Ketamine As An Adjuvant Analgesic - Assignment Example

Ketamine As An Adjuvant Analgesic. Adjuvant analgesics are drugs that have other primary indications, but due to their mode of action and pharmacological properties can act as analgesics in some painful situations in the right dosage regimen (Bell et al, 2006 p.4603). Systemic analgesics were known to be effective in controlling chronic pain for the majority of patients (Doherty et al, 1999 p.1891). However, due to concerns about post operative pain being resistant to most opioid analgesics and the several adverse effects associated with long term use (Weinbroum, 2003 p.789) such as nausea and vomiting, adjuvant treatment with inexpensive opioid sparing drugs such as ketamine as being widely researched for its possibility of better analgesia and lesser adverse effects (Bell et al, 2006 p.4603). Focus of Review. Background. Ketamine (Ketalar), a sundry intravenous anaesthetic with dissociative, analgesic, sedative and amnesic properties, was first synthesized in 1962, patented in 1966 and was approved by the US Food and Drug Administration (FDA) for human and veterinary use in 1970 (Pasero and Margo, 2005 p.60). Ketamine was widely used as anaesthesia because of its several advantages. When used as the sole anaesthetic, it allows the patient to remain awake and responsive. It also rarely causes respiratory depression at sub anaesthetic doses and does not depress cardiovascular function, hepatic blood flow or bowel function. Ketamine is a highly lipid-soluble compound, enabling it to cross the blood-brain barrier rapidly and thus result in extremely fast onset of action, normally within 30second and building up to full effect within a minute, with short duration of 60minutes and a half-life of two-three hours. When administered orally, almost 80% of the drug undergoes hepatic metabolism to the active metabolite called Norketamine, which is excreted in the urine. The only known fact about this metabolite of ketamine is that it has one-third of ketamine's analgesic potency (Pasero and Margo p.60-64). Ketamine exert its anaesthetic effect by binding to receptors in both the peripheral and central nervous systems, including opioid receptors and most essentially, its non-competitive binding to N-methyl D-aspartate (NMDA) receptors (p.62). Thus, the identification of NMDA receptors' role in pain perception brought a new interest in ketamine as a possible adjuvant to multimodal pain treatment (Elia and Martin, 2004 p.61). Evidences. Over the last decade, a vast amount of clinical trials have been published that assessed the utility of the NMDA receptor antagonism of ketamine for postoperative pain management (Elias and Martin p.61). The several clinical studies have been as varied as they were numerous, however, most of the trials have successfully demonstrated the benefits and efficacy of the drug in effectively managing pain. The areas of concern and controversy, though, have being on the safe dosage regimen, as several trials have studied with varying dosages; and the danger of associated adverse effects, especially, the demonstrated psychotomimetic effects of the drug at high dosage (Pasero and Margo pp.60-64; Tucker et al, 2005 p.2253; Elia and Martin, 2004 p.61; Weinbroum, 2003 p.789) For instance, Liou et al (2003), evaluated the pre-treatment of small dose ketamine against normal saline (control) in reducing withdrawal movements induced by rocuronium injection in paediatric patients aged 1-6years. One hundred patients were randomly assigned to one of two groups. The two groups were administered 0.2mg/kg ketamine and normal saline respectively, followed by a 5mg/kg thiopental injection 10s later and intravenous rocuronium (0.8mg/kg) injected over 5sec. Grading the patients response to rocuronium injection based a four point scale, the author reported that the incidence of withdrawal was 83% in the saline group as compared to the 27% observed in the ketamine group. They concluded that pre-treatment with small dose ketamine (0.2mg/kg) provides a single and safe avenue for reducing the incidence of withdrawal movements induced by the recuronium injection, a short acting, non-depolarising, muscle relaxant in paediatric patients (p1294-1297). Several other clinical trials have been published all attesting to the efficiency and usefulness of ketamine in enhancing analgesia, reducing morphine consumption and adverse effects profile. However, most of these trials have been carried out in a wide array of clinical settings and ketamine regimen, making it difficult for both the authors and clinical practitioners to quantify the analgesic effects of ketamine and it harmful side effects. The pronounced interest in this area of study has seen more recent clinical reports been continuously churned out, recently. To enhance clinical decision-making, healthcare professionals, of a necessity, need to have qualitative information about the optimal effective dose, the dose responsiveness and perhaps, the harm associated with ketamine usage. This review attempts to take a look at these areas. Review. For the purpose of this review, ten clinical trials carried out and reported between 2000 and 2006 were critically appraised. The reports were sourced from different electronic journals on the Internet. The search question "Ketamine as an analgesic adjuvant to intravenous morphine for acute post operative pain management, optimising analgesia, reduces morphine consumption and reduces the side effect profile" was employed in searching through PubMed, Medline and other databases for related reports, some of the reports were then retrieved from the respective journals. The reports all conformed to some inclusion criteria set for the review. They were all randomised blinded clinical trials with ketamine