A systematic review and meta-analysis to determine the effect of peri-operative intravenous dexmedetomidine versus control on postoperative pain in ‘head and neck’ and oromaxillofacial surgical inpatients

Introduction

Background

Up to 80% of oromaxillofacial (OMF) surgical patients report moderate to severe pain postoperatively (1), prolonging inpatient length of stay (LOS), increasing postoperative complications (2) and chronic pain (1). Adequate analgesia is crucial for head and neck (HN) patients with free flaps, who not only have additional pain from the donor site, but also because well controlled pain may improve microvascular viability (3).

There is a strong focus on predicting and reducing post-operative pain (2) and promoting multi-modal, opiate-sparing analgesia (1-3). This is particularly important for patients with altered airway anatomy, who are at higher risk of opiate related complications, including respiratory depression and long-term addiction (3). Evidence based, procedure specific recommendations for pain management are advised (4). In addition, pain intensity (at rest and during movement) at 24 h post-operatively (and ideally at least one other time point) is recommended by the Standardised Endpoints in Perioperative Medicine (StEP) initiative as an important, patient-centred outcome to facilitate comparison of pain assessment in meta-analyses (5), as there is significant variability in pain score reporting in the literature. It is noted that these guidelines have been updated following this review, to specify pain intensity (at rest, during movement, and at 12, 24, and 72 h) (6).

Dexmedetomidine is a peripheral and central alpha-2 adrenergic receptor agonist that exerts sympatholysis, sedation, and anxiolysis by acting on the locus coeruleus and dorsal horn (1,7,8). It provides analgesia primarily by reducing the release of nociceptors in the substantia gelatinosa of the spinal cord (8).

Dexmedetomidine also possesses qualities that contribute to analgesia beyond direct spinal and central mechanisms. Its sympatholytic and anti-inflammatory effects last up to 48 h (9) due to reduced plasma cortisol (10) and catecholamines (11,12). Its vagal inhibition (13) and effects on microglia in the dorsal horn (11) may reduce nociception (9). Interactions with other medications may reduce hyperalgesia (11) from reduced remifentantil dosing, or produce synergy with opioids (7,14) and local anaesthetics (7,11). In addition, dexmedetomidine can improve sleep duration and quality (9,10,15,16) through anxiolysis (7), promotion of endogenous sleep pathways that mimic natural restorative sleep (7,8), and indirectly, by reducing inflammation and opioid usage (17), which may contribute to reduced pain perception.

Dexmedetomidine may reduce the duration of postoperative delirium (18-21); pain severity (1,11,22); nausea (22,23); and airway secretion burden (8). It has been shown to reduce peri-operative morphine consumption (1,8,11,12,22-24) without prolonging recovery (22,23) or impacting respiratory function (8,12,25). It is a viable component of a multi-modal opioid-sparing analgesic regimen, exhibiting synergy with opioids (22) and local anaesthetics (7), while facilitating extubation (8,21) and reducing the inflammatory perioperative stress response (9).

Dexmedetomidine has a rapid distribution half-life of 5–10 minutes and a rapid elimination half-life of 2–3 h (8,11,12,26), which may appear incompatible with a postoperative analgesic effect at 24 h. However, metabolism may vary between individuals depending on body mass index (BMI) (7,12), liver function (7), or albumin binding (7,8,12,26). Clearance is proportional to cardiac output (12) which may itself be affected by dexmedetomidine due to bradycardia (7). Cardiac output declines with age, which could account for residual analgesia at 24 h, especially if infusion is prolonged >8 h (27) or albumin levels are low (8), where dexmedetomidine may demonstrate a context-sensitive half-life of 4 h (27).

Intravenous dexmedetomidine is used in several OMF and ear, nose, and throat (ENT) procedures where patients experience moderate to severe postoperative pain (28). Its use as an analgesic adjunct is recommended for paediatric cleft palate repair (28,29) due to its opiate-sparing and anxiolytic effects, with the benefit of minimising emergence agitation and respiratory depression (29). It is recommended as an analgesic and sedative for awake tracheal intubation (ATI) (30,31) as it can also provide antisialagogue, and anterograde amnesic effects (32); it may be superior for reducing time to ATI however further evidence is required (31). Dexmedetomidine may be used for moderate postoperative pain in rhinological surgery [such as functional endoscopic sinus surgery (FESS) or septorhinoplasty] resulting from nasal packing and surgical trauma, with the additional benefits of facilitating hypotensive anaesthesia, minimising bleeding (33) and emergence agitation (34). However, there remains caution over its use due to the potential for dizziness, bradycardia or hypotension with high plasma levels (28,30,35) and postoperative sedation which may limit its use for day surgery (33) in addition to cost concerns (36).

Different patient groups may have variable responses to dexmedetomidine. Patients undergoing abdominal surgery have reported less benefit with dexmedetomidine (11,24) versus those undergoing lumbar discectomy or septorhinoplasty (11), with variable results on post-operative pain at 24 h. Ventilated post-operative patients >50 years old had reduced 90-day mortality and more ventilator-free days with dexmedetomidine sedation, but non-operative patients ≤65 years experienced worse outcomes, which may imply age- (19), illness- (19) or dose-related (37) heterogeneity of treatment effects (19), however, this observational study did not investigate post-operative pain.

