Showing papers on "Opiate published in 2001"

Progressive enhancement of delayed hyperalgesia induced by repeated heroin administration: a sensitization process.

Abstract: It is difficult to conceive that tolerance and sensitization processes, two apparently opposite phenomena, can concomitantly modify one given biological process, i.e., the processing of pain. We have shown recently that opiates produce not only analgesia but also long-lasting hyperalgesia in rats. This suggests that tolerance to the analgesic effect of an opiate, especially heroin, could be in part the result of an actual sensitization of pronociceptive systems. Here, we show that both magnitude and duration of heroin-induced delayed hyperalgesia increase with intermittent heroin administrations, leading to an apparent decrease in the analgesic effectiveness of a given heroin dose. Our observation that a small dose of heroin which is ineffective for triggering a delayed hyperalgesia in non-heroin-treated rats induced an enhancement in pain sensitivity for several days after a series of heroin administrations is in agreement with the sensitization hypothesis. The effectiveness of the opioid receptor antagonist naloxone to precipitate hyperalgesia in rats that had recovered their pre-drug nociceptive value after single or repeated heroin administrations indicates that heroin-deprived rats were in a new biological state associated with a high level balance between opioid-dependent analgesic systems and pronociceptive systems. Because the NMDA receptor antagonist dizocilpine maleate (MK-801) prevented both heroin-induced long-lasting enhancement in pain sensitivity and naloxone-precipitated hyperalgesia, these findings further suggest that tolerance, sensitization, and one withdrawal symptom, hyperalgesia, are issued from a neuroadaptive process in which NMDA systems play a critical role.

Behavioural sensitization after repeated exposure to Delta 9-tetrahydrocannabinol and cross-sensitization with morphine.

Abstract: Rationale: Repeated exposure to several drugs of abuse has been reported to induce behavioural sensitization. So far no evidence has been provided that such a phenomenon also applies to cannabinoids. Objectives: In this study we investigated if repeated exposure to Δ9-tetrahydrocannabinol (Δ9-THC) induces behavioural sensitization. In addition we tested the possibility of cross-sensitization between Δ9-THC and morphine. Methods: Male Sprague-Dawley rats were administered for 3 days, twice daily, with increasing doses of Δ9-tetrahydrocannabinol (2, 4 and 8 mg/kg i.p.) or increasing doses of morphine (10, 20 and 40 mg/kg s.c.) or vehicle. After a washout of 14 days the animals were challenged with Δ9-THC (75 and 150 µg/kg i.v.), with a synthetic cannabinoid agonist WIN55212–2 (75 and 150 µg/kg i.v.) or with morphine (0.5 mg/kg i.v.), through a catheter inserted into the left femoral vein 24 h before, and the behaviour recorded. Results: Rats previously administered with Δ9-THC showed a greater behavioural activation compared to controls in response to challenge with Δ9-THC (150 µg/kg i.v.) and to challenge with morphine (0.5 mg/kg i.v.). Similar to that observed after repeated opiates, this behavioural sensitization was characterized by stereotyped activity. Animals administered with a schedule of morphine that induces behavioural sensitization to morphine also showed a behavioural sensitization to challenge with cannabinoids (Δ9-THC and WIN55212–2, 75 and 150 µg/kg i.v.). The effect of the challenge with Δ9-THC was prevented by the administration of the CB1 antagonist SR141716A (1 mg/kg i.p.), 40 min beforehand. Conclusions: The results of the present study demonstrate that repeated exposure to Δ9-THC induces behavioural sensitization not only to cannabinoids but also to opiates. This cross-sensitization was symmetrical since rats behaviourally sensitized to morphine were also sensitized to cannabinoids. These observations further support the evidence of an interaction between the opioid and the cannabinoid system and might provide a neurobiological basis for a relationship between cannabis use and opiate abuse.

A single exposure to morphine induces long-lasting behavioural and neurochemical sensitization in rats.

