SUBNORMAL ALPHA-2-ADRENOCEPTOR-MEDIATED SEDATION DURING 6 MONTHS OF SOBRIETY IN MALE TYPE 1 ALCOHOL-DEPENDENT SUBJECTS

Ulf Berggren, Kristina Berglund1, Matts Eriksson, Claudia Fahlke1,*, Olof Zachrisson and Jan Balldin

The Sahlgrenska Academy at Göteborg University, Institute of Clinical Neuroscience, Sahlgrenska University Hospital, Mölndal, SE — 431 80 Mölndal and
1 Department of Psychology, Göteborg University, PO Box 500, SE — 405 30 Göteborg, Sweden

Received 10 May 2002; in revised form 12 December 2002; accepted 10 February 2003


    ABSTRACT
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Aims: In the present study, {alpha}2-adrenoceptor function was investigated over 6 months of sobriety in eight male alcohol-dependent subjects. Methods: Subjects were investigated with repeated clonidine (CLON, 2 µg/kg body weight intravenously) challenge tests at days 1 and 7, and months 2 and 6 after the end of a period of heavy alcohol intake. CLON-induced sedation was rated at challenge tests. Mental well-being was self-reported before all challenge tests. Three challenge tests were performed at 1-week intervals in six male healthy controls. Results: Sedation was significantly lower after CLON at all time-points for the challenge tests in alcohol-dependent subjects compared with mean values for three challenge tests in controls. Three dimensions of mental well-being were negatively correlated with scores of CLON-induced sedation at month 6. Conclusions: {alpha}2-Adrenoceptor function is subnormal, as assessed by CLON-induced sedation, for at least 6 months after termination of alcohol intake. Whether this subnormal receptor function is pre-existing and possibly genetically determined or is a consequence of long-term alcohol intake must be further investigated, as should this receptor status in alcohol-dependent subjects with longer time-periods of sobriety.


    INTRODUCTION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Alcohol intake increases the central noradrenaline (NA) metabolism in humans (Ogata et al., 1971Go; Borg et al., 1983Go; Valverius et al., 1993Go). The withdrawal phase, with its signs of overactivity of the sympathetic nervous system, shows symptoms related to increased NA activity such as tremulousness, paroxysmal sweats, and increased systolic and diastolic blood pressure levels and heart rate (Linnoila et al., 1987Go). Increased central NA neurotransmission hypothetically should reduce postsynaptic {alpha}2-adrenoceptor sensitivity. Indeed, this has been confirmed in studies using the dynamic challenge test procedure of growth hormone (GH) responses to the {alpha}2-adrenoceptor agonist clonidine (CLON). Thus, several investigators have found subnormal GH responses to CLON in acute withdrawal (Matussek et al., 1984Go; Nutt et al., 1988Go; Balldin et al., 1992aGo; Fahlke et al., 1999aGo,bGo; Berggren et al., 2000Go; but see also Müller et al., 1989Go) as well as up to 6 months after termination of a period of heavy alcohol intake (Glue et al., 1989Go; Berggren et al., 2000Go). Whether such subsensitive postsynaptic {alpha}2-adrenoceptor function is a result of single or repeated episodes of heavy alcohol intake and/or withdrawal phases remains to be elucidated, as does whether this phenomenon is life-long or perhaps genetically determined.

Another procedure for assessment of {alpha}2-adrenoceptor function is analysis of cardiovascular responses to CLON. Several studies have consistently shown that the CLON-induced maximal reduction of systolic blood pressure is attenuated the first day after the end of heavy alcohol intake, but already normalized after 1 week of withdrawal (Nutt et al., 1988Go; Balldin et al., 1992aGo; Fahlke et al., 2000Go). This phenomenon is therefore suggested to be state-dependent for alcohol withdrawal.

