Synergistic use of anti-inflammatory ketorolac and gentamicin to target staphylococcal biofilms.

BACKGROUND: While antibiotics remain our primary tools against microbial infection, increasing antibiotic resistance (inherent and acquired) is a major detriment to their efficacy. A practical approach to maintaining or reversing the efficacy of antibiotics is the use of other commonly used therapeutics, which show synergistic antibacterial action with antibiotics. Here, we investigated the extent of antibacterial synergy between the antibiotic gentamicin and the anti-inflammatory ketorolac regarding the dynamics of biofilm growth, the rate of acquired resistance, and the possible mechanism of synergy. METHODS: Control (ATCC 12600, ATCC 35984) and clinical strains (L1101, L1116) of Staphylococcus aureus and Staphylococcus epidermidis with varying antibiotic susceptibility profiles were used in this study to simulate implant-material associated low-risk and high-risk biofilms in vitro. The synergistic action of gentamicin sulfate (GS) and ketorolac tromethamine (KT), against planktonic staphylococcal strains were determined using the fractional inhibitory concentration measurement assay. Nascent (6 h) and established (24 h) biofilms were grown on 316L stainless steel plates and the synergistic biofilm eradication activity was determined and characterized using adherent bacteria count, minimum biofilm eradication concentration (MBEC) measurement for GS, visualization by live/dead imaging, scanning electron microscopy, gene expression of biofilm-associated genes, and bacterial membrane fluidity assessment. RESULTS: Gentamicin-ketorolac (GS-KT) combination demonstrated synergistic antibacterial action against planktonic Staphylococci. Control and clinical strains showed distinct biofilm growth dynamics and an increase in biofilm maturity was shown to confer further resistance to gentamicin for both 'low-risk' and 'high-risk' biofilms. The addition of ketorolac enhanced the antibiofilm activity of gentamicin against acquired resistance in staphylococcal biofilms. Mechanistic studies revealed that the synergistic action of gentamicin-ketorolac interferes with biofilm morphology and subverts bacterial stress response altering bacterial physiology, membrane dynamics, and biofilm properties. CONCLUSION: The results of this study have a significant impact on the local administration of antibiotics and other therapeutic agents commonly used in the prevention and treatment of orthopaedic infections. Further, these results warrant the study of synergy for the concurrent or sequential administration of non-antibiotic drugs for antimicrobial effect.

Atomized Intranasal Ketorolac Versus Intravenous Ketorolac for the Treatment of Severe Renal Colic in the Emergency Department: A Double-Blind, Randomized Controlled Trial.

STUDY OBJECTIVE: Atomized intranasal (IN) drug administration offers an alternative to the intravenous (IV) route. We aimed to evaluate the analgesic efficacy of IN versus IV ketorolac in emergency department patients with acute renal colic. METHODS: We conducted a double-blind, randomized controlled trial on adult patients (aged 18 to 64 years) with severe renal colic and numerical rating scale pain ratings ≥7.0. They were randomly assigned (1:1) to receive single doses of either IN or IV ketorolac. Our main outcomes were differences in numerical rating scale reduction at 30 and 60 minutes. A 95% confidence interval (CI) was calculated for each mean difference, with a minimum clinically important difference set at 1.3 points. Secondary outcomes included treatment response, adverse events, rescue medications, and emergency department revisits. We analyzed using intention-to-treat. RESULTS: A total of 86 and 85 patients with similar baseline characteristics were allocated to the IV and IN groups, respectively. Mean numerical rating scale scores were 8.52 and 8.65 at baseline, 3.85 and 4.67 at 30 minutes, and 2.80 and 3.04 at 90 minutes, respectively. The mean numerical rating scale reduction differences between the IV and IN groups were 0.69 (95% CI -0.08 to 1.48) at 30 minutes and 0.10 (95% CI -0.85 to 1.04) at 60 minutes. There were no differences in secondary outcomes. CONCLUSION: Neither IN or IV ketorolac was superior to the other for the treatment of acute renal colic, and both provided clinically meaningful reductions in pain scores at 30 to 60 minutes.

Comparison of the Effect of Intracarpal Injection of Ketorolac With Triamcinolone in Carpal Tunnel Syndrome: A Randomized Controlled Trial.

