Intra-articular dexmedetomidine in knee arthroscopy: A systematic review and meta-analysis

The aim of this meta-analysis is to evaluate the analgesic effects of intra-articular dexmedetomidine (DEX) in arthroscopic knee surgery. A comprehensive literature search was conducted to identify randomized controlled trials (RCTs) comparing intra-articular DEX versus control for postoperative analgesia in knee arthroscopy. Trial sequential analysis (TSA) was applied to determine the reliability of the evidence. Twelve RCTs including 594 patients met the eligibility criteria. DEX treatment significantly improved postoperative pain outcomes, with weighted mean differences (95% confidence interval) between the DEX and control groups of −1.57 (−1.94 to −1.20, P < 0.00001) for pain scores at rest at postoperative 1 h, −8.54 mg (−11.96 to −5.13, P < 0.00001) for morphine-equivalents at postoperative 0–24 h, and 257.57 min (209.86 to 305.28, P < 0.00001) for time to first request for postoperative analgesia. TSA indicated there is sufficient evidence for these outcomes. Intra-articular DEX did not affect the incidence of postoperative nausea and vomiting, hypotension, bradycardia, or somnolence. This meta-analysis demonstrated that intra-articular administration of DEX improved pain outcomes in the early postoperative period after knee arthroscopy. Due to the limited number of trials and patients included in this meta-analysis, more evidence is required to confirm these findings.

participants: adult patients undergoing arthroscopic knee surgery; (3) comparisons: intra-articular DEX versus saline control, or intra-articular DEX combined with a local anesthetic versus local anesthetic alone; and (4) outcomes: postoperative pain scores, opioid requirement, time to first request for postoperative analgesia, and incidence of postoperative nausea and vomiting (PONV), hypotension, bradycardia, or somnolence. Exclusion criteria were: (1) study design other than a RCT; (2) reviews, letters, abstracts, or editorials; or (3) studies that reported insufficient data. Disagreements about study selection were resolved by group discussion and consensus. Data extraction. Two authors (KP, WRC) independently extracted data from each eligible RCTs, including first author, publication year, number of patients, type of anesthesia, type of intraoperative and postoperative analgesia, and outcome measures.
Primary outcome measures were postoperative pain and cumulative opioid consumption. Postoperative pain was measured as pain at rest at postoperative 1, 2, 4, 6, 8, 12, and 24 h and on movement at postoperative 1, 2, and 8 h expressed on a visual analog scale (VAS), where 0 = no pain and 10 = the most severe pain. Opioid consumption during postoperative 0-24 h was expressed in milligrams of morphine equivalent, where intravenous (i.v.) morphine 10 mg = i.v. tramadol 100 mg = i.v. fentanyl 0.1 mg 10,11 . Secondary outcomes were time to first request for postoperative analgesia and incidence of PONV, hypotension, bradycardia, or somnolence.
Disagreements about data extraction were resolved by group discussion and consensus.
Quality assessment. Two authors (KP, XWM) independently graded the methodological quality of each RCT and the quality of evidence for each outcome measure. The methodological quality was assessed with the Cochrane risk of bias tool 9 . Seven domains (random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias [baseline characteristics, funding]) were examined. Risk of bias was categorized as high (one or more domains were high risk), low (all domains were low risk), or unclear (other).
The quality of evidence for each outcome measure was evaluated with Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology (https://gradepro.org) 12 . Evidence was categorized as high, moderate, low, or very low according to five criteria: risk of bias, inconsistency, indirectness, imprecision, and publication bias.
Publication bias was assessed using Begg's rank correlation test and Egger's linear regression test 13,14 .
Disagreements about quality assessment were resolved by group discussion and consensus.
Statistical analysis. Statistical analyses were performed using STATA 14.0 (Stata Corp, College Station, TX).
To describe the effect size of an intervention, risk ratios (RRs) with 95% confidence intervals (CIs) were calculated for dichotomous data, and weighted mean differences (WMDs) with 95% CIs were calculated for continuous variables. A random-effects model was used in this meta-analysis 15 . Heterogeneity was measured and expressed as I 2 , with I 2 > 50% indicating significant heterogeneity 16 . Subgroup analyses were conducted for the outcome measures, stratified by allocation concealment (adequate or unclear), use of local anesthetic (yes or no), type of postoperative analgesic (opioids or none opioids), use of postoperative patient-controlled analgesia (PCA, yes or no), and DEX dose (≤1 µg/kg or >1 µg/kg). Sensitivity analysis was performed by omitting one study at a time to assess the effect of a single comparison on the overall estimates 17 . P < 0.05 denoted statistical significance.
As Type I and Type II errors may arise in a meta-analysis due to small sample size 18 , we assessed the reliability of the current results using TSA (version 0.9.5.5 beta, http://www.ctu.dk/tsa) 18,19 . If the cumulative Z curve crosses the trial sequential monitoring boundary or the futility boundary in the TSA diagram, it is unlikely that an anticipated effect is absent, or that further studies will change the inference. The required information size was calculated using a Type I error of 5%, a power of 80%, and intervention effects in RCTs with adequate allocation concealment 15,20 .

