Management of peripheral vertigo with antihistamines: New options on the horizon

Abstract

Vertigo is associated with a wide range of vestibular pathologies. It increasingly affects the elderly, with a high cost to society. Solutions include vestibular suppressants and vestibular rehabilitation, which form the mainstay of therapy. Antihistamines represent the largest class of agents used to combat vestibular vertigo symptoms. Agents targeting the H₁ and H₃ receptors have been in clinical use for several decades as single agents. Nonetheless, effective management of vertigo proves elusive as many treatments largely address only associated symptoms, and with questionable efficacy. Additionally, the primary and limiting side effect of sedation is counterproductive to normal functioning and the natural recovery process occurring via central compensation. To address these issues, the timing of administration of betahistine, the mainstay H₃ antihistamine, can be fine‐tuned, while bioavailability is also being improved. Other approaches include antihistamine combination studies, devices, physical therapy and behavioural interventions. Recently demonstrated expression of H₄ receptors in the peripheral vestibular system represents a new potential drug target for treating vestibular disorders. A number of novel selective H₄ antagonists are active in vestibular models in vivo. The preclinical potential of SENS‐111 (Seliforant), an oral first‐in‐class selective H₄ antagonist is the only such molecule to date to be translated into the clinical setting. With an excellent safety profile and notable absence of sedation, encouraging outcomes in an induced vertigo model in healthy volunteers have led to ongoing clinical studies in acute unilateral vestibulopathy, with the hope that H₄ antagonists will offer new effective therapeutic options to patients suffering from vertigo.

1. BEHIND THE SCENES OF VERTIGO

Vertigo is principally characterised by an erroneous sensation of spinning motion, frequently accompanied by vestibulo‐oculomotor symptoms of oscillopsia, nystagmus, postural imbalance, and falling,1 along with neurovegetative effects, notably nausea and vomiting. The 12‐month prevalence of vertigo ranges from 2 to 5%, with incidence linked to age.2 Vertigo is associated with a wide range of pathologies, including inner ear diseases such as benign paroxysmal positional vertigo (BPPV), vestibular migraine, Ménière's disease, acute unilateral vestibulopathy (AUV) and labyrinthitis.3, 4 While the occupational impact is poorly qualified, it represents a substantial economic cost to society.5

Vertigo may arise centrally following injury to the balance centres of the central nervous system (CNS), or be of peripheral origin linked to disorders of the vestibule located in the inner ear. Sense of balance and position are derived from input from the 3 semicircular canals and otolith organs in the peripheral vestibular system, integrated with proprioceptive and visual information in the vestibular nuclei. Sensory hair cell damage, synaptic uncoupling and neuronal damage disturb the balance of vestibular signalling. This highly complex process is orchestrated by peripheral and central neurons, which rely on a range of neurotransmitters (glutamate, acetylcholine, γ‐aminobutyric acid and glycine), further modulated by histamine, adrenaline and noradrenaline.6, 7 Nonetheless, in‐depth knowledge of the pathophysiology of vertigo is lacking and a thorough understanding is currently hampered by nonstandardised definitions.

While vestibular rehabilitation is recommended by many international clinical practice guidelines,8, 9, 10 pharmacological approaches form the backbone of vertigo management, composed of agonists and antagonists of neurotransmitters and neuromodulators that modulate vestibular afferent/efferent synaptic input. They are primarily represented by vestibular suppressants which reduce vertigo and nystagmus evoked by vestibular imbalance or motion sickness, while antiemetics are used to combat nausea and vomiting.11 Vestibular suppressants cover 3 main drug groups, anticholinergics, antihistamines and benzodiazepines. The nonselective nature of many of these agents imposes clinical limitations, with most antivertigo agents acting principally through sedation or reduction of nausea rather than addressing the cause of the vertigo itself. Here, we review current antihistamine use in managing vertigo, focusing on efficacy, side effects and impact on central compensation. We also discuss a new area of research targeting vertigo via the type‐4 (H₄) histamine receptor, and present a novel histamine antagonist clinical candidate, SENS‐111 (Seliforant, 6‐[3‐(methylamino)azetidin‐1‐yl]‐2‐(2‐methylpropyl)pyrimidin‐4‐amine; Sensorion).

