Selenium Supplement


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Selenium Toxicity

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Almost every American is taking supplements without knowing the reactions they are causing. Most do not know the ingredients they take daily for years, then they see neurologists for muscle weakness and neuropathy. 90% of the causes of neuropathy are unknown – selenium is one.  Muscle weakness, another. Doctors don’t ask to review labels on supplements.

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The biggest issue (no pun) is insulin resistance that leads to diabetes and obesity.

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From Memorial Sloan Kettering Cancer Center Herbs & Botanicals

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“Excessive intake of selenium induces hepatic insulin resistance through opposite regulation of ROS [Reactive oxygen species].”

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Adverse reactions:

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“Oral consumption of 10 g of sodium selenate supplements for treatment of prostate cancer resulted in the death of a 75-year-old man.”

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Chronic selenosis (doses greater than 1000 µg/day): muscle weakness, fatigue, peripheral neuropathy, dermatitis, nail and hair changes/loss, garlic breath/body odor, irritability, growth retardation, hepatic necrosis” (death).

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Toxicity: “Consumption of gram quantities of selenium can cause severe gastrointestinal and neurological disturbances, acute respiratory distress syndrome, myocardial infarction and renal failure.”

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The material on this site is for informational purposes only.

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It is not legal for me to provide medical advice without an examination.

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

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This site is not for email and not for appointments.

If you wish an appointment, please telephone the office to schedule.

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

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Please IGNORE THE ADS BELOW. They are not from me.

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Proposal: A 5-Year Study of Best Methods to Treat Intractable Pain


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PROPOSAL

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A controlled trial to improve care for chronic pain:

The study to understand prognoses and preferences for

outcomes and risks of treatments

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Model after Joanne Lynn’s 1995 SUPPORT Study

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A controlled trial to improve care for seriously ill hospitalized patients:

The study to understand prognoses and preferences for

outcomes and risks of treatments (SUPPORT)

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Proposal

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A controlled five-year trial to improve care for outpatients with chronic pain. The study will be designed to understand prognoses and preferences related to the outcomes and risks of various treatments.

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The focus:

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Intractable pain, those who have failed pain medications and procedures or those with moderate to severe pain who only partially respond.

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Study polypharmacy, compare medications that may show synergy or that additively improve relief.

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Study and search for glial modulators – medications that reduce proinflammatory cytokines.

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Problem

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Research is needed to give persons with intractable pain the data and the confidence that they can affordably use to choose the best treatment needed to get their lives back again. They have already spent tens of thousands. They may be unable to work. We all need these options.

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There are a few small islands in this country doing a radical experiment in managing pain without opioids [narcotics, the police term] as discussed in the New York Times in May 2014, and the 2008 Mayo Clinic study. Efforts such as these need to be supported with data as soon as possible in order to reduce the burden of disability and pain in our society, especially our youth, our children, our veterans, our aging seniors, well everyone. We can be productive and we want to be.

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I have seen remarkable outcomes, pain that failed to respond to all known pain medications, going into partial and even total remission, lives restored after weaning off opioids and appropriate treatment given.

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We cannot expect any medication to work every time. How often can we achieve better results after opioids are tapered off? Opioids may prolong pain in Complex Regional Pain Syndrome where remission seems possible only after they are stopped, yet opioids may be essential in many forms of chronic pain. We need data on the radical experiment to manage pain without opioids, and determine how best to manage chronic pain with them.

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Opioids have a long history of being the drug of choice to treat chronic intractable pain by doctors who lack information and training about other exciting options now coming to the fore. Compounding the problem is the fact that physicians do not know how to diagnose musculoskeletal pain and do not know how that good physical therapy is actually effective.

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Healthcare providers need data about all the options to begin to address the toll that chronic intractable pain exacts and government worldwide need to know what is cost effective and possible. Many countries cannot obtain opioids.

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We must not be insensitive to the financial burden that frustrates patients when they spend tens of thousands of dollars for drugs that provide little if any benefit.

