Dexmedetomidine as an Adjuvant to Nerve Block for Cancer Surgery: A Systematic Review and Meta-Analysis

Background/Objectives: Our understanding of dexmedetomidine, as an adjuvant to nerve blocks in cancer surgery, is characterized by a current lack of compelling evidence, and it remains unknown whether the potential benefits of use outweigh the risks. The aim of the study was to evaluate the benefit and safety profiles of dexmedetomidine as an adjuvant to nerve blocks in cancer surgery. Methods: Systematic searches were conducted in MEDLINE, ScienceDirect, Cochrane Library, Springer, medRxiv, and Scopus up to 17 May 2024. Risk ratios (RR) for binary outcomes and standardized mean differences (SMDs) for continuous outcomes were quantified. Results: Twenty studies were identified. In breast cancer surgery, the use of dexmedetomidine reduced 24 h total morphine consumption (SMD = −1.99 [95% CI −3.01 to −0.98], p = 0.0001, I2 = 91%, random effects) and prolonged the requirement for morphine rescue analgesia (SMD = 2.98 [95% CI 0.01 to 5.95], p = 0.05, I2 = 98%, random effects). In abdominal cancer surgery, the dexmedetomidine group had lower total sufentanil consumption (SMD = −1.34 [95% CI −2.29 to −0.40], p = 0.005, I2 = 84%, random effects). Dexmedetomidine reduced the VAS score and decreased postoperative nausea and vomiting (PONV). No studies using dexmedetomidine reported serious adverse events. Conclusions: Using dexmedetomidine as an adjuvant to nerve blocks in cancer surgery could lower the VAS pain score and prolong the regional anesthesia duration, which would lead to a decrease in total opioid consumption and possibly contribute to fewer PONV events. Furthermore, the reports of no serious adverse events indicate its good safety profile.


Introduction
Surgery is one of the main treatments for cancer [1].However, despite the apparent complete surgical removal of a tumor, some residual tissue may remain.During surgery, some cancer cells can be released into the bloodstream, leading to the tumor spreading to other organs [2].Surgical stress can activate both the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system.These systems, in turn, influence the immune response, leading to a further decrease in cell immunity.This suppression increases the likelihood of metastatic recurrence.General anesthesia is often used as the main anesthesia for cancer surgery.Some volatile anesthetic agents, like isoflurane and sevoflurane, increase several prometastatic factor transcriptions, enhancing the proliferation of tumor cells [3].In addition to volatile anesthetic agents, opioids also directly influence tumor growth by activating transcription factors.Furthermore, as immunomodulators, opioids have the potential to increase the risk of cancer recurrence [4].
Regional anesthesia effectively lowers the neuroendocrine stress response to surgery by controlling pain or blocking sympathetic activity, decreasing catecholamine levels, and minimizing immunosuppression [3,5].Other mechanisms of regional anesthesia that appear to provide a protective effect against tumor growth and metastasis include direct cytotoxicity; the activation of the apoptotic pathway; the inhibition of tumor cell proliferation, migration, and invasion; the modulation of gene expression through DNA demethylation; and an increase in the number of T-helper (Th) cells while maintaining the ratio of Th1 to Th2 cells [3,6].Regional anesthesia also improves the mobilization time, shortens the time to discharge, and reduces the total opioid dose and level of volatile agents, which inhibits cancer recurrence [7].
In regional anesthesia, the length of analgesic duration is important.One way to prolong the duration of nerve blocks is the addition of adjuvants.Dexmedetomidine is an agonist of the α-2 adrenoceptor, with some anxiolytic, sympatholytic, sedative, and analgesic effects [8].Although it has a weak analgesic effect, dexmedetomidine can be used as a helpful analgesic adjuvant.Multiple pathways, including spinal, supraspinal, ganglionic, and peripheral effects, are responsible for the dexmedetomidine analgesic pathway [8,9].Furthermore, due to its antiemetic properties, dexmedetomidine is associated with a decreased incidence of postoperative nausea and vomiting (PONV) [10], suggesting its potential benefit in postoperative cancer surgery.
Several randomized controlled trials (RCTs) on the use of dexmedetomidine as an adjuvant to nerve blocks for cancer surgery have recently been published.However, at the time of this study being written, the application of dexmedetomidine as an adjuvant to nerve blocks in cancer surgery remains debatable due to conflicting results, demanding further investigation.Therefore, in this systematic review and meta-analysis, we aim to comprehensively evaluate the benefit and safety profiles of dexmedetomidine as an adjuvant to nerve blocks in cancer surgery.

