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Ketamine Intranasal for Rapid Relief of Pain and Depression

01/25/2012 — Nancy Sajben MD

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.’

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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’

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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.”.

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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.

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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.

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Researchers have long suspected that stress and depression weaken some connections among brain cells. Ketamine appears to reverse the process.

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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.

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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

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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.

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

Ketamine is a parenteral anesthetic agent that provides analgesic activity at sub-anesthetic doses. It is an N-methyl-D-aspartate (NMDA) receptor antagonist with opioid receptor activity. Controlled studies and case reports on ketamine demonstrate efficacy in neuropathic and nociceptive pain. Because ketamine is a phencyclidine analogue, it has some of the psychological adverse effects found with that hallucinogen, especially in adults. Therefore, ketamine is not routinely used as an anesthetic in adult patients. It is a frequently used veterinary anesthetic, and is used more frequently in children than in adults. The psychotomimetic effects have prompted the DEA to classify ketamine as a Schedule III Controlled Substance. A review of the literature documents the analgesic use of ketamine by anesthesiologists and pain specialists in patients who have been refractory to standard analgesic medication regimens. Most reports demonstrate no or mild psychotomimetic effects when ketamine is dosed at sub-anesthetic doses. Patients who respond to ketamine tend to demonstrate dramatic pain relief that obviates the desire to stop treatment due to psychotomimetic effects (including hallucinations and extracorporeal experiences). Ketamine is approved by the FDA for intravenous and intramuscular administration. Use of this drug by the oral, intranasal, transdermal, rectal, and subcutaneous routes has been reported with analgesic efficacy in treating nociceptive and neuropathic pain.

http://www.ncbi.nlm.nih.gov/pubmed/15109503 Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomized, double-blind, placebo-controlled, crossover study Daniel Carr, et al, 2004

Crossover, 20 patients. Ketamine reduced breakthrough pain within 10

min of dosing, lasting up to 60

min

http://www.ncbi.nlm.nih.gov/pubmed/15288418 Safety and efficacy of intranasal ketamine in a mixed population with chronic pain

The intranasal route for ketamine administration has been applied only for pain of dressing changes in a single case study (Kulbe, 1998). In this patient, oxycodone and acetaminophen were ineffective to control pain during burn dressing changes in a 96-year-old woman cared for at home. She tolerated the burn dressing changes after three intranasal sprays of 0.1 ml each, in rapid succession, each containing 5 mg ketamine (15 mg total) (Kulbe, 1998).

http://www.acutepainjournal.com/article/S1366-0071%2807%2900167-2/abstract Safety and efficacy of intranasal ketamine for acute postoperative pain

Ketamine delivered intranasally was well tolerated. Statistically significant analgesia, superior to placebo, was observed with the highest dose tested, 50 mg, over a 3 h period. Rapid onset of analgesia was reported (<10 min), and meaningful pain relief was achieved within 15 min of the 50 mg dose. The majority of adverse events were mild/weak and transient. No untoward effects were observed on vital signs, pulse oximetry, and nasal examination. At the doses tested, no significant dissociative effects were evident using the Side Effects Rating Scale for Dissociative Anaesthetics.

The safety profile following treatment with ketamine was comparable to that seen with placebo.

Although patients did report side effects of fatigue, dizziness and feelings of unreality more often following treatment with ketamine than following treatment with placebo, no patient reported hallucinations and the side effects were generally reported to be of mild or moderate severity, and transient. No serious adverse events were reported and the incidences of associated adverse events were comparable for ketamine and placebo. Although study medication was administered intranasally, nasal signs and symptoms were few and inconsequential. A distinctive taste, however, was reported more often following treatment with ketamine than following treatment with placebo.In conclusion this randomized, placebo-controlled, double-blind study, in 20 patients, has demonstrated that intranasal ketamine is safe and effective for BTP [breakthrough pain]. Our findings augment an early but promising literature documenting the effectiveness of nasal administration of a variety of opioids for pain management in adults (Dale et al., 2002) .

