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Naltrexone, an opioid antagonist that blocks the reinforcing properties of opioid agonists, is often prescribed to preclude relapse to opioid use disorder (OUD) following detoxification. However, few laboratory studies have directly investigated the ability of naltrexone to alter relapse-inducing effects of opioid agonists, including their priming strength in reinstatement studies and their impact in brain regions known to be involved in drug-induced reinforcement in MRI studies. Here we directly address this issue by investigating the effects of continuous exposure to naltrexone on 1) fentanyl-induced reinstatement of drug-seeking behavior, 2) fentanyl-induced patterns of blood oxygenation level dependent (BOLD) activation in the nucleus accumbens (NAcc), and 3) fentanyl-induced changes in NAcc functional connectivity (FC) in awake non-human primates that are engaged in ongoing opioid self-administration studies. We found that naltrexone antagonizes the priming strength of fentanyl as shown by a rightward shift in its reinstatement dose-effect curve and that naltrexone surmountably antagonizes the BOLD response induced by fentanyl. However, while naltrexone also countered fentanyl's effects on NAcc FC, the effects were not surmounted by a higher dose of fentanyl. Together, these data suggest that, in contrast to naltrexone's modulation of fentanyl's effects on behavior and BOLD responses, their interactive effects on FC between multiple brain regions do not reflect their receptor-mediated activity. Additionally, we demonstrated opposing effects in the absence and presence of naltrexone on NAcc FC at baseline (i.e., in the absence of any fentanyl prime) suggesting that naltrexone alters FC at baseline, even though naltrexone appears behaviorally silent in the absence of an agonist prime. Together these data provide additional insight into ways in which naltrexone interacts with opioid agonists, both behaviorally and in the brain. Further understanding the effects of opioid agonists on patterns of FC could help elucidate our understanding of the neural processes that contribute to the initiation of and relapse to opioid-seeking behavior in OUD., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: The potent synthetic opioid fentanyl, and its analogs, continue to drive opioid-related overdoses. Although the pharmacology of fentanyl is well characterized, there is little information about the reinforcing effects of clandestine fentanyl analogs (FAs)., Objectives: Here, we compared the effects of fentanyl and the FAs acetylfentanyl, butyrylfentanyl, and cyclopropylfentanyl on drug self-administration in male and female rats. These FAs feature chemical modifications at the carbonyl moiety of the fentanyl scaffold., Methods: Sprague-Dawley rats fitted with intravenous jugular catheters were placed in chambers containing two nose poke holes. Active nose poke responses resulted in drug delivery (0.2 mL) over 2 s on a fixed-ratio 1 schedule, followed by a 20 s timeout. Acquisition doses were 0.01 mg/kg/inj for fentanyl and cyclopropylfentanyl, and 0.03 mg/kg/inj for acetylfentanyl and butyrylfentanyl. After 10 days of acquisition, dose-effect testing was carried out, followed by 10 days of saline extinction., Results: Self-administration of fentanyl and FAs was acquired by both male and female rats, with no sex differences in acquisition rate. Fentanyl and FAs showed partial inverted-U dose-effect functions; cyclopropylfentanyl and fentanyl had similar potency, while acetylfentanyl and butyrylfentanyl were less potent. Maximal response rates were similar across drugs, with fentanyl and cyclopropylfentanyl showing maximum responding at 0.001 mg/kg/inj, acetylfentanyl at 0.01 mg/kg/inj, and butyrylfentanyl at 0.003 mg/kg/inj. No sex differences were detected for drug potency, efficacy, or rates of extinction., Conclusions: Our work provides new evidence that FAs display significant abuse liability in male and female rats, which suggests the potential for compulsive use in humans., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Rationale: G-protein biased mu-opioid receptor (MOR) agonists have been reported to exhibit superior therapeutic windows compared to prototypical MOR agonists when relating antinociception to respiratory depression. However, there is relatively little research on the abuse potential of G-protein biased MOR agonists in relation to other behavioral endpoints., Objectives: The aim of the present study was to quantitatively compare the reinforcing, antinociceptive, and respiratory-depressant effects of the prototypical MOR agonists, fentanyl and oxycodone, to the G-protein biased MOR agonists, SR14968 and SR17018, in male and female rats., Methods: In the self-administration study, four separate groups of Sprague-Dawley (SD) rats self-administered intravenous (i.v.) fentanyl, oxycodone, SR14968, and SR17018 under a progressive-ratio schedule of reinforcement. Using a within-subjects design, separate cohorts of SD rats were tested with i.v. fentanyl, oxycodone, SR14968, and SR17018 using a hot-plate assay, assays of neuropathic and inflammatory antinociception, and whole-body plethysmography., Results: All MOR agonists functioned as reinforcers, but SR14968 and SR17018 were less efficacious relative to oxycodone and fentanyl. Moreover, all MOR agonists produced dose-dependent and fully efficacious antinociception across all nociception modalities. Oxycodone and fentanyl, but not SR14968 or SR17018, produced respiratory depression in a dose-dependent manner., Conclusion: The present results indicate that the G-protein biased MOR agonists tested herein produce MOR-typical antinociception, exhibit reduced but apparent abuse potential, and do not produce respiratory effects at doses that are above the antinociceptive range. Atypical MOR agonists within the SR series should be further studied as foundational molecules for the development of safter analgesics., Competing Interests: Declarations Conflicts of interest On behalf of all authors, the corresponding author states that there is no conflict of interest., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: Individuals with opioid use disorder (OUD) exhibit impaired decision making and elevated risk-taking behavior. In contrast to the effects of natural and semi-synthetic opioids, however, the impact of synthetic opioids on decision making is still unknown., Objectives: The objective of the current study was to determine how chronic exposure to the synthetic opioid fentanyl alters risk-based decision making in adult male rats., Methods: Male rats underwent 14 days of intravenous fentanyl or oral sucrose self-administration. After 3 weeks of abstinence, rats were tested in a decision-making task in which they chose between a small, safe food reward and a large food reward accompanied by variable risk of footshock punishment. Following testing in the decision-making task, rats were tested in control assays that assessed willingness to work for food and shock reactivity. Lastly, rats were tested on a probabilistic reversal learning task to evaluate enduring effects of fentanyl on behavioral flexibility., Results: Relative to rats in the sucrose group, rats in the fentanyl group displayed greater choice of the large, risky reward (risk taking), an effect that was present as long as 7 weeks into abstinence. This increased risk taking was driven by enhanced sensitivity to the large rewards and diminished sensitivity to punishment. The fentanyl-induced elevation in risk taking was not accompanied by alterations in food motivation or shock reactivity or impairments in behavioral flexibility., Conclusions: Results from the current study reveal that the synthetic opioid fentanyl leads to long-lasting increases in risk taking in male rats. Future experiments will extend this work to females and identify neural mechanisms that underlie these drug-induced changes in risk taking., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: Novel synthetic opioids (NSOs) are emerging in recreational drug markets worldwide. In particular, 2-benzylbenzimidazole 'nitazene' compounds are problematic NSOs associated with serious clinical consequences, including fatal respiratory depression. Evidence from in vitro studies shows that alkoxy chain length can influence the potency of nitazenes at the mu-opioid receptor (MOR). However, structure-activity relationships (SARs) of nitazenes for inducing opioid-like effects in animal models are not well understood compared to relevant opioids contributing to the ongoing opioid crisis (e.g., fentanyl)., Objectives: Here, we examined the in vitro and in vivo effects of nitazene analogues with varying alkoxy chain lengths (i.e., metonitazene, etonitazene, isotonitazene, protonitazene, and butonitazene) as compared to reference opioids (i.e., morphine and fentanyl)., Methods and Results: Nitazene analogues displayed nanomolar affinities for MOR in rat brain membranes and picomolar potencies to activate MOR in transfected cells. All compounds induced opioid-like effects on locomotor activity, hot plate latency, and body temperature in male mice, and alkoxy chain length markedly influenced potency. Etonitazene, with an ethoxy chain, was the most potent analogue in MOR functional assays (EC 50  = 30 pM, E max  = 103%) and across all in vivo endpoints (ED 50  = 3-12 μg/kg). In vivo SARs revealed that ethoxy, isopropoxy, and propoxy chains engendered higher potencies than fentanyl, whereas methoxy and butoxy analogues were less potent. MOR functional potencies, but not MOR affinities, were positively correlated with in vivo potencies to induce opioid effects., Conclusions: Overall, our data show that certain nitazene NSOs are more potent than fentanyl as MOR agonists in mice, highlighting concerns regarding the high potential for overdose in humans who are exposed to these compounds., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Rationale: Xylazine has emerged in recent years as an adulterant in an increasing number of opioid-positive overdose deaths in the United States. Although its exact role in opioid-induced overdose deaths is largely unknown, xylazine is known to depress vital functions and cause hypotension, bradycardia, hypothermia, and respiratory depression., Objectives: In this study, we examined the brain-specific hypothermic and hypoxic effects of xylazine and its mixtures with fentanyl and heroin in freely moving rats., Results: In the temperature experiment, we found that intravenous xylazine at low, human-relevant doses (0.33, 1.0, 3.0 mg/kg) dose-dependently decreases locomotor activity and induces modest but prolonged brain and body hypothermia. In the electrochemical experiment, we found that xylazine at the same doses dose-dependently decreases nucleus accumbens oxygenation. In contrast to relatively weak and prolonged decreases induced by xylazine, intravenous fentanyl (20 μg/kg) and heroin (600 μg/kg) induce stronger biphasic brain oxygen responses, with the initial rapid and strong decrease, resulting from respiratory depression, followed by a slower, more prolonged increase reflecting a post-hypoxic compensatory phase, with fentanyl acting much quicker than heroin. The xylazine-fentanyl mixture eliminated the hyperoxic phase of oxygen response and prolonged brain hypoxia, suggesting xylazine-induced attenuation of the brain's compensatory mechanisms to counteract brain hypoxia. The xylazine-heroin mixture strongly potentiated the initial oxygen decrease, and the pattern lacked the hyperoxic portion of the biphasic oxygen response, suggesting more robust and prolonged brain hypoxia., Conclusions: These findings suggest that xylazine exacerbates the life-threatening effects of opioids, proposing worsened brain hypoxia as the mechanism contributing to xylazine-positive opioid-overdose deaths., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Rationale: Discriminative stimuli (DS) are cues that predict reward availability. DS are resistant to extinction and motivate drug seeking even after long periods of abstinence. Previous studies have demonstrated that sign-tracking (ST) and goal-tracking (GT) differences in Pavlovian approach predict distinct cue-modulated vulnerabilities to cocaine reinstatement. GT rats show heightened reinstatement to contextual and DS, while ST rats show heightened reinstatement to discrete stimuli. Here we examine whether DS modulate reinstatement after electric barrier-induced abstinence and whether tracking-related relapse vulnerabilities generalize to opioid relapse., Objectives: We examine whether DS-modulated reinstatement to fentanyl seeking persists in the presence of reduced adverse consequences after electric barrier-induced abstinence. We also examine whether tracking differences predict the magnitude of DS-modulated reinstatement of fentanyl seeking after electric barrier-induced abstinence., Methods: We used Pavlovian lever autoshaping (PLA) training to determine sign-, goal-, and intermediate tracking groups in male and female Sprague Dawley rats. We then trained rats in a DS model of intermittent fentanyl self-administration, and extinguished drug seeking by imposing an electric barrier of increasing intensity. We then measured the level of DS-modulated reinstatement in the presence of a reduced electric barrier intensity., Results: We report that DS strongly modulate fentanyl seeking after electric barrier-induced abstinence. DS-modulation of fentanyl acquisition, electric barrier-induced abstinence, and reinstatement was similar for sign- and goal-tracking groups., Conclusions: Discriminative stimuli powerfully motivate opioid seeking, despite continued aversive consequences. Pavlovian approach differences do not predict the level of DS-modulated reinstatement to fentanyl seeking after conflict-induced abstinence., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: Synthetic opioids like fentanyl are contributing to the rise in rates of opioid use disorder and drug overdose deaths. Sleep dysfunction and circadian rhythm disruption may worsen during opioid withdrawal and persist during abstinence. Severe and persistent sleep and circadian alterations are putative factors in opioid craving and relapse. However, very little is known about the impact of fentanyl on sleep architecture and sleep-wake cycles, particularly opioid withdrawal. Further, circadian rhythms regulate sleep-wake cycles, and the circadian transcription factor, neuronal PAS domain 2 (NPAS2) is involved in the modulation of sleep architecture and drug reward. Here, we investigate the role of NPAS2 in fentanyl-induced sleep alterations., Objectives: To determine the effect of fentanyl administration and withdrawal on sleep architecture, and the role of NPAS2 as a factor in fentanyl-induced sleep changes., Methods: Electroencephalography (EEG) and electromyography (EMG) was used to measure non-rapid eye movement sleep (NREMS) and rapid eye movement sleep (REMS) at baseline and following acute and chronic fentanyl administration in wild-type and NPAS2-deficient male mice., Results: Acute and chronic administration of fentanyl led to increased wake and arousal in both wild-type and NPAS2-deficient mice, an effect that was more pronounced in NPAS2-deficient mice. Chronic fentanyl administration led to decreased NREMS, which persisted during withdrawal, progressively decreasing from day 1 to 4 of withdrawal. The impact of fentanyl on NREMS and arousal was more pronounced in NPAS2-deficient mice., Conclusions: Chronic fentanyl disrupts NREMS, leading to a progressive loss of NREMS during subsequent days of withdrawal. Loss of NPAS2 exacerbates the impact of fentanyl on sleep and wake, revealing a potential role for the circadian transcription factor in opioid-induced sleep changes., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: Opioid use disorder (OUD) is highly comorbid with stress-related disorders, and stress can serve as a trigger for reinstatement of drug seeking. Glucocorticoid receptor (GR) antagonists such as mifepristone (RU-486) may be effective against stress-induced drug seeking. In the current study, PT150 (formerly ORG-34517), a more selective GR antagonist, was tested using two models of stress-induced drug seeking, namely footshock and yohimbine., Methods: Adult male and female Sprague-Dawley rats were trained to self-administer fentanyl (2.5 μg/kg/infusion, i.v.) in a model of escalation. Rats then received 7 days of abstinence, followed by extinction; PT150 (0, 50 or 100 mg/kg in Nutella®; p.o.) treatment started on the first day of extinction training and continued daily until the end of the study. Following 14 days of extinction, rats were tested for reinstatement following footshock and yohimbine (0, 1, or 2 mg/kg; i.p.), tested in counterbalanced order; PT150 or placebo treatment occurred prior to each extinction and reinstatement session., Results: Prior to initiation of PT150 treatment, females self-administered greater levels of fentanyl during 1-h sessions compared to males; however, when switched to 6-h sessions, males and females self-administered similar levels of fentanyl and showed a similar escalation of intake over time. PT150 had no effect on extinction of self-administration. While both footshock and yohimbine reinstated fentanyl seeking, only footshock-induced reinstatement was decreased by PT150 (50 and 100 mg/kg). The effect of PT150 on footshock-induced reinstatement was driven primarily by males., Conclusion: The glucocorticoid antagonist PT150 reduces shock-induced fentanyl seeking, suggesting it may be effective against stress-induced relapse, although the sex difference in response may need further exploration., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale and Objective: Pain-related factors increase the risk for opioid addiction, and pain may function as a negative reinforcer to increase opioid taking and seeking. However, experimental pain-related manipulations generally do not increase opioid self-administration in rodents. This discrepancy may reflect insufficient learning of pain-relief contingencies or confounding effects of pain-related behavioral impairments. Here, we determined if pairing noxious stimuli with opioid self-administration would promote pain-related reinstatement of opioid seeking or increase opioid choice over food., Methods: In Experiment 1, rats self-administered fentanyl in the presence or absence of repeated intraplantar capsaicin injections in distinct contexts to model context-specific exposure to cutaneous nociception. After capsaicin-free extinction in both contexts, we tested if capsaicin would reinstate fentanyl seeking. In Experiment 2, rats self-administered heroin after intraperitoneal (i.p.) lactic acid injections to model acute visceral inflammatory pain. After lactic acid-free extinction, we tested if lactic acid would reinstate heroin seeking. In Experiment 3, we tested if repeated i.p. lactic acid or intraplantar Complete Freund's Adjuvant (CFA; to model sustained inflammatory pain) would increase fentanyl choice over food., Results: In Experiments 1-2, neither capsaicin nor lactic acid reinstated opioid seeking after extinction, and lactic acid did not increase heroin-induced reinstatement. In Experiment 3, lactic acid and CFA decreased reinforcement rate without affecting fentanyl choice., Conclusions: Results extend the range of conditions across which pain-related manipulations fail to increase opioid seeking in rats and suggest that enhanced opioid-addiction risk in humans with chronic pain involves factors other than enhanced opioid reinforcement and relapse.

