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Cardiovascular safety of hydroxypropyl-β-cyclodextrin-diclofenac in the management of acute postsurgical pain: a pooled analysis of 2 randomized, double-blind, placebo- and active comparator-controlled phase III clinical trials.
Gan, TJ, Singla, N, Daniels, SE, Lacouture, PG, Min, LH, Reyes, CR, Carr, DB
Journal of clinical anesthesia. 2016;:249-58
Abstract
STUDY OBJECTIVE Long-term use of nonsteroidal anti-inflammatory drugs, including selective and nonselective cyclooxygenase inhibitors, has been suggested to be associated with cardiovascular (CV) safety risks. Data are limited regarding CV risks associated with short-term nonsteroidal anti-inflammatory drug use, including injectable formulations, although it has been suggested that even a single dose may increase CV adverse event (AE) risk. The objective of this study was to examine the CV safety of an injectable diclofenac formulation solubilized with hydroxypropyl-β-cyclodextrin (HPβCD) when given for ≤5days postoperatively. DESIGN A pooled analysis of CV AEs from 2 pivotal phase III clinical trials examining the efficacy and safety of intravenous (IV) HPβCD-diclofenac vs placebo and the active comparator ketorolac was conducted. SETTING Postoperative, with treatment initiated in the postanesthesia care unit ≤6hours postsurgery. PATIENTS Overall, 608 abdominal/pelvic and orthopedic surgery patients met inclusion criteria and received ≥1 study medication dose. INTERVENTIONS Patients received either HPβCD-diclofenac, ketorolac, or placebo via IV bolus injection every 6hours, for ≤5days postsurgery. MEASUREMENTS CV AEs, reported by study investigators, were evaluated through the treatment period and follow-up (≤37days after last study medication dose), and relative CV AE risks were estimated. MAIN RESULTS IV HPβCD-diclofenac was not associated with increased treatment-emergent CV AE incidence vs placebo (11.6% vs 12.2%; relative risk, 0.96 [95% confidence interval, 0.56-1.62]). Serious CV AEs as well as treatment-related AEs were uncommon, and there were no reports of myocardial infarction or cerebrovascular accident. CV AEs were uncommon during the follow-up period, occurring in 1.3%, 0%, and 1.4% of patients in the HPβCD-diclofenac, ketorolac, and placebo groups, respectively. CONCLUSIONS Although a longer duration follow-up study in a larger patient population would expand our understanding of potential CV risks, the present analysis suggests that postoperative use of HPβCD-diclofenac does not present an added CV safety risk over placebo.
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Acceptable effect of multimodal analgesic treatment after a Bascom cleft lift operation.
Mohamed, SJ, Kristensen, BB, Lindgaard, L, Bisgaard, T
Danish medical journal. 2015;(1):A4985
Abstract
INTRODUCTION Information on multimodal analgesic efficacy in patients undergoing a Bascom cleft lift operation is limited. The aim of this prospective consecutive study was to evaluate early post-operative pain in patients receiving a standardised multimodal analgesic regimen. METHODS A total of 48 patients undergoing a Bascom cleft lift operation were included over an 8-month period in a day-case set-up. The operation was performed under saddle block. In addition, patients received a standardised multi-modal analgesic regimen consisting of gabapentin, ketorolac, dexamethasone, acetaminophen (paracetamol) and ibuprofen. The intensity of pain was registered preoperatively and at 2, 24, 48 h, and 30 days post-operatively. Nausea, vomiting, dizziness, ability to void, morphine consumption and post-anaesthesia care unit (PACU) time were registered. RESULTS Thirty patients were available for analysis. Post-operative visual analogue scale pain scores were low (at 2, 24, and 48 h (median values: 0 (range: 0-40), 25 (0-70), and 30 (0-60), respectively), but changed significantly over time (p < 0.001). The median overall morphine consumption was 0 (range: 0-30). None of the patients experienced vomiting or dizziness. Only two patients reported mild nausea during the stay in the PACU. CONCLUSION This study suggests that the Bascom cleft lift operation is feasible with minimal post-operative pain when using a multimodal analgesic regimen together with saddle block. FUNDING not relevant. TRIAL REGISTRATION ClinicalTrials.gov: NCT02196727. Regional Ethics Committee Reg. no.: H-3-2013-073. Danish Data Protection Agency Reg. no.: HVH-2013-031, with I-Suite no.: 02408.
