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Efficacy and safety of buprenorphine in peripheral nerve blocks: A meta-analysis of randomised controlled trials

Schnabel, Alexander*; Reichl, Sylvia U.*; Zahn, Peter K.; Pogatzki-Zahn, Esther M.; Meyer-Frießem, Christine H.

European Journal of Anaesthesiology: September 2017 - Volume 34 - Issue 9 - p 576–586
doi: 10.1097/EJA.0000000000000628
Locoregional anaesthesia
Free
SDC

BACKGROUND The duration of analgesia provided by nerve blocks is limited if local anaesthetics are administered alone. Therefore, a variety of additives to local anaesthetics have been investigated to prolong postoperative analgesia following single-shot nerve blocks.

OBJECTIVE(S) The aims of the current meta-analysis were to assess the efficacy and safety of the addition of perineural buprenorphine to local anaesthetic compared with local anaesthetic alone, or combined with systemic administration of buprenorphine, or other perineural opioids for peripheral nerve blocks.

DESIGN Systematic review and meta-analysis of randomised controlled trials (RCTs).

DATA SOURCES The following data sources were systematically searched: MEDLINE, CENTRAL and EMBASE (till 03/2016).

ELIGIBILITY CRITERIA All RCTs focusing on the efficacy and safety of perineural buprenorphine combined with local anaesthetic compared with local anaesthetic alone, or in combination with systemic buprenorphine, or other perineural opioids for peripheral nerve blocks were included.

RESULTS We included 13 RCTs (685 patients). Participants treated with perineural buprenorphine combined with local anaesthetic showed a longer duration of analgesia compared with those receiving local anaesthetic alone [mean difference 8.64 h, 95% confidence interval (CI) (6.44 to 10.85); P < 0.01]. However, the buprenorphine group had a significantly higher relative risk (RR) for postoperative nausea and vomiting (PONV) [RR 5.0, 95% CI (1.12 to 22.27); P = 0.03]. The perineural administration of buprenorphine provided a longer duration of analgesia than an intramuscular application [mean difference 6.87 h, 95% CI (4.02 to 9.71); P < 0.01] without evidence of a difference in the incidence of PONV between the modes of administration [RR 0.76, 95% CI (0.28 to 2.03); P = 0.58].

CONCLUSION This meta-analysis revealed that the addition of buprenorphine to a local anaesthetic peripheral nerve block prolongs postoperative analgesia for about 8 h but significantly increases the risk for PONV. Perineural administration is more effective than systemic application but is associated with a similar risk of PONV. However, these results were influenced by heterogeneity so that further trials (especially head-to-head comparisons) are needed in the future.

TRIAL REGISTRATION PROSPERO(www.crd.york.ac.uk) identifier: CRD42016036054.

Supplemental Digital Content is available in the text

From the Department of Anaesthesiology and Intensive Care, University Hospital of Wuerzburg, Wuerzburg, Germany (AS), Department of Anaesthesiology, Perioperative and Intensive Care Medicine, Paracelsus Medical University Salzburg, Salzburg, Austria (SUR), Department of Anaesthesiology, Intensive Care Medicine, Palliative Care Medicine and Pain Management, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil GmbH Bochum, Medical Faculty of Ruhr University Bochum, Bürkle-de-la-Camp-Platz 1, Bochum (PKZ, CHMF); and Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital of Muenster, Albert-Schweitzer-Campus 1, Muenster, Germany (EMPZ)

*Alexander Schnabel and Sylvia U. Reichl have contributed equally to the article.

Correspondence to Alexander Schnabel, MD, PhD, Department of Anaesthesiology and Intensive Care, Postoperative Pain Research Group, University Hospital of Wuerzburg, Oberduerrbacherstr. 6, 97080 Wuerzburg, Germany Tel: +0049 931 2010; e-mail: Schnabel_A@ukw.de

Published online 31 March 2017

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.ejanaesthesiology.com).

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Introduction

Despite several improvements, postoperative pain continues to be a serious problem for patients.1 Peripheral regional analgesia techniques are increasingly used2 and are associated with a low risk of severe adverse events.3 Single-shot nerve blocks are usually performed, which often provide only a short duration of analgesia. Therefore, the efficacy and safety of different additives to local anaesthetics to prolong analgesia have been investigated in recent years.

