Betahistine

ABSTRACT

Vertigo results from a disruption in the tonic firing rate of the vestibular receptors, and can arise from lesions of the labyrinthine receptors or central vestibular structures. The 3 most common classes of prescription medications used to treat vertigo are the anticholinergics, antihistamines, and benzodiazepines. Reduction of vertigo with these agents is predominantly symptomatic, and is derived by suppressing vestibular activity. The purpose of this article is to review the pharmacological agents commonly used to treat vertigo and to discuss the effects of vestibular suppressant drugs on recovery.

INTRODUCTION

Vertigo and dizziness account for almost 1% of all outpatient office based physician visits in the United States annually.1 Among those patients with vertigo or dizziness, 65% were seen by general/family practitioners or internists followed by otolaryngologists (10.1%), neurologists (6.3%), and cardiovascular specialists (5.8%).1 Dizziness is a general term associated with a number of symptoms such as light-headedness, presyncope, disequilibrium, and vertigo that can arise from a wide array of psychogenic and physiologic disorders.2

Vertigo is a subtype of dizziness that is defined as the illusion of motion, generally rotation, of one's self or the environment.3 Vertigo is always associated with a vestibular imbalance, and can occur from lesions anywhere in the peripheral and central vestibular pathways.4,5 The purpose of this article is to review the pharmacological agents commonly used to treat vertigo and to discuss the effects of vestibular suppressants on vestibular compensation.

ETIOLOGY OF VERTIGO

The vestibular nerve sends afferent input from the labyrinthine receptors of the inner ear to the ipsilateral vestibular nuclei in response to changes in head position. In the absence of head movement, the labyrinthine receptors in both ears maintain a baseline tonic firing rate that is symmetrical bilaterally. Head movement increases the firing rate of the ipsilateral labyrinth and decreases the firing rate of the contralateral labyrinth (eg, head movement to the right will cause an increased firing rate of the right vestibular nerve, and a decreased firing rate of the left vestibular nerve). This mechanism provides the central nervous system with input from the vestibular nerves bilaterally, in response to ipsilateral head movement. An acute disruption of this mechanism results in vertigo, spontaneous nystagmus, and vegetative symptoms such as nausea and vomiting, which result from an imbalance in the symmetrical tonic firing rate of the vestibular receptors. Spontaneous nystagmus causes stable objects in the visual environment to appear to be moving away from the side of the lesion. The illusion of movement occurs because the brain interprets movement of the visual image across the retina as motion in the environment rather than the actual eye movements generated by spontaneous nystagmus.5

The association between acute vestibular disruption and nausea and vomiting result from the interconnections between the vestibular and vomiting centers in the brain. Recent studies have found that regions such as the nucleus tractus solitarius and the lateral medullary reticular formation, which produce vomiting, also receive vestibular inputs.6,7 In addition, functional magnetic source imaging found an increase in activity in the inferior frontal gyrus when nausea was induced by vestibular stimulation or by ingestion of an emetic such as ipecac.8

PHARMACOLOGICAL MANAGEMENT OF VERTIGO

Reducing the severe vegetative symptoms associated with acute peripheral vestibular lesions often necessitates pharmacological intervention. The 2 types of drugs prescribed for the symptomatic treatment of vertigo are the vestibular suppressant and antiemetic agents.9 The term vestibular suppressant is used to describe drugs that reduce motion sickness, and reduce nystagmus caused by a vestibular imbalance.10 The 3 classes of drugs that act to suppress vestibular activity are the anticholinergics, antihistamincs, and benzodiazepines. The reduction of vertigo with these agents is predominantly symptomatic, and is achieved by suppressing vestibular activity by modulating one or more neurotransmitters in the 3 neuron are that drives the vestibulo-ocular reflex. The antiemetic drugs act by suppressing the central (reticular formation and postrema) and peripheral (gastrointestinal tract) components of the nervous system associated with vomiting.9 Neurotransmitters such as dopamine, serotonin, histamine, and acetylcholine may act at these sites to induce vomiting.9 The major classes of vestibular suppressants and antiemetics are summarized in Table 1.

Anticholinergics

The precise mechanism by which some anticholinergics exert their antimotion sickness and antivertiginous effects is not well known; however, some anticholinergic agents such as scopolamine have been shown to decrease the spontaneous firing rate of the vestibular nuclei.11 Pyykko and associates12 found transdermal scopolamine reduced optokinetic nystagmus and decreased the maximum velocity of caloric induced nystagmus, as compared with a placebo. There was a significant reduction in nausea, vertigo, and motion sickness in subjects who received transdermal scopolamine.13

Transdermal delivery of scopolamine (Transderm Scop) is detected in the plasma within 4 hours, and reaches peak concentrations within an average of 24 hours. The antiemetic effect begins approximately 4 hours after application of the transdermal system, and lasts up to 72 hours. The membrane-controlled diffusion system is designed to deliver approximately 1 mg of scopolamine to the systemic circulation at a constant rate over a 72-hour life of the system.

Antihistamines

The precise mechanism underlying the antiemetic and antivertiginous effects of most antihistamines is unclear, but may be related to their anticholinergic properties. The anti-histamines diminish vestibular stimulation and depress labyrinthine function.14 Antihistamines prevent responses to acetylcholine that are mediated via muscarinic receptors.14 The antiemetic and antimotion-sickness actions of meclizine result, at least in part, from its central anticholinergic properties. The onset of action of meclizine hydrochloride is about 1 hour and the drug has a prolonged duration of action, with effects lasting 8 to 24 hours following administration of a single oral dose.

