Professional singers often present a difficult diagnostic dilemma concerning their medication use. Most drugs are never formally evaluated for effects on the voice and finding details of rare side effects can be time consuming for the practitioner. Common use of over-the-counter medication and herbal remedies, combined with the interaction of prescription medications used to treat other medical conditions, can cause many physical and psychologic interactions in patients that may not intuitively relate to medication use. Some side effects and interactions may be managed easily, whereas others may be much more severe. An open communication with the patient and knowledge of these issues can be helpful in the management of professional voice users.
Otolaryngologists should be familiar with the potential side effects and interactions of medications that are prescribed commonly to professional voice users. Because some of these side effects are atypical and can be psychiatric symptoms, their relationship to medications might not be obvious. Oropharyngeal dryness, voice changes, movement changes, mood disturbances (eg, agitation, anxiety, depression, and mania), perceptual disturbances (eg, hallucinations and delusions), cognitive disturbances (eg, delirium and confusion), behavioral disturbances (eg, insomnia), and drug interactions are all important possibilities of which the prudent practitioner should be aware. Drug-induced symptoms can occur even with standard dosages and at any time during the course of treatment. An awareness of the potential for side effects caused by adrenocorticoids, antihistamines, decongestants, antisecretory drugs, and other medications will help the clinician to avoid or detect and treat drug-induced disorders, as will an awareness of the potential for side effects caused by combinations of medications. Identification of individual risk factors, such as age, preexisting organic brain disease, a history of drug abuse or dependence, or coexisting or preexisting psychiatric disorders, is important in preventing and detecting drug-induced disorders. The drugs discussed in this article can have serious—and even fatal—interactions with certain medications.
The combination of some of the medications prescribed by several practitioners, including otolaryngologists, psychiatrists, and naturopathic care givers, has the potential to enhance or interfere with the therapeutic effects of one or the other. In addition to psychiatric side effects, other adverse reactions can occur (eg, cardiac arrhythmias, hypertension, and local effects). Certainly, all reactions, particularly psychiatric symptoms, are not caused by medication; however, some can be a manifestation of a coexisting or preexisting psychiatric or other disorder that has been aggravated by a combination of medications.
Drug-induced psychiatric disorders
The manifestations of drug-induced psychiatric disorders can be related to direct drug toxicity or to interference with the brain’s metabolism of certain drugs. The most common psychiatric symptoms include delirium (an acute reaction with fluctuating awareness of self and environment), confusion, disorientation, tremor, ataxia, and mania. Associated behavioral signs include increased physical activity, rapid speech, insomnia, and mood elevation. Psychiatric symptoms that occur during the course of treatment also may be related to the medical or psychiatric condition being treated. For example, anxiety disorders and panic attacks are known to occur in association with thyroid, parathyroid, and adrenocortical disorders; Langhan’s cell endocrinopathies; collagen vascular disorders (eg, systemic lupus erythematosus, rheumatoid arthritis, temporal arteritis, and periarteritis nodosa); neurologic (eg, multiple sclerosis) and neurotologic (eg, Ménière’s disease) . Delusions (the perception that one’s environment and circumstances seem unfamiliar) can occur in association with certain endocrinopathies . Derealization (the feeling that familiar events seem unreal, strange, or dream-like and that colors, objects, and shapes appear to be distorted) and delusions have been reported in systemic lupus erythematosus .
A detailed history aids in the clinician’s assessment of each patient’s risk. The history should include the following questions:
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What prescription medications, over-the-counter (OTC) medications, and herbal remedies are the patient taking?
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Are there any coexisting medical conditions?
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Is there a personal or family history of a psychiatric disorder?
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Is there a history of a reaction to a psychiatric drug?
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Is there a history of drug or alcohol abuse?
The patient’s age also is an important factor when deciding which medications to prescribe. Elderly patients have a greater risk for drug-induced psychiatric disorders because they tend to be taking more medications and, therefore, are more likely to experience drug interactions. Older patients also tend to have other medical conditions that can prolong drug metabolism and increase systemic drug levels.
Preexisting organic brain disease and drug abuse also can be risk factors for the development of psychiatric side effects. Patients who have a history of drug dependence or abuse often manifest delirium. The presence or history of a mood disorder—depression or mania—also is a risk factor for psychiatric side effects to medications . Adrenocorticoids can aggravate or unmask depression or mania in these patients. Even a family history of mania is a risk factor for the development of mania as a side effect .
