Perioperative intravenous ketamine for acute postoperative pain in adults Stable (no update expected for reasons given in 'What's new')
Inadequate pain management after surgery increases the risk of postoperative complications and may predispose for chronic postsurgical pain. Perioperative ketamine may enhance conventional analgesics in the acute postoperative setting.
To evaluate the efficacy and safety of perioperative intravenous ketamine in adult patients when used for the treatment or prevention of acute pain following general anaesthesia.
We searched CENTRAL, MEDLINE and Embase to July 2018 and three trials registers (metaRegister of controlled trials, ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP)) together with reference checking, citation searching and contact with study authors to identify additional studies.
We sought randomised, double‐blind, controlled trials of adults undergoing surgery under general anaesthesia and being treated with perioperative intravenous ketamine. Studies compared ketamine with placebo, or compared ketamine plus a basic analgesic, such as morphine or non‐steroidal anti‐inflammatory drug (NSAID), with a basic analgesic alone.
Data collection and analysis
Two review authors searched for studies, extracted efficacy and adverse event data, examined issues of study quality and potential bias, and performed analyses. Primary outcomes were opioid consumption and pain intensity at rest and during movement at 24 and 48 hours postoperatively. Secondary outcomes were time to first analgesic request, assessment of postoperative hyperalgesia, central nervous system (CNS) adverse effects, and postoperative nausea and vomiting. We assessed the evidence using GRADE and created a 'Summary of findings' table.
We included 130 studies with 8341 participants. Ketamine was given to 4588 participants and 3753 participants served as controls. Types of surgery included ear, nose or throat surgery, wisdom tooth extraction, thoracotomy, lumbar fusion surgery, microdiscectomy, hip joint replacement surgery, knee joint replacement surgery, anterior cruciate ligament repair, knee arthroscopy, mastectomy, haemorrhoidectomy, abdominal surgery, radical prostatectomy, thyroid surgery, elective caesarean section, and laparoscopic surgery. Racemic ketamine bolus doses were predominantly 0.25 mg to 1 mg, and infusions 2 to 5 µg/kg/minute; 10 studies used only S‐ketamine and one only R‐ketamine. Risk of bias was generally low or uncertain, except for study size; most had fewer than 50 participants per treatment arm, resulting in high heterogeneity, as expected, for most analyses. We did not stratify the main analysis by type of surgery or any other factor, such as dose or timing of ketamine administration, and used a non‐stratified analysis.
Perioperative intravenous ketamine reduced postoperative opioid consumption over 24 hours by 8 mg morphine equivalents (95% CI 6 to 9; 19% from 42 mg consumed by participants given placebo, moderate‐quality evidence; 65 studies, 4004 participants). Over 48 hours, opioid consumption was 13 mg lower (95% CI 10 to 15; 19% from 67 mg with placebo, moderate‐quality evidence; 37 studies, 2449 participants).
Perioperative intravenous ketamine reduced pain at rest at 24 hours by 5/100 mm on a visual analogue scale (95% CI 4 to 7; 19% lower from 26/100 mm with placebo, high‐quality evidence; 82 studies, 5004 participants), and at 48 hours by 5/100 mm (95% CI 3 to 7; 22% lower from 23/100 mm, high‐quality evidence; 49 studies, 2962 participants). Pain during movement was reduced at 24 hours (6/100 mm, 14% lower from 42/100 mm, moderate‐quality evidence; 29 studies, 1806 participants), and 48 hours (6/100 mm, 16% lower from 37 mm, low‐quality evidence; 23 studies, 1353 participants).
Results for primary outcomes were consistent when analysed by pain at rest or on movement, operation type, and timing of administration, or sensitivity to study size and pain intensity. No analysis by dose was possible. There was no difference when nitrous oxide was used. We downgraded the quality of the evidence once if numbers of participants were large but small‐study effects were present, or twice if numbers were small and small‐study effects likely but testing not possible.
