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June 18, 2014
This review is written at a continuing medical education level.
More detailed expositions of this material can be found here:
There are at least four major neurotransmitters of the vestibular system involved in the "three neuron arc" between the vestibular hair cells and oculomotor nuclei that drives the vestibulocular reflex. There are also a host of other neurotransmitters which modulate function. Glutamate is the major excitatory neurotransmitter (Serafin et al, 1992), playing a role similar to other regions of the brain. Acetylcholine (ACH) is both a peripheral and central agonist both affecting muscarinic and nicotinic receptors. ACH is a neurotransmitter for both the vestibular efferent system and central pathways. While largely excitatory to firing of vestibular afferents, the vestibular efferents also have been reported to inhibit firing in animals. Centrally, receptors found in the pons and medulla, presumably those involved with dizziness, are almost exclusively of the M2 subtype (Barton et al, 1994). Gamma-aminobutyric acid (GABA) and glycine are inhibitory neurotransmitters found in connections between second order vestibular neurons and onto oculomotor neurons (Spencer et al, 1992). Stimulation of the two types of GABA receptors, GABA-A and GABA-B, have similar effects on vestibular pathways (Neerven et al, 1989), but specific GABA-B agonists, such as baclofen, decrease the duration of vestibular responses in animal models (Cohen et al, 1987).
The circuitry by which several other neurotransmitters affect vestibular responses is less well understood. Histamine is found diffusely in central vestibular structures and centrally acting antihistamines modulate symptoms of motion sickness (Takeda et al, 1989). Both the H1 and H2 subtypes of histamine receptors affect vestibular responses (Serafin et al, 1992). H3 histamine receptors have an unknown role but they may also be involved in vestibular responses. Norepinephrine is involved centrally in modulating the intensity of reactions to vestibular stimulation (Wood, 1979) and also affects adaptation. Dopamine affects vestibular compensation, and serotonin is involved with nausea.
Vestibular suppressant and antiemetic drugs are the mainstay of treatment of vertigo. The term "vestibular suppressant" is a vague one generally used to indicate drugs that reduce nystagmus evoked by a vestibular imbalance or which reduce motion sickness. Table 1 lists commonly used vestibular suppressants, which consist of three major drug groups, the anticholinergics, the antihistamines, and the benzodiazepines.
|Table 1: Vestibular Suppressants (order of preference)|
|Drug||Dose||Adverse Reactions||Pharmacological Class and Precautions|
|Meclizine (Antivert, Bonine)||25-50 mg q 4-6h||sedating||antihistamine anticholinergic precautions if prostatic enlargement|
|Lorazepam (Ativan)||0.5 mg BID||mildly sedating||benzodiazepine drug dependency|
|Clonazepam (Klonopin)||0.5 mg BID||mildly sedating||benzodiazepinedrug dependency|
|Dimenhydrinate (Dramamine)||50 mg q 4-6h||same as Meclizine||antihistamine anticholinergic|
|Diazepam(Valium)||2 bid PO
5 mg IV (1 dose)
|sedating||benzodiazepine drug dependency Precaution in glaucoma.|
|Amitriptyline (Elavil)||10-50 hs||sedating, in overdose cardiac arrhythmia||anticholinergic tricyclic antihistamine|
Doses are all those used routinely for adults, and will generally not be appropriate for children.
Anticholinergics which affect muscarinic receptors, such as scopolamine, increase motion tolerance. Anticholinergics also affect compensation, producing a reversible overcompensation if administered after compensation has been attained to a vestibular imbalance (Zee, 1988). Agents with central anticholinergic effects are most important in treating vertigo, since anticholinergic drugs that do not cross the blood-brain barrier are ineffective in controlling motion sickness (Takeda et al, 1989). Unlike antihistamines which will be discussed subsequently, pure anticholinergics are ineffective if administered after symptoms have already appeared.
All anticholinergics used in the management of vertigo have prominent side effects of dry mouth, dilated pupils, and sedation. Scopolamine and atropine are nonspecific muscarinic receptor antagonists (Barton et al, 1994). It is to be hoped that agents selective for vestibular subtypes of muscarinic receptors will eventually be developed or discovered among our presently available pharmacopoeia, as these agents may provide vestibular suppression with less side effects. While recent evidence suggests that nicotinic ACH receptors may mediate vestibular and cochlear efferents (Vetter et al, 1999), clinical utility of this observation is not apparent. As the only possible function of peripherally acting anticholinergics would be to suppress vestibular efferents, use of anticholinergic agents that do not cause sedation because they do not cross the blood brain barrier, such as Robinul, is irrational.
