Ketamine Nasal Spray for Major Depression – The First Randomized Controlled Trial

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A Randomized Controlled Trial of Intranasal Ketamine in Major Depressive Disorder

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Psychiatrists from Mt. Sinai in New York this month have published the first randomized controlled trial of intranasal ketamine showing it is safe, well tolerated, and rapidly effective in treating symptoms of depression in persons with Major Depressive Disorder.

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This is a small study of 18 patients with treatment resistant depression showing a significant antidepressant effect occurred as early as 40 minutes in some. 44% responded after 24 hours compared to 6% placebo. Ketamine was significantly different from placebo at 40 minutes, 240 minutes, and 48 hours, but not separable from placebo at 72 hours or 7 days thought they were still better. And ketamine was significant at improving anxiety symptoms at 24 hours. There were no clinically significant changes in heart rate or blood pressure and all changes resolved in four hours. “No serious adverse events occurred.”

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“Intranasal ketamine was well tolerated with only very minimal increases in dissociation, psychosis-like symptoms or hemodynamic parameters.” They felt these very minimal behavioral side effects and insignificant changes in blood pressure and pulse were consistent with the lower blood levels of ketamine compared to the higher doses used in studies of IV ketamine. Bioavailability via intranasal route is reported to range from 25% to 50%.

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Their sample had an average of 4.1 ± 3.9 treatment failures, compared to 5.7 and 5.1 in previous studies – those required a minimum of 2 to 3 treatment failures to enroll. Other clinical characteristics did not differ including “duration of illness, length of current depressive episode, and history of ECT.” They allowed ongoing treatment of psychotropic medication.

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They chose a 50 mg dose based on a previous study and on the dose used in persons with a chronic pain disorder (Daniel Carr, et al 2004). It is a lower dose than the 0.5 mg/kg dosage commonly given intravenously. They point out one limitation of the study was the use of the single dose and a standardized protocol, which did not allow them to study optimal dosing. Future study is needed to address optimal dosing, relapse prevention and scheduling of treatment.

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The minimal side effects shown in their study correlates well with my experience. I find the effective dose of ketamine is idiosyncratic. That means it is unpredictable and specific only to that individual. Large males may need only the smallest dose, and tiny elderly females may require far higher doses. That may account for the higher response rate that I believe I am seeing, however, I have not tracked percentage of responders. I have not seen toxicity in years of prescribing either for intractable pain or treatment resistant depression. Importantly, in my opinion, relapse prevention must address not only different neurotransmitters but also neuroinflammation, pro-inflammatory cytokines.

 

 

 

 

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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.

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

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Ketamine Inhaled – Bipolar Child NPR – Review of Ketamine for Depression

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NPR reported yesterday on the beneficial effects of ketamine for depression, this time reporting on a ketamine inhaler prescribed by Demitri Papolos, MD.

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Dr. Papolos is Associate Professor of Clinical Psychiatry at the Albert Einstein College of Medicine and Director of Research of the Juvenile Bipolar Research Foundation.

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He “is one of a handful of psychiatrists in the world who began to see and to speak out about the possible deleterious effects of antidepressants and stimulants in the population of children within the bipolar spectrum.”

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This NPR report described a syndrome Dr. Papolos has identified of Bipolar children & adolescents consumed by fear. They described a boy who had extreme attacks of rage for decades, and horrific violent nightmares.

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The boy had attempted suicide at age 5. He was hospitalized in a psychiatric unit at age 12 and strapped down in a padded room, terrified. He failed many medications for years, some made him worse, and he was literally never able to complete a meal at table with the family without flying off in a rage or someone leaving.

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in 2010, the boy tried Dr. “Papolos’ ketamine treatment. He says he’ll remember the day for the rest of his life. ‘I think we did two puffs, and I remember I sat up and I just started laughing,’ he says. Then his mother picks up the story: ‘You said you had an internal feeling of calm that you had never had before in your life. And when we came home that night, that was the first night that we ever all had dinner at the table without somebody leaving.’”

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This boy, George McCann, now at age 22 is finally able to begin a more normal life. He needs the medication only every third day. “Papolos has treated about 60 young people with ketamine so far and says all but two have had dramatic responses.”

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“The number of patients treated so far is small, and the approach is so new it hasn’t been tested by other researchers yet. Papolos says he’s hoping a study he published late last year will help persuade other researchers to try the drug on other children.”

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“In the meantime, George McCann continues to inhale a prescribed dose of ketamine every third day. The fear and anger that once dominated his life are gone, he says, adding that his mind is free now to work….”

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The relief with ketamine from the prison of mood disorders is deeply important. Severe mood disorders such as Major Depression and Bipolar Disorder can destroy the lives of patients and their loved ones. At worst, they can be lethal.

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A review of published cases of intravenous ketamine for depression asks : “Ketamine for depression: where do we go from here?

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I think the answer is we need to simplify the method of treatment using inhaled ketamine and begin to give their lives back to the patients we see. It is one of the safest medications I have ever prescribed. It does not cause weight gain or loss. It does not cause sexual dysfunction. And although it may increase sedation when used in combination with other sedating medications, at the low doses needed to treat mood disorders, I do not see ketamine interfere with other medication.

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Ketamine can relieve depression from one second to the next. And this young man needs the medication every third day. Is that too much to ask to gain a life?

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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.

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Please understand that it is not legal for me to give medical advice without a consultation.

If you wish an appointment, please telephone my office or contact your local psychiatrist.

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

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RSD/CRPS, Multiple Sclerosis, LDN & Ketamine

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It is rare for me to see a patient who is not complex.

They have failed so many treatments for so many years before they call.

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This is the report of a lovely woman in her early 70′s with progressive Multiple Sclerosis for 30 years and paraplegia that has forced her to use an electric scooter the last 5 years, and power wheelchair the last 2o years. Because of total paralysis of the right lower limb, she fell and shattered her femur, the thigh bone, in August 2009. Tragically, and all too often, the surgeon failed to diagnose Complex Regional Pain Syndrome [CRPS], even failed to visit her in the hospital. CRPS increased the fatigue she had already had from Multiple Sclerosis.

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Thankfully a physical therapist suggested the diagnosis.

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Why is pain management not a required subject for physicians?

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I have written elsewhere that the American Pain Society discovered that our National Institute of Health, NIH, devotes less than half of 1% of their research dollar to pain research. Of 28 NIH institutes, none for pain, three for addiction. This will not change soon. The only hope is that RSDSA.org will succeed in collaborating with all pain organizations, groups with dystonia, chronic fatigue in order to give a voice and research dollar to advances.

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Before seeing me in September, she had 11 sympathetic blocks with no benefit.

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Does it make you wonder why 11 were done?

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How does insurance authorize 11 when 10 had no benefit? I have just learned that a doctor must indicate at least 50% relief before another will be authorized. That explains it.

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Then she was given opioids including tramadal and Butrans patch which rendered her a “zombie,” sedated, poor memory, unable to function. She tried 4 or 5 treatments of Calmare with no benefit but was advised she needed a clear neural pathway for it to work. That was not possible due to the Multiple Sclerosis.
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Lyrica caused severe edema. Gabapentin 1400 mg/day caused weight gain, increased her appetite  more than usual, but she remained on it. She craves sweets more than usual, at times uncontrollably. Perhaps it can be slowly tapered now. Advil 600 mg gave some benefit but caused ulcers that required Nexium.

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Since her initial visit a few weeks ago, she became 60% better during her two week stay.

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I will highlight only two of the new medications started.

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It may also be said that opioids are not the answer.

Opioids may perpetuate pain.
They may produce paradoxical pain or opioid induced hyperalgesia or windup.

They may block the effect of ketamine and other adjuvants that would otherwise lower pain.

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Of importance is that she was not able to tolerate clothing on her right lower limb for three years, not even a sheet, and now she is able to sleep through the night without pain for the first time in three years and able to wear a skirt. This allows her to go out with family to restaurants and even to enjoy shopping with her daughter. Her dose of ketamine is very small relative to most of my patients and she uses it only once or twice a day since most of the new medications have brought her pain down.

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At her first visit one month ago, she rated pain from 6 to 8 on a scale of 10, average 7/10. Now 60% better, ranging from zero to 7, average 4. Yes zero pain, sleeping through the night without pain and waking without pain. She had not been able to tolerate touch to the right thigh or foot and would pull her skirt above the thigh, removing her shoe.

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Now she indicates pain continues to improve.

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Of interest, despite an abundance of concern that low dose naltrexone [LDN] may flare her Multiple Sclerosis, we were easily able to increase the dose to triple what is usually called “LDN.” This did not flare her condition and may be one of the most effective medications she is taking for pain.

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What is LDN?

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The FDA has sanctioned its use in the USA only in doses of 50 to 400 mg for addiction to opioids and alcohol.

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Low dose naltrexone [LDN] is a fascinating medication. It has been used in low dose in persons with Multiple Sclerosis since 1985 when a Harvard trained neurologist in New York City, Dr. Bihari, first discovered that it relieved all disability in some patients with Multiple Sclerosis and prevented recurrent attacks. Since then, doctors in Scotland, where they have the highest incidence of Multiple Sclerosis, find that one of the earliest signs of recovery in this population is relief of neurogenic bladder. It is said that persons with Multiple Sclerosis must remain on LDN for 1.5 years before they might fully assess its value.

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 Multiple Sclerosis may be flared unless very small doses of LDN are used.

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Many with Mulitple Sclerosis cannot tolerate more than 2 or 3 mg, perhaps due to spasticity. There is a great deal of dogma on the web about its mechanism, dosing and timing for off label use. Use the search function on this site to review the prior discussions I posted on LDN, MS, CRPS.

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Naltrexone is a glial modulator.

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What’s that?!

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By serendipity, four years ago I discovered naltrexone in low dose may relieve chronic intractable pain. I had been using it for perhaps eight years in microgram doses but I found in milligram doses it is even more profound.

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The mechanism of naltrexone and a wee bit of glial research is discussed here. The Nobel Prize was awarded last year for the discovery that these glia are your innate immune system. They are profoundly important in many diseases including chronic pain, Major Depression, Multiple Sclerosis, Alzheimers, Parkinsons Disease, ALS, Autism. They produce inflammatory cytokines that lead to inflammation.

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Now that she has been home for two weeks, on a number of medications that I started, not just the ketamine and LDN, I hope she will comment on her experience and her progress since flying back to the east coast after her brief visit here.

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It is often essential to taper off opioids to allow other medication to work.

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I feel she was able to benefit from these low doses of medication because she tapered off all opioid medication prior to her visit, thus allowing her system to recover and respond to these medications. We will know more in the next few months as she slowly titrates up on some of the medications that were started.

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Next year on her return, we may be able to withdraw some of the medications depending on how well she is doing.

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Finally, ketamine does cause her to have brief side effects. Her husband likens the effect the same as half a glass of wine: “She’s really cute.” Thankfully, most people have no side effects and if they do, they rarely last more than 20 minutes.

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She sends an update below, 80 to 90% better. Hopefully this will continue to improve over the next months as she slowly increases the medication we started. And ketamine has an additive effect in some. It is anti-inflammatory.

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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.

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Please understand that it is not legal for me to give medical advice without a consultation.

If you wish an appointment, please telephone my office or contact your local psychiatrist.

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

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Ketamine Rapidly Relieves Depression by Restoring Brain Connections

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This research is one of the most dramatic findings in the field of depression and mood disorders. It was published in Science by researchers from Yale and the National Institute of Mental Health, discussed by PBS here.

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The speed with which ketamine can relieve major depression is deeply moving to witness. In my experience prescribing nasal ketamine it works almost 100% of the time. I have discussed ketamine and previous publications on it for Major Depression and PTSD. It is also effective for suicidal and bipolar depression patients.

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Ronald S. Duman, PhD, the lead scientist, reviews his group’s research in this 2011 video:

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Stress and depression leads to structural changes in the brain and these structural changes are reversible.

