Characteristic Withdrawal Syndrome Research Articles

Pharmacological treatment for methamphetamine withdrawal: A systematic review and meta-analysis of randomised controlled trials.

Cessation of methamphetamine use may result in a characteristic withdrawal syndrome, no medication has been approved for this indication. This systematic review aims to assess the efficacy of pharmacotherapy for methamphetamine withdrawal, the first comprehensive meta-analysis since 2008. MEDLINE (1966-2020), CINAHL (1982-2020), PsychINFO (1806-2020) and EMBASE (1947-2020) were systematically searched. Studies were included if they were randomised controlled trials (RCT) investigating pharmacological treatments for methamphetamine withdrawal, reviewing outcomes of treatment discontinuation, mental health outcomes, withdrawal symptoms (including craving) and patient safety. The relative risk (RR) and weighted mean difference (MD) were used to meta-analyse dichotomous and continuous data respectively, with 95% confidence intervals. Risk of bias and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) assessments were conducted. Nine RCTs of six medications (n=242 participants) met inclusion criteria, however, only six trials of four medications (n=186) could be meta-analysed. Mean sample size across studies was 27 participants, and 88% of participants were male. The quality of evidence in this review varies from low to very low on GRADE assessments. Amineptine may reduce discontinuation rates (RR 0.22, 95% confidence interval [CI] 0.07, 0.72, p=0.01), and improve global state (MD -0.49, 95% CI -0.80, -0.17), compared with placebo, however, this medication is no longer approved. No other medications improved any domain when compared with placebo. Due to lack of reporting safety profiles could not be established. There is insufficient evidence to indicate any medication is effective for the treatment of methamphetamine withdrawal. The poor quality of the evidence indicates a need for better powered, high-quality trials.

Trihexyphenidyl use and dependence: a case report

Trihexyphenidyl is prone for abuse as well as dependence and produces a characteristic withdrawal syndrome. We present the case history of a 55-year-old lady who had an apparent worsening of her psychosis when trihexyphenidyl was withdrawn, and the dramatic resolution of her symptoms once it was re-introduced. Clinicians should consider such a presentation in patients with psychosis who are otherwise well maintained on antipsychotics. In view of the above as well as the known cognitive side effects of anticholinergic medications, long-term use of these agents should be avoided unless clearly indicated.

Neuropathic and chronic pain stimuli downregulate central μ -opioid and dopaminergic transmission

Although morphine and other mu-opioid agonists are the main analgesics for severe pain, these compounds have potential for abuse and/or addiction. This has complicated the use of mu-agonists in the treatment of chronic pain. However, clinical studies show that when mu-agonist analgesics are appropriately used to control pain, actual abuse or addiction does not usually occur, although some risk factors that increase vulnerability need to be considered, including genetic variation. We review recent findings on molecular adaptations in sustained pain models, and propose how these adaptations (including sustained release of the endogenous mu-agonist beta-endorphin) can result in decreased abuse potential of mu-agonists in chronic pain states. We also review data on particular gene polymorphisms (e.g. in the mu-receptor gene) that could also influence the relative abuse potential of mu-agonists in clinical pain populations.

Severe Diphenhydramine Dependence and Withdrawal: Case Report

This report describes a case of diphenhydramine dependence and withdrawal in a 34-year-old woman with schizophrenia. Anticholinergic medications have the potential for dependence. A characteristic withdrawal syndrome can develop after abrupt cessation of high-dose anticholinergics. This patient presented with an anticholinergic withdrawal syndrome manifest by pyrexia, hypertension, bowel and bladder incontinence, and increased muscle tone. Diphenhydramine is considered a relatively safe medication. This case highlights its potential for abuse and reminds us of the features of its characteristic withdrawal syndrome.

Alterations of postsynaptic density proteins in the hippocampus of rat offspring from the morphine‐addicted mother: Beneficial effect of dextromethorphan

