Sunday, March 31, 2013

LDN Therapy and IBD


Low Dose Naltrexone


Naltrexone approved as a treatment of opioid (including heroin) and other chemical (including alcohol) dependence due to its ability to bind opioid receptors and prevent the opioids from binding to them.  It has been shown to be more effective for alcohol dependence treatment than opioid, but is approved for both uses.  It has also been used for general addiction and personality disorder treatments.  Side effects include GI-distress, and high dose Naltrexone has been controversially linked to liver damage.(1)

Low-Dose Naltrexone, or LDN, has a dosage below that which causes liver damage, and has a relatively safe profile.  It has been presented as a cure for everything from cancer to HIV infections to IBD, predicated on the valid (but simplified) concept that immune cells also have opioid receptors that can influence cell function.  In theory, LDN can act as an immunomodulator by effecting the behavior of these cells.(2)

Because they have a valid theory of action, LDN treatments deserve a look for autoimmune diseases.  Though the theory of action is incomplete (the effect on those immune cells with opioid receptors may nor may not end up helping with any given underlying condition), the treatment deserves to be considered in at least pilot studies for efficacy and safety.  Specifically for the treatment of IBD, there is one key pilot study that was performed in 2007.

The study in question enrolled 17 patients and was completely unblended (the doctors and the patients knew what they were getting in terms of medication).  There was no control group, and the subjects all took other medications concurrently.  One subject dropped out due to a flare, and two others stopped their regular meds, resulting in one having a flare.  They included the data from the patients as intent-to-treat, which is generally good and provides a conservative result.  In this case, though, the dropout of the most severe would have resulted in a substantial skew of the end median results reported (all but the worst were averaged…)  That said, the study did have a generally positive trend, with a lowering of CDAI scores (not really a great measure in open label studies) and lab numbers, especially C-Reactive Protein numbers (a much better and more promising indicator).(3)

The next study (I am ignoring the single person case report as having no statistical significance (4)) was on pediatric patients and looked at both safety and efficacy.  The study involved 12 children with moderate-to-severe Crohn’s disease, and was 8 weeks of single blind placebo controlled study and 8 weeks of open label study.  Each group in the initial study had 6 participants.  One patient (implied to be in the LDN group, but not directly stated) suffered a flare.  There was no clinical difference in C-Reactive Protein scores, and there was no statistically significant difference in CDAI scores.  There were minimal side effects identified in the study.(5)

The final (and best) study looked at 40 individuals (really 34 – 6 were excluded from the start) in a true double-blind fashion.  As with the previous 2 studies, the safety profile showed no large side effect issues with the LDN patients.  This study looked not only at CDAI and C-Reactive Protein scores, but also mucosal healing (the patients should be commended for subjecting themselves to 3 colonoscopies over 24 weeks!) 

On the good news front, there were statistically significant CDAI drops on the LDN-treated study.  Additionally, there were positive endoscopic results showing more mucosal healing in the LDN group.  This continued in the open label group after an additional 12 weeks.  On the negative side, the blood markers showed no improvement (this isn’t particularly troubling – most patients started with low CRP numbers).  One issue cropped up in the statistics – the worst patient (one who had a flare) was removed from the LDN group, and two additional patients who flared in the open label portion.  Given the small sample size, the removal of these patients could create fairly significant statistical changes.  Additionally, there were differences in concomitant medications between the 2 groups (more LDN patients on corticosteroids) and the LDN patients started with higher CDAI scores.  This is not a flaw in the study, just the type of anomaly that occurs in small trials.(6)

LDN treatment has some promise for treating IBD based on the preliminary studies, but the data is very, very preliminary at this point and the studies are not conclusive.  The responses shown justify further testing, but they indicate the LDN is not ready to be used to treat IBD at this point (the majority of studies at this pilot stage end up not panning out in the long run).  Dr. Novella at Science Based Medicine provides some valid words of caution for those touting LDN to loudly at this point:

Ironically, LDN promoters may in fact harm research into LDN by giving it a bad name. Researchers may be reluctant to hitch their careers, or funding agencies commit resources, to a treatment that has a dubious reputation. If the research is promising it will still get done, but if anything it is likely to be slowed by the efforts of the LDN promoters.

Bottom Line


·         Low Dose Naltrexone has some positive results and some mixed results in very preliminary early testing to treat IBD.  Larger scale clinical trials are in-progress.
·         Good evidence is not there at this point that LDN can be used to positively treat IBD.  More work is needed before that can be said.
·         If patients are interested in LDN, enroll in one of the clinical studies.  Otherwise, avoid the therapy until further testing is done.
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1.       Marrazzi, Mary Ann, Jill M. Wroblewski, Joseph Kinzie, and Elliot D. Luby. "HighDose Naltrexone and Liver Function Safety." The American Journal on Addictions 6, no. 1 (1997): 21-29.
2.       McCarthy, Lois, Michele Wetzel, Judith K. Sliker, Toby K. Eisenstein, and Thomas J. Rogers. "Opioids, opioid receptors, and the immune response." Drug and alcohol dependence 62, no. 2 (2001): 111-123.
3.       Smith, Jill P., Heather Stock, Sandra Bingaman, David Mauger, Moshe Rogosnitzky, and Ian S. Zagon. "Low-dose naltrexone therapy improves active Crohn's disease." The American journal of gastroenterology 102, no. 4 (2007): 820-828.
4.       Shannon, Angela, Naim Alkhouri, Shadi Mayacy, Barbara Kaplan, and Lori Mahajan. "Lowdose naltrexone for treatment of duodenal Crohn's disease in a pediatric patient." Inflammatory bowel diseases 16, no. 9 (2010): 1457-1457.
5.       Smith, Jill P., Douglas Field, Sandra I. Bingaman, Robert Evans, and David T. Mauger. "Safety and Tolerability of Low-dose Naltrexone Therapy in Children With Moderate to Severe Crohn's Disease: A Pilot Study." Journal of clinical gastroenterology (2012).
6.       Smith, Jill P., Sandra I. Bingaman, Francesca Ruggiero, David T. Mauger, Aparna Mukherjee, Christopher O. McGovern, and Ian S. Zagon. "Therapy with the opioid antagonist naltrexone promotes mucosal healing in active Crohn’s disease: a randomized placebo-controlled trial." Digestive diseases and sciences 56, no. 7 (2011): 2088-2097.
7.       http://www.sciencebasedmedicine.org/index.php/low-dose-naltrexone-bogus-or-cutting-edge-science/

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