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Systematic review

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Ketamine added to morphine or hydromorphone patient-controlled analgesia for acute postoperative pain in adults: a systematic review and meta-analysis of randomized trials.

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Journal Canadian journal of anaesthesia = Journal canadien d'anesthesie
Year 2016
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This article is included in 1 Broad synthesis 36 Broad syntheses (1 reference)

This article includes 36 Primary studies 36 Primary studies (36 references)

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PURPOSE: To determine whether ketamine added to morphine or hydromorphone patient-controlled analgesia (PCA) provides clinically relevant reductions in postoperative pain, opioid requirements, and adverse events when compared with morphine or hydromorphone PCA in adults undergoing surgery. SOURCE: We systematically searched six databases up to June 2, 2015 for randomized controlled trials (RCTs) comparing ketamine plus morphine/hydromorphone PCA vs morphine/hydromorphone PCA for postoperative pain in adults. PRINCIPAL FINDINGS: Thirty-six RCTs including 2,502 patients proved eligible, and 22 of these were at low risk of bias. The addition of ketamine to morphine/hydromorphone PCA decreased postoperative pain intensity at six to 72 hr when measured at rest (weighted mean difference [WMD] on a 10-cm visual analogue scale ranged from -0.4 to -1.3 cm) and during mobilization (WMD ranged from -0.4 to -0.5 cm). Adjunctive ketamine also significantly reduced cumulative morphine consumption at 24-72 hr by approximately 5-20 mg. Predefined subgroup analyses and meta-regression did not detect significant differences across subgroups, including a dose-response relationship. There was no significant difference in patient satisfaction scores at 24 and 48 hr. Nevertheless, the addition of ketamine to morphine/hydromorphone PCA significantly reduced postoperative nausea and vomiting (relative risk, 0.71; 95% confidence interval [CI], 0.60 to 0.85; absolute risk reduction, 8.9%; 95% CI, 4.6 to 12.2). Significant effects on other adverse events (e.g., hallucinations, vivid dreams) were not detected, though only a few studies reported on them. CONCLUSIONS: Adding ketamine to morphine/hydromorphone PCA provides a small improvement in postoperative analgesia while reducing opioid requirements. Adjunctive ketamine also reduces postoperative nausea and vomiting without a detected increase in other adverse effects; however, adverse events were probably underreported.

Systematic review

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Intravenous ketamine during spinal and general anaesthesia for caesarean section: Systematic review and meta-analysis

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Journal Acta Anaesthesiologica Scandinavica
Year 2015
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This article is included in 1 Broad synthesis 12 Broad syntheses (1 reference)

This article includes 12 Primary studies 12 Primary studies (12 references)

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Background Intravenous ketamine has been used during general and regional anaesthesia for caesarean section. No systematic review and meta-analysis on the desired effects and adverse effects of ketamine administration during caesarean section have yet been performed. Methods After a systematic literature search a meta-analysis was conducted with the random effects model. Weighted mean difference (WMD) or risk ratio and 95% confidence intervals (CIs) were computed. Results Twelve randomised controlled double-blind trials comprising 953 patients were included: seven studies reported on spinal anaesthesia and five on general anaesthesia. Significant differences in the aforementioned outcome variables were found only in the spinal anaesthesia studies. In the spinal anaesthesia studies the time to the first analgesic request was significantly longer in ketamine-treated women, the WMD was 49.36 min (95% CI 43.31-55.41); visual analogue scale pain scores at rest 2 h after surgery were significantly lower. No differences were observed for maternal nausea, vomiting, pruritus, and psychomimetic effects. Only few data were found for neonatal outcomes. Conclusions We conclude that ketamine enhances post-operative analgesia after caesarean section under spinal anaesthesia. There is a paucity of data for several maternal adverse effects as well as for neonatal well-being. Further studies are needed for general anaesthesia.

Systematic review

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The Use of Intravenous Infusion or Single Dose of Low-Dose Ketamine for Postoperative Analgesia: A Review of the Current Literature.

