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Title: Ketamine for chronic pain: risks and benefits.
Authors: Niesters, M., Martini, C. and Dahan, A.
Journal: Journal of Clinical Pharmacology
Abstract: The anaesthetic ketamine is used to treat various chronic pain syndromes, especially those that have a neuropathic component. Low dose ketamine produces strong analgesia in neuropathic pain states, presumably by inhibition of the N-methyl-D-aspartate receptor although other mechanisms are possibly involved, including enhancement of descending inhibition and anti-inflammatory effects at central sites. Current data on short term infusions indicate that ketamine produces potent analgesia during administration only, while three studies on the effect of prolonged infusion (4–14 days) show long-term analgesic effects up to 3 months following infusion. The side effects of ketamine noted in clinical studies include psychedelic symptoms (hallucinations, memory defects, panic attacks), nausea/vomiting, somnolence, cardiovascular stimulation and, in a minority of patients, hepatoxicity. The recreational use of ketamine is increasing and comes with a variety of additional risks ranging from bladder and renal complications to persistent psychotypical behaviour and memory defects. Blind extrapolation of these risks to clinical patients is difficult because of the variable, high and recurrent exposure to the drug in ketamine abusers and the high frequency of abuse of other illicit substances in this population. In clinical settings, ketamine is well tolerated, especially when benzodiazepines are used to tame the psychotropic side effects. Irrespective, close monitoring of patients receiving ketamine is mandatory, particularly aimed at CNS, haemodynamic, renal and hepatic symptoms as well as abuse. Further research is required to assess whether the benefits outweigh the risks and costs. Until definite proof is obtained ketamine administration should be restricted to patients with therapy-resistant severe neuropathic pain.
Title: Influence of ketamine and morphine on descending pain modulation in chronic pain patients: a randomized placebo-controlled cross-over proof-of-concept study
Authors: M. Niesters, L. Aarts, E. Sarton and A. Dahan
Journal: British Journal of Anesthesia
Abstract: Background Descending inhibition of pain, part of the endogenous pain modulation system, is important for normal pain processing. Dysfunction is associated with various chronic pain states. Here, the effect of ketamine and morphine on descending inhibition is examined using the conditioned pain modulation (CPM) paradigm in chronic neuropathic pain patients.
Methods: CPM responses were obtained in 10 adult neuropathic pain subjects (two men/eight women). All subjects had peripheral neuropathy as defined by abnormal quantitative sensory testing. The effects of S(+)-ketamine (0.57 mg kg–1 h–1 for 1 h) and morphine (0.065 mg kg−1 h−1 for 1 h) were tested in a randomized, placebo-controlled double-blind study. CPM was measured at baseline and 100 min after the start of treatment and was induced by immersion of the leg into a cold-water bath. The test stimulus was a 30 s static thermal stimulus to the skin of the forearm.
Results: Without treatment, no CPM was detectable. Treatment with ketamine, morphine, and placebo produced CPM responses of 40.2 (10.9)%, 28.5 (7.0)%, and 22.1 (12.0)%, respectively (for all treatments, CPM effect P<0.05), with no statistical difference in the magnitude of CPM among treatments. The magnitude of CPM correlated positively with the magnitude and duration of spontaneous pain relief.
Conclusions: The observed treatment effects in chronic pain patients suggest a role for CPM engagement in analgesic efficacy of ketamine, morphine, and placebo treatment.
Title: The Dose-Dependent Effect of S(+)-Ketamine on Cardiac Output in Healthy Volunteers and Complex Regional Pain Syndrome Type 1 Chronic Pain Patients
Authors: Olofsen, Erik MSc; Sigtermans, Marnix MD, PhD; Noppers, Ingeborg MD, PhD; Niesters, Marieke MD, Msc; Mooren, Rene MSc; Bauer, Martin MD; Aarts, Leon MD, PhD; Sarton, Elise MD, PhD; Dahan, Albert MD, PhD
Journal: Anesthesia & Analgesia
Abstract: BACKGROUND: Ketamine is used as an analgesic for treatment of acute and chronic pain. While ketamine has a stimulatory effect on the cardiovascular system, little is known about the concentration–effect relationship. We examined the effect of S(+)-ketamine on cardiac output in healthy volunteers and chronic pain patients using a pharmacokinetic–pharmacodynamic modeling approach.
