Influence of treatment with inhalable heroin on pulmonary function.

This study aims to asses the influence of inhalable heroin on pulmonary function in chronic heroin-dependent patients treated with inhalable heroin. Among 32 patients (all cigarette smokers), a spirometric test was conducted at baseline and after an average period of 10 months of treatment with medically prescribed heroin. Patients showed a high frequency of pulmonary dysfunction at baseline [34%, with percentage of forced expiratory volume in 1 s (%FEV1)<80%]. However, after excluding those who started pulmonary treatment (n=2) or who used heroin intravenously only (n=2), no statistically significant differences in %FEV1 between baseline and follow-up were observed (n=28; mean %FEV1 86% at baseline vs. 91% at follow-up; p=0.09). This small and relatively brief study suggests that 10 months of co-prescribed inhalable heroine base does not seem to (further) deteriorate pulmonary function in chronic, cigarette smoking treatment refractory heroin addicts. Screening for and treatment of pulmonary dysfunction is recommended for methadone patients with and without co-prescribed heroin.

Increased opioid release in specific brain areas in animals exposed to prenatal morphine and emotional stress later in life.

Prenatal morphine treatment and emotional stress both have been shown to increase sensitivity to reward-related behaviors. It has been postulated that this increased sensitivity to rewarding stimuli may be the result of an enhanced release of endogenous opioids. In the present study, in vivo autoradiography was employed to investigate the endogenous opioid release in specific brain areas in rats. Pregnant animals were exposed to morphine or saline from day 8 of gestation till birth. Development of pups was monitored and play behavior was tested on postnatal day 21. Adult rats were exposed to repeated emotional stress or control treatment for five consecutive days and tested in a small open field 5 days later. [(3)H]-Diprenorphine was injected following this test to investigate endogenous opioid release. Prenatal morphine treatment increased play behavior and endogenous opioid release in a number of cortical and subcortical brain areas after being subjected to an open field challenge later in life. Emotional stress exposure increased locomotor activity in the open field irrespective of the type of prenatal treatment and increased endogenous opioid release in some specific brain areas. It is suggested that the increased release of endogenous opioids in the substantia nigra, the piriform cortex and the septum observed after both types of treatments is related to the increased sensitivity to reward.

Mast cell mediator tryptase levels after inhalation or intravenous administration of high doses pharmaceutically prepared heroin.

BACKGROUND: Opioids like morphine and heroin induce mast cell degranulation in vitro. The release of mast cell mediators like histamine and tryptase may lead to allergic symptoms. In this study it was investigated whether mast cell mediator release also occurs in vivo in addicted patients who participated in a heroin on medical prescription trial, and were under treatment with large doses of heroin in combination with methadone. METHOD: Plasma levels of tryptase, a specific marker for mast cell degranulation, were measured by immuno-assay at baseline and 60 min after heroin administration. Heroin was administered either by intravenous injection (11 subjects) or by inhalation (nine subjects). Single heroin doses varied from 200 to 450 mg. Besides tryptase, the plasma concentrations of heroin, its metabolite morphine and methadone were measured. RESULTS: After heroin injection, the mean tryptase plasma concentration increased dose dependently by on average 23.1% (95% CI 14.6-31.6%). After heroin inhalation, no tryptase release was observed. Heroin and morphine peak plasma concentrations were 3-5 times greater in heroin injectors than in inhalers. In heroin injectors, tryptase levels were related to morphine peak concentrations, but not to heroin concentrations. Tryptase plasma concentrations were not related to methadone levels. Mild allergic reactions were reported in five cases after intravenous heroin use, but not after inhalation. CONCLUSION: This study revealed that mast cell mediator tryptase concentrations increase after intravenous heroin injection in chronic opioid users, but not after heroin inhalation. This may be explained by the higher Cmax levels of metabolite morphine that were achieved after injection than after inhalation. Although statistical significance was reached, the degree of mast cell degranulation after intravenous injection of heroin was mild, and did not lead to clinically relevant side effects in this group of opioid-tolerant subjects.

Volatilisation of diacetylmorphine: in vitro simulation of 'chasing the dragon'.

