Epilepsy is a broad term used to describe people who suffer multiple seizures in their life time.  Seizures are defined as sudden, uncontrolled electrical brain activity.  Depending on how the brain looks at these electrical currents a person may change behavior, display abnormal movement or even lose consciousness.

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As of 2015 about 3.4 million people suffer from epilepsy.1 Most people with epilepsy take one or more medications to prevent seizure activity. However, an estimated 30% of people worldwide do not respond to current FDA approved medications.2 With the rise in popularity of medical marijuana for treatment of epilepsy, scientists have begun to look at opioids again for new uses.  Ultra-low doses of naltrexone along with morphine or cannabis are being studied.

What is low and ultra-low dose naltrexone?

            Naltrexone is currently FDA approved as treatment for opioid and alcohol abuse. Available in pill or as an injection, treatment for opioid and alcohol abuse uses doses from 50mg to 380mg.  Low dose naltrexone broadly refers to dosages below the 50mg mark for opioid and alcohol abuse treatment.3 specifically 0.5mg to 10mg is the studied range when talking about low dose naltrexone. 

Ultra-low dose refers to even smaller doses ranging from 1/1000000000 of a milligram to 1/1000000 of a milligram. To picture how small ultra-low dose naltrexone is think of opioid treatment doses as a swimming pool.  Low doses are a couple of buckets.  Ultra-low doses would be drops.

There is no recommended dose of naltrexone for epilepsy or seizures in humans. The ultra-low doses have only been studied in mice as add-on to opioids and cannabis products.  These doses were administered in injection form.

How does low dose naltrexone work to prevent seizures?

            Ultra-low doses of naltrexone alone do not stop or prevent seizures.  Morphine and cannabis like products work to raise the amount of electrical activity in the brain needed to cause a seizure.  The exact way ultra-low doses of naltrexone works with opioids and cannabis in epilepsy is unknown.  Scientists think ultra-low naltrexone works either to increase the effects of the morphine and cannabis or helps to decrease tolerance.4-6

What are the studies saying about ultra-low dose naltrexone for epilepsy?

            Trials in mice using ultra-low dose naltrexone have been promising.  Data favors further study of ultra-low dose naltrexone with either opioids or cannabis like products.  However, no data yet suggests any safety for trials in humans.  Further animal study is needed to evaluate long term use.  Current trials in mice only looked at one seizure per mouse.4-6 

What are the risks of using low dose naltrexone for seizure control?

            As stated in the above section, current trial data is only for mice after one incident.  The effects of treatment long term have not been evaluated.  Seizure activity may develop again after time on the medications.  Doses tested in mice may not work in humans.

The Medicine Center Pharmacy in New Philadelphia specializes in custom compounded medications in custom dosage forms. The pharmacists are trained experts in low dose naltrexone therapy. LDN therapies can be customized across 23 different dosage forms for 15 different disease state protocols. If you would like to learn more about low dose naltrexone or would like to schedule a phone call or video conference please contact us.

Resources

1.     CDC [Internet]. Epilepsy Fast Facts. Center for disease control: Atlanta (GA); last updated 18 July 2018, accessed 18 April 2020. Available from: https://www.cdc.gov/epilepsy/about/fast-facts.htm

2.     Wahab A. Difficulties in Treatment and Management of Epilepsy and Challenges in New Drug Development. Pharmaceuticals (Basel). 2010 Jul; 3(7): 2090–2110.Published online 2010 Jul 5. Accessed April 2020.

3.     SAMHSA. Naltrexone. Substance Abuse and Mental Health Services Administration. Last updated  September 2019, accessed April 2020. Available from: https://www.samhsa.gov/medication-assisted-treatment/treatment/naltrexone

4.     Honar H, Riazi K, Homayoun H, Sadeghipour H, Rashidi N, Ebrahimkhani MR, et al. Ultra-low dose naltrexone potentiates the anticonvulsant effect of low dose morphine on clonic seizures. Neuroscience. 2004;129(3):733-42.

5.     Bahremand A, Shafaroodi H, Ghasemi M, Nasrabady SE, Gholizadeh S, and Dehpour AR. The cannabinoid anticonvulsant effect on pentylenetetrazole-induced seizure is potentiated by ultra-low dose naltrexone in mice. Epilepsy Res. 2008 Sep;81(1):44-51.

6.     Roshanpour M, Ghasemi M, Riazi K, Rafiei-Tabatabaei N, Ghahremani MH, and Dehpour AR. Tolerance to the anticonvulsant effect of morphine in mice: blockage by ultra-low dose naltrexone. Epilepsy Res. 2009 Feb;83(2-3):261-4.

Physiology of the Disease

Cancer is a condition in which cells within your body divide at an uncontrolled rate. Our body's natural defense against these cells are known as tumor suppressor genes. However, mutations can occur leading to the formation of oncogenes that promote cell growth and reproduction, or suppression of tumor suppressor genes. When this occurs, the cells divide rapidly leading to tumors or large masses and cause your bodies other healthy cells to die. These cancerous cells can then travel to other parts of your body through the bloodstream via a process known as metastasis. When this occurs, the cancer can continue to grow in these areas making it much more difficult to treat.

