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Folia Phoniatr 1992:44:143-154

T.M. Harris Otolaryngology and Head and Neck Surgery Unit. Lewisham Hospital. London. UK

The Pharmacological Treatment of Voice Disorders

Abstract The increasing diversity of purpose-built, synthetic and biogenetically engineered pharmaceuticals has led to a revival of interest in the pharmacological possibili­ ties for the treatment of voice disorders. Where dvsphonias arise as a part of a pathophysiological pro­ cess, the pharmacological treatment of either the pa­ thology or its associated symptoms may improve dys­ phonie voicing patterns. The treatment of symptoms such as cough and vocal fatigue are discussed together with treatment of allergic and other causes of inflam­ mation or stiffening of the vocal tract. The pharmaco­

logical treatment of dysphonia due to defective neuro­ muscular control in dyskinctic and dystonic condi­ tions is also discussed. Dysphonic voicing patterns are commonly multifactorial, and the author wishes to highlight problems encountered when attempting to adjust the performance of the vocal tract: imprecise targeting of the pathophysiological problems either by the physician or by the drug employed, and the sys­ temic and attendant side-effects of drugs which may be thought to be appropriate.

Die medikamentöse Behandlung von Stimmstörungen Die Stimmproduktion ist ein interessanter biomecha­ nischer Prozess mehrerer körperlicher Funktionen. Die medikamentöse Behandlung durch den Phoniatcr beschränkt sich auf diskrete pathologische Prozesse. Die Modifikation verhaltcnsbcdingtcr falscher Stimm­ muster gehört nicht zur Domäne pharmakologischer Behandlung, obwohl das zunehmende Verständnis der zentral wirkenden Neurotransmitter uns für die Zu­ kunft hoffen lässt. Bei der grossen Mehrheit der medi­ kamentös behandelbaren Stimmstörungen kann eine zusätzliche funktionelle Stimmbehandlung zu einem

deutlich besseren Resultat führen. Die neuesten phar­ makologischen Entwicklungen lassen laryngeale Dys­ plasien der Schleimhäute ebenso wie eine selektive Denervation mittels Toxinen möglich werden. Dage­ gen sind nur geringe Fortschritte in der topischen Behandlung durch Aerosole im Bereich der oberen Luftwege erzielt worden. Man darf hoffen, dass mit der empirischen Behandlung der Stimmstörungen durch zusätzliche multizentrische Studien aktueller Medika­ mente ein Fortschritt erzielt werden kann.

L’émission vocale étant un processus biomécanique intéressant plusieurs fonctions corporelles, les pos­ sibilités du phoniatre de soulager une dysphonie par des moyens pharmacologiques se limitent au traite­ ment de processus pathologiques discrets. Modifier des symptômes vocaux dus à un comportement vocal inadéquat ne relève pas du domaine de la pharmacolo­ gie. bien que notre meilleure compréhension des neurotransmetteurs centraux donne quelque espoir. Dans la grande majorité des processus pathologiques abou­ tissant à une dysphonie et pour laquelle le traitement médicamenteux est applicable, le résultat est nette­

ment meilleur si la réhabilitation vocale fait partie de l'ensemble du traitement. De nouveaux développe­ ments médicamenteux laissent prévoir des possibilités de faire régresser les dysplasies muqueuses laryngées, ainsi que d'envisager des processus sélectifs de déner­ vation partielle et permanente à l’aide de nouvelles for­ mes de toxines. Par contre peu de progrès ont été réali­ sés dans l'administration topique d'aérosols pour les voies respiratoires supérieures. On peut espérer que les traitements empiriques actuels de la dysphonie s'amélioreront avec les essais informatisés et multicen­ triques de médicaments en cours.

Dr. Tom Harris. FRCS Otolaryngology and Head and Neck Surgery Unit Lewisham Hospital London SRI36LH (UK)

©1992 S. Karger AG. Basel 0015-5705/92/ 0444-0143Î2.75/0

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Traitement médicamenteux des troubles de la voix

Drugs Which Act on the Vocal Tract

Any disease, condition or symptom which affects the biomechanical function of any part of the vocal tract is of immediate concern both to the dysphonie patient and to phoniatrician who is treating him. Because of the social, professional and financial pressures which dysphonia places on many patients, cli­ nicians are frequently persuaded to try phar­ maceutical measures where, under other cir­ cumstances. only simple conservative mea­ sures would be undertaken. The sheer volume of proprietary pharmaceuticals manufactured and sold, mostly without benefit of medical prescription, for ‘the hoarse or tired voiced’ is enormous, and yet evidence that there is any therapeutic benefit is usually anecdotal at best. Most of the drugs prescribed for voicing problems are not system-specific and are therefore liable to unwanted side-effects. Many have more than one pharmacological mode of action and therefore produce a com­ posite effect, which is less than optimal. It is also apparent that in clinical practice in 1992, many of the drugs prescribed arc being used principally for placebo purposes. This report will disregard cultural and national prescrib­ ing variations and consider only those drugs

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currently available to phoniatricians and other physicians which can be shown to have genuine applications in the treatment of dvsphonias. Most of the drugs have been available to phoniatricians for a number of years, and those in common use in Western, allopathic medical tradition may be summarized as: drugs which affect coughing and viscosity of mucus (cough suppressants, expectorants, mucolytics), drugs which modify allergic or asthmatic symptoms, anti-inflammatory drugs, bronchodilator drugs, antibacterial drugs. Drugs which modify vocal perfor­ mance arc also occasionally prescribed (these may act centrally, on the autonomic nervous system, on the endocrine system or peripher­ ally on the motor end plates).

