麻醉科阿片类镇痛药物应用分析

目的分析近年来该院麻醉科阿片类镇痛药物的应用动态,探讨麻醉用药的合理性。方法利用药品综合查询系统和药品信息网站,收集并分析该院2011∽2013年阿片类镇痛药物（地佐辛、盐酸吗啡、盐酸哌替啶、雷米芬太尼、舒芬太尼、芬太尼）的药品名称、规格、用量、人均用药金额等。结果除盐酸哌替啶使用量、使用金额及用药频度（DDDs）值逐年下降外,其余阿片类镇痛药物（地佐辛、盐酸吗啡、雷米芬太尼、舒芬太尼、芬太尼）近3年使用量、人均使用金额、DDDs值均显著上升。其中地佐辛每年使用量、人均使用金额最高,DDDs值的年增加倍数最大;而芬太尼（0.5 mg×1支）DDDs值最高。结论随着患者对术中、术后镇痛效果及低不良反应的要求提高,新型阿片类镇痛药物在麻醉科的应用日益增加,使用逐渐趋于合理,但新型阿片类镇痛药物的费用值得关注。     

Remifentanil update: clinical science and utility

The anilidopiperidine opioid remifentanil has pharmacodynamic properties similar to all opioids; however, its pharmacokinetic characteristics are unique. Favourable pharmacokinetic properties, minimally altered by extremes of age or renal or hepatic dysfunction, enable easy titration and rapid dissipation of clinical effect of this agent, even after prolonged infusion.Remifentanil is metabolised by esterases that are widespread throughout the plasma, red blood cells, and interstitial tissues, whereas other anilidopiperidine opioids (e.g. fentanyl, alfentanil and sufentanil) depend upon hepatic biotransformation and renal excretion for elimination. Consequently, remifentanil is cleared considerably more rapidly than other anilidopiperidine opioids. In addition, its pKa (the pH at which the drug is 50% ionised) is less than physiological pH; thus, remifentanil circulates primarily in the non-ionised moiety, which quickly penetrates the lipid blood-brain barrier and rapidly equilibrates across the plasma/effect site interface. By virtue of these distinctive pharmacokinetic properties, the context-sensitive half-time (i.e. the time required for the drug's plasma concentration to decrease by 50% after cessation of an infusion) of remifentanil remains consistently short (3.2 minutes), even following an infusion of long duration (> or =8 hours).Remifentanil, a clinically versatile opioid, is useful for intravenous analgesia and sedation in spontaneously breathing patients undergoing painful procedures. Profound analgesia may be achieved with minimal effect on cognitive function. Remifentanil may also provide sedation and analgesia during placement of regional anaesthetic blocks, and in conjunction with topical anaesthesia and airway nerve blocks, it may be useful for blunting reflex responses and facilitating 'awake' fibreoptic intubation.Compared with fentanyl and alfentanil in a day-surgery setting, remifentanil supplementation of general anaesthesia may improve intraoperative haemodynamic control. Both emergence time and the incidence of respiratory depression during post-anaesthetic recovery may be reduced. However, outcomes such as home discharge time, post-emergence adverse effect profile, and patient and provider satisfaction are not significantly improved, and the incidence of intraoperative hypotension and bradycardia is greater. In addition, drug acquisition costs for remifentanil are higher and clinicians may need extra time to familiarise themselves with the drug's unique pharmacokinetics.Ironically, the quick dissipation of opioid analgesic effect following remifentanil discontinuation may be a significant clinical disadvantage. Unless little or no postoperative pain is anticipated, the clinician may wish to treat prospectively using local or regional anaesthesia, non-opioid analgesics, or longer-acting opioid analgesics.     

Tissue distribution of fentanyl and alfentanil in the rat cannot be described by a blood flow limited model

