Naltrexone for Cancer

Naltrexone is an opioid receptor antagonist approved and used for management of alcohol and opioid dependency.  Low dose naltrexone or LDN (at 1/10th of the dose used for drug rehab) however has been proposed as an off-label therapy for a broad range of immune disorders such as HIV, MS, autoimmune thyroiditis, and colitis, and is one of the more popular off-label treatments for cancer thanks to some promising trials, low toxicity, relative low cost and much internet publicity such as found on the Low Dose Naltrexone Homepage and a Low Dose Naltrexone Forum.  But if you don’t have a health science degree you might be wondering, what is the connection between cancer and opioids? And most importantly, does it work?

Opiates and Cancer

First some background on opioids and cancer.  Firstly, there is the difference of endogenous opiates (eg endorphins and enkephalins) vs. exogenous opiates (drugs).  The effects of opioids on cell growth is complex and is believed to be mediated through opioid and non-opioid receptor signalling (See Chen YL et al. The Other side of the Opioid Story: Modulation of Cell Growth and Survival Signalling, Curr Med Chem 2008:15(8):772-8), thus opioids directly modulate cell growth and endogenous opiates can directly suppress cancer growth.  On the other hand, exogenous opiates can suppress the immune system, which is not ideal for treating cancer. It has been known for some time from animal studies that opioids interfere with the immune system ( Sacerdote P, Opioids and the Immune System, Palliat Med 2006;20 Suppl 1:s9-15), and that opioid pain killers such as morphine can decrease and depress immunity.  In animal studies for example, morphine causes worsening of cancer, although the effect is different amongst different opioids, with buprenorphine (“Bupe”) perhaps the least immunosuppressive.

Background 1: Zagon

Now back to Naltrexone, an opioid antagonist.  There is no doubt that Dr. Ian Zagon at Penn State is a major pioneer researcher in endogenous opiates and the major bench-side explorer of “off-label” applications of LDN.  In his own words about the journey of discovery of opioid effects on cancer, he said : “When we discovered the effects of opioid antagonists such as naltrexone and naloxone in 1979, this was purely happenstance. Around 1975, we were interested in the effects of opiates… on children who were born to mothers that were addicted. The scientific literature revealed that these babies and children had neurological difficulties and were lower in body weight. We (myself and Dr. Patricia McLaughlin) developed a model to look at this in animals. Along the way, I was doing another project on neuroblastoma, a childhood tumor. When I found that these exogenous opioids altered growth of these developing animals… This started in 1977-1978. We then progressed to injecting cells into mice and creating cancers, and examined whether these exogenous opioids would repress growth of these cancers. In fact, they did…(as quoted on the LDN forum).

It turns out from Zagon’s research, that the central actor may be one “OGF” or opioid growth factor, or otherwise known technically as [Met5]-enkephalin.  Zagon proposed that OGF is an inhibitory peptide whose action is modulated via an OGF receptor and which modulates cancer cell proliferation and migration, and angiogenesis. Zagon has demonstrated that OGF inhibits pancreatic (BxPC-3), colon (HT-29), renal cell (Caki-2), neuroblastoma, and head and neck (CAL-27) cell lines (Int J Oncol, 2000 Nov;17(5):1053-61). Moreover, OGF also suppressed pancreas cancer in animals (Cancer Lett 1997 Jan 30;112(2):167-75) , and synergistically enhanced the efficacy of chemotherapy against pancreas cancer (Cancer Chemother Pharmacol 2005 Nov;56(5):510-20) and enhanced survival in squamous cell head and neck cancer as well(Cancer Chemother Pharmacol 2005 Jul;56(1):97-104).  Based on such observations, Zagon & McLaughlin filed a patent in 1997 claiming that the administration of an opiate antagonist such as Naltrexone “at an amount sufficient to effect the intermittent blockade of the zeta receptor present in the cancer (and surrounding tissues) thereby producing a subsequent period of elevated endogenous enkephalin levels or receptor numbers to inhibit, arrest and even prevent tumor growth” (US Patent 6136780)

