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Is intravenous magnesium sulphate a suitable adjuvant in postoperative pain management? – A critical and systematic review of methodology in randomized controlled trials

  • Mark Puch Oernskov EMAIL logo , Sofia Gaspar Santos , Mohammad Sohail Asghar ORCID logo and Kim Wildgaard
Published/Copyright: December 7, 2022
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Scandinavian Journal of Pain
From the journal Scandinavian Journal of Pain Volume 23 Issue 2

Abstract

A growing worldwide focus on opioid-free anaesthesia entails multimodal analgesic strategies involving non-opioids such as magnesium sulphate (MgSO4). Several systematic reviews have concluded there is beneficial analgesic effect of MgSO4 administration but do not take considerable heterogeneity among the studies into consideration. Medical literature published until June 2021 was searched in PubMed/Medline, Embase, Central and Web of Science: The final search yielded a total of 5,672 articles. We included only randomised controlled trials assessing the effect of intravenous MgSO4 on opioid consumption and acute postoperative pain when compared to either placebo or standardized analgesic treatment. The primary aim was to compare the homogeneity of essential variables and confounders. A post-hoc meta-analysis demonstrated a reduction in both postoperative morphine consumption (−6.12 mg) and pain score (−12.32 VAS points) in favour of the MgSO4-groups. Data for meta-analysis was missing from 19 studies (45%) on morphine consumption and 29 studies (69%) for pain score, the majority of which reports no effect for either morphine consumption or pain score. The calculated heterogeneity among the included studies was considerable for both outcomes; I2=91% for morphine consumption and I2=96% for pain score. Although we found a per se reduction in opioid consumption and pain score, methodological heterogeneity and clinical shortcomings of pre-, intra-, and post anaesthetic data precludes conclusions on clinical importance of intraoperative intravenous MgSO4. In addition, the reduction is likely less than what can be gained from using standardized analgesic treatment.

Keywords: heterogeneity; magnesium sulphate; postoperative morphine consumption; postoperative pain management; study methodology

Introduction

Adequate perioperative pain management is crucial to postoperative outcomes, patient experience, and enhanced functional recovery after surgery [1]. Traditionally, opioids have been the mainstay of acute postoperative pain management, as they are highly effective analgesics, though with considerable adverse events (AE) [2].

Due to the many AEs of opioids and increasing worldwide focus on the concept of an “opioid-free anaesthesia” [3, 4], multimodal analgesic strategies involving non-opioid pharmacological agents and anaesthesia techniques have gained increasing attention in recent years [5, 6]. Magnesium sulphate (MgSO4), a non-opioid pharmacological agent, has been reported to be a beneficial adjuvant in the management of acute postoperative pain [7], [8], [9], [10]. MgSO4’s analgesic effect is believed to occur through blockade of N-methyl-d-aspartate (NMDA) receptors and subsequent inhibition of the inflammatory response [11].

Previously, five systematic reviews/meta-analysis have examined the effect of intravenous (i.v.) MgSO4 on postoperative pain and postoperative opioid consumption [7], [8], [9], [10, 12]. Here the effect of i.v. MgSO4 varied, but it was predominantly concluded as having a beneficial analgesic effect. However, several reviews have reported a considerable heterogeneity with regard to outcome variables for opioid consumption and pain scores (the heterogeneity (I2) was found to be 84–92%) without reviews reporting details on causes of heterogeneity [7, 8, 10]. A prerequisite for valid systematic reviews and meta-analysis is both homogenous methodology and homogenous data in an effort to minimize bias [13, 14]. In order to learn the underlying causes of bias from intravenous (i.v.) use of MgSO4, we decided to systematically investigate details of study methodology and clinical bias pre, intra, and post anaesthesia in randomised controlled trails. We aimed to describe the homogeneity of essential variables to be controlled, outcomes and adverse events to decide whether i.v. MgSO4 is of value as a single analgesic adjuvant for acute postoperative pain.

If considerable heterogeneity of essential variables can be substantiated by our review, the conclusions from previous systematic reviews/meta-analysis should be reconsidered. Identified heterogeneity would help future researchers in designing randomised controlled trials (RCTs) by identifying which variables need to be controlled.

Aim

The aim of this systematic review of study methodology is to systematically examine the existing literature on i.v. MgSO4 usage for postoperative pain management, in order to compare the homogeneity of essential variables in RCTs assessing the effect of i.v. MgSO4 on morphine consumption and postoperative pain score when compared to either placebo or standardized treatment.

Methods

Our clinical research question, ‘Is intravenous magnesium sulphate in the operative setting supported by clinical effect in postoperative pain management?’, was broken down using the PICOS criteria (a mnemonic used in evidence-based practice to frame and answer a clinical or health care related question) [15]:

Participants: Adults (age > 18) undergoing surgery in general anaesthesia.

Intervention: I.v. MgSO4 administration for postoperative pain management.

Comparisons: Placebo, Standard treatment, No treatment group.

Outcomes: Pre-operative pain and psychosocial assessment, Strategy for MgSO4 administration, Postoperative pain scores and morphine consumption, AEs, and Health Related Quality of life (HRQoL) measurements.

Study design: Randomised placebo-controlled trials.

Search strategy

A formal protocol was submitted to PROSPERO [16] on November 21st, 2019, and accepted on April 29th, 2020. No. 139581.

On November 30th, 2018, an explorative pilot search in PubMed was performed based on a pool of 16 articles known by the authors. The pilot search used synonyms and search terms based on words and phrases from the initial 16 articles and were used to test the precision and relevance of the search criteria in the development of the final primary search strategy.

The final primary search was developed from exact terms and phrases occurring in known articles as text, keywords or qualifying field codes and was performed on January 28th, 2019. This taxonomy was adapted to searched databases, PubMed/Medline (MeSH terms), Embase, Central and Web of Science by an information specialist.

The final primary search yielded 4,228 articles. Duplicate entries were removed, and the titles/abstracts of the remaining articles were manually screened. Inclusion criteria: Human, age > 18 years, English, RCT, report of postoperative pain scores and opioid consumption, comparison to placebo group. Exclusion criteria: Cardiac surgery, preeclampsia, reviews, editorials, abstracts, case reports and the use of i.v. MgSO4 for local and regional anaesthesia. Comparison studies were only accepted if one arm included i.v. MgSO4 and another arm placebo or standard analgesic treatment (the basic analgesic treatment that is normally provided surgical patients to prevent postoperative pain).

Articles were independently screened by two authors (MPO, SGS), using Rayyan QCRI screening tool [17]. Discrepancies were resolved with the help of a third author (MSA or KW). The screening identified 102 articles for full text scrutiny which resulted in a total of 37 articles meeting the search criteria (Figure 1). References of the included full text papers were reviewed for further articles; one additional article was found among the references.

Figure 1: PRISMA flow chart.
Figure 1:

PRISMA flow chart.

In June 2020, the search was updated using identical search criteria but with publication dates limited to January 28th, 2019 to June 22nd, 2020. All 660 articles were screened using the original methodology, one publication met the inclusion criteria in the updated search (Figure 1).

Due to Covid-19 related delays an updated search was again performed in June 2021 using identical search criteria but with publication dates limited to June 22nd, 2020 to June 24th, 2021. An additional 784 articles were screened, three publication met the inclusion criteria. The final and updated search based on the PICOS criteria yielded a total of 5,672 articles (Figure 1)

Statistics

A post-hoc meta-analysis was performed using Review Manager (RevMan Version 5.4. The Cochrane Collaboration, 2020). We estimated the weighted mean differences for morphine consumption and pain scores between i.v. MgSO4 and placebo groups, with an overall estimate of the pooled effect. Data was analysed using a random effects model, as data was expected to be heterogeneous. Data is presented as mean difference with 95% CI. Means and SD were extracted from the text, tables, or graphs from each source study. Authors was not contacted as this analysis was post-hoc. All opioids were converted into equianalgesic doses of i.v. morphine [18] and pain scores reported as verbal or numeric rating scales were converted to a standardised 0–100 analogue scale for quantitative evaluations (Supplementary Tables 4 and 5).

Finally, heterogeneity calculated as I2 higher than 75% indicated a considerable heterogeneity [13, 19].

Data extraction

Ultimately, data on methodology from 42 studies was extracted and is presented, using the PRISMA statement [16], in this systematic review of methodology on the use of i.v. MgSO4 in postoperative pain management (Figure 1). Authors of the included studies were not contacted for additional data.

Data was extracted (by MPO, SGS) and organized according to surgical specialties and presented for pre (before induction), intra (under anaesthesia) and post (after end anaesthesia) anaesthetic periods (Tables 1–3).

Table 1:

Pre-, intra- and post anaesthetic data for gynaecological surgery.

