Effects of (2R,6R)-hydroxynorketamine in assays of acute pain-stimulated and pain-depressed behaviors in mice.

Ketamine has been shown to produce analgesia in various acute and chronic pain states; however, abuse liability concerns have limited its utility. The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) has been shown to produce antidepressant-like effects similar to ketamine without abuse liability concerns. (2R,6R)-HNK produces sustained analgesia in models of chronic pain, but has yet to be evaluated in models of acute pain. The present study evaluated the efficacy of acute (2R,6R)-HNK administration (one injection) in assays of pain-stimulated (52- and 56-degree hot plate test and acetic acid writhing) and pain-depressed behavior (locomotor activity and rearing) in male and female C57BL/6 mice. In assays of pain-stimulated behaviors, (2R,6R)-HNK (1-32 mg/kg) failed to produce antinociception in the 52- and 56-degree hot plate and acetic acid writhing assays. In assays of pain-depressed behaviors, 0.56% acetic acid produced a robust depression of locomotor activity and rearing that was not blocked by pretreatment of (2R,6R)-HNK (3.2-32 mg/kg). The positive controls morphine (hot plate test) and ketoprofen (acetic acid writhing, locomotor activity, and rearing) blocked pain-stimulated and pain-depressed behaviors. Finally, the effects of intermittent (2R,6R)-HNK administration were evaluated in 52-degree hot plate and pain-depressed locomotor activity and rearing. Intermittent administration of (2R,6R)-HNK also did not produce antinociceptive effects in the hot plate or pain-depressed locomotor activity assays. These results suggest that (2R,6R)-HNK is unlikely to have efficacy in treating acute pain; however, the efficacy of (2R,6R)-HNK in chronic pain states should continue to be evaluated.

Noninferiority trials in acute pain research: a valid approach or a slippery slope?

The conduct and reporting of studies with a noninferiority hypothesis is challenging because of the complexity involved in their design and interpretation. However, studies with a noninferiority design have increased in popularity. A recently published trial reported on the noninferiority of lidocaine infusion to epidural analgesia in major abdominal surgeries. Apart from needing a critical appraisal, this draws attention to improve our understanding of noninferiority study framework and its unique features. Given the increasing focus on using various analgesic adjuncts and multiple approaches to fascial plane blocks to avoid more definitive and standard approaches, it is imperative that particular attention is paid to appropriate execution and reporting of noninferiority studies.

Transcutaneous electrical nerve stimulation for reducing postoperative acute pain after hip fracture surgery: a double-blinded randomized clinical trial.

OBJECTIVE: The aim of this study was to assess the effects of two different applications of transcutaneous electrical nerve stimulation (TENS) on the reduction of postoperative acute pain after hip fracture surgery. PATIENTS AND METHODS: In this study, 120 patients undergoing hip surgery were divided into three groups. The first group received patient-controlled analgesia (PCA) with epidural fentanyl and additional medications. The second group received lumbar plexus and sciatic nerve transcutaneous electrical nerve stimulation (LS-TENS) along with the same medication protocol as the first group. The third group received the same medication protocol as the first group, as well as surgical wound transcutaneous electrical nerve stimulation (SW-TENS). Pain levels were measured using a Visual Analog Scale (VAS) score, and the number of opioid analgesics used by each patient was recorded. VAS score and the total consumption of opioid analgesics were meticulously documented. RESULTS: VAS scores were higher in the control group than in the SW-TENS group at 30 min (1.58±2.49 vs. 0.70±2.15, p<0.05) and in the SW-TENS group than in the LS- TENS group at 24 h postoperatively (2.33±1.29 vs. 1.63±1.05, p<0.05). The 48-h total analgesic consumption level of the control group was higher than that of the LS-TENS group (p<0.05). CONCLUSIONS: The findings of this study indicate that TENS application to the surgical wound, lumbar plexus, and sciatic nerve using anatomical landmarks can significantly reduce postoperative pain, as demonstrated by the higher VAS scores, higher total analgesic consumption and high additional analgesic need in the control group after hip fracture surgery. CLINICALTRIALS: gov ID: NCT02642796.

Challenges of acute pain management in older patients.