co-administered with an opioid analgesic, which is morphine in almost all of the cases reviewed, and compared with a standard placebo control group (placed on normal saline) or in some trials other analgesics, like in one trial ketamine was compared with bupivacaine (Panjabi et al, 2004 p.28-31). The trials have a total sample size of more than 600 patients cutting across several countries. One of the clinical trials was conducted each in the United States, Finland, UK, Austria and Israel, while two each from France and Canada respectively. Of the ten trials, three were paediatric studies, while others were carried out with adult subjects. Except for one of the paediatric studies that had a single 2year old girl suffering cancer pain from metastatic neuroblastoma (Tsui et al, 2004 p.678-80) and another adult trial that reviewed 16patients who had been administered ketamine over a 12month period (Fitzgibbon and Viola, 2005 p.49-57), the trials reviewed had fairly large sample size and across a reasonable age range. One of the trials, carried out in Israel, involved 245 patients recovering from a battery of surgical procedures (Weinbroum, 2003 p.789-795). The exclusion criteria was also similar to all of the trials; patients with a history of chronic pain, surgery performed under regional/local anaesthesia, regular medication with analgesics, morbid obesity and cardiovascular, renal or hepatic diseases. The analysis of subjects varied between the major evaluation procedures. The 10point visual analogue scale (VAS) and a five point verbal rating scale (VRS) were both used frequently in the trials to analyse pain in the subjects, except in one of the trials (Panjabi et al, 2004 p.28) where an "All India Institute of Medicine Discomfort Scale" was employed in analysing patients pain perception. Also, a 7point Sedation Agitation Scale (SAS) was also used in three of the trials to assess the wakefulness and responsiveness of the patients. Generally, the analysis and evaluation in all the trials were related. Except for the study with the single 2year girl and one other study with large sample size (Weinbroum, 2003), the average number of subjects that was administered with ketamine was around 30. One of the trials (Kapfer et al, 2005 p.169) compared Nefopam and ketamine to the control group, another one compared three doses of ketamine with bupivacaine (Panjabi et al, 2004) while Guignard et al (2002 p. 108) supplemented Desflurane-remifentamil with sub anaesthetic dose of ketamine. All other trials - Tsui et al 2004; Fitzgibbon et al, 2005; Lahtinen et al 2004; Dix et al, 2003; Menigaux et al, 2005 and Subramaniam et al, 2004 all compared ketamine with a normal saline control group. For two of the trials, the patients recovering from a wide range of surgical procedures were enrolled. Kapfer et al (2005) studied patients, who underwent elective open abdomen (colectomy by laparatomy), urologic and orthopaedic surgeries carried out under general anaesthesia. Weinbroum also studied patients across several surgical procedures. Two of the trials involved Knee arthroscopy and another one was carried out with patients undergoing cardiac surgery (Lahtinen, 2004). Whilst of the three paediatric studies, one involved children undergoing appendicectomy (Dix et al 2003), the other one involved Inguinal Herniotomy (Panjabi et al 2004) and the third involved a single 2year old girl suffering from chronic cancer pain from metastatic neuroblastoma (Tsui et al, 2004). In a few of the trials, a single bolus of ketamine was administered at the induction of anaesthesia, but in most of the trials, intravenous ketamine administration was delayed to include patients who complained of pain after the initial post operative dose of morphine. In Kapfer et al study, for instance, after patients were alert and complained of pain, postoperative analgesia was provided by tiltrating morphine in 3mg increment every 5minutes until adequate pain relief (defined as a VRS pain score of lesser than 2) was achieved. Patients who had adequate pain relief (VRS 2 on the five point scale. Combined data from the trials show a statistically significant decrease in pain intensity at rest with ketamine compared with control at 10mins, 60mins and 24hours, except for Dix et al who reported no different in the ketamine and control group. No evidence of a relationship between the dose of ketamine and the ensuing analgesic efficacy, since various doses were employed in all the studies and none specified a dose-related analgesic quality of ketamine. However, Lahtinen et al (2004) did stated that in their pilot study, all three participants developed delusions and hallucinations with a 150ug/kg bolus and 2.5ug/kg/min infusion of S(+) Ketamine, so for the main study, the dosage was halved. Dix et al also reported serious psychotomimetric effects in children after 500ug/kg and 4ug/kg/minute infusion. These may give clues as to the harmful concentrations of ketamine, though none is conclusive. Four of the trials reported on morphine consumption with patient controlled analgesia (PCA) pump. In these studies, the average morphine consumption in the control was almost 50mg. All studies reported, also, on a statistically significant decrease in morphine consumption with ketamine and the morphine sparing ranged from 40% in Kapfer et al (2003) to about 50% in Adams et al (2005). The combined decrease morphine consumption was quite impressive, despite the result of Dix et al (2003). In one of the studies, ketamine was added to Desflurane-remifantamil and in another it was combined with bupivacaine, in three other studies, ketamine was only co-administrated with morphine, while in the other two, it was administer alone. In almost all of these, the authors concluded that ketamine decreases