concurrent cocaine withdrawal is associated with reduced severity of alcohol withdrawal

Concurrent Cocaine Withdrawal Is Associated With Reduced Severity of Alcohol Withdrawal

Ricardo Castaneda, Harold Lifshutz, Laurence Westreich, and Marc Galanter

The purpose of this study was to implement an empirical assessment of the clinical response to standard alcohol detoxification during withdrawal from both alcohol and cocaine. One hundred forty-nine males consecutively admitted in acute alcohol withdrawal to a hospital-based detoxification unit were studied, All subjects completed a 4-day chlordiazepoxide detoxification. Patients who used drugs other than cocaine were excluded. Fifty-five subjects wi thdrawing only from alcohol and 94 subjects wi thdrawing from both alcohol and cocaine, as evidenced by positive urinaly- sis and history, were studied. Both groups reported similar amounts of daily alcohol intake and had a similar age of onset of alcohol dependence. Parental alcoholism was equally frequent in both groups. Statis- tically, several variables were directly related to severity of alcohol withdrawal, including associated cocaine abuse, age, abnormal laboratory values, and duration of homelessness. As measured by the Alcohol With- drawal Scale (AWS), alcohol wi thdrawal was less severe among cocaine users, not only at intake but

throughout the 4-day detoxification. Singly addicted alcoholics were older and had longer drinking histories, more prior detoxifications, and more abnormal laboratory values than cocaine users. A multiple regression analysis demonstrated a significant relationship between cocaine and severity of alcohol withdrawal. Cocaine users more frequently requested reductions in chlordiazepoxide dosages than singly addicted alcoholics, complaining of dysphoria, sedation, and weakness. The severity of alcohol withdrawal was associated w i th recent cocaine use, age, laboratory abnormalities, and duration of homelessness. Concur- rent cocaine withdrawal in the sample was associated wi th reduced severity of alcohol withdrawal. Possible neurobiological mechanisms, as well as study limitations affecting interpretation of the findings, are dis- cussed. Tailored detoxification as opposed to standard detoxification regimens may be more appropriate for the clinical management of combined alcohol- cocaine withdrawal. Copyright © 1995 by W.B. Saunders Company

T O DATE, there are no empirical studies of combined alcohol and cocaine withdrawal,

a highly frequent clinical phenomenon. In one study, greater than half of withdrawing cocaine addicts also met criteria for alcohol dependence, 1 and in another study, 80% of cocaine addicts reported concurrent use of cocaine and alcohol. 2 Given the reportedly high prevalence of alcohol/cocaine use, especially in light of their contrasting pharmacological effects, the dearth of literature on the interaction of the combined withdrawal syndrome and its treatment is surprising. Without any guidelines for clinical management of simultaneous alcohol- stimulant withdrawal, patients presenting with this condition are generally treated according to established protocols for alcohol detoxification, 3 the applicability of which is uncertain in this situation.

Unlike alcohol withdrawal, 4,~ consensus on the symptomatology of cocaine withdrawal has only recently emerged, 6 and there is no empiri- cally validated justification at present for any- thing other than symptomatic treatment for the condition. A thorough explanation of the clinical phenomena underlying the neurobiology of cocaine withdrawal remains elusive. 7

Given the contrast between the clinical ef-

fects of alcohol and cocaine, it should be expected that combined withdrawal would differ from the withdrawal from each individual substance. For example, tachycardia and hyperten- sion result from the co-use of cocaine and alcohol to levels greater than would be expected from the use of either drug alone) Cardiovascu- lar evaluations of singly addicted and alcohol- abusing cocaine addicts suggest impairment of certain nervous system reflexes and possibly sinus node dysfunction. 9 Drug users often report that the depressant effects of alcohol ame- liorate the dysphoria of the cocaine "crash" when both are used together. 1° Cocaine antagonizes the anxiolytic effects of alcohol, H en- hances alcohol's ataxic effects, 12 and in one study improved ethanol-induced impairment of an arithmetic task. a3

Since alcohol withdrawal--the symptomatol-

From the Department of Psychiatry, New York University at Bellevue Hospital Center, New York, NY..

