Best wishes to all!


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Please ignore the Advertising – has nothing to do with me.

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Companies out of the pain business, NOT a hotbed of innovation, NOT COVERED by insurers


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Bloomberg news published this analysis below that explains much of the dead end in pain medication:

  • companies got out of the pain business.
  • there is no hope in sight for effective analgesics
  • insurers refuse coverage for more and more pain medications
  • insurers refuse coverage for modalities except opioids

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What kind of medical system:

  • forces patients to seek street drugs for pain relief because they are cheaper?
  • fails to treat addicts?
  • fails to allow cannabis (medical marijuana) one of the safest drugs ever discovered for pain and symptom management?

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The whole field is a sham ruled by politicians through CDC fiat and the justice department, subject to radical changes:

  •  a threat to your care
  • a threat to the field of pain management
  • a brick wall to any professional contemplating entering the field
    • pain management is complex & time consuming
    • most chronic pain patients have 3 or more pains
    • each pain requires assessment
    • risks patient addiction and/or suicide
    • risks loss of license
  • constant change
    • prior authorizations from insurers refused on appeal
    • disability refused for disabling pain
    • onerous computerized opioid database that is not nationwide, not fully completed by pharmacists
    • threats from patients, addicts, DEA, attorney general
    • highly politicized
    • good specialists thrown in jail despite expert testimony of foremost pain specialists – after testimony of addicts who reduced their sentence with lies
    • poor coverage of modalities if any for P.T., acupuncture, massage, integrative pain management, psychology, biofeedback, psychiatry, cannabis, compounded medications
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Here’s the article, click title to read in full.
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For the drug industry, building a better pain pill is a problem.

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Pharmaceutical companies have introduced new medicines to treat dependence, reverse overdoses, and deal with opioids’ side effects. But few effective and economically viable alternatives to addictive painkillers have emerged from the laboratory.

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That’s because of broken incentives, according to economists and industry experts. The payment policies of insurers and government health programs, along with pressure from investors, have encouraged drugmakers to treat the symptoms of the opioid epidemic but discouraged innovations that might get to the root of the problem.

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New therapies for pain have generally been too expensive, too cumbersome to use, or targeted at too small a group of patients….

 

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Different Incentives

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The incentives to develop a better pain pill differ sharply from those in other areas of research, such as Alzheimer’s disease.

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Drugmakers have spent billions on more than 100 failed medicines for Alzheimer’s, but a breakthrough would potentially reach a large and lucrative population of elderly patients on Medicare. Any new pain drug would be fighting it out with inexpensive, proven rivals in a politically fraught environment.

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The White House Council of Economic Advisers estimated this week that abuse of opioids cost the economy about $504 billion in 2015, or nearly three percent of that year’s overall economic output in the U.S. Those costs include health-care expenses, spending on criminal justice and first responders, and lost worker productivity.

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“There’s currently a lot more costs of addiction that are being borne by society in a more diffuse way,” said Kosali Simon, a health economist at Indiana University….

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Effort and Expense

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Most opioids are cheap generic drugs that have been prescribed for decades, making the effort and expense of developing new painkillers hard to justify.

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“They’re off-patent, they can be produced by companies that aren’t the original inventors,” said Bertha Madras, a professor of psychobiology at Harvard Medical School and a member of President Donald Trump’s opioid commission. “It becomes a much more expensive proposition to develop and get the approval for an opioid.”

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Drugmakers have instead invested in developing complex medicines for cancer and rare diseases, which can fetch six-figure price tags.

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“Companies got out of the pain business,” said Pratap Khedkar of ZS Associates, a sales and marketing consultant who studies the pharmaceutical industry. “It’s not the hotbed of innovation.”…..

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Wary Payers

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Drug plans have been reluctant to pay for abuse-resistant pain medicines, which often cost more and can be more difficult to administer. A recent report from The Institute for Clinical and Economic Review, a nonprofit that evaluates the value of prescription drugs, found that abuse-deterrent opioids weren’t cost-effective for insurers.

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At the same time, payers are limiting patients’ access to older pain drugsCigna Corp.took OxyContin off its list of preferred drugs for 2018, though it still covers other opioids. CVS Health Corp. said its pharmacy-benefits management arm will limit prescriptions to a seven-day supply, and Express Scripts Holding Co. also said it wouldcurb prescriptions.