Infants passively exposed to morphine or heroin through their addicted mothers usually develop characteristic withdrawal syndrome of morphine after birth. In such early life, the central nervous system exhibits significant plasticity and can be altered by various prenatal influences, including prenatal morphine exposure. Here we studied the effects of prenatal morphine exposure on postsynaptic density protein 95 (PSD-95), an important cytoskeletal specialization involved in the anchoring of the NMDAR and neuronal nitric oxide synthase (nNOS), of the hippocampal CA1 subregion from young offspring at postnatal day 14 (P14). We also evaluated the therapeutic efficacy of dextromethorphan, a widely used antitussive drug with noncompetitive antagonistic effects on NMDARs, for such offspring. The results revealed that prenatal morphine exposure caused a maximal decrease in PSD-95 expression at P14 followed by an age-dependent improvement. In addition, prenatal morphine exposure reduced not only the expression of nNOS and the phosphorylation of cAMP responsive element-binding protein at serine 133 (CREB(Serine-133)), but also the magnitude of long-term depression (LTD) at P14. Subsequently, the morphine-treated offspring exhibited impaired performance in long-term learning and memory at later ages (P28-29). Prenatal coadministration of dextromethorphan with morphine during pregnancy and throughout lactation could significantly attenuate the adverse effects as described above. Collectively, the study demonstrates that maternal exposure to morphine decreases the magnitude of PSD-95, nNOS, the phosphorylation of CREB(Serine-133), and LTD expression in hippocampal CA1 subregion of young offspring (e.g., P14). Such alterations within the developing brain may play a role for subsequent neurological impairments (e.g., impaired performance of long-term learning and memory). The results raise a possibility that postsynaptic density proteins could serve an important role, at least in part, for the neurobiological pathogenesis in offspring from the morphine-addicted mother and provide tentative therapeutic strategy.

Absence of quasi-morphine withdrawal syndrome in adenosine A2A receptor knockout mice

Caffeine and other methylxanthines induce behavioral activation and anxiety responses in mice via antagonist action at A2A adenosine receptors. When combined with the opioid antagonist naloxone, methylxanthines produce a characteristic quasi-morphine withdrawal syndrome (QMWS) in opiate-naive animals. The aim of this study was to establish the role of A2A receptors in the quasi-morphine withdrawal syndrome induced by co-administration of caffeine and naloxone and in the behavioral effects of caffeine. We have used A2A receptor knockout (A(2A)R(-/-)) mice in comparison with their wild-type and heterozygous littermates to measure locomotor activity in the open field and withdrawal symptoms induced by caffeine and naloxone. Naïve wild-type and knockout mice were also examined for enkephalin and dynorphin mRNA expression by in situ hybridization and for mu-opiate receptor by ligand binding autoradiography to check for possible opiate receptor changes induced by A2A receptor inactivation. Caffeine increases locomotion and anxiety in wild-type animals, but it has no psychomotor effects in A(2A)R(-/-) mice. Co-administration of caffeine (20 mg/kg) and naloxone (2 mg/kg) resulted in a severe quasi-morphine withdrawal syndrome in wild-type mice that was almost completely abolished in A(2A)R(-/-) mice. Heterozygous animals exhibited a 40% reduction in withdrawal symptoms, suggesting that there is no genetic/developmental compensation for the inactivation of one of the A(2A)R alleles. A(2A)R(-/-) and wild-type mice have similar levels of striatal mu-opioid receptors, thus the effect is not due to altered opioid receptor expression. Our results demonstrate that A2A receptors are required for the induction of quasi-morphine withdrawal syndrome by co-administration of caffeine and naloxone and implicate striatal A2A receptors and mu-opiate receptors in tonic inhibition of motor activity in the striatum.

Reversal of Caffeine Withdrawal by Ingestion of a Soft Beverage

Following regular use, acute cessation of caffeine is associated with a characteristic withdrawal syndrome. Despite this, caffeine remains popular with its consumers. The aim of this study was to examine the physiologic and psychologic effects of small caffeine doses, administered in the form of a market-leading soft drink, on healthy women who were acutely withdrawn from caffeine. After 48-h abstinence and overnight fast, 11 healthy (22 to 40 years) female volunteers, all regular caffeine users (daily consumption 143 to 773mg) consumed using a double-blind, randomized, controlled cross-over design either 2 tins of regular or caffeine-free Diet Coke. On both visits a Mars bar was eaten to prevent hypoglycaemia. Thus, the caffeine load was 76 or 10 mg respectively. Following ingestion of regular Diet Coke, there was a 10% fall in middle cerebral artery velocity (95%CI [6%–14%], p < 0.005 versus caffeine free) and improvement in feelings of pleasure ( p < 0.046) and energy ( p < 0.037). Intellectual function (4-choice reaction time) was unaffected by caffeine status. On both visits, ingestion of Diet Coke induced a pressor response (maximum rise in systolic pressure +15 ± 2 mm Hg with caffeine and +12 ± 2 mm Hg with caffeine-free beverage, both p < 0.001 compared with baseline). In conclusion, in women acutely withdrawn from caffeine, ingestion of a popular soft beverage containing modest amounts of caffeine is associated with demonstrable physiologic and psychologic effects.

