What is the impact of dexamethasone on postoperative pain in adults undergoing general anaesthesia for elective abdominal surgery: a systematic review and meta-analysis

doi:10.21203/rs.3.rs-558680/v1

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What is the impact of dexamethasone on postoperative pain in adults undergoing general anaesthesia for elective abdominal surgery: a systematic review and meta-analysis

https://doi.org/10.21203/rs.3.rs-558680/v1

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Background

Previous meta-analysis of heterogeneous surgical cohorts demonstrated reduction in postoperative pain with perioperative intravenous dexamethasone, but none have addressed adults undergoing elective abdominal surgery.

Objective

To determine the impact of intravenous perioperative dexamethasone on postoperative pain in adults undergoing elective abdominal surgery under general anaesthesia.

Methods

This review was prospectively registered on the international prospective register of systematic reviews (CRD42020176202). Electronic databases Medical Analysis and Retrieval System Online (MEDLINE), Exerpta Medica Database (EMBASE), (CINAHL) Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science and trial registries were searched to January 28 2021 for randomised controlled trials, comparing dexamethasone to placebo or alternative antiemetic, that reported pain. The primary outcome was pain score, and secondary outcomes were time to first analgesia, opioid requirements and time to post-anaesthesia care unit (PACU) discharge.

Results

Fifty-two studies (5768 participants) were included in the meta-analysis. Pain scores ≤4 hours were reduced in patients who received dexamethasone at rest (mean difference (MD), -0.54, 95% confidence interval (CI) -0.72 to -0.35, I² = 81%) and on movement (MD -0.42, 95% CI -0.62 to -0.22, I² = 35 ). In the dexamethasone group 4–24 hour pain scores were less at rest (MD -0.31, 95% CI -0.47 to -0.14, I² = 96) and on movement (MD -0.26, 95% CI -0.39 to -0.13, I² = 29) and pain scores ≥24 hours were reduced at rest (MD -0.38, 95% CI -0.52 to -0.24, I² = 88) and on movement (MD -0.38, 95% CI -0.65 to -0.11, I² = 71). Time to first analgesia (minutes) was increased (MD 22.92, 95% CI 11.09 to 34.75, I² = 98), opioid requirements (mg oral morphine) decreased (MD -6.66, 95% CI -9.38 to -3.93, I² = 88) and no difference in time to PACU discharge (MD -3.82, 95% CI -10.87 to 3.23, I² = 59%).

Conclusions

Patients receiving dexamethasone had reduced pain scores, postoperative opioid requirements and longer time to first analgesia. Dexamethasone is an effective analgesic adjunct for patients undergoing abdominal surgery.

Surgery

dexamethasone

postoperative pain

abdominal surgery

Pain is a common postoperative problem and can be associated with physical and psychological sequelae. Glucocorticoids can modify the stress response and reduce inflammation. Dexamethasone, a commonly used antiemetic, interferes with the cyclooxygenase and lipoxygenase pathways through phospholipase inhibition and has been proposed to modulate postoperative pain in surgical patients ¹.

Two reviews, Waldron et al. and De Oliveira et al., established a reduction in postoperative pain from a single perioperative dose of dexamethasone in heterogeneous surgical cohorts with debated clinical significance ^1–3. Additionally, they demonstrated dexamethasone’s opioid sparing effects but produced conflicting conclusions regarding the dose-response relationship ^2,3. Therefore, the analgesic benefit of glucocorticoids in abdominal surgery remains unclear ^4,5. Waldron et al. excluded patients who received intrathecal or epidural local anaesthetics or opioids yet regional anaesthesia plays a key role in opioid-sparing analgesia for major abdominal surgery ³. Furthermore, patients who received multiple doses of dexamethasone were excluded potentially limiting their clinical significance considering the surgical stress response extends beyond the period of surgery.

Given the exclusion criteria in reviews to date, it is unclear if any benefit demonstrated from the use of dexamethasone in heterogenous cohorts can be translated into patients undergoing elective abdominal surgery.

Therefore, the aim of this review is to determine the effect of perioperative dexamethasone on postoperative pain in adults undergoing general anaesthesia for elective abdominal surgery.

This study was performed according to a prospectively registered protocol (CRD42020176202) and followed guidance from the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement ^6–8.

Randomised controlled trials (RCT) of adults, aged 18 or over, who received intravenous perioperative dexamethasone undergoing general anaesthesia alone or in combination with regional anaesthesia with pain as a primary or secondary outcome for elective abdominal surgery were included. Gastrointestinal, gynaecological and urological procedures were included but renal or transplant surgery were excluded. As the intention was to assess the impact of dexamethasone on postoperative pain, minor gynaecological procedures that were not considered to be painful for example diagnostic laparoscopy were excluded ⁹. Studies were included if intravenous dexamethasone was given at any time, in any dose, either alone or in combination with other antiemetics with placebo or any combination of antiemetic drugs as the comparator. Other study drugs could be given provided the analgesic effect of dexamethasone could be isolated. The primary outcome of our review was pain scores reported on an 11-point numerical scale (0–10). Secondary outcomes for this study included time to first analgesia, opioid requirements and time to PACU discharge.

Literature Search

Electronic databases MEDLINE, EMBASE, CINAHL, CENTRAL and Web of Science were searched, with no language or date restrictions, for RCTs published up to January 28 2021. When available, a standardised search strategy to identify RCTs was used ¹⁰ and the full search strategy was published ⁸ (see Additional file 1). Grey literature and trial registers were searched as pre-specified however, due to the COVID-19 pandemic the World Health Organisation (WHO) International Clinical Trials Registry Portal (ICTRP) was temporarily closed to external users and not searched as pre-specified ¹¹. The reference lists of identified studies and relevant systematic reviews were scanned for additional evidence.

Two authors, (CM and SJC), independently screened unblinded citations, assessed full texts for eligibility, extracted data, recorded on a predetermined data extraction form (see Additional file 2) and assessed bias at outcome level using Cochrane guidance ¹². When necessary, a third author (CO’D) mediated any disagreements.