LDN – How it Works

At its intended doses of 50-100 mg, naltrexone is an opioid antagonist used in the treatment of addiction. However, when used at much lower doses, naltrexone is known to act as an anti-inflammatory agent. As we used LDN more and more, and involve it in animal and human studies, we have found it to be useful in many other conditions such as cancer. Although we do not know the full mechanism of action for benefit in cancer patients, here are some proposed mechanisms:

●      Intermittent dosing significantly reduced cancer cell development, in contrast to a constant blockade that accelerated tumor growth

●      May enhance natural killer cells, T-Cell, IL-2, and TH-2 activity via the mu receptor and also by binding to receptors on cancer cells themselves. These cells are the major players in our body’s natural immune system

●      LDN causes increased cell death in certain cancers and potentially increases patient response to chemotherapy agents

●      Cells that are treated with LDN up-regulate BAD and BIK1 genes that aid in cell death

●      Some cancer patients treated with intermittent LDN, experienced greater benefit by chemotherapy drugs

o   Example: Priming HCT116 with LDN before treatment with oxaliplatin significantly increased cell ki

Effectiveness

            Naltrexone’s potential for cancer prevention and treatment began mainly from the work of Penn State investigators Ian Zagon and his colleagues. They initially studied and published evidence that a dose of 0.1mg/kg in mice reduced neuroblastoma tumor incidence by 66%, slowed tumor growth by 98% and increased survival by 36% over controls.

            More recent publications include that from Liu et al in 2016 who published that cells treated with LDN followed by chemotherapy always resulted in a greater reduction in cell number and viability when compared to cells cultured with LDN after chemotherapy treatment. However, in cells treated with standard NTX, treatment with any of the cytotoxic drugs did not generally result in dramatic reductions in cell number or viability.

            Another researcher, Dr.Bernard Bihari has reported he has treated about 450 cancer patients with LDN, and he reports that over 270 patients had significant benefits from LDN. Of those patients, 86 of them had shown objective signs of decreased tumor size of at least 75%. Another 125 patients were stabilizing or on a path toward remission.

Dosing

Starting doses can be anywhere from 0.5 mg to 1.5 mg, and is increased up to 4.5 mg; which is the maximum dose for Low Dose Naltrexone. Specifically for cancer patients, the dose should be a goal daily for at least 7 days before starting an "on/off cycle"

●      An "on/off cycle" consists of 3 days on and 3 days off LDN

●      The 3 days off should fall directly before chemotherapy treatment. Although there are no known contraindications with chemotherapy, it is recommended to avoid use together until further research is completed

It has been seen in some cancer patients, that taking a CBD product on the 3 days off increases the anti-tumor effect of LDN

Side Effects

LDN is well tolerated in most patients and limited further when a patient is started on a start low and go-slow method. This means the patient should be started at a low dose and titrated up slowly. When side effects occur, they are usually mild and include:

●      Sleep disturbances

●      Mild headache

●      Mild agitation

●      Nausea/GI effects - consider switching to liquid sublingual LDN to bypass GI tract

It has been found in patients that experienced side effects, that they can be stopped by decreasing the dose by half for 2-3 days, and then continuing with titration again.

Formulations

●      Oral liquid: 1 mg/1 mL daily

●      Capsules or tablets

●      Sublingual drops

o   Drops are placed under the tongue from a dropper bottle

●      Creams: 0.5 mg/mL

o   Useful for children who you have difficulty administering the other formulations, or those who are allergic to additives in other formulations of LDN

Key Resources

Boundless. Overview of Cancer [Internet]. Lumen: Boundless Anatomy and Physiology. Available from: https://courses.lumenlearning.com/boundless-ap/chapter/overview-of-cancer/

Brown N, Panksepp J. Low-dose naltrexone for disease prevention and quality of life. Medical Hypotheses. 2009;72(3):333–7.

How Low Dose Naltrexone Works [Internet]. How does Low Dose Naltrexone Work | LDN Research Trust - Low Dose Naltrexone. Available from: https://www.ldnresearchtrust.org/how-naltrexone-works

Low Dose Naltrexone [Internet]. The Low Dose Naltrexone Homepage. Available from: http://www.ldninfo.org/

Toljan K, Vrooman B. Low-Dose Naltrexone (LDN)—Review of Therapeutic Utilization. Medical Sciences. 2018;6(4):82.

The LDN Research Trust released a documentary earlier this month that provides education for patients that are suffering from chronic pain and are dependent on opioid prescription medication.

At the Medicine Center Pharmacy we strive to help educate patients and the medical profession to use an alternative, inexpensive, effective treatment. Watch Pain Specialists talk about using Ultra and Low Dose Naltrexone to treat their patients with Chronic Pain. Our thanks to the speakers in alphabetical order: Asher Goldstein MD, John Kim MD, Neel Mehta MD, Norman Marcus MD, Pradeep Chopra MD, Samyadev Datta MD. This program is not sponsored by any pharmaceutical manufacturer, it is funded by donations to the LDN Research Trust which has been a driving force in providing LDN education and research around the world.

You can learn more about low dose naltrexone at one of our monthly patient education seminars or by contacting the pharmacy. You can register here for the next seminar: Register Here