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Intracameral phenylephrine and ketorolac during cataract surgery to maintain intraoperative mydriasis and reduce postoperative ocular pain: Integrated results from 2 pivotal phase 3 studies.
Hovanesian, JA, Sheppard, JD, Trattler, WB, Gayton, JL, Malhotra, RP, Schaaf, DT, Ng, E, Dunn, SH
Journal of cataract and refractive surgery. 2015;(10):2060-8
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PURPOSE To evaluate the efficacy and safety of phenylephrine 1.0%-ketorolac 0.3% (Omidria) for maintenance of mydriasis during, and reduction of ocular pain after, cataract surgery. SETTING Twenty centers in the United States and the Netherlands. DESIGN Prospective randomized clinical trials. METHODS Patients having cataract surgery or refractive lens exchange were enrolled in 2 clinical trials. Phenylephrine 1.0%-ketorolac 0.3% or placebo was added to irrigation solution and administered intracamerally during the procedure. Integrated analyses of primary and secondary endpoints were conducted. RESULTS The clinical trials comprised 808 patients (403 treatment and 405 placebo). Phenylephrine 1.0%-ketorolac 0.3% was superior to placebo for the maintenance of mydriasis during, and reduction of ocular pain following, cataract surgery. The mean area under the curve (AUC) change from baseline in pupil diameter was 0.08 mm for treatment compared with -0.50 mm for placebo (P < .0001). The mean AUC of ocular pain visual analog scale scores within 12 hours postoperatively was 4.16 mm for the treatment group and 9.06 mm for the placebo group (P < .001). Results of all secondary efficacy analyses demonstrated a significant treatment effect associated with phenylephrine 1.0%-ketorolac 0.3%. Treatment-emergent adverse events were as expected for a population having cataract surgery; no clinically significant differences in safety measures were observed between treatment groups. CONCLUSION In this integrated analysis, phenylephrine 1.0%-ketorolac 0.3% administered intracamerally with irrigation solution during cataract surgery was safe and effective for maintaining mydriasis during the procedure and reducing postoperative ocular pain. FINANCIAL DISCLOSURE Dr. Schaaf is an employee and holds an equity interest in Omeros Corporation. Drs. Hovanesian, Sheppard, Trattler, Gayton, and Ng are consultants to Omeros Corporation. No other author has a financial or proprietary interest in any material or method mentioned.
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A prospective clinical trial on the influence of a triamcinolone/demeclocycline and a calcium hydroxide based temporary cement on pain perception.
Willershausen, B, Willershausen, I, Ehlers, V, Azaripour, A, Briseño, B
Head & face medicine. 2012;:9
Abstract
INTRODUCTION The aim of this clinical trial was to compare the degree of short term post-operative irritation after application of a triamcinolone/demeclocycyline based or a calcium hydroxide based provisional cement. METHODS A total of 109 patients (55 female and 54 male; mean age: 51 ± 14 years) with primary or secondary dentinal caries were randomly assigned to the two treatment groups of this biomedical clinical trial (phase III). Selection criteria were good systemic health and treated teeth, which were vital and showed no symptoms of pulpitis. Up to three teeth were prepared for indirect metallic restorations, and the provisional restorations were cemented with a triamcinolone/demeclocycyline (Ledermix) or a calcium hydroxide (Provicol) based material. The intensity of post-operative pain experienced was documented according to the VAS (4, 12, 20, 24, and 82 h) and compared to VAS baseline. RESULTS A total of 159 teeth were treated (Ledermix: 83 teeth, Provicol: 76 teeth). The minor irritation of the teeth, experienced prior to treatment, was similar in both groups; however, 4 h after treatment this value was significantly higher in the Provicol group than in the Ledermix group (p < 0.005, t-test). After 12 h, the difference was no longer significant. The number of patients taking analgesics for post-treatment pain was higher in the Provicol group (n = 11/53) than in the Ledermix group (n = 3/56). CONCLUSIONS The patients had no long term post-operative pain experience in both groups. However, within the first hours after cementation the sensation of pain was considerably higher in the Provicol group than in the Ledermix group.