Supported in part by Grant No. BRSG S07 RR05399-28 from the Medical Research Support Grant Program, Division of Research Resources, National Institutes of Health (R. C.).

Address reprint requests to Ricardo Castaneda, M.D., Direc- tor-Inpatient Psychiatry at Bellevue Hospital, New York University Medical Center, 550 First Ave, New York, NY 10016.

Copyright © 1995 by W..B. Saunders Company 0010-440X/95/3606-0011503. 00/0

Comprehensive Psychiatry, Vol. 36, No. 6 (November/December), 1995: pp 441-447 441

442 CASTANEDA ET AL

ogy of which includes seizures, hallucinations, delirium tremens, and death--poses more seri- ous dangers than cocaine withdrawal, it seems probable that any eventual treatment guidelines for combined withdrawal will include modifica- tions of standard alcohol detoxification regimens. This study represents the first empirical assessment of the clinical response to tradi- tional alcohol detoxification among a large co- hort of males withdrawing from both alcohol and cocaine.

M E T H O D

After giving consent for the study and completing a medical and laboratory assessment, all patients were entered onto a standard alcohol detoxification protocol using chlordiazepoxide. Signs and symptoms of alcohol withdrawal were evaluated by highly experienced medical and nursing staff immediately upon admission and every 6 hours throughout the hospitalization. Individual interviews after the second day of detoxification, as well as reviews of old medical records, were performed by clinical social workers and research assistants with extensive training in addiction.

Subjects The subjects were 149 men admitted to the 25-bed

alcohol detoxification unit at Bellevue Hospital Center, a large public facility in New York City. Patients on the unit were drawn from a disadvantaged population, either resid- ing in the surrounding city area or undomiciled. Patients were generally self-referred and entered treatment for alcohol detoxification voluntarily. All subjects were assessed by a registered nurse and a physician immediately upon initial registration. All clinicians involved in patient assessment had more than 5 years of experience with addicted patients. Patients who required acute treatment for any significant medical or psychiatric conditions, including associated addictions, were excluded from the study.

Inclusion Criteria Subjects were included in the study only if, on admission

to the unit, they were found by the admitting physician to exhibit clear signs of acute alcohol withdrawal such as tremors, or elevations in pulse or blood pressure, warrant- ing an Alcohol Withdrawal Scale (AWS) 14 score of at least 4. All patients in the study met DSM-III-R criteria for alcohol dependence. Only subjects who met DSM-III-R criteria for at least cocaine abuse and also had cocaine metabolites in the urine on admission were listed as cocaine users. Other exclusionary criteria included a history of other recent substance abuse or psychosis and the presence of any other drug metabolites in the urine. All subjects gave written consent for voluntary medical detoxification and participation in the study protocol.

Detoxification Protocol All subjects were prescribed a chlordiazepoxide detoxifi-

cation regimen of 50 mg every 6 hours during the first 24

hours, 25 mg every 6 hours on day 2, 10 mg every 8 hours on day 3, and 10 mg twice daily on the fourth and last day. Dosages were omitted at the patient's request, and administration of additional medications was left to the clinical judgment of the physician. Patients were administered a daily comprehensive vitamin supplement regimen, and anal- gesics and antacids as needed.

Assessment

Assessments of signs of alcohol withdrawal were performed by a highly trained nursing team. The AWS score was calculated by totaling individual measurements of pulse rate, blood pressure, respiratory rate, tremors, diaphoresis, and restlessness, recorded at initial intake and every 6 hours thereafter throughout the entire hospital stay. Each cat- egory was rated 0 to 3; the maximum score was 18 according to an established protocol. 14 Additionally, a large battery of other serial measurements and assessments was performed.

During individual interviews, trained research assistants and clinical social workers administered a questionnairO 5 that covers sociodemographic information (ethnicity, mari- tal status, income, and employment and educational histories) and lifelong history of frequency and amount of consumption of alcohol and all other drugs. Housing history was assessed with another questionnaire adapted from Susser et al. 16

Drinking and other drug use history was obtained and included all prior hospital detoxifications, family history of alcoholism, and age at onset of dependence? 7 Age at onset of alcoholism was determined by means of a structured clinical interview. To ascertain the onset of each symptom, patients were queried on each of the criteria for alcohol dependence in the DSM-III-R. Is As in similar investiga- tions, 19 the earliest date of onset was set at the age at which patients first met minimum criteria for diagnosis.

