Withdrawal Phenomena Research Articles

Withdrawal and Discontinuation Phenomena Associated with Tranylcypromine: A Systematic Review

Tranylcypromine (TCP) is an effective antidepressant with a complex pharmacological profile and a relevant risk of abuse and dependence. Withdrawal phenomena (WP, in the case of TCP-abuse/dependence) or discontinuation phenomena (DP, in the case of absent TCP-abuse/dependence) subsequent to abrupt termination of TCP are a potentially severe clinical syndrome. We conducted a systematic review of all previously published WP/DP cases following abrupt termination of TCP in order to identify typical clinical presentations and risk factors of WP/DP and frequency of TCP abuse or dependence within these patients. By searching the Medline and Scopus databases we identified n=25 cases (cohort WP: n=18, cohort DP: n=7). Delirium was found in n=13 patients (cohort WP: 10/55.6%; cohort DP: 3/42.9%), n=6 demonstrated WP/DP without delirium (WP: 6/33.3%; DP: 0/0%) and n=5 rapid relapse in depression (WP: 1/5.6%; DP: 4/57.1%). Mean time until development of WP/DP was 1.9 (WP) and 2.2 (DP) days. Mean duration of WP/DP was 5.7 (WP) and 11.3 (DP) days. All patients of cohort WP were described to feature TCP-abuse/dependence. Patients with delirium were on average older (41.8 years vs. 37.8 years) and featured higher mean prescribed (71.0 mg vs. 38.3 mg) and actually taken daily TCP dosages (285.8 mg vs. 187.7 mg). In conclusion, even termination of lower daily dosages of TCP may result in delirium. Thrombocytopenia features diagnostic value in patients with deliria of unknown etiology. TCP should be administered with great care, especially in dependence-prone patients.·

Internet Highs—Seizures After Consumption of Synthetic Cannabinoids Purchased Online

Since 2004, a new wave of synthetic cannabinoids (SCs) known as "Spice drugs" has come under scrutiny because of their suspected link to neurological and psychiatric sequelae. These "herbal incense" or "potpourri blends" have gained popularity as a result of being more potent than natural cannabinoids, are not detected with current screening tests, and are easily modified by manufacturers to bypass legal restrictions. Unfortunately, cases of withdrawal phenomena, nausea, hypertension, and psychosis are now being reported in the medical literature. In addition, after reports in lay media of seizures and coma attributed to the consumption of the drug, anecdotal reports have emerged of similar findings in the medical literature. We report on a 48-year-old man who, after consuming the herbal blend, lost consciousness and suffered several episodes of seizures. Despite a complicated ICU stay, the patient recovered well with no subsequent neurological sequelae. The authors interpreted the history and findings consistent with the consumption of a large amount of synthetic cannabinoids leading to new-onset seizures and coma. However, at the time of admission, the lack of routine laboratory testing and treatment options delayed the diagnosis and delivery of appropriate therapy.

Attention-deficit/hyperactivity disorder (ADHD) symptoms, craving to smoke, and tobacco withdrawal symptoms in adult smokers with ADHD

BackgroundTobacco withdrawal symptoms may be confounded with attention-deficit/hyperactivity disorder (ADHD) symptoms among smokers with ADHD. Objective(1) To assess overlap between ADHD symptoms and tobacco/nicotine withdrawal symptoms and craving; (2) to assess the relationship between craving or withdrawal symptoms and the effect of osmotic-release oral system methylphenidate (OROS-MPH) on ADHD symptoms; (3) to assess the association of ADHD symptoms, craving, and withdrawal symptoms with abstinence. MethodsSecondary analysis of a randomized, placebo controlled smoking cessation trial assessing the efficacy of OROS-MPH taken in addition to nicotine patch among individuals with ADHD. ADHD symptoms, withdrawal symptoms, and craving were assessed at baseline and 2, 4 and 6 weeks after a target quit day. ResultsWithdrawal symptoms and craving showed limited and modest overlap with ADHD symptoms prior to abstinence but more extensive and stronger correlation after quit day. Compared to placebo, OROS-MPH reduced ADHD symptoms; this effect was attenuated by controlling for withdrawal symptoms, but not by craving. Craving, but not ADHD symptoms and withdrawal symptoms, was associated with abstinence during the trial. ConclusionWhen treating smokers with ADHD (1) craving, rather than tobacco withdrawal symptoms or ADHD symptoms may be the more effective therapeutic smoking cessation targets; (2) careful distinction of craving, withdrawal symptoms, and ADHD symptoms when assessing withdrawal phenomena is needed.

