Caffeine Accelerates Emergence from Isoflurane Anesthesia in Humans: A Randomized, Double-blind, Crossover Study.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: There are currently no drugs clinically available to reverse general anesthesia. We previously reported that caffeine is able to accelerate emergence from anesthesia in rodents. This study was carried out to test the hypothesis that caffeine accelerates emergence from anesthesia in humans. METHODS: We conducted a single-center, randomized, double-blind crossover study with eight healthy males. Each subject was anesthetized twice with 1.2% isoflurane for 1 h. During the final 10 min of each session, participants received an IV infusion of either caffeine citrate (15 mg/kg, equivalent to 7.5 mg/kg of caffeine base) or saline placebo. The primary outcome was the average difference in time to emergence after isoflurane discontinuation between caffeine and saline sessions. Secondary outcomes included the end-tidal isoflurane concentration at emergence, vital signs, and Bispectral Index values measured throughout anesthesia and emergence. Additional endpoints related to data gathered from postanesthesia psychomotor testing. RESULTS: All randomized participants were included in the analysis. The mean time to emergence with saline was 16.5 ± 3.9 (SD) min compared to 9.6 ± 5.1 (SD) min with caffeine (P = 0.002), a difference of 6.9 min (99% CI, 1.8 to 12), a 42% reduction. Participants emerged at a higher expired isoflurane concentration, manifested more rapid return to baseline Bispectral Index values, and were able to participate in psychomotor testing sooner when receiving caffeine. There were no statistically significant differences in vital signs with caffeine administration and caffeine-related adverse events. CONCLUSIONS: Intravenous caffeine is able to accelerate emergence from isoflurane anesthesia in healthy males without any apparent adverse effects.

Phase I Study of Aurora A Kinase Inhibitor Alisertib (MLN8237) in Combination With Selective VEGFR Inhibitor Pazopanib for Therapy of Advanced Solid Tumors.

OBJECTIVES: Pazopanib is a multikinase angiogenesis inhibitor. Alisertib is a highly selective inhibitor of mitotic Aurora A kinase. There is preclinical evidence that mitosis-targeting agents exhibit antiangiogenic effects. Thus, the combination of these 2 agents may have a synergistic effect on tumor vasculature. The primary objective of this study is to determine the optimal tolerated dose (OTD) for alisertib and pazopanib. MATERIALS AND METHODS: This phase 1b study evaluated the OTD of alisertib twice a day, on days 1 to 7 with pazopanib, once a day, continuously in a 21-day cycle, both taken orally. Disease response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1 every 2 cycles. OTD cohort was expanded to assure safety and perform pharmacokinetics analysis. RESULTS: A total of 27 patients received treatment. Seventy-seven percent of the patients had received at least 3 prior chemotherapy regimens. Dose-limiting toxicities occurred in dose level (DL) 2+ (grade 4 thrombocytopenia and grade 3 mucositis) and DL 3 (grade 3 liver transaminases elevation and grade 3 abdominal pain). The OTD was determined to be DL 2: alisertib 20 mg twice daily and pazopanib 600 mg daily. Pharmacokinetic analysis revealed that clearance of alisertib was reduced by ∼40% in the presence of pazopanib compared with clearance in the absence of pazopanib. Fourteen patients had stable disease and 2 patients had a partial response. CONCLUSIONS: The combination of alisertib with pazopanib demonstrates manageable safety and early clinical evidence of antitumor activity in patients with advanced malignancies (NCT01639911).

Within-subject comparison of the psychopharmacological profiles of oral oxycodone and oral morphine in non-drug-abusing volunteers.