BACKGROUND: The most prevalent entrapment neuropathy is carpal tunnel syndrome (CTS). Although nonsteroidal antiinflammatory drugs (NSAIDs) are frequently prescribed for musculoskeletal disorders, oral NSAIDs do not provide any additional benefits for CTS. Nevertheless, the use of NSAID phonophoresis has shown significant improvement, possibly due to increased concentration in the target tissue. The effects of intracarpal injection of NSAIDs on CTS have not been studied. OBJECTIVE: We conducted a controlled trial to compare the efficacy of ketorolac and triamcinolone in treating CTS. METHODS: Mild to moderate CTS patients were randomly assigned to receive either a local injection of 30 mg ketorolac or 40 mg triamcinolone. Patients were evaluated using visual analog scale (VAS) for pain, severity, function, electrodiagnostic findings, patient satisfaction, and any complications at the injection site, at baseline and 12 weeks after the procedures. RESULTS: Fifty patients participated, and 43 completed the study. Both groups showed significant improvement in the VAS, severity, function, and electrodiagnostic scores at 3 months compared with the baseline. A comparison of the groups showed significant differences in VAS, severity, and function, with the improvement being significantly higher in the triamcinolone group. CONCLUSION AND RELEVANCE: The present study showed that injection of triamcinolone or ketorolac into the carpal tunnel relieved pain, increased function, and improved electrodiagnostic findings in patients with mild to moderate CTS. It also showed that triamcinolone was superior to ketorolac in terms of analgesic effect and resulted in greater improvement in symptom severity and function.

The Risk of Kidney Injury in Patients With Sickle Cell Disease Treated With Ketorolac for Acute Pain.

Ketorolac, a nonsteroidal anti-inflammatory drug, is used in combination with opioids to manage vaso-occlusive episodes (VOEs). The relationship between ketorolac use and kidney injury in pediatric patients with sickle cell disease (SCD) remains incompletely understood. We hypothesize that ketorolac is associated with acute kidney injury (AKI) in patients with SCD presenting with pain. All nonsurgical hospitalizations for VOEs treated with ketorolac between January 2014 and December 2022 were included. We used optimal matching methodology to identify control admissions (2:1 ratio) and used nonparametric tests to compare ketorolac administration between cases and controls. A total of 1319 encounters/253 patients were included in this study. AKI was noted in 1.1% of encounters and 5.5% of patients. Cases had significantly higher initial BUN than controls (9.0 vs. 6.0 mg/dL, P =0.012). In cases versus controls, there was significantly lower serum sodium (136.0 vs. 138.0 mmol/L, P =0.021). There was no association between ketorolac dose and development of AKI among children with SCD. Higher BUN and lower sodium in cases suggest that patients with AKI were more volume depleted on admission than controls. This highlights the need for strict assessment of fluid status upon admission for VOE.

Ibuprofen for acute postoperative pain in children.

BACKGROUND: Children often require pain management following surgery to avoid suffering. Effective pain management has consequences for healing time and quality of life. Ibuprofen, a frequently used non-steroidal anti-inflammatory drug (NSAID) administered to children, is used to treat pain and inflammation in the postoperative period. OBJECTIVES: 1) To assess the efficacy and safety of ibuprofen (any dose) for acute postoperative pain management in children compared with placebo or other active comparators. 2) To compare ibuprofen administered at different doses, routes (e.g. oral, intravenous, etc.), or strategies (e.g. as needed versus as scheduled). SEARCH METHODS: We used standard Cochrane search methods. We searched CENTRAL, MEDLINE, Embase, CINAHL and trials registries in August 2023. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in children aged 17 years and younger, treated for acute postoperative or postprocedural pain, that compared ibuprofen to placebo or any active comparator. We included RCTs that compared different administration routes, doses of ibuprofen and schedules. DATA COLLECTION AND ANALYSIS: We adhered to standard Cochrane methods for data collection and analysis. Our primary outcomes were pain relief reported by the child, pain intensity reported by the child, adverse events, and serious adverse events. We present results using risk ratios (RR) and standardised mean differences (SMD), with the associated confidence intervals (CI). We used GRADE to assess the certainty of the evidence. MAIN RESULTS: We included 43 RCTs that enroled 4265 children (3935 children included in this review). We rated the overall risk of bias at the study level as high or unclear for 37 studies that had one or several unclear or high risk of bias judgements across the domains. We judged six studies as having a low risk of bias across all domains. Ibuprofen versus placebo (35 RCTs) No studies reported pain relief reported by the child or a third party, or serious adverse events. Ibuprofen probably reduces child-reported pain intensity less than two hours postintervention compared to placebo (SMD -1.12, 95% CI -1.39 to -0.86; 3 studies, 259 children; moderate-certainty evidence). Ibuprofen may reduce child-reported pain intensity, two hours to less than 24 hours postintervention (SMD -1.01, 95% CI -1.24 to -0.78; 5 studies, 345 children; low-certainty evidence). Ibuprofen may result in little to no difference in adverse events compared to placebo (RR 0.79, 95% CI 0.51 to 1.23; 5 studies, 384 children; low-certainty evidence). Ibuprofen versus paracetamol (21 RCTs) No studies reported pain relief reported by the child or a third party, or serious adverse events. Ibuprofen likely reduces child-reported pain intensity less than two hours postintervention compared to paracetamol (SMD -0.42, 95% CI -0.82 to -0.02; 2 studies, 100 children; moderate-certainty evidence). Ibuprofen may slightly reduce child-reported pain intensity two hours to 24 hours postintervention (SMD -0.21, 95% CI -0.40 to -0.02; 6 studies, 422 children; low-certainty evidence). Ibuprofen may result in little to no difference in adverse events (0 events in each group; 1 study, 44 children; low-certainty evidence). Ibuprofen versus morphine (1 RCT) No studies reported pain relief or pain intensity reported by the child or a third party, or serious adverse events. Ibuprofen likely results in a reduction in adverse events compared to morphine (RR 0.58, 95% CI 0.40 to 0.83; risk difference (RD) -0.25, 95% CI -0.40 to -0.09; number needed to treat for an additional beneficial outcome (NNTB) 4; 1 study, 154 children; moderate-certainty evidence). Ibuprofen versus ketorolac (1 RCT) No studies reported pain relief or pain intensity reported by the child, or serious adverse events. Ibuprofen may result in a reduction in adverse events compared to ketorolac (RR 0.51, 95% CI 0.27 to 0.96; RD -0.29, 95% CI -0.53 to -0.04; NNTB 4; 1 study, 59 children; low-certainty evidence). AUTHORS' CONCLUSIONS: Despite identifying 43 RCTs, we remain uncertain about the effect of ibuprofen compared to placebo or active comparators for some critical outcomes and in the comparisons between different doses, schedules and routes for ibuprofen administration. This is largely due to poor reporting on important outcomes such as serious adverse events, and poor study conduct or reporting that reduced our confidence in the results, along with small underpowered studies. Compared to placebo, ibuprofen likely results in pain reduction less than two hours postintervention, however, the efficacy might be lower at two hours to 24 hours. Compared to paracetamol, ibuprofen likely results in pain reduction up to 24 hours postintervention. We could not explore if there was a different effect in different kinds of surgeries or procedures. Ibuprofen likely results in a reduction in adverse events compared to morphine, and in little to no difference in bleeding when compared to paracetamol. We remain mostly uncertain about the safety of ibuprofen compared to other drugs.

