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Alcohol abuse, substance abuse, and panic disorder
Alcohol Abuse, Substance Abuse, and Panic Disorder DEBORAH
S. COWLEY, M.D., Seattle,
Washington
The purpose of this article is to review the literature concerning the interaction of alcohol and/or substance abuse with panic disorder, the comorbidity of these disorders, possible causal relationships, biologic relationships, and the recognition and treatment of dually disordered patients. A number of studies suggest significant comorbidity between panic disorder and alcoholism or abuse of drugs, especially cocaine and sedatives. Panic may lead to drinking or sedative use and also result from prolonged use or withdrawal of alcohol or other drugs. Possible biologic relationships involve the y-aminobutyric acid (GABA)benzodiazepine receptor complex and the central noradrenergic system. Although treatment of panic in substance abusers has not been studied specifically, guidelines for recognition and management of these patients, including use of antipanic medication, are discussed.
A
lcohol has long been used to relieve stress and anxiety. The calming effects of alcohol have been thought to reinforce further drinking [l]. Although the extensive literature examining this tension-reduction hypothesis of drinking has largely concentrated on the effects of alcohol on stress in psychiatrically normal individuals, the capacity of alcohol to relieve pathologic anxiety has been observed for centuries. For example, Hippocrates noted that “wine drunk with an equal quantity of water puts away anxiety and terrors” 121, while Westphal in 1871 [31 described an agoraphobic individual who was able to confront feared situations with the aid of alcohol. Twenty years ago, Quitkin et al [4] suggested that patients with phobic anxiety might be at high risk for abuse of alcohol or sedatives used to selfmedicate anxiety symptoms. In fact, a number of studies have now documented increased rates of anxiety disorders among alcoholics and of alcoholism among patients presenting with anxiety disorders [5]. Since both anxiety disorders and substance abuse are common problems, recognition and treatment of patients with both conditions is an important challenge for primary-care clinicians. Patients may present with anxiety requesting anxiolytics without discussing their substance use or without recognizing the connection between drugs or alcohol and their symptoms. Others may suffer repeated relapses after attempts at alcohol and drug treatment because underlying anxiety disorders are not diagnosed or treated. This article will discuss the relationship between one specific anxiety disorder, panic disorder, which is commonly seen in primary-care settings, and alcohol and substance abuse or dependence. We will examine the co-occurrence of these disorders, clinical and biologic interactions between them, and an approach to the recognition and treatment of patients with both problems.
COMORBIDITY
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From the Center for Anxiety and Depression, Department of Psychiatry and BehavIoral Sciences, University of Washington, Seattle, Washington. Requests for reprints should be addressed to Deborah S. Cowley, M.D., Department of Psychiatry and BehavIoral Sciences RP-10, University of Washing ton, Seattle, Washington 98195.
Diagnostic criteria for both panic disorder and the substance use disorders have changed considerably over the past lo-20 years. In fact, panic disorder was only described as a separate entity in 1980, and before this was included, together with
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what we would now label generalized anxiety disorder (GAD), under “anxiety neurosis.” Although alcoholism or drug abuse may be quite evident in severely affected individuals, the differentiation of use from abuse or the definition of an “alcoholic” as opposed to a heavy social drinker can be problematic. Currently, as defined by the revised Diagnostic and Statistical Manual of Mental Disorders, third edition (DSM-IIIR), alcohol or substance abuse refers to a maladaptive, recurrent pattern of use despite life problems or danger (e.g., repeatedly driving while drunk or using drugs despite missing work as a result), while alcohol or substance dependence describes loss of control over use, with escalating use, physiologic dependence, or withdrawal symptoms [6]. Differing criteria for alcoholism make comparisons of prevalence studies difficult. However, the lifetime rate of alcoholism (alcohol dependence) appears to be about 10% for men and 3-5% for women in the United States [7]. Panic disorder, by contrast, is more common in women, with lifetime prevalence rates of about 1% in men and 2% in women [S]. Studies of panic disorder in patients in inpatient alcohol treatment programs have yielded lifetime prevalence rates of 2-21% [g-15]. This broad range is in part due to gender differences, with the 21% rate coming from a study including women alcoholics. Most studies have been of men and report rates of 5-8%, which are significantly higher than would be expected based on the general population figures. For example, at our own center, we interviewed 154 consecutive male admissions to our VA Medical Center inpatient alcohol treatment program and found that 8% reported lifetime panic disorder, while 14% had a history of less frequent but bothersome panic attacks [15]. We did not consider patients to have panic if their attacks occurred only during intoxication or withdrawal states. Only two of our patients with panic attacks had ever been diagnosed as having panic and neither had been treated. All of these prevalence studies suffer from limitations. Corroborating history from family members is unavailable or not obtained. Patients are interviewed in an inpatient setting, and many are undergoing alcohol and drug withdrawal. However, a study of 50 male outpatients in our monitored disulfiram program, all of whom had already undergone detoxification and withdrawal, also yielded a lifetime rate of panic disorder of 8% [16]. In general, it appears then that panic disorder is more prevalent in alcoholic cohorts than would be expected on the basis of general population rates. In addition, a re-
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cent study suggests that early-onset alcoholism may be associated with an even greater rate of panic disorder 1171. In 249 male alcoholics, the rate of panic disorder was 15% in those with heavy drinking before age 20, compared with 6% in those with onset after age 20. Alcoholism seems to be prevalent in patients with panic disorder, with the lifetime rates of alcohol dependence or abuse in the range of 7-28% in anxiety disorder clinic samples [B-20]. These rates are particularly high, since the majority of patients with panic disorder are women, who would be expected to have lower rates of alcoholism. The risk of alcoholism in patients with panic disorder is greater than four times that of the general population [21]. Family studies provide further evidence for an association between panic disorder and alcoholism. Crowe et al [22] found that 6% of first-degree relatives of patients with panic disorder had alcohol dependence or abuse, as opposed to 3.8% of relatives of controls. Noyes et al [231 found alcohol dependence or abuse in 7% of relatives of patients with panic disorder, 13% of relatives of agoraphobits, and 4% of relatives of controls. In a study by Harris et al [24], rates of alcohol abuse or dependence were 10% in relatives of panic disorder probands, 17.6% of relatives of agoraphobics, and 5.4% of relatives of controls. Male relatives of agoraphobits appear to be at increased risk for alcoholism, while female relatives of agoraphobics are more likely to have agoraphobia, suggesting that perhaps males are more likely to self-medicate with alcohol, presenting with alcoholism as their primary problem. Families of alcoholic probands do not appear in general to have an increased prevalence of panic or agoraphobia. The comorbidity of panic with other forms of substance abuse has been less well studied. Panic attacks have been reported to begin with or be exacerbated by the use of drugs, including marijuana, cocaine, amphetamines, and other stimulants [25,26]. Data from the Epidemiological Catchment Area (ECA) study show an increased risk of panic disorder in cocaine abusers [271. Interestingly, the risk differed with the concurrent use of marijuana. Abusers of cocaine‘ without marijuana had a 14 times increased risk of panic disorder, whereas those using both cocaine and marijuana had a relative risk of 3.4. Mirin et al [SS] have shown an increased rate of anxiety disorders in sedative/hypnotic abusers with 16% of their sample of 44 (27 men, 17 women) having panic disorder and 9% having GAD. In our study of panic in hospitalized male alcoholics, those with panic attacks did not differ from age-matched
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alcoholics without panic in their patterns of other drug use, except in their increased use of sedatives and opiates [29]. There is clearly significant comorbidity of panic disorder and alcoholism. In addition, it appears that use or abuse of certain other drugs is associated with increased rates of panic. Whether drugs and alcohol precipitate panic attacks or are reinforcing as self-medication for panic and associated phobias or anticipatory anxiety remains an interesting and unanswered question.
