Opioids increase risk of chronic pain – potentiate pain – faster, stronger, longer. Activate TLR4 receptor on microglia, blocked by low dose naltrexone (LDN)


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Professor Linda Watkins was the distinguished keynote speaker at the May 2015 American Pain Society annual meeting and gave the NIH 2015 Kreshover Lecture:

“Targeting Glia to Treat Chronic Pain: Moving from Concept to Clinical Trials.”

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The University of Colorado at Boulder describes her work

She has authored or co-authored over 190 book chapters, review articles and journal articles.

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Dr. Watkins’ research focuses on 3 inter-related areas. Her primary research interest is understanding how to control clinically relevant pathological pain states. Her group’s research points to a novel reason that clinical pain has been impossible to successfully control. That is, pathological pain is being created and maintained by a surprising cell type, namely glia. These cells, upon activation, dysregulate normal pain processing by the spinal cord neurons.

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Medical News Today published news of her recent study April 19, 2018

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“Opioids may increase risk of chronic pain.” They potentiate pain “faster, stronger, longer” and activate the TLR4 receptor on microglia. That receptor is blocked by low dose naltrexone (LDN).

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Opioids trigger inflammation in the brain and spinal cord. This is an elegant study by renowned Prof. Linda Watkins at the University of Colorado Boulder, with Peter Grace. His early work on LDN brought him from Australia to postdoc at her lab and now research at MD Anderson Cancer Center.

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“Having been used in one form or another for millennia, opioids beat pain into submission, quickly making the patient more comfortable. The latest study, which was carried out at the University of Colorado Boulder, turns this firmly held notion on its head.

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Senior author Prof. Linda Watkins, from the Department of Psychology and Neuroscience, says, ominously, “[…] there is another dark side of opiates that many people don’t suspect.”

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In this case, it is not addiciton issues that Prof. Watkins is referring to. Paradoxically, opioids may actually prolong pain following surgery. The results were published recently in the journal Anesthesia and Analgesia.

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Postsurgical pain and opioids examined

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For the study, Prof. Watkins and colleague Peter Grace, of MD Anderson Cancer Center in Houston, TX, carried out laparotomies on male mice. This procedure involves making an incision through the abdominal wall to access the interior of the abdomen, and it is done on tens of thousands of U.S. individuals each year.

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“Opiates are really effective for acute pain relief. There is no drug that works better. But very little research has been done to look at what it is doing in the weeks to months after it’s withdrawn.”

Peter Grace

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Following surgery, one group of rats received the equivalent of a moderate dose of morphine for the next 7 days, while another group received morphine for 8 days, and the dosage was tapered off by day 10.

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Another group was given morphine for 10 days, after which point treatment stopped abruptly. A final group was given saline injections rather than morphine as a control.

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And, in another experiment, a group of rats received a 7-day course of morphine that ended 1 week before surgery was carried out.

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Before the morphine regimes commenced, and after they had been completed, the rats’ sensitivity to touch was measured, as was the activity of genes related to inflammation in the spinal cord.

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Compared with rats given saline, those that received morphine endured postoperative pain for over 3 additional weeks. Also, the longer the morphine was provided, the longer the rats’ pain lasted.

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The study also revealed that tapering of morphine dosage makes no difference. As Grace explains, “This tells us that this is not a phenomenon related to opioid withdrawal, which we know can cause pain. Something else is going on here.”

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How can morphine raise postoperative pain?

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The next question to ask, of course, is what drives this counterintuitive effect. Prof. Watkins calls it the result of a “one-two hit” on glial cells.

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In the brain, glial cells are more numerous than neurons. They protect and support nerve cells and, as part of their role as protector, they direct the brain’s immune response, including inflammation.

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The first “hit” occurs when surgery activates glial cells’ toll-like receptor 4 (TLR4). Prof. Watkins calls these “not me, not right, not O.K.” receptors; they help to orchestrate the inflammatory response. This first hit primes them for action when the second hit occurs.

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The second hit is morphine, which also stimulates TLR4. As Prof. Watkins explains:

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“With that second hit, the primed glial cells respond faster, stronger, and longer than before, creating a much more enduring state of inflammation and sometimes local tissue damage.”

