Dan Med Bul ϧϩ/Ϫ August ϤϢϣϢ DANISH MEDICAL BULLETIN ϣ Linear correlation between phenobarbital dose and concentration in alcohol withdrawal patients Karen Tangmose1, Mogens Kai Nielsen1, Peter Allerup2 & Jakob Ulrichsen1 ABSTRACT definite conclusions about the relative effectiveness and ORIGINAL ARTICLE INTRODUCTION: Barbiturates are potent drugs for treat- safety of benzodiazepines against other alcohol with- 1) Psychiatric Centre ment of alcohol withdrawal symptoms, but they entail a risk drawal drugs [5]. Although barbiturates have never been Gentofte, Copenhagen of over-dosage and respiratory depression. The purpose of tested against placebo in randomized trials, barbital was University Hospital, the present study was to investigate the correlation shown to be more efficient than diazepam in the Denmark between phenobarbital dose and phenobarbital blood treatment of delirium tremens [6]. A major concern in 2) The Danish concentration in patients withdrawing from long-term University of relation to the use of barbiturates, including phenobar- Education, Copen- alcohol intoxication. bital, is that these drugs supposedly carry a risk of fatal hagen, Denmark MATERIAL AND METHODS: A total of 497 patients who were intoxication by causing respiratory depression. In hospitalized for treatment of alcohol withdrawal symptoms another retrospective study conducted at our depart- Dan Med Bul during an 18-month period were enrolled in the study. ment, we only detected two cases with respiratory 2010;57(8):A4141 Phenobarbital 200 mg was administered orally every 30 or depression among 73 patients with delirium tremens 60 minutes in response to the observed symptoms. Within who had been treated with phenobarbital during an the first 24 hours after admission, i.e. at 8 AM, blood was 8-year period. No respiratory problems were registered collected for determination of phenobarbital concentration, among 22 patients with pre-delirium in the same study, and the cumulated dose of phenobarbital at the time of the i.e. patients who had physical withdrawal symptoms and blood sampling was registered. RESULTS: The mean cumulated phenobarbital dose at the visual hallucinations, but showed no clouding of con- time of the blood sampling was 877 mg ± 557 mg, while the sciousness [7]. mean plasma phenobarbital concentration was 104 It is a widespread hypothesis among Danish phys- micromol/l ± 62 micromol/l. A statistically significant linear icians and nurses treating alcohol withdrawal patients correlation between phenobarbital dose and concentration that the absorption rate of phenobarbital may decrease was found for both males and females as 83% and 84% of due to slow gastric emptying, leading to a potential risk the variation in drug concentration, respectively, could of over-dosage if large amounts of phenobarbital remain be explained by the phenobarbital dose. We observed in the gastrointestinal system when sedation caused by no serious complications of the phenobarbital treatment the phenobarbital already absorbed sets in. This hypo th- – including respiratory problems or severe sedation. esis is not based on scientific evidence. In fact, the ab- DISCUSSION: The strong linear correlation between sorption rate in non-alcoholic subjects is quite rapid [8] phenobarbital dose and concentration suggests that and there is no reason to assume that alcoholics should absorption of plasma phenobarbital from the gastrointe s- differ in this regard. The purpose of the current study tinal system is highly predictable. was to investigate the hypothesis of delayed phenobar- bital absorption by analysing blood samples from pa- tients who were being treated for alcohol withdrawal, Alcohol withdrawal symptoms include tremor, agitation, and by studying the correlation between phenobarbital tachycardia and sweating [1]. Some patients develop dose and its concentration. more severe symptoms such as seizures, visual hallu- cinations or delirium tremens. The latter condition is a MATERIAL AND METHODS true medical emergency which, if left untreated, has a This prospective study comprised patients of either sex mortality rate of 15% [2]. In Denmark, barbiturates have who were admitted to Psychiatric Centre Gentofte, been used for a century in the treatment of alcohol Copenhagen University Hospitals, Denmark, for detoxi- withdrawal symptoms including delirium tremens [3]. fication or treatment for alcohol withdrawal symptoms Worldwide, benzodiazepines are regarded as the drug of in the period from 20 February 2007 to 24 August 2008. choice in alcohol withdrawal [4]. In a recent Cochrane For each patient we registered gender, age and blood review, benzodiazepines were found to be more effi - alcohol concentration upon admittance. Blood samples cient than