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That leaves patients with a difficult choice. Abuse-deterrent painkillers might cost as much as $250 out of pocket. But generic opioids cost as little as $2, according to Denis Patterson, a pain specialist in Reno, Nevada.

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Abuse-resistant drugs get “denied 90 percent of the time. But the pain pills will get approved every single time,” said Patterson.

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“Shouldn’t it be flipped,” he said, “in that the things which can get people better should have better coverage?”…..

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The material on this site is for informational purposes only.

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

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

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Comments are welcome.

This site is not for email, not for medical questions, and not for appointments.

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

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

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Insurers Deny Opioids, CVS Refuses to Fill Unless Authorized


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Always something new in this amazing field of pain management where treatment is decided by politicians and insurers.

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Patients and physicians alike have suffered denial of medications without prior authorization for the last 10 years or more. Prior authorization takes enormous time, at times more than one hour for each medication.  Try to picture a full day of seeing patients and an unexpected full day just for prior authorizations that must be fitted into the hours the insurer is open – remember, examiners often leave early, central time, hours ahead of PST. 

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Insurers deny the usual opioid because there is no proof that opioids have ever been proven to help chronic pain and side effects may include constipation, cognitive impairment, overdose and/or death.  

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Insurers routinely deny opioid at lower dosages when I try to taper: giving less is not allowed without prior authorization. Remember, we don’t find out until the patient goes to the pharmacy to fill, and they may wait to fill, then may need the medication that very night to continue their medication. Who is open after hours? 

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One independent 94 year old senior for years has been on fentanyl 12 mcg/hr patch and Oxycontin 10 mg in AM (not PM) for frozen shoulders and arthritis in knees. These are small doses. Denied for 3 or 4 years, so she paid out of pocket, in her 90’s. 

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She walks with a rollator, and wins at bridge games that she plays several times a week. Under my care since 2003, physical therapy has been unsuccessful. With her orthopedist, she receives injections every three months that help arthritis in knees. We had tried appeals including sending entire chart to insurer that included physical therapy note, but insurer insisted on physical therapy again. I asked them to show me one, simply ONE publication that showed physical therapy helpful for severe frozen shoulders present for decades. 

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Now pharmacy refuses to fill her 10 mg Oxycontin and her patch unless insurer authorizes. Her oxygen saturation is 98% which is excellent. Cognitive function is unchanged since 2003. I cannot imagine how she gets dressed as even a few degrees of motion of either shoulder elicits screams of pain. Her daytime caregiver must be dressing her. 

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That’s how we treat our injured, our disabled and our elderly.

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Insurers have authorized $50,000 spinal cord stimulators for years without a single study showing long term proof of efficacy. The potential for permanent damage to spinal cord and potential for accelerated pain syndromes is frightening. See the many comments on this site from patients who have suffered serious medical injury. 

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NIH has failed to adequately fund pain research for decades. But congress has accepted millions from opioid manufacturers and for years FDA approved one new opioid after another, as often as 4 new ones each year. FDA previously approved a nonopioid medication such as Lyrica for neuropathic pain, but in the last few years, a nonopioid Horizant has been approved only for postherpetic neuralgia pain — nerve pain, but only ONE type of nerve pain. Remember, insurers mandate first trying gabapentin for nerve pain, though it was never FDA approved for pain at all. Try to get an off-label non-opioid medication approved for pain. hah!

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Now I have an RN in her 40’s who has severe nerve pain from CRPS in both upper limbs after carpal tunnel surgery. Gabapentin caused severe cognitive dysfunction, improved on Horizant but insurers refused to approve Horizant. The cost for one daily is at least $750, but pain is better using twice daily.

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This week comes a letter from insurer that Revia, naltrexone 50 mg tablet FDA approved for addiction to opioids and alcohol, is no longer covered.

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Psychiatry colleagues tell me the same story. Antidepressants that also help anxiety are not covered but better than taking Xanax that causes memory loss and can be used to overdose.

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Vote for better politicians, not for lies. Insist on NIH research funding for chronic pain management to represent the vast population with chronic pain, not the pittance they allow. 

 

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The material on this site is for informational purposes only.

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

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

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Comments are welcome.

This site is not for email, not for medical questions, and not for appointments.