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Diclofenac pyrrolidine versus Ketoprofen for the relief of pain from episiotomy: a randomized controlled trial.
Facchinetti, F, Casini, ML, Costabile, L, Malavasi, B, Unfer, V
Acta obstetricia et gynecologica Scandinavica. 2005;(10):951-5
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BACKGROUND The treatment of pain from episiotomy or from tearing of perineal tissues during childbirth is often unapplied, although discomfort may be severe. We performed a randomized double-blind controlled trial to compare the effectiveness and side-effects of two analgesics in the management of postpartum perineal pain. Patient preference toward the two medications was also analyzed. METHODS A total of 261 women were randomly assigned to receive either Diclofenac hydroxyethyl pyrrolidine (100 mg) (n = 133) or Ketoprofen (100 mg) (n = 128), both given orally every 12 hr up to 48 hr, as necessary. Inclusion criteria were vaginal birth with episiotomy and/or a second- to third-degree tear. Pain ratings were recorded before the administration of the drugs and at 1, 4, 12, and 24 hr after the first dose, according to a 10-cm visual-analog scale. Side-effects and overall opinion on the two treatments were assessed at 24 hr. RESULTS Diclofenac hydroxyethyl pyrrolidine and Ketoprofen had similar analgesic properties in the first 24 hr postpartum [mean pain rating 3.1 +/- 1.8 and 3.4 +/- 2.0, mean number of doses in 24 hr 1.4 +/- 1.4 and 1.3 +/- 1.5, and proportion of treatment failures 12.8% (17/133) and 16.4% (21/128), respectively]. Significantly fewer subjects in the Diclofenac hydroxyethyl pyrrolidine group than in the Ketoprofen group experienced side-effects (6.8% versus 15.6%; p = 0.038) with an odd risk = 0.39(95% C.I. 0.16-0.95). There were no significant differences in overall patient satisfaction between the two groups. CONCLUSIONS No main differences were found concerning the relief of pain between the two treatments. Diclofenac hydroxyethyl pyrrolidine may be the preferred choice because it is associated with less adverse reactions, together with a faster action in the relief of pain.
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Intrathecal sufentanil is more potent than intravenous for postoperative analgesia after total-hip replacement.
Fournier, R, Weber, A, Gamulin, Z
Regional anesthesia and pain medicine. 2005;(3):249-54
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BACKGROUND AND OBJECTIVES In our clinical experience, sufentanil is more effective when administered intrathecally than intravenously. To test this hypothesis, we compared the analgesic characteristics of 7.5 microg of intrathecal or intravenous sufentanil for pain relief after total-hip replacement. METHODS A randomized, double-blind study was conducted of 40 patients older than 75 years who experienced total-hip arthroplasty in which continuous spinal anesthesia was administered. In the recovery room, as soon as a pain score higher than 3 on a scale of 10 on a visual analog scale was reported, either 7.5 microg intrathecal or 7.5 microg intravenous sufentanil were given. If the pain score remained higher than 3 at 20 minutes after sufentanil administration,1.25 mg of "rescue" intrathecal bupivacaine were given. RESULTS During the first 20 minutes after intrathecal or intravenous injection, a significantly faster relief of pain was observed for the intrathecal group from 2.5 until 20 minutes. Significantly, more patients needed rescue bupivacaine in the intravenous group (7 of 20 v 0 of 20, P < .008), whereas significantly more patients in the intrathecal group reached a pain score of 0 (20 of 20 v 9 of 20, P < .001). The time to the first analgesic intervention for a pain score greater than 3 was significantly longer in the intrathecal group (224 +/- 100 v 98 +/- 60 minutes, P < .001). Pruritus was observed only in 5 patients of the intrathecal group (P < .047), whereas peripheral oxygen saturation under 95% was observed only in 6 patients in the intravenous group (P < .045). CONCLUSIONS After total-hip replacement, intrathecal route of sufentanil administration rapidly offers excellent analgesia of better quality and longer duration when compared with the intravenous route.
