By Marcello Cherchi, MD PhD
For patients
Betahistine is a pill that can be taken every day to reduce the frequency of attacks of Ménière’s disease. Patients usually do not notice any side effects with this medication.
For clinicians
Overview
Betahistine is a centrally acting mixed histamine agonist-antagonist that probably has several effects on neural and vascular structures relevant to cochlear and vestibular function. Its main application in otoneurology is as maintenance therapy (baseline prophylaxis) for medically-managed Ménière’s disease. It is generally very well tolerated. Betahistine was previously approved by the FDA, but the approval was subsequently rescinded because the FDA reviewed data suggesting that betahistine is not superior to placebo (not because the FDA believes it to be dangerous).
1. Pharmacology
Betahistine, also known as N alpha-methyl-2-pyridylethylamine (Arrang, Garbarg et al. 1985), was originally thought to be, “a structural analogue of histamine with weak histamine H(1) receptor agonist and more potent H(3) receptor antagonist properties” (Lacour and Sterkers 2001). Subsequent research suggests that its effects are more nuanced.
1.1. Betahistine catabolites
The pharmacology of betahistine has been difficult to study, as it is hepatically catabolized into multiple other compounds; “Pharmacokinetic studies have in fact demonstrated that betahistine is transformed, mainly at the hepatic level, in aminoethylpyridine (M1), hydroxyethylpyridine (M2) and, finally, in pyridylacetic acid (M3)” (Botta, Mira et al. 2001). Animal studies in frogs suggest that, “both betahistine and one of its metabolites, the aminoethylpyridine (M1), exert effects quite similar on ampullar receptors; both these substances in fact could reduce greatly ampullar receptor resting discharge” (Botta, Mira et al. 2001); see also (Botta, Mira et al. 2000).
1.2. Where does betahistine exert its effects?
It was originally thought that betahistine was “peripherally-acting,” meaning that it only influenced activity in the inner ear. However, subsequent evidence suggested that betahistine is able to cross the blood-brain barrier, and that the drug can be “centrally-acting,” meaning that it has an effect on the brain as well.
1.2.1. Peripheral effects
Animal studies in the axolotl suggest that, “betahistine has a peripheral inhibitory action in the spike discharge of the afferent neurons in the vestibule. This action seems to involve neither NO [nitric oxide] production nor modifications in the release of acetylcholine from the efferent fibers. The inhibitory action of betahistine seems to be due to a postsynaptic binding site on the afferent neurons” (Chavez, Vega et al. 2001).
Studies in frogs suggest that, “endolymphatic administration of betahistine had no effect, whereas its perilymphatic administration could reduce greatly ampullar receptor resting discharge but had little effect on mechanically evoked responses” (Botta, Mira et al. 1998); see also (Valli 2000).
Animal studies in the axolotl suggest that, “the action of betahistine on the spike discharge of afferent neurons seems to be due to a post-synaptic inhibitory action on the primary afferent neuron response to the hair cell neurotransmitter” (Soto, Chavez et al. 2001).
Animal studies in the axolotl suggest that, “betahistine (BH) decreased the electrical discharge of afferent neurons by interfering with the postsynaptic response to excitatory amino acid agonists. These results lend further support to the idea that the antivertigo action of histamine-related drugs may be caused, at least in part, by a decrease in the sensory input from the vestibular endorgans” (Chavez, Vega et al. 2005).
1.2.2. Central effects
Animal experiments in mice and guinea pigs concluded that, “betahistine is a partial agonist at cerebral H1-receptors. Finally, betahistine was not an agonist at histamine H3-autoreceptors but was a rather potent antagonist of the inhibitory effect of exogenous histamine on [3H]histamine release elicited by K+ depolarisation” (Arrang, Garbarg et al. 1985).
Animal studies on cats conclude that, “Betahistine treatment induced symmetrical changes with up-regulation of histidine decarboxylase mRNA in the tuberomammillary nucleus and reduction of [(3)H]N-alpha-methylhistamine labeling in both the tuberomammillary nucleus, the vestibular nuclei complex and nuclei of the inferior olive. These findings suggest that betahistine upregulates histamine turnover and release, very likely by blocking presynaptic histamine H(3) receptors, and induces histamine H(3) receptor downregulation,” and suggest that, “This action on the histaminergic system could explain the effectiveness of betahistine in the treatment of vertigo and vestibular disease” (Tighilet, Trottier et al. 2002).
There is some evidence that betahistine facilitates central compensation from peripheral vestibular lesions (Tighilet, Leonard et al. 1995).
