Memantine for Neuropathic Pain & Complex Regional Pain Syndrome, CRPS


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Neuropathic pain syndromes show an over-expression of NMDA receptors in the brain in animal models. Ketamine blocks the NMDA receptor. Another medication with the same mechanism, but in pill form is memantine. This report on six patients of the use of memantine for Complex Regional Pain Syndrome (CRPS) from 2007 in the Clinical Journal of Pain, six months after treatment with memantine, showed significant decrease in pain, improved motor symptoms and autonomic changes, and fMRI changes on the affected side improving, comparable to the unaffected side of the brain.

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It was approved for Alzheimer’s dementia gradually titrating to a dose of 28 mg/day, but for decades has been very useful off label for neuropathic pain including but not limited to CRPS, at a dose of 55 mg/day, and in recent years often prescribed for migraine.

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Ketamine is highly successful also for treatment resistant depression, and one patient, a psychiatrist disabled from the unfortunate triad of intractable neuropathic pain, migraine and treatment resistant depression, while slowly titrating to a dose of 55 mg/day, a process that takes almost 3 months, found depression relieved for the first time in decades at the dose of 35 mg. It was highly effective as one component of the multi-pronged approach for all three conditions.

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This life is a hard fact. We all need all the help, encouragement and positive attitudes we can get. Complex intractable pain and/or depression requires rational polypharmacy, selectively chosen based upon well known mechanisms, neurotransmitters, receptors, hormones, stress reduction, cognitive behavioral therapy, physical therapy, occupational therapy, nerve blocks, and spiritual understanding, etc. Several choices were summarized almost two years ago here.

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In my experience, memantine is very well tolerated with few if any side effects but covered by insurance only for mild to moderate dementia. Thus, not only is it highly challenging to treat neuropathic pain, but important to creatively meet the challenges of our backwards medical system that barely recognizes the needs of those with chronic pain.

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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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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.

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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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Donate to RSDSA to Relieve Nerve Pain


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*****HAPPY HOLIDAYS*****

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PLEASE DONATE TO RSDSA

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FOR RESEARCH INTO

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TREATMENT OF NERVE PAIN

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There is no more highly focused nonprofit organization than the RSDSA for research and treatment of neuropathic pain and that is why the link to them is always at the **top banner** of these pages describing them in detail.

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For decades, they have led the field — little thanks to NIH that gave less than half of 1% to all pain research in 2008. Why should anyone care when pain doesn’t kill you—–right?

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People die of cardiac disease or cancer. They get all the money for research and we all forget about decades of awful quality of life, career ending disability and worse. 

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Research funding raised by RSDSA is awarded for research into RSD but that almost always applies to nerve pain in general, not to just one rare condition. It is always the most difficult to treat. 

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Please remember them generously. They help so many with education, outreach, conferences among the world’s foremost researchers, and funding to move the work forward.

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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.

~~

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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Medical Marijuana – Cannabis for Pain


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These references include links to peer reviewed journal articles on cannabinoids. They are taken from the Reference Library of the outstanding RSD Association in Connecticut, whose mission is to help relieve pain. They have grouped the articles in helpful folders by subject, and this is one of many folders on the immense subject of pain. Please donate to them as their research helps everyone with pain, not just nerve pain or CRPS. May the references help enrich your lives and help support congress and regulators in legalizing cannabis across the country — the attorney general just now voted in by congress opposes medical marijuana.

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Be aware that states should monitor the plant for bacteria, fungus, pesticides, and heavy metals as discussed in this Smithsonian article:

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“Washington, the second state to legalize recreational marijuana, does require such testing for microbial agents like E. coli, salmonella and yeast mold, and officials there rejected about 13 percent of the marijuana products offered for sale in 2014.”

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Concentrates may be made with toxic butane or heptane. If you have cancer or are immunosuppressed – cancer and autoimmune diseases fall into that category – it is safer not to inhale. Cannabis can be used on the skin or swallowed but be aware when swallowed, it takes 60 to 90 minutes before you feel the effect. It is easy to overdose when swallowed. Check your blood pressure and pulse before use and again while you feel its effect.

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The article also points out that on testing, many of the plants have high THC but no longer have CBD, one of the 86 known cannabinoids, the one that blocks the psychoactive side effects of THC. On its own, CBD has many medical benefits.

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For those who have allodynia, the most intense form of nerve pain, pain that is triggered by a light touch or breath of air:

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Keep in mind that chronic pain is much harder to treat than cancer pain and acute pain. Chronic nerve pain is the hardest of all to treat. We need to be able to prescribe anything that helps. Pain can lead to suicide in these extreme pain conditions.

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Watch out for the munchies – do not get fat.

