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

Emphasis within articles is mine.

.

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

`

`

Coming soon, though these stand on their own:

`

`

Modulation of microglia can attenuate neuropathic pain symptoms and enhance morphine effectiveness.

This research shows efficacy of analgesics decreasing since 2000.

~

“The evidence for pharmacological treatment of neuropathic pain” publication is a good meta-analysis of the current state of evidence-based treatment of neuropathic pain.

~

I have quoted extensively from the article as it is important.

~

“Abstract: One hundred and seventy-four studies were included, representing a 66% increase in published randomized, placebo-controlled trials in the last 5 years. Painful poly-neuropathy (most often due to diabetes) was examined in 69 studies, postherpetic neuralgia in 23, while peripheral nerve injury, central pain, HIV neuropathy, and trigeminal neuralgia were less often studied. Tricyclic antidepressants, serotonin noradrenaline reuptake inhibitors, the anticonvulsants gabapentin and pregabalin, and opioids are the drug classes for which there is the best evidence for a clinical relevant effect. Despite a 66% increase in published trials only a limited improvement of neuropathic pain treatment has been obtained. A large proportion of neuropathic pain patients are left with insufficient pain relief. This fact calls for other treatment options to target chronic neuropathic pain. Large-scale drug trials that aim to identify possible subgroups of patients who are likely to respond to specific drugs are needed to test the hypothesis that a mechanism-based classification may help improve treatment of the individual patients.”

~

~The bla

The black circles are recent circles, the light circles are from the past. Shift to the right means less effect.

~

“Fig. 1. It shows the combined numbers needed to treat (NNT) values for various drug classes in all central and peripheral neuropathic pain conditions (not including trigeminal neuralgia). The figure illustrates the change from 2005 values in light grey to 2010 values in dark grey.  [emphasis mine]The circle sizes indicate the relative number of patients who received active treatment drugs in trials for which dichotomous data were available. Please note that the differences in study design and the patient populations preclude a direct comparison of NNT values across drug classes (see text). BTX-A: botulinum toxin type A; TCAs: tricyclic antidepressants; SNRIs: serotonin noradrenaline reuptake inhibitors; SSRIs: selective serotonin reuptake inhibitor.”

~

“Fig. 2. It shows the combined numbers needed to treat (NNT) values for different drug classes against specific disease etiologies. The symbol sizes indicate the relative number of patients who received active treatment drugs in the trials for which dichotomous data were available.”

~~

 A disease-based classification: fact or fiction?

~ 

“Since (1) there are no clear indications that specific diseases should be treated with specific treatments, (2) symptoms and signs overlap in various neuropathic pain conditions [6], and (3) currently available drugs act with unspecific neurodepressant actions rather on pivotal pathophysiological mechanisms, at present there is no good rationale for a treatment algorithm that discriminates between underlying etiologies [45]. Nevertheless, the vast majority of trials have been done in painful diabetic neuropathy and PHN and few, if any, in certain other conditions (e.g. Guillain–Barré syndrome and small-fiber neuropathy), and recommending a treatment for other conditions may seem to be an unjustified jump.”

~

“Supplementary Figure 1L’Abbé plot showing pain relief for all drugs for different neuropathic pain conditions. Each point illustrates one comparison against placebo (for trials listed in Supplementary Table 1). The axes indicate the percentage of patients with at least 50% pain relief with active and placebo treatment.© 2010 International Association for the Study of Pain”

 ~

Conclusion

~

“Pharmacological treatment still represents the main option for treating chronic neuropathic pain. Our understanding of neuropathic pain-generating mechanisms has grown considerably within the last few decades, but unfortunately this research has not been matched by a similar improvement in treatment efficacy. We are still limited in our efforts in managing neuropathic pain by relying on treating the symptoms of pain rather than identifying the underlying disease mechanisms causing the pain. Although 69 new randomized controlled trials have been published in the past 5years compared with 105 published trials published in the preceding 39years, only a marginal improvement in the treatment of the patients with neuropathic pain has been achieved.”

© 2010 International Association for the Study of Pain

The study is part of the European project, funded by the Innovative Medicines Initiative Joint Undertaking

~

~

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!

~~

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

~

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.

~~

Crossover, 20 patients. Ketamine reduced breakthrough pain within 10min of dosing, lasting up to 60min

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

~

This is a database of persons who have tried low dose naltrexone, their diagnosis, dosage and response to it, if any. The database lists many different medical conditions.

~

For example, persons with Multiple Sclerosis, will choose the link above, that has hundreds of persons with MS who have tried naltrexone. Don’t forget to see more pages once you reach the bottom. For a graph of the overall responses, then go back to the main link on Multiple Sclerosis where you see these choices:

~

To view the database please click HERE

To view the Graph on how people feel about LDN please click HERE

To add your experience with LDN please click HERE – of course first select the condition you have, so your entry falls into the proper category.

~

If your condition is different, just select the condition from the list on left.

~

For example for fibromyalgia:

To view the database please click HERE

To view the Graph on how people feel about LDN please click HERE

To add your experience with LDN please click HERE

~

Here for Irritable Bowel Syndrome, Crohn’s or Ulcerative Colitis.

~

If your condition is not listed, check Other on the left side of the list.

This forum is from LDN Research Trust, a registered non-profit Charity based in the UK, with participants from many countries internationally.

~

I will soon be posting several case reports of my patient responders, persons with intractable pain from various conditions. Some have been pain free one or two years on naltrexone. Some who had years of previously intractable pain have responded to low dose naltrexone and remained pain free more than one year after discontinuing LDN.

~

MECHANISM

for those who like to know the science

~~`

We have known for decades that naltrexone binds to the mu opioid receptor. It blocks the effect of opioids like morphine at the mu receptor. We now know it also acts at another receptor.

~

You may wish to watch this video that explains Toll Like Receptors, TLRs for short. This is a lecture by Dr. Rachel Allen, whose PhD in immunology is from Oxford University. After that, she worked at Cambridge University on innate immune receptors such as the TLR’s.

~

In 2008, it was shown that naltrexone binds at one of the Toll Like Receptors, the TLR4 receptor. There are 13 Toll Like Receptors, and so far they have studied naltrexone only at one of them, the TLR4. That is important because the TLR receptors are part of the innate immune system.

~

The Toll Like Receptors are not like other receptors. Not these snug little pockets where naltrexone binds. Instead the Toll Like Receptors are like an entire football field, with enormous nooks and crannies where it has many interactions with many molecules. Now, in 2010, scientists are asking if naloxone or naltrexone is acting at TLR4 or even higher up in the cascade.

~

The study of immune cell glial interactions is in its infancy. Glial cells are the immune cells in your central nervous system (brain, spinal cord). They are very involved in dysregulation of pain systems, neuroinflammation, and some neurological diseases such as Multiple Sclerosis, Alzheimer’s, Parkinson’s Disease, ALS, infections of the brain, etc.

