Alterations of immune functions in heroin addicts and heroin withdrawal subjects

Conflicting results, both decreased and increased, have been reported concerning the function of T-lymphocytes in heroin addicts. We investigated the alterations of T-lymphocyte proliferative responses and immunophenotypic markers on lymphoid cells in heroin addicts and during different periods of heroin withdrawal in addicted subjects. This study has demonstrated a decrease in the response of T-lymphocytes to 1.2, 2.5, 5 and 10 microg/ml of phytohemagglutinin stimuli in heroin addicts and 1- to 5-day heroin withdrawal subjects compared with controls. Similarly, in an in vitro study, 10(-4), 10(-6) and 10(-8) M concentrations of morphine were shown to suppress 0.6 and 2.5 microg/ml of PHA-stimulated T-lymphocyte obtained from naive subjects. This inhibitory effect of morphine on PHA stimulation was completely abolished by 100 microM naloxone. The immunological parameters of total T-lymphocytes (CD3), T-helper cells (CD4), cytotoxic T-cells (CD8), B-cells and natural killer cells that are the immunophenotypic markers studied by flow cytometric analysis were altered in heroin addicts, 15- to 21-day and 6- to 24-month heroin withdrawal subjects, when compared with controls. These results suggest that heroin addicts and short period (15 to 21 days and 6 to 24 months) of heroin withdrawal have decreases in their immune system functioning and that the heroin withdrawal subjects seem to gradually reverse their immunological parameters to normal levels when withdrawal was sustained >/=2 years. This is the first report examining immune function in heroin withdrawal subjects using the "cold turkey" method. The results are beneficial for further study of the mechanism responsible for the opioid-induced changes in immune function.     

Cerebellar top-of-the-basilar syndrome

In order to determine the fetal-maternal distribution of heroin and its main metabolites (6-monoacetylmorphine and morphine) the drug concentrations were measured in autopsy material. The heroin-related death of a pregnant drug abuser (approximately the 32nd week of gestation) provided the fetal and maternal material. Fetal and maternal hair was analyzed in order to obtain long-term information on the transplacental opiate transfer. Morphine and 6-monoacetylmorphine were detected in toxic concentrations in maternal as well as in fetal tissues and body fluids. The drug concentrations in the fetal blood were significantly lower than in the maternal blood. The ratio of fetal-to-maternal (F/M) blood morphine concentration was found to be 0.39, whereas the F/M ratio of 6-monoacetylmorphine in blood was 0.15. In fetal hair analysis, morphine, heroin, and, for the first time, 6-monoacetylmorphine were measured. The resulting F/M ratios were 0.49, 0.36, and 0.6, respectively.     

Hemodynamic performance of four mechanical bileaflet prosthetic valves in the mitral position: an echocardiographic study

Plasma methadone concentrations and its main metabolite D,L-2-ethylidiene-1,5-dimethyl-3,5-diphenylpyrrolidine (EDDP) were determined in 93 patients under methadone maintenance treatment to assess their relationship with heroin use and opioid withdrawal symptoms. Neither plasma concentrations of methadone nor EDDP were significantly different when patients that used heroin in last 3 months were compared with those testing negative for this drug (methadone, 355 +/- 217 versus 369 +/- 216 ng/ml, t = 0.29, P = NS; EDDP, 49 +/- 28 versus 54 +/- 40 ng/ml, t = 0.51, P = NS). No correlation between opioid withdrawal scale scores and plasma concentrations of methadone (r = 0.02, P = NS) and EDDP (r = -0.14, P = NS) was found. Therapeutic drug monitoring during methadone maintenance seems to be useful for assessing compliance with treatment but not for predicting heroin use and subjective withdrawal symptoms.     