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O’Shaunessy’s today published articles that may be useful for your Senators, healthcare insurers and states:

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“some additional articles published by cannabis clinicians in O’Shaughnessy’s showing the strength of aggregated case reports. We hope the MBC Marijuana Task Force will give them serious consideration.”

 

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Cannabinoids

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Spinal Cord Stimulators – comment on RSD


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Spinal Cord Stimulators 

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 Craig’s comment

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By no means do I mean to say that I or anyone else has better insight into how to treat pain, but I am against spinal cord stimulators [SCS’s] for treatment of pain due to CRPS, and possibly against use in other situations. I demand that the billions in profit they made be put into a retrospective and prospective study of damage caused by them in order for them to give full informed consent.

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I have 3 goals writing this.

  1. SCS’s

  2. Craig’s experience

  3. The Only Real Answer for severe pain, not damaging the system with opioids

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Informed consent is never given for spinal cord stimulators because it requires truth telling, something our corporations have been reluctant to do. Business ethics are not medical ethics, as we keep being reminded daily in the headlines.

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I enclose, below, a generously expressed and detailed comment by a man who had the patience to sit down and  write the painfully gory details so you can weigh-in on your decision whether to follow your pain specialist’s opinion to give you one. I don’t want anyone to feel suckered into choosing them and if I had pain I’ll admit I’d crave relief too. Anything. I’d be in line before the doors open.

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But if you have CRPS, spinal cord stimulators will create more pain. CRPS evolves unpredictably, by a will of its own. I know some very desperate patients with CRPS everywhere including face, mouth, gums, tongue, organs, trunk, limbs. Spinal cord stimulators will create more pain. Keep in mind, I don’t see the 5 year success stories even for lumbar disc pain. They don’t need me if they are pain free.

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But if you have CRPS and desperate need for pain relief because all else has failed — every known drug in highest possible doses of ketamine, propofol, opioids for weeks in ICU fail to even touch pain— there is one thing, and only one thing to do and I will set it out below. I just sent my recommendation to a patient with CRPS in extreme pain.

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My recommendation, below, is for patients who have nowhere else to turn.

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First I’ll mention the problems Craig encountered with SCS’s. He sent his comment to the opening page of this blog, so I will reproduce below. 

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I am currently undergoing a trial Medtronic SCS. I have had to have it reprogrammed 3 times since it was installed 5 days ago. I have had sensations and issues that I have addressed with my rep and my neurosurgeon. I get a severe headache when the unit is turned on. I get the constant feeling of having to urinate. I have current running through my testicles which they can not seem to program out and I am getting little pain relief. I have had to failed back surgeries, many failed injections and I have CRPS. The leads that were inserted when I was in the table covered my mid back and both legs. After I got to my feet and waited while they programmed the unit in another room. They came in and plugged it in and I no longer had coverage on the right side. My crps is in both legs, my hands, arms and face. The lyrica helped to tamp down some of the burning but I am in pain 24/7 and this was my last resort. I have scar tissue completely surrounding my S1 nerve. By the grace of God, I am on my feet, on crutches. I seem to get a look of disbelief when I tell them the unit is causing these issues or it’s not giving me the relief I was counting on. Relief, only to cause greater issues and pain. Is not relief to me. I can not wait to get this trial out of my back. I believe the leads slipped and that is why I am not getting the full coverage I had on the table. The issues I have had are as follows: severe headache, constant feeling of having to urinate, extreme joint pain, abdominal pain, sleeplessness, involuntary jerking, surges in current even when sitting still. Intense pain around the lead insertion site. Current uncomfortably running through my testicles, regardless of setting. It is my opinion there is still not a lot known about crps and I have read evidence of people have great success with these units. Everyone reacts differently. My body obviously creates a lot of scar tissue and my orthopedic surgeon created a fair amount herself. I can’t imagine even more or being forced into a chair for yet another unlucky decision. The medication helps and I have lived this far without the optimism that it would end soon. I had high hoed for this device but I don’t think it is right for me.

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One of my patients with CRPS was hospitalized for weeks with recurring unusual abscesses and required repeated surgery of hand and forearm. Even before surgery, she had failed opioids, failed ketamine, and was in ICU for weeks and weeks while the same medications were still given along with Propofol and IV Tylenol. Nothing helps her extreme pain.

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Anesthesiologists on staff in ICU threw everything they had at the pain for weeks. Most anesthesia pain doctors would have probably done what they did because that is the limit of tools we have.

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When you have hit the limit of benefit from opioids, ketamine, propofol, we have nothing else that treats pain with one exception: drug holiday.

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Stop all analgesics including Tylenol that destroys the liver as severely as cancer, the severity of which was newly discovered and published yesterday.

