Combination paracetamol and ibuprofen for pain relief after oral surgery: a dose ranging study.

PURPOSE: Combined paracetamol and ibuprofen has been shown to be more effective than either constituent alone for acute pain in adults, but the dose-response has not been confirmed. The aim of this study was to define the analgesic dose-response relationship of different potential doses of a fixed dose combination containing paracetamol and ibuprofen after third molar surgery. METHODS: Patients aged 16 to 60 years with moderate or severe pain after the removal of at least two impacted third molars were randomised to receive double-blind study medication as two tablets every 6 h for 24 h of either of the following: two tablet, combination full dose (paracetamol 1000 mg and ibuprofen 300 mg); one tablet, combination half dose (paracetamol 500 mg and ibuprofen 150 mg); half a tablet, combination quarter dose (paracetamol 250 mg and ibuprofen 75 mg); or placebo. The primary outcome measure was the time-adjusted summed pain intensity difference over 24 h (SPID 24) calculated from the 100-mm VAS assessments collected over multiple time points for the study duration. RESULTS: Data from 159 patients were included in the analysis. Mean (SD) time-adjusted SPID over 24 h were full-dose combination 20.1 (18.0), half dose combination 20.4 (20.8), quarter dose combination 19.3 (20.0) and placebo 6.6 (19.8). There was a significant overall effect of dose (p = 0.002) on the primary outcome. Planned pairwise comparisons showed that all combination dose groups were superior to placebo (full dose vs. placebo p = 0.004, half dose vs. placebo p = 0.002, quarter dose vs. placebo p = 0.002). The overall effect of dose was also significant for maximum VAS pain intensity score (p = 0.048), response rate (p = 0.0094), percentage of participants requiring rescue (p = 0.025) and amount of rescue (p < 0.001). No significant dose effect was found for time to peak reduction in VAS or time to meaningful pain relief. The majority of adverse events recorded were of mild (52.75%) or moderate (40.16%) severity and not related (30.7%) or unlikely related (57.5%) to the study medication. CONCLUSION: All doses of the combination provide safe superior pain relief to placebo in adult patients following third molar removal surgery.

A single-center, randomized, double-blind, active, and placebo-controlled study of KAI-1678, a novel PKC-epsilon inhibitor, in the treatment of acute postoperative orthopedic pain.

OBJECTIVE: KAI-1678, a novel inhibitor of the interaction of the epsilon isoform of protein kinase C (εPKC) with its intracellular receptor, has demonstrated activity in countering hyperalgesia in several models of pain. In this controlled randomized trial, KAI-1678 was tested for analgesic activity in an orthopedic acute postoperative pain setting. DESIGN: Following hip or knee replacement surgery, subjects were treated with KAI-1678, ketorolac, or saline. Subjects recorded their pain intensity on a visual analog scale and rated their quality of analgesia. The pain intensity differences between baseline and the evaluations were summed over the first 4 hours. RESULTS: The analysis revealed that, while ketorolac displayed good analgesic activity, KAI-1678 was not significantly different than placebo. Analgesia quality ratings similarly did not show a difference between KAI-1678 and placebo in this pain model. A small excess of infusion site erythema was seen with KAI-1678, but otherwise the drug was safe and well tolerated. CONCLUSIONS: We investigated the safety and efficacy of a novel inhibitor of εPKC and provide clinical evidence that inhibition of εPKC with KAI-1678 is not effective in the treatment of acute postoperative orthopedic pain.

Safety and efficacy of extended-release bupivacaine local anaesthetic in open hernia repair: a randomized controlled trial.

