Glia a Promising Target for Neuropathic Pain – Ketamine Acting on Glia More Than on Neuronal NMDA Receptors?


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

Emphasis within articles is mine.

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

Abstract

Management of chronic pain, such as nerve-injury-induced neuropathic pain associated with diabetic neuropathy, viral infection, and cancer, is a real clinical challenge. Major surgeries, such as breast and thoracic surgery, leg amputation, and coronary artery bypass surgery, also lead to chronic pain in 10-50% of individuals after acute postoperative pain, partly due to surgery-induced nerve injury. Current treatments mainly focus on blocking neurotransmission in the pain pathway and have only resulted in limited success. Ironically, chronic opioid exposure might lead to paradoxical pain. Development of effective therapeutic strategies requires a better understanding of cellular mechanisms underlying the pathogenesis of neuropathic pain. Progress in pain research points to an important role of microglial cells in the development of chronic pain. Spinal cord microglia are strongly activated after nerve injury, surgical incision, and chronic opioid exposure. Increasing evidence suggests that, under all these conditions, the activated microglia not only exhibit increased expression of microglial markers CD 11 b and Iba 1, but also display elevated phosphorylation of p38 mitogen-activated protein kinase. Inhibition of spinal cord p38 has been shown to attenuate neuropathic and postoperative pain, as well as morphine-induced antinociceptive tolerance. Activation of p38 in spinal microglia results in increased synthesis and release of the neurotrophin brain-derived neurotrophic factor and the proinflammatory cytokines interleukin-1β, interleukin-6, and tumor necrosis factor-α. These microglia-released mediators can powerfully modulate spinal cord synaptic transmission, leading to increased excitability of dorsal horn neurons, that is, central sensitization, partly via suppressing inhibitory synaptic transmission. Here, we review studies that support the pronociceptive role of microglia in conditions of neuropathic and postoperative pain and opioid tolerance. We conclude that targeting microglial signaling might lead to more effective treatments for devastating chronic pain after diabetic neuropathy, viral infection, cancer, and major surgeries, partly via improving the analgesic efficacy of opioids.

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Ketamine depresses toll-like receptor 3 signaling in spinal microglia in a rat model of neuropathic pain.

Abstract

Reports suggest that microglia play a key role in spinal nerve ligation (SNL)-induced neuropathic pain, and toll-like receptor 3 (TLR3) has a substantial role in the activation of spinal microglia and the development of tactile allodynia after nerve injury. In addition, ketamine application could suppress microglial activation in vitro, and ketamine could inhibit proinflammatory gene expression possibly by suppressing TLR-mediated signal transduction. Therefore, the present study was designed to disclose whether intrathecal ketamine could suppress SNL-induced spinal microglial activation and exert some antiallodynic effects on neuropathic pain by suppressing TLR3 activation. Behavioral results showed that intrathecal ketamine attenuated SNL-induced mechanical allodynia, as well as spinal microglial activation, in a dose-dependent manner. Furthermore, Western blot analysis displayed that ketamine application downregulated SNL-induced phosphorylated-p38 (p-p38) expression, which was specifically expressed in spinal microglia but not in astrocytes or neurons. Besides, ketamine could reverse TLR3 agonist (polyinosine-polycytidylic acid)-induced mechanical allodynia and spinal microglia activation. It was concluded that intrathecal ketamine depresses TLR3-induced spinal microglial p-p38 mitogen-activated protein kinase pathway activation after SNL, probably contributing to the antiallodynic effect of ketamine on SNL-induced neuropathic pain.

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Microglial Ca(2+)-activated K(+) channels are possible molecular targets for the analgesic effects of S-ketamine on neuropathic pain.

Abstract

Ketamine is an important analgesia clinically used for both acute and chronic pain. The acute analgesic effects of ketamine are generally believed to be mediated by the inhibition of NMDA receptors in nociceptive neurons. However, the inhibition of neuronal NMDA receptors cannot fully account for its potent analgesic effects on chronic pain because there is a significant discrepancy between their potencies. The possible effect of ketamine on spinal microglia was first examined because hyperactivation of spinal microglia after nerve injury contributes to neuropathic pain. Optically pure S-ketamine preferentially suppressed the nerve injury-induced development of tactile allodynia and hyperactivation of spinal microglia. S-Ketamine also preferentially inhibited hyperactivation of cultured microglia after treatment with lipopolysaccharide, ATP, or lysophosphatidic acid. We next focused our attention on the Ca(2+)-activated K(+) (K(Ca)) currents in microglia, which are known to induce their hyperactivation and migration. S-Ketamine suppressed both nerve injury-induced large-conductance K(Ca) (BK) currents and 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one (NS1619)-induced BK currents in spinal microglia. Furthermore, the intrathecal administration of charybdotoxin, a K(Ca) channel blocker, significantly inhibited the nerve injury-induced tactile allodynia, the expression of P2X(4) receptors, and the synthesis of brain-derived neurotrophic factor in spinal microglia. In contrast, NS1619-induced tactile allodynia was completely inhibited by S-ketamine. These observations strongly suggest that S-ketamine preferentially suppresses the nerve injury-induced hyperactivation and migration of spinal microglia through the blockade of BK channels. Therefore, the preferential inhibition of microglial BK channels in addition to neuronal NMDA receptors may account for the preferential and potent analgesic effects of S-ketamine on neuropathic pain.

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The material on this site is for informational purposes only,

The material on this site is for informational purposes only,

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


For My Home Page, click here: 

Welcome to my Weblog on Pain Management!

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CRPS Two Years, Pain Free on Low Dose Naltrexone


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Girl with CRPS cold type two years, pain free on naltrexone 3 mg

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KR, 17 year old seen 11/4/11, with Complex Regional Pain Syndrome [CRPS] involving left lower limb from foot to hip, onset 3/09. She has nonspecific immune system abnormalities and many food sensitivities that caused leaky gut syndrome and 30 lb weight loss with certain foods causing the stomach to be rock hard and vomit. Elimination diet allowed her to regain 30 lbs.

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CRPS diagnosed February 2011, two years after first symptoms. The leg was cold, purple, mottled with allodynia. Pain had been 9 on scale of 10 for weeks prior to my visit when she was started on prednisone 60 mg x 1 week, 40 mg 1 week, and a few days on 20 mg, dropping her average pain to 4/10. Pain at my visit 11/4/11, ranged from 4 to 9, average 5, that was 40% better after prednisone. She takes a wheelchair to school and for distance, is able to walk short distances with cane, and without cane she concentrates walking slowly to avoid limp. She is very bright, highly motivated and described the limb as cold, aching, throbbing, shooting, stabbing, sharp, tender, burning, exhausting, tiring, miserable, unbearable. Pain severely interfered with walking, work, sleep, enjoyment of life, general activity, and relations with others. At rare times, the limb would jump. Numbness was present posteriorly off and on, especially when sitting, not present when standing.