Abstract: Repeated exposure to drugs of abuse causes persistent behavioural sensitization and associated adaptations in striatal neurotransmission, which is thought to play an important role in certain aspects of drug addiction. Remarkably, even a single exposure to psychostimulant drugs such as amphetamine or cocaine can be sufficient to elicit long-lasting sensitization. The present study was designed to evaluate whether long-lasting behavioural and neurochemical sensitization can also be evoked by a single exposure to morphine, an opiate drug of abuse. Rats were pretreated once with morphine (2, 10 or 30 mg/kg). Three weeks later, the locomotor effects of morphine and amphetamine, as well as the electrically evoked release of [3H]dopamine and [14C]acetylcholine from slices of nucleus accumbens and caudate-putamen, was assessed. In morphine-pretreated rats, the psychomotor effects of morphine and amphetamine were sensitized. In addition, the electrically evoked release of [3H]dopamine and [14C]acetylcholine was augmented in slices of nucleus accumbens and caudate-putamen from morphine-pretreated animals. Although the sensitization of the locomotor effect of morphine was less profound than previously observed after repeated intermittent morphine treatment, the enduring behavioural and neurochemical consequences of a single and repeated intermittent morphine treatment appear to be highly comparable. We therefore conclude that a single exposure to morphine induces long-lasting behavioural sensitization and associated neuroadaptations.

Effect of intravenous injection speed on responses to cocaine and hydromorphone in humans

Abstract: Rationale: It is commonly accepted that the relative abuse liability of drugs is positively related to the rate of delivery to the central nervous system; however, few controlled studies have tested this hypothesis in humans. Objectives: The aims of this study were to evaluate systematically the effects of modifying intravenous infusion speed on the pharmacodynamic responses related to abuse liability and toxicity of intravenous cocaine and hydromorphone. Methods: Twelve experienced opiate and cocaine users completed this 3-week inpatient study. After completing a safety session, participants were tested on 9 separate test days with intravenous cocaine (30 mg/70 kg), hydromorphone (3 mg/70 kg), and placebo, each administered under double-blind and randomized conditions at infusion rates of 2, 15, and 60 s. Dependent outcome measures included a range of physiological, subjective, and observer-rated measures, and continuous electrocardiographic monitoring was conducted for safety monitoring. Results: Subjective responses to cocaine (for example, "high," "liking") were significantly greater when cocaine was infused more rapidly. Physiological responses to cocaine were largely unaltered with no evidence of increased toxicity with faster infusion speeds. None of the effects of hydromorphone were altered by varying the speed of infusion. Conclusions: This study provides empirical evidence for the commonly accepted belief that the abuse liability of cocaine can be enhanced by increasing the rate of the intravenous infusion; this principal may not hold true for opioids but further work would be required to rule this out. The data also indicate that moderate doses of cocaine can be administered over a range of infusion speeds commonly used in experimental settings without appreciably altering the apparent medical risks.

Effects of methadone on cognition, mood and craving in detoxifying opiate addicts: a dose-response study.

Abstract: Rationale: Methadone is the most widespread pharmacological treatment for opiate dependency but relatively little is known of its effects on cognitive and psychomotor functioning, drug craving and mood. Objective: The present study aimed to assess the acute effects of methadone in patients admitted to an opiate detoxification programme. Methods: Patients were randomly allocated to one of two groups who received either 50% or 100% of their daily stabilisation dose, and a placebo, in a double-blind, cross-over design. Twenty patients completed the study, all were assessed pre- and post-drug on 2 separate testing days. Results: Performance on a task tapping episodic memory (delayed recall of a prose passage) was significantly impaired following the 100% daily dose of methadone. Methadone treatment had no effect on craving or mood. Patients were unable to distinguish between methadone and placebo treatments. Conclusions: A single dose of methadone can induce episodic memory impairment in patients who have a history of heroin use averaging more than 10 years. Such impairment can be avoided by giving methadone in divided doses.

