Withdrawal Syndrome In Patients Research Articles

Use of sodium oxybate for the treatment of alcohol withdrawal syndrome in patients with acute alcohol-associated hepatitis: A 4-patient case report.

During the treatment of alcohol use disorder, alcohol withdrawal syndrome (AWS) can occur. Benzodiazepines remain the "gold standard" for the pharmacological treatment of AWS. However, other drugs have been approved in some European Countries for the treatment of AWS: namely, clomethiazole in Spain and Germany and sodium oxybate in Italy and Austria. Acute alcohol-associated hepatitis (AAH) is a distinct clinical syndrome characterized by the recent onset of jaundice with or without other signs of liver decompensation in patients with ongoing alcohol consumption. We report 4 paradigmatic clinical cases to analyze the efficacy, safety, and tolerability of the very short half-life (30-45 minutes) sodium oxybate (SO) in the management of AWS with moderate to severe AAH. Compared to SO, "as needed" short-acting benzodiazepines, currently prescribed to treat AWS in patients with AAH, have a much longer half-life (5-25 hours) which increases the risk of drug accumulation. The very short half-life of SO provides a fixed dose approach allowing for a more effective control of AWS than "as needed" therapy throughout the 24 hours. Patients reported anxiety, agitation, diffuse abdominal pain, loss of appetite, and nausea with elevation in serum bilirubin and 2 of them had abdomen distension due to ascites. Patients were affected by moderate or severe AWS and moderate or severe AAH on alcohol-related liver cirrhosis. In order to suppress AWS, all patients were treated with oral sodium oxybate at a dose of 25 mg/kg/day, progressively increased to 50 to 100 mg/kg/day, divided into 3 to 5 administrations. SO was efficient, safe and tolerable in suppressing AWS even in patients with severe AAH. All treated patients showed a rapid improvement of all symptom (via the Clinical Institute of Withdrawal Assessment for Alcohol Scale) and liver test scores (Model for End-Stage Liver Disease). Because of its short half-life, SO can be considered a safe and effective pharmacological option for the AWS in patients with moderate to severe AAH even in comparison to short-acting benzodiazepines, thus avoiding the risk of accumulation. Notably, SO guarantees a fixed approach to cover the possible onset of AWS throughout the 24 hours.

Evaluation of the Use of Phenobarbital and Benzodiazepines in the Management of Alcohol Withdrawal Syndrome in Patients Requiring Neurological/Neurosurgical Critical Care: A Propensity-Matched Analysis.

Objective There is growing interest in the use of phenobarbital for alcohol withdrawal syndrome in critically ill patients, though experience in neurologically injured patients is limited. The purpose of this study was to compare the safety and effectiveness of phenobarbital-containing alcohol withdrawal regimens versus benzodiazepine monotherapy in the neurocritical care unit. Methods We conducted a retrospective cohort study of adult patients admitted to the neurocritical care unit from January 2014 through November 2021 who received pharmacologic treatment for alcohol withdrawal. Treatment groups were defined as benzodiazepine monotherapy versus phenobarbital alone or in combination with benzodiazepines. The primary outcome was the percentage of patients requiring intubation after receiving alcohol withdrawal treatment. Secondary outcomes included all-cause, in-hospital mortality, intensive care unit length of stay, discharge disposition, change in Glasgow Coma Scale (GCS) score, and the use of adjunctive agents. Results We analyzed data from 156 patients, with 77 (49%) in the benzodiazepine group and 79 (51%) in the phenobarbital combination group. The groups were well-balanced for baseline characteristics, though more males (67, 85%) were in the phenobarbital group. Only three (1.9%) patients received phenobarbital monotherapy, and the rest (153, 98.1%) received combination therapy. The percentage of patients requiring mechanical ventilation was significantly higher in the phenobarbital combination group compared to benzodiazepine monotherapy (39% (n=31) versus 13% (n=10); OR: 4.33, 95% CI: 1.94-9.66; p<0.001). The use of adjunctive propofol and dexmedetomidine was higher in the phenobarbital group (propofol 35% (n= 28) versus 9% (n=7) and dexmedetomidine 30% (n=24) versus 5% (n=4), respectively). Patients in the phenobarbital group also had lower GCS scores and higher Clinical Institute Withdrawal Assessment of Alcohol (CIWA-Ar) scores during their intensive care unit admission, possibly suggesting more severe alcohol withdrawal. There was no difference in intensive care unit length of stay, all-cause, in-hospital mortality, discharge disposition, or therapeutic adjuncts. Conclusions Combination therapy of phenobarbital plus benzodiazepines was associated with higher odds of requiring mechanical ventilation. Few patients received phenobarbital monotherapy. Additional studies are needed to better compare the effects of phenobarbital monotherapy versus benzodiazepines in neurocritical patients.