METHODS: In 10 chronic pain patients (diagnosed with complex regional pain syndrome type 1 [CRPS1] with a mean age 43.2 ± 13 years, disease duration 8.4 years, range 1.1 to 21.7 years) and 12 healthy volunteers (21.3 ± 1.6 years), 7 increasing IV doses of S(+)-ketamine were given over 5 minutes at 20-minute intervals starting with 1.5 mg with 1.5-mg increments. Cardiac output (CO) was calculated from the arterial pressure curve obtained from an arterial catheter in the radial artery. Ketamine and norketamine plasma concentrations were measured. A novel pharmacokinetic–pharmacodynamic model was constructed to quantify the direct stimulatory effect of ketamine on CO and the following adaptation/inhibition.
RESULTS: Significant differences in pharmacokinetic estimates were observed between study groups with 15% and 40% larger S(+)-ketamine S(+)-norketamine concentrations in healthy volunteers compared to CRPS1 patients. S(+)-ketamine had a dose-dependent stimulatory effect on CO in patients and volunteers. After infusion an inhibitory effect on CO was observed. Pharmacodynamic model parameters did not differ between CRPS1 patients and healthy volunteers. The concentration of S(+)-ketamine causing a 1 L/min increase in CO was 243 ± 54 ng/mL with an onset/offset half-life of 1.3 ± 0.21 minutes. The inhibitory component was slow (time constant of 67.2 ± 17.0 minutes).
CONCLUSIONS: S(+)-ketamine pharmacokinetics but not pharmacodynamics differed between study populations, related to differences in disease state (CRPS1 or not) or age. The dose-dependent effect of S(+)-ketamine on CO was well described by the biphasic dynamic model. The effect of S(+)-ketamine on CO was similar between study groups with respect to its stimulatory and inhibitory components, despite group differences in age and health.
Title: Intravenous Infusions in Chronic Pain Management
Authors: Boleslav Kosharskyy, MD, Wilson Almonte, MD, Naum Shaparin, MD, Marco Pappagallo, MD, and Howard Smith, MD
Journal: Pain Physician
Abstract: In the United States, millions of Americans are affected by chronic pain, which adds heavily to national rates of morbidity, mortality, and disability, with an ever-increasing prevalence. According to a 2011 report titled Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research by the Institute of Medicine of the National Academies, pain not only exacts its toll on people’s lives but also on the economy with an estimated annual economic cost of at least $560 – 635 billion in health care costs and the cost of lost productivity attributed to chronic pain. Intravenous infusions of certain pharmacologic agents have been known to provide substantial pain relief in patients with various chronic painful conditions. Some of these infusions are better, and although not necessarily the first therapeutic choice, have been widely used and extensively studied. The others show promise, however are in need of further investigations. This article will focus on non-opiate intravenous infusions that have been utilized for chronic painful disorders such as fibromyalgia, neuropathic pain, phantom limb pain, post-herpetic neuralgia, complex regional pain syndromes (CRPS), diabetic neuropathy, and central pain related to stroke or spinal cord injuries. The management of patients with chronic pain conditions is challenging and continues to evolve as new treatment modalities are explored and tested. The following intravenous infusions used to treat the aforementioned chronic pain conditions will be reviewed: lidocaine, ketamine, phentolamine, dexmedetomidine, and bisphosphonates. This overview is intended to familiarize the practitioner with the variety of infusions for patients with chronic pain. It will not, however, be able to provide guidelines for their use due to the lack of sufficient evidence.
Title: The Use of Ketamine in Neuropathic Pain
Authors: Sarah Lee O’Brien • Sanjog Pangarkar • Joshua Prager
Journal: Curr Phys Med Rehabil Rep
Abstract: Hyperactivity of N-methyl-D-aspartate (NMDA) receptors may be one of the factors in the genesis of neuropathic pain (NP). Ketamine is a dissociative anesthetic and analgesic that is the most potent NMDA receptor antagonist currently available for human use. There is a growing body of literature for three decades suggesting efficacy of subanaesthetic doses of ketamine in the treatment of NP, particularly the pain in complex regional pain syndromes. The primary limitations of ketamine use are secondary to psychotomimetic and, to a lesser extent, sympathetic activation. The purpose of this article is to review the history, pharmacology, pharmacodynamics, clinical benefits, and limitations of ketamine for treatment of NP. Methods of administration and management of adverse effects are highlighted based on the clinical experience of the authors.
