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; I2 = 0%].14,18
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; I2 = 93%; 24 to 48 h: mean difference −0.45 NRS Points, 95% CI (−1.51 to 0.61); P = 0.4; I2 = 80%].
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; I2 = 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; I2 = 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].
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
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.
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; I2 = 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; I2 = 93%].13,22 Due to limited data, neither subgroup nor sensitivity analyses were possible.
Number of patients with postoperative nausea and vomiting
Due to missing data, no meaningful analyses could be performed.
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; I2 = 62%].
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.
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 (I2 = 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
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.
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.
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.
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.
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.
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