Living FRIendly Summaries of the Body of Evidence using Epistemonikos (FRISBEE)
Medwave2017;17(Suppl2):e6952 doi: 10.5867/medwave.2017.6952

Is intravenous ketamine effective for postoperative pain management in adults?

Camila Stuardo, Diego Lobos-Urbina, Fernando Altermatt

Abstract

Ketamine is a N-Metil-D-Aspartate receptor antagonist that has been used as adjuvant in the acute postoperative pain management because of its analgesic properties. However, its role is not clearly determined. To answer this question, we searched in Epistemonikos database, which is maintained by screening multiple information sources. We identified 19 systematic reviews including 226 randomized trials overall. We extracted data and generated a summary of findings table using the GRADE approach. We concluded intravenous ketamine probably has little or no effect in reducing postoperative pain.


 
Problem

Postoperative pain management is an important aspect in anesthesiology practice. Opioids are commonly used because of its effectiveness but they have adverse effects, such as nausea, vomiting, sedation and respiratory depression. One alternative strategy is to use adjuvant analgesics that through different pain pathways would reduce the incidence of undesirable effects.

The N-Metil-D-Aspartate receptor is an ionotropic glutamate receptor that has been implicated in pain mechanisms modulation. Ketamine is a non-competitive antagonist of N-Metil-D-Aspartate receptor and it has been used in low doses as adjuvant in postoperative pain management. However, its clinical use is still controversial because of its potential psychomimetic adverse effects such as nausea, vomiting and hallucinations.

Methods

We used Epistemonikos database, which is maintained by screening multiple information sources, to identify systematic reviews and their included primary studies. With this information we generated a structured summary using a pre-established format, which includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), a summary of findings table following the GRADE approach and a table of other considerations for decision-making.

Key messages

  • Intravenous ketamine probably has little or no effect in reducing postoperative pain.
  • Intravenous ketamine probably does not increase postoperative sedation, but it is not clear whether it increases the risk of nausea and vomiting because the certainty of the evidence is very low.
About the body of evidence for this question

What is the evidence.
See evidence matrix  in Epistemonikos later

We found 19 systematic reviews [1-19] including 226
[20-245] randomized trials. One hundred eleven were trials including the use of intravenous ketamine in adult patients, corresponding to the question addressed by this summary [20-130]. 

What types of patients were included*

Thirty trials included patients undergoing abdominal surgery [20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],
[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],
[44],[45],[46],[47],[48],[49], 16 trials patients undergoing pelvic or gynecological surgery [50],[51],[52],[53],[54],[55],
[56],[57],[58],[59],[60],[61],[62],[63],[64] [65], eight trials patients undergoing orthopedic surgery [20],[66] [67],[68],[69],[70],[71],[72], seven trials patients undergoing thoracic surgery [20],[21],[73],[74],[75],[76],[77]  and five trials patients undergoing other types of surgeries [78],[79],[80],[81],[82]. The remaining trials did not report the type of surgery.

What types of interventions were included*

All of the trials used intravenous ketamine.

In 33 trials ketamine was administered in bolus [21],[22],[25],
[26],[27],[32],[33],[35],[38],[39],[41],[44],[50],[51],[52],[53],
[54],[55],[57],[59],[60],[61],[62],[66],[67],[87],[88],[90],[94],
[96],[102],[124], in nine in continuous infusion [49],[58],[74],[76],[81],[85],[93],[100],[119], whereas in 35 trials both types of administration were used [20],[23],[29],[30],[31],[34],[36],
[37],[40],[43],[45],[46],[48],[56],[63],[69],[70],[71],[72],[73],
[75],[78],[79],[80],[82],[84],[86],[89],[91],[107],[112],[116],
[121],[122],[125]. Route of administration was not reported in the remaining 35 trials.

Ketamine was given during the preoperative period in 16 trials [21],[22],[25],[33],[40],[50],[54],[55],[59],[61],[66],[68],
[102],[115],[119],[124], intraoperative in 21 trials [23],[29],
[36],[41],[43],[44],[48],[49],[56],[64],[74],[79],[80],[86],
[87],[90],[94],[97],[98],[107],[121], postoperative in 14 trials [24],[32],[35],[45],[52],[58],[78],[85],[91],[93],[110],[112],
[114],[126], in two trials it was administered both pre and intraoperatively [77],[116], in three trials during preoperative and postoperative phase [38],[67],[89], in 16 trials intraoperatively and then postoperatively [20],[30],[31],[34],
[37],[46],[63],[69],[70],[71],[72],[75],[81],[84],[122],[125], in two trials preoperatively and then intraoperatively and postoperatively [63],[117], and in the rest it was not reported

The doses ranged from 0.05 mg to 2 mg/kg for bolus, and 0.002 to 1 mg/kg/hour for continuous infusion.

Thirty-three trials reported coadministration of opioids [22],
[25],[27],[31],[32],[33],[35],[36],[38],[40],[44],[45],[46],[50],
[54],[56],[58],[59],[63],[66],[67],[68],[71],[78],[79],[80],[82],
[88],[89],[94],[98],[119],[124].