Drugs Which Affect Coughing and Viscosity of Mucus

The cough reflex serves a necessary func­ tion when it removes secretions, exudates or foreign material from the louder respiratory tract (productive cough). Unproductive or dry coughing may be treated symptomatical­ ly. The most effective treatment for all coughs remains removal of the cause. Where there is tracheobronchial irritation, this is best achieved on the afferent side of the reflex arc by soothing irritated mucous membranes with steam inhalations. Benzoin tincture compound or other aromatics such as men­ thol may be added to the steam. The latter stimulates cold receptors in the bronchial tree and gives a temporary illusion of a clear air­ way. It is also an obsolete respiratory stimu­ lant and occasional cases of menthol poison­ ing from proprietary inhalations are still re­ ported. Where the irritation is principally supralaryngeal. simple demulcents or linctuses are soothing. Demulcents arc used in a similar

The Pharmacological Treatment of Voice Disorders

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Over the last decade, the principal thrust of development in the pharmaceutical industry has been the production of drugs of increas­ ingly specific modes of action. This has been achieved in several ways. Synthesis of drugs which bind at a single type of receptor site, or by switching production of manufactured bio­ materials (e.g. insulin) to biogenetically engi­ neered systems only capable of production of a single monoclonal 'pure' product without associated contaminants. How then, have these advances affected the clinical treatment of voice disorders?

is still effectively treated by nasal douching with a spray of normal saline. Further down the respiratory tract, mucolytic drugs may be used to thin mucus, aiding expectoration, and on occasion, an unreliable vocal attack. Ace­ tylcysteine and methylcysteine have free sulfhydryl groups which can open disulphide groups in mucus, thus reducing viscosity. They are adminsitered in aerosol inhalation, although acetylcysteine and the related carbocysteine may also be taken orally. All of these may on occasion cause gastro-intestinal irrita­ tion or allergic reactions. Another mucus­ thinning drug, bromhexine. may also be taken orally, but is no longer universally available. Detergent aerosols such as tyloxapol arc prob­ ably more irritant and not significantly more effective than the above. Expectorant drugs cause hypersecretion of mucus, the rationale for their use being that a dry cough becauses productive and that the resultant expectoration is less viscous. Expec­ torant preparations may contain iodides, chlorides, bicarbonates, citrates, guaifenesin, ipecacuanha, creosotes or squill. They all have undoubted placebo value in clinical practice, although in high doses many exhibit emetic properties as well.

Drugs Which Modify Allergic or Asthmatic Symptoms

Histamine is an inflammatory mediator which occurs widely in the surface mem­ branes of the body in bound form in mast cells. It is released cither in response to nox­ ious stimuli or immunoglobulin (IgE) activity in anaphylactoid (type 1) allergy, or by pre­ cipitating antibodies in the slower type 3 reac­ tion. Histamine release is accompanied by other inflammatory mediators such as pep­ tides (kinins) and arachidonic acid deriva­ tives (leukotrienes and prostaglandins). These

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manner lo saliva substitutes (c.g. Salivart, Sa­ liva Orlhana) or tear substitutes (e.g. Hypromellose), they coat an irritated or dry mu­ cous membrane with a soothing low-viscosity hydrophilic layer. The main constituents are water and carboxymethylcellulose, generally with additional sorbitol and electrolytes. There appear to be no harmful side-effects in clinical practice. All centrally acting antitussives tend to se­ date patients in some degree. Sedation sup­ presses coughing, but may be disastrous if the patient is a performer. Antitussives fall into two main groups: the opiate-based cough sup­ pressants acting in the medulla and on the higher cortical centres as a tranquillizer, and the antihistamine (H, receptor) suppressants which arc used for their anticholinergic and sedating (but not their antihistaminic) ac­ tions. Both classes of drug also produce drying of the mucous blanket, which limits their value in the treatment of dysphonia. The lat­ ter group is commonly marketed in combina­ tion with a non-specific a-sympathomimetic agent such as pseudoephedrine, which may cause insomnia, tachycardia (with occasional rise in blood pressure), cardiac irritability, urinary retention and rashes. The therapeutic value of these medicines is limited, and al­ though significant side-effects are rare, the author feels that they have little place in mod­ ern phoniatry (see section on ‘Drugs and the Modificaiton of Performance’). Respiratory mucus consists largely of wa­ ter containing glycoproteins which are linked by disulphide bonds. Normally, over 100 ml is produced from the respiratory tract and swallowed every day. During respiratory in­ fections. there is an increase in mucus produc­ tion. Protein-containing exudates from dam­ aged membranes bind with the mucus glyco­ proteins increasing viscosity. Mucus stasis, whether due to an upper respirator}' tract infection or even a primary ciliary dyskinesia,

