ASSESSMENT OF DIAZEPAM LOADING DOSE THERAPY OF DELIRIUM TREMENS

Alcohol & Alcoholism Vol. 31, No. 3, pp. 273-278, 1996 ASSESSMENT OF DIAZEPAM LOADING DOSE THERAPY OF DELIRIUM TREMENS DARIUSZ WASILEWSKI*, HALINA MATSUMOTO, EWA KUR, ANNA DZIKLINSKA, ELZBIETA WOZNY, KRYSTYNA STENCKA, MICHAt SKALSKI, PIOTR CHABA and WALDEMAR SZELENBERGER (Received 27 July 1995; in revised form 6 November 1995; accepted 1 December 1995) Abstract — The efficacy of the diazepam loading dose method of treatment of delirium tremens was assessed in comparison with the traditional therapy. The experimental group and the control group comprised 51 and 45 patients respectively. The clinical institute withdrawal assessment for alcohol (CIWA-A) scale was applied to assess the intensity of the symptoms. Diazepam doses in the experimental group oscillated from 40 to 210 mg (mean 86.9 ± 47.2 mg). The control group was receiving diazepam and other psychotropic drugs in divided doses. In the experimental group deliric symptoms were present from 2 to 24 h (mean 6.9 ± 4.8 h), and in the control group from 2 to 123 h (mean 33.8 ± 25.7 h). The results show a large efficacy of the loading dose method corresponding to substantial reduction of the psychosis duration (fivefold in comparison to the control group). The method proved to be safe, with no significant complications. INTRODUCTION The ideal drug to treat delirium tremens should be a compound with anxiolytic, anticonvulsant and antipsychotic effect, reducing the activation of the vegetative system (Busch and Frings, 1988). Unfortunately such a drug does not exist. Commonly, as the activity of GABA-ergic neurons is diminished in the alcohol withdrawal syndrome (Airaksinen and Peura, 1987), benzodiazepines or chlormethiazole monotherapy is recommended, because of the GABA-ergic effect of these drugs. Another reason for their use is their crosstolerance with alcohol (Gross et al, 1974). The choice of benzodiazepines is recommended because of their more significant anticonvulsant activity and lower toxicity; even if therapeutic doses are greatly exceeded, lethal intoxication is seldom observed; usually only when patients take other psychotropic drugs or drink alcohol (Prescott, 1983). As all benzodiazepines act on the same receptor, their efficacy is comparable (Greenblatt, 1992; Hollister et al, 1993). How- * Author to whom correspondence should be addressed. ever, the results of treatment of the alcohol withdrawal syndrome with diazepam in divided doses did not prove to be effective (Shaw et al., 1981; Rewekant et al., 1989; Szelenberger et al., 1989). This method does not ensure a proper therapeutic concentration of diazepam (Rickels, 1983; Long, 1984; Rewekant et al., 1989). This is particularly so during the first life-threatening 48 h. Diazepam-loading is an alternative to the existing methods of treatment. Diazepam is given orally 20 mg every 1-2 h until the improvement of the clinical condition is achieved (Sellers et al., 1983). Therapeutically adequate concentrations are reached during the first 48 h, with no further increase to toxic or even life-threatening levels (Sellers and Naranjo, 1985; Naranjo and Sellers, 1986; Matsumoto et al., 1992). Because of the fact that diazepam and its metabolites have a long biological half-life (Kaplan, 1980), the therapeutic concentration is maintained, after the loading dose, during the following days (Naranjo and Sellers, 1986; Matsumoto et al, 1992). In the present study, we have compared the efficacy of the diazepam loading method with 273 1996 Medical Council on Alcoholism I Department of Psychiatry, Warsaw Medical Academy, Nowowiejska 27, 00 665 Warsaw, Poland 274 D. WASILEWSKI et al. traditional therapy with the drug in the treatment of alcoholic delirium tremens. MATERIALS AND METHODS Treatment and assessment of patients We checked our patients for the presence of alcohol, benzodiazepines or barbiturates in their blood. Then, diazepam (Relanium, Polfa) was administrated per os in 10-20 mg doses every 1-2 h. Clinical state was assessed by means of the clinical institute withdrawal assessment for alcohol (CIWA-A) scale (Shaw et al, 1981): nausea and vomiting (0-7), tremor (0-7), sweating (0-7), occurrence of hallucinations (0-3), tactile disturbances (0-6), auditory disturbances (0-6), visual disturbances (0-6), clouding of sensorium (0-4), quality of contact (0-7), anxiety (0-7), agitation (0-7), thought disturbances (0-3), seizures (0-7), headache (0-7), flushing of face (0-2). The administration of the drug was interrupted when the sum of the points in the CIWA-A scale was <10 (Shaw et al, 1981; Sellers et al, 1983). The duration of psychosis was measured from the start of therapy to the time the patients became asymptomatic. The control group consisted of 45 patients (40 males and 5 females), aged 21-55 years, selected Drug monitoring The concentration of diazepam (D) and desmethyldiazepam (DD) was assessed by the fluorescence polarization immunoassay method (FPIA) with an Abbott Tdx& analyser. D and DD concentrations were examined only in the experimental group. Drug monitoring was performed to: (a) detect the moment of approaching the critical concentration in certain subjects; (b) evaluate the drug level at which adverse events could occur; (c) establish if the therapeutic concentration was achieved within the first 48 h. Blood samples were collected six times: before the start of therapy, 1 h after the administration of the first dose, I h after the last dose, and on the third, the fifth and the seventh days of the hospital stay. The choice of the 1 h interval of blood collection after administration of the drug coincides with the time of attaining diazepam's maximal concentration [1 h after oral administration (Greenblatt and Shader, 1985; Nicholson, 1989)]. In the statistical analysis, the Mann-Whitney test was used (Norusis, 1990). The research was approved by the Local Ethics Committee. RESULTS Table 1 presents the patients' characteristics, from which it is clear that the only significant Patient characteristics and selection The loading dose method was applied in 51 patients of the Nowowiejski Hospital in Warsaw, the Psychiatric Hospital in Pruszkow and the Psychiatric Hospital in Zabki, from April 1990 to October 1994. The experimental group consisted of 46 males and five females, aged 26-60 years, suffering from alcohol withdrawal syndrome with delirium (according to ICD-10) (World Health Organization, 1992). Patients with alcohol withdrawal syndrome without delirium, mixed dependence, other alcoholic and non-alcoholic psychoses, and patients who shortly before the hospitalization received any psychotropic medication (e.g. from emergency doctors) were excluded from the study. We also did not include patients with the following contraindications for diazepam administration: recent head injury, diseases related to a possible respiratory insufficiency, hepatic insufficiency, and presence of alcohol in blood upon admission. on the same p (...truncated)