Types of surgery First authors, year, country N, MgSO4/Placebo Details of blinding/randomization Pre-op pain and psychosocial assessment Anaesthesia type Use of NMBA/reversal of NMBA Neuromuscular monitoring intra/post op Basic pain treatment MgSO4 bolus injection MgSO4 continued infusion Administration of Bolus injection/infusion Post-op. opioid Defined AE measures Plasma Mg Observation period HRQoL measures Effect of MgSO4 vs. placebo No effect of MgSO4 vs. placebo
Abdominal hysterectomy Arikan, 2016, Turkey 40/40 +/+ – Sevoflurane/N2O/Fentanyl Rocuronium/+ −/− – 50 mg kg−1 10 mg kg−1 h−1 Post-op./48 h post-op. PCA-morphine Sedation – 48 h Satisfaction ns NRS
ns opioid cons.
Abdominal hysterectomy Haryalchi, 2017, Iran 20/20 +/+ – Isoflurane/Fentanyl Succinylcholine, Atracurium/+ +/− – None 15 mg kg−1 h−1 15 min pre induction Pethidine None + 24 h – ↓ NRS, 6, 12 h 0, 24 h
↓ opioid cons. 0-24 h
Abdominal hysterectomy Jarahzadeh, 2016, Iran 30/30 −/− – Propofol/Fentanyl Atracurium/− −/− – 50 mg kg−1 None Post induction Morphine None – 12 h – ↓ VAS, 1, 2, 6, 12 h
↓ opioid cons. 0–12 h
Abdominal hysterectomy Kara, 2002, Turkey 12/12 −/− STAI 1-2 Isoflurane/N2O/Fentanyl Vecuronium/+ +/− – 30 mg kg−1 500 mg h−1 Post induction/20 h post-op. PCA-morphine Sedation + 24 h Insomnia ↓ VAS, 30 m, 18 h 6, 12, 24 h
↓opioid cons. 0–24 h
Abdominal hysterectomy Kaya, 2009, Turkey 20/20 −/+ – Sevoflurane/Remifentanil Cisatracurium/+ +/− – 30 mg kg−1 500 mg h−1 15 min pre induction/end of surgery PCA-morphine None – 24 h – ↓ VAS, 15 + 30 m 1, 2, 3, 4, 24 h
↓opioid cons. 0–24 h
Abdominal hysterectomy Ryu, 2008, Korea 25/25 +/+ – Propofol/Remifentanil Rocuronium/+ +/− – 50 mg kg−1 15 mg kg−1 h−1 Pre induction/end of surgery PCA-morphine None + 48 h Satisfaction ↓ VAS, 4, 24, 48 h 0, 30 m
↓ opioid cons. 24, 48 h 0, 30 m, 4 h
Abdominal hysterectomy Taheri, 2015, Iran 20/20 +/+ – Isoflurane/N2O/Fentanyl Succinylcholine, Atracurium/+ +/− – 50 mg kg−1 None 15 min pre induction Pethidine None + 24 h – ↓ NRS, 6, 12, 24 h 0 h
↓ opioid cons. 0–24 h
Abdominal hysterectomy Tramèr, 1996, Switzerland 21/21 −/+ Pain at rest, insomnia, discomfort Isoflurane/N2O/Fentanyl Vecuronium/+ +/− – 3 g 13 g Post induction/20 h post-op. PCA-morphine None + 48 h Insomnia, discomfort ns VAS, ↓ opioid cons. 6 h 12, 24, 48 h
Hysterectomy/myomectomy Asadollah, 2014, Iran 15/15 +/− – Propofol/Remifentanil Atracurium/+ −/− – 50 mg kg−1 8 mg kg−1 h−1 10 min pre induction/end of surgery Pethidine None – 24 h – ↓ VAS, 30 m, 4, 12 h 24 h
↓opioid cons. 0–24 h
Hysterectomy Seyhan, 2006, Turkey 20/20 +/+ – Propofol/Fentanyl Atracurium/+ +/− – 40 mg kg−1 20 mg kg−1 h−1 15 min pre induction/4 h post-op. PCA-morphine None – 24 h – ns VAS, ↓ opioid cons. 24 h 1, 2, 4, 12 h
Laparoscopic gynaecologic surgery Sousa, 2016, Brazil 18/18 +/+ – Propofol/Remifentanil Cisatracurium/+ −/− – 20 mg kg−1 2 mg kg−1 h−1 –/end of surgery PCA-morphine None – 24 h – ↓ VAS, 1, 24 h
↓ opioid cons. 0–24 h
Elective caesarean section Helmy, 2015, Egypt 20/20 −/+ – Sevoflurane/Fentanyl Succinylcholine, Atracurium/+ −/− Paracetamol 30 mg kg−1 None 10 min pre induction Pethidine None – 24 h – ns VAS, ns opioid cons.
Elective caesarean section Mireskandari, 2014, Iran 25/25 +/+ – Isoflurane/N2O/Fentanyl Succinylcholine, Atracurium/+ +/− – 50 mg kg−1 None 15 min pre induction PCA-morphine None – 24 h – ↓ VAS, 1, 6, 12 h 24 h
↓ opioid cons. 0–24 h
Elective caesarean section Rezae, 2014, Iran 35/35 +/− – Isoflurane/N2O/Morphine Succinylcholine, Atracurium/+ −/− – 50 mg kg−1 None 30 min pre induction Morphine None – 24 h – ↓VAS, 24 h 0, 2, 12 h
↓ opioid cons. 0–24 h

  1. −, not reported; +, reported; ns, not significant; ↓, significant reduced.

Table 2:

Pre-, intra- and post anaesthetic data for abdominal surgery.

Types of surgery First authors, year, country N, MgSO4/placebo Details of blinding/randomization Pre-op pain and psychosocial assessment Anaesthesia type Use of NMBA/reversal of NMBA Neuromuscular monitoring intra/post op. Basic pain treatment MgSO4 bolus injection MgSO4 continued infusion Administration of Bolus injection/Infusion Post-op. opioid Defined AE measures Plasma Mg Observation period HRQoL measures Effect of MgSO4 vs. placebo No effect of MgSO4 vs. placebo
Major gastrointestinal surgery Moharari, 2014, Iran 16/16 +/+ – Isoflurane/Fentanyl Atracurium/- −/− – 50 mg kg−1 10 mg kg−1 h−1 15 min pre induction/end of surgery PCA-morphine None – 24 h – ↓ VAS, 1, 2, 4, 12, 24 h 1, 2, 4, 12 h
↓opioid cons. 24 h
Upper abdominal surgery Usmani, 2007, India 30/30 −/+ – Propofol/N2O/Fentanyl Vecuronium/+ +/− – 50 mg kg−1 15 mg kg−1 h−1 15 min pre induction/6 h post-op. Tramadol None – 6 h – ↓ VAS/VRS, 0, 1, 3 h 6 h
↓opioid cons. 0–6 h
Sleeve gastrectomy Kizilcik, 2018, Turkey 40/40 +/+ – Sevoflurane/Remifentanil Rocuronium/+ −/− Paracetamol, dexketoprofen 30 mg kg−1 20 mg kg−1 h−1 30 min pre induction/24 h post-op. PCA-morphine None + 24 h – ↓ VAS, no time data
↓opioid cons. 0–24 h
Colorectal surgery Zarauza, 2000, Spain 23/23 −/+ Anxiety Isoflurane/N2O/Fentanyl Atracurium/+ −/− – 30 mg kg−1 10 mg kg−1 h−1 Post induction/20 h post-op. PCA-morphine None – 48 h/5 days Insomnia ns VAS, ns opioid cons.
Abdominal hernioplasty Mavrommati, 2004, Greece 21/21 +/+ – Sevoflurane/Fentanyl Rocuronium/+ +/− – 30 mg kg−1 6 mg kg−1 h−1 Post induction/end of surgery Fentanyl None + 2 h – ns VAS, ns opioid cons.
Inguinal herniorrhaphy Jalali, 2003, Iran 27/27 −/− – Halotane/N2O/Fentanyl Succinylcholine, Atracurium/+ −/− – 3 g None Post induction Pethidine None – 24 h Length of stay ↓ VAS, 6, 12, 24 h 1 h
↓opioid cons. 24 h 0 h
Inguinal surgery Kiran, 2019, India 50/50 −/+ – Isoflurane/N2O/Pethidine Atracurium/+ −/− – 50 mg kg−1 None 30 min pre induction Pethidine None – 24 h – ↓VAS, 2, 4, 8, 16, 24 h 4, 24 h
↓opioid cons. 8, 16 h
Laparoscopic cholecystectomy Saadawy, 2010, Egypt 40/40 +/+ – Sevoflurane/Fentanyl Cisatracurium/+ +/− – 50 mg kg−1 25 mg kg−1 h−1 15 min pre induction/end of surgery PCA-morphine None + 24 h Insomnia ↓ VAS, 2, 6, 12, 18, 24 h
↓opioid cons.2, 24 h
Laparoscopic cholecystectomy Olgun, 2012, Turkey 30/30 −/+ – Desflurane/Remifentanil Vecuronium/+ −/− – 40 mg kg−1 10 mg kg−1 h−1 15 min pre induction/end of surgery PCA-morphine None + 24 h Satisfaction ↓ VAS, 0, 1, 2, 4, 8, 12, 24 h
↓ opioid cons. 0–24 h
Laparoscopic cholecystectomy Mentes, 2008, Turkey 41/42 −/− – Sevoflurane/Propofol/N2O Cisatracurium/- −/− – 50 mg kg−1 None Post induction PCA-tramadol None – 24 h Satisfaction ↓ VAS, 0, 4, 8, 12 h 2, 24 h
ns opioid cons.
Laparoscopic cholecystectomy Kocman, 2013, Croatia 20/20 −/− Pain N2O/Fentanyl Vecuronium/- −/− – 7.5 mg kg−1 None 45 min pre induction Tramadol None – 24 h – ↓VAS, 1, 3 h 6, 9, 24 h
↓opioid cons. 1 h 24 h
Laparoscopic cholecystectomy Ayoglu, 2004, Turkey 25/25 +/+ – Isoflurane/Alfentanil Rocuronium/+ +/− – 50 mg kg−1 8 mg kg−1 h−1 Post induction/4 h post-op. PCA-morphine None + 20 h Insomnia ns NRS/VRS, ↓opioid cons. 2, 3 h 1, 4, 8, 20 h
Laparotomic cholecystectomy Bhatia, 2004, India 25/25 −/+ Pain at rest, insomnia, discomfort Halotane/N2O/Morphine Vecuronium/+ +/− – 50 mg kg−1 15 mg kg−1 h−1 15 min pre induction/end of surgery Tramadol None – 24 h Insomnia discomfort ↓ VAS, 1, 2 h 6, 24 h
ns opioid cons.

  1. −, not reported; +, reported; ns, not significant; ↓, significant reduced.

Table 3:

Pre-, intra- and post anaesthetic data for other surgery.

Types of surgery First authors, year, country N MgSO4/Placebo Details of blinding/randomization Pre-op. pain and psychosocial assessment Anaesthesia type Use of NMBA/reversal of NMBA Neuromuscular monitoring intra/post op Basic pain treatment MgSO4 bolus injection MgSO4 continued infusion Administration of Bolus injection/Infusion Post-op. opioid Defined AE measures Plasma Mg Observation period HRQoL measures Effect of MgSO4 vs. placebo No effect of MgSO4 vs. placebo
Pars plana vitrectomy Schulz-Stübner, 2001, Germany 25/25 −/+ – Propofol/Remifentanil Cisatracurium/− +/− – 50 mg kg−1 None Post induction Nalbuphine None + 24 h – ns VAS, ns opioid cons.
Supratentorial craniotomy Mahajan, 2019, India 15/15 +/+ – Propofol/Fentanyl Rocuronium/+ −/− – 50 mg kg−1 25 mg kg−1 h−1 15 min pre induction/end of surgery PCA-fentanyl Sedation – 24 h – ↓VRS, 0, 1, 2, 6, 24 h 12 h
↓opioid cons. 0–24 h
Open thyroidectomy Kim, 2015, Korea 41/37 +/+ – Desflurane/Remifentanil Rocuronium/+ −/+ Propacetamol 20 mg kg−1 20 mg kg−1 h−1 Post induction/end of surgery Fentanyl None – 48 h QoR-40 ↓NRS, 24, 48 h
ns opioid cons.
Segmental mastectomy Oliveira, 2013, USA 23/23 +/+ – Sevoflurane/Remifentanil Succinylcholine/– −/− – 50 mg kg−1 15 mg kg−1 h−1 15 min pre induction/end of surgery Hydro-morphone None + 24 h Discharge readiness. QoR-40 ns NRS, ↓opioid cons. 0–24 h
Thoracotomy Abdelgalil, 2019, Egypt 30/30 +/+ – Sevoflurane/Propofol Rocuronium/+ −/− – 50 mg kg−1 None 60 min pre induction PCA-morphine None – 24 h – ns VAS, ns opioid cons.
Thoracotomy Ozcan, 2007, Turkey 12/12 +/− – Propofol/Fentanyl Vecuronium/−- −/− – 30 mg kg−1 10 mg kg−1 h−1 Post-op./48 h post-op. PCA-morphine Sedation – 48 h – ns VAS, ↓opioid cons. 4, 8, 48 h 16, 24 h
Elective laminectomy Ghaffaripour, 2016, Iran 20/20 −/+ – Isoflurane/N2O/Fentanyl Atracurium/+ +/− – 30 mg kg−1 10 mg kg−1 h−1 Post induction/end of surgery PCA-morphine None – 24 h – ns VAS, ns opioid cons.
Lumbar spinal fusion Dehkordy, 2020, Iran 40/40 +/+ – Sevoflurane/N2O/Fentanyl Atracurium/+ −/− Paracetamol 50 mg kg−1 15 mg kg−1 h−1 15 min pre induction/end of surgery PCA-morphine None + 48 h – ↓ VAS, 6,12,24 h 1, 48 h
↓opioid cons.0–48 h
Lumbar disc surgery Demiroglu, 2016, Turkey 25/25 −/− – Sevoflurane/Fentanyl Vecuronium/+ −/− – 50 mg kg−1 None End of surgery PCA-tramadol None – 24 h – ns NRS, ↓opioid cons. 1–24 h 0–1 h
Lumbar disc surgery Oguzhan, 2008, Turkey 25/25 +/− – Desflurane/Remifentanil Atracurium/− +/− – 40 mg kg−1 10 mg kg−1 h−1 Post induction/end of surgery PCA-morphine None – 24 h – ↓VRS, 1, 2, 4, 6, 12, 24 h
↓opioid cons. 0–24 h
Lumbar laminectomy surgery Tsaousi, 2020, Greece 36/36 +/+ – Desflurane/Remifentanil Cisatracurium/− −/− Paracetamol 20 mg kg−1 20 mg kg−1 h−1 15 min pre induction/end of surgery Morphine Sedation – 24 h Satisfaction ↓ VAS, 0, 2, 6, 24 h
↓opioid cons.0–24 h
Major lumbar orthopaedic surgery Levaux, 2003, Belgium 12/12 +/+ – Sevoflurane/Remifentanil Rocuronium/− +/− – 50 mg kg−1 None 30 min pre induction PCA-piritramide None – 24 h Insomnia, satisfaction ↓ VAS, 2, 4, 6 h 12, 24 h
↓opioid cons. 6, 12, 24 h 0, 2, 4 h
Radical prostatectomy Tauzin-Fin, 2006, France 15/15 +/+ – Sevoflurane/Sufentanil Mivacurium/− −/− Paracetamol 50 mg kg−1 None Post induction PCA-tramadol None + 24 h – ns VAS, ↓opioid cons. 0–24 h
Arthroscopic knee surgery Koinig, 1998, Austria 23/23 +/+ – Propofol/Fentanyl −/− +/− – 50 mg kg−1 10 mg kg−1 h−1 Post induction/end of surgery Fentanyl None + 4 h – ns VAS, ↓opioid cons. 0–4 h
Unknown surgery Nidhin, 2016, India 30/30 −/+ – –/Fentanyl −/− −/− – 50 mg kg−1 None 30 min pre induction Fentanyl None – 12 h – ↓VAS, 1, 4, 8, 12 h
ns opioid cons.

  1. −, not reported; +, reported; ns, not significant; ↓, significant reduced.

No ethics approval was required for this study.

Results

A total of 42 RCTs on pre, intra, or post anaesthesia administration of i.v. MgSO4 vs. placebo were included [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58] (Figure 1).

In 14 of the studies the patients underwent gynaecological surgery (33%), in 13 studies abdominal surgery (31%), and in 15 studies other surgeries (36%) (Tables 1–3).

Pre-operative data

Blinding and randomization

Detailed description of both the blinding and randomization process was reported in 21 studies (50%). Detailed description of the blinding process alone was explained in four studies (10%), whereas 11 studies (26%) only described the process used for randomization of study participants and the involved health personnel. Six studies (14%) did not describe either the blinding or randomization method employed (Tables 1–3).

Pre-operative pain and psychosocial assessment

Pre-operative pain measures were reported in three of the studies (7%). The Visual Analog Scale (VAS) or the Numeric Rating Scale (NRS) were used to assess pain pre-operatively. A psychological inventory based on a 4-point Likert scale for the assessment of pre-operative psychosocial factors such as discomfort, insomnia and anxiety were used in three studies (7%). The State-Trait Anxiety Inventory was used in one study (2%) (Tables 1–3).

Intraoperative data

Anaesthesia type

Total intravenous anaesthesia was used in 10 studies (24%). Here a combination of propofol and fentanyl was used in five studies, while propofol and remifentanil were used in the remaining five studies (Tables 1–3).

Inhalation agents were used in 28 studies (67%). Desflurane was used in three studies (7%), isoflurane in three studies (7%), nitrogen oxides (N2O) in one study (2%) and sevoflurane in nine studies (21%). Halothane was used in combination with N2O in two studies (5%), isoflurane in combination with N2O was used in eight studies (19%) and sevoflurane was used in combination with N2O in one study (2%) (Tables 1–3).

Three studies combined both inhalation and intravenous agents (7%); propofol and N2O, sevoflurane and propofol; or propofol, sevoflurane and N2O. One study (2%) did not report details of the anaesthetic method applied (Tables 1–3).

Use of neuromuscular blocking agents (NMBA)

NMBA for intubation and subsequent maintenance of neuromuscular blocking were used in all but two studies (95%). The neuromuscular agents of choice were atracurium in nine studies (21%), rocuronium in nine studies (21%), vecuronium in eight studies (19%), cisatracurium in six studies (14%), mivacurium in one study (2%) and succinylcholine in one study (2%). A combination of succinylcholine and atracurium was used in six studies (14%). Intraoperative neuromuscular monitoring was reported in 18 studies (43%). Reversal of neuromuscular blockade was used at the end of surgery as a standard treatment in 29 studies (69%). Postoperatively neuromuscular function assessment was reported in one study, but the assessment method was not specified (2%) (Tables 1–3).

Basic pain treatment

A basic analgesic strategy was reported in six of 42 studies (14%). Paracetamol (acetaminophen) or propacetamol infusion as a single administration 15–30 min before emergence of anaesthesia was used in four studies. One study used i.v. dexketoprofen administered 30 min before the end of anaesthesia in addition to paracetamol. One other study administered paracetamol infusion every 6 h postoperatively for 24 h, starting in the Post Anaesthetic Care Unit (Tables 1–3).

Strategy for administration of i.v. MgSO4

The administration of i.v. MgSO4 varied among the included studies. A single bolus injection of i.v. MgSO4 without subsequent continued MgSO4 infusion was used in 15 studies (36%). The bolus injection doses varied from 3 g (regardless of weight) to 50 mg kg−1. In total four different bolus injection doses were used, while the most prevalent bolus injection dose was 50 mg kg−1 which was used in 12 studies (29%) (Figure 2).

Figure 2: Differences in MgSO4 administration.
Figure 2:

Differences in MgSO4 administration.

I.v. MgSO4 as bolus injection followed by subsequent continued MgSO4 infusion was used in 26 studies (62%). Here the bolus injection dose varied from 3 g (regardless of weight) to 50 mg kg−1 while the continued MgSO4 infusions doses varied from 2 to 25 mg kg−1 h−1. Among these 26 studies, 14 different combinations of bolus injection doses and continued MgSO4 infusion doses were administrated (Figure 2). The most frequent combination of doses used in five studies was an i.v. MgSO4 bolus injection of 50 mg kg−1 followed by a continued MgSO4 infusion dose of 15 mg kg−1 h−1.

A continued MgSO4 infusion dose of 15 mg kg−1 h−1 without initial bolus injection was administrated in one single study (2%) (Figure 2).

In total 19 different dose combinations of i.v. MgSO4 administration were used (Figure 2).

Timing of administration

Administration of i.v. MgSO4 was initiated pre, intra or post anaesthesia. In 23 studies (55%) the i.v. MgSO4 was initiated in the pre-anaesthetic period. Five different time points were used: 60, 45, 30, 15 and 10 min before anaesthetic induction respectively (Figure 2).

In 15 studies (36%) i.v. MgSO4 was initiated in the intra anaesthetic period. MgSO4 administration was initiated at different time points: post induction, prior to intubation, after intubation, 5–30 min after induction or during initiation of surgery respectively. In four studies the MgSO4 infusion was continued into the post anaesthetic period. Among the 15 studies five different timings of MgSO4 administration were used (Figure 2).

Three studies (7%) administrated a bolus injection of i.v. MgSO4 at the end of anaesthesia and two of these studies continued the MgSO4 infusion for 48 h post anaesthesia. One study (2%) did not report complete details of i.v. MgSO4 administration time (Figure 2).

In total 12 different timings of i.v. MgSO4 administration were used (Figure 2).

Postoperative data

Post-operative opioid use

The use of postoperative pain medication was reported in all studies. A patient-controlled analgesia infusion pump was used to measure opioid consumption in 24 studies (57%). Analgetic used were fentanyl, morphine, tramadol or piritramide (Tables 1–3).

The 18 studies not using a patient-controlled analgesia infusion pump (43%) administrated pethidine, fentanyl, tramadol, morphine, hydromorphone or nalbuphine for analgetic (Tables 1–3).

Reporting of adverse events

Adverse events were reported in 40 studies (95%), but specific definitions of MgSO4 related AEs were absent. The AEs reported in the studies were: cardiovascular events (heart rate, blood pressure) (71%), postoperative nausea and vomiting (67%), sedation (12%), respiratory events (respiratory rate, oxygen saturation) (26%), renal impairment (2%), anxiety (2%), and delirium (2%). The definition of i.v. MgSO4 sedation as an AE was reported in two studies (5%) (Tables 1–3).

Plasma Mg pre-/postoperative

Plasma magnesium concentration was measured both pre- and postoperatively in 15 studies (36%). None of the studies reported any difference between groups regarding i.v. MgSO4 caused AEs. The highest mean plasma concentration reported postoperatively was 1.98 ± 0.97 mmol L−1 (Tables 1–3).

Observation period

The observation period for postoperative opioid consumption, pain score and i.v. MgSO4 caused AEs varied in the 42 included studies; 2 h (2%), 4 h (2%), 6 h (2%), 12 h (5%), 20 h (2%), 24 h (69%) and 48 h (17%) (Tables 1–3).

Health-related quality of life measures

Fifteen studies (36%) reported one or more health-related quality of life (HRQoL) measures. Thirteen studies measured a single measure of HRQoL: insomnia, satisfaction, QoR-40, length of stay, or discharge readiness. Three studies combined different measures of HRQoL: insomnia and discomfort, insomnia and satisfaction, and discharge readiness and quality of recovery (QoR-40) (Tables 1–3).

Postoperative pain measures

A standardized scale for measuring pain postoperatively was used in all 42 studies. The Visual Analogue Scale (VAS) alone was used in 34 studies (81%), the Numerical Rating Scale (NRS) alone was used in six studies (14%). A combination of both the VAS and the Verbal Rating Scale (VRS), was used in one study (2%) and a combination of the NRS and the VRS was used in one study (2%) (Tables 1–3).

Effect of MgSO4 on postoperative pain and morphine consumption

A significant reduction in both morphine consumption and pain score when using i.v. MgSO4 compared to placebo was reported in 23 of the 42 studies (55%). Reduced morphine consumption without reduced pain score was reported in eight studies (19%). Reduced pain score without reduced morphine consumption was reported in four studies (10%), while seven studies found no difference between the MgSO4 and placebo groups (17%) (Tables 1–3).

Our meta-analysis shows a cumulative morphine consumption reduction of - 6.12 mg [−7.69; −4.55] in favour of the MgSO4-group at 24 h postoperatively. Of the 23 studies (55%) providing data in the calculation of morphine consumption effect 16 studies showed a significant reduction, seven studies did not. The heterogeneity among the included studies was calculated to be I2=91% (Supplementary Table 4).

Our meta-analysis also shows a cumulative pain score reduction by a mean difference in VAS/NRS at 4–6 h postoperatively of −12.32 [−18.27; −6.38] out of 100, favouring the MgSO4-group. Of the 13 studies (31%) providing data in the calculation of pain score effect nine studies showed a significant reduction, four studies did not. The heterogeneity among the included studies was calculated to be I2=96% (Supplementary Table 5).

Discussion

In this systematic review of methodology on the analgesic effect of i.v. MgSO4 compared to placebo, we found considerable heterogeneity (I2>75%) in the pre, intra, and post anaesthetic methodology data of the included studies. Consequently, pooled results should be interpreted with utmost care. The following methodological areas show the challenges in assessing the effect of i.v. MgSO4 in postoperative pain management.

Details of blinding and randomization

Validity of pooled results from the included studies is questionable, since only 21 studies (50%) described adequate blinding and randomization. The quality of the studies included in previous systematic reviews were either not analysed [10] or analysed using the Jadad 5-point quality scale. The lack of blinding and randomization that is part of Jadad quality scoring lead to low quality in half of the studies in our review, this in accordance with the previous systematic reviews [7], [8], [9, 12].

Sample size

Notably, only seven of 42 studies (17%) had 40 or more participants per treatment arm. Nevertheless, the majority of the studies reached the conclusion of an analgesic effect, and/or reduced morphine consumption from i.v. MgSO4. Low number of participants reduces chances of detecting significant adverse events, and increases chances of Type II error, biasing the results and decreasing the power of the study, entailing that only very clear statistical differences can be found [59, 60].

Pre-operative pain and psychosocial assessment

Pre-operative pain assessment and psychosocial assessment were only present in five of 42 studies (12%). Pre-operative pain, anxiety and pain catastrophizing have all been shown to be significant predictors for postoperative pain [61], while psychological distress is a significant predictor for postoperative analgesic consumption [62]. Suboptimal treatment of postoperative pain is associated with a higher risk of postoperative complications including delayed recovery and development of chronic postoperative pain [63]. Only one of 42 studies used a pre-operative questionnaire measuring anxiety [22] and consequently pre-operative pain states could have affected outcome measures in our included studies.

Future studies of i.v. MgSO4 should assess pre-operative pain, anxiety and pain catastrophizing using validated psychometrics like The State-Trait Anxiety Inventory or The Hospital Anxiety and Depression Scale to ensure comparable groups in relation to pain, anxiety and depression.

Anaesthesia type

The anaesthetic technique used is well described in all but one study [58]. However, there are 12 different varieties of anaesthesia reported for general anaesthesia, more if counting differences in doses and timing. The many differences in anaesthesia make it difficult to compare data and pool a unidirectional result.

Use of NMBA

The administration of i.v. MgSO4 may prolong neuromuscular blockade following administration of NMBA for surgery [64]. The only study reporting neuromuscular function assessment postoperatively, did not specify how the function was assessed [47]. The speed of onset and the intensity of neuromuscular block increases with higher doses of i.v. MgSO4 [64]. Combining MgSO4 and neuromuscular blocking agents can result in serious adverse events, such as residual neuromuscular blockade and postoperative respiratory complications [65]. Consequently, pulmonary AE must be well-defined and clearly reported in the future to assess safety issues.

Basic analgesic treatment

Optimal basic postoperative pain management is recommended to be with a multimodal nonopioid-based procedure specific guideline, where the type, level and duration of analgesics may vary depending on the evidence relating to type of surgery [66]. A basic analgesic strategy in addition to i.v. MgSO4 was reported in only six studies (14%). Regular analgesics such as paracetamol and Non-Steroidal Anti-Inflammatory Drugs (NSAID) may make the effect of i.v. MgSO4 more difficult to detect. But it could even be considered unethical to withhold established basic analgesic treatment from patients, even when rescue medication is provided [67]. When studies omit basic analgesic treatment, extrapolation to clinical practice, were use of paracetamol/NSAID is standard, becomes difficult. Basic analgesic treatment is an important component in modern multimodal pain management and many procedures require procedure specific analgesia [68]. The use of paracetamol/NSAID has been shown to reduce morphine consumption by 8–16 mg [69]. Our data is consistent with previous reviews [7], [8], [9], [10, 12] showing the relatively low opioid sparing effect compared to i.v. MgSO4 which might save up to 10 mg of postoperative morphine. Accordingly, the effect of i.v. MgSO4 may be substituted by the easier and well-established administration of paracetamol/NSAID.

Strategy for administration of intravenous MgSO4

Unexpectedly our review found 29 different administration regimens of i.v. MgSO4 in the 42 included studies (Figure 2). The wide heterogeneity in administration, timing and dose precludes any conclusions as to which dose and/or timing provides the most effective analgesia. Despite bolus injection and continued MgSO4 infusion doses of i.v. MgSO4 varying immensely over half of the studies showed a positive result indicating that many study participants might be extraordinarily overdosed. But since the positive effect also is seen in low dose studies the beneficial effects may not be attributed i.v. MgSO4 but to other un-controlled factors.

Postoperative pain measures

The majority of the studies did not describe whether pain was measured at rest or during any well-defined activity. Since the 42 studies include a variety of surgical procedures not all patients are likely to be able to perform the same movements. Future studies should include scoring for well-defined activities which are procedure specific and scored at specific times in order to get comparable data [70].

Reporting of adverse events

The literature shows an approximate relation between degree of hypermagnesemia and clinical manifestations. Relevant to the present study is plasma magnesium concentrations in the interval from 2 mmol L−1 to above 5 mmol L−1. This produces the following AEs: drowsiness, somnolence, hypotension, bradycardia, and electrocardiographic changes, muscle paralysis, apnoea and respiratory failure, and cardiac arrest [71], [72], [73]. The most underdiagnosed and therefore dangerous AE of i.v. MgSO4 is the risk of incomplete recovery after administration of NMBA and the ensuing risks of postoperative pulmonary complications and eventually death [64, 65].

Specific pre-study description of AEs is of importance in any study on i.v. MgSO4 to avoid n underreporting of adverse events and subsequent overestimation of safety. Consequently, no assumptions on safety of i.v. MgSO4 should be made from the included studies as no study reported data on all, or the majority of the AEs described above. Underreporting of adverse effects of MgSO4 infusion will leave the readers with the (false) impression that it is (mostly) safe practice to administer routinely iv. MgSO4 for postoperative pain management.

We suggest a minimum list of clinical signs and symptoms of hypermagnesemia to be assessed in future studies to ensure patient safety.

Observation period

Careful observations over a relevant period of time help us to apprehend any harm from adverse drug reactions [74, 75]. I.v. MgSO4 is not metabolized and is excreted solely by the kidney. Urinary excretion is very rapid with a 20-fold increase during MgSO4 infusion. About 38–53% of the total injected MgSO4 is excreted within 4 h of end infusion and >90% is eliminated within 24 h after infusion [74, 75]. Consequently, we suggest future studies should monitor patients for clinical AEs for at least 24 h after the last administration of i.v. MgSO4.

Health-related quality of life measures (HRQoL)

Sixteen studies (38%) reported at least one patient reported outcome.

Two study used QoR-40, a standardized instrument for examining HRQoL [47, 48]. We suggest measuring HRQoL, with instruments measuring the health dimensions specific for the included patients. Quality of Recovery 15-item, Postoperative Quality of Recovery Scale, European Quality of life – five Dimensions, or Short Form 12-item Survey, which are standardized instruments for examining HRQoL and should be used to ensure quality of patient recovery postoperatively. Measuring patients’ perception and the extent to which they can perform daily activities is also very important in analgesic studies where the objective of treatment is to improve the patients’ wellbeing and ability to be self-reliant.

Effect of MgSO4

Twenty-three of the included studies (55%) reported a reduction in both morphine consumption and pain scores. The remaining studies show inconsistent, or no effect on both pain score and morphine consumption. Of the 23 studies with consistent effect, four studies showed effect on pain score the first 1–3 h only while eight studies showed inconsistent effect on pain scores during the first 24 h, one study did not specify time of effect for VAS.

The calculation from our meta-analysis showed a reduction in both postoperative morphine consumption and pain score. But, equivalent to previous systematic reviews [7], [8], [9], [10, 12], the considerable heterogeneity (I2=91% for morphine consumption and I2=96% for pain score) of the included studies precludes any evident conclusions. This renders the question as to whether i.v. MgSO4 is suitable as a single adjuvant in postoperative pain management is still unanswered (Supplementary Tables 4 and 5).

Methodological considerations

Our structured search of literature, subsequent review and meta-analysis is limited by several factors predominantly related to the lack of raw data with a small number of homogeneous studies. We excluded non-English language studies thereby compromising the number of studies included. We also excluded studies on cardiac surgery, preeclampsia, and the use of MgSO4 in local or regional anaesthesia due to the differences in process of recovery and purposes of MgSO4 administration. Finally, our data for the meta-analysis could have been improved by contacting authors of all papers for supplemental data but as the meta-analysis was not protocolized, we abstained from contacting the corresponding authors and only included the described data.

Despite the limitations, our data provides the most detailed analysis of methodological challenges in studies assessing i.v. MgSO4 for postoperative pain management. The strengths of our review is the use of a transparent method, a wide search based on PICOS [15] criteria and the PRISMA statement [16], including an analysis not only of the study findings but also clinically relevant methodological strengths and weaknesses.

Summary

The considerable heterogeneity across 42 mostly small studies in this review precludes any clear conclusions on the clinical effect of i.v. MgSO4 as an adjuvant in postoperative pain management. Only 55% of the studies displayed a clear reduction of both pain scores and morphine consumption. The remaining studies displayed no effect or conflicting results.

Although our meta-analysis shows a reduction in postoperative morphine consumption of 6.12 mg and reduction of VAS pain score of 12.3, both favouring the MgSO4-groups, the result should be interpreted with caution partly due to the low number of studies in the meta-analysis and partly due to the considerable methodological heterogeneity and clinical shortcomings among the included studies. In addition, the found morphine reduction of MgSO4 is likely less than what can be gained from using standardized analgesic treatment with paracetamol and NSAID if part of a multimodal analgesic regimen [68].

Our findings stress the importance of a uniform methodological approach controlling clinical factors in future RCTs on the role of i.v. MgSO4 in postoperative pain management.

Corresponding author: Mark Puch Oernskov, MHS, CRNA, Department of Anaesthesia, Pain and Respiratory Support, Copenhagen University Hospital Rigshospitalet, Glostrup, Valdemar Hansens vej 1-23, 2600 Glostrup, Denmark, E-mail:

Acknowledgement

We thank information specialist Janne Vendt for her help searching for literature.

  1. Research funding: Funding was purely departmental/institutional. No medical company supported this review.

  2. Author contributions: MPO: This author helped with the conception or design of the work, screening process, analysis and interpretation of data, description of result and discussion, making of the first draft of the paper. SGS: This author helped with the conception or design of the work, screening process, contributed to the analysis and interpretation of data, description of result and discussion. MSA: This author helped with the conception or design of the work, contributed to the analysis and interpretation of data, description of result and discussion. KW: This author helped as main supervisor to the conception or design of the work, screening process, analysis and interpretation of data, description of result and discussion, making of the first draft of the paper.

  3. Competing interests: Data analysed is controlled by the authors of the papers included in this review. None of the authors has conflicts of interest to declare.

References

1. Joshi, GP, Schug, SA, Kehlet, H. Procedure-specific pain management and outcome strategies. Best Pract Res Clin Anaesthesiol 2014;28:191–201. https://doi.org/10.1016/j.bpa.2014.03.005.Search in Google Scholar PubMed

2. Mohamadi, A, Chan, JJ, Lian, J, Wright, CL, Marin, AM, Rodriguez, EK, et al.. Risk factors and pooled rate of prolonged opioid use following trauma or surgery: a systematic review and meta-(regression) analysis. J Bone Joint Surg Am 2018;100:1332–40. https://doi.org/10.2106/jbjs.17.01239.Search in Google Scholar PubMed

3. Gupta, S, Mohta, A, Gottumukkala, V. Opioid-free anesthesia – caution for a one- size-fits-all approach. Perioperat Med 2020;16–9. https://doi.org/10.1186/s13741-020-00147-3.Search in Google Scholar PubMed PubMed Central

4. Frauenknecht, J, Kirkham, KR, Jacot-Guillarmod, A, Albrecht, E. Analgesic impact of intra-operative opioids vs. opioid-free anaesthesia: a systematic review and meta-analysis. Anaesthesia 2019;74:651–62. https://doi.org/10.1111/anae.14582.Search in Google Scholar PubMed

5. Shibo, S, Wangbo, X, Songmin, J, Guofang, S, xin, CZ, Wang, Y. Efficacy of intravenous acetaminophen in multimodal management for pain relief following total knee arthroplasty: a meta-analysis. J Orthop Surg Res 2018;13:1–11. https://doi.org/10.1186/s13018-018-0950-7.Search in Google Scholar PubMed PubMed Central