Rationale: Strategies are needed to decrease the abuse liability of mu opioid receptor (MOR) agonists. One strategy under consideration is to combine MOR agonists with kappa opioid receptor (KOR) agonists., Objectives: The effects of KOR agonists (U50488, nalfurafine) on fentanyl-vs.-food choice were compared under conditions where the KOR agonists were added to the intravenously self-administered fentanyl (contingent delivery) or administered as subcutaneous pretreatments (non-contingent delivery) in male and female rats., Methods: Rats were trained to respond under a concurrent schedule of fentanyl (0, 0.32-10 μg/kg/infusion) and food reinforcement. In experiment 1, U50488 and nalfurafine were co-administered with fentanyl as fixed-proportion mixtures (contingent administration). In experiment 2, U50488 (1-10 mg/kg) and nalfurafine (3.2-32 μg/kg) were administered as acute pretreatments (non-contingent administration). The selective KOR antagonist, nor-BNI (32 mg/kg), was administered prior to contingent and non-contingent KOR-agonist treatment in experiment 3., Results: Both U50488 and nalfurafine decreased fentanyl choice when administered contingently, demonstrating that KOR agonists punish opioid choice. However, evidence for punishment corresponded with an elimination of operant responding in the majority of rats. Non-contingent U50488 and nalfurafine administration only decreased the number of choices made during the behavioral session without altering fentanyl choice. Contingent and non-contingent KOR-agonist effects on fentanyl choice were both attenuated by nor-BNI., Conclusions: These results illustrate that the effects of KOR agonists on fentanyl reinforcement are dependent upon the contingencies under which they are administered.

Rationale: Opioid use disorder (OUD) is a major epidemic in the USA. Despite evidence indicating that OUD may be particularly severe for women, preclinical models have yet to establish sex as a major factor in OUD., Objectives: Here, we examined sex differences in vulnerability to relapse following intermittent access fentanyl self-administration and protracted abstinence and used buprenorphine, the FDA-approved treatment for OUD, to test the validity of our model., Methods: Following acquisition of fentanyl self-administration under one of two training conditions, male and female rats were given extended, 24-h/day access to fentanyl (0.25 μg/kg/infusion, 10 days) using an intermittent access procedure. Vulnerability to relapse was assessed using an extinction/cue-induced reinstatement procedure following 14 days of abstinence; buprenorphine (0 or 3 mg/kg/day) was administered throughout abstinence., Results: Levels of drug-seeking were high following extended-access fentanyl self-administration and abstinence; buprenorphine markedly decreased drug-seeking supporting the validity of our relapse model. Females self-administered more fentanyl and responded at higher levels during subsequent extinction testing. Buprenorphine was effective in both sexes and eliminated sex and estrous phase differences in drug-seeking. Interestingly, the inclusion of a time-out during training had a major impact on later fentanyl self-administration in females, but not males, indicating that the initial exposure conditions can persistently impact vulnerability in females., Conclusions: These findings demonstrate the utility of this rat model for determining sex and hormonal influences on the development and treatment of OUD.

