Ketamine for persons with severe pain

cancerIn special circumstances, I may suggest a trial of low dose oral ketamine. It is formulated by a compounding pharmacist as an oral suspension. It is safe to use without significant adverse effects, though you may experience transient symptoms lasting 20 to 40 minutes after the first few doses. For most people, it may relieve pain when all other methods have failed, possibly including total pain relief with no side effects in patients who have then been able to discontinue all opioids.

Keep all your medicine, opioids and ketamine, in a lock box to prevent abuse by others. This is a Schedule III drug like Vicodin.

Achieving control of chronic pain requires a partnership

based upon trust and effort

Requirements: I will work closely with you on ketamine and ask you to keep a log of pain before each dose and 30 minutes after. In addition, for the first week I ask that you log blood pressure and heart rate before each dose and 30 minutes after. This requires that you see me in the office one week later. If you have any questions or problems, I ask that you call me the same day, whether it be weekend or holiday. If you are unable to keep these logs before and after the dose, and the appointment one week later, the trial will be discontinued. You have no authority to continue without my consent.

Blood Pressure: Usually no change occurs in blood pressure. Some have reported that ketamine lowers their blood pressure and they are lightheaded when they stand up. If your blood pressure drops or if you are lightheaded, be very cautious as that may lead to fainting and brief loss of consciousness. Anytime a person faints, that could result in potentially serious injury such as hip fracture, other fractures, bleeding or brain injury if you strike your head. Your blood pressure should be above 100 when standing.  Ketamine has been reported to increase blood pressure and pulse, but I have not found that to occur with these doses.

Side Effects: Ketamine has a very narrow therapeutic window for pain control. This means that once you find the dose that relieves pain, a very slight increase in dose may produce intolerable side effects. Unfortunately some patients reach a dose that produces side effects before they experience any pain relief.

Most patients have no side effects with the low doses used by this protocol, though some may have mild symptoms lasting up to 40 minutes. If you do, then try decreasing the dose a small amount.

It is possible but rare that you may experience severe, frightening hallucinations or may feel you are outside the body observing it do things, called a dissociative reaction.

These side effects are dose related and have been short lasting, usually no longer than 40 minutes.  The antidote is Ativan.

Steps to follow: Read all steps carefully before you begin

  • Take ketamine 30 minutes prior to your other pain medication
  • For the first dose, remain seated or lie down for 20 minutes after you take the dose to avoid risk of falling. Do not take the dose and walk around.
  • A few persons have had severe imbalance lasting 10 or 20 minutes. This has resolved after the first few doses in those persons. It may not happen to you, so test with caution. If it has not occurred at the first dose, it is unlikely to occur at all.
  • Follow the dosing guidelines in the log I give you and which I repeat in this next step:
    Begin with 0.25 mL and increase by increments of 0.25 mL every 6 hours or longer than 6 hours, until you have some pain relief. Do not increase that dose or dosing interval.

Example: begin 0.25 mL, then 0.5, next 0.75, 1.0, 1.25, 1.5, 1.75, 2.0

If you have had no effect on pain by 2.0 mL, schedule an appointment for further instructions.
If your pain decreases only 1 or 2 points, that is your dose.  It will NOT get better by increasing the dose.  Stop increasing.

  • If you have intolerable side effects, you may use 1 or 2 Ativan tablets immediately as an antidote, and every 30 minutes, up to 5 of them.
  • CAUTION: Be alert to the opioid-sparing effects of ketamine!

This means that if ketamine relieves your pain, you do not need to take the opioid as that would be an opioid overdose and may cause serious side effects.

Reduce or temporarily stop your opioid medication if pain is gone after using ketamine.

This is why you take ketamine 30 minutes before the opioid. Some people have been able to completely stop all opioid medication due to pain relief from ketamine alone.

  • CAUTION: Do not drive for 6 hours after a dose.

This is for the protection of you and others. You may not be aware of very subtle side effects.

  • You may take a dose every 6 hours, or longer than 6 hours. Less is more.

If ketamine loses its effect, stop use for 2 or 3 days, then resume. It can be a fickle drug.  That is why increasing the dose causes loss of effect.

Some take ketamine only before sleep. If you do that, use it 30 minutes before sleep in order to log its effect and take blood pressure/pulse before and after. Continue this initially until further changes are approved.