~

One of our distinguished glial scientists, Linda Watkins, PhD, in October 2010, said we are not even sure naltrexone binds to the Toll Like Receptor. Rather, it involves AKT1, close to the TLR4 receptor, very very high up in the cascade at the dimerization step, the recruitment of CD14. This is being worked out now.

~

Dr. Watkins with Kennar Rice, PhD, from NIH/NIDA, et al, has a paper in press in Cell:

~

Glial activation participates in the mediation of pain including neuropathic pain, due to release of neuroexcitatory, proinflammatory products. Glial activation is now known to occur in response to opioids as well. Opioid-induced glial activation opposes opioid analgesia and enhances opioid tolerance, dependence, reward and respiratory depression. Such effects can occur, not via classical opioid receptors, but rather via non-stereoselective activation of toll-like receptor 4 (TLR4), a recently recognized key glial receptor participating in neuropathic pain as well. This discovery identifies a means for separating the beneficial actions of opioids (opioid receptor mediated) from the unwanted side-effects (TLR4/glial mediated) by pharmacologically targeting TLR4. Such a drug should be a stand-alone therapeutic for treating neuropathic pain as well. Excitingly, with newly-established clinical trials of two glial modulators for treating neuropathic pain and improving the utility of opioids, translation from rats-to-humans now begins with the promise of improved clinical pain control.

~

For chronic pain, targets of interest are: glial attenuation, p38 MAPK inhibition.

~

Of interest, a commonly prescribed pain medication, amitriptyline, is a TLR4 inhibitor (Hutchinson, 2010).

~

You can read many new publications on glia that I posted on my site here, or find it from the banner at top:

Donate to Eliminate Neuropathic Pain

~

I am a member of a Neuroinflammation Research Consortium that will be studying these many conditions, some that are painful, others that are not. They involve glia and neuroinflammation.

~

For more discussion of mechanisms of action of naltrexone and other publications I have posted, see here, particularly the paper by Zhang, Hong, Kim et al.

~

Finally, for those who may feel they are losing heart because medicine has been too slow to adopt the use of low dose naltrexone, let me point this out:

~

Dr. Linda Watkins is a University of Colorado Distinguished Professor of Psychology & Neuroscience at the University of Colorado Boulder. She is a world-renown leader in glia research and the neurological applications of glial attenuation, with a focus on alleviation of chronic pain. She is the recipient of the highest award for distinguished basic science research from the American Pain Society and the 2010 John Liebeskind Pain Management Research Award from the American Academy of Pain Management. She has over 300 peer-reviewed publications including articles in Nature, Science, Nature Neuroscience, and Journal of Neuroscience. She received over $2 million in NIH grants supporting 6 generations of IL-10 gene therapy research culminating in XT-101.

~~~~~

The material on this site is for informational purposes only.

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

~~~~~

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

I see long distance patients in my office who generally come for a two week stay, and I wish to encourage their comments on this page. I am sorry I did not post this page for them sooner.

~

Most people I see have been tried on every common approach to treatment for Complex Regional Pain Syndrome, CRPS. I prescribe most of those therapies as well, but I also use an expanded number of neuropharmacology approaches. Some of these are outlined in the case report I filed in March 2010.

~

In my opinion, it is important to use rational polypharmacy. When pain is intense, it is important to look at more than one mechanism. Once pain comes under control and remains at zero, then we can slowly begin to taper off one at a time.

.

The following describe two of the several mechanisms of interest to me.

.~

NMDA Antagonists

~

The glutamate-NMDA receptor is profoundly important in controlling pain pathways. It is responsible for tolerance to medication and centralization of pain. Research in France has shown that with chronic pain in persons with CRPS there is an increase in NMDA receptors in the central nervous system. After pain control, the increased number of NMDA receptors returns to normal.

~

With persistent pain or chronic depression, glutamate increases and becomes excitotoxic. When it attaches to the NMDA receptor, it causes calcium to enter the neuron, creates free radicals, and kills neurons. This leads to brain atrophy and potentially memory loss.

~

The goal is to block this mechanism. I use three medications that work at this level.

~

Morphinans – Glial dysregulation of pain pathways

~

Another important area of focus for me are the morphinans which means morphine-like. Their mechanism of action is at the microglia, the immune cells in the central nervous system. There is important new research on glial dysregulation of pain pathways. Once primed and activated by pain, the next pain insult causes glia to react harder, faster and longer perpetuating pain with cascades of pro-inflammatory molecules. Glial research on pain is very recent, very new, very important, and is a rapidly growing  body of science. It offers an entirely new paradigm for treatment of chronic pain.

.

The Reflex Sympathetic Dystrophy Syndrome Association library has

many research articles that you may wish to read.

.

I am grateful to be invited to their workshop on activated glia.

~

Oth

Contributing Factors

~

I look at the whole person, review all of their medications including their vitamins and botanicals, toxicity and adverse interactions with medication. I check the blood level for 25(OH) vitamin D (done at ARUP labs), parathyroid hormone (PTH) if not already done, and stress the importance of anti-inflammatory diet, fish oil, and adequate levels of vitamin D3.

~

~

Spinal cord stimulators – controversy

~

A recent Wall Street Journal article discusses some of the controversy of interventional techniques in this evolving specialty and mentions that some studies are underway to show efficacy. Implantable devices are controversial “and questions remain about the appropriateness of their use.”

~

In April 2010, new guidelines were published, updating earlier ones from 1997: Practice Guidelines for Chronic Pain Management: An Updated Report by the American Society of Anesthesiologists Task Force on Chronic Pain Management and the American Society of Regional Anesthesia and Pain Medicine.

~

“Spinal cord stimulation: One randomized controlled trial reports effective pain relief for CRPS patients at follow-up assessment periods of 6 months to 2 yr when spinal cord stimulation in combination with physical therapy is compared with physical therapy alone (Category A3 evidence).”

~

A3 evidence was defined as: “The literature contains a single randomized controlled trial.”

~

The guidelines had no references, nor did it indicate how old that study was. A short two year followup and a single limited study after more than 32 years of implanting these devices should call for more research.

.

I do not recommend spinal cord stimulators as there is no research showing long term efficacy and no quality evidence showing they are superior treatment. Success declines after placement and that may occur the first day. In fact, there is one long term 5 year European study showing no efficacy after two years.

.

Often patients are not aware that alternatives exist and are not given fully informed consent on the stimulators. Those risks include increased pain with any invasive procedure in persons with CRPS, paralysis, spasticity, infection, scarring, potential flare into generalized CRPS pain. The fact that these leads are permanent  - they can never be removed – means that person can never undergo MRI scans in future even if they should have cancer or stroke. The leads become scarred into nerve tissue.

