REVIEW ARTICLE sree fmntarnate Antivertigo Medications and Drug-Induced Vertigo A Pharmacological Review Olivier Rascol,! Timothy C. Hain? Christine Brefel,| Michel Ben Michel Clanet** and Jean-Louis Montastruct 1 Laboratory of Medical and Clinical Pharmacology, Faculty of Mealicine, Toulouse, France 2. Department of Neurology, Northwestern University Medical School, Chicago, Ilinois, USA 3 Otoneurological Unit, University Hospital, Toulouse, France 4. Department of Neurology, University Hospital, Toulouse, France Contents summary 1. Pathophysiological Boss of the Drug Treatment of Vertigo LI Neuroangtomica and Neurochemicol Bases 12. Mechanisms to which Vertigo ls Commonly Attiouted Aims of Drug Treatment 2.1 Specific rootment 22. Symptomatic lreatment 22.1 Vestibular Suppression 22.2 Vestibulr Compensation 22.3 Accompanying Symptoms Phormacological Possbilios 3.1 Anfichoinergies 32. Antihistamines 33. Hstominergic Medicotions 3.4. Antidopaminergic Drugs 35. Benzodiazopines 36 Collum Antagonists 37. Sympathorrimetics 3.8 Acetyleucine 39 Micelloneous Therapeutic Use 4.1 General Comments 42. Specie Indications 412.1. Vestiotor Neurtis 422 Bonign Paroxysmal Postionel Vertigo 423 Ménidro’s Disease 42.4 Vertigo of Unknown Origin Vertigo os an Adverse Effect of Drugs 51 Druge Causing Preucoverligo” of Nonvestibulcr Origin 52 Ototoxins| 53. Drugs Inducing Central Vestioular Syndrome 5.4_ Drugs Hindering Vestibular Compensotion ConckisonThe approach to drug treatment of vertigo is almost exclusively symptomatic ‘There are 3 major goals for drug treatment of vertigo. The first one i o eliminate the hallucination of motion. Drugs with vestibular ‘suppressant’ properties are used for this purpose. The major vestibular suppressants are anticholinergic and antihistamine drugs. The second goals to reduce the accompanying neurovegeta- tive and psychoaffective signs (nausea, vomiting, anxiety). Antidopaminergies are used for this purpose. The third goal is to enhance the process of ‘vestibular ‘compensation’ to ullow the brain to find a new sensory equilibrium in spite of the vestibular lesion. Until now, the pharmacological manipulation of vestibular compensation has been assessed in animals but not in humans with vestibular lesions. Vestibular suppressant drugs delay rather than enhance compensation. A variety of other drugs is also used in the treatment of vertigo, including benzodiazepines, histaminergic agents, sympathomimetics and calcium antago- nists, Their mechanism of action is poorly understood. The data base derived from clinical trials evaluating antivertigo medications is often questionable because of methodological limitations. This explains why habits of prescription are mainly empirical, and why striking differences can be ‘noticed from one country to another. We can hope that new tteatments may emerge from the present interest in receptor subclasses and neuromodulators ofthe ves- tubular system, and we must be ready to evaluate these potential new pharmaco- logical agents with reliable clinical methods in humans. This article discusses the treatment of ‘true’ ver- tigo, which is defined as hallucination of motion, generally spinning, caused by a lesion of the ves- tibular system. This definition therefore excludes ‘motion sickness, orthostatic hypotension, phobic syndromes and other conditions of nonvestibular origin. It is important to understand that our present understanding of the pathophysiology of vertigo limits a discussion of antivertigo medication to an approach that is almost exclusively symptom- atic! Vertigo is a symptom common to diverse lesions of the vestibular system, which can vary in location and pathophysiology, Unfortunately, pres- cently available clinical testing and explanations are ‘often inadequate to define the location and extent ‘of many vestibular lesions precisely. 1. Pathophysiological 8asis of the Drug Treatment of Vertigo Healthy persons use a partially redundant sys- tem of motion processing incorporating 3 primary streams of sensation: visual, vestibular (inner ear) and somatosensory. These 3 streams of information Ae eratenalutes Att esned are combined in the brain to form an estimate of head and body orientation and motion. When there is a mismatch between information carried on wo ‘or more senses, vertigo is perceived. ‘Vertigo is primarily of otological origin, caused by dysfunction of the inner ear structures, because the semi-circular canals in the inner ear are rota- tional velocity sensors. Disruption of vestibular CNS circuitry that processes motion can also cause an illusion of motion, 1.1 Neuroanatomical and Neurochemical Bases For reviews of vestibular neurochemistry, see Matsuoka et al! Raymond et al! and Dewaele et a8) ‘Much of the aim of drug treatment is to manip- ulate neurotransmitters involved