Rationale and knowledge gap

There is no consensus on optimal analgesia for many OMF, HN or ENT procedures, despite a need to reduce postoperative pain (2) by utilising multi-modal, opioid-sparing analgesia (1-3) and evidence-based recommendations including those from the Procedure Specific Postoperative Pain Management (PROSPECT) group (4). Only tonsillectomy and cleft palate surgery have PROSPECT guidelines, both of which recommend intravenous dexmedetomidine (28,38). It remains unclear whether the analgesic effect of dexmedetomidine is sustained postoperatively; whether there is an optimal dose; or whether adverse outcomes (e.g., hypotension or bradycardia) (11,22) should limit its use in specific surgical populations.

Few systematic reviews (SRs) have focused on intravenous dexmedetomidine use as an analgesic adjunct in OMF, HN or ENT surgery. To our knowledge, no SRs exist that examine post-operative pain at 24 h in this cohort exclusively.

Objective

Our review aims to examine the impact of peri-operative intravenous dexmedetomidine on postoperative pain scores up to 24 h in OMF, HN and ENT inpatients using the Visual Analogue Scale (VAS) or Numeric Rating Scale (NRS) for pain measurement, as per the original StEP recommendations (5). We present this article in accordance with the PRISMA reporting checklist (available at https://joma.amegroups.com/article/view/10.21037/joma-25-16/rc) (39).

Methods

Study selection and eligibility criteria

References were appraised based on predefined inclusion and exclusion criteria. Randomised controlled trials (RCTs) involving adult inpatients aged ≥18 years, undergoing OMF, HN or ENT surgery, under general anaesthesia, requiring an overnight postoperative stay were included if they compared patients receiving intravenous dexmedetomidine (as an analgesic adjunct) versus placebo (e.g., 0.9% saline or a control group) during the peri-operative period, with measurement of postoperative pain using an 11-point pain scale. The inclusion of ENT patients was determined post-hoc prior to the search as there is anatomical overlap, often with significant airway instrumentation; several procedures such as laryngectomy or complex resections may be performed by either OMF and/or ENT surgeons; and these patients often experience moderate to severe postoperative pain (33,38).

‘Peri-operative’ comprised three phases. ‘Pre-operative’ extended from admission until entry into the anaesthetic room. ‘Intra-operative’ covered entry into the anaesthetic room until discharge from the operating theatre. ‘Postoperative’ spanned from arrival in recovery, intensive care unit (ICU), high dependency unit (HDU), or post-anaesthetic care unit (PACU) until hospital discharge.

Animal, case or cohort studies, retrospective analysis, letters, surveys, meta-analyses or SRs were excluded. Studies involving patients <18 years, undergoing ambulatory surgery, sedation, minor dental surgery, oesophageal or thoracic surgery were excluded. These criteria aimed to eliminate studies utilising dexmedetomidine as a sedative and to reduce clinical heterogeneity. Studies were excluded if they investigated other routes of dexmedetomidine administration, if dexmedetomidine was not the primary intervention or there was no control comparator.

Primary outcomes

The primary outcome was postoperative pain scores measured at 24 h with an 11-point pain scale (0–10, where 0 indicates no pain and 10 indicates the worst possible pain), specifically VAS or NRS. VAS and NRS scores are highly correlated (40,41) and were considered together, consistent with prior studies (11,24,42).

Secondary outcomes and variables

Secondary outcomes were pain scores measured using the VAS or NRS at any other time postoperatively. However, it became evident that the literature had assessed more than 20 different time points. Therefore, consistent with a method previously outlined (24), secondary outcomes for analysis were re-defined post-hoc (prior to data extraction) as VAS or NRS scores at 1, 2, 4, 6, 12 and 48 h in line with the original StEP guidelines (5). It is noted that the guidelines now specify pain intensity (at rest, during movement, and at 12, 24, and 72 h) however the review was completed prior to this update (6).

Trial characteristics and variables reviewed included age, weight, sex, dose regimens, anaesthetic and analgesic protocols and adverse clinical events.

Exploratory analyses

Exploratory analyses were conducted post hoc, including the calculation of approximate morphine equivalents (MEs) between groups and, a narrative review of trends linking dexmedetomidine dose regimens and effect on haemodynamics; specifically, heart rate (HR), blood pressure (BP) and mean arterial pressure (MAP).

Exploratory data were collected post-hoc for anaesthetic and analgesic profiles. These were not initially selected as outcomes of interest, as such variables were not chosen as StEP consensus outcome measures (5). However, these data provide important information regarding potential confounding, or variable analgesic regimens that could explain clinical and statistical heterogeneity (24).

Search methods

A limited pilot search was conducted on PubMed and Ovid EMBASE on 3 November 2023 to establish appropriate Medical Subject Headings (MeSH) terms and the search strategy.