~http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2875542/

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

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

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

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

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

….

“Conclusions

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

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!

Haunted by the dirty work of managed care & that deadly piece of paper: “Denied”

06/17/2009 — Nancy Sajben MD

“I know how managed care maims and kills patients”

I will never forget the snarly laughter of a “medical” reviewer two weeks ago as he denied medication to my patient that the same PPO had been authorizing for years. My patient has been haunted by the man’s laughter since then. Denial of continuing medication is happening more and more despite California law that “grandfathers” in ongoing care for previously covered medication. See my post here.

It is “DESUETUDE.” It refers to the condition where a law has gone unenforced for so long that it is considered ‘obsolete.’ The law has not been repealed, but — here’s the clincher — the law has “collapsed into unenforcibility.” (quote from William M. Lamers, Jr, MD)

For years we have had spreadsheet medicine: Denial only for medication that is costly. It’s getting worse, more brazen.

Now that much new medication is unaffordable, priced far beyond the rate of a decade of inflation, what do we do with lawmakers that will not negotiate volume discount prices with pharmaceutical companies? How long will the middle class be able to afford common medication? There isn’t another first world country on the planet that does not negotiate volume pricing.

Why are safe older pain medications being taken off the formulary?

Did you know that prices on best selling medicines may go up as much as 20 to 30% each year, though they’ve been on the market for years?

What is worse, managed care bloodlessly denies life saving procedures. A bloodless coup that rarely makes the news.

Physician Confesses to Congress, Choking Back Tears

Dr. Lynn DiPino [spelling?], former medical reviewer for Humana went before Congress to make “a public confession.”

This doctor, who acted as a reviewer for an insurance company, denied life saving surgery for a man and thus caused his death, saving “the company half a million dollars.”

Her decision to deny surgery insured her continued advancement in healthcare. “I went from making a few hundred dollars a week as a medical reviewer to an escalating six figure income as a physician executive.” “I was told repeatedly I was not denying care, I was simply denying payment. I know how managed care maims and kills patients. So I am here to tell you about the dirty work of managed care.”

As the video continues on the origins of managed care, it goes back to February 17, 1971, when Ehrlichman discusses Kaiser HMO with President Richard Nixon : “All the incentives are for less medical care because the less care they give, the more profit they make.”

Nixon smiles, his eyes narrow as if he is savoring fine wine, and says, “Not bad.”

Health Insurers Refuse to Limit Rescission of Coverage

withering criticism from Republican and Democratic Congress members

Today in Los Angeles Times

Even Republicans were appalled when “[e]xecutives of three of the nation’s largest health insurers told federal lawmakers in Washington on Tuesday that they would continue canceling medical coverage for some sick policyholders, despite withering criticism from Republican and Democratic members of Congress who decried the practice as unfair and abusive….

An investigation by the House Subcommittee on Oversight and Investigations showed that health insurers WellPoint Inc.[parent of Blue Cross of California], UnitedHealth Group and Assurant Inc. canceled the coverage of more than 20,000 people, allowing the companies to avoid paying more than $300 million in medical claims over a five-year period.

It also found that policyholders with breast cancer, lymphoma and more than 1,000 other conditions were targeted for rescission and that employees were praised in performance reviews for terminating the policies of customers with expensive illnesses.

("Um . . I know this is a bad time but . . . .you're not covered.") shamelessly stolen from crooksandliars.com

…Rescission was largely hidden until three years ago, when The Times launched a series of stories disclosing that insurers routinely canceled the medical coverage of individual policyholders who required expensive medical care.

…A Texas nurse said she lost her coverage, after she was diagnosed with aggressive breast cancer, for failing to disclose a visit to a dermatologist for acne.

The sister of an Illinois man who died of lymphoma said his policy was rescinded for the failure to report a possible aneurysm and gallstones that his physician noted in his chart but did not discuss with him.