Reduction of opioid dependence by the CB1 antagonist SR141716A in mice: evaluation of the interest in pharmacotherapy of opioid addiction

Abstract: Several compounds, mainly opioid agonists such as methadone, are currently used for long term medication of heroin addicts. Nevertheless, these maintenance treatments have the disadvantage to induce a dependence to another opiate. As interactions between opioid and cannabinoid systems have been demonstrated, the ability of the CB1 antagonist, SR141716A to reduce morphine-induced addiction was investigated. The effects of SR141716A on the rewarding responses of morphine were evaluated in the place conditioning paradigm. No significant conditioned preference or aversion were observed after repeated treatment with the CB1 antagonist alone. However, SR141716A was able to antagonize the acquisition of morphine-induced conditioned place preference. SR141716A was co-administered with morphine for 5 days, and the withdrawal syndrome was precipitated by naloxone administration. A reduction in the incidence of two main signs of abstinence: wet dog shakes and jumping was observed while the other were not significantly modified. In contrast, an acute injection of the CB1 antagonist just before naloxone administration was unable to modify the incidence of the behavioural manifestations of the withdrawal, suggesting that only chronic blockade of CB1 receptors is able to reduce morphine-induced physical dependence. Several biochemical mechanisms could explain the reduction of opioid dependence by CB1 antagonists. Whatever the hypotheses, this study supports the reported interaction between the endogenous cannabinoid and opioid systems, and suggests that SR 141716A warrants further investigations for a possible use in opioid addiction. Keywords: Cannabinoid, morphine, dependence, κ opioid systems, mice Introduction Since drug addiction is often considered as a chronic, relapsing disorder, several therapeutical assays to reduce craving are under investigation. In the case of opiate addicts, long-term treatment with opioid agonists such as methadone or buprenorphine, are currently used (review in Kreek, 1997; Fischer et al., 1999; Ward et al., 1999). Nevertheless, there are several reasons why it should be of great interest to use non-opioid substances for maintenance treatments or detoxification of heroin abusers. Firstly, like heroin, methadone and buprenorphine used in maintenance program could generate a psychological dependence and can be diverted to illegal sales. Secondly, as an opioid agonist, methadone is able to trigger a withdrawal syndrome and even though it is less severe than that observed with heroin, it is longer lasting. Furthermore, physical dependence has also been reported to occur after chronic buprenorphine treatment (Kuhlman et al., 1998; Dyer et al., 1999). Opioids and cannabinoids share several pharmacological properties (Dewey, 1986), both leading for example to analgesia (Lichtman & Martin, 1991), hypothermia (Anderson et al., 1975) and reduced locomotor activity at high doses (Anderson et al., 1975). Moreover, several lines of evidence support the occurrence of interactions between both systems (Welch et al., 1995; Tanda et al., 1997; Meng et al., 1998; Ambrosio et al., 1999; reviews in Manzanares et al., 1999; Piomelli et al., 2000). This has been recently confirmed by evaluating the pharmacological properties of morphine in central cannabinoid receptor (CB1) knockout mice (Ledent et al., 1999). Thus, the acute effects of morphine were unaffected in CB1 knockout mice as compared to wild type animals, whereas reinforcing properties of the alkaloid and severity of the withdrawal syndrome were found to be reduced, suggesting that long-term CB1 antagonist administration could be considered for preventing the development of dependence to opiates. However, frequent inconsistencies between observed and expected results are found in knockout mice, probably due to compensatory developmental mechanisms occurring during embryogenesis and early postnatal life (Zimmer et al., 1998; de Felipe et al., 1998). It was therefore of interest to investigate the effect resulting from the blockade of the CB1 receptors by an antagonist using wild type mice. The synthesis of the highly potent and selective CB1 antagonist, SR 141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxy-amide (Rinaldi-Carmona et al., 1994) affords the possibility to evaluate this hypothesis and to determine whether chronic blockade of CB1 receptors could be used to facilitate drug abstinence. We have therefore studied the behavioural changes classically observed following chronic morphine treatment i.e. withdrawal syndrome and rewarding properties (review in Koob & Le Moal, 1997) in mice repeatedly treated with the combination morphine+SR 141716A. Moreover, as numerous studies have reported a link between both κ and cannabinoid systems (Smith et al., 1994; Welch, 1997) we have evaluated the effects of chronic SR 141716A treatment on the levels of κ endogenous opioid peptide, dynorphin, as well as κ opioid receptors. Indeed, stimulation of κ opioid receptors in the nucleus accumbens was shown to negatively modulate the rewarding properties of morphine. This occurs by a decrease in synaptic levels of dopamine induced by opioid activation of the mesolimbic dopaminergic pathway (Di Chiara & Imperato, 1988; Spanagel et al., 1992; Kuzmin et al., 1997).