Traditionally, physiological pharmacokinetic models assume that arterial blood flow to tissue is the rate-limiting step in the transfer of drug into tissue parenchyma. When this assumption is made the tissue can be described as a well-stirred single compartment. This study presents the tissue washout concentration curves of the two opioid analgesics fentanyl and alfentanil after simultaneous 1-min iv infusions in the rat and explores the feasibility of characterizing their tissue pharmacokinetics, modeling each of the 12 tissues separately, by means of either a one-compartment model or a unit disposition function. The tissue and blood concentrations of the two opioids were measured by gas-liquid chromatography. The well-stirred one-compartment tissue model could reasonably predict the concentration-time course of fentanyl in the heart, pancreas, testes, muscle, and fat, and of alfentanil in the brain and heart only. In most other tissues, the initial uptake of the opioids was considerably lower than predicted by this model. The unit disposition functions of the opioids in each tissue could be estimated by nonparametric numerical deconvolution, using the arterial concentration times tissue blood flow as the input and measured tissue concentrations as the response function. The observed zero-time intercepts of the unit disposition functions were below the theoretical value of one, and were invariably lower for alfentanil than for fentanyl. These findings can be explained by the existence of diffusion barriers within the tissues and they also indicate that alfentanil is less efficiently extracted by the tissue parenchyma than the more lipophilic compound fentanyl. The individual unit disposition functions obtained for fentanyl and alfentanil in 12 rat tissues provide a starting point for the development of models of intratissue kinetics of these opioids. These submodels can then be assembled into full physiological models of drug disposition.Supported in part by the National Institute on Aging, RO1-AG-4594, the Anesthesia/ Pharmacology Research Foundation, and a travel grant from Janssen Pharma AB (Sweden).     

“I’ll Be Back”: The Resurrection of Dezocine

Beginning with opium itself, natural and synthetic opioids have been used as analgesics for over 8000 years and were likely abused as drugs of recreation for that long as well. However, the “opioid crisis” resulted in attempts to avoid or limit opioid analgesics in favor of other therapies and methods. Mu opioid agonists can be effective analgesics but suffer from addiction, tolerance, and dangerous, sometimes fatal, side effects. One exception to this generalization is dezocine (Dalgan), a mixed mu/kappa opioid partial agonist. Dezocine is at least as effective as morphine in reducing acute pain in animal models and clinical applications such as postoperative pain. And while dezocine was discontinued in western markets in 2011, it has become the favored opioid analgesic in China, capturing over 40% of the market. Additionally, dezocine possesses norepinephrine uptake inhibitory activity, which may synergize with mu agonism in the case of acute pain treatment and possibly endow the drug with antinociceptive activity in neuropathic pain conditions. This Innovations article summarizes the history and properties of dezocine and presents evidence and rationale for why dezocine has undergone a resurrection.     

Morphine and d-amphetamine nullify each others' hypothermic effects in mice

We have examined the effects of the psychostimulant d-amphetamine and the neuroleptic haloperidol on hypothermia induced by intraperitoneal injection of the centrally penetrating opioids morphine, fentanyl and sufentanil and the peripherally acting opioid loperamide. Measuring rectal body temperatures, dose-response relationships were established for all compounds. Morphine and sufentanil produced hyperthermia at low doses and dose-related hypothermia at higher doses. Fentanyl and loperamide produced dose-related hypothermia. Fixed doses of each opioid producing significant hypothermia were selected for interaction studies.The psychostimulant d-amphetamine was found t o produce biphasic effects with low doses inducing hypothermia and higher doses inducing hyperthemia. Haloperidol produced dose-related hypothermia. The selected doses of the opioids were then injected followed after 15 min. by injection of hypothermia producing doses of d-amphetamine or haloperidol. Hypothermia induced by morphine, fentanyl and sufentanil was reversed by d-amphetamine whereas loperamide-induced hypothermia was unaffected. Rebound hyperthermia was also measured with fentanyl and sufentanil. Haloperidol increased the hypothermic effects of morphine, fentanyl and sufentanil but not of loperamide. In conclusion, the central stimulating effects of opioids and amphetamine may combine resulting in thermogenesis and reversal of hypothermia. Central mechanisms of opioid-induced hypothermia in mice are influenced by drugs which alter the dopamine system, whereas peripheral mechanisms are unaffected. A possible clinical implication for this dopaminergic interaction may be toxicity associated with hyperpyrexia caused by psychostimulant misuse, which is increasingly occurring concomitantly with abuse of opioids.     

