The boundaries between psychiatry and primary care medicine have blurred considerably in reI cent years. This is due in part to an increasing awareness of the many biological factors in psychiatric disease and to a greater recognition of the frequency with which patients suffering from emotional and mental disorders seek help from their physicians. Psychiatrists and primary care physicians alike are increasingly called upon to manage patients with combined medical and psychiatric problems. This requires them to maintain expertise in areas previously considered outside their normal scope of practice. One such area is the use of psychotropic drugs in patients with either symptoms suggesting multiple diagnoses and overlapping etiologies, or those with known concurrent medical and psychiatric illnesses. This article reviews the use of benzodiazepines in several syndromes where both medical and psychiatric factors play a significant role. We will also survey the indications and areas of concern for benzodiazepine therapy in some common medical disorders.
OVERVIEW OF BENZODIAZEPINE USE
Benzodiazepines (BZDs) are frequently administered as specific medicinal agents for anxiety, insomnia, muscle spasms, seizures, detoxification from substance abuse, and sedation prior to procedures and chemotherapy. They are also potentially useful as adjunctive agents when medical or psychiatric conditions result in apprehension, insomnia, or muscular tension. When the many potential psychological responses to being diagnosed with an illness are considered, this latter pattern of use could involve virtually any disease state.
Over 80f# of prescriptions for antianxiety agents are written by primary care physicians,1 and in some studies nearly one in five general medical patients are given BZDs by their physician.2 While monitored use in a medical setting is rarely associated with tolerance to therapeutic effects or dose escalation,' the abuse potential of BZDs is considered in some states to be so great that triplicate prescriptions are mandated in order to track the provision and use of these agents.1
Most BZDs have active breakdown products and are largely metabolized by liver enzymes (with the exception of lorazepam and oxazepam, which are less dependent on hepatic mechanisms).5 For this reason, they must be used with caution in patients with coexistent liver dysfunction or renal insufficiency. Patients with chronic obstructive lung disease given BZDs may suffer from CO., retention and respiratory depression. Common side effects of BZDs, such as cognitive impairment, memory deficits, disinhibition, and sedation, can worsen the clinical status of demented and debilitated patients. Other common side effects include impaired motor function, ataxia, and slurred speech. Benzodiazepines do have a potential for abuse and dependency in patients with addictive disorders or tendencies6 (although individual susceptibility varies widely), and they can contribute to mortality in overdoses of multiple drugs.'
In addition to these rather straightforward areas of concern, there are other caveats to consider. The dictum of diagnostic parsimony encourages clinicians to ascribe a patients symptoms and findings to the smallest number of distinct disorders as possible. This concept is opera - tionalized in the Diagnostic and Statistical Manual of Mental Disorders (Third Edition, Revised), which specifically prohibits making certain diagnoses if another syndrome that could cause similar symptoms is present. When applied to pharmacotherapy as well as diagnosis, this notion exhorts the clinician to use the fewest number of medications that will bring about satisfactory symptom relief Physicians should therefore attempt to achieve therapeutic results initially with drugs that affect the primary underlying pathological processes, rather than employing nonspecific or additional agents targeted at particular symptoms. Benzodiazepines are frequently misused in this fashion, with occasionally unfortunate outcomes.
An obvious example of this dilemma is the use of BZDs for insomnia. While quite useful when prescribed as indicated for limited periods and situational stress, BZDs can be counterproductive when used for insomnia caused by other, more specific conditions. Major depression, which often produces initial insomnia along with the more characteristic early morning awakening, can be made worse by administration of most BZDs (although alprazolam at high doses has been shown to be as effective in the outpatient treatment of depression as many antidepressants).8 It may be preferable to treat such patients with a sedating antidepressant that produces prompt relief of this symptom as a side effect, though even an activating antidepressant will improve sleep over several weeks as its therapeutic effects are realized.
The administration of BZDs for insomnia that is due to a condition in which their use is contraindicated (such as sleep apnea, which often produces poor sleep and morning fatigue) can result in significant morbidity and mortality.9 Clearly, the rational use of BZDs requires:
* attention to accurate diagnosis,
* commitment to pathology-specific agents,
* knowledge of indications and contraindications.