.

A colleague, a prominent Harvard trained anesthesia pain specialist in practice for 37 years, declines to recommend stimulators or pumps for that reason: there is no long term data proving efficacy.

.

Complications of spinal cord stimulators should be published. Perhaps they exist. If anyone has seen them, please advise me. I tend to see the complications or the failures, but those who place them and the corporations that fund them should have a special obligation to study the complications and the long term benefits. Having a spinal cord stimulator does not prevent use of other medication but it may add to the burden of pain to overcome. Nationally there should be an audit of stimulators placed, with patient outcomes including complications and number of revisions made. The risks are too grave not to require this and the cost is too high if there is no lasting efficacy.

~

The excerpt below is from a 2003 review on spinal cord stimulation (SCS) for Complex Regional Pain Syndrome. It may be outdated, however Medtronic failed to provide me with any long term studies when requested:

“The use of SCS for the treatment of pain in CRPS (including RSD and causalgia) has been reported in the literature for over 25 years. The consensus opinion from experts suggests that SCS should be considered in the treatment algorithm when conservative or traditional therapies have failed. However, such considerations are not based on reliable evidence generated through well-designed randomized controlled trials. To date, there has not been a systemic evaluation of the existing literature concerning the efficacy of SCS for patients with CRPS.”

~

~

For those interested in coming to San Diego for two week stay, please see information on long distance patients in banner at top of page.

~

I hope my patients who have come from long distance who stayed nearby for two weeks will feel free to comment on their experience.

~~~

~~~~~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. ~~~~~

~

~

~

~

~

What you can do

“Moving is the best medicine”

~

For headache and neck and shoulder pain

As reported in the leading headache journal, Cephalalgia, office workers with headache, neck and shoulder pain took part in an education and relaxation program in an Italian study over eight months. They kept diaries and did posture and relaxation exercises every two to three hours. Compared to a control group, headache and neck and shoulder pain decreased by more than 40% and use of analgesic drugs was cut in half.

~

For Arthritis Pain

·

Persistent pain has a prevalence of 1 in 5 of the population

at an annual cost of $1.85 billion per 1 million population.

·

Does Pain Management Have a Place in American Healthcare?

Pain focused courses foster affective awareness and shape values formation in medical learners.

·

Symposium on Pain Management Aimed at Medical School Students

·

Yale’s Medical Bulletin, Published: May 16, 2008

New Haven, Conn. — Physicians-in-training learned about an important aspect of patient care — pain management — at a symposium held recently at the Yale School of Medicine.

In recent years, pain has been designated as one of the vital signs indicating a patient’s well-being by the Joint Commission on the Accreditation of Healthcare Organizations, and pain management is being widely accepted as a basic human right. Yet only 3% of the nation’s medical schools, including Yale, currently have a separate course in pain management. [emphasis mine]

As a first step in its efforts to include separate training in pain management as part of its curriculum, the School of Medicine recently hosted the inaugural Yale Multidisciplinary Pain Management Symposium. The event was organized by student Ninani Kombo under the guidance of faculty adviser Dr. Nalini Vadivelu, associate professor of anesthesiology, with support from the medical school’s Offices of Education and of Student Affairs, as well as the Graduate Professional Student Senate.

The symposium featured presentations on “Pain Pathways,” “Clinical Perspectives in Pain Management,” “Interventional Pain Management,” “Psychology and Pain Management” and “Legal Considerations of Pain Management.” The speakers included Vadivelu, Dr. Sam Chung and Dr. Raymond Sinatra of the Department of Anesthesiology; Dr. Michele Johnson of the Department of Interventional Radiology; Layne Goble, a psychologist at the West Haven Veterans Hospital; and Robert Burt, the Alexander M. Bickel Professor of Law at Yale Law School.

Two physicians also brought in patients so the students could talk with them and learn more about their personal experiences and challenges in living with chronic pain. One, who suffers from migraines, is a patient of Dr. Bahman Jabbari, professor of neurology; and the other, who has sickle cell anemia, is a patient of Dr. Thomas Duffy, professor of internal medicine and hematology.

Plans call for the symposium to continue as an annual event, and to be included within the neurology module of the second-year medical curriculum.

“This will continue to be a multidisciplinary pain symposium and in true Yale medical school tradition it will be organized by medical student volunteers,” says Vadivelu, who will continue to serve as faculty adviser for the initiative. “In the near future, the pain management curriculum may be expanded to include didactic case studies in pain management during the third and fourth years of medical school.

“This commitment,” she adds, “makes Yale School of Medicine one of the leaders among U.S. medical schools in formal pain management education.”

PRESS CONTACT: Office of Public Affairs 203-432-1345

A letter from Yale professors April 2009, to the Editor of the Journal of the Association of American Medical Colleges

The Urgent Need for Pain Management Training

Vadivelu, Nalini MD; Kombo, Ninani; Hines, Roberta L. MD

To the Editor: Approximately 50 million people in the United States suffer from persistent pain,¹ and pain treatment cuts across most medical disciplines. Despite huge strides in understanding pain, there is a major gap between that understanding and pain diagnosis and treatment. In the 21st century, pain management is being accepted as a basic human right.² Thus, it is even more important to train medical students to be competent in the areas of pain assessment and treatment. However, few physicians graduating from U.S. medical schools have had comprehensive multidisciplinary pain education as part of their medical school curricula. This was shown in an AAMC survey in 2000-2001, which found that only 3% of medical schools had a separate course in pain management in their curricula¹; the situation is not much better today. [emphasis mine] Although a free, Internet-based CD-ROM textbook on pain was developed for medical students in 2003 by the American Academy of Pain Medicine, we feel there is an urgent need for formal pain management training within the medical school curriculum.

Pain education in medical schools could be in the form of pain symposiums, pain workshops, lecture series, and clinical rotations in pain management, according to what is available and feasible in each school. Interinstitutional elective rotations in pain management and summer research projects with resulting research publications in pain should also be encouraged. Funding for the latter is available from, for example, Foundation for Anesthesia Education and Research grants to medical students from the American Society of Anesthesiologists. We at Yale have incorporated formal pain education into our curriculum using a multidisciplinary pain symposium at the second-year level with case studies for third- and fourth-year students.

We believe that medical schools worldwide should establish formal pain management education in each year of their curricula. [emphasis mine] This will enable graduating physicians everywhere to be well equipped to ease their patients’ pain.

Nalini Vadivelu, MD

Associate professor, Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut; (nalini.vadivelu@yale.edu).

Ninani Kombo

Fifth-year medical student, Yale University School of Medicine, New Haven, Connecticut.

Roberta L. Hines, MD

Professor and chair, Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut.

.

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.

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

.

.

The War on Drugs Sold so Well That Persons With Pain

Often Cannot Get Pain Medication or Treatment

·

Don’t read this. It will upset you.