RATIONALE: Nonmedical use and abuse of prescription opioids is a significant problem in the USA. Little attention has been paid to assessing the relative psychopharmacological profile (including abuse liability-related effects) of specific prescription opioids. OBJECTIVES: The aim of this study is to directly compare the psychopharmacological profile of two oral opioids within the same subject. METHODS: A randomized, placebo-controlled, crossover study was done in which 20 non-drug-abusing volunteers ingested 10 and 20 mg of oxycodone, 30 and 60 mg of morphine, and placebo in separate sessions. Drug doses were equated on an objective measure of opiate effects: miosis. Subjective, psychomotor, reinforcing, and physiological effects of the opioids were assessed. RESULTS: In general, the two opioids at equimiotic doses produced similar prototypic opiate-like effects and psychomotor impairment of similar magnitude. However, several effects were found only with 20 mg oxycodone. Both drugs produced abuse liability-related subjective effects but also dysphoric effects, particularly with 60 mg morphine. Neither drug at either dose functioned as a reinforcer, as measured by the Multiple Choice Procedure. Relative potency ratios indicated an average oxycodone/morphine [corrected] ratio of 1:3 [corrected] CONCLUSIONS: The psychopharmacological profile of oxycodone and morphine at equimiotic doses had many similarities; however, differences were found in producing abuse liability-related and dysphoric effects. In the medical community, it is commonly accepted that oral oxycodone is 1.5 to 2 times as potent as oral morphine in producing analgesia; using this ratio, although patients may experience similar degrees of pain relief, those receiving oxycodone may be experiencing stronger and potentially different psychopharmacological effects.

Nonmedical use of prescription opioids: motive and ubiquity issues.

UNLABELLED: Two issues relating to prescription opioid nonmedical use that to our knowledge have not been comprehensively addressed in the peer-reviewed literature are discussed: Motives for nonmedical use and the extent of nonmedical use of prescription opioids in other countries. The United States' national annual survey on illicit drug use in the general population (National Survey on Drug Use and Health) asks respondents whether they have used prescription opioids for nonmedical purposes but does not assess motives for such use. By not assessing motives, nonmedical users who use only for pain relief and nonmedical users who have other motives for use are grouped together, but 2 recent epidemiological studies suggest that these 2 groups may differ in a propensity to have substance use-related problems. We suggest that the survey add a question that assesses motives for nonmedical use. Regarding whether countries besides the United States have problems associated with nonmedical use of prescription opioids, after searching for epidemiological surveys and other materials potentially relevant to this issue, we were unable to determine the extent of nonmedical use of prescription opioids in other countries or draw cross-national comparisons. We suggest that more countries include specific questions about nonmedical use of prescription opioids in their national epidemiological surveys. PERSPECTIVE: We believe that critical information surrounding the nonmedical use of prescription opioids is not being gathered. Such information would allow for a better understanding of the problem. We invite discussion and commentaries regarding the issues we raise to more effectively address this public health issue.

Choice of nitrous oxide and its subjective effects in light and moderate drinkers.

BACKGROUND: Alcohol-drinking status has been shown to modulate the reinforcing and subjective effects of a number of drugs. We have previously published two studies on the modulating effects of alcohol-drinking status on choice for, and subjective effects of, nitrous oxide, but the results were equivocal. Using a methodology different from our previous studies, we sought to determine in a more definitive fashion the degree to which the choice of nitrous oxide and its subjective effects were modulated by drinking status. METHODS: Four concentrations of nitrous oxide (0, 20, 30, and 40%) were administered to 16 moderate drinkers (MDs) and 16 light drinkers (LDs) across four 3.5-h sessions. During experimental sessions, subjects first completed two 10-min sampling trials in which one of the nitrous oxide concentrations and placebo (100% oxygen) were inhaled. Subjective and psychomotor tests were given 5min into each sampling trial. During the subsequent choice period, subjects were allowed to choose what they wanted to inhale (drug, placebo, or "drug-free air") on nine contiguous 5-min choice trials. RESULTS: Choice of nitrous oxide was modulated by drinking status: MDs but not LDs chose nitrous oxide significantly more times than placebo, and MDs also chose nitrous oxide significantly more times than did LDs. At each active nitrous oxide concentration, MDs reported more abuse liability-related subjective effects, especially at the 20% and 30% concentrations. CONCLUSIONS: The results of the present study provide more conclusive evidence that choice as well as subjective effects of nitrous oxide is modulated by alcohol-drinking status.

Choice of sevoflurane and its subjective and psychomotor effects in light and moderate drinkers.