Adequate management of acute pain in the older population is crucial. However, it is inherently complex because of multiple physiological changes that significantly impact both the pharmacokinetics and pharmacodynamics of medications. Current guidelines promote paracetamol as the first-line analgesic for acute pain in older adults, whereas opioids are advised cautiously for moderate to severe acute pain. However, opioids come with a significant array of side effects, which can be more pronounced in older individuals. Ketamine administered via intranasal (IN) and nebulised inhalation in the emergency department for managing acute pain in older patients shows promising potential for improving pain management and reducing opioid reliance Kampan, Thong-on, Sri-on (2024, Age Ageing, 53, afad255). Nebulised ketamine appears superior in terms of adverse event incidence. However, the adoption of IN or nebulised ketamine in older adult acute pain management remains unclear because of the lack of definitive conclusions and clear guidelines. Nevertheless, these modalities can be valuable options for patients where opioid analgesics are contraindicated or when intravenous morphine titration is impractical or contraindicated. Here, we review these concepts, the latest evidence and propose avenues for research.

Sex differences in pain catastrophizing and its relation to the transition from acute pain to chronic pain.

BACKGROUND AND IMPORTANCE: Differences exist between sexes in pain and pain-related outcomes, such as development of chronic pain. Previous studies suggested a higher risk for pain chronification in female patients. Furthermore, pain catastrophizing is an important risk factor for chronification of pain. However, it is unclear whether sex differences in catastrophic thinking could explain the sex differences in pain chronification. OBJECTIVES: The aim of this study was to examine sex differences in pain catastrophizing. Additionally, we investigated pain catastrophizing as a potential mediator of sex differences in the transition of acute to chronic pain. DESIGN, SETTINGS AND PARTICIPANTS: Adults visiting one of the 15 participating emergency departments in the Netherlands with acute pain-related complaints. Subjects had to meet inclusion criteria and complete questionnaires about their health and pain. OUTCOMES MEASURE AND ANALYSIS: The outcomes in this prospective cohort study were pain catastrophizing (short form pain catastrophizing) and pain chronification at 90 days (Numeric Rating Scale ≥ 1). Data was analysed using univariate and multivariable logistic regression models. Finally, stratified regression analyses were conducted to assess whether differences in pain catastrophizing accounted for observed differences in pain chronification between sexes. MAIN RESULTS: In total 1,906 patients were included. Females catastrophized pain significantly more than males (p < 0.001). Multiple regression analyses suggested that pain catastrophizing is associated with pain chronification in both sexes. CONCLUSIONS: This study reported differences between sexes in catastrophic cognitions in the development of chronic pain. This is possibly of clinical importance to identify high-risk patients and ensure an early intervention to prevent the transition from acute to chronic pain.

Long-Acting Drug Delivery Technologies for Meloxicam as a Pain Medicine.

Meloxicam, a selective COX-2 inhibitor, has demonstrated clinical effectiveness in managing inflammation and acute pain. Although available in oral and parenteral formulations such as capsule, tablet, suspension, and solution, frequent administration is necessary to maintain therapeutic efficacy, which can increase adverse effects and patient non-compliance. To address these issues, several sustained drug delivery strategies such as oral, transdermal, transmucosal, injectable, and implantable drug delivery systems have been developed for meloxicam. These sustained drug delivery strategies have the potential to improve the therapeutic efficacy and safety profile of meloxicam, thereby reducing the frequency of dosing and associated gastrointestinal side effects. The choice of drug delivery system will depend on the desired release profile, the target site of inflammation, and the mode of administration. Overall, meloxicam sustained delivery systems offer better patient compliance, and reduce the side effects, thereby improving the clinical applications of this drug. Herein, we discuss in detail different strategies for sustained delivery of meloxicam.

El tratamiento del dolor agudo pediátrico en España EN 2021: resultado de una encuesta nacional entre anestesiólogos pediátricos / The management of paediatric acute pain in Spain IN 2021: Results of a national survey among paediatric anaesthesiologists

