EMLA anaesthetic cream for debridement of burns: a study of plasma concentrations of lidocaine and prilocaine and a review of the literature.

The lidocaine-prilocaine cream (EMLATM) effectively reduces the pain from debridement of chronic leg ulcers. Studies have demonstrated that when applied to leg ulcers, plasma concentrations of the local anaesthetics are well below the threshold for CNS toxicity. However, there are minimal pharmacokinetic data available from EMLA application to burn wounds. This study evaluated EMLA cream for debridement of burns with regard to plasma concentrations of lidocaine and prilocaine, and reviewed the published literature on safety and efficacy of lidocaine-prilocaine applied epicutaneously to burns. Eight patients aged 22-59 received 5 g of EMLA 5% cream applied to 25 cm2 large 2nd degree burn areas for 30 min. Venous blood samples drawn at set intervals up to 120 min after cream application were analyzed for total plasma concentrations of lidocaine and prilocaine. Pain from debridement was assessed on a 4-point verbal scale and a 100-mm visual analog scale (VAS) with the end points "no pain" and "severe pain". A literature search on the use of lidocaine-prilocaine cream on burn wounds was performed in PubMed. The results showed that six patients felt no pain and two patients mild pain. The median VAS score was 11 (range 2-59). Peak plasma concentrations of lidocaine (mean 205 ng/ml) and prilocaine (mean 97 ng/ml) were observed after 15-60 min. Two published studies and two case reports of overdose of lidocaine-prilocaine cream applied to burns in paediatric patients were retrieved. Peak plasma concentrations of lidocaine and prilocaine combined after application of 5 g EMLA to burns 25 cm2 large for 30 min in adults are far below those associated with toxicity. Bioavailability estimation suggests 5 to 30% of the prilocaine dose applied to burns is percutaneously absorbed. The analgesic efficacy appears satisfactory for debridement of 2nd degree burns.

Population Pharmacokinetic Analysis of Zolmitriptan and Its Metabolite in Adults and Adolescents to Support Dose Selection in Children With Migraine.

Zolmitriptan is a serotonin (5-HT) 1B/1D receptor agonist effective for the treatment of migraine. This analysis aimed to develop a population pharmacokinetic (PK) model for zolmitriptan and its active metabolite in adults and adolescents and provide appropriate dosing regimens to be used in clinical trials for children 6-11 years old. The data from a single-dose clinical study of 5.0-mg zolmitriptan nasal spray (ZNS) conducted in adult and adolescent patients with migraine between migraine attacks was applied. Similar plasma concentration profiles of zolmitriptan and its metabolite, 183C91, were observed in adults and adolescents. A 1-compartment model with first-order absorption and first-order elimination reasonably described the zolmitriptan PK. With a portion of elimination of zolmitriptan being treated as the conversion from zolmitriptan to 183C91, the disposition of 183C91 was described by a 1-compartment model with first-order elimination. The estimated typical apparent volume of distribution and clearance of zolmitriptan were 136 L and 121 L/h, respectively, with 56.5% and 42.6% between-subject variability, respectively. Based on the simulation results with the final population PK model, a body weight-based dosing scheme of 5.0 and 2.5 mg ZNS in children greater than and less than 50 kg is recommended to achieve exposures similar to those of the adult and adolescent population administered 5.0 mg ZNS. The recommended doses for children to achieve exposure similar to that observed in adults given 2.5 mg ZNS are 2.5 mg (≥50 kg) and 1.0 mg (15-50 kg). These dosing regimens could be used in future clinical trials.

Efficacy and tolerability of zolmitriptan nasal spray for the treatment of acute migraine in adolescents: Results of a randomized, double-blind, multi-center, parallel-group study (TEENZ).

