Drug Treatment of Vertigo

Timothy C. Hain, M.D.

Last update: 9/2002


This pharmacological  review is written at a continuing medical education level. Please read our disclaimer.

Pharmacology

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). Acetylcholine (ACH) is both a peripheral and central agonist affecting muscarinic receptors. 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). 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 SUPPRESSANTS

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 Pharmacologic 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 benzodiazepine drug 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.

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 Ménière'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 because it has significant potential toxicity. There is evidence for involvement of several types of histamine receptors. Serafin and others (1993) reported that histamine increases firing in MVN cells, mediated through the H2 receptor. H1 receptors are present in guinea pig vestibular nucleus, but they don't seem to be relevant to vertigo, and it does not appear that the therapeutic effects of H1 receptor blockers can be attributed to blockate of H1 (Timmerman, 1994). H3 receptor agonists appear to cause the same result as blockade of H2 receptors. Most antihistamines also have calcium channel blocking effect (according to Timmerman, 1994).

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 is a particularly useful agent because of its 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), is as effective a vestibular suppressant as lorazepam (Ganaca et al, 2002). 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 Pharmacologic Class
granisetron(Kytril) 1 mg PO BID 10 ug/kg IV daily

headache

sedation

5HT3 antagonist
meclizine (Antivert, Bonine) 12.5-25 mg q4-6h PO sedating Precautions in glaucoma, prostate enlargement antihistamine anticholinergic
metoclopramide(Reglan) 10 mg PO TID or 10 mg IM restlessness or drowsiness extrapyramidal dopamine antagonist stimulates upper gastrointestinal motility
ondansetron (Zofran) 4-8 mg PO TID

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
prochlorperazine(Compazine) 5 mg or 10 mg IM or PO q6-8 hr.

25 rectal q12h

sedating extrapyramidal phenothiazine
promethazine(Phenergan) 12.5 mg PO q6-8h or 12.5 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).  Domperidone (Motilium) is an antiemetic that does not cross the blood brain barrier and thus has less side effects. Although droperidol has been used in the past, it is no longer recommended.

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 pharmacologic actions.

Agents whose whose role is presently uncertain.

Calcium channel blockers are the most promising agents in this group. More detail about these drugs can be found here. 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 associated activity for vestibular suppression has not been determined (Rascol et al, 1989). Another problem is that almost all antihistamines have calcium-entry blocking capacity and/or calmodulin blocking properties, making it difficult to ascertain the mechanism of action (Timmerman, 1994). Calcium channel blockers may be effective in "vestibular Menieres", or "benign recurrent vertigo", 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 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, however, 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. Gabapentin (Neurontin), carbamazepine (Tegretol) and oxcarbazepine (Trileptal) are also sometimes successfully used in treatment of vertigo, although their use has not been studied extensively. Gabapentin has also been successfully used to suppress certain types of central nystagmus (Stahl et al, 1995). As these agents affect GABA, which is important in vertigo, an antivertigo effect is reasonable. Tegretol and Trileptal are particularly useful in paroxysmal disorders such as microvascular compression syndrome, and neuritis of the vestibular nerve. 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.

Another Gaba agonist, Baclofen (Lioresal) has shown some promise in reducing vestibular asymmetry. No human trials have yet been undertaken. This agent might be suitable for patients with uncompensated vestibular asymmetries.

Histamine agonists: This is an interesting group that presently appears poised to move from the uncertain role category to the more conventional category. Whereas the antihistamines used in treating vertigo are usually centrally acting histamine H1-receptor antagonists, in some parts of the world an H1+H2-receptor agonist (and H3 antagonist (?)), Serc (betahistine), is used. According to Timmerman quoting Laurikainen, H1 receptors do not appear to be important at all in vestibular function and the antivertiginous effects of antihistamines are mediated either through non-H1 receptors or other effects of the drugs. Also, the H1 (and H2 effects) are rather minor. Accordingly, Serc's effects might occur through H2 agonism or H3 antagonism (Timmerman, 1994). H3 is an autoreceptor that modulates H1/H2 as well as potentially other neurotransmitter systems. Thus, an agent that primarily affected H3, could at this writing, essentially, pharmacologically do anything. The pharmacological literature is confusing as some authors suggest that betahistine is an H3 agonist (Kingma, 1997) rather than an antagonist (Timmerman, 1994).

Pragmatically, a betahistine 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 betahistine is said to increase circulation to the inner ear (Halmagyi, 1992) or affect vestibular function in some mysterious way through activity of H3 receptors (Kingma et al, 1997; Timmerman, 1994). At this writing, as H2 agonism would be stimulatory, it appears most likely that Serc acts through the H3 receptor. Serc is not fully approved by the FDA in the US but it can be obtained through compounding pharmacies. Histamine is sometimes prescribed as sublingual drops or subcutaneous injections. It is the authors opinion that sublingual or subcutaneous histamine is a placebo as it is rapidly degraded. Nevertheless, in the authors experience, Serc is moderately effective in suppressing symptoms of Meniere's disease. Following the pharmacological discussion above, Serc might be expected to be effective in any peripheral vestibular disorder, not merely Meniere's disease.

Steroids. Corticosteroids such as decadron have been advocated both for treatment of Meniere's disease and Vestibular neuritis, in both cases, in an attempt to reduce the duration of a vertiginous episode. This use has not been studied formally. 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.

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.

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. See here for more information.

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 lightheadedness. For-HEEL and Vertigo-HEEL is also suggested for vertigo. See here for more about these agents.


REFERENCES

(c) 1997-2000 Timothy C. Hain, MD