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She had good health until mononucleosis at age 13 in October 2007. A few weeks later irritable bowel syndrome began (IBS-C), then CRPS began after injury March 2009, reinjury July 2009, then no problems until February 2011. The initial injury occurred when roughhousing with a friend, and her foot pulled her toes in a dorsiflexed position. The next day it was swollen and purple with bruising pain after the first injury. She was in a boot for several weeks. CRPS improved, she went to Peru climbing Machu Pichu when she was reinjured again. The foot was swollen, burning with allodynia. She was taken to a hospital in Chile where they wrapped the foot, advised to take Advil. Once home, she went to physical therapy. It resolved in 6 weeks.

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February 2011, fulfilling PE for high school, she tried out for swim team. Day two, she had pain from kicking in the water and was never able to get back into the water. She was in crutches the next 2.5 months and began physical therapy three times weekly since then. Pain began in the sole of the foot, but a slip and fall in the rain caused pain to spread to the hip. A flare in the past month caused pain much more in the left knee after prolonged sitting for tests. She now takes her wheelchair to school which she began to use early October 2011. She was in the chair consistently two weeks, now only as needed, and never uses it at home. She has used a cane since later April when she got off her crutches. In hot weather, the cold left lower limb sweats profusely. No hair changes. On prednisone, toes nails grow faster. She has used warm and cold compresses to relieve pain. She failed gabapentin when it caused her to be nonfunctional on 900 mg/day with no relief. Lyrica caused hives. Nortriptyline caused personality change, becoming very mean, an Atilla the Hun, opposite her usual good nature. Cymbalta 20 mg – severe dry throat, thick mucous, medications lodged in esophagus. Tried Tramadol 25 mg TID and Naproxen 500 bid.

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Incidentally, she saw a neurologist at Children’s Hospital in 2009 due to sudden onset of diplopia that was found due to allergy to contacts, and resolved with new contacts. She saw an allergist in 2010, and tested positive for nonspecific autoimmune disorder: ANA 1:160 speckled, positive for food sensitivities, and after four months of stopping certain foods, ANA was negative: gluten, dairy, garlic, broccoli, lima beans, banana, asparagus, pineapple, oyster, mushroom. While eating those foods she had IBS-C, stomach would harden, causing vomiting, and she lost 30 lbs, was 120 before —- it is part of the leaky gut syndrome that prevented her to absorb certain nutrients. She has regained weight and all symptoms resolved. She does not have dry mouth or dry eyes. She is sensitive to normal doses of medications like her grandmother.

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Exam: Toes are cold on the left. At the moment, no changes in hair, skin color, temperature, sweating. Stretch reflexes symmetrical, brisk in both lower limbs. She uses a cane but is able to walk slowly without limp, carefully, holding both arms stiffly at her side as she concentrates on walking. Sensory examination was not detailed due to patient discomfort and long trip from home that was very tiring.

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Treatment: Prednisone was rapidly tapered off. Begin 1 mg low dose naltrexone [LDN]. Begin N-acetyl cysteine [NAC] 600 mg x 3/day for “cold” CRPS – it is reported to take 3 or 4 months to help.

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Reponse: Mom wrote a few days later, “On the way home from our visit in La Jolla, K started to experience sensation in her leg. You had asked her at the appointment if she had numbness and she could feel some in the back of her leg. She didn’t realize the extent of it. The Naltrexone [1 mg] seems to be awakening areas of her leg. She has felt more muscle pain as well. She feels this may be because she is able to use more muscles in her leg with the increased feeling. She also had her foot stepped on the next day (Saturday). In the past, she would have been incapacitated with the pain for a couple weeks. With the Naltrexone, she felt very little pain at all. We were both very excited to see these changes. 🙂 She is at about a level 3 to 4 in pain.”

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Encouraged mom to continue increasing LDN as tolerated.

11/16/11, ” K is pain free at 3 mg of Naltrexone. We are not sure of any side effects at that level as she has a cold/flu and has had nausea and headaches. She does not have any sleep issues so far. K thought the Delsym was making her lightheaded. She will start it again as soon as she is feeling better.…

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Needless to say, it makes me very happy to know I am able to help someone in pain, especially a child.

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11/21/11: “We are thrilled too! The only things she is taking is the NAC and the naltrexone. When she tried 2mgs the pain receded to just the upper back of the leg. She also noticed the minor cut she had that day burned a lot. At 3mg all pain just vanished. I can’t tell you how excited we are. Her muscles are a bit sore in the leg as she is exerting herself more in physical therapy…. I am interested to see K’s next autoimmune text results in 6 months. I am wondering whether her Autoimmune test results will be negative from taking the naltrexone.”

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1/15/12, “K has been using the LDN at 4 mg and it is working better for her….Once K has recovered from the mononucleosis and is back on her feet again she will know for sure whether her leg pain is gone when standing in one position. If not, she will try the dose at 5 mg and let you know how that goes.”

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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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For My Home Page, click here:  
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Gliopathic Pain — when Neuropathic Pain Treatment Fails


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Coming soon, though these stand on their own:

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

Abstract

Microglia play a crucial role in the maintenance of neuronal homeostasis in the central nervous system, and microglia production of immune factors is believed to play an important role in nociceptive transmission. There is increasing evidence that uncontrolled activation of microglial cells under neuropathic pain conditions induces the release of proinflammatory cytokines (interleukin – IL-1beta, IL-6, tumor necrosis factor – TNF-alpha), complement components (C1q, C3, C4, C5, C5a) and other substances that facilitate pain transmission. Additionally, microglia activation can lead to altered activity of opioid systems and neuropathic pain is characterized by resistance to morphine. Pharmacological attenuation of glial activation represents a novel approach for controlling neuropathic pain. It has been found that propentofylline, pentoxifylline, fluorocitrate and minocycline decrease microglial activation and inhibit proinflammatory cytokines, thereby suppressing the development of neuropathic pain. The results of many studies support the idea that modulation of glial and neuroimmune activation may be a potential therapeutic mechanism for enhancement of morphine analgesia. Researchers and pharmacological companies have embarked on a new approach to the control of microglial activity, which is to search for substances that activate anti-inflammatory cytokines like IL-10. IL-10 is very interesting since it reduces allodynia and hyperalgesia by suppressing the production and activity of TNF-alpha, IL-1beta and IL-6. Some glial inhibitors, which are safe and clinically well tolerated, are potential useful agents for treatment of neuropathic pain and for the prevention of tolerance to morphine analgesia. Targeting glial activation is a clinically promising method for treatment of neuropathic pain.

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

Source

Department of Anesthesiology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA.

