Intranasal Ketorolac as Part of a Multimodal Approach to Postoperative Pain

Despite recent advances in the knowledge of pain mechanisms and pain management, postoperative pain continues to be a problem. Inadequately managed postsurgical pain has both clinical and economic consequences such as longer recovery times, delayed ambulation, higher incidence of complications, increased length of hospital stay, and potential to develop into chronic pain. Generally, opioids are the mainstay option for pain management in patients with moderate‐to‐severe postsurgical pain; however, opioids have significant side effects and have abuse potential. To improve patient and economic outcomes after surgery, postoperative pain guidelines have suggested incorporating a multi‐modal/multi‐mechanistic approach to pain treatment. A multi‐modal approach is the simultaneous use of a combination of two or more (usually opioid and non‐opioid) analgesics that provide two different mechanisms of actions. Utilizing a multi‐modal approach may result in a greater reduction in pain vs. single therapies in addition to minimizing opioid use, thus reducing opioid related side effects. However, not all approaches may be effective for all types of patients and not all analgesics may be a viable option for outpatient settings, ambulatory surgery, or the fast‐track surgical procedures. In this report, we present a review of the literature with a focus on intranasal ketorolac in order to provide a timely update regarding past, present, and future multi‐modal treatment options for postoperative pain.     

Preparation and evaluation of ketorolac tromethamine gel containing genipin for periodontal diseases

Ketorolac tromethamine gel (KT gel) and ketorolac tromethamine gel containing genipin (KTG gel) were prepared and their therapeutic effects on periodontitis were evaluated. The skin permeation rate of ketorolac from the KT gel and KTG gel was 5.75+/-0.53 and 5.82 +/- 0.74 microg/cm2/ h, respectively. The skin permeation rate of genipin from the KTG gel was 10.13 +/- 1.47 microg/ cm2/h. The tensile strength of the KTG gel was larger than the KT gel. After 4 weeks, the periodontal pocket depth of the KTG gel group (3.22 +/- 0.20 mm) significantly decreased compared with the non-treated group (4.50 +/- 0.25 mm) and the KT group (3.84 +/- 00.26 mm). The KTG gel did not induce separation of the stratum corneum and subcutaneous tissue, and the collagen layers of the corium were closer, more fibrous, and showed longer connections than in the other groups. The KTG gel appears to be effective against gingivitis in the periodontal pocket through its increased anti-inflammatory activity and the crosslinking of genipin with the biological tissue.     

Evaluation of ketorolac tromethamine microspheres by chitosan/gelatin B complex coacervation

Microspheres (MS) of Ketorolac Tromethamine (KT) for oral delivery were prepared by complex coacervation (method-1) and simple coacervation (method-2) methods without the use of chemical crossalinking agent (glutaraldehyde) to avoid the toxic reactions and other undesirable effects of the chemical cross-linking agents. Alternatively, ionotropic gelation was employed by using sodium-tripolyphosphate (Na-TPP) as cross linking agent. Chitosan and gelatin B were used as polymer and copolymer respectively. All the prepared microspheres were subjected to various physico-chemical studies, such as drug-polymer compatibility by Thin Layer Chromatography (TLC) and Fourier Transform Infra Red Spectroscopy (FTIR), surface morphology by Scanning Electron Microscopy (SEM), frequency distribution, encapsulation efficiency, in-vitro drug release characteristics and release kinetics. The physical state of drug in the microspheres was determined by Differential Scanning Calorimetry (DSC) and X-ray powder Diffractometry (XRD). TLC and FTIR studies indicated no drug-polymer incompatibility. All the MS showed release of drug by a fickian diffusion mechanism. DSC and XRD analysis indicated that the KT trapped in the microspheres existed in an amorphous or disordered-crystalline status in the polymer matrix. It is possible to design a controlled drug delivery system for the prolonged release of KT, improving therapy by possible reduction of time intervals between administrations.     

