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Published on December 27, 2017 | http://doi.org/10.5867/medwave.2017.09.7115

Is perioperative pregabalin effective for reducing postoperative pain in major surgery?

¿Es efectiva la pregabalina perioperatoria para reducir el dolor postoperatorio en cirugías mayores?

José Canihuante, Ian Molina, Fernando Altermatt

Abstract

INTRODUCTION Pregabalin is a structural analog of γ-aminobutyric acid that may have a role in acute pain management. It has been used in the perioperative context, but there is controversy regarding its real clinical utility.

METHODS To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach.

RESULTS AND CONCLUSIONS We identified 21 systematic reviews including 77 randomized trials. We concluded the use of perioperative pregabalin in major surgeries probably does not produce a clinically important decrease in acute postoperative pain. Although it could decrease nausea, postoperative vomiting and opioid requirements, it also produces an increase in sedation.

Problem

Postoperative pain management is an important aspect of anesthesiology practice. Among the most commonly used drugs to manage acute pain are opioids, which despite being very effective have adverse effects such as nausea, vomiting, sedation and respiratory depression. One of the strategies to reduce these unwanted effects is to use adjuvant analgesics that act through different pathways involved in pain response.

Pregabalin is a structural analog of γ-aminobutyric acid (GABA) that binds to the α2δ subunit of voltage-dependent calcium channels in the central nervous system decreasing the release of various neurotransmitters. Although it is usually used as an antiepileptic and for chronic pain management, its role for acute postoperative management has also been raised. However, is it not clear if it constitutes an effective alternative in this context. 

Methods

To answer the question, we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others, to identify systematic reviews and their included primary studies. We extracted data from the identified reviews and reanalyzed data from primary studies included in those reviews. With this information, we generated a structured summary denominated FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos) using a pre-established format, which includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), meta-analysis of the total of studies when it is possible, a summary of findings table following the GRADE approach and a table of other considerations for decision-making. 

Key messages

  • Perioperative pregabalin probably does not produce a clinically significant reduction of acute postoperative pain in major surgeries.
  • Perioperative pregabalin increases postoperative sedation.
  • Perioperative pregabalin could decrease postoperative opioid consumption and the incidence of nausea and vomiting, but the certainty of this evidence is low.

About the body of evidence for this question

What is the evidence.
See evidence matrix  in Epistemonikos later

We found twenty one  systematic reviews [1],[2],[3],[4],
[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],
[18],[19],[20],[21] that include seventy seven randomized trials [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],[50],[51],[52],[53],[54],[55],[56],
[57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],
[69],[70],[71],[72],[73],[74],[75],[76],[77],[78],[79],[80],
[81],[82],[83],[84],[85],[86],[87],[88],[89],[90],[91],[92],
[93],[94],[95],[96],[97],[98].

What types of patients were included*

Sixteen trials included patients undergoing abdominal
surgery[22],[23],[24],[26],[29],[30],[31],[35],[37],[42],
[69],[78],[82],[86],[88],[89], twenty one trials included patients undergoing pelvic or gynecological surgery [28],
[39],[43],[45],[49],[50],[52],[56],[58],[59],[60],[65],
[68],[73],[76],[80],[81],[82],[84],[90],[97], thirty trials included patients undergoing trauma surgery [25],[32],
[33],[34],[36],[38],[40],[41],[44],[48],[51],[53],[54],
[55],[57],[62],[63],[67],[70],[71],[72],[74],[75],[77],
[82],[83],[91],[93],[95],[96], five trials included patients
undergoing thoracic surgery [46],[61],[79],[92],[98];
and seven trials included patients undergoing other
types of surgery [27],[47],[64],[66],[85],[87],[94].  

What types of interventions were included*

In all trials oral pregabalin was administered.

In forty-nine trials pregabalin was administered during
the preoperative period [23],[24],[25],[26],[27],[28],
[29],[31],[35],[38],[39],[42],[43],[44],[46],[48],[49],
[50],[51],[52],[54],[55],[56],[60],[64],[65],[67],[68],
[69],[70],[71],[72],[73],[75],[76],[80],[82],[84],[85],
[86],[87],[88],[89],[91],[92],[93],[94],[97],[98], in
twenty six trials during both the preoperative and the
postoperative period [22],[30],[32],[33],[34],[36],[37],
[40],[41],[45],[47],[53],[57],[58],[59],[61],[62],[63],
[66],[77],[78],[79],[83],[90],[95],[96] and in the rest this data was not reported.

Forty-six trials used a single dose of pregabalin [23],
[24],[25],[26],[27],[28],[29],[31],[35],[38],[39],[42],
[43],[46],[48],[50],[51],[54],[55],[56],[60],[64],[65],
[67],[68],[69],[70],[71],[72],[73],[75],[76],[80],[82],
[85],[87],[88],[89],[91],[92],[93],[94],[95],[96],[97],
[98], twenty-seven trials used multiple doses [22],[30],
[32],[33],[34],[36],[37],[40],[41],[44],[45],[47],[49],
[52],[53],[57],[58],[59],[61],[62],[63],[66],[77],[78],
[79],[83],[90] and in the rest this data was not reported.

