Efficacy and adverse events of selective serotonin noradrenaline reuptake inhibitors in the management of postoperative pain: A systematic review and meta-analysis.

STUDY OBJECTIVE: Selective-serotonin-noradrenaline-reuptake inhibitors (SSNRI) might be an interesting option for postoperative pain treatment. Objective was to investigate postoperative pain outcomes of perioperative SSNRI compared to placebo or other additives in adults undergoing surgery. DESIGN: Systematic review of randomised controlled trials (RCT) with meta-analysis and GRADE assessment. SETTING: Acute and chronic postoperative pain treatment. PATIENTS: Adult patients undergoing surgery. INTERVENTIONS: Perioperative administration of SSNRI. MEASUREMENTS: Primary outcomes were postoperative acute pain at rest/during movement (measured on a scale from 0 to 10), number of patients with chronic postsurgical pain (CPSP) and with SSNRI-related adverse events. MAIN RESULTS: Fourteen RCTs (908 patients) were included. We have high-quality evidence that duloxetine has no effect on pain at rest at 2 h (MD: -0.02; 95% confidence interval (CI) -0.51 to 0.47), but probably reduces it at 48 h (MD: -1.16; 95%CI -1.78 to -0.54). There is low- and moderate-quality evidence that duloxetine has no effects on pain during movement at 2 h (MD: -0.42; 95%CI -1.53 to 0.69) and 48 h (MD: -0.91; 95% CI -2.08 to 0.26), respectively. We have very low-quality evidence that duloxetine might reduce pain at rest (MD: -0.45; 95%CI -0.74 to -0.15) and movement (MD: -1.19; 95%CI -2.32 to -0.06) after 24 h. We have low-quality evidence that duloxetine may reduce the risk of CPSP at 6 months (RR:0.35; 95%CI 0.14 to 0.90). There is moderate-quality evidence that duloxetine increases the risk of dizziness (RR:1.72; 95%CI 1.26 to 2.34). CONCLUSION: At the expense of a higher risk for dizziness, SSNRI may be effective in reducing postoperative pain between 24 and 48 h after surgery. However, the results of the meta-analyses are mostly imprecise and duloxetine might only be used in individual cases. Protocol registration: CRD42018094699.

Adductor canal blocks for postoperative pain treatment in adults undergoing knee surgery.