Opioid abuse has been a global menace for centuries, but the proliferation of synthetic opioids and their use within this current decade have created epidemic-level harms in some countries. According to the United Nations Office on Drugs and Crime, almost 12 million years were estimated loss of "healthy" life resulting in premature death and disability attributable to global opioid abuse just in 2015. Law enforcement and regulatory authorities have been particularly challenged abating the spread of synthetic opioids because soon after controlling the currently recognized abused opioids, their structures are tweaked, and new entities replace them. Drug racketeers have most often exploited the fentanyl phenylpiperidine structure in this regard, but non-fentanyl-like and classical morphinan-like structures have been pirated as well. A growing number of anecdotal reports identify respiratory depression induced by these newer synthetic opioids to be especially refractive to reversal by antagonists, with consequently high levels of lethality. This review examines three of these synthetic opioids representing three chemical classes (U-47700, MT-45, and acetylfentanyl) that have emerged to be of such menace that they have been brought under international control in recent years and addresses factors that could make synthetic opioids especially untreatable by opioid antagonists.

Rationale: VRP26 displays mu opioid receptor agonist and delta opioid receptor antagonist activity in vitro, a pharmacological profile purported to produce reduced tolerance, dependence, and rewarding effects. We hypothesized that VRP26 would display reduced adverse effects after chronic administration as compared with the traditional opioid analgesic fentanyl., Objective: The aim of this study is to explore the development of tolerance, dependence, and conditioned place preference of VRP26 as compared with the traditional opioid analgesic fentanyl., Methods: The antinociceptive effects of VRP26 and fentanyl were assessed using the mouse warm water tail withdrawal (WWTW) assay. Measurement of antinociceptive tolerance and physical dependence occurred after 7 days of continuous administration of either fentanyl (0.3 mg/kg/day) or VRP26 (10 mg/kg/day); tolerance was measured by a shift in the antinociceptive dose response curve in the WWTW assay. Physical dependence was determined by observation of withdrawal symptoms after precipitated withdrawal. Rewarding effects were measured by the ability of VRP26 or fentanyl to produce conditioned place preference., Results: Fentanyl produced significant tolerance and dependence, as well as significant conditioned place preference. VRP26 produced neither tolerance nor physical dependence, nor did it produce significant conditioned place preference., Conclusions: These results suggest that chronic treatment with VRP26 may produce less tolerance or physical dependence than chronic treatment with clinically available mu opioid analgesics such as fentanyl. Additionally, VRP26 produces less rewarding effects than fentanyl. This desirable in vivo profile may be due to the mixed efficacy nature of VRP26 and could provide the framework for safer opioid analgesics., Competing Interests: Disclosure. The authors have no conflicts to disclose.

Purpose: To assess heat balance status of newborn infants nursed under radiant warmers (RWs) during intensive care., Methods: Heat balance, thermal status and primary indicators of physiological strain were concurrently measured in 14 newborns nursed under RWs for 105 min. Metabolic heat production (M), evaporative heat loss (E), convective (C) and conductive heat flow (K), rectal temperature (T re) and mean skin temperatures (T sk) were measured continuously. The rate of radiant heat required for heat balance (R req) and the rate of radiant heat provided (R prov) were derived. The rate of body heat storage (S) was calculated using a two-compartment model of 'core' (T re) and 'shell' (T sk) temperatures., Results: Mean M, E, C and K were 10.5 ± 2.7 W, 5.8 ± 1.1 W, 6.2 ± 0.8 W and 0.1 ± 0.1 W, respectively. Mean R prov (1.7 ± 2.6 W) and R req (1.7 ± 2.7 W) were similar (p > 0.05). However, while the resultant mean change in body heat content after 105 min was negligible (-0.1 ± 3.7 kJ), acute time-dependent changes in S were evidenced by a mean positive heat storage component of +6.4 ± 2.6 kJ and a mean negative heat storage component of -6.5 ± 3.7 kJ. Accordingly, large fluctuations in both T re and T sk occurred that were actively induced by changes in RW output. Nonetheless, no active physiological responses (heart rate, breathing frequency and mean arterial pressure) to these bouts of heating and cooling were observed., Conclusions: RWs maintain net heat balance over a prolonged period, but actively induce acute bouts of heat imbalance that cause rapid changes in T re and T sk. Transient bouts of heat storage do not exacerbate physiological strain, but could in the longer term.

Rationale: Chronic pain is becoming a more common medical diagnosis and is especially prevalent in older individuals. As such, prescribed use of opioids is on the rise, even though the efficacy for pain management in older individuals is unclear., Objectives: Thus, the present preclinical study assessed the effectiveness of chronic fentanyl administration to produce antinociception in aging rats (16, 20, and 24 months)., Methods: Animals were tested in a thermal sensitivity procedure known to involve neural circuits implicated in chronic pain in humans. Sensitivity to heat and cold thermal stimulation was assessed during 28 days of fentanyl administration (1.0 mg/kg/day), and 28 days of withdrawal., Results: Fentanyl resulted in decreased thermal sensitivity to heat but not cold stimulation indicated by more time spent in the hot compartment relative to time spent in the cold or neutral compartments. Unlike previous findings using a hot-water tail withdrawal procedure, tolerance did not develop to the antinociceptive effects of fentanyl over a 28-day period of drug administration. The oldest animals were least sensitive, and the youngest animals most sensitive to the locomotor-stimulating effects of fentanyl. The effect on the antinociceptive response to fentanyl in the oldest group of rats was difficult to interpret due to profound changes in the behavior of saline-treated animals., Conclusions: Overall, aging modifies the behavioral effects of opioids, a finding that may inform future studies for devising appropriate treatment strategies.

The objectives of this study were to examine the effects of opioid administration on the acute cardiorespiratory and muscle oxygenation responses during a repetitive lifting and lowering test (RLL) to voluntary fatigue in participants with chronic low back pain (LBP). Written informed consent was obtained from 27 LBP participants (mean age 50.9 +/- 16.4 years) who completed one testing session during which they were administered a saline placebo and opioid (1 microg/kg of fentanyl intravenously) in random order. The participants performed the RLL at a rate that they felt that they could sustain for an 8-h working day. Acute opioid administration increased the total lifting time and total work done during RLL by 35 and 48%, respectively (p < 0.05). However, the increased work capacity was accompanied by a significant (p < 0.05) increase in oxygen cost of 22% per unit amount of work done and significant (p < 0.05) increases in heart rate (7%) and ventilation rate (10%). Near infrared spectroscopic analysis of erector spinae oxygenation and blood volume responses during RLL indicated no significant (p > 0.05) differences between the opioid and placebo phases. These findings suggest that the increased energy cost of lifting as a result of opioid administration was due to enhanced central oxygen transport and not peripheral muscle oxygen extraction.

Background: Radiopharmaceutical uptake of [(18)F]2-deoxy-2-glucose (FDG) in brown adipose tissue is noted on 15-20% of positron emission tomography (PET) scans in children and adolescents. One report suggests that moderate-dose oral diazepam can partly or completely block FDG uptake in brown adipose tissue., Objective: To determine whether [(18)F]FDG uptake in brown adipose tissue can be adequately blocked by pre-medication other than moderate-dose oral diazepam., Materials and Methods: One hundred and eighteen [(18)F]FDG PET body imaging studies were performed in 69 pediatric patients with a variety of solid tumors. The mean age at the time of imaging was 12.9 years (range 1.2-22.6 years), and 33 studies were performed in patients younger than 10 years old. Seventy-six were performed in boys and 42 in girls. Patients were imaged using a dedicated PET camera. Pre-medication was given in 88 studies: 45 received intravenous fentanyl (0.75-1.0 mug/kg), 34 received low-dose oral diazepam (0.06 mg/kg) and 9 received moderate-dose oral diazepam (0.10 mg/kg). Thirty patients received no pre-medication, 7 of whom were known to have received opiates for pain during the 12 h before the study. Six body regions in the neck and chest were reviewed for [(18)F]FDG uptake in brown adipose tissue. Uptake of FDG in brown fat was visually graded: 0 for no FDG uptake, 1 for low-grade uptake, 2 for moderate uptake, and 3 for intense uptake. Visual grades 2 and 3 were considered to interfere potentially with image interpretation in the neck and chest. Data were analyzed by multivariate regression using a Poisson distribution., Results: [(18)F]FDG uptake in brown adipose tissue was most often seen in the lateral neck region and superior and lateral to the lungs (in 36 and 39 studies, respectively). Uptake was also seen near the costovertebral junctions (15 studies), in the superior and central neck in 7 studies and in the anterior mediastinum in 2. Brown adipose tissue uptake was thought to interfere potentially with image interpretation (visual grades 2 and 3) in 19 studies-in 6 of 23 (26.1%) studies after no pre-medication and no opiates for pain, in 10 of 34 (29.4%) after low-dose oral diazepam, in 0 of 9 (0%) after moderate-dose oral diazepam, in 3 of 45 (6.7%) after intravenous fentanyl, and in 0 of 7 (0%) after opiates prescribed for pain. Intravenous fentanyl reduced the grade of brown adipose tissue compared to no drug (P=0.0039) and low-dose diazepam (P=0.0024). Low-dose diazepam had no effect when compared to no drug (P=0.984). There were inadequate data for statistical testing of moderate-dose valium and opiates prescribed for pain. Children younger than 10 years had lower uptake grades (P=0.019) than those older than 10 years., Summary: The frequency of interfering [(18)F]FDG uptake in brown adipose tissue is reduced by intravenous fentanyl pre-medication, which appears to be an effective alternative to the existing standard pre-medication, moderate-dose oral diazepam.