CAUSEAND EFFECT Most attempts to unravel causal relationships between anxiety and alcoholism have involved retrospective examination of the order of onset of the two conditions. In our study of panic in inpatient alcoholics, 18 of the 21 men with a history of panic attacks were able to identify the time of their first panic attack and the age of their first life problem due to heavy drinking [15]. The mean duration of panic attacks, 15 +- 9 years (range l-34 years) was shorter than the mean duration of problem drinking, 19 + 6 years (range 6-25 years). Nine (50%) developed problem drinking first, seven (38%) experienced panic attacks first, and two (12%) noted onset of both problems in the same year and could not recall which came first. These figures are consistent with results of other studies, in which about half of the patients report experiencing panic first, while the other half recall that problem drinking predated panic attacks (51. Of note, patients with agoraphobia and social phobia tend to be more likely than those with panic disorder to report that their anxiety symptoms predated problem drinking [5]. There are clearly some individuals for whom alcohol is indeed effective as self-medication for panic and associated phobias. Problem drinkers are more likely than normal subjects to view alcohol as anxiolytic [30], and alcoholics with panic and phobias frequently report using alcohol to help them confront feared situations [31]. Treatment of panic disorder has been noted in case reports to decrease use of alcohol and sedatives in dually disordered patients 14,321. The efficacy of alcohol as an anxiolytic is consistent with the observed cross-tolerance between ethanol, barbiturates, and benzodiazepines. Recently, increasing attention has been paid to the possibility that not only drugs such as cocaine, marijuana, or stimulants, but also alcohol may actually precipitate anxiety or panic. Prolonged alcohol use has been associated with increases in dysphoria, anxiety, and phobias [33]. For example, Stockwell et al [33] monitored subjective and physiologic
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measures of anxiety in alcoholic men drinking over a S-day period. After an initial decrease in anxiety, subjects displayed increasing anxiety as they continued to drink and stated that they expected to feel even worse if they stopped drinking. Alcohol withdrawal is clearly associated with severe anxiety symptoms. George et al [34] asked 11 alcoholics with panic attacks to rate symptoms of panic and alcohol withdrawal. Ratings of alcohol withdrawal symptoms were strikingly similar to reports of panic symptoms, differing significantly only in that tremulousness was more severe during withdrawal. Roelofs [35,36] has described a more prolonged, subacute alcohol withdrawal characterized by craving for alcohol with anxiety and hyperventilation. In a study of 37 detoxified alcoholics, the severity of this triad of symptoms was significantly related to self-reported duration of physical dependence on alcohol [35]. Twenty-five male alcoholics followed for 18 months showed decreases in hyperventilation symptoms with abstinence but increases in those who relapsed [36]. The authors also raise the possibility that hyperventilation during prolonged withdrawal may increase the likelihood of relapse, since ethanol corrects respiratory irregularities. Interestingly, chronic hyperventilation is often associated with panic disorder [37]. Both hyperventilation and panic may be precipitated or exacerbated by alcohol withdrawal and ameliorated, at least initially, by resumption of drinking, thus reinforcing continued alcohol problems. George et al [38] have suggested that repeated withdrawal episodes may trigger panic through a kindling process. “Kindling” refers to the use of repeated, intermittent, identical subconvulsive stimuli to evoke increasing amounts of electrical excitability, culminating in both provoked and eventually spontaneous seizures. Alcohol withdrawal, with its associated increased central nervous system (CNS) excitability, may have a “kindling” effect in susceptible individuals, sensitizing limbic areas, such as the hippocampus, which has been implicated in the pathophysiology of panic, and resulting in panic attacks at first during withdrawal but eventually also during periods of sobriety. Consistent with this, we have found that alcoholics with panic attacks report histories of more frequent and severe withdrawal symptoms [16]. It has also been suggested that alcohol or drug use may increase anxiety as a result of the many, realistically stressful life problems that result from substance use disorders [5], or from the process of conditioned tolerance, in which a state of hyperarousal occurs in situations associated with use of
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alcohol and sedatives [38]. This is the body’s attempt to offset the sedating effects of such drugs but could lead to increased anxiety if no alcohol or drug is actually consumed. In summary, it appears that alcohol and probably sedative drugs are at least initially anxiolytic and may be used to self-medicate preexisting anxiety. However, prolonged use and especially acute or subacute withdrawal states actually increase anxiety levels. It may often be quite clear that an individual patient has either a primary panic disorder with onset before use of alcohol or drugs or, on the other hand, a primary alcohol or drug problem followed later by anxiety. However, it appears likely that, once initiated, alcohol and panic reinforce each other. That is, panic and phobias lead to drinking as a way to. reduce anxiety symptoms, but continued drinking and subsequent withdrawal exacerbate panic and phobias, reinforcing further drinking.