BACKGROUND: Peripheral regional anaesthesia techniques are well established for postoperative pain treatment following knee surgery. The adductor canal block (ACB) is a new technique, which can be applied as a single shot or by catheter for continuous regional analgesia. OBJECTIVES: To compare the analgesic efficacy and adverse events of ACB versus other regional analgesic techniques or systemic analgesic treatment for adults undergoing knee surgery. SEARCH METHODS: We searched CENTRAL, MEDLINE, and Embase, five other databases, and one trial register on 19 September 2018; we checked references, searched citations, and contacted study authors to identify additional studies. SELECTION CRITERIA: We included all randomized controlled trials (RCTs) comparing single or continuous ACB versus other regional analgesic techniques or systemic analgesic treatment. Inclusion was independent of the technique used (landmarks, peripheral nerve stimulator, or ultrasound) and the level of training of providers. DATA COLLECTION AND ANALYSIS: We used Cochrane's standard methodological procedures. Our primary outcomes were pain intensity at rest and during movement; rate of accidental falls; and rates of opioid-related adverse events. We used GRADE to assess the quality of evidence for primary outcomes. MAIN RESULTS: We included 25 RCTs (1688 participants) in this review (23 trials combined within meta-analyses). In 18 studies, participants underwent total knee arthroplasty (TKA), whereas seven trials investigated patients undergoing arthroscopic knee surgery. We identified 11 studies awaiting classification and 11 ongoing studies. We investigated the following comparisons. ACB versus sham treatment We included eight trials for this comparison. We found no significant differences in postoperative pain intensity at rest (2 hours: standardized mean difference (SMD) -0.56, 95% confidence interval (CI) -1.20 to 0.07, 4 trials, 208 participants, low-quality evidence; 24 hours: SMD -0.49, 95% CI -1.05 to 0.07, 6 trials, 272 participants, low-quality evidence) or during movement (2 hours: SMD -0.59, 95% CI -1.5 to 0.33; 3 trials, 160 participants, very low-quality evidence; 24 hours: SMD 0.03, 95% CI -0.26 to 0.32, 4 trials, 184 participants, low-quality evidence). Furthermore, they noted no evidence of a difference in postoperative nausea between groups (24 hours: risk ratio (RR) 1.91, 95% CI 0.48 to 7.58, 3 trials, 121 participants, low-quality evidence). One trial reported that no accidental falls occurred 24 hours postoperatively (low-quality evidence). ACB versus femoral nerve block We included 15 RCTs for this comparison. We found no evidence of a difference in postoperative pain intensity at rest (2 hours: SMD -0.74, 95% CI -1.76 to 0.28, 5 trials, 298 participants, low-quality evidence; 24 hours: SMD 0.04, 95% CI -0.09 to 0.18, 12 trials, 868 participants, high-quality evidence) or during movement (2 hours: SMD -0.47, 95% CI -1.86 to 0.93, 2 trials, 88 participants, very low-quality evidence; 24 hours: SMD 0.56, 95% CI -0.00 to 1.12, 9 trials, 576 participants, very low-quality evidence). They noted no evidence of a difference in postoperative nausea (24 hours: RR 1.22, 95% CI 0.42 to 3.54, 2 trials, 138 participants, low-quality evidence) and no evidence that the rate of accidental falls during postoperative care was significantly different between groups (24 hours: RR 0.20, 95% CI 0.04 to 1.15, 3 trials, 172 participants, low-quality evidence). AUTHORS' CONCLUSIONS: We are currently uncertain whether patients treated with ACB suffer from lower pain intensity at rest and during movement, fewer opioid-related adverse events, and fewer accidental falls during postoperative care compared to patients receiving sham treatment. The same holds true for the comparison of ACB versus femoral nerve block focusing on postoperative pain intensity. The overall evidence level was mostly low or very low, so further research might change the conclusion. The 11 studies awaiting classification and the 11 ongoing studies, once assessed, may alter the conclusions of this review.

Efficacy and safety of dexmedetomidine in peripheral nerve blocks: A meta-analysis and trial sequential analysis.

BACKGROUND: The duration of analgesia provided by nerve blocks is limited if local anaesthetics are administered alone. Therefore, several additives, including dexmedetomidine (DEX), have been investigated in order to prolong postoperative analgesia following single-shot regional anaesthesia. OBJECTIVES: The aim of this meta-analysis was to assess the efficacy and safety of the addition of perineural DEX to local anaesthetics compared with local anaesthetics alone or local anaesthetics combined with systemic administration of DEX. DESIGN: A systematic review of randomised controlled trials (RCT) with meta-analysis, trial sequential analysis and assessment of the quality of evidence by the GRADE approach. DATA SOURCES: The databases MEDLINE, CENTRAL and EMBASE (to May 2017) were systematically searched. ELIGIBILITY CRITERIA: All RCTs investigating the efficacy and safety of perineural DEX combined with local anaesthetics compared with local anaesthetics alone or local anaesthetics in combination with systemic DEX in peripheral nerve blocks of adults undergoing surgery were included. RESULTS: A total of 46 RCTs (3149 patients) were included. Patients receiving perineural DEX combined with local anaesthetics had a longer duration of analgesia than local anaesthetics alone [mean difference 4.87 h; 95% confidence interval (95% CI) 4.02 to 5.73; P < 0.001; I = 100%; moderate-quality evidence]. The most important adverse events in the DEX group were intraoperative bradycardia [risk ratio 2.83; 95% CI 1.50 to 5.33; P = 0.035; I = 40%; very low-quality evidence] and hypotension (risk ratio 3.42; 95% CI 1.24 to 9.48; P = 0.002; I = 65%; very low quality evidence). In contrast, there were no differences in the duration of analgesia between perineural or intravenous DEX combined with local anaesthetics (mean difference 0.98 h; 95% CI -0.12 to 2.08; P = 0.08; I = 0%). CONCLUSION: This meta-analysis demonstrated that DEX in combination with local anaesthetics increases postoperative analgesia for around 5 h. However, there are higher risks of intraoperative hypotension and bradycardia. Findings on side effects are associated with high uncertainty. Initial evidence suggests no difference in the duration of analgesia associated with systemic or perineural DEX. TRIAL REGISTRATION: CRD42016042486.