A National Analysis of Alcohol Withdrawal Syndrome in Patients with Operative Trauma

BackgroundAlcohol withdrawal syndrome (AWS) presents with a complex spectrum of clinical manifestations that complicate postoperative management. In trauma setting, subjective screening for AWS remains challenging due to the criticality of injury in these patients. We thus identified several patient characteristics and perioperative outcomes associated AWS development. MethodsThe 2016–2020 National Inpatient Sample was queried to identify all non-elective adult (≥18 years) hospitalizations for blunt or penetrating trauma undergoing operative management with a diagnosis of AWS. Patients with traumatic brain injury or with a hospital duration of stay <2 days were excluded. Outcomes of interest included in-hospital mortality, perioperative complications, hospitalization costs, length of stay (LOS) and non-home discharge. ResultsOf an estimated 2,965,079 operative trauma hospitalizations included for analysis, 36,415 (1.23 %) developed AWS following admission. The AWS cohort demonstrated increased odds of mortality (Adjusted Odds Ratio [AOR] 1.46, 95 % Confidence Interval [95 % CI] 1.23–1.73), along with infectious (AOR 1.73, 95 % CI 1.58–1.88), cardiac (AOR 1.24, 95 % CI 1.06–1.46), and respiratory (AOR 1.96, 95 % CI 1.81–2.11) complications. AWS was associated with prolonged LOS, (β: 3.3 days, 95 % CI: 3.0 to 3.5), greater cost (β: +$8900, 95 % CI $7900–9800) and incremental odds of nonhome discharge (AOR 1.43, 95 % CI 1.34–1.53). Furthermore, male sex, Medicaid insurance status, head injury and thoracic operation were linked with greater odds of development of AWS. ConclusionIn the present study, AWS development was associated with increased odds of in-hospital mortality, perioperative complications, and resource burden. The identification of patient and operative characteristics linked with AWS may improve screening protocols in trauma care.

Erratum: Management of alcohol withdrawal syndrome in patients with alcohol-associated liver disease.

Erratum: Management of alcohol withdrawal syndrome in patients with alcohol-associated liver disease.

Management of alcohol withdrawal syndrome in patients with alcohol-associated liver disease.

Alcohol-associated liver disease is a common and severe sequela of excessive alcohol use; effective treatment requires attention to both liver disease and underlying alcohol use disorder (AUD). Alcohol withdrawal syndrome (AWS) can be dangerous, is a common barrier to AUD recovery, and may complicate inpatient admissions for liver-related complications. Hepatologists can address these comorbid conditions by learning to accurately stage alcohol-associated liver disease, identify AUD using standardized screening tools (eg, Alcohol Use Disorder Identification Test), and assess risk for and symptoms of AWS. Depending on the severity, alcohol withdrawal often merits admission to a monitored setting, where symptom-triggered administration of benzodiazepines based on standardized scoring protocols is often the most effective approach to management. For patients with severe liver disease, selection of benzodiazepines with less dependence on hepatic metabolism (eg, lorazepam) is advisable. Severe alcohol withdrawal often requires a "front-loaded" approach with higher dosing, as well as intensive monitoring. Distinguishing between alcohol withdrawal delirium and HE is important, though it can be difficult, and can be guided by differentiating clinical characteristics, including time to onset and activity level. There is little data on the use of adjuvant medications, including anticonvulsants, dexmedetomidine, or propofol, in this patient population. Beyond the treatment of AWS, inpatient admission and outpatient hepatology visits offer opportunities to engage in planning for ongoing management of AUD, including initiation of medications for AUD and referral to additional recovery supports. Hepatologists trained to identify AUD, alcohol-associated liver disease, and risk for AWS can proactively address these issues, ensuring that patients' AWS is managed safely and effectively and supporting planning for long-term recovery.