COMPARISON OF THE EFFECTS OF EIGHT DIFFERENT TOPICAL NONSTEROIDAL ANTI-INFLAMMATORY DRUGS ON REDUCING INTRAVITREAL INJECTION-INDUCED PAIN.

PURPOSE: To compare topical nonsteroidal anti-inflammatory drug (NSAID) efficacy on intravitreal injection-induced pain reduction and determine the most efficient topical NSAID. METHODS: This randomized-controlled study included 662 eyes of 662 patients. Based on the types of NSAID administered before intravitreal injection, eight subgroups were formed. In the control group, a sterile saline solution was applied instead of NSAIDs. The visual analog scale was used to assess pain scores after intravitreal injection. The visual analog scale scores were noted immediately and 6 hours following injection (sixth hour). RESULTS: Nepafenac 0.3%, nepafenac 0.1%, and bromfenac 0.09% had the lowest scores, immediately after and after 6 hours, with no significant differences. Diclofenac and ketorolac had higher visual analog scale scores than the first trio but lower scores than the control group. Flurbiprofen, pranoprofen, and indomethacin did not significantly affect immediate pain; however, at the sixth hour, the visual analog scale scores were significantly reduced. CONCLUSION: Nepafenac 0.3%, nepafenac 0.1%, and bromfenac 0.09% were the most effective NSAIDs for pain reduction. Although some NSAIDs did not have a significant effect on immediate pain, they all provided significant benefits at the sixth hour.

A sequential, multiple-assignment, randomized trial of analgesic strategies for acute musculoskeletal Pain.

BACKGROUND: Most methodologically rigorous, ED-based, comparative effectiveness analgesic studies completed in the last two decades failed to find a clinically important difference between the comparators. We believe that many of these comparative effectiveness studies were biased towards the null hypothesis because some ED patients with intense pain will respond to relatively mild interventions. We hypothesized that including a run-in period would alter the results of an acute pain RCT. METHODS: We conducted a sequential, multiple-assignment, randomized study. Adults with acute moderate/severe musculoskeletal pain were randomized (3:1 ratio) to run-in period or no run-in. We administered 650 mg acetaminophen to run-in participants. Those run-in patients who reported insufficient relief one-hour later were randomized (1:1 ratio) to ibuprofen 800mg PO or ketorolac 20mg PO as were all participants randomized to no run-in. The primary outcome was achieving a clinically important improvement, defined as improvement ≥1.3 on a 0-10 scale. We built a logistic regression model including run-in/no run-in, ketorolac/ibuprofen, age and sex. RESULTS: Of 307 participants who received acetaminophen, 100 (32.6%) reported inadequate relief and were randomized to an NSAID. Of the 100 patients randomized to no run-in, 84/100 (84%) achieved the primary outcome versus 246/287 (86%) run-in participants (95% CI for difference = 2%:-7,10%). Among run-in participants who received an NSAID, 82/99(83%) achieved the primary outcome versus 84/100(84%) no run-in participants (p = 0.82). Among all ibuprofen participants, 44/49(90%) randomized to run-in and 42/50(84%) randomized to no run-in achieved the primary outcome. Among all ketorolac participants, 38/50(76%) randomized to run-in and 42/50 (84%) randomized to no run-in achieved the primary outcome. We observed the following results in a multivariable analysis: OR for ketorolac versus ibuprofen:0.60 (95% CI: 0.28, 1.28); OR for run-in versus no run-in:0.91(95% CI: 0.43, 1.93). CONCLUSIONS: Among patients with acute musculoskeletal pain, using an acetaminophen first strategy did not alter pain outcomes.

