Morphine tolerance increases [3H]MK-801 binding affinity and constitutive neuronal nitric oxide synthase expression in rat spinal cord

N-Methyl-D-aspartate (NMDA) receptor antagonists and nitricoxide synthase (NOS) inhibitors inhibit morphine tolerance.In the present study, a lumbar subarachnoid polyethylene (PE₁₀)catheter was implanted for drug administration to study alterationsin NMDA receptor activity and NOS protein expression in a morphine-tolerantrat spinal model. Antinociceptive tolerance was induced by intrathecal(i.t.) morphine infusion (10 µg h^–1) for 5 days.Co-administered (+)-5-methyl-10,11-dihydro-⁵H-dibenzo[a,d]cyclohepten-5,10-iminemaleate (MK-801) (10 µg h^–1 i.t.) with morphinewas used to inhibit the development of morphine tolerance. Lumbarspinal cord segments were removed and prepared for [³H]MK-801binding assays and NOS western blotting. The binding affinityof [³H]MK-801 was higher in spinal cords of morphine-tolerantrats (mean (SEM) K_D=0.41 (0.09) nM) than in control rats (1.50(0.13) nM). There was no difference in B_max. Western blot analysisshowed that constitutive expression of neuronal NOS (nNOS) proteinin the morphine-tolerant group was twice that in the controlgroup. This up-regulation was partially prevented by MK-801.The results suggest that morphine tolerance affects NMDA receptorbinding activity and increases nNOS expression in the rat spinalcord. Br J Anaesth 2000; 85: 587–91 ^* Corresponding author     

Comparison of intrathecal magnesium, fentanyl, or placebo combined with bupivacaine 0.5% for parturients undergoing elective cesarean delivery

Background: Intrathecal (i.t.) administration of magnesium has been reported to potentiate opioid antinociception in rats and humans. In this prospective, randomized, double-blind, study, we investigated the sensory, motor, and analgesic block characteristics of i.t. magnesium 50 mg compared with fentanyl 25 μg and saline when added to 0.5% bupivacaine (10 mg).
Methods: Ninety ASA I or II adult patients undergoing cesarean section were randomly allocated to receive 1.0 ml of 0.9% sodium chloride in group S, 50 mg of magnesium sulfate (1.0 ml) 5% in group M, or 25 μg of fentanyl (1.0 ml) in group F following 10 mg of bupivacaine 0.5% i.t. We recorded the following: onset and duration of sensory and motor block, maximal sensory block height, the time to reach the maximal dermatomal level of sensory block, and the duration of spinal anesthesia.
Results: Magnesium did not shorten the onset time of sensory and motor blockade or prolong the duration of spinal anesthesia. The duration of sensory ( P <0.032) and motor ( P <0.002) blockade was significantly shorter in M and S groups than in the F group. The time to reach the maximal dermatomal level of sensory block was significantly shorter in the F group than in the S and M groups ( P <0.002).
Conclusion: In patients undergoing cesarean section with spinal anesthesia, the addition of magnesium sulfate (50 mg) i.t. to 10 mg of spinal bupivacaine (0.5%) did not shorten the onset time of sensory and motor blockade or prolong the duration of spinal anesthesia, as seen with fentanyl.     

Dextromethorphan potentiates morphine antinociception at the spinal level in rats

PURPOSE: Morphine is an effective analgesic, but adverse effects limit its clinical use in higher doses. The non-opioid antitussive, dextromethorphan (DM), can potentiate the analgesic effect of morphine and decrease the dose of morphine in acute postoperative pain, but the underlying mechanism remains unclear. We previously observed that DM increases the serum concentration of morphine in rats. Therefore, we investigated the effects of drugs administered at the spinal level to exclude possible pharmacokinetic interactions. As DM has widespread binding sites in the central nervous system [such as N-methyl-D-aspartate (NMDA) receptors, sigma receptors and alpha(3)ss(4) nicotinic receptors], we investigated whether the potentiation of morphine antinociception by DM at the spinal level is related to NMDA receptors. METHODS: We used MK-801 as a tool to block the NMDA channel first, and then studied the interaction between intrathecal (i.t.) morphine and DM. The tail-flick test was used to examine the antinociceptive effects of different combinations of morphine and other drugs in rats. RESULTS: DM (2-20 microg) or MK-801 (5-15 microg) showed no significant antinociceptive effect by themselves. The antinociceptive effect of morphine (0.5 microg, i.t.) was significantly enhanced by DM and reached the maximal potentiation (43.7%-50.4%) at doses of 2 to 10 microg. Pretreatment with MK-801 (5 or 10 microg, i.t.) significantly potentiated morphine antinociception by 49.9% or 38.7%, respectively. When rats were pretreated with MK-801, DM could not further enhance morphine antinociception (45.7% vs 50.5% and 43.3%). CONCLUSION: Our results suggest that spinal NMDA receptors play an important role in the effect of DM to potentiate morphine antinociception.     