in vestibular transmission. There are several neurotransmitters influencing the “3 neuron arc’ between the vestib- ‘ularhair cells and oculomotor nuclei that drives the vestibulocular reflex. Cholinergic, monoaminergic and glutamatergic synapses have been demor bn. 195Antivertgo Medications and Drugrinduced Vertigo strated in both the peripheral and the central ves- tibular circuits, Giotamate is the major excitatory neurotrans- rittr of vestibular nerve fibres! Glutamate may influence vestibular compensation through N- methyleD-aspartate (NMDA) receptors”! Acetyl- ‘choline muscarinic receptors ae found in the pons and medulla. Those involved with dizziness are supposed to be mainly of the Mz type? Amino: butyric acid (GABA) is an inhibitory neurotrans- miter found in connections between second order vestibular neurons and on to oculomotor neu- ons. Stimulation ofthe 2 types ot GABA re ceptors, GABA-A and GABA-B, has similar ef- fects on vestibular pathways,"®) but specific GABA-B agonists, such as baclofen, decrease the duration of vestibular responses in animal mod- ls." Histamine is found diffusely in central ves fibular structures.\"1 Histaminergic receptors are pre oF post-synaptically located on vestibular cells.) Both the Hj and Hz subtypes of histamine receptor affect vestibular responses." Noradrena- line (norepinephrine) is involved centrally in mod- lating the intensity of reactions to vestibular stim- ulations!) and also affects adaptation, Recently, dopamine has been shown to exert modulatory ac tion on the vestibular system." ‘The clinical use of most antivertigo drugs be- came an established practice before modern neuro~ chemical techniques had been developed, and be fore these neurotransmitters had been described in the vestibular system. There is some promise for new antivertigo drugs based on the refinement of our understanding of neurotransmitter circuitry and receptor subclasses. For example, drugs that selectively inhibit muscarinic or histamine sub- types of receptors might provide better control of vertigo symptoms with less adverse effects than broadly acting antagonists do Some neurotransmitters can also influence ves- tibular compensation. Drugs which modify eom- pensation might speed recovery.*! For example, conticotrophin (ACTH) is reported to accelerate vestibular compensation," but this drug is not presently used in clinical practice fortis purpose. 1.2 Mechanisms to which Vertigo is Commonly Attributed We shall not consider surgically curable causes of vertigo such as cerebellopontine angle tumours, or perilymph fistula. We focus instead on the pres- ent pharmacological review of nonsurgical situa- tions. ‘There are only a few examples where a precise knowledge of the cause and mechanism of vertigo supports the use of specific aetiological pharmaco- fogical treatments. These include entities such as migraine," epilepsy." or herpes infection for ‘example, which can justify, if demonstrable, the prescription of corresponding specific drug treat ments. In the case of Méniére’s disease, itis as- sumed that endolymphatic hydrops, leading to periodic dilation and periodic rupture of the endo lymphatic compartment of the inner ear, consti. tutes the pathophysiological basis of te illness. Various drugs considered to reduce hydrops have thus been proposed. ‘In most eases, the mechanisms to which vertigo is attributed are presently unsupported by convine= ing scientific evidence, Most of the time we lack precise knowledge about the cause and mechanism of vertigo. Unfortunately, nature abhors a vacuum, and a large number of highly questionable ‘mech- anisms’ for vertigo are commonly proposed in clin ical contexts In several countries, including France, when dealing with older patients, vertigo is often said to be ‘of vascular origin’, and this term is used to refer toany dizziness of unknown origin occurring after the age of 60. This assumption of a vascular origin corresponds to an obsolete nosological notion aris- ing from the concept of ‘chronic cerebral circula- tory insufficiency’, widely adhered to in the 1960s, but abandoned since. This old theory still justifies, in 1995, the prescription of vasodilators for the treatment of dizziness. We still do not know, how: fever, how these drugs could exert an antivertigo effect, and there is no evidence that an increase in cochleovestibular blood flow reduces dizziness. In fact, itis known that vasodilators can aggravate onan 8 185Resco ea ischaemia of atheromatous areas by disturbing au- toregulation. Except in specific cases where a definite link ‘can be established between ischaemia in the vertebro basilar teritory and dizziness, the term ‘vascu- lar vertigo’ should be dropped and the term ‘vertebrobasilar insufficiency” limited to its strict neurological definition. (1 [In younger patients, itis more difficult to advo- cate vascular problems than in the elderly. A ‘viral infection’ of the inner ear is then considered as a more plausible explanation, Again, itis generally impossible to prove such a mechanism, and antivi- ‘al treatments are not recommended. 