Objetivo: Mejorar el conocimiento acerca de la práctica clínica habitual en el tratamiento del dolor agudo pediátrico en España.MétodosSe llevó a cabo una encuesta telemática a través de Internet en una muestra representativa de profesionales sanitarios involucrados en el tratamiento del dolor agudo pediátrico (concretamente anestesiólogos) en España. La encuesta incluyó 28 cuestiones acerca de su práctica clínica habitual en la valoración y el tratamiento del dolor agudo, así como aspectos formativos y organizativos en el dolor agudo pediátrico.ResultadosLa encuesta fue completada durante el mes de marzo de 2021 por 150 especialistas en anestesiología. Los encuestados presentaron una amplia experiencia en el tratamiento del dolor agudo pediátrico (media de años de experiencia: 14,3; DE: 7,8) y básicamente en dolor agudo postoperatorio (97% casos). Aunque el 80% de los mismos utilizaba de modo habitual escalas validadas de valoración de dolor agudo pediátrico, solo el 2,6% utilizaba las específicas adaptadas para pacientes con discapacidad cognitiva. La mayoría de los encuestados empleaba habitualmente fármacos analgésicos como el paracetamol (99%) o el metamizol (92%), pero solo el 84% los complementaba con alguna técnica de bloqueo loco-regional u otra medicación tipo antiinflamatorio no esteroideo (62%). Además, únicamente un 62,7% reconocía haber recibido formación específica en dolor agudo pediátrico, solo un 45% seguía protocolos institucionales hospitalarios y un escaso 28% lo hacía a través de unidades de dolor infantil.ConclusionesLa encuesta identificó importantes puntos de mejora en la formación y organización del tratamiento del dolor agudo de los pacientes españoles en edad pediátrica. (AU)

Objective: To improve knowledge about routine clinical practice in the management of paediatric acute pain in Spain.MethodsA telematic survey was conducted via the Internet on a representative sample of healthcare professionals involved in the management of paediatric acute pain (specifically anaesthesiologists) in Spain. The survey included 28 questions about their usual clinical practice in the assessment and treatment of acute pain, and also training and organisational aspects in paediatric acute pain.ResultsThe survey was completed during March 2021 by 150 specialists in anaesthesiology. The respondents widely experienced in the management of acute paediatric pain (mean years of experience: 14.3: SD: 7.8), essentially in acute postoperative pain (97% of cases). Although 80% routinely used validated paediatric acute pain assessment scales, only 2.6% used specific scales adapted for patients with cognitive impairment. Most of the respondents routinely used analgesic drugs such as paracetamol (99%) or metamizole (92%), but only 84% complemented these drugs with a loco-regional blocking technique or other non-steroidal anti-inflammatory drugs (62%). Furthermore, only 62.7% acknowledged having received specific training in paediatric acute pain, only 45% followed hospital institutional protocols, and a scant 28% did so through paediatric pain units.ConclusionsThe survey identified important points for improvement in the training and organisation of acute pain management in Spanish paediatric patients. (AU)

Gestión del dolor agudo postoperatorio: condiciones para garantizar la seguridad y la efectividad de los tratamientos analgésicos / Management of acute postoperative pain: Conditions to guarantee the safety and effectiveness of analgesic treatments

La evidencia sobre la gestión del dolor postoperatorio presenta un grado de calidad bajo o insuficiente. El Grupo de Trabajo del Dolor Agudo SEDAR ha elaborado este documento-guía para aplicar la mejor evidencia científica disponible a la práctica clínica habitual, individualizándolo en función de factores propios del paciente y del procedimiento, y englobando las distintas opciones organizativas del control de dolor.El documento profundiza y actualiza conceptos y requisitos mínimos necesarios para una analgesia óptima postoperatoria, el abordaje multidisciplinar y la gestión del dolor agudo postoperatorio. Se definen y se describen líneas estratégicas y los distintos modelos de gestión. Se establece un plan de actuación general perioperatoria basado en la colaboración con los servicios quirúrgicos implicados, en la revisión conjunta de la evidencia y en la elaboración de protocolos por procedimiento. Finalmente, se presenta un plan de seguimiento y los indicadores mínimos necesarios para un control de calidad del dolor postoperatorio. (AU)

The evidence on postoperative pain management is of low or insufficient quality. The SEDAR Acute Pain Working Group has prepared this guideline-document to apply the best available scientific evidence to clinical practice, individualizing it based on factors specific to the patient and the procedure, and encompassing different organizational options, attempting to individualize it based on specific factors of the patient and the procedure, and encompassing the different organizational options for pain control.The document updates concepts and minimum requirements necessary for optimal postoperative analgesia, a multidisciplinary approach and the management of acute postoperative pain. Strategic lines and different management models are defined. A general perioperative action plan is established based on collaboration with the surgical departments involved, on the joint review of the evidence and on preparation of protocols by the procedure. Finally, a follow-up plan and a series of minimum indicators necessary for quality control of postoperative pain are presented. (AU)

Low-dose ketamine safely reduces acute pain in the ED with a more rapid and shorter effect than morphine.

