Abstinence Symptoms Research Articles

Reliability and validity of the cocaine selective severity assessment

This article assesses the reliability and validity of the Cocaine Selective Severity Assessment (CSSA), a measure of cocaine abstinence signs and symptoms. Interrater reliability and scale internal consistency were high. Initial CSSA scores were significantly higher in cocaine-dependent subjects than in alcohol-dependent subjects. Initial CSSA scores were highly correlated with recent cocaine use and with severity measures from the Addiction Severity Index (ASI) including the interviewer severity rating and composite score in the drug section. Among cocaine-dependent subjects, initial CSSA scores were higher for those who failed to achieve abstinence or who subsequently dropped out of treatment. Further, CSSA scores showed consistent and marked declines over time for subjects who continued in treatment and remained abstinent. The CSSA appears to be a reliable and valid measure of cocaine abstinence symptoms and a useful predictor of negative outcomes in cocaine dependence treatment.

A Pilot Open Randomized Trial of Valproate and Phenobarbital in the Treatment of Acute Alcohol Withdrawal

The authors conducted a randomized, open comparison of the GABAergic anticonvulsant sodium valproate (divalproex sodium; Depakote) and phenobarbital as an active control in the management of acute withdrawal from alcohol. Repeated measures ANOVA was used to assess treatment effects in the first 37 inpatients, evaluating mood, hostility, and subjective and objective measures of withdrawal at index, 3, and 5 days of detoxification. Subjective and objective ratings of abstinence symptoms and subjective mood disturbance decreased significantly in intensity in both groups over 5 days, but there were no significant treatment differences nor treatment by time interactions. Hostility scores did not differ overall, but a group by time effect was observed (F = 5.42, df=[1,13], P<0.05), with phenobarbital subjects reporting less hostility/ aggression than those in the valproate group. There were no withdrawal‐related seizures or other acute sequelae. This study offers pilot confirmation that sodium valproate is as effective as phenobarbital in the management of acute alcohol withdrawal, but it is unclear whether valproate offers a clinical advantage with respect to stabilizing changes in mood and interpersonal hostility during detoxification.

Attenuation of precipitated morphine withdrawal symptoms by acute i.c.v. administration of a group II mGluR agonist.

1. We previously showed that chronic i.c.v. antagonism of metabotropic glutamate receptors (mGluRs) concurrently with s.c. morphine significantly attenuated precipitated withdrawal symptoms. Conversely, acute i.c.v. injection of a selective group II mGluR antagonist just before the precipitation of withdrawal exacerbated abstinence symptoms. 2. In the present study, we showed that acute i.c.v. administration of the non-selective mGluR agonist 1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD), as well as the group II selective agonist (2S,1'R,2'R,3'R)-2-(2'.3'-dicarboxycyclopropyl)glycine (DCG-IV), significantly attenuated the severity of precipitated withdrawal symptoms. 3. From these results we hypothesize that chronic opioid treatment may indirectly induce a desensitization of group II mGluRs, which contributes to the development of dependence.

Antisocial personality disorder and aggression in recently abstinent cocaine dependent subjects

To study the relationship between cocaine abstinence symptoms, personality, and aggression, we used the ©Point Subtraction Aggression Paradigm (PSAP) to measure aggression in 18 subjects admitted for the treatment of cocaine dependence. Eight subjects met criteria for antisocial personality disorder (ASPD). There was a significant correlation between presence of ASPD and frequency of aggressive responding by stepwise multiple regression. When presence of ASPD was factored out of the correlations, there was no significant relationship between aggressive responding and cocaine craving, withdrawal symptoms, amount of cocaine used, or length of time since use. These preliminary results suggest that in cocaine dependent individuals seeking treatment, current aggression is most dependent on the individual's previous aggressive behavior.

Advances in dihydroetorphine: From analgesia to detoxification

Dihydroetorphine is the first narcotic analgesic successfully developed and approved for production in China. As an analgesic, it has been used safely and effectively in clinical practice for 12 years. In recent years, it has been used successfully for substitution therapy in detoxification from opiates. As a drug for detoxification from opiates, the main advantages of DHE are its quick onset of effect and thorough control of the abstinence symptoms. DHE can detoxify heroin dependence in 7–10 days and does not cause dependence in reasonable therapeutic regimens. Drug Dev. Res. 39:131–134. © 1997 Wiley-Liss, Inc.