Concurrent Spinal Infusion of MK801 Blocks Spinal Tolerance and Dependence Induced by Chronic Intrathecal Morphine in the Rat

Background: MK801, an N-methyl-D-aspartate receptor antagonist, has recently been reported to attenuate tolerance to, and withdrawal from morphine. This study analyzes tolerance and withdrawal in a chronic intrathecal coinfusion model of morphine and MK801.

Methods: Intrathecal catheters, attached to 7-day miniosmotic infusion pumps, were implanted in rats and infused with saline, 20 nM/h morphine, MK801 (10 and 3 nM/h) + morphine; and 10 nM/h MK801. Analgesia was measured on the hot plate daily. On the day 7, groups received 3 mg/kg intraperitoneal naloxone and six signs of withdrawal were assessed: vocalization to air motion or light touch, abnormal posture, spontaneous vocalization, escape attempts, "wet dog shakes," and ejaculation. Similar groups were tested only on days 1 and 7. Intrathecal morphine dose-response curves were obtained on day 8. A separate morphine-tolerant group received 10 nM MK801 on day 7. Rats from each group received 10 nM intrathecal morphine 1 week later.

Results: Coinfusion of MK801 with morphine resulted in a dose-dependent preservation of effect, and attenuated three of six signs of withdrawal. Coinfusion of MK801 (10 and 3 nM/h) prevented the reduction of potency observed with morphine alone. ED50 values (maximum percent effect, nM morphine) were: saline (16), morphine (496), MK801 (10 nM/h) + morphine (4), and 10 nM/h MK801 (0.3). Acute administration of MK801 was ineffective in restoring sensitivity to morphine. One week after cessation of infusion, there was no significant difference between groups.     

Pharmacokinetics and clinical effects of intramuscular scopolamine plus morphine A comparison of two injection sites

Background: Intramuscular scopolamine plus morphine pre-medication is traditionally used when prominent sedative or antisialogogue effect is needed. Knowledge of the pharmacokinetics of scopolamine is limited due to low plasma concentrations found after therapeutic doses. This investigation compares the pharmacokinetics and the clinical responses of this drug combination injected into two commonly used injection sites.
Methods: Twelve ASA class 1 patients scheduled for minor surgery under spinal anaesthesia received scopolamine 6 μg/kg plus morphine 200 μg/kg injected in either deltoid (group D, n=6) or gluteal (group G, n=6) muscle.
Results: The peak plasma concentrations of scopolamine after deltoid or gluteal injection (2.2 vs 1.6 μg/1) and the time they were reached (17 vs 19 min) were comparable. The absorption of morphine was similar in both groups (T_max 16 min), but the peak plasma concentrations were higher after deltoid injection (71 vs 49 μg/1). The individual variation in the elimination half-lives of both scopolamine and morphine was smaller after deltoid injection (T½ scopolamine 1.9±0.7 vs 2.1±1.1 h, morphine 1.3±0.7 vs 2.3±1.5 h). Moderate slowing (25%) of heart rate was found in both groups. A heavy sedation and antisialogogue effect (VAS) was found in both groups with faster occurrence of maximal effect in group D (60 vs 120–180 min).
Conclusion: More predictable pharmacokinetics and clinical effects of intramuscular scopolamine plus morphine premedication can be achieved after an injection into deltoid muscle.     

