Clinical manifestations

Presentation and course

	• The patient may present with several variations of disturbances of smell and taste – diminished function, distortion, or complete loss.
	• In most of the cases, the symptoms resolve after discontinuation of the drug.

The patient presenting a complaint pertaining to taste or smell may be plotted anywhere along a wide spectrum, which varies from distortion to complete loss of these senses. Various expressions are used by the patients for describing taste and smell alterations. A system for classifying these expressions is shown in Table 1.

Table 1. A Simple Classification of Loss and Distortion of Taste and Smell Function

Loss
	• Ageusia (Greek for no taste) is defined as inability to detect any taste stimuli. • Anosmia (Greek for no smell)
Diminished function
	• Hypogeusia is defined as decreased ability to detect taste. • Hyposmia (smell)
Disturbance (unspecified)
	• Dysgeusia (taste) is the term for either decreased or increased or distorted perception of stimuli. • Dysosmia (smell)
Distortion
	• Phantogeusia (taste) is defined as distorted perception of taste stimuli. • Phantosmia (smell) is perception of odors in the absence of a relevant source of odor.
(11)

Other common terms are cacosmia and parosmia. Cacosmia is characterized by an interpretation of normal odors as being foul, whereas parosmia is characterized by a perception of an odor that is not present. The most common disorder of taste associated with drugs, other than actual taste loss, is "metallic taste." Metallic taste is more clearly specified and described regarding the onset of symptoms. Anosmia may be associated with weight loss due to a decrease in appetite, which results from a loss of perception of the flavor of food.

Although the patient may offer complaints only regarding a disturbance of smell or taste, careful questioning may reveal other drug-induced disturbances and symptoms of other diseases that may be responsible for the disturbances of smell and taste.

Prognosis and complications

Most of the disorders of taste and smell are dose related and resolve after discontinuation of the drug. A patient with cardiac arrhythmia who developed dysosmia and hypogeusia after taking metoprolol and amiodarone, respectively, recovered normal smell and taste following discontinuation of drugs (04). In some cases, the loss of smell or taste or their distortion may be irreversible. Early detection of smell and taste disorders and discontinuation of offending medications prevents irreversible damage. Taste-related problems can cause discomfort and hinder the maintenance of a nutritious diet (20). Complications of loss of taste include weight reduction due to poor eating and inappropriate intake of salt by patients who should have salt restriction because of a cardiovascular disorder.

Biological basis

Etiology and pathogenesis

	• Pathomechanism of drug-induced smell and taste loss is not clear but alteration in zinc metabolism is a possible mechanism.
	• Smell and taste disorders are associated with almost all major categories of drugs, with cardiovascular drugs as the most frequently involved agents.
	• Receptor dysfunction, which impairs the initial step of the sensory process, causes the bulk of drug-related smell and taste dysfunction; CNS is rarely involved.
	• There are large differences among individuals in terms of their susceptibility to taste-related adverse effects and various factors involved include sex, age, body mass, and genetic variations in taste sensitivity.

Disorders of smell and taste have been reported with numerous drugs. It would be impossible to list all of these. Only drugs for which the frequency of these disorders is reported at 1% or higher are listed in Table 2.

Table 2. Drugs Reported to Induce Disorders of Taste and Smell with a Frequency of Occurrence of 1% or More

