Effects of heroin/cocaine combinations in rats trained to discriminate heroin or cocaine from saline.

The effects of heroin and cocaine administered alone or in combination were examined in rats trained to discriminate either heroin (0.56 mg/kg i.p.; n = 6) or cocaine (5.6 mg/kg i.p.; n = 6) from saline. Heroin (0.032-1.8 mg/kg) substituted completely for the heroin training stimulus in all six heroin-trained rats, but failed to substitute for cocaine in any of the cocaine-trained rats. Cocaine (0.1-32 mg/kg) substituted completely for the cocaine training stimulus in all six cocaine-trained rats, and substituted for heroin in two of six heroin-trained rats. The opioid antagonist naltrexone (0.01-1.0 mg/kg) antagonized the discriminative stimulus effects of heroin, but naltrexone at doses up to 10 mg/kg had no effect on the discriminative stimulus effects of cocaine. The dopamine receptor antagonist flupenthixol (0.032-0.56 mg/kg) attenuated the discriminative stimulus effects of heroin and completely blocked the discriminative stimulus effects of cocaine. When heroin-cocaine combinations were administered to the heroin-trained rats, cocaine (1-5.6 mg/kg) did not significantly alter the mean heroin dose-effect curve. Similarly, in the cocaine-trained rats, heroin (0.1-0.56 mg/kg) did not significantly alter the mean cocaine dose-effect curve. These results suggest that combinations of heroin and cocaine usually produce discriminative stimulus effects similar to either heroin or cocaine alone.

Acute and chronic effects of flupenthixol on the discriminative stimulus and reinforcing effects of cocaine in rhesus monkeys.

It has been proposed that the relatively nonselective dopamine receptor antagonist flupenthixol may be useful in the treatment of cocaine dependence. Drugs used in the treatment of cocaine dependence are administered chronically; however, most preclinical studies have examined only the acute effects of flupenthixol treatment on the effects of cocaine. Consequently, the purpose of the present study was to compare the effects of acute and chronic treatment with flupenthixol (0.0032-0.032 mg/kg) on the discriminative stimulus and reinforcing effects to cocaine in rhesus monkeys. One group of six monkeys was trained to discriminate 0.4 mg/kg cocaine (i.m.) from saline in a two-lever, food-reinforced, drug discrimination procedure. A second group of four monkeys was trained to respond for 0.032 mg/kg/injection cocaine (i.v.) and 1-g banana-flavored food pellets during alternating daily cycles of cocaine and food availability. Neither acute nor chronic treatment with a low dose of flupenthixol (0.0032 mg/kg) significantly altered the discriminative stimulus or reinforcing effects of cocaine. Higher doses of flupenthixol (0.01-0.032 mg/kg) produced a surmountable blockade of both the discriminative stimulus and reinforcing effects of cocaine, shifting the dose-effect curves for both cocaine discrimination and cocaine self-administration up to 0.5 log unit to the right. However, doses of flupenthixol that altered cocaine discrimination also decreased response rates. Similarly, doses of flupenthixol that decreased cocaine self-administration also often decreased rates of food-maintained responding. Consequently, nonselective behavioral effects of flupenthixol may have contributed to its effects on cocaine discrimination and self-administration. Moreover, the effects of flupenthixol on cocaine discrimination and self-administration diminished over time. After only 3 to 5 days of chronic treatment, flupenthixol did not consistently shift the cocaine discrimination dose-effect curve to the right. Similarly, rates of cocaine self-administration that were initially decreased by flupenthixol often recovered partially or completely during a 10-day regimen of chronic flupenthixol treatment. These results suggest that flupenthixol may have limited utility in the long-term treatment of cocaine dependence.

Sex differences in plasma cocaine levels and subjective effects after acute cocaine administration in human volunteers.

