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PAIN MEDICINE

Intrathecal and Oral Clonidine as Prophylaxis for Postoperative Alcohol Withdrawal Syndrome: A Randomized Double-Blinded Study

I. Dobrydnjov, MD^*, K. Axelsson, MD PhD^*, L. Berggren, MD PhD^*, J. Samarütel, MD PhD, and B. Holmström, MD PhD^*

*Departments of Anesthesiology and Intensive Care, Örebro University Hospital, Örebro, Sweden; and Tartu University Hospital, Tartu, Estonia

Address correspondence and reprint requests to I. Dobrydnjov, Department of Anesthesiology and Intensive Care, University Hospital, SE 701 85 Örebro, Sweden. Address e-mail to igor.dobrydnjov{at}orebroll.se

	Abstract

Top Abstract Introduction Methods Results Discussion Appendix 1. References

 
In this study, we evaluated the effect of intrathecal and oral clonidine as supplements to spinal anesthesia with lidocaine in patients at risk of postoperative alcohol withdrawal syndrome (AWS). We hypothesized that clonidine would have a prophylactic effect on postoperative AWS. Forty-five alcohol-dependent patients (daily ethanol intake >60 g) scheduled for transurethral resection of the prostate were double-blindly randomized into three groups. All patients received hyperbaric lidocaine 100 mg intrathecally. The diazepam group (DiazG) was premedicated with diazepam 10 mg orally; the intrathecal clonidine group (Clon^i/tG) received a placebo (saline) tablet and clonidine 150 µg intrathecally; and the oral clonidine group (Clon^p/oG) received clonidine 150 µg orally. For patients diagnosed with AWS, the Clinical Institute Withdrawal Assessment for Alcohol, revised scale, was used. Twelve patients in the DiazG had symptoms of AWS, compared with two in the Clon^i/tG and one in the Clon^p/oG. The median Clinical Institute Withdrawal Assessment for Alcohol, revised scale, score was 12 in the DiazG versus 1 in the clonidine-treated groups. Two patients in the DiazG had severe delirium. Patients receiving oral clonidine had a slightly decreased mean arterial blood pressure 6–12 h after spinal anesthesia (P < 0.05); patients in the DiazG had a hyperdynamic circulatory reaction 24–72 h after surgery. In conclusion, preoperative clonidine 150 µg, intrathecally or orally, prevented significant postoperative AWS in ethanol-dependent patients.

IMPLICATIONS: In this randomized, double-blinded study, clonidine 150 µg both intrathecally and orally prevented postoperative alcohol-withdrawal symptoms in alcohol-dependent men. The effect was superior to that with a single dose of diazepam 10 mg orally.

	Introduction

Top Abstract Introduction Methods Results Discussion Appendix 1. References

 
Postoperative alcohol withdrawal is a severe problem among alcohol-dependent patients. Acute withdrawal may induce an increase in the plasma levels of epinephrine and norepinephrine (1,2), resulting in vasoconstriction, increased oxygen consumption (3), tachypnea, and increased work in breathing. Alcohol withdrawal syndrome (AWS) can proceed to delirium tremens. These patients frequently do not respond adequately even to large doses of benzodiazepines or opioids (4,5). Several studies have demonstrated that patients with excessive alcohol consumption are at greater risk of developing postoperative complications resulting in prolonged hospitalization (6–8). Routine pharmacological therapy is based on the combination of benzodiazepine, chlormethiazole, haloperidol, and clonidine, but the optimum treatment has not been determined. ₂-Adrenergic agonists have been notably effective in the treatment of AWS (9). However, the precise mechanism of clonidine action remains to be elucidated. Preemptive therapy for postoperative AWS has not been studied in detail, and we have not found any study about the prophylactic effect of ₂-adrenergic agonists intrathecally in the perioperative setting. The hypothesis in this study was that a single preoperative dose of oral or intrathecal clonidine would have a prophylactic effect in terms of preventing postoperative AWS as compared with a single dose of diazepam.