* awareness of side effects and drug interactions, and
* avoidance of polypharmacy.
BENZODIAZEPINES IN CLASSIC PSYCHOSOMATIC DISORDERS
Theories regarding the relationships between mind, body and disease have been expounded throughout history. In this century, "psychosomatic" illnesses have been hypothesized to be characteristicbodily expressions of specific thwarted drives, symbolic representations of inner conflict, and complex interweavings of biological, psychological, and social factors (to summarize a few of many theories).10
Several ^classic" psychosomatic illnesses and their hypothesized etiologies have been described. While an inevitable causative nature of specific psychic factors has not been demonstrated convincingly in large populations, these models can sometimes be beneficial in understanding and treating individual patients, lliis group of disorders is often included in discussions of patients with combined medical and psychiatric symptomatology for its historical significance and widespread familiarity, while a number of other conditions discussed later in this article may be of more pragmatic interest to practicing physicians. The role of BZDs in these syndromes is as variable as the syndromes themselves, although their utility as primary therapeutic agents is generally low.
Asthma is a pulmonary disorder characterized by spasm of hyperreactive bronchioles and excessive secretion of mucus, 7'esulting in diminished airflow and oxygenation. It affects approximately 3% of Americans, typically causing intermittent attacks of wheezing, coughing, dyspnea, and respiratory compromise, and can be triggered by significant emotional distress. It is this relation between psychological stress and pulmonary dysfunction, along with the frequent onset of asthma in childhood, that originally led clinicians to speculate that dependency and separation anxiety were causative factors in this disorder."
The major pharmacologic treatment of asthma involves agents that reverse or prevent bronchospasm, mobilize secretions, and improve airflow. Theophylline is no longer the mainstay of therapy, as selective ß-adrenergic agents (such as albuterol) and inhaled steroids (such as beclomethasone) have been shown to produce equivalent results with fewer side effects.12 Benzodiazepines and other sedativehypnotics are generally contraindicated in acute attacks of asthma, since the increased work of breathing can lead to exhaustion and ventilatory failure, a situation that could be accelerated by sedation.
However, with individual patients in whom anxiety has been shown to contribute to the initiation or severity of an asthmatic attack, cautious use of BZDs at low doses may be beneficial. A persistently low pCO., on serial arterial blood gas determinations in such a patient (rather than the expected elevated pCO., that results from air trapping and decreased ventilation) suggests hyperventilation, and can help in the determination that BZDs may be useful. However, since this is not a pathognomonic test, the initial administration of BZDs to an asthmatic patient should not be attempted in a setting without the capabilities for full pulmonary support (including intubation and mechanical respiration).
Peptic Ulcer Disease and Dyspepsia
The gastric and duodenal lesions of peptic ulcer disease produce variable descriptions of discomfort from patients. Only half report the type of pain and pattern of symptom exacerbation and relief commonly thought to be characteristic of this malady.
The exact etiology of peptic ulcer disease remains unclear. Gastric acid secretion is necessary for ulcer production, but hyperacidity is not always present. Psychosomatic theorists originally focused on dependency needs and oral tendencies, along with frustrated drives and the effects of anger and other psychological stressors on gastric acid secretion, to explain this disorder.13 While these hypotheses have not been confirmed in prospective controlled trials, it is clear that psychological as well as physiological stress can precipitate ulcer formation in susceptible individuals.
Numerous classes of pharmacological preparations are currently available for the treatment of ulcer sufferers, including antacids, selective histaminereceptor blockers, proton pump inhibitors, prostaglandin analogs, anticholinergics, and local barrier agents. Antibiotics can also be useful in ulcers associated with Helicobacter pylori (formerly known as Campylobacter pylori ) colonization .