Ketorolac Injections for Musculoskeletal Conditions: A Narrative Review.

Musculoskeletal conditions of the upper and lower extremities are commonly treated with corticosteroid injections. Ketorolac, a parenteral nonsteroidal anti-inflammatory drug, represents an alternative injectant for common shoulder, hip, and knee conditions. A review of the current literature was conducted on the efficacy of ketorolac injection in musculoskeletal diseases. Several studies support the use and efficacy of ketorolac injection in subacromial bursitis, adhesive capsulitis, and hip and knee osteoarthritis. Given the systemic effects of glucocorticoid injections, ketorolac may be a safe and effective alternative in patients with musculoskeletal disease. However, more evidence is required to better understand the effects ketorolac has on the human body during inflammatory processes.

Intravenous ibuprofen versus ketorolac for perioperative pain control in open abdominal hysterectomy: a randomized controlled trial.

BACKGROUND: We aimed to compare the analgesic effects of intravenous ibuprofen to ketorolac after open abdominal hysterectomy. METHODS: This randomized double-blinded controlled trial included adult women scheduled for elective open abdominal hysterectomy. Participants were randomized to receive either 30 mg ketorolac (n = 50) or 800 mg ibuprofen (n = 50) preoperatively, then every 8 h postoperatively for 24 h. All participants received paracetamol 1 gm/6 h. Rescue analgesic was given if the visual analogue scale (VAS) for pain assessment was > 3. The primary outcome was the mean postoperative dynamic VAS during the first 24 h. Secondary outcomes were static VAS, intraoperative fentanyl consumption, postoperative morphine consumption, time to independent movement, and patient's satisfaction. RESULTS: Forty-six patients in the ibuprofen group and fifty patients in the ketorolac group were analyzed. The 24-h dynamic and static VAS were similar in the two groups. The median (quartiles) dynamic VAS was 1.1 (0.9, 1.9) in the ibuprofen group versus 1.0 (0.7, 1.3) in the ketorolac group, P-value = 0.116; and the median (quartiles) static VAS was 0.9 (0.6, 1.3) in the ibuprofen group versus 0.7 (0.4, 1.1) in the ketorolac group, P-value = 0.113. The intra- and postoperative analgesic requirements were also similar in the two groups. However, patient satisfaction was slightly higher in the ketorolac group than that in the ibuprofen group (median [quartiles]: 6 [5, 7] versus 5 [4, 7], respectively), P-value: 0.009. CONCLUSION: The two drugs, intravenous ibuprofen and ketorolac produced similar analgesic profile in patients undergoing open abdominal hysterectomy receiving multimodal analgesic regimen. NCT05610384, Date of registration: 09/11/2022 CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05610384. https://clinicaltrials.gov/ct2/show/NCT05610384.

Local ketorolac infiltration for postoperative pain in open trigger finger surgery: a randomized controlled trial.

BACKGROUND: Multimodal analgesia is crucial for effective postoperative pain management in minor hand surgeries, enhancing patient satisfaction. The use of local wound infiltration with Ketorolac as an adjuvant pain management strategy is proposed for open trigger finger release surgery. This study aims to compare pain scores and functional outcomes between local wound infiltration with Ketorolac and oral non-steroidal anti-inflammatory drugs. METHODS: This study is a double-blind, parallel design, randomized controlled trials. Sixty-nine patients underwent trigger finger surgery between December 2021 and October 2022 were randomized into one of three groups: oral Ibuprofen alone group, local Ketorolac alone group and local Ketorolac with oral Ibuprofen group. The assessment included postoperative numeric rating scale (NRS) pain score, Disabilities of the Arm, Shoulder, and Hand (DASH) score, grip strength, mobility of proximal interphalangeal (PIP) joint. and complications. RESULTS: NRS pain scores during movement of the operated fingers were significantly lower at 6 h in local Ketorolac alone group and local Ketorolac with oral Ibuprofen group compared to oral Ibuprofen alone group. However, there were no significant differences between the groups in postoperative DASH scores, grip strength, mobility of PIP joints, and complications. CONCLUSIONS: Local infiltration of Ketorolac as an adjunct in postoperative pain management has been shown to provide superior analgesia during finger movement within the initial 6 h following trigger finger surgery, in comparison to oral NSAIDs. CLINICAL TRIAL REGISTRATION: Thaiclinicaltrials.org identifier: TCTR20210825002. Registered 25/08/2021. https://www.thaiclinicaltrials.org/show/TCTR20210825002.