When the specific surgical procedure was not stated and attempts to contact the author failed, we excluded minor painless surgical procedures based on the length of surgery, anaesthetic and surgical technique, length of hospital stay and postoperative analgesic requirements. Pain scores were defined as early (≤4 hours), intermediate (4–24 hours) and late (≥24 hours) and pain scores presented as a range of times were allocated to the group they most closely corresponded, for example, zero to six hours was allocated to the early group. When multiple pain scores were presented for a single time interval the latest pain score was extracted. Pain scores were assumed to be at rest when this was not stated and converted from a 0-100 to a 0–10 scale as required. Opioids were combined to achieve the total postoperative dose and converted to oral morphine equivalents (see Supplementary Table 1, Additional File 3). Time to first analgesia and PACU discharge were collected in minutes. Authors were successfully contacted for unpublished data or study clarification in seven studies ¹³⁻¹⁹. Data was extracted as mean and standard deviation or converted using verified methods ²⁰⁻²³. Studies containing multiple groups were combined into those with dexamethasone, irrespective of dose or timing, and those not containing dexamethasone. When the analgesic effect of dexamethasone could not be isolated a subset of study data was included to exclude confounding analgesia.

Meta-analysis of outcome data using a random-effects model was performed using Review Manager ((RevMan) [Computer program]. Version 5.4, The Cochrane Collaboration, 2020) and presented as MD with 95% CIs. Statistical heterogeneity was assessed using the method proposed by Higgins et al. (I² test) ²⁴.

Database and trial registry searches revealed a total of 2160 citations. 1846 irrelevant citations were removed, followed by 184 research and publication duplicates leaving 130 articles for eligibility assessment. Twelve articles by Fujii et al. and Schietroma et al. were excluded due to concerns over research validity and multiple retractions ^25–28. We were unable to obtain two full text articles and 13 non-English articles were removed. 103 articles remained for full text eligibility assessment. Studies failed to meet the inclusion criteria and were excluded for the following reasons; 23 articles reported no pain outcomes, three studies were not RCTs, two studies had mixed surgical cohorts, participants did not receive general anaesthesia in three studies, there was no intravenous comparator in four studies and in one the analgesic effect of dexamethasone could not be isolated. Seven studies with minor surgery were excluded ^29–35. A further 12 studies were excluded; two used an alternative method of pain assessment and 10 presented inadequate data for analysis that we were unable to obtain through contacting the authors. 48 full text articles remained, and four additional studies were included after reference list searching resulting in 52 studies with a total of 5758 participants articles (Fig. 1).

Figure 1 PRISMA flow diagram detailing process of study selection.

The final included studies are summarised in the characteristics of included studies table (Table 1). All 52 studies were RCTs of adult patients undergoing general anaesthesia for abdominal surgery published in English. The most common dose of dexamethasone used was 8mg but ranged from 1.25-20mg. Four studies presented the dose of dexamethasone in mg.kg^− 1 and were transformed into total doses using the mean study weights or the average weight of an adult at the time and location of the study ^36–40. No studies administered multiple doses of dexamethasone, but six studies included two or more different doses of dexamethasone ^36,41−45. A further two studies compared the same dose of dexamethasone at different times of administration ^46,47. Opioid doses presented in mg.kg^− 1 were converted in a similar manner to dexamethasone ^16,42,48.