Materials and Methods
This meta-analysis followed the 2020 Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guideline [11], and was registered in the PROSPERO database with a registration number of CRD42023460288.

Eligibility Criteria
We included a randomized controlled trial (RCT) in this systematic review and metaanalysis.The titles and abstracts of all retrieved studies were screened based on the following eligibility criteria: (1) studies considering patients with cancer surgery; (2) patients receiving dexmedetomidine as an adjuvant in truncal regional nerve blocks; (3) research with randomized controlled trial study designs; (4) studies available in the English language; and (5) eligible studies reporting at least one of our outcomes of interest.Our outcomes included clinical outcomes, intraoperative outcomes, postoperative pain scores, laboratory outcomes and adverse events.Review articles, irrelevant studies, non-human studies, and duplicates were excluded.

Search Strategy and Selection of Studies
DAPM and DSB performed a systematic literature search in MEDLINE, ScienceDirect, Cochrane Library, Springer, and Scopus on 17 May 2024.Manual searches (e.g., in medRxiv) and bibliographical searches were also conducted to obtain additional evidence.The following keywords were used: "((Regional anaesthesia) OR (Nerve block) OR (Truncal nerve block)) AND (Dexmedetomidine) AND ((Cancer) OR (Cancer surgery))".Additional details about the search strategy can be found in Supplementary Materials.Any disagreements were resolved among all authors by discussion until a consensus was reached.The details of study selection were documented in a PRISMA flow diagram (Figure 1).disagreements were resolved among all authors by discussion until a consensus was reached.The details of study selection were documented in a PRISMA flow diagram (Figure 1).

Data Extraction
Relevant data were extracted from each selected study using structured and standardized forms.The following data were extracted: first author s name and publication year, study design, country, surgery types, sample size, patient s age, ASA physical status, clinical outcomes, intraoperative outcomes, postoperative pain scores, laboratory outcomes, and adverse events.

Quality Assessment
The quality of each study was assessed independently by two authors (DSB and DAPM) using the Cochrane risk-of-bias tool for randomized trials (RoB 2) which is accessible at https://sites.google.com/site/riskofbiastool/welcome/rob-2-0-tooland accessed on 17 May 2024.Any discrepancies were resolved by discussion until a consensus was reached.The Grading of Recommendation Assessment, Development, and Evaluation (GRADE) system was used to evaluate the quality of the evidence in the findings [12].

Statistical Analysis
Primary analyses were carried out using Review Manager version 5.4 (The Cochrane Collaboration).Pooled risk ratios (RRs) for dichotomous outcomes were evaluated using the Mantel-Haenszel method.Standardized mean differences (SMDs) of continuous outcomes were pooled using the inverse variance method.The heterogeneity of the study was assessed using I2 statistics.The random effects analysis was employed to estimate effect size.We used Begg s funnel plots to perform publication bias analysis.If present,

Data Extraction
Relevant data were extracted from each selected study using structured and standardized forms.The following data were extracted: first author's name and publication year, study design, country, surgery types, sample size, patient's age, ASA physical status, clinical outcomes, intraoperative outcomes, postoperative pain scores, laboratory outcomes, and adverse events.

Quality Assessment
The quality of each study was assessed independently by two authors (DSB and DAPM) using the Cochrane risk-of-bias tool for randomized trials (RoB 2) which is accessible at https://sites.google.com/site/riskofbiastool/welcome/rob-2-0-tooland accessed on 17 May 2024.Any discrepancies were resolved by discussion until a consensus was reached.The Grading of Recommendation Assessment, Development, and Evaluation (GRADE) system was used to evaluate the quality of the evidence in the findings [12].

Statistical Analysis
Primary analyses were carried out using Review Manager version 5.4 (The Cochrane Collaboration).Pooled risk ratios (RRs) for dichotomous outcomes were evaluated using the Mantel-Haenszel method.Standardized mean differences (SMDs) of continuous outcomes were pooled using the inverse variance method.The heterogeneity of the study was assessed using I2 statistics.The random effects analysis was employed to estimate effect size.We used Begg's funnel plots to perform publication bias analysis.If present, the trim-and-fill method was used.All results of statistical analysis with a p-value ≤ 0.05 were considered statistically significant.Leave-one-out sensitivity analysis was conducted to find the source of statistical heterogeneity and demonstrate how each study affected the overall result.