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

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.

Tramadol for postoperative pain treatment in children.

BACKGROUND: According to current recommendations a multimodal approach is believed to be the gold standard for postoperative pain treatment in children. However, several surveys in the last few years demonstrated that postoperative pain in children is still a serious problem, mainly because opioids are avoided. One of the reasons for this is the fear of severe adverse events following opioid administration. Tramadol is a weak mu-opioid agonist and inhibits reuptake of noradrenaline and serotonin (5HT). Because of a relatively wide therapeutic window and a ceiling effect with a lower risk for severe adverse events (for example respiratory depression) tramadol is a widely used opioid in children. However, the exact efficacy and occurrence of adverse events following tramadol (in comparison with placebo or other opioids) for postoperative pain treatment in children and adolescents are currently not clear. OBJECTIVES: To assess the effectiveness and side effect profile of tramadol for postoperative pain relief in children and adolescents undergoing different surgical procedures. SEARCH METHODS: We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 6), MEDLINE via PubMed (January 1966 to July 2014) and EMBASE via Ovid (January 1947 to July 2014). There were no restrictions regarding language or date of publication. The reference lists of all included trials were checked for additional studies. SELECTION CRITERIA: All randomised controlled clinical trials investigating the perioperative administration of tramadol compared to placebo or other opioids for postoperative pain treatment in children and adolescents were included. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed the study eligibility, performed the data extraction and assessed the risk of bias of included trials. MAIN RESULTS: Twenty randomised controlled trials involving 1170 patients were included in this systematic review. The overall risk of bias in included trials was assessed as unclear, because concealment of allocation processes and blinding of outcome assessors were poorly described. Due to inconsistent outcome reporting, data from 17 included trials could be pooled for some endpoints only. Eight trials compared tramadol administration with placebo and five trials found that the need for rescue analgesia in the postoperative care unit (PACU) was reduced in children receiving tramadol (RR 0.40; 95% CI 0.20 to 0.78; low quality evidence). Only one trial investigated the number of patients with moderate to severe pain, but a non-validated pain scale was used (very low quality evidence). Four trials compared morphine with tramadol administration. There was no clear evidence of difference in the need for rescue analgesia in the PACU (RR 1.25; 95% CI 0.83 to 1.89; low quality evidence) with tramadol compared with morphine. No trials could be pooled for the outcome 'number of patients with moderate to severe pain'. Three trials were included for the comparison of tramadol with nalbuphine. There was no clear evidence for the need for rescue analgesia in the PACU (RR 0,63; 95% CI 0.16 to 2.45; low quality evidence). Only one trial reported the number of patients with moderate to severe pain, but used a non-validated pain scale (very low quality evidence). Two out of six included trials, which compared pethidine with tramadol, reported the number of children with a need for rescue analgesia within the PACU and showed no clear evidence (RR 0.93; 95% CI 0.43 to 2.02; very low quality evidence). Two trials reported the number of patients with moderate to severe pain and showed a lower RR in patients treated with tramadol (RR 0.64; 95% CI 0.36 to 1.16; low quality evidence). Only one trial was included, which compared tramadol with fentanyl, reporting the number of patients with the need for rescue analgesia (very low quality evidence). Generally, adverse events were poorly reported. Most data could be pooled for the comparison with placebo focusing on the RR for postoperative nausea and vomiting (PONV) in the postoperative care unit and 24 h postoperation. Children treated with tramadol, compared to placebo, did not show clear evidence of benefit for PONV in the postoperative care unit (RR 0.84; 95% CI 0.28 to 2.52; moderate quality evidence) and 24 h postoperation (RR 0.78; 95% CI 0.54 to 1.12; moderate quality evidence). AUTHORS' CONCLUSIONS: The overall evidence regarding tramadol for postoperative pain in children is currently low or very low and should be interpreted with caution due to small studies and methodological problems (different validated and non-validated pain scales with different pain triggers, missing sample size calculations and missing intention-to-treat analysis). Nevertheless, we demonstrated that tramadol administration might provide appropriate analgesia when compared to placebo; this is based on results showing reduced rescue analgesia in children treated with tramadol compared to placebo. In contrast, the evidence regarding the comparison with other opioids (for example morphine) was uncertain. Adverse events were only poorly reported, so an accurate risk-benefit analysis was not possible.