placebo, whereas it was not possible to draw for measurement of phenobarbital plasma concentra- Ϥ DANISH MEDICAL BULLETIN Dan Med Bul ϧϩ/Ϫ August ϤϢϣϢ tion were collected at 08.00 AM, and the cumulated certified psychiatry specialist who decided whether the phenobarbital doses were registered at the time the patient had Wernicke’s encephalopathy. This syndrome blood samples were taken and upon discharge. The was defined clinically by the presence of any of the phenobarbital concentration in blood was measured by three mentioned symptoms, provided that these could the hospital’s Department of Clinical Chemistry as part not be accounted for by alcohol intoxication or delirium. of their daily routine using Vitros MicroSlide technology Statistical analyses of the relation between pheno- in a fully automated process (Ortho Clinical Diagnostics, barbital concentration (micromol/l) and phenobarbital UK). Since phenobarbital metabolizes slowly with a half- dose (mg) was performed as simple linear regression life of approximately 90 hours [8], patients who had analyses and generalized linear modelling. The latter received phenobarbital 14 days before admission were method was used to compare marginal changes in excluded. Thus, the study did not include those who had plasma phenobarbital (p-phenobarbital) concentration been treated for alcohol withdrawal at the ward within due to differences in the phenobarbital dose between the preceding two weeks of admission. Using the with- males and females. The level of significance was p = 0.05 drawal items tremor, sweating, tachycardia (pulse rate > and all tests were double-sided. Quantitative data are 90), increased psychomotor activity and the patients’ presented as mean ± standard deviation. subjective experience of restlessness, a nurse made a global rating as to whether withdrawal symptoms were RESULTS present or not [9]. In addition, vital signs such as pulse A total of 497 cases, 305 men and 192 women, were rate, blood pressure and temperature were measured admitted for alcohol detoxification or treatment for regularly in patients who were awake. In the sleeping alcohol withdrawal symptoms. The study population patients, a nurse observed if respiration was regular consisted of 241 patients among whom 141 patients without signs of airway obstruction and also recorded were only admitted once while 95 patients were admit- the rate of respiration on an hourly basis. In patients ted twice or more. Two of the 241 patients each de - who were awake, 200 mg phenobarbital was adminis- veloped DT once and were included in the present study tered orally every hour if withdrawal symptoms were as they were not transferred to the closed ward. In present according to the rating of the nurse, i.e. addition, a total of 23 cases (19 patients) who were administration was undertaken if symptoms were either delirious upon admittance or developed DT present. In case of severe symptoms, the same dose of during the withdrawal phase were admitted to a closed phenobarbital was administered every 30 minutes. The ward and not included in the study. The mean age of the need for further phenobarbital was evaluated by the study population was 51.9 ± 9.5 years, the mean physician in charge when 1,200 mg of phenobarbital had duration of hospitalization was 1.34 ± 0.59 day and the been administered and subsequently after administra- mean alcohol concentration at admission was 1.5 ± 1 g/l. tion of each cumulated 600 mg dose, but there was no Some patients did not receive phenobarbital as they did limit to the total cumulated dose of phenobarbital. The not develop withdrawal signs, in some cases blood treatment aimed to terminate the physical withdrawal samples were not collected in the morning on day 2, and symptoms and sleep from which the patient could be some patients were excluded because they had received woken by light or moderate touch. phenobarbital within the previous two weeks. Thus Whereas the present study population was treated correlation be tween phenobarbital dose and concentra- at the Emergency Ward of the Psychiatric Department, tion was performed on a total of 348 patients (212 men the majority of patients who were admitted with deli r- and 136 women). The mean cumulated phenobarbital ium tremens or who developed delirium tremens (DT) dose at the time of blood sampling was 877 mg ± 557 during therapy were transferred to and treated at a and the mean total cumulated phenobarbital dose was closed ward. As blood phenobarbital levels were not sys- 1,005 mg ± 659 mg. The mean p-phenobarbital concen- tematically measured in patients admitted to the closed tration was 104 ± 62 micromol/l. wards, these subjects were not included in the study. Wernicke’s encephalopathy was observed in 49 of The patients