Keywords
betahistine - treatment of vertigo - H
3-receptor - treatment of Ménière’s disease - betahistine in Ménière’s disease
Introduction
Betahistine, a structural analogue of histamine, is the one of the most prescribed
anti-vertigo drugs today, even though adequate authentic scientific evidence in its
favor is lacking. Possibly aggressive marketing and some unscientific promotion may
have catapulted it to its present status. Hence, a thorough scientific analysis is
warranted. The main problem with betahistine is that reasonably authentic, large,
randomized, placebo-controlled, double-blind, multicentric studies proving the efficacy
are generally are not available, whereas less rigorous, observational, and low-quality
studies (mostly class 3) have shown contradictory results and raised doubts on its
clinical efficacy.[1] It provides symptomatic relief by sedating the vestibular labyrinth and is probably
the only nonsedative anti-vertigo drug without any anticholinergic and antidopaminergic
effects. It is a vestibular suppressant that does not cause depression of the central
nervous system (CNS).[2]
[3] Though it is often commercially promoted as a vestibular stimulant, it is not so
as per scientific data; it is actually a vestibular suppressant.[3] There are many conflicting views about the mechanism of action (vestibular suppressant
or vestibular stimulant?), its clinical efficacy (i.e., whether it is a placebo or
has some medicinal/pharmacological effect), the dosage of betahistine,[1]
[2]
[3]
[4]
[5] and whether it is a drug only for Ménière’s disease or for symptomatic relief for
any type of vertigo, etc. This article is an attempt to scan some of the published
literature on betahistine and form a consensus on its status as a pharmaco-therapeutic
agent in the management of vertigo. Any drug that is used for vertigo will have to
serve one or more of the following purposes. It will have to be a drug either for
(1) symptomatic therapy, that is, ameliorate the symptoms of vertigo irrespective
of the cause, or (2) be a specific therapy for some disease, which is manifested as
vertigo, that is, treat or reverse the pathology of the underlying disease where vertigo
is the major symptom, or (3) be a drug for prophylaxis of vertigo, that is, prevent
or reduce the recurrence of the disease that is causing the recurrent vertigo. Though
betahistine is often projected as a drug that serves all the three purposes, yet authentic
scientific evidence in its favor is lacking.
Some Contentious Issues about Betahistine
Some Contentious Issues about Betahistine
The reported mechanism of action of betahistine is not consistent in the literature,
resulting in confusion in understanding its true pharmacological effects. Hence, though
the drug sells very well, the fact remains that most clinicians prescribe it without
understanding its mode of action and are possibly influenced by the robust and aggressive
marketing strategies and biased propaganda.
Betahistine is a vestibular suppressant[3] and hence decreases sensory conflicts in the vestibular system when used after a
vestibular assault. Hence like all other vestibular sedatives, its use should be restricted
to a maximum of 3 to 5 days. Betahistine being a vestibular suppressant, by decreasing
vestibular input, suppresses the vestibular system, resulting in delay in vestibular
compensation. However, as betahistine is not a CNS depressant and not an anticholinergic
drug, the mischief or impediment to vestibular compensation caused by it is expectedly
much less as compared with other anti-vertigo drugs.
The much-hyped histamine (H1)–agonistic action of increasing blood flow to the brain and inner ear with betahistine
is pretty weak, as this action is observed only at much higher levels than the therapeutic
dose as per different studies. Also, the role of hypoxia in the brain or inner ear
and hypoperfusion of the inner ear in the pathophysiology of peripheral vertigo (especially
when it is unilateral) are highly questionable issues as vertigo, in general, is not
known to be caused by decreased blood flow in the inner ear. Therefore, whether the
increase in inner ear blood flow (if at all, in the recommended therapeutic dosage)
is of any clinical benefit to the patient of vertigo is very doubtful and possibly
inconsequential to say the least.