The committee’s investigation found that WellPoint’s Blue Cross targeted individuals with more than 1,400 conditions, including breast cancer, lymphoma, pregnancy and high blood pressure. And the committee obtained documents that showed Blue Cross supervisors praised employees in performance reviews for rescinding policies.

One employee, for instance, received a perfect 5 for “exceptional performance” on an evaluation that noted the employee’s role in dropping thousands of policyholders and avoiding nearly $10 million worth of medical care.

…Late in the hearing, Stupak, the committee chairman, put the executives on the spot. Stupak asked each of them whether he would at least commit his company to immediately stop rescissions except where they could show “intentional fraud.”

The answer from all three executives:

“No.”

Rep. John Dingell (D-Mich.) said that a public insurance plan should be a part of any overhaul because it would force private companies to treat consumers fairly or risk losing them.

“This is precisely why we need a public option,” Dingell said.

…In November 2007, The Times reported that insurer Health Net Inc. paid bonuses to employees based in part on their involvement in rescinding policies. According to internal corporate documents disclosed through litigation, Health Net saved $35 million over six years by rescinding policies.

The disclosures in part led an arbitration judge to levy $9 million in damages against Health Net in a case involving the company’s rescission of the policy of a woman diagnosed with breast cancer.

At the time, Blue Cross told The Times that it did not link employee performance reviews to rescission. Blue Cross also said at the time that it had conducted audits to ensure that claims reviewers were not given any “carrots” for canceling coverage.

The company reiterated that position Tuesday in spite of the committee’s disclosure of two employee performance evaluations from 2003 discussing rescission levels and savings.

Gene Wilder

Gimme Some Money

by Spinal Tap

Posted in Controversy, Insurance, Liability, Medications, Politics of Pain. Tags: Health Insurance, Rescission of coverage. 1 Comment »

Opioids Create Pain via Molecular and Genetic Changes

06/16/2009 — Nancy Sajben MD

Chronic use of opioid pain medication

causes molecular and genetic changes that result in pain

A brief update

American Pain Society May 2009 Symposia: Anti-analgesic Effects of Mu-opioids: Molecular and Genetic Mechanisms

The clinical benefits of opioid analgesics have not been fully realized due to substantial side effects, which include tolerance, dependence and opioid-induced hyperalgesia. Although the precise molecular mechanism of these phenomenon is not understood yet, it is generally thought to result from cellular excitatory effects of mu-opioids which contrast the major inhibitory effects.

Mark Hutchinson, PhD, discussed the new discovery that every clinically relevant class of opioid analgesics non-stereoselectively activates glial cells through TRL4 receptor. Activation of this receptor, primarily expressed by microglia, leads to the release of proinflammatory mediators that counter-regulate acute opioid analgesia.

How can opioid-induced glial activation oppose & augment different aspects of opioid action?

Opioid analgesia is opposed by opioid-induced spinal glial activation since increased neuronal excitability leads to elevated nociception. Increased brain opioid-induced glial activation also leads to increased neuronal excitability & within reward & dependence centers this is believed to increase opioid reward & dependence. Therefore analgesia is decreased & reward/dependence is increased.

Counteracting hyperalgesia with naltrexone and dextromethorphan

In summary, Dr. Hutchinson describes the TRL4 receptor where opioids act to induce activation of microglia, releasing proinflammatory mediators that counteract analgesia and produce more pain.

Naltrexone, a mu opioid antagonist, has profound anti-inflammatory effects centrally on the microglia to produce analgesia. This mechanism of action of low dose naltrexone is discussed here.

Dextromethorphan acts centrally on microglia by the same mechanism, producing analgesia. Both naltrexone and dextromethorphan are classified as morphinans, morphine-like.·

More is less: increasing the dose causes pain.

A steep road to climb, much less to understand.

Posted in Hyperalgesia, Medications, Opioids, Research. Tags: Hyperalgesia, Opioids. 1 Comment »

FDA Restricting Opioids, Patients Lose – NIH Does Not Fund Pain Research – No Access to Nonopioid Treatment

06/13/2009 — Nancy Sajben MD

··

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!