Compared with other opioids, buprenorphine is the agonist that binds most strongly to the μ-opioid receptor.4 It has some κ antagonist activity and is highly lipophilic. Clinically, it behaves as an analgesic4 but under some experimental conditions can exhibit antihyperalgesic properties.5 In the periphery, buprenorphine acts via μ-opioid receptors located on C-fibre axons and blocks sodium channels in a concentration-dependent manner indicating a local anaesthetic action.6,7

Therefore, the aim of our meta-analysis was to assess the efficacy and safety of perineural buprenorphine in combination with local anaesthetics compared with local anaesthetics alone, or in combination with intramuscular buprenorphine or other perineural opioids for peripheral nerve blocks.

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Methods

The current meta-analysis of randomised controlled trials (RCTs) was registered in the PROSPERO database (CRD42016036054) after the beginning of the literature search and data extraction process. We performed the meta-analysis according to the current recommendations of the Cochrane Collaboration8 and reported it according to the criteria of the PRISMA statement.

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Search strategy and study selection

RCTs were identified in a systematic search of the data sources MEDLINE, CENTRAL and EMBASE (until 03/2016) combining indexed and free text terms (‘buprenorphine’ or ‘regional analgesia’ or ‘nerve block’) (AS/SUR). Search terms were modified according to the conditions of each database. Additional articles were found from references of selected studies and on-going registered trials were checked on ‘www.clinicaltrials.gov’. There were no restrictions due to language or year of publication. Two reviewers (AS/SUR) independently reviewed titles and abstracts to exclude irrelevant studies. Differences in literature inclusion/exclusion were decided by consensus or discussed with a third review author (CHMF).

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Inclusion criteria

We included all RCTs investigating the efficacy and safety of perineural buprenorphine combined with local anaesthetics compared with either local anaesthetics alone, or with local anaesthetics in combination with systemic buprenorphine, or with local anaesthetics combined with any other perineural opioids for peripheral nerve blocks. The following criteria for inclusion were used:

  1. RCTs,
  2. human studies that included adult men and women (≥18 years) undergoing upper or lower limb surgeries,
  3. primary outcome was reported.
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Data collection, extraction and quality analysis

Three review authors (AS, SUR, CHMF) independently extracted the data using a self-developed standardised data extraction form (Excel sheet). The following study characteristics were extracted: author, publication year, sample size, type of upper/lower extremity surgery, tested intervention, control intervention, study design, nerve localisation technique, type and dose of local anaesthetics, dose of perineural buprenorphine and type and dose of other perineural opioids administered.

Corresponding authors were contacted for additional unpublished data on methods and results when required. At each step of data extraction differences were discussed within the group of reviewers.

A critical evaluation of study quality was performed by two reviewers (AS/SUR) using a modified seven-point Oxford scale.9 This scale assessed the method of randomisation (two points), concealment of allocation (one point), blinding (three points) and description of dropouts (one point).

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Definition of primary and secondary outcome parameters

The primary outcomes were the duration of analgesia in hours and the number of patients with postoperative nausea and vomiting (PONV).

Postoperative pain intensity (<2 h, 2 to 24 h, 24 to 48 h after surgery), the onset of motor block or sensory block in minutes, the duration of motor block in minutes and the number of patients with opioid-related adverse events (respiratory depression, pruritus, bradycardia, hypotension, sedation or urinary retention) were assessed as secondary outcomes. If postoperative pain was measured with different scales [e.g. a numeric rating scale (NRS) (0 to 10) or visual analogue scale (VAS) (0 to 100 mm)], no transformation into one specific scale was performed.

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Statistical analysis

All statistical analyses were performed with the Review Manager (RevMan; Computer program; version 5.3.3; The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark).