Database and other searches

The systematic search was conducted independently by two investigators (G.F.S., J.H.L.) on 7 November 2023 using: PubMed, Ovid MEDLINE; Ovid EMBASE; Cochrane Central Register of Controlled Trials (CENTRAL); Web of Science, ClinicalTrials.org (43) and Google Scholar. The searches were repeated on 26 February 2024 prior to data extraction and analysis. A final search was carried out on 3 June 2024 per protocol.

The search terms are available in Appendix 1. There were no language or date restrictions. Reference lists of included papers and relevant SRs were searched for additional papers meeting inclusion criteria (G.F.S.). All references were uploaded to Cochrane ReviewManager (44) (RevMan 5.4) (G.F.S.) and EndNote 20 (J.H.L.) where duplicates were removed.

Data collection and analysis

Selection of studies

Two investigators (G.F.S., J.H.L.) independently appraised the titles and abstracts. Trials not meeting the inclusion criteria were excluded; for unclear cases, the full text was reviewed, and if applicable, were appraised with Google Translate to determine eligibility. Attempts were made to contact the study authors and/or obtain a translation. Any disagreements between the two investigators throughout the entire SR were adjudicated by a third author (D.H.B.).

Data extraction and management

The full text of all included articles was evaluated, and data for trial characteristics, primary and secondary outcomes were independently extracted into a Microsoft Excel data collection form.

Authors were contacted up to three times (using email, LinkedIn, or institutional websites) if data were unavailable or for further clarification. Limited data imputation was necessary. Contact with authors was successful in two cases, but did not result in numeric data (45,46), and unsuccessful in one case (10). Therefore, means and standard deviations (SDs) were extracted from graphs using the Adobe Acrobat Reader DC measurement tool (G.F.S./J.H.L. independently). One author provided pain score data (47). The mean and SDs were calculated and rounded to 3 decimal places.

One study provided means and interquartile ranges (IQRs); the authors were uncontactable (15). Attempts were made to convert the IQR into SD using established methods (24,48). However, the IQRs were small, therefore SDs were 0 for both groups and could not be used in the meta-analysis. Imputed SDs using data from a study with similar numbers of participants and effect size (49) is included in the meta-analysis, however the result of the meta-analysis without this study can be seen in the sensitivity analysis results.

Statistical analysis

Data for primary and secondary outcomes were transferred into RevMan 5.4 for meta-analysis (G.F.S., verified by J.H.L.). For continuous data, i.e., VAS/NRS scores, results were reported as means and SDs. All scores were converted into a 0–10-point scale.

For the primary outcome of postoperative pain scores (NRS/VAS) measured at 24 h, the results were visually displayed as a forest plot using mean differences (MDs) and a random-effects, inverse variance model generated in RevMan 5.4. Confidence intervals were calculated using the Wald-type method. Heterogeneity (Tau²) was calculated by the DerSimonian and Laird method. This was updated immediately prior to publication using RevMan Web 9.7.1 (50) to optimise visual display and clarity. All numeric data [MDs and 95% confidence intervals (CIs)] were summarised in a tabular format.

The secondary outcomes of postoperative pain scores (NRS/VAS) measured at 1, 2, 4, 6, 12 and 48 h, and subgroup analyses, all underwent the same statistical analysis and visual display strategies as the primary outcome.

Heterogeneity between studies was assessed using the I² statistic. Clinical heterogeneity was anticipated as demonstrated in previous SRs (24,51,52); therefore, meta-analysis was planned using a random-effects, inverse variance model. Fixed-effects model sensitivity analysis was planned a priori. Sensitivity analysis with sequential exclusion of each trial was conducted to determine if any individual trial [including those at high risk of bias (ROB)] significantly affected the overall outcome. Publication bias was assessed and visually displayed using a funnel plot in RevMan 5.4. This was updated immediately prior to publication using RevMan Web 9.7.1 (50) to optimise visual display and clarity.

Post-hoc decisions for regarding subgroup analysis were made prior to data extraction for hypothesis generation. Several studies included multiple treatment arms, measurements of pain at rest and on movement, or at two anatomical sites. It was decided to exclude irrelevant treatment arms; use ‘rest’ and/or ‘oral/maxillofacial/head’ pain scores as the default; and to perform subgroup analyses of rest and movement pain and different anatomical site pain at 24 h. Subgroup analyses for the primary outcome was completed according to the period of dexmedetomidine administration and according to surgical specialty (OMF/HN surgery and nasal surgery).

Quality assessment

Two authors (G.F.S./J.H.L.) independently assessed the ROB for each trial using the Cochrane ROB2 tool (53-55) and trial registry entries. Each study was assessed for quality of reporting against the CONsolidated Standards Of Reporting Trials (CONSORT) 2010 guidelines (56). The CONSORT 2025 guidelines remained unpublished at the time of writing (57).

The quality of the evidence for the primary outcome was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach (58-60) using the GRADEpro software and Guideline Development Tool (61).