Betahistine is pharmacologically approved only for Ménière’s disease by most pharmacology
or medical regulatory bodies but is universally used and promoted for other causes
of vertigo also, that is, as a general anti-vertigo drug. It is not a Food and Drug
Administration (FDA)-approved drug as there is insufficient evidence of any beneficial
effect.[6] More than 50 years back betahistine was approved by the FDA for sale in the United
States, but the approval was withdrawn after 5 years as there was lack of evidence
for its efficacy and because the major report of effectiveness contained deficiencies
and misrepresentations.[7]
There are wide variations in the dosage of betahistine (24–900 mg/day), and the dose
has to be titrated in patients with Ménière’s disease. This leads to confusion in
the minds of the clinicians as without a definite dosage, use of the drug becomes
difficult as clinicians have to try out gradually increasing doses. Usually a drug
with a fixed dosage or with a narrow dose range is preferred owing to its ease of
usage. Though the pharmacologically approved dosage is only 48 mg/day, many, if not
most, patients especially those with Ménière’s disease need much higher doses for
any clinically observable benefit with this dose. Most diseases presenting with vertigo,
especially Ménière’s disease, have phases of waxing and waning and periods of natural
remissions and cures; hence, it is impossible to gauge whether a period of remission
is actually due to the drug used or due to the natural course of the disease. The
observational studies of betahistine in Ménière’s disease on a small number of patients
in a general ENT (ear-nose-throat) or neurology clinic OPD (many of which are studies
sponsored by the marketers of the drug) that abound in the literature basically chronicle
the phases of natural remission as this is more common than the phases of acute exacerbation.
None of such studies are scientifically authentic class A studies.
Thus, betahistine has not been shown to be better than placebo in many clinical studies,[1] even at dosages three times the approved dosage. Hence, its clinical efficacy remains
at best questionable. Even the Cochrane review (2001)[6] did not find sufficient evidence of definite beneficial effects with betahistine
in Ménière’s disease.
Pharmacology
Betahistine is N-methyl-2- (2-pyridyl) ethylamine dihydrochloride. It is believed to be histamine
agonist. It acts as a vasodilator and appears to act directly on the neurons of the
vestibular nuclear complex. Betahistine is transformed, mainly at the hepatic level,
to aminoethylpyridine, hydroxyethylpyridine, and, finally, to pyridylacetic acid that
is excreted in urine.
Symptom-relieving anti-vertigo drugs with proven efficacy and established/undisputed
mechanisms of action are mostly antihistamines (centrally acting histamine H1-receptor antagonists). Betahistine, which is a histamine analogue with H1-receptor agonist activity (and H3-receptor antagonist) is also proclaimed to be useful in relieving the symptoms of
vertigo,[5] which means that an antihistaminic and a histamine analogue (which is the opposite
of an antihistaminic) both serve the same purpose. This apparently is quite difficult
to accept logically, and it means that there may be some lacunae in our understanding
of the pathomechanism of vertigo. The modes of action are obviously different but
two pharmacological agents with completely opposing pharmacological actions serving
the same purpose raises doubts on the correctness of the perceived mechanism of action.
A study by Botta et al[8] shows that betahistine as well as its metabolite aminoethylpyridine reduces the
resting firing rate of the ampulla of semicircular canals; that is, it sedates the
resting labyrinth, hence its beneficial effect in vertigo. Betahistine acts on four
types of histamine receptors, namely H1, H2, H3, and H4. The action of betahistine on H1, H2, and H4 is weak, but it is very strong on the H3-receptors and most pharmacological effects of betahistine are believed to be due
to the effect on H3-receptors. However, the action on H3-receptors is also controversial as betahistine is claimed in some places to be an
H3-receptor antagonist[4]
[5] and at other places as an H3-inverse agonist,[3]
[9] which indicates that there is a huge confusion in its mechanism of action. There
is a lot of difference between an antagonist and an inverse agonist. The entire issue
of H3-receptor activity of betahistine is very vague and confusing. In an article by Gbahou
et al,[9] it is stated that “betahistine interacts in vitro with H3 receptors as a potent
inverse agonist, a moderate antagonist (Arrang et al, 1985), and a weak agonist. It
acts in vivo as a partial inverse agonist to enhance histamine neuron activity.” All
these only add to the confusion on its mechanism of action. The bottom line is that
there is a lot of ambiguity on mechanism of action of betahistine.