Which potent opioid? Important criteria for selection

Opioids remain the drugs of choice for the treatment of severe pain. In recent years several new potent opioids have become available for clinical use. These newer drugs are generally safer than the older morphine-like compounds and their differing pharmacological and pharmacokinetic properties allow the physician to choose an appropriate drug according to the clinical situation and need of an individual patient. These drugs are classified according to their activity at the opioid receptors. The opioid agonists produce their pharmacological effect by an almost exclusive action at mu-receptors. The agonist-antagonist group are kappa-receptor agonists and either competitive antagonists at the mu-receptor or weak mu-agonists. The use of the potent opioid agonists, because of their potential for causing respiratory depression, is restricted to hospitals. Fentanyl, the oldest drug of this class, is extensively used as a supplement to general anaesthesia, or in high doses as a 'complete' anaesthetic for patients undergoing cardiac surgery. Alfentanil and sufentanil are newer fentanyl derivatives. Alfentanil is unique in having a very short elimination half-life. This is a particular advantage during short operations and for day-case surgery. For longer operations alfentanil can be given as a continuous infusion to supplement nitrous oxide anaesthesia. Sufentanil is about 10 times more potent than fentanyl and is more rapidly eliminated. Initial reports suggest that it may be more effective than fentanyl as an anaesthetic supplement and that recovery may be more rapid. Both sufentanil and alfentanil are also used in cardiac anaesthesia. The newer agonist-antagonist opioids, butorphanol, nalbuphine and buprenorphine, have largely replaced pentazocine in clinical practice. Unlike pentazocine, they cause a low incidence of dysphoric side effects. Like the pure agonists, they cause respiratory depression; however, in contrast to the pure agonists this is not dose related, reaching a 'ceiling' as dose increases. The risk of dependence is also less, so that these drugs are safer for the treatment of chronic pain. Additionally, it is particularly worth noting that buprenorphine and nalbuphine cause minimal cardiovascular changes, and are safe and effective drugs for treatment of pain associated with myocardial infarction. Buprenorphine, which is effective parenterally, orally and sublingually, has a prolonged duration of action (up to 12 hours after a single dose).     

Morphine and d‐Amphetamine Nullify Each Others' Hypothermic Effects in Mice

Abstract: We have examined the effects of the psychostimulant d‐amphetamine and the neuroleptic haloperidol on hypothermia induced by intraperitoneal injection of the centrally penetrating opioids morphine, fentanyl and sufentanil and the peripherally acting opioid loperamide. Measuring rectal body temperatures, dose‐response relationships were established for all compounds. Morphine and sufentanil produced hyperthermia at low doses and dose‐related hypothermia at higher doses. Fentanyl and loperamide produced dose‐related hypothermia. Fixed doses of each opioid producing significant hypothermia were selected for interaction studies. The psychostimulant d‐amphetamine was found to produce biphasic effects with low doses inducing hypothermia and higher doses inducing hyperthemia. Haloperidol produced dose‐related hypothermia. The selected doses of the opioids were then injected followed after 15 min. by injection of hypothermia producing doses of d‐amphetamine or haloperidol. Hypothermia induced by morphine, fentanyl and sufentanil was reversed by d‐amphetamine whereas loperamide‐induced hypothermia was unaffected. Rebound hyperthermia was also measured with fentanyl and sufentanil. Haloperidol increased the hypothermic effects of morphine, fentanyl and sufentanil but not of loperamide. In conclusion, the central stimulating effects of opioids and amphetamine may combine resulting in thermogenesis and reversal of hypothermia. Central mechanisms of opioid‐induced hypothermia in mice are influenced by drugs which alter the dopamine system, whereas peripheral mechanisms are unaffected. A possible clinical implication for this dopaminergic interaction may be toxicity associated with hyperpyrexia caused by psychostimulant misuse, which is increasingly occurring concomitantly with abuse of opioids.     

Different effects of di-isopropylfluorophosphate on the entry of opioids into mouse brain.

Di-isopropylfluorophosphate (DFP) potentiates the antinociceptive activity of alfentanil but has no effect on the activity of morphine or fentanyl. We have studied the effect of DFP on the distribution of these three opioids in the brain. Distribution studies were carried out using 3H-labelled opioids administered subcutaneously to mice. Animals were killed at times of peak antinociceptive activity and 3H-opioid measured in plasma and in eight brain regions. DFP pretreatment (1 mg kg-1) caused a significant increase in the brain:plasma ratio of alfentanil in all brain regions but had no effect on brain:plasma ratios for morphine or fentanyl. The enhanced entry of alfentanil into the brain of DFP-treated mice probably accounts for the increased antinociception observed with this opioid. This drug interaction appears to be opioid specific.     

