ohio, along with the nearby Oak Clinic for the treatment of Multiple Sclerosis, announced a new scientific study of the effects of treating MS with low dose naltrexone. Psychologist David Pincus and his colleagues coordinated the study. It was a 16 week, double-blind, randomized, placebo-controlled, crossover-design analysis of 36 patients with either progressive or relapsing-remitting MS. The study examined symptom severity as well as any changes in quality of life, sleep patterns, and affective states.

In early October 2007, Dr. Pincus wrote as follows:

We have enrolled more than 20 of the 36 people intended; we expect to be fully recruited within the next 3 or 4 weeks, and, three months following the end of enrollment we will have all the data. The study is going well, a couple of people have dropped out or been removed for one reason or another, but none because of a problem with sleep. One patient had sleeping issues for a few nights, but then has been ok. We are looking at the psychoactive properties of LDN as well as assessing improvement of MS symptoms, and hope to find some changes in perception of energy level that correlate with personality type and amount of dreaming reported.
One year later, Dr. Pincus reported problematic outcomes in his study, with little apparent differences between the placebo and treatment groups. After lengthy consideration with his colleagues, he wrote as follows:
We did not exclude patients on existing immunosuppressants....The existing immunosuppressants may have inhibited the LDN effects in this population.

Animal Trials of LDN

> Research on Neurodegeneration at NIEHS Suggests a Protective Naltrexone Role

J.S. Hong, Ph.D., head of the Neuropharmacology Section of the Laboratory of Pharmacology and Chemistry at the National Institute of Environmental Health Sciences, finds that "morphinan" drugs, including naltrexone and naloxone, are able to reduce inflammatory reactions in microglia brain cells in animal studies. Such inflammation is believed to be central to the progressive neurodegenerative effects seen in disorders such as Parkinson’s disease and Alzheimer’s disease. Hong’s report, summarizing the role of microglia in inflammation-related neurodegeneration and the potential of therapy using morphinans, appears in a January 2007 issue of Nature Reviews Neuroscience [8(1):57-69].

> Research at Penn State: LDN for an Animal Model of MS

The National Multiple Sclerosis Society “awarded a small Pilot Award to Ian Zagon [Ph.D.] at Pennsylvania State University in Hershey, PA for the term of 09/01/2006 through 08/31/2007 in the amount of $44,000. The title of his project is ‘Role of opioid peptides and receptors in MS.’ This study [treated] an animal model of MS daily with either a high dose of naltrexone or a low dose of naltrexone to determine whether naltrexone influences disease course.”

Zagon described the project as follows:

This research project raises the question of whether endogenous opioids and opioid receptors influence the course of MS. This is a novel and innovative concept that is valuable to explore. To test this hypothesis, we will subject [rodents] to experimental autoimmune encephalomyelitis (EAE), a model that mimics MS. Animals will be treated daily with a high dose of [naltrexone] (HDN) or a low dose of [naltrexone] (LDN)....Our expectations are that continuous opioid receptor blockade will exacerbate the progression of MS, whereas a low dose of naltrexone will retard the course of this disease. Evidence for the involvement of endogenous opioids and opioid receptors in MS will open a new field of research related to the pathogenesis of this disease, and contribute to the development of strategies for treatment.

Dr. Zagon’s expectations were met, as is clear in the titles of the two poster presentations (below), which he gave to the World Congress on Treatment and Research in Multiple Sclerosis, held in September 2008 in Montreal, Canada. The actual data still awaited journal publication at that date:

Poster 190—Low-dose naltrexone (LDN) prevents development or delays onset and reduces severity of experimental autoimmune encephalomyelitis in mice. K. Rahn, P. McLaughlin (Hershey, Pennsylvania, USA), R. Bonneau, A. Turel, G. Thomas, I. Zagon.

Poster 216—The complete blockade of opioid receptors with naltrexone exacerbates experimental autoimmune encephalomyelitis in a mouse model. I. Zagon (Hershey, Pennsylvania, USA), K. Rahn, R. Bonneau, A. Turel, G. Thomas, P. McLaughlin.

Past Completed Clinical Trials of Low Dose Naltrexone

> Penn State Trial for Crohn's Disease

Endoscopic Improvement in Crohn’s Colitis with Naltrexone


Figure A: Shown is the rectum of a subject with active Crohn’s Disease before starting therapy with naltrexone 4.5 mg/day. The mucosa is ulcerated, edematous, and inflamed.
Figure B: Shows the same area of the rectum in the same patient four weeks after naltrexone therapy. The lining is now healed, ulcers resolved, and the mucosa is healthy.
Copyrights: do not reproduce the above images and captions without written permission from Jill P. Smith, MD, Professor of Medicine, H-045 GI Division, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033

The report on this groundbreaking research—"Low-Dose Naltrexone as a Treatment For Active Crohn's Disease"—was presented on May 23, 2006 at Digestive Diseases Week, a prestigious gastrointestinal conference, by Professor Jill Smith of the Pennsylvania State University College of Medicine. Dr. Smith's research paper, "Low-Dose Naltrexone Therapy Improves Active Crohn’s Disease," has been published by the American Journal of Gastroenterology in its January 11, 2007 edition.

