Intrathecal Ziconotide in the Treatment of Chronic Nonmalignant Pain: A Randomized,Double‐Blind,Placebo‐Controlled Clinical Trial

Objective. The safety and efficacy of intrathecal (IT) ziconotide was studied in a randomized, double‐blind, placebo‐controlled trial. Materials and Methods. Patients (169 ziconotide, 86 placebo) with severe chronic nonmalignant pain unresponsive to conventional therapy and a visual analog scale of pain intensity (VASPI score) ≥ 50 mm were treated over a 6‐day period in an inpatient hospital setting. Initial starting dose was 0.4 µg/hour and was titrated to analgesia or intolerance (maximum dose 7.0 µg/hour). The starting and maximum doses were reduced to 0.1 µg/hour and 2.4 µg/hour, respectively, due to adverse events (AEs). Results. The mean percent reduction in VASPI score from baseline was 31.2% and 6.0% for ziconotide‐ and placebo‐treated patients, respectively (p ≤ 0.001). During the initial titration phase, a significantly greater percentage of patients in the ziconotide group compared to the placebo group reported AEs, including abnormal gait, amblyopia, dizziness, nausea, nystagmus, pain, urinary retention, and vomiting. Conclusion. Ziconotide provided significant analgesia in patients for whom conventional therapy failed. However, there was a considerable incidence of ziconotide‐associated AEs due to the rapid titration and high doses administered.     

Review of case reports of inadvertent intrathecal administration of vincristine: Recommendations to reduce occurrence

Vincristine has been in clinical use for over 40 years with initial publication of the results from successful trials in 1962. Catastrophic neurotoxicity has been associated with the administration of vincristine directly into the cerebrospinal fluid (CSF). Since the first case in 1968 there have been numerous other instances, of which 23 have been reported in the literature. Of these cases 18 resulted in death. The most prominent damage on autopsy was generally in the spinal cord, brain stem and cerebellum, with severity tending to be greater in the neurons adjacent to the CSF. Fatalities appeared due to a progressive ascending myeloencephalopathy. Early recognition and immediate treatment with CSF drainage and intrathecal exchange appears to be the only intervention that has improved patient survival. The volume of injection, dose and time from the incident until the ventriculo‐lumbar washout appear critical, as these factors might contribute to the extent of drug distribution in the CNS. Although several antidotes for vincristine have been suggested, including folinic acid and glutamic acid, supportive evidence for their effectiveness is scant. Several recommendations regarding prevention of this catastrophic event have been proposed.     

内皮素鞘内注射后的脊髓形态学观察

对18只大鼠进行内皮素脊髓鞘内注射,观察及记录大鼠后肢功能状态,并将18只大鼠分为3个不同的时间处死,进行病理形态学观察。结果表明:3组均表现缺血缺氧病理改变。2及4h实验组病变重于30min实验组。脊髓下胸段、腰段病变重于颈段及骶尾段。同时发现,大鼠后肢的功能状态与其脊髓相应的病理形态学变化不呈正比。     

Chemical Stability of an Admixture Combining Ziconotide and Bupivacaine During Simulated Intrathecal Administration

Objective. To determine the stability of an admixture combining ziconotide with bupivacaine hydrochloride during simulated intrathecal infusion under laboratory conditions at 37°. Materials and Methods. An admixture containing ziconotide (25 µg/mL) and bupivacaine hydrochloride (5 mg/mL) was stored in SynchroMed® II pumps at 37° and in control vials at either 37° or 5°. Using high‐performance liquid chromatography, drug concentrations were determined from samples obtained at varying intervals during the 30‐day study. Results. After 30 days, pump ziconotide and bupivacaine hydrochloride concentrations measured an average of 86.9% and 99.4% of their initial concentrations, respectively. Control vials displayed similar degradation rates for both drugs. Statistical evaluation of the ziconotide 95% confidence interval indicated that the ziconotide concentration would meet or exceed 90% and 80% of initial concentration for 22 days and 45 days, respectively. Conclusions. An admixture containing 25 µg/mL ziconotide and 5 mg/mL bupivacaine hydrochloride was 90% stable for 22 days and 80% stable for 45 days (extrapolated) in SynchroMed® II infusion pumps.     

Neurotoxicity after spinal anaesthesia induced by serial intrathecal injections of magnesium sulphate An experimental study in a rat model

We have previously demonstrated in a rat model that the lumbar intrathecal injection of 0.02 ml 6.3% magnesium sulphate, a concentration iso-osmolar with rat plasma, produces a state of spinal anaesthesia and general sedation which reversed completely after 6 h, without evidence of neurotoxicity, immediately or during the week thereafter. Using the same model and five groups of six animals in each, we administered the same volume and concentration of magnesium sulphate and compared its clinical effects with those of 0.02 ml 12.6% magnesium sulphate, 0.02 ml 2% lignocaine and 0.02 ml 0.9% sodium chloride solution, given as a series of 15 injections on alternate days for a period of 1 month. The animals were then killed and their spinal cords and meninges examined histologically. No significant differences were noted in the times of onset, durations of sensory and motor blockade and the times to full recovery throughout the entire period of 1 month's observation in the animals receiving intrathecal 6.3% magnesium sulphate. In the group receiving 12.6% magnesium sulphate, the time of onset of sensory and motor blockade was shorter and the duration of both parameters was significantly longer than in the former group. Full clinical recovery and resumption of normal eating and drinking took place in both groups throughout the entire series of 15 successive intrathecal injections. Identical, mild, uniform histopathological changes in the spinal cord were seen in all the five groups, including the group in which only the intrathecal catheter was implanted. The complete recovery and benign consequences of repeated intrathecal injections of iso-osmolar magnesium sulphate in a rat model indicate a lack of neurotoxicity and provide an impetus for further trials in larger animal species, before initial clinical trials of this substance, given intrathecally, in humans.     