Inhibition of Cell Growth and DNA,RNA, and Protein Synthesis in Vitro by Fentanyl,Sufentanil, and Opiate Analgesics

Abstract: We have studied the cytotoxic nature of two groups of narcotic analgesics. Group I consists of the opioids, morphine, codeine, hydromorphone, thebaine, and etorphine. Group II contains but two phenylpiperidine-type narcotics, fentanyl and sufentanil. To measure cytotoxicity, three different bioassays were employed using an established line of human cells. Specifically, the effects of narcotic analgesics on DNA, RNA, and protein synthesis were measured by following the uptake and incorporation of radiolabeled thymidine, uridine, and amino acids, respectively. Inhibition of cell growth also was studied by measuring population doubling times of logarithmically growing cells in the presence (or absence) of the test compounds. Lastly, cloning efficiencies of cells were determined in the presence of both groups of compounds. Group I compounds were significantly less inhibitory than Group II compounds by all three bioassays. Moreover, flow cytometric DNA analysis of cells treated with 100 and 320 μM etorphine HC1 showed essentially no effects on cell cycle distribution. These in vitro results thus suggest that (1) fentanyl and sufentanil are inherently more cytotoxic than the opioid narcotics in Group I, and (2) the highly potent morphinoid drug etorphine HCl appears to have special promise as a transdermal narcotic to control pain.     

地佐辛和舒芬太尼超前镇痛用于腹腔镜手术患者的疗效观察

目的:考察雷米芬太尼复合丙泊酚静脉全麻的腹腔镜患者应用地佐辛和舒芬太尼超前镇痛的有效性和安全性。方法:选择40例行腹腔镜手术的患者,随机分为2组,各20例,Ⅰ组麻醉诱导前5 min静注地佐辛0.1 mg·kg-1,Ⅱ组麻醉诱导前5 min静注舒芬太尼0.1μg·kg-1,记录拔管时间,术后2 h疼痛视觉模拟评分(VAS)、Ramesay评分、舒适度评分(BCS)、首次使用镇痛药时间及术后相关并发症。结果:Ⅰ组比Ⅱ组的拔管时间早,术后2 h VAS、BCS和术后并发症的发生率2组间差异均无统计学意义,术后2 h Ramesay评分Ⅰ组比Ⅱ组低,Ⅰ组首次使用镇痛药时间较早。结论:地佐辛和舒芬太尼具有同样的镇痛效果,但地佐辛镇痛持续时间较短,舒芬太尼比地佐辛可能会引起拔管时间晚和更深的镇静。     

Radioimmunoassay of the new opiate analgesics alfentanil and sufentanil. Preliminary pharmacokinetic profile in man

The development of two analogous radioimmunoassay (RIA) procedures based on dextran-charcoal separation is described for the quantification of two fentanyl-like analgesics, alfentanil and sufentanil. Immunization of rabbits with conjugates of bovine serum albumin and carboxy-derivatives of the respective drugs resulted in the production of antisera capable of detecting less than 0.05 ng ml^?1 of the parent analgesics with high specificity and almost no cross-reactivity with major metabolites. Excellent agreement was obtained between RIA—without prior extraction—and gas chromatography for alfentanil concentrations in human plasma. Because of sufentanil's low therapeutic plasma levels, no comparison could be made between its RIA and an alternative assay, however, there was strong evidence for the specificity of the assay when applied directly to plasma. With these RIA methods preliminary information was obtained on plasma concentrations and elimination of alfentanil or sufentanil in patients given an intravenous bolus injection of 50 μg kg^?1 of alfentanil, or 5 μg kg^?1 of sufentanil. For both analgesics, the pharmacokinetic profile in man could be described by a three-compartment model. The terminal elimination half-life was 88 min for alfentanil and 140 min for sufentanil. Six hours after a therapeutic dose, plasma levels were in the order of 3 and 0.3 ng ml^?1 for alfentanil and sufentanil respectively.     