Ketorolac in neonates and infants following congenital heart surgery: a retrospective review.

INTRODUCTION: Pain management is essential in the immediate post-surgical period. We sought to describe the ketorolac dose regimen in neonates and infants following cardiac surgery. Secondary outcomes included renal dysfunction, bleeding, and pain management. METHODS: We performed a single-centre retrospective cohort study of neonates and infants (aged < 12 months) who received ketorolac following cardiac surgery, from November 2020 through November 2021 (inclusive). Ketorolac was administered at 0.5 mg/kg every 6 hours. Safety was defined by absence of a clinically significant decline in renal function (i.e., increase in serum creatinine [SCr] by ≥ 0.3 mg/dL from baseline within 48 hours and/or urine output ≤ 0.5 mL/kg/hour for 6 hours) and absence of clinically significant bleeding defined as major by International Society on Thrombosis and Hemostasis paediatric criteria or Severe/Fatal Bleeding Events by Nellis et al. Efficacy measures included pain scores and opioid utilisation. RESULTS: Fifty-five patients met eligibility criteria. The median (range) dose and duration of ketorolac administration was 0.5 mg/kg/dose for 48 (6-90) hours. Among all patients, there was not a statistically significant difference observed in median SCr within 48 hours of baseline (p > .9). There were no major or severe bleeding events. The median (range) opioid requirements (morphine intravenous equivalents per kg per day) at 48 hours post-ketorolac initiation was 0.1 (0-0.8) mg/kg/day. CONCLUSIONS: If validated prospectively, these findings suggest that a ketorolac regimen 0.5 mg/kg/dose every 6 hours in neonates and infants post-cardiac surgery may be safe with regard to renal function and bleeding risk, and effective regarding opioid-sparing capacity.

Intravenous Acetaminophen Versus Ketorolac for Prehospital Analgesia: A Retrospective Data Review.

BACKGROUND: Parenteral ketorolac and intravenous (IV) acetaminophen have been used for prehospital analgesia, yet limited data exist on their comparative effectiveness. STUDY OBJECTIVES: To evaluate the comparative effectiveness of IV acetaminophen and parenteral ketorolac for analgesia in the prehospital setting. METHODS: We conducted a retrospective cross-sectional evaluation of patients receiving IV acetaminophen or parenteral ketorolac for pain management in a large suburban EMS system between 1/1/2019 and 11/30/2021. The primary outcome was change in first to last pain score. Subgroup analysis was performed on patients with traumatic pain. We used inverse probability of treatment weighting (IPTW) and propensity score matching (PSM) to estimate the treatment effect of acetaminophen versus ketorolac among all patients and the subgroup of those with traumatic pain. RESULTS: Of 2178 patients included, 856 (39.3%) received IV acetaminophen and 1322 (60.7%) received parenteral ketorolac. The unadjusted mean change in pain score was -1.9 (SD 2.4) for acetaminophen group and -2.4 (SD 2.4) for ketorolac. In the propensity score analyses, there was no statistically significant difference in pain score change for the acetaminophen group versus ketorolac among all patients (mean difference, IPTW: 0.11, 95% confidence interval [CI] -0.16, 0.37; PSM: 0.15, 95% CI -0.13, 0.43) and among those with traumatic pain (unadjusted: 0.18, 95% CI -0.35, 0.72; IPTW: 0.23, 95% CI -0.25, 0.71; PSM: -0.03, 95% CI -0.61, 0.54). CONCLUSIONS: We found no statistically significant difference in mean pain reduction of IV acetaminophen and parenteral ketorolac for management of acute pain.

Efficacy of a Multimodal Surgical Site Injection for Postoperative Pain Control in Pediatric Patients With Cerebral Palsy Undergoing Hip Reconstruction: A Randomized Controlled Trial.