In preparation for a trial on co-prescription of heroin to chronic treatment-resistant addicts, a pharmaceutical dosage form for smokable heroin was developed. During development of this product (a mixture of diacetylmorphine and caffeine), in vitro experiments were performed simulating 'chasing the dragon': the technique used by addicts for inhalation of heroin after volatilisation. Samples were heated on aluminium foil using a heating device and the vapours were collected and analysed using a HPLC-UV method. The recovery of diacetylmorphine and caffeine in vapours was studied after volatilisation of different powder mixtures at temperatures between 200 and 350 degrees C. Furthermore, the volatilisation set-up was combined with an Andersen sampler to determine the sizes of aerosol particles. Only small differences in recovery of diacetylmorphine and caffeine were found between temperatures and between powder mixtures: 46-62% of diacetylmorphine from the sample was recovered in vapour and 65-83% of caffeine. The only degradation product detected in vapour was 6-acetylmorphine (4.1-7.1%). In the temperature range studied, temperature mainly influenced the volatilisation rate. Mass median aerodynamic diameters of aerosols from diacetylmorphine-containing samples ranged from 1.8-4.1 microm; 45-60% of each sample was recovered as aerosol particles <5 microm. Volatilising pharmaceutical smokable heroin resulted in sufficient amounts of diacetylmorphine in vapour and in particles suitable for effective deposition in the lungs.

Contact allergy and respiratory/mucosal complaints from heroin (diacetylmorphine).

After the start of heroin (diacetylmorphine)-assisted treatment to a selected group of chronic treatment-resistant heroin-dependent patients in the Netherlands, we reported about work-related eczema and positive patch tests to heroin in some nurses and nasal and respiratory complaints. To investigate the prevalence of heroin contact allergy, we started a questionnaire-based study with follow-up by allergological examinations. Of 120 questionnaires sent, 101 (84%) was returned: 67 from nurses and 34 from other employees. Of 101 workers, 38 (38%) had reported work-related complaints: 33 of 67 (49%) nurses and 5 of 34 (15%) other employees. Patch tests to heroin were performed in 24 nurses and were positive in 8 (33%). All the 8 had eyelid or facial eczema and, in 6, accompanied by mucosal or respiratory complaints. The prevalence of heroin contact allergy in this study was 8% (8/101) among all employees and 12% (8/67) among nurses. Respiratory and mucosal complaints could not be ascribed to a contact allergy, and in these cases, serum was analysed for specific immunoglobulin E to heroin. A type 1 allergy to heroin could not be shown. These complaints are possibly due to the histamine-liberating effect of heroin, to atopic constitution, to a combination of these factors or - less likely - to other non-allergic factors.

Chronic cocaine injections attenuate behavioral response of kappa-opioid receptors to U-50,488H agonist.

Chronic injections of cocaine (20 mg/kg daily for 10 days) increase activity and decrease anxiety in male C57Bl/6j mice in comparison with animals chronically injected with normal saline. U-50,488H (kappa-opioid receptor agonist; 2.5 mg/kg) produced an anxiolytic effect in animals preinjected with normal saline and had no effect in animals chronically injected with cocaine. Presumably, chronic activation of dopaminergic systems caused by cocaine injections is paralleled by desensitization of kappa-opioid receptor system.

Increased gabaergic input to ventral tegmental area dopaminergic neurons associated with decreased cocaine reinforcement in mu-opioid receptor knockout mice.

There is general agreement that dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens and prefrontal cortex play a key role in drug reinforcement. The activity of these neurons is strongly modulated by the inhibitory and excitatory input they receive. Activation of mu-opioid receptors, located on GABAergic neurons in the VTA, causes hyperpolarization of these GABAergic neurons, thereby causing a disinhibition of VTA dopaminergic neurons. This effect of mu-opioid receptors upon GABA neurotransmission is a likely mechanism for mu-opioid receptor modulation of drug reinforcement. We studied mu-opioid receptor signaling in relation to cocaine reinforcement in wild-type and mu-opioid receptor knockout mice using a cocaine self-administration paradigm and in vitro electrophysiology. Cocaine self-administration was reduced in mu-opioid receptor knockout mice, suggesting a critical role of mu-opioid receptors in cocaine reinforcement. The frequency of spontaneous inhibitory post-synaptic currents onto dopaminergic neurons in the ventral tegmental area was increased in mu-opioid receptor knockout mice compared with wild-type controls, while the frequency of spontaneous excitatory post-synaptic currents was unaltered. The reduced cocaine self-administration and increased GABAergic input to VTA dopaminergic neurons in mu-opioid receptor knockout mice supports the notion that suppression of GABAergic input onto dopaminergic neurons in the VTA contributes to mu-opioid receptor modulation of cocaine reinforcement.