Gender differences after acute cocaine administration have received little attention in spite of the fact that males and females respond differently to many drugs. Seven male and seven female occasional cocaine users received both an intranasal dose of cocaine hydrochloride (0.9 mg/kg) and placebo powder in a randomized order and reported subjective effects via an instrumental joystick device and various questionnaires. Blood samples were withdrawn at 5-min intervals to assess pharmacokinetic differences. Male subjects achieved the highest peak plasma cocaine levels (144.4 +/- 17.5 ng/ml), detected cocaine effects significantly faster than females and also experienced a greater number of episodes of intense good and bad effects. Women studied during the follicular phase of their menstrual cycle had peak plasma cocaine levels of 73.2 +/- 9.9 ng/ml, which was significantly higher than when they were studied during their luteal phase (54.7 +/- 8.7 ng/ml), but there were no differences in their subjective reports of cocaine effects. In spite of the different cocaine blood levels and subjective effects, peak heart rate increases did not differ between males and females suggesting that women may be more sensitive than males to the cardiovascular effects of cocaine. These data suggest that there are significant gender and menstrual cycle differences in the response to acute intranasal cocaine administration and these differences may have implications for the differential abuse of this drug.

Effects of the putative dopamine D3 receptor agonist 7-OH-DPAT in rhesus monkeys trained to discriminate cocaine from saline.

These studies were designed to evaluate the effects of the putative dopamine D3 receptor agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetraline (7-OH-DPAT), alone and in combination with cocaine, in four rhesus monkeys trained to discriminate cocaine (0.4 mg/kg, IM) from saline under a fixed-ratio 30 schedule of food presentation. Under these conditions, cumulative doses of cocaine (0.013-1.3 mg/kg) produced a dose-dependent and complete generalization to the training dose of cocaine in all monkeys, while producing only minimal effects on response rates. The discriminative stimulus effects of cocaine were antagonized by the non-selective dopamine receptor antagonist flupenthixol (0.018 mg/kg, IM) in all four monkeys. The effects of 7-OH-DPAT (0.01-1.8 mg/kg) were inconsistent across monkeys. In two of the four monkeys (monkeys L990 and L958), 7-OH-DPAT consistently and completely generalized to cocaine and decreased response rates in a dose-dependent manner. Both the cocaine-like discriminative stimulus effects and rate-decreasing effects of 7-OH-DPAT were antagonized by flupenthixol in these two monkeys. Pretreatment with low doses of 7-OH-DPAT (0.01-0.032 mg/kg) had no effect on the cocaine dose-effect curve in monkeys L990 and L958; however, higher doses of 7-OH-DPAT (0.032-0.32 mg/kg) shifted the cocaine dose-effect curve to the left. In the other two monkeys (monkeys 150F and 89B036), 7-OH-DPAT produced a dose-dependent decrease in response rates but did not consistently generalize to cocaine. Flupenthixol did not antagonize the rate-decreasing effects of 7-OH-DPAT in these two monkeys, and pretreatment with 7-OH-DPAT (0.1-0.32 mg/kg) produced a decrease in response rates but had no effect on the cocaine dose-effect curve. Time-course experiments revealed that 7-OH-DPAT (0.32 mg/kg) displayed a slower onset and a longer duration of effect than the training dose of cocaine. Finally, the D3/D2 dopamine agonist quinpirole completely generalized to cocaine in three monkeys, and partially in the fourth monkey. Quinpirole showed the highest potency in those monkeys in which 7-OH-DPAT consistently generalized to cocaine. The results of the present study suggest that, in rhesus monkeys, 7-OH-DPAT produces cocaine-like effects and may modulate the discriminative stimulus effects of cocaine in some monkeys.

Relationship between the discriminative stimulus effects and plasma concentrations of intramuscular cocaine in rhesus monkeys.

The relationship between the discriminative stimulus effects and plasma pharmacokinetics of cocaine was evaluated in six rhesus monkeys trained to discriminate cocaine (0.4 mg/kg, IM) from saline under a FR30 schedule of food presentation. The same monkeys were tested in two procedures. In a cumulative dosing procedure, five cumulative doses of cocaine (0.013-1.3 mg/kg) were administered and discriminative stimulus effects were evaluated 10 min after the administration of each dose. Cocaine plasma concentrations were measured in separate sessions using the same doses and interdose intervals. In a single dosing procedure, the time-courses of the discriminative stimulus effects and plasma concentrations of cocaine were assessed after the administration of cocaine (0.4 mg/kg). A close correspondence between cocaine's discriminative stimulus effects and plasma concentrations was obtained in both procedures. Cocaine was virtually undetectable in plasma at doses that produced saline-appropriate responding (0.013 and 0.04 mg/kg), whereas increasing plasma concentrations were measured at doses that produced primarily cocaine-appropriate responding (0.13 mg/kg or higher). The time-course of the discriminative stimulus effects of cocaine was characterized by a rapid onset (within 1-3 min post-cocaine) and offset (within 20-60 min post-cocaine). Peak plasma levels were obtained at 10 min post-cocaine. No differences in plasma concentrations were found 10 min after the administration of a cumulative versus a single dose of cocaine 0.4 mg/kg (mean, 75.8 and 74.0 ng/ml, respectively). Cocaine plasma concentrations lasted longer than its discriminative stimulus effects. The results of the present study confirm that the cumulative dosing procedure used yields plasma concentrations of cocaine that are similar to the concentrations obtained after single cocaine dosing.