Benzodiazepines are occasionally used adjuncti vely in the treatment of peptic ulcer disease, usually when anxiety symptoms are clinically prominent. While stress management and relaxation techniques can be beneficial for some people with peptic ulcer disease,14 there is little evidence that BZDs alone are effective as sole therapy for acute disease, and their use as prophylactic agents is limited.15
Functional dyspepsia, a common entity with a presentation similar to but usually less severe than peptic ulcer disease, is characterized by indigestion, abdominal discomfort, and other manifestations such as nausea, gas, and irregular bowel movements. It shares many clinical features with irritable bowel syndrome, a motility disturbance of the intestinal tract that has been extensively researched. In both of these disorders there are no specific associated anatomical or pathological changes, and anxiety and affective symptoms are commonly found in addition to somatic complaints.
For irritable bowel syndrome, BZDs (frequently in combination preparations with antispasmodic and anticholinergic agents, such as Librax®) have a limited role in comprehensive treatment regimens that include dietary management and attention to psychosocial factors. 16 Many clinicians find similar regimens helpful in the care of patients with functional dyspepsia.
Another of the classic psychosomatic disorders is ulcerative colitis, one form of inflammatory bowel disease. While much of the following refers specifically to ulcerative colitis, similar considerations apply to Crohn's disease and other inflammatory bowel disorders. As these terms imply afflicted individuals suffer from inflammation and ulceration in portions of the colonic mucosa, giving rise to intermittent episodes of abdominal pain, tenesmus or painful defecation, bloody diarrhea, and various systemic signs such as fever and malaise. Complications include gastrointestinal hemorrhage, peritonitis, sepsis, toxic megacolon, and fistula formation, along with such extracolonic manifestations as arthralgias, ocular irritation, and dermatologie lesions.
Personality characteristics such as rigidity, impulsiveness, intellectualization, and sensitivity to rejection have been ascribed to ulcerative colitis patients, and situations that threaten the stability of their interpersonal relationships or provoke feelings of inadequacy and hopelessness have been posited to precipitate attacks.1.
Medical therapy includes antidiarrheal medications, preparations delivering 5-aminosalicylic acid to the colon such as sulfasalazine and olsalazine. topical or systemic steroids, and immunosuppressive agents such as cyclosporine, azathioprine, and 6-mercaptopurine. Emergent surgical intervention is occasionally required, and ongoing psychotherapy may benefit selected patients with marked characterological features or comorbid psychiatric disease. Benzodiazepines are usually helpful only as adjuncts for the management of persistent anxiety or other appropriate symptoms.
Other Classic Psychosomatic Disorders
Hypertension is often considered to have a large psychophysiologic component, given the nearly universal rise in blood pressure seen in people under conditions that provoke fear, frustration, anger, and other negatively charged emotions. In patients with mild to moderate hypertension, nonpharmacologic measures such as dietary change, exercise, and biofeedback can be effective treatments.
While BZDs can produce a transient lowering of blood pressure as a side effect (particularly when given IV), because of their other actions and potential for addiction they are seldom used as sole therapeutic agents in this disorder.18 As with other conditions, however, they may be useful adjuncts during periods of unusual stress or with patients who have concurrent anxiety disorders.
Neurodermatitis is a general term that encompasses several conditions in which there is intense localized itching leading to recurrent scratching, excoriation, and secondary skin changes of hyperpigmentation and thickening (lichenification). Involved areas can be single and circumscribed (as in pruritus ani), or multiple and diffuse.
The precipitating event is frequently undetermined. It is clear that situational stress and psychologic distress can exacerbate and maintain the symptoms of neurodermatitis. Underlying diseases such as malignancies, parasitic infections, and other dermatological disorders must be ruled out, and symptomatic relief is best obtained with steroid creams and behavioral measures that minimize further scratching.
The use of BZDs in neurodermatitis has not been rigorously studied, but clinical experience suggests they are of limited benefit in the absence of coexisting anxiety disorders.
Rheumatoid arthritis is a chronic disorder of unknown etiology that typically produces widespread symmetrical joint swelling and eventual deformities, with resultant pain and disability of varying degrees. Multiple studies have been performed over the years in an effort to determine a "rheumatic personality" without definitive results.19 There continue to be numerous attempts to elucidate the effects of psychologic stress on immune function in rheumatological (as well as other) disorders.