Treatment options for Insomnia

The frequency of sleep disruption and the degree to which insomnia significantly affects daytime function determine the need for evaluation and treatment. Physicians may initiate treatment of insomnia at an initial visit; for patients with a clear acute stressor such as grief, no further evaluation may be indicated. However, if insomnia is severe or long-lasting, a thorough evaluation to uncover coexisting medical, neurologic, or psychiatric illness is warranted. Treatment should begin with nonpharmacologic therapy, addressing sleep hygiene issues and exercise. There is good evidence supporting the effectiveness of cognitive behavior therapy. Exercise improves sleep as effectively as benzodiazepines in some studies and, given its other health benefits, is recommended for patients with insomnia. Hypnotics generally should be prescribed for short periods only, with the frequency and duration of use customized to each patient's circumstances. Routine use of over-the-counter drugs containing antihistamines should be discouraged. Alcohol has the potential for abuse and should not be used as a sleep aid. Opiates are valuable in pain-associated insomnia. Benzodiazepines are most useful for short-term treatment; however, long-term use may lead to adverse effects and withdrawal phenomena. The better safety profile of the newer-generation nonbenzodiazepines (i.e., zolpidem, zaleplon, eszopidone, and ramelteon) makes them better first-line choices for long-term treatment of chronic insomnia.

Preliminary Web-Based Measures Development for GHB: Expectancies, Functions, and Withdrawal

Background: Much of what is understood regarding gamma hydroxybutyrate (GHB) treatment is based on hospital case studies for overdose and withdrawal, and there are currently no measures developed specifically for GHB or its analogs (e.g., gamma butyrolactone and 1,4-butanediol) to assess drug effect expectancies, reasons for starting use, withdrawal effects, and knowledge and opinions about use. Objectives: This pilot study (N = 61) was conducted to begin measures development to assess experiences, functions of use, and opinions regarding use as indicated by respondents taking a Web-based survey. Methods: Minimum average partial correlation and parallel analysis procedures are employed to create scales. Results: Scales were developed to assess expectancies, reasons for use, withdrawal, and knowledge/opinions of use with median α = .79 and that account for 8.69–24.17% of the variance. Conclusion: Scales have relatively good psychometric properties and replication is needed. Scientific Significance: GHB-specific measures may greatly assist in furthering our understanding of protective and risk factors for use, and withdrawal phenomena.

Perioperative management of the child on long‐term opioids

The strategies used to manage children exposed to long-term opioids are extrapolated from adult literature. Opioid consumption during the perioperative period is more than three times that observed in patients not taking chronic opioids. A sparing use of opioids in the perioperative period results in both poor pain management and withdrawal phenomena. The child's pre-existing opioid requirement should be maintained, and acute pain associated with operative procedures should be managed with additional analgesia. This usually comprises short-acting opioids, regional or local anesthesia, and adjuvant therapies. Long-acting opioids, transdermal opioid patches, and implantable pumps can be used to maintain the regular opioid requirement. Intravenous infusion, nurse controlled analgesia, patient-controlled analgesia, or oral formulations are invaluable for supplemental requirements postoperatively. Effective management requires more than simply increasing opioid dose during this time. Collaboration of the child, family, and all teams involved is necessary. While chronic pain or palliative care teams and other staff experienced with the care of children suffering chronic pain may have helpful input, many pediatric hospitals do not have chronic pain teams, and many patients receiving long-term opioids are not palliative. Acute pain services are appropriate to deal with those on long-term opioids in the perioperative setting and do so successfully in many centers. Staff caring for such children in the perioperative period should be aware of the challenges these children face and be educated before surgery about strategies for postoperative management and discharge planning.