The dose of pregabalin varied between 50 mg and 600 mg.

Dexamethasone was coadministered in one trial [51], remifentanil infusion in two trials [58],[69], nonsteroidal anti-inflammatory drugs  in two trials [60],[70], acetaminophen in one trial [73], acetaminophen and diclofenac in one trial [55], and in the rest of the trials there was no coadministration of drugs.

Regarding postoperative analgesia, acetaminophen with
nonsteroidal anti-inflammatory drugs were used in two
trials [36],[95], acetaminophen with opioids were used in
twelve trials [45],[46],[52],[55],[60],[61],[72],[73],[78],
[79],[86],[93], nonsteroidal anti-inflammatory drugs alone
were used in nine trials [22],[24],[28],[37],[39],[42],[51],
[80],[87], nonsteroidal anti-inflammatory drugs and opioids
were used in thirteen trials [27],[30],[35],[49],[50],[53],
[54],[57],[63],[64],[67],[69],[70], opioids alone were used
in thirty trials [23],[25],[26],[29],[31],[33],[34],[38],[40],
[43],[44],[47],[56],[58],[62],[66],[68],[71],[75],[77],
[82],[83],[84],[88],[89],[90],[92],[94],[97],[98],
acetaminophen, nonsteroidal anti-inflammatory drugs and
opioids were used in three trials [76],[91],[96] and in three
trials this data was not reported [74],[81],[85].

Sixty eight trials compared against placebo [22],[23],
[25],[26],[27],[29],[30],[31],[32],[33],[34],[35],[36],
[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[48],
[49],[50],[51],[52],[53],[54],[55],[57],[58],[61],[62],
[63],[64],[65],[66],[67],[68],[71],[72],[73],[74],[75],
[76],[77],[78],[79],[80],[81],[82],[83],[84],[85],[86],
[88],[89],[90],[91],[92],[93],[94],[95],[96],[97],[98], twenty trials compared against another drug [24],[30],[36],
[38],[47],[50],[56],[58],[59],[60],[62],[67],[69],[70],[71],
[75],[77],[80],[82],[87], three trials compared against pregabalin with another drug [72],[73],[83] and in the rest this data was not reported.

What types of outcomes
were measured

The main outcomes analyzed by the systematic reviews were postoperative pain, sedation, opioid consumption, stay in a postoperative care unit, preoperative anxiety, adverse effects, postoperative nausea and vomiting, and morbidity.

The average follow-up of the trials was 24 hours, with a range that fluctuated between 2 and 72 hours postoperatively.

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

Summary of Findings

The information regarding the effects of perioperative pregabalin is based on 53 randomized trials that include 3543 patients in total [23],[26],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[40],[41],[44],[45],[49],[50],[52],[53],[54],[56],[57],[58],[59],[60],[61],[63],[64],[65],[66],[69],[70],[72],[73],[74],[75],[76],[77],[78],[79],[81],[84],[85],[86],[90],[91],[92],[93],[94],[95],[96],[97]. The rest of the trials did not report any of the outcomes of interest or did it in a way that it was not possible to incorporate into a meta-analysis.

Forty-six trials reported the outcome pain at 24 hours after surgery (3037 patients) [23],[26],[30],[31],[32],[33],[34],[35],[36],[37],[38],[40],[41],[44],[45],[49],[50],[53],[54],[56],[57],[58],[59],[60],[61],[63],[64],[66],[69],[70],[72],[73],[75],[76],[77],[78],[81],[85],[86],[90],[91],[92],[93],[94],[96],[97], 27 trials the outcome opioid consumption (1712 patients) [23],[31],[35],[37],[44],[45],[49],[50],[52],[53],[56],[58],[59],[60],[63],[66],[72],[73],[77],[78],[79],[84],[91],[92],[96],[97], 31 trials the outcome nausea and vomiting (2461 patients) [23],[29],[31],[32],[33],[35],[37],[38],[50],[53],[56],[57],[59],[60],[64],[65],[69],[72],[73],[74],[77],[78],[79],[84],[86],[90],[91],[93],[95],[96],[97]; and 18 trials the outcome sedation (1587 patients) [23],[31],[33],[36],[37],[38],[53],[56],[61],[63],[64],[65],[72],[73],[90],[91],[95],[96]. The summary of findings is the following:

  • Perioperative pregabalin probably does not produce a clinically significant reduction of acute postoperative pain after major surgeries. The certainty of this evidence is moderate.
  • Perioperative pregabalin could decrease postoperative opioid consumption in major surgeries, but the certainty of this evidence is low.
  • The use of perioperative pregabalin in major surgeries could decrease the incidence of postoperative nausea and vomiting, but the certainty of this evidence is low.
  • Perioperative pregabalin in major surgeries produces an increase in postoperative sedation. The certainty of this evidence is high.