The effects of the disease itself and of the various analgesic, antiinflammatory. and remittive agents that are used to treat it can lead to numerous psychiatric symptoms.20 Insomnia is a common complaint, but because of the chronic nature of this condition, many clinicians prefer to avoid BZDs out of concern over possible habituation and tolerance.
Hyperthyroidism, the last of the classic psychosomatic disorders, is a common condition that has become well known to most Americans from the diagnosis in former President Bush and Mrs. Bush of Graves' disease (which, along with toxic nodular goiter and thyroiditis, causes most cases of hyperthyroidism). The conventional picture of thyroid excess resembles that of generalized anxiety, with agitation, restlessness, tremor, and irritability. However, virtually all forms of psychiatric symptomatology can be seen in hyperthyroidism, including psychosis, mania, depression, and dementia.21
Current treatment involves antithyroid medications and radioactive iodine, while surgery is less frequently employed than in the past. Beta-blockers rather than BZDs are usually used to reduce the peripheral signs of thyroid excess (such as tachycardia, hypertension, and tremor) while thyi'oid function is returning to normal, since BZDs have been reported to affect the results of 131I and T3 resin uptake studies.22
BENZODIAZEPINE USE IN OTHER MEDICAL/ PSYCHIATRIC DISORDERS
There are a variety of other common disorders for which BZDs are regularly prescribed as part of the therapeutic regimen, and in which some degree of both medical and psychiatric expertise may be desirable for optimal patient care. This combined specialty approach can be provided by a psychiatrist proficient in biomedical disorders (a "medical psychotherapist"),23 a primary care physician with a biopsychosocial orientation, a graduate of one of the combined internal medicine/ psychiatry residency training programs, or by multiple physicians who consult and collaborate among themselves.
As with the classic psychosomatic disorders, no single explanatory model or therapeutic approach is appropriate for all patients. Individualized assessment and treatment planning are essential to obtain satisfactory results.
Perhaps in no other realm of health care is the interaction between medical and psychiatric factors more evident than in the area of substance abuse. It is axiomatic that BZDs should be used cautiously (if at all) in patients with a history of addictive behaviors, yet through oversight, denial, or lack of awareness the provision of BZDs to this population is unfortunately all too common. These agents are frequently involved in overdose situations, and while intoxication with BZDs alone is reasonably well tolerated in an otherwise healthy patient, ingestion in concert with alcohol or other medications can frequently be lethal.24
BZDs are often useful in the initial detoxification from substance abuse (and are usually avoided in long-term recovery programs). They are the medications of choice in alcohol withdrawal syndromes,25 given their comparatively good side effect profiles and anticonvulsant activity. However, they can occasionally cause or worsen delirium in elderly or cognitively impaired patients.
Pharmacologic treatment of abuse and dependency in other classes of drugs, such as narcotics and sympathomimetics, occasionally includes BZDs as adjunctive medications, although agents such as Clonidine and beta-blockers have been used more extensively.
Coronary Artery Disease and its Sequelae
Angina pectoris can result from atherosclerotic blockage or paroxysmal spasm of the coronary arteries (or both), and is frequently stimulated by emotional arousal. The ensuing ischemia can result in damage or destruction of the underlying myocardium, leading to complications such as recurrent pain, arrhythmias, and congestive heart failure.
As nonspecific anxiolytics, BZDs have long been employed in the period immediately following myocardial infarction to modulate the psychological factors that lead to manifestations of autonomic excess, and therefore reduce myocardial oxygen demand. The euphoria and sense of well-being that some patients experience with these preparations may also contribute to clinical improvement, but can lead to the development or maintenance of delirium (frequently referred to as "ICU psychosis").
While there is some evidence that BZDs can diminish the release of counterregulatory hormones in response to stress, with salutary effects on angina and silent ischemia,26 there are no controlled trials of BZD use in survivors of acute myocardial infarction. In general, BZDs have negligible cardiac side effects when given orally, unlike tricyclic antidepressants (which have a quinidine-like effect on intracardiac conduction) and monoamine oxidase inhibitors (which can cause a hypertensive crisis with concomitant use of sympathomimetics or tyrnmine-contairimg foods).