Zopiclone: is there any dependence and abuse potential?

Both published and unpublished data concerning the rebound, withdrawal, dependence and abuse potential of zopiclone have been reviewed. As expected for an hypnotic drug of about 5 h elimination half-life, rebound has occasionally been detected but is substantially less frequent than with equivalent benzodiazepines. Tolerance to zopiclone does not occur regularly and cross-tolerance to the benzodiazepines may help in a regimen to withdraw from the latter drugs. Dependence on long-term use, as shown by either a characteristic withdrawal syndrome or by psychological craving, is rare considering the world-wide extent of usage. Abuse (addictive non-medical use) is documented but is also rare, in comparison with the widely abused benzodiazepines. It is concluded that zopiclone has substantial advantages over the benzodiazepines in terms of dependence and abuse potential.

Biological mechanisms and perinatal exposure to abused drugs

Use of illicit and licit drugs during pregnancy is a major public health concern, as it can have adverse effects on the developing fetus. Infants born of women addicted to narcotics, cocaine, alcohol, or polydrugs often undergo a characteristic withdrawal syndrome and may have physical, behavioral, and/or neurological abnormalities. As it is not feasible to ascertain whether these functional changes in human infants are produced by abused substance(s) per se or by a combination of complex socioeconomic factors and polydrug use, researchers in recent years have developed and utilized various innovative animal models to assess drug-induced alterations and their biological mechanisms during the developmental period under a controlled environment. To promote interdisciplinary communications as well as to assess the progress and the future needs in this area, the National Institute on Drug Abuse (NIDA) held a technical review at which biomedical researchers discussed their current findings in various physiological systems. This report summarizes the major findings and the methodological and experimental issues discussed at the conference. The meeting was held in Washington, DC, on May 25 and 26, 1994.

Endogenous κ-opioid systems in opiate withdrawal: role in aversion and accompanying changes in mesolimbic dopamine release

The kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI) was recently shown to potentiate certain overt withdrawal signs in morphine-dependent rats. The present study sought to further assess this phenomenon by examining the influence of nor-BNI treatment upon the conditioned place aversion associated with the naloxone-precipitated withdrawal syndrome. In addition, in vivo microdialysis studies were conducted in morphine-dependent rats to determine whether nor-BNI treatment can modify withdrawal-induced changes in basal dopamine (DA) release within the mesolimbic system. Rats were pretreated with either saline or a single dose of nor-BNI and then received ascending doses of morphine for 10 days. A withdrawal syndrome was then precipitated by the administration of naloxone (1 mg/kg SC). In rats which received chronic morphine injections, administration of naloxone produced a characteristic withdrawal syndrome and a marked aversion for an environment previously associated with naloxone-precipitated withdrawal. Nor-BNI treatment potentiated most overt signs of physical dependence. This treatment also resulted in a greater withdrawal-induced place aversion. Morphine-dependent rats exhibited a marked reduction in basal mesolimbic DA release. An even greater decrease in basal DA release was observed in nor-BNI treated rats. These results suggest that endogenous kappa-systems are important in the modulation of mesolimbic DA release and the accompanying place aversion which occurs during opiate withdrawal.

Pharmacology of Opiates and Their Derivatives

Abstract: The opiates or opioids are exogenous substances which bind in a stereospecific and saturable manner to several subspecies of cell membrane receptors which are sites of action of endogenous ligands (enkephalins, B‐endorphine). The opiates, which have common structural features, are agonists or partial agonists, the potency of which generally correlates well with affinity for opiate receptors. Many of the actions of opiates are related to alteration of the release of endogenous neurotransmitters. Inhibition of intracelluar adenylate cyclase and altered transmembrane calcium fluxes also appear to be important consequences of opiate action. Most opiates share the pharmacological properties of morphine. The development of tolerance and physical dependence with chronic administration is a characteristic feature of all opiates limiting their clinical use and creating the liability for abuse. With established opiate tolerance, cessation of the drug is accompanied by a characteristic withdrawal syndrome which is suppressed by opiate administration and can also be precipitated by an opiate antagonist such as naloxone. Many of the differences between opiates are due to different pharmacokinetic properties, particularly oral bioavailability and elimination rate. The search for a non‐addictive opiate analgesic continues but is presently foiled by the inherent pharmacological properties of these drugs.