Study Characteristics
The characteristics and outcomes of the 20 included studies, with a total of 617 patients receiving truncal regional anesthesia combined with dexmedetomidine and 616 subjects in the control group without dexmedetomidine, are shown in Tables 1 and 2. Eleven studies were from Egypt, six studies were from China, and three studies were from India.Surgery was found to be most commonly performed for breast cancer in our meta-analysis, followed by abdominal cancer, thoracic cancer, and radical cystectomy.The dexmedetomidine dosage ranged from 0.5 µg/kg to 2 µg/kg.The summary findings of this review are shown in Table 3, and the certainty of evidence of findings reported using the GRADE system is presented in the Supplementary Materials (Table S3).
In breast cancer surgery, the time until the first use of rescue morphine analgesia was mentioned in three RCTs [13,14,16].The meta-analysis showed that dexmedetomidine treatment prolonged the requirement for morphine rescue analgesia (SMD = 2.98 [95% CI 0.01 to 5.95], p = 0.05, I2 = 98%, random effects).However, the first request for tramadol in the dexmedetomidine group during breast cancer surgery was insignificant (SMD = 0.24 [95% CI −0.06 to 0.55], p = 0.12, I2 = 0%, random effects) [17,20,22] (Figure 3).Although it was not statistically significant, a higher percentage of patients in the erector spinae plane block (ESPB) group without dexmedetomidine required rescue analgesia in the first 24 h following thoracic cancer surgery (71.4% vs. 52.4%,p = 0.204) [28].GRADE certainty ratings were as follows-high: the authors have a lot of confidence that the true effect is similar to the estimated effect; moderate: the authors believe that the true effect is probably close to the estimated effect; low: the true effect might be markedly different from the estimated effect; and very low: the true effect is probably markedly different from the estimated effect. 1 Downgraded to 1 level for risk of bias. 2 Downgraded to 1 level for inconsistency. 3Downgraded to 1 level for imprecision.Making comparisons to the control group, dexmedetomidine use considerably improved the time to discharge (p = 0.021) and allowed for earlier mobilization (p < 0.001) in breast cancer surgery [21].Patient satisfaction ratings were published in three studies [19,24,29].In comparison to the ropivacaine-only group, the overall QoR-15 scores were considerably higher in the group treated with deep serratus anterior plane block (dSAPB) with ropivacaine plus dexmedetomidine 24 h post modified radical mastectomy, indicating a better recovery, p = 0.016 [24].Following lung cancer surgery, twenty out of thirty patients (66.7%) in the dexmedetomidine group scored five points on a 5-point Likert scale, and this difference was significant when compared to the control group (p < 0.001) [29].

Postoperative Mean Pain Score
We included four RCTs, which used morphine as analgesic and reported VAS at 6 h, 12 h, or 24 h postoperative, in our meta-analysis [13,18,25,31].Overall, the dexmedetomidine group had a VAS lower than the control group (SMD = −0.40(95% CI −0.71 to −0.10), p = 0.009, I2 = 53%, random effects) (Figure 4).Although this was significant statistically, it may not be clinically meaningful.The use of a dexmedetomidine adjuvant significantly lowered the rest VAS score at 12 h and 16 h after surgery, with p < 0.001 and p = 0.013 respectively.However, there were no significant changes at the postanesthesia care unit (PACU), 4, 8, 20, and 24 h after surgery [13].Deep-SAPB combined with dexmedetomidine significantly reduced the acute VAS score at rest at 12 h and exercise at 12 and 24 h after surgery (both p < 0.05).There was no significant difference between resting (p = 0.125) and exercise (p = 0.104) at 48 h after surgery [24].