A third procedure for the assessment of {alpha}2-adrenoceptor function is the evaluation of CLON-induced sedation. We have previously found that CLON induced similar increases in levels of sedation as in controls during the first day in withdrawal, but significantly less sedation 1 week later (Fahlke et al., 2000Go). This finding is the opposite of the usual recovery pattern in alcohol withdrawal, where there is more or less rapid normalization in different biological but also psychological parameters. Whether the subnormal capacity of CLON to increase levels of sedation at day 7 persists thereafter during a prolonged withdrawal phase, as has been found for the GH response to CLON (Berggren et al., 2000Go), is investigated in the present study. As a higher dose of CLON was used in this trial, compared with an earlier study (2.0 compared with 1.5 µg/kg body weight; Fahlke et al., 2000Go), we decided to start the investigation from the first day after the end of heavy alcohol intake and continue up to 6 months. The results of the challenge tests were, furthermore, related to self-reported aspects of mental well-being. Earlier studies, using either the Swedish Mood Adjective Check List (sMACL; Sjöberg et al., 1979Go) or the Profile of Mood States (POMS; Pollock et al., 1979Go), have demonstrated low levels in several dimensions of mental well-being in the early withdrawal phase, but a rapid improvement thereafter (Bokström et al., 1989Go, 1991Go; Ruusa et al., 2000Go). Inverse relations between aspects of mental well-being and figures for CLON/GH responses have previously been found at the end of the first week of alcohol withdrawal (Fahlke et al., 1999aGo). Aspects of psychopathology were, however, not related to results of this test procedure (Fahlke et al., 1999bGo). Neither mental well-being nor psychopathology was related to the cardiovascular responses to CLON (Fahlke et al., 2000Go).


    SUBJECTS AND METHODS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Subjects
This study was performed at a university hospital alcoholism treatment unit and was approved by the Ethics Committee of Göteborg University, Sweden. Informed consent was obtained from all subjects. Subjects were not paid for participation in the study. The study was in compliance with the 1975 Declaration of Helsinki. Eight male patients with a diagnosis of alcohol dependence according to the DSM-IV (American Psychiatric Association, 1994Go) were included in the study. They were all type 1 alcoholics according to the criteria of Cloninger et al. (1996)Go and von Knorring et al. (1985)Go. They had consumed high amounts of alcohol for a time-period prior to admission for treatment of a non-delirium withdrawal syndrome. The patients were physically and psychiatrically examined by the investigators and their medical histories recorded. After 1 week of treatment as inpatients, trained research nurses performed follow-up visits every second week. Subjects were monitored for abstinence by breath analyses of alcohol and through repeated analyses of liver function. They also underwent urine analyses for benzodiazepines and narcotic drugs. At each visit they were given non-structured psychosocial support by the research nurses, and the results of liver function analyses were discussed with the patients.

The patients, who were medicated with decreasing doses of clomethiazole and vitamins during their first week of acute alcohol withdrawal, were thereafter, in general, not permitted to use psychotropic drugs; however, four patients were given disulfiram due to high risk of relapse, and one was also medicated with citalopram for 1 month due to depressive symptoms related to a prolonged withdrawal phase. Medication was, however, always terminated at least 2 weeks before the challenge tests at months 2 and 6, respectively.

Six male volunteers from the hospital staff with a mean age of 28 (range 23–34) years were recruited as controls for the challenge tests. Based on interviews, they were all considered somatically and psychiatrically healthy. This was confirmed by normal physical status, ECG and chest X-ray, and by routine laboratory analyses, including liver function tests, with values being well within the laboratory reference ranges. All were light social alcohol consumers with a weekly consumption of < 100 g pure alcohol. They underwent three repeated CLON challenge tests at 1 week intervals. Liver function values were all below the upper reference limit prior to these three challenge tests.

CLON challenge tests
CLON challenge tests were performed the day after admittance (day 1) and after 1 week of inpatient treatment (day 7), and then after about 2 and 6 months. The CLON challenge tests were performed between 08:00 and 09:00 after overnight fasting (from 24:00). The patients were placed in a supine position and a cannula inserted into a brachial vein. Immediately before CLON administration [clonidine hydrochloride (Catapres®), 150 µg/ml; 2.0 µg/kg body weight dissolved in 10 ml of saline and slowly administered intravenously over 10 min] at time 0, blood samples were drawn for analyses of liver function [aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT); upper reference limits 0.8 µkat/l]. Systolic and diastolic blood pressure levels were measured at time 0 with a mercury sphygmomanometer.

Levels of sedation during the challenge tests were assessed at the time points 0 and every 15 min thereafter over 1 h, using a rating scale ranging from 0 to 4, with 0 indicating no sedation, 1 and 2 slight or moderate sedation, respectively, 3 fluctuating wakefulness and 4 sleep.