Methadone Maintenance Therapy after Aneurysmal Subarachnoid Hemorrhage: A Case Report

There is limited information on the effects of continued methadone maintenance therapy following aneurysmal subarachnoid hemorrhage (aSAH). However, with the increasing incidence of opioid use disorder (OUD) in the US, there is a need to define best practices for the management of pain and prevention of acute withdrawal syndrome in patients with pre-existing OUD who develop aSAH. In this case report, we describe the use of MMT in a patient with aSAH and discuss important considerations, including sedation or confusion that might mimic acute neurologic changes seen in cerebral vasospasm or delayed cerebral ischemia, cardiac complications related to QTc prolongation, and liver or kidney interactions associated with aSAH routine treatment. Our patient recovered from her aSAH without any adverse events and, with increased monitoring and collaborative team-based care, including input from those with expertise in OMD or aSAH, we believe MMT can be safely continued in most aSAH patients.

A ketogenic dietary supplement for alcohol withdrawal syndrome in patients with alcohol use disorder – a randomized, placebo-controlled clinical trial

A ketogenic dietary supplement for alcohol withdrawal syndrome in patients with alcohol use disorder – a randomized, placebo-controlled clinical trial

Comparative effects of 15 antidepressants on the risk of withdrawal syndrome: A real-world study using the WHO pharmacovigilance database

BackgroundWhile case reports and clinical trials reported withdrawal syndrome after reduction and/or discontinuation of antidepressant drugs, no large study has been conducted to compare the risk between the different antidepressants. MethodsUsing data recorded from January 1st, 1988, and December 31st, 2020 in VigiBase®, the World Health Organization's Global Individual Case Safety Reports database, we performed disproportionality analysis to investigate the risk of reporting withdrawal syndrome in patients treated by short half-life antidepressants compared with patients treated by long half-life antidepressants. In addition, we aimed to better inform clinical practice by comparing 15 antidepressants for the risk of reporting withdrawal syndrome. ResultsAmong the 338,498 reports with antidepressants of interest, we found 15,507 cases of withdrawal syndrome. Short half-lives antidepressants were associated with an increased risk of reporting a withdrawal syndrome compared to long half-life antidepressants (ROR 5.38; 95% CI 5.16–5.61). The risk was higher for 18–44 years old (ROR 6.88; 95% CI 6.17–7.62), women (ROR 1.38; 95% CI 1.33–1.43) and patients treated with Paroxetine, Desvenlafaxine, Venlafaxine and Duloxetine. LimitationsThe limitations of this study stem from the case-reporting process. ConclusionsThis large observational study in a real-world setting suggests that the use of short half-life antidepressants increases the risk of reporting withdrawal syndrome compared to long half-life antidepressants. Among the most common antidepressants, paroxetine and serotonin-noradrenaline reuptake inhibitors are associated with a greater risk of reporting withdrawal syndrome, while agomelatine and vortioxetine present a lower risk. Additional studies are needed to corroborate our results.

Dexmedetomidine and Iatrogenic Withdrawal Syndrome in Critically Ill Children.

Iatrogenic withdrawal syndrome is a well-known adverse effect of sedatives and analgesics commonly used in patients receiving mechanical ventilation in the pediatric intensive care unit, with an incidence of up to 64.6%. When standard sedative and analgesic treatment is inadequate, dexmedetomidine may be added. The effect of supplemental dexmedetomidine on iatrogenic withdrawal syndrome is unclear. To explore the potentially preventive effect of dexmedetomidine, used as a supplement to standard morphine and midazolam regimens, on the development of iatrogenic withdrawal syndrome in patients receiving mechanical ventilation in the pediatric intensive care unit. This retrospective observational study used data from patients on a 10-bed general pediatric intensive care unit. Iatrogenic withdrawal syndrome was measured using the Sophia Observation withdrawal Symptoms-scale. In a sample of 102 patients, the cumulative dose of dexmedetomidine had no preventive effect on the development of iatrogenic withdrawal syndrome (P = .19). After correction for the imbalance in the baseline characteristics between patients who did and did not receive dexmedetomidine, the cumulative dose of midazolam was found to be a significant risk factor for iatrogenic withdrawal syndrome (P < .03). In this study, supplemental dexmedetomidine had no preventive effect on iatrogenic withdrawal syndrome in patients receiving sedative treatment in the pediatric intensive care unit. The cumulative dose of midazolam was a significant risk factor for iatrogenic withdrawal syndrome.