Medical history and examination were completed at intake. Serum laboratory analysis included complete blood cell count (white blood cell [WBC], red blood cell, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentra- tion, red cell distribution width, platelets, metochlopramide, and WBC count and differential); thyroid function tests (thyrotropin, thyroxine, and total triiodothyronine); and folate, vitamin B12, and chemical profile (alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, direct bilirubin, albumin, globu- lin, sodium, potassium, chloride, CO2, urea nitrogen, creatinine, glucose, creatine, calcium, amylase, gamma-glutamyl transferase [GGT], and lactate dehydrogenase). Drugs identified by thin-layer chromatography at admission included barbiturates, benzodiazepines, cocaine metabolites, methadone, and opiates.

RESULTS

Demographics and Differences Between Singly Addicted and Cocaine-Addicted Alcoholics

O n e h u n d r e d f o r t y - n i n e m e n c o n s e c u t i v e l y

a d m i t t e d fo r a l c o h o l d e t o x i f i c a t i o n w h o m e t

c r i t e r i a f o r i n c l u s i o n w e r e s e l e c t e d fo r t h e s tudy .

CONCURRENT COCAINE AND ALCOHOL WITHDRAWAL 443

One hundred four (69.8%) were black, 29 (19.5%) Hispanic, 12 (8.1%) white, and four (2.7%) of other ethnic extractions. The study population was characterized by alcohol dependence and a generally disadvantaged and socially disaffiliated life-style. For example, 66% were single, 13% divorced, and 16% separated. With only four exceptions, the patients were unemployed (145 patients, or 97.3%). The pre- cariousness of their living situation is illustrated by the fact that during the 2 months preceding hospitalization, half (72, or 50.3%) were reportedly living on the streets, 23 (16.1%) had their own home, and 16 (11.2%) had stayed at a friend's house. Only eight (5.6%) additional patients had stayed in a shelter.

There were 94 alcoholics addicted to cocaine and 55 exclusively addicted to alcohol. Cocaine- addicted alcoholics were younger (35 _+ 6.9 v 39.8 + 9.3 years, F = 11.059, df = 1,P = .0011). No difference was found in the age at which patients in both groups initially met DSM-III-R criteria for alcohol dependence (mean, 23.7 __ 8.1 years). Singly addicted alcoholics had longer drinking histories (mean, 15.52 _+ 9.87 v 12.13 _+ 7.9 years, F = 5.28, df = 1, P = .022) and more prior hospital detoxifications for alcohol (mean, 1.9 _+ 1.7 v 1.2 +- 1.5, F = 5.14, df = 1, P = .024). Singly addicted alcoholics had significantly more frequent elevations of ALT, AST, GGT, bilirubin, and alkaline phosphatase (mean, 1.9 _+ 1.7 v 1.3 _+ 1.2, F = 5.91, df = 1, P = .01) and more frequently abnormal hemoglobin, platelet counts, and granulocyte counts (mean, 1.4 _+ 1.0 v 1.0 -+ 1.0, F = 4.78, df = 1, P < .05). No differences in self-reported alcohol intake were found between the two groups. Both groups reported daily drinking of very high amounts of alcohol, the equivalent of a quart of whisky, a gallon of wine, or three cases of beer.

The prevalence of alcoholic biological parents was similar in both groups: 66.3% had at least one alcoholic parent. Thirty-seven percent had alcoholic fathers, 13% alcoholic mothers, and 16.3% two alcoholic parents.