BIOLOGY Biologic aspects of the panic-substance abuse overlap have been the subject of few studies. We will review these but also examine some possible biologic interactions that might underlie the mutually reinforcing clinical relationships discussed previously. Panic attacks can be reproduced in the laboratory in susceptible individuals using a variety of pharmacologic stimuli. The most extensively studied of these is sodium lactate infusion. Intravenous administration of sodium lactate provokes panic symptoms in about 60-70% of patients with panic attacks and O-10% of control subjects or psychiatric patients without panic attacks [39]. As yet, the mechanism of lactate-induced panic is unknown, although patients vulnerable to lactate show resting increases in right parahippocampal blood flow on positron emission tomography (PET) scans [40], suggesting a possible link between lactate susceptibility and altered regional brain metabolism. There have been to date two studies of lactate infusions in alcoholics with panic attacks, both of which have shown significant increases in anxiety in these subjects. In one, male alcoholics with panic were less likely to ask to stop the infusion than a group of female panic disorder patients, although their self-rated anxiety was similar [41]. In the other study, male alcoholics with panic attacks were similar in response to lactate to male panic disorder patients and reported significantly more panic symptoms than did male alcoholics without panic attacks [42]. It appears that alcoholics with panic attacks are more similar to patients with
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panic disorder than to patients without panic attacks in response to lactate. Whether there are differences in lactate response between alcoholics with preexisting versus “secondary” panic attacks remains to be determined. A study of cerebrospinal fluid (CSF) biochemistry in 10 normal controls, 10 alcoholics, and 10 alcoholics with panic disorder showed no differences between groups in dopamine, catecholamine, or serotonin metabolites (homovanillic acid [HVA], 3-methoxy-4-hydroxyphenylethyleneglycol [MHPGI, 5-hydroxyindoleacetic acid [5-HIAA]) or in diazepam binding inhibitor [43]. Alcoholics with panic did show increased CSF /3-endorphin, an endogenous opiate. Increases in CSF p-endorphin have also been reported in patients with panic disorder [44], so that this fmding gives further evidence of biologic similarities between patients with alcoholism and panic disorder and those with panic disorder alone. Possible biologic interactions between panic and alcoholism have been discussed recently in an excellent review by George et aZ [38] and will be summarized briefly here. The two neurotransmitter systems providing the strongest theoretical links between alcoholism and panic disorder are the y-aminobutyric acid (GABA)-benzodiazepine receptor system and central noradrenergic pathways. Benzodiazepines (anxiolytics that have proven effective in the treatment of panic disorder and generalized anxiety disorder) act by binding to specific, high-affinity receptor sites and enhancing the effects of GABA, the major inhibitory neurotransmitter in the mammalian CNS. Ethanol and barbiturates, which act at different sites on this macromolecular GABA-receptor complex, also increase the actions of GABA [45]. Animal studies suggest that ethanol may exert its sedating and motor incoordinating effects through GABA receptors. In addition, this receptor complex appears to be involved in alcohol withdrawal and the development of tolerance 1461. Given this common mode of action, it is not surprising that benzodiazepines and barbiturates show cross-tolerance with ethanol, that these drugs can be used to treat alcohol withdrawal, and that ethanol has anxiolytic effects. Receptor adaptations to chronic use of ethanol, with decreased receptor sensitivity or numbers or an increase in the action of excitatory neuronal systems, may lead to tolerance and to increased anxiety with withdrawal. Patients with panic disorder display decreased sensitivity to benzodiazepines [47], suggesting possible abnormalities in the function of their GABA-benzodiazepine receptor system, which may be reversed ini-
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tially with use of ethanol or sedatives. Conversely, repeated episodes of withdrawal may cause changes in GABA-benzodiazepine receptor function, increasing vulnerability to panic attacks. Many symptoms of panic attacks, such as palpitations, sweating, and tremulousness, suggest increased sympathetic nervous system activity. Indeed, stimulation of the locus coeruleus, a major site controlling central noradrenergic activity, provokes fear responses in animals [48]. Drugs decreasing locus coeruleus activity, such as tricyclic and monoamine-oxidase inhibitor (MAOI) antidepressants, decrease panic symptoms, while those increasing locus coeruleus firing, such as yohimbine, provoke panic [49]. Studies of catecholamine levels in patients with panic disorder have yielded equivocal results. However, challenge tests with clonidine, an aa-agonist, and yohimbine, an aaantagonist, which decrease and increase locus coeruleus activity, respectively, show exaggerated responses in patients with panic disorder [49,50], suggesting a hyperactive noradrenergic system in these patients. Acute administration of ethanol increases norepinephrine levels and urinary MHPG. In addition, alcohol withdrawal is accompanied by increases in urinary and plasma catecholamines and in CSF MHPG, as well as decreased sensitivity of both preand postsynaptic a,-adrenoreceptors [51]. To the extent that increased noradrenergic activity is involved in panic, alcohol use, and particularly withdrawal states, would be expected to provoke or exacerbate panic in vulnerable individuals. Other biologic systems perhaps involved in panic, such as serotonergic pathways, adenosine receptors, or medullary chemoreceptors await study in alcoholics with panic attacks. To date, our preliminary data regarding the biology of panic and of alcohol intoxication and withdrawal suggest common pathophysiologic mechanisms that may increase the likelihood of an individual with either disorder developing the other, given an underlying vulnerability.
CLINICALRECOGNITIONAND TREATMENT Panic disorder is often difficult to diagnose in primary-care settings, since these patients frequently present complaining of somatic symptoms. In addition, many of us are ill-equipped by our training to identify or manage patients with alcohol or substance dependence. The first step in recognizing dually disordered patients is to know the diagnostic criteria for these disorders [6] and to be willing to question patients specifically about alcohol and substance use. Two
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commonly used screening tests, the Michigan Alcohol Screening Test (MAST) [52] and the CAGE [531 may be helpful. The MAST detects life problems related to substance use, while the CAGE is a general first screening measure for alcohol problems. Asking patients about the amounts of alcohol or other substances consumed is frequently unreliable. Before asking how many drinks the patient consumes, it is important to be very specific about the definition of one drink. Amounts per day or per week may be inaccurate in sporadic users. In this case, it may be better to use a calendar to review the past week or month in detail, using significant dates or events to jog the patient’s memory [541. In addition, a more useful test of dependence or tolerance may be to ask how many drinks it takes until the patient feels an effect. Once either panic disorder, or indeed any anxiety disorder, or substance dependence is identified, the clinician should be careful to look for the other disorder and for associated problems, such as major depression, suicidal ideation, and phobias. Alcohol or substance use or withdrawal is probably the most significant medical differential diagnosis for panic disorder, while anxiety is often overlooked in treating chemically dependent patients. The treatment of dually disordered patients is often a clinical dilemma, involving such difficult questions as which disorder to treat first, whether to use anxiolytic medications to bring the patient into treatment or during withdrawal, and whether to treat the anxiety specifically at all. In all cases, substance use must be specifically addressed, and in general sobriety is the first goal of treatment. Pharmacologic interventions for anxiety are not as helpful and in fact may be dangerous in the face of continued alcohol or drug use. A general approach to diagnosing and treating the chemically dependent patient is given by Ries [551, who points out that one of the major obstacles in managing these patients is our own lack of familiarity with these disorders and the treatment options available. As with any referral, the patient is more apt to follow through if we are knowledgable about the alternatives and can offer specific suggestions. Whether recommended treatment is inpatient, outpatient, or through a group such as Alcoholics Anonymous (AA) or Narcotics Anonymous (NA) depends on the severity of the substance dependence, their past history of treatment, and any past history of withdrawal symptoms, including seizures or delirium tremens (DTs). Patients with a history of failing outpatient treatment or of severe withdrawal symptoms may need inpatient hospitalization.
