Nimodipine in acute alcohol withdrawal state

J. psychiat. Res., Vol. 26, No. 2, pp. 117-123, 1992.

0022-3956/92 $5,00 + .00 Pergamon Press Ltd

Printed in Great Britain.

NIMODIPINE

IN ACUTE

ALCOHOL

WITHDRAWAL

M . B A N G E R , l O . B E N K E R T , l J . R()SCHKE, 1 T. H E R T H , l

and J. B.

M.

HEBENSTREIT, 1

STATE M.

PHILIPPl

ALDENHOFF 2

1Department of Psychiatry, University of Mainz, D-6500, Mainz, Germany and 2Central Institute of Mental Health, Mannheim, Germany

(Received 29 May 1991; revised 7 November 1991) S u m m a r y - - T h e effect of the calcium channel blocker, nimodipine, in acute alcohol withdrawal was investigated in a randomized, placebo controlled, double blind study. Thirty-two male patients with a history of alcohol dependence according to DSM-Ill criteria, but no other substance abuse, were included. A new rating instrument which fulfilled theoretical test criteria was applied to determine the severity of the alcohol withdrawal state. The patients received nimodipine or a placebo on four separate occasions (4 × 60 mg) and, in addition, clomethiazole, according to a standardized procedure. Our investigation has shown that, in the first 48-72 h of alcohol withdrawal, both groups consumed similar a m o u n t s of additional clomethiazole medication. Thus, no significant effect of nimodipine on the acute alcohol withdrawal state could be demonstrated. There was some tendency for nimodipine to ameliorate psychosensory dysfunction.

Introduction CLOMETHIAZOLEand benzodiazepines are often recommended in Europe for treatment of the alcohol withdrawal syndrome. However, their somatic side effects, particularly drug dependence problems, require a search for lower risk medication (Busch & Frings, 1988). Normal neuronal activity is characterized by an equilibrium state between excitation and inhibition, maintained by negative feedback mechanisms at the cellular, synaptic and neuronal level (Aldenhoff, 1989). Excitatory calcium currents are antagonized physiologically by the inhibitory action of calcium dependent potassium currents. This might be the reason why calcium antagonists have only a slight influence on normal neuronal function (Walden & Speckmann, 1988). They become effective in states of calcium overdrive such as epileptic discharge or overactivity due to neuromodulatory effects, as demonstrated for corticotropin-releasing factor (Aldenhoff, 1986). In ethanol dependent animals, Dolin, Little, Hudspith, Pagonis, and Littleton (1987) demonstrated an increased number and enhanced functional activity of the dihydropyridine sensitive subtype of voltage operated calcium channels on neuronal membranes. This finding can be considered as a structural basis for increased excitability in the acute alcohol withdrawal state. Further, dihydropyridines can prevent the ethanol withdrawal syndrome in rats (Little, Dolin, & Halsey, 1986). From the clinical point of view, the withdrawal syndrome can be interpreted as a state of general disinhibition, characterized by symptoms such as tremor, hyperhidrosis, hypertension, tachycardia, hyper-suggestibility, Please address all correspondence to: Markus Banger, Klinik ffir Allgemeine Psychiatrie, Rheinische Landesu n d Hochschulklinik Essen, Virchowstr. 174, 4300 Essen 1, Germany. 117

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M. BANGER et al.