Pharmacological Role of Betahistine
Pharmacological Role of Betahistine
Role as a Vestibular Sedative or Suppressant
The article on betahistine by Botta et al shows that betahistine and its main metabolite
aminoethylpyridine reduce resting discharge rate from the ampulla of the semicircular
canals, thus providing a vestibular suppressant effect, thereby leading to a symptomatic
relief in vertigo. There are many other articles too that hypothesize that betahistine
is a vestibular suppressant or a vestibular sedative as it reduces the discharge rate
in the vestibular labyrinth and vestibular nuclei. Timmerman[10], Lacour,[3] and even the SERC (betahistine) product manual of Abbott that I could get very clearly
state that betahistine is a vestibular suppressant. Lacour[3] has suggested that it decreases the vestibular input, and Timmerman[10] has suggested that betahistine causes inhibition of activity in the vestibular nuclei,
both of which means that it is a vestibular suppressant.
Role of Enhancing Blood Flow in Inner Ear
Betahistine is being promoted as an anti-vertigo drug on the logic that it increases
blood flow to the brain and inner ear, which is proposed by two mechanisms:
-
By an H1-receptor–mediated agonist action, causing vasodilation[5]; however, the H1-receptor agonistic action of betahistine is pretty weak.[1]
[2]
[3]
[4]
[5] Hence, whether this is at all of any clinical consequence at the recommended therapeutic
dose is questionable as this effect has been shown in animal studies at very high
doses—much higher than the therapeutic dose in humans. It will not be out of place
to mention here that the H3 antagonistic effect of betahistine possibly augments the
H1 agnostic effect of betahistine by some complex mechanism and so some H1 agnostic
effect, i.e., increased microcirculation may be indirectly achieved by betahistine
in spite of the very weak effect of betahistine on the H1 receptors.
-
By virtue of its H3-antagonistic action or its so-called inverse agonist action (?), betahistine increases
histamine release from the histaminergic nerve endings. This histamine is hypothesized
to stimulate H1-receptors, resulting in vasodilatory effects in the inner ear.[5]
However, such an action of betahistine is not easy to understand and accept logically,
as it is difficult to increase only the cochlear blood flow without increasing the
blood flow in other organs.[4] It is hard to comprehend what is so very unique anatomically and physiologically
in the cochlea that betahistine will increase blood flow only in the cochlea (or for
that matter in the inner ear) but not in other organs. Moreover, there are other questionable
issues that crop in here such as (1) there is no scientific evidence that all peripheral
vertigo including Ménière’s disease is primarily caused by hypoperfusion of the inner
ear and (2) even if increase in blood flow is beneficial in stopping vertigo, other
agents that are known to augment blood flow, such as aspirin, clopidogrel, and xanthine
nicotinate, should be equally, if not more effective in increasing blood flow and
enhancing micro-circulation and agents that inhibit blood flow should cause vertigo.
This is possibly not true either.
Role of Enhancing Arousal and Acceleration of Vestibular Compensation
Betahistine is claimed to enhance arousal and accelerate vestibular compensation as
there has been a consensus on the relevance of vestibular compensation in patients
of vertigo especially those of peripheral origin. However, this action of betahistine
has been shown in experimental animals (cats) at high doses (100 mg/kg vs. human dose
of 24 mg/day equivalent to 0.4 mg/kg in a 60-kg person).[11] The mechanism of compensation is said to be by “rebalancing the vestibular nuclei”
and by inducing arousal.
It is difficult to understand how a medication can improve rebalancing the vestibular
nucleus when it is only used in Ménière’s disease (or even in other cases of vertigo)
and not in any other condition in which CNS adaptation is required.[4] The issue of inducing arousal is undisputedly a very desirable effect as the opposite;
that is, drowsiness and CNS depression are known to jeopardize central vestibular
compensation. However, drugs such as caffeine, the most widely used psychoactive compound,
which promotes wakefulness by blocking adenosine A2A-receptors (A2ARs) in the brain and possibly acts on the nucleus accumbens, should serve this purpose
much better. However, drugs that promote wakefulness are naturally expected to cause
sleeplessness that is not known to be caused by betahistine in the doses at which
it is commonly prescribed. Therefore, here again this proposed effect of betahistine
is suspect at least at recommended therapeutic doses.