SOURCE CITATION: Guo J, Zhao F, Bian J, et al. Low-dose ketamine versus morphine in the treatment of acute pain in the emergency department: a meta-analysis of 15 randomized controlled trials. Am J Emerg Med. 2024;76:140-149. 38071883.

The crucial role of locus coeruleus noradrenergic neurons in the interaction between acute sleep disturbance and headache.

BACKGROUND: Both epidemiological and clinical studies have indicated that headache and sleep disturbances share a complex relationship. Although headache and sleep share common neurophysiological and anatomical foundations, the mechanism underlying their interaction remains poorly understood. The structures of the diencephalon and brainstem, particularly the locus coeruleus (LC), are the primary sites where the sleep and headache pathways intersect. To better understand the intricate nature of the relationship between headache and sleep, our study focused on investigating the role and function of noradrenergic neurons in the LC during acute headache and acute sleep disturbance. METHOD: To explore the relationship between acute headache and acute sleep disturbance, we primarily employed nitroglycerin (NTG)-induced migraine-like headache and acute sleep deprivation (ASD) models. Initially, we conducted experiments to confirm that ASD enhances headache and that acute headache can lead to acute sleep disturbance. Subsequently, we examined the separate roles of the LC in sleep and headache. We observed the effects of drug-induced activation and inhibition and chemogenetic manipulation of LC noradrenergic neurons on ASD-induced headache facilitation and acute headache-related sleep disturbance. This approach enabled us to demonstrate the bidirectional function of LC noradrenergic neurons. RESULTS: Our findings indicate that ASD facilitated the development of NTG-induced migraine-like headache, while acute headache affected sleep quality. Furthermore, activating the LC reduced the headache threshold and increased sleep latency, whereas inhibiting the LC had the opposite effect. Additional investigations demonstrated that activating LC noradrenergic neurons further intensified pain facilitation from ASD, while inhibiting these neurons reduced this pain facilitation. Moreover, activating LC noradrenergic neurons exacerbated the impact of acute headache on sleep quality, while inhibiting them alleviated this influence. CONCLUSION: The LC serves as a significant anatomical and functional region in the interaction between acute sleep disturbance and acute headache. The involvement of LC noradrenergic neurons is pivotal in facilitating headache triggered by ASD and influencing the effects of headache on sleep quality.

A Case of Doxycycline-Induced Pancreatitis.

INTRODUCTION: Acute pancreatitis is a common cause of hospitalizations in the United States, causing approximately 230 000 to 275 000 annual admissions We present the case of a patient with acute pancreatitis likely due to doxycycline. CASE PRESENTATION: A 64-year-old male was admitted after developing acute epigastric pain radiating to his back, a lipase of 6611 (units/L), and a computed tomography scan showing moderate peripancreatic inflammation. He had no recent alcohol use, his gallbladder was surgically absent, and he had no gallbladder pathology on evaluation; however, he had been started on doxycycline 10 days prior. While hospitalized, he was treated with pain medications, fluids, and antibiotics for aspiration pneumonia. His acute symptoms resolved, except for minor intermittent abdominal pain 2 months after discharge. DISCUSSION: Doxycycline-induced pancreatitis has been reported within 3 to 17 days of medication initiation. Given the temporal correlation and lack of other inciting etiologies, we determined the most likely etiology was doxycycline. CONCLUSIONS: Further study is needed to understand the pathophysiology and incidence of doxycycline-induced pancreatitis.

A novel manual therapy approach for managing acute interscapular pain following median sternotomy for open cardiac surgery: A clinical comparative analysis.