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Convincing the patient of the need for substance dependence treatment is often difficult, since he or she will be likely to deny the seriousness of alcohol or drug problems. Confrontation with clear-cut evidence of associated life problems or evidence of dependence, in the presence of family members or significant others, may be necessary. Patients who attribute their drinking or drug use to anxiety or stress should be told that the clinician recognizes the seriousness of the anxiety symptoms or stress for them and that this will be addressed, but that they must be sober before these problems can be treated effectively. With abstinence, it appears that anxiety or panic symptoms may lessen or resolve over a period of months [56]. The use of specific pharmacologic antipanic treatment early in alcohol or drug treatment is controversial and as yet has not been studied systematically. As a general clinical guideline, it seems at this point that patients should be reassessed after 3-6 months of sobriety and treated then if panic attacks persist. However, obviously if panic is severe, has predated the onset of alcohol or drug use, or interferes with substance dependence treatment, more aggressive early treatment of panic will be needed. The treatment of panic disorder will be reviewed in this supplement by Dr. Roy-Byrne. A newer and very effective treatment that is particularly exciting in the management of substance abusers with panic is cognitive-behavioral psychotherapy. As a nonpharmacologic measure, this could be started immediately in conjunction with alcohol or drug treatment. In addition, patients can be advised to avoid caffeine and educated about panic attacks and their possible interaction with substance use. These approaches by themselves are often very helpful in the treatment of panic disorder. Medication treatment of panic involves primarily the use of antidepressants or benzodiazepines. Alcohol potentiates the CNS depressant effects of all of these agents. In addition, tricyclic antidepressants lower the seizure threshold and increase the risk of withdrawal seizures. Alcohol decreases the therapeutic efficacy of MAO1 antidepressants and may cause hypo- or hypertension in combination with these medications. Antidepressants are the pharmacologic treatment of choice for panic disorder in alcoholics or substance abusers because of their low abuse potential. Although the “kindling” hypothesis of panic in these patients would suggest the use of anticonvulsants, this has not been studied. Many patients develop bothersome side effects on antidepressants, including initial increases in anxiety, or overstimulation. This raises the question of whether it lA46S
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is ever appropriate to use benzodiazepines to treat panic in this population. The use of benzodiazepines in alcoholics has been reviewed recently by Ciraulo et al [5’7]. About 3040% of alcoholics use benzodiazepines at some point. This is higher than the rate of use among the general population but comparable to that of psychiatric patients. One of the major uses of benzodiazepines in these patients is for alcohol withdrawal. The few studies of benzodiazepine abuse or dependence in alcoholics have examined primarily the effects of short-term prescription of these medications for withdrawal symptoms. Overall, lo-30% of alcoholics have been noted to show abuse or dependence in these studies. Both alcoholics and their sons report more euphoria and “drug liking” than do controls when given a single dose of alprazolam [58]. Baron et al [59] have reported three cases in which patients diagnosed with alcoholism and panic were found to panic with lactate infusion and to respond dramatically to the benzodiazepine clonazepam. One of the three escalated his dose of clonazepam and was then lost to follow-up. These data support the general clinical impression that alcoholics are at increased risk for abuse or dependence if prescribed benzodiazepines. Indeed, it appears that this increased risk may also apply to their first-degree relatives. Nevertheless, not all alcoholics develop problems with benzodiazepines. There may be cases’in which the treatment of panic with benzodiazepines could decrease pathologic drinking, while refusal to use benzodiazepines would perpetuate a vicious cycle of panic and alcoholism. The following clinical guidelines apply whenever benzodiazepines are prescribed but are particularly important in treating patients with a history of substance dependence. First, both the physician and the patient should understand clearly the diagnosis to be treated and the goals of benzodiazepine treatment. Regular visits and a careful record of amounts and dates of prescriptions will help to monitor for excessive use. Oxazepam and halazepam probably have less abuse potential than other benzodiazepines [58] and so would be preferred whenever possible in this population. Medication should be tapered periodically to reassess the need for it. Finally, benzodiazepines should be prescribed in these patients only in consultation with a psychiatrist, preferably one familiar with substance dependence, and with ongoing discussion with the patient’s other care providers, including their addiction treatment program. Since most of these programs are understandably wary of giving such patients any medications with abuse potential, the rationale and goals of the treatment should be dis-
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cussed in detail with the individuals patient.
treating
the
CONCLUSION Substance abuse, especially alcoholism, and panic disorder are common problems in primary care that frequently occur together. While some patients use alcohol or drugs to self-medicate primary panic disorder and phobias, prolonged alcohol use and repeated withdrawal episodes may exacerbate or provoke panic in susceptible individuals. Exposure to marijuana and stimulants may also precipitate panic. Once present, alcoholism and panic are probably mutually reinforcing. On a receptor level, panic and alcoholism may interact via noradrenergic or GABAergic mechanisms. Recognition of patients with both substance dependence and panic requires a high index of suspicion. Patients with either condition should be questioned closely about symptoms of the other. Treatment of dually disordered patients involves addressing the substance dependence, use of nonpharmacologic treatments for panic, and prescription of anti-panic medication, as indicated.
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22. Crowe RR, Noyes R Jr., Pauls DL, Slymen D. A family study of panic disorder. Arch Gen Psychiatry 1983; 40: 1065-g. 23. Noyes R Jr., Clarkson C, Crowe RR, Yates WR, McChesney CM. A family study of generalized anxiety disorder. Am J Psychiatry 1987; 144: 1019-24. 24. Harris EL, Noyes R Jr., Crowe RR, Chaudhty DR. Family study of agoraphobia. Arch Gen Psychiatry 1983; 40: 1061-4. 25. Moran C. Depersonalization and agoraphobia associated with marijuana use. Br J Med Psycho1 1986; 59: 187-96. 26. Aronson TA, Craig TJ. Cocaine precipitation of panic disorder. Am J Psychiatry 1986; 143: 643-5. 27. Anthony JC, Tien AY, Petronis KR. Epidemiologic evidence on cocaine use and panic attacks. Am J Epidemiol 1989; 129: 543-9. 28. Mirin SM, Weiss RD, Griffin ML, Michael JL. Psychopathology and their families. Comp Psychiatry 1991; 32: 36-51.
in drug abusers
29. Jensen CF, Cowley DS, Walker RD. Drug preferences in alcoholic polydrug abusers with and without panic. J Clin Psychiatry 1990; 51: 189-91. 30. Cahalan K. Problem drinkers. San Francisco: Jossey-Bass, 1970. 31. Smail P, Stockwell T, Canter S, Hodgson R. Alcohol dependence and phobic anxiety states, I: a prevalence study. Br J Psychiatry 1984; 144: 53-7. 32. Hudson CJ, Perkins SH. Panic disorder and alcohol misuse. J Stud Alcohol 1984; 45: 462-4. 33. Stockwell T, Hodgson R, Rankin H. Tension reduction and the effects of prolonged alcohol consumption. Br J Addict 1982; n: 65-73. 34. George DT, Zerby A, Noble S, Nutt DJ. Panic attacks and alcohol withdrawal: can subjects differentlate the symptoms? Biol Psychiatry 1988; 24: 240-3. 35. Roelofs SM. Hypetventllation, anxiety, craving for alcohol: a subacute alcohol withdrawal syndrome. Alcohol 1985; 2: 501-5. 36. Roelofs SM, Dikkenberg GM. Hyperventilation and anxiety: alcohol withdrawal symptoms decreasing with prolonged abstinence. Alcohol 1987; 4: 215-20. 37. Cowley DS, Roy-Byrne PP. Hyperventilation and panic disorder. Am J Med 1987; 83: 929-37. 38. George DT, Nutt DJ, Dwyer BA, Lmnolla M. Alcoholism and panic disorder: is the comorbidity more than coincidence? Acta Psychiatr Stand 1990; 81: 97-107. 39. Cowley DS, Arana GW. The diagnostic utility of lactate sensitivity in panic disorder. Arch Gen Psychiatry 1990; 47: 277-84. 40. Reiman E, Raichle M, Robins E, et a/. The application of positron emission tomography to the study of panic disorder. Am J Psychiatry 1986; 143: 469-77. 41. George DT, Nutt DJ, Waxman RP, Linnoila M. Panic response to lactate admlnistration in alcoholic and non-alcoholic patients with panic disorder. Am J Psychiatry 1989; 146: 1161-5. 42. Cowley DS, Jensen CF, Johannessen DJ, Parker L, Dager SR, Walker RD. Response to sodium lactate infusion in alcoholics with panic attacks. Am J Psychiatry 1989; 146: 1479-83. 43. George DT, Adinoff B, Ravitz B, et al. A cerebrosplnal fluid study of the pathophysiology of panic disorder associated with alcoholism. Acta Psychlatr Stand 1990; 82: l-7. 44. Eriksson E, Westberg P, Thuresson K, Modigh K, Ekman R, Wlderlov E. Increased cerebrospinal fluid levels of endorphin immunoreactivlty in panic disorder. Neuropsychopharmacology 1989; 2 225-8. 45. Tlcku MK, Burch TP, Davis WC. The interactions of ethanol with benzodiazepineGABA receptor-ionophore complex. Pharmacol Biochem Behav 1983; 18: 15-8. 46. Cowen P, Nutt D. Abstinence symptoms after withdrawal of tranquilizing drugs: IS there a common neurochemical mechanism? Lancet 1982; ii: 360-2. 47. Roy-Byrne PP, Cowley DS, Greenblatt DJ, Shader RI, Hommer DW. Reduced benzodiazepme sensitivity in panic disorder. Arch Gen Psychiatry 1990; 47: 534-8. 48. Redmond DE, Huang YH, Snyder DR, Maas JW. BehavIoral effects of stimulation of the nucleus locus coeruleus In the slump-tailed monkey Macaca arctoides. Brain Res 1976; 116: 502-10. 49. Charney DS, Heninger GR, Breier A. Noradrenerglc function I” panic anxiety.