6. Dowell, D, Haegerich, TM, Chou, R. CDC guideline for prescribing opioids for chronic pain – United States. Morb Mortal Wkly Rep 2016;65:295.10.15585/mmwr.mm6511a7Search in Google Scholar PubMed

7. De Oliveira, GJr, Castro-Alves, L, Khan, J, McCarthy, R. Perioperative systemic magnesium to minimize postoperative pain. Anesthesiology 2013;119:178–90. https://doi.org/10.1097/aln.0b013e318297630d.Search in Google Scholar

8. Albrecht, E, Kirkham, KR, Liu, SS, Brull, R. Peri-operative intravenous administration of magnesium sulphate and postoperative pain: a meta-analysis. Anaesthesia 2013;68:79–90. https://doi.org/10.1111/j.1365-2044.2012.07335.x.Search in Google Scholar PubMed

9. Guo, B-L, Lin, Y, Hu, W, Zhen, C-X, Bao-Cheng, Z, Wu, H-H, et al.. Effects of systemic magnesium on post-operative analgesia: is the current evidence strong enough? Pain Physician 2015;18:405–18.10.36076/ppj.2015/18/405Search in Google Scholar

10. Arumugam, S, Lau, CSM, Chamberlain, RS. Perioperative adjunct magnesium decreases postoperative opioid requirements – a meta-analysis. Int J Clin Med 2016;7:297–308. https://doi.org/10.4236/ijcm.2016.75032.Search in Google Scholar

11. Srebro, D, Vuckovic, S, Milovanovic, A, Kosutic, J, Vujovic, SA, Prostran, M. Magnesium in pain research: state of the art. Curr Med Chem 2017;24:424–34. https://doi.org/10.2174/0929867323666161213101744.Search in Google Scholar PubMed

12. Lysakowski, C, Dumont, L, Czarnetzki, C, Tramer, MR. Magnesium as an adjuvant to postoperative analgesia: a systematic review of randomized trials. Anesth Analg 2007;104:1532. –contents. https://doi.org/10.1213/01.ane.0000261250.59984.cd.Search in Google Scholar PubMed

13. Deeks, JJ, Higgins, JP, Altman, DG. Systematic Reviews of Interventions, Chapter 10. Analysing data and undertaking meta-analyses. Cochrane Handbook for Systematic Reviews of Interventions. Chapter 10.10, Heterogeneity. Hoboken, New Jersey, United States: Wiley Blackwell; 2019.10.1002/9781119536604.ch10Search in Google Scholar

14. Møller, AM, Myles, PS. What makes a good systematic review and meta-analysis? Br J Anaesth 2016;117:428–30.10.1093/bja/aew264Search in Google Scholar PubMed

15. Schardt, C, Adams, MB, Owens, T, Keitz, S, Fontelo, P. Utilization of the PICO framework to improve searching PubMed for clinical questions. BMC Med Inf Decis Making 2007;7:1–6. https://doi.org/10.1186/1472-6947-7-16.Search in Google Scholar PubMed PubMed Central

16. Liberati, A, Altman, DG, Tetzlaff, J, Mulrow, C, Gøtzsche, PC, Ioannidis, JPA, et al.. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 2009;62:1–34. https://doi.org/10.1371/journal.pmed.1000100.Search in Google Scholar PubMed PubMed Central

17. Ouzzani, M, Hammady, H, Fedorowicz, Z, Elmagarmid, A. Rayyan-a web and mobile app for systematic reviews. Syst Rev 2016;5:1–10. https://doi.org/10.1186/s13643-016-0384-4.Search in Google Scholar PubMed PubMed Central

18. Treillet, E, Laurent, S, Hadjiat, Y. Practical management of opioid rotation and equianalgesia. J Pain Res 2018;11:2587–601. https://doi.org/10.2147/jpr.s170269.Search in Google Scholar

19. Higgins, JPT, Thompson, SG, Deeks, JJ, Altman, DG. Measuring inconsistency in meta-analyses. J Intell Inf Syst 2006;27:159–84.10.1007/s10844-006-2974-4Search in Google Scholar

20. Haryalchi, K, Abedinzade, M, Khanaki, K, Mansour Ghanaie, M, Mohammad Zadeh, F. Whether preventive low dose magnesium sulphate infusion has an influence on postoperative pain perception and the level of serum beta-endorphin throughout the total abdominal hysterectomy. Rev Esp Anestesiol Reanim 2017;64:384–90. https://doi.org/10.1016/j.redare.2017.05.006.Search in Google Scholar

21. Jarahzadeh, MH, Harati, ST, Babaeizadeh, H, Yasaei, E, Bashar, FR. The effect of intravenous magnesium sulfate infusion on reduction of pain after abdominal hysterectomy under general anesthesia: a double-blind, randomized clinical trail. Electron Physician 2016;8:2602–6. https://doi.org/10.19082/2602.Search in Google Scholar PubMed PubMed Central

22. Kara, H, Sahin, N, Ulusan, V, Aydogdu, T. Magnesium infusion reduses perioperative pain. Eur J Anaesthesiol 2002;19:52–6. https://doi.org/10.1017/s026502150200008x.Search in Google Scholar PubMed

23. Kaya, S, Kararmaz, A, Gedik, R, Turhanoglu, S. Magnesium sulfate reduces postoperative morphine requirement after remifentanil-based anesthesia. Med Sci Monit 2009;15:PI5–9.Search in Google Scholar

24. Ryu, JH, Kang, MH, Park, KS, Do, SH. Effects of magnesium sulphate on intraoperative anaesthetic requirements and postoperative analgesia in gynaecology patients receiving total intravenous anaesthesia. Br J Anaesth 2008;100:397–403. https://doi.org/10.1093/bja/aem407.Search in Google Scholar PubMed

25. Taheri, A, Haryalchi, K, Mansour Ghanaie, M, Habibi Arejan, N. Effect of low-dose (single-dose) magnesium sulfate on postoperative analgesia in hysterectomy patients receiving balanced general anesthesia. Anesthesiol Res Pract 2015;2015:306145. https://doi.org/10.1155/2015/306145.Search in Google Scholar PubMed PubMed Central

26. Tramèr, MR, Schneider, J, Marti, R, Rifat, K. Role of magnesium sulfate in postoperative analgesia. Anesthesiology 1996;84:340–7. https://doi.org/10.1097/00000542-199602000-00011.Search in Google Scholar PubMed

27. Asadollah, S, Vahdat, M, Yazdkhasti, P, Nikravan, N. Jinekolojik ameliyatlarda postoperatif analjezi gereksinimleri, magnezyum sülfat etkisi. Turk Jinekoloji ve Obstet Dern Derg 2015;12:34–7. https://doi.org/10.4274/tjod.02439.Search in Google Scholar PubMed PubMed Central

28. Seyhan, TO, Tugrul, M, Sungur, MO, Kayacan, S, Telci, L, Pembeci, K, et al.. Effects of three different dose regimens of magnesium on propofol requirements, haemodynamic variables and postoperative pain relief in gynaecological surgery. Br J Anaesth 2006;96:247–52. https://doi.org/10.1093/bja/aei291.Search in Google Scholar PubMed

29. Sousa, AM, Rosado, GMC, Neto, JDS, Guimarães, GMN, Ashmawi, HA. Magnesium sulfate improves postoperative analgesia in laparoscopic gynecologic surgeries: a double-blind randomized controlled trial. J Clin Anesth 2016;34:379–84. https://doi.org/10.1016/j.jclinane.2016.05.006.Search in Google Scholar PubMed

30. Helmy, N, Badawy, AA, Hussein, M, Reda, H. Comparison of the preemptive analgesia of low dose ketamine versus magnesium sulfate on parturient undergoing cesarean section under general anesthesia. Egypt J Anaesth 2015;31:53–8. https://doi.org/10.1016/j.egja.2014.12.006.Search in Google Scholar

31. Mireskandari, SM, Pestei, K, Hajipour, A, Jafarzadeh, A, Samadi, S, Nabavian, O. Effects of preoperative magnesium sulphate on post-cesarean pain, a placebo controlled double blind study. J Fam Reprod Health 2015;9:29–33.Search in Google Scholar

32. Rezae, M, Naghibi, K, Taefnia, AM. Effect of pre-emptive magnesium sulfate infusion on the post-operative pain relief after elective cesarean section. Adv Biomed Res 2014;3:164. https://doi.org/10.4103/2277-9175.139127.Search in Google Scholar PubMed PubMed Central

33. Moharari, RS, Motalebi, M, Najafi, A, Zamani, MM, Imani, F, Etezadi, F, et al.. Magnesium can decrease postoperative physiological ileus and postoperative pain in major non laparoscopic gastrointestinal surgeries: a randomized controlled trial. Anesthesiol Pain Med 2014;4:1–7. https://doi.org/10.5812/aapm.12750.Search in Google Scholar PubMed PubMed Central

34. Usmani, H, Quadir, A, Alam, M, Rohtagi, A, Ahmed, G. Evaluation of perioperative Magnesium Sulphate infusion on postoperative pain and analgesic requirements in patients undergoing upper abdominal surgery? J Anaesthesiol Clin Pharmacol 2007;23:255–8.Search in Google Scholar

35. Kizilcik, N, Koner, O. Magnesium sulfate reduced opioid consumption in obese patients undergoing sleeve gastrectomy: a prospective, randomized clinical trial. Obes Surg 2018;28:2783–8. https://doi.org/10.1007/s11695-018-3243-7.Search in Google Scholar PubMed