BACKGROUND: One in 4 children with cerebral palsy (CP) will undergo orthopaedic surgery during their childhood. Despite its ubiquity, postoperative pain control has been poorly studied in this patient population. Moreover, poor pain management has been associated with adverse surgical outcomes. Multimodal analgesic injections have been well studied in the adult population, demonstrating safety and efficacy in reducing postoperative pain and narcotic consumption, but this modality has not been studied in pediatric patients undergoing similarly complex procedures. The objective of this study was to evaluate the efficacy of a multimodal surgical site injection for postoperative pain control following operative management of hip dysplasia in patients with CP. METHODS: After obtaining IRB approval, a multicenter, randomized double-blind placebo control trial was completed. Patients below 18 years old with a diagnosis of CP who were scheduled for varus derotation osteotomy (VDRO) of the proximal femur were randomized to receive a surgical-site injection with either a combination of ropivacaine (3 mg/kg), epinephrine (0.5 mg), and ketorolac (0.5 mg/kg) (experimental group) or normal saline (control). All included patients had identical postoperative care, including immobilization, physical therapy, and standardized, multimodal postoperative pain control. Pain scores and narcotic consumption were recorded at regular intervals and compared between groups utilizing two-tailed t test or a nonparametric Mann-Whitney test for quantitative variables and a Fischer exact test for categorical variables. RESULTS: Thirty-four patients were included, evenly divided between study arms. There were no significant differences in demographic variables, gross motor function classification system (GMFCS), comorbidities, preoperative radiographic parameters, or concomitant surgeries between groups. Patients in the experimental group required significantly lower narcotic medications at all postoperative time points from PACU until hospital discharge compared with controls (0.41 ± 0.42 vs. 1.87 ± 2.05 total morphine mEQ/kg, P =0.01). Similarly, patients in the experimental group were found to have significantly lower pain scores throughout their hospital stays compared with controls (1.0 ± 0.6 vs. 2.4 ± 1.1 mean pain score, P <0.001). There were no significant differences in operative time, OR time, blood transfusion requirements or hospital length of stay between groups. There were no adverse medication reactions or injection site complications in either group. CONCLUSIONS: In patients with CP undergoing hip reconstruction, surgical-site injection with a multimodal analgesic combination improves pain control and reduces narcotic consumption in the early postoperative period with no observed adverse effects. SIGNIFICANCE: Local multimodal analgesic injections should be adopted as part of standard multimodal pain control in this patient population for all osseous surgeries. LEVEL OF EVIDENCE: Level I-therapeutic.

Revisiting and Updating the Interaction between Human Serum Albumin and the Non-Steroidal Anti-Inflammatory Drugs Ketoprofen and Ketorolac.

Ketoprofen (KTF) and ketorolac (KTL) are among the most primarily used non-steroidal anti-inflammatory drugs (NSAIDs) in humans to alleviate moderate pain and to treat inflammation. Their binding affinity with albumin (the main globular protein responsible for the biodistribution of drugs in the bloodstream) was previously determined by spectroscopy without considering some conventional pitfalls. Thus, the present work updates the biophysical characterization of the interactions of HSA:KTF and HSA:KTL by 1H saturation-transfer difference nuclear magnetic resonance (1H STD-NMR), ultraviolet (UV) absorption, circular dichroism (CD), steady-state, and time-resolved fluorescence spectroscopies combined with in silico calculations. The binding of HSA:NSAIDs is spontaneous, endothermic, and entropically driven, leading to a conformational rearrangement of HSA with a slight decrease in the α-helix content (7.1% to 7.6%). The predominance of the static quenching mechanism (ground-state association) was identified. Thus, both Stern-Volmer quenching constant (KSV) and binding constant (Kb) values enabled the determination of the binding affinity. In this sense, the KSV and Kb values were found in the order of 104 M-1 at human body temperature, indicating moderate binding affinity with differences in the range of 0.7- and 3.4-fold between KTF and KTL, which agree with the previously reported experimental pharmacokinetic profile. According to 1H STD-NMR data combined with in silico calculations, the aromatic groups in relation to the aliphatic moiety of the drugs interact preferentially with HSA into subdomain IIIA (site II) and are stabilized by interactions via hydrogen bonding and hydrophobic forces. In general, the data obtained in this study have been revised and updated in comparison to those previously reported by other authors who did not account for inner filter corrections, spectral backgrounds, or the identification of the primary mathematical approach for determining the binding affinity of HSA:KTF and HSA:KTL.

Neuropeptide W facilitates chronic gastric ulcer healing by the regulation of cyclooxygenase and NF-κB signaling pathways.

AIMS: Putative beneficial effects of neuropeptide W (NPW) in the early phase of gastric ulcer healing process and the involvement of cyclooxygenase (COX) enzymes were investigated in an acetic acid-induced gastric ulcer model. MAIN METHODS: In anesthetized male Sprague-Dawley rats, acetic acid was applied surgically on the serosa and then a COX-inhibitor (COX-2-selective NS-398, COX-1-selective ketorolac, or non-selective indomethacin; 2 mg/kg/day, 3 mg/kg/day or 5 mg/kg/day; respectively) or saline was injected intraperitoneally. One h after ulcer induction, omeprazole (20 mg/kg/day), NPW (0.1 µg/kg/day) or saline was intraperitoneally administered. Injections of NPW, COX-inhibitors, omeprazole or saline were continued for the following 2 days until rats were decapitated at the end of the third day. KEY FINDINGS: NPW treatment depressed gastric prostaglandin (PG) I2 level, but not PGE2 level. Similar to omeprazole, NPW treatment significantly reduced gastric and serum tumor necrosis factor-alpha and interleukin-1 beta levels and depressed the upregulation of nuclear factor kappa B (NF-κB) and COX-2 expressions due to ulcer. In parallel with the histopathological findings, treatment with NPW suppressed ulcer-induced increases in myeloperoxidase activity and malondialdehyde level and replenished glutathione level. However, the inhibitory effect of NPW on myeloperoxidase activity and NPW-induced increase in glutathione were not observed in the presence of COX-1 inhibitor ketorolac or the non-selective COX-inhibitor indomethacin. SIGNIFICANCE: In conclusion, NPW facilitated the healing of gastric injury in rats via the inhibition of pro-inflammatory cytokine production, oxidative stress and neutrophil infiltration as well as the downregulation of COX-2 protein and NF-κB gene expressions.

