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      Ketamine for pain

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          Abstract

          The efficacy of the N-methyl-D-aspartate receptor antagonist ketamine as an analgesic agent is still under debate, especially for indications such as chronic pain. To understand the efficacy of ketamine for relief of pain, we performed a literature search for relevant narrative and systematic reviews and meta-analyses. We retrieved 189 unique articles, of which 29 were deemed appropriate for use in this review. Ketamine treatment is most effective for relief of postoperative pain, causing reduced opioid consumption. In contrast, for most other indications (that is, acute pain in the emergency department, prevention of persistent postoperative pain, cancer pain, and chronic non-cancer pain), the efficacy of ketamine is limited. Ketamine’s lack of analgesic effect was associated with an increase in side effects, including schizotypical effects.

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          Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy.

          Teijo Saari, Klaus T Olkkola, Nora Hagelberg … (2016)
          Ketamine is a phencyclidine derivative, which functions primarily as an antagonist of the N-methyl-D-aspartate receptor. It has no affinity for gamma-aminobutyric acid receptors in the central nervous system. Ketamine shows a chiral structure consisting of two optical isomers. It undergoes oxidative metabolism, mainly to norketamine by cytochrome P450 (CYP) 3A and CYP2B6 enzymes. The use of S-ketamine is increasing worldwide, since the S(+)-enantiomer has been postulated to be a four times more potent anesthetic and analgesic than the R(-)-enantiomer and approximately two times more effective than the racemic mixture of ketamine. Because of extensive first-pass metabolism, oral bioavailability is poor and ketamine is vulnerable to pharmacokinetic drug interactions. Sublingual and nasal formulations of ketamine are being developed, and especially nasal administration produces rapid maximum plasma ketamine concentrations with relatively high bioavailability. Ketamine produces hemodynamically stable anesthesia via central sympathetic stimulation without affecting respiratory function. Animal studies have shown that ketamine has neuroprotective properties, and there is no evidence of elevated intracranial pressure after ketamine dosing in humans. Low-dose perioperative ketamine may reduce opioid consumption and chronic postsurgical pain after specific surgical procedures. However, long-term analgesic effects of ketamine in chronic pain patients have not been demonstrated. Besides analgesic properties, ketamine has rapid-acting antidepressant effects, which may be useful in treating therapy-resistant depressive patients. Well-known psychotomimetic and cognitive adverse effects restrict the clinical usefulness of ketamine, even though fewer psychomimetic adverse effects have been reported with S-ketamine in comparison with the racemate. Safety issues in long-term use are yet to be resolved.
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            Intravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization, Placebo-Controlled Study.

            Jaskaran Singh, Maggie Fedgchin, Ella Daly … (2016)
            The purpose of this study was to assess the efficacy and safety and to explore the dose response of esketamine intravenous (IV) infusion in patients with treatment-resistant depression (TRD).
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              A systematic review of intravenous ketamine for postoperative analgesia.

              Kevin Laskowski, Catrina Stirling, Wai H. Lim … (2011)
              Perioperative intravenous ketamine may be a useful addition in pain management regimens. Previous systematic reviews have included all methods of ketamine administration, and heterogeneity between studies has been substantial. This study addresses this issue by narrowing the inclusion criteria, using a random effects model, and performing subgroup analysis to determine the specific types of patients, surgery, and clinical indications which may benefit from perioperative ketamine administration. We included published studies from 1966 to 2010 which were randomized, double-blinded, and placebo-controlled using intravenous ketamine (bolus or infusion) to decrease postoperative pain. Studies using any form of regional anesthesia were excluded. No limitation was placed on the ketamine dose, patient age, or language of publication. Ninety-one comparisons in seventy studies involving 4,701 patients met the inclusion criteria (2,652 in ketamine groups and 2,049 in placebo groups). Forty-seven of these studies were appropriate for evaluation in the core meta-analysis, and the remaining 23 studies were used to corroborate the results. A reduction in total opioid consumption and an increase in the time to first analgesic were observed across all studies (P < 0.001). The greatest efficacy was found for thoracic, upper abdominal, and major orthopedic surgical subgroups. Despite using less opioid, 25 out of 32 treatment groups (78%) experienced less pain than the placebo groups at some point postoperatively when ketamine was efficacious. This finding implies an improved quality of pain control in addition to decreased opioid consumption. Hallucinations and nightmares were more common with ketamine but sedation was not. When ketamine was efficacious for pain, postoperative nausea and vomiting was less frequent in the ketamine group. The dose-dependent role of ketamine analgesia could not be determined. Intravenous ketamine is an effective adjunct for postoperative analgesia. Particular benefit was observed in painful procedures, including upper abdominal, thoracic, and major orthopedic surgeries. The analgesic effect of ketamine was independent of the type of intraoperative opioid administered, timing of ketamine administration, and ketamine dose.
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                Author and article information

                Journal
                Journal ID (nlm-ta): F1000Res
                Journal ID (iso-abbrev): F1000Res
                Journal ID (pmc): F1000Research
                Title: F1000Research
                Publisher: F1000Research (London, UK )
                ISSN (Electronic): 2046-1402
                Publication date (Electronic): 20 September 2017
                Publication date Collection: 2017
                Volume: 6
                Electronic Location Identifier: F1000 Faculty Rev-1711
                Affiliations
                [1 ]Department of Anesthesiology, Anesthesia & Pain Research Unit, Leiden University Medical Center, Leiden, Netherlands
                Author notes

                Competing interests: Research conducted by AD has received support from Eurocept BV, The Netherlands.

                Author information
                https://orcid.org/0000-0003-3161-3945
                Article
                DOI: 10.12688/f1000research.11372.1
                PMC ID: 5609085
                SO-VID: 00dd6a40-54f6-42d4-9399-1a4b67bd2a9c
                Copyright © Copyright: © 2017 Jonkman K et al.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date accepted : 21 September 2017
                Funding
                The author(s) declared that no grants were involved in supporting this work.
                Categories
                Subject: Review
                Subject: Articles
                Subject: Emergency Medicine
                Subject: Neuropharmacology & Psychopharmacology
                Subject: Pain Management: Acute Clinical
                Subject: Perioperative Critical Care
                Subject: Pharmacokinetics & Drug Delivery

                Keywords: ketamine,pain,postoperative pain,analgesia
                Data availability:
                Keywords: ketamine, pain, postoperative pain, analgesia

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