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Depression affects 17% of the population, almost one in five of the population. Only one third of patients are effectively treated by existing antidepressants, even after many weeks. Nerve growth factors, in particular BDNF, are decreased by stress, with a very significant loss in depressed patients. BDNF produces antidepressant behavior in rodent models of depression.

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BDNF is important for influencing the survival and function of neurons.

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There are certain neurogenic zones in the brain that produce new neurons. Stress decreases the number of new neurons. Chronic antidepressant use increases the numbers and proliferation of these new neurons. Antidepressant treatment increases neurogenesis and this is dependent upon BDNF, this neurotrophic factor.

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[His slide shows] Exercise, Prozac, ECT, antipsychotics, antidepressants increase neurogenesis.

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Not only are there more synapses made by ketamine, but they are a larger size which is indicative of ones that are more functionally connected. Antidepressants take many weeks. A single dose of ketamine rapidly reverses depressive behaviors and loss of connections and completely reverses the decrements that had occurred over several weeks.

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In suicidal patients given ketamine at Yale in the Emergency Room, within a matter of hours, the suicidality is completely reversed. These people are better for weeks after a single dose of ketamine treatment. [emphasis mine]

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Therapeutically ketamine is even more rapidly acting than ECT.

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Ketamine increases BDNF. But research shows its effects are blocked in mice that are deficient in BDNF. Riluzole also influences BDNF, but the side effect profile is so serious that I would not consider prescribing it without more data on safety.

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Safety concerns are often raised in publications regarding chronic ketamine use. Most of my patients have no side effects at all. It is one of the safest medications we have and only a small percentage experience transient side effects. The favorable side effect profile, simplicity and low cost is key. The results for nasal ketamine are not 100%, neither is IV ketamine, but I have patients who respond to nasal spray when they failed IV ketamine. More importantly, they can carry it in their pocket and use as needed.

 

My experience prescribing ketamine goes back almost to the year 2000 for persons with chronic pain who have used ketamine several times daily, and since Spring 2012 for Major Depression. Its effect for depression lasts longer than for chronic intractable pain where it is short lasting. In the past, I prescribed it orally, by mouth, but since late 2011 I have prescribed it in a nasal spray and that form works for depression.

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The neuroprotective action of ketamine has been published since at least 1988.

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Patients can use nasal ketamine as needed. Schedules vary, everyone is different. It is short acting, but it does not stop working.

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However, the use of other adjuvants, such as glial modulators, in treatment of depression is essential to understand, and is now work in progress. The role of inflammation and glia in the pathogenesis of depression has been well established since 2000, and discussed here.

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Does ketamine also restore brain connections in patients with chronic pain? Chronic pain and major depression both lead to brain atrophy and memory loss. Both cause the same imbalance in glial cytokines. Both may respond to glial modulators, e.g. low dose naltrexone among others that have worked in some patients.

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“The original link between ketamine and relief of depression was made at the Connecticut Mental Health Center in New Haven by John Krystal, chair of the department of psychiatry at Yale, and Dennis Charney, now dean of Mt. Sinai School of Medicine, who helped launch clinical trials of ketamine while at the National Institute of Mental Health,” reported by Yale  here.

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I hope to add new approaches to treatment of anxiety that has failed to respond to other interventions.

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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.

~

Please understand that it is not legal for me to give medical advice without a consultation.

If you wish an appointment, please telephone my office or contact your local psychiatrist.

~

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

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Ketamine IV vs Nasal Spray or Sublingual

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Patients ask me to compare IV ketamine to other routes of administration such as intranasal or sublingual. No one has done comparisons. Even if they had, every person is different and may have several pain syndromes.

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I have outlined one case below. One disadvantage of IV ketamine is the cost and the need to schedule for an IV treatment with your physician often weeks in advance. For some, this may mean setting aside two weeks to travel and make other arrangements. The alternative is carrying this low cost medication in your pocket and using as needed to relieve pain when you have pain, or to prevent pain when you know your activity will flare it.

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Ketamine is an important medication for pain.  It is considered a third line choice for pain relief, but it is almost a first line choice for Complex Regional Pain Syndrome, CRPS  – the old term is RSD. And I prescribe it for other conditions that have been refractory to treatment. But, far more than any other pain syndrome, pain from CRPS can be flared by emotional stress or minor injury and it can spread to other areas.

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Ketamine is a short acting medication. It is both analgesic and anti-inflammatory.

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Opioids create pain; ketamine not only relieves pain, it also relieves inflammation. In fact, opioids may prevent ketamine from helping at all.

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A small number of pain specialists in the USA, most at university centers, provide IV ketamine for CRPS. Not all people respond. A lucky few may get months of pain relief, but may require monthly boosters, i.e. it may be a short acting medication only during the infusion or it may offer relief for weeks or months but not years. I do not believe anyone has published comparisons showing duration of effect.

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I view ketamine as a short acting medication that requires other combination medications to “clamp” the relief and prevent pain from recurring.

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Here is a case report posted a few years ago of my patient who had 8 months of relief from IV ketamine. It was given 24 hours/day for 5 days in May 2007, followed by four hour IV boosters two days every month. Unfortunately all ketamine stopped having any effect after 8 months. I then added multiple medications that were selected because of specific mechanisms — no opioids, no ketamine — and she has been pain free since December 2009 on a single drug.

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CASE REPORT

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Today was the 5th visit in the last two weeks with an out of state patient who has had CRPS since 1999. She also has sciatic neuropathy, chronic lumbar pain after 360 degree spinal fusion, shoulder pain, and two types of headache. Medications are now significantly helping all pain syndromes.

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Before seeing me, she had had a total of 9 infusions of IV ketamine most of them given at doses of 300mg/hr — a very high dose. She had no side effects from ketamine. One of those infusions was given for 6 days over 4 hours each day. She had failed a lidocaine infusion at high dose. A spinal cord stimulator was reprogrammed 10 times, but only made pain worse.

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I then started her on a combination of medications. With addition of the first new medication, she had 50% improvement in the first 24 to 36 hours, that lasted beyond the relief from nasal ketamine that was also started. Unfortunately, on day 8, she and another family member, came down with a virus that causes headache and severe vertigo. Nevertheless, all pain is markedly better.

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With ketamine she is able to reduce pain down to 1 on a scale of 10 for a few hours. Best of all she can carry it with her and use it as needed. She no longer needs to take two weeks out of her life to schedule IV ketamine infusions.

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It will take almost 3 months to slowly increase the other medications we started. Hopefully this combination will “clamp” the pain and prevent it from increasing so that she may become pain free without needing ketamine.

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After that, if she is able to become pain free, the plan is that we will then be able to slowly remove most of the new medications we started this week and still maintain relief of pain. I will see her again in the future.

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Sierra wildflowers

Click to embiggen

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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.

.

Please understand that it is not legal for me to give medical advice without a consultation.

If you wish an appointment, please telephone my office.

.

~

For My Home Page, click here: 

Welcome to my Weblog on Pain Management!

~

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Depression, Ketamine, Naltrexone, Glia and Inflammation – A Case Report

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Current antidepressant therapies are only modestly effective, may have significant side effects and do not provide universal efficacy.

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The role of inflammation and immune systems in the pathogenesis of depression has become well-established since 2000. Immune system activity is mediated by pro-inflammatory cytokines that change behavior.

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This 2012 review is the first to summarize genetic variants of the inflammatory system involved in immune activation and Major Depressive Disorder, Major Recurrent Depression, Dysthymia, Childhood Onset Major Depression and Geriatric Depression: The role of immune genes in the association between depression and inflammation: A review of recent clinical studies. They reviewed 52 papers of which 27 are case-controlled studies. 

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Pro- and anti-inflammatory cytokines are produced by glial cells in the central nervous system (CNS). Glial cells make up 90% of the cells in the CNS; 10% are nerve cells, neurons. When glia are activated, they produce cytokines that lead to inflammation. Glia and inflammatory cytokines play a role in infection, stroke, trauma, chronic pain, Multiple Sclerosis, Alzheimer’s Disease, Parkinson’s Disease, ALS and Major Depression. The Nobel Prize was awarded in 2011 for discoveries of the innate immune system, in particular the mammalian Toll-like receptor 4 (TLR-4) which is the receptor for naltrexone. That discovery incidentally was made by Bruce Beutler at Scripps Research Institute.

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You can read more about glia and the inflammatory response posted January 2011: Pain and the Immune System – It’s Not Just About Neurons – Naltrexone. This is not specific to pain but also relates to some with major depression.

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Ketamine is a major anti-inflammatory and glial modulator. Naltrexone is a glial modulator that I have prescribed for chronic pain in low dose for almost four years in patients who are not taking opioids, and in ultra low microgram dose for more than eight years in patients who are on opioids for pain. Some of those case reports are posted on this site.

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Low dose naltrexone, LDN, may be effective for Autism, Multiple Sclerosis, and some autoimmune diseases. Jarred Younger at Stanford has shown fibromyalgia symptoms are improved by LDN; Jill Smith at Pennsylvania State University, Hershey, has shown remission in Crohn’s Disease with LDN; and Bruce Cree at UCSF has shown improved quality of life in a small study of Multiple Sclerosis that he is pursuing with larger multi-center studies.

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Case Report

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This week I saw a young man who traveled from Northern California for me to possibly treat major depression with nasal ketamine. Depression prevented him from working for the last two years. He scored 34 on the Hamilton Depression Rating Scale. Scores over 24 indicate severe depression. On June 4, 2012, we started his treatment using ketamine nasal spray. The daily dose was increased but has not yet reached an effective level. In my experience of prescribing ketamine for pain and depression in the last eleven years, the dose differs for everyone and is not related to age, gender or body weight.

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As conveyed by him to me, his progress thus far:

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ON JUNE 7, 2012, early morning, he used 40 mg of ketamine by nasal spray. He reported feeling dizzy, experiencing spinning sensation for two hours and then was his usual self, i.e. he felt bad the rest of the day as his usual self but vision was better. His strabismus (lazy eye) usually depends on better mood, but mood was unchanged.

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At 3:00 pm, he took naltrexone, a very low dose approximately 4 mg.

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ON JUNE 8th: approximately 12 hours later, he woke at 2 AM. He later told me that he was feeling “extremely sharp! I felt great! Clear in mind, quiet and calm. I didn’t realize how noisy my mind is till everything felt calm.” He returned back to sleep.

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He woke again at 6 AM feeling great! Not thinking negative thoughts, but no other change, i.e. did not like or love activities or people anymore than in recent years with his depression.

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At 1:15 PM, in the office his self-rated improvement of depression was 40% due to the low dose of naltrexone taken yesterday afternoon. He had no effect from ketamine as yet, and had not used any in more than 24 hours.

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My plan has been to trial low dose naltrexone for persons with treatment resistant depression. If it is effective, then ketamine is not needed. Ketamine is a short acting medication and may pose issues such as tolerance, whereas low dose naltrexone is simple, once daily, used with few side effects and has never caused tolerance in my clinical experience.

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It is very possible that with such rapid improvement overnight and continued treatment, his depression will continue to improve over coming weeks and months.

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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.

.

Please understand that it is not legal for me to give medical advice without a consultation.

If you wish an appointment, please telephone my office or contact your local psychiatrist.

~

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For My Home Page, click here: 

Welcome to my Weblog on Pain Management!

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RSD, Complex Regional Pain Syndrome – a case report

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Severe Pain for Three Years,

 80% better in 10 days

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“This has been life altering.”

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This is a very bright young woman who was an all state volleyball player until onset of Complex Regional Pain Syndrome three years ago in the right hand and wrist. It began after blood was drawn from the hand for a chemistry study and, one week later, the fingers turned black, lost blood flow, followed by emergency surgery for removal of a blood clot from the back of her hand. She woke after surgery, tearing the sheet off due to intense pain on light touch — that is called allodynia — and then developed severe edema from the hand to the shoulder.