INTRODUCTION: Acute interscapular pain is a frequent postoperative complication observed in patients who have undergone median sternotomy. This study aimed to assess a novel approach to manual therapy utilizing the Regional Interdependence (RI) concept for managing interscapular pain in post-sternotomy patients. MATERIALS AND METHODS: In an observational study, a cohort of 60 consecutively admitted patients undergoing median sternotomy was enrolled. Data collection involved standardized clinical evaluations conducted at specific time points: prior to manual treatment (T0), following five manual treatments (T5), and at post-treatment days 10 (T10) and 30 (T30). The Experimental Group (EG) received manual treatment based on the RI concept, performed in a seated position to accommodate individual clinical conditions and surgical wound considerations. The Control Group (CG) received simulated treatment involving identical exercises to the EG but lacking the physiological or biomechanical stimulation. RESULTS: Among the initial 60 patients, 36 met the inclusion criteria, while 24 were excluded due to one or more exclusion criteria. Treatment outcomes revealed a statistically significant improvement in the EG compared to the CG, not only in terms of pain reduction but also in functional recovery and consequent disability reduction. DISCUSSION: The RI concept emerges as a potentially valuable therapeutic approach for addressing interscapular dysfunction, particularly in highly complex post-sternotomy patients. This study highlights the clinical relevance of the RI concept in the management of interscapular pain and highlights its potential utility in improving patient outcomes in the challenging context of sternotomy surgery.

Could generative artificial intelligence replace fieldwork in pain research?

BACKGROUND: Generative artificial intelligence (AI) models offer potential assistance in pain research data acquisition, yet concerns persist regarding data accuracy and reliability. In a comparative study, we evaluated open generative AI models' capacity to acquire data on acute pain in rock climbers comparable to field research. METHODS: Fifty-two rock climbers (33 m/19 f; age 29.0 [24.0-35.75] years) were asked to report pain location and intensity during a single climbing session. Five generative pretrained transformer models were tasked with responses to the same questions. RESULTS: Climbers identified the back of the forearm (19.2%) and toes (17.3%) as primary pain sites, with reported median pain intensity at 4 [3-5] and median maximum pain intensity at 7 [5-8]. Conversely, AI models yielded divergent findings, indicating fingers, hands, shoulders, legs, and feet as primary pain localizations with average and maximum pain intensity ranging from 3 to 4.4 and 5 to 10, respectively. Only two AI models provided references that were untraceable in PubMed and Google searches. CONCLUSION: Our findings reveal that, currently, open generative AI models cannot match the quality of field-collected data on acute pain in rock climbers. Moreover, the models generated nonexistent references, raising concerns about their reliability.

Wunderlich syndrome in a patient with pyelonephritis.

An elderly female patient with left pyelonephritis developed worsening left flank pain, hypotension and a drop in haemoglobin (Hb) from 97 g/L to 67g/L on the third day of her admission. There was no recent trauma, history of coagulopathy or risk factors for renal malignancy or vascular disease.A contrasted CT scan of the kidneys revealed a 3.8 cm left renal subcapsular haematoma with no active contrast extravasation. Her atraumatic subcapsular haematoma fulfils two out of three clinical features of Lenk's triad (acute flank pain, hypovolaemic shock), suggestive of Wunderlich syndrome. Urine and blood cultures grew Klebsiella pneumoniae and she was managed conservatively with culture-directed antibiotics, fluids and blood products.Wunderlich syndrome is a rare complication of pyelonephritis and should be considered in patients with pyelonephritis who develop acute severe flank pain, Hb drop and haemodynamic instability. Appropriate medical and surgical therapies need to be instituted early to ensure good outcomes.

The acute pain crisis in sickle cell disease: What can be done to improve outcomes?

The acute pain crisis (APC) is the commonest complication of sickle cell disease (SCD). Severe episodes may require treatment in hospital with strong opioid analgesic drugs, combined with additional supportive care measures. Guidelines for APC management have been produced over the past two decades gathering evidence from published studies, expert opinion, and patient perspective. Unfortunately, reports from multiple sources indicate that guidelines are often not followed, and that acute care in emergency departments and on acute medical wards is suboptimal. It is important to understand what leads to this breakdown in health care, and to identify evidence-based interventions which could be implemented to improve care. This review focuses on recently published articles as well as information about on-going clinical trials. Aspects of care which could potentially make a difference to patient experience include availability and accessibility of individual care plans agreed between patient and treating specialist, innovative means of delivering initial opioids to reduce time to first analgesia, and availability of a specialist unit away from the ED, where expert care can be delivered in a more compassionate environment. The current evidence of improved outcomes and health economic advantage with these interventions is inadequate, and this is hampering their implementation into health care systems.

Real-time monitoring of cortical brain activity in response to acute pain using wide-area Ca2+ imaging.