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Journal Pain medicine (Malden, Mass.)
Year 2015
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This article is included in 1 Broad synthesis 39 Broad syntheses (1 reference)

This article includes 39 Primary studies 39 Primary studies (39 references)

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OBJECTIVE: As an analgesic and N-methyl-D-aspartate receptor antagonist, ketamine has been increasingly used as an adjunct in the management of acute perioperative pain. Although several meta-analyses have examined low-dose intravenous (IV) ketamine, they do not distinguish between different types of infusions. Additionally, the many clinical trials published on ketamine vary by regimen of administration and surgical site. This review seeks to exclusively examine the evidence supporting the use of low-dose IV infusion of ketamine for the management of perioperative pain. METHODS: We searched Medline for any clinical trials or meta-analyses that were conducted on low-dose IV infusion of ketamine between 1966 and November 2013. Using six equations, we were left with 695 references. Of those, five meta-analyses and 39 clinical trials met the criteria to be included our review. These clinical trials represent 2,482 patients, 1,403 of whom received ketamine. We then examined the efficacy of low-dose IV ketamine by regimen and site of surgery using pain scores and opioid consumption as endpoints. Finally, we assessed the safety and long-term impact of low-dose ketamine. RESULTS: Low-dose IV ketamine reduces opioid consumption by 40%. It also lowers pain scores, but these findings are less clear. No major complications have been reported with low-dose IV infusion of ketamine when given up to 48 hours after surgery. While our review lends support to using low-dose IV infusion of ketamine in the management of perioperative pain, its optimal dose and regimen remain to be determined. CONCLUSIONS: Thirty-nine clinical trials assessed a continuous infusion or a bolus of low-dose ketamine for postoperative analgesia using reduction of pain scores or reduction of the opioid consumption as the primary endpoint. The mean reduction of opioid consumption when using low-dose IV infusion ketamine (infusion rate less than 1.2 mg/kg/h) is 40%. Ketamine also reduces pain scores, but the amplitude of the effect is less clear. No major complications have been reported with low-dose IV infusion of ketamine up to 48 hours following surgery.

Systematic review

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Preventive analgesia in hip or knee arthroplasty: a systematic review.

Journal Revista espanola de cirugia ortopedica y traumatologia
Year 2015
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This article includes 36 Primary studies 36 Primary studies (36 references)

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OBJECTIVE: To analyze the efficacy and safety of preventive analgesia in patients undergoing hip or knee arthroplasty due to osteoarthritis. METHODS: A systematic literature review was performed, using a defined a sensitive strategy on Medline, Embase and Cochrane Library up to May 2013. The inclusion criteria were: patients undergoing knee and/or hip arthroplasty, adults with moderate or severe pain (≥4 on a Visual Analog Scale). The intervention, the use (efficacy and safety) of pharmacological treatment (preventive) close to surgery was recorded. Oral, topical and skin patch drugs were included. Systematic reviews, meta-analysis, controlled trials and observational studies were selected. RESULTS: A total of 36 articles, of moderate quality, were selected. The patients included were representative of those undergoing knee and/or hip arthroplasty in Spain. They had a mean age >50 years, higher number of women, and reporting moderate to severe pain (≥4 on a Visual Analog Scale). Possurgical pain was mainly evaluated with a Visual Analog Scale. A wide variation was found as regards the drugs used in the preventive protocols, including acetaminophen, classic NSAID, Cox-2, opioids, corticosteroids, antidepressants, analgesics for neuropathic pain, as well as others, such as magnesium, ketamine, nimodipine or clonidine. In general, all of them decreased post-surgical pain without severe adverse events. CONCLUSIONS: The use or one or more pre-surgical analgesics decreases the use of post-surgical drugs, at least for short term pain.

Systematic review

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Opioid-induced hyperalgesia in patients after surgery: a systematic review and a meta-analysis.

Authors Fletcher D , Martinez V
Journal British journal of anaesthesia
Year 2014
Links Pubmed DOI Google Scholar

This article includes 27 Primary studies 27 Primary studies (27 references)

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BACKGROUND: Opioids can increase sensitivity to noxious stimuli and cause opioid-induced hyperalgesia. We performed a systematic review to evaluate the clinical consequences of intra-operative doses of opioid. METHODS: We identified randomized controlled trials which compared intra-operative opioid to lower doses or placebo in adult patients undergoing surgery from MEDLINE, EMBASE, LILAC, Cochrane, and hand searches of trial registries. We pooled data of postoperative pain intensity, morphine consumption, incidence of opioid-related side-effects, primary and secondary hyperalgesia. For dichotomous outcomes relative risks [95% confidence intervals (CIs)] and for continuous outcomes mean differences (MDs) or standardized mean difference (SMD; 95% CI) were calculated. RESULTS: Twenty-seven studies involving 1494 patients were included in the analysis. Patients treated with high intra-operative doses of opioid reported higher postoperative pain intensity than the reference groups (MD: 9.4 cm; 95% CI: 4.4, 14.5) at 1 h, (MD: 7.1 cm; 95% CI: 2.8, 11.3) at 4 h, and (MD: 3 cm; 95% CI: 0.4, 5.6) at 24 h on a 100 cm visual analogue scale. They also showed higher postoperative morphine use after 24 h (SMD: 0.7; 95% CI: 0.37, 1.02). There was no difference in the incidences of nausea, vomiting, and drowsiness. These results were mainly associated with the use of remifentanil. The impact of other opioids is less clear because of limited data. DISCUSSION: This review suggests that high intra-operative doses of remifentanil are associated with small but significant increases in acute pain after surgery.