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

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

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Cannabis Overwhelmingly Preferred over Opioids for Pain – UC Berkeley / HelloMD Opioid Study


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Congratulations and thanks to HelloMD’s email, posted below, that describes a new study. They are doing important work for people who can be helped by cannabis. We need help in the treatment of chronic pain.

I’ve seen pharma pressure pain specialists to refuse to treat patients who also use cannabis. For Pete’s sake it helps relax deep muscle like nothing else, helps anorexia, can bring up extremely low energy a tiny bit, helps depression, and pain. Shock and awe. What an awful thing to pressure doctors to do just to punish the plant based industry and extinguish the competition. I’m sure TV ads brainwash even more. Professionals in healthcare and politics need our help to know good studies already exist and even without that rigorous proof, our dispensaries can recreate what the world has safely used for thousands of years.

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HelloMD is a trusted source of information. 

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The HelloMD Advisor

Opinions from Industry Experts


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Hi Nancy,

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Yesterday we announced the results of our landmark study examining the use of cannabis as a substitute for opioid and non-opioid based pain medication. Performed in collaboration with University of California Berkeley, HelloMD surveyed 3,000 participants from our patient database….[– click on below link to article]

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[They showed the]

overwhelming majority of cannabis patients (92%) prefer using cannabis to opioids when managing their chronic pain.”

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Your participation in HelloMD studies is invaluable as it takes us one big step closer to showing healthcare professionals, elected officials and the public at large the potential for cannabis to alleviate the opioid crisis our nation is experiencing.

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HelloMD also recently launched in New York state offering patients the ability to get their medical marijuana certification online. This week we highlight PharmaCannis, a shining example of the eastern US cannabis scene, with five dispensaries statewide, professionals from the pharmaceutical industry, and an eye towards making cannabis a part of the future of healthcare.

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Finally, we highlight Dr. Gary Richter, the ‘Cannabis Pet Vet’, who has made it his mission to help animals and their owners lead happy, healthy lives.

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Be happy & healthy,

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Pamela Hadfield – Co Founder

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This is an important study for people to learn about and to help our legislators understand we need help to use this plant for billions who are needlessly suffering. We all need help. And simple is best. This medication has been safely used by grandmothers for thousands of years. Silly to think we cannot begin. Silly to deny millennia of use. We need help:

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  1. Low cost medication is essential.

  2. Healthcare insurers must reimburse patients for the cost of medical marijuana. This is done in New Mexico and should be in every state.

  3. We must all stop weaponizing a simple healing plant that can be effective. Truth beats fear. Every study helps to open minds.

  4. Support the work of good groups like HelloMD, NORML

  5. Get politics out of science and healthcare

  6. Teach our doctors – require 1 hour CME for all who see patients.

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I have so many senior patients terrified to try cannabis, and one who just had a once-in-a-lifetime result with a few cannabis drops under the tongue. She worked with a dispensary that mixed a personalized ratio of THC:CBD. It Worked! Nothing else had, her life spent in years of constant headache. It’s gone! yet she is still terrified of cannabis.

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Such has been the insanity about the American gung-ho opioid boosters vs the shoot ’em dead plant loving criminals and addicts – that’s what these little old ladies think they have become. Criminals and addicts. This sweet woman’s intractable migraine has taken her life every day for years, failing to respond to the best care in the nation, is now gone with cannabis! Yet she’s going to have a heart attack because for decades the GOP has trained her to think she’s a criminal addict. She was referred by one of the foremost migraine experts whose final suggestion was to try cannabis. A few weeks later when she came to her first visit with me, she was headache free.

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Had her family doctor been able to recommend someone who works with cannabis patients many years ago, she would not have wasted her life and fortune. It can be simple and life-saving to try, and always nice to have a helpful hand from the dispensary to show you how.  Again HelloMD helps with that.

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I am very grateful for HelloMD. For their great organization, a smoothly developed, simple, cost effective model that is affordable and convenient for my patients who are too ill to travel or simply too uncomfortable at the thought of hanging with a waiting room crowd so far from their better healed comfort zone.

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After all, they don’t look disabled, but I see disabled kids as young as 8 through 90’s.

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Do not judge disability by how someone looks. Young disabled veterans wearing artificial legs, have been attacked for not looking disabled when they park in disability spaces.