Table 1

Included studies characteristics, intervention and control groups extracted, primary study outcome and pain outcomes reported.
Study 1st author year	Country	Procedures	Participants Included, no	Participant characteristics	Intervention(s) and Control(s)	Primary outcome(s)	Pain outcome(s) reported
Alghanem 2010⁶⁸	Jordan	Laparoscopic cholecystectomy	180	ASA ≤2 Age 18–70 Mix M/F	I: Intraoperative dexamethasone 8mg IV C: Ondansetron or saline	PONV	Pain scores
Areeruk 2016⁴⁹	Thailand	Gynaecological laparotomy via pfannenstiel incision	49	ASA ≤2 Age 18–65	I: Intraoperative dexamethasone 8mg IV C: Saline	Total morphine consumption	Pain scores Opioid consumption
Badawy 2015⁸³	Egypt	Total abdominal hysterectomy	38	ASA ≤2 Age 40–70	I: Preoperative dexamethasone 8mg IV + gabapentin 800mg PO C: Saline + gabapentin	Time to first analgesia	Pain scores Time to first analgesia Opioid consumption
Bataille 2016¹³	France	Laparoscopic sleeve gastrectomy	117	ASA ≤3 Age 18–75 BMI > 40 ≥2 RFs PONV Mix M/F	I: Intraoperative dexamethasone 4mg + ondansetron 4mg IV C: Saline	PONV	Pain scores
Batistaki 2019⁶⁷	Greece	Laparoscopic cholecystectomy	44	ASA ≤3 Age 18–75 Predominantly female	I: Intraoperative dexamethasone 5mg C: Saline	Reversal NMB	Pain scores
Benevides 2013⁷¹	Brazil	Laparoscopic sleeve gastrectomy	60	ASA 1–3 Age 18+ BMI ≥35	I: Intraoperative dexamethasone 8mg + ondansetron 8mg IV C: Saline + ondansetron	PONV Rescue antiemetic use	Opioid consumption PACU LOS
Bianchin 2007⁵⁰	Italy	Laparoscopic cholecystectomy	73	ASA ≤2 Predominantly female	I: Preoperative dexamethasone 8mg IV C: Saline	PONV	Pain scores
Biligin 2010⁶⁹	Turkey	Total abdominal hysterectomy + bilateral salpingoophorectomy	160	ASA ≤2 Age 20–60	I: Preoperative dexamethasone 8mg IV C: Saline or ondansetron or metoclopramide	PONV	Pain scores
Bisgaard 2003⁵¹	Denmark	Laparoscopic cholecystectomy	80	ASA ≤2 Age < 75 Predominantly female	I: Preoperative dexamethasone 8mg IV C: Saline	Pain Fatigue	Pain Scores Opioid consumption PACU LOS
Coloma 2002⁵²	USA	Laparoscopic cholecystectomy	140	ASA ≤2 Predominantly female	I: Intraoperative dexamethasone 4mg IV C: Saline	Recovery times	Time to first analgesia Opioid consumption PACU LOS
Corcoran 2017⁵³	Australia	Major laparoscopic gynaecological surgery	31	ASA ≤2 Age 18–60 Surgery > 90mins ≥1-night stay	I: Intraoperative dexamethasone 4mg IV C: Saline	Immune response	Pain scores
De Oliveira 2011³⁶	USA	Laparoscopic gyanecological surgery	106	ASA ≤2	I: Preoperative dexamethasone 0.05 or 0.1mg.kg^− 1 IV C: Saline	QoR-40	Pain scores Time to first analgesia Opioid consumption
Elhakim 2002⁴¹	Egypt	Laparoscopic cholecystectomy	180	Predominantly male	I: Preoperative dexamethasone 2 or 4 or 8 or 16mg IV C: Saline or ondansetron	PONV	Pain scores Time to first analgesia Opioid consumption
Feo 2006⁵⁴	Italy	Laparoscopic cholecystectomy	101	ASA ≤3 F > M	I: Preoperative dexamethasone 8mg IV C: Saline	Pain PONV Analgesic and antiemetic requirements	Pain scores
Fukami 2009⁵⁵	Japan	Laparoscopic cholecystectomy	80	Mix M/F	I: Preoperative dexamethasone 8mg IV C: Saline	PONV Pain Fatigue Analgesic and antiemetic requirements	Pain scores
Gautam 2008⁷²	Nepal	Laparoscopic cholecystectomy	142	ASA ≤2 Age 23–65	I: Preoperative dexamethasone 8mg IV or dexamethasone 8mg IV + ondansetron 4mg C: Ondansetron	PONV	Pain scores Time to first analgesia Opioid consumption
Hammas 2002⁸²	Sweden	Cholecystectomy, Inguinal hernia repair	76	ASA ≤2 Predominantly male	I: Intraoperative dexamethasone 4mg + ondansetron 4mg + droperidol 1.25mg + metoclopramide 10mg IV C: Propofol infusion	PONV	Opioid consumption
Ionescu 2014⁵⁶	Romania	Laparoscopic cholecystectomy	42	ASA ≤2 Predominantly female	I: Preoperative dexamethasone 4mg IV C: Saline	Immune response	Opioid consumption
Jo 2012¹⁴	Korea	Laparoscopic cholecystectomy	120	ASA ≤2 Female Age 21–64 BMI < 35	I: Preoperative dexamethasone 8mg IV + saline intraoperative or preoperative dexamethasone 8mg IV + ramosetron 0.3mg IV intraoperative C: Saline + ramosetron	PONV	Pain scores
Jokela 2009⁴²	Finland	Laparoscopic hysterectomy +/- oophorectomy	120	ASA ≤3 BMI < 35	I: Preoperative dexamethasone 5 or 10 or 15mg IV C: Saline	Pain Opioid consumption	Pain scores Time to first analgesia Opioid consumption
Kasagi 2013⁷³	Japan	Hysterectomy, cystectomy, myomectomy	60	ASA ≤2 Age 20–50 Benign disease	I: Preoperative dexamethasone 8mg IV C: Droperidol	PONV	Pain scores
Kassim 2018³⁷	Egypt	Laparoscopic gyanecological surgery for infertility	50	ASA ≤2 Age 25–35	I: Preoperative dexamethasone 0.1mg.kg^− 1 IV + duloxetine 60mg PO C: Saline + duloxetine	Pethidine requirements	Pain scores Time to first analgesia Opioid consumption
Ko-iam 2015¹⁶	Thailand	Laparoscopic cholecystectomy	100	ASA ≤2 Age 18–75 Predominantly female	I: Intraoperative dexamethasone 8mg + metoclopramide 10mg IV C: Metoclopramide	PONV	Pain scores Opioid consumption
Kurz 2015⁸⁴	USA	Colorectal resection	555	Age ≤80 Surgery 2–6 hours	I: Intraoperative dexamethasone 4mg IV & 30% oxygen or intraoperative dexamethasone 4mg IV & 80% oxygen C: Saline + oxygen	Surgical site infection	Pain scores
Lee 2017⁴⁰	Republic of Korea	Laparoscopic cholecystectomy	380	ASA ≤2 Age 18–45 Mix M/F	I: Preoperative dexamethasone 5mg IV C: Saline	Morphine requirements	Pain scores Time to first analgesia Opioid consumption