Sensation seeking amongst healthy volunteers participating in phase I clinical trials.

1. Phase I clinical trials are usually carried out in healthy volunteers. In addition to economic gain, factors that may influence willingness to participate include scientific interest, curiosity and choice for risky activities. 2. We assessed the relationship between personality variables and volunteering for clinical pharmacology research. Two personality questionnaires, the Sensation Seeking Scale (SSS, form V) and the Eysenck Personality Questionnaire (EPQ), were administered to 48 male healthy university students who volunteered to participate in a phase I clinical trial and to 43 male university students who were not willing to participate in phase I clinical trials. General norm data were also used for the comparison of results. 3. When healthy volunteers were compared with unwilling subjects, significant differences were found in thrill-and-adventure seeking (7.9 vs 6.7, P = 0.0034), experience seeking (6.4 vs 5.2, P = 0.0012), disinhibition (6.2 vs 4.3, P < 0.0001), boredom susceptibility (3.9 vs 2.8, P = 0.0073), total sensation seeking trait (24.3 vs 19.0, P < 0.0001), extraversion (15.1 vs 13.3, P = 0.0490), and psychoticism (4.4 vs 3.5, P = 0.0086). When healthy volunteers were compared with general norm data similar statistically significant differences were found in all these scales, except for boredom susceptibility and psychoticism. 4. The personality profile of healthy volunteers was characterized by a higher sensation seeking trait and extraversion as compared with individuals who were not willing to participate in phase I clinical trials and general norm data.

Effects of morphine in postaddict humans: a meta-analysis.

The literature on assessment of abuse liability of opioid drugs in humans was reviewed, and meta-analysis (a statistical method designed to combine results of different studies) was performed to study a dose-effect relationship for some variables commonly used for the evaluation of the subjective and physiological effects of morphine. Thirty-five studies, published between 1964 and 1991, including the i.m. or s.c. administration of morphine to non-dependent subjects with prior history of opioid abuse, were selected. Logistic regression models were applied for categorically dependent variables, and linear regression models were used for quantitative dependent variables. The log-transformation of the dose of morphine, stratifying by studies, acted as predictor variable. A dose-effect function was demonstrated. Doses producing an average effect across studies ranged from 7 mg (observers-reported 'liking') to 12 mg (subjects-reported 'liking'). Average effect on pupil diameter decreases was obtained for a dose of 8 mg. Doses producing a 50% of maximum positive responses were 10 mg for subjects' opioid classification, and 20 mg for the ARCI-MBG scale. The heterogeneity between studies obtained, along with the large variability present in most of the variables, supports the usefulness of a concurrent assessment of several indexes when assessing the effects of morphine.

Spanish version of the 49-item short form of the Addiction Research Center Inventory (ARCI).

The Spanish version of the 49-item short form of the Addiction Research Center Inventory (ARCI) was assessed in simulated drug conditions. After the translation process was completed, the questionnaire was administered to forty-five adult polydrug abusers who were residing in a general hospital. Subjects answered the questionnaire on four occasions, describing the feelings they usually experienced under the effects of four classes of drugs of abuse (morphine-like opioids, alcohol, stimulants and hallucinogens). The scales showed an acceptable level of internal consistency. A characteristic pattern of response was obtained for each condition. A discriminant analysis revealed that four scales PCAG (pentobarbital-chlorpromazine-alcohol group), MBG (morphine-benzedrine group), LSD (lysergic acid dyethylamide scale) and BG (benzedrine group) significantly discriminated between the conditions studied. Sixty percent of the questionnaires answered were correctly classified according to the discriminant functions constructed. The results from this study are similar to those obtained with the English ARCI, and suggest that the Spanish version of the 49-item ARCI may be an useful instrument for the evaluation of subjective effects produced by psychoactive drugs in Spanish populations.