Discriminative stimulus effects of a cocaine/heroin "speedball" combination in rhesus monkeys

Cocaine and heroin often are abused together in a combination known as a "speedball," but relatively little is known about ways in which cocaine and heroin may interact to modify each other's abuse-related effects. The present study evaluated the discriminative stimulus effects of a speedball combination of cocaine and heroin. Three rhesus monkeys were trained to discriminate vehicle from a 10:1 ratio of cocaine (0.4 mg/kg) in combination with heroin (0.04 mg/kg). Both cocaine alone and heroin alone substituted completely for the cocaine/heroin combination, although cocaine and heroin were more potent when administered together than when administered alone. Combined pretreatment with the dopamine antagonist flupenthixol and the opioid antagonist quadazocine dose-dependently antagonized the discriminative stimulus effects of the cocaine/heroin combination, but pretreatment with either antagonist alone was less effective. These findings suggest that either cocaine or heroin alone was sufficient to substitute for the cocaine/heroin training combination. To characterize the discriminative stimulus properties of this speedball more fully, a series of cocaine-like and heroin-like agonists were studied in substitution tests. The indirect dopamine agonists CFT, amphetamine and bupropion and the mu opioid agonists alfentanil, fentanyl and morphine produced high levels of speedball-appropriate responding. However, the indirect dopamine agonist GBR12909, the D1 dopamine agonist SKF82958, the D2 dopamine agonist quinpirole and the partial mu opioid agonist nalbuphine did not substitute for the cocaine/heroin combination. Because these compounds produce discriminative stimulus effects similar to either cocaine or mu opioid agonists alone, these findings suggest that the discriminative stimulus effects of the cocaine/heroin combination do not overlap completely with the effects of cocaine and heroin alone. Finally, a series of compounds that produce partial or no substitution for cocaine or mu agonists alone also did not substitute for the cocaine/heroin combination, which indicates that the discriminative stimulus effects of the combination were pharmacologically selective. Taken together, these findings suggest that a combination of cocaine and heroin produces a pharmacologically selective discriminative stimulus complex that includes aspects of both component drugs.     

Advantages and disadvantages of studying the process of relapse in rats: Reply to Baker and Curtin (2002), Bardo (2002), Goeders (2002), Marlatt (2002), and Tiffany and Conklin (2002).

The authors investigated the effects of an episode of heroin self-administration (i.e., lapse) after extinction on subsequent drug seeking in the absence of heroin (i.e., relapse). Reexposure to heroin in the presence of drug seeking was identified as a critical element of a lapse experience, leading to elevated drug seeking on the test of relapse. T. B. Baker and J. J. Curtin (see record 2002-06535-002), G. A. Marlatt (see record 2002-06535-005), and S. T. Tiffany and C. A. Conklin (see record 2002-06535-006) indicate that animal studies fail to model important aspects of human addiction. M. T. Bardo (see record 2002-06535-003) and N. E. Goeders (see record 2002-06535-004) point out specific methodological problems. In spite of these difficulties, the authors' research makes a valuable contribution to the study of relapse by focusing on aspects of learning and memory involved in the transition from lapse to relapse. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Lack of evidence for an involvement of nucleus accumbens dopamine D1 receptors in the initiation of heroin self-administration in the rat

The involvement of dopamine D1 receptor systems in the reinforcing properties of opiate reward was studied by examining the effect of the dopamine D1 antagonist SCH23390 on the initiation of heroin self-administration in rats. The D1 antagonist was administered daily systemically or locally in the nucleus accumbens (NAC), after which the animals were allowed to self-administer heroin (IV) in a 3-h session for 5 consecutive days. Systemic treatment with SCH23390 (0.17 and 0.5 mg.kg-1) significantly decreased heroin intake during initiation of heroin self-administration, while a dose of 0.06 mg.kg-1 was not effective. Local administration of SCH23390 (0.5 and 2.5 micrograms/site) in the NAC did not affect heroin intake. Both systemic and intra-accumbal administration of SCH23390 dose dependently decreased motor behavior measured in a small open field. The attenuation of heroin intake during initiation of heroin self-administration by blockade of dopamine D1 receptor systems may be due to a decrease in the reinforcing effects of heroin or more likely to a reduction in non-reinforcement-related behavior. The dopamine D1 receptors present in the NAC are probably not involved in opiate reward.     