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increased bronchial reactivity, a vocal equiva­ lent of exercise- or cold-induced asthma [2], As in the case of asthma, any alteration in the characterstics of a vocalist’s lung function can significantly alter their technique for breath support. These patients respond satisfactorily to treatment with bronchodilators. Bronchodilators in current clinical prac­ tice come in two categories: (T-adrenorcceptor agonists, e.g. salbutamol. rimiterol, terbutaline. fenoterol and rcproterol. and xanthine derivatives, e.g. theophyline, aminophylline. The first group have limited activity at the (cardiac) ()| receptor, but act on mainly bron­ chial tissue at the mast cell and smooth mus­ cle by increasing intracellular cycle AMP. which diminishes mediator release (see be­ low) and produces bronchodilatation. The second group reduce the breakdown of cyclic AMP. achieving a similar effect by a different route. Unsurprisingly, the actions of the two groups are additive. The most troublesome side-effect that may occur in vocalists is an occasional increase in reflux oesophagitis with the use of xanthines. Glucocorticoid steroids have enjoyed a place in the laryngologist's armamentarium since the 1950s, when the first semi-synthetic preparations were marketed. They produce their anti-inflammatory effect in the delayed allergic response by entering mast cells pas­ sively and inducing production of the protein lipocortin. This in turn inhibits the enzymatic production of arachidonic acid, the precursor of the prostaglandin and leukotriene media­ tors. They also have anti-inflammatory effects by reduction of the vascular response, inhibi­ tion of the cellular component of the inflam­ matory response, together with diminution of capillary proliferation and fibrin deposition of chronic inflammation. All this may be of clinical benefit to the dysphonic patient in the short term. Other effects of steroids are less desirable in phoniatry: muscle bulk is reduced

The Pharmacological Treatment of Voice Disorders

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mediators act on intracellular cyclic AMP and GMP and produce the changes found in asthma - constriction of bronchial smooth muscle, production of bronchial mucosal oe­ dema and excessive mucus production. Hi receptor sites are found in the respiratory tract (H2 in the alimentary tract). The most successful treatment of allergic symptoms remains identification and exclu­ sion of identifiable allergens from the pa­ tients’ environment. Taking a medical history usually identifies probable candidates, and this is confirmed by skin prick testing with known allergen preparations. Raised allergenspecific IgE levels in type 1 are more expen­ sively identified by RAST testing the patient's serum. In asthmatic conditions, allergens may be identified by provocation testing, although this latter test is not without risk. Antihistamines are competitive inhibitors at receptor sites and are most useful if admin­ istered prior to allergen exposure in e.g. hay fever. They generally have associated anticho­ linergic effects, and while they are useful in the prevention and treatment o f allergic man­ ifestations in the nose, eye and larynx, they are also commonly associated with increase in the viscosity of the mucosal blanket and seda­ tion. Insomnia, nervousness and tremor are also common. Astemizole. terfenadine and ketotifen are relatively recent examples among many which are relatively free from side-effects. They are not useful in the treat­ ment of intrinsic, delayed-tvpe asthma [ 1]. Mast-cell stabilizers such as sodium cromoglvcate inhibit release of mediators from sensitized mast cells. Aerosol preparations are useful in the prevention of allergic symptoms of the respiratory tract as they have minimal side-effects. Sodium cromoglycate is not nearly so effective in the prevention of food allergy. On occasion, singers complain of perfor­ mance-related vocalization problems due to

[ 10].

Antibiotics

Despite the universal awareness that anti­ biotics are intended for the treatment of bac­ terial infection, there is still a widespread ten­ dency to administer them to vocal performers suffering from (usually viral) upper: respira­ tory tract infections ‘prophylactically’, even where there are minimal dysphonic symp­ toms. The usual justification of this practice is

that it allays the patient's anxiely. Many of the antibiotics prescribed are broad-spectrum, which docs not obviate the risk of superinfec­ tion. but instead increases the likelihood of laryngopharyngeal candidiasis. It is to be hoped that in the future the use of antibiotics for their placebo value will decline.