Abstract

Management of chronic pain, such as nerve-injury-induced neuropathic pain associated with diabetic neuropathy, viral infection, and cancer, is a real clinical challenge. Major surgeries, such as breast and thoracic surgery, leg amputation, and coronary artery bypass surgery, also lead to chronic pain in 10-50% of individuals after acute postoperative pain, partly due to surgery-induced nerve injury. Current treatments mainly focus on blocking neurotransmission in the pain pathway and have only resulted in limited success. Ironically, chronic opioid exposure might lead to paradoxical pain. Development of effective therapeutic strategies requires a better understanding of cellular mechanisms underlying the pathogenesis of neuropathic pain. Progress in pain research points to an important role of microglial cells in the development of chronic pain. Spinal cord microglia are strongly activated after nerve injury, surgical incision, and chronic opioid exposure. Increasing evidence suggests that, under all these conditions, the activated microglia not only exhibit increased expression of microglial markers CD 11 b and Iba 1, but also display elevated phosphorylation of p38 mitogen-activated protein kinase. Inhibition of spinal cord p38 has been shown to attenuate neuropathic and postoperative pain, as well as morphine-induced antinociceptive tolerance. Activation of p38 in spinal microglia results in increased synthesis and release of the neurotrophin brain-derived neurotrophic factor and the proinflammatory cytokines interleukin-1β, interleukin-6, and tumor necrosis factor-α. These microglia-released mediators can powerfully modulate spinal cord synaptic transmission, leading to increased excitability of dorsal horn neurons, that is, central sensitization, partly via suppressing inhibitory synaptic transmission. Here, we review studies that support the pronociceptive role of microglia in conditions of neuropathic and postoperative pain and opioid tolerance. We conclude that targeting microglial signaling might lead to more effective treatments for devastating chronic pain after diabetic neuropathy, viral infection, cancer, and major surgeries, partly via improving the analgesic efficacy of opioids.

 

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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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For My Home Page, click here:  
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Painkiller Efficacy in 2010 Less Than in 2000


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This research shows efficacy of analgesics decreasing since 2000.

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

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

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

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

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

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

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 A disease-based classification: fact or fiction?

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

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

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Conclusion

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

© 2010 International Association for the Study of Pain

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

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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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For My Home Page, click here: 

Welcome to my Weblog on Pain Management!

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Spine Fusions: No Better Than Cognitive Behavioral Therapy & Exercise


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Spine Fusions: no better than Cognitive Behavioral Therapy and Exercise

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This reportfrom the Academy of Neurology may help guide you in decision making: 

Deaths, Complications, Higher Costs Accompany Increase in Complex Spine Fusions Among Elderly.

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“Fusion is usually performed for degenerative disc disease for chronic low back pain, but a number of studies have shown that their outcomes are no better than a combination of graded exercise and cognitive behavioral therapy.”

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Tragically, dementia can result from extensive spine surgery. Many factors can contribute to that. If I were having spine surgery, I would look at the data of dementia following open heart surgery and the protective benefits of ketamine given prior to surgery. Ketamine can spare neuronal function. It is neuroprotective. I link to a publication on that in this post. The problem may be that so few physicians are willing to provide ketamine as they may lack information on its use, yet it is one of the safest medications we have, nontoxic and neuroprotective.

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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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For My Home Page, click here: 

Welcome to my Weblog on Pain Management!

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Case Reports – Fibromyalgia, Spinal Stenosis, Disc Disease, CRPS, Transverse Myelitis, Central Pain


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Glial research key to intractable pain?

These are not ordinary cases.

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These patients have failed every known treatment for years under the care of well known specialists.

They show a remarkable and lasting response to these simple medications.

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The response is important because these medications are 

(1) available, low dose, nontoxic medications largely ignored by the medical community for pain,

(2) glial modulators, and

 (3) more glial research is urgently needed for millions with intractable pain.

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May 2011: The World Health Organization says undertreated pain is America’s #1 public health problem

Department of Health and Human Services says that patients with chronic pain

outnumber patients with heart disease, diabetes and cancer combined

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Fibromyalgia Disabling, Responds to LDN & Dextromethorphan

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AP, 75 years old with scoliosis, restless legs syndrome, anxiety, seen 8/6/04: Onset of fibromyalgia in 2000 after losing half her investment portfolio. It began with acute onset of severe arthralgias, myalgias, fatigue without fever, that prevented her from returning to her business as an art dealer for corporations, private collections. It disappeared without a trace suddenly in 2 months. She was nearly bedridden, just able to sit in a chair, diagnosed as fibromyalgia by a rheumatologist.

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Two years ago, pain, fatigue and “brain fog” returned in 2002, now disabled with intense muscle ache across upper and lower back, circumferentially in thighs/legs, everywhere except head, trunk, feet, fingers – stable since acute onset, markedly interferes with activity, mood, thinking, walking, sleeping, doing her checking account and driving. Pain ranges 2 to 10, average 4 to 5. Burning pain is recent, across upper thoracic and arms, avoids simple activity to avoid flare.  She rated moderate depression due to pain and inability to be active and live a social life. She has been unable to resume walking, a favorite activity. Exam: very anxious, muscle tenderness 18 points, including buttocks, calves, iliotibial bands, right cervical-thoracic paraspinal more than left. Spine tender at almost every level, maximal at L4-5. Sciatic notches tender. Both legs severely discolored brown from chronic venous insufficiency. Gait very slow, wide based later found due to cerebellar atrophy (MRI).

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Oxycontin was started and changed to fentanyl 50 mcg/hr every 72 hours. Fentanyl was then decreased to 25 mcg/hr after adding Fentora 100 mcg twice daily, Lyrica 50 mg at bedtime, with mirtazepine 15 mg and temazepam 15 mg for sleep. She continued to have marked difficulty walking, concentrating, thinking, and was unable to drive or do her checking account. Constant issues with constipation required multiple preparations for stool softener, laxatives, anti-emetics; hypertension was difficult to control, and she had high anxiety and stress.

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Fibromyalgia was then helped somewhat by pramipexole 0.5 mg twice daily, amitriptyline 20 to 50 mg/day, Lidoderm 5% patches 3 per day, clonidine 0.1 mg twice daily, that allowed fentanyl patch to be discontinued and lowered her opioid requirement down to Fentora 100 mcg bid, still with some constipation but less.

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11/3/08, started low dose naltrexone [LDN] 1 mg – slept only 3 hours that night. On 4 mg, no sleep at all, 1 mg somewhat better, 2 nights after that back to usual sleep but Pain levels low 0 to 3 limited to low back ache.  Before LDN,  pain ranged from 3 to 8, average 5. She had no withdrawal from opioids.  BM’s were excellent for at least 3 days.  Sinemet 25/100 replaced Fentora for restless legs syndrome.

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However, LDN was discontinued a few weeks later as she had so much energy she was hypomanic. Months later she again developed some pain.

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4/8/09 started Delsym 2 teaspoons every 12 hours. Pain dropped to zero. She never needed opioid again, had no withdrawal. A dose of Delsym is the same as long acting dextromethorphan [DM] 60 mg capsules, but 60 mg was too strong for her —- she became hypomanic again. DM allowed her to become pain free. She stopped DM 10 days, feeling so great she forgot to take it until low back pain returned initially mild, then severe. “I started getting back pain, I thought it was just back pain. I have scoliosis, then it became very severe, then realized am I getting fibromyalgia again.”