Psychopathology at times of the different challenge tests was assessed using the Alcohol Withdrawal Psychopathology scale (AWIP; Bokström and Balldin, 1992Go) comprising 17 items (range of total scores 0–102). Ten items in AWIP scale are identical to items in the Montgomery–Åsberg Depression Scale (MADRS; Montgomery and Åsberg, 1979Go) with scores ranging from 0 to 60. All ratings were performed by trained research nurses immediately before the start of challenge tests.

Patients also self-reported their levels of mental well-being about an hour before the start of each of the challenge tests using the Swedish Mood Adjective Check List (sMACL; Sjöberg et al., 1979Go). This checklist is designed to give a bipolar comprehensive assessment of mental well-being, and consists of 71 mood-associated adjectives, arranged in a symmetrical response format with two acceptance and two rejection categories. The patients have to decide whether the various adjectives correspond to their momentary state of mental well-being. The adjectives are subdivided into six bipolar dimensions: (1) pleasantness/unpleasantness; (2) activation/deactivation; (3) extraversion/introversion; (4) calmness/tension; (5) positive/ negative social orientation; and (6) control/lack of control. Dimensions 1, 2 and 4 are considered as basic dimensions, whereas the other dimensions are better related to social situations (Sjöberg et al., 1979Go).

The sMACL has been validated in double-blind studies (Svensson et al., 1980Go), and for replicability following intake of various quantities of alcohol (Persson et al., 1980Go). Changes in mental well-being have been found in the early (Bokström et al., 1989Go) and late (Bokström et al., 1991Go) alcohol withdrawal phases, and after medication with placebo or citalopram during alcohol consumption (Eriksson et al., 2002Go). A group of 225 normal subjects have been tested with the sMACL, making possible comparison of patient group values with those of this control group (Persson and Sjöberg, 1981Go). Patients with alcohol dependence, after 1 week of treatment for alcohol withdrawal, have been found to have levels of mental well-being similar to those of the control group (Bokström et al., 1989Go).

Statistical evaluation
Baseline scores of sedation were calculated at time 0. The scores of maximum CLON-induced sedation were defined as the differences between the highest post-injection levels and those at time 0. For controls, mean values for the three challenge tests were used in all statistical calculations. All statistical calculations were performed using the statistical programme StatView (Abacus Concepts, Inc., Berkeley, CA, USA). Between-group comparisons were performed with an unpaired t-test and within-group comparisons with a paired t-test. The Spearman rank correlation test was used to evaluate the relationship between CLON-induced maximum responses of sedation and background data, and levels of the dimensions of the sMACL.


    RESULTS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
The eight patients had a mean ± SD (range) age of 48 ± 8 (36–61) years. None reported any somatic or psychiatric disorder other than alcohol dependence, or misuse/dependence of drugs other than alcohol and nicotine. Their reported length of excessive consumption of alcohol was 13 ± 8 (6–30) years. They had used alcohol for 41 ± 69 (7–180) days prior to admission with an estimated daily consumption of 224 ± 95 (110–360) g of pure alcohol. Two patients relapsed before the challenge tests at month 6, and therefore only 30 of 32 possible challenge test results could be evaluated. Table 1Go illustrates the mean (± SD) levels for liver function parameters, blood pressure levels and scores of psychopathology prior to each challenge test.


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Table 1. Liver function tests, blood pressure, alcohol withdrawal psychopathology scores (AWIP) and depression scores (MADRS) in alcohol-dependent subjects before clonidine challenge tests
 
Levels of ALT and GGT, systolic and diastolic blood pressure, and total sums of scores of the AWIP and MADRS were significantly higher before the first (day 1) compared with the last (month 6) CLON test. Total scores of the AWIP and MADRS were significantly reduced already at day 7 compared with day 1. Levels of the six dimensions of self-reported mental well-being before each challenge test are given in Table 2Go. Compared with day 1, higher levels were reported already after 1 week in the two dimensions calmness/ tension and control/lack of control, and after 2 months in extraversion/introversion. At month 6, levels in all dimensions, with the exception of extraversion/introversion, were higher than at the start of the study. Table 3Go presents scores of baseline and CLON-induced levels of sedation at all challenge tests. Patients had significantly less CLON-induced maximum levels of sedation at all four challenge tests compared with the mean levels of three challenge tests in controls. For significance levels see Tables 1–3GoGoGo.