Neonatal Withdrawal Reactions Following Late in Utero Exposure to Antidepressant Medications

Late in utero exposure to antidepressants has been suspected of compromising neonatal adaptation. Objectives: To analyze published information on the risk of neonatal withdrawal phenomena associated with antidepressant use during late pregnancy. Methods: Computerized searches on MEDLINE, PsycINFO, ENBASE, and Cochrane Library (up to October 2010) were performed for selecting literature information published in English and investigating the safety of antidepressants when used during late pregnancy (50 articles). Results: Antidepressant treatment during late pregnancy may significantly increase the rate of neonatal discontinuation symptoms of various degree of severity. Conclusions: Further, prospective, large cohort studies are needed to clarify whether such symptoms can be prevented by suspending antidepressant treatment within the final month before parturition. Keywords: Pregnancy, antidepressants, perinatal complications, behavioral teratogenicity, TCAs

Prolonged-release melatonin for insomnia – an open-label long-term study of efficacy, safety, and withdrawal

BackgroundProlonged-release melatonin (PRM) 2 mg is indicated for insomnia in patients aged 55 years and older. A recent double-blind placebo-controlled study demonstrated 6-month efficacy and safety of PRM in insomnia patients aged 18–80 and lack of withdrawal and rebound symptoms upon discontinuation.ObjectiveTo investigate the efficacy, safety, and withdrawal phenomena associated with 6–12 months PRM treatment.MethodsData from a prospective 6–12-month open-label study of 244 community dwelling adults with primary insomnia, who had participated in a placebo-controlled, double-blind dose-ranging trial of PRM. Patients received PRM nightly, followed by a 2-week withdrawal period. Main outcome measures were patient-reported sleep quality ratings (diary), adverse events, vital signs, and laboratory tests recorded at each visit, and withdrawal symptoms (CHESS-84 [Check-list Evaluation of Somatic Symptoms]). Nocturnal urinary 6-sulfatoxymelatonin excretion, a measure of the endogenous melatonin production, was assessed upon discontinuing long-term PRM.ResultsOf the 244 patients, 36 dropped out, 112 completed 6 months of treatment, and the other 96 completed 12 months of treatment. The mean number of nights by which patients reported sleep quality as “good” or “very good” was significantly higher during PRM than before treatment. There was no evidence of tolerance to PRM. Discontinuation of PRM was not associated with rebound insomnia or withdrawal symptoms; on the contrary, residual benefit was observed. PRM was well tolerated, and there was no suppression of endogenous melatonin production.ConclusionResults support the efficacy and safety of PRM in primary insomnia patients aged 20–80 throughout 6–12 months of continuous therapy. PRM discontinuation even after 12 months was not associated with adverse events, withdrawal symptoms, or suppression of endogenous melatonin production.

WARNING: LEGAL SYNTHETIC CANNABINOID‐RECEPTOR AGONISTS SUCH AS JWH‐018 MAY PRECIPITATE PSYCHOSIS IN VULNERABLE INDIVIDUALS

Synthetic cannabinoid-receptor agonists may precipitate psychosis in vulnerable individuals, as shown by recent experience within a New Zealand forensic psychiatric in-patient service. Since 2006, a number of novel products such as K2, Spice, Aroma and Dream have appeared, masquerading as ‘herbal incense’ but marketed as cannabis substitutes. These products are surprisingly psychoactive. Mass spectrometry reveals the reason for their potency: the benign ‘herbal’ ingredients specified on the packaging have been deliberately adulterated with unlisted synthetic cannabinoid-receptor agonists such as CP47,497 1, JWH-018 1 and HU-210 2. These cannabimimetics have been declared illegal in some countries, but JWH compounds remain unregulated in many countries, including New Zealand and the United States (although banned recently in seven American states). While there is a significant growing body of evidence that cannabis is associated with the development and exacerbation of psychosis in some individuals (e.g. 3), almost nothing is known about the metabolism, toxicology and psychiatric effects of these new cannabimimetic agents. A recent literature search found two case reports relating to Spice (which at that time contained JWH-018 and CP47,497): one report involved tolerance and withdrawal phenomena 4 and the other described drug-induced psychosis 5. During the last year some patients within our service have been surreptitiously smoking a cannabimimetic called Aroma which, like K2, has been shown to contain JWH-018 (personal communication, Mark Heffernan, Analyst—National Drug Policy, New Zealand Ministry of Health). JWH-018 has similar receptor activity to 9-delta-tetrahydrocannabinol (THC), but its greater affinity to CB1 and CB2 cannabinoid receptors may make it more potent 6. JWH compounds cannot be detected currently by conventional urinalysis, limiting the ability to identify and regulate these substances. The mental states of at least five forensic patients have deteriorated significantly after using products containing CP47,497 and/or JWH-018. This has manifested as the sudden re-emergence of florid psychosis; predominantly agitation, disorganization and delusional beliefs (paranoid and grandiose types) in previously stable patients with histories of mental illness. We are conducting further research into the use and effects of synthetic cannabimimetics in our forensic population. However, until additional information becomes available, our experience suggests that JWH-018 and CP47,497 compounds may precipitate psychosis in a similar fashion to cannabis. People with risk factors for psychosis should be educated as to the potential risks and advised to avoid these substances. Clinicians should also consider the possible use of synthetic cannabimimetics in patients with unexplained psychotic relapses and negative drug screening. None.