hallucinations, anxiety and epileptic seizures (Feuerlein, 1974). Accordingly, we investigated the effect of nimodipine, a 1,4-dihydropyridine derivative, during the acute alcohol withdrawal state in a randomized, placebo controlled, double blind procedure. Nimodipine binding sites have been found in the hippocampus, cortex and thalamus (Meyer, Anderson, Sundt, & Sharbrough, 1986); further nimodipine can cross the blood-brain barrier, as demonstrated by Kerckhoff and Drewes (1985). Its efficacy was tested by the need for additional clomethiazole consumption during the first 72 h of detoxification. The hypothesis was that patients who receive additional nimodipine need a lower dosage of clomethiazole than patients who receive additional placebo. Methods Thirty-two male patients aged between 18 and 60 years (mean 42 years), with a history of alcohol dependence according to DSM-III criteria, were included in the study. Exclusion criteria were: additional substance abuse, severe medical disease, hypo- or hypertension, psychosis, epileptic seizures, delirium, involvement in legal proceedings, and contraindications to calcium antagonists or pretreatment with a calcium antagonist. Patients were fully informed about the object of the study and gave written consent. Patient's alcohol withdrawal syndrome was rated every hour by clinicians, employing a recently developed rating instrument (Mainz Alcohol Withdrawal Scale, MAWS, Table 1) which fulfilled theoretical test criteria (Banger, Philipp, Hebenstreit, Herth, & Aldenhoff, 1991). With its aid, the severity of the alcohol withdrawal syndrome could be quantified. This instrument allowed us to measure mild and moderate states of alcohol withdrawal and could be used repeatedly for the control of medication and an assessment of its efficacy in the withdrawal syndrome. The following items on a defined four point scale were included: (a) "disorientation"; (b) "hallucinations"; (c) "inattentiveness"; (d) "disturbance of contact"; (e) "agitation"; (f) " t r e m o r " ; (g) "hyperhidrosis"; and (h) "anxiety" (Table 1). Patients were included in the study when they reached a MAWS score of at least 6.0, corresponding to a moderate alcohol withdrawal syndrome. This level was determined arbitrarily. Thirty-two patients fulfilled these criteria. Twenty more did not qualify for the study because their withdrawal state was too slight. After initial study, patients received a defined dosage of nimodipine (60 mg) or placebo on four separate occasions (every 6 h) in a randomized, double-blind fashion. This dosage was similar to that employed for the oral nimodipine treatment of strokes. For patients with an organic brain syndrome, a lower dosage (3 x 30 mg) is normally used, but we considered this dosage unlikely to be effective in alcohol withdrawal state. Additionally, both groups received capsules containing 0.192 g clomethiazole according to a standardized procedure as follows: the first 3 days of the study were defined as the phase of intense supervision. During this phase, patients were rated every hour by a nursing scale which included tachycardia, hypertension, agitation, tremor, hyperhidrosis and disorientation on a four point scale (NAWS). To receive one capsule of clomethiazole, patients must reach 4-6 points, for two capsules 7-9 points and so forth. As mentioned above, measurements were repeated every hour. At night, patients were allowed to sleep for a maximum of 3 h without measurements being made. When

NIMODIPINE AND ALCOHOL WITHDRAWAL STATE

119

Table 1. Mainz Alcohol Withdrawal Scale (MAWS) Reference period last hour! (a) Disorientation

(b) Hallucinations

(c) Inattentiveness

(d) Disturbance of contact

(e) Agitation

(f) Tremor

(g) Hyperhidrosis

(h) Anxiety

0 = none 1 = mild 2 = marked 3 = severe

(full orientation, but sluggish answers) (blurred orientation in at least one quality) (disorientation in at least one quality)

0 = none 1 = mild 2 =marked 3 = severe

(occasional, distancing possible) (frequent, sometimes distancing still possible) (nearly constant, no distancing at all)

none 1= mild 2= marked 3= severe

(slip of the tongue, misunderstanding) (high suggestibility: string catching, reading) (spontaneous illusions)

0 = none 1 =mild 2 = marked 3 - severe

(good contact with investigator, but not with environment) (sometimes poor contact with investigator) (no contact with investigator)

0 = none 1 =mild 2 =marked 3 = severe

(feeling nervous) (physical restlessness) (absolute psychomotor agitation)

none 1= mild 2= marked 3= severe

(extended fingers) (extended hands) (tremor of hands or body when resting)

0 = none 1 = mild 2 = marked 3 = severe

(palpable on hands and forehead) (visible on hands and forehead) (visible on total body)

0 = none 1 = mild 2=marked 3 = severe

(reported on questioning only) (expressed by behaviour) (panic)

0 =

0~

the measured severity of the acute alcohol withdrawal syndrome did not increase over a time period of 6 h the phase of intense supervision was complete. Clomethiazole medication was applied according to this standardized procedure. Thus, the number of clomethiazole capsules consumed was related to the severity of the alcohol withdrawal syndrome. After 3 d a y s at t h e m o s t , all p a t i e n t s p r o c e e d e d t o t h e r e d u c t i o n p h a s e . D u r i n g t h i s p h a s e (7 days), clomethiazole dosage was reduced by two capsules per day and patients were rated once a day with the M A W S scale. P a t i e n t s were m o n i t o r e d weekly by E E G , E C G a n d routine laboratory tests. Significant differences between mean values of clomethiazole c o n s u m p t i o n were calculated by S t u d e n t ' s t-test.