Efficacy of a low-dose spinal morphine with bupivacaine for postoperative analgesia in children undergoing hypospadias repair

Background:  Children undergoing hypospadias repair need to be protected from highly unpleasant sensory and emotional experiences during and after surgery. We designed a double-blinded, randomized, and placebo-controlled study to compare the efficacy of a low-dose (2 μg·kg⁻¹) of intrathecal morphine with placebo for postoperative pain control of children undergoing repair of hypospadias surgery with spinal anesthesia.
Methods:  Fifty-four children were randomly assigned to one of two spinal anesthesia groups. Group M ( n  = 27) received hyperbaric bupivacaine plus 2 μg·kg⁻¹ of preservative-free morphine and group P ( n  = 27) received hyperbaric bupivacaine plus 0.9% NaCl (placebo) under inhalation anesthesia. General anesthetics were discontinued subsequent to the block. The primary outcome was the presence of pain-requiring analgesics during the first 12 h after the spinal block. Side effects were also recorded. The analgesic effects were evaluated by using the Children's Hospital of Eastern Ontario Pain Scale.
Results:  Forty-nine patients completed the trial. Fifteen patients (60%) in group P received supplementary analgesics within the first 12 h compared to only four patients (16.7%) in group M ( P  = 0.005). Mean duration of analgesia was 480 ± 209 and 720 ± 190 min in group P and group M respectively ( P  = 0.009). The groups were similar in postoperative side effects.
Conclusion:  Spinal anesthesia provided by hyperbaric bupivacaine is adequate for distal hypospadias repair in children, but adding 2 μg·kg⁻¹ intrathecal morphine provides better postoperative pain control when compared to placebo in these children.     

Comparison of spinal anesthesia with general anesthesia on morphine requirement after abdominal hysterectomy

Purpose: The aim of this study was to compare morphine consumption with patient-controlled analgesia (PCA) between spinal anesthesia (SA) (bupivacaine, morphine and fentanyl) and general anesthesia (GA) (sufentanil) after an abdominal hysterectomy.
Methods: Forty women were randomly assigned to receive SA with bupivacaine 15 mg, 0.15 mg of intrathecal morphine and 15 μg of fentanyl or GA with sufentanil, both combined with PCA. The primary outcome was morphine consumption with the PCA device. The secondary outcomes were post-operative pain at rest and under stress on a visual analog scale, nausea, pruritus and respiratory depression on a standardized scale. Outcome measures were recorded at 6, 12, 18, 24 and 48 h post-anesthesia. The duration of post-anesthesia care unit (PACU) and hospital stay were recorded.
Results: Patients in the SA group consumed at least two times less morphine at each time interval than the GA group: at 48 h, they used 19 ± 17 vs. 81 ± 31 mg ( P <0.0001). Post-operative pain at rest was lower in the SA group until the 18th hour and under stress until the 48th. There was more sedation in the GA group until the 18th hour. Little difference was observed in the incidence of pruritus. Nausea was more intense at the 6th hour in the GA group. There was no difference in the respiratory rate. The duration of PACU stay was shorter for the SA group (52 ± 9 vs. 73 ± 11 min, P <0.0001) as was the duration of hospital stay (2.2 ± 0.4 vs. 3.3 ± 0.7 days, P =0.01).
Conclusions: It is concluded that intrathecal morphine 0.15 mg with 15 μg of fentanyl decreases post-operative pain and morphine consumption by PCA without increasing adverse reactions for women undergoing an abdominal hysterectomy.     

吗啡耐受大鼠脊髓NR2B与mGluR5的相互作用

目的 评价吗啡耐受大鼠脊髓含2B亚基的NMDA受体(NR2B)和代谢型谷氨酸受体5(mGluR5)的相互作用.方法 雄性SD大鼠,体重220～280 g,取鞘内置管成功的大鼠16只,随机分为2组(n=8).对照组(C组)鞘内注射生理盐水10 μl;吗啡组(M组)鞘内注射吗啡10 μg(10 μl).每日给药2次,连续7 d.于给药前和给药后30 min采用热水缩尾法测定痛阈,计算最大镇痛效应百分比(MPE).最后1次痛阈测定结束后第2天,处死大鼠,取L4-5,脊髓背角,采用Western blot法测定NR2B和mGluRS蛋白表达水平;应用免疫共沉淀技术,NR2B抗体沉淀提取蛋白,Western blot法检测沉淀物.结果 与C组比较,给药1～5 d时M组MPE升高(P<0.01),给药7 d时差异无统计学意义(P>0.05).与C组比较,M组NR2B蛋白表达差异无统计学意义(P>0.05),mGluRS蛋白表达上调(P<0.01).免疫共沉淀法证实NR2B与mGluR5存在相互作用.结论 吗啡耐受大鼠脊髓NR2B与mGluR5存在相互作用.     