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Bring peace and healing to all whenever you can. Learn to use the plant and to enjoy the plant too. To be able to let off the weight of the world…. that alone is healing. Nothing is working right. Well, so what? Let go. We have to let go, let peace, breathe. You know you do the best you can as always, so now do the best and let go. Bring peace.

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Cannabis is a sacred plant. Treat it with respect. Fear is ignorance. Teach the truth. 

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“Democracy dies in darkness.”

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Bring peace and healing

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The material on this site is for informational purposes only.

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

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

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This site is not for email and not for appointments.

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

~~~~~

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

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

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A New Class of Pain Medicine from Cancer Cells – PD-L1 inhibits acute & chronic pain


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For the nonscientist, this report may explain better:

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Cancer actually yields a painkiller

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Scientists have discovered a potent painkiller in an unlikely place — cancer cells.

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This painkiller strongly inhibits acute and chronic pain in mouse models of melanoma, according to a study published Monday in Nature Neuroscience.

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Called PD-L1, the molecule is known to inhibit immune function, which helps cancers evade immune surveillance. It’s also produced in neurons. If it can be used to make an analgesic drug, it would represent a new class of painkillers, something badly needed.

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The molecule acts by targeting a cellular receptor called PD-1 and has been a longstanding target of cancer therapies called checkpoint inhibitors seeking to activate the immune system. But its painkilling effect is news.

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Ru Rong Ji of Duke University was senior author. Gang Chen and Yoang Ho Kim, also of Duke University, were first authors. The study can be found online at j.mp/cancerspain.

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…..Dr. Patel, oncologist from UCSD says: “This could result in a therapy that helps patients in a year or two years, just because so much has been done in the field.”

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The relationship between cancer and pain is complex, Patel said. PD-L1 suppresses inflammation, which activates the immune system, and also causes pain, Patel said. But there are other ways of activating the immune system, such as with the new cancer immunotherapy treatments, which don’t increase pain, he said.

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….The increased pain response is also caused by the cancer drug nivolumab. The drug, sold under the name Opdivo, targets PD-1 and shows success in treating melanomalymphoma and lung cancer. It produced strong allodynia for five hours in the mice, according to the study.

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Nivolumab is one of the new checkpoint inhibitor cancer drugs that targets PD-L1 receptors with immunomodulatory antibodies that are used to enhance the immune system. They can produce a wide spectrum of side effects termed immune-related adverse events (irAEs) with inflammation due to immune enhancement involving several organ systems.

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This is not my field and perhaps I am wrong. But if treating those cancers with immunotherapy causes the worst known neuropathic pain by blocking checkpoint inhibitors, is it possible that a new pain drug having the opposite mechanism could relieve pain but cause cancer?

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This Nature publication references the growing body of work from the lab of Linda Watkins, PhD, et al, published in 2014:

.Pathological pain and the neuroimmune interface

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Reciprocal signalling between immunocompetent cells in the central nervous system (CNS) has emerged as a key phenomenon underpinning pathological and chronic pain mechanisms. Neuronal excitability can be powerfully enhanced both by classical neurotransmitters derived from neurons, and by immune mediators released from CNS-resident microglia and astrocytes, and from infiltrating cells such as T cells.

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The material on this site is for informational purposes only.

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

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

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This site is not for email and not for appointments.

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

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

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

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After Ketamine for pain, complaints of depression dropped in half & pain reports were lower


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KPBS Radio highlighted a new study today by UCSD School of Pharmacy

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San Diego Scientists Find Further Evidence A Club Drug Could Treat Depression

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In a new analysis published Wednesday in the journal Scientific Reports, UC San Diego researchers said millions of FDA side effect records reveal that people who took ketamine for pain relief reported lower rates of depression.

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“The occurrence of complaints about depression dropped in half after ketamine administration,” said UC San Diego Skaggs School of Pharmacy professor Ruben Abagyan, who led the study.

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The researchers focussed on the FDA’s Adverse Effect Reporting System, a database that tracks negative side effects among people who take various drugs. But the researchers were not primarily interested in bad outcomes.

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Instead, they looked for a positive outcome: declining rates of depression among people taking drugs not typically thought of as antidepressants.

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They found signs that other common drugs — including Botox, a pain reliever called diclofenac and the antibiotic minocycline — also reduced depression among patients in the FDA database.