We considered that an intention-to treat analysis was performed on the original data, when not reported otherwise. For dichotomous data, we calculated the risk ratio (RR) with 95% confidence interval (95% CI), whereas for continuous endpoints, we estimated the mean difference with 95% CI. For the outcome ‘postoperative pain’, we used the standardised mean difference, if different scales were used within the included trials; otherwise, we calculated the mean difference. If continuous outcomes were not reported as mean (±SD), missing data were calculated as previously described.9 For dichotomous data, we used the Mantel–Haenszel fixed-effect or random-effects model, whereas for continuous data the inverse variance fixed-effect or random-effects model was used. Statistical significance (P < 0.05) was assumed, if the 95% CI did not cross zero. A number-needed-to-harm (NNH) was calculated for dichotomous outcomes, if more than at least two trials reported patients suffering from that adverse event, and the results were significant.

Statistical heterogeneity was assessed with the I 2 test and considered as relevant, if an I 2 value higher than 50% was observed; the analysis was then carried out using a random-effects model. To evaluate the effects of heterogeneity, subgroup analyses were performed to calculate the RR or mean difference in conjunction with the corresponding CI for each subgroup, if more than four trials were included for the outcome. The following subgroups were analysed:

  1. doses of perineural or systemic (e.g. intramuscular) buprenorphine administered (0.1, 0.15, 0.2 and 0.3 mg),
  2. type of local anaesthetics used [long-lasting versus mixture of local anaesthetics (intermediate-lasting; short-lasting and long-lasting)],
  3. addition of perineural adrenaline (1 : 200 000),
  4. location of nerve block (interscalene, supraclavicular, axillary, femoral and sciatic nerve block),
  5. guiding method used (landmark, nerve stimulation and ultrasound).

If weight-based doses of buprenorphine were used, we calculated the average applied dose of buprenorphine by using the average weight (rounded up or down into decades) reported within each trial. In addition, a sensitivity analysis was performed to detect the influence of study quality [high-quality trials (modified Oxford scale above or equal to the median of modified Oxford scales) versus low quality trials (modified Oxford scale below the median of modified Oxford scales)].10 We constructed a funnel plot to detect potential publication bias.

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Results

Description of included and excluded studies

Our systematic literature search revealed 338 potentially relevant publications, whereas 15 RCTs potentially satisfied the inclusion criteria according to the title and abstract (Fig. 1). In addition, we identified three other potentially relevant ongoing trials in the database ‘clinicaltrials.gov’, but these results did not satisfy our inclusion criteria. Two studies11,12 were excluded, because the authors used different doses of local anaesthetics in their study groups. Finally, we included 13 RCTs (685 patients)13–25 in this meta-analysis (Table 1). The number of participants in each trial ranged from 20 to 50 per group. Eleven trials13–17,19–24 explored the analgesic efficacy of perineural buprenorphine combined with local anaesthetics in comparison with local anaesthetics alone. In addition, six studies14–16,18,20,24 compared perineural versus intramuscular buprenorphine combined with local anaesthetics. Finally, three trials compared buprenorphine with other perineural opioids (morphine/fentanyl/sufentanil)13,22,25 combined with local anaesthetics. In most trials, surgical procedures were performed without general anaesthesia; one trial mentioned that single-shot nerve block was combined with general anaesthesia,15 whereas another trial reported that the nerve block was performed after surgery – intraoperatively, patients received spinal anaesthesia.19 Most authors performed a nerve-stimulation guided single-injection nerve block, whereas two investigators performed nerve blocks on the basis of anatomical landmarks.18,21 Only one author used the combination of nerve-stimulation and ultrasound,19 and one study did not describe the guiding technique.25 There was only one trial which applied fentanyl before peripheral nerve block for analgosedation,14 whereas the other included trials did not regularly use nonopioids or opioids for multimodal analgesia. Different nonopioid analgesics (acetaminophen, traditional nonsteroidal anti-inflammatory drugs and coxibs) were given in seven out of 13 trials14–18,23,24 for rescue analgesia. In addition, three trials combined nonopioid analgesics with opioids,14–16 whereas Kosel et al. 19 gave only opioids as rescue analgesics. None of the included trials reported the use of a prophylactic drug against PONV.