Studies in experimental animals have shown the involvement of histaminergic system
in the vestibulo-hypothalamo-vestibular loop and researchers have hypothesized a possible role of betahistine in effecting arousal that promotes vestibular compensation and
in the control of vestibular response after a vestibular assault. Electrophysiological
recordings have reportedly shown that unilateral and bilateral stimulation of the
labyrinth in which there is asymmetrical vestibular nuclei activity (as happens after
a peripheral vestibular lesion) triggers an increase in histamine release in the vestibular
nuclei and associated structures (inferior olive, autonomic nuclei) and the tuberomammillary
of the posterior hypothalamus (the portion of the brain involved in effecting arousal)
in healthy rats.[12]
[13]
[14]
[15] This may have therapeutic implications, and if it induces arousal in humans at the recommended
therapeutic doses of betahistine, it is a welcome therapeutic measure. However, currently
these experimental findings are all based on animal studies and are possibly only
at the laboratory level now. A lot of it is hypothetical, and extrapolation to humans
at this stage may not be prudent at the present state of knowledge. There is no relevant
human study that the authors came across, nor is there any indication whether the
effect of histaminergic stimulation occurs in the recommended therapeutic dosage of
betahistine in humans. The actual mechanism of betahistine showing any beneficial
effect in restoration of balance in humans by effect of betahistine in the vestibulo-hypothalamo-vestibular
loop is basically conjectural now. It needs to be confirmatively ascertained whether
in the therapeutic dose of betahistine in humans there is any positive effect induced
either in arousal or in vestibular recovery (or for that matter “control of vestibular
response”) through involvement of the histaminergic system in the vestibulo-hypothalamo-vestibular
loop before this aspect is capitalized upon for promoting betahistine in humans. The
effects of histamine in the brain have been extensively studied. The interested readers
are referred to an article by Passani et al.[16] It states that “brain histamine promotes wakefulness and orchestrates disparate
behaviors and homeostatic functions. Recent evidence suggests that aberrant histamine
signaling in the brain may also be a key factor in addictive behaviors and degenerative
disease such as Parkinson’s diseases and multiple sclerosis.” It is also reported
that histaminergic stimulation is also involved in the appetitive, food anticipatory
responses, and in food consumption, and it has been suggested that it may have an
important role in abnormal appetites not only for food but also for alcohol consumption
and substances of abuse.[16]
[17] Therefore, there is much more to stimulating the histaminergic system in the brain,
and it is not just as simple as enhancing arousal only, and by extrapolating the logic
thereby stimulating vestibular compensation. New paths should be very cautiously treaded,
especially in the medical field. Clinicians should be very discerning and not be influenced
by a one-line picked up from some scientific article (often out of context) by some
pharma company for promoting betahistine or for that matter any other medicinal agent.
It is true that stimulation of the histaminergic system in the brain promotes wakefulness,
but should it be the reason enough to try so in all patients with vertigo, considering
its systemic effects is highly debatable and may not be conducive to the patient’s
general health and the clinician’s objectives of treatment?
Drug or Placebo?
The clinical studies evaluating the efficacy of betahistine in Ménière’s disease have
not shown it to be superior to placebo. The BEMED (the medical treatment of Ménière’s
disease with betahistine)[1] trial was a multicentric, double-blind, randomized, placebo-controlled trial, and
was published in the British Medical Journal in January 2016. The results of this trial showed that the incidence of attacks related
to Ménière’s disease did not differ between the three treatment groups: (1) the low-dose
betahistine dose of 48 mg/day, (2) high-dose betahistine of 144 mg/day, and (3) placebo
(p = 0.759). This study showed that placebo has the same effect as betahistine even
at pretty high doses of betahistine in Ménière’s disease even after 9 months of treatment.
This is an authentic evidence on the lack of clinical efficacy with betahistine in
Ménière’s disease.[1] A Cochrane review published in 2001[6] contained a systematic review of seven selected randomized controlled trials (involving
242 patients) treated with betahistine versus placebo in Ménière’s disease. It concluded
that there are insufficient data on the efficacy of betahistine in Ménière’s disease.
The results of several other studies too endorse the findings that the efficacy of
betahistine in Ménière’s disease is questionable. A study[18] evaluated clinical benefits and side effects of high dosages (288–480 mg/day) of
betahistine in patients with severe Ménière’s disease. It was observed that the drug
was only effective at high doses.[18] This means that if 16 mg tablets are used, then 18 to 30 tablets of betahistine
per day would be required, which is not very practicable as compliance would be an
issue with many patients. Some authorities promote even higher doses for which even
50 or 60 tablets per day would be required. It would not be out of place here to mention
that a chemical agent is now being tried to be combined with betahistine to improve
its bio-availability such that smaller doses work, but that too is possible in the
experiential stage now.