Systematic review

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Morphine with adjuvant ketamine versus higher dose of morphine alone for acute pain: a meta-analysis.

Authors Ding X , Jin S , Niu X , Wang T , Zhao X , Ren H , Tong Y , Li Q
Journal International journal of clinical and experimental medicine
Year 2014
Links Pubmed PubMed Central

This article is included in 1 Broad synthesis 7 Broad syntheses (1 reference)

This article includes 7 Primary studies 7 Primary studies (7 references)

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PURPOSE: Ketamine is currently the N-methyl-D-aspartate receptor channel blocker in clinical use. Morphine in pain management is usually limited by adverse effect such as nausea and vomiting. Adjuvant treatment with ketamine may be value in giving better analgesia with fewer adverse effects. The purpose of this meta-analysis was to evaluate the differences when patients received morphine with adjuvant ketamine (MK) compared with higher dose of morphine (MO) for acute pain. METHODS: The PubMed, EMBASE and the Cochrane Library databases were searched (Last search performed on July 1, 2014) by two reviewers independently. Data were extracted independently by the same two individuals who searched the studies. RESULTS: A total of 7 trials involving 492 patients were included in the current analysis. We found pain scores were lower in the MK group compared to the MO group [MD 2.19, 95% CI (1.24, 3.13) P<0.00001]. And more patients in the MO required diclofenac [OR 1.97, 95% CI (1.06, 3.67) P=0.03]. Furthermore, morphine plus ketamine can reduced post-operative nausea and vomiting (PONV) [OR 3.71, 95% CI (2.37, 5.80) P<0.00001]. Importantly, the wakefulness scores for the MK group were consistently and significantly better than those for the MO group [MD -1.53, 95% CI (-2.67, -0.40) P=0.008]. CONCLUSION: The use of ketamine plus 1/4~2/3 the dose of morphine is better than higher dose of morphine alone in reducing pain scores, and rescuing analgesic requirement. It also improved PONV and wakefulness.

Systematic review

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A systematic review of intravenous ketamine for postoperative analgesia.

Journal Canadian journal of anaesthesia = Journal canadien d'anesthésie
Year 2011
Links Pubmed DOI

This article is included in 1 Broad synthesis 70 Broad syntheses (1 reference)

This article includes 70 Primary studies 70 Primary studies (70 references)

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PURPOSE: 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. SOURCE: 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. PRINCIPAL FINDINGS: 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. CONCLUSION: 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.

Systematic review

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Ketamine for perioperative pain management in children: a meta-analysis of published studies.

Journal Paediatric anaesthesia
Year 2011
Links Pubmed DOI

This article is included in 1 Broad synthesis 34 Broad syntheses (1 reference)

This article includes 34 Primary studies 34 Primary studies (34 references)

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INTRODUCTION: Balanced analgesia, using both opioid and nonopioids agents, has become the standard care for postoperative pain management. Ketamine, a compound with analgesic and antihyperalgesic properties, has been shown to decrease postoperative pain and opioid requirements in adults. The goal of the present meta-analysis was to investigate postoperative analgesic properties of ketamine in pediatric patients. MATERIAL AND METHODS: A comprehensive literature search was conducted to identify clinical trials that used ketamine as a perioperative analgesic compound in children and infants. Outcomes measured were postoperative analgesic consumption, pain intensity and duration of sensory block (when ketamine was used by caudal route) during the postoperative care unit (PACU) stay and the early postoperative period (6-24 h after leaving the operative room). The data from each trial were combined to calculate the pooled odds ratios or standard mean differences and their 95% confidence intervals. RESULTS: Thirty-five randomized, blinded controlled studies were retrieved from the literature. Systemic ketamine was effective in decreasing PACU pain intensity and analgesic requirement but failed to influence early (6-24 h) pain intensity and analgesic requirement. Ketamine administered locally during tonsillectomy, decreased PACU and early (6-24 h) pain intensity and PACU analgesic requirements. Used as an adjuvant for caudal analgesia, ketamine increased the duration of sensory block and PACU analgesic requirement without impacting PACU pain intensity. Ketamine failed to exhibit a postoperative opioid-sparing effect. CONCLUSIONS: This meta-analysis found that administration of ketamine was associated with decreased PACU postoperative pain intensity and nonopioid analgesic requirement. However, ketamine failed to exhibit a postoperative opioid-sparing effect.