2. THE VESTIBULAR HISTAMINE RECEPTOR LANDSCAPE

The 4 known histamine receptors—type‐1 (H₁), type‐2 (H₂), type‐3 (H₃) and H₄—belong to the large G‐protein coupled receptor (GPCR) family, consisting of 7 transmembrane‐spanning helices. The structure, functioning and mechanisms of action of these receptors is beyond the scope of this review and have been described in depth elsewhere.12 In the nervous system, histamine is involved in signalling at several levels, and histamine receptors are present heterogeneously on pre‐ and postsynaptic nerve terminals throughout the CNS. Histamine is known to be involved in many CNS activities including wakefulness and cognition, and histamine antagonists form part of the treatment arsenal for many CNS disorders, including somnolence.13

Histaminergic ligands also act in the vestibular system, both peripherally and centrally, and there is accumulating evidence for the involvement of multiple histamine receptors in modulating vestibular function. To reach the central parts of the vestibular system, antihistamines must pass the blood–brain barrier, while the peripheral parts of the vestibular system are also protected by the similarly restrictive blood–labyrinth barrier.14 In the inner ear, protein expression of all 4 histamine receptors has been reported in mice and rats, including in the organ of Corti, the spiral ganglion, vestibular ganglion, vestibular sensory epithelium and the endolymphatic sac.15, 16 The H₁ and H₃ receptors have also been identified in human endolymphatic sac tissue.17 Functional in vitro and in vivo studies performed over the last 3 decades further support a role for histamine in the context of vertigo.18, 19, 20, 21, 22 These studies demonstrated its excitatory effect on the vestibular system in rats and guinea pigs, with membrane depolarisation and transient increased neuronal firing activity in the central vestibular nuclei (inferior, medial, lateral and superior), which controls the vestibulo‐ocular reflex. Furthermore, this activity was selectively blocked by H₁, H₂ and H₃ receptor antagonists, although not by an H₄ receptor antagonist. Unilateral electrical and caloric stimulation of the inner ear in rats increases CNS production of histamine,23 confirming that sensory mismatch signals activate the histaminergic neuron system in the brain. Preclinical studies have also shown that the H₁ receptor is upregulated in vestibular neurons during motion stimulation24 and that symptoms of motion sickness in the house musk shrew can be alleviated via this receptor.25

3. TRANSLATING IN VIVO ANTIHISTAMINE MODELS INTO THE CLINIC

Validated predictive preclinical models are essential for ensuring the translational success from the preclinical setting to the clinic. Such models have been slow to emerge for vestibular diseases, in part due to the lack of understanding of their pathophysiology, and the subjective nature of symptoms. A mechanism‐based model of unilateral vestibular insult in rats was developed by inducing transient excitotoxicity from transtympanic injections of kainic acid in 1 ear resulting in swelling of the primary vestibular neuronal terminals and synaptic uncoupling. This model generates a number of established vertigo‐associated symptoms such as spontaneous nystagmus, postural deviations, reflex deficits and gastric paresis, all of which can be quantified.26

Adequately evaluating antivertigo treatments in humans requires identification of objective clinical variables accurately reflecting vertigo. Earlier studies tended to focus on improvements in the neurovegetative symptoms of nausea and vomiting, while more recent studies focus on vertigo symptom‐rating for specific symptoms along with frequency and severity of attacks, often using validated questionnaires (e.g. Dizziness Handicap Inventory), as well as quality of life scores. As 1 of the few translationally measurable symptoms of vertigo, nystagmus can be recorded—typically by electro‐ or videonystagmography of spontaneous or calorically evoked nystagmus, with infrared videonystagmography being considered a gold standard. As technology has improved, caloric testing with maximum slow phase velocity (SPV) is increasingly considered a reliable means of evaluating vestibular function imbalance, despite intrapatient variation,27 with higher SPV levels reflecting greater imbalance between the 2 labyrinths.28

4. AN HISTORICAL SNAPSHOT OF H₁, H₂ AND H₃ ANTAGONIST USE IN VERTIGO

Histamine antagonists have been reported to be of value to individuals suffering from vertigo since the 1940s,29 preventing motion sickness and/or reducing the severity of symptoms, including when taken postonset. Nonetheless, insights into their role in central and peripheral vestibular processing have only emerged relatively recently.30 The value of antihistamines in treating vertigo was reported in a recent meta‐analysis evaluating 13 randomised placebo‐controlled studies using single‐agent antihistamines (primarily betahistine) published between 1977 and 2006, including a total of nearly 900 patients. This confirmed a clear benefit for antihistamines, with an odds ratio of 5.37, 95% confidence interval (3.26–8.84).31