Factors Predicting Severity of Alcohol Withdrawal Alcohol withdrawal measurements (the AWS)

showed an easily discernible daily decrement pattern from the day of admission through the

7

w 5

~ 4 a , 3

2

e

o e

M

l k i l l . . . . . . . . A cohoio rou • ~ Singly Addicted

~ m Cocaine Abusing

Intake Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 (N-148) (N-148) (N,148) (N,145) (N-136) (N-112) {N,84)

Fig 1. A W S scores among 94 cocaine-using and 55 singly addicted alcoholics at intake and during detoxification. Signifi- cant differences between groups: intake, F = 21 .5 ,P < .01; day 1, F = 25.1, P < .01; day 2, F = 32.4, P < .01; day 3, F = 32.9, P < .01; day 4, F = 11.9, P < .01; days 5 and 6, NS.

subsequent 5 days of detoxification (Fig 1). Mean AWS scores at different stages were as follows: on admission, 5.35 +_ 1.6; first day of chlordiazepoxide detoxification, 2.0 + 1.56; and fifth day, upon cessation of detoxification, 0.25 _+ .7.

Several clinical and demographic variables were significantly correlated with severity of AWS scores on admission and throughout the 4-day detoxification. The two demographic variables were age (r = .317, N = 149, P < .0001) and duration of homelessness (measured in months) immediately preceding admission (r = .23, n = 139, P < .005).

Several abnormal laboratory values were associated with higher AWS scores in both alcoholic groups, including elevated creatinine and urea nitrogen (r = .175, N = 149, P < .05), hypergly- cemia (r = .18, N = 149, P < .05), elevated ALT, AST, and G G T (r = .182, N = 149, P < .05), abnormal thyrotropin, thyroxine, and triiodothyronine (r = .188, N = 149, P < .05), abnormally low hemoglobin (r = - .20, N = 149, P < .05), abnormal WBC (r = .24, N = 149, P < .005), mainly elevations of granulocytes (r = .243, N = 149, P < .0005) or decreased lymphocytes (r = - .28, N = 149, P < .001), and various hematological abnormalities such as decreased platelet count (r = - .174, N = 149, P < .05) and perhaps elevated mean corpuscular hemoglobin (r = .15, N = 149, P < .06).

Finally, patients with abnormally high serum concentrations of sodium (r = .22, N = 149, P < .05) and those with low potassium (r = - .20, n = 148, P < .05) also had higher AWS scores, probably reflecting electrolyte im-

444 CASTANEDA ET AL

balances associated with more severe withdrawal.

Chlordiazepoxide Detoxification and A WS

No differences in body weight were found between the two groups (mean, 166 _ 30.37 lb). A significant correlation was found between AWS score and daily dosage of chlordiazepoxide among singly addicted alcoholics (r = .37, n = 54, P < .001), but not among cocaine- addicted alcoholics. This last group received fewer 50-mg chlordiazepoxide dosages during the first day of detoxification (mean, 3.8 __..5 v 4.1 _ .97 dosages, F = 5.76, df = 1, P < .01). Both alcoholic groups received a similar number of 25- and 10-mg dosages during the second, third, and fourth days. The total amount of chlordiazepoxide administered during detoxification tended to be smaller among cocaine- addicted alcoholics (mean, 332--+ 111.27 v 305.8 _ 61.3 mg, F = 3.45, dr= 1, P < .06). Patients who requested reductions of medication complained of dysphoria and lethargy as complications of chlordiazepoxide administration.

Differences in Alcohol Withdrawal Severity Between Singly Addicted and Cocaine-Addicted Alcoholics

Cocaine-addicted alcoholics had significantly lower AWS scores than singly addicted alcoholics, not only on admission (mean AWS, 4.9 _ 1.2 v6.16 ___ 1.9, F = 23.89, df = 1,P < .00001) but also throughout the 4-day detoxification (Fig 1).

To determine whether any other variable accounted for the association between cocaine and AWS score, we conducted a multiple regression analysis with initial AWS score as the dependent variable and including, in a stepwise fashion, each of the variables that had shown an association with AWS, including age, duration of homelessness, and abnormal laboratory results. We found that the relationship between cocaine and AWS score remained significant after removing the effect of each of these other variables.

DISCUSSION

Cocaine abuse was associated with reduced severity of alcohol withdrawal at intake and throughout detoxification. This is particularly

significant given the similarities in the drinking histories of both dually and singly addicted alcoholic groups. Both reported very high amounts of daily alcohol intake and first met criteria for alcohol dependence at the same age. Although the singly addicted alcoholics were older and had longer drinking histories and more laboratory abnormalities, all variables related to severity of withdrawal, multiple regression analysis confirmed an independent relationship between cocaine and withdrawal severity.

