Central vestibular disorders differ from peripheral vestibular disorders (such as vestibular neuritis or Meniere's disease), in that the damage to the person is within the nervous system -- usually the brainstem or cerebellum. This usually adds great complexity to the overall situation, as while there are only a few major drug targets in the periphery (acetylcholine -- ACH, glutamate), there are numerous potential targets in the brain including, again, ACH, but also GABA, histamine, norepinephrine, dopamine, glycine (inhibitory), serotonin, and cannabinoids. Soto et al (2013). See this page for a neurotransmitters used to signal in the vestibular system.
Generally speaking, one's goals in treatment of central disorders would be to preserve peripheral function (which is not the problem), suppress central responses if they are inappropriate, and to encourage repair processes (i.e. compensation). Thus in general, one would (in theory) want to avoid vestibular suppressants (such as ACH blockers -- e.g. scopolamine), avoid Glutamate blockers (such as Memantine), and focus on GABA agonists such as benzodiazepines and baclofen (to suppress central responses), and consider drugs that increase compensation (generally drugs that increase dopamine or norepinephrine), but also 4-AP. The role of cannabinoids, and histamine agonists (such as betahistine) is little studied, and perhaps worth a try if the side effects are small.
We have attempted to present rational thinking about these agents. Practically, the drugs can be grouped into "reasonable", "unreasonable", "placebo", and "lets just throw the kitchen sink at the problem" type of drugs. We understand that choices of drugs that may have little evidence behind them, i.e. "kitchen sink or placebo", might still be considered in very bad situations.
Drugs worth considering in central vestibular problems (these are reasonable ones).
Drugs probably best to avoid in central vestibular problems (unreasonable ones).
Drugs of uncertain role (probable placebos and "kitchen sink" category drugs).
As discussed briefly above, peripheral vestibular suppressants such as ACH blockers, which include common drugs such as meclizine and scopolamine, would seem to have little rationale for use in central vertigo. On the other hand, benzodiazepines and GABA drugs (such as baclofen), might be worth considering. The jury is out on cannabis and antidepressants (such as venlafaxine). The table below provides a summary of the most commonly used benzodiazepines used for treatment of dizziness. These are "reasonable" category drugs.
|Table 1: GABA agonist type vestibular suppressants (order of preference)|
|Drug||Dose||Adverse Reactions||Pharmacologic Class and Precautions||Pregnancy Category|
|Lorazepam (Ativan)||0.5 mg BID||mildly sedating||benzodiazepine drug dependency, 12-18 hour half life.|
|Clonazepam (Klonopin)||0.5 mg BID||mildly sedating||benzodiazepine drug dependency, 30 hour half life.|
|Diazepam(Valium)||2 bid PO
5 mg IV (1 dose)
|sedating||benzodiazepine drug dependency Precaution in glaucoma. Complex timing. Complex half life.||D|
Doses are all those used routinely for adults, and will generally not be appropriate for children. Pregnancy category varies from A (controlled human studies have failed to demonstrate a risk to the fetus) through D (there is positive evidence of human fetal risk, use only in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective.
Benzodiazepines are GABA modulators, acting centrally to suppress vestibular responses. See this page for a longer discussion. They increase the affinity of chloride channel opening (Soto et al, 2013). There are differential effects across benzodiazepines on Gaba-A receptor subtypes. In small doses, these drugs are extremely useful. Addiction, impaired memory, increased risk of falling, and possibly impaired vestibular compensation are their main shortcomings.
Lorazepam and clonazepam 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. Note that lorazepam and clonazepam have quite different time constants (i.e. durations of action), with lorazepam being shorter, which makes for some interesting trade-offs. Other problems with benzodiazepines include higher incidence of car accidents (risk x1.5), and hip fractures (risk x 1.8) (Ray, Griffin et al. 1987; Ray, Fought et al. 1992). Fall risk is increased in the elderly by roughly the same proportions.
Similarly, low doses of diazepam (Valium) (2 mg) can be quite effective for dizziness. 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.