Antihistamines. While the precise role of histamine in central vestibular processing is uncertain, there are data indicating that centrally acting antihistamines prevent motion sickness and reduce the severity of its symptoms even if taken after the onset of symptoms (Takeda et al, 1989). All the antihistamines in general use for control of vertigo also have anticholinergic activity. With the possible exception of astemizole (Hismanal) in Meniere's disease (Turner and Jackson, 1989), antihistamines that do not cross the blood brain barrier, are not used to control vertigo. Unfortunately, astemizole does not appear to be generally useful as it is ineffective in preventing motion sickness (Kohl et al, 1987) and it is also associated with an unfortunate drug interaction profile. Some authors hold that antihistamines, per se, do not suppress vertigo and that reduction of symptoms is due to other activities of these drugs.
Benzodiazepines are GABA modulators, acting centrally to suppress vestibular responses. In small doses, these drugs are extremely useful. Addiction, impaired memory, increased risk of falling, and impaired vestibular compensation are their main shortcomings. Lorazepam and Klonazepam are particularly useful agents because of their effectiveness and simple kinetics. Addiction, the biggest problem, can usually be avoided by keeping the dose to 0.5 mg BID or less. Similarly, low doses of diazepam (Valium) (2 mg) can be quite effective. Clonazepam (Klonopin), appears as effective a vestibular suppressant as lorazepam. The author prefers to avoid use of alprazolam (Xanax) for vestibular suppression, because of the potential for a difficult withdrawal syndrome. Long acting benzodiazepines are not helpful for relief of vertigo.
Antiemetics: Table 2 lists the drugs that are commonly used for control of nausea in vertiginous patients. Relatively new are the 5HT3 agents (Zofran, Kytril). In theory, these agents might not be ideal for emesis related to vestibular imbalance. The choice of agent depends mainly on considerations of the route of administration and the side effect profile. The oral agents are used for mild nausea. Suppositories are commonly used in outpatients who are unable to absorb oral agents because of gastric atony or vomiting. Injectables are used in the emergency room or inpatient settings. The new agents are used when all else fails.
Some antihistamines commonly used as vestibular suppressants have significant antiemetic properties (e.g. meclizine). When an oral agent is appropriate, this agent is generally the first to be used, because it rarely causes adverse effects any more severe than drowsiness. Phenothiazines, such as prochlorperazine (Compazine) and promethazine (Phenergan), are effective antiemetics, probably because of their dopamine blocking activity, but they also act at other sites. For example, promethazine is also an H1 blocker. Because these drugs can induce significant side effects, such as dystonia, they are considered second-line drugs whose use should be brief and cautious.
|Table 2: Antiemetics|
|Drug||Usual Dose (Adults)||Adverse Reactions||Pharmacological Class|
|2.5 or 5 mg, SL||sedating hypotension||neuroleptic|
|1 mg PO BID 10 ug/kg IV daily||headachesedation||5HT3 antagonist|
|12.5-25 mg q4-6h PO||sedating Precautions in glaucoma, prostate enlargement||antihistamine anticholinergic|
|10 mg PO TID or 10 mg IM||restlessness ordrowsiness extrapyramidal||dopamine antagonist stimulates upper gastrointestinal motility|
|ondansetron (Zofran)||4-8 mg PO
32 mg IV one dose
|precaution in hepatic dysfunction||5HT3 antagonist|
|perphenazine(Trilafon)||2 - 4 mg PO, up to QID or 5mg IM, up to TID||sedating extrapyramidal||phenothiazine|
|5 mg or 10
mg IM or PO q6-8 hr.
25 rectal q12h
|12.5 mg PO q6-8h or12.5 mg IM q 6-8h||sedating extrapyramidal||phenothiazine|
|trimethobenzamide(Tigan)||200 mg IM TID||extrapyramidal sedating||similar to phenothiazine|
|thiethylperazine(Torecan)||10 mg PO, up to TID or 2 ml IM, up to TID||sedating extrapyramidal||phenothiazine|
Doses are all those used routinely for adults, and will generally not be appropriate for children.
Drugs that speed gastric emptying, such as metoclopramide (Reglan) and powdered ginger root may be helpful in managing emesis (Grontved et al, 1988). Metoclopramide, a dopamine antagonist and a potent central antiemetic, is ineffective in preventing motion sickness (Kohl, 1987). Of these agents, droperidol is probably the most effective as it can be administered sublingually, making it possible to use in most situations.
There is a possible role for new antiemetics which are a 5-HT3 antagonists (ondansetron, Zofran; granisetron, Kytril) used in treating the nausea associated with chemotherapy and post-operative nausea and vomiting. The high cost of these agents presently limits their usefulness in the treatment of vertigo, but they are reasonable agents to try in situations where the more usual agents are ineffective or contraindicated. These agents do not appear to be helpful in preventing motion sickness (Stott et al, 1989). In theory, these agents might be less effective for vestibular elicited emesis than agents with other pharmacological actions.
Corticosteroids such as decadron have been shown to be useful both for treatment Vestibular neuritis, and are routinely used in Meniere's disease. In vestibular neuriitis the rationale is to reduce the duration of a vertiginous episode and improve long-term outcome (Strupp et al, 2004). In Meniere's disease, the rationale is to reduce the duration of an episode, and possibly reduce the activity of the immune system, which is implicated in the pathogenesis of Meniere's disease. Steroids also are reportedly beneficial in acute vertigo (Ariyasu et al, 1990). Oral steroids are used very commonly in the otologic community for acute Meniere's disease, and in particular for hearing loss.