Fig. 1

Fig. 1

Table 1

Table 1

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Description of the quality of included trials

The overall methodological quality was good [median modified Oxford score: 5 (range: 3 to 7)]. Only four included trials were rated as low-quality RCTs, because their modified Oxford score was below the median of all Oxford scales.13,17,20,21 The main methodological problems were missing descriptions of allocation concealment in eight trials13,16–18,20,21,23,25 and method of randomisation in seven trials.13,17,18,20,21,23,25

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Comparison of perineural buprenorphine combined with local anaesthetics versus local anaesthetics alone

Primary outcomes

Duration of analgesia

Nine trials including 510 participants reported the duration of analgesia defined as ‘time to first analgesic request’13–16,22,23 or ‘duration of postoperative analgesia measured on a VAS [0 (=no pain) to 10 (=worst pain) points] (VAS ≤ 5,17 VAS ≤ 4 points24)’. Kosel et al. 19 did not explicitly define the duration of analgesia within their article. Patients treated with 0.1 to 0.3 mg perineural buprenorphine combined with local anaesthetics for peripheral nerve blocks showed a significantly longer duration of analgesia compared with those who received only local anaesthetics [mean difference 8.64 h, 95% CI (6.44 to 10.85); P < 0.001, Fig. 2]. However, the latter result was significantly influenced by heterogeneity (I 2 = 98%). Therefore, subgroup and sensitivity analyses were performed to explore possible reasons for this heterogeneity. The subgroup analyses are described in Table 2. However, differences between the subgroups were not significant. The sensitivity analysis investigating the influence of trial quality demonstrated no significant difference between high [mean difference 8.69 h, 95% CI (5.49 to 11.89); P < 0.001]14–16,19,22–24 and low-quality trials [mean difference 8.6 h, 95% CI (8.14 to 9.05); P < 0.001].13,17 The funnel plot showed an asymmetry indicating a possible publication bias (Fig. S1, http://links.lww.com/EJA/A116).

Fig. 2

Fig. 2

Table 2

Table 2

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Number of patients with postoperative nausea and vomiting

The number of patients with PONV were reported by three studies (210 participants).14,21,22 The meta-analysis demonstrated that the risk for PONV was five times higher in patients treated with 0.15 to 0.3 mg perineural buprenorphine combined with local anaesthetics compared with local anaesthetics alone [RR: 5.0, 95% CI (1.12 to 22.27); P = 0.03; I 2 = 0%; NNH = 12.5].

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Secondary outcomes

Postoperative pain intensity (numeric rating scale: 0 to 10 points) at three time points (<2 h, 2 to 24 h, 24 to 48 h postoperatively)

Two included trials reported data focusing on postoperative pain intensity.15,19 Patients receiving perineural buprenorphine in combination with local anaesthetics reported significantly lower pain scores compared with those treated with local anaesthetics alone during the time period 2 to 24 h [mean difference −0.89 NRS points, 95% CI (−1.49 to −0.29); P = 0.004; I 2 = 16%] and during the time period 24 to 48 h [mean difference −1.25 NRS points, 95% CI (−2.08 to −0.41); P = 0.003; I 2 = 15%].15,19

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Onset of motor blockade or sensory blockade, duration of motor blockade

The onset of motor blockade (quantified by Hollmen scale,21 Lovett scale14 or defined as ‘time to complete motor block’23,24) was described in four trials (264 participants). Sensory blockade in minutes (determined by pinprick test,14,24 quantified by Hollmen scale21 or defined as ‘time to loss of cold perception’23) was described in five trials (304 participants). One trial did not mention a definition for the onset of sensory blockade.20 In patients receiving buprenorphine in combination with local anaesthetics, the onset of motor blockade was slightly faster [mean difference −0.34 min, 95% CI (−0.67 to −0.02); P = 0.04; I 2 = 0%]. However, there was no evidence for a difference in the onset of sensory blockade [mean difference −0.15 min, 95% CI (−0.71 to 0.41); P = 0.6; I 2 = 76%]. The duration of motor blockade (minutes) was defined as ‘time from initial drug injection to complete return of motor power’23 or ‘time from onset of motor blockade to full recovery’.21,24 Sarkar et al. 22 did not explicitly define the duration of motor blockade. The pooled analysis of four included studies (215 participants)21–24 showed only a slightly longer duration of motor blockade following the administration of buprenorphine in combination with local anaesthetics [mean difference 12.6 min, 95% CI (3.6 to 21.6); P = 0.006; I 2 = 49%].