Ketamine was approved for use as an anesthetic by the FDA in 1970

It’s use for pain is “off label” as it was approved only in high doses for anesthesia. It has been used safely in babies. Unlike opioids, it does not depress breathing or bowel function, and usually does not depress cardiovascular function. Since the late 1980’s, numerous scientific articles have been published on its use as a third line choice for some pain conditions; there are few double blind control studies, one is listed below. If you search ketamine on various internet search engines you find it is abused by addicts just as other drugs are. You find medical articles when you search the literature using Google Scholar or PubMed in the National Library of Medicine. If you find a medical article with adverse effects, let me know. I have spoken to leading brain and psychiatric researchers who have verified there are no lasting side effects from its use.

Many publications on ketamine use multi-day infusions at much higher dosages than the oral dosages in my protocol. Drexel University has treated over 3,000 patients with infusions of 40 mg/hour for 5 days with no lasting adverse effects. Even higher doses than that are used for surgical anesthesia. Ketamine is a powerful tool for treating pain.

Medical Publications

You can click and download each reference in blue below

High dose ketamine improves neurological outcome after stroke in rats, Reeker et al, Canadian J Anesth 47:572-578, 2000

Ketamine, Pasero C, McCaffery M, Amer J Nursing, 105:60-64, 2005
An excellent review, more clinical, easier to read than some more technical papers

Ketamine in Chronic Pain Management: An Evidence Based Review, Hocking & Cousins, Anesth Analg, 97(6):1730-1739, 2003This nine page article is the best comprehensive review of ketamine’s use in almost every known pain condition including post stroke pain.  Easier to read; a catalogue of pain syndromes and references.

Ketamine Stops Aura in Familial Hemiplegic Migraine, Neurology, 55:139-141, 2000 Two mechanisms may account for this. First, ketamine can increase cerebral blood flow, which may counteract the marked hypoperfusion induced by cortical spreading depression, as observed in migraine with aura. Second, in experimental animals, ketamine accelerates the  restitution of neuronal function after hypoxia.

Ketamine oral use in 8 chronic pain patients, Canadian J. of Anesthesia, 2004


The Reflex Sympathetic Dystrophy Association library has many articles on RSD, CRPS and ketamine. Remember most of the articles are written for scientists and physicians.

From their library I particularly recommend the first article, below.  The last two are very technical but important new research.

Expectations of Pain: I Think, Therefore I Am, Jones-London M, National Institute of Neurological Disorders and Stroke

For pain mechanisms, read
Beyond Neurons: Evidence that Immune and Glial Cells Contribute to Pathological Pain States, Watkins L and Maier SF, Physiology Review. 2003;82:981-1011.

For pain mechanisms, read
Complex Regional Pain Syndrome (CRPS): Evidence of focal small-fiber axonal degeneration in complex regional pain syndrome-I (reflex sympathetic dystrophy),  Oaklander AL et al., Pain. 2006;120:235-243.

There is no link to the following double blind controlled research publication:

Mercadante S, Arcuri E, Tirelli W, Casuccio A. Analgesic effect of intravenous Ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study. J Pain Symptom Manage 2000;20:246-252. Mercadante et al compared intravenous infusions of Ketamine (0.25 and 0.5 mg/kg) with placebo in a double-blind, crossover study of 10 cancer patients with neuropathic pain.

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~~~~~The material on this site is for informational purposes only, and is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider. ~~~~~

Low Dose Naltrexone “LDN” and Dextromethorphan off label for Pain, RSD, Chronic Fatigue, Fibromyalgia, MS, Crohn’s Disease


Low Dose Naltrexone


Low dose naltrexone, or LDN, has been prescribed “off label” for persons with many conditions including intractable pain, chronic fatigue syndrome, complex regional pain syndrome, RSD, Multiple Sclerosis, Parkinsons Disease, IBS, inflammatory bowel disease, autoimmune diseases and Crohn’s Disease to mention only a few. Low dose naltrexone is not a cure but may be potentially helpful for selected persons with these conditions. It appears to have little or no toxicity at this low dose – a few persons report transient insomnia, nausea or vivid dreams.

Naltrexone and and naloxone are both classified as morphinans, meaning morphine-like. The action of the morphinans and dextromethorphan is on the glia. This discussion relates to those medications. Refer to the paper titled Morphinan Neuroprotection by Zhang, below.