Drug-induced reinstatement of heroin- and cocaine-seeking behaviour following long-term extinction is associated with expression of behavioural sensitization

The present study was designed to evaluate the relationship between reinstatement of drug-seeking behaviour following long-term extinction of intravenous (i.v.) drug self-administration (an animal model for craving) and long-term behavioural sensitization. Rats were allowed to self-administer heroin (50 microg/kg per inj., 14 daily sessions), cocaine (500 microg/kg per inj., 10 daily sessions) or saline. Following a 3-week extinction period, reinstatement tests were performed to evaluate priming effects of amphetamine, cocaine and heroin on nonreinforced drug-seeking behaviour. In addition, the occurrence of long-term behavioural sensitization in rats with a history of heroin or cocaine self-administration was determined. Heroin-seeking behaviour was reinstated by heroin (0.25 mg/kg), amphetamine (1.0 mg/kg) and cocaine (10 mg/kg). In addition, animals with a history of heroin self-administration displayed locomotor sensitization to both heroin and amphetamine. Cocaine-seeking behaviour was reinstated by cocaine and amphetamine, but not by heroin. Interestingly, locomotor sensitization to amphetamine, but not heroin, was observed in animals with a history of cocaine self-administration. In other words, the induction of drug-seeking behaviour following a prolonged drug-free period was found to be associated with the expression of long-term behavioural sensitization. These data provide experimental evidence for a role of behavioural sensitization in the incentive motivation underlying drug-seeking behaviour. If drug hyperresponsiveness would indeed be a crucial factor in drug-induced craving in human addicts, pharmacological readjustment of the neuroadaptations underlying drug sensitization may prevent relapse to drug use long after detoxification.     

Naloxone blocks reinforcement but not motivation in an operant runway model of heroin-seeking behavior.

Examined the effects of opiate receptor antagonism on both the motivation to seek heroin and the reinforcing consequences of heroin administration. Male rats were trained to discriminate between olfactory cues predicting either the delivery of intravenous heroin reinforcement (S+) or saline (S-). Subjects were then tested in the presence of the opiate receptor antagonist, naloxone (0.5, 1.0, or 3.0 mg/kg intraperitoneally) in a straight-arm runway. Naloxone had no effect on either S+ or S- trials. However, 24 hr later on the first posttreatment trial, Ss that had received heroin in the presence of naloxone (on the previous trial) now traversed the alley more slowly when presented with the S+. These data suggest that although the motivation to seek heroin was not disrupted by naloxone, the reinforcing consequences of heroin administration were. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Death from heroin overdose: findings from hair analysis

BACKGROUND: Morphine analysis of hair is used in forensic toxicology to study the addiction history of heroin addicts. To clarify the features underlying fatal heroin intake, we measured hair morphine content in a group of deceased heroin addicts, to verify a possible correlation between fatal heroin overdoses and the addiction behaviour of these individuals before death. METHODS: 91 deaths were attributed to heroin overdose in Verona, Italy, in 1993-96. We analysed the hair of 37 of these individuals, and of 37 active heroin addicts, 37 former heroin users abstinent from the drug for several months, and 20 individuals with no evidence of exposure to opioids. From each individual, a hair sample of about 150 mg was analysed by RIA and high-performance liquid chromatography, to measure the morphine content. FINDINGS: The mean morphine content in the hair of the addicts who had died was 1.15 ng/mg (SD 2.35 ng/mg; range 0-12.25 ng/mg) compared with 6.07 ng/mg (4.29; 1.15-17.0) in the active heroin addicts, 0.74 ng/mg (0.93; 0.10-3.32) in the abstinent former addicts, and values below the detection limit in the non-exposed group. Hair morphine content among those who had died was significantly lower than that in active heroin consumers (p<.00001), but not significantly different from that in the former addicts (p=0.978). INTERPRETATION: Although our findings may be subject to selection bias, since suitable hair samples were available for only 37 of the 91 addicts who had died, these findings support the theory of high susceptibility to opioid overdose after periods of intentional or unintentional abstinence, due to loss of tolerance. Medical staff running detoxification programmes should be aware of the risk inherent in relapse to heroin after a period of abstinence. Moreover, occasional heroin use without a build-up of tolerance could also give a high risk of overdose.     

Smoked heroin and cocaine based (speedball) combinations in Rhesus monkeys.