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Number of patients with respiratory depression, pruritus, bradycardia, hypotension, sedation or urinary retention

Opioid-related adverse events were only poorly reported. No patient with respiratory depression was mentioned in seven included trials.13–15,17,21,22,24 The most common adverse event following the perineural administration of buprenorphine in combination with local anaesthetics was pruritus [RR: 6.0; 95% CI (0.75 to 47.88); P = 0.09; I 2 = 0%].13,14,17,23,24 No patient complained about urinary retention, whereas one patient treated with 0.15-mg perineural buprenorphine combined with local anaesthetics required treatment due to intraoperative hypotension14 and another patient treated with 3 μg kg−1 buprenorphine suffered from bradycardia.21 Finally, another patient suffered from sedation following the administration of 3 μg kg−1 buprenorphine in combination with local anaesthetics.13

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Comparison of perineural buprenorphine combined with local anaesthetics versus systemic buprenorphine combined with local anaesthetics

Primary outcomes

Duration of analgesia

The duration of analgesia defined as ‘time to first analgesic request’14–16,18 or ‘duration of postoperative analgesia (VAS ≤ 4 points24)’ was investigated in five trials including 294 patients. The meta-analysis revealed that patients receiving 0.1 to 0.3 mg perineural buprenorphine showed a longer duration of analgesia [mean difference 6.87 h, 95% CI (4.02 to 9.71); P < 0.001] than patients treated with intramuscular buprenorphine, but this result was influenced by heterogeneity (I 2 = 95%) (Fig. 3). The results of the subgroup analyses are shown in Table 3. The overlapping 95% CIs suggest that there are no significant differences between the subgroups. All included trials were high-quality trials. The funnel plot is asymmetrical indicating a possible publication bias (Fig. S2, http://links.lww.com/EJA/A116).

Fig. 3

Fig. 3

Table 3

Table 3

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Number of patients with postoperative nausea and vomiting

Two trials reported the number of patients with PONV, but there was no evidence for a difference in the risk of PONV [RR: 0.75, 95% CI (0.27 to 2.05); P = 0.58; I 2 = 0%].14,18

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Secondary outcomes

Postoperative pain intensity (numeric rating scale: 0 to 10 points) at three time points (<2 h, 2 to 24 h, 24 to 48 h postoperatively)

Two trials focused on postoperative pain intensity and reported lower NRS scores in patients treated with perineural compared with intramuscular buprenorphine combined with local anaesthetics.15,20 However, data could be pooled for only two time periods and showed no significant differences [2 to 24 h: mean difference −0.95 NRS Points, 95% CI (−2.91 to 1.00); P = 0.34; I 2 = 93%; 24 to 48 h: mean difference −0.45 NRS Points, 95% CI (−1.51 to 0.61); P = 0.4; I 2 = 80%].

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Onset of motor blockade or sensory blockade, duration of motor blockade

Three RCTs including 185 patients compared the onset of motor blockade in minutes,14,18,24 whereas four trials reported the onset of sensory blockade in minutes.14,18,20,24 One trial did not define onset of sensory blockade.20 Only the onset of motor blockade was significantly faster following perineural administration of buprenorphine [mean difference −0.38 min, 95% CI (−0.72 to −0.04); P = 0.03; I 2 = 0%], whereas there was no evidence of a difference in the onset of sensory blockade [mean difference −0.29 min, 95%CI (−1.43 to 0.85); P = 0.62; I 2 = 94%]. Only one trial reported the duration of motor blockade defined as ‘time between onset of motor blockade to restoration of full hand and wrist mobility’.24 In this trial, there was no evidence of a difference in the duration of motor blockade [mean difference −6.6 min, 95% CI (−23.4 to 10.2); P = 0.44].