Sixty-two trials compared to placebo [20],[21] [23],[25],[26],
[29],[31],[32],[34],[35],[37],[38],[39],[41] [43],[44],[45],[46],
[48],[49],[50][51],[53],[55],[56],[58],[60],[61],[64],[66],[67],
[68],[69],[70],[71],[72],[73],[74],[75],[76],[78],[79],[80],[81],
[82],[84],[85],[89],[93],[94],[96],[98],[100],[102],[107],[112],
[116],[119],[121],[122],[124],[125], 13 trials compared against other drugs, especially opioids [22],[33],[36],[40],[52],[54],[57],[59],[62],[63],[88],[91],[96] and it was not reported in the rest of the trials.

What types of outcomes
were measured

The trials reported multiple outcomes, however they were grouped but the different systematic reviews as follows: postoperative pain, perioperative consumption of analgesia (opioids and others), time to need of first analgesic, surgical time, anesthesia time, postoperative nausea and vomiting and other adverse effects (such as unpleasant dreams, cognitive and psychological effects, hypotension and chills).

* The information about primary studies is extracted from the systematic reviews identified, unless otherwise specified.

Summary of findings

It was not possible to extract sufficient information from the reviews identified as to rebuild the meta-analysis and the summary of findings table. Therefore, the information presented is based on the separate conclusions of the nine systematic reviews that performed meta-analyses for some of the outcomes of interest [5],[6],[7],[10],[11],[14],[16],[19]; pain at 24 hours after surgery [5],[6],[7],[10],[11],[16], postoperative nausea and vomiting [5],[6],[7],[10],[11],[16],[19] and sedation [9],[10],[14].

  • Intravenous ketamine probably has little or no effect in reducing postoperative pain. The certainty of the evidence is moderate.
  • It is not clear whether intravenous ketamine is associated to postoperative nausea and vomiting, because the certainty of the evidence is very low.
  • Intravenous ketamine probably does not increase postoperative sedation. The certainty of the evidence is moderate.

Other considerations for decision-making

To whom this evidence does and does not apply

  • The evidence presented in this summary are applicable to adults patients undergoing abdominal, traumatological, thoracic, pelvic or gynecological surgeries, with general or neuraxial anesthesia.
About the outcomes included in this summary
  • The outcomes presented are those considered as critical for decision-making by the authors of this summary. They coincide in general with those used by the identified systematic reviews.
Balance between benefits and risks, and certainty of the evidence
  • It is an intervention that probably has no benefit, so it does not correspond to estimate a benefits/risk balance.
What would patients and their doctors think about this intervention
  • In view of the evidence presented in this summary, most clinicians should lean against its use.
Resource considerations
  • It is an intervention that probably has no benefits, so it does not correspond to estimate a balance between benefits and costs.

Differences between this summary and other sources

  • The systematic reviews identified differ in their conclusions. One of the main reasons is they incorporate a low proportion of the trials identified in this summary.
  • The main clinical guidelines also provide discordant recommendations. For example, the Practice Guidelines for Acute Pain Management in the Perioperative Setting [246] of the American Society of Anesthesiologists do not make an explicit statement about the use of ketamine as analgesic adjuvant; the guideline of the Australian and New Zealand College of Anaesthetists [247] recommends intravenous ketamine for pain reduction, postoperative nausea and vomiting reduction, and reduction of time to first analgesia request, especially in patients undergoing thoracic, upper abdominal and orthopedic surgery. It should be noted that this guideline is mainly based on only one systematic review identified in this summary [10].
Could this evidence change in the future?
  • The likelihood that future evidence changes the conclusion of this summary is low, due to the certainty of the evidence.
  • A search in the International Clinical Trial Registry Platform of the World Health Organization did not retrieve ongoing trials addressing this question. In a PubMed search we identified at least three [248],[249],[250] randomized trials that are not included in the identified systematic reviews.
  • Considering the abundance of trials found, the scarce coverage of existing systematic reviews and the methodological limitations of these, it is very likely that a new systematic review with rigorous methods of identification and analysis could bring new insights on this topic.
  • In a search in the Prospective register of systematic reviews (PROSPERO), we did not identify any ongoing review addressing this question.
How we conducted this summary

Using automated and collaborative means, we compiled all the relevant evidence for the question of interest and we present it as a matrix of evidence.

Follow the link to access the interactive version: Ketamine for postoperative pain

Notes

The upper portion of the matrix of evidence will display a warning of “new evidence” if new systematic reviews are published after the publication of this summary. Even though the project considers the periodical update of these summaries, users are invited to comment in Medwave or to contact the authors through email if they find new evidence and the summary should be updated earlier. After creating an account in Epistemonikos, users will be able to save the matrices and to receive automated notifications any time new evidence potentially relevant for the question appears.

The details about the methods used to produce these summaries are described here http://dx.doi.org/10.5867/medwave.2014.06.5997.

Epistemonikos foundation is a non-for-profit organization aiming to bring information closer to health decision-makers with technology. Its main development is Epistemonikos database (www.epistemonikos.org).

These summaries follow a rigorous process of internal peer review.

Conflicts of interest
The authors do not have relevant interests to declare.

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