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After resuming DM, it took only 3 days for pain to come down from 10 to 3-4, then less and less to 1-2 on scale of 10. She was back on DM 4 days. Today, after being off DM and getting return of pain, she is now still using a Lidoderm 5% patch daily to the low back and occasional Aspercreme to groin qhs. Did not need to use these when pain was zero.

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She is 80 years old feeling better than she felt when she was 50!  “My biggest problem is slowing down. I’m 80. I enjoy doing what I’m doing. I like being alive. I’m a little hyper so I stopped drinking coffee.  Hyper because so excited about life, and catching up to what I could have done.” She is now able to clean and organize things she put off for years while in pain. She began designing bathrooms and kitchens for more than one location and waking up after 6 hours of sleep to begin work all day. Her husband describes her as having the energy of ten people. He needs to interrupt her to stop work and have lunch.

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“It changed my outlook, I’m so much happier. I am in heaven. I am back to my mental age of 50. I feel alive with energy, vibrance, lust for life. I drive clearly, I have a brain, my reaction to the wheel, to moving and turning and seeing things is better.”

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10-19-09, with mild recurrence of pain, she was advised to continue DM 60 mg  AM and PM, add naltrexone 4.5 mg PM, continue both for 1 or 2 weeks and discontinue if no more pain.

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7-26-10, experimented with timing and dosage, 4.5 mg LDN best at 5 or 7 AM, 2 to 4 PM, and bedtime.  DM 60 mg twice daily. Voltaren gel qd < 1/2 tsp total in AM only at times variously at hips, back, medial arms, groin, thighs, behind knees where pain occurs when it occurs. Rates pain 0 to 2, avg 0. Has pain if waits too long to take LDN too long.

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“I feel wonderful. I don’t feel high. Normal, comfortable at ease, mentally clear – more than in years, memory is better – even helped dyslexia. Now I’m able to skim reading.” She reads faster, is able to multitask ten things at once and get them all done. Husband says, ”She has boundless energy.” Biggest problem is instability gait, wobbles. Fear of falling. Fell backwards in bedroom one month ago,a  trip and fall onto her back, bruised posterior thoracic and right arm. Had home PT. She works out in gym, treadmill daily. Exam: 2/3 of proximal legs and both feet now normal skin color. Gait slowed. Wide based. MS and mood – excellent. Drowsy [never sits still at home].

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Fall 2010, husband reports her gait markedly improved, faster, more stable after dental prothesis. She is walking faster. She is now 82 and full of energy. Visits initially were monthly for several years while on opioid analgesics, now seen 2 or 3 times a year for minor adjustments and off opioids since 2008.

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Of course all specialists have stories of unusual responses,

but these are responses to the combination of medications that I use, that are not used by other MD’s.

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Transverse Myelitis Responding to Low Dose Naltrexone

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There is currently no known treatment for Transverse Myelitis. It is very rare, if ever possible, to be able to reverse lesions of the brain and spinal cord seen on MRI, especially if chronic. This man is responding to this tiny dose of naltrexone, 1/6th or 1/8th of the smallest tablet.

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FB, 47 year old male triathlete seen 11/1/10. He was in excellent health until 11/09. He began to have interscapular pain worse on the left, days later a band around the waist approximately T8-T10 described as “muscular” discomfort, later with numbness in the same area, followed by weakness, spasticity of the left lower limb and atrophy. Intermittent Lhermitte’s, now resolved. Hypersensitivity to sensation of his shirt across his chest and shoulders lasted 4 to 6 weeks with initial onset. Initially misdiagnosed as Multiple Sclerosis. MRI and spinal fluid led to diagnosis of transverse myelitis.

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On 3/11/10, MRI cervical and thoracic cord [probably the second MRI of two sets of MRI’s] showed extensive parenchymatous lesions extending at least 10 segments from T1-T10 with extra-axial fluid collection that appears as an extensive arachnoid cyst over multiple levels. No obvious cord compression. CSF Mixed lymphocytes with reactive pleocytosis, WBC 2/cu mm, 97% lymphs, 3% monos.

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Diagnoses  11/1/10:  Transverse myelitis with foot drop, spastic monoparesis, atrophy of the left lower extremity, neurogenic bladder, constipation, band around the lower thoracic “waist” onset 11/09, self-treated by injections of B12 with declofenac.   He also had gluten intolerance – eating gluten flares above symptoms

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1/27/11, return visit: “I feel l ike I’ve come light years away” compared to one year ago.

Low dose naltrexone [LDN]  prescribed November 2010, took for few months. Felt immediate effects, improved in strength at left lower extremity, foot drop still present but no longer catches toes on curbs or steps.

He increased dose to 7 or 8 mg, began to feel slightly weird, mild insomnia, like head felt a little weird. Stopped LDN a couple months.

Resumed LDN April 2011,  and again began to feel positive effects; used it daily since then, probably 6 to 7 mg/day.

Resolved: burning pain both feet had radiated up the calves when seen 11/10 ––> discontinued gabapentin one year ago, about 1/10.

Resolved: banding around the waist.

Improved strength 30%  in left lower extremity, still unable to push off with the left foot, but no pain.

Improved: Occasionally used to get a trembling in the left leg evenings 7 or 8 pm, shaking every 20 secs for an hour, at times preventing sleep – resolved about 4 months ago, occurs now perhaps 1 or 2 days a month.

Improved bladder urgency, must find toilet 3 minutes before he voids, now limited to the first 3 hours of the morning.  Before, he could not be far from restroom. Rectal sphincter feels weak.

~

In December 2011, he felt symptoms were plateauing, slowly getting better. Went on vacation in January, ran out of LDN for 11 days and is today 30% weaker. That was the longest time he has been off LDN in the last 9 months. The left leg feels a little like spaghetti. When on LDN, he felt stronger when lifting the leg.

~

Sleep: When began LDN, had 3 or 4 months of vivid dreaming, but urinated during sleep 2 or 3 times a month while have the vivid dream that he was voiding. That resolved.

Still has weird sensations: right foot a little burning sensation, not pain, of the whole foot, lasting 1 or 2 hours, quite tolerable, nothing like it was before when pain radiated to the calves of both legs.

His medications:  LDN, vitamin D3, alpha lipoic acid, Fish oil 2 or 3/day,

Every couple weeks he gets an injection of B12 and diclofenac 2 vials to buttock and feels definite benefit – I warned not to use diclofenac due to high risk of heart attack, cardiac arrhythmias with this NSAID.

~

~

Spinal Stenosis Pain Responds to Nasal Ketamine

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ML, 81 year old diabetic woman with heart surgery 9 months ago, reports that she was able to walk 26 miles a day in Snow Canyon Utah 10 years ago, but barely able to walk room to room the last year due to lumbar pain and weakness from spinal stenosis. Function failed to benefit from tramadol 100 mg x 3/day and she disliked the side effects. Gabapentin failed to help, but when she tried to stop, she had severe nausea and she lost so much weight in four days that her endocrinologist advised her to resume it.