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Investment in developing nonopioid treatments for pain does not even begin to compare to the investment in opioids for pain. The few medication choices we have are not enough. Often they fail to help. Expensive drugs are not the best choice if they are not affordable or they are limited to diabetic neuropathy when more than 100 types of peripheral neuropathy have been identified, plus many more types of even more severe neuropathic pain not classified as neuropathy. Shall we continue to ignore all those because FDA has classed these few new drugs for diabetic neuropathy exclusively?

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Let me be clear, prescription of opioids is justified and they are valuable. Opioids are on the World Health Organization list of ten essential drugs. BUT there is little or no research on treatment of intractable pain without opioids.

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Neuropathic pain, nerve pain, is the most difficult to treat. Neuropathy, radiculopathy, transverse myelitis, adhesive arachnoiditis, central pain, RSD, Guillain-Barre, trigeminal neuralgia, Tic Douloureaux, post herpetic neuralgia, to name a few. It is not enough to limit research of neuropathic pain to diabetic neuropathy when it fails to address all other causes. When FDA approves a drug only for diabetic neuropathy, insurers deny the drug for the other 95% of you without diabetes. Insurers may choose to read guidelines as mandates, fiats,  marching orders.

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Neuropathic pain is not the only concern. Physicians do not know how to diagnose musculoskeletal pain. How can they if only 3% of medical schools teach pain management and when doctors do not know how to assess ineffective physical therapy when they have never seen better.

A patient dislocated her hip 7 times, manually repositioned each time in ER. The 6th surgeon impinged a wide band of muscle in the joint causing muscle all down the thigh to bulge 5 to 7 mm high, of rock hard spasm with intense relentless pain. The 7th surgeon had the gentle ability to restore position and release the entrapment. A light touch across the thigh even through clothing can detect the cause. Would a surgeon have discovered to release the entrapment unless she had dislocated a 7th time? Simple muscle strain, undiagnosed by a surgeon who deals with muscle all the time, was not even noticed and he ignored the acute pain it caused. She has now learned how to avoid dislocating that new hip. Had the muscle not been appropriately identified as cause, she would not be able to move by now. But the surgeon should have had the skills to notice instantly before those muscles became chronically strangled. She was referred for manual physical therapy and thankfully, before all else could occur, she dislocated and was repositioned by the 7th surgeon. A wonderful teaching case for a teaching hospital that should be every hospital. Grand Rounds for pain cases.

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MAJOR FUNDING DECLINE IN PAIN RESEARCH

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 BEFORE 2008

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 BEFORE CONGRESS CUT NIH BUDGET BY UNTHINKABLE 30% IN 2010

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Perhaps the biggest impediment to gathering data about pain management is the lack of government funding for pain research and lack of a Pain Institute at NIH. If not, funding will continue to be fragmented and split elsewhere, not to learn about one of the most costly problems in every society.

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In 2008, before the worldwide depression, pain research was in major decline. The AAAS, the American Association for Advancement of Science told us then:

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“Federal funding for pain research is declining sharply, more than 9 percent a year since 2003, according to a new study published in The Journal of Pain. Pain research, as a result, now accounts for only 0.6 percent of all grants awarded by the National Institutes of Health (NIH), despite the high prevalence of chronic pain in the U.S.

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“This startling finding shows the government’s meager investment in pain research is seriously out of proportion with the widespread chronic pain incidence in our society, which is estimated at one in four Americans and accounts for more than 20 percent of all physician office visits,” said Charles E. Inturrisi, president of the American Pain Society and professor of pharmacology at Weill Cornell Medical College, New York. “And this disparity is not attributable to years of budget cuts at NIH because the Journal of Pain study clearly shows pain research has a higher percentage decline than the overall NIH budget. So the drop in agency funding has not affected all research areas equally.”

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[emphasis mine.]

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Research in pain was sharply declining prior to 2008. Then a 30% cut across the board in 2010. Thank the American Pain Society for those ancient 2008 figures. No one had ever asked – which is why we need a Pain Institute at NIH.

