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A Novel Pharmacologic Activity of Ketorolac for Therapeutic Benefit in Ovarian Cancer Patients.
Guo, Y, Kenney, SR, Cook, L, Adams, SF, Rutledge, T, Romero, E, Oprea, TI, Sklar, LA, Bedrick, E, Wiggins, CL, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2015;(22):5064-72
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Abstract
PURPOSE We previously identified the R-enantiomer of ketorolac as an inhibitor of the Rho-family GTPases Rac1 and Cdc42. Rac1 and Cdc42 regulate cancer-relevant functions, including cytoskeleton remodeling necessary for tumor cell adhesion and migration. This study investigated whether administration of racemic (R,S) ketorolac after ovarian cancer surgery leads to peritoneal distribution of R-ketorolac, target GTPase inhibition in cells retrieved from the peritoneal cavity, and measureable impact on patient outcomes. EXPERIMENTAL DESIGN Eligible patients had suspected advanced-stage ovarian, fallopian tube or primary peritoneal cancer. Secondary eligibility was met when ovarian cancer was confirmed and optimally debulked, an intraperitoneal port was placed, and there were no contraindications for ketorolac administration. R- and S-ketorolac were measured in serum and peritoneal fluid, and GTPase activity was measured in peritoneal cells. A retrospective study correlated perioperative ketorolac and ovarian cancer-specific survival in ovarian cancer cases. RESULTS Elevated expression and activity of Rac1 and Cdc42 was detected in ovarian cancer patient tissues, confirming target relevance. Ketorolac in peritoneal fluids was enriched in the R-enantiomer and peritoneal cell GTPase activity was inhibited after ketorolac administration when R-ketorolac was at peak levels. After adjusting for age, AJCC stage, completion of chemotherapy, and neoadjuvant therapy, women given perioperative ketorolac had a lower hazard of death (HR, 0.30; 95% confidence interval, 0.11-0.88). CONCLUSIONS Ketorolac has a novel pharmacologic activity conferred by the R-enantiomer and R-ketorolac achieves sufficient levels in the peritoneal cavity to inhibit Rac1 and Cdc42, potentially contributing to the observed survival benefit in women who received ketorolac.
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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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Efficacy of nonsteroidal anti-inflammatory medications for prevention of atrial fibrillation following coronary artery bypass graft surgery.
Cheruku, KK, Ghani, A, Ahmad, F, Pappas, P, Silverman, PR, Zelinger, A, Silver, MA
Preventive cardiology. 2004;(1):13-8
Abstract
This study was designed to test whether nonsteroidal anti-inflammatory medications could reduce the frequency of atrial fibrillation after coronary artery bypass graft surgery. The study was designed as an open-label, randomized trial. Patients undergoing first-time coronary artery bypass graft surgery were considered eligible. Patients with a history of atrial fibrillation, serum creatinine >2.0 mg/dL, on antiarrhythmic treatment, and those undergoing concomitant valvular surgery were excluded. The study was conducted in a single, university-affiliated community hospital. The researchers' role in the study was restricted to randomizing the patients and collecting data. The primary clinical care team made all decisions regarding patient care. One hundred patients were randomized to two groups: one received 30 mg ketorolac intravenously every 6 hours until able to take oral medications, at which point the patients were switched to 600 mg ibuprofen orally three times a day; the other group received conventional treatment. The primary end point of the study was incidence of atrial fibrillation in the immediate postoperative period. Atrial fibrillation occurred in 14 patients (28.6%) in the conventional treatment group vs. five patients (9.8%) in the ibuprofen group (p<0.017). Nonsteroidal anti-inflammatory medications were relatively safe and effective in significantly reducing the incidence of atrial fibrillation after coronary artery bypass graft surgery.
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Quantitative sensory testing and human surgery: effects of analgesic management on postoperative neuroplasticity.