Ketamine

05/26/2009 — Nancy Sajben MD

Ketamine for persons with severe pain

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, 2003 This 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. Tags: CRPS, Failed back surgery, intractable pain, Ketamine, Neuropathy, RSD, Sciatica. Comments Off

“Heavy NSAID Use Linked to Higher Dementia Risk” – Exercise, Antidepressants Both Help Neurogenesis

04/24/2009 — Nancy Sajben MD

NSAIDs are anti-inflammatory drugs used to treat pain, inflammation, or fever. The only NSAIDs that are NOT associated with increased risk of heart attack or arrhythmia are naproxen (Aleve) or aspirin. Taking high doses of aspirin has a greater risk of GI bleed than naproxen, which is why I usually recommend naproxen.

Background:

Several past studies have shown NSAIDs delay or prevent dementia, but there have been contradictory results. Last year Neurology published a study of 49,349 patients’ usage ranging from ≤1 year to ≥7 years done at Boston University and Bedford VA. They showed long term use of NSAIDs protects against Alzheimers:

Compared with no NSAID use, the relative risk of Alzheimer’s disease decreased from 0.98 for ≤1 year of use (95% CI 0.95 to 1.00) to 0.76 for >5 years of use (95% CI 0.68 to 0.85).

Among patients who specifically cited use of ibuprofen, the risk of Alzheimer’s disease declined from 1.03 (95% CI 1.00 to 1.06) to 0.56 (95% CI 0.42 to 0.75).

Ibuprofen came out ahead in that study perhaps because it is the most commonly used.

They also sought to answer whether NSAIDs known to suppress Aβ1-42 amyloid would more likely protect . Aβ1-42 amyloid is a major component of plaques found in Alzheimer’s Disease.

Aβ1-42 amyloid suppressors include ibuprofen, diclofenac, flurbiprofen — but as for suppressing Alzheimer’s, these were found to be no different than other NSAIDs, putting that theory to rest.

methusala-tree

Risk of dementia and Alzheimer’s Disease with prior exposure to NSAIDs in an elderly community-based cohort:

This new study by Breitner et al, from the University of Washington School of Medicine was published online April 22, 2009, before the print edition in Neurology.

Their outcome contradicts earlier protective studies possibly because they started with an older cohort, healthy adults 65 and older, which “could be enriched for cases [of Alzheimer's] that would otherwise have appeared earlier.”

They prospectively followed 2,736 persons in a Seattle health plan. Before starting the study, they reviewed pharmacy records as much as 17 years earlier.

Findings:

12.8% of the study participants [were] heavy NSAID users at baseline. Heavy use was defined as taking 500 or more standard daily doses over a two-year period.

Another 3.9% of participants became heavy users during follow-up.

Ibuprofen, naproxen, indomethacin, and sulindac accounted for about 80% of all NSAIDs used.

Through follow-up, 476 participants developed dementia; for 356 of them, it was Alzheimer’s disease.

After controlling for age, gender, education, APOE status, hypertension, diabetes, obesity, osteoarthritis, and physical activity, the risk of developing all-cause dementia was 66% higher among heavy users than among those with little or no NSAID use (HR 1.66, 95% CI 1.24 to 2.24).

The risk of developing Alzheimer’s disease was 57% higher (HR 1.57, 95% CI 1.10 to 2.23).

Strengths of the study: the community-based sample, biennial assessment of dementia, rigorous exposure classification, and large numbers of dementia cases, outweigh the limitations.

Limitations: lack of generalizability to a younger patient population, the lack of exact dosing information, and the possibility of bias from unmeasured confounders.

Can we draw conclusions on one study alone? We know that exercise is protective against Alzheimer’s Disease and pain may have prevented this older age group from being active. Though they did control for that, this research needs to be supported by further studies. What is helpful is to remain as active as you can. Keep and maintain every bit of function you can and get help for depression and anxiety as they may profoundly affect memory, morbidity and mortality. For a review of the literature on the morbidity and mortality of stress and mood, refer to my post on Cognitive Behavioral Therapy and the importance of a positive outlook.