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It was four excruciating weeks before the diagnosis of complex regional pain syndrome was made.

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CRPS or RSD is a diagnosis that every MD,

every surgeon, every ER doctor,

every psychiatrist and psychologist, every nurse and therapist should know how to diagnose.

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Because she was a minor, they would not do nerve blocks.

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She developed contractures of the fingers and hand,

was unable to move the fingers.

  A major university hospital diagnosed Munchausen Syndrome;

mom was diagnosed with Munchausen’s by proxy.

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This happens so often. This is 2012.

If it’s not the doctors,

it’s the insurance companies

creating roadblocks to diagnosis or treatment or both.

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Why is pain management not taught at medical schools?

Only 3% of schools today give 30 hours instruction in four years, Yale most recently.

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At a major university hospital two hours away, she failed to respond to 14 stellate and brachial plexus blocks. But the wound reopened by itself, the stitch fell out. The psychiatry department evaluated her after she was so drugged with methadone, she does not even recall the interview. They diagnosed Munchausen Syndrome. That changed everything. Relationship went sour. Distrust of MD’s began and was confirmed many times in many places along the northeastern corridor and Texas.

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That fall, she became a student at the university of her dreams. The diagnosis of CRPS was confirmed at their university medical center hospital where they wanted to continue the same blocks that had failed. Elsewhere, the chief of a renowned ivy league university pain service wanted to talk to her only about spinal cord stimulators, declined by the family.

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In May 2010, she qualified for an NIH study of neurotropin double blind 6 weeks on, 6 weeks placebo. Failed.

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She was seen by Dr. Schwartzman in Philadelphia October 2011, and sent from there to NYC to rule out neuroma dorsum right hand, negative.

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On Lyrica, she gained 20 lbs, then back to 130 lbs baseline when off of Lyrica. Intolerance to Morphine – hives, Duragesic – total body itching. Ambien – hallucinations, Lunesta – hyper. Benadryl helped somewhat. Detoxing from Nucynta – lips were bright red.

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Her weight dropped from 130 to 115. Many medications were trialed and failed. Marinol helps pain slightly and gives the best sleep in years, better appetite. It does cause anxiety, but she had not slept in three years, and it gives 4 to 6 hours of good sleep. She developed sharp bitemporal headaches. I advised headache is a side effect of Pristiq —- now thankfully discontinued and better.

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Since August 2011, she has had CRPS pain in the right leg, worse walking, weight bearing.  There is discoloration of the dorsum hand usually, at times along proximal forearm, recently at right foot and leg. She had edema up to the shoulder measuring 30 cm. Nails growth faster at the right hand, possibly less hair growth right hand. Temperature usually cooler on the right hand, at times at night the hand and foot become hotter. No change in sweating noted.

The first year, she had almost total loss of function in the hand with pain and contractures —and forced herself to move the fingers with OT and PT, then home exercise. She still has days when the fingers remain flexed, but 98% of the time there is full movement as she continually tries to use the hand/fingers to write and type. Nose may become ice cold and tingly since CRPS spread to right side of face and right lower limb. At times tingling fingers. She struggles with memory when pain is severe and with lack of sleep.

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Pain ranges 7 to 10, average 8. Edema was significant for one year, now comes and goes. Allodynia is present hands and feet, now a different scale than before when she could not even be in the car.

However, with weight bearing and walking, pain of the right lower limb became most intense.  She will be 21 in July, but on a bad day was unable to leave her bedroom to walk downstairs as pain was too severe. She would communicate with family by loudly calling or texting. It was unthinkable to make plans for the next week due to severe pain. She has osteoporosis with atrophy of the right upper limb, and has had color changes and edema of the hand.

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She lives in an eastern state inland, two hours away from the mid Atlantic seaboard and major medical center. She failed ketamine infusion at a major university medical center on the east coast. The cost and inconvenience was significant and the family did not know that ketamine may fail to have any effect if taking opioid analgesics. Once mom discovered that, she was able to wean off the opioid medication. Ultimately, after many more interventions, much later, in crisis, she did benefit from IV ketamine infusion, and was able to regain some movement of her fingers on the right hand, but there was no lasting relief. It was a struggle to obtain approval through her insurance.

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She has been spending a great deal of time in bed for months. Morning stiffness is widespread for one to two hours. Bending is difficult, feels as if “hit by a bus,” but she does stretching, moving, distraction and Yoga when able.

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Much better in 10 days

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Day one: pain of the entire right side, face, trunk, limbs, rated 7 to 10 on a scale of 10, average 8. She guards the dominant right hand and the signature is difficult. Atrophy of the right upper limb is present, nails longer on the right hand, dusky dark erythema and long jagged scar over the dorsum right hand, mild erythema of the right upper and right lower limbs.

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On the first day, in the office, she tried the first dose of ketamine nasal spray and after a repeat dose, she was puzzled, thinking to herself, then let us know she realized she was able to concentrate. A small dose is not enough to relieve severe pain, but even major depression can vanish at that dose. Two sprays relieved the brain fog of depression; pain was still 8 on a scale of 10. Blood pressure and pulse did not change before and after doses. She felt hopeful.

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In the next few days she was able to do the unthinkable: make plans with friends, walk 45 minutes, become active, and remain active in a way that had not been possible. She was far more active with much less pain.  Over the weekend, six days after she arrived, after we had sequentially added several new medications, she found the dosage of nasal and sublingual ketamine that worked for her. She has actually had times when she was pain free. As noted during prior ketamine infusions, she requires a far higher dose than most patients to achieve effect. The plan now is to use higher doses at home when time permits for best effect, and booster sprays of nasal ketamine as needed when away from home. She can carry it in her pocket. There is no need for ICU infusions and the fight to get insurance coverage for those stays.

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Of great significance, she has even made plans for the entire summer.

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More details of her case will be added, as time permits. For now, this page is here to allow the patient and family and others to send comments. She will continue slow titration of other medications that will take three months before reaching the target dose, before we can assess efficacy. Based on my experience treating chronic intractable neuropathic pain including CRPS, it is possible these medications will be able to stabilize and relieve pain without ketamine.

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See other case reports of treatment of CRPS here, here, and here.

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You can read some of the science of pain, glia and inflammation. Ketamine is significantly anti-inflammatory. Three of her new medications are glial modulators. Treatment of severe chronic pain usually involves rational polypharmacy, not one medication and not medication alone. It requires a holistic approach to heal: P.T., O.T., massage, cognitive behavioral therapy, guided imagery, visualization, positive thinking, remaining active, and other modalities that depend upon the underlying cause: physical, emotional, spiritual, and financial. The treatment for CRPS is not specific for that condition alone, but the gains can be possible with tremendous discipline, effort, single minded determination and the loving support of friends and family.

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Be cautious of spinal cord stimulators. Try everything else first.

They can create pain and scarring or tether the spinal cord.

Be proactive.

Remember that guidelines and strategies for diagnosis and treatment are outdated.

Support RSDSA.org if you can.

They support high quality pain research.

You can go directly to their site or donate to them (not me)

using the link at the top of my site here.

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Patients and doctors do not understand that opioids create pain.

A 2006 publication from Vanderbilt shows how much better pain can be to taper off.

The abstract:

Significant pain reduction in chronic pain patients after detoxification from high-dose opioids.

The article:

Significant pain reduction in chronic pain patients after detoxification from high-dose opioids.

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More on this young woman’s journey coming.

It’s been busy!

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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.

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Please understand that it is not legal for me to give medical advice without a consultation.

If you wish an appointment, you will need to telephone my office.

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For My Home Page, click here: 

Welcome to my Weblog on Pain Management!

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Glia a Promising Target for Neuropathic Pain – Ketamine Acting on Glia More Than on Neuronal NMDA Receptors?

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 Three important new articles from March, August and November 2011, show ketamine acts on glia.

Emphasis within articles is mine.

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Microglia: a promising target for treating neuropathic and postoperative pain, and morphine tolerance.

Abstract

Management of chronic pain, such as nerve-injury-induced neuropathic pain associated with diabetic neuropathy, viral infection, and cancer, is a real clinical challenge. Major surgeries, such as breast and thoracic surgery, leg amputation, and coronary artery bypass surgery, also lead to chronic pain in 10-50% of individuals after acute postoperative pain, partly due to surgery-induced nerve injury. Current treatments mainly focus on blocking neurotransmission in the pain pathway and have only resulted in limited success. Ironically, chronic opioid exposure might lead to paradoxical pain. Development of effective therapeutic strategies requires a better understanding of cellular mechanisms underlying the pathogenesis of neuropathic pain. Progress in pain research points to an important role of microglial cells in the development of chronic pain. Spinal cord microglia are strongly activated after nerve injury, surgical incision, and chronic opioid exposure. Increasing evidence suggests that, under all these conditions, the activated microglia not only exhibit increased expression of microglial markers CD 11 b and Iba 1, but also display elevated phosphorylation of p38 mitogen-activated protein kinase. Inhibition of spinal cord p38 has been shown to attenuate neuropathic and postoperative pain, as well as morphine-induced antinociceptive tolerance. Activation of p38 in spinal microglia results in increased synthesis and release of the neurotrophin brain-derived neurotrophic factor and the proinflammatory cytokines interleukin-1β, interleukin-6, and tumor necrosis factor-α. These microglia-released mediators can powerfully modulate spinal cord synaptic transmission, leading to increased excitability of dorsal horn neurons, that is, central sensitization, partly via suppressing inhibitory synaptic transmission. Here, we review studies that support the pronociceptive role of microglia in conditions of neuropathic and postoperative pain and opioid tolerance. We conclude that targeting microglial signaling might lead to more effective treatments for devastating chronic pain after diabetic neuropathy, viral infection, cancer, and major surgeries, partly via improving the analgesic efficacy of opioids.

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Ketamine depresses toll-like receptor 3 signaling in spinal microglia in a rat model of neuropathic pain.

Abstract

Reports suggest that microglia play a key role in spinal nerve ligation (SNL)-induced neuropathic pain, and toll-like receptor 3 (TLR3) has a substantial role in the activation of spinal microglia and the development of tactile allodynia after nerve injury. In addition, ketamine application could suppress microglial activation in vitro, and ketamine could inhibit proinflammatory gene expression possibly by suppressing TLR-mediated signal transduction. Therefore, the present study was designed to disclose whether intrathecal ketamine could suppress SNL-induced spinal microglial activation and exert some antiallodynic effects on neuropathic pain by suppressing TLR3 activation. Behavioral results showed that intrathecal ketamine attenuated SNL-induced mechanical allodynia, as well as spinal microglial activation, in a dose-dependent manner. Furthermore, Western blot analysis displayed that ketamine application downregulated SNL-induced phosphorylated-p38 (p-p38) expression, which was specifically expressed in spinal microglia but not in astrocytes or neurons. Besides, ketamine could reverse TLR3 agonist (polyinosine-polycytidylic acid)-induced mechanical allodynia and spinal microglia activation. It was concluded that intrathecal ketamine depresses TLR3-induced spinal microglial p-p38 mitogen-activated protein kinase pathway activation after SNL, probably contributing to the antiallodynic effect of ketamine on SNL-induced neuropathic pain.

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Microglial Ca(2+)-activated K(+) channels are possible molecular targets for the analgesic effects of S-ketamine on neuropathic pain.

