Low dose naltrexone

Low dose naltrexone (LDN), where naltrexone is used in doses approximately one-tenth those used for drug/alcohol rehabilitation purposes, is being used as an "off-label" treatment for certain immunologically-related disorders. The use of LDN for such diseases as cancer was first proposed by Ian Zagon, PhD, and LDN's broader clinical effects in humans were proposed by Bernard Bihari, MD.

Naltrexone is an opioid receptor antagonist. Opioids include natural compounds such as endorphins (responsible for the feeling of reward, or as experienced in a "runner's high", but also synthetic and semi-synthetic drugs such as morphine, methadone, fentanyl and heroin. Naltrexone, is used in high doses to counteract the effects of alcohol dependence, and presumed to work by the same mechanism, inhibition of the feelings of reward received by alcohol administration via endogenous opioids.  Low Dose Naltrexone has not been approved for use by the FDA.

The only published data on the use of low-dose naltrexone has been in Crohn's disease and irritable bowel syndrome. These were both open-label pilot studies. The fact that it is open label indicates that there was no placebo group to compare to, making it impossible to differentiate the effects from a placebo effect. Also, as in all pilot studies the purpose of these studies is to design a future clinical study and not enough patients are included to be able to determine whether a result is statistically significant (as the range of responses needs to be determined first by a previous pilot study.

To date, there have been no published studies of LDN in other diseases. No one has been able to show a benefit for multiple sclerosis patients in any published study over the more than two decades that some individuals have promoted its use.

In Milan, Italy, a sixth month pilot study with a low dose of the opiate antagonist Naltrexone (LDN) was carried out in 40 patients with primary progressive multiple sclerosis (PPMS). The endpoints of the trial were to determine the psychoactive benefits of LDN. No measure of disease progression, or modification of disease was tested. Moreover the main measure was safety and tolerability, not the efficacy of the drug. The secondary endpoints were spasticity, pain, depression, and quality of life. The design and endpoints for the trial indicate that no conclusions can be drawn about the ability of LDN to modify disease activity. These are measures of psychological change to a drug that acts, psychological function. Similarly other drugs have effects on the symptoms of disease without combatting the disease itself such as Ampyra are tested in a similar manner. Their trials similarly do not test disease modifying endpoints  The study did not look at any of the measures typically looked at in an MS trial to determine how effective the drug is in combating the physical effects and mechanisms of the disease rather than just symptoms. Typical disease modifying endpoints would have included the change of lesions on an MRI, a typical and devastating aspect of MS, or a change in disability as measured by EDSS. MS trials are generally in the hundreds of patients, doing so few patients virtually guarantees that no changes in disability are seen. . It reported that neurological disability progressed in only one patient, and that a significant reduction of spasticity was measured at the end of the trial. It also reported that BE (β-endorphins) concentration increased during the trial, but that no association was found between OPRM1 (µ-opiod receptor gene variants) and improvement of spasticity. There were two major adverse events and five dropouts from the trial, resulting in an extremely small sample group. Transient increases in liver enzymes, urinary tract infections, mild agitation and sleep disturbance were the most common adverse events. An elevation of liver enzymes may indicate that the drug had liver toxicity in those patients. Multiple Sclerosis. 2008 Sep;14(8):1076-83. A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis. http://msj.sagepub.com/cgi/content/abstract/14/8/1076

Low-dose naltrexone (LDN) may be useful in treating symptoms of pain in fibromyalgia, according to statements by Jarred Younger, Ph.D., and Sean Mackey, M.D., of the Stanford University School of Medicine in Palo Alto, Calif. The study does not demonstrate effectiveness in treating the causes of fibromyalgia, and was too small to conduct a proper statistical measure in even by this measure. With only ten patients enrolled it is impossible to dermine efficacy. 40% of patients saw no difference. The physicians made no statement that the drug was definitively effective in treating fibromalgia. To date, this data has never been reported or published in a medical journal. The physician states: "We conclude that LDN is a drug that should be researched more thoroughly for the treatment of fibromyalgia, and perhaps more generally for conditions associated with elevated erythrocyte sedimentation rate." The American Fibromyalgia Syndrome Association provided financial support for the study. http://snapl.stanford.edu/research/ldn.html. However, no data has been published by this group or any other for the use of LDN in fibromyalgia.