BACKGROUND: Sevoflurane, an inhalant of the volatile anesthetic class, has neurobiological and behavioral effects in common with abused inhalants and ethanol. We sought to determine if choice for subanesthetic doses of sevoflurane, and its subjective and psychomotor effects, would differ as a function of alcohol-drinking status in healthy volunteers. METHODS: The effects of four concentrations of sevoflurane (0, 0.2, 0.4, 0.8% sevoflurane in oxygen) were studied in 16 light drinkers and 16 moderate drinkers. During each of four sessions, subjects sampled a concentration of sevoflurane and 100% O(2) (placebo) for 10 min each. Subjective and psychomotor testing commenced 5 min into each sampling trial. Later, within the session, subjects chose nine times, once every 5 min, among sevoflurane (e.g., "Agent A"), placebo (e.g., "Agent B," 100% O(2)), or neither (and were administered 100% O(2), identified as "drug-free air"). RESULTS: Choice for sevoflurane at the 0.4% concentration was significantly higher in the moderate drinkers than in the light drinkers. A number of subjective effects reported during inhalation of sevoflurane were markedly lower in the moderate-drinking group than in the light-drinking group. However, psychomotor impairment induced by sevoflurane was similar in magnitude in both groups. CONCLUSIONS: Alcohol-drinking status affected sevoflurane choice. The results are consistent with several studies comparing light and heavier drinkers, using other drugs. Although both drinking groups were similarly impaired by sevoflurane, the moderate drinkers reported less of a subjective response than light drinkers, suggestive of cross-tolerance.

Subjective, psychomotor, and physiological effects profile of hydrocodone/acetaminophen and oxycodone/acetaminophen combination products.

OBJECTIVES: To compare within the same individuals two typically prescribed doses of hydrocodone/acetaminophen and oxycodone/acetaminophen products for their subjective, psychomotor, and physiological effects in healthy volunteers. DESIGN: A randomized, placebo-controlled, double-blind, crossover, six-session clinical laboratory study, enrolling 16 healthy participants (27.2 +/- 4.4 years of age). Participants received 5 mg hydrocodone/325 mg acetaminophen, 10 mg hydrocodone/650 mg acetaminophen, 5 mg oxycodone/325 mg acetaminophen, 10 mg oxycodone/650 mg acetaminophen, 650 mg acetaminophen, and placebo in different sessions. RESULTS: Oxycodone/acetaminophen and hydrocodone/acetaminophen at the 5-mg opioid dose produced few subjective effects and no significant psychomotor impairment. Relative to placebo, the 10-mg oxycodone combination produced a wider spectrum of subjective effects that were statistically significant than did the 10-mg hydrocodone combination. The 10-mg oxycodone combination also produced a greater degree of miosis than the 10-mg hydrocodone combination. Both drug combinations impaired psychomotor performance at the 10-mg opioid dose. CONCLUSIONS: The results of this study, albeit in pain-free individuals, may inform physicians who prescribe, and pharmacists who dispense, two widely prescribed opioid/acetaminophen combination products on how patients might be feeling from the drugs. Patients prescribed either of the two opioid/acetaminophen combination products may experience a number of subjective effects, including effects that would contraindicate certain activities, and they should be cautioned accordingly. However, this study documented rather large differences in magnitude of subjective effects between 10 mg oxycodone/650 mg acetaminophen and placebo, and physicians and pharmacists, and ultimately patients, should be aware of these differences.

Within-subject comparison of the subjective and psychomotor effects of a gaseous anesthetic and two volatile anesthetics in healthy volunteers.

Inhalant abuse is a serious public health problem throughout the world. The present study compared the states of intoxication produced by three inhaled anesthetics that represent two of the three major classes of abused inhalants, as classified by [Balster, R.L., 1998. Neural basis of inhalant abuse. Drug Alcohol Depend 51, 207-214.]. Isoflurane and sevoflurane represent the class of volatile substances, and nitrous oxide (N2O) comprises a class of its own. Fourteen healthy volunteers inhaled the vehicle (100% O2) and two concentrations each of isoflurane (0.1 and 0.2%), sevoflurane (0.2 and 0.4%), and N2O (15 and 30%) for 40 min each, across seven separate sessions. Drug concentrations were chosen to produce similar ratings of drug effect strength and similar impairment on a psychomotor test, the digit-symbol substitution test (DSST). Ratings of drug effect strength and performance on the DSST were similar across drugs; however, the volatile anesthetics produced greater sedation and greater impairment on three other psychomotor tests than N2O, whereas N2O produced a greater magnitude of putatively pleasant and psychedelic-like subjective effects. These results are consistent with the drugs' putative receptor mechanisms of action and confirm Balster's classification of the volatile anesthetics into a class distinct from N2O.

The Role of Forkhead Box Protein M1 in Breast Cancer Progression and Resistance to Therapy.