It could be expected that combined alcohol/ cocaine withdrawal would promote an earlier presentation for treatment while alcohol withdrawal is still at the initial stage. However, both groups, singly and dually addicted alcoholics, presented similarly for treatment within a few hours of their last drink. Both groups were initially assessed at the same "phase" of alcohol withdrawal, so this explanation does not suffice.

More relevant to the discussion of the findings is the consideration that neurophysiologic phenomena associated with cocaine withdrawal oppose some of the manifestations of alcohol withdrawal assessed in this study. Withdrawal from stimulants may reduce some aspects of simultaneous sedative withdrawal. Clinically at least, some symptoms of cocaine withdrawal stand in contrast to those of alcohol withdrawal. According to DSM-IV, cocaine withdrawal includes psychomotor retardation, fatigue, sleep disorders, increased appetite, depressed mood, and occasional agitation. 6 Alcohol withdrawal, on the other hand, is characterized by three main components, which patients experience with varying and unpredictable degrees of inten- sity. The major component is autonomic nervous system hyperactivity, accounting for tachycardia, high blood pressure, tremors, diaphoresis, and restlessness. A second component, neuronal excitation, is associated with generalized tonic clonic seizures, and the third, distortions of perception, sensation, and arousal, may account for illusions, hallucinosis, insom- nia, and delirium. 3 Most of the withdrawal symptoms reflected in AWS scores in this study are associated with the first component, autonomic hyperactivity. In fact, only two patients had hallucinosis and only one patient had seizures. The neurobiology of this component has been partially elucidated. Alcohol withdrawal is


characterized by increased catecholamine activity. 2°-23 Levels of the main norepinephrine me- tabolite, 3-methoxy-4 hydroxyphenylethyl glycol, correlate with symptoms of the first component of alcohol withdrawal, including degree of autonomic hyperactivity, 21 diastolic blood pressure, tremor, anorexia, and diaphoresis. 24 Increased CNS norepinephrine turnover probably accounts for most of the symptomatology during alcohol withdrawal and detoxification. 25 Interestingly, preclinical studies suggest that disturbances in catecholamine metabolism may also contribute to the neurobiology of cocaine withdrawal symptomatology. 26 Cocaine potently blocks norepinephrine synaptic uptake. 27 Recently, a study has demonstrated that dopamine responsivity is higher during early cocaine abstinence than during later abstinence, suggesting a state of dopamine depletion following continued cocaine use. 28 Positron- emission tomographic studies have also demonstrated reversible reductions of postsynaptic dopamine receptor availability within 1 week of cessation of sustained cocaine intoxication. 29 These findings support the dopamine-depletion hypothesis of cocaine addiction proposed by Dackis and Gold, 3° which suggests that chronic blockade of catecholamine reuptake leads to a depletion of presynaptic dopamine stores. Such a catecholaminergic depletion may contribute to the anhedonia and depression seen during cocaine withdrawal. Adrenergic dysregulation in early cocaine abstinence has recently been reported. 31 Cocaine-induced depletion of other catecholaminergic neurons results in central dopaminergic, a-adrenergic, and 13-adrenergic receptor supersensitivity? 2 In dually addicted alcoholics, sustained cocaine use may induce a parallel reduction in presynaptic adrenergic availability, which may decrease the adrenergic hyperactivity otherwise seen following onset of alcohol withdrawal.