Analgesics/antiinflammatory drugs
	• Diclofenac: dysgeusia • opioids
		- morphine: hyposmia
Anesthetics, local
	• benzocaine: dysgeusia (due to nerve injury during dental anesthesia) • lidocaine: dysgeusia (due to nerve injury during dental anesthesia) • procaine: dysgeusia (due to nerve injury during dental anesthesia)
Anorectic drugs
	• amphetamines: dysgeusia, hyposmia • fenfluramine: dysgeusia • mazindol: dysgeusia • phenmetrazine: dysgeusia
Antiasthmatics
	• flunisolide: dysgeusia, hypogeusia, hyposmia • pirbuterol: taste disturbances
Antihistamines
	• fluticasone nasal spray: dysosmia • terfenadine: dysgeusia • loratadine: dysgeusia • promethazine: hypogeusia, hyposmia
Antimicrobial agents
	• antifungals
			- griseofulvin: dysgeusia - terbinafine: hypogeusia, metallic taste
	• anthelminthics
			- levamisole: taste alteration
	• antiprotozoals
			- metronidazole: metallic taste, hypogeusia - pentamidine: hyposmia, metallic taste, hypogeusia
	• antivirals
			- acyclovir: taste disturbances - amantadine: bitter taste - didanosine: dysgeusia - foscarnet: dysgeusia - idoxuridine: dysgeusia - interferon-alpha: phantogeusia, anosmia - maribavir: bitter, metallic taste - zalcitabine: taste distortion - zidovudine: dysgeusia
	• cephalosporins
			- cephacetrile: hypogeusia - cefadroxil: dysgeusia - cefamandole: dysgeusia - cefpodoxime: dysgeusia - cephalexin: dysgeusia
	• chlorhexidine mouth wash • lincosamides
			- clindamycin: dysgeusia - streptomycin: anosmia
	• macrolide antibiotics
			- azithromycin: dysgeusia
	• penicillins
			- ampicillin: hypogeusia - procaine penicillin: hypogeusia - piperacillin: hypogeusia
	• quinolones
			- enoxacin: phantogeusia - ofloxacin: smell and taste distortions
	• tetracyclines
			- minocycline: dysgeusia
Anticancer drugs
	• bleomycin: hypogeusia • doxorubicin: hypogeusia • 5-fluouracil: hypogeusia • gallium: dysgeusia • interleukin-2: hypogeusia, hyposmia • methotrexate: hypogeusia • sonidegib • vincristine: hypogeusia • vismodegib: hypogeusia
Antirheumatic drugs
	• gold: hypogeusia, phantogeusia • penicillamine: hypogeusia, dysgeusia
Antismoking agents
	• nicotine polacrilex: dysgeusia
Cardiovascular drugs
	• ACE (angiotensin converting enzyme) inhibitors
			- captopril: sweet and salt; phantogeusia, hypogeusia - enalapril: hypogeusia, dysgeusia - fosinopril: hypogeusia, dysgeusia - lisinopril: hypogeusia, dysgeusia
	• calcium channel inhibitors
			- amlodipine: dysgeusia, dysosmia - nifedipine: dysosmia, hypogeusia - diltiazem: hypogeusia
	• angiotensin II receptor (subtype 1) antagonists
			- losartan: dysgeusia, reversible ageusia diuretics - acetazolamide: dysgeusia - amiloride: hypogeusia - eprosartan: dysgeusia - ethacrynic acid: hypogeusia - metolazone: bitter phantogeusia - triamterene: hypogeusia
	• antiarrhythmics
			- amiodarone: abnormal taste and smell - flecainide: dysgeusia, altered taste - metoprolol: dysosmia - moricizine: bitter phantogeusia - procainamide: bitter phantogeusia
	• antihyperlipidemics
			- atorvastatin: taste disturbance - cholestyramine: hyposmia - fluvastatin: taste disturbance - gemfibrozil: hyposmia - lovastatin: hyposmia - pravastatin: hyposmia
	• miscellaneous cardiovascular drugs
			- clopidogrel: ageusia - diazoxide: hypogeusia - digitalis: hyposmia and hypogeusia - isosorbide nitrates: bitter phantogeusia - labetalol: dysgeusia - nitroglycerin: hypogeusia - phenindione: dysgeusia
Drugs for autonomic failure/alfa-adrenergic agonist
	• midodrine
Drugs for endocrine disorders
	• antithyroid drugs
			- carbimazole: hypogeusia, hyposmia - methimazole: hypogeusia
	• antihyperglycemic agents
			- tolbutamide: taste alterations - glipizide: severe taste changes
	• antihypoglycemic agents
			- diazoxide: taste loss - glucocorticoids: hypogeusia, hyposmia
Drugs for gastrointestinal disorders
	• famotidine: dysgeusia • granisetron (antiemetic): dysgeusia • scopolamine (antispasmodic): hyposmia, hypogeusia
Drugs for neurologic disorders
	• antiparkinsonian drugs
			- bromocriptine: phantosmia - levodopa: dysosmia, hypogeusia, dysgeusia - pergolide: dysgeusia
	• antiepileptic drugs
			- carbamazepine: ageusia, bitter phantogeusia, dysgeusia, ageusia - lamotrigine: dysgeusia - phenytoin: taste disturbances - topiramate: taste
	• muscle relaxants
			- baclofen: hypogeusia - cyclobenzaprine: ageusia
	• antimigraine drugs
			- dihydroergotamine: taste disturbances - naratriptan: taste disturbances - rizatriptan: taste disturbances - sumatriptan nasal spray: taste disturbances
Nasal decongestants
	• oxymetazoline: hyposmia • phenylephrine: hyposmia • pseudoephedrine: dysgeusia
Nonsteroidal anti-inflammatory drugs
	• aspirin: hypogeusia, dysgeusia • diclofenac: taste disorder • etodolac: dysgeusia • flurbiprofen: taste change, dysosmia • ibuprofen: hypogeusia • indomethacin: hypogeusia • nabumetone: taste alteration • phenylbutazone: hypogeusia • piroxicam: taste alteration • sulindac: metallic bitter taste
Ophthalmologic drugs
	• dorzolamide: anosmia • topical silver nitrate (chronic): hypogeusia, anosmia
Psychotropic drugs
	• anxiolytics/hypnotics
			- alprazolam: hypogeusia - buspirone: taste disturbances - estazolam: dysgeusia - flurazepam: dysgeusia - oxazepam: hypogeusia - zolpidem: dysgeusia
	• antidepressants
			- amitriptyline: hypogeusia - bupropion: dysgeusia - clomipramine: dysgeusia - desipramine: dysgeusia - duloxetine: dysosmia and dysgeusia (33) - imipramine: hypogeusia - paroxetine: dysgeusia - sertraline: dysgeusia - trazodone: phantogeusia
	• antipsychotics
			- fluphenazine: phantogeusia - risperidone: bitter phantogeusia - lithium: dysgeusia, metallic taste
Retinoids
	• etidronate: hypogeusia • etretinate: dysgeusia
Drugs for sexual disorders
	• erectile dysfunction
				- sildenafil: hyposmia
Table based on publications plus drug safety data released by pharmaceutical manufacturers.

