M Zakowski

HOT PLATE VERSUS TAIL FLICK : EVALUATION OF ACUTE TOLERANCE TO CONTINUOUS MORPHINE INFUSION IN THE RAT MODEL

The development of tolerance to continuous morphine infusion (2, 4 and 6 mg x kg(-1) x hr(-1) was assessed in rats using two different methods for evaluation of nociception, tail flick (TF) and hot plate (HP). The influence of repeated testing on nociception was evaluated using two regimens; series 1 was tested repeatedly 1, 2, 4, 6, and 8 hr after initiating the morphine infusion and series 2 was tested only twice, at maximum morphine effect and at 8 hr. Both, TF and HP showed pain threshold elevation after the morphine administration of 4 or 6 mg x kg(-1) x hr(-1), which reached a maximum at 2 hr after the start of the infusion. HP: reduction of the effect was found in group 4 mg x kg(-1) x hr(-1) in the series subjected to repeated testing; group 6 mg x kg(-1) x hr(-1) showed reduced effect in both sides. TF: the response latencies did not show reduction at 8 hr. Since TF is predominantly a spinal response and HP is predominantly supraspinal, the results suggest that tolerance during the first 8 hr of morphine infusion develops mainly at supraspinal level.

Wound infiltration with liposomal bupivacaine prolongs analgesia in rats

Background:Wound infiltration with local anesthetics does not reliably produce satisfactory postoperative analgesia, and the dose of local anesthetic which may be safely administered is limited by the potential for systemic toxicity. This study evaluated the efficacy of a slow‐release liposomal bupivacaine formulation on duration of wound analgesia.

Hemodynamic effects of intrathecal fentanyl in nonlaboring term parturients

STUDY OBJECTIVE To determine the effect of intrathecal fentanyl on maternal hemodynamics. DESIGN Prospective. SETTING Labor and delivery suite of a university medical center. PATIENTS 23 ASA status I nonlaboring term parturients presenting for elective cesarean section. INTERVENTIONS Patients were given either 1,200 ml lactated Ringers Solution (Group 1, n = 12) or no intravenous (i.v.) fluid (Group 2, n = 11). A combined spinal-epidural technique was then performed. Fentanyl 25 micrograms was administered intrathecally through a 24-gauge Sprotte or 25-gauge Whitacre spinal needle. After completion of the hemodynamic study, a catheter was threaded into the epidural space for local anesthetic administration. MEASUREMENTS AND MAIN RESULTS Baseline hemodynamic data [systolic (SBP), diastolic, and mean arterial pressure, heart rate, stroke volume, cardiac output, end-diastolic volume, and ejection fraction] were obtained in triplicate using noninvasive blood pressure monitoring and impedance cardiography. After administration of intrathecal fentanyl, hemodynamic measurements were recorded at 3-minute intervals for 30 minutes. These values were compared with baseline for both groups. Ten patients in each group completed the study. Intrathecal fentanyl administration did not result in any maternal hemodynamic changes in Group 1, and a few small statistically significant changes in Group 2. Measured SBP was always greater than 100 mmHg in all patients during the study. CONCLUSION Intrathecal administration of fentanyl 25 micrograms in nonlaboring term parturients does not produce clinically important maternal hemodynamic changes.

Assessing local anesthetic effect using the mouse tail flick test

We used the tail flick test to quantify duration of local anesthetic-induced conduction block in the mouse. Using a baseline tail flick latency (TFL) between 1.0 and 2.5 sec, sensory block was considered present if TFL was > or = 4 sec. Two 20-microL local anesthetic injections were made on opposite sides of the tail base. TFL was tested every 10 min, and local block duration was interpreted as the time to return of TFL to < 4 sec. We tested three different concentrations of procaine (1%, 2%, and 4%), tetracaine (0.125%, 0.5%, and 1%), and lidocaine (0.5%, 1%, and 2%) with and without epinephrine. The testing method could discriminate between the duration of the various local anesthetic concentrations used. For the 1% concentrations, the duration of sensory block was 2 +/- 4 min (S.D.) for procaine, 20 +/- 10 min for lidocaine, 40 +/- 10 min for tetracaine, and 66 +/- 15 min for lidocaine with epinephrine. We found this to be a simple and reliable means of assessing local anesthetic conduction block in the mouse.