The federal government has always been more interested in addicts than in persons who are disabled with intractable pain. Billions are spent to imprison addicts rather than pay for addiction programs which would be far less expensive.

Only 3% of medical schools have a course in pain management, Yale announced in 2008. According to the International Association for the Study of Pain, the IASP, education on pain is poor “at either the preclinical or clinical levels and information is poorly integrated.” Fewer than 3% of recent graduates have had a few hours of training. This means that unless your doctor is among that small 3% that has recently graduated, they have had no training in pain control. None. And the FDA ignores the extensive training of pain specialists when approving limitations on new medications.

Worst of all, 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 the conditions are more prevalent among the elderly. Addiction funding is the only reason neuroscientists in the early 1970′s were able to identify opioid receptors and then to clone them, which legitimized pain in cancer patients and led to use of opioids for cancer pain in the 1970′s and for noncancer pain in the 1990′s.

·

Pain Epidemic:

Does Pain Management Have a Place in American Healthcare?

Today, there is too much reliance on opioids for pain because there is little or no NIH research on alternatives. Or maybe because your doctor does not know any other treatment than to prescribe an opioid. Or because Medicare will not pay for the amount of physical therapy you need. Opioids are overprescribed. This increases the risk of opioids being diverted and falling into the hands of addicts, leading to deaths and headlines that will no doubt limit your ability to be treated for pain. How many of you know Medicare has been limiting physical therapy for years? If you use all your treatment by mid February, they will not pay for more no matter how often you fracture your hip or herniate a disc. Is it right for them to pay for opioid pain medication and not physical therapy?

Just think of it. Before the early 1970′s, we had no pain societies, no hospices, no use of opioids for cancer patients (unless they happened to be hospitalized), no oral opioids, no oral morphine — why the very thought that oral morphine could work was argued against vehemently by the chief of the pain service at Memorial Sloan Kettering Cancer Center in NYC, in December 1975 at the first meeting of the IASP. The first meeting. 1975. Think of it. He argued that oral morphine would be metabolized so rapidly that it would pass out of the body and not be there to help.

William M. Lamers, Jr., MD

In the early 1970′s if you had pain, you were not legitimate because we simply did not know there were such things as opioid receptors nor did we have oral opioid medication.

Now re-imagine that vehement argument in 1975 again, knowing that my dear friend William M. Lamers, Jr., MD, was the first in the world to use oral morphine when he founded home hospice in America 5 or 6 years before that date. He invited Dr. Cicely Saunders to California to teach her how to use oral morphine at her hospice, and following that, St. Christopher’s Hospice in London stopped using the ineffective Brompton’s Cocktail that caused so many side effects with so much less pain relief. Their research a few years later enabled Dr. Robert Twycross from St. Christopher’s Hospice to stride to the stage in 1975 at the IASP meeting, and report their work with oral morphine, to the applause of the Brits.

Let me be clear, I am gravely concerned that the use of opioids for nonmalignant pain will lead to a dire problem with opioid induced hyperalgesia in our large population of pain patients. If not hyperalgesia, the benefit of relief is undercut by the pain they create as shown by recent research on glia. Opioids create pain at the same time they relieve pain.

·

We Are Not Getting Access to Effective Nonopioid Treatments

Worst of all, unless opioids are low cost, your insurance – PPO, Medicare, Medicaid – will not authorize several profoundly important nonopioid medications that help and/or relieve intractable disabling pain in many of my patients:

• Namenda an NMDA antagonist that was shown in European research in 2001 to be effective for severe pain at a dose of 55 mg per day; in the US it is approved only for dementia at a dose of 20 mg per day. Insurance will not cover the dose needed; patients cannot afford it.
• Compounded capsules and ointments may be the only thing that helps others, but are often not approved.
• Naltrexone and other morphinans – see my post on naltrexone -  may relieve disabling pain, but compounded medications are often not approved
• Medical marijuana research has been forbidden by the federal government despite active research and use of approved compounds in Canada and UK for severe intractable pain. Marijuana is in a class of chemicals called cannabinoids. Our brain makes cannabinoids and has receptors where they act. A synthetic cannabinoid  is FDA approved in the US for chemotherapy induced vomiting. The cost of one mg capsules is $400 for 20 – who can afford that?  In Canada, it is used for pain patients at bedtime to relieve severe pain that prevents sleep. Yet in California where inexpensive medical marijuana is legal, the Obama Department of Justice has continued the prosecution of Charles Lynch, a legitimate marijuana dispensary owner.  He was convicted on federal drug charges despite carefully following state and local law in setting up and running his business and being fully licensed by the state. He had the full support of the mayor and city council, yet he was sentenced to a year and a day in jail last week – the Obama DOJ pushed for a mandatory 5 years jail. Federal law prevented him from testimony in his own defense, presumably because federal law excludes states rights and the issue that marijuana sales may interfere with interstate commerce. For discussion of this and the bill introduced Thursday by Rep. Barney Frank, HR 2835, to legalize medical marijuana, see here. There was a time in the recent past when hospice doctors in the US made marijuana suppositories to relieve severe pain and nausea in dying cancer patients. In Mexico, marijuana is used in ointments by the elderly to relieve arthritis pain. 100 years ago, it was mentioned in some medical textbooks in America. And U.S. Rep. Mark Kirk calls for 25 years in prison for first time trafficking offense.
• Marijuana: Effective for severe pain, safe, nontoxic, inexpensive and illegal.
• The legal status of prescribing as well as the legal status of using marijuana is needlessly complicated. The Federal Government is clear… prescribing and use are both criminal offenses. Nothing is for certain except that the legal status is a mess.
• Unrelieved suffering leads to an intensification of pain that may result in depression, withdrawal, irritability, anger and sometimes even hostility to caregivers.

NSAID –  nonsteroidal anti-inflammatory drug – use is discouraged in the elderly.  NSAIDs pose severe risk to the elderly and cannot be used in others due to heart disease, gastric intolerance, ulcers, GERD, anemia, bleeding, kidney disease, asthma, and those who are on various medications such as Plavix or Coumadin. Further, heavy NSAID use leads to higher dementia risk (see my post on this).

Some nonopioid alternatives cannot be used in those with liver or kidney conditions, men over 50 who still have a prostate, persons who wish to avoid suddenly becoming obese (Lyrica), those with allergies or intolerance to their side effects because the drug makes the fall backwards or suppresses their bone marrow.

Worse than those issues, we have only a few opioids which work on specific opioid receptors, some are more specific for neuropathic pain or for allodynia, yet since September 2008, the FDA has removed several of the older opioids from the shelf with no reason given to pharmacists or MD’s. I have spent hours calling pharmacies to see if they stock a medication I wrote for a patient hours before they left the office holding their specialized prescription. You know very well that if a patient called asking about opioids in stock they’d be looked upon as an addict, and many pharmacies will not stock opioids with the excuse they would be robbed. No matter you are in severe pain, you must wait 72 hours until they stock it. 