Early amygdala damage disrupts performance on medial prefrontal cortex-related tasks but spares spatial learning and memory in the rat.

Recent studies have demonstrated that the postnatal development of connections between the basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) mature around postnatal days 13-15 (pd13-15), whereas these between the BLA and other structures such as the nucleus accumbens and the mediodorsal thalamus are completed by pd7. Accordingly, it is hypothesized that mPFC cytoarchitecture and hence its function may be specifically affected by neonatal (i.e. on pd7) but not later induced (i.e. on pd21) damage to the BLA. To test this hypothesis, rats received excitotoxic lesions to the BLA on either pd7 or pd21 and were subjected to two tests putatively sensitive to mPFC dysfunction, namely food hoarding and spontaneous alternation. In addition, rats were tested for spatial learning and memory, to determine any possible effects on hippocampal function. Consistent with the documented effects of mPFC lesions, pd7 damage to the BLA impaired spontaneous alternation and food hoarding performance, an effect that was not found in rats with BLA lesions induced on pd21. Spatial learning and memory, however, were not affected by the (neonatal) lesion procedure. Together, these results indicate that neonatal BLA damage affects species-specific sequential behavior and flexibility, which may be attributed to abnormal functioning of the mPFC.

Development and manufacture of diacetylmorphine/caffeine sachets for inhalation via 'chasing the dragon' by heroin addicts.

In 1998, two clinical trials were started in The Netherlands to evaluate the effect of coprescription of heroin and methadone on the mental and physical health and social functioning of chronic, treatment-resistant, heroin-dependent patients. Since 75-85% of the heroin addicts in The Netherlands use their heroin by "chasing the dragon," one of the two study arms concerned the coprescription of inhalable heroin. A pharmaceutical dosage form for inhalable heroin was developed for this trial, consisting of a 3:1 powder mixture of diacetylmorphine base and caffeine anhydrate. We describe the manufacturing process that was developed for filling sachets with this mixture in four dosages using a micro dose auger filler. In order to control product quality, in-process controls were developed to monitor the filling process and quality control tests were performed on the finished product. In-process control results have shown the filling process to be accurate and precise. The diacetylmorphine/caffeine sachets were shown to comply with the specifications for content and uniformity of mass. The finished product was found to be stable for 2 years when stored at 25 degrees C, 60% relative humidity and for 6 months when stored at 40 degrees C, 75% relative humidity.

['Pharmacologic interventions in drug addiction': an advisory report from the Health Council of the Netherlands]. / 'Medicamenteuze interventies bij drugverslaving'; een advies van de Gezondheidsraad.

Addiction is a relapsing brain disease with a tendency towards chronicity. Biological, psychological and socio-cultural factors play a role in the onset and course of this disease. The Health Council of the Netherlands has issued a report on pharmacotherapeutic interventions. The treatment of addiction should be regarded as a medical intervention. A growing number of effective pharmacotherapies are becoming available for the treatment of heroin addiction, although not all of those are available in the Netherlands. Currently, no effective pharmacotherapies are available for the treatment of cocaine addiction. In polydrug addicts, pharmacotherapeutic interventions should be directed at the various separate addictions. In the majority of cases pharmacotherapy is part of an integrated treatment approach in which supportive psychosocial interventions are also important. The long-term continuation of treatment is usually indicated. The Health Council recommends that addiction physicians be put in charge of the multidisciplinary treatment. Medical schools should pay attention to the practical aspects of the treatment and management of addicts. The organisation and workforce of addiction treatment services should comply with the demands that are placed upon healthcare services. Public information campaigns about addiction and the treatment options for addicts can contribute to the destigmatisation of this patient category.

Hyperresponsiveness to phencyclidine in animals lesioned in the amygdala on day 7 of life. Implications for an animal model of schizophrenia.