Nalbuphine for postoperative pain treatment in children.

BACKGROUND: Several surveys over the past few years have demonstrated that postoperative pain in children is not treated appropriately. One pharmacological treatment option in a multimodal approach for postoperative pain treatment is the systemic administration of opioids. However, opioids are rarely used for postoperative pain treatment in children due to fear of adverse events. One long-standing opioid for systemic use is nalbuphine, a kappa-receptor agonist and µ-receptor antagonist. The efficacy of nalbuphine is believed to be similar to morphine. Increased dosing might result in a ceiling effect, and thus less analgesia than expected. In addition, there might be a lower risk for opioid-induced side effects (nausea, vomiting) and severe adverse events (respiratory depression) due to the antagonistic effect of the µ-receptor. Nalbuphine may be an useful opioid for postoperative use in children, but exact efficacy (e.g. compared to other commonly used opioids) has not been determined yet. OBJECTIVES: To assess the efficacy and adverse events of nalbuphine for acute postoperative pain treatment in children undergoing surgery. SEARCH METHODS: We systematically searched the following databases: The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 7), MEDLINE via Pubmed (January 1966 to July 2013) and EMBASE via Ovid (January 1947 to July 2013). We did not impose any restrictions regarding language or publication date. We checked all reference lists of retrieved articles for additional references. SELECTION CRITERIA: All randomised controlled trials (RCTs) investigating nalbuphine compared with placebo or other opioids were included. DATA COLLECTION AND ANALYSIS: Two review authors independently scanned the retrieved articles and made a decision regarding inclusion or exclusion of studies for this review. The same authors also performed the data extraction and the assessment of risk of bias. MAIN RESULTS: Ten RCTs including 658 patients were finally included in this systematic review. Five trials compared nalbuphine with placebo. Data from one out of five studies for the outcome moderate/severe pain following nalbuphine compared to placebo gave a risk ratio (RR) 1 hour postoperatively (postop) of 0.1 (95% confidence interval (CI) 0.01 to 0.71; low quality evidence) and a RR 2 hours postop of 0.14 (95% CI 0.02 to 1.06; low quality evidence). The estimated RR based on data from a single study indicated that nalbuphine reduced the requirement for analgesia two hours postop (RR 0.47; 95% CI 0.27 to 0.84; low quality evidence). Two included trials compared nalbuphine with morphine and showed a nonsignificant lower or comparable RR for moderate/severe pain at 1 hour postop (RR 0.84; 95% CI 0.12 to 5.74; low quality evidence), and 2 hours postop (RR 1.09; 95% CI 0.59 to 2.01; low quality evidence) for nalbuphine versus morphine. Four trials compared nalbuphine with tramadol for postoperative pain; data from one trial (per outcome) revealed a lower but nonsignificant RR for the need of additional rescue analgesics in children receiving nalbuphine (RR 2 hours postop 0.75; 95% CI 0.39 to 1.43; low quality evidence) (RR 12 hours postop 0.33; 95% CI 0.04 to 2.77; low quality evidence). One out of three trials comparing nalbuphine with pethidine demonstrated that the RR was not significantly lower following nalbuphine administration compared to pethidine (RR 2 hours postop 1.07; 95% CI 0.52 to 2.23; low quality evidence) (RR 24 hours postop 1.13; 95% CI 0.52 to 2.44; very low quality evidence). The most common adverse event was postoperative nausea and vomiting (PONV). Only one included trial reported that the RR for PONV in the postoperative care unit (PACU) was not significantly higher following nalbuphine compared to placebo (RR 1.00; 95% CI 0.16 to 6.42; low quality evidence) nor to morphine (RR 1.33; 95% CI 0.64 to 2.77; low quality evidence). AUTHORS' CONCLUSIONS: Because the overall quality of available evidence was low, this systematic review could not definitively show that the analgesic efficacy of nalbuphine is superior compared to placebo. Furthermore, due to the lack of significant results the comparison with other common opioids is also unclear. The same holds true for the evidence focusing on adverse events following nalbuphine compared to placebo or other opioid administration. The evidence is limited, because studies did not report conclusively all important postoperative pain outcomes (e.g. number of patients with the need for rescue analgesia, postoperative pain scores). Thus, a quantitative analysis was not possible for many major aspects (e.g. rescue analgesia, pain scores) and heterogeneity could not be further explored.