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[minocycline is a glial modulator and it can prevent CRPS from spreading.]

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University of Miami psychiatry professor Charles Nemeroff wrote that the study was, “very interesting.”

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“The findings are of considerable interest. However the interpretation of the findings are key,” he wrote, saying it will be important to understand whether ketamine is directly treating depression or simply relieving pain, which can indirectly help people experience less depression.

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The UC San Diego researchers said they controlled for this variable by comparing people who took ketamine with those who took other pain medications. They said they still found a larger drop in depression among those who took ketamine.

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This is the open source (free) article in Nature with brief excerpts below:

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Population scale data reveals the antidepressant effects of ketamine and other therapeutics approved for non-psychiatric indications

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.Isaac V. Cohen, Tigran Makints, Rabia Atayee, Ruben Abagyan

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We found that patients listed in the FAERS database who received ketamine in addition to other therapeutics had significantly lower frequency of reports of depression than patients who took any other combination of drugs for pain (LogOR −0.67 ± 0.034) (Fig. 1c). This reduction in depression is specific to ketamine and is known to be much more rapid than current antidepressants, making this observed effect very promising for treatment of patients with acute depressive or suicidal episodes. These patients cannot afford to wait up to six weeks for reductions in their depressive symptoms. Pain reports were also significantly lower for ketamine patients (LogOR −0.41 ± 0.019) (Fig. 1c).

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The analysis of the whole FAERS database revealed several other unintentional depression reducing drugs among antibiotics, cosmeceuticals and NSAIDS (Fig. 2). Our data supported previous studies that observed the psychiatric polypharmacology of minocycline [my emphasis], a tetracycline antibiotic14 (Fig. 2). The NSAID, diclofenac [that has highest incidence of heart attack and cardiac arrhythmia of any NSAID], was also observed to have some antidepressant properties (Fig. 2). It is theorized that both of these drugs may accomplish antidepressant effects through an anti-inflammatory mechanism. Because of the antidepressant activity of several NSAIDs, we further separated the non-ketamine pain cohort. Ketamine patients were then compared to patients who received any other combination of drugs for pain excluding NSAIDs. It was observed that depression event rates remained low (LogOR −0.56 ± 0.035) (Fig. 2)..The reduction of depression rates in ketamine patient records makes a case for study of ketamine as a psychiatric drug. These results imply that ketamine may be further explored as a monotherapy or adjunct therapy for depression. It should also be noted that FAERS data revealed that ketamine use [may] lead to renal side effects and awareness and caution in patients with renal or hepatic impairment may be warranted (Fig. 1a and b). [my emphasis].

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As an important side note, we also evaluated efficacy and side effects with the use of ketamine for pain management. We found that patients who were on ketamine had reduced opioid induced side effects including constipation (LogOR −0.17 ± 0.023), vomiting (LogOR −0.16 ± 0.025), and nausea (LogOR −0.45 ± 0.034) than patients who received any other combination of drugs for pain indications (Fig. 1d). Our data supports ketamine’s opioid-sparing properties and alludes to the fact that patients may receive benefits of improved pain, reduced requirement of opioids, and ultimately less opioid reduced side effects.

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The results of this study support previous small scale studies’ conclusions that ketamine is a good monotherapy or adjunct therapy for depression. In clinical practice ketamine would be especially useful for depression because of the quick onset of its action compared to existing first line therapies. Regardless of the causative mechanism ketamine appears to have therapeutic potential for TRD. Further, the potential to reduce many of the most complained side effects of opioid treatment makes ketamine adjunct therapy for pain seem desirable.

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Overall, this study demonstrates that the therapeutic potential of ketamine can be derived from appropriate statistical analysis of existing population scale data. This study also outlines a methodology for discovering off label pharmacology of existing approved drugs. This method can be applied to other indications and may reveal new important uses of already approved drugs, providing reliable justification for new indications without large investments in additional clinical trials.

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FDA Adverse Event Reporting System. The FAERS database was created to support FDA’s post marketing surveillance on drugs and biologic therapeutics. It contains adverse reaction and medication error reports sent to the FDA through MedWatch, the FDA Safety Information and Adverse Event Reporting Program. Reporting is voluntary and is done by patients, family members, legal representatives, doctors, pharmacists and other health- care providers. If any party reports an adverse effect to the manufacturer, the manufacturer is legally obligated to forward the report to the FDA. Data is available online in quarterly format for AERS from the first quarter of 2004 to the third quarter of 2012 and for FAERS from the fourth quarter of 2012 to the first quarter of 2016.

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The study used over 8 million adverse event reports from first quarter of 2004 to the first quarter of 2016. All the quarterly files from 2004 to 2016 were combined into a master file which was used as the primary source for analysis. . . .

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Out of 8 million reports, 279,853 reports were used for analysis of ketamine in Fig. 1. Two cohorts for ketamine (K) patients and pain (P) patients with 41,337 and 238,516 patients respectively....

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The material on this site is for informational purposes only.

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

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

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This site is not for email and not for appointments.

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