Meclizine HCL is approved by the US Food and Drug Administration (TDA) for the prophylaxis and treatment of nausea, vomiting, and dizziness associated with motion sickness or radiotherapy. The FDA has classified meclizine as effective in the management of nausea and vomiting, dizziness associated with motion sickness, and possibly effective in the management of vertigo associated with diseases affecting the vestibular system.14

Dimenhydrinate and diphenhydramine are indicated for the prevention and treatment of the nausea, vomiting, dizziness, or vertigo associated with motion sickness. In addition to their antihistaminic effect, dimenhydrinate and diphenhydramine have central nervous system depressant, anti-cholinergic, and antiemetic effects. However, the mechanism of action is thought to derive from their anticholinergic effects.

Promethazine (Phenergan) is a phenothiazine-derivative antihistamine and dopamine blocking agent indicated for the prevention and treatment of the nausea and vomiting associated with motion sickness. The antiemetic effect is derived from blocking the excitatory neurotransmitter dopamine in the medullary chemoreceptive trigger zone and vomiting center.15,16

Benzodlazepines

The benzodiazepine class of drugs act as central nervous system depressants. Although the exact mechanism of action has not been established, it is believed that the benzodiazepines act to depress the central nervous system by facilitating the action of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) by causing it to bind more tightly to the GABA^sub A^ receptor complex.14 This receptor complex, which resides on the neuronal membrane, functions mainly in the gating of the chloride channel. Activation of the GABA receptor opens the chloride channel, allowing the flow of chloride ions into the neuron.14 Neuronal inhibition is achieved by the influx of the negatively charged chloride ions that hyperpolarize the neuronal membrane.

Alternative Remedies

A number of homeopathic and natural remedies for motion sickness and vertigo have been advocated as an alternative to conventional vestibular suppressant drugs. Ginger root and Vertigoheel (Heel/BMI Inc., Albuquerque, NM) are the most noteworthy.

Ginger root (Zingiber officinale Roscoe) has been used by sailors for centuries to combat the symptoms associated with sea sickness. Medicinal use of ginger to treat travel sickness and nausea was used throughout Europe in the Middle Ages, and dates back to ancient China and India.17 Recent studies have found ginger to be an effective antiemetic for individuals with motion sickness and post-operative nausea, without the sedative side effects associated with traditional vestibular suppressant drugs used for nausea.18-20 Studies which suggest that ginger can be used to manage the same symptoms traditionally treated with vestibular suppressants, without the sedative side effects, have made ginger an attractive alternative to contemporary drug therapy. However, the efficacy of ginger for vertigo and nausea associated with vestibular dysfunction has not been established. Ginger has not been shown to reduce experimentally induced nystagmus, which suggests its antiemetic effects may derive from an action on gastric function, unlike vestibular suppressants, which reduce vertigo and nausea by acting on the central nervous system.21

Vertigoheel is a homeopathic preparation available by prescription in the United States. The FDA has classified Vertigoheel as effective for the treatment of vertigo and other related imbalance disorders, and related symptoms such as nausea. A recent study found Vertigoheel was as effective and safe as betahistine hydrochloride, a drug commonly used to treat vertigo in Canada and Europe.22

CLINICAL CONSIDERATIONS

Although vertigo is always associated with asymmetrical vestibular function, the presence of vertigo as a symptom docs not indicate where in the vestibular system the imbalance originates.4,5 Factors such as the intensity, frequency, and duration of vertigo and the conditions that precipitate and alleviate vertigo, in addition to the identification of associated symptoms play a critical role in determining the site of the lesion.4

Although the pharmacological management of vertigo is predominantly symptomatic, there are some drugs that reduce vertigo by altering the underlying disease process. For example vasodilators and diuretics are used to reduce the endolymphatic pressure associated with Meniere disease. Migraine-associated vertigo is managed pharmacologically using drugs designed to prevent the onset of migraine or abort attacks of migraines once they occur. Recurrent vertigo occurs in approximately 25% of patients with associated migraine.23 Currently, propranolol, timolol, methysergide, and divalproex sodium are the only drugs approved for migraine prophylaxis by the Food and Drug Administration, although many others are used based on limited clinical studies.24

The vestibulo-ocular reflex maintains a stable visual image by generating compensatory eye movements relative to angular and linear displacement of the head. Gaze stabilization is achieved when the gain, defined as the ratio of eye movement to head movement, is 1.0. A stable visual image on the retina results from an equal but opposite rotation of the eyes relative to head displacement.25

The vestibulo-ocular contribution to visual stability is clinically demonstrated in patients with acute vestibular dysfunction. Labyrinthine dysfunction results in oscillopsia and aversive reactions to head movement, secondary to inadequate compensatory eye movement relative to the head.25,26 Inadequate ocular compensation results in gain values less than 1.0 with head motion toward the affected labyrinth, and gain values greater than 1.0 with head motion toward the intact labyrinth.27 The inadequate ocular compensation results in a slip of the visual image on the retina, causing oscillopsia with head movement. Retinal slip is the error signal that the brain attempts to correct by increasing the gain of the vestibular responses.

The use of vestibular suppressant drugs is an important clinical consideration for the physical therapist managing individuals with vestibular dysfunction. Creating an error signal in order to restore vestibulo-ocular reflex gain is the rationale for physical therapy interventions that provoke retinal slip, postural instability, and vertigo. Vestibular suppressants that act by reducing vestibular activity also reduce the error signals that prompt recovery.10,15,16,28,29 Ideally, the use of vestibular suppressants should be limited to controlling the severe vertiginous symptoms during the first few days after the onset of acute vertigo.5 Ultimately the patient and the physical therapist must weigh the need to control vertigo against the possibility of prolonging recovery with the use of vestibular suppressants.

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Toni A. Zuccaro, PT, MA, NCS1

1Assistant Professor, Physical Therapy Program, State University of New York, Downstate Medical Center and doctoral student, Physical Therapy Program, Temple University

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