Trial registration and protocol available on PROSPERO: CRD 42023481553. The trial protocol and search strategy were submitted to the PROSPERO register on 9 November 2023, with progress updated on 3 April 2024. Amendments to trial protocol discussed in review. Template data collection forms and any other data or queries available on request from G.F.S.

Results

Selection of studies

The initial search in November 2023 identified 1,575 records (including 54 trial registry entries). After removing 253 duplicates, 1,322 remained for screening. The repeat search in February 2024 identified seven new records; after removing one duplicate and excluding six others, no additional studies were included. The final search in June 2024 yielded 52 additional records; six duplicates were removed, and 46 were excluded. No additional records were identified through reference searching or ClinicalTrials.gov. The search is summarised in Figure 1.

Figure 1 PRISMA flow diagram summarising the screened, retrieved, excluded and included RCTs (62). PACU, post-anaesthetic care unit; RCT, randomised controlled trial.

Of the 183 papers appraised, 161 were excluded. In 13 cases, authors did not reply when requested for further information (34,63-73) excluding these studies. In one case an overnight stay was confirmed (46). Two studies met inclusion criteria for the primary outcome, but remained ‘pending classification’: one did not explicitly use an 11-point pain scale (63); in another, it was impossible to extract VAS scores and SDs (64).

Seven RCTs met the inclusion criteria for the primary outcome, comprising 586 participants, with 50% receiving peri-operative dexmedetomidine (10,15,16,45,49,74,75). Sample sizes ranged from 40–160 participants. Six trials compared dexmedetomidine with 0.9% saline (10,15,16,45,49,75). One trial had three treatment arms (74). The two arms which compared identical care except for dexmedetomidine were suitable for inclusion. This study originally had 90 participants, 30 of whom were excluded.

Two additional trials contributed to secondary outcomes (150 participants) (46,47). One study alluded to NRS scores at 24 h but the author supplied data up to 12 h only (47). Another study met the inclusion criteria but for secondary outcomes only (46).

Study characteristics

The characteristics of the included trials are summarised in Table 1. The mean age of participants was 49.8 years (range, 24.3–72.1 years). For the primary outcome, female participants comprised 39.9% of the dexmedetomidine groups and 38.2% of the controls. Seven trials used the VAS (10,16,45-47,49,74), two studies used the NRS (47,75). Two studies reviewed pain at rest and movement (15,16), and one study reviewed pain at two anatomical sites: oral/maxillofacial and fibular (75).

For the primary outcome, two trials studied ENT patients undergoing FESS (10) and septorhinoplasty (45). Four trials studied OMF/HN patients undergoing orthognathic surgery (49), oral cancer resection (74), resection with fibular free flap (75) or unspecified OMF surgery (16). One trial studied total or partial laryngectomy patients however it is unclear whether this was conducted by ENT or OMF/HN surgeons (15).

For secondary outcomes the two additional trials studied unspecified OMF or cervicofacial surgical patients (47) and ENT patients undergoing FESS (46).

Most trials administered dexmedetomidine intra-operatively, with a bolus at induction followed by an infusion until the end of surgery, or 30 minutes prior to the end of surgery (10,16,45-47,74). Bolus doses ranged from 0.5 to 1.2 µg·kg⁻¹ over 10–30 minutes, and infusion rates from 0.2–0.6 µg·kg⁻¹ h⁻¹. One trial administered dexmedetomidine intra-operatively and continued postoperatively until 06:00 the next morning (75). Another administered it exclusively overnight postoperatively until 06:00 (15). One study reported pre-operative dexmedetomidine administration, with unclear time of cessation (49).

Only one study examined pain scores as the primary outcome (49) with the rest reporting them as secondary outcomes (10,15,16,45,46), or variables of interest (47,75). In two studies, primary and secondary outcomes were not explicitly stated (45,74).

Results from included studies are described in Table 2 and conclusions are summarised in Table 3.

ROB and quality assessment

The ROB assessment using the ROB2 tool (53) evaluated the intention-to-treat effect for postoperative pain scores (Figure 2).

Figure 2 ROB table (53,76). ROB, risk of bias.

Two trials were assessed as having overall high ROB due to concerns regarding lack of blinding of assessors (74) or inadequate reporting of results (10). Most trials had ’some concern’ for ROB in multiple domains (15,16,45,46,49), due to lack of allocation concealment (15,45,46,49,74), lack of blinding of clinicians (49) or assessors (45,46), unclear intentions for analysis (16,45) or issues with data reporting (15). Two trials only lacked information regarding pre-specified analysis plans for pain scores (47,75), however these were appropriately reported as trial variables, and were considered to have low ROB.

Regarding the CONSORT guidelines (56), three studies demonstrated poor adherence with approximately 40% compliance (45,46,74); four studies showed moderate (69–88%) compliance (10,15,16,49); and two studies exhibited high adherence, at 97% (47,75) (Appendix 2). Only these two studies scored highly for both measures of quality (47,75).

The GRADE assessment (Table 3) demonstrated that all outcomes were graded as ‘Very low quality (Å)’ evidence due to concerns regarding ROB, heterogeneity, imprecision of data or publication bias, except for 48 h data, which was rated as Moderate quality (ÅÅÅ), rated down for imprecision.