Abstract

Ketamine is an important analgesia clinically used for both acute and chronic pain. The acute analgesic effects of ketamine are generally believed to be mediated by the inhibition of NMDA receptors in nociceptive neurons. However, the inhibition of neuronal NMDA receptors cannot fully account for its potent analgesic effects on chronic pain because there is a significant discrepancy between their potencies. The possible effect of ketamine on spinal microglia was first examined because hyperactivation of spinal microglia after nerve injury contributes to neuropathic pain. Optically pure S-ketamine preferentially suppressed the nerve injury-induced development of tactile allodynia and hyperactivation of spinal microglia. S-Ketamine also preferentially inhibited hyperactivation of cultured microglia after treatment with lipopolysaccharide, ATP, or lysophosphatidic acid. We next focused our attention on the Ca(2+)-activated K(+) (K(Ca)) currents in microglia, which are known to induce their hyperactivation and migration. S-Ketamine suppressed both nerve injury-induced large-conductance K(Ca) (BK) currents and 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one (NS1619)-induced BK currents in spinal microglia. Furthermore, the intrathecal administration of charybdotoxin, a K(Ca) channel blocker, significantly inhibited the nerve injury-induced tactile allodynia, the expression of P2X(4) receptors, and the synthesis of brain-derived neurotrophic factor in spinal microglia. In contrast, NS1619-induced tactile allodynia was completely inhibited by S-ketamine. These observations strongly suggest that S-ketamine preferentially suppresses the nerve injury-induced hyperactivation and migration of spinal microglia through the blockade of BK channels. Therefore, the preferential inhibition of microglial BK channels in addition to neuronal NMDA receptors may account for the preferential and potent analgesic effects of S-ketamine on neuropathic pain.

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The material on this site is for informational purposes only,

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.


For My Home Page, click here: 

Welcome to my Weblog on Pain Management!

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Spine Fusions: No Better Than Cognitive Behavioral Therapy & Exercise

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Spine Fusions: no better than Cognitive Behavioral Therapy and Exercise

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This reportfrom the Academy of Neurology may help guide you in decision making: 

Deaths, Complications, Higher Costs Accompany Increase in Complex Spine Fusions Among Elderly.

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“Fusion is usually performed for degenerative disc disease for chronic low back pain, but a number of studies have shown that their outcomes are no better than a combination of graded exercise and cognitive behavioral therapy.”

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Tragically, dementia can result from extensive spine surgery. Many factors can contribute to that. If I were having spine surgery, I would look at the data of dementia following open heart surgery and the protective benefits of ketamine given prior to surgery. Ketamine can spare neuronal function. It is neuroprotective. I link to a publication on that in this post. The problem may be that so few physicians are willing to provide ketamine as they may lack information on its use, yet it is one of the safest medications we have, nontoxic and neuroprotective.

~

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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.

~
~

For My Home Page, click here: 

Welcome to my Weblog on Pain Management!

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~

Case Reports – Fibromyalgia, Spinal Stenosis, Disc Disease, CRPS, Transverse Myelitis, Central Pain

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Glial research key to intractable pain?

These are not ordinary cases.

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These patients have failed every known treatment for years under the care of well known specialists.

They show a remarkable and lasting response to these simple medications.

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The response is important because these medications are 

(1) available, low dose, nontoxic medications largely ignored by the medical community for pain,

(2) glial modulators, and

 (3) more glial research is urgently needed for millions with intractable pain.

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May 2011: The World Health Organization says undertreated pain is America’s #1 public health problem

Department of Health and Human Services says that patients with chronic pain

outnumber patients with heart disease, diabetes and cancer combined

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Fibromyalgia Disabling, Responds to LDN & Dextromethorphan

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AP, 75 years old with scoliosis, restless legs syndrome, anxiety, seen 8/6/04: Onset of fibromyalgia in 2000 after losing half her investment portfolio. It began with acute onset of severe arthralgias, myalgias, fatigue without fever, that prevented her from returning to her business as an art dealer for corporations, private collections. It disappeared without a trace suddenly in 2 months. She was nearly bedridden, just able to sit in a chair, diagnosed as fibromyalgia by a rheumatologist.

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Two years ago, pain, fatigue and “brain fog” returned in 2002, now disabled with intense muscle ache across upper and lower back, circumferentially in thighs/legs, everywhere except head, trunk, feet, fingers – stable since acute onset, markedly interferes with activity, mood, thinking, walking, sleeping, doing her checking account and driving. Pain ranges 2 to 10, average 4 to 5. Burning pain is recent, across upper thoracic and arms, avoids simple activity to avoid flare.  She rated moderate depression due to pain and inability to be active and live a social life. She has been unable to resume walking, a favorite activity. Exam: very anxious, muscle tenderness 18 points, including buttocks, calves, iliotibial bands, right cervical-thoracic paraspinal more than left. Spine tender at almost every level, maximal at L4-5. Sciatic notches tender. Both legs severely discolored brown from chronic venous insufficiency. Gait very slow, wide based later found due to cerebellar atrophy (MRI).

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Oxycontin was started and changed to fentanyl 50 mcg/hr every 72 hours. Fentanyl was then decreased to 25 mcg/hr after adding Fentora 100 mcg twice daily, Lyrica 50 mg at bedtime, with mirtazepine 15 mg and temazepam 15 mg for sleep. She continued to have marked difficulty walking, concentrating, thinking, and was unable to drive or do her checking account. Constant issues with constipation required multiple preparations for stool softener, laxatives, anti-emetics; hypertension was difficult to control, and she had high anxiety and stress.

~
Fibromyalgia was then helped somewhat by pramipexole 0.5 mg twice daily, amitriptyline 20 to 50 mg/day, Lidoderm 5% patches 3 per day, clonidine 0.1 mg twice daily, that allowed fentanyl patch to be discontinued and lowered her opioid requirement down to Fentora 100 mcg bid, still with some constipation but less.

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11/3/08, started low dose naltrexone [LDN] 1 mg – slept only 3 hours that night. On 4 mg, no sleep at all, 1 mg somewhat better, 2 nights after that back to usual sleep but Pain levels low 0 to 3 limited to low back ache.  Before LDN,  pain ranged from 3 to 8, average 5. She had no withdrawal from opioids.  BM’s were excellent for at least 3 days.  Sinemet 25/100 replaced Fentora for restless legs syndrome.

`

However, LDN was discontinued a few weeks later as she had so much energy she was hypomanic. Months later she again developed some pain.

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4/8/09 started Delsym 2 teaspoons every 12 hours. Pain dropped to zero. She never needed opioid again, had no withdrawal. A dose of Delsym is the same as long acting dextromethorphan [DM] 60 mg capsules, but 60 mg was too strong for her —- she became hypomanic again. DM allowed her to become pain free. She stopped DM 10 days, feeling so great she forgot to take it until low back pain returned initially mild, then severe. “I started getting back pain, I thought it was just back pain. I have scoliosis, then it became very severe, then realized am I getting fibromyalgia again.”

`

After resuming DM, it took only 3 days for pain to come down from 10 to 3-4, then less and less to 1-2 on scale of 10. She was back on DM 4 days. Today, after being off DM and getting return of pain, she is now still using a Lidoderm 5% patch daily to the low back and occasional Aspercreme to groin qhs. Did not need to use these when pain was zero.

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She is 80 years old feeling better than she felt when she was 50!  “My biggest problem is slowing down. I’m 80. I enjoy doing what I’m doing. I like being alive. I’m a little hyper so I stopped drinking coffee.  Hyper because so excited about life, and catching up to what I could have done.” She is now able to clean and organize things she put off for years while in pain. She began designing bathrooms and kitchens for more than one location and waking up after 6 hours of sleep to begin work all day. Her husband describes her as having the energy of ten people. He needs to interrupt her to stop work and have lunch.

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“It changed my outlook, I’m so much happier. I am in heaven. I am back to my mental age of 50. I feel alive with energy, vibrance, lust for life. I drive clearly, I have a brain, my reaction to the wheel, to moving and turning and seeing things is better.”

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10-19-09, with mild recurrence of pain, she was advised to continue DM 60 mg  AM and PM, add naltrexone 4.5 mg PM, continue both for 1 or 2 weeks and discontinue if no more pain.

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7-26-10, experimented with timing and dosage, 4.5 mg LDN best at 5 or 7 AM, 2 to 4 PM, and bedtime.  DM 60 mg twice daily. Voltaren gel qd < 1/2 tsp total in AM only at times variously at hips, back, medial arms, groin, thighs, behind knees where pain occurs when it occurs. Rates pain 0 to 2, avg 0. Has pain if waits too long to take LDN too long.

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“I feel wonderful. I don’t feel high. Normal, comfortable at ease, mentally clear – more than in years, memory is better – even helped dyslexia. Now I’m able to skim reading.” She reads faster, is able to multitask ten things at once and get them all done. Husband says, ”She has boundless energy.” Biggest problem is instability gait, wobbles. Fear of falling. Fell backwards in bedroom one month ago,a  trip and fall onto her back, bruised posterior thoracic and right arm. Had home PT. She works out in gym, treadmill daily. Exam: 2/3 of proximal legs and both feet now normal skin color. Gait slowed. Wide based. MS and mood – excellent. Drowsy [never sits still at home].

`

Fall 2010, husband reports her gait markedly improved, faster, more stable after dental prothesis. She is walking faster. She is now 82 and full of energy. Visits initially were monthly for several years while on opioid analgesics, now seen 2 or 3 times a year for minor adjustments and off opioids since 2008.

`

Of course all specialists have stories of unusual responses,

but these are responses to the combination of medications that I use, that are not used by other MD’s.

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Transverse Myelitis Responding to Low Dose Naltrexone

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There is currently no known treatment for Transverse Myelitis. It is very rare, if ever possible, to be able to reverse lesions of the brain and spinal cord seen on MRI, especially if chronic. This man is responding to this tiny dose of naltrexone, 1/6th or 1/8th of the smallest tablet.

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FB, 47 year old male triathlete seen 11/1/10. He was in excellent health until 11/09. He began to have interscapular pain worse on the left, days later a band around the waist approximately T8-T10 described as “muscular” discomfort, later with numbness in the same area, followed by weakness, spasticity of the left lower limb and atrophy. Intermittent Lhermitte’s, now resolved. Hypersensitivity to sensation of his shirt across his chest and shoulders lasted 4 to 6 weeks with initial onset. Initially misdiagnosed as Multiple Sclerosis. MRI and spinal fluid led to diagnosis of transverse myelitis.

~

On 3/11/10, MRI cervical and thoracic cord [probably the second MRI of two sets of MRI’s] showed extensive parenchymatous lesions extending at least 10 segments from T1-T10 with extra-axial fluid collection that appears as an extensive arachnoid cyst over multiple levels. No obvious cord compression. CSF Mixed lymphocytes with reactive pleocytosis, WBC 2/cu mm, 97% lymphs, 3% monos.

~

Diagnoses  11/1/10:  Transverse myelitis with foot drop, spastic monoparesis, atrophy of the left lower extremity, neurogenic bladder, constipation, band around the lower thoracic “waist” onset 11/09, self-treated by injections of B12 with declofenac.   He also had gluten intolerance – eating gluten flares above symptoms

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1/27/11, return visit: “I feel l ike I’ve come light years away” compared to one year ago.

Low dose naltrexone [LDN]  prescribed November 2010, took for few months. Felt immediate effects, improved in strength at left lower extremity, foot drop still present but no longer catches toes on curbs or steps.

He increased dose to 7 or 8 mg, began to feel slightly weird, mild insomnia, like head felt a little weird. Stopped LDN a couple months.

Resumed LDN April 2011,  and again began to feel positive effects; used it daily since then, probably 6 to 7 mg/day.

Resolved: burning pain both feet had radiated up the calves when seen 11/10 ––> discontinued gabapentin one year ago, about 1/10.

Resolved: banding around the waist.

Improved strength 30%  in left lower extremity, still unable to push off with the left foot, but no pain.

Improved: Occasionally used to get a trembling in the left leg evenings 7 or 8 pm, shaking every 20 secs for an hour, at times preventing sleep – resolved about 4 months ago, occurs now perhaps 1 or 2 days a month.

Improved bladder urgency, must find toilet 3 minutes before he voids, now limited to the first 3 hours of the morning.  Before, he could not be far from restroom. Rectal sphincter feels weak.

~

In December 2011, he felt symptoms were plateauing, slowly getting better. Went on vacation in January, ran out of LDN for 11 days and is today 30% weaker. That was the longest time he has been off LDN in the last 9 months. The left leg feels a little like spaghetti. When on LDN, he felt stronger when lifting the leg.