The effect of dried barberry root on the symptoms of opiate withdrawal syndrome in patients undergoing methadone maintenance therapy-double-blind clinical trial

The effect of dried barberry root on the symptoms of opiate withdrawal syndrome in patients undergoing methadone maintenance therapy-double-blind clinical trial

Opioid and Benzodiazepine Iatrogenic Withdrawal Syndrome in Patients in the Intensive Care Unit.

Iatrogenic withdrawal syndrome is an increasingly recognized issue among adult patients in the intensive care unit. The prolonged use of opioids and benzodiazepines during the intensive care unit stay and preexisting disorders associated with their use put patients at risk of developing iatrogenic withdrawal syndrome. Although research to date is scant regarding iatrogenic withdrawal syndrome in adult patients in the intensive care unit, it is important to recognize and adequately manage iatrogenic withdrawal syndrome in order to prevent possible negative outcomes during and after a patient's intensive care unit stay. This article discusses in depth 8 studies of iatrogenic withdrawal syndrome among adult patients in the intensive care unit. It also addresses important aspects of opioid and benzodiazepine iatrogenic withdrawal syndrome, including prevalence, risk factors, and assessment and considers its prevention and management.

The Impact of Saffron on Symptoms of Withdrawal Syndrome in Patients Undergoing Maintenance Treatment for Opioid Addiction in Sabzevar Parish in 2017.

Background and Objective Drug dependence is one of the serious problems around the world. Saffron is one of those beneficial medicinal plants which is embedded with a similar mechanism to methadone (e.g., inhibition of serotonin reuptake). Thus, it can be helpful in reducing the withdrawal symptoms. The aim of this study was to reduce the daily dose of methadone usage and reduce its side effects using saffron in the form of medicinal supplements. Methodology This study was categorized as a clinical trial. Accordingly, 44 clients of addiction treatment centers in Sabzevar parish were randomly selected to participate in this study in 2016–2017. While the experimental group was treated with methadone syrup and self-made saffron capsules, the control group received methadone syrup and placebo capsules. Results The results showed that the use of saffron and methadone alleviated the symptoms of withdrawal syndrome (p<0.001). Conclusion Having reviewed the research participants, it was indicated that the introduction of saffron alleviated the symptoms of withdrawal syndrome in patients undergoing maintenance treatment for opioid addiction. Thus, it seems rational to make use of saffron in combination with methadone in order to alleviate the symptoms of withdrawal syndrome.

High doses of benzodiazepine predict analgesic and sedative drug withdrawal syndrome in paediatric intensive care patients.

Critically ill children can develop withdrawal syndrome after prolonged analgesia and sedation in a paediatric intensive care unit (PICU), when treatment is stopped abruptly or reduced quickly. The aim of this study was to evaluate the incidence of withdrawal syndrome in patients after three or more days of analgesic or sedative drug therapy, using a validated scale. We also analysed the association between withdrawal syndrome and the patients' outcome and factors related to analgesia and sedation treatment. This prospective observational study analysed 89 periods of weaning from analgesia and sedation in 60 children between October 2010 and October 2011. Of these, 65% were less than six months old and 45% were admitted to the PICU after heart surgery. Withdrawal syndrome was assessed using the Withdrawal Assessment Tool-1 (WAT-1) scale. The incidence of withdrawal syndrome was 37%, and the only variable that predicted its presence was the highest administered dose of benzodiazepine. The duration of weaning, Sophia Observational Withdrawal Symptom scale score and nurse judgment were also associated with positive WAT-1 scores. Withdrawal syndrome should be considered after three or more days of analgesic or sedative treatment. A high dose of benzodiazepine increases the risk of developing withdrawal symptoms.