Acute effects of pentazocine, naloxone and morphine in opioid-dependent volunteers.

The purpose of this study was to evaluate the agonist and antagonist properties of pentazocine, an opioid mixed agonist-antagonist analgesic, in relation to prototypic opioid agonist and antagonist drugs in opioid-dependent human subjects. Pentazocine (45 and 60 mg), naloxone (0.1 and 0.2 mg), morphine (20, 40 and 60 mg) and saline placebo were administered intramuscularly to six male volunteers maintained on methadone (30 mg/24 hr p.o.), following a double-blind, randomized block order design. Drugs were administered 20 hr after the last dose of methadone. Subject-reported effects and physiological measures were collected before drug administration and during 4 hr postadministration. Morphine produced significant dose-related increases in subjective measures characteristic of mu agonist effects, decreased pupil diameter and was classified as an opioid agonist. Naloxone precipitated a dose-related opioid withdrawal syndrome which was measurable on several subject-rated measures, and significantly increased pupil diameter. Subjects consistently identified naloxone as an antagonist. Pentazocine precipitated a withdrawal syndrome, but the effects were not dose-dependent, and produced symptoms of confusion and dysphoric changes that were not observed after naloxone administration. Pentazocine was classified as an antagonist by some individuals, and as alcohol or hallucinogen by others. The results of the present study indicate that pentazocine acts in humans as a partial mu agonist with a non-mu component of activity.

Acute effects of tramadol in methadone-maintained volunteers.

The opioid agonist and antagonist properties of tramadol were assessed in 6 male opioid-dependent volunteers enrolled in a methadone maintenance programme. Subjects participated in 3 experimental sessions in which the effects of intramuscular tramadol 100 and 300 mg and placebo were evaluated. Tramadol neither produced morphine-like effects nor precipitated a withdrawal syndrome; its subjective, behavioural and physiological effects were not different from those of placebo. Although the results of this study suggest that tramadol has a low abuse liability in opioid-dependent subjects, higher doses should be tested to confirm these data.

Alcohol and cocaine interactions in humans.

The effects of 100 mg of intranasal cocaine (COC) in acute alcohol intoxication (1 g/kg) was assessed in nine experienced and non-dependent healthy volunteers in a double-blind, controlled, randomized, cross-over clinical trial. Alcohol alone impaired psychomotor performance, whereas COC alone produced subjective effects related to euphoria and well-being, improved the reaction time and increased heart rate and blood pressure. The combination of COC and alcohol induced a nonsignificant decrease in the subjective feelings of drunkeness, an increase in COC-induced euphoria, a significant improvement in alcohol-related changes in psychomotor performance and a marked increase in heart rate. Subjects experienced subjective and performance effects that could be self-interpreted as more pleasant compared to the effects of alcohol alone. When alcohol was given simultaneously, COC plasma levels were higher (possibly as a result of an inhibition of hepatic metabolism of COC produced by alcohol), norcocaine plasma levels almost doubled and cocaethylene was detected in plasma, so that its basic pharmacokinetic profile could be described. The simultaneous use of both drugs produced changes in heart rate and blood pressure that could increase the risk of cardiovascular toxicity associated with the use of COC.

[Treatment of acute pain in a general hospital: opinions of physicians and nurses]. / Tratamiento del dolor agudo en un hospital general: opiniones de médicos y enfermeras.

A survey was carried amongst physicians and nurses of a general hospital, in order to know their opinion about acute pain treatment. Out of 106 physicians and 153 nurses questioned, 72 and 105 respectively answered the questionnaire. Two thirds of them though that analgesic treatment was currently good, although, it could be improved if they increased their knowledge about it. Twenty nine per cent of physicians thought that their patients were receiving lower doses than what they had prescribed and that this fact could be responsible for the treatment failure. Those questioned believed that approximately 30% of patients treated with opium derivatives for over a week could develop addiction problems. Our study confirmed the existence of inadequate attitudes towards the need for analgesics in patients with acute pain.