Background 2. Bihari

Almost working in parallel as Zagon, but from the clinical side and not in the laboratory, there is one Dr. Bernard Bihari, who is an addiction specialist who used Naltrexone and claims to have discovered the immunomodulatory benefits of Naltrexone in 1985.   The story goes that Dr. Bihari began noticing in the 1980s that some of his addict patients with immune deficiency (subsequently discovered to be HIV/AIDS) had symptomatic improvement on lower doses of Naltrexone, so he conjectured that Naltrexone somehow upregulated their immune system (See AIDS Patient Care 1995 Feb;9(1):3).  Along this line of thinking and based on some reports that lymphoma responded to endorphin treatment in animals, he had treated a recurrent lymphoma patient with low dose naltrexone and the lymphoma got better.  He subsequently also treated a woman named CP with advanced melanoma and the cancer responded. Then from 1999 onwards, Dr. Bihari investigated the effects of LDN in private patients, using a low dose of 3mg given at night and theorizing that the treatment induced an increase in endorphins, especially metenkephalin, in the pre-dawn hours.  The endorphins would in turn directly suppress cancer growth and upregulate the immune system.  This theory coincided with Zagon’s animal work on how OGF may inhibit cancer and is consistent with the actions of naltrexone.  Unfortunately, there has not been any organized clinical trial or even published case series on this, except for what has been presented in the Low Dose Naltrexone website, that “as of March 2004 … medication by Dr. Bihari in some 450 patients with cancer, almost all of whom had failed to respond to standard treatments, suggests that more than 60% of patients with cancer may significantly benefit from LDN. Of the 354 patients with whom Dr. Bihari had regular follow-up, 86 have shown objective signs of significant tumor shrinkage, at least a 75% reduction. 125 patients have stabilized and/or are moving toward remission” Apparently,  of patients treated, “88 LDN-only group includes five breast cancer patients, one patient who had widespread metastatic renal cell carcinoma, three with Hodgkin’s disease and six with non-Hodgkin’s lymphoma. Reportedly, other cases, some on LDN for as long as four years, included a score of patients with non-small cell lung cancer, as well as patients with ovarian cancer, uterine cancer, pancreatic cancer (treated early), untreated prostate cancer, colon cancer, malignant melanoma, throat cancer, primary liver cancer, chronic lymphocytic leukemia, multiple myeloma and some others” according to another website.  Again reportedly, in June 2002 an oncologist and an oncology physician’s assistant from the National Cancer Institute reviewed some 30 charts of cancer patients at Dr. Bihari’s office, and about half were chosen as appearing to have responded to LDN without question.  Supposedly, copies of these records were sent to the NCI for further data collection on its part for consideration for NCI’s Best Case Series. Four cases of prostate cancers responding to LDN was reported as well in a patent “Method of Treating Cancer of the Prostate” Bihari filed in 2000. But again, regretfully, none of any of these cases ended up being published in the medical literature, and they circulate as quasi-anecdotal mentions online.

How might Naltrexone work in cancer?

In summary, based mainly on Zagon’s work, naltrexone at low dose administered nocturnally could bne postulated to work via 1) a stimulation of endogenous opiates as well as the number and density of opiate receptors on tumor cell membranes making them more responsive to the inhibitory effects of circulating opiates, which in turn suppresses tumor growth directly, 2) an enhancement of cellular immunity as a result of effects of higher levels of endogenous opiates, and 3) metabolites such as methylnaltrexone which exert antiangiogenic effects.

What does the medical literature say?

Bihari had published nothing on LDN and cancer in the medical literature.

Zagon had reported on using naltrexone in a mouse neuroblastoma model showing inhibition of growth and prolonged survival in those mice that develop tumors and protected some mice from developing tumors altogether (Brain Res 1989 Feb 20;480(1-2):16-28).  At a similar dose of 0.1mg/kg, his team was also able to retard implanted human colon cancer in mice (Cancer Lett 1996 Mar 29;101(2):159-64), apparently via an stimulation of metenkephalins, which is in line of his research hypothesis.

Clinically, only two single case reports of 1) a long surviving metastatic pancreas cancer treated with LDN and alpha-lipoic acid (Integr Cancer Ther 2006; 5(1):83-9), and 2) a B-cell lymphoma with clinical reversal using only LDN Integr Cancer Ther 2007; 6(3):293-296) can be found in the medical literature that I can find.

Along these lines, an OGF plus gemcitabine for pancreas cancer trial is on the way (starting this month!) at Penn State, but while there are several trials on LDN for Crohn’s and MS and other conditions on the way, there is nothing on the horizon testing LDN for cancer per se.

My Take

I have been prescribing off-label Naltrexone to my cancer patients for many years.  I remember being asked by organizers from Drs. Bihari’s camp to present at the 1st Annual LDN Conference in 2005 but declined to attend because I had no clear cut cases to report  (Then they asked me to report on the tolerability of the treatment, which is not meaningful, and I didn’t go).  Indeed, over the years, I have not seen any definitive responses that I can attribute to LDN with certainty.  I wish to give some credence to the cases of response found online, but such are anecdotes that cannot strictly be considered admissible evidence in clinical science, only suggestive leads for further investigations. There are inherent limitations for testing LDN of course: not every patient is a candidate (eg if on narcotics for cancer pain) for LDN and most who take it are on at least a few other treatment modalities making a judgement of LDN efficacy difficult.  Then also, the drug itself is cheap and generic and thus there is no industry interest in funding formal trials.  However, I still prescribe LDN to this day since the theoretical background is not unsound, the side-effects are minimal, and the substance is readily available and at such a reasonably low cost that I usually do not mind the addition of LDN to a patient’s treatment, especially if requested and especially in cases of pancreas or colon ca, melanoma, SCCHN where there has been studies or prostate cancer where there has been a patent filed.  Personally, I think LDN may perhaps have greater promise in other conditions such as Crohn’s and MS rather than cancer, and OGF may be a more direct opioid treatment option for cancer in the future.