Primary and secondary outcomes

The primary outcome was studied in 586 patients in seven trials, including one study with imputed SD data (15). Dexmedetomidine was associated with reduced pain scores at 24 h compared with the control interventions (MD −1.11; 95% CI: −1.66, −0.57; P<0.0001, I²=97%) (Figure 3).

Figure 3 Forest plot of the effect of dexmedetomidine vs. placebo/standard care on VAS/NRS scores at 24 hours. For each trial, the mean difference is depicted by a green square; the horizontal lines represent the 95% CI. The summary result is presented as a diamond. CI, confidence interval; IV, inverse variance; SD, standard deviation; VAS/NRS, Visual Analogue Scale/Numerical Rating Scale.

Results for secondary outcomes are presented in Tables 2,3.

Dexmedetomidine was associated with statistically significant reductions in pain scores at 1 hour (MD −0.33; 95% CI: −0.60, −0.07; P=0.01, I²=74%), 4 hours (MD −1.45; 95% CI: −1.72, −1.18; P<0.00001, I²=0%), 6 hours (MD −0.74; 95% CI: −1.06, −0.42; P<0.00001, I²=65%), and 12 h (MD −0.57; 95% CI: −0.82, −0.32; P<0.00001, I²=73%), compared with controls. A difference in pain scores was detected at two hours, but this did not reach statistical significance (MD −0.51; 95% CI: −1.60, 0.57; P=0.35, I²=91%). No differences were detected at 48 h (MD −0.05; 95% CI: −0.13, 0.03; P=0.21, I²=0%). Forest plots for secondary outcomes are demonstrated in Appendix 3.

Sensitivity analyses

A priori sensitivity analyses were conducted (Appendix 4). Fixed effect analysis demonstrated a reduced effect size that remained statistically significant. Sequential removal of each trial, with an additional analysis excluding two trials with high ROB (45,74) did not meaningfully change the size or significance of the result. Removal of the trial where SDs were imputed (15) also had minimal impact on the primary outcome result (MD −1.13; 95% CI: −1.73, −0.54; P=0.0002; I²=98%).

The removal of a high ROB outlier using a ‘usual care’ group and regional anaesthesia (74) slightly reduced the effect size (MD −0.84; 95% CI: −1.22, −0.46; P<0.0001; I²=94%). Sequential removal coincidentally excluded pre-operative (49) combined intra/postoperative (75) and postoperative (15) dexmedetomidine administration, but this produced minimal changes in the results.

Subgroup analyses

A post-hoc subgroup analysis based on timing of dexmedetomidine administration (Figure 4) demonstrated a statistically significant subgroup effect (Chi² =12.51, df =3, P=0.006, I²=76%) in which the combined intra/postoperative administration provided superior postoperative pain scores (MD −1.90; 95% CI: −2.30, −1.50; P<0.0001).

Figure 4 Forest plot of the effect of dexmedetomidine vs. placebo/standard care on VAS/NRS scores at 24 hours: subgroup analysis by timing of administration. For each trial, the mean difference is depicted by a green square; the horizontal lines represent the 95% CI. The summary result is presented as a diamond. CI, confidence interval; IV, inverse variance; SD, standard deviation; VAS/NRS, Visual Analogue Scale/Numerical Rating Scale.

Heterogeneity was also unchanged at 98% within the intra-operative subgroup.

It was recognised that heterogeneity remained high, with a potential cause being clinical differences between surgical procedures, particularly the nasal surgery cohort (10,45) compared to the OMF/HN surgical cohort (15,16,49,74,75). This was explored in another post-hoc subgroup analysis based on surgical categories (Figure 5). OMF/HN patients experienced a greater reduction in pain scores with dexmedetomidine (MD −1.36; 95% CI: −2.33, −0.38; P<0.0001) than the nasal surgery cohort (MD −0.51; 95% CI: −1.03, 0.00; P=0.05) but this did not demonstrate a significant subgroup effect (Chi² =2.26, df =1, P=0.13, I²=55.7%) with heterogeneity remaining high within both subgroups (OMF/HN I²=98%, nasal I²=87%).

Figure 5 Forest plot of the effect of dexmedetomidine vs. placebo/standard care on VAS/NRS scores at 24 hours: subgroup analysis by surgical type (OMF/HN vs. nasal). For each trial, the mean difference is depicted by a green square; the horizontal lines represent the 95% CI. The summary result is presented as a diamond. CI, confidence interval; IV, inverse variance; OMF/HN, oromaxillofacial/head and neck; SD, standard deviation; VAS/NRS, Visual Analogue Scale/Numerical Rating Scale.

It was not possible to conduct subgroup analysis of pain scores at rest and during movement. Liu et al. [2022] demonstrated reduced pain scores during movement at 24 h (1.3±0.5 dexmedetomidine, 1.6±0.5 control, P=0.013) (16). Huang et al. demonstrated a reduction in movement pain scores of −1 (2 dexmedetomidine, 3 control, P<0001) (15).