Effects of morphine,fentanyl, sufentanil,and the short-acting morphine-like analgesic alfentanil on the EEG in dogs

Visual and computerized methods were used to analyze the effects of intravenously injected narcotic analgesics on the EEG of dogs implanted with cortical and subcortical electrodes. The drugs were morphine (1.6 mg/kg), fentanyl (0.004 mg/kg), sufentanil (0.0004 mg/kg), and a new potent and very short-acting compound under clinical trial in anaesthesia, alfentanil (0.04, 0.16 and 0.63 mg/kg). All compounds increased the amplitude of the EEG, decreased the frequency of the EEG, and produced spindle-like bursts of biphasic waves. These bursts were more frequent and of a higher amplitude following alfentanil than after the other compounds. A computerized on-line power spectral analysis was applied to three derivations (frontal-occipital cortex, dorsal hippocampus, amygdala). The power of the total band width (0–40 Hz) increased following all narcotic analgesics. The duration of this increase was coincident with the period of loss of righting. Spectral analysis of various frequency bands revealed significant differences between the compounds, specifically with regard to fentanyl and alfentanil as compared to morphine and sufentanil. Sleep-wake patterns of the night following injection of alfentanil were studied. This compound did not produce significant post-drug effects.     

Synthetic opioids compared with morphine and ketamine: catalepsy, cross-tolerance and interactions in the rat

Previously it has been shown in rats that both ketamine and morphine induced analgesia and, at larger doses, catalepsy and loss of the righting reflex, all of which were reversed by naloxone at widely different doses. Tolerance developed rapidly to either ketamine or morphine and there was cross-tolerance from ketamine to morphine. However, morphine potentiated the cataleptic effect of ketamine, whether fully-effective doses of morphine were given before ketamine or subeffective doses of both were given concurrently. The present study extends these observations to three specific mu-receptor agonists (sufentanil, fentanyl and alfentanil) and two mu- and kappa-agonist, mu-antagonist opioids (nalbuphine and butorphanol). All five of these opioids potentiated the cataleptic effect of ketamine. Each of the three specific mu agonists showed rapid development of tolerance. Fentanyl and alfentanil showed mutual cross-tolerance with ketamine, but sufentanil did not. This lack of sufentanil-ketamine cross-tolerance may reflect separation of the sites of agonist action and the sites of development of tolerance for the opioids and for ketamine. The potentiating effects of nalbuphine and butorphanol suggest that they potentiate ketamine-induced catalepsy, either by kappa-receptor interactions or by a mu agonist effect. It is suggested that the cataleptic effect of a combination of individually-subeffective doses of ketamine and morphine, rather than ketamine and one of the synthetic opioids, might be of more potential clinical usefulness.     

地佐辛与苏芬太尼用于术后静脉镇痛的临床效果比较

目的比较术后应用地佐辛与苏芬太尼进行患者静脉自控镇痛（PCIA）的临床效果和安全性。方法60例择期全麻下胸腹部及盆腔手术患者,ASAⅠ-Ⅲ级,随机分为地佐辛组（A组）和苏芬太尼组（B组）,每组30例。镇痛泵药物配方：A组为地佐辛0．6mg／kg＋恩丹西酮8mg＋0．9％氯化钠注射液至100ml;B组为苏芬太尼2．5μg／kg＋恩丹西酮8mg＋0．9％氯化钠注射液至100ml;首次剂量A组为地佐辛0．1mg／kg＋恩丹西酮4mg,B组为苏芬太尼0．1μg/kg＋恩丹西酮4mg;镇痛泵注射速度为2ml／h,自控剂量为1ml,锁定时间为15min。观察并记录患者的生命体征（BP、HR、SPO2）及1h、2h、4h、12h、24h、48h疼痛评分（VAS）、镇静评分（Ramsay）、舒适度评分（BCS）及不良反应。结果所有患者的生命体征均平稳;A、B两组的Ramsay、VAS、BCS评分在各时间点间差异均无统计学意义（均P〉0．05）。两组不良反应发生率差异无统计学意义（P〉0．05）。结论地佐辛用于术后静脉镇痛可以取得和舒芬太尼一样的满意效果。     

Pulmonary distribution of alfentanil and sufentanil studied with system dynamics analysis

We applied a system dynamics approach to the study of the pulmonary distribution of alfentanil and sufentanil in anesthetized pigs and patients, respectively. This method allows estimation of the mean transit time through the lungs and calculation of the volume of distribution of alfentanil in the lungs. In the first part of the study the pulmonary distribution of alfentanil was studied in six anesthetized pigs during three hemodynamic states (control, partial clamping of the inferior vena cave, and complete clamping of the right pulmonary artery). In the second part of the study the pulmonary distribution of sufentanil was studied in 10 patients, scheduled for elective CABG, during and after a constant rate infusion of 10 min. Pulmonary passage of the opioids was characterized by functions of transit times, derived from the pulmonary arterial and systemic arterial concentration curves. Pulmonary distribution volumes were calculated from the mean transit time and pulmonary blood flow. Pulmonary distribution volume of alfentanil during the control measurement was significantly higher (486±88 ml) than during either partial caval clamping (346±89 ml, p<0.05) or right pulmonary artery clamping (336±56 ml, p<0.05). There was no change in the extravascular volume of distribution of alfentanil with each hemodynamic state. Pulmonary volume of distribution of sufentanil in the patients was 22.6 (10.9) L. Pulmonary distribution of opioids can be studied using system dynamics analysis, both after bolus injection and during and after infusion. This method can be used for periods beyond the initial passage of the drug through the lungs.     