~

Nasal ketamine was started with excellent results allowing her to walk again. Unfortunately, on her own, she abruptly and almost immediately stopped tramadol which resulted in severe opioid withdrawal: severe vomiting, dry heaves and watery diarrhea for 48 hours. She was admitted via ER with chest pressure and muscle strain of abdominal muscles from vomiting. EKG and chemistry ruled out heart attack. Low potassium was corrected and she returned home the next day delighted with pain control.

~

A few days after hospital discharge she reports: “Feeling good, actually exercising in the pool every day, 30 minutes without stopping.” Weather here has been sunny 80 degrees this January. “I never built back my stamina after the heart surgery because of the pain.  I think I am finally on the right  track and it feels good!!” Her son is coming over to walk around the block with her tomorrow.

~

~

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 Complex Regional Pain Syndrome 70% Better in 6 Weeks after Opioid Detox,

Responding to Low Dose Naltrexone, Ketamine, Lamotrigine, Memantine

~

AD, 23 year old male athlete with Complex Regional Pain Syndrome [CRPS] caused him to be bedridden 4.5 years on opioids. Pain was so severe he was unable to eat and lost 30 pounds of muscle. He was slowly able to bear weight and walk 5 or 6 steps with an underarm crutch, but used a wheelchair when not in bed. Fatigue was severe and unbearable just to be out of bed a few minutes. Pain involved all limbs, but focused at the cold right lower extremity, particularly the knee where he had maximal pain. He is tall and weighed 110 pounds when first seen July 2011.

~

I advise patients that opioids create pain.  I am guided by a colleague who detoxed thousands of persons in pain over a 20 year period and never once found the patient had more pain after detox. Confirming this, Baron and McDonald published Significant pain reduction in chronic pain patients after detoxification from high-dose opioids in 2006. Some of the science  is discussed here.

~in 2006

This young man decided the night of his first visit to stop opioids and was admitted for symptom control with opioid withdrawal. He was started on low dose naltrexone [LDN], N-acetyl cysteine, dextromethorphan, slow titration of lamotrigine and memantine slow titration, and oral ketamine. Six weeks later he returned and rated himself 70% better, no longer in a wheelchair, not needing a crutch, but still with significant fatigue that caused him to need to lie down during the day. However, he was able to return to his MBA program by September and is doing well in college.

~

~

  CRPS pain 70% Better in 6 weeks on Low Dose Naltrexone [LDN], Patient with ALS

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FG,  a 71 year old woman with Complex Regional Pain Syndrome [CRPS] and severe burning pain in the legs that markedly interfered with sleep, was seen in fall 2011 for pain in the legs that began two years ago after thoracic fusion October 2009, with cage and titanium rods T4-T9. Disc at T5-6 was compressing the spinal cord and there was an asymptomatic T4-T5 compression fracture 4 to 5 years ago. After thoracic fusion she was able to use a walker for a time, but had weakness progressing to paraplegia and had been in a wheelchair for 6 months. ALS was diagnosed at two university medical centers. Her feet were deep purple, swollen twice their size. and now back to normal size after 7 low power laser treatments. She was now having a frequent ache in both deltoids for a few months from needing to use her arms to push up from the wheelchair. Recently she had severe weight loss with shortness of breath, and during sleep used CPAP for obstructive sleep apnea. Polymyalgia rheumatic from year 2000 was in remission – she’d been on prednisone 5 years until 2005. Breathing was shallow, FVC 1.72 is 54% of predicted.

~

She had a spinal cord stimulator at T10-11.

Medications tried and failed: Cymbalta 30 mg maximum dose, Neurontin 400 mg BID maximum dose, Lyrica dose unknown. Fentanyl patches no effect.

Methadone 25 mg/day for 1.5 years, is the only medication that helps, estimated 80% relief, nevertheless described pain as severe. She used it 5 of 7 days. With ALS causing progressive respiratory difficulty consistent with neuromuscular disease, it was deemed dangerous to continue an opioid. 

~

Low dose naltrexone 4.5 mg to be started after all methadone is out of her system. She was started on N-acetyl cysteine 600 mg capsules x 3/day – the standard of care in Netherlands since 1995 for cold CRPS. Lamictal 25 mg, to begin 1 daily for 2 weeks and slowly titrate to 300 mg per day.

~

On return 6 seeks later, she was delighted to report 70% relief of pain. She plans to return if pain progresses.

~

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Complex Lumbar Disc Disease Markedly Better with Low Dose Naltrexone 

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CL, first seen age 57, December 2004, for pain right buttock radiating to right leg due to degenerative disc disease with lumbar radiculitis. She injured the right knee four weeks prior after giveaway weakness of the right leg. After the recent lumbar laminectomy in June 2003, she had done well only during the months of October, November, December before she herniated the lumbar disc at L3-4 and declined further surgery. The flare occurred after sitting in a chair for 4 hours taking a class. Symptoms were similar to those she had prior to extensive lumbar surgery but she declined repeat surgery. On Exam, she had positive straight leg raising at 45 degrees bilaterally and diminished reflex right knee, but motor, sensory exam was otherwise intact.

  ~

She had received epidurals perhaps 6 per year from 1999 until December 2004, posing a risk for osteoporosis, and she had symptoms of probable ulcer disease from a steroid dose pack. She had extreme pain during the epidural, but got fairly good relief for only one to two months. Pain in the leg now is 50% less from the recent epidural but will it last?

~

Past Surgery: Cervical laminectomy and fusion C5-C7 with anterior plate, lumbar hemi-laminotomies L3 to S1 on the right and discectomy right L3-L4 in June 2003. MRI done after surgery 4/30/04: 1.  Large right paracentral recurrent disc herniation filling right lateral recess at L3-4. 2.  Asymmetrical right foraminal & extraforaminal disc protrusion at L4-5.  3. L5-S1, mild right foraminal stenosis due to facet hypertrophy & asymmetrical disc bulging on the right.

~

She was started with a Fentanyl patch then changed to Oxycontin but continued difficulty walking, standing, lifting. Flying to Boston to see her son would result in being bedridden for the week in Boston and after returning home. However, a few days prior to another trip to Boston, Namenda 5 mg profoundly helped back pain. She was no longer bedridden but was able to travel up and down the East coast and fly home with markedly improved function. Stretching, doing yoga. Walked briskly on beach with son for quite some time.

~

On  8/31/09 , surgery for hyperparathyroidism removed two parathyroid glands on left side, biopsied on right.  Back pain “killing me” on left lumbar side postop, hospital 1-1/2” mattress caused flare. She was not back on Namenda 5 mg as it was too painful to swallow and expensive on her budget.