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Although the study is in an animal model and will need replicating in humans, it does line up with previous findings.

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For instance, in 2016, the same scientists published another animal study, which found that a few days of opiate treatment for peripheral nerve pain exacerbated and prolonged pain. In that study, the activation of inflammatory pathways was also implicated.

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“An unusually high number of people end up with postoperative chronic pain,” explains Prof. Watkins. In fact, millions of U.S. individualssuffer with chronic pain. “This new study lends insight into one explanation for that.”

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Interestingly, the rats that received a course of morphine that ended a week before surgery did not experience prolonged postsurgical pain, leading the study authors to conclude that there is “a critical window for morphine potentiation of pain.”

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Because opioids are currently considered the best course of action to deal with postoperative pain, if these results are replicated in humans, it leaves medical science in a difficult situation.

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This is why Prof. Watkins is focusing much of her energy on designing drugs that could be given alongside opioids to dampen down the inflammatory response. She is also exploring alternative painkillers, such as cannabinoids.”

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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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Families Refusing Opioids for Pain in Dying Loved Ones


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Refusal of care in the palliative care setting, lack of cooperation in treating pain. Fear the pain medicine will kill. Addicts dying of overdoses. Fear the dying grandmother will be addicted or die from the pain medicine. Fear of addiction in the family, unsafe to keep opioid for the patient. So many fears, myths and misunderstandings.

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Fear has taken over in so many levels of our consciousness. That is why we all need to educate ourselves so that we are prepared to safely help those we love when the time arises.

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Death and dying need not mean agonizing pain. Strong pain may require strong opioids for relief, and strong opioids can be safely adjusted to allow good mental function so you and your loved ones can be present in the last days. Not, not in shock and anguish from screaming pain going on for weeks.

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Yes, I have been called to help a family whose mother was in her last days, on palliative care. Her only communication for weeks was loudly moaning with grimacing and wincing the muscles of her face. They were refusing to give even the tiniest drops of morphine under her tongue, as recommended weeks ago by the palliative care physician.

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Refusal of care will only get worse, not just for the dying but millions with chronic pain. Physicians refusing to treat pain or being firmly uncooperative with family or pain team recommendations. This is a huge issue in cancer hospitals and cancer wards. The old way was never to give opioids for cancer. The standards in medicine are set by the old guys who pass it on and control all coming up the ranks. Don’t step out of line. Fear is in control.

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Dispel that fear. Inform yourself in proper care recommendations by leaders in the field or you will live with regret when your loved ones died screaming in pain and you refused care. I have seen many oncologists refuse pain care and threaten patients, families and staff.

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Read some of the myths and issues that are too frequently encountered by caregivers all across the country – click here.

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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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Medicare & Insurers Crack Down on Opioids – Patients Suffer


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Individualized pain management does not exist.

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Correction from reader: 

“Individualized treatment does exist, but insurance companies are not paying for it. This has to change.” 

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The New York Times reports “Medicare is Cracking Down on Opioids” (link below).

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Last year an insurer denied 10 mg daily Oxycontin for one of my seniors who had been safely taking this for many years. That is less than 1 mg per hour for 12 hour relief. Pharmacy refused to fill unless insurer approved. That’s one way to reduce healthcare costs without an uprising. There is little tolerance for someone with pain. Are they viewing patients as addicts? Would they do this for cancer? 

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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.

~~

Comments are welcome.