Drugs and the Modification of Performance

Phoniatricians today are in a privileged posi­ tion when it comes to the pharmacological modification of voicing. It is not an illegal act for a medical practitioner to prescribe a ste­ roid. a strong opiate analgesic of a sympatho­ mimetic amine for a performer, whereas if the performance was to be regarded as athletic and subject to international rules of competi­ tion. then the use of such drugs could lead to a lifetime ban from competition. Bodies such as the International Olympic Committee (IOC) seek nol only to prevent athletic competitors from gaining an unfair advantage, but also to prevent athletes from seriously damaging themselves by their inappropriate use of drugs in their pursuit of excellence [11, 12], It is therefore useful to be aw'are of those drugs which are banned by the IOC and to compare them with those commonly prescribed for voice users. More than 40 sympathomimetic amines or respiratory stimulants such as ephedrine, pseudoephedrine, phenylpropa­ nolamine, many of which are freely available in "cold cures’ and hay fever preparations, are all banned drugs. Athletes with asthma may only use one of four aerosols of the [T-adrenoreceptor agonists: bitolterol, orciprenaline, rimiterol. salbutamol and terbutaline. Of the narcotic analgesics, only dextromethorphan is acceptable as an antitussive. Diuretics for the purpose of weight loss are banned as are pep­ tide hormones and [3-blockers. Anabolic ste-

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by most steroids by gluconeogenesis and asso­ ciated fat redistribution; immunosuppressive actions and mineralocorlicoid water retention cannot be entirely avoided. Dysphonia is a common complication of inhaled steroid therapy and is usually due to a steroidinduced dyskinesia of the intrinsic laryngeal musculature producing bowing of the vocal folds [3, 4], Inhaled steroids may also exacer­ bate many dvsphonias associated with stress or clinical hypothyroidism [4] and on occa­ sion precipitate oesophageal candidiasis where maintenance dosage is required fre­ quently [5]. They are also prone to exacerbate reflux oesophagitis especially when used in conjunction wdth bronchodilator xanthines such as theophylline. Delivery systems affect where the drug is deposited in the airway [6. 7], Where it is necessary to treat asthma in a performer, the routine use of a spacer with the inhaler and postinhalational breath holding maximize the steroid deposited in the lower respiratory tract and minimize deposition in the laryngopharynx [8], In general, there arc fewer side-effects associated with inhaled ste­ roids than with therapeutically equivalent doses of systemic steroids such as predniso­ lone [9], but phoniatricians contemplating re­ challenging patients with a history of inhaled steroid-induced hoarseness should be aware that on study found a 60% recurrence rate

Treatment of the Dysphonia of Ageing

Ageing of the human vocal tract produces perceptual, acoustic and anatomical changes many of which arc apparent to the patient and observer alike. Proposed mechanisms for age­ ing abound: Free radical oxidation due to loss of mixed-function oxidases: covalent and hy­ drogen bond cross-linkage between molecules and even genetically programmed cell death have been postulated [ 16], Age changes in the larynx include structural modifications such as calcification, bowing of the arytenoid vocal

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processes, muscle atrophy and degeneration of the vocal ligament [17], Workers such as Bicver and Bless [18] have tied acoustic and aerodynamic measures to videostroboscopic findings in the elderly and have identified the most striking stroboscopically observed changes in vocal function: greater aperiodicity, incomplete glottal closure, mucosal wave alterations and reduced amplitude of vibra­ tions. Acoustic and aerodynamic measures exhibited greater shimmer and more intersub­ ject variability in F0 and mean airflow rates. Age-related changes in the body’s metabo­ lism and function are at present irresistible, although in the short term, many patients with characteristically ageing voices may seek help in delaying the change. From the phar­ macological viewpoint there is little to offer the patient with early phonasthenia other than hormonal support. At the present time, only hormonal support in women in and after the climacteric has been adequately re­ searched to the point where it may be offered in clinical practice. Oestrogen and the Larynx Research has demonstrated that the epi­ thelial cells of the human larynx have high affinity membrane receptors for 17-(i-oestradiol. The numbers of these receptors are com­ parable with those found in breast, ovary and uterine tissue [19]. According to studies with labelled hormone in adult baboons [20], re­ ceptors are distributed in the nuclei of vocal cord mesenchyme, laryngeal aditus and vocalis muscle. It was suggested as early as 1961 by Schiff and Burns that oestrogen could affect the quality of the mesenchymal extra­ cellular matrix or ‘ground substance’ by caus­ ing a breakdown of mucopolysaccharides into smaller units, thus shifting the normal sol-gel equilibrium towards the sol state. More recent work [21] has suggested that surface sites when triggered induce changes in calcium

The Pharmacological Treatment of Voice Disorders

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raids having a structure and activity related to testosterone are, of course, banned. It is worthwhile for the phoniatrician to remem­ ber that anabolic steroids may cause psycho­ logical effects, liver and cardiovascular dam­ age which may be lethal. Even in the dose range that phoniatricians may be tempted to use. there may be subfertility in males and vir­ ilization in women with its attendant and irre­ versible alteration in pitch range and timbre [ 13], The author feels that there is no place in clinical practice for the treatment of ‘vocal fatigue' by steroids. Centrally acting benzodiazepine tranquil­ lizers and peripherally acting (3-blockers arc banned from competition requiring fine mo­ tor control. They might be thought to provide a legitimate advantage if applied to vocalists. They do not. The only dysphonia transitorily amenable to a (high) dose of benzodiazepine is a true hysterical conversion. Vocal perfor­ mance after low-dose tranquillizers may suf­ fer in a similar manner to prc-performance alcohol ingestion: p-blockade appears to re­ duce symptoms of abnormal anxiety in musi­ cians and may actually improve performance [14] , but the same is sadly not true of young singers whose performance is not improved [15] .