Advances in dihydroetorphine: From analgesia to detoxification

Dihydroetorphine is the first narcotic analgesic successfully developed and approved for production in China. As an analgesic, it has been used safely and effectively in clinical practice for 12 years. In recent years, it has been used successfully for substitution therapy in detoxification from opiates. As a drug for detoxification from opiates, the main advantages of DHE are its quick onset of effect and thorough control of the abstinence symptoms. DHE can detoxify heroin dependence in 7–10 days and does not cause dependence in reasonable therapeutic regimens. Drug Dev. Res. 39:131–134. © 1997 Wiley-Liss, Inc.

Cigarette Smoking and Abstinence: Comparative Effects Upon Cognitive Task Performance and Mood State over 24 Hours

Twenty regular smokers were assessed over 24-h of normal cigarette smoking, and an equivalent period of abstinence. In both conditions, a non-deprived baseline was followed by performance tests 2, 6 and 24 h later, while subjective feelings were assessed every 2 h. Compared to normal smoking, abstinence led to reduced heart rate, worse task performance, feelings of depression, stress, irritability, restlessness, poor concentration, and urges to smoke. Letter cancellation and number vigilance task performance were significantly poorer after 2 and 6 h of abstinence. Subjective feeling states were significantly worse after 4 h of abstinence, and became increasingly impaired over the rest of the day. However many abstinence symptoms (except heart rate), were reduced in severity at the 24-h session, held on the morning of the following day. This suggests that many of the psychological effects of smoking abstinence, may build-up afresh each day.

NeuRecover-SATM in the Treatment of Cocaine Withdrawal and Craving

The efficacy of NeuRecover-SA™ (formerly called Tropamine+™, and TropaGen™) in the treatment of cocaine withdrawal and craving was evaluated at a state psychiatric hospital. This double-blind, placebo-controlled study was conducted in hospitalised patients with a DSM-III-R diagnosis of cocaine dependence. Eight patients received NeuRecover-SA™ and 4 patients received placebo. No significant difference in patient demographics was found. The mean number of abstinent symptoms (± SEM) declined over the first 4 days of treatment, 10.63 ± 1.32 on day 1 vs 4 ± 1.65 on day 4 in the NeuRecover-SA™ group compared with 7.25 ± 2.93 on day 1 vs 4.25 ± 3.61 on day 4 in the placebo group. Cocaine craving in the NeuRecover-SA™ group on day 1 was 7.88 ± 1.22 vs 2.71 ± 1.22 on day 4 and 5 ± 2.89 on day 1 vs 2 ± 1.68 on day 4 in the placebo group. A Mann-Whitney U test showed no statistically significant differences in abstinent symptomatology between or within treatment groups, or treatment effect in the placebo group. However, a significant decrease (p < 0.05) in cocaine craving occurred in the NeuRecover-SA™ group.

The antagonists of metabotropic glutamate receptors produce anxiolytic-like effects and attenuate morphine abstinence symptoms in animals

The antagonists of metabotropic glutamate receptors produce anxiolytic-like effects and attenuate morphine abstinence symptoms in animals

Role of noradrenergic hyperactivity in neonatal opiate abstinence

Despite the existence of a well-defined abstinence syndrome in offspring of opiate-dependent mothers, the mechanisms involved in neonatal abstinence remain unclear. The goal of the present study was to determine the contribution of noradrenergic neurons in the opiate abstinence syndrome in neonatal rats (10 days old). First, the ability of the α2-adrenergic agonist, clonidine to attenuate the symptoms of neonatal opiate abstinence precipitated by naloxone was determined. Secondly, the activity of noradrenergic neurons was determined by measuring postmortem levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) in the hypothalamus, hippocampus and cortex in opiate-abstinent pups. Neonatal opiate abstinence was characterized by an increased incidence of wall climbing, tremors and mouthing. Acute treatment with morphine and naloxone in chronic saline-treated pups also produced the tremor, albeit less severe than in pups treated chronically with morphine. Clonidine (0.2 mg/kg) attenuated the expression of tremor and mouthing in neonates, but increased wall climbing. Clonidine elicited wall climbing in opiate-naive neonates. Treatment with morphine followed by naltrexone increased MHPG levels in all of the brain areas examined, irrespective of the chronic treatment, but naltrexone treatment elicited a larger increase in MHPG levels in pups treated chronically with morphine. Acute morphine treatment increased MHPG levels only in the hypothalamus. The results of the present study provide behavioral and neurochemical data supporting the hypothesis that noradrenergic hyperactivity plays a role in neonatal opiate abstinence.