The purpose of this investigation was to compare the self-administration of heroin and cocaine base, alone and in combination, in rhesus monkeys (Macaca mulatta) self-administering a combination of heroin (0.1 mg/kg/delivery) and cocaine base (1.0 mg/kg/delivery) via the smoking route. Smoke deliveries were contingent on completion of a chained fixed ratio (FR; lever press), FR 5 (inhalation) schedule. The lever press FR values (64, 128, 256, 512, and 1,024) represented increasing drug price. Demand functions (Consumption x Price) were obtained for the heroin and cocaine combination and compared with previously determined demand functions for smoked heroin and cocaine alone. As the FR increased and the number of responses emitted increased, the number of drug deliveries decreased. The demand functions were not different for heroin versus cocaine alone or for cocaine alone versus the cocaine-heroin combination. However, the demand for heroin alone was significantly less than the demand for the cocaine-heroin combination, suggesting that smoked cocaine base enhances the behavioral effects of smoked heroin. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Assessing the relationship between maternal opiate use and neonatal mortality

We undertook a number of meta-analyses to estimate more precisely the relationship between neonatal mortality and use of opiates in three groups of women. First, women who continued to use illicit heroin throughout pregnancy; secondly, women stabilized on methadone at the time of conception or shortly after and thirdly, women who use heroin well into pregnancy with late entry into methadone treatment, or who continued to use illicit heroin during pregnancy while receiving methadone. FINDINGS: The pooled estimates of the relative risks of neonatal mortality for separate heroin and methadone use were both near unity: 1.47 (95% CI 0.88-2.33) and 1.75 (95% CI 0.60-4.59), respectively. The result for heroin may be due to the inclusion in the meta-analysis of a particularly large study, which, unlike the two other smaller studies included found a relative risk near unity. When this study was excluded from the meta-analysis the pooled estimate of the relative risk of neonatal mortality for heroin use was 3.27 (95% CI 0.95-9.60). In contrast to the results for use of methadone only, the pooled relative risk associated with heroin and methadone use was 6.37 (95% CI 2.57-14.68). CONCLUSIONS: The increased relative risk for neonatal mortality associated with women using heroin and methadone during pregnancy, compared to those stabilized on methadone, is probably due to the chaotic and high-risk life-style associated with illicit heroin use and not solely to the use of heroin and methadone per se. It is recommended tht women who use heroin well into pregnancy with late entry into methadone treatment, or who continue to use illicit heroin during pregnancy while receiving methadone, receive special attention over and above that provided to women stabilized on methadone.     

Granulocyte defects and opioid receptors in chronic exposure to heroin or methadone in humans

In order to elucidate better the immunological effect of opioid abuse in the absence of HIV infection as a confounding factor, granulocyte function was investigated in three groups of HIV-negative subjects, including 20 active parenteral heroin abusers (H), 20 long-term methadone-maintained former opiate abusers (M) and 20 healthy controls (C). Chemotaxis to N-formyl methionyl-leucyl-phenylalanine (fMLP), casein and activated plasma were markedly and similarly reduced (approx. 50%) in both H and M groups, as was true for superoxide production after fMLP and PMA stimulation, 47% decrease of C values. Polymorphonuclear (PMN) of H and M subjects also exhibited a very marked and similar reduction in the expression of CD11b/CD18 integrin receptors after fMLP treatment, with values that were less than 10% of those in controls, as observed by flow cytometry. In parallel, PMN of H and M individuals presented an approximately four-fold increase in opioid receptors numbers compared to controls, a significant inverse correlation existing between the increase in opiate receptors and defective chemotaxis. The possible mechanism underlying the observed changes in PMN of H and M individuals is discussed.     

Shift in sodium chloride sources in past 10 years of salt reduction campaign in Japan

We compared the prevalence of injuries requiring medical treatment in the general population, in cocaine users and in heroin users, and we studied the factors associated with the occurrence of injuries in these groups, using data from two interview surveys carried out in 1993 in Spain: the National Health Interview Survey, a national representative sample of the non-institutionalized general population, and a survey of a non-probability sample of heroin or cocaine users selected from the community. The subjects included in the study were persons 16-40 years of age in urban areas: 4261 persons from the general population, 369 cocaine users and 215 heroin users. The annual prevalence of injuries requiring medical treatment was 7.9 percent in the general population, 10.8 percent in cocaine users and 35.2 percent in heroin users. There was a statistically significant positive association of injury occurrence (1) among the general population: with male sex, alcohol use, use of tranquillizers/sleeping pills, and the use of antidepressants or stimulants; (2) in cocaine users: with the use of opiates other than heroin; and (3) in heroin users: with alcohol use, the use of tranquillizers/sleeping pills, and the injected route. The only statistically significant negative association was with the amount of cocaine consumed among heroin users. The results suggest that other psychoactive substances besides alcohol are positively associated with injury occurrence, and that cocaine use may contribute to a reduced risk of injuries associated with the use of depressants (alcohol, tranquillizers, heroin).     

