|Epidural fentanyl, adrenaline and clonidine as adjuvants to local anaesthetics for surgical analgesia: meta-analyses of analgesia and side-effects
|Curatolo M, Petersen-Felix S, Scaramozzino P, Zbinden A M
To assess the effectiveness of adding fentanyl, adrenaline and clonidine to local anaesthetics for intra-operative epidural analgesia not combined with general anaesthesia.
MEDLINE (from 1966), Excerpta Medica (from 1974), and the Science Citation Index (from 1980) were searched using the keywords 'anesthetic techniques', 'epidural', fentanyl', 'epinephrine' and 'clonidine'. In addition, the authors' databases, abstracts of anaesthesia meetings (details listed in the paper), textbooks, and the reference lists of the retrieved articles were searched for additional studies. Studies reported in any language were considered.
Study designs of evaluations included in the review
Prospective studies where the treatment group received fentanyl or adrenaline or clonidine in addition to a local anaesthetic, and the control group received only the same anaesthetic as the treatment group, were included. In addition, for the inadequate analgesia outcome, studies were included where the participants were blind to the type of anaesthetic solution administered.
To be included, studies had to have a methodological score of at least 0.5.
Specific interventions included in the review
Fentanyl, adrenaline or clonidine, added to local anaethestics. The local anaesthetics used were mepivacaine, bupivacaine, lignocaine, etidocaine and chloroprocaine. The control groups received the same anaesthetic solution as the treatment group.
Participants included in the review
Patients undergoing surgery (orthopaedic or lower abdominal) with planned epidural block, without general analgesia. Women in labour were not included unless they were having Caesarean section.
Outcomes assessed in the review
Inadequate analgesia and the occurrence of side-effects were assessed. Inadequate analgesia was defined as pain at any intensity at the site of surgery, occurring during operation. The side-effects included respiratory depression, nausea/vomiting, pruritis, sedation, hypotension, urinary retention, local anaesthesia toxicity, and bracdycardia. In obstetric cases, respiratory depression of the newborn and Apgar scores could be reported.
How were decisions on the relevance of primary studies made?
The authors do not state how the papers were selected for the review, or how many of the authors performed the selection.
Assessment of study quality
The studies were scored for methodological quality using the following criteria: randomisation, outcome measures, inclusion and exclusion criteria, intervention, and statistical analysis. The maximum number of points for a study was 21. The content and process of the scoring system were tabulated in the review. The papers were evaluated by two assessors, each blinded to the other's decision, according to a quality score. The assessors were blinded to the journal, title, authors, institutions and results. When all the papers had been scored by both assessors, the evaluations were compared. If a value of at least 0.5 was obtained by both assessors the paper was included. Papers selected by only one assessor were discussed by both assessors and a final decision was made. The extent of agreement was measured using the intraclass correlation coefficient between scores.
All data were independently entered by the assessors on a form, and consistency was checked by one of them. The data extracted included: dose of fentanyl; type of dose of local anaesthetic; site of injection of anaesthetic solution; administration of sedatives; type of operation; presence of pre-op; and maternal or foetal disease for obstetric patients.
The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each outcome in each trial.
Methods of synthesis
How were the studies combined?
Publication bias was tested by calculating the number of unpublished studies required to raise the pooled p-value to 0.05, assuming that the average sample size of the unpublished studies was the same as the average sample size which has been analysed.
The pooled ORs and 95% CIs were computed using the method proposed by Yusuf et al. (see Other Publications of Related Interest). The number of patients who needed to receive fentanyl in order to prevent one case of inadequate analgesia was calculated.
The mean values of the Apgar scores were analysed using a t-test.
How were differences between studies investigated?
All included studies were included in the primary meta-analysis; only double-blind randomised trials were included in the secondary meta-analysis.
Subgroup analyses were conducted to investigate the effect of the dose of fentanyl at 50 to 75 microg and at 100 microg. Tests of heterogeneity were not reported. A sensitivity analysis was performed using only double-blind randomised controlled trials.
Results of the review
Twenty-six papers met the inclusion criteria: there were 18 trials included in the analysis for fentanyl (541 patients in the fentanyl group and 479 patients in the control group), 7 trials on adrenaline, and 1 on clonidine.
An evaluation of adrenaline and clonidine as epidural adjuvants was not possible because there was a very low number of trials on these drugs.
The number-needed-to-treat with fentanyl was 4.2.
The publication bias test estimated that 94 additional studies would be required to bring the overall p-value to 0.05.
Compared with the control (local anaesthetic without fentanyl), fentanyl decreased the likelihood of pain (OR 0.21, 95% CI: 0.15, 0.30, p<0.001), and increased the incidence of pruritus (OR 5.59, 95% CI: 3.12, 10.05, p<0.001) and sedation (OR 1.88, 95% CI: 1.19, 2.98, p=0.003).
Fentanyl had no effect on respiratory depression, nausea, vomiting, urinary retention, headache, respiratory depression of newborn or Apgar score.
The results for inadequate analgesia and Apgar score did not change when only double-blind randomised controlled trials were analysed. The subgroup analysis found no relevant differences between the two subgroups of level of fentanyl (50 to 75 microg and 100 microg).
The analysis of the current literature showed that the addition of fentanyl to local anaesthetics for intra-operative epidural anaesthesia was safe and advantageous. Further, the authors stated that the reduction in the incidence of pain during surgery was quantitatively high, and therefore clinically significant, and that the side-effects were mild.
The authors clearly stated the research question and the inclusion and exclusion criteria, and conducted a quality assessment of the included studies. The literature search was good and tests for publication bias were conducted. The authors also stated who, and how many of the authors, were involved in the assessment of the methodological quality of the included studies, and the data extraction; this was not reported for the selection of the studies. The authors found that the data for two of the treatments (adrenaline and clonidine) could not be combined because of the very low number of studies available, but they have combined the fentanyl data. The authors tested the heterogeneity of these studies with regard to study design and dose, but they did not discuss the differences among participants in the different studies (e.g. orthopaedic versus obstetric versus general surgery) which could influence the review outcomes. The results reported in this review for the use of fentanyl should be viewed with caution.
Implications of the review for practice and research
Practice: The authors did not state any implications for practice.
Research: The authors state that further randomised controlled trials should be performed in order to clarify the role of adrenaline and clonidine as epidural adjuvants for surgical analgesia, since there was insufficient evidence available to do so in this review.
Curatolo M, Petersen-Felix S, Scaramozzino P, Zbinden A M. Epidural fentanyl, adrenaline and clonidine as adjuvants to local anaesthetics for surgical analgesia: meta-analyses of analgesia and side-effects. Acta Anaesthesiologica Scandinavica 1998; 42(8): 910-920
Other publications of related interest
Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta-blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 1985;27:335-71.
Subject indexing assigned by NLM
Adjuvants, Anesthesia /administration & Analgesia, Epidural /adverse effects; Anesthetics, Local; Clonidine /administration & Epinephrine /administration & Fentanyl /administration & Humans; MEDLINE; Randomized Controlled Trials as Topic; Surgical Procedures, Operative; Treatment Outcome; dosage /adverse effects; dosage /adverse effects; dosage /adverse effects; dosage /adverse effects
Date bibliographic record published
Date abstract record published
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.