~~~~~

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

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

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Metformin – Nerve Pain & Microvascular Pain (angina)


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Metformin & Pain

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A diabetes drug used for many who have no diabetes. Recent discussion on metformin here and here.

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Metformin “can lead to a long-lasting reversal of pain hypersensitivity even long after treatment cessation, indicative of disease modification.” [ref below]

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References:

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A successful case of pain management using metformin in a patient with adiposis dolorosa.

International Journal of Clinical Pharmacology and Therapeutics

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In this case report, we describe a patient with Dercum’s disease who was successfully managed with metformin. The administration of metformin reduced pain intensity from 9/10 to 3/10 and favorably affected the profile of inflammatory cytokines (i.e., TNF a, IL-1β, IL-6, and IL-10), adipokines (i.e., adiponectin, leptin, and resistin), and β-endorphin. Because each variable was affected moderately by the drug, in the range of 20 – 30%, it follows that these effects are additive, i.e., they act independently of each other. However, taking into account advances in the pharmacology of metformin, it seems that other phenomena, such as modulation of synaptic plasticity, activation of microglia, and autophagy of the afferents supplying painful lipomas should be taken into consideration. Nonetheless, metformin deserves further exploration in the biology of pain.

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The use of metformin is associated with decreased lumbar radiculopathy pain

Journal of pain [2013], from University of Arizona Tucson, Ted Price’s lab, and USC

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Abstract:

Lumbar radiculopathy pain represents a major public health problem, with few effective long-term treatments. Preclinical neuropathic and postsurgical pain studies implicate the kinase adenosine monophosphate activated kinase (AMPK) as a potential pharmacological target for the treatment of chronic pain conditions. Metformin, which acts via AMPK, is a safe and clinically available drug used in the treatment of diabetes. Despite the strong preclinical rationale, the utility of metformin as a potential pain therapeutic has not yet been studied in humans. Our objective was to assess whether metformin is associated with decreased lumbar radiculopathy pain, in a retrospective chart review. We completed a retrospective chart review of patients who sought care from a university pain specialist for lumbar radiculopathy between 2008 and 2011. Patients on metformin at the time of visit to a university pain specialist were compared with patients who were not on metformin. We compared the pain outcomes in 46 patients on metformin and 94 patients not taking metformin therapy. The major finding was that metformin use was associated with a decrease in the mean of “pain now,” by −1.85 (confidence interval: −3.6 to −0.08) on a 0–10 visual analog scale, using a matched propensity scoring analysis and confirmed using a Bayesian analysis, with a significant mean decrease of −1.36 (credible interval: −2.6 to −0.03). Additionally, patients on metformin showed a non-statistically significant trend toward decreased pain on a variety of other pain descriptors. Our proof-of-concept findings suggest that metformin use is associated with a decrease in lumbar radiculopathy pain, providing a rational for larger retrospective trials in different pain populations and for prospective trials, to test the effectiveness of metformin in reducing neuropathic pain.

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The anti-diabetic drug metformin protects against chemotherapy-induced peripheral neuropathy in a mouse model.