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Number of patients with respiratory depression, pruritus, bradycardia, hypotension, sedation or urinary retention

Opioid-related adverse events were reported in four included trials.14,15,18,24 Respiratory depression was the most common adverse event, but only one study14 reported two patients receiving 0.15-mg intramuscular buprenorphine, which required oxygen treatment postoperatively [RR:0.2; 95% CI (0.01 to 4.06); P = 0.29]. No patient suffered from pruritus or bradycardia, whereas one patient in the perineural and one in the intramuscular buprenorphine group suffered from postoperative hypotension.14 Finally, one trial reported one patient treated with 2 μg kg−1 intramuscular buprenorphine who complained of postoperative urinary retention.24

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Comparison of perineural buprenorphine combined with local anaesthetics versus perineural morphine or sufentanil/fentanyl combined with local anaesthetics

Only two trials investigated the comparison of perineural buprenorphine combined with local anaesthetics versus perineural morphine combined with local anaesthetics,13,25 or perineural sufentanil/fentanyl.13,22 Meta-analyses were only possible for the comparison perineural buprenorphine versus morphine for a selected number of outcomes, whereas data could only be pooled for the outcome ‘duration of analgesia’ within the study groups treated with perineural sufentanil/fentanyl or buprenorphine in combination with local anaesthetics.

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Primary outcomes

Duration of analgesia

Two trials compared the perineural administration of morphine in combination with local anaesthetics with buprenorphine in combination with local anaesthetics; combining the results there was no significant difference between the groups [mean difference 7.82 h, 95% CI (−9.62 to 25.27); P = 0.38; I 2 = 98%].13,25 Two other trials investigating the comparison of perineural buprenorphine combined with local anaesthetics versus perineural sufentanil/fentanyl combined with local anaesthetics revealed an almost comparable duration of analgesia [mean difference −0.36 h, 95% CI (−8.11 to 7.39); P = 0.93; I 2 = 93%].13,22 Due to limited data, neither subgroup nor sensitivity analyses were possible.

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Number of patients with postoperative nausea and vomiting

Due to missing data, no meaningful analyses could be performed.

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Number of patients with respiratory depression, pruritus, bradycardia, hypotension, sedation or urinary retention

The number of patients with respiratory depression, pruritus or sedation was mentioned in two trials only.13,25 There were no cases of respiratory depression; there was no evidence of a difference in the risk for sedation [RR 3.0; 95% CI (0.13 to 69.52); P = 0.49] or pruritus [RR 1.08; 95% CI (0.06 to 20.19); P = 0.96; I 2 = 62%].

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Discussion

The present meta-analysis including 13 RCTs (496 participants received either perineural or intramuscular buprenorphine) showed that the addition of perineural buprenorphine to local anaesthetics compared with local anaesthetics alone significantly prolonged the duration of analgesia provided by peripheral nerve blocks by around 8 h. However, the perineural administration of buprenorphine in combination with local anaesthetics compared with local anaesthetics alone significantly increased the risk for PONV, but PONV prophylaxis was not used.

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Efficacy of perineural buprenorphine in peripheral nerve blocks

A recently published analysis showed that the use of peripheral nerve blocks compared with neuraxial regional analgesia is increasing probably due to the use of ultrasound.26 In children, single-shot nerve blocks are more commonly performed than continuous nerve blocks.27,28 However, the duration of analgesia following single-shot nerve blocks is limited by the pharmacokinetics and pharmacodynamics of current local anaesthetics 29,30 as well as side effects such as motor blockade at higher doses. Several additives have been investigated to prolong postoperative analgesia without extending side effects.

First, our meta-analysis revealed that patients treated with 0.1 to 0.3 mg buprenorphine combined with local anaesthetics required rescue analgesia around 9 h later compared with those receiving only local anaesthetics, indicating a large effect. This compares favourably with results from the addition of perineural dexamethasone (∼6 h),31 clonidine (∼2 h)10 or dexmedetomidine (∼5 h).32 However, the quality of evidence in our meta-analysis has to be interpreted with caution, because a funnel plot indicated a high risk of publication bias. Furthermore, we observed a large heterogeneity, which could not be explained within the subgroup analyses and might suggest an inconsistency of data.