Several H₁, H₂ and H₃ receptor antagonists have been approved for vertigo and/or motion sickness by international health authorities, although availability varies by region. All antihistamines currently in clinical use for vertigo are H₁ and H₃ antagonists, the most common of which are summarised in Table 1, while there are currently no H₂ receptor blockers available. Current agents include the H₁ antagonists diphenhydramine (typically administered as dimenhydrinate in combination with 8‐chlorotheophylline), meclizine and its derivate cyclizine, cinnarizine, and promethazine. Diphenhydramine, a first‐generation H₁ antagonist is widely used. Current evaluations include its complementary pharmacotherapy role in rehabilitation and recovery, as well as in combination with other agents. In a recent randomised controlled study in patients with BPPV, dimenhydrinate was administered after successful canalith repositioning manoeuvres to evaluate its effect on residual symptoms.32 A significant reduction in light‐headedness was observed compared to placebo, although not in Dizziness Handicap Inventory questionnaire scores. Meclizine, which was first shown to be superior than placebo in 1972 for the treatment of vertigo33 is widely used in the USA, was recently shown to be equivalent to diazepam for effectiveness in relief of symptoms in acute peripheral vertigo in a randomised double‐blind study.34 The value of single agent cinnarizine for improving vertigo has been reported in both prospective and retrospective studies,35, 36 and an advantage in combination with dimenhydrinate is seen compared to betahistine in randomised clinical studies and routine practice.37, 38, 39, 40, 41

Table 1.

Antihistamines currently used to manage vertigo

Drug	Receptor	Principal adverse reactions in the vertigo setting	Regional specificities
	Other activity
Betahistine	H3/H1	Headache, nausea, upset stomach, vomiting, diarrhoea	Not authorised in the USA due to lack of evidence of activity
Cinnarizine	H1	Drowsiness, depression and parkinsonism	Not authorised in the USA and Canada
	Calcium channel blocker
Cyclizine (meclizine derivative)	H1	Drowsiness, dry mouth, constipation, visual troubles
	Anticholinergic
Diphenhydramine	H1	Drowsiness, poor coordination, stomach upset
	Anticholinergic
Flunarizine (cinnarizine derivative)	H1	Weight gain, somnolence, depression, rhinitis	Not authorised in the USA and Japan due to lack of evidence of activity
	Calcium channel blocker
Promethazine	H1 anticholinergic	Drowsiness, akathisia, lethargy
Meclizine	H1 anticholinergic	Drowsiness, headache, dry mouth, stomach upset

Among the H₃ antagonists used today, betahistine is the best‐known. It acts as both a H₃ presynaptic antagonist and a weak H₁ postsynaptic agonist.42 A thorough review of its preclinical and clinical status was published recently.43 While today betahistine is the most widely‐used agent for the treatment of Ménière's disease and vestibular drop attacks in Europe, Canada and Latin America,44, 45, 46 controversy still exists over the validity of its use. In the USA, betahistine has a chequered history with approval initially attributed but subsequently withdrawn, and today it remains unapproved. Many studies support its positive impact on vertigo symptoms, with several meta‐analyses all reporting a favourable outcome, including randomised controlled studies comparing betahistine to placebo published over 3 decades leading up to 2006.31, 47, 48, 49 Similarly, the post‐marketing surveillance OSVaLD study collected data from over 2000 patients on dizziness and quality of life,50 and confirmed a significant improvement compared to baseline in patients with peripheral vestibular vertigo. Nonetheless, the heterogeneity in the methodologies used (assessment of outcome, including investigator vs patient perspective) and pathologies included, call for caution to be exercised when interpreting these meta‐analyses. A recent Cochrane review by Murdin et al. highlighted the poor quality of the evidence in their meta‐analysis.49 Further doubts are raised by the outcome of the recent double‐blind, randomised, placebo‐controlled BEMED study in 221 patients which failed to show a significant difference in incidence rates of Ménière's attacks with either low or high‐dose betahistine vs placebo after 9 months of treatment.51 The interpretation of the clinical data is further complicated by questions around the mechanism of action, since even plasma concentrations of betahistine associated efficacy in a preclinical vertigo model were in the nanomolar range, while H₁ and H₃ receptor affinities are in the micromolar range.42, 52 This raises questions around a direct effect through the histaminergic receptors, and even about another potential mechanism of action by increased histamine turnover through upregulated histidine decarboxylase in the tuberomammillary nuclei and blockade of H₃ receptors in the vestibular nuclei and tuberomammillary nuclei after very high preclinical doses of betahistine.53, 54