Even with insurance, your PPO will not authorize many if not most of the medications I prescribe and the cost of medication is surely the #1 reason.  That is true for opioids and nonopioid medication I use for pain control. Many are off label for pain, others are off label for anyone  who does not have cancer despite severe disabling pain, therefore not covered. If you are wealthy, you can purchase any medication prescribed.

Opioids are a distinct issue and outrageously expensive compared to the pennies cost of the raw drug. There is never a discussion of reducing costs of new drugs. Imagine $45 per unit, used 12 or 20 times per day in extreme, rare cases. Then imagine your PPO allowed prior authorization for 1 year, but then it was 6 months, then 2 months. What will happen next month? Hours and hours of non-reimbursed physician time is spent on these.  They could just save us all time if they published a list telling us what they will never ever ever reimburse no matter what. No wonder a radiologist or cardiologist or a doctor who does procedures makes millions every year. They don’t have to deal with the deafening “no.” The California law is never enforced that guarantees continuation of medication that is being used and that has been approved in the past for years. Requesting an independent appeal is a sham, the fox guarding the henhouse, paid by the same company that refused authorization.

The FDA has limited use of short acting fentanyl to cancer pain, thus PPO’s will often not authorize it without a cancer diagnosis.  News flash: there is no such thing as cancer pain. Patients without cancer have the same categories of pain that you do: involving abberent signals from nerve, viscera or other tissues. At the American Pain Society’s annual meeting in San Diego, May 2009, an FDA official admitted there were only 3 pain specialists on a panel of 11 MD’s that reviewed short acting fentanyl. It is likely the other 8 had no training in use of opioids.  Fewer than 3% of medical schools spend less than 30 hours over 4 years teaching pain management to medical students, and that is only in recent years, which means almost all physicians in practice today have had no training in use of opioids. Oncologists included. Do they think that pain specialists who have spent decades in the field have no understanding of opioids? If so, then why do they not limit all strong opioids to persons with cancer? or is this coming? Politicians do not like headlines about addicts who overdose themselves.

The special case of Subutex and Suboxone which is buprenorphine alone or with naloxone. Buprenorphine is an old drug, a long acting opioid that has unique effect at kappa opioid receptors and it is said it may help allodynia better than other opioids. PPO insurance will not authorize Subutex (buprenorphine) for my patients with pain, or if they do, they will authorize only one of the two, Subutex, but not the other, even though the one they will pay for causes intractable migraine but not the other. In Europe, both are approved for pain or for addiction, just like we use methadone here.  But our FDA has limited use to addicts, though it is an important opioid that we might use for pain. This means PPO insurance will not pay for it. This new formulation of Suboxone or Subutex in a sublingual tablet means it is very expensive, and I have patients in pain, weeping that they cannot afford it and must go back on their Oxycontin that works less well.

Unique issues for oral short acting fentanyl and Subutex or Suboxone: both will absorb directly in the mouth which is important for some persons with colitis, abdominal surgery, bariatric surgery, other conditions with poor GI absorption of tablets such as celiac disease, and those who are unable to use fentanyl patches due to skin allergies.

·

Need for Balance between Risk of Substance Abuse

vs  Suffering and Disability Caused by Untreated Pain?

The FDA and Congress voice concern about addiction, but how much do they care about pain? Actions speak louder than words and the lack of NIH funding for pain research is shocking. Pain does not make newspaper headlines though pain is the #1 reason people seek medical help, more so as the population ages.

Here are more policy and headline issues that will make it harder for people with pain to get the care they need:

FDA, Pain Docs Look to Cut Abuse of Pain Killers“FDA said it was working on a plan to make it tougher for people to abuse certain prescription painkillers….” From the comments: “Regardless of great efforts to reverse this trend, physicians who legitimately prescribe opioids for pain may still feel ‘damned if they do and damned if they don’t.’ It seems as though we have simultaneously raised consciousness of the need for pain control and increased the risks to physicians of being part of the solution. If this dilemma is not resolved, advancing the cause of pain management as a fundamental human right may, in part, serve to polarize the medical community.”

F.D.A. to Place New Limits on Prescriptions of Narcotics “This is going to be a massive program,” according to Dr. John K. Jenkins, director of the F.D.A.’s new drug center.”  ”…a law passed in 2007 gave the agency a new, intermediate weapon — Risk Evaluation and Mitigation Strategies. Known as REMS, these programs allow the agency to place strong restrictions on the distribution of certain drugs.”

Increased Scrutiny of Opioids Could Alter Prescribing Practice “If a formal risk reduction plan for opioid painkillers increases the regulatory burden on physicians, they may simply stop prescribing such drugs, to the detriment of patients in severe pain, the FDA was told Thursday.” Most physicians have no training in pain management, yet instead of requiring more education, regulation of doctors makes it harder to treat persons with legitimate pain and may have no effect on addicts and illegal diversion that they are really trying to regulate. Suggestions were made at a public hearing, quoted here:

• If a REMS does end up imposing requirements on physicians, positive incentives should be put in place to fund and support training in pain management, such as waiving or reducing the fee clinicians now must pay to the DEA for the privilege of prescribing Schedule II drugs
• But clinicians do not currently have the tools to enforce proper distribution and use of narcotics, and need more support and training, said Jennifer Bolen, founder of the Legal Side of Pain and the Pain Law Institute. ”It’s dangerous and irresponsible to use physicians to teach the law,” Bolen said. She said state medical licensing boards, health insurance plans, and law enforcement officials must play a big role in enforcing the REMS.
• But the FDA is not a criminal enforcement agency, said John Jenkins, M.D., director of the Office of New Drugs at the FDA.
• One suggestion from a number of speakers is that the FDA require opioid manufacturers to put serial numbers or microchips in opioid tablets, linked to the prescription that released them to a patient. That way, if law enforcement officials seize pills, the prescriber and patient can be easily traced.
• The FDA is already considering serial numbers on some classes of medication for a different reason — to confirm the integrity of the supply chain.
• Other speakers suggested creating opioid medications that are “less abusable” such as crush-proof pills. However, formulations intended to thwart abuse have been tried before. That was the original intent behind Oxycontin, the brand of extended-release oxycodone that ended up widely abused.While it’s up to the FDA to decide what a REMS will look like, it’s the responsibility of drug companies to enforce the new regulations.
• the two-day hearing was peppered with emotional testimonies from people whose family members overdosed on opioid drugs that they obtained illegally.
• the FDA might convene an advisory committee before any REMS is finalized.