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Effects of yohimbine in healthy subjects and patients with agoraphobia and panic disorder. Arch Gen Psychiatry 1984; 41: 751-63. 50. Charney DS, Heninger GR. Abnormal regulation of noradrenergic function in panrc disorders. Effects of clonidine rn healthy sublects and patients with agoraphobia and panic disorder. Arch Gen Psychiatry 1986; 43: 1042-54. 51. Nutt DJ. Altered central alpha-2-adrenoreceptor sensitivrty rn panic disorder. Arch Gen Psychratry 1989; 46: 165-9. 52. Seizer ML. The Michigan Alcoholism Screening Test: the quest for a new diagnostic instrument, Am J Psychiatry 1971; 127: 89-94. 53. Clark WD. Alcoholism: blocks to diagnosis and treatment. Am J Med 1981; 71:
27546. 54. Sobell L, Sobell M, Leo G, Cancilia A. Reliability of a timeline method: assessing normal drinkers’ reports of recent drinking and a comparative evaluation across
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several populations. Br J Addic 1988; 83: 393-402. 55. Ries R. Alcoholism and anxiety. In: Roy-Byrne PP, ed. Anxiety: new findings for the clinician. Washrngton, DC.: American Psychiatric Press, 1989: 123-48. 56. Schuckit MA, Irwin M, Brown SA. The history of anxiety symptoms among 171 primary alcoholics. J Stud Alcohol 1990; 51: 34-41. 57. Ciraulo DA, Sands BF, Shader RI. Crrtical review of liability for benzodiazeprne abuse among alcoholrcs. Am J Psychiatry 1988; 145: 1501-6. 58. Ciraulo DA, Sarid-Segal 0. Benzodiazepines: abuse liability. In: Roy-Byrne PP, Cowley DS, eds. Benzodiazepines in clinical practice: risks and benefits. Washington, D.C.: American Psychiatric Press, 1991: 157-74. 59. Baron DH, Sands BF, Ciraulo DA, Shader RI. The dragnosis and treatment of panic disorder in alcoholics: three cases. Am J Drug Alcohol Abuse 1990; 16: 28795.
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Washington
The purpose of this article is to review the literature concerning the interaction of alcohol and/or substance abuse with panic disorder, the comorbidity of these disorders, possible causal relationships, biologic relationships, and the recognition and treatment of dually disordered patients. A number of studies suggest significant comorbidity between panic disorder and alcoholism or abuse of drugs, especially cocaine and sedatives. Panic may lead to drinking or sedative use and also result from prolonged use or withdrawal of alcohol or other drugs. Possible biologic relationships involve the y-aminobutyric acid (GABA)benzodiazepine receptor complex and the central noradrenergic system. Although treatment of panic in substance abusers has not been studied specifically, guidelines for recognition and management of these patients, including use of antipanic medication, are discussed.
A
lcohol has long been used to relieve stress and anxiety. The calming effects of alcohol have been thought to reinforce further drinking [l]. Although the extensive literature examining this tension-reduction hypothesis of drinking has largely concentrated on the effects of alcohol on stress in psychiatrically normal individuals, the capacity of alcohol to relieve pathologic anxiety has been observed for centuries. For example, Hippocrates noted that “wine drunk with an equal quantity of water puts away anxiety and terrors” 121, while Westphal in 1871 [31 described an agoraphobic individual who was able to confront feared situations with the aid of alcohol. Twenty years ago, Quitkin et al [4] suggested that patients with phobic anxiety might be at high risk for abuse of alcohol or sedatives used to selfmedicate anxiety symptoms. In fact, a number of studies have now documented increased rates of anxiety disorders among alcoholics and of alcoholism among patients presenting with anxiety disorders [5]. Since both anxiety disorders and substance abuse are common problems, recognition and treatment of patients with both conditions is an important challenge for primary-care clinicians. Patients may present with anxiety requesting anxiolytics without discussing their substance use or without recognizing the connection between drugs or alcohol and their symptoms. Others may suffer repeated relapses after attempts at alcohol and drug treatment because underlying anxiety disorders are not diagnosed or treated. This article will discuss the relationship between one specific anxiety disorder, panic disorder, which is commonly seen in primary-care settings, and alcohol and substance abuse or dependence. We will examine the co-occurrence of these disorders, clinical and biologic interactions between them, and an approach to the recognition and treatment of patients with both problems.
COMORBIDITY
ti
From the Center for Anxiety and Depression, Department of Psychiatry and BehavIoral Sciences, University of Washington, Seattle, Washington. Requests for reprints should be addressed to Deborah S. Cowley, M.D., Department of Psychiatry and BehavIoral Sciences RP-10, University of Washing ton, Seattle, Washington 98195.