	Methods

Top Abstract Introduction Methods Results Discussion Appendix 1. References

 
After IRB approval and informed verbal and written consent, 45 alcohol-dependent men with a daily alcohol intake of >60 g of pure ethanol who were undergoing transurethral prostatectomy were studied in a randomized, controlled, double-blinded trial. Daily alcohol intake was evaluated by a standardized interview protocol. The assumption of alcohol abuse and the subsequent risk of AWS were considered to be confirmed by a history of an average intake of >60 g of ethanol per day. Exclusion criteria were any signs of AWS before surgery, known allergy to clonidine or to lidocaine, concomitant consumption of clonidine or benzodiazepines, sinus bradycardia (<50 bpm), severe cardiac (ejection fraction <35%) or hepatic (transaminase aspartate aminotransferase and/or alanine aminotransferase 5 times the upper limit of normal or bilirubin >50 mmol/L) dysfunction, and contraindications for spinal anesthesia. After verbal and written informed consent, patients were randomly allocated to one of three treatment groups in a double-blinded manner by using sealed envelopes.

One anesthesiologist who was not involved in the study prepared the mixture of study drugs and tablets according to the randomization procedure. Another anesthesiologist, who was blinded to the premedication and to the spinal anesthetic, performed and evaluated the intrathecal anesthesia. All patients received identically designed study tablets (clonidine, diazepam, or placebo) as premedication 60 min before the spinal block. The lumbar puncture was performed at the L3-4 interspace with a 26-gauge Quincke spinal needle with the patient in a sitting position. The following drug combinations were administered: patients in the diazepam group (DiazG) received 2 mL of 5% hyperbaric lidocaine intrathecally and 10 mg of diazepam orally as premedication; patients in the intrathecal clonidine group (Clon^i/tG) received 2 mL of 5% lidocaine and 150 µg of clonidine intrathecally and a placebo tablet (saline) as premedication; and patients in the oral clonidine group (Clon^p/oG) received 2 mL of 5% lidocaine intrathecally and clonidine 150 µg orally as premedication. In the DiazG and the Clon^p/oG, the intrathecal lidocaine solution was diluted with saline to the same volume as in the Clon^i/tG (3.0 mL).

Repeated doses of ephedrine 5 mg were given IV when indicated to treat hypotension (systolic blood pressure reduced by >20%). Bradycardia (heart rate (HR) <50 bpm) was treated with atropine 0.5 mg IV. Except for the premedication, no sedatives were administered during or after surgery. Morphine IV on demand was used to achieve a postoperative pain intensity 3 on a 10-cm visual analog scale. The following variables were recorded during the 72-h test period (1, 3, 6, 12, 24, 48, and 72 h after spinal injection): AWS criteria (see below); level of sedation according to the Ramsay scale (1, anxious and agitated or restless; 2, cooperative, oriented, and tranquil; 3, responding to command only; 4, brisk response; 5, sluggish response; 6, no response) (10); HR; mean arterial blood pressure (MAP); rate pressure product (RPP; systolic blood pressure x HR) (11); ventilatory frequency; oxygen saturation; and body temperature.

The diagnosis of AWS was made according to the criteria of the 4th edition of the Diagnostic and Statistical Manual (DSM) of Mental Disorders. The patient was considered to have AWS if at least two of the following symptoms were present: autonomic hyperactivity (e.g., sweating or a pulse rate >100 bpm); increased hand tremor; insomnia; nausea or vomiting; transient visual, tactile, or auditory hallucinations or illusions; psychomotor agitation; anxiety; or grand mal seizures.

The AWS diagnosis was confirmed by an independent neurologist who was unaware of the group assignment. For those diagnosed with AWS, the Clinical Institute Withdrawal Assessment for Alcohol, revised scale (CIWA-Ar) (12) was used four times daily to obtain a quantitative assessment of the intensity of the different symptoms (Appendix 1). A CIWA-Ar score 15 was regarded as indicating mild withdrawal, 16–20 as moderate withdrawal, and >20 as severe withdrawal.