Assessing Alcohol Versus Baclofen Withdrawal Syndrome in Patients Treated With Baclofen for Alcohol Use Disorder

Baclofen is a γ-aminobutyric acid B (GABA-B) receptor agonist that is approved for spasticity. Recently, the off-label use of baclofen for alcohol use disorder (AUD) has increased. However, baclofen is known to induce a neuroadaptation process, which may be identified by the occurrence of a specific baclofen withdrawal syndrome (BWS), that is, confusion, agitation, seizures, and delirium. The same set of symptoms characterizes alcohol withdrawal syndrome (AWS), which could lead to mistaking BWS for AWS in some situations. We report the cases of 3 patients under a chronic baclofen treatment for AUD. The patients emergently presented with a clinical state of confusion that was initially diagnosed and treated as AWS, with limited effect of benzodiazepines. Retrospectively, using a validated algorithm for assessing drug-induced withdrawal, we determined that all of these clinical cases were consistent with BWS. Both AWS and BWS should be considered in the case of acute confusion or delirium occurring in patients treated with baclofen for AUD. Moreover, further research should investigate to what extent GABA-A and GABA-B induce shared or distinct neuroadaptation processes and withdrawal syndromes.

Alcohol Withdrawal Prevention: A Randomized Evaluation of Lorazepam and Ethanol--A Pilot Study

Alcohol withdrawal syndrome, characterized by confusion, agitation, and hallucinations, decreases the safety of patients with acute myocardial infarction. Unexpected hospitalization and sudden cessation of alcohol consumption may increase in-hospital complications and length of stay and even precipitate death. To perform a randomized evaluation of lorazepam and ethanol/lorazepam to evaluate the safety and efficacy of these 2 strategies for preventing alcohol withdrawal syndrome in patients with acute coronary syndromes. Patients (n = 57) with myocardial infarction were screened for alcohol dependence by using the CAGE questionnaire and randomized to treatment with lorazepam or ethanol with lorazepam. Demographics and complication rates were analyzed by using χ² tests (categorical variables) and t tests (continuous variables). Safety (composite complication rates) of the treatment strategy was evaluated by using the Fisher exact test, and length of stay by using the Wilcoxon rank-sum test. Safety-associated complication rates (self-extubation, delirium tremens, reinfarction) did not differ between groups (24% lorazepam vs 18% ethanol; P = .56). Days spent in the cardiac intensive care unit (7% lorazepam vs 2% ethanol; P = .32) and overall hospital stay (6% lorazepam vs 6% ethanol; P = .72) did not differ between the 2 groups. These preliminary findings suggest that a randomized evaluation of treatment strategies to prevent complications associated with alcohol withdrawal in patients with acute myocardial infarction is safe and feasible.

Reply: Dopamine agonist withdrawal syndrome and non-motor symptoms after Parkinson's disease surgery

We would like to thank Dr Nirenberg for her thoughtful comments on our prospective study reporting the occurrence of a delayed withdrawal syndrome in patients with Parkinson’s disease treated with bilateral subthalamic stimulation. This syndrome, which includes depression, apathy and anxiety, is the consequence of a marked decrease in dopaminergic treatment rendered possible by a major improvement in motor symptoms (Thobois et al ., 2010). This study identified preoperative non-motor fluctuations as predictors of post-operative apathy and demonstrated that non-motor psychic symptoms of Parkinson’s disease can be explained by mesolimbic dopaminergic denervation. In order to examine and discuss the points raised by Dr Nirenberg (2010), several aspects of our study need to be highlighted and clarified. The fact that Parkinson’s disease surgery that preferentially targets the sensorimotor rather than the limbic subthalamic nucleus deep brain stimulation produces better motor than non-motor effects provides an almost experimental model with which to study non-motor psychic symptoms of Parkinson’s disease. This study was designed to obtain a better understanding of post-operative non-motor withdrawal symptoms, their time course and mechanisms. In accordance with our study protocol, dopaminergic treatment was reduced drastically, with complete arrest of dopamine agonists at time of surgery and marked reduction of levodopa depending on patients’ motor state in the two weeks following surgery, when stimulation parameters were increased. Reduction of dopaminergic treatment after surgery is a normal procedure, which is necessary for the adjustment of subthalamic stimulation parameters and the establishment of satisfactory control of motor fluctuations and dyskinesias (Krack et al ., 2002; Thobois et al ., 2003). It is important to note that the management of medication in our study differs from routine practice, where medication is adapted more individually and where low-dosage dopamine agonists are often maintained in order to prevent the delayed appearance of …