Your comments welcome.

  1. Garnet
    August 9, 2009 at 3:09 pm

    I want to thank Dr Chang for an excellent summary of LDN’s potential to treat Cancer. His conclusion that OGF might hold more promise for treatment than LDN is not without merit. I would simply point out that OGF is at least 100 times more expensive than LDN and not available for use as a prevention, but LDN is easy to obtain, inexpensive and used widely as a preventative for cancer and other auto-immune disorders.

    More studies and better funding are needed to clarify the reported benefits of LDN. Until then we have evidence based medicine to support the use of LDN in many disorders including those mentioned by Dr Chang. As well it is being used in dogs and cats, a use that most pet owners are not aware of. While we await more clinical studies it is important to continue to make patients and their families aware of LDN’s potential to stop progression of disorders such as MS, Alzheimers, Parkinsons, Infertility, HIV/AIDS, CFS, FM, immune deficiency and more. For more information please Google LDN !

  2. Jim Garter
    March 23, 2010 at 11:03 pm

    Thanks Dr. Chang, What an informative piece!!

    I found a lot of info on a new site – http://www.ldnscience.org – it has all of Dr. Zagon’s studies there and gives some good explanations of how LDN and OGF work.

    Thanks again

    Jim

  3. Cris Kerr
    June 14, 2010 at 7:31 am

    Dear Dr Chang,

    Thank you for this article.

    You’ll find 47 patient case histories here, as well as interviews with 9 health professionals;

    (1) ‘Those Who Suffer Much, Know Much’ 2009 edition
    http://www.ldnresearchtrustfiles.co.uk/docs/2009.pdf

    and you’ll find 100 patient testimonies in this book:

    (2) ’100 Reasons Why… You Should Know about LDN’ 2009 edition contains 100 patient testimonies of improved health using LDN.
    http://www.ldnresearchtrustfiles.co.uk/docs/International%20LDN%20Awareness%20Week%20eBook.pdf

    Here are other links that may be of interest:

    (3) ‘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.
    http://www.ncbi.nlm.nih.gov/pubmed/18728058

    (4) Stanford Univ – Fibromyalgia & LDN
    URL: http://www.snapl.stanford.edu/research/ldn.html

    (5) A Randomized Placebo-Controlled, Crossover-Design Study of the Effects of Low Dose Naltrexone for Multiple Sclerosis – Phase III Study – Principal Investigator: Bruce Kornyeyva, MD, PhD MS Center, University of California, San Francisco http://www3.interscience.wiley.com/journal/123289912/abstract

    (6) ‘Low Dose Naltrexone Therapy Improves Active Crohn’s Disease’, American Journal of Gastroenterology, Prof Jill Smith, Professor of Gastroenterology, Pennsylvania State University, Jan 11 2007
    http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=17222320

    If it’s not listed here, you’ll likely find it on lowdosenaltrexone.org or ldnresearchtrust.org.

    All my best,
    Cris Kerr

  4. Stephen Strum, MD, FACP
    November 1, 2010 at 1:58 am

    I have also extensively reviewed the Naltrexone literature and corresponded with Dr. Zagon and other members of his staff at Penn State. I communicated years ago with Bihari and tried LDN in my PC (prostate cancer) patients since this is my sole focus as a medical oncologist. I did not see any evidence of response per PSA declines and just stopped using the drug. Unfortunately, I was too busy in my practice to write up the negative report. There is clearly a need for some clinical trials using LDN to put the issue of its value as an anti-cancer agent to rest. I feel that those who use LDN for cancer, Crohn’s disease, fibromyalgia, MGUS, and multiple sclerosis may wish to work together and use an agreed upon clinical protocol so that answers as to efficacy can be expedited.
    The published articles on LDN & MS are difficult for me to assess given the clinical endpoints which I am not familiar with. What would be worthwhile would be some form of objective clinical assessment tool and a patient self-rating pre and post LDN. I believe you contributed a very nice review of this subject.

  5. November 1, 2010 at 2:13 pm

    There are many of us patients willing to try LDN and many of us see benefits. But, the issue that keeps recurring is that none of us know for sure if this works. Only proper trials can settle this and surely, when so many patients are choosing to use LDN, we have the required case for public funding of a trial that cannot attract private money.
    We have never asked for anything else except the trials so we can all one day sleep sound in the knowledge that LDN works or doesn’t. Or maybe, researchers don’t really care for patients, maybe our ‘expert’ opinions are considered trivial. Well, I have read widely on cytokines and such for my MS, and as the author here says, the theory is sound. Research trials are needed and have become very important in this case.

  1. May 11, 2009 at 5:14 am

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

Follow

Get every new post delivered to your Inbox.

Join 27 other followers

%d bloggers like this: