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British Journal of Anaesthesia Jun 2023Chronic postsurgical pain is common after surgery. Identification of non-opioid analgesics with potential for preventing chronic postsurgical pain is important, although... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Chronic postsurgical pain is common after surgery. Identification of non-opioid analgesics with potential for preventing chronic postsurgical pain is important, although trials are often underpowered. Network meta-analysis offers an opportunity to improve power and to identify the most promising therapy for clinical use and future studies.
METHODS
We conducted a PRISMA-NMA-compliant systematic review and network meta-analysis of randomised controlled trials of non-opioid analgesics for chronic postsurgical pain. Outcomes included incidence and severity of chronic postsurgical pain, serious adverse events, and chronic opioid use.
RESULTS
We included 132 randomised controlled trials with 23 902 participants. In order of efficacy, i.v. lidocaine (odds ratio [OR] 0.32; 95% credible interval [CrI] 0.17-0.58), ketamine (OR 0.64; 95% CrI 0.44-0.92), gabapentinoids (OR 0.67; 95% CrI 0.47-0.92), and possibly dexmedetomidine (OR 0.36; 95% CrI 0.12-1.00) reduced the incidence of chronic postsurgical pain at ≤6 months. There was little available evidence for chronic postsurgical pain at >6 months, combinations agents, chronic opioid use, and serious adverse events. Variable baseline risk was identified as a potential violation to the network meta-analysis transitivity assumption, so results are reported from a fixed value of this, with analgesics more effective at higher baseline risk. The confidence in these findings was low because of problems with risk of bias and imprecision.
CONCLUSIONS
Lidocaine (most effective), ketamine, and gabapentinoids could be effective in reducing chronic postsurgical pain ≤6 months although confidence is low. Moreover, variable baseline risk might violate transitivity in network meta-analysis of analgesics; this recommends use of our methods in future network meta-analyses.
SYSTEMATIC REVIEW PROTOCOL
PROSPERO CRD42021269642.
Topics: Humans; Analgesics, Non-Narcotic; Network Meta-Analysis; Ketamine; Analgesics; Pain, Postoperative; Lidocaine; Analgesics, Opioid
PubMed: 37059625
DOI: 10.1016/j.bja.2023.02.041 -
BMJ (Clinical Research Ed.) Oct 2021To assess the effectiveness and safety of different preparations and doses of non-steroidal anti-inflammatory drugs (NSAIDs), opioids, and paracetamol for knee and hip...
OBJECTIVE
To assess the effectiveness and safety of different preparations and doses of non-steroidal anti-inflammatory drugs (NSAIDs), opioids, and paracetamol for knee and hip osteoarthritis pain and physical function to enable effective and safe use of these drugs at their lowest possible dose.
DESIGN
Systematic review and network meta-analysis of randomised trials.
DATA SOURCES
Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, regulatory agency websites, and ClinicalTrials.gov from inception to 28 June 2021.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES
Randomised trials published in English with ≥100 patients per group that evaluated NSAIDs, opioids, or paracetamol (acetaminophen) to treat osteoarthritis.
OUTCOMES AND MEASURES
The prespecified primary outcome was pain. Physical function and safety outcomes were also assessed.
REVIEW METHODS
Two reviewers independently extracted outcomes data and evaluated the risk of bias of included trials. Bayesian random effects models were used for network meta-analysis of all analyses. Effect estimates are comparisons between active treatments and oral placebo.
RESULTS
192 trials comprising 102 829 participants examined 90 different active preparations or doses (68 for NSAIDs, 19 for opioids, and three for paracetamol). Five oral preparations (diclofenac 150 mg/day, etoricoxib 60 and 90 mg/day, and rofecoxib 25 and 50 mg/day) had ≥99% probability of more pronounced treatment effects than the minimal clinically relevant reduction in pain. Topical diclofenac (70-81 and 140-160 mg/day) had ≥92.3% probability, and all opioids had ≤53% probability of more pronounced treatment effects than the minimal clinically relevant reduction in pain. 18.5%, 0%, and 83.3% of the oral NSAIDs, topical NSAIDs, and opioids, respectively, had an increased risk of dropouts due to adverse events. 29.8%, 0%, and 89.5% of oral NSAIDs, topical NSAIDs, and opioids, respectively, had an increased risk of any adverse event. Oxymorphone 80 mg/day had the highest risk of dropouts due to adverse events (51%) and any adverse event (88%).
CONCLUSIONS
Etoricoxib 60 mg/day and diclofenac 150 mg/day seem to be the most effective oral NSAIDs for pain and function in patients with osteoarthritis. However, these treatments are probably not appropriate for patients with comorbidities or for long term use because of the slight increase in the risk of adverse events. Additionally, an increased risk of dropping out due to adverse events was found for diclofenac 150 mg/day. Topical diclofenac 70-81 mg/day seems to be effective and generally safer because of reduced systemic exposure and lower dose, and should be considered as first line pharmacological treatment for knee osteoarthritis. The clinical benefit of opioid treatment, regardless of preparation or dose, does not outweigh the harm it might cause in patients with osteoarthritis.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO number CRD42020213656.
Topics: Acetaminophen; Administration, Oral; Administration, Topical; Aged; Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Female; Humans; Male; Middle Aged; Minimal Clinically Important Difference; Network Meta-Analysis; Osteoarthritis, Hip; Osteoarthritis, Knee; Pain Management
PubMed: 34642179
DOI: 10.1136/bmj.n2321 -
British Journal of Sports Medicine Jan 2022To assess the effectiveness of interventions for acute and subacute non-specific low back pain (NS-LBP) based on pain and disability outcomes. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To assess the effectiveness of interventions for acute and subacute non-specific low back pain (NS-LBP) based on pain and disability outcomes.
DESIGN
A systematic review of the literature with network meta-analysis.
DATA SOURCES
Medline, Embase and CENTRAL databases were searched from inception until 17 October 2020.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES
Randomised clinical trials (RCTs) involving adults with NS-LBP who experienced pain for less than 6 weeks (acute) or between 6 and 12 weeks (subacute).
RESULTS
Forty-six RCTs (n=8765) were included; risk of bias was low in 9 trials (19.6%), unclear in 20 (43.5%), and high in 17 (36.9%). At immediate-term follow-up, for pain decrease, the most efficacious treatments against an inert therapy were: exercise (standardised mean difference (SMD) -1.40; 95% confidence interval (CI) -2.41 to -0.40), heat wrap (SMD -1.38; 95% CI -2.60 to -0.17), opioids (SMD -0.86; 95% CI -1.62 to -0.10), manual therapy (SMD -0.72; 95% CI -1.40 to -0.04) and non-steroidal anti-inflammatory drugs (NSAIDs) (SMD -0.53; 95% CI -0.97 to -0.09). Similar findings were confirmed for disability reduction in non-pharmacological and pharmacological networks, including muscle relaxants (SMD -0.24; 95% CI -0.43 to -0.04). Mild or moderate adverse events were reported in the opioids (65.7%), NSAIDs (54.3%) and steroids (46.9%) trial arms.
CONCLUSION
With uncertainty of evidence, NS-LBP should be managed with non-pharmacological treatments which seem to mitigate pain and disability at immediate-term. Among pharmacological interventions, NSAIDs and muscle relaxants appear to offer the best harm-benefit balance.
Topics: Adult; Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Humans; Low Back Pain; Network Meta-Analysis; Treatment Outcome
PubMed: 33849907
DOI: 10.1136/bjsports-2020-103596 -
Lancet (London, England) Jun 2022Excessive opioid prescribing after surgery has contributed to the current opioid crisis; however, the value of prescribing opioids at surgical discharge remains... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Excessive opioid prescribing after surgery has contributed to the current opioid crisis; however, the value of prescribing opioids at surgical discharge remains uncertain. We aimed to estimate the extent to which opioid prescribing after discharge affects self-reported pain intensity and adverse events in comparison with an opioid-free analgesic regimen.
METHODS
In this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Library, Scopus, AMED, Biosis, and CINAHL from Jan 1, 1990, until July 8, 2021. We included multidose randomised controlled trials comparing opioid versus opioid-free analgesia in patients aged 15 years or older, discharged after undergoing a surgical procedure according to the Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity definition (minor, moderate, major, and major complex). We screened articles, extracted data, and assessed risk of bias (Cochrane's risk-of-bias tool for randomised trials) in duplicate. The primary outcomes of interest were self-reported pain intensity on day 1 after discharge (standardised to 0-10 cm visual analogue scale) and vomiting up to 30 days. Pain intensity at further timepoints, pain interference, other adverse events, risk of dissatisfaction, and health-care reutilisation were also assessed. We did random-effects meta-analyses and appraised evidence certainty using the Grading of Recommendations, Assessment, Development, and Evaluations scoring system. The review was registered with PROSPERO (ID CRD42020153050).
FINDINGS
47 trials (n=6607 patients) were included. 30 (64%) trials involved elective minor procedures (63% dental procedures) and 17 (36%) trials involved procedures of moderate extent (47% orthopaedic and 29% general surgery procedures). Compared with opioid-free analgesia, opioid prescribing did not reduce pain on the first day after discharge (weighted mean difference 0·01cm, 95% CI -0·26 to 0·27; moderate certainty) or at other postoperative timepoints (moderate-to-very-low certainty). Opioid prescribing was associated with increased risk of vomiting (relative risk 4·50, 95% CI 1·93 to 10·51; high certainty) and other adverse events, including nausea, constipation, dizziness, and drowsiness (high-to-moderate certainty). Opioids did not affect other outcomes.
INTERPRETATION
Findings from this meta-analysis support that opioid prescribing at surgical discharge does not reduce pain intensity but does increase adverse events. Evidence relied on trials focused on elective surgeries of minor and moderate extent, suggesting that clinicians can consider prescribing opioid-free analgesia in these surgical settings. Data were largely derived from low-quality trials, and none involved patients having major or major-complex procedures. Given these limitations, there is a great need to advance the quality and scope of research in this field.
FUNDING
The Canadian Institutes of Health Research.
Topics: Humans; Analgesia; Analgesics, Opioid; Patient Discharge; Practice Patterns, Physicians'; Randomized Controlled Trials as Topic; Vomiting; Pain, Postoperative; Surgical Procedures, Operative
PubMed: 35717988
DOI: 10.1016/S0140-6736(22)00582-7 -
Anaesthesia May 2021Caesarean section is associated with moderate-to-severe postoperative pain, which can influence postoperative recovery and patient satisfaction as well as breastfeeding...
Caesarean section is associated with moderate-to-severe postoperative pain, which can influence postoperative recovery and patient satisfaction as well as breastfeeding success and mother-child bonding. The aim of this systematic review was to update the available literature and develop recommendations for optimal pain management after elective caesarean section under neuraxial anaesthesia. A systematic review utilising procedure-specific postoperative pain management (PROSPECT) methodology was undertaken. Randomised controlled trials published in the English language between 1 May 2014 and 22 October 2020 evaluating the effects of analgesic, anaesthetic and surgical interventions were retrieved from MEDLINE, Embase and Cochrane databases. Studies evaluating pain management for emergency or unplanned operative deliveries or caesarean section performed under general anaesthesia were excluded. A total of 145 studies met the inclusion criteria. For patients undergoing elective caesarean section performed under neuraxial anaesthesia, recommendations include intrathecal morphine 50-100 µg or diamorphine 300 µg administered pre-operatively; paracetamol; non-steroidal anti-inflammatory drugs; and intravenous dexamethasone administered after delivery. If intrathecal opioid was not administered, single-injection local anaesthetic wound infiltration; continuous wound local anaesthetic infusion; and/or fascial plane blocks such as transversus abdominis plane or quadratus lumborum blocks are recommended. The postoperative regimen should include regular paracetamol and non-steroidal anti-inflammatory drugs with opioids used for rescue. The surgical technique should include a Joel-Cohen incision; non-closure of the peritoneum; and abdominal binders. Transcutaneous electrical nerve stimulation could be used as analgesic adjunct. Some of the interventions, although effective, carry risks, and consequentially were omitted from the recommendations. Some interventions were not recommended due to insufficient, inconsistent or lack of evidence. Of note, these recommendations may not be applicable to unplanned deliveries or caesarean section performed under general anaesthesia.
Topics: Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Cesarean Section; Dexamethasone; Female; Humans; Injections, Spinal; Pain Management; Pain, Postoperative; Pregnancy
PubMed: 33370462
DOI: 10.1111/anae.15339 -
Journal of Palliative Medicine May 2023The objective of this systematic review is to consolidate the existing evidence on opioid use, including administration, dosing, and efficacy, for the relief of dyspnea... (Review)
Review
The objective of this systematic review is to consolidate the existing evidence on opioid use, including administration, dosing, and efficacy, for the relief of dyspnea at end of life. The overarching goal is to optimize clinical management of dyspnea by identifying patterns in opioid use, improving opioid management of dyspnea, and to prioritize future research. Opioids are commonly used in the management of dyspnea at end of life, yet specific administration guidelines are limited. A greater understanding of the effectiveness of opioids in relieving end-of-life dyspnea with consideration of study design, patients, and opioids, including dyspnea evaluation tools and outcomes, will leverage development of standardized administration and dosing. A PRISMA-guided systematic review using six databases identified quality studies of opioid management for patients with dyspnea at end of life. Twenty-three references met review inclusion criteria, which included terminally ill cancer and noncancer patients with various diagnoses. Studies included two randomized controlled trials, and three nonrandomized experimental, three prospective observational, one cross-sectional, and one case series. Thirteen retrospective chart reviews were also included due to the limited rigorous studies rendered by the search. Thirteen studies evaluated morphine, followed by fentanyl (6), oxycodone (5), general opioid use (4), and hydromorphone (2). Routes of administration were parenteral, oral, combination, and nebulization. Dyspnea was evaluated using self-reporting and non-self-reporting evaluation tools. Sedation was the most reported opioid-related adverse effect. Challenges persist in conducting end-of-life research, preventing consensus on standardization of opioid treatment for dyspnea within this specific palliative time frame. Future robust prospective trials using specific, accurate assessment with reassessment of dyspnea/respiratory distress, and consideration of opioid tolerance, polypharmacy, and comorbidities are required.
Topics: Humans; Analgesics, Opioid; Prospective Studies; Retrospective Studies; Cross-Sectional Studies; Drug Tolerance; Morphine; Dyspnea; Death; Observational Studies as Topic
PubMed: 36453988
DOI: 10.1089/jpm.2022.0311 -
Pharmacotherapy May 2022Buprenorphine possesses many unique attributes that make it a practical agent for adults and adolescents with opioid use disorder (OUD) and/or acute or chronic pain.... (Review)
Review
Buprenorphine possesses many unique attributes that make it a practical agent for adults and adolescents with opioid use disorder (OUD) and/or acute or chronic pain. Sublingual buprenorphine has been the standard of care for treating OUD, but its use in pain management is not as clearly defined. Current practice guidelines recommend a period of mild-to-moderate withdrawal from opioids before transitioning to buprenorphine due to its ability to displace full agonists from the μ-opioid receptor. However, this strategy can lead to negative physical and psychological outcomes for patients. Novel initiation strategies suggest that concomitant administration of small doses of buprenorphine with opioids can avoid the unwanted withdrawal associated with buprenorphine initiation. We aim to systematically review the buprenorphine initiation strategies that have emerged in the last decade. Embase, PubMed, and Cochrane Databases were searched for relevant literature. Studies were included if they were published in the English language and described the transition to buprenorphine from opioids. Data were collected from each study and synthesized using descriptive statistics. This review included 7 observational studies, 1 feasibility study, and 39 case reports/series which included 924 patients. The strategies utilized between the literature included traditional initiation (47.9%), microdosing with various buprenorphine formulations (16%), and miscellaneous methods (36.1%). Traditional initiation and microdosing initiation were compared in the data synthesis and analysis; miscellaneous methods were omitted given the high variability between methods. Overall, 95.6% of patients in the traditional initiation group and 96% of patients in the microdosing group successfully rotated to sublingual buprenorphine. Initiation regimens can vary widely depending on patient-specific factors and buprenorphine formulation. A variety of buprenorphine transition strategies are published in the literature, many of which were effective for patients with OUD, pain, or both.
Topics: Adolescent; Adult; Analgesics, Opioid; Buprenorphine; Chronic Pain; Humans; Observational Studies as Topic; Opioid-Related Disorders; Pain Management
PubMed: 35302671
DOI: 10.1002/phar.2676 -
JAMA Internal Medicine Jan 2020Mind-body therapies (MBTs) are emerging as potential tools for addressing the opioid crisis. Knowing whether mind-body therapies may benefit patients treated with... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Mind-body therapies (MBTs) are emerging as potential tools for addressing the opioid crisis. Knowing whether mind-body therapies may benefit patients treated with opioids for acute, procedural, and chronic pain conditions may be useful for prescribers, payers, policy makers, and patients.
OBJECTIVE
To evaluate the association of MBTs with pain and opioid dose reduction in a diverse adult population with clinical pain.
DATA SOURCES
For this systematic review and meta-analysis, the MEDLINE, Embase, Emcare, CINAHL, PsycINFO, and Cochrane Library databases were searched for English-language randomized clinical trials and systematic reviews from date of inception to March 2018. Search logic included (pain OR analgesia OR opioids) AND mind-body therapies. The gray literature, ClinicalTrials.gov, and relevant bibliographies were also searched.
STUDY SELECTION
Randomized clinical trials that evaluated the use of MBTs for symptom management in adults also prescribed opioids for clinical pain.
DATA EXTRACTION AND SYNTHESIS
Independent reviewers screened citations, extracted data, and assessed risk of bias. Meta-analyses were conducted using standardized mean differences in pain and opioid dose to obtain aggregate estimates of effect size with 95% CIs.
MAIN OUTCOMES AND MEASURES
The primary outcome was pain intensity. The secondary outcomes were opioid dose, opioid misuse, opioid craving, disability, or function.
RESULTS
Of 4212 citations reviewed, 60 reports with 6404 participants were included in the meta-analysis. Overall, MBTs were associated with pain reduction (Cohen d = -0.51; 95% CI, -0.76 to -0.26) and reduced opioid dose (Cohen d = -0.26; 95% CI, -0.44 to -0.08). Studies tested meditation (n = 5), hypnosis (n = 25), relaxation (n = 14), guided imagery (n = 7), therapeutic suggestion (n = 6), and cognitive behavioral therapy (n = 7) interventions. Moderate to large effect size improvements in pain outcomes were found for meditation (Cohen d = -0.70), hypnosis (Cohen d = -0.54), suggestion (Cohen d = -0.68), and cognitive behavioral therapy (Cohen d = -0.43) but not for other MBTs. Although most meditation (n = 4 [80%]), cognitive-behavioral therapy (n = 4 [57%]), and hypnosis (n = 12 [63%]) studies found improved opioid-related outcomes, fewer studies of suggestion, guided imagery, and relaxation reported such improvements. Most MBT studies used active or placebo controls and were judged to be at low risk of bias.
CONCLUSIONS AND RELEVANCE
The findings suggest that MBTs are associated with moderate improvements in pain and small reductions in opioid dose and may be associated with therapeutic benefits for opioid-related problems, such as opioid craving and misuse. Future studies should carefully quantify opioid dosing variables to determine the association of mind-body therapies with opioid-related outcomes.
Topics: Analgesics, Opioid; Chronic Pain; Cognitive Behavioral Therapy; Humans; Meditation; Pain Management
PubMed: 31682676
DOI: 10.1001/jamainternmed.2019.4917 -
European Journal of Anaesthesiology Sep 2021Complex spinal procedures are associated with intense pain in the postoperative period. Adequate peri-operative pain management has been shown to correlate with improved...
BACKGROUND
Complex spinal procedures are associated with intense pain in the postoperative period. Adequate peri-operative pain management has been shown to correlate with improved outcomes including early ambulation and early discharge.
OBJECTIVES
We aimed to evaluate the available literature and develop recommendations for optimal pain management after complex spine surgery.