A Review of a Few Often-quoted Studies Conducted on Betahistine
A Review of a Few Often-quoted Studies Conducted on Betahistine
-
One observational placebo-controlled study by Redon et al[19] report the influence of betahistine dihydrochloride on vestibular compensation in
humans. The study was conducted on 16 patients with Menière’s disease who underwent
a curative unilateral vestibular neurectomy (UVN) by retrosigmoid approach for therapeutic
reasons. All 16 patients had a postoperative bithermal caloric test evidence of a
pure unilateral vestibular deficit (complete areflexia on the operated side). Eight
of these 16 patients had betahistine (48 mg/day) and 8 had placebo for 3 months post-surgery.
The authors report that time to recovery was reduced for most of the static postural,
oculomotor, and perceptive symptoms tested with laboratory equipment, as well as for
the patients’ self-evaluation of stability in the eight patients who had betahistine
as compared with the eight patients of the placebo group. The study reports that in
self-evaluation of stability, the patients under betahistine treatment reported being
stable after 5 weeks as compared with 9 weeks for the placebo group. The researchers
conclude that betahistine dihydrochloride facilitates functional recovery after unilateral
vestibular loss and speculate that the effects of betahistine on vestibular compensation
may be related to the action of betahistine at the level of the vestibular nuclei
by “rebalancing the neural resting activity between the lesioned and healthy sides.”
Author’s view: The study group is too small to be indicative of any trend, and whether
the mechanism of how betahistine is at all responsible for an early functional recovery
is vague and at best speculative. It is not comprehensible how betahistine can “rebalance
the neural resting activity of the vestibular nuclei between the lesioned and healthy
sides.” Even if so (for argument sake), why should such rebalancing of resting neural
activity be limited only to the vestibular system? The term “rebalancing” is very
vague and appears to be more of a promotional gimmick rather than a scientific entity.
All mechanisms of action for betahistine suggested are at best conjectural and prefixed
by terms such as “may” and “possibly.” There is no scientific evidence available to
label it as a “vestibular stimulant.” Betahistine is not a CNS depressant, true, but
that does not mean that it is a vestibular stimulant. This is stretching imagination
too very far. Even if there is increase in histamine release in the vestibular nuclei
of the lesioned side, we do not know whether that facilitates recovery in any way
or whether that even decreases recovery, as histamine has never been proved to be
a repairer of neural tissue or enhancer of neural function. Moreover, there is no
definite evidence to show that there is increased histamine release in the vestibular
nuclei of the lesioned side or even at the tuberomammillary nucleus at the recommended
therapeutic dose in humans.
-
A review article by Ramos[20] observes that betahistine is effective and safe in the treatment of Ménière’s disease,
benign paroxysmal positional vertigo (BPPV), vestibular neuronitis, and other types
of peripheral vertigo as demonstrated by clinical studies and meta-analyses. The researchers
have concluded that efficacy and safety of betahistine have been demonstrated in numerous
clinical trials but have very clearly mentioned that “the precise mechanism of action
of betahistine is still not completely understood, though the clinical experience
demonstrated the benefit of betahistine in different types of peripheral vertigo.”
Author’s view: This is as good as promoting any placebo for any disease. Peripheral
vertigo is in most cases a self-limiting disorder and the symptomatic relief obtained
with betahistine or for that matter any other vestibular suppressant is not disputed.
In BPPV, the researchers have mentioned use of betahistine “primarily as a coadjuvant
of vestibular compensation for cases with recurrent disease.” This logic too is scientifically
untenable because vestibular compensation is not required in BPPV as there is no vestibular
weakness in BPPV. Also, BPPV is very well treatable by the correct maneuvers only
and there is no question of any coadjuvant therapy at all. In the rare cases of post-BPPV
syndrome that may be psychogenic in origin or due to the postmaneuver utricular overload,
there is no logical role of betahistine. This is usually treated with a short course
of benzodiazepines or anxiolytics or antidepressants and sometimes along with a vestibular
sedative, but the latter is also usually not required.
-
An article by Lacour[3] discusses probable mechanisms for role of betahistine in reducing vertigo due to
Ménière’s disease and other etiologies and enhancing vestibular compensation. This
is one of the most comprehensive articles on betahistine and has been referenced several
times in this review article as well as in most scientific articles related to betahistine.