Differential effects of pre-treatment with intrathecal or intravenous morphine on the prevention of spinal cord hyperexcitability following sciatic nerve section in the rat

The effect of intrathecal (i.t.) and intravenous (i.v.) morphine on spinal hyperexcitability following unilateral section of the sciatic nerve was studied in decerebrate, spinalized, unanesthetized rats. Sciatic nerve section evoked a biphasic, prolonged hyperexcitability of the flexor reflex. Either i.v. (0.2, 1 or 10 mg · kg^-1) or i.t. (3 or 10 μg) morphine was administered prior to sciatic nerve section. All doses of morphine significantly depressed the baseline flexor reflex and abolished the less intense prolonged second component of reflex hyperexcitability. One and 10, but not 02, mg · kg^-1 i.v. morphine significantly depressed the first phase of spinal cord sensitization. However, both 3 μg and 10 μg i.t. morphine were significantly more effective than i.v. morphine in suppressing spinal cord hyperexcitability. The present results suggest that moderate doses of i.t. morphine decrease spinal hyperexcitability following nerve transection more than even extremely large i.v. doses. The poorer effect of i.v. morphine on preventing spinal hyperexcitability may be due to low spinal concentration after systemic administration.     

Comparison of analgesic efficacy of oxycodone and morphine in postoperative intravenous patient-controlled analgesia

Background : Morphine has been the standard opioid in patient-controlled analgesia (PCA). Oxycodone, the analgesic potency of which in i.v. administration has been suggested to be slightly greater than that of morphine, has not yet been studied for its efficacy in PCA.
Methods : Fifty patients, undergoing a plastic reconstruction of the breast or a major operation of the vertebrae, such as lumbar spinal fusion, used PCA for postoperative pain. Patients were randomized to receive either morphine 45 μg/kg or oxycodone 30 μg/kg as i.v. bolus doses. Patients were assessed for pain with a visual analogue scale (VAS) and side effects at 3, 9 and 24 h. Venous blood samples for the measurement of plasma concentration of oxycodone and that of morphine and its metabolites were taken.
Results : In this study patients needed, on average, the same amount of oxycodone and morphine in the recovery room and on the ward. There was no difference in the quality of analgesia (VAS) or incidence of side effects, such as nausea, vomiting, pruritus and urinary retention. The plasma concentrations of morphine-6-glucuronide showed that this metabolite might contribute to the analgesia resulting from morphine administration.
Conclusions : The same dose of intravenous oxycodone and morphine administered by PCA pump was needed for immediate postoperative analgesia. The two drugs appear to be equipotent.     

Unilateral spinal anaesthesia for outpatient surgery: a comparison between hyperbaric bupivacaine and bupivacaine–clonidine combination

Backround: Low-dose hyperbaric bupivacaine has been used to produce unilateral spinal anaesthesia for outpatient surgery. Unilateral spinal anaesthesia is associated with reduction of hypotension, faster recovery and increased patient satisfaction. Small doses of clonidine have shown effectiveness in intensifying spinal anaesthesia. We investigated the effect of adding 15 μg of clonidine to 5 mg hyperbaric bupivacaine on unilaterality.
Methods: Sixty patients undergoing outpatient knee arthroscopy were randomly allocated to receive either 1.2 ml (6 mg) of hyperbaric bupivacaine or a 1.2 ml solution containing 1.0 ml (5 mg) hyperbaric bupivacaine, 0.1 ml (75 μg) clonidine and 0.1 ml sterile water. The motor block was assessed by a modified Bromage scale and the sensory block by a pinprick.
Results: There was a significant difference in the spread of anaesthesia between the operated and contralateral sides in both groups. Seventy-seven per cent of the blocks were unilateral in group B and 73% in group B-C. There was no significant difference between the groups, in unilaterality. The motor block was prolonged in group B-C but it did not affect home-readiness. Patients receiving clonidine needed more vasopressors. There was a significant difference in blood pressures between the groups, being lower in group B-C after 1 h 45 min.
Conclusion: Using 5 mg hyperbaric bupivacaine with 15 μg of clonidine, the unilaterality can be achieved and spinal anaesthesia intensified without affecting home-readiness. More vasopressors are needed in the beginning, but after the surgery patients experienced less pain.     