Author, year Country Groups and interventions (n)
Age (y), % males

Results
The initial literature search identified 125 articles. Of these, 113 were excluded because they failed to meet the eligibility criteria or were duplicates. A total of 12 RCTs involving 594 participants were finally included in this meta-analysis 7,21-31 . The PRISMA flow diagram is shown in Fig. 1. The characteristics of the included trials are provided in Table 1. Five trials compared intra-articular DEX with saline 7,21,22,25,30 , and seven trials compared a combination of DEX and a local anesthetic to local anesthetic alone 23,24,[26][27][28][29]31 . The risk assessment is presented in Fig. 2. All trials were randomized and double-blind, with adequate allocation concealment in 6 trials 7,21,24,26-28 .
The primary and secondary outcomes are summarized in Table 2. The meta-analysis demonstrated significantly lower postoperative pain intensity at rest (1 h postoperatively: WMD, −1.57 [95% CI −1.94 to −1.20]; P = 0.0001) in patients treated with intra-articular DEX or a combination of DEX and local anesthetic compared to saline or local anesthetic alone (Fig. 3a). This statistically significant difference was also observed at postoperative 2 to 24 h and at 3 time points for pain intensity on movement. According to the TSA, the required information size of 147 patients was reached and the cumulative Z curve crossed the trial sequential monitoring boundary, indicating there is sufficient evidence for this outcome (Fig. 3b). Sensitivity analysis demonstrated these findings were robust (Fig. 3c), with pooled WMDs ranging from −1.65 (95% CI −2.04 to −1.26) to −1.44 (95% CI −1.78 to −1.10). Begg's funnel plot (P = 0.002, Fig. 3d) and Egger's test (P < 0.0001) indicated publication bias.
At postoperative 0-24 h, opioid consumption was significantly reduced with a WMD of −8.54 mg morphine-equivalents in patients treated with intra-articular DEX or a combination of DEX and local anesthetic compared to saline or local anesthetic alone (Fig. 4a,b). Sensitivity analysis demonstrated these findings were robust, with pooled WMDs ranging from −9.48 mg (95% CI −12.37 to −6.58) to −7.16 mg (95% CI −9.33 to −5.00) (Fig. 4c). No evidence of publication bias was observed on Begg's funnel plot (P = 0.707, Fig. 4d) or Egger's test (P = 0.328).
The use of intra-articular DEX or a combination of DEX and local anesthetic led to a longer time to first request for postoperative analgesia compared to saline or local anesthetic alone (WMD = 257.57 min) (Fig. 5a,b). Sensitivity analysis demonstrated these findings were robust, with pooled WMDs ranging from 244.42 min (95% CI 199.35 to 289.49) to 272.65 min (95% CI 218.34 to 326.96) (Fig. 5c). Begg's funnel plot (P = 0.064, Fig. 5d) and Egger's test (P = 0.002) indicated publication bias.  For adverse effects, there were no significant differences in the incidence of PONV, hypotension, bradycardia, or somnolence between the DEX and control groups (Fig. 6a-d).
Subgroup analyses are shown in Table 3. Use of local anesthetic (yes or no) and postoperative PCA (yes or no) and DEX dose (≤1 µg/kg or >1 µg/kg) may account for the heterogeneity in some of the findings.
The GRADE evidence profiles for the outcome measures are shown in Table 4. The level of evidence was moderate for pain intensity at rest at postoperative 1 h, and low for pain intensity on movement at postoperative 1 h, morphine-equivalents at postoperative 0-24 h, time to first request for postoperative analgesia, PONV, hypotension, and bradycardia.