A multiple regression analysis confirmed an independent relationship between cocaine and severity of withdrawal. However, the reduced alcohol withdrawal in cocaine addicts could conceivably be explained by the older age, longer drinking histories, and larger number of prior alcohol detoxifications that differentiated singly addicted from dually addicted alcoholics. With the exception of previous detoxifications,

all of these variables were significantly correlated with alcohol withdrawal severity. Adrener- gic responsivity has been reported to increase with age in both normal people 33 and alcoholics in withdrawal.34 Such increased adrenergic activity in older alcoholics could be expected to correlate with alcohol severity. The possible effects on the study results of an underesti- mated number of previous detoxifications among singly addicted alcoholics need to be noted. Indeed, alcohol withdrawal increases in severity with each subsequent episode of detoxification, possibly through "kindling," a phenomenon associated with progressively larger neuronal recruitment and "sensitization. ''35

Abnormal laboratory values were associated with increased alcohol withdrawal severity. Sin- gly addicted alcoholics had more abnormal laboratory values than cocaine users. Although both groups reported similar drinking habits and became alcoholic at a similar age, singly addicted subjects had been drinking for 5 more years. However, the length of drinking history bore no relation to the likelihood of abnormal laboratory findings. Although we did not con- trol for specific illnesses in this study, the relationship between alcohol withdrawal and other medical disorders clearly warrants further research attention. Nonetheless, coexisting medical problems may herald more severe alcohol withdrawal and may constitute an indication for inpatient detoxification. 3

Duration of homelessness was also directly related to withdrawal severity. Homeless subjects were not more likely to have abnormal laboratory values than domiciled subjects, but in our highly disadvantaged study population, housing instability is more the rule than the exception. Stressful living situations during epi- sodes of homelessness may specifically contribute to the severity of withdrawal. Differences in drinking practices, including the type and qual- ity of alcoholic beverages consumed, between homeless and domiciled populations might have contributed to this finding and warrant further study.

Cocaine addicts received less chlordiazepoxide than singly addicted alcoholics. This oc- curred not because the latter were prescribed higher medication dosages, but because cocaine users, despite the fact that they were experienc-

446 CASTANEDA ET AL

ing CNS depressant withdrawal, occasionally rejected sedative administration. Often, while still experiencing tremors, their request to decrease chlordiazepoxide dosages was coupled with complaints of aggravated sedation, depressed mood, and weakness. Tailored detoxification, as opposed to standard detoxification, regimens may be more appropriate for the clinical management of dual cocaine-alcohol withdrawal.

Several limitations in the study design warrant clarification. Assessments of alcohol withdrawal were performed by a team of physicians and nurses who, although highly experienced, based their assessments on individual clinical observations whose contributions to variances in the data cannot be ascertained. The AWS, as a tool for assessment of alcohol withdrawal severity, allowed quantification of most withdrawal symptoms associated with increased autonomic activity. However, other symptoms of withdrawal such as illusions and hallucinosis were not recorded. Additional assessment instru- ments for alcohol withdrawal, such as the Clini- cal Institute Withdrawal Assessment for Alco- hol revised 36 scale, in future studies may clarify these issues. Additionally, although self-report of alcoholic behaviors has been regarded as a reliable research tool, 37 data obtained through direct interviews should be interpreted with caution. This is particularly relevant given the social and ethnic characteristics of the sample, who were mostly black and Hispanic, nonpsy- chotic, socially disenfranchised, often homeless, and severely alcoholic men. The phenomenol- ogy associated with the psychoactive substance

use practices among inner-city residents de- scribed here may not be applicable to other demographic groups. The generalizability of our findings to other alcoholic populations is further affected by reports in the literature of ethnic differences in the severity of with- drawa138,39 and in the veracity of self-report of symptoms and behavior. 4°

The method used for urinary drug screening (thin-layer chromatography) does not allow for identification of certain psychoactive substances such as lysergic acid (LSD), ethchlorvynol, phen- cyclidine (PCP), and methaqualone, which, although rarely used by this population, can influence the clinical course of alcohol withdrawal. Only replication studies including more sensitive screening methods would clarify the relevance of these other substances.

Finally, since we gathered these data, DSM-IV has replaced DSM-III-R. We reviewed our data and found that all patients meet both DSM- III-R and DSM-IV criteria for alcohol dependence. The stability of our patients' diagnoses under evolving diagnostic rubrics was due to the profound and obvious nature of their substance use disorders.

Further research is needed to corroborate and clarify our findings, particularly neurobiological studies of the catecholaminergic events associated with combined withdrawal from seda- tives and stimulants.

ACKNOWLEDGMENT

Murray Alpert, Ph.D., and Enrique R. Pujet, NYU- Milhauser Laboratories, provided statistical analysis.

