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      The analgesic effect of combined treatment with intranasal S-ketamine and intranasal midazolam compared with morphine patient-controlled analgesia in spinal surgery patients: a pilot study

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          Ketamine is a well-known analgesic and dose-dependent anesthetic used in emergency and disaster medicine. Recently, a new formulation of S-ketamine, as an intranasal spray, was developed and tested in our institution in healthy volunteers. The authors investigated the effect of intranasal S-ketamine spray combined with midazolam intranasal spray in postoperative spinal surgery patients.

          Materials and methods

          In this prospective, computer-randomized, double-blinded noninferiority study in spinal surgery patients, the effects of intranasal S-ketamine and midazolam were compared with standard morphine patient-controlled analgesia (PCA). The primary end point was the numeric rating scale pain score 24 hours after surgery.


          Twenty-two patients finished this study, eleven in each group. There were similar numeric rating scale scores in the morphine PCA and the S-ketamine-PCA groups at 1, 2, 4, 24, 48, and 72 hours after surgery during rest as well as in motion. There were no differences in the satisfaction scores at any time between the groups. The number of bolus demands and deliveries was not significantly different.


          In our study, we found that an S-ketamine intranasal spray combined with intra-nasal midazolam was similar in effectiveness, satisfaction, number of demands/deliveries of S-ketamine and morphine, and number/severity of adverse events compared with standard intravenous PCA with morphine. S-ketamine can be regarded as an effective alternative for a traditional intravenous morphine PCA in the postoperative setting.

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          Most cited references 25

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          A systematic review of intravenous ketamine for postoperative analgesia.

          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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            There are two optical isomers of the 2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone ketamine: S(+) ketamine and R(-) ketamine. Effects of this drug are mediated by N-methyl-d-aspartate (NMDA), opioid, muscarinic and different voltage-gated receptors. Clinically, the anaesthetic potency of the S(+)-isomer is approximately three to four times that of the R(-)-isomer, which is attributable to the higher affinity of the S(+)-isomer to the phencyclidine binding sites on the NMDA receptors. Ketamine is water- and lipid-soluble, allowing it to be administered conveniently via various routes and providing extensive distribution in the body. Ketamine metabolism is mediated by hepatic microsomal enzymes. It causes bronchodilation and stimulation of the sympathetic nervous system and cardiovascular system. In clinics, ketamine and particularly S(+)-ketamine are used for premedication, sedation, and induction and maintenance of general anaesthesia, which is than termed "dissociative anaesthesia". Ketamine and its S(+)-isomer are ideal anaesthetic agents for trauma victims, patients with hypovolemic and septic shock and patients with pulmonary diseases. Even subanaesthetic doses of this drug have analgesic effects, so ketamine is also recommended for post-operative analgesia and sedation. The combination of ketamine with midazolam or propofol can be extremely useful and safe for sedation and pain relief in intensive care patients, especially during sepsis and cardiovascular instability. In the treatment of chronic pain ketamine is effective as a potent analgesic or substitute together with other potent analgesics, whereby it can be added by different methods. There are some important patient side-effects, however, that limit its use, whereby psycho-mimetic side-effects are most common.
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              Perioperative ketamine for acute postoperative pain.

              Postoperative pain management is often limited by adverse effects such as nausea and vomiting. Adjuvant treatment with an inexpensive opioid-sparing drug such as ketamine may be of value in giving better analgesia with fewer adverse effects. To evaluate the effectiveness and tolerability of ketamine administered perioperatively in the treatment of acute postoperative pain in adults. Studies were identified from MEDLINE (1966-2004), EMBASE (1980-2004), the Cochrane Library (2004) and by handsearching reference lists from review articles and trials. The manufacturer of ketamine (Pfizer) provided search results from their in-house database, PARDLARS. Randomised controlled trials (RCTs) of adult patients undergoing surgery, being treated with perioperative ketamine or placebo. Studies where ketamine was administered in addition to a basic analgesic (such as morphine or NSAID) in one study group, and compared with a group receiving the same basic analgesic (but without ketamine) in another group, were also included. Two independent reviewers identified fifty five RCTs for potential inclusion. Quality and validity assessment was performed by two independent reviewers. In the case of discrepancy, a third reviewer was consulted. Patient reported pain intensity and pain relief was assessed using visual analogue scales or verbal rating scales and adverse effects data were collated. Thirty-seven trials were included (2240 participants). Eighteen trials were excluded.Twenty-seven of the 37 trials found that perioperative subanaesthetic doses of ketamine reduced rescue analgesic requirements or pain intensity, or both. Quantitative analysis showed that treatment with ketamine reduced 24 hour PCA morphine consumption and postoperative nausea or vomiting (PONV). Adverse effects were mild or absent. Ketamine in subanaesthetic dose (that is a dose which is below that required to produce anaesthesia) is effective in reducing morphine requirements in the first 24 hours after surgery. Ketamine also reduces postoperative nausea and vomiting. Adverse effects are mild or absent.

                Author and article information

                J Pain Res
                J Pain Res
                Journal of Pain Research
                Journal of Pain Research
                Dove Medical Press
                13 February 2015
                : 8
                : 87-94
                [1 ]Department for Anesthesia, Surgical Intensive Care, Prehospital Emergency Medicine and Pain Therapy, University of Basel, Basel, Switzerland
                [2 ]Clinical Pharmacology, University of Basel, Basel, Switzerland
                [3 ]Hospital Pharmacy, University of Basel, Basel, Switzerland
                [4 ]Clinical Trial Unit, University of Basel, Basel, Switzerland
                [5 ]Orthopedic Department, University Hospital Basel, University of Basel, Basel, Switzerland
                Author notes
                Correspondence: Wilhelm Ruppen, Department for Anesthesia, Surgical Intensive Care, Prehospital Emergency Medicine and Pain Therapy, University Hospital Basel, 21 Spitalstrasse, Basel 4031, Switzerland, Tel +41 61 328 6496, Fax +41 61 265 7320, Email wruppen@ 123456gmail.com

                *These authors contributed equally to this work

                © 2015 Riediger et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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