Diagnostic criteria for both panic disorder and the substance use disorders have changed considerably over the past lo-20 years. In fact, panic disorder was only described as a separate entity in 1980, and before this was included, together with
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what we would now label generalized anxiety disorder (GAD), under “anxiety neurosis.” Although alcoholism or drug abuse may be quite evident in severely affected individuals, the differentiation of use from abuse or the definition of an “alcoholic” as opposed to a heavy social drinker can be problematic. Currently, as defined by the revised Diagnostic and Statistical Manual of Mental Disorders, third edition (DSM-IIIR), alcohol or substance abuse refers to a maladaptive, recurrent pattern of use despite life problems or danger (e.g., repeatedly driving while drunk or using drugs despite missing work as a result), while alcohol or substance dependence describes loss of control over use, with escalating use, physiologic dependence, or withdrawal symptoms [6]. Differing criteria for alcoholism make comparisons of prevalence studies difficult. However, the lifetime rate of alcoholism (alcohol dependence) appears to be about 10% for men and 3-5% for women in the United States [7]. Panic disorder, by contrast, is more common in women, with lifetime prevalence rates of about 1% in men and 2% in women [S]. Studies of panic disorder in patients in inpatient alcohol treatment programs have yielded lifetime prevalence rates of 2-21% [g-15]. This broad range is in part due to gender differences, with the 21% rate coming from a study including women alcoholics. Most studies have been of men and report rates of 5-8%, which are significantly higher than would be expected based on the general population figures. For example, at our own center, we interviewed 154 consecutive male admissions to our VA Medical Center inpatient alcohol treatment program and found that 8% reported lifetime panic disorder, while 14% had a history of less frequent but bothersome panic attacks [15]. We did not consider patients to have panic if their attacks occurred only during intoxication or withdrawal states. Only two of our patients with panic attacks had ever been diagnosed as having panic and neither had been treated. All of these prevalence studies suffer from limitations. Corroborating history from family members is unavailable or not obtained. Patients are interviewed in an inpatient setting, and many are undergoing alcohol and drug withdrawal. However, a study of 50 male outpatients in our monitored disulfiram program, all of whom had already undergone detoxification and withdrawal, also yielded a lifetime rate of panic disorder of 8% [16]. In general, it appears then that panic disorder is more prevalent in alcoholic cohorts than would be expected on the basis of general population rates. In addition, a re-
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cent study suggests that early-onset alcoholism may be associated with an even greater rate of panic disorder 1171. In 249 male alcoholics, the rate of panic disorder was 15% in those with heavy drinking before age 20, compared with 6% in those with onset after age 20. Alcoholism seems to be prevalent in patients with panic disorder, with the lifetime rates of alcohol dependence or abuse in the range of 7-28% in anxiety disorder clinic samples [B-20]. These rates are particularly high, since the majority of patients with panic disorder are women, who would be expected to have lower rates of alcoholism. The risk of alcoholism in patients with panic disorder is greater than four times that of the general population [21]. Family studies provide further evidence for an association between panic disorder and alcoholism. Crowe et al [22] found that 6% of first-degree relatives of patients with panic disorder had alcohol dependence or abuse, as opposed to 3.8% of relatives of controls. Noyes et al [231 found alcohol dependence or abuse in 7% of relatives of patients with panic disorder, 13% of relatives of agoraphobits, and 4% of relatives of controls. In a study by Harris et al [24], rates of alcohol abuse or dependence were 10% in relatives of panic disorder probands, 17.6% of relatives of agoraphobics, and 5.4% of relatives of controls. Male relatives of agoraphobits appear to be at increased risk for alcoholism, while female relatives of agoraphobics are more likely to have agoraphobia, suggesting that perhaps males are more likely to self-medicate with alcohol, presenting with alcoholism as their primary problem. Families of alcoholic probands do not appear in general to have an increased prevalence of panic or agoraphobia. The comorbidity of panic with other forms of substance abuse has been less well studied. Panic attacks have been reported to begin with or be exacerbated by the use of drugs, including marijuana, cocaine, amphetamines, and other stimulants [25,26]. Data from the Epidemiological Catchment Area (ECA) study show an increased risk of panic disorder in cocaine abusers [271. Interestingly, the risk differed with the concurrent use of marijuana. Abusers of cocaine‘ without marijuana had a 14 times increased risk of panic disorder, whereas those using both cocaine and marijuana had a relative risk of 3.4. Mirin et al [SS] have shown an increased rate of anxiety disorders in sedative/hypnotic abusers with 16% of their sample of 44 (27 men, 17 women) having panic disorder and 9% having GAD. In our study of panic in hospitalized male alcoholics, those with panic attacks did not differ from age-matched
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alcoholics without panic in their patterns of other drug use, except in their increased use of sedatives and opiates [29]. There is clearly significant comorbidity of panic disorder and alcoholism. In addition, it appears that use or abuse of certain other drugs is associated with increased rates of panic. Whether drugs and alcohol precipitate panic attacks or are reinforcing as self-medication for panic and associated phobias or anticipatory anxiety remains an interesting and unanswered question.
CAUSEAND EFFECT Most attempts to unravel causal relationships between anxiety and alcoholism have involved retrospective examination of the order of onset of the two conditions. In our study of panic in inpatient alcoholics, 18 of the 21 men with a history of panic attacks were able to identify the time of their first panic attack and the age of their first life problem due to heavy drinking [15]. The mean duration of panic attacks, 15 +- 9 years (range l-34 years) was shorter than the mean duration of problem drinking, 19 + 6 years (range 6-25 years). Nine (50%) developed problem drinking first, seven (38%) experienced panic attacks first, and two (12%) noted onset of both problems in the same year and could not recall which came first. These figures are consistent with results of other studies, in which about half of the patients report experiencing panic first, while the other half recall that problem drinking predated panic attacks (51. Of note, patients with agoraphobia and social phobia tend to be more likely than those with panic disorder to report that their anxiety symptoms predated problem drinking [5]. There are clearly some individuals for whom alcohol is indeed effective as self-medication for panic and associated phobias. Problem drinkers are more likely than normal subjects to view alcohol as anxiolytic [30], and alcoholics with panic and phobias frequently report using alcohol to help them confront feared situations [31]. Treatment of panic disorder has been noted in case reports to decrease use of alcohol and sedatives in dually disordered patients 14,321. The efficacy of alcohol as an anxiolytic is consistent with the observed cross-tolerance between ethanol, barbiturates, and benzodiazepines. Recently, increasing attention has been paid to the possibility that not only drugs such as cocaine, marijuana, or stimulants, but also alcohol may actually precipitate anxiety or panic. Prolonged alcohol use has been associated with increases in dysphoria, anxiety, and phobias [33]. For example, Stockwell et al [33] monitored subjective and physiologic
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measures of anxiety in alcoholic men drinking over a S-day period. After an initial decrease in anxiety, subjects displayed increasing anxiety as they continued to drink and stated that they expected to feel even worse if they stopped drinking. Alcohol withdrawal is clearly associated with severe anxiety symptoms. George et al [34] asked 11 alcoholics with panic attacks to rate symptoms of panic and alcohol withdrawal. Ratings of alcohol withdrawal symptoms were strikingly similar to reports of panic symptoms, differing significantly only in that tremulousness was more severe during withdrawal. Roelofs [35,36] has described a more prolonged, subacute alcohol withdrawal characterized by craving for alcohol with anxiety and hyperventilation. In a study of 37 detoxified alcoholics, the severity of this triad of symptoms was significantly related to self-reported duration of physical dependence on alcohol [35]. Twenty-five male alcoholics followed for 18 months showed decreases in hyperventilation symptoms with abstinence but increases in those who relapsed [36]. The authors also raise the possibility that hyperventilation during prolonged withdrawal may increase the likelihood of relapse, since ethanol corrects respiratory irregularities. Interestingly, chronic hyperventilation is often associated with panic disorder [37]. Both hyperventilation and panic may be precipitated or exacerbated by alcohol withdrawal and ameliorated, at least initially, by resumption of drinking, thus reinforcing continued alcohol problems. George et al [38] have suggested that repeated withdrawal episodes may trigger panic through a kindling process. “Kindling” refers to the use of repeated, intermittent, identical subconvulsive stimuli to evoke increasing amounts of electrical excitability, culminating in both provoked and eventually spontaneous seizures. Alcohol withdrawal, with its associated increased central nervous system (CNS) excitability, may have a “kindling” effect in susceptible individuals, sensitizing limbic areas, such as the hippocampus, which has been implicated in the pathophysiology of panic, and resulting in panic attacks at first during withdrawal but eventually also during periods of sobriety. Consistent with this, we have found that alcoholics with panic attacks report histories of more frequent and severe withdrawal symptoms [16]. It has also been suggested that alcohol or drug use may increase anxiety as a result of the many, realistically stressful life problems that result from substance use disorders [5], or from the process of conditioned tolerance, in which a state of hyperarousal occurs in situations associated with use of
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alcohol and sedatives [38]. This is the body’s attempt to offset the sedating effects of such drugs but could lead to increased anxiety if no alcohol or drug is actually consumed. In summary, it appears that alcohol and probably sedative drugs are at least initially anxiolytic and may be used to self-medicate preexisting anxiety. However, prolonged use and especially acute or subacute withdrawal states actually increase anxiety levels. It may often be quite clear that an individual patient has either a primary panic disorder with onset before use of alcohol or drugs or, on the other hand, a primary alcohol or drug problem followed later by anxiety. However, it appears likely that, once initiated, alcohol and panic reinforce each other. That is, panic and phobias lead to drinking as a way to. reduce anxiety symptoms, but continued drinking and subsequent withdrawal exacerbate panic and phobias, reinforcing further drinking.