Cases of disturbances of smell and taste continue to be reported with medications that have not been associated with these disturbances previously. For example, several antibiotics are associated with loss of smell. Evidence for several individual chemicals as well as therapeutics as causes of olfactory and gustatory deficits remains limited but several studies have collectively demonstrated moderately strong evidence for an association between manganese dust exposure and olfactory deficits (01).

Metallic taste is associated with the use of numerous medications. Pathomechanism is not clear, but alteration in zinc metabolism, which may occur with botulinum toxin administration, has been suggested as a possible mechanism.

Pathogenesis of drug-induced disturbances of smell and taste. Zinc-induced anosmia syndrome occurs after the exposure of olfactory epithelium to zinc contained in intranasal zinc gluconate gel used as a remedy for the common cold. Drugs used for local application in ophthalmology can produce disturbances of smell through systemic absorption. For example, dorzolamide, a topical carbonic anhydrase inhibitor for treatment of glaucoma, can produce anosmia.

A case of dysosmia has been reported in which a sensation of smelling something burning 15 minutes after drug intake of pyrazinamide, a prodrug of pyrazinoic acid used for the treatment of tuberculosis, occurred (07). Smell disturbance resolved after withdrawal and recurred after rechallenge. In another case report, a patient with pulmonary tuberculosis treated with antitubercular drugs including pyrazinamide complained of smell disturbance as change of the original smell of food to a disgusting odor (27). Pyrazinamide was identified as the agent responsible for this symptom, which resolved after discontinuation of the drug but recurred after its reintroduction. General anesthesia with use of fentanyl, propofol, and sevoflurane can possibly induce anosmia, as reported in 1 case (13). This patient recovered after 4 months of retraining therapy.

In addition to therapeutic drugs, environmental toxins can also produce disturbances of smell and taste. Workers exposed to moderate airborne cadmium levels may show subclinical impairment of olfactory function that can be detected only with laboratory tests. The action of the metal seemed to be due to an elective tropism for the olfactory epithelium and not to a nonspecific irritant effect on the nasal cavity.