How does it work?

Naltrexone and dextromethorphan are anti-inflammatory. They act centrally and are very different from, and without the toxicity of commonly used anti-inflammatory medications such as ibuprofen or steroids.

They inhibit Superoxide, a free radical, and reduce the toxicity of peroxynitrate metabolism and the excitotoxic effects of glutamate. The mechanism of action occurs at the microglia in spinal cord and brain where they are neuroprotective. Microglia are the immune cells of the central nervous system. Microglia are not only the hallmark of pathology in Multiple Sclerosis but they also play a major role in pain and other degenerative neurological conditions. Reducing the damaging effect of these potent neurotoxins improves function of the immune system and various organ tissues including the spinal cord and brain.

There is evidence that they also increase the release of neurotrophic factors BDNF and GDNF (Jau-Shyong Hong, PhD, at the NIEH/NIH,personal communication).

Chronic pain alters central processing by changing the neurochemistry and the anatomy. This can lead to premature aging of the brain with loss of gray matter and brain atrophy as reported on MRI’s of persons with chronic low back pain. This may also occur in other stress-related disorders, such as chronic depression or post-traumatic stress disorder.

There has been a blossoming of basic neuroscience research on microglia that began in the 1980’s. At the American Pain Society meetings in San Diego in May 2009, there were hours of lectures for several days on the basic science of microglia and pain mechanisms.  This confirms the experience that I have seen clinically.

I am grateful to have the guidance of patients, physicians, and scientists in learning about the use and mechanisms of low dose naltrexone, with special thanks to Dr. Jau-Shyong Hong, PhD, Chief of Neuropharmacology at NIEH/NIH. He is one of the country’s leading experts on microglia, opioid antagonists and morphinans and has published some of the references below.

New science shows naltrexone to be a potent anti-inflammatory — much stronger and with a much different mechanism than the weaker cox inhibitors such as ibuprofen, Vioxx, Celebrex, Naproxen with none of those adverse side effects. Dr. Hong reports that in animal studies, dextromethorphan is even stronger than naltrexone.

Naltrexone is one of a few compounds called morphinans, meaning it has a structure similar to morphine, but naltrexone blocks morphine-like medication:  it is an antagonist.  For detailed discussion of morphinans refer to the article by Zhang et al, listed below.

There are links to further understand the basic science in medical publications and references below. We all owe thanks to patients whose clinical recovery with the use of low dose naltrexone has kept this work alive since its effect on the immune system in Multiple Sclerosis and HIV/AIDS was discovered by Bernard Bihari, MD, in 1984. He was a Harvard trained academic neurologist based in NYC. Their testimony can be found in the book mentioned below or in many web sources. The excitement of their recovery and their fundraising prompted UCSF and Stanford to begin double blind studies now 25 years later.

Recent clinical research

In 2009, Drs. Younger and Mackey of Stanford Pain Center reported a double blind study of low dose naltrexone in persons who had fibromyalgia more than 10 years and showed 30% improvement in pain and fatigue. They now plan a larger study. Bruce Cree, MD, of the UCSF Multiple Sclerosis Clinic in 2008 reported improvement usinglow dose naltrexone in a masked placebo controlled study to evaluate quality of life in MS [reference below] testing only pain, cognitive function and mental health. They propose doing a larger study to measure other functions in MS. In the 2007 study by Jill Smith, MD, at Hershey Medical Center [reference below], 67% of persons with Crohn’s Disease achieved remission in a few weeks, and total 89% had a response to therapy. As described in their publication: Endogenous opioids and opioid antagonists have been shown to play a role in healing and repair of tissues.”Dr. Smith has received a $500,000 grant from NIH to continue research on low dose naltrexone for Crohn’s Disease.

Multicenter studies on LDN for persons with Multiple Sclerosis have been done in Italy and Scotland.  New research is starting in Scotland that will include study of the toxicity of peroxynitrate metabolism in MS first proposed by a Nobel winning scientist in 1991, see the reference on peroxynitrate metabolism and Dr. Gilhooly’s references, below.  Scotland has the highest incidence of MS in the world, even higher than Great Britain and Ireland.  Dr. Gilhooly’s patients reported remarkable improvement in function on LDN that led to him starting this work.