~

Sleep: When began LDN, had 3 or 4 months of vivid dreaming, but urinated during sleep 2 or 3 times a month while have the vivid dream that he was voiding. That resolved.

Still has weird sensations: right foot a little burning sensation, not pain, of the whole foot, lasting 1 or 2 hours, quite tolerable, nothing like it was before when pain radiated to the calves of both legs.

His medications:  LDN, vitamin D3, alpha lipoic acid, Fish oil 2 or 3/day,

Every couple weeks he gets an injection of B12 and diclofenac 2 vials to buttock and feels definite benefit – I warned not to use diclofenac due to high risk of heart attack, cardiac arrhythmias with this NSAID.

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Spinal Stenosis Pain Responds to Nasal Ketamine

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ML, 81 year old diabetic woman with heart surgery 9 months ago, reports that she was able to walk 26 miles a day in Snow Canyon Utah 10 years ago, but barely able to walk room to room the last year due to lumbar pain and weakness from spinal stenosis. Function failed to benefit from tramadol 100 mg x 3/day and she disliked the side effects. Gabapentin failed to help, but when she tried to stop, she had severe nausea and she lost so much weight in four days that her endocrinologist advised her to resume it.

~

Nasal ketamine was started with excellent results allowing her to walk again. Unfortunately, on her own, she abruptly and almost immediately stopped tramadol which resulted in severe opioid withdrawal: severe vomiting, dry heaves and watery diarrhea for 48 hours. She was admitted via ER with chest pressure and muscle strain of abdominal muscles from vomiting. EKG and chemistry ruled out heart attack. Low potassium was corrected and she returned home the next day delighted with pain control.

~

A few days after hospital discharge she reports: “Feeling good, actually exercising in the pool every day, 30 minutes without stopping.” Weather here has been sunny 80 degrees this January. “I never built back my stamina after the heart surgery because of the pain.  I think I am finally on the right  track and it feels good!!” Her son is coming over to walk around the block with her tomorrow.

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 Complex Regional Pain Syndrome 70% Better in 6 Weeks after Opioid Detox,

Responding to Low Dose Naltrexone, Ketamine, Lamotrigine, Memantine

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AD, 23 year old male athlete with Complex Regional Pain Syndrome [CRPS] caused him to be bedridden 4.5 years on opioids. Pain was so severe he was unable to eat and lost 30 pounds of muscle. He was slowly able to bear weight and walk 5 or 6 steps with an underarm crutch, but used a wheelchair when not in bed. Fatigue was severe and unbearable just to be out of bed a few minutes. Pain involved all limbs, but focused at the cold right lower extremity, particularly the knee where he had maximal pain. He is tall and weighed 110 pounds when first seen July 2011.

~

I advise patients that opioids create pain.  I am guided by a colleague who detoxed thousands of persons in pain over a 20 year period and never once found the patient had more pain after detox. Confirming this, Baron and McDonald published Significant pain reduction in chronic pain patients after detoxification from high-dose opioids in 2006. Some of the science  is discussed here.

~in 2006

This young man decided the night of his first visit to stop opioids and was admitted for symptom control with opioid withdrawal. He was started on low dose naltrexone [LDN], N-acetyl cysteine, dextromethorphan, slow titration of lamotrigine and memantine slow titration, and oral ketamine. Six weeks later he returned and rated himself 70% better, no longer in a wheelchair, not needing a crutch, but still with significant fatigue that caused him to need to lie down during the day. However, he was able to return to his MBA program by September and is doing well in college.

~

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  CRPS pain 70% Better in 6 weeks on Low Dose Naltrexone [LDN], Patient with ALS

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FG,  a 71 year old woman with Complex Regional Pain Syndrome [CRPS] and severe burning pain in the legs that markedly interfered with sleep, was seen in fall 2011 for pain in the legs that began two years ago after thoracic fusion October 2009, with cage and titanium rods T4-T9. Disc at T5-6 was compressing the spinal cord and there was an asymptomatic T4-T5 compression fracture 4 to 5 years ago. After thoracic fusion she was able to use a walker for a time, but had weakness progressing to paraplegia and had been in a wheelchair for 6 months. ALS was diagnosed at two university medical centers. Her feet were deep purple, swollen twice their size. and now back to normal size after 7 low power laser treatments. She was now having a frequent ache in both deltoids for a few months from needing to use her arms to push up from the wheelchair. Recently she had severe weight loss with shortness of breath, and during sleep used CPAP for obstructive sleep apnea. Polymyalgia rheumatic from year 2000 was in remission – she’d been on prednisone 5 years until 2005. Breathing was shallow, FVC 1.72 is 54% of predicted.

~

She had a spinal cord stimulator at T10-11.

Medications tried and failed: Cymbalta 30 mg maximum dose, Neurontin 400 mg BID maximum dose, Lyrica dose unknown. Fentanyl patches no effect.

Methadone 25 mg/day for 1.5 years, is the only medication that helps, estimated 80% relief, nevertheless described pain as severe. She used it 5 of 7 days. With ALS causing progressive respiratory difficulty consistent with neuromuscular disease, it was deemed dangerous to continue an opioid. 

~

Low dose naltrexone 4.5 mg to be started after all methadone is out of her system. She was started on N-acetyl cysteine 600 mg capsules x 3/day – the standard of care in Netherlands since 1995 for cold CRPS. Lamictal 25 mg, to begin 1 daily for 2 weeks and slowly titrate to 300 mg per day.

~

On return 6 seeks later, she was delighted to report 70% relief of pain. She plans to return if pain progresses.

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Complex Lumbar Disc Disease Markedly Better with Low Dose Naltrexone 

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CL, first seen age 57, December 2004, for pain right buttock radiating to right leg due to degenerative disc disease with lumbar radiculitis. She injured the right knee four weeks prior after giveaway weakness of the right leg. After the recent lumbar laminectomy in June 2003, she had done well only during the months of October, November, December before she herniated the lumbar disc at L3-4 and declined further surgery. The flare occurred after sitting in a chair for 4 hours taking a class. Symptoms were similar to those she had prior to extensive lumbar surgery but she declined repeat surgery. On Exam, she had positive straight leg raising at 45 degrees bilaterally and diminished reflex right knee, but motor, sensory exam was otherwise intact.

  ~

She had received epidurals perhaps 6 per year from 1999 until December 2004, posing a risk for osteoporosis, and she had symptoms of probable ulcer disease from a steroid dose pack. She had extreme pain during the epidural, but got fairly good relief for only one to two months. Pain in the leg now is 50% less from the recent epidural but will it last?

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Past Surgery: Cervical laminectomy and fusion C5-C7 with anterior plate, lumbar hemi-laminotomies L3 to S1 on the right and discectomy right L3-L4 in June 2003. MRI done after surgery 4/30/04: 1.  Large right paracentral recurrent disc herniation filling right lateral recess at L3-4. 2.  Asymmetrical right foraminal & extraforaminal disc protrusion at L4-5.  3. L5-S1, mild right foraminal stenosis due to facet hypertrophy & asymmetrical disc bulging on the right.

~

She was started with a Fentanyl patch then changed to Oxycontin but continued difficulty walking, standing, lifting. Flying to Boston to see her son would result in being bedridden for the week in Boston and after returning home. However, a few days prior to another trip to Boston, Namenda 5 mg profoundly helped back pain. She was no longer bedridden but was able to travel up and down the East coast and fly home with markedly improved function. Stretching, doing yoga. Walked briskly on beach with son for quite some time.

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On  8/31/09 , surgery for hyperparathyroidism removed two parathyroid glands on left side, biopsied on right.  Back pain “killing me” on left lumbar side postop, hospital 1-1/2” mattress caused flare. She was not back on Namenda 5 mg as it was too painful to swallow and expensive on her budget.

~

Low dose naltrexone [LDN] was started 12/12/08, after stopping the Fentanyl patch 2 days previously. On January 2009, she reported: “My pain level dropped to about 2-3 at that time and was down to 1 by Dec. 15th. With the patch still in by bloodstream for those few days my pain level never really spiked.  There was a very even transition from the patch to the LDN. What I do know is that my pain level has remained at about a 1-2 for the past month, even with an increased stress level and much time spent on my feet. [She has had lifelong insomnia.] It hasn’t changed my sleep pattern at all.  I still take the Temazepam several times to help me sleep a little bit better. I’m very happy that the LDN has given me so much relief from the pain I’ve dealt with for over 5 years.”

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1/29/12, she emails, “Although my lower back pain is pretty well controlled, my right knee pain prohibits me from doing many things that I would like to do. However, I had a significant event last night.

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I awoke at 3AM with terrible stabbing pain going from my right knee to my right foot. I was in too much pain to deal with the Ketamine spray on a Q-tip, so I just used 3 sprays in each nostril, pinched my nostrils together, and tilted my head back slightly. The pain was completely gone in 30 seconds and I was able to go back to sleep immediately. 

.

I used the 50mg/ml dose since I haven’t picked up the stronger spray yet. It was amazing! I’ve continued to use the nasal Ketamine today and it has helped considerably, though not as dramatically as it did at 3AM.

[P.T.] told me there’s nothing more he can do for me.  He said he’d be happy to help me with my re-hab after my knee replacement.  So now I guess I will just have to hope that [my rheumatologist] will be able to offer me some pain relief with hyaluronic acid injections until I can convince myself that a replacement is the only solution.

So the LDN and the Ketamine spray are my constant companions for now.

~~

~

`

 Right Upper Quadrant & Ribs After Laparoscopic Gall Bladder Surgery Better with LDN

~`

CR, 40 year old engineer with scoliosis who had been a triathlete. She first saw me on 6/6/05 for persistent, intense, right upper quadrant abdominal and rib pain that began immediately after laparoscopic gall bladder surgery on 11/17/04, associated with severe fatigue. Pain in the abdominal area was so acute after surgery that she couldn’t swim for four months. Pain impaired breathing and ability to stand erect. She became a long distance swimmer as she now could not do a flip in a pool, run, bike or take part in other sports. Severe pain was triggered even by slight jogging, jarring, vibrations forcing her to buy another car. Positions that relieved right rib pain, made scoliosis worse. Prednisone last year caused loss of memory for  > 1 month of work projects.

~

Spasm along the right lower rib was so severe she once fell out of bed. A cardiologist and neurologist advised removing the lower ribs.

~

Pain was constant mild to moderate at right lower ribs with muscle spasm at the right epigastric area,  intermittently severe stabbing, tender, penetrating, burning.  She describes the pain as a scorpioin tailed dragon that stabs with its scorpion tail and blows fire breath inside the ribs. Pain ranged from 1 to 7, average 4 to 5, and severely interferes with function including ability to concentrate, general activity, enjoyment of life, sleep, work, relations with others and moderately interferes with walking and mood. Each of the 2 times she started P.T., she heard a “pop” when the ribs were released; spreading the ribs relieves pain/spasm.  She tried acupuncture, yoga, Feldenkrais.

 ~

Exam: hyperalgesia over the tender T8 dermatome at the lower right ribs shading off toward T10; easily palpable tender trigger point at right epigastric area that radiates to the right anterior lateral iliac crest suggesting visceral ligamentous problems. Physical therapist noted a stiff band in the right upper quadrant but there are no ligaments in this area of the anatomy. She had temporary relief with adjustments, poor response with opioids and failed gabapentin. Intercostal blocks T8-T10 or T11 and right upper quadrant field blocks using Marcaine gave transient 50% relief. MRI and CT scans failed to disclose any etiology.