Cloning of a thermostable ascorbate oxidase gene from Acremonium sp. HI-25 and modification of the azide sensitivity of the enzyme by site-directed mutagenesis

Concurrent abuse of cocaine and opioids is frequently observed clinically, and we have developed a model of "speedball" self-administration involving the simultaneous injection of cocaine and heroin combinations in rhesus monkeys (Mello et al. (1995) J Pharmacol Exp Ther 274:1325). In the present study, we evaluated the effects of buprenorphine (0.0075-0.75 mg/kg/day i.v.) and saline on speedball combinations of cocaine [0.001, 0.01 or 0.10 mg/kg/inj] and heroin [0.0001-0.032 mg/kg/inj]. We also examined the effects of buprenorphine (0.075 and 0.237 mg/kg/day i.v.) on self-administration of heroin alone (0.0001-0.01 mg/kg/inj). Drug and food (1-g banana pellets) self-administration were maintained on a second-order FR4 (VR16:S) schedule in four 1-hr sessions each day. Each buprenorphine or saline control treatment was evaluated for 10 consecutive days, and monkeys returned to base-line performance between each treatment condition. Buprenorphine (0.075-0.75 mg/kg/day) selectively reduced self-administration of speedball combinations of low-dose cocaine (0.001 mg/kg/inj) and heroin (0.001 or 0.0032 mg/kg/inj) (P < .05-.01), and buprenorphine (0.237 mg/kg/day) shifted dose-effect curves for speedball combinations of cocaine (0.001 mg/kg/inj) and heroin (0.0001-0.032 mg/kg/inj) downward (P < .05-.01) and approximately 1 log unit to the right. Buprenorphine treatment was less effective in decreasing responding maintained by speedball combinations of heroin and 0.01 and 0.10 mg/kg/inj cocaine. Buprenorphine treatment (0.075 and 0.237 mg/kg/day) also shifted the heroin dose-effect curve downward (P < .01-.001) and to the right. Both speedball and heroin self-administration were associated with dose-dependent decreases in food-maintained responding during saline control treatment. However, food-maintained responding was often higher than control levels during buprenorphine treatment (P < .05-.001), which suggests that buprenorphine antagonized the rate-decreasing effects of speedballs and of heroin. Buprenorphine's selective reduction of speedball and heroin self-administration is consistent with clinical treatment trials in opioid abusers and polydrug abusers. Thus, these primate models of speedball and heroin self-administration should be useful for preclinical evaluation of novel drug abuse treatment medications.     

Choice between money and intranasal heroin in morphine-maintained humans

Five morphine-maintained individuals participated in an inpatient study evaluating the effects of a monetary alternative ($10, $20, $40) on intranasal (i.n.) heroin (placebo, 12.5, 25, 50, 100 mg) self-administration, using a procedure in which subjects chose between money and heroin. Each money amount was tested in combination with each heroin dose. Subjects responded under a progressive-ratio schedule (PR 50, 100, ..., 2800); the PR value increased independently for each option. Subjective, performance, and physiological effects were also measured during each session. Heroin breakpoint values increased in a dose-related manner, relative to placebo, when $10 or $20 was available. In contrast, only the highest dose produced a heroin breakpoint value that was significantly different from placebo when $40 was available. Heroin also produced dose-related increases in several ratings of drug effect, including "I feel ..." "a good drug effect", "high", "mellow", and "stimulated". These effects were not significantly affected by the alternative money condition. These results demonstrated: (1) the dose-related reinforcing effects of i.n. heroin in opioid-dependent individuals; (2) that i.n. heroin self-administration can be modified by the availability of an alternative reinforcer (i.e. money); and (3) that self-reported drug effects can be differentiated from drug self-administration.     