OBJECTIVE: The primary objective of the TEENZ Study (NCT01211145) was to assess the efficacy of zolmitriptan nasal spray in the acute treatment of adolescent migraine patients (ages 12 to 17 years), as measured by the primary outcome variable of pain-free status at 2 hours post-treatment. METHODS: This randomized, double-blind, placebo-controlled, four-arm parallel group study compared zolmitriptan nasal spray with placebo in the treatment of a single episode of adolescent migraine. Patients completed a 30-day run-in period to treat a single migraine attack with single-blind placebo nasal spray. Eligible patients, who had not responded to placebo, were randomized to one of three zolmitriptan nasal spray doses (5, 2.5, or 0.5 mg) or placebo in a ratio of 5:3:3:5 according to a computer-generated randomization scheme. Patients completed diaries for 24 hours after treatment, recording headache pain scores, adverse events (AEs), and medications taken. RESULTS: In an interim futility analysis, zolmitriptan nasal spray doses of 0.5 and 2.5 mg were declared futile relative to placebo and further randomization to these treatment arms was discontinued. Of 1653 patients enrolled into the study, 855 patients failed to meet study eligibility criteria and were considered screen failures. The most common reason for screen failure was response to placebo challenge (325 patients [38.0%]). Of the 798 patients who were randomized to treatment, 721 (90.4%) completed the study period. Of these, 657 (82.3%) treated a migraine within the study period and contributed data for analysis. Zolmitriptan nasal spray 5 mg was significantly more effective than placebo in achieving pain-free status at 2 hours after treatment (P < .001), with 30% of patients achieving pain-free status at 2 hours vs 17% of placebo-treated patients (OR 2.18; 95% CI 1.40, 3.39). Zolmitriptan nasal spray 5 mg was also more effective than placebo in achieving pain-free status at 3 and 4 hours post-treatment (45 vs 24%, and 56 vs 39%; both P < .001). Zolmitriptan nasal spray 5 mg was also more effective than placebo in achieving headache response at 2, 3, and 4 hours after treatment (51 vs 39%, 61 vs 48%, and 69 vs 57%, respectively; all P ≤ .011). Zolmitriptan nasal spray was well-tolerated at all doses. Dysgeusia was the most frequently reported AE, with greater frequencies reported in active treatment groups versus placebo. No serious AEs or AEs leading to discontinuation were reported. Most AEs were mild or moderate in severity, and consistent with the known profile of zolmitriptan in adult and adolescent populations. CONCLUSION: Zolmitriptan nasal spray was well-tolerated in the acute treatment of adolescent (ages 12 to 17 years) migraine. Zolmitriptan 5 mg nasal spray demonstrated superior efficacy compared with placebo for the primary efficacy endpoint of pain-free status 2 hours after treatment and the efficacy of the 5 mg dose was supported by the majority of secondary efficacy endpoints.

Ropivacaine for continuous wound infusion for postoperative pain management: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The use of continuous wound infusion (CWI) of local anaesthetics has been suggested as a safe and effective alternative technique to epidural anaesthesia/analgesia that allows surgeons to provide postoperative pain relief while reducing opioid consumption and associated adverse events. A previous meta-analysis by Liu et al. [Am Coll Surg 2006;203:914-932] reported results mainly from studies of bupivacaine. Subsequently, several new randomized controlled trials (RCTs) of ropivacaine have been published. This systematic review and quantitative meta-analysis evaluates the efficacy of ropivacaine for CWI. METHODS: Systematic literature searches (EMBASE, MEDLINE) were performed to retrieve studies which met the following criteria: double-blind RCT of ropivacaine versus either placebo or an active comparator; use of ropivacaine solution without added active agents, and prohibition of other routine analgesics during the study period except rescue patient-controlled analgesia. For each included study, standardized effect sizes for ropivacaine versus placebo were calculated for opioid rescue use, pain score at rest, and pain score at mobilization. Meta-analyses were conducted for each endpoint. RESULTS: Fourteen RCTs comparing ropivacaine (n = 376) versus placebo (n = 380) were identified. Effect size estimates revealed significantly less opioid rescue use for ropivacaine patients (-1.3; 95% CI -1.5 to -1.1) and significantly less pain for ropivacaine patients both at rest (-1.1; 95% CI -1.3 to -0.9) and on mobilization (-1.5; 95% CI -1.7 to -1.3). The weighted mean reduction in opioid rescue use was 22.4 mg. CONCLUSION: This systematic review and meta-analysis presents substantial evidence that ropivacaine provides clinically meaningful reductions in opioid use and pain outcomes. Ropivacaine CWI is effective for postoperative pain management in a wide range of surgical procedures.