A meta-analysis of topical Ketorolac's effect on surgical site wound healing post-cataract surgery.

This meta-analysis evaluates the impact of topical ketorolac on surgical site wound healing and scar formation after cataract surgery. A thorough literature search, adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, identified eight relevant studies from 2348 articles. The selected studies were analysed for wound healing efficacy, using the redness, edema, ecchymosis, discharge and approximation (REEDA) scale, and scar formation, assessed by the Manchester scar scale (MSS). Results indicated that ketorolac significantly improved wound healing, with lower REEDA scores 1 week post-surgery (I2 = 97%; Random: standardised mean difference (SMD): -10.93, 95% CI: -13.85 to -8.00, p < 0.01), and reduced scar formation, evidenced by lower MSS scores 3 months post-surgery (I2 = 74%; Random: SMD: -9.67, 95% CI: -11.03 to -8.30, p < 0.01). The findings suggest that topical ketorolac is beneficial in post-cataract surgery care, enhancing wound healing and reducing scarring.

Ketorolac and bone healing: a review of the basic science and clinical literature.

Although the efficacy of ketorolac in pain management and the short duration of use align well with current clinical practice guidelines, few studies have specifically evaluated the impact of ketorolac on bony union after fracture or surgery. The purpose of this study was to review the current basic science and clinical literature on the use of ketorolac for pain management after fracture and surgery and the subsequent risk of delayed union or nonunion. Animal studies demonstrate a dose-dependent risk of delayed union in rodents treated with high doses of ketorolac for 4 weeks or greater; however, with treatment for 7 days or low doses, there is no evidence of risk of delayed union or nonunion. Current clinical evidence has also shown a dose-dependent increased risk of pseudoarthrosis and nonunion after post-operative ketorolac administration in orthopedic spine surgery. However, other orthopedic subspecialities have not demonstrated increased risk of delayed union or nonunion with the use of peri-operative ketorolac administration. While evidence exists that long-term ketorolac use may represent risks with regard to fracture healing, insufficient evidence currently exists to recommend against short-term ketorolac use that is limited to the peri-operative period. LEVEL OF EVIDENCE V: Narrative Review.

Comparison between ketorolac- and fentanyl-based patient-controlled analgesia for acute kidney injury after robot-assisted radical prostatectomy: a retrospective propensity score-matched analysis.

PURPOSE: It is unclear whether ketorolac-based patient-controlled analgesia (PCA) leads to acute kidney injury (AKI) after robot-assisted radical prostatectomy (RARP) in patients susceptible to AKI. We compared the postoperative AKI incidence with ketorolac- and fentanyl-based PCA after RARP. METHODS: After medical record review, eligible patients were divided in ketorolac and fentanyl groups. We conducted propensity score matching of 3239 patients and assigned 641 matched patients to each group, and compared the AKI incidence. We investigated potential risk factors for postoperative AKI, defined according to the Kidney Disease Improving Global Outcomes criteria. We collected preoperative data (age, height, weight, body mass index, American Society of Anesthesiologists physical status, medical history, creatinine level, estimated glomerular filtration rate, and hemoglobin level) and intraoperative data (maintenance anesthetics, surgery duration, anesthesia duration, crystalloid amount, colloid use, total amount of fluid administered, estimated blood loss, norepinephrine use, phenylephrine use, and PCA type). RESULTS: The postoperative AKI incidence was significantly higher in the ketorolac than in the fentanyl group, both before (31.1% vs. 20.4%; p < 0.001) and after (31.5% vs. 22.6%; p < 0.001) matching. In the univariate analysis, ketorolac was significantly associated with postoperative AKI, both before (odds ratio [OR], 1.762; 95% confidence interval [CI], 1.475-2.105; p < 0.001) and after (OR, 1.574; 95% CI, 1.227-2.019; p < 0.001) matching. In the multivariate analysis, ketorolac-based PCA was independently associated with development of postoperative AKI in the matched groups (OR, 1.659; 95% CI, 1.283-2.147; p < 0.001). CONCLUSION: Ketorolac-based PCA may increase postoperative AKI incidence after RARP; thus, renal function should be monitored in these patients.