By 11/17/05, P.T. had freed several structures about the rib cage, but was not able to loosen the lower ribs that no longer flare out as the left side. P.T. has helped far more than nerve blocks (duration of nerve block effect 2 to 4 weeks if cortisone used, or 5 to 14 days if a field block after miserable numbness 48 hours). Pain is focal at the MCL inferior to the lower right rib, deep under the incisional scar triggered by crunches  (as with use of dishwasher, etc).  She is now able to swim butterfly, but not flip turns – flip turns are a crunch flexion. Right levator scapulae trigger point is flared with the same crunches and “feels related.”  She continues Feldenkrais but avoids flexion,no longer has difficulty breathing and since P.T. has been able to get the inspiration spirometer to the top. Inflammatory pain along the costochondral margins anterior and posterioly from T2 to T12 and below the right lower ribs fairly resolved with the topical ointment ketoprofen 20%, lidocaine 10%. She tried Bengay at the levitator scapulae but stopped Daypro due to burning mid sternum, uses aspirin with yogurt.

~

New spine x-rays were reviewed at Boston Children’s Hospital compared with her most recent 10 year old spine MRI: The ribs are splinted upward where they should be down.  Scoliosis then measured 31 degrees at T1-6, and 28 degrees at T6-11 with the superior iliac crest 1 cm down.

~

February 2009, she started low dose naltrexone [LDN] 1 mg:  For years, pain was 8 to 9, like I had swallowed a fire burning. After LDN it was gone in one hour, zero for 18 hours later returned but much lower 1.5 on scale of 10. Premenstrual pain also was there lower abdominal, prior 3 to 4, down to 1 while taking LDN. A morning swim in ocean usually takes a couple hours of swimming to warm up to get that endorphin high, since LDN now occurs in 20 min. Begins with complete feeling of ease and well being because you’re swimming in cold water, everything is cold and you’re tired, suddenly you’re not tired, its easy, nothing is terrrible anymore, all the frustration melts away. There are no long life threatening events, everything seems easier, you’re happier, and you love everyone. Everyone you see a that moment is beautiful and you love them.  The world is a little slower.  You always feel like you could swim [or run] forever, whereas before that point you feel you can go maybe 5 more minutes.

~
Since mid morning a little hyper – sometimes I am if I have lots of sugar or caffeine [had none], talking faster, less patient slightly -  entire family has ADD or ADHD. 
Slept really well  —- usually has light sleep, poor quality.
I got my desk cleared off for the first time in weeks.
Had sinus headache 1-2 weeks, the head was still unchanged after LDN.
Had night sweats > 10 years, at 4 am none last night, in fact the opposite.  

~

Sleep improves for some while on LDN. It is a morphinan, i.e. morphine like. “I sleep well on LDN… the neuroma in my foot is not gone but hurts less, one of those items I’ve been ignoring because the rib/abdominal pain kept me from hiking enough to care.  So far that’s what I’ve got, for some reason the best dosing for me seems to be alternating 2mg and 3mg. I don’t know why that is. I still get a good endorphin rush pretty early into exercise, even walking which I can do again.  Last week I accidentally walked 6 miles, longest I’ve walked in years!  Next I want to try hiking once the snow is gone.

~

A stingray stabbed her the top of her foot on 4-28-11. Lifeguards usually call EMT for morphine as the injury causes so much pain that people black out. There was profuse bleeding, estimated one cup of blood, and swelling the size of an egg. The entire foot was covered with blood as were the footsteps on the beach. Pain quickly increased to 7 on scale of 10 but never went above ankle, then pain dropped to a 3 before they were able to put her foot into hot water. She was laughing with the lifeguard while being treated.  Swelling was almost gone 4 days later. It was a little tender to pressure, the puncture was still visible. She did not wear a shoe to avoid pressure over the wound, and to keep the wound clean to avoid bacterial infection. People were asking why she was not walking with crutches – not remotely necessary.

~

She has scoliosis and wore braces for it as a child. “I’ve been using the SalonPas patches on my lower back, they give me a minor skin rash but work great. I suspect a combination of topicals and stretches will be the key.  For meds we’d have to be in the office with my records (allergic to tylenol and bad reactions to naproxen/Aleve though I may try it again some day).  Its more a question of what to do about the underlying cause -the spine- and avoiding the pain. I know having the pain isn’t good long term but its minor enough that I really didn’t feel it all this time because my front hurt more.  Peeling the onion!  While I was having a lot of rib pain I would get pulled forward and my lower back would go “out.” P.T. could help that by loosening the front and working the back.  Now it seems more complex to address.  I used to do lots of sit-ups and crunches to stabilize it but P.T. says no to those and my core is pretty stable.  I have been able to do yoga again (another LDN success) and I thought that helped in the past.  I’ll have to continue with that and see if it helps things in the long run….  I have to seek out the spine experts now that I can move more.  My ski turns are uneven, always have been becuase I turn easier to the left than the right (so I’ll turn one cheek more readily than the other).”

>

Vibrations from dolphins ease the pain for days. She has experienced more encounters with dolphins and whales since the surgery. One day when she was aware of squid in the water, she noticed what she thought was the world’s biggest squid swimming 10 feet below her, except that it was a gray whale, which soon surfaced and blew water. Her reasoning for why marine life are attracted to her: scar tissue built up around her surgical scar, which she says makes a squeaking sound in the water. “It might be similar to how they perceive pain and illness.They might be coming together to try to help.”

.