Ketamine increased the time for the first postoperative analgesic request by 54 minutes (95% CI 37 to 71 minutes), from a mean of 39 minutes with placebo (moderate‐quality evidence; 31 studies, 1678 participants). Ketamine reduced the area of postoperative hyperalgesia by 7 cm² (95% CI −11.9 to −2.2), compared with placebo (very low‐quality evidence; 7 studies 333 participants). We downgraded the quality of evidence because of small‐study effects or because the number of participants was below 400.
CNS adverse events occurred in 52 studies, while 53 studies reported of absence of CNS adverse events. Overall, 187/3614 (5%) participants receiving ketamine and 122/2924 (4%) receiving control treatment experienced an adverse event (RR 1.2, 95% CI 0.95 to 1.4; high‐quality evidence; 105 studies, 6538 participants). Ketamine reduced postoperative nausea and vomiting from 27% with placebo to 23% with ketamine (RR 0.88, 95% CI 0.81 to 0.96; the number needed to treat to prevent one episode of postoperative nausea and vomiting with perioperative intravenous ketamine administration was 24 (95% CI 16 to 54; high‐quality evidence; 95 studies, 5965 participants).
Perioperative intravenous ketamine probably reduces postoperative analgesic consumption and pain intensity. Results were consistent in different operation types or timing of ketamine administration, with larger and smaller studies, and by higher and lower pain intensity. CNS adverse events were little different with ketamine or control. Perioperative intravenous ketamine probably reduces postoperative nausea and vomiting by a small extent, of arguable clinical relevance.
Elina CV Brinck, Elina Tiippana, Michael Heesen, Rae Frances Bell, Sebastian Straube, R Andrew Moore, Vesa Kontinen
Plain language summary
Ketamine venous injection for acute pain after operation in adults
Ketamine injected into a vein at the time of operation reduces pain, nausea and vomiting, and use of opioid (morphine‐like) painkillers after operation.
Poor pain management after an operation increases the risk of complications, decreases quality of life, and increases the risk for chronic pain. Painkillers such as paracetamol and non‐steroidal anti‐inflammatory drugs (ibuprofen, diclofenac), alone may be insufficient. Opioids (strong painkillers), often cause side effects. Studies suggested that ketamine used by injection during an operation helps to relieve pain after the operation.
In July 2018 we searched for randomised clinical trials where ketamine was injected before, during, or after operation in adults having an operation under general anaesthesia. Important outcomes were opioid use and pain at 24 and 48 hours after the operation, time to first request for a painkiller, and ketamine‐related side effects. We found 130 eligible studies with 8341 participants.
Compared to people given control treatment, those given intravenous ketamine used less opioid painkiller (by about 1 part in 10), and had less pain (by about 2 parts in 10; moderate‐ or high‐quality evidence). Ketamine may be more effective in operations that are likely to cause more intense pain. People given ketamine requested painkillers 54 minutes later than those who did not receive ketamine (moderate‐quality evidence). Ketamine reduced the risk of postoperative nausea and vomiting by a small amount (high‐quality evidence). Ketamine produced no increased risk of central nervous system side effects (hallucination, nightmares or double vision) (high‐quality evidence).
Future research should assess ketamine's effect after operations that are accompanied by intense pain such as thoracotomy, back surgery, or amputations. Additionally, assessing ketamine's effects among particular patient groups, for example, the elderly or individuals with a history of substance abuse would be of interest.
Quality of the evidence
We rated the quality of the evidence from studies using four levels: very low, low, moderate, or high. Very low‐quality evidence means that we are very uncertain about the results. High‐quality evidence means that we are very confident in the results.
We found the quality of evidence for most outcomes to be moderate. Many of the studies were small, which was the main reason for downgrading the evidence from high to moderate. We tested the results by operation type, timing of ketamine injection, and by looking at larger studies, and those with more pain were consistent, and provided confidence in the results. There was sufficient evidence to allow conclusions about ketamine's effect on pain, painkiller consumption and side effects after operation.