BACKGROUND: Pain relief remains a major problem in hernia surgery. SABER-Bupivacaine is an investigational extended-release formulation of bupivacaine in a resorbable matrix, which may provide up to 72 h of local pain relief. METHODS: A double-blinded, randomized controlled trial was undertaken to evaluate the safety and efficacy of SABER-Bupivacaine. Consented patients (n = 124) undergoing open inguinal hernia repair at five sites in Australia and New Zealand were randomized to receive either 2.5 (330 mg) or 5.0 mL (660 mg) of SABER-Bupivacaine or SABER-Placebo administered to the surgical wound at the end of the procedure. Analgesic efficacy and safety was evaluated. RESULTS: SABER-Bupivacaine appeared safe with no difference in the incidence of side effects compared with SABER-Placebo. The 5.0 mL dose of SABER-Bupivacaine reduced the mean area under the curve of pain intensity on movement compared with SABER-Placebo (2.47 versus 3.60; P = 0.0033) and decreased the number of patients requiring supplemental opioids by 26% (although not statistically significant; P = 0.0909). Normal wound healing was reported throughout the trial and at 3- and 6-month follow-up in every treatment group. CONCLUSION: After open inguinal hernia repair, SABER-Bupivacaine administered at the surgical site was safe and provided pain relief, reduced the need for supplemental (oral and parenteral) analgesia and did not impair wound healing.

Intranasal ketorolac for acute postoperative pain.

BACKGROUND: Efficacy and tolerability of intranasal ketorolac (SPRIX(R)) was assessed in abdominal surgery patients. METHODS: Adult patients were randomly assigned to receive ketorolac 31.5 mg (n = 214) or placebo (n = 107) every 6 hr after surgery for 48 hr, then up to 4 times/day for up to 5 days. Morphine sulfate via patient controlled analgesia was available in both groups as needed. RESULTS: Least square mean 6 hr summed pain intensity difference scores were significantly greater in the ketorolac group indicating better analgesic efficacy compared to placebo (117.4 vs. 89.9, p = 0.032; difference 27.6, 95% CI 2.5-52.7). Pain intensity difference indicated significantly better pain relief in the ketorolac group at 20 min after the first dose (p = 0.01). Morphine use over 48 hr decreased 26% in the ketorolac group compared to placebo (p = 0.004). Day 1 global pain control scores were significantly higher in the ketorolac group compared to placebo (p = 0.009). Quality of analgesia was rated significantly higher (p = 0.009) in the ketorolac group by 20 min after first dose. Adverse event and serious adverse event incidences were similar in both groups. Rhinalgia and nasal irritation, generally mild and transient in nature, occurred more frequently in the ketorolac group. CONCLUSION: Intranasal ketorolac was well tolerated and provided effective pain relief within 20 minutes with reduced opioid analgesia use. While IN ketorolac was assessed in an inpatient, conventional surgery setting in this study, IN ketorolac use may have more relevance for use in outpatient settings and ambulatory surgery or fast-track surgical procedures.

Intranasal ketorolac for postoperative pain: a phase 3, double-blind, randomized study.

OBJECTIVE: Analgesic efficacy and tolerability of intranasal (IN) ketorolac was evaluated in postoperative patients in a randomized, double-blind, placebo-controlled study. METHODS: Patients received IN ketorolac (31.5 mg) [DOSAGE ERROR CORRECTED] or placebo three times daily for up to 5 days, with access to morphine by patient controlled analgesia (PCA). Patients in a single-dose phase were removed from PCA 3 hours prior to the first study dose the day after surgery, and received a single IN ketorolac or placebo dose when visual analog scale scores were > or =40. RESULTS: Three hundred patients (N = 199 ketorolac, N = 101 placebo) were enrolled following primarily hysterectomies (135/300, 45%) and hip replacements (100/300, 33%); 189 (N = 115 ketorolac, N = 74 placebo) entered the single-dose phase. Mean age was 52 years (range 19-81) and 69% of patients were women. The primary efficacy endpoint, the single-dose summed pain intensity difference score at 6 hours, was significantly higher in the ketorolac group compared with placebo (83.3 vs 37.2, P < 0.007), indicating greater pain reduction with ketorolac. Morphine use was reduced by 34% in the ketorolac group compared with the placebo group. The incidence of adverse events ( approximately 98%) was similar in the two groups. The most common adverse events in both groups were nausea and vomiting. There was a trend in the ketorolac group for a lower incidence of opioid-related side effects such as constipation and pruritus. Nasal irritation occurred more frequently with ketorolac vs placebo (24% vs 2%). CONCLUSION: IN ketorolac was well tolerated and effective in treating moderate-to-severe postoperative pain in inpatients; the convenience of IN dosing suggests that its usefulness in the ambulatory care setting should be evaluated.