~

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Further information will be posted on these cases, and more cases will be added as time permits.
They will include persons who had years of intractable chronic pain that severely limited function, who are now pain free
on low dose naltrexone [LDN] and/or other medications.  Some with intractable chronic pain have now been pain free off LDN and all pain medications for three years.
~
~~~~~

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.

~

~

For My Home Page, click here: 

Welcome to my Weblog on Pain Management!

~~

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Ketamine Intranasal for Rapid Relief of Pain and Depression

~

Poorly managed pain can evolve into chronic disease of the nervous system

~

Ketamine is an important analgesic, more important than opioids. It can dramatically reduce pain, and rapidly relieve depression and PTSD.  Please read my earlier posts here and here. And the NPR report here just after I posted this (skip to their last section). Yes, it is FDA approved and legal. One woman said:

.

 ‘It was almost immediate, the sense of calmness and relaxation.

‘No more fogginess. No more heaviness. I feel like I’m a clean slate right now. I want to go home and see friends or, you know, go to the grocery store and cook the family dinner.’

.

NPR again reports ketamine’s rapid relief of depression. A 28 year old man whose refractory depression began at age 15, after ketamine, says:

.

‘I Wanted To Live Life’

.
Stephens himself has vivid memories of the day he got ketamine. It was a Monday morning and he woke up feeling really bad, he says. His mood was still dark when doctors put in an IV and delivered the drug.”Monday afternoon I felt like a completely different person,” he says. “I woke up Tuesday morning and I said, ‘Wow, there’s stuff I want to do today.’ And I woke up Wednesday morning and Thursday morning and I actually wanted to do things. I wanted to live life.”.
.
Since then, they treated him with Riluzole that is FDA approved for ALS and has one of the dirtiest side effect profiles I have ever seen in medicine with serious organ toxicity. Ketamine rarely causes mild transient side effects, usually none. It appears the concern is how ketamine is used on the street with potential for abuse. I do not see ketamine abuse in my patients, some of whom are on opioids for pain or Valium family medicines from their psychiatrist. All of those have a greater potential for abuse, also not occurring in my patients. Pain and/or depression can lead to suicide.
.
About 18 months ago, researchers at Yale found a possible explanation for ketamine’s effectiveness. It seems to affect the glutamate system in a way that causes brain cells to form new connections.
.
Researchers have long suspected that stress and depression weaken some connections among brain cells. Ketamine appears to reverse the process.

.

It would be of interest to see a case report of the bladder problems they mention. Is this in a single drug addict who used many unknown medications on the street? Several physicians have infused IV ketamine for persons with pain for many years, in far higher doses than I prescribe, with no report of any but transient minor symptoms.

.

David Barsook’s 2009 review, reference below, describes changes that cause memory loss and brain atrophy with chronic pain, in particular, Complex Regional Pain Syndrome (CRPS), and they also occur with chronic depression:

~

With the onset of chronic pain (including CRPS) a number of changes in brain function occur in the human brain including but not limited to: (1) central sensitization ; (2) functional plasticity in chronic pain and in CRPS; (3) gray matter volume loss in CRPS ; (4) chemical alterations; and (5) altered modulatory controls. Such changes are thought to be in part a result of excitatory amino acid release in chronic pain. Excitatory amino acids are present throughout the brain and are normally involved in neural transmission but may contribute to altered function with excessive release producing increased influx of calcium and potentially neural death.

.

Brain atrophy and memory loss has also been shown in chronic low back pain as well as in chronic depression.

~

Barriers to management of chronic pain are many:

~

Although opioids are effective for acute pain, effective treatment of chronic pain is often daunting, particularly neuropathic pain.

~

Opioids have been shown to create pain causing imbalance in the glial cytokines that favor pain rather than relief of pain. Opioids carry the risk of opioid-induced hyperalgesia which is a severe pain sensitivity. They affect the brain and endocrine system. Opioids may fail to offer significant relief, fail to improve function, and risk misuse, abuse, diversion and death. Their costs are astronomic, insurance coverage is increasingly limited, the potential for complications may be life threatening in a hectic medical setting, side effects can be lethal, lack of physician training in use of opioids and alternatives to pain control lead to increasing deaths, addiction and diversion. It has become a national emergency and a trillion dollar war on drugs.

~

Complications can be greatly reduced through use of a scrupulous history and physical examination, but reimbursement is directly proportional to the shortest time spent with a patient. Will that help assessment and care?

~

Individuals may have dramatically different responses to opioid therapy; some may not tolerate any, and relief must be balanced with side effects that increase as the dose increases. Patient status may change and require IV, rectal or tube delivery instead of oral formulas; drug-drug interactions may require rapid changes, and disease of kidney, liver or brain may require modifications or stopping altogether. They may increase risk of falls and cause central sleep apnea with drop in oxygen because the brain fails to give a signal to breathe.

~

Chronic pain can lead to loss of sleep, hopelessness, depression, anger and other mood disorders such as panic, anxiety, hypochondriasis and post traumatic stress disorder [PTSD]. Treatment of mood disorders are shown to profoundly reduce pain perception and/or ability to cope with pain.

~

Ketamine is anti-inflammatory and can reduce the need for opioid use, thus reducing the pain and side effects caused by opioids.

~

Nasal ketamine is more effective than oral ketamine for pain relief; oral dosing has no effect on depression.

~

Nasal delivery of ketamine is now possible due to advances in metered nasal sprayers that deliver a precise dose. No needle is required, no IV access, no travel to a specialist needed.

~

You can carry pain relief with you and use it as directed when it is needed.

~

Ketamine is an NMDA antagonist: it antagonizes the NMDA receptor which plays a profound role in pain systems and centralization of pain.

~

Ketamine is neuroprotective and it can help other disease states as noted by Barsook, 2009:

~

Besides improvement in pain, “there may be lessons from other diseases that affect the brain; it is noteworthy that acute ketamine doses seem to reverse depression and ketamine decreased prevalence of post-traumatic stress disorder (PTSD) in soldiers receiving ketamine during their surgery for treatment of their burns. In addition ketamine attenuates post-operative cognitive dysfunction following cardiac surgery that has been known to produce significant changes in cognition. [emphasis mine] The data suggest that the drug can alter or prevent other conditions based on its NMDAR activity where other drugs NMDA receptor antagonists are perhaps not as effective in these or pain conditions. Lastly, NMDA antagonists have been used in degenerative disease (and pain may be considered a degenerative disease as defined by loss of gray matter volume, see above) with mixed effects perhaps relating to how they act on specific NMDA subtypes. Taken together, ketamine may act not only on sensory systems affecting pain intensity, but also on a constellation of brain regions that are involved in the pain phentype. [sic, phenotype]“

~

Side Effects

~

Ketamine is more frequently used in babies and children than in adults because high doses of ketamine can induce hallucinations in the adult. Importantly, it is used in high dose in adults for treatment of Complex Regional Pain Syndrome.

Low doses, cause little or no side effects in adults. If present, they are transient and often resolve in 20 minutes. Patient who respond to ketamine report good acceptance as they find the relief of pain and/or depression far outweighs any short term minimal discomfort.

~

Pain care reform is urgently needed.

~

Research funding for pain is less than half of one percent of the NIH budget. More research is needed, but research on low dose ketamine for treatment of pain and depression has gone on for twenty years.

The public health crisis of untreated pain, which often results in disability, parallels the country’s struggle to halt the cost of health care. The longer a person remains with untreated pain, the less likely they are to return to work or to be employable.

~

Conclusion

~

Pain control requires urgent attention. It is past time to put into practice the use of this valuable medication so people can get on with life instead of being mired in chronic pain that for many risks suicide and ensures continuing decades of disability. Academic studies are usually limited by defining a predetermined dose rather than clinically titrating to effect. Thus no surprise, they find no effect as every patient will have no response until they reach their dose. And that dose, in my experience, falls into a bell shaped curve. One size does not fit all. Some respond at very low dose, others require much more, and the majority fall between.

~

In my experience prescribing ketamine for ten years, only a rare person has problems. Almost all find it has returned function or significantly relieved pain. Some have been able to entirely eliminate opioids that did nothing for their pain for decades, though they dutifully returned to the MD every month to chronicle that pain. Pain continued to be rated ten on a scale of ten; patient always compliant despite side effects of constipation and often depression. My patients find the benefits of nasal ketamine far outweigh the relief of oral ketamine and at much lower doses with fewer side effects.

~

Further, while the pain relief may be short lived, some find it gets better with repeat dosing, and relief of depression may last one to two weeks with a single dose.

~

References

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http://www.wjgnet.com/1007-9327/10/1028.asp  Ketamine suppresses intestinal NF-kappa B activation and proinflammatory cytokine in endotoxic rats.

~

CONCLUSION: Ketamine can suppress endotoxin-induced production of proinflammatory cytokines such as TNF-a and IL-6 production in the intestine. This suppressive effect may act through inhibiting NF-kappa B.

~~

http://informahealthcare.com/doi/abs/10.1080/J354v16n03_03  Ketamine as an Analgesic Parenteral, Oral, Rectal, Subcutaneous, Transdermal and Intranasal Administration

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Ketamine is a parenteral anesthetic agent that provides analgesic activity at sub-anesthetic doses. It is an N-methyl-D-aspartate (NMDA) receptor antagonist with opioid receptor activity. Controlled studies and case reports on ketamine demonstrate efficacy in neuropathic and nociceptive pain. Because ketamine is a phencyclidine analogue, it has some of the psychological adverse effects found with that hallucinogen, especially in adults. Therefore, ketamine is not routinely used as an anesthetic in adult patients. It is a frequently used veterinary anesthetic, and is used more frequently in children than in adults. The psychotomimetic effects have prompted the DEA to classify ketamine as a Schedule III Controlled Substance. A review of the literature documents the analgesic use of ketamine by anesthesiologists and pain specialists in patients who have been refractory to standard analgesic medication regimens. Most reports demonstrate no or mild psychotomimetic effects when ketamine is dosed at sub-anesthetic doses. Patients who respond to ketamine tend to demonstrate dramatic pain relief that obviates the desire to stop treatment due to psychotomimetic effects (including hallucinations and extracorporeal experiences). Ketamine is approved by the FDA for intravenous and intramuscular administration. Use of this drug by the oral, intranasal, transdermal, rectal, and subcutaneous routes has been reported with analgesic efficacy in treating nociceptive and neuropathic pain.
~
http://www.ncbi.nlm.nih.gov/pubmed/15109503  Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomized, double-blind, placebo-controlled, crossover study  Daniel Carr, et al, 2004
Crossover, 20 patients. Ketamine reduced breakthrough pain within 10min of dosing, lasting up to 60min
~
http://www.ncbi.nlm.nih.gov/pubmed/15288418  Safety and efficacy of intranasal ketamine in a mixed population with chronic pain
~
The intranasal route for ketamine administration has been applied only for pain of dressing changes in a single case study (Kulbe, 1998). In this patient, oxycodone and acetaminophen were ineffective to control pain during burn dressing changes in a 96-year-old woman cared for at home. She tolerated the burn dressing changes after three intranasal sprays of 0.1 ml each, in rapid succession, each containing 5 mg ketamine (15 mg total) (Kulbe, 1998).
~
http://www.acutepainjournal.com/article/S1366-0071%2807%2900167-2/abstract  Safety and efficacy of intranasal ketamine for acute postoperative pain
~
Ketamine delivered intranasally was well tolerated. Statistically significant analgesia, superior to placebo, was observed with the highest dose tested, 50 mg, over a 3 h period. Rapid onset of analgesia was reported (<10 min), and meaningful pain relief was achieved within 15 min of the 50 mg dose. The majority of adverse events were mild/weak and transient. No untoward effects were observed on vital signs, pulse oximetry, and nasal examination. At the doses tested, no significant dissociative effects were evident using the Side Effects Rating Scale for Dissociative Anaesthetics.
The safety profile following treatment with ketamine was comparable to that seen with placebo.
Although patients did report side effects of fatigue, dizziness and feelings of unreality more often following treatment with ketamine than following treatment with placebo, no patient reported hallucinations and the side effects were generally reported to be of mild or moderate severity, and transient. No serious adverse events were reported and the incidences of associated adverse events were comparable for ketamine and placebo. Although study medication was administered intranasally, nasal signs and symptoms were few and inconsequential. A distinctive taste, however, was reported more often following treatment with ketamine than following treatment with placebo.In conclusion this randomized, placebo-controlled, double-blind study, in 20 patients, has demonstrated that intranasal ketamine is safe and effective for BTP [breakthrough pain]. Our findings augment an early but promising literature documenting the effectiveness of nasal administration of a variety of opioids for pain management in adults (Dale et al., 2002) .
~
~http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2875542/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2875542/  Ketamine and chronic pain – Going the distance, David Barsook, 2009

~

This important paper covers essential points not mentioned by many, thus quoted at length below:

“Ketamine, brain function and therapeutic effect – neuroprotective or neurotoxic

With the onset of chronic pain (including CRPS) a number of changes in brain function occur in the human brain including but not limited to: (1) central sensitization ; (2) functional plasticity in chronic pain and in CRPS; (3) gray matter volume loss in CRPS ; (4) chemical alterations ; and (5) altered modulatory controls. Such changes are thought to be in part a result of excitatory amino acid release in chronic pain. Excitatory amino acids are present throughout the brain and are normally involved in neural transmission but may contribute to altered function with excessive release producing increased influx of calcium and potentially neural death. Here lies the conundrum the use of an agent that potentially deleteriously affect neurons that may already be compromised but may also have neuroprotective properties by mechanisms that include reducing phosphorylation of glutamate receptors resulting in decreased glutamatergic synaptic transmission and reduced potential excitotoxicity . Alternatively, ketamine may affect glia regulation of glutamate and inhibit glutamate release within glia. However, by whatever mechanism ketamine acts on CRPS pain, there does seem to be a dose/duration effect in that longer doses at levels tolerated by patients seem to prove more effective in terms of the duration of effects.

So what could be happening in the brain and what is required to alter brain systems and reverse the symptomatic state? Ketamine may diminish glutamate transmission and “resets” brain circuits, but it seems that a minimal dose and/or duration of treatment is required. Alternatively, ketamine may produce neurotoxicity and damage or produce a chemical lesion of affected neurons. These two issues are important to be understood in future trials. Reports from patients who have had anesthetic doses have included prolonged pain relief for many months. While the authors did not address issues such as the effect of dosing duration or repetitive dosing at say 6weeks, they did show a level of efficacy based on NNT that equals or betters most drug trials for this condition.”

….

“Conclusions

As a community we have a major opportunity to define the efficacy and use of a drug that may offer more to CRPS (and perhaps other) patients than is currently available. This is clearly an opportunity that needs urgent attention and a number of questions remain to be answered. For example, is ketamine more effective in early stage disease? How does ketamine provide long-term effects? Further controlled trials evaluating dose, duration, anesthetic vs. non-anesthetic dosing are needed. Few of us really understand what it is like to suffer from a chronic pain condition such as CRPS. Ketamine therapy may be a way forward that can be brought into our clinical practice through further controlled studies that will allow for appropriate standards for use in patients.”

 

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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.
.
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Please understand that it is not legal for me to give medical advice without a consultation.

If you wish an appointment, please telephone my office or contact your local psychiatrist.

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For My Home Page, click here:  Welcome to my Weblog on Pain Management!
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Depression PTSD – Ketamine Rapid Relief

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  • PTSD has a more direct link to suicide than previously thought, a current Texas A&M University study concludes – references below.

  • A high lifetime risk of suicide occurs in women who have been sexually and physically abused as young girls.

  • More than 300,000 veterans have been diagnosed with PTSD or major depression – many not yet diagnosed.