5. RETHINKING THE USE OF BETAHISTINE

The long history of a lack of clarity over the use of betahistine has led to the emergence of new approaches for optimising its use. Combination therapy may improve outcomes over single agent. In a small study in patients with Ménière's disease, when betahistine was combined with cinnarizine as a prophylactic measure, vertigo attacks decreased in patients poorly responsive to betahistine alone.55 Similarly, the addition of flunarizine to betahistine significantly decreased the frequency of vertigo episodes in a small randomised controlled study.56 The addition of high‐dose betahistine to intratympanic dexamethasone improved vertigo control compared to dexamethasone alone.57 Large‐scale controlled studies are required to confirm the usefulness of this approach.

Bioavailability may pose limitations on the effective implementation of betahistine. Preclinical studies in cats have demonstrated a link between betahistine plasma concentrations and both reduced persistent vertigo symptoms and improved balance.52, 53 In humans, the oral betahistine molecule is rapidly and almost completely metabolised into 2‐pyridylacetic acid, which is pharmacologically inactive,58 resulting in very low bioavailability and limited clinical utility. A nasal formulation of betahistine, AM‐125, demonstrated improved bioavailability over the oral formulation in a phase 1 clinical study reported by Auris Medical in October 2018,59 and a phase 2 randomised controlled study evaluating AM‐125 as treatment for acute peripheral vertigo is planned (TRAVERS; NCT03908567).

Various in vitro and in vivo models point towards a role for histamine in modulating vestibular plasticity during the process of vestibular central compensation. This innate spontaneous functional recovery mechanism triggered after vestibular damage, has been well described.60, 61 It is a complex, multi‐factorial process in which feedback from the vertigo episode triggers different types of central plasticity to compensate for peripheral lesions. The time course and ultimate extent of recovery vary considerably between individuals, and failure of this process results in chronic vertigo or dizziness/imbalance.

Several studies have shown that H₁, H₂ and H₃ receptors are upregulated in the central vestibular system during the first few days of vestibular compensation following labyrinthectomy.30, 62, 63, 64 The sedative side effect of antihistamines, notably H₁ antagonists, probably plays a role in delaying this process in vivo.65 Betahistine has been shown to facilitate behavioural recovery in cats and reduce H₃ receptor binding in vestibular nuclei.66 The effect of betahistine on the time course of vestibular compensation was investigated in the clinic in terms of the effect on various symptoms including postural and oculomotor disorders, in a double‐blind study in patients who underwent a unilateral vestibular neurotomy for Ménière's disease. In this setting, betahistine reduced the time to reach compensation by a month.67 Likewise, the authors of the VIRTUOSO study suggested that the use of betahistine for 2 months in patients with vestibular vertigo could improve compensation.68 However, the data are difficult to interpret, given that only 40% of patients had peripheral vertigo, including patients with BPPV, and compensation was only measured in terms of lasting symptom control.

For compensation to be fully effective, vertigo symptoms and vestibular imbalances must be actively experienced. Patients should undergo interventions to stimulate plasticity and allow the brain to substitute alternative information in lieu of the lost peripheral input.69 The use of vestibular suppressants both sedates the brain and suppresses vertigo centrally, and, in consequence, reduces the feedback to the brain indicating a sensory mismatch. Thus the use of suppressants comes at the cost of decreasing or slowing this natural recovery process.70 It is thus generally considered that vestibular suppressants, including antihistamines, should only be administered during the acute phase of vertigo and for a maximum of 3 consecutive days.71, 72, 73 Nonetheless, Kiroglu et al. recently reported a randomised controlled clinical study in patients with vertigo and dizziness suggesting a deleterious effect of betahistine compared to dimenhydrinate when administered during acute episodes of vertigo, based on higher mean SPV values.72 The authors consequently recommend that betahistine not be used during the acute phase, to avoid its H₁ agonist effects, cautioning against the concomitant use of dimenhydrinate with betahistine due to their paradoxical effects in terms of compensation.

