Timothy C. Hain, MD
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May 21, 2013
There is some evidence that calcium channel blockers may be useful in the treatment of vertigo, but these medications are not commonly used for this purpose in the US. Here we attempt to review the mainly European literature, which is more favorable (e.g. Olesen, 1988) in an even handed fashion, hoping to establish a reasonable approach to the use of these agents. At this writing, while there are many reports that these drugs are helpful, it is presently not entirely clear why they are helpful (i.e. whether it is the calcium channel blocking effect or some other effect), as well as in which group of patients they might be helpful.
A positive interpretation of these studies is that the vestibular system, either peripherally or centrally, uses calcium channels, and that these drugs block them, causing vestibular suppression effects. There is good evidence for calcium channels peripherally, which are predominantly the L-type (Fuchs et al., 1990; Zidanic & Fuchs, 1995). Centrally, Serafin et al (1990, 1991) have demonstrated the existence of high-threshold (L or N type) and low-threshold (T-type) calcium channels in the vestibular nucleus. Recently Perin and others reported that in frog, all calcium channel blockers tested reduce resting rate and that L-channel blockers, such as nimodipine and perhaps verapamil, reduce mechanically evoked activity. Reducing the resting rate might reduce spontaneous nystagmus and reducing mechanically evoked activity might correlate with reduction in movement-induced symptoms. They suggested that L-type channels were involved in hair cell synaptic transmission and that another receptor was also involved with modulating afferent firing (2000).
A negative interpretation is that these are sloppy drugs, and their vestibular suppressant effects are related to slop -- antihistamine or anticholinergic activity, or perhaps just sedation. In support of the idea that the calcium channel effect is not important, Sansom et al (1993) reported that L-type calcium channels do not contribute to static vestibular function in the guinea pig vestibular nucleus (Sansom et al, 1993). However, if L-type blockers affect the peripehery as Perin et al reported (2000), the effect on the vestibular nucleus only means that these drugs do not act there.
A third possibility is that these drugs are good anti-migraine agents, and they work when migraine is confused with Menieres. The reality is probably a mixture of all three.
Calcium channel blockers also have numerous other effects beyond their effects on dizziness. They are generally negative inotrophic agents, which means that they decrease how strongly the heart pumps. Some of them are anti-apoptotic -- in other words, the reduce programmed cell death. The flip side of this is they may slightly increase cancer. In the Syst-Euro trial, nitrendipine (a long-acting dihydropyridine) was found both cardioprotective as well as reduced the prevalence of dementia by 50%. Verapamil also has been reported to improve thinking. Verapamil is protective in an animal model against kanamycin ototoxicity (Zhuravskii et al. 2002)
Other long-acting dihyropyridines in the US are amlodipine, felodipine, nicardipine, and long-acting nifedipine. Verapamil and nimodipine are also effective drugs in preventing Migraine.
Cinnarizine, not available in the US, is mainly marketed elsewhere as a H1 antihistamine. It also antagonizes noradrenaline, nicotine and angiotension, as well as is a calcium channel blocker. Because Cinnarizine has so many actions, it is difficult to know if positive affects can be attributed to calcium channel blocking vs. actions at other receptors. Pianese et al (2002) found Cinnarizine very effective for peripheral vertigo. Bartual et al (1989) reported cinnarizine plus dihydroergocristine effective in 90% of 122 patients with vertigo of cervical origin. As the criteria for the diagnosis of cervical vertigo are presently very unclear, the meaning of this observation is uncertain. Doweck et al (1994) found that cinnarizine reduces VOR gain on rotatory testing. The usual dose is 12.5 mg three times daily. Sedation is a common side effect. We see no particular reason to use cinnarizine when flunarizine is available.
Flunarizine, also not available in the US, is a fluorinated derivative of Cinnarizine, which is more potent and has a much longer half-life. Flunarizine has been extremely well studied in Europe, and a recent search (2013) turned up 533 references concerning Flunarizine.
Ell and Gresty (1983) found flunarizine not to reduce vestibular gain, but rather to reduce or abolish after-nystagmus, and in particular, abolish secondary phases. There was no effect on pursuit or voluntary saccades, but vestibular saccades were of lower and more uniform amplitude. On the other hand, Lee et al (1986) reported flunarizine to be a "powerful peripherally acting labyrinthine suppressant", in a study of 10 military personnel. The peak velocity of VOR slow phase was reduced to approximately 70%, at 2 hours after ingestion. Drowsiness occurred in about 5%. Oosterveldt (1974) also reported a reduction in the velocity or rotatory nystagmus. It has also been suggested that flunarizine may facilitate or accelerate vestibular compensation in hemilabyrinthectomized guinea pigs (Tolu and Mameli, 1984). These authors further suggested that flunarizine results in excitation of cerebellar cortex (1988). The usual dose is 10 mg daily.
Flunarizine has also been suggested to be protective against cis-platinum and iron. We find this somewhat dubious.
Flunarizine has also been used for treatment of migraine in both adults and children (Luo et al, 2012; Verspeelt et al, 1997; Kim et al, 2013). It is roughly as effective as topirimate, and works well when the two are combined. Sedation is a common side effect, but numerous other side effects, including weight gain and Parkinsonism, are possible. In regards to the latter, flunarizine induced Parkinsonism due to chronic use is the second most common cause of parkinsonism in many countries (Tieve et al, 2004).
Generally speaking, medications which are not available in the USA can be obtained through overseas pharmacies legally, as long as they are for treatment of an important health problem and only for personal use.
This poorly named drug which looks somewhat biochemically like GABA, does not interact with the GABA receptor, but rather has a high binding affinity for the Ca(2+)-channel subunit alpha(2)delta, and is a calcium channel blocker.
Verapamil is available in the US. The usual dose is 120 to 240mg, SR, once per day. SR means sustained release. This drug is an dihydropyridine L-channel calcium channel blocker, similar to other dihydropyridine drugs like nifedipine, nimodipine and diltiazem. Verapamil is effective about 75% of the time for migraine but it takes about 2 weeks to work. This drug also may be helpful in Menieres disease, although this has not yet been documented by a controlled study. The main side effect of verapamil is constipation, suggesting that anticholinergic activity might be, in part, the mechanism of action.
Nimodipine has been reported to be helpful, but in the US, nimodipine is extremely expensive and there seems little reason to use it rather than verapamil.
Side effects of verapamil
About 50% of users develop mild constipation. Sometimes lowers blood pressure but this is generally not a big problem if it is started gradually. About 1% of users develop palpitations (fluttering feeling in chest). Stop taking this drug if you develop palpitations. A few individuals develop swelling of the ankles. Verapamil is safe in patients with asthma, and especially good in patients who also have high blood pressure. Should start with dose mg. roughly = weight of patient.
Precautions and Concerns
If possible, stop verapamil before major surgery as there is some evidence of increased bleeding tendencies. Whether or not verapamil, like aspirin, prevents stroke is presently unclear. Stop taking verapamil if significant palpitations develop. Verapamil should not be taken in pregnancy.
There are several concerns about verapamil that should limit its use to situations where its advantages outweigh the risks. Because of studies suggesting increased mortality from heart disease, verapamil and related drugs in the calcium channel blocker family are not favored in individuals aged 55 and older. One study suggested an increased risk of cancer (about 2 fold) in persons taking calcium channel blockers.
Nimodipine is an extremely expensive calcium channel blocker, marketed largely for treatment of subarachnoid hemmorage. It has been used for Menieres disease(Lassen et al, 1996), as well as peripheral vertigo (Pianese et al, 2002) with positive results . We feel that the cost of this drug is prohibitive and see no advantage over the much less expensive verapamil.
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