36. Zarauza, R, Sáez-Fernández, AN, Iribarren, MJ, Carrascosa, F, Adame, M, Fidalgo, I, et al.. A comparative study with oral nifedipine, intravenous nimodipine, and magnesium sulfate in postoperative analgesia. Anesth Analg 2000;91:938–43. https://doi.org/10.1097/00000539-200010000-00032.Search in Google Scholar PubMed

37. Mavrommati, PD, Gabopoulou, ZT, Papadimos, CN, Petsikopoulos, MG, Vrettou, VA, Konstantinidou, MG, et al.. The perioperative infusion of low doses of magnesium sulfate reduces analgesic requirements in patients undergoing abdominal hernioplasty. Acute Pain 2004;5:81–7. https://doi.org/10.1016/j.acpain.2004.01.002.Search in Google Scholar

38. Jalali, A. Magnesium sulfate reduces postoperative pain. Med J Islam Repub Iran 2003;17:117–21.Search in Google Scholar

39. Kiran, S, Gupta, R, Verma, D. Evaluation of a single-dose of intravenous magnesium sulphate for prevention of postoperative pain after inguinal surgery. Indian J Anaesth 2011;55:31–5. https://doi.org/10.4103/0019-5049.76605.Search in Google Scholar PubMed PubMed Central

40. Saadawy, IM, Kaki, AM, Abd El Latif, AA, Abd-Elmaksoud, AM, Tolba, OM. Lidocaine vs. magnesium: effect on analgesia after a laparoscopic cholecystectomy. Acta Anaesthesiol Scand 2010;54:549–56. https://doi.org/10.1111/j.1399-6576.2009.02165.x.Search in Google Scholar PubMed

41. Olgun, B, Oǧuz, GO, Kaya, M, Şalvi, S, Eskiçirak, HE, Güney, I, et al.. The effects of magnesium sulphate on desflurane requirement, early recovery and postoperative analgesia in laparascopic cholecystectomy. Magnes Res 2012;25:72–8. https://doi.org/10.1684/mrh.2012.0315.Search in Google Scholar PubMed

42. Mentes, O, Harlak, A, Yigit, T, Balkan, A, Balkan, M, Cosar, A, et al.. Effect of intraoperative magnesium sulphate infusion on pain relief after laparoscopic cholecystectomy. Acta Anaesthesiol Scand 2008;52:1353–9. https://doi.org/10.1111/j.1399-6576.2008.01816.x.Search in Google Scholar PubMed

43. Kocman, IB, Krobot, R, Premužić, J, Kocman, I, Stare, R, Katalinić, L, et al.. The effect of preemptive intravenous low-dose magnesium sulfate on early postoperative pain after laparoscopic cholecystectomy. Acta Clin Croat 2013;52:289–94.Search in Google Scholar

44. Ayoglu, H, Karadeniz, U, Kunduracilar, Z, Ayoglu, FN, Erdemli, O. The analgesic effect of magnesium sulfate and ketamine in patients undergoing laparoscopic cholecystectomy. Pain Clin 2005;17:45–53. https://doi.org/10.1163/1568569053421771.Search in Google Scholar

45. Bhatia, A, Kashyap, L, Pawar, DK, Trikha, A. Effect of intraoperative magnesium infusion on perioperative analgesia in open cholecystectomy. J Clin Anesth 2004;16:262–5. https://doi.org/10.1016/j.jclinane.2003.08.012.Search in Google Scholar PubMed

46. Schulz-Stübner, S, Wettmann, G, Reyle-Hahn, SM, Rossaint, R. Magnesium as part of balanced general anaesthesia with propofol, remifentanil and mivacurium: a double-blind, randomized prospective study in 50 patients. Eur J Anaesthesiol 2001;18:723–9. https://doi.org/10.1046/j.1365-2346.2001.00921.x.Search in Google Scholar PubMed

47. Kim, MH, Kim, MS, Lee, JH, Kim, ST, Lee, JR. Intravenously administered lidocaine and magnesium during thyroid surgery in female patients for better quality of recovery after anesthesia. Anesth Analg 2018;127:635–41. https://doi.org/10.1213/ane.0000000000002797.Search in Google Scholar PubMed

48. De Oliveira, GS, Bialek, J, Fitzgerald, P, Kim, JYS, McCarthy, RJ. Systemic magnesium to improve quality of post-surgical recovery in outpatient segmental mastectomy: a randomized, double-blind, placebo-controlled trial. Magnes Res 2014;26:156–164. https://doi.org/10.1684/mrh.2014.0349.Search in Google Scholar PubMed

49. Abdelgalil, AS, Shoukry, AA, Kamel, MA, Heikal, AMY, Ahmed, NA. Analgesic potentials of preoperative oral pregabalin, intravenous magnesium sulfate, and their combination in acute postthoracotomy pain. Clin J Pain 2019;35:247–51. https://doi.org/10.1097/AJP.0000000000000673.Search in Google Scholar PubMed

50. Ozcan, PE, Tugrul, S, Senturk, NM, Uludag, E, Cakar, N, Telci, L, et al.. Role of magnesium sulfate in postoperative pain management for patients undergoing thoracotomy. J Cardiothorac Vasc Anesth 2007;21:827–31. https://doi.org/10.1053/j.jvca.2006.11.013.Search in Google Scholar PubMed

51. Ghaffaripour, S, Mahmoudi, H, Eghbal, H, Rahimi, A. The effect of intravenous magnesium sulfate on post-operative analgesia during laminectomy. Cureus 2016;8:6–11. https://doi.org/10.7759/cureus.626.Search in Google Scholar PubMed PubMed Central

52. Dehkordy, ME, Tavanaei, R, Younesi, E, Khorasanizade, S, Farsani, HA, Oraee-Yazdani, S. Effects of perioperative magnesium sulfate infusion on intraoperative blood loss and postoperative analgesia in patients undergoing posterior lumbar spinal fusion surgery: a randomized controlled trial. Clin Neurol Neurosurg 2020;196:105983. https://doi.org/10.1016/j.clineuro.2020.105983.Search in Google Scholar PubMed

53. Demiroglu, M, Ün, C, Ornek, DH, Kici, O, Yildirim, AE, Horasanli, E, et al.. The effect of systemic and regional use of magnesium sulfate on postoperative tramadol consumption in lumbar disc surgery. BioMed Res Int 2016;2016:3216246. https://doi.org/10.1155/2016/3216246.Search in Google Scholar PubMed PubMed Central

54. Oguzhan, N, Gunday, I, Turan, A. Effect of magnesium sulfate infusion on sevoflurane consumption, hemodynamics, and perioperative opioid consumption in lumbar disc surgery. J Opioid Manag 2008;4:105–10. https://doi.org/10.5055/jom.2008.0015.Search in Google Scholar PubMed

55. Levaux, C, Bonhomme, V, Dewandre, PY, Brichant, JF, Hans, P. Effect of intra-operative magnesium sulphate on pain relief and patient comfort after major lumbar orthopaedic surgery. Anaesthesia 2004;58:131–5. https://doi.org/10.1046/j.1365-2044.2003.02999.x.Search in Google Scholar PubMed

56. Tauzin-Fin, P, Sesay, M, Delort-Laval, S, Krol-Houdek, MC, Maurette, P. Intravenous magnesium sulphate decreases postoperative tramadol requirement after radical prostatectomy. Eur J Anaesthesiol 2006;23:1055–9. https://doi.org/10.1017/s0265021506001062.Search in Google Scholar

57. Koinig, H, Wallner, T, Marhofer, P, Andel, H, Mayer, N. Magnesium sulfate reduces intra and postoperative analgesic requirements. Anesthesiology 1997;87:A286. https://doi.org/10.1097/00000539-199807000-00042.Search in Google Scholar PubMed

58. Nidhin, N, Abraham, AA. Effect of preoperative magnesium infusion on postoperative pain in patients under general anaesthesia. J Evol Med Dent Sci 2016;5:838–41. https://doi.org/10.14260/jemds/2016/194.Search in Google Scholar

59. Button, KS, Ioannidis, JPA, Mokrysz, C, Nosek, BA, Flint, J, Robinson, ESJ, et al.. Power failure: why small sample size undermines the reliability of neuroscience. Nat Rev Neurosci 2013;14:365–76. https://doi.org/10.1038/nrn3475.Search in Google Scholar PubMed

60. Faber, J, Fonseca, LM. How sample size influences research outcomes. Dental Press J Orthod 2014;19:27–9. https://doi.org/10.1590/2176-9451.19.4.027-029.ebo.Search in Google Scholar PubMed PubMed Central

61. Dunn, LK, Durieux, ME, Fernández, LG, Tsang, S, Smith-Straesser, EE, Jhaveri, HF, et al.. Influence of catastrophizing, anxiety, and depression on in-hospital opioid consumption, pain, and quality of recovery after adult spine surgery. J Neurosurg Spine 2018;28:119–26. https://doi.org/10.3171/2017.5.spine1734.Search in Google Scholar

62. Ip, HYV, Abrishami, A, Peng, PWH, Wong, J, Chung, F. Predictors of postoperative pain and analgesic consumption: a qualitative systematic review. Anesthesiology 2009;111:657–77. https://doi.org/10.1097/aln.0b013e3181aae87a.Search in Google Scholar