Voucher-based reinforcement of opiate plus cocaine abstinence in treatment-resistant methadone patients: Effects of reinforcer magnitude

Abstract: The study tested a voucher-based abstinence reinforcement procedure for reducing opiate and cocaine use in a population of treatment-resistant opiate- and cocaine-abusing methadone patients. Vouchers exchangeable for goods and services were contingent on abstinence from both opiates and cocaine. In two conditions, participants could earn up to $374 or $3,369 in vouchers for providing opiate- and cocaine-free urine samples. Participants received a daily 60-mg dose of methadone. The dose was increased in a second phase, and the voucher conditions were replicated. Analyses of both phases revealed trends toward greater abstinence under the high voucher condition and suggested that higher doses may enhance the efficacy of voucher reinforcement. The results show that reinforcement for abstinence from 2 drugs simultaneously can be effective even in a treatment-resistant population.

Opiate-sensitivity: clinical characteristics and the role of skin prick testing

Abstract: Background The value of skin prick testing in opiate-sensitive individuals is uncertain as opiates cause non-specific weals by direct degranulation of mast cells. Objective To define whether skin prick test (SPT) responses to opiates in opiate-sensitive individuals are different to those seen in the normal population and to describe the clinical characteristics of this group of subjects. Methods The SPT responses of eight opiate-sensitive subjects to morphine 10 mg/mL, pethidine (meperidine) 50 mg/mL and papaveretum 15.4 mg/mL at four different concentrations (undiluted, 1/10, 1/50 and 1/100) were compared with the responses of 100 (32 atopic) non-opiate-sensitive control subjects. Four of the opiate-sensitive subjects had a clinical history of asthma, rhinitis or urticaria on occupational exposure to morphine. One subject developed urticaria with codeine, one developed urticaria and asthma with morphine and diamorphine and two subjects reacted to intravenous papaveretum with anaphylaxis or urticaria. Five out of the eight cases had opiate sensitivity confirmed by single-blind placebo-controlled oral challenge. Results Skin prick tests to all three opiates were not significantly different when the eight opiate-sensitive subjects were compared with either the entire normal control group or the subgroup of 47 definite opiate-tolerant controls that had previously received opiates for clinical indications. Furthermore, there were no significant differences in size of opiate SPT responses between atopic and non-atopic control subjects. In the control subjects, there was a positive correlation in SPT weal size between the three opiates. Conclusion Skin prick testing is not useful in the diagnosis of opiate sensitivity and placebo-controlled challenge should be considered.

Analgesic effects of peripherally administered opioids in clinical models of acute and chronic inflammation.

Abstract: A series of double-blind, placebo-controlled clinical trials demonstrated that low doses of morphine (0.4, 1.2, and 3.6 mg) administered into the intraligamentary space of a chronically inflamed hyperalgesic tooth produced a dose-related naloxone-reversible analgesia. This analgesic effect is mediated by a local mechanism in the inflamed tissue, because subcutaneous administration of a 1.2 mg dose of morphine failed to elicit an analgesic response. In contrast, submucosal administration of 1.2 mg morphine or 50 microg fentanyl to the site of extraction of an impacted third molar after the onset of acute pain failed to elicit an analgesic response despite demonstration of a sensitive bioassay. These data indicate that peripheral opioid analgesia can be evoked in a model of chronic, but not acute, inflammatory pain, suggesting a temporal dependent mechanism needed for the expression of peripheral opiate analgesia during inflammation in humans.