PLoS One [2014] from MD Anderson Cancer Center

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Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) characterized by loss of sensory sensitivity and pain in hands and feet is the major dose-limiting toxicity of many chemotherapeutics. At present, there are no FDA-approved treatments for CIPN. The anti-diabetic drug metformin is the most widely used prescription drug in the world and improves glycemic control in diabetes patients. There is some evidence that metformin enhances the efficacy of cancer treatment. The aim of this study was to test the hypothesis that metformin protects against chemotherapy-induced neuropathic pain and sensory deficits. Mice were treated with cisplatin together with metformin or saline. Cisplatin induced increased sensitivity to mechanical stimulation (mechanical allodynia) as measured using the von Frey test. Co-administration of metformin almost completely prevented the cisplatin-induced mechanical allodynia. Co-administration of metformin also prevented paclitaxel-induced mechanical allodynia. The capacity of the mice to detect an adhesive patch on their hind paw was used as a novel indicator of chemotherapy-induced sensory deficits. Co-administration of metformin prevented the cisplatin-induced increase in latency to detect the adhesive patch indicating that metformin prevents sensory deficits as well. Moreover, metformin prevented the reduction in density of intra-epidermal nerve fibers (IENFs) in the paw that develops as a result of cisplatin treatment. We conclude that metformin protects against pain and loss of tactile function in a mouse model of CIPN. The finding that metformin reduces loss of peripheral nerve endings indicates that mechanism underlying the beneficial effects of metformin includes a neuroprotective activity. Because metformin is widely used for treatment of type II diabetes, has a broad safety profile, and is currently being tested as an adjuvant drug in cancer treatment, clinical translation of these findings could be rapidly achieved.

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Proteomic and functional annotation analysis of injured peripheral nerves reveals ApoE as a protein upregulated by injury that is modulated by metformin treatment

from Mol Pain [2013], from University of Arizona

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Abstract

BACKGROUND:

Peripheral nerve injury (PNI) results in a fundamental reorganization of the translational machinery in the injured peripheral nerve such that protein synthesis is increased in a manner linked to enhanced mTOR and ERK activity. We have shown that metformin treatment, which activates adenosine monophosphate-activated protein kinase (AMPK), reverses tactile allodynia and enhanced translation following PNI. To gain a better understanding of how PNI changes the proteome of the sciatic nerve and ascertain how metformin treatment may cause further change, we conducted a range of unbiased proteomic studies followed by biochemical experiments to confirm key results.

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CONCLUSIONS:

These proteomic findings support the hypothesis that PNI leads to a fundamental reorganization of gene expression within the injured nerve. Our data identify a key association of ApoE with PNI that is regulated by metformin treatment. We conclude from the known functions of ApoE in the nervous system that ApoE may be an intrinsic factor linked to nerve regeneration after PNI, an effect that is further enhanced by metformin treatment.

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Volume 107 of the series Experientia Supplementum [2016] from University of Texas Dallas

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Abstract:

Chronic pain is a major clinical problem that is poorly treated with available therapeutics. Adenosine monophosphate-activated protein kinase (AMPK) has recently emerged as a novel target for the treatment of pain with the exciting potential for disease modification. AMPK activators inhibit signaling pathways that are known to promote changes in the function and phenotype of peripheral nociceptive neurons and promote chronic pain. AMPK activators also reduce the excitability of these cells suggesting that AMPK activators may be efficacious for the treatment of chronic pain disorders, like neuropathic pain, where changes in the excitability of nociceptors is thought to be an underlying cause. In agreement with this, AMPK activators have now been shown to alleviate pain in a broad variety of preclinical pain models indicating that this mechanism might be engaged for the treatment of many types of pain in the clinic. A key feature of the effect of AMPK activators in these models is that they can lead to a long-lasting reversal of pain hypersensitivity even long after treatment cessation, indicative of disease modification. Here, we review the evidence supporting AMPK as a novel pain target pointing out opportunities for further discovery that are likely to have an impact on drug discovery efforts centered around potent and specific allosteric activators of AMPK for chronic pain treatment.

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Targeting adenosine monophosphate-activated protein kinase (AMPK) in preclinical models reveals a potential mechanism for the treatment of neuropathic pain.

Mol Pain [2011] from University of Arizona

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Abstract

Neuropathic pain is a debilitating clinical condition with few efficacious treatments, warranting development of novel therapeutics. We hypothesized that dysregulated translation regulation pathways may underlie neuropathic pain. Peripheral nerve injury induced reorganization of translation machinery in the peripheral nervous system of rats and mice, including enhanced mTOR and ERK activity, increased phosphorylation of mTOR and ERK downstream targets, augmented eIF4F complex formation and enhanced nascent protein synthesis. The AMP activated protein kinase (AMPK) activators, metformin and A769662, inhibited translation regulation signaling pathways, eIF4F complex formation, nascent protein synthesis in injured nerves and sodium channel-dependent excitability of sensory neurons resulting in a resolution of neuropathic allodynia. Therefore, injury-induced dysregulation of translation control underlies pathology leading to neuropathic pain and reveals AMPK as a novel therapeutic target for the potential treatment of neuropathic pain.