Oxycodone vs. fentanyl in the treatment of early post-operative pain after laparoscopic cholecystectomy: a randomised double-blind study

Background: It has been suggested that oxycodone is superior to other opioids in the treatment of visceral pain. We therefore compared the effect of intravenous (i.v.) oxycodone and i.v. fentanyl on post-operative abdominal (visceral) pain after outpatient laparoscopic cholecystectomy.
Methods: Seventy-eight patients were randomised to intra- and post-operative pain treatment with either oxycodone ( n =39) or fentanyl ( n =39). The patients received 10 mg oxycodone/100 μg fentanyl at the end of anaesthesia. In the post-anaesthetic care unit (PACU), 5 mg oxycodone/50 μg fentanyl was administered to patients with moderate pain [3–5 on a numeric rating scale (NRS)], and 10 mg oxycodone/100 μg fentanyl was administered to patients with severe pain (>5 on an NRS). The following measures were recorded: intensity of pain at arrival, after 30, 60 and 90 min and at discharge from the PACU; total consumption of oxycodone/fentanyl; nausea; vomiting; sedation and pressure tolerance thresholds.
Results: The median intra- and post-operative consumption of oxycodone was 15 mg (range: 10–40 mg) and the consumption of fentanyl was 200 μg (range: 100–500 μg). The intensity of abdominal pain was significantly lower in the oxycodone group at arrival ( P <0.05), after 30, 60 and 90 min, and at discharge from the PACU ( P <0.01). There was a strong tendency towards more side effects with oxycodone.
Conclusions: Oxycodone provided better analgesia but also more side effects, suggesting that the doses used in the present study may not be equipotent.     

Ketamine blocks enhancement of spinal long-term potentiation in chronic opioid treated rats

Background: Long-term opioid treatment is associated with the development of hyperalgesia. In a rat model we wanted to study if chronic opioid treatment changed the induction and maintenance of spinal long-term potentiation (LTP), a form of hyperexcitability in the spinal cord. We also wanted to investigate if the clinically available NMDA receptor antagonist ketamine inhibited the effect of chronic opioid treatment on LTP.
Methods: The animals were randomized into four groups (saline, morphine 20 mg/kg/day, ketamine 20 mg/kg/day, morphine 20 mg/kg/day and ketamine 20 mg/kg/day). Drugs were given as continuous subcutaneous infusions by means of osmotic minipumps. After 7 days of treatment and during ongoing treatment single unit extracellular recordings were made from the lumbar deep dorsal horn under urethane anesthesia. Single electrical stimuli were applied to the sciatic nerve, and the C-fiber evoked responses of WDR neurons were recorded before and during 3 h following low frequency (3 Hz) electrical conditioning stimulation.
Results: The potentiation of C-fiber evoked responses by conditioning stimulation was significantly increased in the morphine-treated group compared to the saline group, while there was no significant difference between the saline, the ketamine and the morphine/ketamine groups. The potentiated responses in the morphine/ketamine group were significantly reduced compared to the morphine group ( P =0.01).
Conclusion: Our results indicate that animals treated with long-term opioid show amplification of stimulus-induced central sensitisation compared to opioid naïve animals. Ketamine inhibited the morphine-induced enhancement of LTP, supporting the role of ketamine in prevention of opioid induced hyperalgesia.     