Opposing regulation of the locus coeruleus by corticotropin-releasing factor and opioids. Potential for reciprocal interactions between stress and opioid sensitivity.

Abstract: Rationale: Substantial clinical and preclinical findings support an association between stress and opiate abuse. To understand the mechanisms underlying this association, it is important to identify substrates of the stress response and endogenous opioid systems that interact and specific points at which stress circuits and endogenous opioid systems intersect. Objective: This review focuses on corticotropin-releasing factor (CRF), a critical substrate of the stress response, and its potential for interactions with endogenous opioid systems within the pontine nucleus, locus coeruleus (LC), a brain region that has been implicated as a target in response to stress and opiates. Results: Evidence is reviewed supporting the hypothesis that CRF and endogenous opioids interact to co-regulate the LC. Thus, CRF- and enkephalin-immunoreactive fibers innervating LC dendritic fields overlap, and some axon terminals in this region co-localize CRF and enkephalin. CRF and opioids have opposing effects on LC neuronal discharge and on intracellular signaling mechanisms within LC neurons. Finally, a history of stress or opiate use induces plasticity in CRF–LC or opiate–LC interactions, respectively. Disruptions in the CRF/opioid balance as a result of this plasticity are proposed to result in hyperactivity or hyperresponsiveness of the LC–norepinephrine (NE) system. Conclusions: Co-regulation of the LC–NE system by CRF and opioids may be important in acute adaptation to stress. Potential clinical consequences of an imbalance in this regulation as a result of prior stress include increased risk of opiate self administration and decreased sensitivity to opiates used in clinical settings. Conversely, chronic exposure to opiates may predispose individuals to stress-related psychiatric disorders.

Passionflower in the treatment of opiates withdrawal: a double-blind randomized controlled trial.

Abstract: Objective: Clonidine-based therapies have been utilized as the main protocol for opiate detoxification for several years. However, detoxification with clonidine has its limitations, including lack of efficacy for mental symptoms. Accumulating evidence shows the efficacy of Passiflora incarnata extract in the management of anxiety. In our continuing study of traditional medicines, which have neurotropic effects, this plant had an anxiolytic effect, which may be used as an adjuvant agent in the detoxification of opiates by clonidine. We present the results of a double-blind randomized controlled trial of clonidine plus passiflora extract vs. clonidine plus placebo in the outpatient detoxification of 65 opiates addicts. Methods: A total of 65 opiates addicts were assigned randomly to treatment with passiflora extract plus clonidine tablet or clonidine tablet plus placebo drop during a 14-day double-blind clinical trial. All patients met the DSM IV criteria for opioid dependence. The fixed daily dose was 60 drops of passiflora extract and a maximum daily dose of 0·8 mg of clonidine administered in three divided doses. The severity of the opiate withdrawal syndrome was measured on days 0, 1, 2, 3, 4, 7 and 14 using the Short Opiate Withdrawal Scale (SOWS). Conclusion: Both protocols were equally effective in treating the physical symptoms of withdrawal syndromes. However, the passiflora plus clonidine group showed a significant superiority over clonidine alone in the management of mental symptoms. These results suggested that passiflora extract may be an effective adjuvant agent in the management of opiate withdrawal. However, a larger study to confirm our results is warranted.

Mouse strain differences in opiate reward learning are explained by differences in anxiety, not reward or learning.

Abstract: Gene-targeting techniques to produce null mutations provide a powerful method for evaluating the contribution of particular candidate genes involved in motivation. The embryonic stem cell lines in which homologous recombination is undertaken are derived from 129 mice, but because of the impoverished performance of 129 mice on a number of behavioral tasks, mice chimeric for the mutation are often bred with a C57BL/6 mouse strain. Thus, an examination of both parental strains is important in the study of the knock-out mice. Although the C57BL/6 behavioral phenotype is well documented, details of the 129 phenotype have not been the focus of study until recently. We investigated opiate motivation in both 129/SvJ and C57BL/6J mouse strains to determine whether, and under what circumstances, the 129/SvJ mouse exhibited motivated behavior toward opiates. 129/SvJ mice required both drug and contextual cues to demonstrate morphine conditioned place preferences on test day, whereas C57BL/6J mice required only contextual cues to express opiate place conditioning. Pentobarbital and diazepam but not saline, cocaine, or naloxone could substitute for morphine on test day in 129/SvJ mice, demonstrating that morphine indeed has rewarding motivational valence in the 129/SvJ mouse strain. This critical, interoceptive cue in 129/SvJ mice on test day may be the anxiolytic properties of the effective drugs. Therefore, some deficits observed in 129 mice and mice harboring this genetic background may be attributed to high levels of anxiety during the retrieval period rather than to sensory, learning, or motivational deficits.