The results of an open-label pilot study at Pennsylvania State University College of Medicine were reported to an international gastroenterology conference in Los Angeles in May 2006, however the data has never been published in a medical journal. The trial examined the safety and efficacy of LDN in a group of patients with Crohn's disease. As a small pilot study, this study is not able to determine if the treatment is effective with statistical accuracy and is for the purpose of designing a phase II clinical trial. Dr. Jill Smith, Professor of Gastroenterology at Pennsylvania State University's College of Medicine concluded that "LDN therapy appears effective and safe in subjects with active Crohn’s disease." Smith and her colleagues have since received a NIH grant and are proceeding with a definitive Phase II placebo-controlled clinical trial.

There is some in vitro data that may suggest the potential benefits of LDN therapy. Despite the claims of "thousands of patients" who take LDN there have only been anecdotal accounts, personal opinions and case reports cited in favor of LDN therapy Those Who Suffer Much Know Much, July 2009 is the first book to contain LDN patient testimony in detail, as case studies. It contains 47 low dose naltrexone patient case studies, researched over many years and produced by Cris Kerr of Case Health as a community service. Some of the many conditions for which LDN has been reported as beneficial include multiple sclerosis (in particular, the primary progressive variant ), Crohn's disease, HIV/AIDS, chronic fatigue syndrome, irritable bowel syndrome, psoriasis, fibromyalgia, ALS, autism in children, depersonalization disorder, and cancer. Several clinical trials have been planned and a few are currently taking place.

Various low doses of Naltrexone have also been used as part of the "NaProTECHNOLOGY" fertility treatment, a commercially trademarked and heavily marketed product aimed at religious adherents who may have moral objections to common birth control and fertility treatments. 

Pharmacology
It has been theorized that LDN works in multiple modalities. It's known mechanism of action is in binding the opioid receptor and blocking binding at this site. Opioid receptors affect reward and various psychoactive functions of behavior and emotion.

The evidence of an interaction of endorphins to the immune system is limited and it is likely that endorphins are only a minor player in the immune system. The most cited literature is indeed not how endorphins modify the immune system, but rather the reverse. Specifically, during infection, when the immune system is elevated endorphins may be released, not to affect the immune system but to modulate feelings of pain and discomfort. Rather than endorphins modifying the immune system the major effects are in the opposite direction and well known in common experience: the immune system can make us feel better or worse. However, perhaps implicated in the connection between stress and immune function, there is some evidence that opioids may cause some immunosuppression at high doses.

Although opioids are widely used for the treatment of severe pain it is also known that opioids, in particular morphine, cause immunosuppression. Therefore, their use may complicate treatment of persons with an already impaired immune system, e.g., patients suffering from cancer or AIDS. However, there is no evidence that doing the opposite, blocking opioid receptors, has any effect on the immune system

Although in vitro endorphins increase the effects of the immune system, in vivo, they are immunosuppressive. This apparent contradiction can be explained, because, at least in the case of morphine, the site of opiate action appears to be in the central nervous system (CNS). Moreover, the effects appear to be mediated by the adrenal gland, most probably by catecholamines. Much of the debate regarding LDN seems to confuse the results in vitro with those of in vivo work where opioids are immunosuppressive

It is unlikely that opioid blockade with naltrexone has any effect on the immune system, as none has been demonstrated in the scientific literature in vivo or in live patients. The proposed mechanisms of LDN on the immune system are self contradictory indicating that it is immunomodulatory when no such evidence exists. Opioids are immunosuppressive and there is no known effect of lose dose blockade of opioids, nor is there any evidence in the literature that low dose blockade with LDN results in a release of opioids at some later time, not just at a therapeutic dose but also not at any detectable dose at all.