Second, we showed that the administration of perineural buprenorphine in combination with local anaesthetics compared with local anaesthetics alone is only associated with a slightly longer duration of motor blockade (∼13 min), which is not relevant in daily practice. In contrast meta-analyses focusing on the use of dexamethasone or clonidine reported longer durations of motor blockade (dexamethasone: ∼5 h31; clonidine: ∼2 h10). Furthermore, the addition of buprenorphine to local anaesthetics (compared with local anaesthetics alone) was associated with a slightly faster clinically insignificant onset of motor blockade (<1 min), but not sensory blockade. This is similar to dexamethasone,31 but clonidine10 is not associated with faster onset of motor blockade.

Third, although the available evidence is currently limited (only two included trials within the present meta-analysis), the addition of perineural buprenorphine to local anaesthetics compared with local anaesthetics alone might also lead to slightly reduced postoperative pain intensity within 24 to 48 h following surgery. In contrast, the meta-analyses focusing on the additive effects of clonidine10 or dexamethasone31 did not show this. Nevertheless, potential reduction of pain scores by perineural buprenorphine needs clarification in the future, because the difference [∼1 NRS (0 to 10 points scale) point] might not be clinically relevant.33

Fourth, the addition of perineural buprenorphine combined with local anaesthetics was associated with a significantly longer duration of analgesia compared with intramuscular administration of buprenorphine combined with local anaesthetics. This important finding indicates a specific perineural effect of buprenorphine. In contrast, it is currently not clear whether perineural administration of dexamethasone or clonidine is more effective than intravenous application of the same drug.10,31 Experimental data showed a peripheral action of opioids, because membranous μ-opioid receptors along the axon of C-fibres of opioid-naïve rats have been characterised.6 The quality of evidence for the outcome ‘duration of analgesia’ for this comparison has to be interpreted with caution due to an asymmetry of the funnel plot and inconsistency of data [large unexplained heterogeneity (I 2 = 95%), subgroup analyses with nonsignificant differences].

Fifth, due to limited data, comparisons of perineural buprenorphine with other opioids were not possible. However, as mentioned in a recently published qualitative review focusing on perineural additives, buprenorphine might be the most interesting opioid due to its pharmacology.34

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Safety of perineural buprenorphine in peripheral nerve blocks

Overall, adverse events following buprenorphine administration were only poorly reported. The most important adverse event following the perineural administration of buprenorphine in combination with local anaesthetics versus local anaesthetics was a five times higher risk of PONV. The calculation of the number-needed-to-harm for this comparison and outcome showed that every thirteenth patient treated with perineural buprenorphine in combination with local anaesthetics suffered from PONV. However, it is important to mention that all patients included in this meta-analysis did not receive any prophylactic drugs (e.g. dexamethasone, 5-HT3-receptor antagonists) against PONV. Other possible opioid-related adverse events were rare (pruritus, hypotension, bradycardia, sedation) or absent (respiratory depression, bradycardia, urinary retention); but this has to interpreted with caution, because adverse events were only poorly reported.

Another important issue is a potential neurotoxicity of buprenorphine. A recently published experimental trial demonstrated that buprenorphine alone was only neurotoxic in supraclinical high concentrations to isolated sensory neuron cells. Furthermore, the addition of buprenorphine to ropivacaine did not increase ropivacaine-induced neurotoxicity even in high supraclinical concentrations.35 Another in-vivo experimental trial in animals showed that perineural buprenorphine combined with bupivacaine did not produce any behavioural changes or any histopathological damage to the sciatic nerve.36 Although the latter trials were performed by the same group and the results should be confirmed by other authors in other animal models, the addition of buprenorphine (in clinically relevant doses) to long-lasting local anaesthetics does not seem to be neurotoxic.