2. Aims of Drug Treatment 2.1 Specific Teatment Drug treatments aimed specifically at correcting, oo eliminating the cause of vertigo are few. Anti ‘migraine or antiepileptic drugs can be useful in very special cases. In Ménidre’s disease, salt re striction and diuretics are proposed to reduce endo: lymphatic pressure, but « nihilistic approach advo- cating no specific treatment is still considered acceptable, as at this time there are no large and well controlled studies to demonstrate that any treatment is better than no treatment. In most cases, we lack understanding of the mechanism of vertigo, and our approach of vertigo treatment re- ‘mains, therefore, almost exclusively symptomatic, 2.2 Symptomatic Treatment Drug treatments of vertigo aim for 3 goals: (i) the elimination of vertigo; (it) the enhancement Cr at least noncompromise ~ of the processes of “vestibular compensation’ to allow the brain to find anew sensory equilibrium in spite ofthe vestibular lesion; and (it) the reduction of neurovegetative and psychoaffective signs (nausea, vomiting, anxiety) that often accompany vertigo. 2.2.1 Vestiouiar Suppression The sensation of dizziness is supposed to be ‘caused by a functional imbalance within the ves- tibular nuclei secondary to alesion ofthe vestibular ‘Aa nematonl Lec ig saved ‘Table Vosibulrsupeessan “Arilchotinrgice Homatropne ‘Seopolamin ryoeie) ‘Antiistamines| Diphesnyeramine Ojetane Dimeyente Hyronine Promethanne Cimartne Furattne Benzodtarepines Diazepam system. There is generally, especially after a peri- pheral vestibular lesion, a “good” side and a “bad” side, with a resulting imbalance in vestibular fune- tion between the 2 ears, In this situation, vestibular suppressants reduce asymmetry in vestibular tone between the ears, and thereby reduce vertigo (table I), The term vestibu- Jar suppressant isin fact a vague one generally used to indicate drugs which reduce motion sickness, which reduce nystagmus evoked by a vestibular imbalance, or which reduce the spontaneous activ- ity of the central vestibular neurones and theit re- sponse to the stimulation of the vestibular nerves {in animal experiments, The reduction in vertigo ‘comes atthe price of a reduction in vestibular Func- tion, as both the normal and abnormal side are sup pressed to accomplish a reduction in the difference between the 2 sides. 2.2.2 Vestibular Compensation Ideally, medication for vertigo should in the ‘same time facilitate (or not hinder) the healing pro- cess." The natural evolution of most examples of dizziness does in fact lead to the improvement and finally the spontaneous disappearance of the symp- tom. ‘This healing process represents one of the best examples of the plasticity of the CNS and its ca pacity to reorganise its internal connections (ves- ges 188Antivertigo Medications and Drugelnduced Vertigo ‘abular but also visual and proprioceptive) to return to normal function in spite of the inital lesion. The brain requires the sensory feedback, or in other ‘words, requites some vertigo in order to guide and control this reorganisation.) Unfortunately, ves tibular suppressant drugs decrease or slow down the vestibular compensation by reducing vertigo and the necessary feedback indicating that a sen- sory mismatch exists, The 2 goals of antivertigin- ‘ous drugs (elimination of vertigo and facilitation ‘of compensation) are therefore often incompatible. 22.3 Accompanying Symptoms Vertigo almost always occurs alongside a mul + titude of disagreeable neurovegetative signs (nau- sea and vomiting) and psychoaffective symptoms (anxiety). These symptoms may be more trouble some than the vertigo itself, Accordingly, in addi- tion to the reduction of vertigo, we also aim to Control these symptoms to improve the patient's quality of life. 3. Pharmacological Possibilities In the following section we deseribe the main classes of drugs used in the treatment of vertigo. Medication practices are often empirical and there are noticeable differences from one country to an- other 3.1 Anticholinergics ‘These were the first drugs to be used in the treat- ‘ment of vertigo, commonly used examples being scopolamine (hyoscine) and homatropine. In France, these 2 agents are associated together (for obscure reasons) in fixed doses in a commercial antivertigo ‘medication, These agents are nonselective, reproducing the effects of atropine, and blocking all the muscarinic receptors subtypes. Molecular biological studies have revealed the presence of at least 5 different muscarinic receptors (termed