Discussion
Studies on the use of adjuvants to maximize the duration of analgesia during regional anesthesia are interesting because dexmedetomidine has been increasingly reported as one of the potential agents that could improve perioperative and postoperative outcomes.
Since the introduction of dexmedetomidine as an adjuvant anesthesia, the usage of opioids, inhalational anesthetics, and intravenous anesthetics has decreased significantly [8].Its opioid-sparing effect is able to reduce opioid requirements without increasing the incidence of opioid side effects, particularly respiratory depression [33].In this meta-analysis, dexmedetomidine was shown to reduce the amount of opioids needed during various types of cancer surgery, prolong the requirement for morphine rescue analgesia, and lower the VAS score at 6 h, although this may not be clinically meaningful.Additionally, the administration of dexmedetomidine reduced PONV.Meanwhile, the incidence of hypotension and bradycardia was numerically higher in the dexmedetomidine group compared to the control group, although it did not reach the level of statistical significance for the incidence of hypotension.The mechanisms of dexmedetomidine action in peripheral nerve blocks include maintaining hyperpolarized cells by inhibiting the next action potential through the potassium channel, maintaining the depolarization of the cell, and having local action [34,35].Dexmedetomidine prolongs nerve blocks via a number of processes, including direct action on the nerve, the attenuation of local anesthetic-induced neurotoxicity, a reduction in local blood flow, and local vasoconstriction at the spinal and supraspinal levels [34,36,37].
Dexmedetomidine, as an adjuvant to local analgesia, can reduce the inflammation and perineural damage caused by local anesthetics [37].In transabdominal plane (TAP) blocks, adjuvant dexmedetomidine is often distributed systemically and has direct central effects on the locus coeruleus [38].Another central action of dexmedetomidine is the inhibition of substance-p release into the nociceptive pathway [21].During gastric cancer surgery, the group receiving intravenous dexmedetomidine uses less propofol and remifentanil than the control group [39].In addition to cancer surgery, the continuous infusion of dexmedetomidine has been demonstrated to decrease the overall opioid use in orthopedic surgery compared to the midazolam group.The group administered with dexmedetomidine would receive 62.06% fewer opioids than the group administered with midazolam [36].Opioids, however, are able to induce hyperalgesia, which increases pain and opioid consumption.An option for opioid-induced hyperalgesia treatment might be the adjuvant dexmedetomidine [40].Dexmedetomidine has also been shown to reduce the need for various analgesics, such as paracetamol [41,42]; flurbiprofen [18]; and ketorolac [43].
The adjuvant dexmedetomidine can extend the duration of the anesthetic agent's effect, resulting in a prolonged first rescue analgesic time in the dexmedetomidine group [13,14,16,17,20,22,25,32]. The analgesic duration of dexmedetomidine injected locally, compared to intravenous dexmedetomidine administration in mid-forearm blocks, is significantly longer (997 ± 243 min vs. 654 ± 159 min, respectively) [35].Perineural dexmedetomidine administration can prolong the duration of analgesia because of the absorption and redistribution of the perineural dexmedetomidine, triggering systemic effects [44].At the peripheral level, by activating α2 adrenoceptors in peripheral blood vessels, this causes vasoconstriction, delaying the absorption of local anesthetics and lengthening their block time [27].With 0.75% ropivacaine, the perineural injection of dexmedetomidine can prolong ultrasound-guided ulnar nerve blocks by approximately 60%, as compared to 10% when administered systemically [45].In another study on lobectomy surgery, by mixing 0.5% ropivacaine with 1 µg/kg of perineural dexmedetomidine, ESPB was prolonged by about 120% [46].When administered around the nerve, dexmedetomidine enhanced the cation channel, which prevented cell depolarization.Consequently, dexmedetomidine combined with regional anesthesia can improve nerve conduction and have more potent analgesic effects than the use of local anesthetics alone [24].
In our study, dexmedetomidine was able to shorten the time to discharge [21].An epidural block with dexmedetomidine could potentially reduce the duration of hospitalization following colorectal cancer surgery (7.6 ± 2.0 vs. 10.3 ± 1.8 days, p < 0.001) [47].Similar to the findings of Ke et al., 2023 [33], patients in the opioid group had significantly longer postoperative hospital stays and total hospital stays than the dexmedetomidine group.These effects might be attributed to opioid-related side effects postoperatively.The study showed that dexmedetomidine did not require rescue analgesia within two hours of the procedure, and 88% patients undergoing modified radical mastectomy or breast conservative surgery could be discharged on the same day [48].The use of dexmedetomidine as an adjuvant in ESPB may also reduce postoperative hospital stays compared to adjuvant dexamethasone administration.The combination of ropivacaine and dexmedetomidine extend the sensory block to 18 h.Patients who receive an adequate analgesic report better comfort, earlier mobilization, and a lower risk of pulmonary problems, all of which result in shorter hospital stays [46].Another study showed that there were no differences in terms of the length of hospital stays in the dexmedetomidine group [49].