Addiction is a very important issue. Families are best in a position to see what is happening to members who have addiction problems, but addiction programs are poorly funded and many Americans are uninsured, especially the young who are most vulnerable to chemical dependency. Can families help someone who does not want to be helped?

I want to make it very clear that all of us, myself included, are responsible for reducing addiction, misuse of prescription drugs, and diversion in this country. Yes, that means anyone who gives someone else a pill from their prescribed medication, no matter how harmless it may seem. If that is a pain drug, your pain specialist can go to jail for 30 years even if he or she did not know about it. Never give one of your prescription pills to anyone else.

Designing high tech remedies to prevent opioid tablets from being injected or inhaled by addicts will increase the cost of your pain medication.  It is already difficult to afford without new technology, and why is it so expensive since many are now old drugs and the raw material costs pennies?

If we become disabled or develop chronic pain, there is often no money for the multidisciplinary approach to pain management that is essential for treatment: extreme limits on physical therapy, no cognitive behavioral therapy, no coverage at all for many medications that I prescribe. Some of my patients who are still working are afraid they will be laid off at work if they limp, are slow or show they have pain. This is not unlike my cancer patients who fear public knowledge they have cancer. But the rising insurance cost to their employer is Darwinian evolution at its cruelest, untouched by the human mind and heart. Free for the rich, for profiteering off the most vulnerable.

Cost of high tech pills to deter addicts. We thank the FDA for their guidance in requiring opioid manufacturers to make it more difficult for addicts to abuse these drugs, but does the cost of that new technology make these medications unaffordable for the average person, especially the disabled and elderly who may need them more than others. Is the FDA pulling older and more affordable opioids off the shelf because they do not have this new technology? Is the cost of medical care and denial of coverage being driven by the 5% of addicts in this country, by expensive prison empires to house them, by headlines and politicians?

Cost is the issue that limits care. When Medicare & PPO coverage is cut for all of us, will the cost of drugs be one of the major reasons? Answer: it already is.

Remember, the FDA does not have a majority of pain specialists on pain-related advisory committees, only 3 out of 11 MD’s sat on the FDA committee that limited use of short acting fentanyl medication for cancer pain. Opioids may be an essential option for some of my patients yet their PPO will not pay for it — it’s restricted to cancer patients. PPO’s will not pay for many nonopioids used for pain either.

Does the FDA think oncologists know more about treating pain than a pain specialist? The answer is definitely no! Oncologists do not, and some abuse their power to prevent pain relief. Research has shown severe untreated pain in 34% of cancer patients among oncology specialists in the Northeastern US, and likely far more in other areas. There are many untold stories about oncologists who do not treat pain or who use poor practice treating pain, even at major cancer centers. Pain is not their priority and most spend no time learning the needed expertise.

So no coverage for PT, for off label medication, for compounded medication, for opioids restricted to cancer pain, for expensive medication, and increasing regulation for older and more affordable opioids if they have not been pulled off the shelf by the FDA.

Cost cuts imposed major losses in pain management. PPO cuts were severe at least as far back as the mid 1980′s. In 1990, UCLA closed its Anesthesiology Interdisciplinary Pain Center, only 15 years after the first international pain society meeting. Laid off with two weeks notice was the President of the American Pain Society and distinguished researchers in the field. Soon after that, in the hallways of the annual pain society meeting, whispered rumors spread that almost all university centers had closed their interdisciplinary pain centers. Only a few remained, but there was silence on the subject from the platforms and leadership and media. UCLA paved over the only therapeutic swimming pool in the greater Los Angeles area in order to build yet another radiology center.

·

The Era for Procedures

There has been a rapid increase in interventional procedures with almost all pain specialists shifting to high reimbursement and easily funded techniques, but where’s the science? Read the practice guidelines of the Academy of Neurology and American Pain Society on epidurals and nerve blocks. Where are the studies that show their benefit? Are they suitable as the best choice?

Pain management requires individualized care that involves analysis and specific treatment based upon many factors. Medicare and PPO’s will pay for procedures which are inversely proportional to the time needed for analysis. There is no single evidence based protocol that can be applied to every one such as there is for chest pain.

With so little research funding and so little training going into pain management,  politics may make the treatment of pain subject to more and more irrational or unaffordable choices.

.

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.

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

.

.

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

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

Achieving control of chronic pain requires a partnership

based upon trust and effort

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

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

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

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

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

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

Steps to follow: Read all steps carefully before you begin

• Take ketamine 30 minutes prior to your other pain medication

• For the first dose, remain seated or lie down for 20 minutes after you take the dose to avoid risk of falling. Do not take the dose and walk around.
• A few persons have had severe imbalance lasting 10 or 20 minutes. This has resolved after the first few doses in those persons. It may not happen to you, so test with caution. If it has not occurred at the first dose, it is unlikely to occur at all.

• Follow the dosing guidelines in the log I give you and which I repeat in this next step:
  Begin with 0.25 mL and increase by increments of 0.25 mL every 6 hours or longer than 6 hours, until you have some pain relief. Do not increase that dose or dosing interval.

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

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

• If you have intolerable side effects, you may use 1 or 2 Ativan tablets immediately as an antidote, and every 30 minutes, up to 5 of them.

• CAUTION: Be alert to the opioid-sparing effects of ketamine!

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

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

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

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

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

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

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

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

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

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

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

Medical Publications

You can click and download each reference in blue below

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

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

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

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

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

§

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

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

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

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

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

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

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

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. ~~~~~

Posted in Back Pain, Chronic Pain, Complex Regional Pain Syndrome, CRPS, Failed back surgery, intractable pain, Ketamine, Medications, Neuropathy, Pain Management, medicine, Radiculopathy, RSD, Sciatica Tagged: CRPS, Failed back surgery, intractable pain, Ketamine, Neuropathy, RSD, Sciatica ]]> http://painsandiego.com/2009/05/26/ketamine/feed/ 0 painsandiego cancer Yellow rose blue hibiscus http://painsandiego.com/2009/04/22/463/ http://painsandiego.com/2009/04/22/463/#comments Wed, 22 Apr 2009 09:07:29 +0000 Nancy Sajben MD http://painsandiego.wordpress.com/?p=463 ]]>

I don’t know how the Great Recession may be affecting your mood, but for those with chronic pain, it is often difficult to nurture and maintain a positive attitude.  At times when we need the most help, we may be most reluctant to appreciate the benefits of Cognitive Behavioral Therapy, but that’s how we get help to reorder our thoughts in positive ways that are healing.

A Randomized Trial of a Cognitive-Bahavior Intervention

Compared to information giving and educational approaches, the risk for developing a long-term disability was lowered nine-fold for the cognitive-behavior intervention group. The cognitive-behavior group also demonstrated a significant decrease in physician and physical therapy use as compared with two groups receiving information, in which such use increased. These findings underscore the significance of early interventions that specifically aim to prevent chronic problems.