Assessment of all risk factors is important because multiple factors in a particular patient can be additive. The overall low incidence of psychiatric side effects with a particular medication might increase in the presence of other factors. An understanding of the risks in each individual patient is essential in selecting medications. Physicians should routinely ask patients to bring in or to make a list of all medications that they have taken during the previous 2 months. Clinicians also should inquire if a patient has ever experienced any side effects or abnormal reactions from medication ( Table 1 ).
| Drug | Side effect |
|---|---|
| Adrenocorticoids | Agitation, anxiety, confusion, delirium, depression, hallucinations, mania, paranoia, psychoses, sleep disturbances |
| Antihistamines and decongestants | |
| Azatadine | Agitation, anxiety, euphoria, hallucinations, hypomania, mania, nervousness, somnolence |
| Loratadine | Agitation, anxiety, confusion, delirium, depression, nervousness |
| Fexofenadine | Somnolence |
| Phenylpropanolamine a /guaifenesin | Agitation, anxiety, nervousness |
| Pseudoephedrine b /guaifenesin | Hallucinations |
| Antisecretory agents | |
| Cimetidine | Confusion, delirium, depression, hallucinations, mania, paranoia |
| Famotidine | Agitation, anxiety, depression, nervousness |
| Lansoprazole | Hallucinations |
| Nizatidine | Agitation, anxiety, nervousness, somnolence |
| Omeprazole | Aggression, agitation, anxiety, depression, hallucinations, hostility, nervousness, violence |
| Ranitidine | Confusion, delirium, depression, hallucinations, mania |
a Agents containing phenylpropanolamine also can cause confusion, delirium, depression, euphoria, hallucinations, hypomania, mania, and paranoia.
b Agents containing pseudoephedrine also can cause agitation, anxiety, euphoria, hypomania, mania, nervousness, and paranoia.
Side effects of specific common medications
Steroids
Adrenocorticoids are known to cause side effects. Gastrointestinal upset and ulcers, increased appetite, mucosal drying, blurred vision, and aggravation of blood glucose levels, particularly in diabetics, are documented side effects . Delirium, depression, insomnia, mania, and psychoses are not uncommon psychiatric effects. Symptoms tend to be proportional in incidence to the dosage and duration of steroid use. Iatrogenic Cushing’s syndrome, which can be caused by long-term steroid use, also can manifest these signs . A personal or family history of affective mental illness can predispose a patient to the psychiatric side effects of steroids. Some drugs, such as corticotropin, can cause an increase in endogenis corticosteroids causing similar effects. The potential for steroid abuse in professional voice users cannot be overemphasized, and the side effects should not be dismissed as insignificant.
Treatment of side effects may need to be considered when steroid use is required. A concomitant use of a histamine-2 receptor antagonist (H 2 blocker) or proton pump inhibitor (PPI) can assist with gastrointestinal upset. A carefully titrated insulin sliding scale can help to control blood sugar elevation in diabetics . Severe depression might require antidepressant treatment, and an antipsychotic medication or a mood stabilizer may become necessary to treat steroid-induced mania. Insomnia—as an isolated side effect or as part of a manic episode—also could require medical intervention.
Inhaled steroids are used primarily for respiratory disorders and present more local than systemic effects. Nasal steroids have had few documented effects on the voice; however, orally inhaled steroids have demonstrated oral candidiasis, dysphonia, pharyngitis, and cough and often are not recommended for use in professional voice users unless absolutely needed for asthma control because of the common voice effects . Ipratropium bromide, a nasally or orally inhaled medication used primarily for pulmonary symptoms, has shown side effects that include hoarseness and cough. Fluticasone, one of the more common medications used for asthma and used also as a primary nasal steroid, lists a prevalence of 2% for hoarseness and sore throat for the orally inhaled preparation. Salmeterol xinafoate and fluticasone propionate (Advair) lists the same incidence of hoarseness and throat irritation, attributing it to either drug. It does not seem to be dose dependent. Triamcinolone, pirbuterol acetate, and albuterol list voice changes as part of their common side effects. Voice difficulties due to lack of respiratory support in uncontrolled asthma need to be taken into consideration when evaluating the use of these medications in professional voice users.
Antihistamines and decongestants
These medications can be particularly troublesome because many antihistamines and decongestants can be purchased and are consumed without physician supervision. Moreover, some patients do not realize that their OTC medications include antihistamine and decongestant components; they are part of several OTC sleep aids as well. Some patients do not regard OTC medications as “real medicines”; therefore, they do not report them as part of their medical history unless they are asked specifically about them.