An interesting area for future investigation is the use of BZDs and other psychoactive medications as pharmacologic aids to improve the quality of life for patients with audible prosthetic heart valves and surgically implanted automatic defibrillators, who frequently report distress over the intrusive nature of their lifesaving devices.
Chronic Obstructive Pulmonary Disease
Patients with chronic obstructive pulmonary disease are a heterogeneous group, as some have predominantly emphysematous changes (with alveolar wall destruction and terminal bronchiolar enlargement) while others primarily display the hallmarks of chronic bronchitis (with cyanosis and a productive cough due to excessive mucus secretion). Many patients have elements of both, often with bronchospasm and superimposed bacterial infection. The common symptomatic consequence of these diverse abnormalities is dyspnea. This feeling of breathlessness and suffocation is quite uncomfortable and frightening to many patients, and anxiety is a frequent concomitant feature of pulmonary dysfunction.27
The severity of lung pathology as measured by objective means does not always correlate well with patients' perceptions of dyspnea, although for some there is an association between their emotional state and their sensation of breathlessness. The issue is clouded by the knowledge that hypoxia and several pulmonary medications can also produce symptoms of anxiety.
When anxiety is judged to play a significant role in a patient's distress, small doses of BZDs may reduce dyspnea and increase comfort. The same precautions taken when treating asthmatic patients with BZDs (low dosing and careful monitoring) should be followed here, and those agents with relatively short halflives should be used. Numerous drugs have been used for the relief of dyspnea in unselected patients with chronic obstructive pulmonary disease, and there may be a role for the nonbenzodiazepine anxiolytic buspirone in this situation.
Fibromyalgia is one of the disorders in which a patient's symptoms often seem out of proportion to the objective physical and laboratory data. The muscle pains, fatigue, disturbed sleep, and emotional distress reported by patients, along with the paucity of associated findings, may lead clinicians to consider anxiety states, affective disease, or somatoform conditions such as somatization disorder in their differential diagnosis.
While tricyclic antidepressants are an established part of the comprehensive treatment of fibromyalgia (along with nonnarcotic analgesics, physical therapy, and patient education), BZDs are generally used only for persistent associated anxiety.
Nocturnal myoclonus, another of the sleep disorders, is characterized by episodes of muscular jerking in the lower extremities at intervals during the night. Although it can disrupt sleep and lead to various somatic and psychological symptoms, it is frequently the bed partner who provides the necessary history for diagnosis. Clonazepam is usually prescribed for control of this myoclonic condition and is generally effective.28
Various other disorders may benefit from the use of BZDs as adjuncts to primary treatment modalities. In several cancer chemotherapy regimens, lorazepam is used in the overall management of drug-related nausea (although by itself it has little antiemetic action). It frequently provides a desirable amnestic effect for the treatment period as well.24
Benzodiazepines have also been used in conjunction with neuroleptics for the acute management of psychotic states, since the combination provides adequate control of behavioral symptoms with a lower total dose of neuroleptic and with fewer side effects. There have been numerous reports on the use of BZDs in the geriatric population and in pregnant patients.
Several conditions are considered primarily psychiatric in nature but are frequently seen by medical specialists and primary care physicians. Panic disorder and other anxiety states, depression accompanied by physical complaints, somatoform disorders, and malingering are among the most common of these. Their diagnostic and pharmacologic treatment strategies, as well as that of insomnia (and the recent controversies concerning triazolam), are well covered elsewhere in the literature.
There are a number of conditions in which somatic and psychiatric factors interact to produce the final clinical scenario. Benzodiazepines are useful as either primary or adjunctive treatment in a number of these disorders, although much of their use is based on case reports and anecdotal evidence rather than rigorously controlled studies. Clinicians should exercise caution in patients with complicating medical or psychiatric diseases, concurrent medication use, or a history of addictive behaviors. As with all therapies, the risks and benefits of treatment (and of not receiving treatment) must be discussed with the patient, and compliance should be continuously monitored.
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