The message conveyed in this article is that betahistine efficacy can be explained
by mechanisms targeting the histamine receptors (H1, H2, H3, H4) at three different levels: (1) the vascular tree, with an increase in cochlear and
vestibular blood flow involving the H1-receptors; (2) the CNS, with an increase in histamine turnover implicating the H3-receptors, and (3) the peripheral labyrinth, with a decrease in vestibular input
implying the H3- and H4-receptors. The article contends that clinical data from vestibular loss patients
show the impact of betahistine treatment for the long-term control of vertigo, improvement
of balance, and quality of life can be explained by the above-mentioned three mechanisms
of actions, provided it is used in the right dose and for the right duration. It also
states that though antihistaminics are most commonly used in the medical treatment
of vertigo, yet because of the sedation induced, they are detrimental for the recovery
process whereas betahistine has no sedative effects and hence is more suited for the
treatment of Menière’s disease and patients with vertiginous syndromes of peripheral
origin.
Author’s view: Most issues presented in this article have been analyzed in the review.
The researcher’s contention that as betahistine does not have a sedative effect, it
is better placed than the antihistaminics for symptomatic treatment of vertigo is
acceptable and undeniable. However, it is reiterated that betahistine not having a
sedative effect does not make it a vestibular stimulant as very often claimed by the
pharmaceutical companies marketing the drug. As it is not a CNS depressant, it does
not induce sedation such as the antihistaminic anti-vertigo drugs, but as stated in
the article, it “decreases vestibular input”; hence, it suppresses the vestibular
labyrinth or nuclei and is a vestibular sedative and not a vestibular stimulant. The
implications of being a vestibular sedative and its effect on vestibular compensation
are well known and established. Any vestibular suppressant will automatically reduce
the sensory conflicts in the vestibular system and thereby jeopardize or inhibit compensation.
The issue of increasing cochlear and vestibular blood flow by its H1-receptor agnostic action too has been discussed already. To repeat again, first of
all, the H1-receptor agnostic action of betahistine is very mild and is possibly not of much
clinical significance in the recommended therapeutic dose, and second, there is no
evidence that all peripheral vestibular disorders including Ménière’s disease are
due to hypoxia of the inner ear or brain and so increasing cochlear and vestibular
blood flow in all patients with vertigo, even if achieved by betahistine in the recommended
therapeutic dosage (which again is questionable), may not be a clinically beneficial
pharmacological action. The issue of increased histamine turnover by betahistine at
the recommended therapeutic dosage and its benefit in humans, if any, is at best conjectural
at the present state of knowledge. However, betahistine-induced upregulation of histamine
possibly induces a general brain arousal favoring sensorimotor activity as proposed
by the researcher, and this may enhance vestibular compensation. It is known that
vestibular compensation is hampered by sedation but how much it is enhanced by augmenting
brain arousal is not known with certainty, but if so, then drugs such as caffeine
should also help.
Therefore, after reviewing all this literature, it is difficult to authentically prove
any beneficial effects of betahistine. The supportive scientific logic in its support
is suspect, and proposed mechanism of action is confusing and vague and clinical implications
are at best conjectural.
Controversies Related to Dosage and Duration of Therapy
Controversies Related to Dosage and Duration of Therapy
Betahistine is available as:
Dose at which Betahistine Is Used Shows Wide Variations
Dose at which Betahistine Is Used Shows Wide Variations
The hydrochloride salt is more common and is prescribed in a wide range of dosage
24 to 900 mg/day although the recommend therapeutic dose is 48 mg/day. However, some
centers promote 600 to 900 mg/day or even more in Ménière’s disease as the drug is
ineffective in many cases at the recommended therapeutic dosage. This raises a question
that whether the cases where the vertigo is symptomatically relieved at the recommended
therapeutic dose are a natural recovery or is the recovery due to the effect of the
drug. Most cases of peripheral vertigo are self-limiting, and natural recovery is
very common in vertigo.