~

Low dose naltrexone [LDN] was started 12/12/08, after stopping the Fentanyl patch 2 days previously. On January 2009, she reported: “My pain level dropped to about 2-3 at that time and was down to 1 by Dec. 15th. With the patch still in by bloodstream for those few days my pain level never really spiked.  There was a very even transition from the patch to the LDN. What I do know is that my pain level has remained at about a 1-2 for the past month, even with an increased stress level and much time spent on my feet. [She has had lifelong insomnia.] It hasn’t changed my sleep pattern at all.  I still take the Temazepam several times to help me sleep a little bit better. I’m very happy that the LDN has given me so much relief from the pain I’ve dealt with for over 5 years.”

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1/29/12, she emails, “Although my lower back pain is pretty well controlled, my right knee pain prohibits me from doing many things that I would like to do. However, I had a significant event last night.

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I awoke at 3AM with terrible stabbing pain going from my right knee to my right foot. I was in too much pain to deal with the Ketamine spray on a Q-tip, so I just used 3 sprays in each nostril, pinched my nostrils together, and tilted my head back slightly. The pain was completely gone in 30 seconds and I was able to go back to sleep immediately. 

.

I used the 50mg/ml dose since I haven’t picked up the stronger spray yet. It was amazing! I’ve continued to use the nasal Ketamine today and it has helped considerably, though not as dramatically as it did at 3AM.

[P.T.] told me there’s nothing more he can do for me.  He said he’d be happy to help me with my re-hab after my knee replacement.  So now I guess I will just have to hope that [my rheumatologist] will be able to offer me some pain relief with hyaluronic acid injections until I can convince myself that a replacement is the only solution.

So the LDN and the Ketamine spray are my constant companions for now.

~~

~

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 Right Upper Quadrant & Ribs After Laparoscopic Gall Bladder Surgery Better with LDN

~`

CR, 40 year old engineer with scoliosis who had been a triathlete. She first saw me on 6/6/05 for persistent, intense, right upper quadrant abdominal and rib pain that began immediately after laparoscopic gall bladder surgery on 11/17/04, associated with severe fatigue. Pain in the abdominal area was so acute after surgery that she couldn’t swim for four months. Pain impaired breathing and ability to stand erect. She became a long distance swimmer as she now could not do a flip in a pool, run, bike or take part in other sports. Severe pain was triggered even by slight jogging, jarring, vibrations forcing her to buy another car. Positions that relieved right rib pain, made scoliosis worse. Prednisone last year caused loss of memory for  > 1 month of work projects.

~

Spasm along the right lower rib was so severe she once fell out of bed. A cardiologist and neurologist advised removing the lower ribs.

~

Pain was constant mild to moderate at right lower ribs with muscle spasm at the right epigastric area,  intermittently severe stabbing, tender, penetrating, burning.  She describes the pain as a scorpioin tailed dragon that stabs with its scorpion tail and blows fire breath inside the ribs. Pain ranged from 1 to 7, average 4 to 5, and severely interferes with function including ability to concentrate, general activity, enjoyment of life, sleep, work, relations with others and moderately interferes with walking and mood. Each of the 2 times she started P.T., she heard a “pop” when the ribs were released; spreading the ribs relieves pain/spasm.  She tried acupuncture, yoga, Feldenkrais.

 ~

Exam: hyperalgesia over the tender T8 dermatome at the lower right ribs shading off toward T10; easily palpable tender trigger point at right epigastric area that radiates to the right anterior lateral iliac crest suggesting visceral ligamentous problems. Physical therapist noted a stiff band in the right upper quadrant but there are no ligaments in this area of the anatomy. She had temporary relief with adjustments, poor response with opioids and failed gabapentin. Intercostal blocks T8-T10 or T11 and right upper quadrant field blocks using Marcaine gave transient 50% relief. MRI and CT scans failed to disclose any etiology.

By 11/17/05, P.T. had freed several structures about the rib cage, but was not able to loosen the lower ribs that no longer flare out as the left side. P.T. has helped far more than nerve blocks (duration of nerve block effect 2 to 4 weeks if cortisone used, or 5 to 14 days if a field block after miserable numbness 48 hours). Pain is focal at the MCL inferior to the lower right rib, deep under the incisional scar triggered by crunches  (as with use of dishwasher, etc).  She is now able to swim butterfly, but not flip turns – flip turns are a crunch flexion. Right levator scapulae trigger point is flared with the same crunches and “feels related.”  She continues Feldenkrais but avoids flexion,no longer has difficulty breathing and since P.T. has been able to get the inspiration spirometer to the top. Inflammatory pain along the costochondral margins anterior and posterioly from T2 to T12 and below the right lower ribs fairly resolved with the topical ointment ketoprofen 20%, lidocaine 10%. She tried Bengay at the levitator scapulae but stopped Daypro due to burning mid sternum, uses aspirin with yogurt.

~

New spine x-rays were reviewed at Boston Children’s Hospital compared with her most recent 10 year old spine MRI: The ribs are splinted upward where they should be down.  Scoliosis then measured 31 degrees at T1-6, and 28 degrees at T6-11 with the superior iliac crest 1 cm down.

~

February 2009, she started low dose naltrexone [LDN] 1 mg:  For years, pain was 8 to 9, like I had swallowed a fire burning. After LDN it was gone in one hour, zero for 18 hours later returned but much lower 1.5 on scale of 10. Premenstrual pain also was there lower abdominal, prior 3 to 4, down to 1 while taking LDN. A morning swim in ocean usually takes a couple hours of swimming to warm up to get that endorphin high, since LDN now occurs in 20 min. Begins with complete feeling of ease and well being because you’re swimming in cold water, everything is cold and you’re tired, suddenly you’re not tired, its easy, nothing is terrrible anymore, all the frustration melts away. There are no long life threatening events, everything seems easier, you’re happier, and you love everyone. Everyone you see a that moment is beautiful and you love them.  The world is a little slower.  You always feel like you could swim [or run] forever, whereas before that point you feel you can go maybe 5 more minutes.

~
Since mid morning a little hyper – sometimes I am if I have lots of sugar or caffeine [had none], talking faster, less patient slightly –  entire family has ADD or ADHD. 
Slept really well  —- usually has light sleep, poor quality.
I got my desk cleared off for the first time in weeks.
Had sinus headache 1-2 weeks, the head was still unchanged after LDN.
Had night sweats > 10 years, at 4 am none last night, in fact the opposite.  

~

Sleep improves for some while on LDN. It is a morphinan, i.e. morphine like. “I sleep well on LDN… the neuroma in my foot is not gone but hurts less, one of those items I’ve been ignoring because the rib/abdominal pain kept me from hiking enough to care.  So far that’s what I’ve got, for some reason the best dosing for me seems to be alternating 2mg and 3mg. I don’t know why that is. I still get a good endorphin rush pretty early into exercise, even walking which I can do again.  Last week I accidentally walked 6 miles, longest I’ve walked in years!  Next I want to try hiking once the snow is gone.