Lim 2011⁴⁶	Korea	Laparoscopic cholecystectomy	120	ASA ≤2 M > F	I: Preoperative dexamethasone 8mg + intraoperative saline or preoperative saline + intraoperative dexamethasone 8mg IV C: Saline	Pain	Pain scores Opioid consumption
Liu 1998⁵⁷	Taiwan	Major gynaecological surgery	60	ASA ≤2	I: Intraoperative dexamethasone 10mg C: Saline	PONV Pain	Pain scores Opioid consumption
Liu 1999⁴³	Taiwan	Abdominal and radical hysterectomy, myomectomy	150	ASA ≤2	I: Preoperative dexamethasone 1.25 or 2.5 or 5 or 10mg IV C: Saline	PONV	Pain scores Time to first analgesia Opioid consumption
Lopez-Olaondo 1996⁷⁴	Spain	Major abdominal gynaecological surgery	100	ASA ≤2 Age 18–65 45-90kg	I: Preoperative dexamethasone 8mg + ondansetron 4mg IV C: Saline + ondansetron	PONV	Pain scores Opioid consumption
Maddali 2003⁷⁵	Oman	Laparoscopic gyanecological surgery	120	ASA ≤2 Age ≤60	I: Preoperative dexamethasone 8mg + ondansetron 4mg IV or dexamethasone 8mg + metoclopramide 10mg C: Saline	PONV	Pain scores
Mathiesen 2009⁸⁵	Denmark	Abdominal hysterectomy +/- salpingoophorectomy	76	ASA ≤2 Age 18–75 BMI 18–32	I: Preoperative dexamethasone 8mg IV + paracetamol 1g PO + pregabalin 300mg PO C: Saline + paracetamol + gabapentin	Morphine consumption	Pain scores Opioid consumption
McKenzie 1997⁸⁰	USA	Abdominal or vaginal hysterectomy, laparotomy, anterior and posterior repair	80	ASA ≤3 Age 18–65	I: Intraoperative dexamethasone 20mg IV + ondansetron 4mg IV C: Saline + ondansetron	PONV	Pain scores Opioid consumption
Murphy 2011⁵⁸	USA	Laparoscopic cholecystectomy	115	ASA ≤3 F > M	I: Preoperative dexamethasone 8mg IV C: Saline	QoR-40	Pain scores Opioid consumption PACU LOS
Murphy 2014⁴⁴	USA	Laparoscopic or open hysterectomy	195	ASA ≤3 Age 18–80	I: Intraoperative dexamethasone 4 or 8mg IV C: Saline	Perioperative glucose concentration	Pain scores Opioid consumption PACU LOS
Nesek-Adam 2007⁷⁶	Croatia	Laparoscopic cholecystectomy	160	ASA ≤2 Predominantly female	I: Intraoperative dexamethasone 8mg IV + saline or dexamethasone 8mg + metoclopramide 10mg C: Saline or saline + metoclopramide	PONV	Pain scores Time to first analgesia
Olajumoke 2013⁵⁹	Nigeria	Total abdominal hysterectomy, myomectomy	96	ASA ≤2 Age 18–65	I: Intraoperative dexamethasone 4mg IV C: Saline	PONV	PACU LOS
Pan 2008⁷⁷	USA	Laparoscopic gynecological surgery	60	ASA ≤2 Age ≥18 ≥3 emetic risk factors	I: Intraoperative dexamethasone 8mg + ondansetron 4mg IV + ondansetron PO D0,1,2 C: Saline + ondansetron	PONV	Pain scores Opioid consumption PACU LOS
Pauls 2015⁶⁰	USA	Major vaginal reconstructive surgery	63	ASA ≤3	I: Preoperative dexamethasone 8mg IV C: Saline	Quality of recovery	Pain scores Opioid consumption
Regasa 2020⁸¹	Ethiopia	Major gynaecological surgery	96	ASA ≤2 Age 18–65	I: Intraoperative dexamethasone 8mg IV + saline or dexamethasone 8mg + metoclopramide 10mg C: metoclopramide	PONV	Opioid consumption
Rothenberg 1998³⁸	USA	Laparoscopic gynaecological surgery	95	ASA ≤2	I: Intraoperative dexamethasone 0.17mg.kg^− 1 IV C: Droperidol	PONV	Pain scores Opioid consumption PACU LOS
Ryu 2013⁷⁸	Korea	Laparoscopic cholecystectomy	72	ASA ≤2 Age 25–65	I: Intraoperative dexamethasone 8mg + ramosetron 0.3mg IV C: Saline + ramosetron	PONV	Pain scores
Sanchez-Ledesma 2002¹⁵	Spain	Hysterectomy, myomectomy/ adnexectomy, oncological gynaecological reduction	90	ASA ≤2 Age 18–65 45-90kg	I: Intraoperative dexamethasone 8mg + droperidol 1.25mg IV + postoperative droperidol or dexamethasone 8mg + ondansetron 4mg and postoperative saline C: Ondansetron + droperidol	PONV	Pain scores Opioid consumption
Sanchez-Rodriquez 2010⁶¹	Mexico	Laparoscopic cholecystectomy	210	ASA ≤2 Age ≤80 F > M	I: Preoperative dexamethasone 8mg IV C: Placebo	PONV Pain Fatigue Additional analgesic & antiemetic drugs	Pain scores
Shrestha 2014⁷⁹	Nepal	Laparoscopic cholecystectomy	120	ASA ≤2 Age 17–75 Predominantly female	I: Preoperative dexamethasone 8mg + pheniramine 45.5mg IV C: Saline	Pain Systemic acute phase response	Pain scores
Sistla 2009⁶²	India	Laparoscopic cholecystectomy	70	Predominantly female	I: Preoperative dexamethasone 8mg IV C: Saline	Morphine consumption	Pain scores Opioid consumption
Thangaswamy 2010⁴⁵	India	Total laparoscopic hysterectomy	55	ASA ≤2 Age 18–60	I: Preoperative dexamethasone 4 or 8mg IV C: Saline	Fentanyl consumption	Pain scores Time to first analgesia Opioid consumption
Tolver 2012⁶³	Denmark	Transabdominal preperitoneal groin repair	73	ASA ≤2 Age 18–85	I: Preoperative dexamethasone 8mg IV C: Saline	Pain	Pain scores Opioid consumption
Viriyaroj 2015⁶⁴	Thailand	Laparoscopic cholecystectomy	80	Predominantly female	I: Preoperative dexamethasone 8mg IV C: Saline	Pain Analgesic consumption	Pain scores Opioid consumption
Wang 1999⁶⁵	Taiwan	Laparoscopic cholecystectomy	78	ASA ≤2 Age 30–55 Predominantly female	I: Preoperative dexamethasone 8mg IV C: Saline	PONV	Pain scores Opioid consumption
Wang 2000⁴⁷	Taiwan	Total abdominal hysterectomy	120	ASA ≤2 Age 35–45	I: Preoperative dexamethasone 10mg IV + postoperative saline or preoperative saline + postoperative dexamethasone 10mg IV C: Saline	PONV	Pain scores Opioid consumption
Wu 2009⁶⁶	Taiwan	Anorectal surgery	60	ASA ≤2 Predominantly female	I: Preoperative dexamethasone 5mg IV C: Saline	PONV	Pain scores Opioid consumption
Yuksek 2003⁷⁰	Turkey	Laparoscopic gyanecological surgery	60	ASA ≤2 19–62	I: Preoperative dexamethasone 8mg IV C: Saline or ondansetron	PONV	Pain scores Time to first analgesia
PONV postoperative nausea and vomiting, NMB neuromuscular blockade, PACU LOS post-anaesthesia care unit length of stay