The relationship between maternal use of heroin and methadone and infant birth weight

AIMS/DESIGN: Reduction in mean birth weight and increased incidence of low birth weight are both associated with exposure to illicit heroin in pregnancy. Many studies examining neonatal outcomes in pregnant heroin users treated with methadone report improvements in birth weight. As a consequence, methadone treatment has become the 'gold standard' for the management of the pregnant heroin user. However, not all studies report significant birth weight increases associated with methadone. We undertook a number of meta-analyses on reduction in mean birth weight and incidence of low birth weight to estimate more precisely the effect of illicit heroin and methadone. FINDINGS: Results showed mean reduction in birth weight associated with heroin use: 489 g (95% CI 284-693 g), compared with methadone: 279 g (229-328 g). Similarly, the pooled relative risk estimate for low birth weight for maternal heroin use was 4.61 (95% CI 2.78-7.65), compared with 1.36 (0.83-2.22) for methadone. Analysis of data on combined heroin and methadone use produced a pooled mean reduction in birth weight of 557 g (403-710 g), with a pooled relative risk estimate for low birth weight of 3.28 (2.47-4.39). Pooling 'any' methadone data, regardless of heroin use, produced an estimated reduction in birth weight of 395 g (311-478 g) and a relative risk estimate for low birth weight of 1.90 (1.29-2.81). Combining all data in an 'any' opiate use analysis also produced a mean reduction in birth weight of 483 g (386-583 g) and a relative risk estimate for low birth weight of 3.81 (2.57-5.65). CONCLUSIONS: The current findings suggest that heroin use while receiving methadone may counteract the birth weight advantage gained from methadone alone. Whether this is due to fetal exposure to heroin plus methadone, to reduced antenatal care, other behavioural and environmental factors associated with concurrent use of heroin and methadone or a combination of these is unclear. Nevertheless, these results challenge the current belief that the pregnant user is always better off receiving methadone than not, and suggests that methadone may not be the appropriate treatment for the pregnant women who continue to use illicit heroin.     

The consequences of different "lapses" on relapse to heroin seeking in rats.

Although human studies have shown that a lapse, the first violation of abstinence, often induces resumption of drug taking, or relapse, it is not known what aspect of a lapse is critical to relapse or whether this phenomenon can be studied in other species. Rats were trained to self-administer heroin accompanied by a discrete light stimulus. After extinction, different groups experienced different "lapses." Twenty-four hours later, all groups received a test for relapse. It was found that a lapse during which heroin was self-administered, or was presented in close temporal contiguity with lever pressing, induced subsequent heroin seeking. Simple exposure to heroin, or to heroin-related stimuli, during the lapse had little effect on responding in the test for relapse. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Synergistic elevations in nucleus accumbens extracellular dopamine concentrations during self-administration of cocaine/heroin combinations (Speedball) in rats

The abuse of cocaine/opiate combinations (speedball) represents a growing trend in illicit drug use. Delineation of neurobiological substrates mediating the reinforcing effects of the combination may increase our knowledge of reinforcement mechanisms and provide useful new information for the development of pharmacotherapies. Several studies suggest dopaminergic innervations of the nucleus accumbens (NAc) have a central role in the brain processes underlying drug reinforcement. The present study was undertaken to determine the relationship between the self-administration of cocaine/heroin combinations and NAc extracellular dopamine concentrations ([DA]e) using in vivo microdialysis and microbore high-pressure liquid chromatography. Rats were assigned randomly to one of three groups to self-administer i.v. cocaine (125, 250, and 500 micrograms/infusion; n = 5), heroin (4.5, 9, and 18 micrograms/infusion; n = 5), or cocaine/heroin combinations (125/4.5; 250/9, and 500/18 micrograms/infusion; n = 4) under a fixed ratio (FR) 10: 20-s time-out schedule of reinforcement/multicomponent dosing session. After stable rates of responding were engendered and maintained, microdialysis samples were collected in 10-min intervals during the self-administration session. Self-administration of cocaine/heroin combinations produced synergisitic elevations in NAc [DA]e (1000% baseline) compared with cocaine (400% baseline) and heroin (not significantly different from baseline levels). Neither the number of infusions nor the interinfusion intervals was significantly different between the groups across the self-administration session. Moreover, cocaine concentrations were not significantly different between the cocaine and cocaine/heroin groups. These results demonstrate that heroin interacts with cocaine to produce synergistic elevations in [DA]e, providing a neurochemical basis for understanding the abuse liability of cocaine/opiate combinations.