Title: Ketamine: a growing global health-care need
Authors: T. T. Dong, J. Mellin-Olsen and A. W. Gelb
Journal: British Journal of Anesthesia
Abstract: Ketamine was first synthesized in 1962, patented in Belgium in 1963, and approved for human use by the US Food and Drug Administration in 1970. Unlike inhalation anaesthetics, ketamine provides analgesia, preserves airway reflexes, offers haemodynamic stability, and maintains respiratory drive, which gives ketamine an excellent safety profile. It is therefore a favoured choice for trauma triage, use in man-made and natural disasters, and for many other patients with compromized haemodynamic stability. However, side-effects, such as agitation, hallucinations, and panic attacks, have limited its clinical use as an anesthetic in affluent countries. Lately, ketamine has found new uses in clinical medicine in addition to renewed threats to its availability.
Title: Interventions for treating pain and disability in adults with complex regional pain syndrome- an overview of systematic reviews
Authors: Neil E O’Connell, Benedict M Wand, James McAuley, Louise Marston, G Lorimer Moseley
Journal: Cochrane Database of Systematic Reviews
Abstract: Complex regional pain syndrome (CRPS) is characterised by persistent pain, usually in the hands or feet, that is not proportionate inseverity to any underlying injury. It often involves a variety of other symptoms such as swelling, discolouration, stiffness, weakness and changes to the skin. This over view sought to summarize and report all of the available evidence arising from systematic reviews for all treatments for this condition regarding how well they work and any potential harm that they might cause. We identiﬁed six Cochrane reviews and 13 non-Cochrane systematic reviews that included evidence relating to a broad range of treatments, from drugs to surgical procedures, rehabilitation and alternative therapies. For most treatments there were only a small number of published trials and the quality of these trials was mixed. As such, most of the evidence for most treatments is of low or very low quality and can not be regarded as reliable.We found low quality evidence that a daily course of the drug ketamine delivered intravenously may effectively reduce pain, although it is also associated with a variety of side effects. We found low quality evidence that the bisphosphonate class of drugs, calcitonin and programmes of graded motor imagery may be effective for CRPS, and that mirror therapy may be effective in people who develop CRPS after suffering a stroke. Low quality evidence suggested that physiotherapy and occupational therapy did not lead to clinically important beneﬁts at one year follow up, and that blocking sympathetic nerves with local anaesthetic is not effective. There is moderate quality evidence that an intravenous regional blockade using the drug guanethidine is not effective and may be associated with complications.For a range of other interventions we found only very low quality evidence or no evidence at all. No conclusions should be drawn regarding the value of these interventions based on this level of evidence.Based on the existing evidence it is difﬁcult to draw ﬁrm conclusions as to which therapies should be offered to patients with CRPS.Better quality research is vital to reduce uncertainty in this area and is necessary before conﬁdent recommendations can be made.
Title: Glutamate Receptor Antagonists as Fast-Acting Therapeutic Alternatives for the Treatment of Depression: Ketamine and Other Compounds
Authors: Mark J. Niciu, Ioline D. Henter, David A. Luckenbaugh, Carlos A. Zarate Jr., and Dennis S. Charney
Journal: Annu Rev Pharmacol Toxicol.
Abstract: The N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has rapid and potent antidepressant effects in treatment-resistant major depressive disorder and bipolar depression. These effects are in direct contrast to the more modest effects seen after weeks of treatment with classic monoaminergic antidepressants. Numerous open-label and case studies similarly validate ketamine’s antidepressant properties. These clinical findings have been reverse-translated into preclinical models in an effort to elucidate ketamine’s antidepressant mechanism of action, and three important targets have been identified: mammalian target of rapamycin (mTOR), eukaryotic elongation factor 2 (eEF2), and glycogen synthase kinase-3 (GSK-3). Current clinical and preclinical research is focused on (a) prolonging/maintaining ketamine’s antidepressant effects, (b) developing more selective NMDA receptor antagonists free of ketamine’s adverse effects, and (c) identifying predictor, mediator/moderator, and treatment response biomarkers of ketamine’s antidepressant effects.