卡前列素氨丁三醇治疗产后出血的临床观察与护理

目的探讨卡前列素氨丁三醇（欣母沛）治疗产后出血的临床效果与护理措施。方法 95例产后出血患者随机分为观察组50例和对照组45例。对照组给予卡孕栓治疗,观察组给予欣母沛治疗,观察2组治疗前与治疗后30min出血量变化情况与临床疗效。结果观察组总有效率为96.0%高于对照组的86.7%,差异有统计学意义（P〈0.05）。2组用药30min后剖宫产产妇与阴道分娩产妇出血量均较治疗前减少,且观察组改善情况优于对照组,差异均有统计学意义（P〈0.05）。结论欣母沛治疗产后出血安全有效,临床应用时应综合考虑患者的情况,给予合理的治疗和护理措施。     

Methylprednisolone and ketorolac rapidly reduce hyperalgesia around a skin burn injury and increase pressure pain thresholds

BACKGROUND: Glucocorticoids and non-steroidal anti-inflammatory drugs (NSAIDs) decrease acute postoperative pain and hyperalgesia. The objectives of this study were to investigate the effects of methylprednisolone and ketorolac on hyperalgesia around a skin burn injury and on pressure pain thresholds. METHODS: In a double-blind, placebo-controlled, randomized trial with cross-over design, methylprednisolone 125 mg, ketorolac 60 mg or placebo was administered intravenously in 12 male volunteers on three separate days at least 4 days apart. Primary and secondary hyperalgesia were produced by a first-degree burn injury on abdominal skin 45 min before injection of the test medicines. The area of secondary mechanical hyperalgesia outside the site of injury was measured. Pressure pain stimuli were applied on the base of a fingernail, increasing until the pressure pain detection threshold (PPDT) and pressure pain tolerance threshold (PPTT) were reached. RESULTS: Compared with placebo, the active drugs reduced the area of secondary hyperalgesia (methylprednisolone, P < 0.001; ketorolac, P < 0.01). Ketorolac but not methylprednisolone increased PPDT compared with placebo (P < 0.05). Both active drugs increased PPTT compared with placebo (methylprednisolone, P < 0.01; ketorolac, P < 0.001). Ketorolac increased PPTT more than methylprednisolone (P < 0.05). CONCLUSIONS: Methylprednisolone and ketorolac increased PPTT attenuated secondary hyperalgesia around a skin burn injury. PPTT increased after both methylprednisolone and ketorolac. The present study demonstrates analgesic and anti-hyperalgesic properties of a glucocorticoid and a non-selective NSAID that have not been demonstrated previously in human subjects.     

Protective effect of intrathecal ketorolac in spinal cord ischemia in rats: a microdialysis study

BACKGROUND: The prevention of ischemic paraplegia after thoracoabdominal aortic surgery is challenging for both anesthesiologists and surgeons. In a previous study, we showed that intrathecal ketorolac pre-treatment protects rats against ischemic spinal cord injury. In the present study, using a microdialysis method, we investigated whether this neuroprotective effect was related to changes in the spinal cord release of nitric oxide (NO) or the excitatory amino acids (EAAs) aspartate and glutamate. METHODS: Rats were randomized to receive either intrathecal saline or ketorolac 60 microg (10 rats per group), 1 h before spinal cord ischemic injury induced by balloon inflation of a 2F Fogarty catheter in the thoracic aorta with maintenance of the proximal arterial blood pressure at 40 mmHg for 11 min, followed by reperfusion. Another 10 animals were used as the sham-operated control group. Ischemic injury was assessed by hind limb motor function. Cerebrospinal fluid dialysates were collected at baseline (before ischemia) and at 1, 2, 3, 4, 6, 12 and 24 h after the start of reperfusion, and were analyzed for EAAs using high-performance liquid chromatography and for NO metabolites using an NO analyzer. RESULTS: The results showed that intrathecal ketorolac attenuated spinal cord ischemic injury. Dialysate concentrations of NO and EAAs were increased after spinal cord ischemia, and this effect was inhibited by intrathecal administration of ketorolac. CONCLUSIONS: The results of this study suggest that the neuroprotective effect of intrathecal ketorolac in spinal cord ischemia in rats may be caused by a decrease in the spinal cord release of NO and EAAs.     