丙戊茶碱对吗啡耐受大鼠脊髓星型胶质细胞的影响

目的 观察脊髓星型胶质细胞(AST)在吗啡耐受过程中的变化。方法 建立慢性吗啡耐受大鼠模型，用丙戊茶碱(propentofylline)进行干预，用免疫组织化学方法测定脊髓后角AST活性在吗啡耐受过程中的变化，用热辐射抬足法测定痛阈。结果 吗啡耐受形成过程中胶质纤维酸性蛋白(GFAP)免疫反应呈强阳性，丙戊茶碱有部分抗吗啡耐受作用，并且可以使吗啡耐受过程中GFAP免疫反应阳性产物减少。结论 吗啡耐受的机制可能涉及脊髓AST的激活，丙戊茶碱可能通过抑制脊髓AST激活而具有部分抗吗啡耐受作用。     

大鼠骨癌痛-慢性吗啡耐受模型的建立

目的 建立大鼠骨癌痛-慢性吗啡耐受模型.方法 鞘内置管成功的成年雌性SD大鼠36只,体重180～200 g,采用随机数字表法,将大鼠随机分为3组(n=12):假手术组(S组)、慢性吗啡耐受组(M组)和骨癌痛+慢性吗啡耐受组(BM组).BM组右侧胫骨上段骨髓腔注入Walker256癌细胞10 μl(4×102个细胞/μl)制备骨癌痛模型,M组注射热灭活的Walker256癌细胞10μl,接种后10 d开始鞘内注射吗啡20μg/kg,2次/d,连续9 d.S组仅暴露右侧胫骨上段.分别于接种Walker256癌细胞前、接种后1、3、6、9 d、给予吗啡1、3、5、7、9 d时测定机械缩足阈值(MWT)和机械缩足持续时间(MWD),并于接种后9 d时行放射学检查,进行骨质破坏评分.最后1次测定痛周后,对右侧足底进行触摸刺激,停止刺激后3 h时取脊髓L4-6节段,测定脊髓背角Foa表达水平.结果 与S组比较,M组MWT降低,MWD延长,脊髓背角Fos表达上调(P＜0.05或0.01);与M组比较,BM组MWT降低,骨质破坏评分升高,MWD延长,脊髓背角Fos表达上调(P＜0.05或0.01).结论 成功制备了大鼠骨癌痛-慢性吗啡耐受模型.

Abstract：

Objective To establish a rat model of bone cancer pain-chronic morphine tolerance. Methods Thirty-six adult female Sprague-Dawley rats weighing 180-200 g in which intrathecal catheters were successfully placed without complications were randomly divided into 3 groups ( n = 12 each) :group sham operation (group S),group chronic morphine tolerance (group M) and group bone cancer pain + chronic morphine tolerance (group BM). Bone cancer pain was induced by intra-tibia inoculation of Walker256 mammary gland carcinoma cells (4 ×102 cells/μl) in group BM, while in group M heat-inactivated Walker256 mammary gland carcinoma cells were given instead, and then 10 days later, intrathecal morphine 20 μg,/kg was administered twice a day for 9 consecutive days. The mechanical paw withdrawal threshold (MWT) and mechanical paw withdrawal duration (MWD) were measured before inoculation, at day 1, 3, 6 and 9 after inoculation, and at day 1, 3, 5, 7 and 9 of morphine administration. The degree of bone destruction was assessed by radiological analysis at day 9 after inoculation. After the last measurement of pain threshold, the rats were given innoxious touch-stimulus. The rats were sacrificed 3 h after stopping the stimulus, and L4-6 segment of the spinal cord was isolated to determine the expression of Fos protein in the spinal dorsal horn. Results Compared with group S, MWT was significantly decreased, MWD was significantly prolonged and the expression of Fos protein was up-regulated in group M ( P ＜ 0.05 or 0.01 ). MWT was significantly decreased, MWD was significantly prolonged, bone destruction scores were significantly increased,and the expression of Fos protein was up-regulated in group BM compared with group M ( P ＜ 0.05 or 0.01 ). Conclusion A rat model of bone cancer pain-chronic morphine tolerance is successfully established.     