Discussion
In this meta-analysis, intra-articular DEX use significantly decreased postoperative pain and opioid consumption in patients undergoing arthroscopic knee surgery. The analgesic effect of DEX was also indicated by a longer time to first request for postoperative analgesia. The evidence for each outcome measure was verified by TSA. No difference was found in the incidence of PONV, hypotension, or bradycardia between the DEX and control groups.
Arthroscopic surgery is a minimally invasive orthopedic surgical procedure. However, postoperative pain can be underestimated. Al-Metwalli et al. showed that patients treated with intra-articular and i.v. saline reported pain intensity of 5 points on a VAS up to 12 h postoperatively 7 . This pain, if left untreated, delays patient discharge and postoperative rehabilitation. Considering the adverse effects associated with systemic opioid use, intra-articular analgesia administration is simple and may provide a better alternative. In this meta-analysis, DEX treatment decreased VAS pain scores by 1.57 points at rest and 1.71 points on movement at postoperative 1 h. The reduction in postoperative pain decreased to 0.34 points at 24 h, but the difference remained significant. Further, morphine-equivalents were 8.54 mg lower and the time to first request for postoperative analgesia was 257.57 min longer in the DEX treatment group compared to the control group. To the authors' knowledge, these are the first data to demonstrate that the analgesic effects of intra-articular DEX occur mainly in the early postoperative period.
The mechanism underlying the effects of intra-articular DEX is unknown. There may be direct local action, but central action by systemic absorption should not be excluded. A recent study revealed simultaneous perineural administration of clonidine and DEX prolonged sensory and motor blockade by local anesthetics 32,33 . Supraspinal, spinal, and peripheral mechanisms could be involved in the analgesic effects of α2 adrenergic receptor agonists 34 . Similar to clonidine, DEX acts on presynaptic receptors and inhibits the release of norepinephrine at peripheral afferent nociceptors 6 . Some evidence suggests that α2 adrenoceptor stimulation causes analgesia by facilitating inhibitory synaptic responses in the superficial dorsal horn 35 . Notably, the effects of DEX are not limited to its interactions with α2 adrenergic receptors. A direct inhibition of tetrodotoxin-resistant Na + channels may contribute to the antinociceptive effects of clonidine and DEX when used in addition to local anesthesia 36 . Another study indicated that DEX inhibited neuronal delayed-rectifier potassium currents and sodium currents to produce local anesthetic effects 37 .
Systemic DEX infusion potentiates intra-and postoperative analgesia, and perineural DEX may improve the onset and quality of neuraxial and peripheral nerve block 33,38 . However, hemodynamic changes such as hypotension, bradycardia, or both have been reported. In this meta-analysis, intra-articular DEX did not increase the incidence of hypotension or bradycardia compared to that in the control group. The low incidence of adverse effects may be related to the lack of vessels in the articular surface and the relatively small dose of DEX administered.
This meta-analysis has several limitations. First, only 12 trials met the inclusion criteria, and the number of patients was relatively small. Second, substantial heterogeneity was found for some outcome measures. According to subgroup analyses, inconsistencies in the use of local anesthetic and in the postoperative PCA and DEX doses may account for the heterogeneity. Third, although TSA indicated sufficient evidence for the conclusions, the level of evidence achieved by the GRADE methodology was low or moderate. Therefore, the current results should be interpreted with caution. Finally, there are no data on the long-term effects of intra-articular DEX administration; therefore, this study is only relevant to the early postoperative period, specifically, up to postoperative 24 h. Consequently, further well-conducted prospective studies with adequate power to evaluate short-and long-term outcomes after intra-articular administration of DEX are warranted.
In conclusion, intra-articular administration of DEX improved pain outcomes in the early postoperative period after knee arthroscopy. More evidence is required to confirm these findings.