Often, antihistamines are paired with sympathomimetic or parasympatholytic medications, which thicken and reduce mucosal secretions, causing significant drying and consequent voice changes and pathologies. Sedation also is a side effect of these medications, with some preparations, such as loratadine and fexofenadine, causing less. Medications that contain phenylpropanolamine, pseudoephedrine, and phenylephrine are contraindicated in patients who are taking monoamine oxidase inhibitors (MAOIs) . These medications can produce dangerously high levels of norepinephrine because the MAOIs impair the metabolism of sympathomimetic medications .
Sympathomimetic medications by themselves also can cause psychiatric side effects. Young children and elderly patients who have organic brain syndrome are the most vulnerable. It may become necessary to discontinue the suspected culprit medication or to prescribe sedation or treatment with a high-potency antipsychotic, such as haloperidol. Low-potency antipsychotics, such as thioridazine or chlorpromazine, should not be taken with phenylpropanolamine because the combination can cause hypotension.
The antihistamine and anticholinergic components of a combination antihistamine and decongestant can produce an atropine-like psychosis, typically manifesting as confusion, disorientation, agitation, hallucinations, and memory deficits. Agitation can be treated with a short-acting, nonanticholinergic sedative, such as lorazepam. Severe agitation or psychotic symptoms can be treated with low doses of haloperidol. Recovery of the patient’s mental status following the administration of physostigmine confirms the diagnosis of atropine-like psychosis . Symptoms should resolve completely after the suspected medication is discontinued.
The hepatic metabolism of many medications is mediated by certain cytochrome P-450 enzymes, and the antidepressants fluvoxamine and nefazodone interfere with certain P-450 enzymes . When these antidepressants are prescribed with other medications that are metabolized by the same P-450 enzymes, competition between the medications for the enzymes impairs the liver’s ability to metabolize each as efficiently as usual. This can cause blood levels of these medications to become dangerously high and lead to significant side effects or even a fatal reaction . These antidepressants cannot be used in combination with astemizole for the same reason. Loratadine, fexofenadine, and cetirizine can be used with these antidepressants because they are metabolized by a different cytochrome P-450 isozyme .
Reflux medications
Laryngopharyngeal reflux is a common disorder treated in otolaryngology . The condition is often detected in patients who have voice complaints. Antisecretory medications, which decrease stomach acid production, are commonly used in the treatment of reflux laryngitis. The two primary classes of drugs prescribed for this condition are the PPIs and the H 2 blockers. The former includes agents such as omeprazole, lansoprazole, and esomeprazole; the latter includes drugs such as famotidine, nizatidine, ranitidine, and cimetidine. Even OTC antacids demonstrate significant side effects, including constipation, bloating, diarrhea, and a drying effect .
Documented side effects of PPIs include diarrhea, abdominal pain, nausea, elevation of hepatic enzymes, dry mouth, esophageal candidiasis, muscle cramps, depression, tremors, dizziness, fatigue, and headaches. H 2 blockers can cause dryness, but it usually is not significant. A recent study from England indicated an increased risk for hip fractures with long-term and high-dose PPIs and, to a lesser extent, H 2 blockers, particularly in men. The investigators recommended that in patients older than 50 years of age, an absorbable form of calcium should be taken with high-dose or long-term use of these medications .
All H 2 blockers have been associated with some psychiatric side effects . Although the overall prevalence of these side effects in outpatients is less than 0.2%, it is significantly higher among hospitalized patients, the elderly, the seriously ill, and patients who have hepatic or renal failure . These effects of the H 2 blockers vary with respect to their time of onset, but they usually resolve within 3 days of discontinuing the drug. For example, ranitidine can cause depression beginning at 4 to 8 weeks after the initiation of treatment. Cimetidine was reported to cause adverse events within 2 to 3 weeks and even caused delirium within 24 to 48 hours . The discontinuation of ranitidine and cimetidine has been associated with a withdrawal syndrome that includes anxiety, insomnia, and irritability . Cimetidine can increase the blood level and action of tricyclic antidepressants, such as amitriptyline, doxepin, imipramine, and nortriptyline; blood levels of these antidepressants can reach toxic levels, resulting in tachycardia and other side effects. The inhibition of the cytochrome P-450 enzymes by ranitidine or cimetidine also can lead to potentially dangerous side effects with certain other cytochrome P-450 metabolized medications. Cimetidine is the more potent inhibitor of the two; ranitidine is one fifth to one tenth as potent. Famotidine and nizatidine do not inhibit this enzyme system at all .