Analgesia before a spinal block for femoral neck fracture: fascia iliaca compartment block

Background: In this prospective randomized study, the authors compared the analgesic effect of a fascia iliaca compartment (FIC) block with that of intravenous (i.v.) alfentanil when administered to facilitate positioning for spinal anaesthesia in elderly patients undergoing surgery for a femoral neck fracture.
Methods: The 40 patients were randomly assigned to one of two groups, namely, the FIC group (fascia iliaca compartment block, n =20) and the IVA group (intravenous analgesia with alfentanil, n =20). Group IVA patients received a bolus dose of i.v. alfentanil 10 μg/kg, followed by a continuous infusion of alfentanil 0.25 μg/kg/min starting 2 min before the spinal block, and group FIC patients received a FIC block with 30 ml of ropivacaine 3.75 mg/ml (112.5 mg) 20 min before the spinal block. Visual analogue pain scale (VAS) scores, time to achieve spinal anaesthesia, quality of patient positioning, and patient acceptance were compared.
Results: VAS scores during positioning (mean and range) were lower in the FIC group than in the IVA group [2.0 (1–4) vs. 3.5 (2–6), P =0.001], and the mean (± SD) time to achieve spinal anaesthesia was shorter in the FIC group (6.9 ± 2.7 min vs. 10.8 ± 5.6 min; P =0.009). Patient acceptance (yes/no) was also better in the FIC group (19/1) than in the IVA group (12/8)( P =0.008).
Conclusions: An FIC block is more efficacious than i.v. alfentanil in terms of facilitating the lateral position for spinal anaesthesia in elderly patients undergoing surgery for femoral neck fractures.     

Distribution, tolerability and tissue compatibility of intrathecal tizanidine in the sheep

Background : Tizanidine (TZD) is an alpha-2-adrenergic drug with potential spinal analgesic action and could be a substitute or additive for intrathecal (i.t.) opiates in chronic pain treatment. However, long-term tolerability and tissue compatibility are not yet established.
Methods : Three sheep were infused intrathecally with TZD up to 4000 μg/d over a time period of up to 440 d using implantable drug administration devices; one control animal was infused with vehicle only; standard values were collected from untreated sheep. CSF samples and blood samples were analyzed to determine pharmacokinetics and systemic redistribution. Behavioral effects were studied. The spinal cord tissue was investigated using standard laboratory histology.
Results : Bolus kinetics after i.t. injection of TZD are best described by a two-phase model. Elimination half-lives of TZD in CSF were 15 min and 152 min, respectively. Clearance of TZD from lumbar CSF was 0.48 ml/min. Doses higher than 500 μg i.t. caused dose-dependent motor inactivity and sleepiness. Continuous i.t. TZD up to 4 mg/d was well tolerated regarding behavior, physical activity, heart rate, muscle strength, and coordination. Minor elevations of CSF cell counts and total protein were detected both in saline and TZD-treated animals, presumably due to local irritation by the catheter and repeated sampling procedures. Histological evaluation of the spinal cord and adjacent tissues showed no abnormalities.
Conclusion : The long-term intrathecal infusion of TZD is well tolerated and non-toxic in the sheep. The data favor clinical trials in patients with chronic pain.     

Intrathecal cyclooxygenase inhibitor administration attenuates morphine antinociceptive tolerance in rats

Several lines of evidence suggest that the N-methyl-D-aspartatereceptor (NMDA) and nitric oxide (NO) systems are involved inmorphine tolerance. Cyclooxygenase (COX) inhibitors may alsoplay a role in morphine tolerance by interacting with both systems.In the present study, we examined the effects of the COX inhibitorsN-(2-cyclohexyloxy-4-nitrophenyl) methanesulphonamide (NS-398,selective COX₂ inhibitor) and indomethacin (non-selective COXinhibitor) on the development of antinociceptive tolerance ofmorphine in a rat spinal model. The antinociceptive effect wasdetermined by the tail-flick test. Tolerance was induced byinjection of morphine 50 µg intrathecally (i.t.) twicedaily for 5 days. The effects of NS-398 and indomethacinon morphine antinociceptive tolerance were examined after administeringthese drugs i.t. 10 min before each morphine injection.Neither NS-398 nor indomethacin alone produced an antinociceptioneffect at doses up to 40 µg. NS-398 and indomethacindid not enhance the antinociceptive effect of morphine in naïveand morphine-tolerant rats. However, they shifted the morphineantinociceptive dose–response curve to the left when co-administeredwith morphine during tolerance induction, and reduced the increasein the ED₅₀ of morphine (dose producing 50% of the maximum response)three- to four-fold. Collectively, these findings and previousstudies suggest that COX may be involved in the developmentof morphine tolerance without directly enhancing its antinociceptiveeffect. Br J Anaesth 2000; 85: 747–51 ^* Corresponding author: Department of Anesthesiology, NationalDefense Medical Center and Tri-Service General Hospital, #8Section 3, Tingchow Road, Taipei, Taiwan     