The Forkhead box M1 (FOXM1) is a transcription factor that has been implicated in normal cell growth and proliferation through control of cell cycle transition and mitotic spindle. It is implicated in carcinogenesis of various malignancies where it is activated by either amplification, increased stability, enhanced transcription, dysfunction of regulatory pathways, or activation of PI3K/AKT, epidermal growth factor receptor, Raf/MEK/MAPK, and Hedgehog pathways. This review describes the role of FOXM1 in breast cancer. This includes how FOXM1 impacts on different subtypes of breast cancer, that is, luminal/estrogen receptor positive (ER+), expressing human epidermal growth factor receptor 2 (HER2), basal-like breast cancer (BBC), and triple negative breast cancer (TNBC). The review also describes different tested preclinical therapeutic strategies targeting FOXM1. Developing clinically applicable therapies that specifically inhibit FOXM1 activity is a logical next step in biomarker-driven approaches against breast cancer but will not be without its challenges due to the unique properties of this transcription factor.

Profiling the subjective, psychomotor, and physiological effects of tramadol in recreational drug users.

Tramadol is a mu opioid agonist that also inhibits the reuptake of norepinephrine and serotonin. Because non-medical use of prescription opioids, including tramadol, has increased in the U.S. over the last several years, we sought to profile its subjective, psychomotor, and physiological effects in recreational drug users. Twenty-two subjects received placebo, 50 or 100 mg tramadol, morphine, or 2 mg lorazepam in a randomized, crossover, double-blind design. The last 12 subjects in the study received 25 mg morphine, a dose that is putatively equianalgesic to 100 mg tramadol. In these subjects, morphine induced miosis and several other mu agonist subjective effects; 100 mg tramadol increased "feel drug effect" and drug liking ratings, and decreased pupil size, but the miotic effect was not statistically significant. Lorazepam, but neither tramadol nor morphine, impaired psychomotor performance. When the placebo, tramadol, and lorazepam data from all 22 subjects were analyzed, 100 mg tramadol induced miosis, and several subjective effects were increased significantly, including ratings of drug liking and "want to take again." The present results indicating that a clinically-prescribed dose of oral tramadol has abuse liability-related effects in recreational drug users suggest the need for further abuse liability testing of the oral formulation in opioid abusers.

Profiling the subjective, psychomotor, and physiological effects of a hydrocodone/acetaminophen product in recreational drug users.

BACKGROUND: Hydrocodone (HYD) is a mu opioid agonist. Hydrocodone/acetaminophen HYD/ACET compounds are both widely prescribed and abused prescription painkillers in the United States. In the present study, we profiled the subjective, psychomotor, and physiological effects of the compound. It was of particular interest to determine if HYD/ACET had abuse liability-related subjective effects in a population of recreational drug users. METHODS: Eighteen volunteers participated in a crossover, randomized, double-blind study in which they received, all p.o., placebo; 5 mg HYD/500 mg ACET; 10mg HYD/500 mg ACET; 20 mg HYD/1000 mg ACET; 40 mg morphine (MOR) sulfate; and 1000 mg ACET. Measures were assessed before and for 300 min after drug administration. RESULTS: HYD/ACET produced effects that were dose-related, and the highest dose produced a similar magnitude of effect to that of MOR. There were some abuse liability-related subjective effects produced by 20 mg HYD/ACET and MOR, but there were also unpleasant effects. Some unpleasant subjective effects were experienced only by females. Overall liking and "take again" ratings assessed 24 h post-session were not significant, but several subjects had elevated liking and "take again" ratings at this time in one or more of the HYD/ACET conditions and/or in the MOR condition. Both 20 mg HYD/1000 mg ACET and MOR impaired psychomotor performance. HYD/ACET and MOR produced miosis. CONCLUSIONS: HYD/ACET produced some abuse liability-related subjective effects in recreational drug users, which is consistent with the widespread non-medical use and abuse of this product.

Methylnaltrexone: its pharmacological effects alone and effects on morphine in healthy volunteers.