Prolongation of Spinal Anesthesia Differential Action of a Lipid Drug Carrier on Tetracaine, Lidocaine, and Procaine

This study evaluates prolongation of spinal anesthesia by incorporating local anesthetics in lipid formulation. The duration and intensity of local anesthetic effect produced by different concentrations of procaine (1%, 2%, 4%), lidocaine (1%, 2%, 4%), or tetracaine (0.5%, 1%, 2%) dissolved in normal saline were compared to those produced by the same concentration of drugs in lipid (iophendylate) solution. Fifty rabbits with chronic indwelling subarachnoid catheters were divided into ten equal groups. Three days after the operation the catheters were injected with aqueous solutions of the anesthetics, and 24 h later each animal received an equivalent dose of the corresponding drug in free-base form dissolved in iophendylate. The duration and intensity of motor blockade were assessed using a modified Bromage scale. A separate group of animals received plain normal saline and, 24 h later, iophendylate alone. The Kruskal-Wallis test followed by the Tukey-type test for nonparametric multiple comparisons and the Mann-Whitney and Friedman tests were used for statistical analysis at P less than 0.05. Normal saline or iophendylate alone did not produce any motor blockade. Our data show that iophendylate preparations of local anesthetics produce prolonged but less intense motor blockade than the aqueous solutions, except for tetracaine 0.5% in iophendylate, which produced shorter duration of motor blockade. The reduced intensity of motor blockade may be explained by decreased availability of local anesthetic at the nerve tissue due to storage of drug in the lipid depot. The increased duration of blockade signifies a sustained release of drug from the depot.

A two‐dose epidural morphine regimen in cesarean section patients: pharmacokinetic profile

The maternal pharmacokinetics, metabolism of, and possible neonatal transmission of epidural morphine in cesarean section patients were investigated. Maternal plasma, breast milk, and maternal and neonatal urine concentrations of unconjugated and conjugated (UM and CM) morphine were measured in patients given two 5‐mg doses of epidural morphine for post‐cesarean section analgesia. The first dose was administered after delivery and the second dose 24 h later. Maternal venous blood samples (n = 10) were collected at times 0, 0.25, 0.5, 1, 2, 3, 4, 6, 12, and 24 h after each dose, and maternal urine was collected for three consecutive 24‐h periods (n = 30). Maternal breast milk (n = 30), and neonatal urine samples (n = 20) were also collected. Serum, urine, and breast milk UM and CM levels were measured using radioimmunoassay. Pharmacokinetic values were calculated using noncompartmental analysis. The results were expressed as mean ± 1 s.e. mean and analyzed using repeated measures analysis of variance and the paired t‐test. Maternal serum UM remained 40–50% higher, and CM 50–100% higher in the first hour following dose 2 than the respective values after dose 1 (P < 0.05). Values for AUC, AUMC, Tl/2, and MRT increased 28%, 83%, 35% and 36%, respectively, with the second dose (P < 0.05), while CI decreased 19% (P < 0.05) with no significant difference in Vss. Total urinary excretion of morphine decreased significantly from 1.98 ± 0.15 mg on day 1 to 1.6 ± 0.2 mg and 0.19 ± 0.002 mg on days 2 and 3, respectively (P < 0.01). Breast milk and neonatal urine contained negligible amounts of morphine, signifying minimal neonatal transfer.

A two-dose epidural morphine regimen for cesarean section patients: therapeutic efficacy

A single dose of epidural morphine (EM) usually produces 24 h of post‐cesarean section (CS) analgesia and patients require supplemental analgesics beyond this period. This study assesses if a second dose of EM administered 24 h after the first one offers superior therapeutic efficacy compared to conventional analgesics. Patients (n = 100) were randomized to receive one or two doses of epidural morphine. In all patients, EM 5 mg was administered after delivery. After 24 h patients received epidurally either normal saline (n = 50, Group 1) or morphine 5 mg (n = 50, Group 2). An independent observer used a visual analogue scale to assess nausea, itching, and analgesia 24 h after each injection. Results were expressed as mean ± 1 s.e. mean and analyzed using nonparametric methods. The second dose of EM produced a significantly lower incidence and severity of nausea and itching than did the first dose (P<0.01) in Group 2 with no difference in analgesia. The second day postoperative pain score in Group 1 was significantly greater than the first day score in the same group, and significantly greater than the severity score in Group 2. Only 36% of patients receiving two doses of EM required supplemental analgesics beyond 48 h compared to 76% of those receiving one dose (P<0.01). No serious complications were noted. In summary, the use of a second dose of EM for post‐CS analgesia produces better analgesia and reduces the need for oral analgesics. The second dose produced fewer side‐effects, probably due to acute tolerance to morphine.