Mivazerol inhibits intrathecal release of glutamate evoked by halothane withdrawal in rats

Background : Mivazerol is a new and selective α₂-adrenergic receptor agonist devoid of hypotensive effects (1, 2). Previous studies have demonstrated that mivazerol prevents hemodynamic instability during emergence from halothane anesthesia in rats (3). The present study was to determine whether glutamate and aspartate are involved in this action of mivazerol, at the second to third thoracic segments (T2–T3) of the spinal cord.
Methods : In vivo microdialysis in combination with high-performance liquid chromatography (HPLC) was employed in the study. Blood pressure (BP) and heart rate (HR) were recorded along with intrathecal (i.t.) microdialysis perfusion.
Results : BP, HR and i.t. release of glutamate (GLU, pmol/μl) were stable in the rats under 1.1% halothane anesthesia. However, halothane withdrawal immediately increased BP, HR, and i.t. release of GLU, and remained elevated for at least 2 h after withdrawal of halothane. Thirty minutes prior to halothane withdrawal, intravenous (i.v.) infusion of mivazerol (15 μg · kg^–l · h^–) almost completely prevented the increases in HR (Δ18±7 vs Δ79±7 beats/min), and in the i.t. release of GLU (Δ10.3±3.7 vs Δ30.6±5.9; 112% vs 167%). Local i.t. microinjection of mivazerol (2.5 μg/kg) 2 min prior to withdrawal of halothane also blocked the HR responses, as well as on the i.t. release of GLU following halothane withdrawal.
Conclusion : The present study demonstrates that emergence from halothane anesthesia increases i.t. release of GLU, and that mivazerol has an inhibitory effect on the above, through its direct action on the spinal cord.     

Intrathecal neostigmine with bupivacaine for infants undergoing lower abdominal and urogenital procedures: dose response

Background: Intrathecal (IT) neostigmine produces dose-dependent analgesia in adults. However, the dose of spinal neostigmine has not been investigated in infants. The purpose of this study was to assess spinal anesthesia (SA) duration provided by four doses of spinal neostigmine added to bupivacaine for lower abdominal and urogenital procedures in infants.
Methods: Seventy-five infants were randomized into five groups. The control group B received IT plain 0.5% hyperbaric bupivacaine. Groups BN.25, BN.50, BN.75, and BN1.0 received bupivacaine with 0.25, 0.5, 0.75, and 1 μg/kg of neostigmine, respectively. The primary variable was the duration of anesthesia assessed by recovery of hip flexion. Postoperative pain with facial expression, leg activity, arm activity, crying and consolability scale score,and rescue analgesic requirements were the secondary variables measured, and the side effects were noted.
Results: Seventy-three infants completed the study. There was a significant linear increase in SA duration with IT neostigmine to 65.2 (4.3) min with 0.5 μg/kg ( P <0.01), 88.2 (5.1) with 0.75 μg/kg ( P <0.001) and 92 (4.3) with 1 μg/kg ( P <0.001) from 52.4 (4.3) min with bupivacaine alone. SA duration showed no significant difference between plain bupivacaine and BN.25 ( P =0.100) or between groups BN.75 and BN1.0 ( P =0.451). Groups BN.75 and BN1.0 had significantly reduced pain scores, and the median duration before the first dose rescue analgesic was requested prolonged significantly ( P <0.001) compared with the other three groups.
Conclusions: IT neostigmine at a dose of 0.75 μg/kg added to bupivacaine significantly prolonged SA duration with reduced postoperative pain scores and rescue analgesic requirements in infants undergoing lower abdominal and urogenital procedures. No additional benefits were provided on increasing it to 1 μg/kg.