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Limitations

First, despite an intensive literature search, we identified mainly small trials with ‘positive’ results for the outcome ‘duration of analgesia’. Accordingly, the funnel plots (Figs. S1 and S2, http://links.lww.com/EJA/A116) showed an asymmetry indicating a high risk of publication bias for both comparisons ‘buprenorphine combined with local anaesthetics versus local anaesthetics’ and ‘perineural buprenorphine combined with local anaesthetics versus systemic buprenorphine combined with local anaesthetics’. Second, although several subgroup and sensitivity analyses were performed, we could not finally explain the large heterogeneity influencing the primary outcome ‘duration of analgesia’. Possibly, the different definitions for duration of analgesia and for onset or duration of sensory or motor blockade might have influenced the results. However, standardised definitions for outcomes of regional analgesia research are lacking37 but are urgently needed to compare different study results. Therefore, the quality of evidence in this meta-analysis should be interpreted with caution, and further RCTs are needed to study other possible influencing factors (e.g. buprenorphine dose, local anaesthetics dose). Third, almost all trials used nerve-stimulation as the primary guiding technique, whereas only one included trial19 used nerve-stimulation in combination with ultrasound. However, ultrasound is now the gold standard as the guiding technique for peripheral nerve blocks and catheters,38,39 and much lower volumes can be administered very close to the nerve40 with a higher success rate and a lower risk of adverse events. The efficacy and safety of the addition of buprenorphine to local anaesthetics should be studied only in ultrasound-guided nerve blocks in the future. Fourth, intramuscular buprenorphine application was the comparator in studies investigating systemic buprenorphine effects, but intramuscular injections of analgesics are obsolete. Thus, sublingual or intravenous buprenorphine should be investigated as the comparator in the future.

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Implications for research

The present meta-analysis did not demonstrate any buprenorphine dose-dependent effect on the duration of analgesia, although according to a retrospective data analysis patients treated with more than 0.2 mg (compared with those receiving less than 0.2 mg) buprenorphine reported a longer duration of analgesia and lower rebound pain scores.41 Prospective dose-finding studies (e.g. 0.1 to 0.3 mg perineural buprenorphine) are currently lacking but are urgently needed to clarify this point. In addition, different types (e.g. long-lasting or short-lasting) and doses of local anaesthetics in combination with perineural buprenorphine might influence the duration of analgesia, but the present meta-analysis did not show an influence of the type of local anaesthetics used. There is a need for trials investigating this issue in the future, because perineural buprenorphine in combination with lower doses of local anaesthetics or short-lasting local anaesthetics might be associated with a comparable duration of analgesia with a lower duration of motor blockade (compared with the use of perineural buprenorphine combined with higher doses of local anaesthetics or long-lasting local anaesthetics). Focusing on the risk of PONV following perineural buprenorphine, the use of prophylactic drugs might be another important issue. A recently published RCT comparing the analgesic efficacy of perineural and intravenous dexamethasone in combination with perineural buprenorphine (combined with local anaesthetics) for sciatic nerve blocks showed that following administration of 4-mg ondansetron and 4-mg dexamethasone the RR for PONV was as low as in patients not receiving buprenorphine.42 Therefore, future RCTs should investigate the benefits and harms of perineural buprenorphine combined with local anaesthetics compared with local anaesthetics alone in patients receiving modern recommended PONV prophylaxis, because the RR presented in this meta-analysis might be overestimated. Generally, head-to-head comparisons with other perineural additives (e.g. dexamethasone, dexmedetomidine) are missing but are urgently needed to define the role of buprenorphine in peripheral regional anaesthesia.

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Conclusion

The present meta-analysis demonstrates a benefit of perineural buprenorphine in combination with local anaesthetics (versus local anaesthetics alone) by prolonging analgesia by around 9 h, but it is associated with a five times higher risk of PONV. The perineural administration of buprenorphine in combination with local anaesthetics produces a longer duration of analgesia than systemic buprenorphine combined with local anaesthetics. However, there is no evidence for a difference on the risk for PONV between the latter groups. Due to the fact that no included study administered a prophylactic drug with the aim to prevent PONV, the role of the increased risk of PONV following perineural buprenorphine is unclear and might be overestimated from the presented results. Buprenorphine may be a promising adjuvant for local anaesthetic peripheral nerve blockade, but the level of evidence of this meta-analysis has to be interpreted with caution due to the high risk of publication bias and large heterogeneity.

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Acknowledgements relating to this article

Assistance with the study: the authors thank Dr Med. Hua Zheng (Department of Anaesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China) for the translation of one included trial.20

Financial support and sponsorship: none.

Conflicts of interest: none.

Presentation: none.

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