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Frustration is compounded the last few years by insurers no longer willing to authorize many opioids and non-opioid medications, even generics.

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As for the cost of opioids,  a single opioid for one patient may exceed $80,000 per month when the patient is required to use with another long acting opioid, and often several nonopioid adjuncts just to bring pain down from 9 on scale of 10, to a slightly more bearable 7 or 8 which is severe, relentless and prevents sleep and ability to concentrate. One drug that costs pennies to make, sells for $80,000 a month to allow 4 a day when at least 6 a day are needed and it is only one of many for pain every day.

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Prescription of opioids is justified and may be invaluable.

but there is little or no research on

 treatment of intractable pain without opioids.

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We need national consensus guidelines based on data

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We must do a better job treating intractable pain. We need guidelines that have more to offer than the few opioids and few adjuvants we now have, so few in number, so great the need. Can we know when is it true that opioids are indicated? Our use is many times more than all the other First World countries?

 

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Treatment must be individualized

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Data is needed to guide choice

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Compounded Medications are among the

most useful drugs we have for treatment of intractable pain

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Compounded medications may be the only ones that help, and can reduce pain to zero. We can re-purpose the delivery of any medication, as long as it has been FDA approved. But the last few years insurers have been discontinuing coverage for compounded medications and Medicare has never covered them.

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This must change. Who is funding that political blockade that denies coverage for compounded medicine? The cost may be $120 for one compounded medication vs $80,000 for one opioid. Either way, the person with intractable pain likely needs 3 or 4 or 5 or 6 medications, compounded or not. Who can afford $400 per month out of pocket for compounded medications that work, when insurance will not cover the affordable drugs. Who can afford that out-of-pocket expense if insurers cover nothing for your pain, neither the bright shiny opioid or the compounded sprays, capsules, suspensions, creams, troches, as well as the essential solutions instilled into the bladder for interstitial cystitis?

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This must change. Lawmakers must be called to account for allowing and perpetuating the inhumane taking advantage of those who suffer intractable pain.

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A first step in getting lawmakers to pay attention is to amass a body of compelling data.

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BALANCE IS NEEDED

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The United States as a society cannot afford for pain research to die and go bankrupt and leave only opioids as the standard treatment for hundreds of types of pain. Someone has to begin the needed studies. It does not just bankrupt the patient, it leaves us all bankrupt, the country most importantly. It ends marriages, tears apart families. To be struck down as a child with intractable nerve pain the rest of your life, or be struck in your prime, is devastating. And disability gets routinely denied for pain. Why? Perhaps because pain is taught in only 3% of university medical schools. How are doctors to imagine that pain can end lives when they have no experience seeing how disabling it can be?

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 If doctors cannot see the devastating toll that pain takes,

how can we expect accountants to see it?

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The Study We Need

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Solution

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 To gain a comprehensive and compelling picture of how pain impacts the population and how to effectively treat it we need a large-scale study:

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  • Five years in duration

  • 10,000 outpatients – statistically this must be adjusted to obtain multiple outcomes

  • At five major university teaching hospitals for regional differences

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 Outcomes

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The study will yield important information about the following:

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  • Efficacy

  • Pain Numeric Rating Scores, Percent Improvement

  • Functional Improvement, etc

  • Compounded medications

  • Racial and Gender Disparities

  • Addicts who have chronic pain

  • Top notch manual physical therapy* [see below], not for what passes in most places. This must change ASAP. United States is far behind other countries. Even if the condition is neuropathic, it often becomes musculoskeletal after splinting for months, years

  • Interventional procedures

  • Meditation

    How you brain can heal your body and your body heal your brain.

  • Pain changes DNA, neurotransmitters. Have we permanently changed them with opioids?

  • Polypharmacy. When employing one drug alone is unlikely to lead to a successful outcome.