In vivo evidence for the selectivity of ICI 154129 for the delta-opioid receptor

The in vivo selectivity of the novel delta opioid-receptor antagonist N, N-bisallyl-Tyr-Gly-Gly-Ψ-(CH 2S)-Phe-Leu-OH (ICI 154129) was examined in several opioid-selective models. Antagonism at the delta receptor was demonstrated in the striatal head-turn model in the rat. Intrapallidal injection of the relatively selective delta-receptor agonist d-Ala 2 d-Leu 5-enkephalin (0.5μg) slowed the head-turn time and this effect was completely prevented by prior subcutaneous administration of ICI 154129 (30 mg/kg). The role of delta receptors in two classical test situations was studied using the mixed opioid agonist etorphine and the antagonists naloxone and ICI 154129. The drug ICI 154129 (30 mg/kg, s.c.) failed to prevent the antinociceptive effects and stimulation of locomotor activity produced by etorphine, whereas the relatively selective mu-opioid receptor antagonist, naloxone was effective in both test situations. The possible involvement of delta receptors in morphine-induced dependence was studied by monitoring the abstinence behaviour precipitated in rats given pellets of morphine by either ICI 154129 or naloxone. Naloxone (0.5 mg/kg, i.p.) precipitated a characteristic withdrawal syndrome in conscious rats and, at a much smaller dose (0.02 mg/kg, i.p.), induced shaking behaviour in pentobarbitone-anaesthetised rats. No withdrawal signs were observed in either model after injection of ICI 154129 (30 mg/kg, s.c.), suggesting that the delta receptors are not involved in dependence on morphine.

Influence of Morphine Tolerance and Withdrawal on Intestinal Salt and Water Transport in the Rat In Vivo and In Vitro

Intestinal water and electrolyte transport was investigated in vivo and in vitro in rats made tolerant to morphine and subsequently withdrawn with naloxone. Rats were rendered tolerant by injection of a slow-release emulsion containing morphine (75 mg/rat over 48 h), and when challenged with naloxone, they exhibited a characteristic withdrawal syndrome that included acute diarrhea. Morphine tolerance did not influence water absorption from ileal or colonic loops in vivo but naloxone-induced withdrawal provoked a rapid and sustained reduction in absorption. Naloxone did not affect absorption in control animals. In further experiments, sodium and chloride fluxes were measured in isolated stripped ileal mucosa derived from animals made tolerant to morphine and withdrawn with naloxone. Net sodium and chloride absorption was markedly reduced in mucosa derived from withdrawn animals compared with that derived from tolerant animals (Na+: 1.12 +/- 0.76 vs. 5.52 +/- 0.46, and Cl-: 0.60 +/- 0.52 vs. 4.70 +/- 0.80 microEq/cm2 X h, in withdrawn and tolerant animals, respectively; n = 8; p less than 0.001 and p less than 0.005). When an attempt was made to induce withdrawal by adding naloxone in vitro to isolated mucosa derived from tolerant animals, no effect on transport was detected whether the mucosa was stripped of muscle layers or not. Thus naloxone had to be given in vivo to produce withdrawal effects in mucosa studied subsequently in vitro. Naloxone also had an effect in control rats when a 50% reduction in net chloride absorption was observed in isolated ileal mucosa derived from these animals. Net sodium absorption was unaffected. These data support a role for endogenous opiates in the control of intestinal transport and provide a mechanism for the diarrhea associated with opiate withdrawal.

Pathophysiology of the alcohol withdrawal syndrome

A characteristic withdrawal syndrome appears following the interruption of chronic heavy consumption of alcoholic beverages. The pathophysiological elaborations of the various withdrawal signs and symptoms are considered. Among the unlikely, although plausible, pathophysiologic mechanisms of the tremulousness and skeletal muscle hyperreactivity of withdrawal is the accumulation or the sustained production of one or more circulating “toxic substances”. Evidence consistent with such a mechanism includes the reported alleviation by dialysis of an impending withdrawal syndrome in alcoholic patients, the appearance of reflex hyperreactivity in withdrawing animals below the level of a chronic section of the spinal cord, and the time course of the appearance and disappearance of withdrawal syndromes. The various potential pathophysiological and neurochemical manifestations of the withdrawal illness are discussed—alterations in neural inhibition, in α-aminobutyric acid, catecholamines, acetylcholine, dopamine, prostaglandin, and in peptides. Experimental tests whereby a “toxic substance hypothesis” of withdrawal can be ruled in or out are proposed.