Hormone Replacement Therapy (URT) [25] The menopause now occurs in European women at an average of 51 years as judged by the last monthly period. The ‘climacteric’ is a term which may be used to cover the 5 or more years preceding this event during which symptoms of oestrogen withdrawal may be­ come apparent. In addition to a perceived loss of timbre and loss of the top of the vocal range, phoniatricians should be aware of other age-related findings in the following

broad categories: vasomotor dysfunction (hot Hushes, night sweats): these are an immediate manifestation of oestrogen withdrawal; psy­ chosocial troubles (mood changes, insomnia, loss of memory, etc.): implicated by associa­ tion. but no causal link yet established with hormonal changes; urogenital dysfunction (vaginal dryness etc.): typically set in only a few years after the menopause: osteoporosis and cardiovascular disease: may appear in later years. Oestrogen replacement is generally succesful in the symptomatic relief of the first three categories. It also reduces osteoporosis and the death rate from cardiovascular disease. Its disadvantage is that it can also affect the breast and other sensitive tissue. Although HRT is not contra-indicated in cases of be­ nign breast disease, and its short-term use does not matter, with long-term use (10-20 years) there is an increased level of risk of 50% of developing breast cancer. This risk is reduced if a combination HRT dose of oestro­ gen plus progestogen is given: it should be noted, however, that in 10% of women pro­ gestogen causes either premcnstural tension syndrome or migraine. HRT is contra-indi­ cated where there is a history of breast or endometrial cancer. Some women may find it 'unacceptable' because of continuing cyclical withdrawal bleeds. HRT may be absorbed either orally, by implants or patches or vaginally. Contrary to popular belief, it does not in itself lead to an increase in blood pressure or two weight gain. Between 7 and 8% of post­ menopausal women in Britain are on HRT and then usually only for a brief period. The percentage in the United States is much higher.

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equilibrium which in turn triggers cytoplas­ mic synthesis and nuclear breakdown. The biochemistry of the stimulation of the oestro­ gen receptor which was originally researched in primary breast carcinoma has shed some further light on the mode of action of the oes­ trogen receptor [22], Parker [22] states that binding of the oestradiol ligand primarily fa­ vours dimerization and hence DNA binding and secondarily activates the oestrogen-de­ pendent transcriptional activation factor (TAF-2). From a clinical standpoint, the se­ ries of Abitbol et al. [23] found that cyclical changes in cytological smears taken from the vocal folds followed pari passu the menstrual changes found in cervical smears. These find­ ings support the clinical observations of vocal changes noted in the female voice in the pre­ menstrual period and during the climacteric. Abrahamson ct al. [24] performed a detailed evaluation of a large group of trained singers' subjective impressions of premenstrual changes in vocal quality in 1984 and com­ mented that the findings confirmed the im­ pression that there is a small drop in funda­ mental frequency together with a loss of vocal quality. They added that the changes could not be accounted for in terms of absolute oes­ trogen levels, but seemed more dependent on changes in level, especially where there was a small sharp drop.

Spasmodic dysphonia was first described as a clinical entity in a paper by Traube [26] in 1871. Unfortunately, further research into this affliction virtually ceased for the next 70 years as the disorder was held to be a hysteri­ cal phenomenon since most sufferers were women. Many of them could associate the problem with stress, their vocal folds looked 'normal' and the singing voice was affected less than the speaking voice. As hysteria be­ came a less popular diagnosis, the cause of the condition was relabelled psychoneurosis, and it is only within the last 15 years that the underlying organic factors have begun to be generally recognized. Spasmodic dysphonia is a condition w'hich has been described as 'trying to talk while being choked' [27], More recent work suggests that the condition properly belongs to the group of focal dystonias, and it is now fre­ quently referred to as laryngeal dystonia [28]. This is a neurological disorder of central mo­ tor processing characterized by action-in­ duced spasms of the vocal folds which are poorly controlled by the patient and which are exacerbated by stress. Related focal and seg­ mental presentations of dystonia may include blepharospasm, oromandibular dystonia and hemifacial spasm, spasmodic torticollis, crani­ al-cervical dystonia or Meige's syndrome and writer's cramp and other task-specific dysto­ nias. These syndromes may be dominated by involuntary sustained (tonic) or repetitive pat­ terned muscle contractions. Tremor often ac­ companies dystonia [29-32], 17% of the series of patients with primary laryngeal dystonia described by Blitzcr and Brin [28] had a family history of dystonia. Family studies have iden­ tified an autosomal-dominant inheritance with incomplete penetrance, and a recent de­ velopment is the identification of a gene locus marker in the q32-34 region on chromosome