In addition, patient satisfaction is higher in the dexmedetomidine group [19,24,29].The findings further show that, during day-care breast cancer surgery, the dexmedetomidine group had higher overall patient satisfaction than the normal saline group (p < 0.0001).Fewer side effects and early ambulation could be the cause of this [48].The dexmedetomidine group has an mini mental state examination (MMSE) score higher than that of the control group [47].Dexmedetomidine may have a protective effect on the incidence of postoperative delirium and POCD (postoperative cognitive dysfunction) [47,50].There is an association between POCD pathogenesis and the inflammatory response.Intraoperative dexmedetomidine reduces inflammation because it substantially decreases the level of proinflammatory cytokiness [51].The improved patient satisfaction with the dexmedetomidine adjuvant could be attributed to these effects.
The use of adjuvant dexmedetomidine could reduce the pain score after surgery [13,14,17,18,20,[23][24][25][30][31][32]37,47].We found significance in the statistic [(SMD = −0.40(95% CI −0.71 to −0.10), p = 0.009)], but it may not be clinically meaningful due to the fact that the numbers are too small.Dworkin et al. [52] stated that individual pain intensity scores should decrease by 1.0 points to represent "minimal" or "little" change, and decrease by 2.0 to 2.7 points to be more clinically significant for patients.Within major abdominal cancer surgery, an epidural infusion of dexmedetomidine considerably reduces pain intensity within the first 48 h following surgery [9].The use of 1 µg/kg of dexmedetomidine as an adjuvant in ESPB significantly decreases VAS score in the PACU and 2, 4, 12, and 24 h after surgery [46].The opioid-free group, which used dexmedetomidine in lobectomy surgery, had a lower postoperative VAS score at 0, 6, 12, and 24 h [53].Most studies found potential benefits in terms of acute pain scores.Another study found that the group receiving dexmedetomidine had a decreased brief pain inventory (BPI), a measure of chronic pain severity, at three months following the mastectomy.Additionally, those in the dexmedetomidine groups had a higher quality of life [41].
During the first half-hour of intraoperative hemodynamics, dexmedetomidine produces an average heart rate and blood pressure, with levels lower than those in the control; nevertheless, both of these parameters will subsequently return to baseline.This is because dexmedetomidine takes around 15 min to start acting, and it peaks after an hour.For adults, the distribution half-life (t½α) of dexmedetomidine is 6 min at doses ranging from 0.2 to 0.7 µg/kg/jam, while the elimination half-life (t½β) is around 2.0 to 2.5 h and the clearance is 39 L/min.A stable plasma concentration may be achieved by both adults and children with the same infusion rate [54,55].These dexmedetomidine properties will prevent surgery stress responses by decreasing blood pressure and heart rate [56].
Our results show that hypotension and bradycardia events are increasing in the dexmedetomidine group.This suggests the dexmedetomidine adjuvant should be monitored carefully.In addition, dexmedetomidine use could decrease PONV incidence compared to the control group.These benefits could be due to the antiemetic effect related to α2 agonist, but as of now, the connection remains unclear [57].The antiemetic effect of dexmedetomidine may be explained by decreased sympathetic activity.Furthermore, elevated blood levels of catecholamine might induce nausea and vomiting.The higher total opioid dose in the control group was attributed to an increase in PONV incidence.Opioid use was associated with the PONV incidence in many studies [58,59].POhNV could be minimized by adding dexmedetomidine as an adjuvant, which also decreases opioid use.
Finally, this meta-analysis had several limitations.First, the included RCTs had a low number of participants and three out of twenty-five RCTs were open-label [30][31][32].The open-label design had the potential to lead to a higher selection bias and a lower quality of evidence.Second, the inclusion of studies from different clinical settings complicated the results.Third, the different surgical types and length of operation contributed to the heterogeneity in opioid consumption and efficacy of dexmedetomidine.Fourth, there were limited data regarding cancer outcomes.Lastly, further well-powered studies with the more extensive adjustment of confounders, as well as larger double-blind RCTs, are warranted to address some limitations of our current meta-analysis.

Conclusions
Overall, our systematic review and meta-analysis highlighted the observed benefits of using dexmedetomidine as an adjuvant in truncal nerve blocks for cancer surgery, including reduced total analgesic consumption, prolonged nerve block duration, and a shortened time to discharge with a higher patient satisfaction score.Meanwhile, postoperatively, dexmedetomidine may lower the VAS pain score and the PONV incidence.Nevertheless, this study found that hypotension and bradycardia incidence were numerically higher in the dexmedetomidine group compared to the control group.Although it did not reach statistical significance for the incidence of hypotension, careful monitoring is warranted.

Figure 1 .
Figure 1.PRISMA flow diagram of study selection process.

Figure 1 .
Figure 1.PRISMA flow diagram of study selection process.

Table 1 .
Characteristics of the included studies.

Study Design Country Surgery Sample Size Age (y) ASA Physical Status Dosage and Administration Comparison Mean ± SD or Median (IQR) Intervention Control Intervention Control Intervention Control N N
GA + BRSB: 20 mL of 0.25% bupivacaine + dexmedetomidine 2 µg/kg GA + BRSB: 20 mL of 0.25% bupivacaine

Table 2 .
Outcomes of individual studies.

Table 3 .
Summary of findings: dexmedetomidine compared with control group.