Phencyclidine (PCP) has been described to exacerbate psychotic symptoms in patients suffering from schizophrenia. In rats, PCP, dose-dependently, induces hyperactivity, stereotyped behaviour and social isolation, postulated to represent the positive (hyperactivity, stereotypy) and negative (social isolation) symptoms of schizophrenia. Based on previous studies, ibotenic acid lesions in the amygdala on day 7 of life have been proposed as an animal model of psychiatric neurodevelopmental disorders like schizophrenia. The purpose of the present study was to determine whether the responsiveness to PCP on locomotor activity in animals lesioned in the amygdala on day 7 of life is different from the response to this drug in sham-operated animals. The effect of graded doses of PCP on behaviour was assessed in a small open field. Animals lesioned in the amygdala on day 7 of life appeared to be hyperresponsive to PCP compared to sham-operated animals. The hyperresponsiveness to PCP in rats lesioned in the amygdala on day 7 of life further contributes to the validation of this putative animal model of schizophrenia.

ERK1/2 activation in rat ventral tegmental area by the mu-opioid agonist fentanyl: an in vitro study.

Opioid receptors in the ventral tegmental area, predominantly the mu-opioid receptors, have been suggested to modulate reinforcement sensitivity for both opioid and non-opioid drugs of abuse. The present study was conducted to study signal transduction proteins, which may mediate the functioning of mu-opioid receptors in the neurons of the ventral tegmental area. Therefore, brain slices of the ventral tegmental area were exposed in vitro to the specific mu-opioid agonist fentanyl and immunohistochemically stained for four different activated proteins using phospho-specific antibodies. Fentanyl dose-dependently activated extracellular signal-regulated protein in brain slices of the ventral tegmental area. This activation was reversible with naloxone. Furthermore, naloxone itself also activated extracellular signal-regulated protein kinase. Under the present conditions fentanyl did not affect extracellular signal-regulated protein kinase 1 and 2, Stat and cyclic AMP-response element-binding protein activity. The direct activation of extracellular signal-regulated protein kinase in ventral tegmental area slices by the mu-opioid agonist fentanyl may suggest a role of extracellular signal-regulated protein kinase in reward processes.

[Involvement of kappa-opioid receptors in mechanisms of aggressive and submissive types of behavior in male mice]. / Vovlechenie opioidnykh kappa-retseptorov v mekhanizmy formirovaniia agressivnogo i submissivnogo tipov povedeniia u samtsov myshei.

Effects of the kappa-opioid receptor agonist U-50.488H (0.0, 0.6, 1.25, 2.5 mg/kg. s.c., 30 min) on behavior of the winner with repeated experience of victories and the losers with repeated experience of social defeat in 20 daily agonistic confrontations as well as the control mice were investigated in the tests estimating exploratory activity (open-field) and communication (partition test). Different effects of drug on behaviors of animals with different social story were shown in both tests. In the losers, all doses of U-50.488H had anxiolytic effect, increasing the communication in the partition test. In the winners, the drug induced an increase of aggressive motivation. The control mice were less sensitive to the treatment. In the open-field test, U-50.488H increased the locomotor and exploratory activity in high anxious losers. Winners significantly differed in their reaction to drug treatment in most behavioral forms in comparison with the controls and losers. It was concluded that kappa-opioid receptors are specifically involved into mechanisms of formation of aggressive or submissive types of behaviors under positive or negative social experience.

Decrease in basal dopamine levels in the nucleus accumbens shell during daily drug-seeking behaviour in rats.