Power analysis was based on the assumption that it would be of interest to detect differences in the frequency of postoperative AWS (the primary end-point) between the DiazG and the clonidine treatment groups. Assuming an error of 0.05 and a ß error of 0.8 (power of 80%), 15 patients would be adequate for detecting the difference that was of interest (a decrease in the incidence of AWS from 50% to 10%). This is based on power calculation from a two-group analysis. Power calculation for >2 groups is more complex, but in the literature it has been reported that a similar number of patients as in a 2-group analysis should be added for each extra group studied, i.e., 3 groups = 45 patients (13). Unless otherwise stated, results are expressed as means ± SD, median (range), or n (%). All normally distributed continuous variables were analyzed by one-way analysis of variance or analysis of covariance with the factor treatment. Group means of interest were tested by using Tukey’s test. The nonparametric data for the three groups were assessed with the Kruskal-Wallis test. If there were significant differences, the analysis was continued with post hoc comparisons of differences between pairs of groups by using the Mann-Whitney U-test. Nominal categorical data for study groups were tested by a ² test. A P value <0.05 was considered to be statistically significant.

	Results

Top Abstract Introduction Methods Results Discussion Appendix 1. References

 
Age, weight, and ASA classification were comparable among groups (Table 1). Patients in the Clon^i/tG and the Clon^p/oG had significantly less frequent postoperative AWS as compared with the DiazG (Table 2). Fifteen patients in our study developed postoperative AWS. Twelve patients in the DiazG (80%) and 3 in the clonidine-treated groups (2 patients [13%] in the Clon^i/tG and 1 patient [7%] in the Clon^p/oG) developed AWS (P < 0.002). The median CIWA-Ar score for patients in the DiazG was 12, and it was 1 in each of the clonidine-treated groups (P < 0.002). In the DiazG, 2 patients had severe AWS, and 10 patients had mild or moderate AWS. Two patients had mild AWS after intrathecal clonidine. One patient had moderate AWS after oral clonidine. Anxiety, agitation, and headache were significantly more frequent in the DiazG as compared with the clonidine groups. Oral clonidine also significantly decreased the frequency of postoperative nausea and vomiting and paroxysmal sweating compared with the DiazG.

There were no significant differences among the three groups in the incidence of agitation/restlessness during the first 24 h when this was evaluated with the Ramsay score. During the next 24 h, agitation and restlessness were recorded in 6 patients in the DiazG as compared with 3 patients (not significant) in the Clon^i/tG and 1 patient (P < 0.05) in the Clon^p/oG. Only 1 patient (P < 0.05) in each clonidine-treated group had agitation and restlessness 72 h after surgery as compared with 6 patients in the DiazG.

Changes in HR or MAP during the 72 h after spinal injection are shown in Figure 1. Because of individual variability in MAP and HR, the differences (MAP and HR) between the preoperative baseline values and the measured values were calculated. Both the oral and intrathecal clonidine-treated groups had a significant decrease in HR compared with the initial value during the first 1 and 3 h, respectively (P < 0.05). One patient in the Clon^p/oG required atropine perioperatively because of bradycardia. A significantly increased HR was recorded in the Clon^p/oG 24 h after spinal injection and in the DiazG 24–72 h after surgery as compared with the initial value (P < 0.05).

View larger version (31K): [in this window] [in a new window]   Figure 1. Change in heart rate (HR) and in mean arterial blood pressure (MAP) from baseline for 72 h after surgery. Data are mean ± SEM. DiazG = diazepam 10 mg orally; Cloni/tG = clonidine 150 µg intrathecally; Clonp/oG = clonidine 150 µg orally. *P < 0.05 versus the initial HR or MAP value.