卡前列素氨丁三醇在剖宫产术中使用时机及药物经济性探讨

目的:回顾性分析卡前列素氨丁三醇在剖宫产术中使用时机,评价其使用价值。方法:在该产科剖宫产使用卡前列素氨丁三醇治疗156例病人,部分预防性使用,部分经徒手按摩子宫,追加催产素20～40U注射后子宫收缩仍然不良时,宫体注射卡前列素氨丁三醇。重复使用时,间隔时间大于15min。结果:卡前列素氨丁三醇注射后子宫变硬,出血减少,86%的病人在接受注射1针(250μg)情况下有效,96%的病人在用量为250μg或500μg时有效。不良反应颜面潮红、恶心、呕吐,症状轻微。结论:卡前列素氨丁三醇治疗剖宫产术中出血,适时使用,疗效迅速且不良反应少,且药费比输等量血费用更低,同时减少失血对患者身体的损害及输血风险,可作为产科急救用药或预防性用药。     

Comparative effects of intravenous ketorolac and pethidine on perioperative analgesia and postoperative nausea and vomiting (PONV) for paediatric strabismus surgery

BACKGROUND: Corrective strabismus surgery is associated with moderate pain and a very high incidence of postoperative nausea and vomiting (PONV). Ketorolac tromethamine, a nonsteroidal anti-inflammatory drug, is a popular analgesic in adults. There are only limited published data on the use of intravenous ketorolac for paediatric analgesia perioperatively. This study evaluated and compared the emetic and analgesic effect of ketorolac with pethidine and its suitability for this kind of surgery. METHODS: Following institutional ethics committee approval and parental consent, 52 ASA class I children of age 2.5 to 15 yr were randomised to receive either ketorolac 0.9 mg kg-1 or pethidine 0.5 mg kg-1 given intravenously (i.v.). A blinded observer assessed recovery by Steward's method immediately after arrival at the post anaesthesia care unit (PACU), pain by validated Objective Pain Score (OPS) at 0 h, 1/2 h and 1 h after arrival at the PACU and PONV by Numeric Rank Score at specified time intervals. RESULTS: There were no differences in demographic data, anaesthesia time or surgery duration. Recovery scores, OPS and postoperative analgesic requirement were similar in both groups. PONV at various time intervals for the first 24 h, occurred more frequently in the pethidine group as compared to the ketorolac group (P < 0.001) There were no side effects observed with either drug. CONCLUSION: Ketorolac in a dose of 0.9 mg kg-1 i.v. at the induction of anaesthesia is as effective as pethidine 0.5 mg kg-1 i.v. as an analgesic and is associated with significantly less PONV.     

Postoperative Pain After Lumbar Disc Surgery: A Comparison Between Parenteral Ketorolac and Narcotics

Summary  Objective. Lumbar discectomy is a common elective surgical procedure but many patients still experience postoperative back pain which may delay hospital discharge. We therefore evaluated the efficacy of a parenteral non-steroidal antiinflammatory agent, ketorolac, for the management of post-surgical pain.  Methods. Fifty three patients undergoing lumbar discectomy at a Medical School affiliated Veterans Administration hospital were randomly assigned to receive either: 1) 30 mg intramuscular ketorolac upon surgical closure and every 6 hours for 36 hours and narcotic analgesics as needed (PRN); or 2) only narcotic analgesics as needed. A blinded observer recorded the average, minimum and maximum postoperative pain intensity using a Numeric Pain Intensity Scale; total postoperative narcotic consumption, complications, length of hospitalization (from surgery to discharge) and outcome at 6 weeks.  Results. The patients who received ketorolac reported significantly lower average (p<0.001), minimum (p<0.001), and maximum (p<0.001) pain scores than patients receiving only narcotic analgesics. Cumulative narcotic doses (standardized to parenteral morphine) were significantly lower in the ketorolac group (p< 0.001). There was no significant difference between groups in the frequency of side effects, and no complication specifically associated with ketorolac use was observed. Mean length of hospitalization was significantly shorter (p=0.05) in patients receiving ketorolac than in patients receiving only narcotics. Six weeks after surgery 5 (19.2%) patients who received only narcotics were troubled by persistent back pain. By contrast, all patients who received ketorolac were free of back pain at follow-up (p=0.03).  Conclusions. These results suggest that ketorolac, when used with PRN narcotics, is more effective than PRN narcotics alone for postoperative pain following lumbar disc surgery. In addition, this strategy also may contribute to early discharge from hospital after lumbar disc surgery.