DESIGN AND DATA SOURCES
A systematic review using the PROcedure SPECific postoperative pain managemenT methodology was undertaken. Randomised controlled trials and systematic reviews published in the English language from January 2008 to April 2020 assessing postoperative pain after complex spine surgery using analgesic, anaesthetic or surgical interventions were identified from MEDLINE, EMBASE and Cochrane Databases.
RESULTS
Out of 111 eligible studies identified, 31 randomised controlled trials and four systematic reviews met the inclusion criteria. Pre-operative and intra-operative interventions that improved postoperative pain were paracetamol, cyclo-oxygenase (COX)-2 specific-inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs), intravenous ketamine infusion and regional analgesia techniques including epidural analgesia using local anaesthetics with or without opioids. Limited evidence was found for local wound infiltration, intrathecal and epidural opioids, erector spinae plane block, thoracolumbar interfascial plane block, intravenous lidocaine, dexmedetomidine and gabapentin.
CONCLUSIONS
The analgesic regimen for complex spine surgery should include pre-operative or intra-operative paracetamol and COX-2 specific inhibitors or NSAIDs, continued postoperatively with opioids used as rescue analgesics. Other recommendations are intra-operative ketamine and epidural analgesia using local anaesthetics with or without opioids. Although there is procedure-specific evidence in favour of intra-operative methadone, it is not recommended as it was compared with shorter-acting opioids and due to its limited safety profile. Furthermore, the methadone studies did not use non-opioid analgesics, which should be the primary analgesics to ultimately reduce overall opioid requirements, including methadone. Further qualitative randomised controlled trials are required to confirm the efficacy and safety of these recommended analgesics on postoperative pain relief.
Topics: Analgesia, Epidural; Analgesics, Opioid; Anesthetics, Local; Humans; Pain Management; Pain, Postoperative
PubMed: 34397527
DOI: 10.1097/EJA.0000000000001448 -
Acta Anaesthesiologica Scandinavica Feb 2022Opioid-based treatment is used to manage stress responses during surgery and postoperative pain. However, opioids have both acute and long-term side effects, calling for... (Meta-Analysis)
Meta-Analysis Review
Total opioid-free general anaesthesia can improve postoperative outcomes after surgery, without evidence of adverse effects on patient safety and pain management: A systematic review and meta-analysis.
BACKGROUND
Opioid-based treatment is used to manage stress responses during surgery and postoperative pain. However, opioids have both acute and long-term side effects, calling for opioid-free anaesthetic strategies. This meta-analysis compares adverse events, postoperative recovery, discharge time from post-anaesthesia care unit, and postoperative pain, nausea, vomiting, and opioid consumption between strict opioid-free and opioid-based general anaesthesia.
METHODS
We conducted a systematic review and meta-analysis. We searched PubMed, Embase, Cinahl, Cochrane Library, selected reference lists, and Google Scholar. We included randomised controlled trials (RCTs) published between January 2000 and February 2021 with at least one opioid-free study arm, i.e. no opioids administered preoperatively, during anaesthesia induction, before skin closure, or before emergence from anaesthesia.
RESULTS
The study comprised 1934 patients from 26 RCTs. Common interventions included laparoscopic gynaecological surgery, upper gastrointestinal surgery, and breast surgery. There is firm evidence that opioid-free anaesthesia significantly reduced adverse postoperative events (OR 0.32, 95% CI 0.22 to 0.46, I = 56%, p < 0.00001), mainly driven by decreased nausea (OR 0.27, (0.17 to 0.42), p < 0.00001) and vomiting (OR 0.22 (0.11 to 0.41), p < 0.00001). Postoperative opioid consumption was significantly lower in the opioid-free group (-6.00 mg (-8.52 to -3.48), p < 0.00001). There was no significant difference in length of post-anaesthesia care unit stay and overall postoperative pain between groups.
CONCLUSIONS
Opioid-free anaesthesia can improve postoperative outcomes in several surgical settings without evidence of adverse effects on patient safety and pain management. There is a need for more evidence-based non-opioid anaesthetic protocols for different types of surgery as well as postoperative phases.
Topics: Analgesics, Opioid; Anesthesia, General; Humans; Pain, Postoperative; Patient Safety
PubMed: 34724195
DOI: 10.1111/aas.13994