Duration of Therapy
The duration for which the drug can be prescribed is controversial and doubtful as
there is lack of clarity on its use and mechanism of action. If betahistine is used
as a vestibular suppressant and only for symptomatic relief of vertigo, the duration
should be limited to a maximum of 3 to 5 days and not more than that just like any
other vestibular sedative. However, here the question is that if symptomatic relief
is the purpose, drugs, such as dimenhydrinate or meclizine or even prochlorperazine
or a combination of a low fixed dose of dimenhydrinate and cinnarizine, are possibly
better choices. If the clinician still wants to use betahistine for symptomatic relief,
on account of it being a non-CNS depressant, nonanticholinergic, nondopaminergic,
and non–calcium channel blocker drug that are obvious virtues of the drug, the dose
should be at least 96 or 144 mg daily (if not more) instead of the 24 to 48 mg daily
dose as recommended and in four instead of three divided doses as the mean plasma
elimination half life is just 3 to 4 hours. This of course is the authors’ personal
experience. The dosage in confirmed Ménière’s disease is completely controversial.
First question is whether betahistine is at all of any help in Ménière’s disease in
the recommended dosage, as the published authentic literature[1] says it is not and that it is merely a placebo. Second question is whether all patients
with Ménière’s disease really require a long continued prophylactic treatment, as
in most cases of Ménière’s disease the attacks are usually once in a few months or
once in several weeks and in all such cases just aborting the occasional attacks suffices
and long continued prophylactic/preventive therapy is not required. It is only in
cases in which there are very frequent attacks does the question of long-term prophylactic
therapy arise. In such cases, there may be some scope of using betahistine on a long-term
basis, but the dose needs to be titrated in each individual case. The starting dose
may be 72 to 96 mg/day, and if that does not control symptoms, the dosage can be gradually
increased to 248 or 480 mg/day for several months,[6] but the basis of this dosage and the outcome are not on solid authenticated scientific
rationale; hence, many clinicians rely more on diuretics, such as acetazolamide, tiamterene,
hydrochlorthiazide, and spironolactone, instead of betahistine for prophylactic treatment
of Ménière’s disease. There is a lot of natural waxing and waning in the course and
severity of Ménière’s disease, and the phase of very frequent attacks usually does
not persist for more than a few weeks at a stretch; hence, it is impossible to confirmatively
know whether there is a natural recovery or is the recovery (if at all) is due to
the high dose of betahistine.
Adverse Effects
Various allergic and skin-related side effects and hypersensitivity reactions such
as tingling, numbness, burning sensation, and respiratory distress can occur due to
increased histamine level. Betahistine should be used with caution in asthmatics and
peptic ulcer patients as it is a mild H2-agonist and can augment gastric secretion. However, as already stated, the H1 and H2 effects are so mild that this probably is of negligible clinical impact. Compared
with all other anti-vertigo drugs, betahistine has the least adverse effects and is
a safe drug even at reasonably high doses.
Systemic administration of betahistine causes peripheral vasodilatation and a fall
in systemic blood pressure; hence, it should be used with caution when prescribed
at very high doses.
Summary
In summary, betahistine appears to offer some symptomatic relief in vertigo as it
is a vestibular suppressant as per scientific literature,[3] and clinical experience also suggests that betahistine offers some palliative effect
in patients with mild to moderate vertigo, especially in patients without much of
vegetative symptoms. It is devoid of major adverse effects and is more or less a safe
drug with no anticholinergic, antidopaminergic, and antiserotonergic properties and
is not a CNS depressant. It may be having some beneficial effects in Ménière’s disease
but only at very high doses that are much higher than the recommended therapeutic
dosage. At commonly prescribed doses, it has been established to be no better than
a placebo. It is a common experience that some patients with Ménière’s disease and
even patients with other causes of vertigo do well when on betahistine, but whether
it is due to betahistine or due to the natural course of the disease is debatable.
Ménière’s disease has a natural history of waxing and waning, and the disease has
phases of heightened activity and inactivity when there are no attacks. In most cases,
there is a phase of burnout after which there are no episodes of head spinning; hence,
gauging the success of pharmacotherapy in Ménière’s disease is also not easy. However,
there is no denying that it is a much hyped-up anti-vertigo drug without solid scientific
evidence of its much-advertised beneficial effects. Its pharmacological mechanism
of action in vertigo is confusing and controversial and is very difficult to comprehend;
hence, clinicians should use it with scientific discretion and clinical logic based
on authentic scientific studies and not be influenced by the very aggressive propaganda
with which it is marketed.