Chronic inhibition of intracellular Ca 2+ release or protein kinase C activation significantly reduces the development of morphine dependence

We have previously shown that chronic antagonism of metabotropic glutamate receptors in the brain attenuates naloxone-precipitated withdrawal symptoms in rats treated chronically with subcutaneous (s.c.) morphine. Several subtypes of metabotropic glutamate receptors are directly linked, through a guanine nucleotide regulatory protein, to the phosphatidylinositol (PI) second messenger system. In the present investigation, we assessed the effect of inhibiting the products of PI hydrolysis on the development of opioid dependence. Thus, concurrently with subcutaneous morphine, we infused intracerebroventricularly (i.c.v.) in rats, various doses of chelerythrine, which selectively inhibits the activation of protein kinase C, and thapsigargin, which inhibits the release of intracellular Ca 2+ when given chronically. Both chelerythrine and thapsigargin reduced the severity of naloxone-precipitated abstinence symptoms when infused i.c.v. at a dose of 10 nmol/day. A single injection of either chelerythrine or thapsigargin immediately prior to the precipitation of withdrawal failed to decrease the severity of abstinence symptoms. Our results suggest that by chronically inhibiting activity of the phosphatidyl-inositol system, the development of morphine dependence can be attenuated.

Neuronal degeneration in rat cerebrocortical and olfactory regions during subchronic "binge" intoxication with ethanol: possible explanation for olfactory deficits in alcoholics.

Severe, repetitive ("binge") ethanol intoxication in adult rats (intragastric delivery 3 times daily for 4 days in a modification of the Majchrowicz method) precipitates neuronal degeneration in selected cerebral cortical regions involved in memory and olfaction, confirming the results of Switzer and colleagues (Anat. Rec. 202: 186a, 1982). Neuronal damage was visualized with the de Olmos cupric silver technique for degenerating neurons and processes (argyrophilia), and was quantitated by total counts and densities of argyrophilic cells/fields. The specificity of the degeneration provides a neuropathological basis for the olfactory memory deficits in chronic alcoholics. In highly intoxicated rats, argyrophilia was most extensive among hippocampal dentate gyrus granule cells, pyramidal neurons in layer 3 of the entorhinal cortex, and olfactory nerve terminals in the olfactory bulb. Degenerating pyramidal neurons were also consistently seen in the insular cortex and olfactory cortical regions, such as the piriform and perirhinal cortices. There were few argyrophilic neurons in the CA regions of the hippocampus and none in the cerebellum--regions generally shown to have cell loss in long-term ethanol feeding models--but degenerating mossy fibers in the CA2 region were observed. Degeneration was maximal before the peak period of abstinence symptoms in this model, because argyrophilic densities were no greater 36 hr, compared with 8 hr after the last ethanol dose. High blood ethanol levels were required, because argyrophilia, absent from isocaloric controls, also was only evident in ethanol-intoxicated rats with mean blood ethanol levels for days 2 to 4 above 300 mg/dl; however, it increased substantially between 350 and 550 mg/dl. The resemblance of the argyrophilic distribution to the regional neuropathology that occurs in experimental seizures indicates that the ethanol-induced degeneration may have an excitotoxic basis. Progressive reductions in the seizure threshold (e.g., kindling phenomena that have been documented during binge ethanol intoxication) might be associated with excitotoxic hyperactivity during the repetitive nadirs between high blood and brain ethanol peaks. However, direct toxic actions of ethanol or its metabolites could also be involved. Overall, the model should be useful for studying mechanisms of ethanol-induced selective cortical and olfactory brain damage.

Inhibition of morphine withdrawal by lamotrigine: involvement of nitric oxide

We studied the effects of lamotrigine [3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine], a new antiepileptic compound, on naloxone-precipitated morphine withdrawal in mice. Pretreatment with lamotrigine (5–100 mg/kg, s.c.) reversed in a dose-dependent way the withdrawal-induced increase in cerebellar Ca 2+-dependent nitric oxide (NO) synthase activity and reduced the number of escape jumps and other motor symptoms of abstinence, at doses that did not modify locomotor activity (25–50 mg/kg). Pretreatment with the NMDA receptor antagonist MK-801 [(+)-5-methyl-10,11-dihydroxy-5 H-dibenzo[ a,d]cyclohepten-5,10-imine; dizocilpine] (0.1–0.3 mg/kg, s.c.) also reversed the increase in cerebellar Ca 2+-dependent NO synthase activity. However, although MK-801 reduced the number of escape jumps and other motor symptoms of abstinence, its effects were not clearly dose-dependent. Furthermore, the highest dose of MK-801 tested (0.3 mg/kg) caused an impairment of the locomotor behaviour in naive mice. Thus, lamotrigine may represent a new and useful agent for the treatment of opiate abstinence.