View larger version (37K): [in this window] [in a new window]   Figure 2. Evolution of the changes in rate pressure product (RPP) (systolic blood pressure x heart rate) for 72 h. Data are mean ± SEM. DiazG = diazepam 10 mg orally; Cloni/tG = clonidine 150 µg intrathecally; Clonp/oG = clonidine 150 µg orally. *Significant difference between the DiazG and the Clonp/oG; **significant difference between the DiazG and clonidine groups (Clonp/oG and Cloni/tG); ***significant difference between Cloni/tG and Clonp/oG.

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix 1. References

 
In this double-blinded, randomized, placebo-controlled study prophylactic preoperative treatment with intrathecal or oral clonidine resulted in a significant reduction of postoperative AWS symptoms in alcohol-dependent men. The clonidine effect was superior to that of a single dose of oral diazepam, because the frequency of AWS and AWS-related symptoms was reduced from 80% in the group treated with diazepam to 7%–13% in the clonidine-treated groups. The incidence of AWS-related symptoms in our DiazG was substantially more frequent than previously reported (14,15). The dose of diazepam 10 mg is not regarded as dose equivalent to 150 µg of clonidine. Diazepam 5–10 mg (14) is the routine premedication at our institution to prevent postoperative AWS. Moreover, the long-acting benzodiazepine diazepam has active metabolites that offer a tapering effect and often preclude additional dosing.

The more frequent rate of AWS might be explained by a larger intake of ethanol in our study population than that reported in previous studies. The symptoms of AWS are thought to be dose dependent; i.e., the larger the amount of alcohol consumed, the more severe the manifestations of withdrawal (16). The inclusion criterion in our study was an agreed-upon daily intake of >60 g of pure ethanol. However, only a minority of the patients agreed to give more precise data concerning their daily ethanol consumption. The largest reported intake in our study was as much as 1000 mL of vodka daily, corresponding to 400 g of pure ethanol. Clinically, all patients were considered to be heavy social alcohol abusers.

Another explanation might be that the DSM criteria for AWS are not specifically applicable to the postoperative setting. Symptoms such as postoperative nausea and vomiting, anxiety, clouding of the sensorium, and headache might be related in part to the ordinary postoperative course, especially after spinal anesthesia. Further, the CIWA-Ar instrument was not intentionally developed for evaluating postoperative AWS. However, no other documented scoring instrument is available for this purpose (12). There is an obvious need for an instrument specifically designed for evaluating postoperative AWS. In our study, an experienced neurologist evaluated and classified all patients; this might decrease errors in evaluation. For a CIWA-Ar score >10, chlordiazepoxide 50 mg was given IV; thiamine 100 mg IM and diazepam 5 mg IV were given as needed for agitation. Phenobarbital was used to treat severe delirium in one patient.

Chronic alcohol consumption causes downregulation of gamma-aminobutyric acid receptors, resulting in decreased sensibility to benzodiazepines and cross-tolerance between ethanol and benzodiazepines (17). This might explain the relative tolerance to benzodiazepines in our alcohol-dependent patients (i.e., diazepam 10 mg orally does not seem to be a large-enough dose to affect AWS-related symptoms).

Bohrer et al. (18) found that clonidine has sedative-sparing effects that improve the quality of sedation in patients with AWS. During alcohol withdrawal, clonidine reduces increased concentrations of both central and peripheral norepinephrine, as well as its major metabolites (19). Despite the sedative effect of clonidine, the use of a single dose of clonidine 150 µg orally or intrathecally did not produce any clinically important oversedation, as documented by the Ramsay score. On the contrary, in patients at high risk of postoperative AWS, the anxiolytic effect of clonidine 150 µg orally seems to predominate in comparison to the sedative effect. This sedative effect occurred in a few patients only during the first three hours after spinal injection.