Dexamethasone was directly compared to placebo in 27 studies ^{36,40,42–47,49−67} with a further four comparing dexamethasone to placebo or another antiemetic ^41,68−70. Intravenous anti-emetic drugs were included in the intervention or control groups in 17 studies ^{13–16, 38,71–82}. One study compared dexamethasone with an intraoperative and postoperative propofol infusion ⁸². Four studies included additional study drugs, but groups were extracted to ensure the analgesic effect of dexamethasone was isolated ^37,83−85.

The timing of dexamethasone varied from two hours preoperatively to immediately after extubation ^37,45,47. Dexamethasone was most frequently given preoperatively ^{14,36,37,40–43,45−47,50,51,54–56,58,60–66,69,70,72–75,79,81,83,85}, but when administered intraoperatively this was more commonly postinduction pre-incision ^{13,15,38,44,49,52,53,57,59,67,68,71, 76–78,80,82,84} than during the surgical procedure ^16,46. In one study dexamethasone was given immediately post extubation ⁴⁷.

The primary outcome was most commonly related to PONV in 26 studies ^{13–16,38,41,43,47,50,59,65,66,68–78,80−82}. Pain outcomes were the primary outcome in 11 studies ^{37,40,42,45,46,49, 62–64,83,85} and was a joint primary outcome in a further six studies ^{51,54,55,57,61,79}. The primary outcome was quality or timing of recovery in four studies ^36,52,58,60, the immune or stress response in two studies ^53,56, surgical site infection in one study⁸⁴, perioperative glucose concentration in one study ⁴⁴ and reversal of neuromuscular blockade in one study⁶⁷. In general, study outcomes were poorly documented with 25 studies not specifically stating study outcome ^{14,16,38, 41–43,46,47,50,52,53,56,57,59,62,65, 68–70,72,76,78,79,81,82}, seven studies documenting primary outcome only ^{15,36,51,66,75,77,83} and ambiguity over primary or secondary outcomes in a further five studies ^{54,55,61,64,73}.

Pain was presented on an 11-point numerical scale in the majority of studies and divided by 10 when presented as 0-100 ^{14,40,44,45,58,63,78,85}. Six studies did not report pain scores ^{52,56,59,71,81,82} and we were unable to extract pain scores in a further four studies ^37,51,57,74. The pain outcomes extracted from each study are presented in Table 2.

Table 2

Pain outcomes extracted from each study
	Pain Scores
Study Year	Early Rest	Early Movement	Intermediate Rest	Intermediate Movement	Late Rest	Late Movement	Time to First Analgesia	Opioid Consumption	PACU LOS
Alghanem 2010⁶⁸	yes				yes
Areeruk 2016⁴⁹			yes	yes	yes	yes		yes
Badawy 2015⁸³	yes		yes		yes		yes	yes
Bataille 2016¹³	yes	yes			yes	yes
Batistaki 2019⁶⁷	yes		yes		yes
Benevides 2013⁷¹								yes	yes
Bianchin 2007⁵⁰	yes		yes		yes
Bilgin 2010⁶⁹			yes
Bisgaard 2003⁵¹								yes	yes
Coloma 2002⁵²							yes	yes	yes
Corcoran 2017⁵³	yes	yes
De Oliveira 2011³⁶	yes						yes	yes
Elhakim 2002⁴¹					yes	yes	yes	yes
Feo 2006⁵⁴	yes		yes		yes
Fukami 2009⁵⁵	yes		yes		yes
Gautam 2008⁷²	yes		yes		yes		yes	yes
Hammas 2002⁸²								yes
Ionescu 2014⁵⁶								yes
Jo 2012¹⁴	yes		yes
Jokela 2009⁴²	yes	yes	yes	yes	yes	yes	yes	yes
Kasagi 2013⁷³	yes		yes
Kassim 2018³⁷							yes	yes
Ko-iam 2015¹⁶			yes					yes
Kurz 2015⁸⁴	yes		yes
Lee 2017⁴⁰		yes		yes		yes	yes	yes
Lim 2011⁴⁶	yes		yes		yes			yes
Liu 1998⁵⁷								yes
Liu 1999⁴³					yes		yes	yes
Lopez-Olaondo 1996⁷⁴								yes
Maddali 2003⁷⁵			yes
Mathiesen 2009⁸⁵	yes	yes			yes	yes		yes
McKenzie 1997⁸⁰	yes				yes			yes
Murphy 2011⁵⁸	yes	yes	yes	yes				yes	yes
Murphy 2014⁴⁴	yes	yes						yes	yes
Nesek-Adam 2007⁷⁶	yes	yes	yes	yes			yes
Olajumoke 2013⁵⁹									yes
Pan 2008⁷⁷	yes		yes		yes			yes	yes
Pauls 2015⁶⁰					yes			yes
Regasa 2020⁸¹								yes
Rothenberg 1998³⁸			yes					yes	yes
Ryu 2013⁷⁸	yes		yes		yes
Sanchez-Ledesma 2002¹⁵	yes		yes	yes	yes	yes		yes
Sanchez-Rodriquez 2010⁶¹	yes		yes		yes
Shrestha 2014⁷⁹					yes
Sistla 2009⁶²	yes	yes	yes	yes	yes	yes		yes
Thangaswamy 2010⁴⁵	yes	yes	yes	yes	yes	yes	yes	yes
Tolver 2012⁶³			yes	yes	yes	yes		yes
Viriyaroj 2008⁶⁴	yes		yes		yes			yes
Wang 1999⁶⁵	yes							yes
Wang 2000⁴⁷	yes							yes
Wu 2009⁶⁶	yes
Yuksek 2003⁷⁰			yes				yes
PACU LOS, post-anaesthesia care unit length of stay

Bias assessment judged seven studies to be low risk ^{15,37,45,58,63,72,80}, 20 studies to have some concerns, ^{13,14,38,40,44,46,52,54,55,59,61,64,68,71,73,74,76,77,79, 83} and 25 to be high risk ^{16,36, 41–43,47, 49–51,53,56,57,60,62, 65–67,69,70,75,78,81,82,84,85}. For ROB assessment see Supplementary Table 2, Additional File 4 and Supplementary Figs. 1 and 2, Additional File 5.