Cimetidine lengthens the half-life of the antianxiety medications clorazepate, chlordiazepoxide, and diazepam to a greater degree than does ranitidine . Lower dosages of these long-acting benzodiazepines should be considered when they are prescribed for a patient who is taking cimetidine. An alternative is to use a short-acting benzodiazepine, such as oxazepam or lorazepam. The metabolism of these short-acting antianxiety medications is not affected by ranitidine or cimetidine . Cimetidine also can increase the blood levels of serotonin reuptake inhibitors and antipsychotic medical anticonvulsants . Whenever possible, lower dosages of these medications should be given when they are used in combination with cimetidine. The blood levels of these medications should be monitored periodically, and their dosages should be adjusted accordingly. Another option is to use a different H 2 blocker, such as famotidine or nizatidine.
Hormones
Significant voice effects have been documented with androgens and anabolic steroids . Irreversible lowering of the fundamental pitch and coarsening of the voice can be the result of danazol, which is commonly used in the treatment of endometriosis and postmenopausal sexual dysfunction . High-dose progesterone birth control pills, generally not available in the United States, can cause similar androgen-like changes in the voice . Most low-dose contraceptives have a significantly lower chance of voice changes, usually reversible when the medication is discontinued. Van Lierde and colleagues evaluated 24 professional voice users during the use of oral contraceptives and found no objective voice differences. Depo-Provera (medroxyprogesterone acetate) has demonstrated hoarseness as a side effect.
Estrogen replacement has become a controversial area in medicine for numerous health reasons. In professional voice users, estrogen replacement may help to prevent postmenopausal voice changes . Low-dose progesterone supplements, such as found in Premarin, are not believed to cause significant voice changes; however, some synthetic substitutes may cause androgenic effects .
Hypothyroidism, with thyroid hormone replacement, is one of the more common disorders found in women. Sometimes diagnosed in professional voice users by voice changes alone, careful monitoring of supplemental thyroid hormone replacement can be particularly important in a professional voice user.
Antivirals
Antivirals are used for many disorders. Their use in chronic disease (eg, HIV and herpes) and in acute viral illnesses is common. Several of the medications cause side effects. Hoarseness, cough, pharyngitis, nervousness, muscle spasm, and tremor have been reported with zidovudine; because HIV disease alone can demonstrate these signs, it can be difficult to differentiate. More common antivirals, such as oseltamivir, have not shown documented voice changes; however, swelling of the face and tongue has been reported. Oseltamivir phosphate is not recommended in patients who have airway disease, secondary to reports of bronchospasm and decreased lung capacity. Amantadine hydrochloride, used in Parkinson’s disease, has antiviral effects with side effects of agitation, tachycardia, and xerostomia .
Analgesics
Aspirin, several nonsteroidal anti-inflammatory medications (NSAIDs), and acetaminophen are OTC medications that are used commonly for the relief of minor pain and fever. Delay in clotting is a known complication of aspirin and all NSAIDs, so avoidance of these medications is recommended often for professional voice users. A low dosage of aspirin is used often for cardiac prevention and is a situation where the minimal bleeding risk likely is outweighed by the cardiac prevention benefit. Newer cyclooxygenase-t inhibitors, now available by prescription, do not have the same bleeding issues or gastrointestinal upset because of a different pathway, but they do have other significant cardiac side effects .
Topical anesthesia and narcotic use in professional voice users, particularly before a performance, should be discouraged. Narcotics can be associated with signs of dysarthria, in addition to mental impairment . Impairment of physical feedback of the voice by these types of agents can predispose the user to injury and more significant long-term voice disabilities and can be more career-ending than a performance cancellation may be.
Diuretics
Diuretics are used to eliminate fluid in medical conditions such as cardiac or renal failure. In premenstrual women, excess fluid can be found in Reinke’s space and other tissues because of increased circulation of antidiuretic hormone. This fluid is bound and not affected by the use of diuretics. In fact, diuretics can add to the dehydration of the performer. Diuretics also are used in conjunction with other antihypertensive medications. Several angiotensin-converting enzyme inhibitors, such as captopril and enalapril, have had case reports of hoarseness, cough, and aphonia . Careful monitoring of the voice is important when these medications are needed for other health concerns.
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