Correlation between brain nitric oxide synthase activity and opiate withdrawal.

The opiate withdrawal induced by administration of naloxone to morphine-dependent mice correlates with an increment of calcium- dependent nitric oxide synthase (NOS) activity in the cerebellum. L-NAME, an irreversible competitive inhibitor of NOS (0.5, 5, 25, 50 mg/kg) injected sc. 45 min. prior to naloxone significantly reduced the number of escape jumps and other motor symptoms of abstinence. In addition, L-NAME also decreased NOS activity in cerebellum. L-arginine, but not D-arginine, when coadministered with L-NAME, prevented both the inhibition of NOS activity and the reduction of withdrawal symptoms induced by L-NAME in morphine-withdrawn animals. These results demonstrate a hyperactivity of the L-arginine: NO pathway in opiate withdrawal and suggests the possibility of a therapeutic use of NOS inhibitors in this state.

Vasculitis attributed to the nicotine patch (Nicotinell)

Nicotine-containing patches are used to facilitate tobacco withdrawal by mitigating abstinence symptoms and diminishing craving. We describe two patients who developed vasculitis in association with the use of a nicotine patch. The first concerns a patient who developed fever, arthritis, a generalized erythema and purpuric lesions, after 3 days use of nicotine patches. Laboratory results and a skin biopsy confirmed the diagnosis of a leucocytoclastic vasculitis. After stopping use of the patch, the patient recovered. On challenge, the symptoms reappeared. The second patient developed purpuric lesions during the use of nicotine patches, and recovered fully after these were stopped. In these patients, nicotine patches seem to be causally related to the development of vasculitis.

Effect of activity at metabotropic, as well as ionotropic (NMDA), glutamate receptors on morphine dependence

1. The contribution of various excitatory amino acid (EAA) receptors (NMDA, AMPA/kainate and metabotropic) in the brain to the development of morphine dependence was examined. This was performed by measuring the severity of the precipitated withdrawal syndrome following chronic subcutaneous (s.c.) morphine and intracerebroventricular (i.c.v.) EAA antagonist treatment. 2. Continuous subcutaneous (s.c.) treatment with morphine sulphate (36.65 mumol day-1) produced an intense and reliable naloxone-precipitated withdrawal syndrome. 3. Chronic i.c.v. treatment with antagonists selective for metabotropic and NMDA receptors, but not AMPA/kainate receptors, significantly attenuated abstinence symptoms. Conversely, EAA antagonists had very little effect on non-withdrawal behaviours. 4. These results suggest that, as well as changes elicited by activation of NMDA receptors, metabotropic receptors and intracellular changes in the phosphatidylinositol (PI) second-messenger system or the cyclic adenosine 3',5'-monophosphate (cAMP) second messenger system, to which EAA metabotropic receptors are linked, may be involved in the development of opioid dependence with chronic morphine treatment.

A cognitive-behavioral therapeutic community for substance dependent and homeless veterans: Treatment outcome

This paper presents data regarding a residential rehabilitation program that integrates cognitive-behavioral and therapeutic community techniques to treat homelessness and substance abuse. The study cohort was 110 military veterans admitted to a Domiciliary Care for Homeless Veterans program of the Department of Veterans Affairs. The cohort had multiple psychosocial problems at admission, and all had drug/alcohol abstinence as a treatment goal. Structured interviews conducted at 3, 6, 9, and 12 months postdischarge revealed that a substantial proportion had positive outcomes with respect to housing, substance abuse abstinence, employment, and self-rated psychological symptoms. This integrated cognitive-behavioral therapeutic community approach appears to be a viable treatment for this subset of homeless and also may be effective for other populations with similar clinical characteristics.

Development after prenatal exposure to cocaine, heroin and methadone

In Amsterdam a longitudinal, prospective and multidisciplinary study on the development of infants of drug-dependent mothers (IDDM) was started in 1983: 35 IDDM and 35 reference infants were originally enrolled. The drug-dependent women had used combinations of methadone, heroin, cocaine and other drugs during pregnancy. Of the IDDM, 80% had to be treated pharmaceutically for neonatal abstinence symptoms (NAS). Physical, neurological, cognitive and the socio-emotional development of the children were studied regularly from birth until 5.5 years of age. Differences between the reference group and the IDDM were found most clearly in cognitive development. The IDDM also had more behavioural problems at some of the ages studied. No group differences were seen in motor development. So far the results of the study show that IDDM and their caregivers need extra support in order to improve early communication and the children's cognitive development.