My experience prescribing LDN

I have been prescribing naltrexone for 6 years in ultra-low microgram doses, and more recently prescribing low dose naltrexone at doses of 1 to 4.5 mg.  It is one of the most exciting developments in pain medicine and neurodegenerative diseases that I have ever seen.  It was previously unimaginable to me to see some persons with intractable pain now pain free and off opioids because of low dose naltrexone or a similar medication that will soon be posted on this weblog.

I have not yet been able to predict who will respond to low dose naltrexone with decrease in symptoms, but many patients have had profound relief. Often it may reduce intractable pain to zero despite failing to respond for many years to all known therapies. Inability to predict a response to pain is true of many classes of medication that we trial “off label” for pain relief and even those that are FDA approved for pain. Paradoxically, the same is true for morphine and similar strong opioids.  In fact, opioids relieve pain and opioids create pain at the same time, and it is not uncommon for pain specialists to see individuals with severe pain despite using high dose opioids.

“Off label” use means it is not FDA approved for these purposes.  Instead, low dose naltrexone is used in small doses of 1 to 4.5 mg at bedtime that must be made by a compounding pharmacist, rather than the 50 mg tablets or higher doses that are FDA approved for prevention of addiction and alcoholism.

Many thanks to the sponsors and speakers of the Fourth Annual Conference on Low Dose Naltrexone which was held for the first time on the West Coast at USC on October 8, 2008 – they have provided other references attached below.

Naltrexone became available as a generic drug many years after 1984, and thus there is no profit in this use for pharmaceutical companies.  Only recently, has the science progressed enough to understand its new uses.  Therefore what you may read in various sources on the web may be the “old science,” whereas the articles below are the “new science.”

I will be updating this page in the near future but wanted to make these recent publications and documents available now.


Update June 22, 2010: Check back for patient case reports I will be publishing soon now that I have more specific information on how morphinans work on path pathways and on the central nervous system.

I recommend this book:

The Promise of Low Dose Naltrexone Therapy

by Elaine A. Moore & Samantha Wilkinson, McFarland & Company Inc., 2009

The Promise of Low Dose Naltrexone Therapy

“Grounded in clinical and scientific research, this book describes the history of naltrexone, its potential therapeutic uses, its effects on the immune system, its pharmacological properties, and how the drug is administered. It also lists … patient resources, and includes interviews with LDN patients and researchers.”


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Download sizes are in parentheses to the right of each download link.


Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone, involvement of toll-like receptor 4 (TLR4)

Morphinan Neuroprotection by Zhang, Hong, Kim, et al, Crit.Rev.Neurobiol. 16(4):271-302, 2004 (PDF)  450k

Microglia Mediated Neurotoxicity Molecular Mechanisms. Block Zecca Hong, Nature Reviews Neurosci 8:57, 2007 (PDF) 529k

Peroxynitrites in MS,  Dr Tom Gilhooly, Scotland, USC 4th Annual LDN Conference 2008 (PDF)  77k

LDN research on MS in Scotland Dr Tom Gilhooly, USC 4th Annual LDN Conference, 2008 (Powerpoint)  12M

LDN In MS, Bruce Cree MD, UCSF Poster, 2008 (PDF)  154k

A Pilot Trial of LDN in Primary Progressive MS, Gironi et al, Multiple Sclerosis 14:1076–1083, 2008 (PDF)  222k

LDN for Treatment of MS – Clinical Trials Are Needed, Patel, Ann Pharmacotherapy 41 (9):1549, 2007 (PDF)  114k

LDN Improves Active Crohns Disease, Jill Smith MD et al, Am J Gastroenterology 2007 (PDF) 121k

LDN Immune System Autism & HIV, Vojdani, USC 4th Annual LDN Conference, 2008(Powerpoint)  5.7M

LDN Immune System Autism & HIV, Vojdani Part 2, USC 4th Annual Conference, 2008 (Powerpoint)  3.6M

Naltrexone ULD Decreases Side Effects and Potentiates the Effect of Methadone 2003 JP&SM Cruciani Arbuck  (PDF) 80KB


Update December 10, 2010:  For further research publications on glia, please refer here.

Refer here for a case report of severe RSD responding primarily to naltrexone.


The material on this site is for informational purposes only.

It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.


For My Home Page, click here:  Welcome to my Weblog on Pain Management!


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