Wilder-Smith, OH, Tassonyi, E, Crul, BJ, Arendt-Nielsen, L
Anesthesiology. 2003;(5):1214-22
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BACKGROUND Altered central nervous system sensory processing (neuroplasticity) is a basic mechanism underlying postoperative pain that can be made visible using quantitative sensory testing. Using quantitative sensory testing, the authors investigated how perioperative analgesia affects postoperative neuroplasticity and how this relates to clinical pain measures. METHODS Patients undergoing back surgery received placebo, fentanyl, or ketorolac (n = 15 per group) before isoflurane-nitrous oxide anesthesia. Preoperatively to 5 days postoperatively, we measured thresholds to electrical skin stimulation at the incision site, arm, and leg; pain scores; and morphine patient-controlled analgesia consumption. RESULTS Decreased pain thresholds versus preoperatively were seen 5 days postoperatively, with decreases greater for ketorolac (-63%; P = 0.00005 vs. preoperatively) than placebo (-45%; P = 0.008 vs. preoperatively) but nonsignificant for fentanyl (-36%; P = 0.9 vs. preoperatively). Mainly nonnociceptive thresholds were increased up to 24 h postoperatively. Postoperative clinical pain measures were similar across drug groups. Postoperative pain tolerance threshold changes did not correlate with preoperative clinical pain measures but were inversely related to preoperative thresholds for placebo and ketorolac but not fentanyl. CONCLUSIONS Without analgesia, neuroplasticity after surgery was inhibitory the first 24 h and followed at 5 days by excitation. Fentanyl efficiently preempted this hyperalgesia, but hyperalgesia was greater with ketorolac than with placebo. Clinical pain measures neither reflected the different effects of ketorolac and fentanyl on postoperative neuroplasticity nor permitted prediction of postoperative neuroplasticity. The information obtained by perioperative quantitative sensory testing is separate from and additional to that from clinical pain measures and may enable more mechanism-based approaches to surgical analgesia management in the future.
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Intra-muscular ketorolac administered as a supplemental analgesic for removal of impacted third molar teeth: a prospective study.
Wright, G, Smith, A
Australian dental journal. 2002;(1):41-4
Abstract
BACKGROUND Post-operative pain follows dentalveolar oral surgery. Ketorolac is a potent non-steroidal analgesic with moderate anti-inflammatory effects. The purpose of this study was to test whether a single supplementary dose of ketorolac reduced post-operative pain experienced by patients having third molar teeth removed. METHODS A prospective double-blind trial utilizing 30mg of ketorolac and a standard anaesthetic and surgical technique was performed on 65 female patients having impacted third molar teeth removed. Assessment was made by means of a patient questionnaire and visual analogue pain scales and subjected to statistical analysis. RESULTS There was a statistically significant difference confirming improved pain relief for patients receiving ketorolac 30mg at the early postoperative stage (two hours) but at later time intervals (four and six hours) there was no significant difference. Seventy two per cent of patients found ketorolac to be a satisfactory analgesic for postoperative pain. There were minimal side effects. CONCLUSION A single supplemental dose of ketorolac 30mg provides improved pain relief in the immediate post-operative phase following the removal of third molar teeth. Oral ketorolac can be recommended as a oral analgesic for post-operative pain, with minimal side effects.
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Preemptive analgesic effects of ketorolac in ankle fracture surgery.