The D2 receptor is critical in mediating opiate motivation only in opiate-dependent and withdrawn mice

Abstract: According to the dual systems model for opiate reward, dopamine mediates opiate motivation when an animal is in a deprived motivational state (i.e. opiate-dependent and in withdrawal) and not when an animal is in a nondeprived state (i.e. previously drug-naive). To determine the role of the D2 dopamine receptor subtype in mediating opiate motivation, we examined the behaviour of N5 congenic D2 receptor knockout mice and their wild-type siblings in opiate-naive and opiate-dependent and withdrawn place conditioning paradigms. Opiate-naive D2 receptor knockout mice demonstrated acquisition of morphine-conditioned place preference but failed to acquire place preference when conditioned in the deprived state. We propose that D2 receptor function is critical in mediating the motivational effects of opiates only when the animal is in an opiate-dependent and withdrawn motivational state. These findings also underscore the important influence of the genetic background to a given phenotype, as evidenced by the observation that increasing the allelic contribution from the 129/SvJ strain abolishes morphine place preference in C57BL/6 wild-type mice.

Neuroadaptive responses in brainstem noradrenergic nuclei following chronic morphine exposure.

Abstract: Opiate dependence and withdrawal involve neuroadaptive responses in the central nervous system. A host of studies have previously implicated the A6 noradrenergic neurons of the pontine nucleus locus coeruleus (LC) as an important mediator of somatic signs observed upon withdrawal from opiates. Recent studies, however, are showing that noradrenergic neurons of the LC may not be solely involved in mediating somatic signs of withdrawal. The A2 noradrenergic neurons of the nucleus of the solitary tract (nucleus tractus solitarius [NTS]) in the caudal brainstem may be another possible site. Neurons in the nucleus paragigantocellularis lateralis (PGi), located in the rostral ventral medulla, which are known to send collateral projections to both the LC and the NTS, may co-modulate both noradrenergic nuclei in a parallel fashion, which may represent an anatomical substrate underlying the behavioral expression of opiate withdrawal. The PGi provides glutamatergic and opioid innervation to LC neurons. Hyperactivity of LC during opiate withdrawal arises, in part, from increased glutamate transmission in this pathway. The authors have recently shown that the excitatory transmitter, glutamate, co-exists with the endogenous opioid peptide, enkephalin, in a subset of axon terminals in the LC. Decreases in endogenous opioids in afferents to LC and NTS, following chronic opiate administration, may be equally important in modulating noradrenergic neurons following chronic opiate exposure, by removing a neurochemical system that would inhibit noradrenergic neurons. A persistent decrease in opioid peptide release from afferents during withdrawal would result in glutamate acting on postsynaptic targets, in an unopposed fashion. A parallel effect in opioid projections from PGi to the NTS would potentially support similar actions in this noradrenergic nucleus. The authors' recent data show that opioid-containing neurons in the PGi project to the NTS, and that enkephalin levels are decreased in opioid afferents to the NTS. This review summarizes data that the authors have collected regarding opioid expression changes in brainstem circuits (PGi-LC and PGi-NTS), following chronic morphine treatment, which may represent a model for understanding of adaptations in endogenous opioid circuits during drug dependence and withdrawal.

Anxiogenic-like effects of opiate withdrawal seen in the fear-potentiated startle test, an interdisciplinary probe for drug-related motivational states.