Rationale: Drugs of abuse can affect the functioning of the hypothalamic-pituitary-adrenal (HPA) axis. Acute administration of drugs that serve as reinforcers have been observed to stimulate the rat HPA axis, leading to the suggestion that these stimulatory effects may contribute to the development of drug-maintained behaviors., Objectives: To determine whether reinforcing drugs that are dissimilar with respect to their mechanisms of action have similar effects on HPA axis activity at doses that are self-administered. Rhesus monkeys were randomly assigned to self-administer the mu-opioid agonist fentanyl, the psychomotor stimulant cocaine, or the NMDA antagonist ketamine., Methods: Each monkey was trained to press a lever in order to receive an intravenous injection of drug or saline. Blood samples were obtained before, during, and after the self-administration sessions and assayed for ACTH and cortisol by radioimmunoassay., Results: Fentanyl, cocaine, and ketamine were each self-administered across a range of doses. However, the three drugs differed in their effects on ACTH and cortisol. Cocaine stimulated ACTH and cortisol secretion, a finding that is consistent with previous rat and primate studies. Self-administration of both fentanyl and ketamine inhibited HPA axis activity. HPA inhibition by fentanyl is consistent with other monkey and human studies, and contrasts with the stimulatory effects of mu-opioids in rodents. The inhibitory effect of ketamine on ACTH and cortisol secretion contrasts with findings in the few primate studies that have evaluated NMDA antagonists. Neither fentanyl nor cocaine, at doses that maintained maximum rates of responding, produced significant changes in ACTH and cortisol levels., Conclusions: There appears to be little commonality between different classes of abused drugs and their effects on the HPA axis, which calls into question the necessity for HPA axis stimulation in the reinforcement of drug-maintained behavior.

Oculomotor symptoms such as downbeat nystagmus can be due to side effects of drugs. We investigated the clinical effects as well as the eye movement symptoms after intravenous administration of opiates (pethidine and fentanyl). Eye movements were recorded with the magnetic search coil technique. All four normal subjects showed a transient disturbance of eye fixation with downbeat nystagmus, a range of saccadic intrusions and oscillations, including square wave jerks and saccadic pulses, lasting from 10 to 15 minutes. The gain of sinusoidal VOR and smooth pursuit was moderately decreased; in particular the vertical pursuit showed an upward velocity offset. On the basis of the clinical findings and of recent diprenorphine PET findings in humans, which detected opiod binding sites in the cerebellum and the known inhibitory action of opiates, we hypothesized that a cerebellar dysfunction occurs after opiate administration which could possibly be mediated by inhibition of the parallel fiber activation of the Purkinje cells. Furthermore, opiate binding sites in the vestibular nuclei could be responsible for the vertical vestibular tonus imbalance involved in the pathophysiolgy of downbeat nystagmus.

Rationale: Associative tolerance to the analgesic effects of morphine is most pronounced when morphine is paired with a distinctive context at a long interdose interval (IDI). In contrast, morphine administered at a short IDI promotes the development of non-associative tolerance and disrupts the acquisition of associative tolerance. The impact of IDI on the development of associative tolerance to opioids other than morphine has not been investigated previously., Objectives: This research examined associative and non-associative tolerance to the analgesic effects of fentanyl in rats. Cross tolerance for these two forms of tolerance with morphine (mureceptor agonist) and U50,488H (kappa-receptor agonist) analgesia was also investigated., Methods: Animals were given eight fentanyl injections (0.10 mg/kg) paired or unpaired with a distinctive context at either a 3-h (short) or 96-h (long) IDI. Subjects were then tested for tolerance in the distinctive context using the tail-flick procedure and dose-response curve methodology., Results: At the short IDI, animals developed non-associative tolerance to fentanyl that was receptor specific, i.e., cross tolerant with morphine analgesia but not with U50,488H analgesia. At the long IDI, fentanyl-tested animals displayed tolerance that appeared to be controlled primarily by associative processes. This associative form of tolerance was also receptor specific, displaying cross tolerance with morphine but not with U50,488H., Conclusions: The impact of IDI on the development of non-associative and associative fentanyl tolerance is consistent with findings obtained with morphine showing that conditions conducive to the development of non-associative tolerance disrupt the acquisition of associative tolerance. The cross-tolerance data, however, did not parallel previous research examining the cross-tolerance profiles of associative and non-associative morphine tolerance.

Rationale: Discriminative stimulus effects of mu opioids vary systematically as a function of training dose. Differences among training doses may arise from multiple mechanisms., Objectives: In vivo apparent pA(2) analyses were used to examine the contributions of opioid mechanisms to stimulus control by low and high training doses of the mu opioid fentanyl., Methods: Saline and one of two doses of fentanyl, administered s.c., were established as discriminative stimuli in two groups of rats (low training dose group: 0.01 mg/kg; high training dose group: 0.04 mg/kg). Generalization tests and in vivo apparent pA(2) analyses were used to evaluate receptor mechanisms of stimulus control., Results: Fentanyl, etonitazene, methadone, and morphine evoked full fentanyl generalization in both groups but were more potent in the low-dose group. Spiradoline and d-amphetamine did not evoke generalization in either group. Naltrexone antagonized stimulus and rate-altering effects of fentanyl in both groups, with apparent pA(2) values of 7. 6 in the low-dose group and 7.5 in the high-dose group. Nalbuphine and nalorphine evoked full generalization in the low-dose group but less than 40% generalization in the high-dose group. In the high-dose group, nalbuphine and nalorphine antagonized the stimulus and rate-altering effects of fentanyl with apparent pA(2) values of 5.3 and 6.1, respectively, demonstrating lower efficacy mu actions., Conclusions: Changes in fentanyl training dose preserved the mu opioid selectivity of stimulus control but altered the intensity of the transduced mu opioid stimulus required for generalization. These differences in intensity of the fentanyl stimulus determined whether low efficacy mu opioids would evoke or antagonize fentanyl generalization.

Previous research in squirrel monkeys has shown enhancement of the discriminative stimulus effects of cocaine by mu-opioid agonists, but not by the delta agonist BW373U86. To examine further the role of mu and delta receptor stimulation in the ability of opioid drugs to modulate the discriminative stimulus effects of cocaine, the present study assessed the effects of cocaine alone and combined with SNC 80, a selective high-efficacy delta agonist, and fentanyl, a selective high-efficacy mu agonist. Five adult male squirrel monkeys were trained to discriminate i.m. injections of 0.3 mg/kg cocaine from saline under a fixed-ratio 10 schedule of food presentation. Cumulative doses of cocaine (0.03-1.0 mg/kg) engendered dose-related increases in drug-lever responding to a maximum of 100%, with a decrease in response rate observed at 1.0 mg/kg. Cumulative doses of SNC 80 (0.03-1.0 mg/kg) or fentanyl (0.001-0.01 mg/kg) resulted in a maximum of 22% and 48% drug-lever responding, respectively, accompanied by pronounced decreases in response rate. Administration of either SNC 80 (0.1-1.0 mg/kg) or fentanyl (0.001-0.01 mg/kg) prior to cumulative doses of cocaine produced dose-dependent leftward shifts in the cocaine dose-response function. When the selective delta antagonist naltrindole (1.0 mg/kg) was combined with SNC 80 (1.0 mg/kg) or fentanyl (0.01 mg/kg) prior to cumulative doses of cocaine, the leftward shift of the cocaine dose-response function produced by SNC 80 was blocked, whereas the leftward shift produced by fentanyl was not. By contrast, the mu antagonist naltrexone (0.3 mg/kg) blocked the cocaine-enhancing effects of fentanyl, but not of SNC 80. Combinations of SNC 80 (0.03-0.3 mg/kg) with fentanyl (0.001-0.003 mg/kg) resulted in leftward shifts in the cocaine dose-response function that were comparable in magnitude to the shifts in the cocaine dose-response function produced by either drug alone. These results suggest that opioid enhancement of the discriminative stimulus effects of cocaine is mediated independently by delta- and mu-receptor mechanisms.

The purpose of the present investigation was to examine the development of tolerance to the rate-suppressing effects of mu and kappa opioids in rats administered either 3.0 (low) or 30 (high) mg/kg per day of butorphanol, an opioid with low relative efficacy at the mu receptor. The mu opioids butorphanol, buprenorphine, morphine, fentanyl and sufentanil, and the kappa opioid U50,488 dose-dependently suppressed responding under all conditions examined. In rats administered the low maintenance dose of butorphanol, tolerance developed to the effects of butorphanol, buprenorphine and morphine, but not to fentanyl and sufentanil. In rats administered the high maintenance dose, tolerance developed to all of the mu opioids examined. In both treatment groups, the degree to which tolerance developed was greater for butorphanol and buprenorphine than for morphine, fentanyl and sufentanil; and the degree to which tolerance developed to these mu opioids was greater in rats administered the high maintenance dose of butorphanol. The tolerance that developed to morphine, fentanyl and sufentanil was not altered when tested at both 23 and 47 h following the previous maintenance dose of butorphanol, suggesting that these changes were not due to any acute pharmacological interactions between butorphanol and the test compound (i.e., antagonism). Tolerance was also conferred to the kappa opioid U50,488 in both groups of rats, and in rats administered the high maintenance dose, this effect was obtained when tested 23 and 47 h following the previous maintenance dose of butorphanol. Physical dependence developed in rats administered the high maintenance dose of butorphanol, as evidenced by the development of enhanced sensitivity to the rate-suppressing effects of naloxone, and the finding that 30 mg/kg naloxone decreased body weight in a time-dependent manner. No physical dependence was apparent in rats administered the low maintenance dose of butorphanol. These data suggest that during chronic treatment with butorphanol, (1) greater degrees of tolerance are conferred to drugs possessing low efficacy at the mu opioid receptor, (2) tolerance is enhanced as the maintenance dose of the toleragen is increased, and (3) mu-opioid tolerance may be observed under conditions that do not produce mu-opioid dependence.