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9, [30, 31 ]. This finding may open up the pos­ sibility of reduction in the incidence of dys­ tonias in the future by genetic means. Psychotherapy, biofeedback and speech therapy rarely objectively improve voicing by more than a modest and unreliable margin. Occasionally marked relief of dystonic symp­ toms may be achieved pharmacologically, but results arc likewise not reliable. The most use­ ful drugs in current clinical practice at the present time are muscle relaxants and anti­ cholinergic drugs such as bcnzhexol (known as trihexyphenidyl in the USA. Artane) [33] either singly or in combination. Drugs sug­ gested as adjuncts in more severe cases are. DOPAmine receptor-blocking drugs such as pimozide (Orap). an antipsychotic of the di­ phenyl butyl piperidine group: reserpine-like drugs such as tetrabenazine (Nitoman). which acts on biogenic amines such as serotonin and noradrenaline (norepinephrine) principally in the brain and which depletes dopamine and blocks dopamine receptors [34], Examples of other drugs currently used in attempts to re­ lieve dystonic and tremulous symptoms are: benztropine (Cogentin), a drug with powerful anticholinergic effects mostly used to treat parkinsonian tremor; ethopropazine (in the USA), a phenothiazine derivative developed for the symptomatic relief of parkinsonism: benzodiazepine tranquillizcr/anticonvulsants. e.g. clonazepam ('Rivotril') and carbamazepine ('Tegretol'); levodopa and related dopadecarboxylase inhibitors, e.g. 'Sinement, Larodopa’ developed to treat parkinsonian rigidity/spasticity. Treatment of focal or segmental dystonias with any of the above drugs is directed at symptomatic relief, and none deal precisely with the underlying neurological problem. All of these drugs are accompanied by significant side-effects and interactions. Good control of symptoms without the development of (occa­ sionally severe) attendant problems, e.g. tar­

The Pharmacological Treatment of Voice Disorders

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Drugs Affecting Neurological Problems

Treatment is commonly carried out by di­ rect injection under electromyographic con­ trol of diluted toxin into the laryngeal muscu­ lature. using a monopolar hollow 26-gauge Teflon-coated needle electrode. Ford and Bless [38] have recently suggested that an indirect laryngoscopic approach and place­ ment of the injection under visual guidance is more accurate. The principal drawback to this current means of treatment of laryngeal dystonia is the temporary nature of the induced paralysis. Laboratories in Britain and the USA have synthesized a conjugate of the heavy chain of botulinum toxin with another potent and per­ manent toxin, ricin. This substance has not as yet undergone any laboratory trials for recep­ tor specificity or clinical applicability, but may in the future provide a more permanent pharmacological solution in the treatment of dystonias.

Oesophageal Acid Reflux and Dysphonia

During the last decade it has often been reported that dysphonia may be concomitant with oesophageal acid reflux [39]. There is still controversy as to whether the dysphonia reported in some patients with acid reflux arises as a direct result of mucosal irritation from laryngeal overspill on to the posterior third of the larynx or from (possibly protec­ tive) reflex hyperkinetic activity of the vocal tract. In one trial [39], over 50% of patients with hoarseness who reported symptoms of reflux more than once per week proven to have significant reflux by ambulatory pH ma­ nometry and fibre endoscopy. Treatment with H? blockers, e.g. cimetidine ranitidine coupled with antacids over a period of 6 weeks produces an improvement in voicing in approximately 65% of patients. Where con­ trol of symptoms from proven acid reflux is

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dive dyskinesia, is unusual, hence the recent interest in treating the problem at the periph­ ery. Surgery to interrupt motor nerves sup­ plying dystonic muscle groups provides one such solution. In 1976 Dcdo [35] published results of recurrent laryngeal nerve section for spasmodic dysphonia and produced satisfac­ tory improvement in many cases of poor voic­ ing. The prinicipal advantage of recurrent laryngeal nerve section is that surgical treat­ ment is usually required once, and the vocal results is in most cases permanent. The ob­ vious disadvantage is that the treatment pro­ duces a gross ‘all or nothing' qualitative change, without any means of control to pro­ duce a quantitative incremental response. Other surgical variants have been published since then, but still suffer from the problem that any return of innervation is accompanied by a return of dysphonia. It was for these rea­ sons that chemical means of highly selective denervation were sought, which would prefer­ ably be permanent and could be used to pro­ duce a subtotal response. The most effective agent introduced into clinical practice to date has been purified botulinum toxin A. a neuro­ toxin consisting of a light and heavy protein chain linked by a disulphide bridge. Experi­ ments were begun in 1973 in rhesus monkeys [36] and first applied in clinical practice in 1980 for the treatment of strabismus [37], The toxin works preferentially on peripheral cholinergic motor end plates and has the great advantage over many other neurotoxins that it is extremely specific to this site. Blockade of acetylcholine release is produced by the light chain fraction within the nerve end. the heavy chain fraction being necessary for selective binding to the motor end plate and the disul­ phide bridge for internalization of the toxin into the nerve. The two most important sources of purified toxin at present are in the UK Porton Products (Dyspon) and in the USA Allergan Corp (Occulinum).