Rapidly Developing Tolerance to Acute Exposures to Anesthetic Agents

Following the observation that mice manifest a characteristic withdrawal syndrome after an hour of exposure to nitrous oxide, the authors reasoned that there might be a very rapidly developing tolerance to nitrous oxide. Thus, they determined the inspired concentrations that cause loss of the righting reflex in mice (i.e, the ED50), in the presence of 1 atm of oxygen, of: 1) nitrous oxide alone; 2) cyclopropane alone; 3) nitrous oxide plus 13.6 atm helium; 4) ethylene plus 13.6 atm helium. In each instance the ED50 was determined after averages of 6,34 and 64 min of exposure to the anesthetic agents. For nitrous oxide alone the ED50 at 6 min was 1.18 +/- 0.049 atm, increasing to 1.39 +/- 0.061 atm at 64 min. For ethylene plus helium the ED50 increased from 1.21 +/- 0.033 atm at 6 min to 1.31 +/- 0.039 atm at 64 min, indicating the development of acute tolerance. Neither cyclopropane alone nor nitrous oxide plus helium caused acute tolerance. This absence of tolerance may have resulted from a slower development of an alveolar anesthetic concentration.

Drug Self-Administration by Laboratory Animals: Control by Schedules of Reinforcement

A common factor underlying all concepts of drug dependence is the persistent maintenance of behavior that leads to drug self-administration (I, 2). Early studies of drug self-administration by laboratory animals involved morphine and employed subjects that were made physiologically (physically) dependent by repeated injec­ tions prior to the initiation of self-administration behavior (3-9). This emphasis on physiological dependence strengthened the belief that drugs were self-administered by laboratory animals chiefly because their administration terminated or postponed the characteristic withdrawal syndrome induced by drug abstinence. While physio­ logical dependence may profoundly influence drug self-administration behavior, it is not necessary for the maintenance of that behavior. With psychomotor stimulant drugs, for example, no clear signs of withdrawal occur after chronic administration is terminated, yet these drugs are persistently self-administered by laboratory ani­ mals (10-16). Even with drugs such as narcotic analgesics, barbiturates, and ethanol that can induce physiological dependence, the initiation of drug self-administration by drug-naive animals must result from other factors (17). Moreover, many experi­ ments have shown that self-administration can be maintained by these drugs in the absence of any demonstrable physiological dependence when access to drug is limited to short periods of time each day and when small doses of drug are used (18-28). Considerations such as these have prompted the investigation of behavioral factors underlying drug dependence.

Hepatic drug-metabolising enzyme activity and duration of hexobarbitone anaesthesia in barbitone-dependent and withdrawn rats

The activity of several hepatic drug-metabolising enzymes and the duration of hexobarbitone anaesthesia were determined in barbitone-dependent and withdrawn rats. Rats were made dependent on barbitone sodium by the administration of increasing amounts in the drinking water over a 32-day period. Abrupt withdrawal was accompanied by a characteristic withdrawal syndrome. The body weight, liver weight and body weight/liver weight ratio were found to be increased during barbitone treatment and to fall after withdrawal. The liver protein and glycogen content did not change during barbitone treatment. Withdrawal produced a transient reduction in hepatic glycogen content but did not affect protein levels. The capacity of hepatic microsomal preparations to metabolise hexobarbitone, aminopyrine and prontosil and to conjugate o-aminophenol was increased by barbitone treatment. Following withdrawal, the enzyme activity fell below that of control animals Four months after withdrawal the liver enzyme activity was still subnormal. The acute administration of phenobarbitone to 4-month withdrawn animals was found to restimulate hepatic microsomal drug-metabolising enzymes but the level attained was not as high as that found in phenobarbitone-treated control rats. The same degree of tolerance to injected hexobarbitone, as indicated by reduction in sleeping time, was found at all stages of barbitone treatment. A hypersensitivity to hexobarbitone was produced by withdrawal. It is concluded that both the tolerance in barbitone-dependent rats and the hypersensitivity of withdrawn animals can be adequately explained by altered hepatic drug-metabolising enzyme activity.