Efficacy and safety of intraoperative dexmedetomidine for acute postoperative pain in children: a meta-analysis of randomized controlled trials.

BACKGROUND: Aim of the current meta-analysis was to assess the effects of intraoperative dexmedetomidine on postoperative pain, analgesic consumption, and adverse events in comparison with placebo or opioids in children undergoing surgery. METHODS: This meta-analysis was performed according to the recommendations of the PRISMA statement and the Cochrane collaboration. For dichotomous and continuous outcomes of efficacy and adverse events, the Revman(®) (The Nordic Cochrane Centre, Copenhagen, Denmark) statistical software was used to calculate relative risk (RR), mean difference (MD), and 95% confidence intervals (CI). RESULTS: We included 11 randomized controlled trials - 434 children received dexmedetomidine, 440 received control. In comparison with placebo, children receiving dexmedetomidine showed a reduced RR for postoperative opioids (0.4; 95% CI: 0.26-0.62; P < 0.00001) and postoperative pain (0.51; 95% CI: 0.32-0.81; P = 0.004). Similar results were obtained for the comparison with intraoperative opioids: reduced RR for postoperative pain (0.49; 95% CI: 0.25-0.94; P = 0.03) and the need for postoperative opioids (0.77; 95% CI: 0.60-1.09; P = 0.05). CONCLUSIONS: This meta-analysis revealed a lower risk for postoperative pain and the need for postoperative opioids following intraoperative dexmedetomidine in comparison with placebo or opioids in children undergoing surgery; however, the influence of dexmedetomidine on postoperative opioid consumption is less clear. Although there were only a limited number of adverse events, further studies focusing on procedure specific dexmedetomidine dosing and adverse events are urgently needed.

The assessment of cold hyperalgesia after an incision.

BACKGROUND: Although cold hypersensitivity is a well-documented phenomenon in animals and humans with inflammatory and neuropathic pain, little is known about the presence of cold hyperalgesia after surgery. Therefore, we studied primary cold hyperalgesia after a surgical incision in mice. METHODS: Before and after plantar incision, inflammation with complete Freund adjuvant, and spared nerve ligation, unrestrained male animals were placed on a Peltier-cooled cold plate with a surface temperature of 0 degrees C and withdrawal latencies were measured. Additionally, incision-induced cold hyperalgesia was also assessed in female animals. Furthermore, skin temperature before and after plantar incision and inflammation were assessed by using infrared thermography (Varioscan LW 3011; Infratec, Dresden, Germany). RESULTS: Cold hyperalgesia to a noxious cold stimulus was observed after inflammation and nerve injury but not after a surgical incision. Similar results were demonstrated for female animals after incision. Furthermore, a significant increase in skin temperature was recorded after inflammation but not after incision, indicating that a surgery evokes only minor inflammatory effects. CONCLUSION: The present data give strong evidence that a surgical incision does not cause cold hyperalgesia. Furthermore, a lack of cold hyperalgesia in unrestrained male and female mice after incision was not due to increased skin temperature after incision. Finally, we demonstrated that in contrast to a surgical incision, inflammation and nerve injury generate intense cold hyperalgesia and an increase in skin temperature, suggesting that different mechanisms are involved in surgical and inflammatory or neuropathic pain.