The purpose of the present study was to determine the relative intrinsic efficacy of various opioids using the irreversible mu opioid antagonist beta-funaltrexamine (betaFNA). To this end, pigeons were trained to discriminate 3.0 (n=6) or 1.8 (n=1) mg/kg morphine from distilled water in a two-key, food-reinforced, drug discrimination procedure. The mu opioids fentanyl, l-methadone, buprenorphine, butorphanol, nalorphine, nalbuphine and levallorphan, as well as the delta opioid BW373U86, substituted completely for the morphine stimulus. The stimulus effects of morphine were antagonized (i.e., produced a significant increase in the ED50 value) by a 10 mg/kg but not a 5 mg/kg dose of betaFNA. Antagonist effects of betaFNA were observed following a 2-h pretreatment, but not following 26-, 50-, 74-, 98- or 146-h pretreatments. The stimulus effects produced by fentanyl, l-methadone and buprenorphine were not antagonized by doses of betaFNA as high as 20, 10 and 10 mg/kg, respectively. The lowest dose of betaFNA required to antagonize the stimulus effects of butorphanol was 10 mg/kg, whereas the effects of nalorphine, nalbuphine and levallorphan were antagonized by a dose of betaFNA as low as 5 mg/kg. The delta BW373U86 substituted for the morphine stimulus, and this effect was not antagonized by 10 mg/kg betaFNA. The pkB values for naloxone (1.0 mg/kg) against the stimulus effects of fentanyl (6.70) and morphine (6.52) were considerably higher than that for BW373U86 (4.60), indicating further that the morphine-like stimulus effects produced by BW373U86 were not mediated by activity at the mu opioid receptor. These findings indicate that the strategy of irreversible antagonism can be used effectively to differentiate opioids with varying degrees of intrinsic efficacy at the mu opioid receptor in a pigeon drug discrimination procedure. In particular, the ranking of these drugs by relative intrinsic efficacy at the mu opioid receptor is: l-methadone=fentanyl> or =buprenorphine> or =morphine> or =butorphanol>nalorphine=nalbuphine=levallorphan. Additionally, the short-acting effect of betaFNA in the pigeon suggests that the recovery of mu opioid receptor function varies across species.

Mirfentanil is a fentanyl derivative with non-opioid actions, including non-opioid antinociceptive effects in rhesus monkeys. The current study examined the rate-altering effects of mirfentanil and several other compounds in pigeons to assess: 1) the opioid and non-opioid actions of acutely-administered fentanyl derivatives; and 2) the development of cross-tolerance between each of these compounds and morphine. Seven pigeons responded under a fixed-ratio 20 (FR20) schedule of food delivery. In untreated pigeons, fentanyl, morphine, naltrexone, ketamine and three fentanyl derivatives (mirfentanil, OHM3463 and OHM3295) decreased rates of key pecking in a dose-related manner. Naltrexone (0.1-1.0 mg/kg) attenuated the effects of OHM3463 and not mirfentanil or OHM3295, suggesting non-opioid mediation of the rate-decreasing effects for the latter two fentanyl derivatives. Subjects were treated daily with morphine for 9 weeks, up to a dose of 100 mg/kg per day, during which time the dose-effect curves for morphine, fentanyl and OHM3463 shifted rightward 6-, 10- and 2-fold, respectively, indicating the development of tolerance to morphine and cross-tolerance to fentanyl and OHM3463. Dose-effect curves for ketamine, OHM3295 and mirfentanil were not shifted to the right during morphine treatment, and the dose-effect curve for naltrexone was shifted leftward 180-fold. To the extent that rate-decreasing effects are predictive of antinociceptive effects, these data suggest that some fentanyl derivatives might be useful therapeutics under conditions where tolerance develops to morphine-like opioids.

The purpose of these experiments was to examine the relationship of agonist relative efficacy to the pattern of tolerance and cross-tolerance to the morphine-like stimulus effects of three opioid agonists. Rats were trained to discriminate 3.2 mg/kg morphine from saline under fixed-ratio 15 schedule of food reinforcement. Morphine, nalbuphine, and fentanyl produced dose-dependent increases in morphine-like stimulus effects and decreases in response rates. Repeated treatment with 20 mg/kg per day morphine increased the ED50 for stimulus control by fentanyl, morphine, or nalbuphine two-, four-, or 40-fold, respectively. Repeated treatment with 64 mg/kg per day nalbuphine increased the ED50 for stimulus control for morphine by two-fold, but lower or higher treatment doses had no significant effect. Treatment with 100 mg/kg per day nalbuphine increased the ED50 for nalbuphine by six-fold. Repeated treatment with 0.22 mg/kg per day fentanyl increased the ED50 for stimulus control by fentanyl or morphine by approximately two-fold. Comparisons among treatment conditions suggested that magnitude of tolerance to morphine-like stimulus effects did not vary as an inverse function of the relative efficacy of the agonist used for repeated treatment. Rather repeated morphine and fentanyl treatments produced comparable tolerance, whereas repeated nalbuphine treatment did not evoke substantial tolerance. Comparisons within treatment conditions, however, suggested that magnitude of tolerance may vary inversely with relative efficacy of the agonist tested for morphine-like stimulus effects. During treatment with morphine or fentanyl, greater tolerance was observed to the morphine-like stimulus effects of the lower efficacy agonist relative to the higher efficacy agonist.

The delta opioid agonist BW373U86 was examined alone and in combination with mu agonists in pigeons trained to discriminate the mu agonist fentanyl (0.056 mg/kg), the kappa agonist bremazocine (0.017 mg/kg), and distilled water in a three-choice drug discrimination procedure. BW373U86 (0.01-10 mg/kg) produced a dose-dependent increase in fentanyl-appropriate responding and complete generalization to fentanyl in four of five subjects. BW373U86 did not elicit bremazocine-appropriate responding in any of the subjects. Fentanyl-appropriate responding elicited by BW373U86 was antagonized by the delta selective antagonist naltrindole (0.1-10 mg/kg) but not by the mu selective antagonist naloxone (0.1-30.0 mg/kg). When BW373U86 was administered in combination with the mu agonists fentanyl, morphine and nalbuphine, a low dose of BW373U86 (0.01 mg/kg) that elicited primarily water-appropriate responding when administered alone did not produce a significant change in the ED50 values for fentanyl, morphine or nalbuphine. Higher doses of BW373U86 (0.1-1.0 mg/kg) increased levels of fentanyl-appropriate responding elicited by low doses of fentanyl, morphine and nalbuphine to levels similar to those produced by BW373U86 alone. These results indicate that BW373U86 shares discriminative stimulus properties with the mu agonist fentanyl in pigeons, possibly by acting at delta opioid receptors. However, BW373U86 does not potentiate the discriminative stimulus effects of mu agonists or share discriminative stimulus effects with the kappa agonist bremazocine.

The ability of mu and kappa opioids to alter the discriminative-stimulus and rate-decreasing effects of the 5-HT1A receptor agonist 8-OH-DPAT was examined in rats trained to discriminate either a low (0.1 mg/kg) or a high (0.3 mg/kg) dose of 8-OH-DPAT from water using a two-lever food-reinforced drug discrimination procedure. The mu opioids, morphine and fentanyl, and the kappa opioids, U50,488 and bremazocine, failed to substitute for the 8-OH-DPAT stimulus, even when tested up to doses that substantially reduced rates of responding. During antagonism tests, selected doses of the mu opioids, morphine and fentanyl, administered at various pretreatment times, attenuated the stimulus effects of both training doses of 8-OH-DPAT. Moreover, morphine (135-min pretreat) and fentanyl (15-min pretreat) produced rightward shifts in the 8-OH-DPAT dose-effect curve that were partially surmountable and naltrexone-reversible. In contrast to the effects of the mu opioids, the kappa opioids, U50,488 and bremazocine, failed to alter the stimulus effects of the training dose of 8-OH-DPAT, regardless of dose or pretreatment time. The rate-decreasing effects of 8-OH-DPAT were not altered substantially by either the mu or kappa opioids examined. The present study demonstrates that the stimulus effects, but not the rate-decreasing effects, of 5-HT1A receptor agonists can be modulated by mu opioids, whereas neither of these effects are changed by kappa opioids.

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.

The effects of the opioids alfentanil (A), fentanyl (F), and sufentanil (S) on cerebral blood flow (CBF) and intracranial pressure (ICP) have been discussed in several recent publications. The purpose of this review is to describe the results of studies in animals, healthy volunteers, and patients with and without intracranial diseases. Clinical relevance and mechanisms of the reported ICP and CBF increases are analysed. METHODS. Approximately 70 original articles and abstracts were retrieved by a systematic literature search using the key word list at the end of this abstract. The cited studies came from computerised database systems like Silver Platter and DIMDI, the SNACC reference list, and the bibliographies of pertinent articles and books. These studies were classified into three groups: significant increase of ICP and/or CBF; no significant or clinically relevant alterations; and significant decreases of ICP and/or CBF. RESULTS. The numerical relationship was 6:7:3 for A, 7:16:9 for F, and 5:11:8 for S. Increases of previously normal or only slightly elevated ICP were registered in some studies in connection with a decrease in mean arterial pressure (MAP). On the other hand, in patients with brain injury and elevated ICP opioids did not further increase ICP despite MAP decreases. In studies monitoring ICP and/or CBF continuously, transient and moderate increases of questionable clinical relevance became apparent a few minutes after bolus injection of opioids. Alterations of systemic and cerebral haemodynamics observed after bolus application were not registered during continuous infusion of A and S. DISCUSSION AND CONCLUSIONS. The cerebral effects of opioids are dependent on several factors, e.g., age, species, ventilation, anaesthesia before and during measurements, systemic haemodynamics, and underlying diseases. The probable mechanism of ICP increase during decreasing MAP is cerebral vasodilatation due to maintained autoregulation. With increasing severity of the cerebral lesion autoregulation is often disturbed. Therefore, ICP often remains unaltered despite MAP decreases. However, the resulting decrease in cerebral perfusion pressure makes such patients more susceptible to develop ischaemic neurological deficits. Induction of somatic rigidity or (with high doses) convulsions, exceeding the upper limit of autoregulation, histamine release, cerebral vasodilatation, increased cerebral oxygen consumption, or carbon dioxide accumulation during spontaneous breathing were discussed as mechanisms for transient ICP/CBF increases. It is concluded that opioids are often beneficial and not generally contraindicated for patients with cerebral diseases and compromised intracranial compliance. However, since negative side effects cannot be excluded, opioid effects and side effects should be monitored (MAP, ICP, cerebrovenous oxygen saturation, transcranial Doppler sonography) in patients at risk. It has to be stressed that opioids should be administered only to patients with stable haemodynamic situations and preferably in well-titrated, continuous infusions.