63. Lindberg, MF, Miaskowski, C, Rustøen, T, Rosseland, LA, Paul, SM, Lerdal, A. Preoperative pain, symptoms, and psychological factors related to higher acute pain trajectories during hospitalization for total knee arthroplasty. PLoS One 2016;11:1–20. https://doi.org/10.1371/journal.pone.0161681.Search in Google Scholar PubMed PubMed Central

64. Queiroz Rangel Micuci, AJ, Verçosa, N, Filho, PAG, De Boer, HD, Barbosa, DD, Cavalcanti, IL. Effect of pretreatment with magnesium sulphate on the duration of intense and deep neuromuscular blockade with rocuronium: a randomised controlled trial. Eur J Anaesthesiol 2019;36:502–8. https://doi.org/10.1097/eja.0000000000001003.Search in Google Scholar

65. Checketts, MR. AAGBI recommendations for standards of monitoring during anaesthesia and recovery 2015. Anaesthesia 2016;71:470–1. https://doi.org/10.1111/anae.13421.Search in Google Scholar PubMed

66. Barazanchi, AWH, MacFater, WS, Rahiri, JL, Tutone, S, Hill, AG, Joshi, GP. PROSPECT collaboration. Evidence-based management of pain after laparoscopic cholecystectomy: a PROSPECT review update. Br J Anaesth 2018;121:787–803. https://doi.org/10.1016/j.bja.2018.06.023.Search in Google Scholar PubMed

67. Lee, B, Schug, SA, Joshi, GP, Kehlet, H, Beloeil, H, Bonnet, F, et al.. Procedure-specific pain management (PROSPECT) – an update. Best Pract Res Clin Anaesthesiol 2018;32:101–11. https://doi.org/10.1016/j.bpa.2018.06.012.Search in Google Scholar PubMed

68. Malek, J, Sevcik, P. Postoperative Pain Management. Prague: Mladá fronta a. s. 2017;22–64 pp.Search in Google Scholar

69. Thybo, KH, Hägi-Pedersen, D, Dahl, JB, Wetterslev, J, Nersesjan, M, Jakobsen, JC, et al.. Effect of combination of paracetamol (acetaminophen) and ibuprofen vs either alone on patient-controlled morphine consumption in the first 24 hours after total hip arthroplasty: the PANSAID randomized clinical trial. JAMA, J Am Med Assoc 2019;321:562–71. https://doi.org/10.1001/jama.2018.22039.Search in Google Scholar PubMed PubMed Central

70. Srikandarajah, S, Gilron, I. Systematic review of movement-evoked pain versus pain at rest in postsurgical clinical trials and meta-analyses: A fundamental distinction requiring standardized measurement. Pain. Washington, WC: International Association for the Study of Pain; 2011, vol 152:1734–9 pp.10.1016/j.pain.2011.02.008Search in Google Scholar PubMed

71. Celi, LA, Scott, DJ, Lee, J, Nelsona, R, Alpera, SL, Mukamala, KJ, et al.. Association of hypermagnesemia and blood pressure in the critically ill. J Hypertens 2013;31:2136–41. https://doi.org/10.1097/hjh.0b013e3283642f18.Search in Google Scholar PubMed PubMed Central

72. Agus, ZS, Morad, M. Modulation of cardiac ION channels by magnesium. Annu Rev Physiol 1991;53:299–307. https://doi.org/10.1146/annurev.ph.53.030191.001503.Search in Google Scholar PubMed

73. Gröber, U, Schmidt, J, Kisters, K. Magnesium in prevention and therapy. Nutrients 2015;7:8199–226.10.3390/nu7095388Search in Google Scholar PubMed PubMed Central

74. Sahu, RK, Yadav, R, Prasad, P, Roy, A, Chandrakar, S. Adverse drug reactions monitoring: prospects and impending challenges for pharmacovigilance. SpringerPlus 2014;3:1–9. https://doi.org/10.1186/2193-1801-3-695.Search in Google Scholar PubMed PubMed Central

75. George, C, Nathanson, V, Seddon, C, Jayesinghe, N, Jackson, G. Reporting adverse drug reactions a guide for healthcare professionals. BMA Board Sci 2006;6:147–58.Search in Google Scholar

Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/sjpain-2022-0048).

Received: 2022-03-21
Accepted: 2022-11-10
Published Online: 2022-12-07
Published in Print: 2023-04-25

© 2022 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Editorial Comment
  3. Chronic pain and health inequalities: why we need to act
  4. Systematic Reviews
  5. Resilience as a protective factor in face of pain symptomatology, disability and psychological outcomes in adult chronic pain populations: a scoping review
  6. Is intravenous magnesium sulphate a suitable adjuvant in postoperative pain management? – A critical and systematic review of methodology in randomized controlled trials
  7. Topical Review
  8. Pain assessment 3 × 3: a clinical reasoning framework for healthcare professionals
  9. Clinical Pain Researches
  10. The treatment lottery of chronic back pain? A case series at a multidisciplinary pain centre
  11. Parameters of anger as related to sensory-affective components of pain
  12. Loneliness in patients with somatic symptom disorder
  13. The development and measurement properties of the Dutch version of the fear-avoidance components scale (FACS-D) in persons with chronic musculoskeletal pain
  14. Observational Studies
  15. Can interoceptive sensitivity provide information on the difference in the perceptual mechanisms of recurrent and chronic pain? Part I. A retrospective clinical study related to multidimensional pain assessment
  16. Distress intolerance and pain catastrophizing as mediating variables in PTSD and chronic noncancer pain comorbidity
  17. Stress-induced headache in the general working population is moderated by the NRCAM rs2300043 genotype
  18. Does poor sleep quality lead to increased low back pain the following day?
  19. “I had already tried that before going to the doctor” – exploring adolescents’ with knee pain perspectives on ‘wait and see’ as a management strategy in primary care; a study with brief semi-structured qualitative interviews
  20. Problematic opioid use among osteoarthritis patients with chronic post-operative pain after joint replacement: analyses from the BISCUITS study
  21. Worst pain intensity and opioid intake during the early postoperative period were not associated with moderate-severe pain 12 months after total knee arthroplasty – a longitudinal study
  22. Original Experimentals
  23. How gender affects the decoding of facial expressions of pain
  24. A simple, bed-side tool to assess evoked pressure pain intensity
  25. Effects of psychosocial stress and performance feedback on pain processing and its correlation with subjective and neuroendocrine parameters
  26. Participatory research: a Priority Setting Partnership for chronic musculoskeletal pain in Denmark
  27. Educational Case Report
  28. Hypophosphatasia as a plausible cause of vitamin B6 associated mouth pain: a case-report
  29. Short Communications
  30. Pain “chronification”: what is the problem with this model?
  31. Korsakoff syndrome and altered pain perception: a search of underlying neural mechanisms
https://doi.org/10.1515/sjpain-2022-0048
Keywords for this article
heterogeneity; magnesium sulphate; postoperative morphine consumption; postoperative pain management; study methodology

Articles in the same Issue

  1. Frontmatter
  2. Editorial Comment
  3. Chronic pain and health inequalities: why we need to act
  4. Systematic Reviews
  5. Resilience as a protective factor in face of pain symptomatology, disability and psychological outcomes in adult chronic pain populations: a scoping review
  6. Is intravenous magnesium sulphate a suitable adjuvant in postoperative pain management? – A critical and systematic review of methodology in randomized controlled trials
  7. Topical Review
  8. Pain assessment 3 × 3: a clinical reasoning framework for healthcare professionals
  9. Clinical Pain Researches
  10. The treatment lottery of chronic back pain? A case series at a multidisciplinary pain centre
  11. Parameters of anger as related to sensory-affective components of pain
  12. Loneliness in patients with somatic symptom disorder
  13. The development and measurement properties of the Dutch version of the fear-avoidance components scale (FACS-D) in persons with chronic musculoskeletal pain
  14. Observational Studies
  15. Can interoceptive sensitivity provide information on the difference in the perceptual mechanisms of recurrent and chronic pain? Part I. A retrospective clinical study related to multidimensional pain assessment
  16. Distress intolerance and pain catastrophizing as mediating variables in PTSD and chronic noncancer pain comorbidity
  17. Stress-induced headache in the general working population is moderated by the NRCAM rs2300043 genotype
  18. Does poor sleep quality lead to increased low back pain the following day?
  19. “I had already tried that before going to the doctor” – exploring adolescents’ with knee pain perspectives on ‘wait and see’ as a management strategy in primary care; a study with brief semi-structured qualitative interviews
  20. Problematic opioid use among osteoarthritis patients with chronic post-operative pain after joint replacement: analyses from the BISCUITS study
  21. Worst pain intensity and opioid intake during the early postoperative period were not associated with moderate-severe pain 12 months after total knee arthroplasty – a longitudinal study
  22. Original Experimentals
  23. How gender affects the decoding of facial expressions of pain
  24. A simple, bed-side tool to assess evoked pressure pain intensity
  25. Effects of psychosocial stress and performance feedback on pain processing and its correlation with subjective and neuroendocrine parameters
  26. Participatory research: a Priority Setting Partnership for chronic musculoskeletal pain in Denmark
  27. Educational Case Report
  28. Hypophosphatasia as a plausible cause of vitamin B6 associated mouth pain: a case-report
  29. Short Communications
  30. Pain “chronification”: what is the problem with this model?
  31. Korsakoff syndrome and altered pain perception: a search of underlying neural mechanisms
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