Pain scores

Early pain scores at rest were recorded in 30 studies (3408 patients) ^{13–15, 36,42, 44–47,50, 53–55,58,61,62, 64–68,72,73, 76–78,80, 83–85} with a statistically significant reduction in pain in patients receiving dexamethasone (MD -0.54; CI -0.72, -0.35; I² 81%; n = 3408) (Fig. 2). The direction of result remained unchanged when the analysis was restricted to studies with pain (MD -0.8; CI -1.22, -0.38; I² 91%; n = 950) and non-pain (MD -0.4; CI -0.62, -0.19; I² 63%; n = 2458) primary outcomes.

Figure 2 Forest plot for early (≤4 hours) VAS pain scores at rest.

Ten studies (1319 patients) reported early pain scores on movement ^{13,40,42,44,45,53,58,62,76,85} with a statistically significant reduction in pain in patients who received dexamethasone (MD -0.42; CI -0.62, -0.22; I² 35%; n = 1319). The result trend did not vary when the analysis was limited to studies with non-pain (MD -0.47; CI -0.84, -0.10; I² 52%; n = 618) or pain (MD -0.43; CI -0.68, -0.18; I² 17%; n = 701) as the primary outcome.

Intermediate pain scores at rest were recorded in 27 studies (3022 patients) ^{14–16, 38,42,45,46,49,50,54,55,58, 61–64,67,69,70,72,73, 75–78,83,84} and on movement in nine studies (1112 patients) ^{15,40,42,45,49,58,62,63,76}. There was a statistically significant reduction in intermediate pain scores both at rest (MD -0.31; CI -0.47, -0.14; I² 96%; n = 3022) and on movement (MD -0.26; CI -0.39, -0.13; I² 29%; n = 1112) in patients receiving dexamethasone. When analysis of intermediate pain scores at rest was restricted to studies with pain as the primary outcome the direction of result remained (MD -0.57; CI -0.92, -0.22; I² 89%; n = 996), however, lost statistical significance when restricted to non-pain primary outcomes (MD -0.18; CI -0.39, 0.03; I² 97%; n = 2026). Restricting the results for intermediate pain scores on movement to pain (MD -0.33; CI -0.45, -0.21; I² 0%; n = 747) and non-pain (MD -0.16; CI -0.25, -0.07; I² 0%; n = 365) primary outcomes did not change the direction of the result.

Late pain scores at rest were recorded in 25 studies (2443 patients) ^{13,15, 41–43,45,46,49,50,54,55, 60–64,67,68,72, 77–80,83,85}. There was a statistically significant reduction in pain scores in patients who received dexamethasone (MD -0.38; CI -0.52, -0.24; I² 88%; n = 2443). The direction of the result was unchanged when the study outcome was restricted to pain (MD -0.42; CI -0.68, -0.16; I² 90%; n = 1192) and non-pain (MD -0.34; CI -0.57, -0.11; I² 77%; n = 1251) primary outcomes.

Ten studies (1210 patients) ^{13,15, 40–42,45,49,62,63,85} reported late pain on movement with a statistically significant reduction in pain scores in patients who received dexamethasone (MD -0.38; CI -0.65, -0.11; I² 71%; n = 1210). Confining the results to non-pain primary outcomes did not change the result trend (MD -0.49; CI -0.95, -0.03; I² 59%; n = 387) but limiting to studies with pain as the primary outcome demonstrated no statistical significance (MD -0.3; CI -0.61, 0.00; I² 66%; n = 823).

Analgesic requirements

Time to first analgesia was recorded in 12 studies (1581 patients) ^{36,37, 40–43,45,52,70,72,76,83}. There was a statistically significant increase in time to first analgesia (minutes) in patients who received dexamethasone (MD 22.92.; CI 11.09, 34.75; I² 99%; n = 1581) (Fig. 3). Restricting the analysis to studies with pain (MD 31.97; CI 13.35, 50.60; I² 99%; n = 643) and non-pain primary outcomes (MD 15.17; CI 0.33, 30.02; I² 91%; n = 938) did not affect the trend.

Figure 3 Forest plot for time to first analgesia in minutes.

Postoperative opioids were recorded in 33 studies (3339 patients) ^{15,16,36–38,40−47,49,51,52,56–58,60,62–65,71,72,74,77,80–83,85}. However, there was variability in the type, administration and time of recorded opioids varying from one hour to five days postoperatively. There was a statistically significant reduction in opioid use (mg of oral morphine equivalents) in patients who received dexamethasone (MD -6.66; CI -9.38, -3.93; I² 88%; n = 3339) (Fig. 4). Statistical significance remained when the result was restricted to pain (MD -8.35; CI -11.64, -5.07; I² 58%; n = 1251) and non-pain (MD -5.50; CI -9.15, -1.85; I² 91%; n = 2088) primary outcomes. Visual inspection of the funnel plots for total opioid requirements and early pain scores at rest do not suggest evidence of significant reporting or publication bias (see Supplementary Fig. 3 and Fig. 4, Additional File 6).

Figure 4 Forest plot for total postoperative opioid use in mg of oral morphine equivalents.

Time to PACU discharge

Nine studies (947 patients) reported time to discharge from PACU ^{36,38,44,51,52,58,59,71,77}. There was no difference in time to PACU discharge between patients who received dexamethasone and those who did not (MD -3.82; CI -10.87, 3.23; I² 59%; n = 947). Removing the single study with pain as the primary outcome and restricting the analysis to non-pain (MD -4.37; CI -12.10, 3.37; I² 54%; n = 867) had no impact on the result.

Subgroup analyses

Subgroup analyses of general anaesthesia in combination with either central neuraxial blockade (GA + CNB) or regional anaesthesia (GA + RA) were previously documented (CRD42020176202) ⁸. Patients received GA + CNB in three studies; spinal with intrathecal morphine ¹⁵, epidural administration of morphine and fentanyl ⁷⁰ and a small proportion of both the intervention and control groups received an epidural in one study ⁸⁴. The subset of study data was not available in this study.⁸⁴ One study documented the use of regional anaesthesia with either transversus abdominal plane block or rectus sheath block⁸¹. Given the limited data these predefined subgroup analyses were not undertaken.