More recent research is reported by London’s syndication, The Independent, that tells us how much our attitude is harming ourselves.  Don’t forget, it harms everyone you love and constricts their lives too.  But the right frame of mind can lower your pain and other health risks.

PAIN

People showing dispositional optimism may be better able to cope with pain and need less medication. A study at Michigan State University on cancer patients shows that those who were more optimistic tended to report less severe pain. A study at the University of Alabama showed that patients who were optimistic used less medication for pain relief. “More optimistic adolescents are better able to match their medication use to their pain severity. Future research should examine how other psycho-social factors might influence pain medication use in adolescents and adults, and clinicians should take into account psychosocial factors when working with pain populations.”

CANCER

Women who are happy and optimistic may have a lower risk of developing breast cancer. The research also show that adverse life events, such as loss of a loved one or divorce , can increase the risk. Results from the study at Ben Gurion University in Israel show that exposure to more than one adverse life event was associated with a 60 per cent increased risk of disease, while happy and optimistic women were 25 per cent less likely to have the disease. “A general feeling of happiness and optimism seems to play a protective role,” say the researchers. “The relationship between happiness and health should be examined in future studies and possible relevant preventive initiatives should be developed,” say the researchers.

MORTALITY

A review of research into the association between positive wellbeing and mortality shows a signifciant link. The University College London analysis of 35 studies showed that positive psychological wellbeing was associated with an 18 per cent reduced mortality in healthy people and a 24 per cent lower risk in sick people. “Positive feelings – emotional well-being, positive mood, joy, happiness, vigour, energy – and life satisfaction, hopefulness, optimism, sense of humour, were associated with reduced mortality. Results suggest that positive psychological wellbeing has a favourable effect on survival in both healthy and diseased populations.

HEART DISEASE

The positive-minded have a 55 per cent lower risk of dying from heart disease, according to the results of a study which followed 500 men aged 54 to 84 for 15 years. “Our results demonstrate a strong and consistent association between dispositional optimism and lower risk of cardiovascular mortality,” says the researchers from The Netherlands Institute of Mental Health, Delft. Just how low optimism may lead to cardiovascular death, is, say the authors, an intriguing, but unanswered question. One possible mechanism, they say, is that optimism is related to better coping behaviour. Another study at the University of Pittsburgh, and based on 200 women diagnosed with thickening of the arteries, showed that over a 15-year period, the disease progressed more slowly in those women classed as optimists. Other research has shown that optimists have a lower risk of rehospitalisation after coronary artery bypass graft surgery.

The article also covers the field of research as it applies to blood pressure, longevity, infections, even the common cold……..

Practice makes perfect.  Take time out to give yourself some love.  Doctors too.

And read Diana’s blog to see how the addition of 3 kittens have added so much to her family’s mood.  Even if you can’t have a pet, you can still enjoy a friend’s.

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

The scientific evidence to prove efficacy simply was not there.  More importantly, even with fluoroscopy and accurate placement of the needle, the solution reached the desired area only 26% of the time.  The author called for research to test efficacy.

From the current review, we must conclude that lumbar epidural steroid injections and sympathetic nerve blocks produce a large amount of money, with very little science to support their application. Does this mean they are useless? Obviously not; these techniques have some value in acute pain management and should not be completely abandoned. However, their use as a mainstream ( almost knee-jerk ) intervention for acute or chronic low back pain does not appear to be at all justifiable at the scientific level.

The fundamental recommendation is quite obvious. Those pain specialists who use these techniques on a regular basis need to support and initiate some clinical research trials that adequately test these procedures’ efficacy. Without this, the routine application of epidural steroid injections and lumbar sympathetic nerve blocks for acute or chronic low back pain is not evidence based. Therefore, when can it be recommended remains an empirical question.

More recently in March 2007, the American Academy of Neurology studied the issue in depth and published  Practice Guidelines on the Use of Epidural Steroid Injections to Treat Radicular [sciatic] Lumbosacral Pain.

They also found no Level A quality research and did not recommend routine use:

Based on the available evidence, the Therapeutics and Technology Assessment subcommittee concluded that

1) epidural steroid injections may result in some improvement in radicular lumbosacral pain when assessed between 2 and 6 weeks following the injection, compared to control treatments (Level C, Class I-III evidence). The average magnitude of effect is small and generalizability of the observation is limited by the small number of studies, highly selected patient populations, few techniques and doses, and variable comparison treatments;

2) in general, epidural steroid injection for radicular lumbosacral pain does not impact average impairment of function, need for surgery, or provide long-term pain relief beyond 3 months. Their routine use for these indications is not recommended (Level B, Class I-III evidence);

3) there is insufficient evidence to make any recommendation for the use of epidural steroid injections to treat radicular cervical pain (Level U).

This subject will be an intense topic of interest for the Anesthesiology Subcommittee at the annual meeting of the American Pain Society that meets in San Diego May 2009.   At best, epidural injections and nerve blocks are temporizing measures.  If the first one is less than effective, they are often done in a series of three.  One risk of frequent steroid injections is osteoporosis.

.

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!

The Sunshine Vitamin Controversy

What should normal values  be for calcium homeostasis?

My attention was drawn to Vitamin D several years ago when a review appeared in the journal Neurology, published by the Academy of Neurology, that linked low levels of Vitamin D to Multiple Sclerosis.  The article was unusual for its length and the breadth of research cited over several decades.  More recently, a Johns Hopkins article published “the most conclusive evidence to date” that Low Vitamin D Levels Pose Large Threat to Health.

New publications on Vitamin D seem to appear every week with the focus on levels of 25-hydroxyvitamin D, also written as 25(OH)D. Its half life in serum is ~ 10 days to 3 weeks.

The biologically active form 1,25-dihydroxyvitamin D, written as 1,25(OH)D²,  is made in the kidneys and has a much shorter serum half-life of ~ 4-6 hours, thus making it less useful as a serum marker for measuring.

Sources & Metabolism: Vitamin D is a fat soluble vitamin that’s absorbed in the small intestine from  foods such as egg yolks, fatty fish, fish liver oils, fortified milk, margarine, and cereals.  Bile salts are required for absorption.  Sunlight stimulates the skin to synthesize vitamin D, but exposure of hands and face as little as 15 minutes may not be sufficient and it is not as effective for everyone.  It won’t work in winter months, it won’t work for the aged, for those who have pigmented skin, and it won’t work for those who cover their skin.

Vitamin D Metabolism

The Controversy –  How Do We Determine Normal Values?