In our study, clonidine administered both orally and intrathecally had prophylactic effects on AWS during the 72-hour test period, despite the fact that clonidine has an elimination half-life of approximately 8 hours. Tonnesen et al. (20) showed that alcohol abusers, as compared with nonabusers, have an enhanced stress response to surgical trauma that is characterized by a triple peak concentration of adrenaline, noradrenaline, and cortisol in plasma. This is due to increased sympathetic nervous system activity during alcohol withdrawal in combination with increased ₂-adrenergic receptor sensitivity. In an earlier study (21), we reported that a single preoperative dose of clonidine, either orally or intrathecally, significantly decreased the intensity of postoperative pain during the first 24 h. Moreover, systemic clonidine (injected systemically or redistributed from cerebrospinal fluid) exerts its action mainly in the locus ceruleus via stimulation of ₂-adrenergic receptors and opiate receptors, resulting in anxiolysis and sedation. These anxiolytic and sedative effects in conjunction with a better quality of analgesia might inhibit additional release of stress hormones and suppress delirium trigger factors during the first postoperative hours. Suppressing development of AWS prophylactically before, during, and immediately after surgery seems to be a rational approach, because AWS usually develops rapidly, within 6–36 hours of alcohol abstinence (16).

Oral clonidine is absorbed rapidly and almost completely and reaches a peak plasma level within 60 to 90 minutes. Intrathecal clonidine, because of its high lipid solubility, crosses tissue barriers rapidly and therefore also has systemic effects (22,23). Thus, both oral and intrathecal clonidine seem to have similar systemic effects, which may explain why the incidence of AWS did not differ significantly between the clonidine groups. The oral administration of clonidine to prevent postoperative delirium seems to be a more rational approach. It is a simple technique that might be suitable in different surgical settings, and it also has a tendency to give a more pronounced sedation compared with intrathecal clonidine.

The predominant cardiovascular effects of ₂-adrenoceptor agonists are hypotension and bradycardia. These effects are also mediated by a central sympatholytic effect via inhibition of efferent sympathetic neurons in the locus ceruleus. However, in our study, the circulatory effects of both intrathecal and oral clonidine administration were small. There was a slight reduction in MAP after oral clonidine, but not after intrathecal clonidine. However, further studies are warranted to determine whether there is a difference in effect in this respect. In contrast to the clonidine groups, the benzodiazepine group showed a slight hyperdynamic reaction from 48 to 72 hours after surgery, in parallel with the increased frequency of AWS. The RPP is a surrogate end-point of myocardial demand, and the combination of a rapid HR and a high systolic blood pressure suggests a high level of myocardial oxygen consumption. Heavy chronic abusers frequently have cardiac symptoms as well, such as angina pain, fatigue, breathlessness, and cough (24). The incidence of cardiomyopathy attributed to alcohol is frequent in heavy abusers (41.9%) (25). The safe level of RPP is 12,000 min/mm Hg, and an increased RPP reflects a high myocardial oxygen demand. In the DiazG, the mean RPP 48 h after spinal injection was increased to more than 12,000, and 5 of 15 patients in this group exceeded this limit; 3 patients in this group had a RPP ranging from 16,428 to 19,394. Only one patient in the clonidine-treated groups had a slightly increased RPP (12,441). It is probable that clonidine decreases postoperative cardiac stress in alcohol-dependent patients. However, the number of patients in our study was small. There is a need for future dose-dependent studies of diazepam and clonidine, using more precise methods, in alcohol-dependent patients. Even though oral administration of clonidine seems to be more suitable for use in alcohol-dependent patients, because it is a simple technique and is useful in different surgical settings, this study demonstrates that oral administration also leads to more pronounced sedation in comparison with intrathecal clonidine.

In conclusion, our findings suggest that clonidine administered intrathecally or orally is superior to a moderate dose of oral diazepam in preventing postoperative AWS, or withdrawal-related symptoms, in ethanol-dependent men undergoing prostatectomy.

	Appendix 1.

Top Abstract Introduction Methods Results Discussion Appendix 1. References

 

	Acknowledgments

We wish to thank Anders Magnusson, BSc, Center of Clinical Research, Örebro University Hospital, for helpful suggestions concerning statistical analysis of the data.

	References

Top Abstract Introduction Methods Results Discussion Appendix 1. References

 

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999