Another GABA agonist, Baclofen (Lioresal) has shown been suggested as a method to reducing vestibular asymmetry. A human trial indicated that it is not useful in speeding up vestibular compensation (de Valc et al, 2009), but nevertheless this agent may have other uses. GABA drugs would be more likely to slow down compensation. This agent might be suitable for patients with uncompensated vestibular asymmetries. It does help in a rare type of central vertigo, PAN. In our clinical practice, we use Baclofen very rarely because it just doesn't seem to help..
Although some seizure medications act mainly on GABA, there is little reason to choose them over the more commonly understood Benzodiazepine category. Usually these drugs can be spotted because they are controlled substances.
Antihistamines in central vertigo
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). 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 blockade 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). Histamine agonists that act on receptor subtypes are also used for treatment of vertigo (e.g. betahistine). Their role in central vertigo is unclear. Overall, there is little rationale for antihistamine drugs in central vertigo.
Histamine agonists in central vertigo.
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-H4 antagonist, Serc (betahistine), is used. This is an interesting group that has been poised to move from the uncertain role category to the more conventional category for decades. The main problem with it is that rigorous studies proving efficacy are generally are not available, although unrigorous studies abound. 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 minor. 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. Recently a 4th histamine receptor (H4) has been identified. H4 antagonists are reported to suppress rat primary vestibular neuron firing (Desmadryl et al, 2012). Also, according to these authors, betahistine does not have a significant effect on the H4 receptor in conventional doses. This may account for the recent suggestions to push the dose up to very high levels (e.g. Strupp et al, 2008).
In the rat brainstem, betahistine produces a slight excitatory response in MVN neurons, and it reduces the excitatory effect of histamine (Soto et al, 2013).
Pragmatically, a betahistine dose of 16 mg twice to three times/day is usually prescribed, although greater effect is obtained for doses as high as 48 mg (Strupp,et al. 2008). At this writing, as H2 agonism would be stimulatory, it appears most likely that Serc acts through the H3 or H4 receptor. Serc is approved by the FDA in the US but only if dispensed through compounding pharmacies. It was categorized, in essence, as a harmless substance. Histamine is sometimes prescribed as sublingual drops or subcutaneous injections. It is the author's opinion that sublingual or subcutaneous histamine is a placebo as it is rapidly degraded. As a bottom line, histamine agonists (such as Serc) have an unclear role (if any) in central vertigo. It is possible that very large doses might have a good effect, but this is simply a conjecture.
Mechanisms of effect of antidepressants for dizziness
- Anticholinergic (such as amitriptyline and nortriptyline)
- Antimigraine (such as amitriptyline, nortriptyline or venlafaxine)
- Antidepressant (improved well being)
All antidepressants increase ataxia and many cause nausea as well as hypotension. Thus one would think that their role would be limited. However, the ability of antidepressants to manage the psychological fallout from dizziness is often helpful (Horii, Mitani et al. 2004) Horii, A., K. Mitani, et al. (2004). Some antidepressants such as amitriptyline have strong anticholinergic properties which can be of use in managing dizziness. There are several reports of a positive effect, lacking an explanation (e.g. Grubb et al, 1996). Some antidepressants modulate migraine (such as venlafaxine) or increase norepinephrine.
In general, anticonvulsants reduce neural activity, and thus can be suppressants of inappropriate central circuits. Anticonvulsants often have dizziness as a side effect, especially at high doses, and sometimes are cerebellar toxins. These are reasons that we might not want to use them. The following is organized roughly by the utility of the drugs.
Gabapentin has been successfully used to suppress certain types of central nystagmus (Stahl et al, 1995). This drug, as well as pregabalin (a close relative) may be worth a try in central vertigo.
Topiramate, sodium valproate and lamotrigine are seizure medications used for suppression of migraine, which can cause central vertigo (vestibular migraine).
The sodium channel blockers carbamazepine and oxcarbazepine are particularly useful in paroxysmal disorders such as microvascular compression syndrome, and neuritis of the vestibular nerve. They are also occasionally used for tinnitus. Because the both lower serum sodium, they are also sometimes used for treatment of hydrops (i.e. Meniere's disease).
Gabapentin (Neurontin), carbamazepine (Tegretol) and oxcarbazepine (Trileptal) are also sometimes successfully used in treatment of the "vestibular paroxysmia" peripheral type of vertigo.
While anticonvulsants are used to treat epileptic vertigo, this situation is usually best managed by an epileptologist, as there are a very large repertoire of medications available for treatment of seizures. This is beyond the scope of this review.