Surprisingly, in a well designed multicenter study of healthy young Hawaiians in their 20′s who were exposed to at least 29 hours of sun per week, 51% were found to have vitamin D deficiency using the usual cut off of 30 ng/ml for normal.  This study from 2007 found the mean concentration of 31.6 ng/ml, and the highest of 62 ng/ml.  It raises the question whether

“it seems prudent to use this value [60 ng/ml] as an upper limit when prescribing vitamin D supplementation,”

rather than the generally published normal range of 30 to 80 ng/ml or even 100 ng/ml quoted in some labs.  This study is important in discussing the controversial question of what normal values should be for calcium homeostasis and reviews several possible explanations for inadequate production of D3 including genetic differences.

They note the highest reported values in “Nebraska outdoor workers… were between 81 and 84 ng/ml” but the assay system differed compared to theirs and results in a higher value.   Reviewing this study that was published in the Journal of Clinical Endocrinology & Metabolism has allowed me just now to readjust my own patient practice.

Laboratory Testing:  results can differ from one laboratory to another.  My hospital sends specimens to ARUP for testing, whereas Quest has acknowledged errors in laboratory testing and problems with standardization as reported by the New York Times here.

Function:  It is important for absorption of calcium and phosphorous from the small intestine, for bone health, osteoporosis, risk of falls, certain cancers(colon, breast, prostate), and possibly 6 to 7 years of longevity.  Deficiency of vitamin D is associated with suboptimal health and possibly increased pain; it is linked to infections, gum disease, hypertension, diabetes, coronary disease, neurological diseases such as Multiple Sclerosis, Parkinson’s Disease, dementia and Alzheimer’s Disease though it may not be causal. Its receptor is found all over the body including the brain.

I recommend this review by one of the best web resources at Memorial Sloan Kettering Cancer Center Herbs & Botanicals.

They quote a reference showing it reduces postmenopausal weight gain and “In adults with impaired fasting blood glucose, giving calcium and vitamin D reduced increases in plasma glucose and insulin resistance….”

It is the only vitamin that is a steroid hormone, and my interest increased on learning that it functions as an anti-inflammatory.  But as I tested blood levels for 25(OH) vitamin D and parathyroid hormone (PTH), I discovered more than 90% of my patients had vitamin D deficiency and a few had hyperparathyroidism.  There are four parathyroid glands next to the thyroid, and for some reason doctors have rarely tested their hormone levels.

***Persons with hyperparathyroidism should NOT take calcium or vitamin D.

It may lead to kidney stones and bone pain:  stones, bones and groans.***

Evidence for Optimizing Vitamin D Concentrations

On the other hand, if vitamin D is low, there is some evidence that replacement with vitamin D3 so that blood levels are in the high normal range, may help pain.  That is, it may raise the pain threshold and possibly have other benefits for health and longevity. It is desirable to avoid toxic levels of D as it causes hypercalcemia with depression, drowsiness, weakness, headache, polydipsia,  bone loss, and metastatic calcifications of many organs, soft tissues and blood vessels.  The generally quoted range of normal for 25(OH) vitamin D is 30 to 80, that varies with the lab.

Doesn’t that photo of the Great Western Divide make you want to get outside into the sun?

Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes was reviewed by Heike Bischoff-Ferrari et al, in 2006,  though it has been superseded by much additional work since then.

To quote from their article:

This review summarizes the evidence for optimal serum  25(OH)D concentrations. The endpoint selection for this review was based the strongest evidence to date—ie, that from RCTs [randomized controlled trials], consistent evidence from prospective and cross-sectional epidemiologic studies, and strong mechanistic evidence or dose response relations.  BMD [bone mineral density], fracture prevention, lower-extremity function, falls, oral health, and colorectal cancer met these criteria. Weaker evidence exists of a beneficial effect of vitamin D on other diseases, including multiple sclerosis (15), tuberculosis (16), insulin resistance (17, 18), cancers other than colorectal (19 –22), osteoarthritis (23, 24), and hypertension (25–27), but these diseases are not considered here.

They did not review pain studies.  I would add that “weaker” evidence merely means that it must be confirmed by more studies, not that it excludes those conditions.  There is an epidemic of vitamin D deficiency in the country, and the incidence is very high in pain clinics as reported in several studies.

A new multi-center epidemiology study  ”Demographic Differences and Trends of Vitamin D Insufficiency in the US Population, 1988-2004“  by Ginde, et al, in 2006,  ”demonstrate a marked decrease in serum 25(OH)D levels from the 1988-1994 to the 2001-2004 NHANES data collections.”  And like others before them, they point out:

“Current recommendations for vitamin D supplementation are inadequate to address the growing epidemic of vitamin D insufficiency.”

Summary:

Make sure your doctor checks both your 25(OH)Vitamin D and parathyroid hormone level (PTH) – not thyroid – to determine if you have hyperparathyroidism or if you have normal or low vitamin D.  That will determine if you need replacement or if you should stop using calcium and D as it will cause kidney stones and calcium deposits on your bones leading to pain.

If vitamin D levels are low it may result in increased physical pain and may cause or aggravate many medical conditions.

If PTH levels are high indicating hyperparathyroidism it will cause new painful conditions.

Intake does vary with the patient, the season, the age, but the recommended daily allowance may perhaps be double what it is now.  It is unclear when the federal government will adjust that dosage.   As always, your physician’s recommendation will be based upon blood levels of 25(OH)D and PTH.

Do not make changes in your dosage without careful evaluation.

Could this possibly be one of the most important areas of research this century?

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.

~

Chronic pain is often much more difficult to treat than cancer pain. It is tragic that < 1% of NIH budget goes for pain research, though 10 to 20% of the population in the US suffers from chronic pain, an estimated 60 million Americans, and the conditions are more prevalent among the elderly. Persons of all ages that I see tend to be more debilitated, often with anywhere from 3 to 14 different identifiable pain syndromes.

Many, including physicians, mistake pain as a symptom, failing to understand the reorganization that has occurred in the central nervous system due to neuro-plasticity; and they overlook the associated co-morbidity causing insomnia, weight gain due to medication or inactivity, depression, anxiety, spiritual and financial burdens. The lives of families and friends are diminished along with the person who has pain.

In the future, as time permits, I’ll be adding publications and articles to the site and occasionally posting with a frequency yet to be determined, hopefully twice a month.

Goals:

• This website is dedicated to providing educational resources to patients and healthcare professionals regarding the current understanding of pain medicine, an interdisciplinary field
• To discuss evidence-based information to improve the lives of patients who choose to use these therapies under the direction of informed physicians
• To distinguish between harmful treatments, beneficial treatments, and treatments that can be safely integrated with conventional treatment
• To encourage communication between patients, families and providers
• To educate both patients and health care providers who need a more comprehensive knowledge base with current and accurate information
• To promote ongoing professional growth through networking in a setting where treatments can be examined together to enhance lives

Please bear in mind, no information in this blog is intended to diagnose or treat any condition.

The opinions expressed here are my own, and are subject to change as new research becomes available.

.

Join me on this journey……