Parkinson disease and Neuroleptic withdrawal

Background Abrupt cessation of most psychiatric drugs leads to varying withdrawal symptoms. Although Clozapine withdrawal symptoms are well documented, this case presentation addresses issues pertaining to the severity of the withdrawals and the similarities to Neuroleptic Malignant Syndrome (NMS). This patient who was only on 100mg of Clozapine required ventilation in Intensive care unit. Neurologist found no causative factor but treated the patient symptomatically to recovery. Family history however revealed that both the patient’s parents suffered from severe Parkinson disease. This case presentation discusses the association between NMS like symptoms and neuroleptic withdrawal syndrome in patients with a family history of Parkinson disease.

Serotonergic anti-depressants and ethanol withdrawal syndrome: A review

To review laboratory findings on the effects of anti-depressant agents that interact with the serotonergic system on signs of ethanol withdrawal syndrome in rats. Adult Wistar rats received a modified liquid diet to produce ethanol dependence. Signs of ethanol withdrawal, locomotor hyperactivity, stereotyped behaviour, tremor, wet dog shakes, agitation, and audiogenic seizures, were evaluated for the first 6 h of ethanol withdrawal. The effects of the anti-depressants fluoxetine, venlafaxine, escitalopram, tianeptine, and extract of Hypericum perforatum (St. John's wort) (HPE) were examined. Some beneficial effects of fluoxetine, tianeptine, HPE, escitalopram and venlafaxine on ethanol withdrawal signs were observed, ranked as follows: fluoxetine = tianeptine > HPE > escitalopram > venlafaxine. Tianeptine and fluoxetine seem to be potent pharmacologically active agents on ethanol withdrawal syndrome in rats. Thus, these anti-depressants may be useful in treatment of ethanol withdrawal syndrome in patients with alcoholism. In addition to serotonergic effects, interactions with nitrergic, glutamatergic, and adenosinergic systems may also provide a significant contribution to the beneficial effects of these drugs on ethanol withdrawal syndrome.

Why does milnacipran produce so few discontinuation syndromes following abrupt withdrawal?