Effects of the complexation of various fentanyl analogs in hydroxypropyl-β-cyclodextrin after epidural and intrathecal administration in rats

Complexation of various equipotent doses of fentanyl-like opioids in hydroxypropyl-β-cyclodextrin (HP-β-CD) results in a potentiation of the spinal activity of these opioids after both epidural and intrathecal administration in a fixed diluent volume of 10 μl. The first active and mot optimal concentrations of HP-β-CD after epidural administration differed between the opioids and varied from 1 to 20% HP-β-CD. The duration of deep surgical analgesia increased at optimal concentrations of HP-β-CD with a factor 3 for fentanyl (15% HP-β-CD), 3.6 for sufentanil (5–10% HP-β-CD), respectively. Increasing the concentrations of HP-β-CD above these optimal concentrations did not further potentiate the analgesic activity of the opioids. The complexation of the opioids in HP-β-CD also increased the duration of supraspinal side-effects. However, except for lofentanil, the potentiations of the analgesic activity were always longer lasting than those for the secondary side-effects. As a consequence, there was a gain in the total time of analgesia without side-effects. After intrathecal administration, there was no gain in the duration of deep surgical analgesia after complexation of fentanyl, carfentanil and alfentanil in HP-β-CD. For both sufentanil and lofentanil, maximal potentiation of analgesia was measured at 10% HP-β-CD with, respectively, 2.8- and 1.7-fold increases in the duration of analgesia. Also intrathecally, there was some gain in the duration of duration of analgesia without supraspinal side-effects. These results on the potentiation of the opoids with HP-β-CD are discussed in relation to the lipophilicity of the tested opioids. © 1993 Wiley-Liss, Inc.     

The safety of remifentanil by bolus injection

Remifentanil is the newest of the fentanyl family of short-acting phenylpiperidine derivatives to be released into clinical practice. Remifentanil is a pure agonist at the mu opioid receptor with relatively little binding at the kappa, sigma or delta receptors. This is precisely the same profile as the other opioids currently popular in anaesthetic practice (fentanyl, alfentanil, sufentanil) and it offers the same advantages (profound analgesia, sedation, attenuation of the stress response). This has led to widespread use of remifentanil as an adjunct to general anaesthesia in a variety of clinical settings. The unique pharmacology of remifentanil, in particular its rapid offset, has more recently attracted clinicians and investigators to the use of remifentanil by bolus injection, especially for procedures requiring a brief, intense, opioid effect. The clinical effects of remifentanil, both therapeutic and adverse, are consistent with that of the other fentanyl congeners. However, the pharmacokinetic profile of remifentanil, that is, its rapid effect site equilibration, has also revealed a significant potential for therapeutic misadventure. The untoward effects of remifentanil, given by continuous infusion, are well-described in the literature. They are predictable and easily managed by experienced clinicians. This review will concentrate on the adverse effects of remifentanil given by bolus injection, either alone or in the context of a background infusion.     

Cognitive and EEG recovery following bolus intravenous administration of anesthetic agents