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Table 2. Mean ±SD values for the six dimensions of the Swedish Mood Adjective Check List (sMACL)
 

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Table 3. Clonidine (CLON)-induced sedation in alcohol-dependent subjects
 
No correlations were observed between figures obtained for CLON-induced maximum sedation at day 1 and age, length of excessive alcohol consumption or duration of last drinking episode. Estimated daily alcohol consumption during this episode was, however, found to correlate positively with levels of CLON-induced sedation (r = 0.69, P < 0.05). No correlations were observed between scores for CLON-induced sedation and levels in the six dimensions of the sMACL when analysing day 1 or 7, or month 2. At month 6, on the other hand, negative correlations were observed with the dimensions pleasantness/unpleasantness (r = –0.98, P < 0.05), activation/ deactivation (r = –0.83, P < 0.05) and calmness/tension (r = –0.88, P < 0.05).


    DISCUSSION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
In the present study, after 1 week of hospital treatment, eight male type 1 alcohol-dependent subjects were repeatedly controlled for sobriety through visits to research nurses, with breath analyses performed every second week for 6 months. Negative breath, as well as urine analyses, confirmed that patients were abstinent and drug free, as did the clinical status. Decreasing levels in liver function values and blood pressure also confirmed abstinence, although lack of statistical significance between consecutive figures could be attributed to a greater variation in figures obtained in the first part of the study. In addition, the swift decrease in psychopathology scores, seen just 1 week after the end of alcohol intake, provided indirect evidence of sobriety. This is well in line with the findings of other studies using the same rating scales (Fahlke et al., 1999bGo; Berggren et al., 2000Go). The increase in levels of mental well-being is in line with findings of other studies that used sMACL and POMS in withdrawal and recovery phases after heavy alcohol intake (Bokström et al., 1989Go, 1991Go; Fahlke et al., 1999aGo; Ruusa et al., 2000Go).

The main result of this study is that CLON-induced sedation is reduced in male alcohol-dependent patients compared with controls over a 6-month period subsequent to cessation of alcohol intake. Since similar test results, showing subnormal {alpha}2-adrenoceptor function, have been obtained by CLON/GH challenge tests (Berggren et al., 2000Go), evidence is thus provided for subnormal function in different postsynaptic {alpha}2-adrenoceptor systems, probably localized in different regions in the brain, such as the brainstem and hypothalamus (Tulen et al., 1992Go). Whether any of these dynamic test procedures is normalized during longer periods (more than 6 months) of sobriety should be investigated in further studies.

In our earlier study (Fahlke et al., 2000Go), we used a dose of CLON 25% lower than in the present study to assess the increase in sedation by CLON during the first week of withdrawal. The increase in scores of sedation obtained in that study was generally only about 50% of scores found in the present study. In contrast to the present study, no difference was observed between patients and controls at day 1 in our earlier study. On further analysis of the CLON-induced scores of sedation in both studies, at day 1 the increase in scores of sedation after CLON was 69% of the mean levels for controls in the earlier study, and 72% of mean levels for controls in the present study (the corresponding figures in the present study for the other time-points were 79, 85 and 70% at day 7, month 2 and month 6, respectively). The lack of statistical difference from controls at day 1 in our earlier study should therefore be attributed to a much greater variance of the sedative response to CLON in the controls used previously (SD = 1.6) compared with the controls in the present study (SD = 0.2). In the earlier study, the figures obtained for the increase in sedation induced by CLON at day 7 were extremely low (0.2 ± 0.4; 13% of the mean for controls). Consequently, the lower dose of CLON used in the earlier study seemed unable to increase sedation to any appreciable degree at this time-point during withdrawal. The higher dose of CLON used in the present study thus caused a more marked increase in scores of sedation, although these still remained below those for control subjects. One explanation for this different outcome at day 7 in the two studies may be that a more inert receptor setting exists at this time-point in the withdrawal phase. Using the CLON/GH challenge test procedure, different GH responses, reflecting {alpha}2-adrenoceptor function in the hypothalamus, have also been suggested to occur between days 1, 3 and 7 in the acute withdrawal phase (Balldin et al., 1992aGo). Taken together, findings from our earlier study (Fahlke et al., 2000Go) and the present study suggest subnormal {alpha}2-adrenoceptor function during the first week of withdrawal, with perhaps more inert receptor function at the end of this week. The subnormal {alpha}2-adrenoceptor function persists thereafter for at least half a year.