Abstract: Rationale: Anxiety-like effects may be universal to withdrawal from drugs of abuse. The study of withdrawal would benefit from the acoustic startle response (ASR), a discrete, cross-species reflex which is increased by fear-related states. However, existing reports of opiate-related effects on baseline ASR have not validated ASR as a measure of drug-related motivation. Objective: The effects of opiate treatment and withdrawal were examined using fear-potentiated startle, a startle test more sensitive to fear than baseline changes. Methods: Fear-conditioned rats were treated with Alzet osmotic pumps delivering 0.25 mg/kg per day fentanyl or placebo pumps. Experiment 1 examined changes before and during opiate treatment on locomotor activity and baseline, prepulse inhibition, and fear-potentiated startle. Experiment 2 examined the same responses during withdrawal precipitated after 4–7 days of treatment using IV naloxone. Results: Experiment 1 revealed an attenuated fear-potentiated startle on the first test after the start of fentanyl treatment (4 h); this was not seen on subsequent tests and suggested tolerance to this acute effect. Experiment 2 found an enhancement of fear-potentiated startle precipitated in fentanyl-treated rats after injection of 0.025 and 0.16 mg/kg naloxone; this was not seen at 1 mg/kg naloxone, even though more physical withdrawal signs were most prevalent at this dose. In neither experiment did locomotor activity, baseline ASR, or prepulse inhibition of the ASR show any treatment effect. Conclusions: Fear-potentiated startle may provide a specific and valid measure of anxiety-like effects of drug withdrawal. Discussed were conditions needed to see this effect and the relevance of the findings for different mechanisms of withdrawal discomfort.

The effect of tobacco smoking on subjective symptoms of inadequacy ("not holding") of methadone dose among opiate addicts in methadone maintenance treatment.

Abstract: The objective of this study was to examine the relationship between subjective symptoms of inadequacy of methadone dose (not feeling "held") and tobacco smoking in patients in methadone maintenance treatment (MMT). This was a cross-sectional study of smoking behaviour, investigating subjective, physiological and psychological symptoms. The study took place in a community-based methadone maintenance clinic of a psychiatric teaching hospital in South London. Fifty adult opiate addicts (37 males and 13 females) were on a stable daily methadone dose; the number of cigarettes smoked during the day and previous day of investigation, salivary cotinine measurements and carbon monoxide (CO) from expired air were measured. The Methadone Symptom Checklist (MSC) was used to score withdrawal symptoms encountered in patients not feeling "held" during MMT The Hamilton Anxiety Score was also used. The prevalence of tobacco-smoking was high (98%), with two-thirds (68%) smoking self-fabricated cigarettes ("roll-ups"). Scores from rating scales measuring symptoms of not being "held" correlated with number of cigarettes smoked the previous day (p < 0.05). A similar correlation was found with the Hamilton Anxiety Score. However, there was no correlation between rating scale scores and either salivary cotinine concentration or CO from expired air. Methadone patients who smoke more are significantly more likely to report problems of not feeling "held" by their methadone dose and they also show a higher level of anxiety. However, this increased cigarette consumption is not reflected in increased salivary continine levels or levels of CO in expired air, and it may be that the raised level of anxiety leads to a smoking-pattern consisting of frequent lighting-up of cigarettes or "roll-ups" which are consumed incompletely and/or not smoked by inhalation.

Laboratory Analysis of Remotely Collected Oral Fluid Specimens for Opiates by Immunoassay

Abstract: The performance characteristics of a method for detecting opiates (morphine, codeine, heroin, and 6-acetylmorphine [6-AM]) in oral fluid specimens were examined and compared with methods for urine specimens. The oral fluid was easily obtained using a simple device that collects between 1 and 1.5 mL of fluid for laboratory analysis. Simultaneously collected specimens from 60 known opiate abusers from a drug-treatment center were first tested using an immunoassay cutoff of 10 ng/mL in oral fluids and 2,000 ng/mL in urine. Using a second aliquot, opiate confirmation in urine was performed by gas chromatography-mass spectrometry (GC-MS) and in oral fluids by GC-MS-MS. The combined immunoassay and GC-MS-MS procedures were completed with less than 250 pL of oral fluid. Opiates identified in oral fluid specimens from heroin users included morphine, codeine, heroin, and 6-AM. The immunoassay was tested for precision, stability, and the effects of potential cross-reactants. The results yielded 93.6% agreement between oral fluid and urine, suggesting that oral fluid may be a reliable matrix for opiate detection.