Several selective serotonin reuptake inhibitors (SSRI), especially paroxetine, have been reported to produce a number of post-treatment emergent adverse events following abrupt withdrawal (Coupland et al 1996; Haddad 1997). More recently a SSRI-induced neonatal withdrawal syndrome has been described (Sanz et al 2005) in infants born of mothers treated with SSRI during pregnancy. In both of these situations, paroxetine has been associated with the greatest incidence (Warner et al 2006; Sanz et al 2005). Other SSRIs and the selective serotonin and noradrenaline reuptake inhibitor (SNRI) venlafaxine can, however also cause a withdrawal syndrome in patients (Trenque et al 2002). In contrast, milnacipran, another SNRI, has been reported to present a lower risk of withdrawal-induced adverse events (Vandel et al 2004). Furthermore the spectrum of the symptoms was different from that produced by paroxetine. In our clinic, a discontinuation syndrome is sometimes seen when SSRIs or SNRIs are discontinued suddenly, or when doses are missed or forgotten. In a total cohort of 2675 depressed patients, we identified 124 cases of antidepressant withdrawal syndrome. Sixty-three of the cases resulted from withdrawal from fluvoxamine (from a total of 1306 treated patients), 55 were withdrawn from paroxetine (from a total of 453 treated patients), while 6 were withdrawn from milnacipran (from a total of 916 treated patients). With paroxetine and fluvoxamine, respectively, the incidence of discontinuation syndrome was 18.4 times greater and 7.3 times greater than that found with milnacipran (Table 1). These differences were highly significant as determined by the χ2 test. These results are qualitatively similar to those obtained in a double-blind comparative study of milnacipran and paroxetine by Vandel et al (2004), who found an incidence of discontinuation syndrome of 13% with milnacipran and 32% with paroxetine following withdrawal after 6 weeks of treatment. Table1 Number and ratios of discontinuation syndrome with SSRIs and SNRI in our clinic Paroxetine has systematically been found to have the highest incidence of discontinuation syndrome (Warner et al 2006) while fluvoxamine has an incidence 10-fold lower and fluoxetine 100-fold lower (Westenberg and Sandner 2006). Paroxetine is the most potent inhibitor of the serotonin transporter (Sanchez and Hyttel 1999) and this potency may be a significant factor in the frequency of discontinuation syndromes for paroxetine in comparison with fluvoxamine (Westenberg and Sandner 2006) and milnacipran (Moret et al 1985). Furthermore, paroxetine is unique among the SSRI because its relatively high affinity for muscarinic receptors is similar to that of imipramine (Schatzberg et al 1997; Sanchez and Hyttel 1999). A cholinergic rebound, as observed on withdrawal of tricyclic antidepressants (Dilsaver et al 1987), could also partly explain the discontinuation syndrome paroxetine. Neither fluvoxamine nor milnacipran have any significant affinity for the muscarinic receptor (Moret et al 1985; Sanchez and Hyttel 1999). Pharmacokinetics are thought to play an important role in the incidence of withdrawal effect, with compounds with shorter half-lives having the greatest incidence of withdrawal effects. The apparent correlation between the occurrence of SSRI discontinuation syndrome and shorter drug half-lives has been highlighted (Schatzberg et al 1997). The half-life of paroxetine (21 h) may explain the relatively high incidence of discontinuation syndromes compared with fluoxetine which has a long half-life (parent compound 1–6 days, active metabolite 7–9 days). Pharmacokinetic factors, however, do not explain the low incidence of withdrawal effects with milnacipran, since the half-life of the SNRI (8 h) is shorter than that of paroxetine (Puozzo et al 1998). It is possible that low incidence of withdrawal effects with milnacipran may be related to its dual action on the reuptake of noradrenaline and serotonin compared with the selective effect of SSRI such as paroxetine on the reuptake of serotonin. It seems unlikely, however, that a simple action on the noradrenaline transporter is sufficient to explain the situation. Firstly, paroxetine is the SSRI with the highest affinity for the noradrenaline transporter (Sanchez and Hyttel 1999) and, secondly, the SNRI venlafaxine has an incidence almost as high as paroxetine (Trenque et al 2002). Although venlafaxine is considered to be a SNRI, it is, in fact, a preferential serotonin reuptake inhibitor and produces clinically relevant inhibition of noradrenaline reuptake only at high doses where serotonin reuptake is very extensively inhibited (Harvey et al 2000). A unique property of milnacipran which may be relevant is the fact that it inhibits both noradrenaline and serotonin reuptake with similar potency (Moret and Briley 1997). A recent study of changes in long-term potentiation following repeated treatment with milnacipran (Tachibana et al 2006) has shown that interactions between noradrenergic and serotonergic mechanisms play an important role in the modulation of synaptic plasticity. It is thus possible that the balance between serotonergic and noradrenergic neurotransmission may be essential in determining the nature and extent of withdrawal-related symptoms. Further preclinical and clinical studies are required to test this hypothesis.

Pharmacokinetic Dosing of Phenobarbital in the Treatment of Alcohol Withdrawal Syndrome

We used a pharmacokinetically derived phenobarbital dosing protocol to treat alcohol withdrawal syndrome in patients admitted to a family medicine inpatient service. We describe the protocol and include two case reports documenting its efficacy. Although benzodiazepine agents are considered by many to be the primary agents of choice, based upon our experience and its ease of administration, relative safety, therapeutic efficacy, and lower cost, phenobarbital should be reconsidered as a promising alternative. Comparative trials between these two therapeutic classes will clarify their roles in the treatment of alcohol withdrawal syndrome.