There were insufficient studies to assess for publication bias. Several studies had small numbers of participants and generally reported favourable results for dexmedetomidine for pain scores at ≤24 h (15,45,49,74). A preliminary funnel plot is provided in Appendix 5 which alludes to publication bias for the primary outcome due to asymmetry.

Exploratory data and analyses

Exploratory data and narrative analyses were conducted for hypothesis generation, however formal statistical analysis was not conducted.

Anaesthesia and analgesic protocols are summarised in Appendix 6. For the primary outcome, two utilised multimodal analgesia with topical or regional anaesthesia (45,74) and two used opiate analgesia only (15,75). No trial used the same regimen, with variable thresholds and protocols for rescue analgesia.

Exploratory peri-operative MEs were estimated in order to review analgesia administration (Appendix 6) using opioid conversion tables (77-80). This was impossible for three studies (15,46,49); this increases the risk of confounding bias as it is unclear what additional analgesia was received. In addition, there are no standardised MEs for non-steroidal anti-inflammatory drugs (NSAIDs) or local anaesthesia, which may also demonstrate synergy with dexmedetomidine (7). In the remainder, the MEs were approximately equivalent between control and dexmedetomidine groups (16,47,75) or the control group received more opioids (45,74).

Four studies specified for rescue analgesia to be given if VAS scores >3 (47), >4 (45), ≥4 (16), or ≥7 (49), others reported no rescue instructions (10,15,46,74). Rescue analgesia included non-opioids (16,45,74) and opioids (15,47,74)—in one case the dose and/or rescue drug was unclear (“5 mg acetaminophen”) (49). Four studies used a morphine or sufentanil patient-controlled analgesia (PCA) for routine and rescue analgesia (15,16,45,75). Several studies reported a greater use of rescue analgesia in their control groups (15,45,49,74) which may have reduced the difference in scores between groups.

Analgesia was often used to manage hypertension or tachycardia (49,74,75), or management was unspecified (15,45). It is beyond the scope of this review to assess optimal dosing, however lower doses of dexmedetomidine (≤0.5 µg kg⁻¹ bolus followed by ≤0.4 µg kg⁻¹ h⁻¹ infusion) demonstrated no statistically (16,75) or clinically significant (15,74) difference in HR or BP and/or no difference in vasopressor usage (10). These studies all demonstrated beneficial effects on pain scores at 24 h.

Studies using higher infusion rates (≥1 µg kg⁻¹ bolus then ≥0.5 µg kg⁻¹ h⁻¹ infusion) reported significant differences in MAP and HR (46,47). More patients in the dexmedetomidine group required vasopressors, however this did not reach significance. The study showing the least difference in pain scores used the highest infusion rate of dexmedetomidine (47), suggesting no clear dose-response effect; however, these observations are hypothesis-generating only.

Discussion

Key findings

Our findings indicate that peri-operative intravenous dexmedetomidine is associated with a significant reduction in postoperative pain scores up to 24 h compared with controls (MD −1.11; 95% CI: −1.66, −0.57; P<0.0001, I²=97%) in inpatients undergoing OMF, HN and ENT surgery. As demonstrated by multiple sensitivity analyses, dexmedetomidine could be a valuable analgesic adjunct in this patient cohort. Post hoc subgroup analyses indicated that the most favourable analgesic effect occurred with combined intra/postoperative administration (75) (MD −1.90; 95% CI: −2.30, −1.50; P<0.0001), however, this data comes from a single study. OMF/HN patients experienced improved post-operative pain scores when compared to nasal surgery patients, but this did not reach statistical significance. Subgroup analyses failed to reduce the high heterogeneity within the results.

Dexmedetomidine was associated with reduced pain scores at 1, 4, 6, and 12 h postoperatively, but this was not demonstrated at 2 or 48 h. This has been observed in other meta-analyses, noting no difference in pain scores at 36 h (81) or 48 h postoperatively (22). Several studies used analgesia to manage haemodynamic instability (49,74,75), or had unclear rescue analgesia triggers (10,15,46,74). This resulted in at least equivalent analgesia being given to the controls, thereby reducing the difference in pain scores and potentially underestimating the analgesic benefit of dexmedetomidine. However, the clinical protocols (including anaesthesia and analgesia administration) were highly variable, which may account for some of the heterogeneity demonstrated.

Comparison with similar research

Our results are consistent with other SRs which have shown a modest reduction of pain scores at 24 h. A meta-analysis of multi-route dexmedetomidine in abdominal surgery noted a MD in 24 h pain scores of −0.6 (95% CI: −0.9, −0.2) (22). Another study focussing on intra-operative dexmedetomidine, including five ENT/OMF studies (82), observed smaller effects on postoperative pain scores at 24 h (MD −0.47; 95% CI: −0.83, −0.11). A meta-analysis comparing dexmedetomidine to placebo (11), including four ENT/OMF studies, demonstrated significantly lower pain scores in 271 participants at 24 h (MD −0.52; 95% CI: −0.87, −0.16). Our overall effect at 24 h was larger than these findings, which may be attributed to differences in surgical cohorts and patient characteristics.