Norman, PH, Daley, MD, Lindsey, RW
Anesthesiology. 2001;(4):599-603
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BACKGROUND Preemptive analgesia has been difficult to show in human experiments. If ketorolac has preemptive effects, then there may be an advantage to administering it at the beginning of surgery despite the potential for increased blood loss. METHODS The authors performed a randomized, double-blind, controlled trial of 48 patients scheduled for ankle fracture surgery in a county trauma hospital. Anesthesia management was standardized and included adequate opioid analgesia (5 microg/kg fentanyl and 0.1 mg/kg morphine). Intravenous 30 mg ketorolac was administered to 23 patients before tourniquet inflation and to 25 patients after tourniquet inflation. Visual analog scale pain scores, morphine patient-controlled analgesia consumption, nausea-vomiting, and postoperative bleeding were measured. RESULTS The 23 patients given ketorolac before tourniquet inflation had no increase in pain postoperatively compared with their preoperative baseline (P = 0.280). The 25 patients who received ketorolac minutes later after tourniquet inflation had significant increases in their postoperative pain compared with their preoperative baseline (P = 0.00116). This effect was short-lived, and by 6 h the pain score in this group was not significantly more than it was preoperatively. Intergroup comparison showed a lower visual analog scale score at 2 (P = 0.0203) and 4 h (P = 0.00549) in the preemptive group and lower nausea scores at hour 6 (P = 0.00704). There was no difference in patient-controlled analgesia consumption between groups. CONCLUSIONS Intravenous 30 mg ketorolac appears to have preemptive analgesic effects in patients undergoing ankle fracture repair. Ketorolac administered before tourniquet inflation prevents postoperative pain being perceived as more intense than preoperative pain.
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Pretreatment with ketorolac and venous occlusion to reduce pain on injection of propofol.
Yull, DN, Barkshire, KF, Dexter, T
Anaesthesia. 2000;(3):284-7
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We performed a randomised, double-blind, prospective trial to discover whether intravenous ketorolac 10 mg made up to 2 ml with saline, with or without venous occlusion for 2 min, reduces the pain on injection of propofol. In 90 patients, pain scores were obtained during injection of propofol following pretreatment of the vein with saline, ketorolac or ketorolac with venous occlusion. Pain on injection of ketorolac was more common than with saline (p = 0.02). The incidence of severe pain following propofol was reduced by ketorolac with venous occlusion (p = 0.019) compared with saline or ketorolac without venous occlusion. There was no difference in venous sequelae at 7 days postoperatively between the groups. Our results suggest that pain on injection of propofol may be related to release of local kininogens and that nonsteroidal anti-inflammatory drugs may have a role in reducing that pain.
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Ketorolac versus meperidine: ED treatment of severe musculoskeletal low back pain.
Veenema, KR, Leahey, N, Schneider, S
The American journal of emergency medicine. 2000;(4):404-7
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Abstract
The study objective was to assess the efficacy and patient acceptance of ketorolac as an alternative to meperidine for the treatment of severe musculoskeletal low back pain (LBP). A double blinded prospective trial in a convenience sample of patients >18 years of age presenting to an urban university hospital emergency department (ED) was conducted over a 19-month period. Patients were included if the pain was musculoskeletal in origin and was severe enough to warrant parenteral analgesics. Patients were randomized to receive 1 mg/kg meperidine intramuscularly (IM) or 60 mg ketorolac IM. Pain intensity was measured preadministration and at 60 minutes via a 100 mm Visual Analog Scale (VAS). Outcomes measured at 60 minutes were pain intensity decrease (PID), patient satisfaction, rescue analgesia requirement, sedation level, and adverse effects. Clinically significant pain reduction was defined as a PID of at least 13 mm or a reduction in pain of least 30%. One hundred fifty-five patients were enrolled (meperidine = 75, ketorolac = 80) and 153 patients completed the study. At 60 minutes the mean PID was 7 mm less in the ketorolac group (95% confidence interval [CI] - 15 mm to 2.6 mm). Pain reduction of at least 30% occurred in 63% of the ketorolac group versus 67% of the meperidine group (95% CI, odds ratio [OR] .43 to 1.61). Rescue analgesia was required in 35% of the ketorolac group versus 37% of the meperidine group (95% CI, OR .47 to 1.74). Patient satisfaction was less in the ketorolac group (ketorolac 68% satisfied versus meperidine 74% satisfied) however this was not significant (95% CI, OR .66 to 2.72). Sedation level and adverse effects were significantly greater in the meperidine group. Ketorolac shows comparable single dose analgesic efficacy to a single moderate dose of meperidine with less sedation and adverse effects in an ED population with severe musculoskeletal LBP. The trend for greater pain reduction and patient satisfaction with meperidine needs further investigation.