The brain makes new neurons – neurogenesis. I will write more in the future on exercise, mood, stress, brain atrophy and memory loss. Exercise improves depression and anxiety, and exercise stimulates neurogenesis. It appears that the action of antidepressants also may be to stimulate neurogenesis. Chronic low back pain has been reported to cause brain atrophy. Chronic depression leads to brain atrophy and memory loss with atrophy occurring in the hippocampus, the area essential for memory. This important publication from Vancouver reviews the topic in great detail and proposes a hypothesis: Antidepressant effects of exercise: Evidence for an adult-neurogenesis hypothesis?

Further medication is being tested to reduce neuronal cell death that leads to Alzheimer’s Disease, using a very simple compound that blocks free radicals and inflammation. More on this later.

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!

Posted in Antidepressants, Dementia, Exercise, Medications, Memory Loss, NSAIDs. Tags: Antidepressants, Exercise, Memory Loss, NSAIDs. Leave a Comment »

Medical Library

04/22/2009 — Nancy Sajben MD

Desert Fairy Duster

This page at the National Library of Medicine or Medical Library may be useful to you, allowing you to search for the explanation of Medical Conditions, Medications, Procedures, Tests, and general questions.

Vitamins and Herbs – Risks and Benefits

04/17/2009 — Nancy Sajben MD

Rum Soaked Salmon with Apple Ginger Puree from Dan Atkinson's Salmon House on the Hill Cookbook

Most doctors have little if any training in vitamins and supplements

except as they relate to their specialty.

My field of neurology concerns itself with metabolic and nutritional diseases more than most areas of expertise, and I have an interest in several vitamins because of research related to major causes of mortality in the United States.

During the period I taught at a cancer center, I was concerned that research protocols may be misleading as these supplements were not accounted for, however since that time in the mid 90′s, I’m glad that public interest has pushed this field into the fore. Major cancer centers now have active research in Complementary and Integrative Medicine (CAM) because there are risks and benefits, and some have significant herb-drug interactions as discussed below.

Check your vitamins and supplements for toxicity

Because of the growing science on toxicity, usefulness, and drug interactions, if you use vitamins, review each one carefully with your physician and with the websites listed in the column on your right. Some “vitamins” are simply brand names that have over 20 different vitamins, minerals and various ingredients. This means you must review each one for current research benefits and risks.

At special risk for vitamin deficiencies are those who have highly restricted diets, abdominal resection, intestinal conditions, colitis, Celiac Disease, gastric bypass, HIV, or the elderly.

Pregnant women have special needs that are essential not only for their own health but to reduce the risk of neurological defects in the fetus. It is essential in their case to work closely with their obstetrician, especially if morning sickness prevents them from taking their daily supplement.

Resources

One of the best resources I have found is Memorial Sloan Kettering Cancer Center’s Herbs and Botanicals, also linked on the column at right. Their website is updated frequently with an excellent review of the literature. It is hosted by a senior physician who has specialized in the field for decades and is actively involved in research at their center as well as NIH.

MD Anderson Cancer Center’s Complementary/Integrative Medicine Education Resources website and Columbia University’s Rosenthal Center for Complementary and Alternative Medicine are two others, but there are other resources on the web and books that are excellent.

Recipe for Rum Soaked Salmon with Apple Ginger Puree is found here.

VITAMINS & SUPPLEMENTS

Vitamin D has become a major research topic in recent years. It may play a more important role than any listed below. I have written separately on it and its controversy in greater detail. Please refer to the last post by scrolling down.