The planned dosing subgroup analyses were undertaken for a single but not multiple doses of dexamethasone. Doses were grouped pragmatically into three categories to correspond with clinical practice; low dose 1.25-5mg, intermediate dose 6.4-10mg and high dose 11-20mg. For early pain scores at rest both low (MD -0.55; CI -1.04, -0.07; I² 66%; n = 1023) and intermediate (MD -0.55; CI -0.76, -0.34; I² 83%; n = 2265) demonstrated benefit with no impact from high dose (MD -0.21; CI -1.02, 0.60; I² 0%; n = 120). For early pain scores on movement only intermediate dose (MD -0.48; CI -0.75, -0.21; I² 47; n = 587) demonstrated benefit with no impact from low (MD -0.34; CI -0.67, 0.00; I² 0%; n = 692) or high dose (MD -0.40; CI -1.79, 0.99; n = 40).

For 4–24 hour pain scores, again, there was evidence of dose response for intermediate dose at rest (MD -0.36; CI -0.53, -0.18; I² 96%; n = 2221) and on movement (MD -0.25; CI -0.37, -0.13; I² 22%, n = 1005). There was a lack of statistical significance for low (MD 0.22; CI -0.15, 0.58; I² 0%, n = 666) and high dose (MD -0.05; CI -0.76, 0.66; I² 0%; n = 135) at rest and low (MD -0.12; CI -0.77, 0.54; I² 0%; n = 67) and high dose (MD -0.70; CI -2.62, 1.22; n = 40) on movement.

Intermediate dose remained statistically significant (MD -0.42; CI -0.62, -0.22; I² 84%; n = 1847) for late pain scores at rest but low (MD -0.08; CI -0.22, 0.06; I² 19%; n = 431) and high (MD -0.51; CI -1.32, 0.30; I² 66%; n = 165) dose dexamethasone demonstrated no difference (Fig. 5). This pattern was mirrored in late pain scores on movement; low (MD -0.25; CI -0.5, 0.00; I² 0%; n = 274), intermediate (MD -0.47; CI -0.83, -0.10; I² 70%; n = 851) and high dose (MD -0.31; CI -1.43, 0.82; I² 74%; n = 85).

Figure 5 Forest plot for dexamethasone dosing late (≥24 hours) VAS pain scores at rest.

Time to first analgesia was increased with intermediate dose (MD 27.76; CI 13.96, 41.55; I² 98%; n = 1034) but low (MD 11.58; CI -0.34, 23.5; I² 89%; n = 462) and high dose had no impact (MD 25.44; CI -2.23, 53.12; I² 86%; n = 85). Again, a statistically significant reduction in postoperative opioid requirements was maintained for intermediate dose (MD -7.20; CI -9.77, -4.64; I² 80%; n = 2402) but low (MD -8.14; CI -16.72, 0.44; I² 89%; n = 677) and high dose dexamethasone (MD -19.26; CI -57.79, 19.28; I² 94%; n = 260) demonstrated no difference.

Subgroup analysis did not impact time to PACU discharge with no difference from low (MD 0.27; CI -6.72, 7.27; I² 40%; n = 385), intermediate (MD -9.56; CI -24.56, 5.44; I² 65%; n = 467) or high (MD -3.76; CI -15.77, 8.25; n = 95) dose dexamethasone (see supporting information, Appendix 3).

Timing of administration subgroup analyses of dexamethasone were also performed. This was categorised as preoperative (before anaesthetic induction), intraoperative (anaesthetic induction and to extubation) and postoperative (after extubation). The timing subgroup analyses demonstrated a global reduction in pain scores from preoperative administration of dexamethasone for all pain scores both at rest and on movement. In contrast, intraoperative administration only reduced late pain scores at rest.

Preoperative dexamethasone significantly increased time to first analgesia (MD 28.13; CI 14.57, 41.68; I² 98%; n = 1281), but there was no difference from intraoperative administration (MD -0.01; CI -6.24, 6.21; I² 0%; n = 300). Additionally, preoperative dexamethasone decreased total opioid administration (MD -8.55; CI -12.34, -4.76; I² 89%; n = 2214) with no effect from intraoperative administration (MD -2.18; CI -5.93, 1.56; I² 83%; n = 1065). Postoperative dexamethasone (MD -12.00; CI -17.45, -6.55; n = 40) decreased opioid administration but this was based on results from a single study.⁴⁷ Time to PACU discharge remained unaffected by dexamethasone timing; preoperative (MD -12.55; CI -30.73, 5.63; I² 62%; n = 361), intraoperative (MD -0.56; CI -7.41, 6.29; I² 57%; n = 586) (For additional forest plots see Additional File 7).

To our knowledge this is the largest systematic review and meta-analysis investigating the effect of perioperative dexamethasone on postoperative pain in adults undergoing elective abdominal surgery under general anaesthesia and the first to demonstrate an important analgesic effect in this surgical cohort.

Our analyses demonstrated a statistically significant reduction in early, intermediate and late pain scores both at rest and on movement. Sub-group analyses revealed that intermediate dose (6.4-10mg) effectively decreased pain at all time intervals both at rest and on movement. However, low dose (1.25-5mg) only affected early pain scores at rest while high dose (11-20mg) had no impact on any pain scores. Preoperative administration of dexamethasone demonstrated a global reduction on all pain scores. Intraoperative administration was more beneficial in reducing late pain scores at rest but failed to impact pain at any other time period. Dexamethasone also reduced the total postoperative opioid requirements and increased the time to first analgesia with intermediate dose (6.4-10mg) and preoperative administration demonstrating the greatest impact. Time to PACU discharge was not altered by dexamethasone at any dose or time and is likely to be influenced by external factors ⁸⁶. However, this is contrary to previous findings which have questionable clinical significance ³.