~

A stingray stabbed her the top of her foot on 4-28-11. Lifeguards usually call EMT for morphine as the injury causes so much pain that people black out. There was profuse bleeding, estimated one cup of blood, and swelling the size of an egg. The entire foot was covered with blood as were the footsteps on the beach. Pain quickly increased to 7 on scale of 10 but never went above ankle, then pain dropped to a 3 before they were able to put her foot into hot water. She was laughing with the lifeguard while being treated.  Swelling was almost gone 4 days later. It was a little tender to pressure, the puncture was still visible. She did not wear a shoe to avoid pressure over the wound, and to keep the wound clean to avoid bacterial infection. People were asking why she was not walking with crutches – not remotely necessary.

~

She has scoliosis and wore braces for it as a child. “I’ve been using the SalonPas patches on my lower back, they give me a minor skin rash but work great. I suspect a combination of topicals and stretches will be the key.  For meds we’d have to be in the office with my records (allergic to tylenol and bad reactions to naproxen/Aleve though I may try it again some day).  Its more a question of what to do about the underlying cause -the spine- and avoiding the pain. I know having the pain isn’t good long term but its minor enough that I really didn’t feel it all this time because my front hurt more.  Peeling the onion!  While I was having a lot of rib pain I would get pulled forward and my lower back would go “out.” P.T. could help that by loosening the front and working the back.  Now it seems more complex to address.  I used to do lots of sit-ups and crunches to stabilize it but P.T. says no to those and my core is pretty stable.  I have been able to do yoga again (another LDN success) and I thought that helped in the past.  I’ll have to continue with that and see if it helps things in the long run….  I have to seek out the spine experts now that I can move more.  My ski turns are uneven, always have been becuase I turn easier to the left than the right (so I’ll turn one cheek more readily than the other).”

>

Vibrations from dolphins ease the pain for days. She has experienced more encounters with dolphins and whales since the surgery. One day when she was aware of squid in the water, she noticed what she thought was the world’s biggest squid swimming 10 feet below her, except that it was a gray whale, which soon surfaced and blew water. Her reasoning for why marine life are attracted to her: scar tissue built up around her surgical scar, which she says makes a squeaking sound in the water. “It might be similar to how they perceive pain and illness.They might be coming together to try to help.”

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Further information will be posted on these cases, and more cases will be added as time permits.
They will include persons who had years of intractable chronic pain that severely limited function, who are now pain free
on low dose naltrexone [LDN] and/or other medications.  Some with intractable chronic pain have now been pain free off LDN and all pain medications for three years.
~
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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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For My Home Page, click here: 

Welcome to my Weblog on Pain Management!

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Ketamine Intranasal for Rapid Relief of Pain and Depression


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

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Ketamine is an important analgesic, more important than opioids. It can dramatically reduce pain, and rapidly relieve depression and PTSD.  Please read my earlier posts here and here. And the NPR report here just after I posted this (skip to their last section). Yes, it is FDA approved and legal. One woman said:

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 ‘It was almost immediate, the sense of calmness and relaxation.

‘No more fogginess. No more heaviness. I feel like I’m a clean slate right now. I want to go home and see friends or, you know, go to the grocery store and cook the family dinner.’

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NPR again reports ketamine’s rapid relief of depression. A 28 year old man whose refractory depression began at age 15, after ketamine, says:

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‘I Wanted To Live Life’

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Stephens himself has vivid memories of the day he got ketamine. It was a Monday morning and he woke up feeling really bad, he says. His mood was still dark when doctors put in an IV and delivered the drug.”Monday afternoon I felt like a completely different person,” he says. “I woke up Tuesday morning and I said, ‘Wow, there’s stuff I want to do today.’ And I woke up Wednesday morning and Thursday morning and I actually wanted to do things. I wanted to live life.”.
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Since then, they treated him with Riluzole that is FDA approved for ALS and has one of the dirtiest side effect profiles I have ever seen in medicine with serious organ toxicity. Ketamine rarely causes mild transient side effects, usually none. It appears the concern is how ketamine is used on the street with potential for abuse. I do not see ketamine abuse in my patients, some of whom are on opioids for pain or Valium family medicines from their psychiatrist. All of those have a greater potential for abuse, also not occurring in my patients. Pain and/or depression can lead to suicide.
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About 18 months ago, researchers at Yale found a possible explanation for ketamine’s effectiveness. It seems to affect the glutamate system in a way that causes brain cells to form new connections.
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Researchers have long suspected that stress and depression weaken some connections among brain cells. Ketamine appears to reverse the process.

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It would be of interest to see a case report of the bladder problems they mention. Is this in a single drug addict who used many unknown medications on the street? Several physicians have infused IV ketamine for persons with pain for many years, in far higher doses than I prescribe, with no report of any but transient minor symptoms.

.

David Barsook’s 2009 review, reference below, describes changes that cause memory loss and brain atrophy with chronic pain, in particular, Complex Regional Pain Syndrome (CRPS), and they also occur with chronic depression:

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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.

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Brain atrophy and memory loss has also been shown in chronic low back pain as well as in chronic depression.

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Barriers to management of chronic pain are many:

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Although opioids are effective for acute pain, effective treatment of chronic pain is often daunting, particularly neuropathic pain.

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Opioids have been shown to create pain causing imbalance in the glial cytokines that favor pain rather than relief of pain. Opioids carry the risk of opioid-induced hyperalgesia which is a severe pain sensitivity. They affect the brain and endocrine system. Opioids may fail to offer significant relief, fail to improve function, and risk misuse, abuse, diversion and death. Their costs are astronomic, insurance coverage is increasingly limited, the potential for complications may be life threatening in a hectic medical setting, side effects can be lethal, lack of physician training in use of opioids and alternatives to pain control lead to increasing deaths, addiction and diversion. It has become a national emergency and a trillion dollar war on drugs.

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Complications can be greatly reduced through use of a scrupulous history and physical examination, but reimbursement is directly proportional to the shortest time spent with a patient. Will that help assessment and care?

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Individuals may have dramatically different responses to opioid therapy; some may not tolerate any, and relief must be balanced with side effects that increase as the dose increases. Patient status may change and require IV, rectal or tube delivery instead of oral formulas; drug-drug interactions may require rapid changes, and disease of kidney, liver or brain may require modifications or stopping altogether. They may increase risk of falls and cause central sleep apnea with drop in oxygen because the brain fails to give a signal to breathe.

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Chronic pain can lead to loss of sleep, hopelessness, depression, anger and other mood disorders such as panic, anxiety, hypochondriasis and post traumatic stress disorder [PTSD]. Treatment of mood disorders are shown to profoundly reduce pain perception and/or ability to cope with pain.

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Ketamine is anti-inflammatory and can reduce the need for opioid use, thus reducing the pain and side effects caused by opioids.

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Nasal ketamine is more effective than oral ketamine for pain relief; oral dosing has no effect on depression.

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Nasal delivery of ketamine is now possible due to advances in metered nasal sprayers that deliver a precise dose. No needle is required, no IV access, no travel to a specialist needed.

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You can carry pain relief with you and use it as directed when it is needed.

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Ketamine is an NMDA antagonist: it antagonizes the NMDA receptor which plays a profound role in pain systems and centralization of pain.