Despite scientific evidence to the contrary alternate theories have been posited originally by Dr. Bihari is as follows (It should be noted that Dr. Bihari is neither a pharmacologist nor a biochemist, but a psychiatrist).

Naltrexone, which is a pure antagonist to opiates, causes an artificial blockade of the endorphin/opioid receptors in the brain. Dr. Bihari proposes that unlike the normal (~50 mg) dose of naltrexone used to treat drug addiction, which maintains this blockade continuously for 24 hours (preventing any derived pleasure from taking the forbidden drugs), low dose naltrexone (~3 mg to 4.5 mg) may block the endorphin receptors for only a couple of hours. During that time, endorphins may fail to attach to the receptors and the body compensates by creating more endorphins. (Note that Dr. Bihari prescribes LDN to be taken at bedtime to take advantage of the body's pre-dawn boost in endorphin production.) Once the low dose naltrexone dose has been metabolized, Dr. Bihari conjectures that the body is left with a "normal" amount of endorphins as compared to healthy controls, which consequently "normalizes" the immune function. The link between endorphins and immune system regulation is a good candidate for more research.

There is no published scientific evidence that the mechanism of action proposed by Dr. Bihari actually occurs. Additionally, any change in endogenous endorphin levels theorized does not explain how they would simultaneously increase immune function in HIV as well as decrease it in multiple sclerosis.

Since 2005, at least 3 separate scientific reports have described an underlying immunodeficiency as being characteristic of four different autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, Crohn's disease and chronic fatigue syndrome. In addition, recent scientific research has demonstrated abnormally low beta-endorphins in all forms of multiple sclerosis.

Criticism
A need for clinical trial data on the effects of low-dose naltrexone has been identified. Most MS physicians refuse to prescribe LDN without an adjunctive therapy that modifies disease, such as those demonstrated to effective in clinical trials. There is no data that LDN modifies the immune system in any kind of way. There has been no demonstration in a reduction of MS relapses, no reduction shown for MRI lesions such as T1 black holes, new or enhancing T2 lesions, or gadolinium enhancing lesions (which indicate new immune infiltration). The limited pilot studies in LDN have generally used LDN in combination with the already effective therapy. Although MS physicians often prescribe symptomatic therapy for erectile dysfunction, mood, spasticity and other MS symptoms, they generally prefer disease modifying therapy Conflicting claims have been made about LDN including that it "boosts" the immune system (which is detrimental to patients suffering from autoimmune disorders, or that LDN is believed to restore "normality" to the immune system (although no test in humans, animals, or even in vitro has demonstrated this), which leads to "correct" immune system behavior. Additionally, although many mechanisms of action have been proposed, none have been demonstrated in actual MS patients. Additionally, no effect beyond that of psychoactive effects have been demonstrated in any system.  Additionally, conflicting claims of its mechanism of action indicate, that even if it to work by these unproven mechanisms, some of these mechanisms are detrimental to MS patients. For instance, it is proposed to work for HIV+ patients by increasing CD4+ helper T-cells. An increase in CD4+ helper T-cells is exactly what is proposed to be the main mechanism by which the disease is aggravated.

Conferences
The most recent LDN Conference was held on 19 October 2009 at the National Institutes of Health, near Washington D.C.

Last year's Annual LDN Conference was held on 11 October 2008 at USC Health Sciences Campus, Los Angeles, California, USA.

The first European LDN Conference was held on 25 April 2009 at The Western Infirmary, Glasgow, Scotland, UK. The next is on 23–24 April 2010.

http://birmingham2010.ldnresearchtrust.org/ The LDN Research Trust: LDN AWARE Birmingham Conference, October 23, 2010