BIOLOGY Biologic aspects of the panic-substance abuse overlap have been the subject of few studies. We will review these but also examine some possible biologic interactions that might underlie the mutually reinforcing clinical relationships discussed previously. Panic attacks can be reproduced in the laboratory in susceptible individuals using a variety of pharmacologic stimuli. The most extensively studied of these is sodium lactate infusion. Intravenous administration of sodium lactate provokes panic symptoms in about 60-70% of patients with panic attacks and O-10% of control subjects or psychiatric patients without panic attacks [39]. As yet, the mechanism of lactate-induced panic is unknown, although patients vulnerable to lactate show resting increases in right parahippocampal blood flow on positron emission tomography (PET) scans [40], suggesting a possible link between lactate susceptibility and altered regional brain metabolism. There have been to date two studies of lactate infusions in alcoholics with panic attacks, both of which have shown significant increases in anxiety in these subjects. In one, male alcoholics with panic were less likely to ask to stop the infusion than a group of female panic disorder patients, although their self-rated anxiety was similar [41]. In the other study, male alcoholics with panic attacks were similar in response to lactate to male panic disorder patients and reported significantly more panic symptoms than did male alcoholics without panic attacks [42]. It appears that alcoholics with panic attacks are more similar to patients with
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panic disorder than to patients without panic attacks in response to lactate. Whether there are differences in lactate response between alcoholics with preexisting versus “secondary” panic attacks remains to be determined. A study of cerebrospinal fluid (CSF) biochemistry in 10 normal controls, 10 alcoholics, and 10 alcoholics with panic disorder showed no differences between groups in dopamine, catecholamine, or serotonin metabolites (homovanillic acid [HVA], 3-methoxy-4-hydroxyphenylethyleneglycol [MHPGI, 5-hydroxyindoleacetic acid [5-HIAA]) or in diazepam binding inhibitor [43]. Alcoholics with panic did show increased CSF /3-endorphin, an endogenous opiate. Increases in CSF p-endorphin have also been reported in patients with panic disorder [44], so that this fmding gives further evidence of biologic similarities between patients with alcoholism and panic disorder and those with panic disorder alone. Possible biologic interactions between panic and alcoholism have been discussed recently in an excellent review by George et aZ [38] and will be summarized briefly here. The two neurotransmitter systems providing the strongest theoretical links between alcoholism and panic disorder are the y-aminobutyric acid (GABA)-benzodiazepine receptor system and central noradrenergic pathways. Benzodiazepines (anxiolytics that have proven effective in the treatment of panic disorder and generalized anxiety disorder) act by binding to specific, high-affinity receptor sites and enhancing the effects of GABA, the major inhibitory neurotransmitter in the mammalian CNS. Ethanol and barbiturates, which act at different sites on this macromolecular GABA-receptor complex, also increase the actions of GABA [45]. Animal studies suggest that ethanol may exert its sedating and motor incoordinating effects through GABA receptors. In addition, this receptor complex appears to be involved in alcohol withdrawal and the development of tolerance 1461. Given this common mode of action, it is not surprising that benzodiazepines and barbiturates show cross-tolerance with ethanol, that these drugs can be used to treat alcohol withdrawal, and that ethanol has anxiolytic effects. Receptor adaptations to chronic use of ethanol, with decreased receptor sensitivity or numbers or an increase in the action of excitatory neuronal systems, may lead to tolerance and to increased anxiety with withdrawal. Patients with panic disorder display decreased sensitivity to benzodiazepines [47], suggesting possible abnormalities in the function of their GABA-benzodiazepine receptor system, which may be reversed ini-
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tially with use of ethanol or sedatives. Conversely, repeated episodes of withdrawal may cause changes in GABA-benzodiazepine receptor function, increasing vulnerability to panic attacks. Many symptoms of panic attacks, such as palpitations, sweating, and tremulousness, suggest increased sympathetic nervous system activity. Indeed, stimulation of the locus coeruleus, a major site controlling central noradrenergic activity, provokes fear responses in animals [48]. Drugs decreasing locus coeruleus activity, such as tricyclic and monoamine-oxidase inhibitor (MAOI) antidepressants, decrease panic symptoms, while those increasing locus coeruleus firing, such as yohimbine, provoke panic [49]. Studies of catecholamine levels in patients with panic disorder have yielded equivocal results. However, challenge tests with clonidine, an aa-agonist, and yohimbine, an aaantagonist, which decrease and increase locus coeruleus activity, respectively, show exaggerated responses in patients with panic disorder [49,50], suggesting a hyperactive noradrenergic system in these patients. Acute administration of ethanol increases norepinephrine levels and urinary MHPG. In addition, alcohol withdrawal is accompanied by increases in urinary and plasma catecholamines and in CSF MHPG, as well as decreased sensitivity of both preand postsynaptic a,-adrenoreceptors [51]. To the extent that increased noradrenergic activity is involved in panic, alcohol use, and particularly withdrawal states, would be expected to provoke or exacerbate panic in vulnerable individuals. Other biologic systems perhaps involved in panic, such as serotonergic pathways, adenosine receptors, or medullary chemoreceptors await study in alcoholics with panic attacks. To date, our preliminary data regarding the biology of panic and of alcohol intoxication and withdrawal suggest common pathophysiologic mechanisms that may increase the likelihood of an individual with either disorder developing the other, given an underlying vulnerability.
