This study will examine how dextromethorphan, a drug that alters reflexes of the larynx
(voice box), might change voice symptoms in people with voice disorders due to uncontrolled
laryngeal muscle spasms. These include abductor spasmodic dysphonia (breathy voice breaks),
adductor spasmodic dysphonia (vowel breaks), muscular tension dysphonia (tight strained
voice), and vocal tremor (tremulous voice). Dextromethorphan-one of a group of drugs called
NMDA antagonists-has been used for years in over-the-counter cough suppressant medicines. In
animal studies, the drug has blocked one of the reflexes in the larynx that may be
associated with spasms in the laryngeal muscles. This study will compare the effects of
dextromethorphan, lorazepam (a valium-type drug), and a placebo (inactive substance) in
patients with the four types of voice disorders described above.
Patients with spasmodic dysphonia, muscular tension dysphonia and vocal tremor may be
eligible for this study. Individuals who smoke or use tobacco, who have vocal nodules or
polyps, or who have a history of airway obstruction may not participate. Candidates will be
screened with a medical history and physical examination, a questionnaire, voice recording
(repeating sentences into a microphone), and nasolaryngoscopy (examination of the larynx
with a tube advanced through the nose). For the nasolaryngoscopy, the inside of the nose is
sprayed with a decongestant (to open the nasal passages) and possibly a local anesthetic. A
small, flexible tube called a nasolaryngoscope is passed through the nose to look at the
larynx during speech and other tasks, such as singing, whistling and prolonged vowels.
Participants will be admitted to the NIH Clinical Center for each of three visits, which
will last from the afternoon of one day to late afternoon of the following day. At each
visit, patients will complete a questionnaire, baseline speech recording, and a test for
sedation level. They will take three pills-either dextromethorphan, lorazepam, or
placebo-one every 6 hours. Vital signs will be checked every 6 hours and the level of
sedation during waking hours will be monitored. One to three hours after taking the third
pill, speech recording, questionnaire and test of sedation will be repeated to check for
possible voice changes. Patients will be given a different pill at each visit.
Studies of spasmodic dysphonia (SD) have increasingly pointed to the possibility of a
central sensori-motor control disorder. Sensori-motor processing has been found abnormal in
both adductor and abductor spasmodic dysphonia based on reflex conditioning studies. These
studies demonstrated an increased frequency of R2 muscle responses during rapid paired
presentation of electrical stimuli to the superior laryngeal nerve in spasmodic dysphonia.
Thus, uncontrolled R2 responses were hypothesized to be the basis for the uncontrolled
muscle bursts in these patients. Selective suppression of late R2 laryngeal adductor
responses by N-methyl-D-Aspartate (NMDA) blockade in cats was demonstrated by Ambalavanar
et.al. In particular, dextromethorphan reduced the frequency of R2 responses from 95% to 25%
(P = 0.015). Dextromethorphan is a widely used antitussive agent that has been in use for
over 30 years. In a double-blind randomized crossover design, 3 groups of patients will
receive be randomly assigned to one of 6 order cohorts. They will then receive either
dextromethorphan at a 8 mg/kg/d dose divided in a Q6 hour dosing schedule with only 3 doses
administered PO every 6 hours for 3 dosages, 04 mg/kg/d of lorazepam PO every 6 hours for 3
dosages or a placebo administrated in the same way during Phase A. After a minimum of a
1-week washout interval, the patients will be given either the other medication or placebo
during Phase B and then the remaining medication or placebo during Phase C.
Our hypothesis is that dextromethorphan, an NMDA receptor blocker, will reduce voice breaks
in spasmodic dysphonia to a greater degree than lorazepam, which has similar sedating side
effects, but does not affect NMDA receptors with a different mechanism. On the other hand,
patients with other idiopathic voice disorders, muscular tension dysphonia and vocal tremor,
are hypothesized not to have a similar benefit from dextromethorphan. During the
double-blind randomized cross-over study, three groups will be included, 10 patients with
adductor or abductor spasmodic dysphonia, 10 with muscular tension dysphonia and 10 with
vocal tremor. The results will determine if dextromethorphan has potential as a treatment
option for patients with adductor or abductor SD.
- INCLUSION CRITERIA:
Patients with Spasmodic Dysphonia will meet the following criteria:
1. No structural abnormalities affecting the larynx such as vocal fold nodules, polyps,
carcinoma, cysts, contact ulcers, inflammation (laryngitis).
2. Symptoms of adductor or abductor spasmodic dysphonia present during speech and not
apparent at rest,
3. Symptoms of adductor or abductor spasmodic dysphonia less evident during whisper,
singing or falsetto.
4. Symptoms of adductor or abductor spasmodic dysphonia become worse with prolonged
speaking, practice or anxiety.
5. Reflexive and emotional aspects of voice function are unaffected, such as coughing
and laughter or crying.
Patients with Muscular Tension Dysphonia will meet the following criteria:
1. Increased phonatory muscle tension in the paralaryngeal and suprahyoid muscles on
2. Constant elevation of the larynx in the neck during speech.
3. A consistent hypertonic laryngeal posture for phonation, either an open posterior
glottic chink between the arytenoid cartilages on phonation, an anterior-posterior
squeeze (pin hole posture) or ventricular hyperadduction.
4. A normally appearing larynx.
Patients with vocal tremor will have tremor isolated to the larynx without noticeable
tremor of the head and pharynx. Tremor of the vocal folds should be evident during a
prolonged vowel and also noticeable in the larynx during connected speech containing
Subjects in all three groups will be without:
1. Cardiac, pulmonary, neurological, psychiatric or speech and hearing problems as
determined by medical history and examination by a physician and an EKG. Any patient
with a history of airway obstruction will be excluded from the study.
2. Reduction in the range of vocal fold movement during non-speech tasks such as
whistling suggesting either paralysis or paresis, joint abnormality or neoplasm.
3. No smokers or tobacco users will be included in the study.
4. Exclude mucosal changes such as vocal nodules or polyps.
5. Subjects with a history of a psychiatric disorder, under the care of a psychiatrist,
or on medications for treatment of a psychiatric disorder will be excluded from
study. Examples of psychiatric disorders to be excluded are: somatoform disorders,
conversion disorders, currently under treatment for a major depression, or a history
of schizophrenia or a bipolar disorder. However, a history of a previous episode of a
minor reactive depression would not exclude a person from participation.
6. Subjects taking carbonic anhydrase inhibitors, cimetidine, hydrochlorthiazide,
nicotine, quinidine, ranitidine, sodium or calcium bicarbonate and triamterene must
either discontinue these medications or be excluded from study.
7. Subjects with grade 2 or higher hepatic or renal dysfunction will be excluded from
8. Pregnant women will be excluded from the study as it is not known if the study drugs
are harmful to the fetus. If a woman becomes pregnant during the study, she will be