RATIONALE: Methylnaltrexone bromide (MTNX) is a peripherally acting mu-opioid receptor antagonist, prescribed for the treatment of opioid-induced constipation in patients with advanced illness who are receiving palliative care. Studies have used this drug to determine if other opioid-induced effects besides constipation are altered by MTNX in humans and have suggested, based on their results, that these other effects are altered by peripheral opioid actions. OBJECTIVE: The primary objective of this report is to present results that provide indirect evidence that MTNX has centrally mediated effects, albeit slight, and secondarily to describe the effects of MTNX on psychopharmacological effects of morphine. METHODS: In a crossover, randomized, placebo-controlled, double-blind study, 29 healthy volunteers received 0.45 mg/kg MTNX or saline subcutaneously, followed by saline intravenously. In three other conditions, 0.143 mg/kg of morphine sulfate administered intravenously was preceded by subcutaneous administration of 0, 0.225, or 0.45 mg/kg MTNX. Before and after drug administration, subjective and physiological measures, including pupil diameter, were assessed. RESULTS: Two separate analyses confirmed that 0.45 mg/kg MTNX alone induced a slight degree of miosis, a centrally mediated opioid agonist effect. This dose had minimal subjective effects. MTNX at either or both the 0.225 and 0.45 mg/kg dose reduced some subjective effects of morphine without altering miosis. CONCLUSIONS: We present indirect evidence that MTNX crosses the blood-brain barrier in humans. Therefore, whether the reductions in subjective effects of morphine by MTNX that were observed in past studies and in this study can be attributed to peripheral mechanisms is open to question.

Treatment of multiple unresectable basal cell carcinomas from Gorlin-Goltz syndrome: a case report.

BACKGROUND: Nevoid basal cell carcinoma syndrome (NBCCS), which is also known by other names, including Gorlin-Goltz syndrome and multiple basal-cell carcinoma (BCC) syndrome, is a rare multi-systemic disease inherited in a dominant autosomal manner with complete penetrance and variable expressivity. The main clinical manifestations include multiple BCCs, odontogenic keratocysts of the jaw, hyperkeratosis of the palms and soles, skeletal abnormalities, intracranial calcifications and facial deformities. PATIENTS AND METHODS: A 31-year-old male diagnosed with Gorlin-Goltz syndrome with multiple unresectable facial BCCs was treated with the Hedgehog inhibitor vismodegib. RESULTS: After one month of therapy on vismodegib, there were significant reductions in the size of multiple BCCs on the patient's face. The patient remains on this therapy. CONCLUSION: Hedgehog pathway inhibition is an effective strategy to treat unresectable BCCs from Gorlin-Goltz syndrome. Although vismodegib shows some promising clinical results in the early phase of its use, there are concerns of possible resistance developing within months. Duration of therapy, role of maintenance treatment and drug modification to reduce resistance need to be explored in future case studies.

Effects of naloxone on nitrous oxide actions in healthy volunteers.

A number of studies have examined the effects of naloxone on nitrous oxide-induced analgesia with conflicting results. In the present study the effects of a relatively high dose of naloxone was examined to determine its effects on nitrous oxide-induced analgesia, as well as on the subjective and psychomotor effects of nitrous oxide. Fourteen subjects participated in a four-session crossover trial in which they received intravenous injections of either saline or 30mg/70kg naloxone 10min into a 35min period in which they were inhaling either 100% oxygen or 30% nitrous oxide in oxygen. Ten minutes after the naloxone administration, subjects were tested on the cold pressor test. Mood and psychomotor performance were also assessed before, during and after the inhalation period. Subjects reported higher pain ratings after the naloxone injection than the saline injection, but there was no evidence of naloxone reversing the analgesic effects of nitrous oxide. Similarly while naloxone also affected mood and impaired psychomotor performance, there was no evidence of naloxone reversing the effect of nitrous oxide on these measures. The results of this study call into question the role of the opioidergic system in mediating various effects of nitrous oxide in humans.

Characterizing the subjective, psychomotor, and physiological effects of a hydrocodone combination product (Hycodan) in non-drug-abusing volunteers.