The introduction of the new opioid, sufentanil, into clinical practice should focus on the following questions: (1) What are the pharmacokinetic features of sufentanil that make it different from the well-established congeners alfentanil and fentanyl and open the way to new perspectives? and (2) Does sufentanil offer any particular advantages for specialised surgical procedures that make it the drug of first choice? Pharmacokinetics. Sufentanil is a potent analgesic with a very high receptor affinity and specificity, high lipid solubility, marked protein binding, and a shorter elimination half-life than fentanyl. Due to the high hepatic extraction ratio, metabolic degradation and elimination depend more on hepatic perfusion than on enzyme activity or renal clearance. However, changes in plasma protein concentration, volume of distribution, protein binding, or acid-base status may significantly alter the pharmacokinetic profile and prolong clinical effects. Pharmacodynamics. Several clinical trials have focused on the haemodynamic response to surgical manipulation, stress protection, induction time, and recovery time: 1. Induction of anaesthesia with low, medium, or high doses of sufentanil generally provide a stable haemodynamic profile comparable to that of fentanyl following intubation and surgical manipulation, even in cardiovascular risk patients. 2. Severe decreases in systolic blood pressure and bradycardia may occur in the dehydrated patient or in combination with vecuronium, however. 3. Despite some evidence of endocrinologic and metabolic stress protection in cardiac surgery in particular, an increase of hormonal stress parameters can only be ascertained prior to extracorporeal circulation. However, the clinical value of endocrinologic stress protection in terms of mortality and outcome has yet to be verified. 4. Induction time is significantly shorter with sufentanil compared to fentanyl, indicating a central sedative effect. 5. Despite experimental evidence of cerebral vasodilatation and increased intracranial pressure, there seems to be no disruption of cerebrovascular autoregulation in patients with normal intracerebral pressure. 6. Common side effects such as nausea, vomiting, and truncal rigidity occur in up to 30% of patients and are comparable to those after other opioids. 7. In the postoperative period the advantage of an intermediate elimination half-life seems to be out-weighed by the effects of volatile anaesthetics or sedatives on respiratory depression and postoperative recovery following balanced anaesthesia. 8. Epidural application of 10-50 micrograms sufentanil provides rapid and effective pain relief within 5-7 min for a period of 3-7 h. Doses of more than 50 micrograms seem to increase the risk of respiratory depression without further improvement of analgesia. Analgesia may be enhanced by combination with local anaesthetics or clonidine.(ABSTRACT TRUNCATED AT 400 WORDS)

The effect of 15 min/day of immobilization (IM) stress on oral self-administration (SA) of morphine (0.5 mg/ml) or fentanyl (25 micrograms/ml) and withdrawal was examined in rats. In addition, the role of conditioning factors in these effects was assessed. For each drug, four groups of subjects were exposed for 50 days to IM stress prior to the drug SA period [Paired-Stress (P-S) groups], to IM stress prior to the drug SA period on half of the days and after the drug SA period on the rest of the days [Partial Paired-Stress (PP-S) groups], to IM stress several hours after the drug SA period [Unpaired-Stress (UP-S) groups], or to no IM stress [Control (C) groups]. The P-S and PP-S groups increased their drug SA during choice days in which both the opioid solution and water were available, and tended to manifest a more severe withdrawal syndrome after a naloxone challenge compared with the UP-S and C groups. Reinstatement of the opioid SA under conditions of paired-stress or no stress was further examined after 3 weeks without exposure to either stress or drugs. The paired stress animals had higher levels of drug SA and manifested a more severe withdrawal syndrome than those tested without stress. These results indicate that the learned association between exposure to stress and the drug availability may mediate, in part, the stress-induced enhancement of opioid SA and withdrawal effects.

Whereas the efficacy of flumazenil (Fl) for improving vigilance in the presence of other benzodiazepine agonists (BZA) is undoubted, its effect on BZA- and/or opioid agonists (OA)-induced respiratory depression is the subject of controversies. Some authors describe an improvement of a midazolam (Mi)-induced increase in paCO2, whereas others cannot find any influence on diazepam-induced respiratory depression. In two studies in which Fl was used to antagonize Mi/Fentanyl (Fe) anaesthesia we found even worse oxygen saturation values than with placebo (Pl). All our previous studies indicate a slight intrinsic activity of Fl on respiration in the presence of opioids. We therefore investigated the influence of Fl and Pl on expiratory pCO2 and oxygen saturation (SAT). METHODS. A group of 15 male, healthy volunteers aged 20-30 years gave written informed consent to participate in this double blind study, which was approved by our Institutional Review Board. Each subject received 3 micrograms/kg body wt. Fe + 0.5 mg Fl and 1 week later 3 micrograms/kg body wt. Fe + 5 ml NaCl 0.9% (Pl) i.v., in random order. They were undisturbed and breathed spontaneously. The following parameters were measured: SAT, pCO2 and heart rate (HR) continuously, using a pulse oximeter (SAT, H) and CO2 infrared absorption monitor (Oscar, Messrs., Datex). The blood pressure was recorded before and after a 5-min preinjection period (baseline) and at the end of the procedure (25 min). The data were stored in a microcomputer (Multitalent, Messrs. ZAK) and transmitted to a PC after each trial. STATISTICS. The groups were compared with the Wilcoxon rank sum test. P less than 0.05 is significant. RESULTS. In trials 1 and 2 there was an increase of pCO2 and a drop in SAT. The changes in pCO2 and SAT were more pronounced after Fe+Fl in 12 subjects (80%), as against 1 subject with the opposite result. There were 2 subjects who showed no difference between trials 1 and 2. The combination of Fe and Fl caused significantly higher increases in pCO2 (P = 0.007) and more pronounced decreases in SAT (P = 0.04) than Fe and Pl. DISCUSSION. These results indicate a slight enhancement of Fe-induced respiratory depression by Fl. In a previous study it could be shown that Fl antagonized the respiratory depressive effect of Mi, but baseline paCO2 was not completely recovered. In previous studies respiratory function impaired by Mi+Fe was initially improved by Fl, but rebound effects on SAT were observed, which were more pronounced than those after Pl. Therefore, respiratory function must be closely monitored in Fl-antagonized patients after Mi/Fe anaesthesia.

The recent synthesis of fentanyl derivatives, some of which appear to have novel profiles of pharmacological effects, has provided compelling evidence that mu opioid efficacy might be altered systematically by modifications in the parent compound fentanyl. In the present study a new 4-(heteroanilido)-piperidine, compound 28, was studied for its effects in rhesus monkeys. In self-administration studies compound 28 maintained rates of lever pressing similar to those maintained by alfentanil; the reinforcing effects of compound 28 were attenuated by the opioid antagonist quadazocine. In drug discrimination studies compound 28 did not substitute for the kappa agonist ethylketocyclazocine and did substitute for the mu agonist alfentanil. In morphine-treated subjects discriminating between saline and naltrexone, compound 28 did not substitute for naltrexone; however, in morphine-abstinent subjects compound 28 reversed naltrexone lever responding. Moreover, this discriminative stimulus effect in morphine-abstinent subjects was antagonized by naltrexone and by quadazocine in a manner consistent with mu receptor mediation. Compound 28 also was an effective analgesic in a warm-water, tail-withdrawal procedure and it decreased markedly respiratory function. The analgesic effects as well as the respiratory depressant effects of compound 28 were antagonized by quadazocine. Together, these results show compound 28 to be a potent, efficacious mu agonist of similar potency to alfentanil. Large differences in apparent efficacy at mu receptors between compound 28 and another compound in this series (mirfentanil), clearly demonstrate that, within this chemical family, small chemical changes can confer significant differences in pharmacologic effect.

Fentanyl is a mu opiate agonist which is occasionally abused by medical personnel who have ready access to the drug. We examined in healthy volunteers (N = 13) the subjective and psychomotor-impairing effects of intravenous fentanyl (0-100 micrograms/70 kg). A randomized, placebo-controlled, crossover design was used in which subjects were injected with 0, 25 (N = 6), 50 and 100 micrograms/70 kg fentanyl in a double-blind fashion. Subjects completed several questionnaires commonly used in abuse liability testing studies before drug injection and at periodic intervals for up to 3 h after drug injection. Subjects also completed several psychomotor tests at these times. Some aspects of psychomotor functioning (e.g., eye-hand coordination) were impaired by fentanyl. Fentanyl produced dose-related increases in ratings of "high" and "sedated," but also tended to produce dysphoria and somatic symptomatology. Most subjects reported liking the effects of the two higher doses of fentanyl for at least a brief time after injection, but they varied widely in their linking ratings across the 3-h post-drug injection period. Despite the transient increases in liking ratings, fentanyl did not increase scores on a widely-used measure of drug-induced euphoria (morphine-benzedrine group scale of the Addiction Research Center Inventory). The present results suggest that some medical personnel who experiment with fentanyl may like it, and thus be at increased risk for abusing the drug in the future.