The safety and analgesic efficacy of intranasal ketorolac in patients with postoperative pain.

BACKGROUND: We evaluated the safety and efficacy of multiple doses of intranasal ketorolac tromethamine (ketorolac) for postoperative pain. METHODS: This was a double-blind, placebo-controlled study in patients undergoing major surgery who were randomized to receive intranasal ketorolac, 10 mg or 31.5 mg, [DOSAGE ERROR CORRECTED]or placebo every 8 h for 40 h. After surgery, patients with pain intensity of at least 40 on a 100-mm visual analog scale were assessed at 30 min and at 1, 2, 3, 4, 5, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 h after receiving the study drug. Patient-controlled i.v. morphine provided supplemental analgesia. RESULTS: Among 127 patients enrolled, morphine use during the first 24 h was significantly less in patients receiving 31.5 mg [DOSAGE ERROR CORRECTED] of ketorolac (37.8 mg) than in the placebo group (56.5 mg) and in the 10-mg ketorolac group (54.3 mg). Over 48 h, the 31.5-mg ketorolac [DOSAGE ERROR CORRECTED] group used significantly less morphine than the placebo group. Summed pain intensity differences at 4 and 6 h significantly favored the 31.5-mg ketorolac [DOSAGE ERROR CORRECTED]group over the other groups. The rates of pyrexia and tachycardia were significantly lower in the ketorolac 31.5-mg [DOSAGE ERROR CORRECTED]group than in the placebo group. Other adverse events were reported with similar frequency in all treatment groups and most were considered unrelated to treatment. CONCLUSION: Thirty milligrams of intranasal ketorolac demonstrated significant analgesic efficacy compared to 10 mg of intranasal ketorolac and placebo.

Predictive value of early IOP in mitomycin-C augmented trabeculectomy.

PURPOSE: To determine whether early intraocular pressure (IOP) after mitomycin-C (MMC) augmented trabeculectomy has any predictive value for intermediate IOP outcome. METHODS: Retrospective case note review. All cases of trabeculectomy using MMC augmentation and at least 1-year follow-up during the study period were included. Cases where a bleb leak occurred were excluded from the analysis. Only first eyes operated upon during the study period were included. Patient demographics and postoperative course were documented and analyzed. Early IOP measurements at day 1, day 7, and month 1 postoperatively were correlated to IOP at 1 year or final follow-up. RESULTS: One hundred nineteen trabeculectomies were identified. Of these 27 (22.7%) had an early bleb leak and were excluded. Further analysis was carried out on the remaining 92 cases. Mean age of cases was 70.8 years. Nine cases (9.8%) were repeat trabeculectomies. Mean follow-up time was 18.5 months (range 12 to 60 mo). Patients with a final IOP of < or =16 mm Hg (without drops or further surgery) (unqualified successes) had a mean day 1 IOP of 12.5 mm Hg compared with 17.4 mm Hg in those with an IOP more than 16 mm Hg at final follow-up (P=0.02). Patients with a final IOP of < or =16 mm Hg (with or without drops) (qualified successes) had mean day 1 IOP of 13.3 mm Hg compared with 17.1 mm Hg in those with an IOP of >16 mm Hg at final follow-up (P=0.06). At 1 month the mean IOPs were 10.7 mm Hg and 19.5 mm Hg, respectively (P<0.001). By logistic regression analysis at final recorded visit those cases in the lowest IOP quartile at 1 month were 14 times more likely to have an IOP < or =16 mm Hg without treatment than those in the highest quartile at 1 month. CONCLUSIONS: Our data suggests that a low early postoperative IOP measurement is a predictive factor for IOP value and success after intermediate length follow-up in patients undergoing trabeculectomy surgery augmented with MMC.