RATIONALE: The subjective, psychomotor, and physiological effects of prescription compounds containing the opioid hydrocodone have not been studied in a population of non-drug-abusing people who might be prescribed these compounds for cough or pain relief. OBJECTIVES: To characterize the effects of a hydrocodone combination product, Hycodan, which contains hydrocodone and a peripherally-acting anticholinergic, homatropine, in non-drug-abusing volunteers. METHODS: Eighteen volunteers participated in a crossover, double-blind study in which they received placebo; 5 mg hydrocodone/1.5 mg homatropine, 10 mg hydrocodone/3 mg homatropine, 20 mg hydrocodone/6 mg homatropine (all PO); 40 mg morphine (PO); and 2 mg lorazepam (PO). Measures were assessed before and for 300 min after drug administration. End-of-session and 24-h measures were taken to assess residual drug effects and overall subjects' assessment of the drug effects. RESULTS. Subjective effects of the hydrocodone/homatropine combination were dose-related, although the majority of statistically significant effects were limited to the highest dose combination tested. A combination of 20 mg hydrocodone/6 mg homatropine and morphine had a similar profile of subjective effects, which included both pleasant and unpleasant effects. Peak liking ratings were increased by 20 mg hydrocodone/6 mg homatropine and morphine, and trough ratings of liking (dislike) were lower in the 20 mg hydrocodone/6 mg homatropine condition, relative to the placebo condition. Post-session ratings of overall liking were not significant, either at the end of the session or 24 h later. Cognitive and psychomotor impairment were more marked with lorazepam than with hydrocodone/homatropine and morphine. Miosis and exophoria were increased in a dose-related manner by hydrocodone/homatropine. CONCLUSIONS: Hycodan at the highest dose tested had effects similar to that of a prototypic mu agonist, morphine. Both drugs produced pleasant (including drug liking) as well as unpleasant subjective effects. Post-session ratings of overall liking and "want to take drug again" were not significant.

Characterizing the subjective, psychomotor, and physiological effects of oral oxycodone in non-drug-abusing volunteers.

RATIONALE: The subjective, psychomotor, and physiological effects of a widely prescribed and abused prescription opioid, oxycodone, have not been studied in a population of non-drug-abusing people. OBJECTIVES: To characterize the effects of oxycodone in non-drug-abusing volunteers. METHODS: Eighteen volunteers participated in a crossover, randomized, double-blind study in which they received, all p.o., placebo, 10 mg oxycodone, 20 mg oxycodone, 30 mg oxycodone, 40 mg morphine, and 2 mg lorazepam. Measures were assessed before and for 300 min after drug administration. End-of-session and 24-h post-session measures were taken to assess residual drug effects and overall subjects' assessments of the drug effects. RESULTS: Subjective effects of oxycodone were dose related, with the majority of statistically significant effects limited to the two higher doses tested. Oxycodone produced a profile of subjective effects that included both pleasant and unpleasant effects. Morphine in general produced effects similar in magnitude to those of 10 mg and 20 mg oxycodone. Peak liking and drug-wanting ratings were increased by all doses of oxycodone and by morphine, and trough ratings of liking (dislike) were lower in the 20-mg and 30-mg oxycodone conditions, relative to the placebo condition. Post-session ratings of overall liking and drug wanting were not statistically significant, either at the end of the session or 24 h later. Cognitive and psychomotor impairment were obtained with the higher doses of oxycodone, but to a much lesser degree than that of lorazepam. Miosis and exophoria were increased in a dose-related manner by oxycodone. CONCLUSIONS: Oxycodone produced effects similar to those of other mu opioid agonists. Although oxycodone produced abuse liability-related subjective effects, it also produced unpleasant effects, a phenomenon we have observed in other opioid studies in non-drug-abusing volunteers.

Characterizing the subjective, psychomotor, and physiological effects of oral propoxyphene in non-drug-abusing volunteers.

BACKGROUND: The subjective, psychomotor, and physiological effects of a widely prescribed prescription opioid, propoxyphene, have not been studied in a population of non-drug-abusing people. The drug also has potential for abuse and it was of interest in the present study to determine if the drug had any abuse liability-related subjective effects in this population. METHODS: Eighteen volunteers participated in a crossover, randomized, double-blind study in which they received, all p.o., placebo; 50 mg propoxyphene napsylate; 100 mg propoxyphene napsylate; 200 mg propoxyphene napsylate; 40 mg morphine sulfate; and 2 mg lorazepam. Measures were assessed before and for 300 min after drug administration. RESULTS: Both morphine and lorazepam produced subjective effects. There were no statistically significant subjective effects obtained with any dose of propoxyphene in the group as a whole, but approximately 30-50% of the subjects did appear to experience subjective effects from the drug. Drug liking was not consistently observed in this subset. Propoxyphene, unlike lorazepam, did not impair psychomotor or cognitive performance. Both propoxyphene and morphine produced miosis. CONCLUSIONS: There was a lack of statistically significant subjective effects of propoxyphene in the group as a whole, including a propoxyphene dose that was twice as high as the typical clinically-prescribed dose of 100 mg. However, there were some subjects who did report effects, consistent with the notion that patients differ in their sensitivity to opioid effects.