Dexamethasone’s established anti-inflammatory properties has ensured it is a widely used effective perioperative anti-emetic ^1,5,87. In abdominal surgery glucocorticoids reduce pro-inflammatory mediators and phospholipase required for pain pathways allowing its analgesic benefits to be increasingly recognized ^{1–3, 5}. Enhanced recovery pathways encouraging earlier mobility have boosted the demand for opioid-sparing multimodal analgesia in patients undergoing abdominal surgery ^88–91. Dexamethasone has, therefore, an important role in postoperative analgesia with additional benefit for multimodal analgesic regimes in this patient population. However, full analgesic effect is unlikely from the commonly used lower anti-emetic dose and intermediate dose (6.4-10mg) is necessary to produce global reductions in pain scores, increase time to first analgesia and reduce opioid requirements ^1,87. Additionally, timing of administration is crucial as the analgesic benefits of preoperative dexamethasone far outweigh administration at induction as recommended for antiemetic effect ⁹².

One of the major strengths of this review is inclusion of a large number of studies and participants of a relatively homogenous surgical population. This allows the results to inform future clinical practice and guidelines in moderate and major abdominal surgery. A previous systematic review failed to demonstrate a reduction in early pain scores on movement from dexamethasone administration, likely due to small numbers ³. This new finding is potentially significant for enhanced recovery regimes where early movement after abdominal surgery is encouraged ^88–91. In addition, investigation of dexamethasone’s effect on intermediate pain scores is novel and provides further evidence of its analgesic effects ^2,3. Through subgroup analyses we have provided clarification on the debated perioperative dosing and given strength to the previously suggested preoperative timing ^2,3. Despite demonstrating a globally statistically significant reduction in postoperative pain scores it is important to remember that the clinical significance of this is uncertain. The increase in time to first analgesia and reduction in postoperative opioids is likely to have more clinical impact on patients undergoing abdominal surgery. When studies with regional anaesthesia were removed a statistically significant reduction in postoperative opioids (MD -6.87; CI -9.70, -4.05; I² 89%; n = 3153) and increased time to first analgesia (MD 23.01; CI 11.14, 34.88; I² 98%; n = 1521) remained.

There are a number of limitations in our review. Firstly, results could potentially be biased by selective reporting and missing outcome data, but the funnel plots were reassuring ^{17–19,93−100}. Secondly, as the latest pain score was extracted from each time interval there could be significant variation in the timing which may explain some of the statistical heterogenicity in intermediate and late pain scores. Late pain scores varied from 24 hours to four days, with later pain scores less likely to demonstrate statistical significance potentially influencing the results. The variation in timing of recorded postoperative opioid consumption, from one hour to five days, may also account for some of the statistical heterogenicity. Thirdly, results from the high dose and postoperative subgroup analyses should be interpreted with caution given the low numbers available. In addition, we did not investigate the impact of adverse effects of dexamethasone administration as this has previously been done ^2,3,101. However, when reported, adverse features reported were similar between intervention and control groups and not attributed to dexamethasone administration.

Furthermore, pain was the primary outcome in less than half the studies but when analyses were restricted to studies with pain as the primary outcome all results remained statistically significant except late pain scores on movement. In addition, pain scores on movement were less likely to be reported potentially reducing the strength of the sensitivity analyses. Pain scores on movement should be the focus of future studies given the drive for postoperative mobilisation.

Additionally, due to lack of data we were unable to perform our prespecified subgroup analyses GA + CNB and GA + RA. Dexamethasone may impact on postoperative pain in combination with general and regional anaesthesia, but it is unclear if this can be translated to the general surgical population ^102–104. It is our opinion that this question remains unanswered and should guide future research.

Unfortunately, nearly half of all studies were deemed high ROB, frequently due to selection of the reported result with failure to report all measured pain scores. As the majority of studies had a non-pain primary outcome, ROB assessment at study rather than outcome level would have impacted these results. ROB assessment highlighted issues with study methodology, with inadequate allocation concealment in nearly half of all studies, and trialists should be reminded of reporting guidelines for RCTs ¹⁰⁵. Additionally, the type of analysis was infrequently documented, and we judged nearly half of all studies undertook a per-protocol analysis due to exclusions of protocol violations and post-randomisation participants for reasons not pre-specified. Some exclusions are justified in a modified intention-to-treat (mITT) analysis, but we exercised caution using this label due to ambiguity over the definition ^106,107. We feel clarification of mITT criteria is essential to avoid subjectivity of future ROB assessments. However, the completeness of outcome data provides some reassurance over the safety and lack of adverse features of dexamethasone.

In conclusion a single perioperative dose of intravenous dexamethasone reduces early, intermediate and late pain scores both at rest and on movement, opioid requirements and increases time to first analgesia in patients undergoing elective abdominal surgery. Preoperative administration of intermediate dose is likely to have the greatest impact on outcomes.

CENTRAL Cochrane Central Register of Controlled Trials; CI: Confidence Interval; CINAHL: Cumulative Index to Nursing and Allied Health Literature; CNB: Central Neuraxial Blockade; EMBASE: Exerpta Medica Database; GA: General Anaesthesia; ICTRP: International Clinical Trials Registry Portal; MEDLINE: Medical Analysis and Retrieval System Online; MD: Mean Difference; mITT: modified Intention to Treat; PACU: Post Anaesthesia Care Unit; PRISMA: preferred reporting items for systematic reviews and meta-analysis; RA: Regional Anaesthesia; RevMan: Review Manager; RCT; Randomised Controlled Trial; ROB: Risk of Bias; PONV: Postoperative Nausea and Vomiting; WHO: World Health Organisation.

Ethics approval and consent to participate

Not applicable.

Availability of data and materials

All data collected and analysed for the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare they have no competing interests.

Funding

Dr S Bampoe is supported by an award from the NIHR UCLH Biomedical Research Centre.

Authors’ contributions

CM and SB contributed to the conception and design. CM and SJC contributed to the data collection, data analysis, manuscript writing. COD, SB and DW contributed to the manuscript writing. All authors have read and approved the final manuscript.

Acknowledgements

We would like to thank Mrs. Angela Thompson, Librarian, Queen’s University Belfast for her assistance in reviewing the search strategy and Hazel Neale, Healthcare Librarian, Healthcare Library of Northern Ireland at Craigavon Area Hospital, for her assistance in obtaining certain texts.

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What is the impact of dexamethasone on postoperative pain in adults undergoing general anaesthesia for elective abdominal surgery: a systematic review and meta-analysis

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