An epilepsy drug, sodium channel blocker, phenytoin (Dilantin), has also been 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. Dilantin causes dizziness in otherwise normal people, and also is a long term neurotoxin to the cerebellum. Not something we want in central dizziness.
Recent agents have been developed for epilepsy which are glutamate antagonists, but at this writing, they have not been tried as treatments of vertigo.
Calcium channel blockers, such as flunarizine and cinnarizine, are popular antivertiginous agents outside of the U.S. (Rascol et al, 1989). Flunarizine however is also a dopamine blocker, and cinnarizine an antihistamine. 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).
According to Soto et al (2013), Cinnarizine also blocks pressure sensitive potassium channels, which may provide it with a separate mechanism for treatment of hydrops.
Calcium channel blockers may be effective in "vestibular Meniere's", 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. According to Soto et al (2013) the most commonly used calcium channel blockers for vertigo are nimodipine, nitrendipine (long lasting) and verapamil. Other long lasting dihydropyridines such as amlodipine, felodipine, nicardipine and nifedipine are seldom used. One of the authors has found daily verapamil to be helpful in a roughly 2% of his patients with classic Meniere's, 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 Meniere's. In the US, our experience is that only verapamil is used to any great extent.
Gabapentin is also a calcium channel blocker (it is not a GABA agonist in spite of the name). It is generally not useful for vertigo (or migraine), and causes some dizziness itself as a side effect.
There is no reason to use most diuretics (such as Triamterine/HCTZ) in central vertigo. The same goes for loop diuretics (such as furosemide).
Carbonic anhydrase inhibitors (such as acetazolamide), are occasionally tried, and can be helpful in episodic ataxia.
3-4 DAP (diaminopyridine) as well as its close relative, 4AP, has been reported useful for persons with ataxia and downbeating nystagmus.
This drug is sometimes used for fatigue in MS, as well as for a rare neuromuscular disorder (Eaton Lambert). Side effects include headache, fatigue perioral and/or distal paraesthesia 30-60 minutes after a dose, difficulty in sleeping. Excessive dosage can lead to seizures. The typical starting dose is 10 mg three times/day. 4-AP is a similar agent that has better CNS absorption. We have had occasional success with this drug at all in treating suitable patients in our clinical practice. Note that the brand-name version of 4AP is priced about 20 times higher than the compounded version of the similar 3-DAP chemical. The barriers involved inobtaining this drug in the US are high, in part perhaps due to its obtaining FDA approval for a limited indication (MS).
There are a large assortment of dopamine blockers used for emesis. These drugs may also treat migraine (as they are often effective migraine abortive drugs). In fact, Flunarizine is the dominant migraine prevention drug used in Europe. All are limited by their propensity to cause movement disorders (such as drug induced parkinsonism) as well as others. In our view, these drugs should be "last resort" for treatment of chronic vertigo conditions. We are, for example, against the use of Stugeron (cinnarizine) for any chronic dizzy condition. Flunarizine is a close relative to cinnarizine. These drugs are generally considered acceptable for acute use however.
Opioids often cause constipation, and drugs that cause constipation usually also reduce dizziness. Our thought is that these drugs are far too dangerous to use for dizziness. There are also occasional reports of hearing loss from large amounts of these drugs.
There is little rationale for use of steroids for central vestibular disorders. In these few instances, the symptom of vertigo reflects involvement of vestibular-sensitive neuroanatomical structures that happen to be affected by a broader disease process whose management involves steroids. For example, steroids might be used for an exacerbation of MS, but the rationale here is to treat the MS disease process, not the central vertigo specifically.
These drugs increase norepinephrine. Examples 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. Sympathomimetics are generally pregnancy category C. There is some rationale for these drugs as they increase compensation in animals. Addiction is the main issue.
Dopamine agonists reduce firing rate in the frog hair cells and also reduces response to glutamine (the excitatory transmitter) (Soto et al, 2013). On the other hand, dopamine antagonists are uncommonly used to treat vertigo (e.g. Droperidol, phenothiazines), suggesting that the net effect is against using dopamine agonists.