Previous human and rodent studies indicated that nociceptive stimuli activate many brain regions that is involved in the somatosensory and emotional sensation. Although these studies have identified several important brain regions involved in pain perception, it has been a challenge to observe neural activity directly and simultaneously in these multiple brain regions during pain perception. Using a transgenic mouse expressing G-CaMP7 in majority of astrocytes and a subpopulation of excitatory neurons, we recorded the brain activity in the mouse cerebral cortex during acute pain stimulation. Both of hind paw pinch and intraplantar administration of formalin caused strong transient increase of the fluorescence in several cortical regions, including primary somatosensory, motor and retrosplenial cortex. This increase of the fluorescence intensity was attenuated by the pretreatment with morphine. The present study provides important insight into the cortico-cortical network during pain perception.

Transforaminal Epidural Block and Erector Spinae Plane Block to Manage Acute Zoster-Associated Pain: A Retrospective Case-Control Study.

Background and Objectives: Achieving adequate pain reduction in the acute phase of herpes zoster is essential for preventing postherpetic neuralgia (PHN). For this purpose, appropriate antiviral medications, oral analgesic medications, and various nerve block methods could be applied. Erector spinae plane block (ESPB) is a simple, novel ultrasound-guided block technique, and its use has increased because the procedure is convenient and relatively safe. Although several cases have reported the zoster-associated pain (ZAP) control effect of ESPB, the efficacy of ESPB has not been compared with that of other types of nerve blocks for managing ZAP. This study aimed to compare the efficacy of ESPB with that of other types of nerve blocks for managing ZAP. Study Design: Retrospective case-control study. Materials and Methods: Medical records of 53 patients with acute thoracic herpes zoster were reviewed. We divided the participants into two groups: patients who received transforaminal epidural injection (TFEI) (n = 32) and those who received ESPB (n = 21). The efficacy of the procedure was assessed by a numerical rating scale (NRS) and by recording patient medication doses before the procedure and at 1 week, 1 month, 2 months, and 3 months after the procedure. Results: The time required for pain intensity to decrease to NRS ≤ 2 was not significantly different between the groups. The rate of medication discontinuation also was not different between the groups. There was no significant difference between the two groups in the proportion of clinically significant PHN (NRS ≥ 3) at any time point. Limitations: The relatively small sample size from a single center and the retrospective nature of the study served as limitations. Conclusions: The clinical effects of ESPB and TFEI were similar in patients with acute thoracic herpes zoster. ESPB could be considered an interventional option for ZAP management.

Opioids for Acute Musculoskeletal Pain: A Systematic Review with Meta-Analysis.

OBJECTIVE: To evaluate the efficacy of opioids for people with acute musculoskeletal pain against placebo. STUDY DESIGN: Systematic review and meta-analyses of randomised, placebo-controlled trials of opioid analgesics for acute musculoskeletal pain in any setting. The primary outcomes were pain and disability at the immediate timepoint (< 24 h). DATA SOURCES: Multiple databases were searched from their inception to February 22nd, 2023. DATA SYNTHESIS: Continuous outcomes were converted to a 0-100 scale. Dichotomous outcomes were presented as risk differences. Risk of bias and certainty of evidence was assessed. RESULTS: We located 17 trials (1 intravenous and 16 oral route of administration). For adults, high certainty evidence from 11 comparisons shows that oral opioids provide small benefits relative to placebo in the immediate term for pain (mean difference [MD] - 8.8 95% confidence interval [CI] - 12.0 to - 5.6). For disability, the difference is uncertain (MD - 6.2, 95% CI - 17.8 to 5.4). Opioid groups were at higher risk of adverse events (MD 14.3%, 95% CI 8.3-20.4%, very low certainty). There was moderate certainty evidence of a large effect of IV morphine on sciatica pain (MD -42.5, 95% CI - 49.9 to - 35.1, n = 197, 1 study). In paediatric populations, moderate certainty evidence from 3 trials shows that oral opioids probably do not provide benefit beyond that of placebo for pain (MD 6.1, 95% CI - 1.7 to 12.8) and there was no evidence for disability. There was low certainty evidence that there may be no difference in adverse events (MD 10.4%, 95% CI - 0.6 to 21.4%). DISCUSSION: Intravenous morphine likely offers benefits, but oral opioids may not provide clinically meaningful benefits. PROSPERO REGISTRATION: CRD42021249346.