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M. BANGER et al.

Results Fifty-four patients were rated every hour, but only 32 reached the defined level of severity of the alcohol withdrawal syndrome and therefore were allowed to participate in the therapy study. Four of these patients were removed from the trial: 1 consumed alcohol during detoxification, 2 suffered from an alcohol withdrawal seizure, and 1 developed severe delirium. Patients tolerated the medication well and no severe side effects were observed. As shown in Table 2, placebo and active group were similar, as far as age, duration of alcohol abuse, gamma-glutamyl transferase activity (GGT), mean corpuscular volume (MCV) and number of previous detoxifications were concerned. Table 2.

Description o f the study groups

Age (years) Number of previous detoxifications Duration of abuse (years) GGT a at study admission ( U / l ) MCV b at study admission (U/I) n

Placebo group

Active group

41.3 ± 7.1 2.64-4.6 17.2 4- 8.5 226.0±305 97.3 ± 4 . 8 15

42.0 ± 5.9 2 . 0 ± 3.8 16.6 ± 7.7 223.0±320 102.3 ±9.1 13

aGGT = gamma-glutamyl transferase; bMCV = mean corpuscular volume

Figure 1 shows clomethiazole consumption during the first 48-72 h after study onset in both groups. The placebo group needed an average of 26 + 13 capsules of clomethiazole during the first 48 h of treatment, whilst the active group received 23 + 11 capsules of clomethiazole. This difference was not statistically significant. During the first 72 h of detoxification, patients with additional placebo medication received 33 + 18 capsules of clomethiazole and the mean dose in patients with additional active medication was 30 ± 15. This difference was not statistically significant.

Placebo group (48h)

Verum group (48h) /

]

Placebo group (72h) [

Verum group (72h) [

0

I

I0

I

20

I

30

J

40

I

50

6'0

Ctornethiazote capsules

Figure 1. Clomethiazole consumption in placebo and active group during the first 48 and 72 h of therapy. Values represent mean ± SD.

121

NIMODIPINE AND ALCOHOL WITHDRAWAL STATE

The first four items of the MAWS are measuring disturbances of perception and attention and were described as psychosensory items, which might be linked to cognitive functions. Items (e)-(h) of the M A W S detect autonomic symptoms of the alcohol withdrawal syndrome. Items (a)-(d) and (e)-(h) were averaged in order to define a psychosensory (data not shown) and an autonomic factor (Figure 2). Patients in the placebo group, as well as in the active group, manifested more autonomic than psychosensory symptoms immediately before treatment. After 3 days of treatment, there were no longer any psychosensory symptoms to be observed either in the placebo or active group. Even so, autonomic symptoms could be detected at day 3 of the study. In fact, there was a statistically significant (p < .05) reduction of both the psychosensory and autonomic factors of the alcohol withdrawal syndrome. ~o 8

6

T

T

4

Before treatment

(doy O) r~

During treatment Before treatment During treatment

(day 3)

PLacebo group

(day O) I

(day 3)

I Active group

Figure 2. Calculated autonomic alcohol withdrawal factor before and under treatment. The factor was calculated from items (e)-(h) of the Mainz alcohol withdrawal scale. Values represent mean 4-SD. For explanations see text.