The effect of subhypnotic doses of propofol on the incidence of pruritus after intrathecal morphine for Caesarean section

The effect of subhypnotic doses of propofol on intrathecal morphine-induced pruritus was studied in a prospective, randomly allocated, double-blind controlled trial. Fifty-eight women undergoing elective lower segment Caesarean section for a singleton fetus received spinal anaesthesia with 2.5 ml hyperbaric 0.5% bupivacaine and 0.2 mg of preservative-free morphine. They then received propofol 1 ml (10 mg) or Intralipid 1 ml (control group) intravenously after delivery. Pruritus was assessed using a five-point verbal rating scale at hourly intervals for 8 h. A second dose of their allocated treatment drug was administered at the first recording of significant pruritus. The pruritus score was reassessed after 5 min and the treatment was repeated if pruritus remained. There were no differences between the groups in the onset of pruritus or its successful treatment. No adverse side-effects were associated with this dose of propofol. There were no differences in the incidence of post-operative nausea and vomiting between the two groups. Subhypnotic propofol is not an effective treatment for intrathecal morphine-induced pruritus in women following Caesarean section.     

钾离子通道的活性状态对蛛网膜下腔注射腺苷抗伤害性作用的影响

目的探讨ATP敏感型钾离子通道的活性状态对鞘内注射腺苷类似物R-phenylisopropyladenosine(R-PIA)抗伤害性作用的影响.方法雄性SD大鼠在苯巴比妥钠麻醉下,蛛网膜下腔留置PE-10导管,测定注药后鼠尾对光热刺激的反应(抗伤害作用).结果蛛网膜下腔注射R-PIA产生剂量依赖性的甩尾时间曲线上移(P＜0.05).蛛网膜下腔注药后10min起效,镇痛时间长达60min.ATP敏感型通道开放剂nicorandil和阻滞剂glibenclamide单独蛛网膜下腔应用无镇痛作用(P＞0.05),但nicorandil明显增强R-PIA的抗伤害性作用,相反glibenclamide明显减弱R-PIA的抗伤害性作用(P＜0.05).结论蛛网膜下腔注射R-PIA可产生明显的剂量依赖性抗伤害作用,此作用受ATP敏感型钾离子通道活性调节.     

F wave studies after intrathecal methotrexate administration

Electrophysiological examinations were done on 20 patients aged 40–71 years with recently diagnosed high grade non-Hodgkin's lymphomas. General chemotherapy and intrathecal chemotherapy in order to prevent central nervous system (CNS) involvement were begun. On the first day of chemotherapeutic cycle patients received intrathecally methotrexate (ITMTX) and prednisolone. Electrophysiological study was carried out twice in each subject: before ITMTX injection and a day after injection. The study procedure included: a conventional nerve conduction examination (peripheral conduction velocity and compound muscle action potential amplitude), the F wave latency and amplitude measurement and F ratio (F-M-1/2M) calculation for peroneal and tibial nerve bilaterally. Results of the first and the second examinations were statistically compared by t-Student's test. No significant differences between values of estimated parameters were found. The study revealed no recent alterations in proximal, paraspinal motor conduction and motor neuron excitability due to antidromical activation after single ITMTX administration.     

鞘内注射两性霉素B治疗隐球菌性脑膜炎的临床观察

目的观察鞘内注射两性霉素B（amphotericin B，AMB）治疗隐球菌性脑膜炎的疗效和不良反应。方法回顾性分析1995-2006年作者医院治疗的8例隐球菌性脑膜炎患者的临床资料，8例患者均采用同时鞘内注射和静脉注射AMB并联合应用氟康唑或氟胞嘧啶治疗。结果痊愈4例，好转3例，死亡1例；鞘内注射后均有头疼、恶心呕吐及下肢麻痛等症状，并出现短暂性双下肢截瘫2例，尿潴留1例，意识障碍2例。结论反复行腰穿放脑脊液控制颅压并联合鞘内注射AMB治疗隐球菌性脑膜炎疗效肯定，但患者有不同程度不良反应。     

Adjuvant agents in regional anaesthesia

The addition of adjuvant agents to intrathecal and epidural anaesthetic techniques is well established, in particular opioids and clonidine. These adjuvants are utilized to improve the quality of anaesthesia and analgesia. Several other adjuvants have been studied but ongoing concerns surrounding safety and efficacy may limit their use in clinical practice. Epinephrine has for many years been administered in combination with local anaesthetic although more recently a diverse range of adjuvants have been added to peripheral nerve block solutions, again with the aim of prolonging surgical anaesthesia. The evidence to support or refute the benefit of these agents is increasing, as is our understanding of which agents have demonstrable efficacy and safety at clinically appropriate doses. Clinicians must be aware that many adjuvants are not licensed for central neuraxial or perineural use and should be aware of the risks, in particular of neurotoxicity and unwanted side effects.