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Ketamine is neuroprotective and it can help other disease states as noted by Barsook, 2009:

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Besides improvement in pain, “there may be lessons from other diseases that affect the brain; it is noteworthy that acute ketamine doses seem to reverse depression and ketamine decreased prevalence of post-traumatic stress disorder (PTSD) in soldiers receiving ketamine during their surgery for treatment of their burns. In addition ketamine attenuates post-operative cognitive dysfunction following cardiac surgery that has been known to produce significant changes in cognition. [emphasis mine] The data suggest that the drug can alter or prevent other conditions based on its NMDAR activity where other drugs NMDA receptor antagonists are perhaps not as effective in these or pain conditions. Lastly, NMDA antagonists have been used in degenerative disease (and pain may be considered a degenerative disease as defined by loss of gray matter volume, see above) with mixed effects perhaps relating to how they act on specific NMDA subtypes. Taken together, ketamine may act not only on sensory systems affecting pain intensity, but also on a constellation of brain regions that are involved in the pain phentype. [sic, phenotype]”

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Side Effects

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Ketamine is more frequently used in babies and children than in adults because high doses of ketamine can induce hallucinations in the adult. Importantly, it is used in high dose in adults for treatment of Complex Regional Pain Syndrome.

Low doses, cause little or no side effects in adults. If present, they are transient and often resolve in 20 minutes. Patient who respond to ketamine report good acceptance as they find the relief of pain and/or depression far outweighs any short term minimal discomfort.

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Pain care reform is urgently needed.

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Research funding for pain is less than half of one percent of the NIH budget. More research is needed, but research on low dose ketamine for treatment of pain and depression has gone on for twenty years.

The public health crisis of untreated pain, which often results in disability, parallels the country’s struggle to halt the cost of health care. The longer a person remains with untreated pain, the less likely they are to return to work or to be employable.

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Conclusion

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Pain control requires urgent attention. It is past time to put into practice the use of this valuable medication so people can get on with life instead of being mired in chronic pain that for many risks suicide and ensures continuing decades of disability. Academic studies are usually limited by defining a predetermined dose rather than clinically titrating to effect. Thus no surprise, they find no effect as every patient will have no response until they reach their dose. And that dose, in my experience, falls into a bell shaped curve. One size does not fit all. Some respond at very low dose, others require much more, and the majority fall between.

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In my experience prescribing ketamine for ten years, only a rare person has problems. Almost all find it has returned function or significantly relieved pain. Some have been able to entirely eliminate opioids that did nothing for their pain for decades, though they dutifully returned to the MD every month to chronicle that pain. Pain continued to be rated ten on a scale of ten; patient always compliant despite side effects of constipation and often depression. My patients find the benefits of nasal ketamine far outweigh the relief of oral ketamine and at much lower doses with fewer side effects.

~

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

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References

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http://www.wjgnet.com/1007-9327/10/1028.asp  Ketamine suppresses intestinal NF-kappa B activation and proinflammatory cytokine in endotoxic rats.

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CONCLUSION: Ketamine can suppress endotoxin-induced production of proinflammatory cytokines such as TNF-a and IL-6 production in the intestine. This suppressive effect may act through inhibiting NF-kappa B.

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

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Ketamine is a parenteral anesthetic agent that provides analgesic activity at sub-anesthetic doses. It is an N-methyl-D-aspartate (NMDA) receptor antagonist with opioid receptor activity. Controlled studies and case reports on ketamine demonstrate efficacy in neuropathic and nociceptive pain. Because ketamine is a phencyclidine analogue, it has some of the psychological adverse effects found with that hallucinogen, especially in adults. Therefore, ketamine is not routinely used as an anesthetic in adult patients. It is a frequently used veterinary anesthetic, and is used more frequently in children than in adults. The psychotomimetic effects have prompted the DEA to classify ketamine as a Schedule III Controlled Substance. A review of the literature documents the analgesic use of ketamine by anesthesiologists and pain specialists in patients who have been refractory to standard analgesic medication regimens. Most reports demonstrate no or mild psychotomimetic effects when ketamine is dosed at sub-anesthetic doses. Patients who respond to ketamine tend to demonstrate dramatic pain relief that obviates the desire to stop treatment due to psychotomimetic effects (including hallucinations and extracorporeal experiences). Ketamine is approved by the FDA for intravenous and intramuscular administration. Use of this drug by the oral, intranasal, transdermal, rectal, and subcutaneous routes has been reported with analgesic efficacy in treating nociceptive and neuropathic pain.
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http://www.ncbi.nlm.nih.gov/pubmed/15109503  Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomized, double-blind, placebo-controlled, crossover study  Daniel Carr, et al, 2004
Crossover, 20 patients. Ketamine reduced breakthrough pain within 10min of dosing, lasting up to 60min
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http://www.ncbi.nlm.nih.gov/pubmed/15288418  Safety and efficacy of intranasal ketamine in a mixed population with chronic pain
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The intranasal route for ketamine administration has been applied only for pain of dressing changes in a single case study (Kulbe, 1998). In this patient, oxycodone and acetaminophen were ineffective to control pain during burn dressing changes in a 96-year-old woman cared for at home. She tolerated the burn dressing changes after three intranasal sprays of 0.1 ml each, in rapid succession, each containing 5 mg ketamine (15 mg total) (Kulbe, 1998).
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http://www.acutepainjournal.com/article/S1366-0071%2807%2900167-2/abstract  Safety and efficacy of intranasal ketamine for acute postoperative pain
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Ketamine delivered intranasally was well tolerated. Statistically significant analgesia, superior to placebo, was observed with the highest dose tested, 50 mg, over a 3 h period. Rapid onset of analgesia was reported (<10 min), and meaningful pain relief was achieved within 15 min of the 50 mg dose. The majority of adverse events were mild/weak and transient. No untoward effects were observed on vital signs, pulse oximetry, and nasal examination. At the doses tested, no significant dissociative effects were evident using the Side Effects Rating Scale for Dissociative Anaesthetics.
The safety profile following treatment with ketamine was comparable to that seen with placebo.
Although patients did report side effects of fatigue, dizziness and feelings of unreality more often following treatment with ketamine than following treatment with placebo, no patient reported hallucinations and the side effects were generally reported to be of mild or moderate severity, and transient. No serious adverse events were reported and the incidences of associated adverse events were comparable for ketamine and placebo. Although study medication was administered intranasally, nasal signs and symptoms were few and inconsequential. A distinctive taste, however, was reported more often following treatment with ketamine than following treatment with placebo.In conclusion this randomized, placebo-controlled, double-blind study, in 20 patients, has demonstrated that intranasal ketamine is safe and effective for BTP [breakthrough pain]. Our findings augment an early but promising literature documenting the effectiveness of nasal administration of a variety of opioids for pain management in adults (Dale et al., 2002) .
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~http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2875542/

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

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

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

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

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

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“Conclusions

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

 

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