A recent preclinical publication delved into the molecular mechanism behind vestibular compensation, providing supporting evidence of the role of the H₁ receptor. Chen et al. used a rat model to demonstrate that the H₁ receptor selectively mediates asymmetric activation of the commissural inhibitory system in ipsilesional medial ventricular nuclei, with the H₁ antagonists diphenhydramine and mepyramine both slowing vestibular compensation and blocking the beneficial effect of betahistine H₁ agonism on central compensation.74 This study further emphasizes an additional potential direct negative impact of H₁ receptor antagonists such as meclizine, dimenhydrinate and cinnarizine on central compensation, in addition to their established sedative effect.

6. NEW DIRECTIONS FOR MANAGING VERTIGO

In currently active interventional clinical trials for vestibular problems, vestibular vertigo and dizziness, 23 of 31 studies identified on Clinicaltrials.gov are testing devices or exercise/physical therapy‐based and behavioural interventions, while only 8 are testing drug‐based interventions. Despite the many antihistamines used in the management of vertigo, with a general lack of robustness in many trials in this domain (nonrandomised, uncontrolled and single‐centre studies, an absence of proven reference treatment and small sample sizes), along with the negative impact associated with sedation both in terms of quality of life and central compensation, new pharmacotherapeutic options for alleviating vertigo and avoiding long‐term complications are needed. H₁ antagonists can exhibit functional plurality complicating the understanding of their mechanism of action in vertigo, having calcium channel blocking effects in addition to their antihistamine activity,75 further complicating clarification of the antivertigo mechanism of action and the potential efficacy of antihistamines. The antihistamines cinnarizine and flunarizine are both classed as calcium channel antagonists.70 Anticholinergic properties of promethazine and diphenhydramine have also been reported in vivo.76

In terms of H₁, H₂ or H₃ antivertigo agents, recent research is limited to combination studies of betahistine or dimenhydrinate with cinnarizine, and investigation of an intranasal formulation of betahistine, and new clinical candidates under investigation in vertigo are lacking. However preclinical and clinical investigations have recently opened up a promising new therapeutic avenue targeting the H₄ receptors.

6.1. Preclinical evidence for the potential of H₄ antagonism in vertigo

The H₄ receptor is the most recent member of the histamine receptor family to have been identified. H₃ and H₄ receptors share significant homology,77 although less is known about the intracellular signalling cascade for the H₄ receptor across tissues and cell types. Involvement of the H₄ receptor in inner ear pathologies has recently been raised, with evidence supporting a potential role in the vestibular system. In rodents, H₄ receptors have been immunolocalised in vestibular primary neurons, with preferential sub‐membranous and cytoplasmic expression, along with in the organ of Corti, spiral ganglions, vestibular ganglions, vestibular sensory epithelium and endolymphatic sac cells.16, 78, 79, 80 H₄ receptor expression has been found in the CNS of humans and rats,81 although it is reported to be sparse or absent in the cortex of humans, guinea pigs and rats.82, 83

Emerging H₄ antagonists have shown activity in preclinical vestibular models.78, 79 A pronounced inhibitory effect on vestibular neuron activity was seen in vitro and ex vivo in the presence of the selective H₄ antagonist JNJ7777120 and its derivate JNJ10191584. When administered in 2 rat vestibular lesion models—1 bilateral and 1 unilateral—both agents rapidly improved scored behavioural abnormalities associated with vestibular deficits, whereas neither betahistine nor the dual H₃/H₄ antagonist thioperamide had significant acute effects. Improvement occurred rapidly (within the first hour) and, in the case of JNJ7777120, lasted for up to 24 hours. Beneficial treatment effects on vestibular deficit syndrome, locomotor activity and exploratory behaviour in the acute phase after unilateral or bilateral vestibular lesions in a rat model were independently reported for JNJ7777120 administration by another research group.84

Another novel antagonist has shown promising results in vivo. SENS‐111, a novel oral small molecule, is a first‐in‐class H₄ antagonist, binding with high affinity to both human and animal receptors. Preclinical evaluations show it to be selective for the H₄ receptor over the H₁, H₂ and H₃ receptors as well as a wide panel of receptors, enzymes, ion channels and bioamine transporters.85 Similar H₄ receptor binding affinity was seen with the main pharmacological and toxicological species (mouse, rat and monkey), and it is a potent antagonist in primary vestibular neurons. Administration of SENS‐111 in a rat model during the acute phase of peripheral vertigo induced with kainic acid, gave a bell‐shaped dose/efficacy relationship.86 At the optimal dose, a 20–30% reduction in symptoms was seen within 1 hour of administration compared to placebo, while higher doses resulted in a loss of efficacy. SENS‐111 concentrations in blood plasma, cerebrospinal fluid and the perilymph had equilibrated 1‐hour postadministration.