Title: Ketamine-induced affective switch in a patient with treatment-resistant depression
Authors: Girish Banwari, Prutha Desai, and Prahlad Patidar
Journal: Indian Journal of Pharmacology
Abstract: There is growing evidence to support the rapid, albeit short-lived antidepressant effect of subanesthetic dose of ketamine, a noncompetitive glutamate N-methyl-D-aspartate receptor antagonist in treatment-resistant unipolar and bipolar depression. Ketamine is known to cause transient mood elevation or euphoria, psychotomimetic effects, and dissociative symptoms, but its use in unipolar or bipolar depression has not been reported to induce an affective switch amounting to persistent or prolonged hypomania/mania or manic-like syndrome. We report the case of a 52-year-old male with first episode, continuous, nonpsychotic, treatment-resistant, unipolar major depression of 10 years duration, who manifested a switch from depression to mania while being treated with subanesthetic dose of ketamine, given intramuscularly. This case suggests that polarity switch should be considered as a potential side effect while using ketamine for treatment-resistant depression.
Title: Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial
Authors: James W. Murrough, , M.D., Dan V. Iosifescu, , M.D., Lee C. Chang, , M.D., Rayan K. Al Jurdi, , M.D., Charles E. Green, , Ph.D., Andrew M. Perez, , M.D., Syed Iqbal, , M.D., Sarah Pillemer, , B.A., Alexandra Foulkes, , M.S., Asim Shah, , M.D., Dennis S. Charney, , M.D., Sanjay J. Mathew, , M.D.
Journal: American Journal of Psychiatry
Abstract:Intravenous ketamine demonstrated rapid antidepressant effects in an optimized study design, improving depression severity in 64% of treatment-resistant patients 24 hours after a single dose. The double-blind trial provides evidence for the role of the N-methyl-d-aspartate glutamate receptor in depression, a receptor not currently activated by existing antidepressant drugs.
Ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, has shown rapid antidepressant effects, but small study groups and inadequate control conditions in prior studies have precluded a definitive conclusion. The authors evaluated the rapid antidepressant efficacy of ketamine in a large group of patients with treatment-resistant major depression.
This was a two-site, parallel-arm, randomized controlled trial of a single infusion of ketamine compared to an active placebo control condition, the anesthetic midazolam. Patients with treatment-resistant major depression experiencing a major depressive episode were randomly assigned under double-blind conditions to receive a single intravenous infusion of ketamine or midazolam in a 2:1 ratio (N=73). The primary outcome was change in depression severity 24 hours after drug administration, as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS).
The ketamine group had greater improvement in the MADRS score than the midazolam group 24 hours after treatment. After adjustment for baseline scores and site, the MADRS score was lower in the ketamine group than in the midazolam group by 7.95 points (95% confidence interval [CI], 3.20 to 12.71). The likelihood of response at 24 hours was greater with ketamine than with midazolam (odds ratio, 2.18; 95% CI, 1.21 to 4.14), with response rates of 64% and 28%, respectively.
Ketamine demonstrated rapid antidepressant effects in an optimized study design, further supporting NMDA receptor modulation as a novel mechanism for accelerated improvement in severe and chronic forms of depression. More information on response durability and safety is required before implementation in clinical practice.
Title: Intravenous Therapies in the Management of Neuropathic Pain: A Review on the Use of Ketamine and Lidocaine in Chronic Pain Management
Authors: Harsha Shanthanna
Journal: Neuropathic Pain
Abstract: Neuropathic Pain is a term referred to “pain arising as a direct consequence of a lesion affecting the somatosensory system”. As a first line option, oral medications are mostly used, as they are easily available, relatively safe, and do not need much resources. They include antidepressants in the form of tricyclics, newer selective reuptake inhibitors of serotonin and norepinephrine, gabapentin, pregabalin etc. Although neuropathic pain conditions do share some common clinical features, they are quite diverse when considered individually according to their etiology and pathogenesis. Hence not all patients and not all types of neuropathic pain respond to such oral therapy. In practice patients are given a form of such neuropathic pain medication along with or without an opioid, depending upon the extent of pain that the patient suffers. Opioids are potent analgesics but are not a good choice for neuropathic pain conditions. With time the clinician is left with fewer alternatives and furthermore, with the the increasing knowledge that escalation of opioid therapy will perhaps lead to hyperalgesia and tolerance, it becomes necessary to explore other options. Among the other options one can always consider to explore treatment with intravenous medication such as Ketamine, Lidocaine, and Magnesium etc. This chapter would highlight the use of ketamine and lidocaine in the form of drug profile, the pharmacological basis behind its use, strategies to use, important side effects and limitations and available evidence base, including a review of randomised controlled studies. Both are considered separately in two different parts. References for both the parts are given at the end, in separate sections.