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The receptors for these analgesic drugs have up-regulated to such an extent they have caused the situation. Again, I stress, everything that was done during the ICU admissions would be done by any anesthesiology pain specialist. Those are the only tools. They cause the problem. The same for opioid induced hyperalgesia. We used to do it with Parkinson’s drugs in the 80’s.

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The only way to rehabilitate the up-regulation of all those receptors that have now exploded in numbers, immune to anything you throw at them, is stop the drugs.  Stop all of them for weeks, maybe months, years, no one knows, you are all the human guinea pig waiting to happen. But if we restart them, how long do we wait, how quickly will it again lead to this massive hyper-excitable state of pro-inflammatory cytokines that we know have gone wild, flooding the CNS. A flooded engine will not restart.

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Ketamine at least is known to reduce pro-inflammatory cytokines, but the system is too busy exploding, birthing new receptors that take over, and you’ve got a 55 car pile up. Well, more like millions I’d guess. No scientist here. Clnically, when can we resume something after a drug holiday, how soon and which drug? I’d avoid opioids because they create more pro-inflammatory cytokines. Choose ketamine, because they reduce pro-inflammatory cytokines, but if it works at all, stop it at first sign of tolerance, which is the need for increased dose. It becomes less effective. Walk a fine line, endure more pain because unless you do, it will no longer help. Opioids, analgesics of many kinds. 

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How do we get you through a drug holiday because we know withdrawing these drugs will trigger even more pain for possibly weeks until the system settles down?

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Pain storms, hurricanes

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This is complex regional pain syndrome where we see this insanity of pain storms. There is no other condition, unless several neuropathic pains in people with cancer, nowhere I have seen this type of pain in decades except CRPS – comparable to pain of subarrachnoid hemorrhage, blinding pain.

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No one has answers. None. One university does outpatient infusions of ketamine six hours daily for 8 to 12 weeks. Does it help? A small percentage. Outpatient, 6 hours daily, 5 days a week, staying at a hotel, 8 weeks.

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This is CRPS/RSD. No one has answers. It is futile to throw more of the drug in the system. That is my opinion. You have a choice and may choose otherwise. It is your body. You may stay on monthly opioids for decades, until you finally admit how poorly they work. A drug holiday is what we did in the 70s during my ancient training with Parkinson’s patients. They needed full 24-hour support. The American medical system has changed since then and those are not options currently available—cost.

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You need full psychological and psychiatric support.

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The Only Real Answer

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The country needs to invest $10 million to complete the clinical trials needed for an injectable, long-lasting interleukin 10 [IL-10], the anti-inflammatory cytokine. It already has full scientific and animal studies performed by and with the world’s foremost glial scientist at University of Colorado Boulder. Professor Linda Watkins has won awards from many countries. She has been the keynote speaker at the annual academy pain meetings for years. IL-10 can relieve pain for three months in animals that have intractable chronic neuropathic pain. This is not new —–NIH I’m looking at you to fund clinical trials. And those of you who care, do a Kickstarter to fund the clinical trials.

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This is the power of the innate immune system. NIH would rather fund research on the unknowns like stem cells rather than the known. It’s known for decades, NIH does not like to fund pain research. Glia are not all about pain. They are the innate immune system, the key to Alzheimer’s, neurodegenerative diseases, almost all known disease including atherosclerosis. It’s all about inflammation. We need the trials to stop giving drugs that cause inflammation, opioids —–CDC fiats are not as good as a drug that relieves pain, a drug that really works on mechanism. Where will the addicts go if the ER only has IL-10 for pain? That is one way to overspend on ER visits.  And NIH, please get us some real clinical research funding on how to use glia for our benefit. Get us some research on the entourage effect, combining medications to achieve relief especially for neuropathic pain.

Then bring on some crack negotiating teams from insurers to do some negotiation about pharmaceutical prices. Our new president has mentioned that.

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Please bring this to everyone’s attention. One way to get a grip on pain and/or depression is to build hope, help others, and energize behind a goal.

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Kickstarters work to raise tens of millions overnight. 

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IL-10 – animals have been shown to be pain free for three months, already proven in animal studies, by one of the world’s most widely acknowledged pain specialists Professor Linda Watkins, PhD. We need the final steps to fund the clinical trials in humans.

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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.

~~
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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Neuropathic Pain Medications – review & metanalysis of 229 studies


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This review was done by many of the best pain specialists from all over the world. You will not find answers in that large review if neuropathic pain has already failed tricyclic antidepressants (Elavil, amitriptyline, Norpramin desipramine, others), gabapentin (Neurontin), pregabalin (Lyrica), lidocaine, capsaicin, or opioids. That is the current paradigm. A new paradigm – glial modulators  – that I discuss on this site, may or may not give relief.