Explanations of findings

The clinical significance of our findings depends on the definition of minimal clinically important difference (MCID) in pain scores (i.e., the smallest difference in pain that a patient deems important) (42,83-86). There is no expert consensus for an MCID for acute postoperative pain as MCID is context-specific (42), varying with different surgical populations and pain baselines. MCIDs proposed include an absolute reduction of 1–2 points (40,42,85,87-89), a percentage reduction e.g., 30–50% (84,85,88-90) or any score <3.3 (40) signifying acceptable pain control (40,86). In addition, higher baseline pain scores require a larger absolute reduction to be clinically meaningful (42,86,88,89).

No agreed MCID exists for our patient cohort. An MCID of: ±2.5 for acute pain in maxillofacial trauma (91); ±1.3 by Cepeda et al., with 14.6% of these patients having HN surgery (89); or ±1 for patients in mild-moderate postoperative pain (40), although only 2.2% of these patients had ENT/OMF surgery, have all been recommended.

In our meta-analysis several studies demonstrated an MCID at 24 h of ≥1 (15,49,74,75), reflected in the overall effect of −1.11. This effect was reduced once high ROB studies (45,74) were removed, with an overall effect of −0.85. One high quality study demonstrated reduction of pain scores of ≥30% with an absolute reduction of −1.9 (75) meeting the majority of MCID definitions (40,42,85,87,89). The timing and duration of dexmedetomidine administration in this study are likely significant contributors to this result. Removing this study in sequential analysis still produced a MD of −0.98. It is therefore likely that OMF, HN and ENT patients would benefit from peri-operative intravenous dexmedetomidine by experiencing reduced pain at 24 h postoperatively.

Strengths and limitations

Our review investigates patient-centred pain outcomes in line with those recommended by StEP (5,6), specifically postoperative VAS/NRS scores at 12 and 24 h (6). Our results are applicable to patients aged 27–72 years, from varied ethnic backgrounds, undergoing a variety of procedures. The cohort included older, comorbid patients, for whom dexmedetomidine demonstrated significant benefit (75). Some studies reported other beneficial effects, including improved sleep quality and duration (10,15,16) and reduced incidence of post-operative pulmonary complications (PPCs) contributing to reduced hospital LOS (75). Others demonstrated no significant difference in hospital LOS (10,47), 30-day mortality (75), bradycardia (10,45,75), hypotension (10,75), or hypoxaemia (10,15,47). However, these studies may have been under-powered for these outcomes. No significant adverse events were reported.

Dexmedetomidine is known to cause hypotension (8,12). This may be desirable for FESS or orthognathic surgery, but less desirable for microvascular free flap reconstruction. However, adverse haemodynamic adverse effects were not observed for this surgical cohort at the infusion dose of 0.4 µg·kg⁻¹ h⁻¹ (75). There were no differences in fluid or blood transfusions, and no flap failures were reported (75). No studies reported statistically higher usage of vasopressors in the dexmedetomidine group, which may be consistent with enhanced vasopressor responsiveness (13).

There are limitations to our observations and the results should be interpreted with caution. Most studies excluded patients with cardiac or hepatic conditions (10,15,45,47,74,75), probably to improve the perioperative safety profile. Several studies excluded patients at higher risk of postoperative pain, e.g., those with chronic pain (74), psychiatric diagnoses (10,16,49,75) or pre-existing analgesia use (45,49), limiting the generalisability of these results. Given the risk of hypotension and bradycardia, demonstrated in our study at higher infusion rates of ≥1 µg·kg⁻¹ bolus then ≥0.5 µg·kg⁻¹ h⁻¹ infusion (46,47), clinicians should consider administering lower doses, a slower bolus dose, and/or limiting dexmedetomidine to patients without cardiac or hepatic disease in line with British National Formulary guidance (92), however our findings do not have sufficient data to support any specific dosage regimen. It is noted that dexmedetomidine is currently only licensed in the UK for maintenance of sedation during intensive care (92). There is also caution over its use for sedation in ventilated ICU patients ≤65 years, resulting in increased mortality versus standard care, however this effect was less prominent in patients admitted for postoperative care (19,37,92).

Much data from the literature is missing; many excluded papers did not specify time frames (e.g., ‘PACU’ scores), used other pain measurements such as ‘pain intensity scores’ (63) or quality of recovery (QoR) scores (34), or provided insufficient data. This highlights the need to report consensus outcome measures to increase the data available for meta-analysis (5,93). That said, VAS/NRS scores are unidimensional and may be inferior to multidimensional scores, such as QoR-40, when considering direct patient-centred outcome assessments (35).

We conducted post-hoc changes to our secondary outcomes for clarity of reporting, although these were selected prior to data extraction and analysis. There was also imputation of data (15,45-47) risking inaccurate interpretation or unintentional bias.

The meta-analysis results demonstrated high heterogeneity of I²=97%. This was investigated with subgroup analyses. Some heterogeneity was explained by the timing of administration (I²=76%). However, the heterogeneity likely persisted due to clinical differences in the surgical procedures studied and the variability in anaesthetic and analgesic protocols.