Fish Oil

Omega 3 Fish Oils are polyunsaturated fatty acids that are essential for health yet cannot be made by the body. Unless you eat several servings per week of fatty fish or wild salmon, not farmed salmon, it is one of the most important supplements that any adult of any age can take. They are needed for building cell membranes in the brain but our body does not make them. Fish oil helps your lipid profile by reducing triglycerides as much as 45%. It reduces platelet clotting, lowers risk of heart attack and cardiac arrhythmia, and is an important anti-inflammatory reducing pain for many particularly those with arthritis. One of the best references on Omega 3 Fatty Acids is by Dr. Frank Sacks, Professor of Cardiovascular Disease Prevention, Department of Nutrition, Harvard School of Public Health. He mentions high doses “are used to treat depression. New studies are identifying potential benefits for a wide range of conditions including cancer, inflammatory bowel disease, and other autoimmune diseases such as lupus and rheumatoid arthritis.”

One high quality fish oil, Lovaza, has been approved by the FDA and is prescription only. Fish oil and cod liver oil available over the counter should be checked for adequate dosages of EPA and DHA that will vary with your needs as determined by your lipid profile, and should be purified to remove cholesterol, dioxin, PCB’s and other pesticides.

Co-Enzyme Q10 is also called CoQ10. CoQ10 is present in every cell of the body which is why it is also called ubiquinone. It is important in the electron transport chain to produce intracellular energy.

Statins deplete CoQ10. Vitaline’s CoQ10 product has been used in NIH funded trials for cardiovascular, neurological and brain disorders. Two mitochondrial disorders have been shown to benefit from Co-Q10: migraine and Parkinsons Disease.

My preferred manufacturer is Vitaline because of their research with NIH which requires that they validate and verify dosages. Their website discusses other advantages and gives guidance on dosages that have shown benefit for various conditions. They offer a discount of 25% if you request scheduled delivery every 3 months. Use the code code DEF25. Their product is in the form of wafers that are about the size of a quarter and are very easy to break into 2 or 4 with your hands.

Vitamin B supplements in the elderly may help reduce the risk of dementia and B12 deficiency may result in neurological conditions such as peripheral neuropathy, dementia, hematologic and psychiatric disorders, Subacute Combined Degeneration of spinal cord & brain, increased fracture risk, and may increase the risk of cardiovascular diseases. A good B complex vitamin is not likely to harm and may benefit. The best source of all is food: leafy green vegetables, beans and peas.

B Vitamins

Thiamine (Vitamin B1) in high doses of 300 mg per day may reduce kidney disease in type 2 diabetes and may prevent early diabetic cardiomyopathy (heart disease). As many as 70% to 90% of people with diabetes, both type 1 and type 2, are thiamine deficient. The research is still a little early to draw firm conclusions. It is being done by Charity Diabetes UK which finds that “thiamine works by helping protect cells against the harmful effects of the high blood sugar levels.”

Vitamin A is associated with a 45% risk of hip fracture. There are four major adverse effects of high levels: birth defects, liver abnormalities, reduced bone mineral density that may result in osteoporosis, and central nervous system disorders.

Vitamin E may actually increase mortality and there are significant risks to its use including increased risk of some cancers. Several studies were reviewed by one of the foremost science writers, Jane Brody, in the New York Times on March 23, 2009. It does not reduce the risk of cardiovascular disease, stroke, dementia, mild cognitive impairment, and there is no evidence that it slows the progression of macular degeneration. In the Physicians’ Health Study II it has been shown to actually increase the risk of hemorrhagic stroke since it decreases the clotting tendency of blood.

Vitamin C was recently shown to markedly increase the growth of cancers. It’s healthy for them too. It blunts the effect of cancer drugs by as much as 30 to 70% depending upon the drug tested.

Zinc may prevent the absorption of copper which is necessary for the brain and spinal cord thus resulting in progressive neurological conditions. Herb-drug interaction reduces the bioavailability of some antibiotics, tetracycline and fluoroquinolones. Intake of 100-300 mg/day may result in chronic toxicity including copper deficiency, depressed immune function, headache, chills, fever, and fatigue. It concentrates in the prostate and consumption of more than 100 mg per day may increase risk of prostate cancer.