CLINICALRECOGNITIONAND TREATMENT Panic disorder is often difficult to diagnose in primary-care settings, since these patients frequently present complaining of somatic symptoms. In addition, many of us are ill-equipped by our training to identify or manage patients with alcohol or substance dependence. The first step in recognizing dually disordered patients is to know the diagnostic criteria for these disorders [6] and to be willing to question patients specifically about alcohol and substance use. Two
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commonly used screening tests, the Michigan Alcohol Screening Test (MAST) [52] and the CAGE [531 may be helpful. The MAST detects life problems related to substance use, while the CAGE is a general first screening measure for alcohol problems. Asking patients about the amounts of alcohol or other substances consumed is frequently unreliable. Before asking how many drinks the patient consumes, it is important to be very specific about the definition of one drink. Amounts per day or per week may be inaccurate in sporadic users. In this case, it may be better to use a calendar to review the past week or month in detail, using significant dates or events to jog the patient’s memory [541. In addition, a more useful test of dependence or tolerance may be to ask how many drinks it takes until the patient feels an effect. Once either panic disorder, or indeed any anxiety disorder, or substance dependence is identified, the clinician should be careful to look for the other disorder and for associated problems, such as major depression, suicidal ideation, and phobias. Alcohol or substance use or withdrawal is probably the most significant medical differential diagnosis for panic disorder, while anxiety is often overlooked in treating chemically dependent patients. The treatment of dually disordered patients is often a clinical dilemma, involving such difficult questions as which disorder to treat first, whether to use anxiolytic medications to bring the patient into treatment or during withdrawal, and whether to treat the anxiety specifically at all. In all cases, substance use must be specifically addressed, and in general sobriety is the first goal of treatment. Pharmacologic interventions for anxiety are not as helpful and in fact may be dangerous in the face of continued alcohol or drug use. A general approach to diagnosing and treating the chemically dependent patient is given by Ries [551, who points out that one of the major obstacles in managing these patients is our own lack of familiarity with these disorders and the treatment options available. As with any referral, the patient is more apt to follow through if we are knowledgable about the alternatives and can offer specific suggestions. Whether recommended treatment is inpatient, outpatient, or through a group such as Alcoholics Anonymous (AA) or Narcotics Anonymous (NA) depends on the severity of the substance dependence, their past history of treatment, and any past history of withdrawal symptoms, including seizures or delirium tremens (DTs). Patients with a history of failing outpatient treatment or of severe withdrawal symptoms may need inpatient hospitalization.
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Convincing the patient of the need for substance dependence treatment is often difficult, since he or she will be likely to deny the seriousness of alcohol or drug problems. Confrontation with clear-cut evidence of associated life problems or evidence of dependence, in the presence of family members or significant others, may be necessary. Patients who attribute their drinking or drug use to anxiety or stress should be told that the clinician recognizes the seriousness of the anxiety symptoms or stress for them and that this will be addressed, but that they must be sober before these problems can be treated effectively. With abstinence, it appears that anxiety or panic symptoms may lessen or resolve over a period of months [56]. The use of specific pharmacologic antipanic treatment early in alcohol or drug treatment is controversial and as yet has not been studied systematically. As a general clinical guideline, it seems at this point that patients should be reassessed after 3-6 months of sobriety and treated then if panic attacks persist. However, obviously if panic is severe, has predated the onset of alcohol or drug use, or interferes with substance dependence treatment, more aggressive early treatment of panic will be needed. The treatment of panic disorder will be reviewed in this supplement by Dr. Roy-Byrne. A newer and very effective treatment that is particularly exciting in the management of substance abusers with panic is cognitive-behavioral psychotherapy. As a nonpharmacologic measure, this could be started immediately in conjunction with alcohol or drug treatment. In addition, patients can be advised to avoid caffeine and educated about panic attacks and their possible interaction with substance use. These approaches by themselves are often very helpful in the treatment of panic disorder. Medication treatment of panic involves primarily the use of antidepressants or benzodiazepines. Alcohol potentiates the CNS depressant effects of all of these agents. In addition, tricyclic antidepressants lower the seizure threshold and increase the risk of withdrawal seizures. Alcohol decreases the therapeutic efficacy of MAO1 antidepressants and may cause hypo- or hypertension in combination with these medications. Antidepressants are the pharmacologic treatment of choice for panic disorder in alcoholics or substance abusers because of their low abuse potential. Although the “kindling” hypothesis of panic in these patients would suggest the use of anticonvulsants, this has not been studied. Many patients develop bothersome side effects on antidepressants, including initial increases in anxiety, or overstimulation. This raises the question of whether it lA46S
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is ever appropriate to use benzodiazepines to treat panic in this population. The use of benzodiazepines in alcoholics has been reviewed recently by Ciraulo et al [5’7]. About 3040% of alcoholics use benzodiazepines at some point. This is higher than the rate of use among the general population but comparable to that of psychiatric patients. One of the major uses of benzodiazepines in these patients is for alcohol withdrawal. The few studies of benzodiazepine abuse or dependence in alcoholics have examined primarily the effects of short-term prescription of these medications for withdrawal symptoms. Overall, lo-30% of alcoholics have been noted to show abuse or dependence in these studies. Both alcoholics and their sons report more euphoria and “drug liking” than do controls when given a single dose of alprazolam [58]. Baron et al [59] have reported three cases in which patients diagnosed with alcoholism and panic were found to panic with lactate infusion and to respond dramatically to the benzodiazepine clonazepam. One of the three escalated his dose of clonazepam and was then lost to follow-up. These data support the general clinical impression that alcoholics are at increased risk for abuse or dependence if prescribed benzodiazepines. Indeed, it appears that this increased risk may also apply to their first-degree relatives. Nevertheless, not all alcoholics develop problems with benzodiazepines. There may be cases’in which the treatment of panic with benzodiazepines could decrease pathologic drinking, while refusal to use benzodiazepines would perpetuate a vicious cycle of panic and alcoholism. The following clinical guidelines apply whenever benzodiazepines are prescribed but are particularly important in treating patients with a history of substance dependence. First, both the physician and the patient should understand clearly the diagnosis to be treated and the goals of benzodiazepine treatment. Regular visits and a careful record of amounts and dates of prescriptions will help to monitor for excessive use. Oxazepam and halazepam probably have less abuse potential than other benzodiazepines [58] and so would be preferred whenever possible in this population. Medication should be tapered periodically to reassess the need for it. Finally, benzodiazepines should be prescribed in these patients only in consultation with a psychiatrist, preferably one familiar with substance dependence, and with ongoing discussion with the patient’s other care providers, including their addiction treatment program. Since most of these programs are understandably wary of giving such patients any medications with abuse potential, the rationale and goals of the treatment should be dis-
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cussed in detail with the individuals patient.
treating
the
CONCLUSION Substance abuse, especially alcoholism, and panic disorder are common problems in primary care that frequently occur together. While some patients use alcohol or drugs to self-medicate primary panic disorder and phobias, prolonged alcohol use and repeated withdrawal episodes may exacerbate or provoke panic in susceptible individuals. Exposure to marijuana and stimulants may also precipitate panic. Once present, alcoholism and panic are probably mutually reinforcing. On a receptor level, panic and alcoholism may interact via noradrenergic or GABAergic mechanisms. Recognition of patients with both substance dependence and panic requires a high index of suspicion. Patients with either condition should be questioned closely about symptoms of the other. Treatment of dually disordered patients involves addressing the substance dependence, use of nonpharmacologic treatments for panic, and prescription of anti-panic medication, as indicated.
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