6.2. Clinical evaluation of H₄ antagonists

A number of H₄ antagonists have reached clinical evaluation in nonvestibular indications87; however, concerns over potentially associated, compound‐specific toxicities have seen development programmes prematurely terminated.88, 89 To date, SENS‐111 is the only H₄ antagonist with ongoing clinical evaluation. Oral SENS‐111 has been administered in nearly 200 healthy volunteers and allergic rhinitis patients in pharmacokinetic and single and repeat dosing studies90, 91 (NCT03110458; NCT01260753). A recent randomised, double‐blind, placebo‐controlled and meclizine‐calibrated crossover phase 2a trial, confirmed that unlike, meclizine, SENS‐111 was not associated with sedation or impairment of memory or cognitive performance in healthy volunteers (unpublished data). In an early‐stage first‐in‐man phase 1 study, H₄ receptor antagonism of SENS‐111 (then called UR‐63325) in humans was confirmed in preliminary findings, as demonstrated by reduced histamine‐induced eosinophil cell shape change ex vivo.92 The effect of SENS‐111 on nystagmus and vertigo induced via caloric irrigation has been evaluated in a randomised double‐blind dose escalation study in healthy volunteers.91 Latency of vertigo appearance improved by 10 to 30% with an exposure–response relationship, with a similar pattern of improvement for vertigo duration. The bell‐shaped response seen in the preclinical model was also observed clinically; this probably reflects a dual site of action, with an initial positive peripheral vestibular response at low exposure, while at higher exposures with loss of selectivity, efficacy is reduced due to a central effect on vestibular nuclei neurons in the brainstem. The effect of SENS‐111 on vertigo symptoms in patients suffering from AUV is currently being evaluated in a phase 2 clinical trial (NCT03110458).

7. COMPARING ANTIVERTIGO EFFECTS OF ANTIHISTAMINES IN THE CLINIC

While the first clinical comparison of SENS‐111 with the H₁ antihistamine meclizine was recently completed confirming that it does not impact vigilance or cognitive performance (unpublished data), with the AUV clinical trial still ongoing, SENS‐111 efficacy vs other antihistamines in patients is awaited. Studies of vestibular modulation by current antihistamines in healthy volunteers are limited, with very few trials specifically evaluating vertigo itself rather than other associated parameters (vertigo sensation intensity, frequency and duration; associated symptoms such as nausea and vomiting, quality of life). Evaluation of calorically‐induced vertigo sensation in healthy volunteers showed that the magnitude of SENS‐111 treatment effects fell within the realm of those seen with other agents used to treat vertigo, albeit with differences in vertigo induction methodology. Using cold caloric tests in healthy volunteers, dimenhydrinate significantly prolonged the time to onset and duration of nystagmus (by ~20%) compared to controls.93 Cinnarizine (albeit at a much higher dose than normally administered for vertigo) was compared to placebo in healthy volunteers using parallel swing tests evaluated by electronystagmography. The duration of nystagmus and of the sensation of the test were significantly reduced with cinnarizine (~27 and 19% in cupolometric tests respectively) with intra‐subject variability significantly complicating pharmacodynamic measurements.94 In a study evaluating Antivert (meclizine combined with nicotinic acid), bithermic caloric tests in healthy volunteers did not show a significant change in SPV vs baseline for either Antivert or placebo‐treated patients (−2.2 and − 0.5% °/s, respectively) 1 hour after treatment.95 However, studies with torsion and parallel swing challenge in healthy volunteers showed that Antivert significantly decreased eye movement frequency (by up to 13.4%, torsion swing) and amplitude (by up to 20.8%, parallel swing) 1.5–2 hours post‐treatment, compared to minimal changes in patients receiving placebo.