The intracranial hemodynamic and metabolic effects of 20 micrograms/kg sufentanil were studied in ten mongrel dogs. Anesthesia was maintained with 0.7 vol.% end-tidal isoflurane and 50% nitrous oxide in oxygen. Catheters were inserted into both femoral arteries and veins, the superior sagittal sinus, the left atrium, and the lateral cerebral ventricle for blood pressure measurement, arterial and sagittal sinus blood sampling, radioactive microsphere injections, and intracranial pressure (ICP) monitoring. Cardiac output (CO) was measured using an electromagnetic flow probe on the pulmonary artery. Following baseline measurements, sufentanil was injected and data were recorded at 5, 15, and 30 min. RESULTS. In group 1 (n = 5) blood pressure was not controlled, while in group 2 (n = 5) blood pressure was maintained at baseline level with a phenylephrine infusion. Arterial blood pressure decreased by 32% in response to sufentanil in group 1 and remained constant in group 2 according to the protocol. CO decreased by 40%-50% in both groups. Regional and global cerebral blood flow (CBF) decreased by 25%-40% with no difference between groups. The cerebral hemodynamic changes were associated with a decrease of 35%-40% in cerebral oxygen consumption. ICP did not change over time. DISCUSSION. These data are in contrast to studies in dogs, where sufentanil produced non-dose-dependent increases in CBF and ICP. Our results are more consistent with studies in humans and rats where administration of sufentanil was associated with either no change or decreases in cerebral hemodynamics, metabolism, and ICP. We conclude that in dogs with normal intracranial physiology sufentanil decreases regional and global CBF in response to a decrease in cerebral metabolic demand without significantly affecting ICP.

Use of the benzodiazepine antagonist flumazenil may inhibit the effects of benzodiazepines in a competitive manner. The only known partially agonistic effect of flumazenil is a weak anticonvulsive action at high doses. However, reports have claimed that flumazenil reduces the MAC of isoflurane in animal studies. Other reports have found that antagonizing midazolam-induced sedation or anesthesia by flumazenil led to an increase in respiratory depression. The aim of this study was to examine whether flumazenil i.v. increases fentanyl-induced respiratory depression. METHODS. In two separate sessions, ten healthy young volunteers were given either 0.0027 mg/kg fentanyl alone or 0.0027 mg/kg and 1 mg flumazenil i.v. over 4 min each time. The CO2 rebreathing method was used to determine the ventilatory response. RESULTS. Fentanyl alone brought about a significant reduction in CO2 response, characterized by a shift to the right and a decrease in the slope of the rebreathing curve (from 1.95 +/- 0.76 l.min-1.mmHg-1 to 0.86 +/- 0.53 l.min-1.mmHg-1). The infusion of additional flumazenil caused similarly significant respiratory depression (from 2.21 +/- 1.0 l.min-1.mmHg-1 to 0.77 +/- 0.38 l.min-1.mmHg-1). In both groups changes persisted for at least 120 min. No statistically significant differences between the two groups could be detected. CONCLUSION. Flumazenil does not enhance fentanyl-induced respiratory depression. Flumazenil's weak, partially agonistic action is therefore of no clinical importance.

Numerous reports have concluded that propofol is suitable for maintenance of anesthesia by continuous infusion. The aim of this study was to evaluate the use of propofol and fentanyl for coronary bypass surgery in patients with good left ventricular function. The effects of this anesthetic combination on quality of anesthesia, hemodynamic status, and endocrine and metabolic responses were assessed. Postoperative recovery and side effects were also noted. The effects were compared with those of a standard method using etomidate, midazolam, and fentanyl. METHODS. Twenty patients who presented for aortocoronary bypass surgery (NYHA class II-III) were randomly allocated to one of two groups: propofol-fentanyl (group A) or etomidate-midazolam-fentanyl (group B). In each patient the dosage of the drugs was adjusted to obtain the optimum responses during induction and maintenance. RESULTS. Propofol in combination with fentanyl diminished mean arterial pressure (-28.7%) and heart rate (-17.3%) when used for induction in patients with ischemic heart disease, even in low doses and with slow administration. In 5 of the 10 patients it was impossible to prevent a critical fall in coronary perfusion without active intervention. However, during maintenance anesthesia, stable circulatory parameters were obtained with both drug regimens. Clinical signs thought to reflect myocardial ischemia were not observed. In both groups reductions in basal and stimulated catecholamine secretion were demonstrated. Similarly, perioperative cortisol secretion was reduced with both techniques. Despite all the complicated metabolic inhibitory effects seen, preoperative hormonal levels were restored within 1 h of the end of anesthesia. The magnitude and duration of the metabolic changes were found to be related to the duration of surgery. There was no evidence of non-homogeneous tissue perfusion as assessed by increases in lactate concentration, cardiac ischemia, or liver dysfunction in any of the patients. There were no postoperative complications in either group, but the return of consciousness, adequate spontaneous ventilation, and psychomotor activity was more rapid in the propofol patients. CONCLUSION. In summary, it can be concluded that a propofol infusion technique positively enhances the recovery period after cardiac surgery and provides good control during anesthesia. However, the use of propofolfentanyl for induction of anesthesia in patients with limited coronary perfusion is not recommended because of its hypotensive effect.

Unlabelled: AIM OF THE INVESTIGATION: The effects of fentanyl on spontaneous respiration have been investigated in both animals and humans. The investigations in humans have been performed under circumstances and using methods that do not relate the results to clinical practice, e.g., predicting the effects of opioids used for postoperative pain relief on the ward. We investigated the effects of fentanyl on mechanical parameters, oxygen saturation (SAT), and end-expiratory CO2 (exCO2) in humans., Methods: Fifteen male volunteers took part in this study, which was approved by the local ethics committee. Each received 3 micrograms/kg fentanyl intravenously after 5 min measurement of base-line values and were observed for 30 min. We continuously registered thoracic (A1) and abdominal (A2) extension and respiratory rate (RR) using piezoceramic elements. SAT, heart rate (HR), and exCO2 were measured with a pulse oximeter and infrared absorption (OSCAR, Datex). All data were transferred to a high-performance microcomputer (Multitalent, ZAK). The statistical analysis included descriptive and correlation statistics., Results: After the injection of fentanyl A1, A2, RR, HR, and SAT were reduced; exCO2 increased. After a few minutes A1 increased, occasionally exceeding the base-line value. A2, RR, HR, and SAT increased without reaching base-line values. ExCO2 remained increased. The best overall correlation was found between A2 and SAT (r = 0.87)., Discussion: As far as comparable, our results are in accordance with those of the majority of other investigators. The difference between thoracic and abdominal extension, the latter being closely correlated with tidal volume, has not previously been described quantitatively. We attribute this result to the different innervation of the phrenic and intercostal nerves. Whereas the influence of fentanyl on SAT and exCO2 during the first 8 min can easily be explained, the varying behavior in the following minutes has not previously been described and may be due to the different binding characteristics of O2 and CO2. Alteration of the CNS setting for pCO2 may also contribute to this result. The time course of the measured parameters seems to be of clinical importance for the detection of respiratory problems in spontaneously breathing patients.

Sufentanil, a synthetic opioid that is 5-10 times as potent as fentanyl, has been suggested for use during neurosurgical procedures because it maintains cardiovascular stability and produces hypnosis without the use of additional anesthetic agents. Doses as low as 2.5 micrograms.kg-1 are reported to create deep levels of anesthesia as demonstrated by EEG changes to high-amplitude delta-waves. However, there are no reports concerning the effects of sufentanil on blood flow and metabolism in the human brain. The present study was designed to investigate the influence of high-dose sufentanil-O2 anesthesia on the cerebral circulation, metabolism, and the cerebrovascular response to CO2 in man. METHODS. Nine male and 2 female patients between 41 and 60 years of age who were scheduled for coronary artery bypass surgery were studied. Premedication consisted of flunitrazepam 2 mg orally and piritramide 15 mg and promethazine 50 mg i.m. 1 h before arrival in the induction room. Measurements were performed with the patients awake (I), after sufentanil 10 micrograms.kg-1 as an induction dose followed by 0.15 micrograms.kg-1.min-1 as an infusion with normocapnia (pa CO2 42.1 +/- 2 mmHg) (II), during hypercapnia (pa CO2 53.7 +/- 3.5 mmHg) (III), and during hypocapnia (pa CO2 31.7 +/- 2 mmHg) (IV). Cerebral blood flow (CBF) was measured using the argon wash-in technique. Cerebral venous blood was obtained from a catheter in the superior bulb of the right internal jugular vein. Cerebral metabolic rates of oxygen (CMRO2) glucose (Mgluc) lactate (CMlac) were calculated by multiplying the arterial-cerebral venous oxygen and substrate differences by CBF. The Anaerobic Index was calculated from the equation avD lactate x 100/2 x avD glucose = ANI (%) Cerebral electrical activity was recorded by aperiodic analysis of the EEG (Lifescan). RESULTS AND DISCUSSION. In the EEG sufentanil anesthesia was characterized by a decrease in the number of high-frequency waves and an increase in the number and amplitude of delta-waves, a pattern that did not change throughout the study period. Concomitantly, under normocapnic conditions high-dose sufentanil led to the significant decrease in CBF by 29% accompanied by an 18% increase in cerebral vascular resistance (CVR). CMRO2 decreased by 22% while CMRgluc and CMRlac changed only insignificantly such that the ANI, which represents the percentage of anaerobically metabolized glucose, essentially remained unchanged. Mean perfusion pressure declined by 18% but stayed within the range of autoregulation. Hypoventilation (III) was followed by an 82% increase in CBF as a result of a 55% reduction in CVR, whereas cerebral metabolic parameters did not show important changes when compared to measurement II. Hyperventilation (IV), on the other hand, produced a distinct fall in CBF by 56% to a value that was 21% below the one obtained under normocapnia. This was due to an increase in CVR of the same magnitude. There was a 31% rise in CMRO2, resulting in a decrease in cerebral venous oxygen tension, but in no case did it fall below the critical value of 20 mmHg at which tissue hypoxia becomes severe. Although CMRlac increased and CMRgluc did not significantly change, the ANI remained essentially unchanged, which suggests a predominantly aerobic metabolism. The increase in metabolic activity with sufentanil during hypocapnia might be caused by an alkalosis-induced stimulation of glycolysis. It might also be related to a reduction in the depth of anesthesia, although neither the EEG nor the hemodynamic parameters indicated this. This study shows that the coupling between CBF and metabolism is well maintained and that the cerebrovascular response to CO2 is unimpaired during high-dose sufentanil anesthesia.