  • Stem cells for joint pain – autologous lipid derived mesenchymal stem cells

  • rTMS, experimental after 20 years, is it still better for acute than for chronic pain?
    Who will benefit, for how long? How many weeks of relief for that $15,000 investment?

  • Glia, the Innate Immune System

Opioids create pro-inflammatory cytokines that create pain and opioid tolerance.

Restore cytokine balance, reduce inflammation and pain.

Which of our existing medications either trigger or reduce inflammatory cytokines in the CNS?

  • Pain in the person with Alzheimers dementia

  • Danger of combining opioids with benzodiazepines

  • Danger of long term use of opioids (regardless if short or long acting)

  • Appropriateness of using opioids as a first choice in acute pain (loss of a milk tooth, sore throat in a teenager, acute back pain, ankle strain, etc.)

  • Appropriateness of opioid holidays.

  • Post op pain can be avoided completely with combined use of oral low dose naltrexone and ketamine IV anesthesia. Patients discharged directly from recovery room with no need for pain medication for months or years

  • Cost Benefit Analysis

 

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Five Conditions Will Be Studied

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Strong emphasis must be placed on neuropathic pain that so often fails to respond to any intervention

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1. Complex Regional Pain Syndrome

The Netherlands invested €25 million over 5 years to study this one devastating pain condition, far out of proportion to the incidence in that small country. There are pain specialists who cannot recognize it and/or doctors who routinely deny disability for this devastating pain, like death in life.

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2. Low Back Pain

Define criteria for surgery.

If we wait too long before surgery is done, will we ever reverse the chronic pain that has set in?

Have we condemned that patient to monthly visits for opioid the remaining 50 years of their life?

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3. Other neuropathic pain conditions such as adhesive arachnoiditis, trigeminal neuralgia, transverse myelitis, Tic Douloureaux, Post Herpetic Neuralgia, Interstitial Cystitis, Vulvodynia, Proctalgia, Pudendal Neuropathy


4. Painful peripheral neuropathy nondiabetic and Painful Small Fiber Neuropathy  all forms of painful neuropathy

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5. You choose – central pain?

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What We Must Do Now

 

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  • Find a pain advocate like the cancer advocate of the 1950’s that changed attitudes for research

  • Fund the pain SUPPORT study

  • This will spin off enormous research ideas that we must begin separately to implement with research as each develops, the need is beyond urgent. How many more years can we make everyone wait?

  • Write letters, to congress, the White House. Real letters, not email, not signature lists. Congress will not hear us unless we speak in very, very large numbers.

  • Help the topic of intractable pain become a part of the 2016 presidential conversation.

  • Incentivize teaching hospitals to teach pain management and to develop options for nonopioid treatment of chronic intractable pain. Pain is a multidisciplinary field, not limited to Anesthesiology procedures.

  • Create an Institute for Pain Management in addition to the 28 institutes at NIH, three of which are for addiction, none for pain. Pain is the number one reason people seek medical help.

  • Require that pain specialists sit on the FDA advisory committees for pain medication – none recently.

  • Require insurance coverage for compounded medications.

  • Prevent FDA from limiting medication to cancer pain.
    Cancer pain does not exist.

    There are basic types of pain that occur in persons who have cancer, neuropathic pain being worse than other forms of “cancer pain.” It has the same medication response or failure to respond as persons whose pain is not due to cancer.

  • How do we restrict the use of opioids to severe pain when there is nothing else to offer and after everyone is started on opioids by their family doctor years before they see a pain specialist?

  • Novel and ancient methods for treatment of pain should be explored including cannabis and possibly hallucinogens

  • Isolation of pharmacologically important medicine from rainforest and deep seas must be done before they disappear.