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Intraperitoneal and intravenous routes for pain relief in laparoscopic cholecystectomy.
Jabbour-Khoury, SI, Dabbous, AS, Gerges, FJ, Azar, MS, Ayoub, CM, Khoury, GS
JSLS : Journal of the Society of Laparoendoscopic Surgeons. 2005;(3):316-21
Abstract
BACKGROUND Postoperative abdominal and shoulder pain are the most common complaints after elective laparoscopic cholecystectomy. Postoperative pain is multifactorial in origin, and therefore multimodal therapy may be needed to optimize pain relief. METHODS We conducted a double-blind study where patients were randomly allocated to 1 of 5 groups of 20 patients each. Statistical significance was considered P<0.05. Group 1 received 40 mL bupivacaine 0.25% intraperitoneal spray. Group 2 received 40 mL bupivacaine 0.25% intraperitoneal spray mixed with 200 mg ketoprofen. Group 3 received 40 mL bupivacaine 0.25% intraperitoneal spray and intravenous 200 mg ketoprofen. Group 4 received 200 mg ketoprofen intravenously. Group 5 was the control group. RESULTS Demographic data were similar in the 5 groups. As compared with the control group, group 1 had significantly lower abdominal pain scores at 6 hours; group 2 at 0, 1, 2, and 6 hours; group 3 at 0, 1, 2, 6, 12, and 24 hours; and group 4 at 2 hours. Group 1 had significantly lower shoulder pain scores at 1 and 6 hours; group 2 at 0 and 6 hours; and groups 3 and 4 at 0, 1, and 6 hours. The number of patients requiring postoperative rescue analgesics and the incidence of postoperative vomiting were significantly lower in group 3 only. CONCLUSIONS A multimodal approach to pain management following elective laparoscopic cholecystectomy is best achieved with a combination of 40 mL bupivacaine 0.25% intraperitoneal spray and 200 mg intravenous ketoprofen, achieving the least incidence of postoperative vomiting.
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The preoperative administration of ketoprofen improves analgesia after laparoscopic cholecystectomy in comparison with propacetamol or postoperative ketoprofen.
Boccara, G, Chaumeron, A, Pouzeratte, Y, Mann, C
British journal of anaesthesia. 2005;(3):347-51
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BACKGROUND Non-opioid analgesics, paracetamol and non-steroid anti-inflammatory drugs (NSAIDs) are proposed for pain relief after laparoscopy. We compared perioperative propacetamol (P) and ketoprofen (K) to provide analgesia after laparoscopic cholecystectomy. METHODS After ethical committee approval, we included 104 ASA I-II patients, without preoperative analgesic drugs, who were scheduled to undergo laparoscopic cholecystectomy. Anaesthesia was standardized using propofol, fentanyl, atracurium, isoflurane and N(2)O 50%. Ketoprofen 100 mg or propacetamol 2 g or a saline drip (a 100-ml unit of saline in 10 min) was infused blindly and randomly. Patients received either ketoprofen (group K1) or propacetamol (group P1) before induction of anaesthesia and saline after surgery, or saline before surgery and ketoprofen (group K2) or propacetamol (group P2) after surgery. Postoperative visual analogue pain scores (VAS 0-100 mm) were recorded during 24 h. If VAS was >30, a second dose (placebo, ketoprofen or propacetamol) was infused. Nalbuphine 0.2 mg kg(-1) i.v. was given as rescue analgesic if VAS was > or =50. RESULTS Ninety-eight patients were studied The number of patients not requiring the second analgesic was greater in K1 (33.5%) than the others (K2 0%, P1 0%, P2 7.5%). VAS scores were significantly lower in K1 (P=0.001), with less nalbuphine consumption compared with P1. VAS and opioid request were similar in K2 and P2. CONCLUSION Preoperative administration of ketoprofen improves postoperative analgesia after laparoscopic cholecystectomy compared with its postoperative administration and pre- and postoperative propacetamol.