If different populations of opioid receptors mediate the actions of mu and kappa opioid agonists, then tolerance induced by the chronic administration of a mu agonist should confer cross-tolerance to other mu agonists but not necessarily to those compounds whose effects are mediated by the kappa receptor. This hypothesis was evaluated in the present investigation by examining the effects of the mu agonists morphine, l-methadone and fentanyl, the kappa agonists U50,488 and bremazocine, and the mixed kappa/mu agonist ethylketocyclazocine in rats responding under a fixed-ratio 30 schedule of food presentation before, during and after exposure to a regimen of chronic morphine administration. For comparison, naloxone was evaluated as a representative mu antagonist and the phenothiazine chlorpromazine as a control drug. During all phases of the experiment, each of these compounds produced dose-related decreases in rate of responding. During the daily administration of 40 mg/kg morphine, tolerance developed to the rate-decreasing effects of morphine, l-methadone and fentanyl, and an enhanced sensitivity to the effects of naloxone. In contrast to the effects obtained with these mu opioids, there was no evidence that chronic morphine administration produced tolerance or enhanced sensitivity to the rate-decreasing effects of U50,488, bremazocine, ethylketocyclazocine and chlorpromazine. The present findings demonstrate that the chronic administration of morphine results in the selective development of tolerance to other mu agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

A group of 36 patients in the last trimester of pregnancy and scheduled for cesarean section were examined during the induction of standardized general anesthesia (methohexitone 1.5 mg/kg, succinylcholine 1.5 mg/kg). No other inhalation anesthetics than N2O/O2 (50%:50%) were administered. In addition, 18 of the women received 0.005 mg/kg fentanyl prior to intubation. The remaining 18 patients served as a control group. In the study group maternal fentanyl plasma levels were determined 1 min after injection and again at the time of omphalotomy (radioimmunoassay). Immediately after clamping of the umbilical cord the fetal fentanyl plasma levels and the pH, pCO2 and pO2 values in both umbilical vein and artery were measured. The feto-maternal ratio and the fetal uptake were calculated. RESULTS. Maternal fentanyl plasma levels decreased significantly, from 7.84 (3.55-17.24) ng/ml 1 min after injection to 5.92 (2.01-14.15) ng/ml during omphalotomy. The corresponding fentanyl plasma levels in the umbilical vein were 2.08 (0.88-3.42) ng/ml. The feto-maternal ratio was 0.44 (0.08-1.00). The induction-delivery time ranged from 2 to 8 min. There was a significant correlation between umbilical-venous fentanyl concentration and the induction-delivery time: the longer the induction-delivery time the lower the fentanyl concentration in the umbilical vein. The 1-min Apgar score was 8 (5-9), the 5-min Apgar score 9 (8-10) and the 10-min Apgar score 10 (9-10) in neonates born to the fentanyl group. Only the 1-min Apgar score was significantly lower than in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

A model of drug discrimination based on a lithium chloride (LiCl) flavour aversion was described and examined. Mildly thirsty rats were presented daily with 4 ml of a distinctly flavoured solution which was followed on 50% of the days by an IP injection of LiCl. Prior to the flavour presentation, the rats were injection SC with saline or a training drug (0.04 mg/kg fentanyl or 20 mg/kg pentobarbital) to signal whether LiCl would follow. Almost all rats eventually exhibited stable behaviour that involved drinking most or all of the fluid when it was not to be followed by LiCl and little or no drinking when it was. Such discrimination occurred regardless of whether drug predicted LiCl (learned-discomfort) or predicted no LiCl (learned-safety). However, with fentanyl there were clear differences between rats trained with drug under learned-safety and under learned-discomfort conditions for 1) the rate of acquisition of stable performance as a function of LiCl dose, 2) generalization of the training dose to a test dose that was lower, and 3) elicitation of fentanyl responses by pentobarbital. These findings, together with indications that such effects did not always occur with pentobarbital as the training drug, were discussed from theoretical and practical perspectives.

The present study was designed to explore the nature of the interaction between mu and kappa opioid agonists in the rat drug discrimination procedure. In rats trained to discriminate the kappa agonist U50,488 (5.6 mg/kg) from water, the other kappa agonist bremazocine substituted completely for the U50,488 training stimulus, and the additional kappa agonist tifluadom substituted in three of five of rats tested. In contrast, the mu agonists morphine, fentanyl, and buprenorphine produced primarily vehicle-appropriate responding. When morphine, fentanyl, and buprenorphine were combined with the training dose of U50,488, all three mu agonists reduced U50,488-appropriate responding. In rats trained to discriminate the mu agonist morphine (10.0 mg/kg) from saline, the other mu agonists morphine and buprenorphine all substituted in a dose-dependent manner for the morphine training stimulus, whereas U50,488, bremazocine, and tifluadom produced primarily vehicle-appropriate responding. When combined with the training dose of morphine, bremazocine antagonized morphine's discriminative stimulus effects, whereas U50,488 and tifluadom had no effect. The barbiturate pentobarbital neither substituted for, nor antagonized, the discriminative stimulus effects of either U50,488 or morphine. These results suggest that mu agonists and kappa agonists produce interacting effects in the drug discrimination procedure in rats.

In 36 patients with acquired heart disease effects of 0.15 mg/kg piritramide on hemodynamics, inotropic state and myocardial oxygen consumption were investigated during and after cardiac surgery (basic neuroleptanalgesia). It could be demonstrated, that piritramide is not inducing any negative inotropic effects compared to a control group (n = 36) and a fentanyl group (0.003 mg/kg, n = 31). There were only small changes in HR, SV, PRA and PLA. A slight decrease in Part, PLV, and arterial perfusion pressure during extracorporeal circulation is interpreted as a peripheral vasodilatation. The resulting decrease in heart work caused a significant decrease in myocardial oxygen consumption (-18%), which is of special advantage in patients with coronary heart disease.

The hemodynamics and the myocardial oxygen consumption during sleep and induction of anesthesia was studied in 10 patients with good left heart function (group I) and in 8 patients with bad left function (group II). Anesthesia was induced with diazepam (0.1 mg/kg BW), fentanyl (0.01 mg/kg BW), etomidate (0.2 mg/kg BW), and pancuronium (0.1 mg/kg BW). Four min after induction under ventilation with mask the cardiac index (CI) in both groups and the whole body oxygen consumption (VO2) diminished in exact the same degree. After intubation in patients of group I the CI and the VO2 decreased further, the arterio-venous oxygen content difference (avDO2) remained constant. In patients of group II the CI decreased to 0.9 1/min x m2, the avDO2 increased to 9.9 Vol%.

Favorable clinic experiences with an anaesthetic involving rohypnol (flunitrazepam) and fentanyl led to an investigation of the haemodynamic effect of this procedure in a group of 9 geriatric patients, aged from 86 to 95 years. Anaesthesia was induced with 0.5 mg rohypnol and 0.1 to 0.2 mg fentanyl depending on the narcotic effect of rohypnol, intubation was performed under relaxation with suxamethonium and long term relaxation was achieved with pancuronium. The patients were normoventilated with nitrous oxide/oxygen. The individual values of the changes in cardiac output and total peripheral resistance showed a great variation. There was a significant correlation between the relative changes in mean arterial pressure and total peripheral resistance (r = 0.69, p less than 0.05) but no correlation between mean arterial pressure and cardiac output (r = 0.09). This indicates that the pronounced drop in arterial pressure which occurred in 4 patients can be explained by a decrease in total peripheral resistance. Careful dosage of the drugs, in particular of fentanyl, and knowledge of adequate measures to treat a decrease in blood pressure if it occurs, appears to be a prerequisite for the use of this type of anaesthesia in poor risk patients.

Different groups of rats were trained to discriminate fentanyl (F) (0.03, 0.02, or 0.01 mg/kg) from saline or to discriminate 0.03 mg/kg fentanyl (F) from alternative stimulus conditions (saline, 0.15 mg/kg nicotine, or 0.01 mg/kg F). When percentage of responses on the drug lever and percentage of time spent responding on the drug lever were used as dependent variables, it was found that training dose and alternative stimulus condition both affected the ED50 and the slope of the F generalization gradient. ED50 and slope values based on group data were not significantly different from values based on individual data. Differences between from values based on individual data. Differences between the results of the first and second 2.5-min period of the extinction test were not significant. ED50 and slope values were unaffected by the preceding training session, except in the group trained to discriminate 0.03 from 0.01 mg/kg F. A lever selection measure showed a significant effect of alternative stimulus condition on ED50 values only. Training dose and alternative stimulus condition also affected the generalization to morphine. Under none of the conditions explored in this study did generalization occur to amphetamine or nicotine. The results are discussed in terms of the relative nature of drug generalization.