It may be useful for tinnitus and for short term use to reduce symptoms of the common cold when used topically or in lozenges

HERBS & BOTANICALS

Don’t forget seeds, beans and whole grains that help digestion and keep the system moving!

seeds-beans

This is a very brief summary of a few of the more commonly used herbs. Please refer to Memorial Sloan Kettering Herbs and Botanicals website for detailed information on risks and benefits.

Arnica – a topical anti-inflammatory may help sprains and osteoarthritis.

Aloe Vera – apply immediately after sunburn or burning the skin to prevent blister formation

Chamomile – calming sedative, may use for intestinal colic or gas

Cat’s Claw - anti-inflammatory activity may be caused by the inhibition of TNF-alpha production. It may be useful for refractory oral ulcers of unknown etiology in persons with HIV/AIDS that have not responded to other known remedies.

Echinacea may shorten the duration of common cold, useful in sinusitis, and respiratory infections. Because of the lack of standardization of various products, I recommend a high quality organic liquid product by HerbPharm. Avoid use in autoimmune conditions, Multiple Sclerosis, HIV/AIDS. “Echinacea was shown to stimulate phagocytosis, enhance mobility of leukocytes, stimulate TNF and interleukin 1 secretion from macrophages and lymphocytes, and improve respiratory activity… both in vitro and in vivo.”

Goldenseal is anti-inflammatory, antimicrobial with activity against pathogens such enterotoxigenic E. coli and V. cholera that may be useful for bacterial sinusitis and respiratory infections. Warning it may prolong the QTc interval in persons with heart disease or those on methadone and it is contraindicated in persons with hypertension. A high quality organic liquid product is made by HerbPharm.

Medicinal Marijuana is a vast subject. I would be happy to schedule time to discuss its medical use with you. Refer here for some of the known research and patient information.

Red Yeast Rice, a naturally occurring statin, the same as Lovastatin, often used in China. Make sure your doctor knows this and monitors liver function. Statins may cause severe muscle and joint pain that may potentially lead to rhabdomyolysis (sudden death of muscles), kidney failure, vasculitis, lupus-like syndrome, and many other symptoms, however most people tolerate them without side effects and they have dramatically reduced the incidence of heart attacks and stroke. They may also reduce the risk of dementia including Alzheimer’s type dementia.

Turmuric (Curcumin) – may alleviate irritable bowel syndrome and ulcerative colitis. There is a suggestion of improved cognitive performance from epidemiology studies but studies show no benefit for Alzheimer’s Disease. Avoid use if you have gallstones. It may inhibit the action of some chemotherapy drugs, such as used for breast cancer, but may be beneficial for certain cancers and other chemotherapy drugs.

Wheat grass- a natural source of vitamins and minerals (Chlorophyll, Vitamins A, C, E, K and B-complex, Iron, Calcium, Magnesium, Selenium, Amino acids); may have antioxidant effects.

Willow Bark – contains salicin, the precursor of aspirin

Arnica

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

’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’

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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.

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Researchers have long suspected that stress and depression weaken some connections among brain cells. Ketamine appears to reverse the process.

.

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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:

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.

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?

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:

Side Effects

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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.

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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

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

References

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“I know how managed care maims and kills patients”

Physician Confesses to Congress, Choking Back Tears

Health Insurers Refuse to Limit Rescission of Coverage

withering criticism from Republican and Democratic Congress members

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Chronic use of opioid pain medication

causes molecular and genetic changes that result in pain

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The War on Drugs Sold so Well That Persons With Pain

Often Cannot Get Pain Medication or Treatment

Pain Epidemic:

Does Pain Management Have a Place in American Healthcare?

We Are Not Getting Access to Effective Nonopioid Treatments

Need for Balance between Risk of Substance Abuse

vs Suffering and Disability Caused by Untreated Pain?

The Era for Procedures

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Ketamine for persons with severe pain

Achieving control of chronic pain requires a partnership

based upon trust and effort

Steps to follow: Read all steps carefully before you begin

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

Medical Publications

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