REFERENCES

1. Miller NS, Summers GL, Gold MS. Cocaine dependence: alcohol and other drug dependence and withdrawal characteristics. J Addictive Dis 1993;12:25-35.

2. Miller NS, Gold MS. Cocaine and alcoholism: distinct of part of a spectrum. Psych Ann 1988;18:538-539.

3. Castaneda R, Cushman P Jr. Alcohol withdrawal: a review of clinical management. J Clin Psychiatry 1989;50:278- 283.

4. Victor M, Adams RD. The effects of alcohol on the nervous system. Res Publ Assoc Res Nerv Ment Dis 1953;32:526-573.

5. Nutt D J, Glue P. Neuropharmacological and clinical aspects of alcohol withdrawal. Ann Med 1990;22:275-281.

6. American Psychiatric Association. Diagnostic and Sta- tistical Manual of Mental Disorders. Ed. 4. Washington, DC: American Psychiatric, 1994.

7. Gawin FH, Kleber HD. Abstinence symptomatology and psychiatric diagnosis in cocaine abusers. Arch Gen Psychiatry 1986;43:107-113.

8. Perez-Reyes M, Jeffcoat AR. Ethanol/cocaine interaction: cocaine and cocaethylene plasma concentrations and their relationship to subjective cardiovascular effects. Life Sci 1992;51:553-564.

9. Moskowitz RM, Errichetti AJ. Cardiovascular evalua- tion after withdrawal from chronic alcohol or cocaine- alcohol abuse. J Addictive Dis 1991;10:47-65.

10. Miller NS, Summers GL, Gold MS. Cocaine dependence: alcohol and other drug dependence and withdrawal characteristics. J Addictive Dis 1993;12:25-35.

11. Aston-Jones S, Aston-Jones G, Koob G. Cocaine antagonizes the anxiolytic effects of alcohol. Psychopharma- cology (Berlin) 1984;84:28-31.


12. Jatlow P, Hearn WL, Elsworth JD, Roth RH, Brad- berry CW, Taylor JR. Cocaethylene inhibits uptake of dopamine and can reach high concentrations following combined cocaine and ethanol use. Natl Inst Drug Abuse Res Monogr Ser, 1990;105:572-573.

13. Farre M, Llorente M, Ungea B, Cami J. Interactions of cocaine with alcohol. Natl Inst Drug Abuse Res Monogr Ser 1990;105:570-571.

14. Cushman P Jr, Forbes R, Lerner W, Stewart M. Alcohol withdrawal syndromes: clinical management with lofexidine. Alcohol Clin Exp Res 1985;9:103-108.

15. Herman M, Galanter M, Lifshutz H. Combined substance abuse and psychiatric disorders in homeless and domiciled patients. Am J Drug Alcohol Abuse 1991;17:415- 422.

16. Susser E, Struening EL, Conover S. Psychiatric problems in homeless men. Lifetime psychosis and substance abuse, current distress in new arrivals at NYC shelters. Arch Gen Psychiatry 1989;46:845-850.

17. Castaneda R, Lifshutz H, Galanter M, Franco H. Age at onset of alcoholism as a predictor of homelessness and drinking severity. J Addictive Dis 1993;12:65-77.

18. American Psychiatric Association Work Group to Revise DSM-III. Diagnostic and Statistical Manual of Mental Disorders. Ed. 3. Rev. Washington, DC: American Psychiatric, 1987.

19. Irwin M, Schuckit M, Smith TL. Clinical importance of age at onset in type 1 and type 2 primary alcoholics. Arch Gen Psychiatry 1990;47:320-324.

20. Ogata M, Mendelson JH, Mello NK, Majchroxicz E. Adrenal function and alcoholism. Psychosom Med 1971;33: 159-180.

21. Fujimoto A, Nagao T, Ebara T, Sato M, Otsuki S. Cerebral spinal fluid monoamine metabolites during alcohol withdrawal syndrome and recovered state. Biochem Psychiatry 1983;18:1141-1146.

22. Borg S, Kvande H, Mossberg D, Svendall G. Central nervous system noradrenaline metabolism and alcohol consumption in man. Pharmacol Biochem Behav 1983;18:335- 337.