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Physical Therapy is the #1 Key to Chronic Pain

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Manual Physical Therapy was introduced to the United States in the late 1970’s but is rarely practiced or not done well. It does not mean “hands on.” It derives from techniques brought to us by British Commonwealth and Scandinavian countries. Our healthcare providers do not know how to differentiate between good and useless practices. Fortunes and lives are wasted hinging on that distinction. Pills never can undo the harm brought about by common musculoskeletal issues – and our providers have no training in recognizing simple muscle trigger points, let alone intractable connective tissue contractures. My patients have been misdiagnosed as histrionic, drug seeking, personality disorders, and worse. It boils down to ignorance and lack of basic training, let alone believing what the patient says and not having the tools to help.

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The trend is for year long residency programs following the 3 year Doctorate of Physical Therapy (DPT).  The year long residency program is a very positive step.  The limitations are that it is a year with a clinical staff that may have a specific perspective.  The push towards evidence based practice is a reasonable step but should not exclude considerations of outside the box treatment options.

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The osteopathic manipulative technique has been a cornerstone of best education for physical therapists.  The craniosacral approach is an offshoot from that tradition.  When we get to visceral mobilization, the evidence is much harder to produce but that does not have me shy away from its application.

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Movement is critical for the hormonal regulation of the body.  Chronic stasis leads to numerous changes that compound an underlying medical diagnosis.  We see that with a 16 y/o female, Lyme’s disease, CRPS diagnosis, bedridden for years.  She is significantly benefiting from stretching dysfunction and improving axial extension.  Another who quit walking had global lower limb connective tissue contracture.  Walking is currently limited by soft tissue contracture through the tarsal tunnel, affecting the plantar nerves and the burning and tingling with walking greater than 5 minutes at a time.  Mobilizing the soft tissues will ultimately restore function. This 20 year old quit college due to pain and one first visit requested motorized wheelchair and Social Security Disability. This young person will walk again.

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There is no end point to this educational process except when we think we know it all.  No certification, no degree, no one course signifies competency.  Ongoing intellectual curiosity is the most important element in preparation.

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Prescription painkiller overdose epidemic in the U.S.

Not in other countries

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Pain Management centers at major universities closed in 1991. They lose money, are time consuming, require team conferences that are not reimbursable. Thus began the era when prescription opioids took off for noncancer pain, and no one was generating nonopioid approaches to chronic pain. Anesthesiologists shifted to procedures – that is their focus after all. Procedures are not applicable to many types of pain.

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“Since 1999, the amount of prescription painkillers prescribed and sold in the U.S. has nearly quadrupled, yet there has not been an overall change in the amount of pain that Americans report.”

from the CDC report of prescription painkiller overdose epidemic

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I feel I have failed when I have to point out to my own patient whose pain is severe, that the high dose opioid I have prescribed is not helping, or is creating pain; when I know there are other options which are not available because the FDA has not approved them or because they are prohibitively expensive. I have failed when so many medications I prescribe are not on the formulary.

 

We need a mandatory formulary available for those with intractable pain.

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There were 16,651 deaths from prescription opioids in the U.S.in 2010, “Starting with 4,030 deaths in 1999….” “…nearly 60 percent of the drug overdose deaths (22,134) involved pharmaceutical drugs. Opioid analgesics, such as oxycodone, hydrocodone, and methadone, were involved in about 3 of every 4 pharmaceutical overdose deaths (16,651).” It’s far higher now. A CDC report stated that one in every 20 U.S. adults has a history of [opioid] use – not abuse, but use.

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Monitor risk, yes, but that should not get all the investment. Many addicts would not be there if there were better treatments for pain, if they had not been given opioids after a minor procedure or injury that is better treated with real therapy, not drugs.

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People with pain do not mention the pain has taken their lives. We may see them as weak. That young child with fractures on the ball field is going to need the best care so pain does not become chronic. Give him or her opioids and opioids cause pain, pain becomes worse, intractable before the 6th grade. That is not an addict, but that child and his or her parents are often treated like addicts, at least with suspicion, drug seeking. What is best for that child with chronic pain when she becomes pregnant? When nursing? Think of our young veterans, some with 3 or 4 different pains, and each type addressed differently. What if either of them was an addict before the pain? If we don’t treat them, they will turn to drugs. What are the best, most efficient, options for treatment of intractable pain? When will we learn? We need to identify and treat before it becomes chronic.