The Pharmacological Treatment of Voice Disorders in Other Traditions

Most allopathic Western medicine has its roots, quite literally, in much older herbal tra­ ditions. Technological advances have made possible synthetic drugs of increasing receptor specificity with well-defined modes of action. This Western medicine is not available to a very large part of the world population who rely on traditional, principally herbal medi­ cine. Well over a third of the population of China rely exclusively on traditional herbal medicines, and there are some 26 medical col­ leges teaching traditional Chinese medicine exclusively. Knowledge of all the active con­ stituents of the hundreds of herbs in common use is less than complete, and it is normal practice to prescribe a decoction of several herbs simultaneously, as the actions of the many constituents are thought to be synergis­ tic (cf. Western ‘polypharmacy’). The use of Western drugs in combination with tradi­ tional remedies is also common, e.g. the fresh juice of Houttuynia cordata (Yuxingcao) and its adduct with sodium hydrogen sulphite Houttuvnine combined with a small dose of dexamelhasone is thought to be very effica­ cious in the treatment of acute larvngotracheobronchitis. Among the many active com­ ponents of Yuxingcao. decanoyl acetaldehyde has been shown to be an effective antimicro­ bial against Staphylococcus aureus, Pneumo­ coccus, Haemophilus influenzae. Neisseria catarrhalis and haemolytic streptococcus amongst others (CTM1). Another example, Ma Bo, Lasiosphaera fenslii, the fruiting body of puffball, has antimicrobial and haemo­ static activity. As is normal practice, it may be used in combination with Shan Dou Gen

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(mountain bean root. Sophora subprostrata) or other medicináis such as the roots of wood (Bán Lán Gen), sage (Dung Sheye). Scrophularia (Xuan Shen) and anemone (Zhi Mu) for sore throats. There is little doubt that many of these her­ bal medicines are effective, most of our West­ ern pharmacopoeia us full of drugs of diverse herbal origins ranging from digoxin. quinine, papain, aspirin and cocaine to steroids for the contraceptive pill. Unfortunately many her­ bal remedies of complex and uncharactcrized structure also contain a variety of toxic alka­ loids. and it is principally because herbalists have poor control of exactly what and howmuch is being administered to the patient that Western physicians have been slow to return to herbal remedies.

Conclusion

Because voicing is a biomechanical activ­ ity involving many body systems, the ability of the phoniatrician to alleviate the symptoms of dysphonia by pharmacological means is limited to the treatment of discrete pathologi­ cal processes. Modification of vocal symp­ toms precipitated by inefficient vocal behav­ ioural patterns frequently remains outside the remit of pharmacology, although our increas­ ing understanding of central neurotransmit­ ters suggests that this will not always be the case. In the great majority of pathological pro­ cesses producing dysphonia. where drug treat­ ment is applicable, the result is improved if vocal rehabilitation therapy is also part of the treatment plan. Future Possibilities New areas of drug development suggest that there may soon be pharmaceuticals capa­ ble of reversing dysplastic change in laryngeal mucosa and new forms of toxin for highly

The Pharmacological Treatment of Voice Disorders

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poor with H2 blockers, proton pump inhibi­ tors such as omeprazole are highly effective.

selective partial and permanent denervation procedures. There has as yet been little ad­ vance on the aerosol for practical, selective topical administration of drugs to the upper vocal tract. Selective coating of troublesome lesions such as arytenoid granulomata with established drugs such as sulfacrate might of­ fer marked improvement on conventional

therapy. In 1992, much of the pharmacologi­ cal treatment of dysphonia is still the product of anecdote, conjecture and idiosyncratic per­ sonal experience. It is hoped that with the increasing use of computer networks, it will become easier to run well-designed multi­ centre trials of drugs in the treatment of dys­ phonia.

For a report such as the pharmaco­ logical treatment of dysphonia. clearly a comprehensive bibliography is imprac­ tical, therefore the following references, generally to recent work, are meant only as a guide for further reading for those interested. 1 Lawrence DR. Bennet PN: Clinical pharmacology. Edinburgh. Chur­ chill Livingstone. 1987. 2 Cohon JR. Sataloff RT. Spiegel JR. Fish JF. Kennedy K: Airway reac­ tivity-induced asthma in singers (ar­ ias). J Voice 1991:5:332-337. 3 Williams AJ. Baghat MS. Stableforth DE. C'ayton RM. Shcnoi PM. Skinner C: Dysphonia caused by in­ haled steroids: Recognition of a characteristic laryngeal abnormali­ ty. Thorax 1983;38:813-821. 4 Toogood JH: Complications of topi­ cal steroid therapy for asthma. Am Rev Respir Dis 1990;141:S89-S96. 5 Toogood J11. Jennings B. Greenway RW, Chuang L: Candidiasis and dysphonia complicating beclomethasone treatment of asthma. J Allergy Clin Immunol 1980:65:145-153. 6 Moren F: Drug deposition of pres­ surised inhalation aerosols. I. In­ fluence of actuator tube design. Int J Pharmacol 1978:1:205-212. 7 Dolovich M. Ruffin R. Ncwhouse MT: Clinical evaluation of a simple demand inhalation device: MDI aerosol delivery device. Chest 1983: 84:36-41.