In this study, we also investigated whether {alpha}2-adrenoceptor function, as assessed by CLON-induced sedation, was related to different aspects of behaviour. We have previously proposed that sleep disturbance, a common and long-standing symptom in the withdrawal period, is due to changes in {alpha}2-adrenoceptor function (Fahlke et al., 2000Go). The lack of correlation to this item in both rating scales used in the present study (AWIP and MADRS) do not, however, support such a relationship. Taken together, no correlations to any of the psychopathology items, representing either withdrawal or depressive psychopathology, were found by our test procedure for {alpha}2-adrenoceptor function. The rapid decrease in total scores in these rating scales in combination with stable levels of maximum sedation scores in consecutive CLON challenge tests is further evidence for the lack of a relationship between this assessment of {alpha}2-receptor function and psychopathology. The lack of a relationship between psychopathology and other indices for {alpha}2-receptor function (GH and cardiovascular responses to CLON) has been presented previously (Fahlke et al., 1999bGo, 2000Go).

Aspects of mental well-being have been found to be related to CLON/GH responses (Fahlke et al., 1999aGo), although not to cardiovascular responses to CLON (Fahlke et al., 2000Go). These relationships were observed after only 1 week of withdrawal (day 7), but not immediately after the end of alcohol intake (day 1). Contrary to our expectations, the correlations to the dimensions pleasantness/unpleasantness and activation/ deactivation were negative, i.e. the more positive self-reports from patients in these dimensions, the more subnormal {alpha}2-adrenoceptor function, as assessed by the GH response to CLON. In the present study, correlations to the sedative responses of CLON were not observed at any of the three challenge tests performed during the first 2 months of withdrawal. However, at the end of the investigation (month 6), correlations were observed with the same dimensions of mental well-being as reported at day 7 for CLON/GH test procedures, e.g. pleasantness/unpleasantness and activation/ deactivation, but also to calmness/tension. Again, against our expectations, the correlations were negative, i.e. the more subnormal the levels of scores of maximum CLON-induced sedation, possibly reflecting postsynaptic {alpha}2-adrenoceptor function in the brainstem region (Tulen et al., 1992Go), the more positive were the self-reports from patients in these dimensions of sMACL. Several possible explanations for these negative correlations could be considered. One explanation may be that indices of presynaptic NA metabolism and release and postsynaptic function, as assessed by the procedure described in this paper, are inter-related. Some support for this explanation is given by findings in studies of both pre- and postsynaptic dopamine (DA) function in another two patient groups. Thus, a negative relationship between GH responses to the DAD2 receptor agonist apomorphine, reflecting postsynaptic DAD2 receptor function and levels of the DA metabolite homovanillic acid in the cerebrospinal fluid, reflecting presynaptic DA metabolism and release, have been found both in schizophrenics (Zemlan et al., 1985Go) and in subjects with Alzheimer-type dementia (Balldin et al., 1992bGo). The negative correlations between some dimensions of mental well-being and postsynaptic NA function seen in this study could thus alternatively be positive correlations to presynaptic NA function. Accordingly, an increase in presynaptic NA metabolism and release may thus be related to higher levels in some of the dimensions of mental well-being. Another explanation may be that earlier frequent or pronounced episodes of stress or heavy alcohol intake successively downregulate {alpha}2-adrenoceptor function. After a certain time-period the {alpha}2-adrenoceptor function is inert, with reduced ability for recovery (upregulation), or may even be permanently changed to a subnormal functional status. Whether this is the case should be investigated in further studies; e.g. in long-term (several years) sober alcohol-dependent subjects. Whether these explanations are plausible remains to be confirmed. The present study should furthermore be repeated, due to the low number of, all male, patients investigated, particularly in order to perform correlation analyses including data on mental well-being.


    ACKNOWLEDGEMENTS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
This study was supported by grants from the Swedish Alcohol Monopoly Foundation for Alcohol Research (02/3:1), the Swedish Medical Research Council (K02-21X-13447–03C), Eva and Oscar Ahréns Foundation, and Sigurd and Elsa Goljes Minne.


    FOOTNOTES
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
* Author to whom correspondence should be addressed. Back


    REFERENCES
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
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