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Effect of administration of ketorolac and local anaesthetic infiltration for pain relief after laparoscopic-assisted vaginal hysterectomy.
Kim, JH, Lee, YS, Shin, HW, Chang, MS, Park, YC, Kim, WY
The Journal of international medical research. 2005;(4):372-8
Abstract
The efficacy of local anaesthetic infiltration and/or non-steroidal anti-inflammatory drugs for post-operative analgesia following laparoscopic-assisted vaginal hysterectomy (LAVH) was investigated in 83 patients, randomized into four groups in this double-blind, placebo-controlled study: group BK, local infiltration with bupivacaine and pre-incisional intramuscular (IM) ketorolac; group NN, saline local infiltration IM; group BN, local infiltration with bupivacaine and saline IM; group NK, local infiltration with saline and ketorolac IM. Post-operative pain scores were assessed at 1 h, 3 h, 6 h, 12 h and 24 h using a visual analogue scale (VAS). The major pain site, first analgesic request time and incidence of analgesic requests were also recorded. At 1 h, 3 h and 6 h after surgery, group BK patients had significantly lower VAS pain scores than group NN patients. The first analgesic request time was significantly longer in group BK than in groups NN, BN and NK. Pre-incisional treatment with ketorolac IM and local infiltration with bupivacaine reduced post-operative pain after LAVH.
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Double-blind, randomized, placebo-controlled trial comparing rofecoxib with dexketoprofen trometamol in surgical dentistry.
Jackson, ID, Heidemann, BH, Wilson, J, Power, I, Brown, RD
British journal of anaesthesia. 2004;(5):675-80
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BACKGROUND Rofecoxib, a selective cyclooxygenase-2 inhibitor, and dexketoprofen trometamol, a single isomer non-steroidal anti-inflammatory drug (NSAID), are available for the treatment of acute pain. Both are claimed to have fewer adverse effects than traditional NSAIDs. We have compared them in a clinical setting. METHODS We performed a double-blind randomized controlled trial involving 120 patients undergoing surgical removal of a single mandibular third molar at the Edinburgh Dental Institute. Those who developed moderate pain within 4 h of the procedure were allocated to one of three groups: rofecoxib 50 mg (Group RO, n=37); dexketoprofen trometamol 25 mg (Group DE, n=42); or placebo (Group PL, n=41). Participants monitored pain intensity and pain relief for 24 h using visual analogue scales (VAS) and verbal rating scales (VRS). The summed, time-weighted pain relief score to 8 h derived from the VRS (TOTPAR 8) was used as the primary outcome variable. RESULTS No significant difference was demonstrated between Groups RO and DE using TOTPAR 8 as the primary outcome variable. Both drugs were significantly different compared with placebo. Rescue analgesia during the trial period was required by only 15 out of 37 subjects in Group RO, but 35 out of 42 subjects in Group DE. The median times to use of rescue medication were 150 (Group PL), 398 (Group DE) and 1440 min (Group RO). Both drugs were well tolerated and adverse events reported were mild to moderate in severity. CONCLUSIONS Rofecoxib and dexketoprofen trometamol are effective treatments for acute pain using a dental pain model and are well tolerated. Rofecoxib has a longer duration of action as a single dose and gave adequate analgesia for over half of that study group; patients in the dexketoprofen trometamol group needed more rescue analgesia.