How globalization and market innovation challenge how we think about and respond to drug use: ‘Spice’ a case study

How globalization and market innovation challenge how we think about and respond to drug use: ‘Spice’ a case study

Alcohol Pathophysiology

There is no specialized alcohol addiction area in the brain; rather, alcohol acts on a wide range of excitatory and inhibitory nervous networks to modulate neurotransmitters actions by binding with and altering the function of specific proteins. With no hemato-encephalic barrier for alcohol, its actions are strongly related to the amount of intake. Heavy alcohol intake is associated with both structural and functional changes in the central nervous system with long-term neuronal adaptive changes contributing to the phenomena of tolerance and withdrawal. The effects of alcohol on the function of neuronal networks are heterogeneous. Because ethanol affects neural activity in some brain sites but is without effect in others, its actions are analyzed in terms of integrated connectivities in the functional circuitry of neuronal networks, which are of particular interest because of the cognitive interactions discussed in the manuscripts contributing to this review. Recent molecular data are reviewed as a support for the other contributions dealing with cognitive disturbances related to alcohol acute and addicted consumption.

PW01-230 - [18F]fallypride pet measurement of striatal and extrastriatal dopamine D2/3 receptor availability in patients with alcohol use disorder

AimDopaminergic pathways are implicated in motivational aspects of substance use disorders, and might contribute to withdrawal phenomena, as well as an increased long-term risk of relapse. Molecular imaging with positron emission tomography (PET) revealed reductions in the availability of binding sites for D2/3receptor ligands in striatum of withdrawn abusers of cocaine; corresponding results in alcoholics have been inconsistent so far. In the present study, we used the D2/3ligand [18F]fallypride to investigate dynamic changes in receptor availability in the striatum of patients with alcohol use disorder before and after undergoing a detoxification protocol.Methods18 male patients (mean age 44±5.3y) with alcohol use disorder were recruited and scanned with 180MBq [18F]fallypride upon hospital admission, and again 1-2 weeks later after detoxification. The control group consisted of 10 age-matched healthy volunteers. PET acquisition time was 180min, consisting of 39 frames of increasing duration. Within each group binding potentials (BPND) were calculated in the striatum using the cerebellum as reference.ResultsIn the patients, the mean BPND in whole striatum was 17.2±4.2 at baseline, with a trend towards a decline at follow-up. In addition there were inverse correlations of BPNDwith age (r-0.45) and with daily alcohol consumption (r-0.2). The age-dependence of BPNDwas less pronounced in healthy controls. However, mean striatal BPNDwas only slightly lower in the patient group. No pronounced group differences were evident for extrastriatal [18F]fallypride binding.ConclusionsRegressions with age suggest an accelerated loss of dopamine D2/3 receptors in the striatum of subjects with alcohol use disorder.