Opioid-free percutaneous nephrolithotomy: an initial experience.

INTRODUCTION: The opioid epidemic in the United States is an ongoing public health crisis that is in part fueled by excessive prescribing by physicians. Percutaneous nephrolithotomy (PCNL) is a procedure that conventionally involves opioid prescriptions for adequate post-operative pain control. We aimed to evaluate the feasibility of a non-opioid pain regimen by evaluating post-operative outcomes in PCNL patients discharged without opioids. MATERIALS AND METHODS: As a quality improvement measure to reduce opioid consumption our department began routinely prescribing oral ketorolac instead of oxycodone-acetaminophen for pain control after PCNL. We retrospectively compared patients undergoing PCNL who had received ketorolac prescriptions (NSAID) to those who received oxycodone-acetaminophen prescriptions (NARC). Demographic, operative, and post-operative factors were obtained and compared in both groups. Peri-operative factors and demographics were compared using either Chi-squared tests, Mann-Whitney U tests. Surgical outcomes were compared between the two groups using Chi-squared tests and Fisher's exact tests. Multivariate logistic regression analysis was performed to determine whether ketorolac use was an independent predictor of post-surgical pain-related encounters. Primary outcome was unplanned pain-related healthcare encounters inclusive of office phone calls, unscheduled office visits, and emergency department (ED) visits. Secondary outcome measures were non-pain-related healthcare encounters, hospital readmissions, pain-related rescue medications prescribed, and post-op complications. RESULTS: There were similar demographics and peri-operative characteristics amongst patients in both cohorts. There was no significant difference identified between NSAID and NARC regarding unplanned pain-related encounters (8/70, 11.4% vs. 10/70, 14.3%, p = 0.614). However, NARC experienced more unplanned phone calls (42, 60% vs. 24, 34.3%, p = 0.004). Multivariate analysis revealed only prior stone surgery was predictive of pain-related encounters after PCNL (p = 0.035). CONCLUSION: Our results show that there were no significant differences in pain-related encounters between those who received ketorolac and oxycodone-acetaminophen following PCNL. A non-opioid pathway may mitigate the potential risk associated with opioid prescription without compromising analgesia. Prospective comparative studies are warranted to confirm feasibility.

The efficacy and safety of metoclopramide in relieving acute migraine attacks compared with other anti-migraine drugs: a systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Many drugs are prescribed in relieving acute migraine attacks, we aim to compare metoclopramide with other antimigraine drugs. METHODS: We searched online databases like PubMed, Cochrane Library, Scopus, and Web of Science till June 2022 for RCTs that compared metoclopramide alone with placebo or active drugs. The main outcomes were the mean change in headache score and complete headache relief. The secondary outcomes were the rescue medications need, side effects, nausea and recurrence rate. We qualitatively reviewed the outcomes. Then, we performed the network meta-analyses (NMAs) when it was possible. which were done by the Frequentist method using the MetaInsight online software. RESULTS: Sixteen studies were included with a total of 1934 patients: 826 received metoclopramide, 302 received placebo, and 806 received other active drugs. Metoclopramide was effective in reducing headache outcomes even for 24 h. The intravenous route was the most chosen route in the included studies and showed significant positive results regarding headache outcomes; however, the best route whether intramuscular, intravenous, or suppository was not compared in the previous studies. Also, both 10 and 20 mg doses of metoclopramide were effective in improving headache outcomes; however, there was no direct comparison between both doses and the 10 mg dose was the most frequently used dosage. In NMA of headache change after 30 min or 1 h, metoclopramide effect came after granisetron, ketorolac, chlorpromazine, and Dexketoprofen trometamol. Only granisetron's effect was significantly higher than metoclopramide's effect which was only significantly higher than placebo and sumatriptan. In headache-free symptoms, only prochlorperazine was non-significantly higher than metoclopramide which was higher than other medications and showed significantly higher effects only with placebo. In rescue medication, metoclopramide's effect was only non-significantly lower than prochlorperazine and chlorpromazine while its effect was higher than other drugs and showed higher significant effects only than placebo and valproate. In the recurrence rate, studies showed no significant difference between metoclopramide and other drugs. Metoclopramide significantly decreased nausea more than the placebo. Regarding side effects, metoclopramide showed a lower incidence of mild side effects than pethidine and chlorpromazine and showed a higher incidence of mild side effects than placebo, dexamethasone, and ketorolac. The reported extrapyramidal symptoms with metoclopramide were dystonia or akathisia. CONCLUSION: A dose of 10 mg IV Metoclopramide was effective in relieving migraine attacks with minimal side effects. Compared to other active drugs, it only showed a lower significant effect compared with granisetron regarding headache change while it showed significantly higher effects only with placebo in both rescue medication needs and headache-free symptoms and valproate in only rescue medication need. Also, it significantly decreased headache scores more than placebo and sumatriptan. However, more studies are needed to support our results.