Dr. Smith and her colleagues concluded that "LDN therapy offers an alternative safe, effective, and economic means of treating subjects with active Crohn's disease."

According to the news from Penn State, the National Institutes of Health has already granted $500,000 for Dr. Smith's group to continue the study. This funding should help assure a full-fledged placebo-controlled scientific trial of LDN in Crohn's disease. (Notably, Dr. Smith and her research teams are also involved in exploring the direct effects of using a form of endorphin by infusion in order to treat pancreatic and colon cancer.)

For further details, see Penn State's online news, and our multimedia coverage of Dr. Smith's keynote address at the Second Annual LDN Conference, April 7, 2006.

Below are some extracts from the trial summary that was published online by the gastroenterology conference:


Low-Dose Naltrexone as a Treatment For Active Crohn's Disease

J. P. Smith1; H. E. Stock1; S. I. Bingaman1; D. T. Mauger2; I. S. Zagon3
  1. Medicine, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
  2. Health Evaluation Sciences, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
  3. Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
Methods: Eligible subjects with histologically and endoscopically confirmed active Crohn's disease with a Crohn's Activity Index (CDAI) score of 220-450 were enrolled in a study using 4.5 mg naltrexone/day. Subjects were required to be off infliximab for at least 8-weeks, and this medication was not allowed during the trial. Other drug therapy for Crohn's disease utilized 4 or more weeks prior to enrollment was continued at the same dosages.... Drug [LDN] was administered orally each evening for a 12-week period. Laboratory tests, erythrocyte sedimentation rates, C-Reactive protein, and CDAI scores were assessed monthly and 4 weeks after discontinuing the medication.

Results: Seventeen patients with a mean initial CDAI* score of 356 ± 27 were enrolled in the study. CDAI scores decreased significantly (p<0.01) with LDN, and remained statistically lower than baseline 4-weeks after completing therapy (see Figure).

Penn State Crohn's Trial: graph of CDAI scores during and after the trial shows significant decrease.

Eighty-nine percent of patients exhibited a response to therapy (>70-point decrease in CDAI, p<0.001) and 67% achieved remission (CDAI score <150). QOL* surveys indicated marked improvement with LDN. No laboratory abnormalities were noted. One subject undergoing routine endoscopic procedures showed healing of the intestinal mucosa. In both subjects with open fistulas, closure was noted with LDN. The most common side effect of LDN was sleep disturbances (7 patients).

Conclusions: LDN therapy offers an alternative safe, effective, and economic means of treating subjects with active Crohn's disease.

*[Editor's Note: CDAI = Crohn's Disease Activity Index; QOL = Quality of Life]

> Pain Therapeutics Ends Irritable Bowel Syndrome Trials of Ultra-low Naltrexone Dosage

In December 2005, Pain Therapeutics, Inc. announced results of its Phase III study with PTI-901. [Editor's Note: PTI-901 contains only 0.5mg of naltrexone, which is well below the therapeutic dosage range for LDN—normally from 1.75mg to 4.5mg every night. LDN in the normal dosage range has been anecdotally reported quite beneficial in halting IBS.] Excerpt from PTI's announcement:


This randomized, double-blinded, multi-center U.S. study compared a daily dose of PTI-901 against placebo in 600 women with documented IBS over a three-month treatment period. PTI-901 showed a favorable safety profile and patients reported statistically meaningful relief of IBS symptoms in the second month of treatment (p<0.02), but the drug did not demonstrate a meaningful benefit in the third month of treatment, which was defined as the primary endpoint. According to current regulatory standards, an experimental drug for chronic IBS needs to show efficacy at the end of a three-month treatment period.

The Company believes this study was well designed to detect any durable benefits of PTI-901 versus placebo in a large patient population with IBS. Based on the adequacy of the study itself, coupled with today's clinical results, the Company is discontinuing all further clinical development activities with PTI-901.

> Dr. Evers Trial in Germany for Multiple Sclerosis (MS)

Conducted in the Multiple Sclerosis Clinic of Dr. Evers Hospital in Sundern, Germany, the starting date was October 15, 2004. It is described as a short-term scientific, randomized, placebo-controlled, double-blind study involving patients with either secondary-progressive MS (SPMS) or primary-progressive MS (PPMS).

[Editor’s Note: Unfortunately, because of some early complaints of sleep disturbance, the principal investigator of this trial switched all of the study group to taking LDN at 9am in the morning, a questionable dosage time. It is generally recognized that the most effective time to take LDN is at bedtime, between 9pm and 3am, due to the fact that the endorphins for each day are always produced at their peak rate in the pre-dawn hours. A 9am dosage time, as was used in this trial, might conceivably suppress—rather than boost—a patient's immune system.]

The purpose of the study was to investigate what MS-associated symptoms are positively influenced by LDN (low dose naltrexone, 3 mg per day). The principal investigator, Dr. Mir, reported his findings at the First Annual LDN Conference in 2005, as well as on his website.