Elina CV Brinck, Elina Tiippana, Michael Heesen, Rae Frances Bell, Sebastian Straube, R Andrew Moore, Vesa Kontinen
Implications for practice
For people with acute postoperative pain
Perioperative intravenous ketamine reduces postoperative opioid consumption and pain intensity, especially after thoracic surgery, major orthopaedic surgery and major abdominal surgery. In a non‐stratified study population, perioperative intravenous ketamine administration reduces postoperative pain and opioid consumption to a lesser extent. Traditionally, 30% reduction in pain intensity and opioid consumption has been considered meaningful. However, even a smaller reduction in opioid consumption may be beneficial to those who are vulnerable to opioid‐induced adverse events, for example, elderly people or those susceptible to postoperative nausea and vomiting, as well as individuals with opioid dependency. In a non‐stratified study population, perioperative intravenous ketamine delays time to first request for analgesia. Ketamine may also reduce postoperative hyperalgesia, though more data are needed to support this preliminary result. Perioperative intravenous ketamine does not increase the risk of central nervous system (CNS) adverse events. The risk for postoperative nausea and vomiting is reduced.
Perioperative intravenous ketamine is beneficial for individuals undergoing thoracic, major orthopaedic, or major abdominal surgery. It may be more effective in situations with a higher background level of pain. Ketamine reduces postoperative opioid consumption and the risk for postoperative nausea and vomiting and may therefore be beneficial for individuals who are vulnerable to opioid‐induced adverse events, for example, the elderly, those susceptible to postoperative nausea and vomiting, as well as individuals with opioid tolerance or dependency. Ketamine may also reduce postoperative hyperalgesia, but more data are needed to support this finding.
For policy makers
Perioperative intravenous ketamine should be targeted to those who are likely to benefit from ketamine's analgesic and opioid‐sparing effect.
The amount and quality of evidence around the benefits and harms of perioperative intravenous ketamine is moderate or high. The results are buttressed by several subgroup and sensitivity analyses that support the main findings. These include type of surgery, co‐administration with nitrous oxide or use of benzodiazepine premedicant, timing of use, and level of pain intensity with controls. There is no evidence that perioperative intravenous ketamine increased the risk of CNS adverse events.
Implications for research
This review of intravenous perioperative ketamine revealed no major problems with the evidence available, other than the generally small size of studies. While this pattern has not been uncommon in anaesthetic research, there is growing evidence that small study size is associated with potential major biases. These are such as to raise ethical as well as scientific considerations for future studies of similar size. This might mean reconsideration of how studies are performed in future. Perhaps multicentre, randomised, controlled study design with more than 200 participants per treatment arm, compared to randomised studies with fewer than 50 participants per treatment arm, would increase confidence in any findings.
Many of the studies in this review had low pain intensity with controls. That is good, because low pain intensity is valued by people in pain, including postoperatively (Mhuircheartaigh 2009; Moore 2013). The value of pain intensity reduction is probably more highly regarded by people with moderate or severe pain than with those with moderate or no pain. For future studies, it may be more informative to explore multimodal anaesthesia with intravenous ketamine with one component in situations with higher levels of pain.
Mean opioid consumption has been shown to be highly skewed, and probably meaningless (Moore 2011). Future studies might usefully concentrate on reporting the number of people with high opioid consumption. Relevant endpoints could also include patient‐reported outcome measures for postoperative recovery, for example, patient satisfaction.
Future studies should assess the effect of ketamine's different timing and dosing regimens on postoperative pain, opioid consumption and adverse events. Additionally, subgroups who may benefit from ketamine's analgesic and opioid‐sparing effect warrant more research. These subgroups are, for example, the elderly and other individuals who are sensitive to adverse events that often accompany opioid medication. So far, the data on ketamine's effect on individuals with a history of substance abuse are limited. Additionally, determining whether specific study populations are more susceptible to ketamine‐related adverse events, as well as clarifying ketamine's role in prevention of persistent postsurgical pain among patients with a high risk of chronic pain, would also be of clinical interest. Ketamine's antihyperalgesic effect also warrants more research because so far the data are sparse. Studies examining the effect of ketamine as adjuvant to specific opioids would also be of interest, since recent animal data suggest that ketamine and morphine have beneficial interactions (Lilius 2015).Get full text at The Cochrane Library
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