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

~~~~~

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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Editorial from PAIN: Hijacking the endogenous opioid system


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Neuropathic pain responds poorly to opioids, often not at all, and may become worse with treatment.

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I have seen pain improve in many after tapering off.

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Then you must treat pain without opioid; it doesn’t just disappear, but it will not be as intense. This editorial explains some of the reasons opioids become a problem.

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Excerpted from an editorial in the current issue of PAIN

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[emphasis mine]

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[COT = chronic opioid therapy]

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…..This review highlights why we may see some of the more insidious problems that occur with COT, which are summarized below.

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Individuals on COT may continue to “need” opioids to replicate the functions of endogenous opioids that are no longer being released (or are in competition with the exogenous opioids). As the review by Ballantyne and Sullivan states, “a new homeostasis is reached that can only be maintained by continued drug taking”.1 Individuals on COT lose the ability to endogenously improve mood, decrease stress, and socially engage because the endogenous opioid system becomes inherently less responsive. In pain management, we know of this need for increasing opioid dose over time to maintain analgesia as opioid tolerance. But a similar physiological phenomenon likely occurs with any endogenous opioid function. Although we have mainly anecdotal reports from individuals who have been weaned off of opioids, the change in personality, social engagement, motivation, fatigue, and mood is often profound when individuals on COT successfully taper to lower doses or off opioids. These insidious side effects of COT would all be expected to inhibit individuals from maximally engaging in the patient-centric, disease management strategies that are now recommended for all chronic pain states.

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This may also explain why it is often very difficult to taper individuals on COT completely off opioids and underscores the importance of a slow, structured weaning protocol with appropriate psychological support. It may take months or years for endogenous opioid function to return to normal after cessation of opioids, or perhaps this system never returns to normal in some patients (as seems to occur in heroin addicts).5

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This paralysis of the endogenous opioid system by COT could render ineffective many other treatments that are recommended for chronic pain and that work in part via the endogenous opioid system. Many if not most nonpharmacological therapies for pain, such as exercise, acupuncture, and many other mind-body therapies are believed to work in part by engaging endogenous analgesic pathways that are partly opioid dependent.

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Opioids have acute antistress and antidepressant effects, and many of our patients with chronic pain are taking opioids chronically to medicate their co-morbid depression, despair or distress more so than to treat pain. Brain imaging studies indicate that many brain regions typically involved in pain and sensory processing are also involved in affective regulation. Patients having chronic pain who show higher degrees of psychological comorbidity or stress might therefore desire opioids because of their temporary salutary effects on these domains, rather than for their intended analgesic effects. We need to develop better cognitive-behavioral and psychosocial interventions that target the needs of the many patients with pain experiencing more harm than benefit from opioids, but still seek these drugs to reduce their affective symptoms.

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The endogenous opioid system may actually participate in the pathogenesis of some chronic pain conditions making this class of drugs particularly problematic for some patients. Many lines of evidence suggest that individuals with more centralized pain conditions such as fibromyalgia are particularly unresponsive to opioids, and the endogenous opioid system may be participating in the pathogenesis of these conditions.2,7 This has tremendous clinical implications because it means that we may actually make these patients’ pain worse by administering opioids. These same individuals may also be those at highest risk for prolonged use of opioids initially given for acute pain, both because they need higher doses for longer durations, and they are more likely to have the psychological comorbidities that drive unintended use and misuse.

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We clearly need to re-think the focus of opioid education and screening programs in light of some of these observations. After any exposure to an opioid, especially following the very common use in the United States for treating acute pain, patients can become addicted or can misuse these drugs to treat concomitant despair, depression, or pain elsewhere in the body that would not be expected to be responsive to an opioid. As we contemplate risk evaluation and mitigation strategies to curb further opioid misuse and addiction, we need to better appreciate these common alternate paths to unintended uses of opioids.

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We are not the first field to underappreciate the consequences of hijacking a critical endogenous system for one purpose, only to eventually find that there are significant consequences. Following the discovery of the endogenous corticosteroid system, Hench and others found that cortisone was an extremely effective treatment for rheumatoid arthritis, and this revolutionized our treatment of inflammatory processes. But it took several decades to fully appreciate all of the intermediate and long-term side effects of chronic corticosteroid use.4 Nearly all of these under-recognized issues were due to off target effects of exogenous corticosteroids on critical endogenous functions of these hormones. Although the short-term effects of opioids have been understood for centuries, long-term, high-dose opioids have only been advocated for a few decades. It is likely that we are now witnessing a similar clinical phenomenon, and as we increasingly appreciate the off-target effects of repurposing a critical endogenous system, the pendulum needs to rapidly swing back towards caution with prescribing a class of drugs that have a plethora of serious side effects other than addiction and death from overdose.

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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.

~~

Comments are welcome.

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

~~~~~

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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Best wishes to all!


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

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.

~~

Comments are welcome.

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

~~~~~

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.

.

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

.

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

~~

Comments are welcome.

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

~~~~~

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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