8 Newman SP. Pavia D. Garland N: Effects of various inhalation modes on the deposition of radioactive pressurised aerosols. Eur J Respir Dis 1982:63(suppl) 119:57-65. 9 Toogood JH: Efficiency of inhaled versus oral steroid treatment of chronic asthma. N Engl Regional Al­ lergy Proc 1987:8:98-103. 10 Settipane GA. Kalliel JN. Klein DE: Rechallenge of patients who devel­ oped oral candidiasis or hoarseness w ith beclomethasone dipropionatc. N Engl Regional Allergy Proc 1987; 8:95-97. 11 International Olympic Committee: List of doping classes and treatment guidelines. Br Sports Council Dop­ ing Control Information Booklet No. 2.1989. 12 British Sports Council: Drugs and Sport: A Comprehensive Guide. Midhursl. Liphok. Media Mcdica MIMS. 13 Bedford NS. Rood SR. Schaid D: Androgen stimulation and laryngeal development. Ann Otol Rhinol Laryngol 1985:94:634-640. 14 James JM. Pearson RM. Griffith DNM. el al: Effect o f oxprenolol on stage-fright in musicians. Lancet 1977;ii:952—954. 15 Gates GA. Montalbo P.I: The effect of low-dose p-blockade on perfor­ mance anxiety in singers. J Voice 1987:1:105-108. 16 Chodzko-Zajko W.I. Ringcl RL: Physiological aspects of aging. J Voice 1987;1:18-26.

17 Hirano M. Kurita S. Nakashima T: Growth, development and aging of human vocal folds: in Bless DM. Abbs JM (eds): Vocal Fold Physiolo­ gy. San Diego, College-Hill Press. 1983. pp 22-43. 18 Bicvcr DM. Bless DM: Vibratory characteristics of the vocal folds in young adult and geriatric women. J Voice 1989:3:120-131. 19 Abramson A. Essman F. Steinberg B: Membrane receptors for 17-p-oeslradiol in the human larynx. Transcripts 12th Symp Care Professional Voice. 198.3. vol 2. pp 292-294. 20 Aufdemortc TB. Sheridan PJ. Holt GR: Autoradiographic evidence of sex steroid receptors in laryngeal tis­ sues of baboon (papiocynoccphalus). Laryngoscope 1983:93:16071611. 21 Fergusson BJ, Hudson WR, McCarty KS: Sex steroid receptor distribution in the human larynx and lary ngeal carcinoma. Arch Oto­ laryngol Head Neck Surg 1987:113: 1311-1315. 22 Parker M: Oestrogen receptors in breast carcinoma. 73rd Annu Meet Endocrine Soc. Washington. 1991. 23 Abithol J. de Brux J, et al: Does a hormonal vocal cord cycle exist in women? Study of vocal premen­ strual syndrome in voice performers bv videostroboscopy-glottography and cytology on 38 women. J Voice 1989:3:162. 24 Abramson AJ. cl al: Estrogen recep­ tors in the human larynx: Clinical study of the singing voice: Franscipts 13th Symp Care Professional Voice. 1984. vol 2. pp 4 0 9-413.

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36 Scott AB. Rosenbaum A. Collins CC: Pharmacological weakening of extraocular muscles. Invest Oph­ thalmol 1973:12:924-927. 37 Scott AB: Botulinum toxin injec­ tions into extraocular muscles as an alternative to strabismus sur­ gery. Ophthalmology I980;87: 1044-1049. 38 Ford CN, Bless DM. Lowery JD: Indirect laryngoscopic approach for injection of botulinum toxin in spas­ modic dysphonia. Otolaryngol I lead Neck Su’rg 1990:103:752-758. 39 Jones NS. et al: Acid reflux and hoarseness. .1 Voice 1990:4:355358. 40 Pharmacology and Applications of Chinese Materia Medica. World Scientific 827-832.

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25 Cardozo L, McPherson K: Mcdicalising the menopause: Hormone re­ placement therapy - solution or problem? J R Soc Med 1991:84: 567-569. 26 Traube L.: Spastische Form der ner­ vösen Heiserkeit. Gesamm Beitr Pathol Physiol 1871:2:677. 27 Critchley M: Spastic dysphonia (’in­ spiratory speech'). Brain 1939:62: 96-103.' 28 Blitzer A. Brin M: Laryngeal dysto­ nia: A series with botulinum toxin therapy.. Ann Otol Rhinol I .aryngol 100:2:85-89. 29 Jancovic J. Brin MF: Therapeutic uses of botulinum toxin. N Engl J Med 1991:324:1186-1194. 30 Brcssman SB. de Leon D. Brin MF; et al: Idiopathic dystonia among Ashkenazi Jews: Evidence for autos­ omal dominant inheritance. Ann Neurol 1989;26:612-620.

The pharmacological treatment of voice disorders.

The increasing diversity of purpose-built, synthetic and biogenetically engineered pharmaceuticals has led to a revival of interest in the pharmacolog...
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