1.2.3. Peripheral and central effects
In view of the research cited earlier, it seems likely that betahistine has both peripheral and central effects, though it is still incompletely understood why it should have the effects that it does. A review concluded that, “betahistine may reduce peripherally the asymmetric functioning of the sensory vestibular organs in addition to increasing vestibulocochlear blood flow by antagonising local H(3) heteroreceptors. Betahistine acts centrally by enhancing histamine synthesis within tuberomammillary nuclei of the posterior hypothalamus and histamine release within vestibular nuclei through antagonism of H(3) autoreceptors. This mechanism, together with less specific effects of betahistine on alertness regulation through cerebral H(1) receptors, should promote and facilitate central vestibular compensation. Elucidation of the mechanisms of action of betahistine is of particular interest for the treatment of vestibular and cochlear disorders and vertigo” (Lacour and Sterkers 2001).
1.2.4 Vascular effects
There is evidence that betahistine functions as a vasodilator both cerebrally (Barak 2008), and in the cochlea (Jimenez, Anton et al. 1996).
1.3. Summary of possible pharmacologic mechanisms of action
In summary, data predominantly from animal experiments suggest several pharmacologic mechanisms of action.
- Vasodilation, including the cochlear vascular supply.
- Histamine H1 receptor agonist at cerebral receptors in the tuberomammillary nucleus, vestibular nuclei complex, and the nuclei of the inferior olive.
- Histamine H3 receptor antagonism at a post-synaptic site, resulting in inhibition of the tonic (resting) discharge rate of afferent neurons in the vestibule.
- The mixed agonist-antagonist activity may facilitate central compensation from peripheral vestibular lesions.
2. Clinical application
Betahistine has been studied in the treatment of a number of diseases (Barak 2008). The main purpose in the practice of vestibular medicine is in the treatment of Ménière’s disease. Fewer studies have been done on diseases such as benign paroxysmal positional vertigo and vestibular neuritis.
A number of studies have explored the use of betahistine as a baseline prophylactic strategy for Ménière’s disease. Both older (James and Burton 2001) and more recent (Holmes, Lalwani et al. 2021) analysis of multiple trials concluded that evidence is lacking regarding whether betahistine is superior to placebo for management of Ménière’s disease. Holmes and colleagues (Holmes, Lalwani et al. 2021) commented that a larger number of studies, using more standardized diagnostic and grading criteria, following patients over a longer period of time, will be required to ascertain whether betahistine is superior to placebo.
Betahistine has been studied as an adjunctive treatment (along with canalith repositioning maneuvers) for benign paroxysmal positional vertigo. Several studies suggest that outcomes from using canalith repositioning maneuvers plus betahistine are superior to maneuvers alone (Cavaliere, Mottola et al. 2005, Stambolieva and Angov 2010, Guneri and Kustutan 2012, Kaur and Shamanna 2017, Jalali, Gerami et al. 2020, Sanchez-Vanegas, Castro-Moreno et al. 2020, Hui, Lei et al. 2022, Sayin, Koc et al. 2022). Other studies report that betahistine confers no added benefit (Kulcu, Yanik et al. 2008, Acar, Karasen et al. 2015, Inan and Kirac 2019).
Few studies have been performed regarding the use of betahistine in the treatment of vestibular neuritis (Scholtz, Steindl et al. 2012).
3. Tolerability
Multiple studies in diverse patient populations report betahistine as generally well tolerated (Bradoo, Nerurkar et al. 2000, Cirek, Schwarz et al. 2005, Gananca, Caovilla et al. 2009, Benecke, Perez-Garrigues et al. 2010, Lezius, Adrion et al. 2011, Bajenaru, Roceanu et al. 2014, Moorthy, Sallee et al. 2015, Morozova, Alekseeva et al. 2015, Kirtane and Biswas 2017).
This reflects our own experience. A modest proportion of patients (we would estimate less than 10%) describe either headache or stomachache during the first few days of taking betahistine, but these are generally transient symptoms.
Since betahistine is not currently FDA approved, it is absent from databases that check for drug-drug interactions.
Logically, since betahistine does have some peripheral pro-histaminic effects (as an H1-receptor agonist), it seems likely that simultaneously taking a conventional antihistamine (which tends to block all sub-types of histamine receptors) would probably partially work against the mechanism of betahistine’s action.
4. Approval status
Betahistine previously was approved in the United States by the FDA. The approval was subsequently rescinded, as the FDA judged that additional data showed non-superiority of betahistine over placebo.
There are two consequences to betahistine’s non-approval status. First, health insurance companies in the United States will almost never cover this drug. Second, the drug’s availability is limited to compounding pharmacies.
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