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Chronic pain can be reduced or eliminated in many situations now even possibly without drugs, provided the issue is properly identified – and that will never happen until providers are educated in how to identify first class physical therapy. Further research will help to release persons with intractable pain from the prison that too often makes them feel that life is unbearable and that they can more easily face death. We all need to wake up to this situation.

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If we continue to passively allow nothing to be done, then there may be nothing to help us when we fall into the sudden bind of intractable pain when we wake up one day with shingles or a pinched nerve or when pain of the face prevents us from eating or sleeping or speaking or even wanting to live. It will be too late.

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Sharp like a razor’s edge is the path,
The sages say, difficult to traverse.

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Shall we let those we love hang on the edge while we fail to move this multi-tentacled monster forward? How do we light the fire that enables us to solve this fearful fragmentation of choices?

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See how beautifully it works when the right combinations are brought together?

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Yellow rose blue hibiscus

 

 

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The material on this site is for informational purposes only.
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It is not legal for me to provide medical advice without an examination.

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

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This site is not for email and not for appointments.

If you wish an appointment, please telephone the office to schedule.

~~~~~

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

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Please ignore the ads below. They are not from me.

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PeaPure – Palmitoylethanolamide for Nerve Pain or Migraine


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PeaPure is a glial modulator. It is available in Italy and the Netherlands as a food supplement and has been studied in multicenter clinical trials in Europe for several years. It is well tolerated with no side effects and is very helpful for neuropathic pain, headache, and osteoarthritis. It is anti-inflammatory and neuroprotective.

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Because it inhibits astrocyte activation and the over-expression of pro-inflammatory molecules and signals, it is being investigated in Alzheimer’s Disease.

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The mechanism of action of PEA was discovered in 1993 by Nobel laureate Rita Levi-Montalcini in her work on nerve growth factors. She found it is involved in metabolism of mast cells and published a series of papers on its self-healing effect of the body in response to inflammation and pain. Two recent publications from Jan M Keppel Hesselink, MD, PhD, and his colleagues at the Institute for Neuropathic Pain, Amsterdam, The Netherlands, describe case reports, one of which is the case of a woman with CRPS.

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The purpose of this post is to clarify dosing of PeaPure and how to take it for a sudden flare of pain. My apologies for failing to recall the source of these instructions which I believe was from the manufacturer and from here and here. The latter includes an excellent review of its mechanism.

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Description of PeaPure® 400 mg capsules
PeaPure® is a food supplement based on a natural and fatty-acid like compound.
The substance palmitoylethanolamide (PEA) is a physiologically active molecule that the body produces naturally.
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What the user should know prior to ingestion:
•    There are no known significant side effects.
•    PeaPure® can be taken simultaneously with other medicine. In case of doubt, it is recommended to first consult your doctor or a pharmacist.
•    Use during pregnancy is NOT recommended.
•    PeaPure® does not contain sugar, yeast, allergens, sorbitol, magnesium stearate, povidone or other ingredients.

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Dosage and administration – please refer to the manufacturer.

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UPDATE SEPTEMBER 2014

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It is with a heavy heart that I report this news:

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Palmitoylethanolamide is

now available only from the Netherlands,

sold as PeaPure, a food supplement.

  It is no longer able to be imported by a pharmacy, but we are hoping

that may change if we can interest a supplement manufacturer to make it available for the US.

Patent rights, attorneys are far beyond the resources of my local pharmacy.

 

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I have published this year, 2014, on the treatment of

vulvodynia and proctodynia with PeaPure and a topical cream.

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There are no studies to show us how often it may relieve nerve pain, but it is astonishing when it works. No toxicity, no side effects. Your brain makes it, plants make it. There is a growing literature on it and I have posted on some of its mechanisms. And in particular, its Anti-inflammatory, Analgesic, Neuroprotective Mechanisms.

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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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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.


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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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