Morphine stimulates iNOS expression via a rebound from inhibition in human macrophages: nitric oxide involvement.

Abstract: We have previously demonstrated that exposure of human macrophages to morphine results in transient inhibition of cell migratory behavior and adoption of an inactive conformation followed by a return from inhibition resulting in a significant increase in migration velocity and number of activated cells. In the current report, we demonstrate that the return to activation is nitric oxide dependent and inhibited by prior exposure to the opiate antagonist, naloxone. Exposure of macrophages to morphine for 6 hours resulted in a marked inhibition of cell activity and shift of the cell confirmation from amoeboid to round. The inactivation period lasted approximately 2 hrs and was followed by a period of hyperactivity. Incubation of macrophages with naloxone, prior to addition of morphine, inhibited both inactivation and hyper activation phases whereas, naloxone administration just prior to the hyper activation phase did not affect subsequent hyper activation. Morphine acutely stimulates the transient release of nitric oxide (NO) resulting in subsequent macrophage rounding and inactivation. Prolonged observation of the cells revealed another phase of NO release 12 hours following initial morphine exposure that was characterized by prolonged NO production. These data are consistent with acute constitutive NO synthase activation and inducible NO synthase activation following prolonged morphine exposure. Release of NO and changes in cellular activation mediated by morphine was abrogated by NOS, or morphine inhibitors, added prior to morphine exposure. In contrast, NOS, or morphine inhibitors, added during the inhibitory phase had no impact on the subsequent hyper activation phase. It did, however, have an impact on the hyper activation phase when added prior to morphine. These data demonstrate that morphine is capable of induction of both cNOS and iNOS coupled NO release that regulates the macrophage activation state. This may provide insight into the functioning of morphine following periods of trauma or stress when the levels of the opiate increase and, subsequently, inflammatory function is markedly altered.

Diamorphine treatment for opiate dependence: putative markers of concomitant heroin misuse.

Abstract: The supply of substitute opioid medication as a treatment for heroin dependence is now common practice. There is growing international interest in the prescription of injectable diamorphine for subgroups of patients who are unable to stop injecting opiate drugs; in the United Kingdom it is estimated that there are currently 300 patients prescribed diamorphine for this purpose. The detection of illicit heroin misuse (through urinary diamorphine metabolites) is confounded in subjects prescribed diamorphine. We investigated the potential to distinguish between the use of street heroin and pharmaceutical diamorphine through the detection in urine of various opiate alkaloids originating in the opium poppy, Papaver somniferum. Over a 7-week period, 532 clients of an urban substance misuse service provided a total of 1122 urine samples for clinical purposes. Using a novel mixed-mode solid-phase extraction and gas chromatography/mass spectrometry technique, we screened samples for morphine, 6-monoacetylmorphine, codeine, meconine, papaverine, noscapine, thebaine and their metabolites. All urine samples from diamorphine-treated patients were positive for morphine. Of samples from patients receiving other treatments, 30% (95%CI: 27-33%) were positive for morphine, indicating probable street heroin misuse. Of morphine-positive samples, 61% (95%CI: 55-67%), from the "other treatments" group were positive for at least one of codeine, meconine and putative noscapine or papaverine metabolites. This was reduced to 56% (95%CI: 50-62%) when excluding codeine. Only one sample (0.1%) was positive for any one of these putative markers in the absence of morphine, when excluding codeine. These findings show that the detection of urinary noscapine and papaverine metabolites is useful in distinguishing between use of pharmaceutical diamorphine and street heroin. This may be of benefit to promote safer and more effective prescribing of diamorphine in opiate dependency, and as an outcome measure in trials of diamorphine prescribing.