Post-Treatment Lyme Syndrome
Title: Post-Treatment Lyme Syndrome and Central Sensitization
Authors: Shweta Batheja, , M.B, B.S., Jenifer A. Nields, , M.D., Alla Landa, , Ph.D., Brian A. Fallon, , M.D., M.P.H.
Journal: Journal of Neuropsychiatry
Abstract: The authors of this clinically important article describe the process whereby chronic Lyme disease and its CNS sequelae can result in various treatment-resistant pain and anxiety disorders that are characterized by hypersensitivity to noxious and non-noxious stimuli. These may include skin reactions, fatigue, muscle weakness, extreme sensitivity to sound or smell, and, also, mood and cognitive symptoms. The article reviews several treatment approaches beyond antibiotics, including antidepressants and anti-epileptic drugs. Central sensitization is a process that links a variety of chronic pain disorders that are characterized by hypersensitivity to noxious stimuli and pain in response to non-noxious stimuli. Among these disorders, treatments that act centrally may have greater efficacy than treatments acting peripherally. Because many individuals with post-treatment Lyme syndrome (PTLS) have a similar symptom cluster, central sensitization may be a process mediating or exacerbating their sensory processing. This article reviews central sensitization, reports new data on sensory hyperarousal in PTLS, explores the potential role of central sensitization in symptom chronicity, and suggests new directions for neurophysiologic and treatment research.
Title: Review of pharmacological therapies in fibromyalgia syndrome
Authors: Winfried Häuser, Brian Walitt, Mary-Ann Fitzcharles and Claudia Sommer
Journal: Arthritis Research & Therapy
Abstract: This review addresses the current status of drug therapy for the management of fibromyalgia syndrome (FMS) and is based on interdisciplinary FMS management guidelines, meta-analyses of drug trial data, and observational studies. In the absence of a single gold-standard medication, patients are treated with a variety of drugs from different categories, often with limited evidence. Drug therapy is not mandatory for the management of FMS. Pregabalin, duloxetine, milnacipran, and amitriptyline are the current first-line prescribed agents but have had a mostly modest effect. With only a minority of patients expected to experience substantial benefit, most will discontinue therapy because of either a lack of efficacy or tolerability problems. Many drug treatments have undergone limited study and have had negative results. It is unlikely that these failed pilot trials will undergo future study. However, medications, though imperfect, will continue to be a component of treatment strategy for these patients. Both the potential for medication therapy to relieve symptoms and the potential to cause harm should be carefully considered in their administration.
Title: Effects of Intravenous Ketamine Infusions in a Neuropathic Pain Patient with Lichen Sclerosus et Atrophicus
Authors: Ashraf F. Hanna, Josh S. Armstrong, Adam J. Smith
Journal: Karger Open Access
Abstract: A patient reported to the Florida Spine Institute (Clearwater, Fla., USA) with severe lichen sclerosus of the anogenital region and legs. The patient’s pain presentation was neuropathic with hypersensitivity, allodynia, swelling, and weakness. The patient had failed multiple pain management modalities including opioid therapy, anticonvulsants, and antidepressants. The patient completed a standard intravenous ketamine infusion regimen developed at the Florida Spine Institute and reported complete abolishment of her pain syndrome. For the first time, we report that ketamine infusions also dramatically improved a patient’s lichen sclerosus. That ketamine is known to have immunomodulatory properties, and given the clinical observations described in this case report,suggests that ketamine should be explored as a possible new therapeutic option for managing lichen sclerosus, especially in cases that are refractory to conventional therapies.