8. SIDE EFFECTS OF ANTIHISTAMINES IN VERTIGO

Sedation and drowsiness are by far the most common side effects characterising antihistamines. While they can be considered manageable, they can have a large impact on daily and professional functioning, notably in the context of the workplace and driving. More importantly, sedation poses a contradiction for optimal vertigo management in the context of vestibular compensation as part of the natural recovery process, as demonstrated for betahistine. Second‐ and third‐generation molecules with lower brain permeability were developed in an attempt to overcome this effect as well as to improve efficacy.96 These drugs do indeed have lower levels of drowsiness; however, as most do not pass the blood–brain barrier or blood–labyrinth barrier and thus cannot modulate central or peripheral vestibular activity, they are of limited value in vertigo. It should also be borne in mind that patients taking antihistamines may poorly evaluate their sedative effect,97 and that the patient may feel that this effect diminishes with longer‐duration administration.

In addition to sedation and drowsiness, common H₁ antagonist side effects including somnolence, lethargy, other neural side effects (headache and insomnia) and gastrointestinal effects (dry mouth, nausea and stomach upset).98, 99, 100 The H₃ antagonist betahistine was considered well tolerated in clinical studies with no differences in side effects or treatment discontinuation compared to placebo in several randomised studies.43 There is notably no apparent effect on driving motor skills, supporting the absence of drowsiness.101 Associated side effects include headache and mild gastric alterations such as nausea, vomiting, dyspepsia, abdominal pain and abdominal distension, which are typically mild to moderate and can be managed with dose modifications. Post‐marketing surveillance reported gastrointestinal symptoms and headaches as the principal side effects.50

The safety profile associated with SENS‐111, the first H₄ antagonist to be evaluated clinically, in clinical investigations is extremely encouraging, with the maximal tolerated dose not reached and adverse events being nonspecific (headache, back pain), mild to moderate, transient and comparable to placebo.90, 91 Importantly, neither sedation nor drowsiness has been reported—a key finding allowing treatment of the acute vertigo symptoms while permitting vestibular compensation.

Combination of 2 antihistamines does not appear to impact the antihistamine safety profile. No difference was seen when flunarizine was added to betahistine, with weight gain and somnolence being the most common side effects in both arms.56 Analysis of cinnarizine combined with dimenhydrinate in a real‐life setting of over 1250 patients suffering from vertigo, showed that the most common adverse events were gastrointestinal and neurological (both in <2% of patients), in particular somnolence, dry mouth, nausea and headache.39

9. CONCLUSION

Despite a paucity of robust evidence of efficacy, antihistamines have played a primary role in vertigo management for over half a century. Clear progress has been made since the initial treatments used, with widespread administration of betahistine in Europe as well as various H₁ receptor antagonists depending on the geographical region. Our understanding of the molecular mechanisms affecting vertigo modulation has advanced, and the quality and sensitivity of measures has improved. The principal burden associated with antihistamines today remains their sedative side effects which have a strong impact on optimal central compensation and daily functioning, in addition to their direct modulation of central vestibular signalling. Although later‐generation H₁ and H₃ antihistamines show fewer side effects in terms of sedation, they do not achieve significant local target exposure, limiting their clinical value for treating vertigo. While betahistine may not be an appropriate choice for managing acute vertigo symptoms, it has potential for use in the recovery phase of vertigo management by enhancing central compensation via its H₁ agonism properties, thus reducing chronic symptoms. This will be contingent on current efforts on improving betahistine bioavailability to increase exposure.

New approaches in clinical management include behavioural studies and also combination studies with agents targeting different histamine receptors, to date, primarily betahistine combinations. More recently, preclinical evaluations of different H₄ antagonists have shown promise for a potential role of this drug class as new potential treatments for vertigo, with the first clinical evaluations of the novel H₄ antagonist agent SENS‐111 in patients suffering from AUV currently ongoing. The clinical effect of the H₄ antagonist SENS‐111 on vertigo induced in healthy volunteers compares favourably to the magnitude reported for other antihistamines. The benefits of SENS‐111 demonstrated in animal models of severe acute vertigo support a role for symptomatic treatment of vertigo of peripheral origin such as in AUV, Ménière's disease and migraine‐associated vertigo, which would allow patients to maintain the ability to function normally and benefit fully from the natural processes of central compensation.

COMPETING INTERESTS

J.D.‐J. and P.A. are shareholders and current/former employees of Sensorion.

Dyhrfjeld‐Johnsen J, Attali P. Management of peripheral vertigo with antihistamines: New options on the horizon. Br J Clin Pharmacol. 2019; 85: 2255–2263. 10.1111/bcp.14046