Withdrawal Phenomena and Dependence Syndrome After the Consumption of „Spice Gold“

"Spice" and other herbal blends were marketed in Germany until January 2009 as substances purportedly exerting similar effects to cannabis, yet containing no cannabinoids. These products were recently forbidden in Germany under the provisions of the German Narcotics Law after they were found to contain undeclared, synthetic cannabinomimetic substances. The authors describe physical withdrawal phenomena and a dependence syndrome that developed after the consumption of "Spice." A 20-year old patient reported that he had smoked "Spice Gold" daily for 8 months. He developed tolerance and rapidly increased the dose to 3 g per day. He felt a continuous desire for the drug and kept on using it despite the development of persistent cognitive impairment. His substance use led him to neglect his duties in his professional training position. Urinary drug screens were negative on admission to the hospital, as they were again on discharge. On hospital days 4-7, he developed inner unrest, drug craving, nocturnal nightmares, profuse sweating, nausea, tremor, and headache. His blood pressure was elevated for two days, with a maximal value of 180/90 mm Hg accompanied by a heart rate of 125/min. The patient stated that he had experienced a similar syndrome a few weeks earlier during a phase of abstinence owing to a short supply, and that it had quickly subsided after he had started consuming "Spice" once again. The authors interpret the symptoms and signs described above as a dependence syndrome corresponding to the ICD-10 and DSM-IV criteria for this entity. The physical withdrawal syndrome closely resembles that seen in cannabis dependence. The authors postulate that the syndrome in the patient described was due to an admixture of synthetic cannabinomimetics such as JWH-018 and CP 47497 in "Spice Gold," in combination with the patient's daily consumption in very large amounts.

Ein- und Ausschleichen von Psychopharmaka – Empfehlungen zur Depressionsbehandlung

The knowledge of diagnostic procedures and therapy of depressive disorders is very important for every physician because of the high incidence of the disease. Particularly with regard to the critical phases of therapy, onset and discontinuation of antidepressive medication, a close contact between patient and physician is needed to identify adverse effects of the medication and withdrawal phenomena. The following article reviews current antidepressants and recommendations for starting and stopping antidepressive therapy mainly based on clinical experience because only limited evidence-based treatment schedules are available.

Arterielle Hypertonie – Arzneimittel-Dosierung am Anfang und Ende einer Therapie

In the treatment of arterial hypertension different dosing strategies like slow dose escalation at the beginning of antihypertensive therapy and gradual dose taper or abrupt withdrawal of drugs may be appropriate. In general treatment should be initiated with a long acting drug at a low dose and doses should only slowly be increased under close blood pressure control. The dose-response curve usually is very flat, whilst adverse effects may rise disproportionately with higher doses. Therefore dose increases to maximal doses are no longer desirable in modern antihypertensive therapy and combinations of two drugs as fixed combinations at low doses should be preferred. Modern antihypertensive drugs can be abruptly and safely withdrawn in most patients. However, a gradual dose taper can be necessary in patients with coronary heart disease treated with cardioselective beta-blockers. Withdrawal is easier and safer under telemetric blood pressure control than self measured blood pressure. The same treatment approach applies to reserve medications like alpha-blockers, centrally acting drugs as clonidine, methyldopa, moxonidine, the vasodilators hydralazine and minoxidil, and other antihypertensives like reserpine and guanethidine. Withdrawal phenomena have to be considered in individual cases and particularly with clonidine after long-term use.

Chronic Benzodiazepine Administration Potentiates High Voltage-Activated Calcium Currents in Hippocampal CA1 Neurons

Signs of physical dependence as a consequence of long-term drug use and a moderate abuse liability limit benzodiazepine clinical usefulness. Growing evidence suggests a role for voltage-gated calcium channel (VGCC) regulation in mediating a range of chronic drug effects from drug withdrawal phenomena to dependence on a variety of drugs of abuse. High voltage-activated (HVA) calcium currents were measured in whole-cell recordings from acutely isolated hippocampal CA1 neurons after a 1-week flurazepam (FZP) treatment that results in withdrawal-anxiety. An approximately 1.8-fold increase in Ca(2+) current density was detected immediately after and up to 2 days but not 3 or 4 days after drug withdrawal. Current density was unchanged after acute desalkyl-FZP treatment. A significant negative shift of the half-maximal potential of activation of HVA currents was also observed but steady-state inactivation remained unchanged. FZP and diazepam showed use- and concentration-dependent inhibition of Ca(2+) currents in hippocampal cultured cells following depolarizing trains (FZP, IC(50) = 1.8 microM; diazepam, IC(50) = 36 microM), pointing to an additional mechanism by which benzodiazepines modulate HVA Ca(2+) channels. Systemic preinjection of nimodipine (10 mg/kg), an L-type (L)-VGCC antagonist, prevented the benzodiazepine-induced increase in alpha-amino-3-hydroxy-5-methylisoxasole-4-propionic acid receptor (AMPAR)-mediated miniature excitatory postsynaptic current in CA1 neurons 2 days after FZP withdrawal, suggesting that AMPAR potentiation, previously linked to withdrawal-anxiety may require enhanced L-VGCC-mediated Ca(2+) influx. Taken together with prior work, these findings suggest that enhanced Ca(2+) entry through HVA Ca(2+) channels may contribute to hippocampal AMPAR plasticity and serve as a potential mechanism underlying benzodiazepine physical dependence.