Pentoxifylline is a "rheologic" agent, intended to improve blood flow mainly in persons with intermittent claudication of the legs. It might have a rationale in situations where central blood flow is poor such as vertebrobasilar insufficiency. We do not know of any literature about this use.
Acetyl-leucine. : This medication/supplement 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. The evidence for it working is not the best. There is a questionable rationale for it's use in central 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. There is very little rationale for this drug in central vertigo.
Cocculus is advocated for the temporary relief of lightheadedness. For-HEEL and Vertigo-HEEL is also suggested for vertigo.
N-acetyl Cysteine (NAC) is another agent suggested for dizziness or tinnitus.. NAC is also sometimes recommended for hearing disorders. See here for more about these agents.This drug is probably a placebo
Lipoflavenoids -- basically vitamin-C. This is probably an expensive placebo.
Varenicline (Chantix). -- kitchen sink drug.
This drug, approved by the FDA for smoking cessation, has recently been reported useful for treatment of cerebellar ataxia (Zesiewicz et al, 2009). It is extremely surprising to find an agent that will ameliorate disorders caused by genetic damage to neurons. It is also disturbing that the number of individuals in the trial (7) was exactly the same as the number of authors on the study. In other words, it would seem to us that if this drug was effective, the number of subjects should be larger as patients with cerebellar disorders are easily located in clinical settings. We are frankly very dubious. We have never encountered a patient who responded to this mediation (who wasn't attempting to stop smoking).
Trimetazidine -- kitchen sink.
This drugs is a medication developed for angina (cardiac disturbance). It has been reported useful in diverse disorders (Soto et al, 2013), including Meniere's disease. The evidence for this drug working is presently weak. Trimetazidine can also induce a myriad of CNS disorders, largely similar to those produced by dopamine antagonists (i.e. similar to haloperidol -- Haldol). Limited studies found trimetazidine's efficacy to be similar to betahistine in the management of Ménière's disease (Kluyskens, Lambert et al. 1990, Martini and De Domenico 1990). One placebo-controlled study of 45 patients with undifferentiated "cochleovestibular disorders of ischemic origin" reported trimetazidine as superior to placebo (Coyas 1990). These limited data suggest that trimetazidine may be relevant for peripheral, rather than central, vestibular disorders. Trimetazidine is currently not FDA-approved.We are not sure about this drug in central vertigo.
Glutamate drugs: varies between reasonable, placebo, and dangerous (memantine only reasonable)
Glutamate is an excitatory neurotransmitter and thus glutamate blockers might reduce central excitation.
Memantine (suppresses glutamate)
This drug is mainly a glutamate blocker (NMDA), and thus might be a vestibular suppressant. It was approved in the US for prevention of progression of Alzheimer's disease. It also is reported to act on 5HT3, D2, and various cholinergic receptors (Soto et al, 2013). We have never encountered a dizzy patient who responded to memantine. Although there are reports to the contrary, we have also never encountered a patient whose pendular nystagmus responded to memantine. This is hardly surprising as it is a low-affinitive NMDA antagonist.
Low side effect drugs (like memantine) are more likely to be placebos for central vertigo.
A similar drug is caroverine, that is a glutamate AMPA receptor antagonist. This drug is not absorbed orally.
Hallucinogenic NMDA drugs (inhibits glutamate receptor) -- dangerous
These include MK-01, phencyclidine (PCP, "angel dust"), and Ketamine ("special K") among others. Of course, side effects and abuse are a problem. Ketamine produces a general "lack of responsive awareness", as well as dizziness (Soto et al, 2013). There is no rationale for use of these drugs in central vertigo.
Riluzole -- kitchen sink
Riluzole is approved by the FDA for treatment of ALS. It blocks sodium channels, which are associated with damaged neurons, and inhibits some NMDA glutamate receptors as well as potentiates GABA-a. So this drug would seem to be an inhibitor of central circuits, resembling a mixture of memantine and a benzodiazepine. According to Bryson et al, "Gastrointestinal effects, anorexia, asthenia, circumoral paraesthesia and dizziness were reported more frequently with riluzole than placebo. " So it can cause dizziness. There are reports as of 2022 of Riluzole being used as treatment for central dizziness.
We suspect that Riluzole use for central vertigo is an example of "kitchen sink" type reasoning. Hopefully more evidence will develop over time.