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Contrasting effects of chronic, systemic treatment with mTOR inhibitors rapamycin and metformin on adult neural progenitors in mice.

Age [20124, from University of Arizona

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Abstract:

The chronic and systemic administration of rapamycin extends life span in mammals. Rapamycin is a pharmacological inhibitor of mTOR. Metformin also inhibits mTOR signaling but by activating the upstream kinase AMPK. Here we report the effects of chronic and systemic administration of the two mTOR inhibitors, rapamycin and metformin, on adult neural stem cells of the subventricular region and the dendate gyrus of the mouse hippocampus. While rapamycin decreased the number of neural progenitors, metformin-mediated inhibition of mTOR had no such effect. Adult-born neurons are considered important for cognitive and behavioral health, and may contribute to improved health span. Our results demonstrate that distinct approaches of inhibiting mTOR signaling can have significantly different effects on organ function. These results underscore the importance of screening individual mTOR inhibitors on different organs and physiological processes for potential adverse effects that may compromise health span.

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Two Weeks of Metformin Treatment Enhances Mitochondrial Respiration in Skeletal Muscle of AMPK Kinase Dead but Not Wild Type Mice

.PLoS One from University of Copenhagen [2013].

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Abstract:

Metformin is used as an anti-diabetic drug. Metformin ameliorates insulin resistance by improving insulin sensitivity in liver and skeletal muscle. Reduced mitochondrial content has been reported in type 2 diabetic muscles and it may contribute to decreased insulin sensitivity characteristic for diabetic muscles. The molecular mechanism behind the effect of metformin is not fully clarified but inhibition of complex I in the mitochondria and also activation of the 5′AMP activated protein kinase (AMPK) has been reported in muscle. Furthermore, both AMPK activation and metformin treatment have been associated with stimulation of mitochondrial function and biogenesis. However, a causal relationship in skeletal muscle has not been investigated. We hypothesized that potential effects of in vivo metformin treatment on mitochondrial function and protein expressions in skeletal muscle are dependent upon AMPK signaling. We investigated this by two weeks of oral metformin treatment of muscle specific kinase dead α2 (KD) AMPK mice and wild type (WT) littermates. We measured mitochondrial respiration and protein activity and expressions of key enzymes involved in mitochondrial carbohydrate and fat metabolism and oxidative phosphorylation. Mitochondrial respiration, HAD and CS activity, PDH and complex I-V and cytochrome c protein expression were all reduced in AMPK KD compared to WT tibialis anterior muscles. Surprisingly, metformin treatment only enhanced respiration in AMPK KD mice and thereby rescued the respiration defect compared to the WT mice. Metformin did not influence protein activities or expressions in either WT or AMPK KD mice.

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We conclude that two weeks of in vivo metformin treatment enhances mitochondrial respiration in the mitochondrial deficient AMPK KD but not WT mice. The improvement seems to be unrelated to AMPK, and does not involve changes in key mitochondrial proteins.

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Effects of metformin on microvascular function and exercise tolerance in women with angina and normal coronary arteries

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Journal of the American College of Cardiology [2006], from University of Glasgow Cardiovascular Research Centre
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Abstract:

We conducted an 8-week double-blind, randomized, placebo-controlled study of metformin 500 mg twice a day in 33 women with a prior history of normal coronary angiography but 2 consecutive positive (ST-segment depression ≥1 mm) exercise tolerance tests. Women randomized to metformin (n = 16) showed significant improvements in endothelium-dependent microvascular function (p < 0.0001) and maximal ST-segment depression (p = 0.013), and a trend (p = 0.056) toward reductions in chest pain incidence relative to placebo recipients. Hence, metformin may improve vascular function and decrease myocardial ischemia in nondiabetic women with chest pain and angiographically normal coronary arteries. Larger controlled trials of longer duration are warranted.

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