PATIENT EXPERIENCE OF DIALYSIS REFUSAL OR WITHDRAWAL—A REVIEW OF THE LITERATURE

Aim. The aim of this literature review was to advance understanding of dialysis refusal and withdrawal in relation to the experiences of patients and carers and to explore the trajectory to death of those abating dialysis. Method. Databases searched included CINAHL, Medline, PsycINFO, British Nursing Index, International Bibliography of the Social Sciences, ASSIA and Cancerlit. Forty-four quantitative papers and two qualitative papers were identified. Findings. The patient and carer experience is rarely explored in the literature but issues related to 'Making decisions to withhold/forego or withdraw treatment', 'Length of survival without dialysis', Prevalence of symptoms in end-stage renal disease', 'The utilisation of Advance Directives' and 'The impact on families' throw some light on the phenomena of dialysis refusal and withdrawal. Conclusions. Little is known about those patients who withdraw from or decide not to commence dialysis. Empirical studies related to those who opt not to embark on dialysis are limited to four worldwide. There is an urgent need for further research to determine the experiences and needs of this population and a more patient-centred approach is required, consistent with modern palliative medicine.

Withdrawal phenomena after chronic beta-blockade. Causes and therapeutic consequences

Drug Prescribing for Patients with Chronic Kidney Disease in General Practice: a Cross-Sectional Study

Sleep-Stabilizing Effects of E-6199, Compared to Zopiclone, Zolpidem and THIP in Mice

Gamma aminobutyric acid (GABA)A receptor modulators constitute the majority of clinically used sedative-hypnotics. These compounds have the capacity to initiate and maintain sleep, but decrease REM sleep and delta activity within NREM sleep. In order to avoid such sleep adverse effects, the development of novel compounds remains of interest. The present study aimed at characterizing the acute effects of a novel putative hypnotic compound, E-6199, compared to zopiclone, zolpidem, and THIP on sleep-wakefulness patterns in mice. We also investigated whether repeated administration (daily injection during 10 days) of E-6199 was associated with tolerance and sleep disturbances at cessation of treatment. Polygraphic recordings were performed during 8 h after acute treatment with the various compounds. Under such conditions, E-6199 (5-20 mg/kg i.p.), zopiclone and zolpidem (2-10 mg/kg i.p.), but not THIP (2-10 mg/kg i.p.), exerted a marked sleep-promoting effect. Furthermore, E-6199 specifically increased the duration of NREM and markedly improved sleep continuity by lengthening NREM sleep episodes and reducing short awakenings and microarousal frequency. It also intensified NREM sleep by enhancing the slow wave activity within NREM at wake-NREM transitions. These effects were sustained and became even larger during chronic administration. Finally, abrupt E-6199 withdrawal did not elicit negative sleep effects. Our findings demonstrate that E-6199 may be an effective hypnotic compound that promotes and improves NREMS, without producing EEG side effects, tolerance or withdrawal phenomena, when administered under chronic conditions.

Long-term use of benzodiazepines: tolerance, dependence and clinical problems in anxiety and mood disorders.

This paper reviews the literature on the epidemiological, biological and clinical features of benzodiazepine dependence and withdrawal syndrome, focusing on clinical problems associated with the long-term use of benzodiazepine (BZs) in mood and anxiety disorders. These conditions represent the most frequent mental disorders for which BZs are overprescribed. In addition to dependence and withdrawal phenomena, the presence of chronic subtle toxicity and the interference with the underlying psychopathology observed with BZ use suggests a need for a more careful evaluation of the risk-benefit ratio in the long-term administration of BZs.