postoperative pain intensity. Also, only two of the studies reported on the time interval before the patient first requested an analgesic postoperatively, and in both the average delay was more than 10mins. None of the studies, however, reported on long term follow up on patients. Most of the studies were focused on determining the morphine consumption or analgesia quality within a 24hr period, with 48hours being the longest duration of the studies. Finally, on the adverse effect profiles, most of the studies reported very mild, acceptable or absent adverse effects, with no difference in the frequency of postoperative nausea and vomiting between the control and the study group. However, the two main disturbing reports about ketamine adverse effects were from Dix et al (2003) and Lahtinen (2006). Dix et al reported increased hallucinations, delusions and increased need for rescue analgesic with ketamine infusion in children while Lahtinen et al reported hallucination and delusion suffered by the three participants in the pilot study. Though, somehow, the authors felt that the dosage they administered was on the side and subsequently halved the dosage regimen for the main study. Discussion Knowing that ketamine effect some analgesic effect in post-surgical patients begs the question as to whether it should be used more frequently as an adjuvant to multimodal perioperative analgesia. When administered intravenously during or after anaesthesia, ketamine decreases postoperative pain intensity for up to 48hours, decreases cumulative morphine consumption in 24hours, and delays the time to first request of rescue analgesic. When assessing the clinical relevance of these potentially beneficial effects, several issues come to mind. For instance, pain intensity was decreased by about 1-2 on a 10 point pain scale at 6hours, subsequently, this benefit further decreased but the effect was still statistically significant at 48hours. In control groups, pain intensity was about 4 on the 10 scale; thus, patients who received ketamine had a decline in pain intensity of about 25% at 6hours and of about 20% at 24hours compared with those who received a placebo. However, since patients in control groups did not experience very severe pain, the clinical relevance of this improvement becomes questionable. Also, there seem to be no decrease in the incidence of morphine-related adverse effects although morphine consumption was clearly reduced with ketamine. One reason may be that these trials mainly concentrated on efficacy and did not systematically evaluate and report on adverse effects. Another reason may be that the decrease in morphine consumption was not strong enough to impact the incidence of morphine-related adverse effects; this would weaken the clinical relevance of the opioid sparing. Finally, with ketamine, the delay until patients requested the first rescue analgesic was prolonged by about 20min (averagely). This result was statistically significant but of no clinical importance; however, it was consistent with the overall analgesic efficacy of ketamine. In children, there was some evidence for an analgesic effect with intravenous or caudal ketamine. All paediatric trials reviewed, except for one (Dix et al, 2003) concluded that ketamine may be of use. However, the role of ketamine as an adjunct to morphine-PCA, however, remains unclear. Another point that requires in depth consideration when assessing the utility and efficacy of ketamine as a component of perioperative analgesia is adverse effects. The risk of psychomimetic adverse effects such as hallucinations is perhaps the main reason why many clinicians are still unwilling to use ketamine. Though, some analyses show that vigilance and the use of benzodiazepines had a reducing impact on the possibility of hallucinations. Finally, ketamine should be given very carefully to patients who are not anaesthetised; patients should be informed about this potential risk and they should be carefully observed during the procedure. Limitation This critical appraisal has several limitations; most of them are related to methodological weaknesses of the original studies. For example, some of the original trials did not allow to identify patient-related predictive factors for the emergence of hallucinations or to distinguish between the efficacy of different benzodiazepines. Also, it was difficult to establish a dose-response for efficacy or harm, nor quantify the impact of perioperative ketamine on the emergence of chronic pain. One of the major problems was the wide variability in clinical settings, ketamine regimens and reported outcomes. Several trials were conducted in several countries. This illustrates worldwide interest in Ketamine. However, most trials were of limited size. There was a large variety in outcome measures, and those outcomes that might be regarded as clinically relevant (i.e. opioid-related adverse effects) were inconsistently reported. Finally, before administering ketamine to patients who are not anaesthetised, a careful evaluation of the expected benefits and risks should be established. References. Adam F, Chauvin M, Du Manoir B, Langlois M, Sessler DI, Fletcher D (2005). Small-Dose Ketamine Infusion Improves Postoperative Analgesia And Rehabilitation After Total Knee Arthroplasty. Anesth Analg. 100(2):475-80. Bell R, Dahl J, Moore R, Kalso E (2006). Perioperative Ketamine For Acute Postoperative Pain. Jan 25;(1):CD004603. Dix, P.S. Martindale and p.a. Stoddart (2003). 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BMC Anesthesiology 5:2 Doi:10.1186/1471-2253-5-2 Weinbroum, Avi A (2003). A Single Small Dose Of Postoperative Ketamine Provides Rapid And Sustained Improvement In Morphine Analgesia In The Presence Of Morphine-Resistant Pain. Anesth Analg 96:789-795. Read More