23. Borg S, Czamecka A, Kvande H, Mossberg D, Sedvall G. Clinical conditions and concentrations of MOPEG in the cerebrospinal fluid of male alcoholic patients during withdrawal. Alcohol Clin Exp Res 1985;9:103-108.

24. Hawley JR, Major LF, Schulman EA, Linnoila M. Cerebrospinal fluid 2-methoxy-4 hydroxyphenyleneglycol and norepinephrine levels in alcohol withdrawal. Correla- tions with clinical signs. Arch Gen Psychiatry 1987;42:1056- 1062.

25. Linnoila M, Mefford I, Nutt D, Adinoff B. Alcohol withdrawal and noradrenergic function. Ann Intern Med 1987;107:875-889.

26. Gawin FH, Ellinwood EH Jr. Cocaine and other stimulants: actions, abuse, and treatment. N Engl J Med 1988;318:1173-1182.

27. Hoffman BB, Lefkowitz RJ. Catecholamines and drug abuse. In: Gilman AG, Rail TW, Nies AS, Taylor P (eds): Goodman and Gilman's The Pharmacological Basis of Therapeutics (ed 8). New York, NY: Pergamon, 1990:187- 220.

28. McDougle C J, Price LH, Palumbo JM, Kosten TR, Heninger GR, Kleber HD. Dopaminergic responsivity during cocaine abstinence: a pilot study. Psychiatr Res 1994;43: 77-85.

29. Volkow VD, Fowler JS, Wolf AP, Schyler D, Shiue C-Y, Alpert R, et al. Effects of chronic cocaine abuse on postsynaptic dopamine receptors. Am J Psychiatry 1990;147: 719-724.

30. Dackis CA, Gold MS. New concepts in cocaine addiction: the dopamine depletion hypothesis. Neurosci Biobehav Rev 1987;9:469-477.

31. McDougle CJ, Black JE, Malison RT, Zimmermann RC, Kosten TR, Heninger GR, et al. Noradrenergic dysregulation during discontinuation of cocaine use in addicts. Arch Gen Psychiatry 1994;51:713-719.

32. Callahan PM, Appel JB, Cunningham KA. Dopa- mine D1 and D2 mediation of the discriminative stimulus properties of D-amphetamine and cocaine. Psychopharma- cology (Berlin) 1991;103:50-55.

33. Halbreich U, Sharpless N, Asnis GM. Afternoon continuous plasma levels of 3-methoxy-4 hydroxy phenyl- ethyl glycol and age. Arch Gen Psychiatry 1987;44:804-812.

34. Halbreich U, Castaneda R, Galanter M, Mandola R, Sharpless N. Plasma MHPG and age in detoxified alcoholics. Biol Psychiatry 1990;27:626-630.

35. Ballenger JC, Post RM. Kindling as a model for the alcohol withdrawal syndromes. Br J Psychiatry 1978;133:1- 14.

36. Sellers EM, Sullivan JT, Somer G, Skyora K. Charac- terization of DSM-III-R criteria for uncomplicated alcohol withdrawal provides an empirical basis for DSM-IV. Arch Gen Psychiatry 1991 ;48:442-447.

37. Sobell LC. Reliability of alcohol abusers' self-reports of drinking behavior. Behav Res Ther 1979;17:157-160.

38. Castaneda R, Galanter M. Ethnic differences in drinking practices and cognitive impairment among detoxi- fying alcoholics. J Stud Alcohol 1988;49:335-339.

39. Fernandez-Pol B, Bluestone H, Missouri C, Morales G, Mizruchi MS. Drinking patterns of inner-city black Americans and Puerto Ricans. J Stud Alcohol 1986;47:156- 160.

40. Alcocer AM. Alcohol use and abuse among the Hispanic American population. In: National Institute of Alcohol Abuse and Alcoholsim (ed): Special Population Issues. Alcohol and Health Monograph No. 4. DHHS Publication No. (ADM) 82-1193. Washington, DC: Govern- ment Printing Office, 1982:361-382.

concurrent cocaine withdrawal is associated with reduced severity of alcohol withdrawal

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