  • Risk of suicide is the highest during the first month of standard antidepressant therapy, and a significant number of patients do not have adequate improvement even after months, resulting in harm to personal and professional lives.

  • Patients are at suicide risk upon discharge from psychiatric hospitals.

  • Significant predictors of both suicide attempts and preoccupation with suicide are guilt and anger and impulsive behaviors.

    ~
    ~

  • Ketamine is the most important breakthrough in treatment of major depression with rapid and lasting effects.

  • Ketmine can help immediately, unlike all other antidepressants that may require weeks or months to work, if they help at all. See NPR report here - that appeared soon after I posted this (skip to their last section). It is FDA approved and legal. NPR again reports ketamine’s rapid relief of depression. A 28 year old man whose refractory depression began at age 15, after ketamine, says:

    .

    ‘I Wanted To Live Life’

    .
    Stephens himself has vivid memories of the day he got ketamine. It was a Monday morning and he woke up feeling really bad, he says. His mood was still dark when doctors put in an IV and delivered the drug.”Monday afternoon I felt like a completely different person,” he says. “I woke up Tuesday morning and I said, ‘Wow, there’s stuff I want to do today.’ And I woke up Wednesday morning and Thursday morning and I actually wanted to do things. I wanted to live life.”.
    .
    Since then, they treated him with Riluzole that is FDA approved for ALS and has one of the dirtiest side effect profiles I have ever seen in medicine with serious organ toxicity. Ketamine rarely causes mild transient side effects, usually none. It appears the concern is how ketamine is used on the street with potential for abuse. I do not see ketamine abuse in my patients, some of whom are on opioids for pain or Valium family medicines from their psychiatrist. All of those have a greater potential for abuse, also not occurring in my patients. Pain and/or depression can lead to suicide.
    .
    About 18 months ago, researchers at Yale found a possible explanation for ketamine’s effectiveness. It seems to affect the glutamate system in a way that causes brain cells to form new connections.
    .
    Researchers have long suspected that stress and depression weaken some connections among brain cells. Ketamine appears to reverse the process.

    .

    It would be of interest to see a case report of the bladder problems they mention. Is this in a single drug addict who used many unknown medications on the street? Several physicians have infused IV ketamine for persons with pain for many years, in far higher doses than I prescribe, with no report of any but transient minor symptoms.

    .

    Memory loss and brain atrophy occur with chronic depression, reported by the National Institute of Mental Health ~2001. The mechanism is described by Barsook referenced here.

    ~

  • You do not need to be hospitalized.

  • A single low dose ketamine treatment, given nasally, may reduce core symptoms of PTSD and depression. It can save your life.

  • Relief of depression may occur in 2 minutes to 2 hours and may last 1 to 2 weeks.

  • National Institute of Mental Health published 100% relief in a group with depression refractory to all treatment that failed as long as 43 years.

  • You cannot anticipate when suicidal thoughts occur, but you can carry ketamine with you for instant relief.

  • Ketamine is not toxic, not expensive, side effects if any are transient – usually none. It is compounded by pharmacy.

    ~

  • I can help. I’ve prescribed this medication for 11 years, spoken with some of the world’s foremost psychiatrists. Some of my patients with profound pain/depression travel to Germany for high dose ketamine coma treatment of RSD/CRPS and tolerate those doses. Ketamine is safe even in babies and children. Very few MD’s prescribe ketamine, and even fewer have much experience with it.

    ~

  • I need to examine you in person.

  • I can meet with you at my office and it is essential that you meet with my colleagues, a psychologist and psychiatrist.

  • Time is of the essence because we may need to adjust the concentration of ketamine. We need to determine your comfort level with its use.

  •  This must be a team approach.

  •  Please ask your psychiatrist to call me with your diagnoses and speak with me in person.

  • If you live long distance, this team should include your local psychiatrist, or one nearby, who will prescribe ketamine for depression.

  • Alternately, I will need to see you in my office every few months to renew the medication.

    ~

  • The medical literature on ketamine use is profoundly important. There are over 6,800 medical publications. Ketamine has potent healing powers. Karl Jansen, psychiatrist in London, believes that “ketamine has potent healing powers when used as an adjunct to psychotherapy.” There is nothing like it; however, treatment for serious depression still requires team support, not medication only.

  •  The World Health Organization reports that disability to due depression is second only to heart disease.

  • Suicide is a catastrophic medical emergency. I cannot stress this enough. Depression is treatable.

  • Your death is unnecessary. It would be a terrible loss to all who love you.

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    References
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    http://emedicine.medscape.com/article/2013085-clinical#aw2aab6b3b3
    Suicide Clinical Presentation

http://www.ptsd.va.gov/professional/pages/ptsd-suicide.asp The Relationship Between PTSD and Suicide  

PTSD alone out of six anxiety diagnoses was significantly associated with suicidal ideation or attempts. Anger and impulsivity have also been shown to predict suicide risk in those with PTSD.

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Articles, below, support use of ketamine for rapid relief of depression, even for resistant bipolar depression. The lead author of the first three studies is Carlos Zarate, M.D., Chief of the Mood and Anxiety Disorders Research Unit of the National Institute of Mental Health, NIMH:

http://www.ncbi.nlm.nih.gov/pubmed/20673547   Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder

100% response in persons with refractory depression: 29% went into remission, another 71% were responders.

http://archpsyc.ama-assn.org/cgi/content/full/67/8/793  A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression It even works for resistant bipolar depression

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2726824/figure/F1/  Ketamine and the next generation of antidepressants with a rapid onset of action

Potential targets for ketamine and similar agents induce rapid and sustained antidepressant effects. A diagram scientists and physicians will find useful for mechanisms. “Notably, ketamine’s rapid antidepressant effects have been shown to be modulated by AMPA relative to NMDA throughput. Excessive glutamate also stimulates the extrasynaptic NMDA receptors, which antagonizes the activation of neurotrophic cascades. The potential sustained (sub-acute) antidepressant effects of ketamine are hypothesized to be mediated by increases in CREB and BDNF expression, as well as the anti-apoptotic protein Bcl-2.”

https://www.sciencemag.org/content/329/5994/959.abstract mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists

“The rapid antidepressant response after ketamine administration in treatment-resistant depressed patients suggests a possible new approach for treating mood disorders compared to the weeks or months required for standard medications….Our results demonstrate that these effects of ketamine are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant actions of ketamine.”

http://psychiatry.jwatch.org/cgi/content/full/2010/1008/5 Ketamine’s quick antidepressant actions

“The resulting protein synthesis and neuronal alterations in the medial prefrontal cortex are the opposite of those produced by chronic stress….”

 

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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..

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Please understand that it is not legal for me to give medical advice without a consultation.

If you wish an appointment, please telephone my office or contact your local psychiatrist.

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

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RSD – Complex Regional Pain Syndrome – A Case Report

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Rational Polypharmacy

Naltrexone is a remarkable drug for intractable pain

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I first saw this RN in June 2006.

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She is now 60 years old.  She was an OR scrub nurse for almost 30 years, but was disabled for the last 5 years before seeing me. She had Reflex Sympathetic Dystrophy [RSD] of both legs with “arthritis” of the feet/ankle that felt like she was “90 years old” with cold allodynia. Allodynia is pain from a stimulus such as light touch or a breath or air that is not normally painful. Imagine a light touch that feels like severe nerve pain, one of the most disturbing pains a person could have. The temperature of her feet was 81 degrees, hands 92 degrees.

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Pain of both feet felt like a vise grip, gnawing, penetrating, “like broken bones in the feet,” variable at different times but always worse as the day progressed, with a crushing sensation that penetrated through foot and ankle. She was unable to tolerate socks or anything on her feet after 5 pm, unable even to tolerate air on the area, unable to tolerate coolness below waist, but felt hot above waist. She wore a blanket and covers on the hottest 120 degree days, and forced herself to tolerate touch at the legs in order to desensitize them, as we instruct patients to do. She felt constant tingling numbness of the soles of feet for 3 years, with weakness, stiffness “almost solid” like a block. Spasm in soles of feet had resolved the last 6 months before seeing me.

Pain ranged from 2 to 9 on a scale of 10, where 10 is the worst pain imaginable, worst after 5 pm. Average pain was 3. It interfered with sleep at times, and she used a tented frame to keep blankets off her feet, preheated the bed to avoid any coolness, and avoided cold under all circumstances. In the morning, the joints felt like she had a broken ankle. She would massage the feet with lotion, put on alpaca socks, and slowly begin to walk. Then tried to mobilize the joints. Walking made pain worse though walking had always been a favorite activity.~

Before seeing me she had had more than 10 sympathetic blocks, was hospitalized 11 days due to headache from prednisone 60 mg that had been trialed to relieve her pain. She had been prescribed Procardia to relieve the “vascular” disease that she did not have but the drug led to gangrene of the gall bladder; she had been prescribed almost every “adjuvant” used to relieve pain and as much as 9 grams of Neurontin daily, all of this to attempt to relieve the severe pain in her legs and feet.

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This is how she got better

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When I first saw her in 2006, I prescribed low dose oral ketamine that gave relief lasting up to 3 hours from each dose. She then requested referral to Dr. Schwartzman, chief of neurology at Drexel University in Philadelphia, for continuous 5 day ketamine infusion that was done May 2007. She was pain free but it completely lost effect after 8 months, despite booster infusions every 4 to 6 weeks for 4 hours daily over 2 days during those 8 months. After insurance the cost out of pocket was $45,000 in 2007 alone. Dr. Schwartzman had nothing more to offer after it failed and said most patients have relief for less than 6 months if at all.

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In March 2007, I started her on a combination of Namenda 55 mg daily with lamotrigine 350 mg daily that relieved 90% of the pain, but once every 6 to 8 weeks she needed 12.5 to 25 mg low dose oral ketamine for breakthrough pain. Even more rarely, she used oxycodone 10 to 20 mg.

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In October 2008, adding naltrexone 1 mg by mouth, she became pain free. Since then she has not needed anything for breakthrough pain and on 3/5/09, she reported that her last use of ketamine and oxycodone occurred with the addition of low dose naltrexone.

 

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In 2009, she hiked 30 miles down the Grand Canyon and back up in 3 days.

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Naltrexone was later increased to 4.5 mg as she completely tapered off lamotrigine.

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By December 2009, the RSD was 98% better and she reported that it was not pain anymore. Medications then were naltrexone 12.5 mg at bedtime and Namenda 55 mg daily in divided doses. She had just a “remnant” of a little buzz, but no crushing except when active, late in the day.

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A few months later she slowly tapered off Namenda with no increase in pain; and in October 2010, on my advice she tapered naltrexone 12.5 mg from daily to every third day. There has been no increase in pain but she is reluctant to discontinue naltrexone for fear that RSD may recur.

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She hikes 2 miles 3 to 4 times a week, does Iron Mountain once a week, does “Silver Sneekers” exercise 1 hour 3 times a week and sleeps well 8 to 10 hours a night without a sleeping pill.

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She remains on low dose naltrexone as her sole medication for this

previously disabling neuropathic pain syndrome~

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She has returned to part time work and spends a few weeks a month traveling the world, hiking, volunteering, sightseeing.

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Research funding is needed to view whether we can detect

activated glia in the spinal cord, as discussed here.

If there are no signs of activated glia, she may feel reassured that the condition has resolved.

Naltrexone is an immune modulator.

The site of action of naltrexone is at the Toll-like receptor (TLR4) attached to the cell surface membrane of glia.

The ability to view activated glia would help greatly in treatment of so many conditions including neuropathic pain.

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Naltrexone

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I have found that naltrexone is a remarkable medication for various pain conditions, and going through the steps of rational polypharmacy may be very rewarding for some patients though at times it may work all on its own. It has caused me to completely reassess how I approach the treatment of intractable pain – not just RSD or CRPS but arthritis, sciatica and various forms of mechanical pain. And it has led to further changes in the timing and dosing of naltrexone based upon the experiences patients have reported back to me over the years. It is hoped that further research will lead to better understanding of how naltrexone acts upon pain pathways. Surprisingly we already know quite a fair amount.

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My deepest gratitude to Dr. Jau-Shyong Hong, Chief of Neuropharmacology at NIH, whose many generous discussions, emails and research publications have helped me to understand it’s profound anti-inflammatory effect in the central nervous system through its actions on microglia. I previously posted a discussion of mechanisms of naltrexone and dextromethorphan in greater detail here. Naltrexone and dextromethorphan are classified as morphinans, morphine-like. They suppress Superoxide, a free radical that destroys neurons which may cause or contribute to Alzheimers and Parkinsons Disease. That research goes back to the late 1980′s and continues to grow. Phase II studies with morphinans are now being done on those conditions. Studies are also going on now with naltrexone/Wellbutrin combination for weight loss. The drug is called Contrave, from Orexigen Therapeutics Inc. and the dose I believe is 32 mg naltrexone – I do not know how they decided upon that dosage.

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In my experience, naltrexone is a very benign drug at these low doses, though colleagues who prescribe 400 mg for the FDA approved use at that high dose may see some liver toxicity. I always begin at 1 mg or 4.5 mg, depending upon whether or not the patient is a slow drug metabolizer, i.e. may lack one of the CYP P450 chromosomes for metabolizing drugs. I have long suspected it also has an effect on the hypothalamus because a few patients with profound postmenopausal hot flashes have reported that is no longer a problem and that their husbands simply cannot believe the bonus, and this may explain the effect upon appetite that Orexigen has found. At higher doses than I generally use there may be some constipation which is treatable. It may cause vivid dreaming in some, and a small percentage may have insomnia for a few days. Pharmacology and safety is discussed here.

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Stay tuned. I’ll be adding more case reports of different pain conditions in the near future. They are truly fascinating. It has changed my entire approach to treating pain.

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Cost

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Wouldn’t it be nice if NIH funded more for pain research? Imagine how much money that would save the country and save the lives of each person with disability who could recover? As I posted here, the American Pain Society has shown that NIH spends 0.67% of its budget on pain research – less than 1% – though 10 to 20% of the population in the US suffers from chronic pain, an estimated 60 million Americans, and pain conditions are more prevalent among the elderly.

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I am told by my pharmacist that perhaps 70% of the time insurance will approve coverage for compounded low dose naltrexone. It is very affordable but some insurance carriers deny payment for naltrexone. Medicare will not pay for compounded medication either. Compare this low cost compound to the wholesale price for 100 tablets of Oxycontin, $1300, which may not be relieving pain – then multiple that by 2 or 3 each month for one patient. Imagine if the $22 billion of federal money for health insurance technology, for software which is untested and will expire in a few years, instead went into NIH funding for pain research. What a lovely thought.

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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.

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

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Ketamine

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


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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.

Please note that the free Adobe Acrobat Reader is needed to read some references.

You can download the free reader now.

~~~~~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. ~~~~~

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