In a second approach, we analyzed the individual items of the MAWS. In the active group, only the item disturbance of contact was not significantly reduced at day 3 compared with at the onset of treatment. All other items had reductions which were statistically significant (p < .05). Under placebo conditions, there were two items, disturbance of contact and inattentiveness, which were not significantly reduced after 3 days of treatment. Additionally, in both groups the two items tachycardia and hypertension of the NAWS (Table 3) showed a statistically significant reduction 60 < .05), comparing day 0 and day 3 of the study. A specific effect of nimodipine on blood pressure or pulse frequency could Table 3. NA WS (Nurse Alcohol Withdrawal Scale) scores o f the items hypertension and tachycardia before and during treatment on day 3 in the placebo and active group Before

During treatment at day 3

Tachycardia placebo group Tachycardia active group

1.46 1.69

0.27 0.50

Hypertension placebo group Hypertension active group

2.26 2.38

0.64 0.50

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M. BANGERet al.

not be ruled out. Recently Horstmann, Weber, Wingender, Rfimsch, and Kuhlmann (1989) reported similar results in the interaction of nimodipine with beta adrenergic blocking agents. Taking all these results together, we were unable to show any specific effects of nimodipine in the treatment of an acute (mild and moderate) alcohol withdrawal state. Discussion Our investigation of the possible therapeutic effect of nimodipine on the alcohol withdrawal syndrome was prompted by animal research: neuronal membranes of ethanol dependent animals showed an increased number of voltage sensitive calcium channels, as measured by dihydropyridine binding sites (Dolin et al., 1987). This finding pointed to an increased excitability due to calcium current as an explanation of the psychopathology of the withdrawal syndrome, as well as suggesting a possible therapeutic action of calcium antagonists. However, in the clinical trial presented here, nimodipine was not found to be superior to the placebo in the treatment of alcohol withdrawal syndrome. This finding confirms the results of an open study of Deckert, Mfiller, Lanczik, and Fritze (1990). On the contrary, Koppi, Eberhardt, Hailer, and KOnig (1987) found that the non-specific calcium channel blocking agent, caroverine, was as effective as m e p r o b a m a t e . It should be mentioned that they did not use any specific alcohol withdrawal scale, and had a flexible dose regime with individual dosage based upon the patients' clinical states. No information was given as to how the clinical state was quantified. Our results might be explained in the following manner: 1. An increased number of calcium channels in the CNS of ethanol dependent individuals might go some way to explaining the psychosensory aspects of withdrawal psychopathology. However, our patients manifested mainly autonomic symptoms in the withdrawal state. This finding might be expected because of the selection criteria of a mild withdrawal syndrome resulting from the ethical constraints of the study. Autonomic symptomatology, indeed, might be less dependent on m e m b r a n e changes of central neurons and, in consequence, be less sensitive to calcium antagonists than psychosensory symptomatology. The psychosensory factor, the sum of the psychosensory items, was seldom positively coded before and during treatment as compared to the autonomic factor. It seems possible that a significant effect of nimodipine can only be expected in a severe alcohol withdrawal syndrome. Comparing the last rating immediately before therapy with the rating on day 3 after therapy onset in the placebo group, the item disturbance of contact and inattentiveness did not differ significantly. In the active group, only the item disturbance of contact was not significantly reduced at day 3. This may point to a tendency of nimodipine to ameliorate psychosensory dysfunction. 2. A recent post-mortem analysis of calcium channel antagonist binding in m e m b r a n e samples obtained at autopsy from alcoholic and nonalcoholic patients, revealed no differences in binding (Marks, Watson, Carpenter, Messing, & Greenberg, 1989). It is concluded that ethanol induced changes in calcium channel expression are more likely to be related to acute withdrawal than to chronic ethanol exposure alone.

NIMODIPINE AND ALCOHOL WITHDRAWALSTATE

123

3. Hithero, it has not been demonstrated that the mechanisms of the alcohol withdrawal syndrome are similar in animals and man. 4. We cannot exclude the possibility that a higher dose of nimodipine would be effective in the alcohol withdrawal state. Comparing our dosage of 240 mg to the 90 mg dose used in patients with an organic brain damage syndrome, it seems to be adequate. A higher dosage might well lead to more severe side effects. It might be interesting to investigate more severe alcohol withdrawal syndromes in future studies. Acknowledgements--This work was supported by Bayer AG, Germany. We would like to thank the nurses of Division No. 4, Psychiatric Clinic, University of Mainz, for their support.

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