Comparative effects of NG-monomethyl- d-arginine and MK-801 on the abstinence syndrome in morphine-dependent mice

The effects of N G-monomethyl- l-arginine ( l-NMMA), an inhibitor of nitric oxide (NO) synthase and MK-801, an NMDA receptor antagonist on abrupt and naltrexone-precipitated abstinence symptoms were determined in male Swiss-Webster mice rendered dependent on morphine by subcutaneous implantation of a pellet containing 75 mg of morphine base for 3 days. Mice which served as controls were implanted with placebo pellets. Six hours after pellet removal, mice were injected intraperitoneally with either the vehicle or MK-801 (0.03, 0.1 and 0.3 mg/kg). Thirty minutes later the animals were injected with naltrexone subcutaneously (50 μg/kg) and the intensity of abstinence symptoms were determined. Of the three doses of MK-801 used, only 0.1 mg/kg dose inhibited the jumping behavior precipitated by naltrexone in morphine-dependent mice. Whereas the lower dose (0.03 mg/kg) of MK-801 increased, the higher doses of MK-801 (0.1 and 0.3 mg/kg) displayed a decrease in the formation of fecal boli. Administration of MK-801 did not affect the body weight loss observed during abrupt withdrawal (induced by removal of the pellets) in morphine-dependent mice. MK-801 at 0.1 mg/kg dose further decreased the body temperature during abrupt withdrawal in morphine-dependent mice. Other two doses of MK-801 (0.03 and 0.3 mg/kg) did not modify the hypothermia observed during abrupt morphine withdrawal. On the other hand, l-NMMA (0.02 to 4.0 mg/kg) injected intraperitoneally 15 min prior to the naltrexone administration blocked the stereotyped jumping response in a dose-dependent manner. Higher doses of l-NMMA 2.0 and 4.0 mg/kg also decreased the number of fecal boli formation. l-NMMA (0.2 to 4.0 mg/kg) also significantly reduced the abrupt withdrawal-induced body weight loss in morphine-dependent mice. Thus MK-801 has very little effect, which is not dose-dependent, on abrupt and antagonist-precipitated withdrawal in morphine-dependent mice. However, the l-NMMA has more profound dose-dependent effects on both the abrupt and antagonist-precipitated withdrawal in morphine-dependent mice. It is concluded that the inhibitors of NO synthase may be more beneficial than NMDA receptor antagonists in managing the symptoms of morphine abstinence syndrome.

Adaptive changes in the excitability of central catecholaminergic neurons upon chronic activation of μ- and κ-opioid receptors

Primary neuronal cultures of noradrenergic neurons, originating from the rat locus coeruleus, exclusively possess release-inhibiting μ-opioid receptors, whereas cultured dopaminergic neurons from rat ventral mesencephalon contain release-inhibiting κ-opioid receptors only. Chronic (4 day) activation of μ and κ receptors, respectively, induces neuronal supersensitivity for various excitatory stimuli. Moreover, this supersensitivity is persistent for at least 5 days after treatment, suggesting that adaptive changes have long-term implications for neuronal functioning. Thus, whereas opioid receptor activation inhibits neurotransmitter release, chronic activation augments neuronal sensitivity towards excitatory input in a long-lasting manner. Central catecholaminergic neurotransmission has been implicated to play a pivotal role in conveying the reinforcing properties of morphine (dopamine, DA) as well as abstinence symptoms upon morphine withdrawal (noradrenaline, NA). Acute and chronic morphine administration to rats results in an increase in dialysable DA in striatum and nucleus accumbens (1) which rapidly declines after morphine withdrawal (2). In addition, noradrenergic neurons, originating in the locus coeruleus, become hyperactive upon morphine-withdrawal (3). Furthermore, in vitro studies demonstrated that stimulated NA release from cortical slices of morphine-dependent rats was increased (4,5). Interestingly, these latter studies did not reveal desensitization of μ-opioid receptors located in the presynaptic NA nerve terminal membranes. In order to study the adaptive changes in opioid-catecholamine interactions at the cellular level upon chronic exposure to opioids, we used primary neuronal cultures of rat locus coeruleus and ventral mesencephalon. In addition, we focused on possible changes in apparent affinity of opioid receptors during chronic exposure to opioids as this might underlie drug tolerance in vivo.