m, to ms in ehrono- logical order of discovery), each of which isa prod- uct of distinct genes.) It is possible that in the future, more selective muscarinic antagonists may prove to have a higher benefit-o-risk ratio than these nonselective agents Nonsclective anticholinergics exhibit vestibu- lar suppressant properties and also afect vestibular compensation: reversible overcompensation has been reported in animals after anticholinergic ad- ministration.) Agents with central anticholiner- gic effects are probably most important in treating vertigo, as anticholinergic drugs that do not cross the blood-brain bartier are ineffective in control- ling motion sickness. Anticholinergic effects after oral ingestion typically persist for 4 hours. However, a recent development has been to treat motion sickness with a drug that is gradually administered trans. cutaneously via a patch applied behind the car !"!221 This preparation lasts approximately 4 days ‘Adverse effects of anticholinergics arise mainly from blockade of muscarinic receptors located out- side the vestibular system. In the CNS, blockade can causes memory disturbances and confusion The elderly are particularly prone to this adverse effect. In the peripheral parasympathetic nervous system, blockade can cause dry mouth, visual dis- turbances, constipation and dysuria, The existence Of closed-angle glaucoma and prostatic hypertro- phy contraindicate their prescription. 3.2 Antiistarines ‘The Hy-blockers are currently the most numer ‘ous of the drugs prescribed for vertigo, and include diphenhydramine, eyclizine, dimenhydrinate, mec~ lozine and promethazine."34! This class of drug is the only one being quoted as having antivertigo properties in the index of a reference textbook of pharmacology, Goodman and Gilman's The Phar macological Basis of Therapeutics:°°) In France, meclozine is marketed associated with another antihistamine (hydroxyzine) in fixed doses (for obscure reasons). Cinnarizine and flunarizine are 2 antivertigo rugs available in Europe. They are generally classed as calcium channel antagonists. Both drags in fact have significant H-blocking effects which een. 198may well explain their antivertigo properties (see section 3.6) ‘The mechanism of action of antihistamines as vestibular suppressants remains poorly under- stood, butis felt to involve central effects. Antihis- amines may prevent or improve motion sick ‘ness 85) Dimenhydrinate has adeleterious effecton ‘compensation in the eat.27 The H, antihistamines also have antimuscarinic properties, which could account for some of their vestibular suppressant effects. However, astem- izole, an H, antihistamine with few anticholinergic properties, has been claimed 10 have antivertigo properties 7) Hy-blockers are not used for vertigo. Sedation is a common adverse effect of the Hi- blockers. These drugs are usually administered orally. Their duration of action varies from 4 hours (for cyclizine) to 12 hours (for mectozine). 3.3 Hstaminergic Medications ‘This class of drugs is represented by betahistine, which is used as an antivertigo drug in several Eu- ropean countries but not in the US (for a review, see Schmidt and Huizing!*}, Histamine itself, ad- ‘ministered by injection or sublingual drops, is oc- casionally encountered in the US. Because hista- ‘mine has a very brief duration of action, in this context, it is given with the rationale that it may “desensitise’ the patient. Betahistine is an analogue of L-histidine, the immediate precursor of histamine. The antivertigi ous properties of betahistine are sometimes ex plained as a vasodilatory effect, improving blood flow in the microcirculation ofthe internal auditory and vestibular systems.0®1 Betahistine, however, is also supposed to be effective in vestibular syn- dromes unrclated to vascular problems. Betahistine appears indeed to have complex effects on hista- mine receptors, being both a partial Hy postsynap- tic agonist and a Hs presynaptic antagonist, leading to a final facilitation of histaminergic neurotrans- mission. (#842) It is not at all clear how facilitation of histamine explain the antivertigo effect ofthe drug. A nonspe~ cific action increasing vigilance is not excluded. A ‘Ae nematonal Untea. arr rveven ‘more specific effect on the vestibular cells activity possible.) Betahistine, like stimulants, facili ties vestibular compensation in the cat! Betahistine is well absorbed on oral administra tion and is thought to act via an active metabolite, ‘with a peak effect around the fourth hour. Adverse cffects are rare but include headaches and nausea. Betabistine should not be used in cases of gastro =T ‘opine, seaplane (hyo) vata antago ‘ctl, pheolamine rAminoutytc 2s (GABA) antagonist" not even marketed in the US. 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