The physiology literature suggests that vestibular compensation may be speeded up by glucocorticoid agonists (Cameron and Dutia, 1999). If true, steroids are a reasonable tool to promote vestibular compensation, although of course, their use must be tempered by steroid side effects. Steroids given systemically might reasonably affect vestibular compensation, but steroids given by injection into the middle ear would seem not to be logical. In other words, only the oral or IV route for steroids would seem likely ones to improve compensation.
The author will occasionally use a few day course of decadron (4 mg qd), when faced with a severe and unremitting vertigo attributed to Menieres disease. The author will also routinely use a "medrol dose pack" for vestibular neuritis, uncomplicated by other serious medical disorders such as diabetes.
4 DAP is a cerebellar modulator, which has been shown recently to be helpful for certain cerebellar syndromes.
Agents whose whose role is presently uncertain.
Calcium channel blockers are the most promising agents in this group. Calcium channel blockers, such as flunarizine and cinnarizine, are popular antivertiginous agents outside of the U.S. (Rascol et al, 1989). Some calcium channel blockers, such as verapamil, have quite strong constipating effects, which may be helpful in managing diarrhea caused by vestibular imbalance. However, calcium channel blockers often have anticholinergic and/or antihistaminic activity and the relative importance of calcium channel blocking vs associated activity for vestibular suppression has not been determined (Rascol et al, 1989). Calcium channel blockers may be effective in "vestibular Menieres", as persons with this diagnosis have a high prevalence of migraine (Rassekh and Harker, 1992), for which calcium channel blockers can be very effective. The author has found daily verapamil to be moderately helpful in a roughly 1/3 of his patients with classic Menieres, causing amelioration or suppression of attacks as long as a reasonable dose is taken. This use of verapamil for vertigo has not been studied or approved in the US. Nimodipine has recently been reported to be effective as prophylaxis of Menieres.
A sodium channel blocker, phenytoin (Dilantin), has also been recently reported to be protective against motion sickness (Knox et al, 1994). The author of this review has had no success in limited trials in patients with severe motion sickness unresponsive to the usual agents. Neurontin and Tegretol are also sometimes successfully used in treatment of vertigo, although their use has not been studied extensively. Neurontin has also been successfully used to suppress certain types of central nystagmus. As these agents affect GABA, which is important in vertigo, an antivertigo effect is reasonable.Recent agents have been developed for epilepsy which are glutamate antagonists, but at this writing, they have not been tried as treatments of vertigo. Anticonvulsants are promising agents for treatment of vertigo.
Histamine agonists: Whereas the antihistamines used in treating vertigo are usually centrally acting histamine H1-receptor antagonists, in some parts of the world an H1/H3-receptor agonist, Serc (betahistine), is used. A dose of 8mg three times/day is usually prescribed, although greater effect is obtained for doses as high as 32 mg.. The rationale for this use is that Serc is said to increase circulation to the inner ear (Halmagyi, 1992) or suppress vestibular function through stimulation of H3 receptors (Kingma et al, 1997). Serc is currently approved by the FDA in the US only for compounding pharmacies. It has very little in the way of side effects. Histamine is sometimes prescribed as sublingual drops or subcutaneous injections. It is the authors opinion that histamine administered in this way is a placebo.
Sympathomimetics. These include ephedrine and the amphetamines. Sympathomimetics may increase alertness and thereby counterbalance the sedative effects of vestibular suppressants. Sympathomimetics also may increase compensation. However, if used for this purpose, the combination of a vestibular suppressant with a drug targeted to increase compensation seems somewhat illogical. Amphetamines are little used because of their addiction potential but they are known to increase and speed plasticity (Butefisch et al, 2002)
Acetyl-leucine. This medication is marketed and largely used in France (Rascol et al, 1995). It is claimed to exert a rapid antivertiginous effect when administered intravenously in humans and also to act as a vestibular suppressant. It is not used in the US for vertigo.
Ginkgo Biloba. This extract is widely used in France, but its efficacy is in question (Rascol et al, 1995). It has been reported to suppress vertigo and to enhance vestibular compensation in animals. Ginkgo is also thought to decrease tinnitus and improve memory.
Selective ACH antagonists. The ACH receptor has numerous subtypes, and it would seem reasonable that a selective antagonist to the M2 receptor might cause vestibular suppression without many of the untoward side effects of the more general anti-ACH agents. Unfortunately, little research has been pursued in this direction at the present time.
Alternative medicine agents. Cocculus is advocated for the temporary relief of light-headedness. For-HEEL and Vertigo-HEEL is also suggested for vertigo. The author has no experience with these medications and has no comment.
(c) 1997-2007 Timothy C. Hain, MD