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A member of the International Association for Study of Pain, IASP, published a brief critique of that comprehensive review of 229 trials of medications for neuropathic pain published in Lancet Neurology February 2015. The critique is posted below, done by a member of the Neuropathic Pain Special Interest Group, NeuPSIG.

 

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To understand the metanalysis of these 229 trials, you need to understand the simple concept of number needed to treat, NNT.

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NNT is an estimate of “the number of patients that need to be treated in order to have an impact on one person.”

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The smaller the number, the more effective the drug. Example, NNT of 7.2 for gabapentin means you need to treat  7.2 people before a response. If 3, need to treat 3 before a response.

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Barsook (Harvard, ref. below) reviewed ketamine studies in 2009:  “they did show a level of efficacy (of ketamine) based on NNT that equals or betters most drug trials for this condition.”

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“NeuPSIG has just published an up to date systematic review on the effectiveness of pharmacotherapy in Lancet Neurology. They have negotiated with the journal to make it available beautifully open access. You can download it for free here.”

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Neil O’Connell, Brunel University London

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“This is a comprehensive review, containing 229 trials of the full range of pharmacological agents using robust methods, to synthesize, summarise and make value judgements about the quality of the available evidence. So what are the take home messages?”

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“Using a primary outcome of achieving at least 50% pain relief trial outcomes were described as “generally modest”. The number of patients needed to treat with the drug compared to a placebo for one more person to achieve this outcome ranged from a relatively rosy 3.6 (95% confidence interval 3 to 4.4) for tricyclic antidepressants such as amitryptiline, 4.3 (95%CI 3.4 to 5.80 for strong opioids to a less impressive 7.2 (95%CI 5.9 to 9.21) for gabapentin, and 7.7 (6.5 to 9.4) for pregabalin (often sold under the brand-name Lyrica). It’s interesting, at least to me, how much better the older more traditional agents seem to have fared compared on effectiveness to the more modern (and commonly more expensive) agents although the safety and tolerability of gabapentin seems superior.”

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“The spectre of publication bias also raises its head. The reviewers carefully took a number of routes to try to unpick this notoriously difficult issue and estimate that there has been overall a 10% overstatement of treatment effects. Published studies reported larger effect sizes than did unpublished studies. This is not a problem restricted to the field of pain trials. It is a burning issue across the world of clinical trials. It is very important because if we fail to base our clinical recommendations on the totality of relevant evidence (because some data are hidden from us) we are in danger of mis-estimating the benefits and the harms and as a result patients are put at risk. If you think that is pretty important then there are ways that you can help. Check out the All-Trials campaign.”

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“Overall what does this mean? Many drugs are effective but not as effective as we would wish them to be. No pharmacological agent really impresses and for any drug the most probable outcome is failure to produce 50% pain relief. There are various potential reasons for this. The first is that the drugs may only be moderately or marginally effective, another is that neuropathic pain includes quite a mixed bag and our ability to accurately diagnose and to target drugs to specific mechanisms in the clinic is currently fairly poor.”

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“The NeuPSIG review team formulate a number of recommendations for revision of their clinical guideline for managing NP pain, balancing the benefits, harms, costs and strength of the evidence.”

  • a strong recommendation for use and proposal as a first-line treatment in neuropathic pain for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin;

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    • a weak recommendation for use and proposal as a second line treatment for lidocaine patches, capsaicin high-concentration patches, and tramadol; and a weak recommendation for use and proposal as third line for strong opioids and botulinum toxin A. Topical agents and botulinum toxin A are recommended for peripheral neuropathic pain only.

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“This email [from IASP’s NeuPSIG] is also published as a blogpost at www.bodyinmind.org”

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References

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Finnerup NB, Attal N, Haroutounian S et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14:2:162-73.

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Glial modulators – another paradigm

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From my January 2012 brief review of publications on ketamine, only one of a handful of glial modulators, this author says reviews “show a level of efficacy based on NNT that equals or betters most drug trials for this condition.

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Ketamine and chronic pain – Going the distance, David Barsook, Director, P.A.I.N. Group, Massachusetts General, McLean and Children’s Hospitals, Harvard Medical School, Boston, MA;

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

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Our current therapeutic armamentarium is quite limited in terms of analgesic efficacy in controlled trials. Some would argue that the small efficacy (both at a population level and the magnitude of change in VAS score) this is related to the fact that we need to consider mechanistic approaches to chronic pain subgroups. However, patients and clinicians find themselves in a position of “what to do now”.

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Ketamine, brain function and therapeutic effect – neuroprotective or neurotoxic

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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.

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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.”

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Conclusions

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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.

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The material on this site is for informational purposes only, and is not a substitute for medical advice,

diagnosis or treatment provided by a qualified health care provider.

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Please understand that it is not legal for me to give medical advice without a consultation.

If you wish an appointment, please telephone my office.

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

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