Analysis of the reinforcing and subjective effects of different doses of nitrous oxide using a free-choice procedure.

The reinforcing and subjective effects of five doses of nitrous oxide (0, 10, 20, 30, 40% N(2)O in O(2)) were studied in 20 non-drug-abusers using a free-choice procedure. During each of five sessions, subjects sampled a dose of N(2)O and 100% O(2) (placebo) for 10 min each. Later they chose nine times, once every 5 min, among N(2)O (e.g. 'Agent A'), placebo (e.g. 'Agent B'), or a no-drug option. Mean preference ratios (N(2)O choices/[N(2)O choices+placebo choices]) and total N(2)O choice increased with increasing N(2)O dose. Individual preference ratios suggested that at least one active dose of N(2)O functioned as a reinforcer in 80% of subjects, and the doses that functioned as reinforcers varied across subjects. N(2)O choice was positively correlated with end-of-session and post-session ratings of N(2)O liking and of wanting to inhale N(2)O again, but not with ratings of those effects during sampling. Placebo was chosen significantly less than the no-drug option, even though both were 100% O(2). More robust reinforcing effects of N(2)O were observed in this subject population than in previous studies. Choice data emphasize the importance of examining a range of doses, and of examining those effects within-subject, when assessing reinforcing effects of drugs. Inclusion of the no-drug option eliminated the 'forced' choice of placebo, making preference ratios easier to interpret than in previous, forced-choice procedures. Reinforcing effects were more correlated with subjective effects assessed after the session than with subjective effects obtained while subjects were under the influence of the drug.

Reinforcing and subjective effects of the volatile anesthetic, sevoflurane.

Sevoflurane is a volatile anesthetic that is chemically similar to volatile substances of abuse and can be safely administered to humans in laboratory research. In this study, the reinforcing and subjective effects of five concentrations of sevoflurane (0, 0.2, 0.4, 0.6, 0.8% sevoflurane in O2) were studied in 20 non-drug-abusers. During each of five sessions, subjects sampled a concentration of sevoflurane and 100% O2 (placebo) for 10 min each. Later, within the session, they chose nine times, once every 5 min, among sevoflurane (e.g. "Agent A"), placebo (e.g. "Agent B"), or neither (and were administered 100% O2, identified as "drug-free air"). Although "neither" was selected most frequently, mean preference ratios (sevoflurane choices/[sevoflurane choices+placebo choices]) and total sevoflurane choice peaked at the 0.4% concentration. Choice patterns varied across subjects, with some subjects never choosing sevoflurane and other subjects showing monotonic increasing or bitonic concentration-choice functions. Concentration-related increases in subjective effects were observed, including effects that are putatively associated with abuse liability. Ratings of drug liking and of wanting to inhale the drug again were positively correlated with sevoflurane choice. This study shows that sevoflurane can function as a reinforcer and produce abuse liability-related subjective effects in some healthy volunteers.

Bitonic dose-response functions for reinforcing and self-reported effects of nitrous oxide in humans.

The reinforcing and self-reported effects of nitrous oxide (10%, 30%, and 50% N(2)O in O(2)) were examined in 13 humans. During each of three sessions, subjects sampled one dose of N(2)O and 100% O(2) (placebo) for 10 min each, separated by 30-min recovery periods. The agents were identified by letter code, and later in the session, subjects chose nine times, once every 5 min, among N(2)O (e.g., "Agent A"), placebo (e.g., "Agent B"), or "neither" (also 100% O(2), identified as "drug-free air"). Self-reported and psychomotor effects were measured at various times. Dose-response functions varied across subjects and included bitonic, monotonic increasing, monotonic decreasing, U-shaped, and flat dose-response functions for reinforcing and/or self-reported effects. For subjects who showed bitonic reinforcing effects, the descending limb of the dose-response function could not be attributed to behavioral impairment. This study replicates previous studies showing dose-dependent effects of N(2)O, as well as between-subject variability in N(2)O effects. Bitonic dose-response functions for some subjects extend the generality of the phenomenon of bitonicity of drug effects to N(2)O effects in humans.