Bolus intravenous (IV) administration of commonly used IV anesthetic agents such as fentanyl and the fentanyl analogues, alfentanil, remifentanil, and sufentanil, etomidate and propofol, produced anesthesia in rats as measured by the loss of righting (LOR) with calculated ED₁₅₀ doses of 0.06, 0.09, 0.037, 0.007, 2.51 and 6.12 mg/kg, respectively. Animals trained in an eight arm radial maze (RAM) were assessed for cognitive recovery, as measured by response efficiency (percentage of correct arm entries within 10 min), immediately, 15 min and 30 min following IV administration of the calculated ED₁₅₀ dose of each of these agents, and the subsequent return of righting (ROR). Animals administered fentanyl or sufentanil were unable to successfully complete the maze throughout the testing periods. Animals receiving remifentanil showed cognitive recovery within the first testing interval (immediately following the return of righting), while animals receiving alfentanil, etomidate or propofol showed recovery at the 15-min testing interval following ROR. In a separate experiment, bolus IV administration of the ED₁₅₀ dose of these agents was evaluated in an acute rat EEG model. Following ROR, return to baseline EEG levels occurred at 0.30, 2.88, 5.06, 16.25, 31.29 and 43.98 min for remifentanil, propofol, alfentanil, etomidate, fentanyl and sufentanil, respectively. These data show that the return to efficient cognitive functioning corresponds to the return to normal baseline EEG waveforms.     

Antinociceptive effects of opioids following acute and chronic administration of butorphanol: influence of stimulus intensity and relative efficacy at the mu receptor

  Rationale: A common treatment strategy for the management of severe pain involves the co-administration of multiple opioid analgesics. Due to the increasing popularity of this practice, it is becoming increasingly important to understand the interactions between clinically employed opioids under a wide range of conditions. Objective: The purpose of the present investigation was to examine the effects of opioid combinations following acute and chronic administration of the low-efficacy mu-opioid butorphanol, and to determine if the effects of these combinations are modulated by the intensity of the nociceptive stimulus. Methods: In a warm-water, tail-withdrawal procedure, rats were restrained and the latencies to remove their tails from 50°C (low temperature) and 55°C (high temperature) water were measured following both acute and chronic administration of butorphanol. Opioids possessing both high (etorphine, levorphanol, morphine) and low [dezocine, (–)-pentazocine, nalbuphine] relative efficacy at the mu receptor were examined. Results: Under acute conditions, etorphine, levorphanol, morphine and dezocine increased tail-withdrawal latencies at both low and high temperatures, whereas (–)-pentazocine, nalbuphine and butorphanol increased latencies only at the low temperature. A dose of 30 mg/kg butorphanol increased the effects produced by these opioids at the low temperature, but antagonized the effects of etorphine, levorphanol, morphine and dezocine at the high temperature. During chronic treatment with 30 mg/kg per day butorphanol, tolerance was conferred to the antinociceptive effects of all the opioids examined, with greater degrees of tolerance conferred to those opioids possessing low efficacy at the mu receptor. During butorphanol treatment, etorphine, levorphanol and morphine increased tail-withdrawal latencies at both water temperatures, dezocine increased latencies at only the low temperature, and (–)-pentazocine, nalbuphine and butorphanol failed to increase latencies at either temperature. A dose of 30 mg/kg butorphanol antagonized the antinociceptive effects of etorphine, levorphanol, morphine and dezocine during chronic treatment, and these effects were observed at both water temperatures. Conclusions: These findings indicate that the interactions between butorphanol and other mu opioids vary quantitatively between low and high stimulus intensities, and between acute and chronic conditions. In most instances, however, these interactions can be predicted from the effects of the drugs when administered alone. Received: 27 June 1998 / Final version: 7 November 1998     

Inhibition of cell growth and DNA, RNA, and protein synthesis in vitro by fentanyl, sufentanil, and opiate analgesics.

We have studied the cytotoxic nature of two groups of narcotic analgesics. Group 1 consists of the opioids, morphine, codeine, hydromorphone, thebaine, and etorphine. Group II contains but two phenylpiperidine-type narcotics, fentanyl and sufentanil. To measure cytotoxicity, three different bioassays were employed using an established line of human cells. Specifically, the effects of narcotic analgesics on DNA, RNA, and protein synthesis were measured by following the uptake and incorporation of radiolabeled thymidine, uridine, and amino acids, respectively. Inhibition of cell growth also was studied by measuring population doubling times of logarithmically growing cells in the presence (or absence) of the test compounds. Lastly, cloning efficiencies of cells were determined in the presence of both groups of compounds. Group I compounds were significantly less inhibitory than Group II compounds by all three bioassays. Moreover, flow cytometric DNA analysis of cells treated with 100 and 320 microM etorphine HCl showed essentially no effects on cell cycle distribution. These in vitro results thus suggest that (1) fentanyl and sufentanil are inherently more cytotoxic than the opioid narcotics in Group I, and (2) the highly potent morphinoid drug etorphine HC1 appears to have special promise as a transdermal narcotic to control pain.