Accumbal dopamine (DA) is generally accepted to participate in the neural mechanisms underlying drug dependence. Recently the involvement of accumbal DA in drug-seeking behaviour has gained more experimental attention. To study an involvement of accumbal DA in drug-seeking behaviour within and between daily self-administration behaviour, changes in extracellular DA concentration in the nucleus accumbens (NAc) shell were measured during the daily dynamics of intravenous heroin and cocaine self-administration. Groups of drug naive rats were allowed to intravenously self-administer heroin (30 microg/infusion) and cocaine (30 microg/infusion) during five consecutive daily 3 h sessions. Extracellular DA concentrations in the NAc were measured before and after a single 3 h session (acute) and before and after 5 consecutive 3 h sessions (repeated). Following acute and repeated heroin and cocaine self-administration the extracellular DA concentration in the NAc shell was increased by two-fold to three-fold over baseline. These changes in DA concentrations are thought to reflect a direct effect of heroin and cocaine on DA neurotransmission in the NAC shell. Measurement of basal DA concentrations before the self-administration sessions revealed that just before the scheduled 5th self-administration session the (absolute) basal DA levels in the NAc in heroin or cocaine self-administering animals were decreased by approximately halve, as compared to drug-naive animals. It is assumed that just before a scheduled next session the (daily) desire for the drug is high. This decrease in basal DA neurotransmission in the NAc shell may, therefore, reflect an involvement of accumbal DA in drug-seeking behaviour during daily self-administration behaviour. The results demonstrate that initiation of i.v. heroin and cocaine self-administration is linked with changes in extracellular levels of DA in the NAc shell. Moreover, the present data suggest that accumbal DA might be involved in processes underlying the motivational aspects involved in daily drug-seeking behaviour, and that neuroadaptive changes in the mesolimbic DA system due to repeated drug intake lead to an tonic decrease in overall DA activity in the NAc.

Adaptation and habituation to an open field and responses to various stressful events in animals with neonatal lesions in the amygdala or ventral hippocampus.

A rat model of neurodevelopmental psychopathological disorders, designed to determine neurodevelopmental deficits following damage to the brain early in life, was used to investigate behavioural changes in adaptation and habituation to an open field and responses to different kinds of stressful events. Animals with bilateral ibotenic acid lesions in the amygdala or ventral hippocampus on day 7 or 21 of life were compared to sham-operated animals. According to the model it was assumed that behavioural changes in animals lesioned on day 7, but not in animals lesioned on day 21 of life, were caused by maldevelopment of one or more structures connected to the damaged area. Animals lesioned in the amygdala or ventral hippocampus on day 7, but not animals lesioned in these structures on day 21 of life, displayed decreased (within-session) adaptation and (between-session) habituation to the open field and a decrease in immobility in the forced swim test, whereas only animals lesioned in the amygdala displayed enhanced general activity. These results were indicative of neurodevelopmental deficits. No changes in stress-induced hyperthermia were found, while animals lesioned in the amygdala both on day 7 or 21 of life exhibited decreased conditioned ultrasonic vocalizations. These latter results suggest that the amygdala is implicated in the conditioned stress-induced response. The contribution of the present findings to the animal model of neurodevelopmental disorders like schizophrenia and possible brain structures and neurotransmitter systems involved in the neurodevelopmental deficits are discussed.

Long-term impairment of social memory in the rat after social defeat is not restored by desglycinamide-vasopressin.

Repeated social defeat followed by individual housing caused a long-term impairment of social memory in male rats. Social memory, as assessed in the social discrimination test using an intertrial interval of 3 min, was impaired for at least 8 weeks after the social defeat experience. Since social memory of male rodents depends on proper functioning of the sexually dimorphic vasopressin system, it was investigated whether a centrally active vasopressin fragment could restore the impaired social memory. Subcutaneous administration of 6 microg/kg of the vasopressin fragment desglycinamide-vasopressin (VP1-8) 40 days after social defeat slightly improved social memory in both control and socially defeated rats. It is concluded that social defeat followed by individual housing caused a long-term impairment of social memory, which was not restored by treatment with VP1-8.

Heroin self-administration by means of 'chasing the dragon': pharmacodynamics and bioavailability of inhaled heroin.

In this controlled clinical study, the bioavailability and pharmacodynamics of inhaled heroin are evaluated and compared between 'chasing the dragon' and inhalation from a heating device, and at three dose levels, 25, 50 and 100 mg heroin, in two separate study phases. In study phase 1, no differences between the inhalation methods were detected on any of the physiological or behavioral measures, nor in bioavailability. Subjectively, the participants had a strong preference for the method of chasing, which was therefore used in study phase 2. In phase 2, heroin produced a dose-related increase in subjective drug-liking, body temperature and heart rate, and a clear, dose-related decline in reaction time. Linearly dose-related differences were found in the amount of total morphine in urine, amounting to an average of 45% of the parent heroin base received. Based on these findings, it is concluded that chasing is quite an effective route of heroin administration, producing rapid, dose-related subjective and objective effects and a sufficiently high and reproducible bioavailability.