Systematic review

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Adding ketamine to morphine for intravenous patient-controlled analgesia for acute postoperative pain: a qualitative review of randomized trials.

Authors Carstensen M , Møller AM
Journal British journal of anaesthesia
Year 2010
Links Pubmed DOI

This article is included in 1 Structured summary of systematic reviews 11 Structured summaries of systematic reviews (1 reference) 1 Broad synthesis 11 Broad syntheses (1 reference)

This article includes 11 Primary studies 11 Primary studies (11 references)

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In experimental trials, ketamine has been shown to reduce hyperalgesia, prevent opioid tolerance, and lower morphine consumption. Clinical trials have found contradictory results. We performed a review of randomized, double-blinded clinical trials of ketamine added to opioid in i.v. patient-controlled analgesia (PCA) for postoperative pain in order to clarify this controversy. Our primary aim was to compare the effectiveness and safety of postoperative administered ketamine in addition to opioid for i.v. PCA compared with i.v. PCA with opioid alone. Studies were identified from the Cochrane Library 2003, MEDLINE (1966-2009), and EMBASE (1980-2009) and by hand-searching reference lists from review articles and trials. Eleven studies were identified with a total of 887 patients. Quality and validity assessment was performed on all trials included using the Oxford Quality Scale with an average quality score of 4.5. Pain was assessed using visual analogue scales or verbal rating scales. Six studies showed significant improved postoperative analgesia with the addition of ketamine to opioids. Five studies showed no significant clinical improvement. For thoracic surgery, the addition of ketamine to opioid for i.v. PCA was superior to i.v. PCA opioid alone. The combination allows a significant reduction in pain score, cumulative morphine consumption, and postoperative desaturation. The benefit of adding ketamine to morphine in i.v. PCA for orthopaedic or abdominal surgery remains unclear. Owing to huge heterogeneity of studies and small sample sizes, larger double-blinded randomized studies showing greater degree of homogeneity are required to confirm these findings.

Systematic review

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Ketamine and postoperative pain--a quantitative systematic review of randomised trials.

Authors Elia N , Tramèr MR
Journal Pain
Year 2005
Links Pubmed DOI

This article is included in 1 Structured summary of systematic reviews 53 Structured summaries of systematic reviews (1 reference) 1 Broad synthesis 53 Broad syntheses (1 reference)

This article includes 53 Primary studies 53 Primary studies (53 references)

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Ketamine, an N-methyl-D-aspartate receptor antagonist, is known to be analgesic and to induce psychomimetic effects. Benefits and risks of ketamine for the control of postoperative pain are not well understood. We systematically searched for randomised comparisons of ketamine with inactive controls in surgical patients, reporting on pain outcomes, opioid sparing, and adverse effects. Data were combined using a fixed effect model. Fifty-three trials (2839 patients) from 25 countries reported on a large variety of different ketamine regimens and surgical settings. Sixteen studies tested prophylactic intravenous ketamine (median dose 0.4 mg/kg, range (0.1-1.6)) in 850 adults. Weighted mean difference (WMD) for postoperative pain intensity (0-10 cm visual analogue scale) was -0.89 cm at 6 h, -0.42 at 12 h, -0.35 at 24 h and -0.27 at 48 h. Cumulative morphine consumption at 24 h was significantly decreased with ketamine (WMD -15.7 mg). There was no difference in morphine-related adverse effects. The other 37 trials tested in adults or children, prophylactic or therapeutic ketamine orally, intramuscularly, subcutaneously, intra-articulary, caudally, epidurally, transdermally, peripherally or added to a PCA device; meta-analyses were deemed inappropriate. The highest risk of hallucinations was in awake or sedated patients receiving ketamine without benzodiazepine; compared with controls, the odds ratio (OR) was 2.32 (95%CI, 1.09-4.92), number-needed-to-harm (NNH) 21. In patients undergoing general anaesthesia, the incidence of hallucinations was low and independent of benzodiazepine premedication; OR 1.49 (95%CI 0.18-12.6), NNH 286. Despite many published randomised trials, the role of ketamine, as a component of perioperative analgesia, remains unclear.