Other considerations for decision-making

To whom this evidence does and does not apply
  • The evidence presented in this summary applies to adult patients undergoing abdominal, pelvic or gynecological, trauma, thoracic and other major surgeries; and who receive general or neuraxial anesthesia.
  • It is not possible to determine if there is a different effect in any of the subgroups evaluated in this summary.
About the outcomes included in this summary
  • The outcomes presented in the summary of findings table are those considered critical for health decision-making by the authors of this article. These generally coincide with those evaluated in the systematic reviews identified.
Balance between benefits and risks, and certainty of the evidence
  • Perioperative pregabalin probably produces a decrease of acute postoperative pain of 0.45 points (VAS 0-10), which is below the minimally important difference established in the literature in a perioperative pain context [99].
  • Perioperative pregabalin may decrease opioid consumption and the incidence of postoperative nausea and vomiting, however, the certainty of the evidence is low.
  • In addition, perioperative pregabalin probably produces an increase in sedation.
  • It is not possible to make an adequate balance between benefits and risks, due to the uncertainty associated to the benefits. However, considering that it has no clinically important benefit on the main outcome, and that it has adverse effects, it is probably an intervention whose balance is not favorable.
Resource considerations
  • It is a relatively low-cost intervention in the perioperative context.
  • It is not possible to make an adequate balance between benefits and costs, due to the uncertainty associated to the benefits. However, it is probably an intervention whose balance is not favorable.
What would patients and their doctors think about this intervention
  • Faced with the evidence presented in this summary, most clinicians should lean against the use of pregabalin for postoperative pain.
  • Variability in decision-making for this intervention can be expected, considering there is some possibility of benefit, and the adverse effects are not severe. This could be reinforced by the existence of recommendations in favor of this intervention in the main clinical guidelines.

Differences between this summary and other sources
  • The conclusions of this summary coincide with the different systematic reviews identified, which propose that the use of pregabalin could have a role in postoperative pain management, but which is of low impact and depends on the type of surgery. Its indication for routine use is discussed and must take into account the associated risks and benefits. They also emphasize that the quality of existing evidence is low.
  • Regarding the main clinical guidelines, The American Society of Anesthesiologists Practice Guidelines for Acute Pain Management in the Perioperative Setting states that pregabalin should be considered in post-operative multimodal analgesia, since pain reduction and reduced postoperative opioid consumption have been described [100]. On the other hand, the Australian and New Zealand College of Anaesthetists (ANZCA) Acute pain management: scientific evidence guideline mentions pregabalin as part of the options for acute neuropathic pain treatment in surgery and trauma context [101].
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 involving some of the outcomes.
  • In a search in the Prospective register of systematic reviews (PROSPERO), we did identify at least seven ongoing reviews addressing this question [102],[103],[104],[105],[106],[107],[108]. Their conclusions could provide relevant clinical information.
  • Also, there are at least 6 ongoing trials addressing this question according to the International Clinical Trials Registry Platform of the World Health Organization [109],[110],[111],[112],[113],[114].

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: Perioperative pregabalin for acute postoperative pain in major surgeries

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 matrixes and to receive automated notifications any time new evidence potentially relevant for the question appears.

This article is part of the Epistemonikos Evidence Synthesis project. It is elaborated with a pre-established methodology, following rigorous methodological standards and internal peer review process. Each of these articles corresponds to a summary, denominated FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos), whose main objective is to synthesize the body of evidence for a specific question, with a friendly format to clinical professionals. Its main resources are based on the evidence matrix of Epistemonikos and analysis of results using GRADE methodology. Further details of the methods for developing this FRISBEE 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).

Potential conflicts of interest

The authors do not have relevant interests to declare.

This work is licensed under a Creative Commons Attribution 4.0 International License. Esta licencia permite el uso, distribución y reproducción del artículo en cualquier medio, siempre y cuando se otorgue el crédito correspondiente al autor del artículo y al medio en que se publica, en este caso, Medwave.

Authors

José Canihuante

Ian Molina

Fernando Altermatt

fernando.altermatt@gmail.com.

Centro Evidencia Uc, Pontificia Universidad Católica de Chile, Centro de Innovación UC Anacleto Angelini, Avda

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History

Citation Canihuante J, Molina I, Altermatt F. Is perioperative pregabalin effective for reducing postoperative pain in major surgery?. Medwave 2017;17(09):e7115 doi: 10.5867/medwave.2017.09.7115

Submission date 24/11/2017

Acceptance date 21/12/2017

Publication date 27/12/2017

Metrics

Not available at the moment.

Notes

Origin and peer review

Con revisión por pares sin ciego por parte del equipo metodológico del Epistemonikos Evidence Synthesis Project.

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