We included ENT patients in the cohort due to potential anatomical overlap and procedural similarities, however we concede that this likely introduced heterogeneity into the study due to differences in severity of the procedures compared to the OMF and HN cases. We are unaware of any evidence to suggest that patients experience similar postoperative pain following, e.g., FESS in contrast to free flap reconstructions. Sub-group analysis separating the OMF/HN and nasal surgery cohorts failed to demonstrate statistically significant sub-group differences. In our study, the control patients had 24 h mean pain scores of 1.68 (45) and 2.81 (10) for septorhinoplasty and FESS respectively; for the OMF/HN cohort, the 24 h pain scores for controls ranged from 1.5 for unspecified OMF surgery (16) and 2 for laryngectomy (10) to 3.8 for orthognathic surgery (49) and 5.07 for oral cancer surgery (74). This highlights the subjective nature of pain score reporting, and may suggest that for our cohort, the ENT and OMF/HN patients experienced broadly similar post-operative pain without dexmedetomidine, however this is speculative without formal statistical analysis and in light of potentially confounding differences in procedural and analgesic protocols.

Without the high ROB studies, the most significant clinical effect appeared from the largest high-quality study, which administered intra-operative dexmedetomidine continued overnight until 06:00 the next morning (65).

All included studies had relatively small sample sizes, increasing the risk of publication bias, and several were deemed low quality. Several studies were at risk of confounding bias due to protocols that allowed for analgesia usage to manage haemodynamic instability (49,74,75), or unclear rescue analgesic protocols (10,15,46,74). However, in all cases this would have resulted in more analgesia being given to the control group, thereby reducing the overall effect on pain scores between groups.

Nonetheless, this highlights the issue that the analgesic protocols in the included studies were highly variable and may not have adequately isolated dexmedetomidine. Several studies included medications such as opioids that may demonstrate synergy with dexmedetomidine (7), thus it is possible that the effect on VAS/NRS scores may not be solely attributed to the dexmedetomidine, but due to its inclusion in a multimodal analgesic regimen. These protocols do reflect “real world” anaesthesia techniques, as it would be unusual to administer dexmedetomidine as the sole analgesic, but the variability of protocols, dexmedetomidine doses and complexity of the multimodal drug interactions make it challenging to recommend any one dexmedetomidine protocol.

Implications and actions needed

Our meta-analysis generates questions for future research. Comparison to other analgesics has been explored in a similar patient cohort, with dexmedetomidine demonstrating superior reductions in postoperative pain scores versus clonidine (94,95). Other benefits of dexmedetomidine include greater morphine sparing effects (22), reduced incidence of rebound hypertension (96), and better haemodynamic stability for an equivalent analgesic dose (1,97,98). Future research should focus on whether dexmedetomidine is superior to other analgesics for specific surgical cohorts, and whether it can enhance a multimodal analgesic strategy. This would require carefully designed trials that minimise interaction with other medications to facilitate isolation of dexmedetomidine. Future research should also establish whether dexmedetomidine is cost-effective as an analgesic adjunct and test optimal timing and dosage regimens that minimise peri-operative adverse outcomes. This research should use standardised patient-centred endpoints in line with those recommended by StEP, specifically including pain at rest, on movement, and up to 72 h postoperatively (6).

Conclusions

This SR demonstrates that peri-operative intravenous dexmedetomidine reduces postoperative pain scores (by −1.11 score on the VAS/NRS scales) up to 24 h in OMF, HN and ENT surgical inpatients when compared with control (MD −1.11; 95% CI: −1.66, −0.57; P<0.0001, I²=97%). There were no differences in post-operative pain scores by 48 h. Subgroup analysis demonstrated that combined intra/postoperative administration provided superior postoperative pain scores, but there was no statistically significant difference between the OMF/HN and nasal surgical cohorts. Patients on lower doses of dexmedetomidine had improved pain scores and did not experience hypotension, bradycardia, or other adverse clinical events. Perioperative dexmedetomidine could be a valuable component of postoperative analgesia. However, as this meta-analysis evaluated low quality evidence and demonstrated high heterogeneity, future research should establish optimal timing and dosage regimens, and consider cost-benefit analysis to determine its viability as a peri-operative, opioid-sparing analgesic adjunct in this patient cohort.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://joma.amegroups.com/article/view/10.21037/joma-25-16/rc

Peer Review File: Available at https://joma.amegroups.com/article/view/10.21037/joma-25-16/prf

Funding: This work was originally written by GS as part of a UCL Master’s degree (MSc) within the UCL Centre for Peri-operative Medicine, for which she received funding from University College London Hospitals for her tuition fees.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://joma.amegroups.com/article/view/10.21037/joma-25-16/coif). G.F.S. received funding from University College London Hospitals for her tuition fees. D.H.B. received payment to his company for delivering educational content and received funding to attend educational event in Copenhagen including travel and accommodation from Medtronic. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Ethical approval was not required, as all information was available on public databases.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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