Injury and impairment of the smell and taste sensory systems may occur at 3 levels. Further, both sensations may be affected by the same drug. Less than 5% of cases involve either the central nervous system or sensory neural transmission. Receptor dysfunction, which impairs the initial step of the sensory process, causes the bulk of drug-related smell and taste dysfunction. Receptor dysfunction is caused by receptor pathology in 45% of cases and impairment of receptor-mediated mechanisms in 45% of cases.

Drugs may affect the receptors directly or indirectly by producing vitamin and essential element (zinc and copper) deficiencies. Zinc metalloproteins (gustin and lumicarmines for taste; a gustin-like protein for smell) are critical for maintaining receptor integrity. Molecular events underlying these disturbances can involve alteration of the primary, secondary, or tertiary receptor protein structure. Zinc deficiency is frequently mentioned as a cause of drug-induced taste disturbances and could be caused by the zinc-chelating effect of some drugs. A comparative study of losartan, an angiotensin II receptor blocker, and perindopril, an angiotensin-converting enzyme inhibitor, showed that detection thresholds of basic tastes by the paper-disc test and electrogustometry were significantly worsened with both drugs but showed no changes in zinc concentration in either plasma or blood (28). As a quantitative measure of the chelating ability of drugs with zinc ions, Fukasawa and colleagues estimated the chelating ability from the electrode potential change of the Zn2+/Zn(Hg) system during the addition of a drug, which showed a positive correlation to the frequency of the drug-induced taste disorder caused by the drug (09). Paradoxically, local application of zinc-containing substances to the nasal mucous membrane can produce anosmia.

Several explanations have been offered for chemotherapy-induced taste disturbances including zinc deficiency. Results of a prospective observation study showed that chemotherapy changes the gene expression of T1R3 and T2R5 in head and neck cancer patients with mild/moderate stomatitis, resulting in dysgeusia as well as phantogeusia (29).

Regardless of the triggering cause, subsequent events may be as follows:

	• Decreased receptor sensitivity
	• Inhibition of receptor turnover
	• Inactivation of events in the receptor-coupled “on” system that normally involve G protein synthesis, cyclic adenosine monophosphate activity, and activation of sodium or calcium ion channels. Drug-induced impairment of these events can lead to lack of generation of action potential, which is transmitted along taste and smell nerve pathways to the central nervous system.
	• Drug-induced events in the receptor-coupled “off” mode usually involve taste and smell distortions. These may involve direct receptor pathology, a binding abnormality due to activation of an inhibitory G protein, receptor kinases, or cytochrome p450 proteins. The receptor is not erased or turned off, and the smell or taste may persist in a distorted manner.

Preclinical studies. Our knowledge of how drugs can modify taste is limited because taste is a subjective sensation and cannot be verified objectively. The knowledge of neurotransmitters responsible for relaying the taste and olfactory information from the periphery to the brain is still incomplete. Preclinical studies for drug safety in animals usually fail to detect sensory disturbances such as drug-induced smell and taste disorders that may not be reported until the drug is in clinical use for a few years. Impact of drug candidates on taste is rarely evaluated in preclinical toxicology studies during the early stage of drug development and knowledge of methods for investigating these adverse effects is scarce in toxicology (32). However, in experimental studies on mice the anticancer drug sonidegib, a Hedgehog-pathway inhibitor, led to rapid loss of taste buds in both fungiform and circumvallate papillae (15). Taste buds were not restored in all fungiform papillae even with prolonged recovery for several months, and this finding can explain the partial recovery of dysgeusia after discontinuation of sonidegib.

Research technicians should be trained to improve their ability to identify and document subtle changes in behavior that will serve to increase the likelihood of early detection of biomarkers predictive of drug-induced loss of smell and taste (10).

Clinical studies. Evaluation of drug-induced taste disturbances is difficult because some of the complaints are due to the taste of the drug itself rather than a pathologic change in the taste system. Even if the galenic preparation masks the unpleasant taste of the drug, it may reach the taste receptors by excretion in the saliva or by vascular route. Furthermore, many patients have diseases that can contribute to or cause smell and taste disturbances.

There are large differences among individuals in terms of their susceptibility to taste-related adverse effects, and various factors involved include sex, age, body mass, and genetic variations in taste sensitivity. The role of genetic factors in the pathogenesis of drug-induced smell and taste disturbances has not been defined, but it is likely that genetic factors interacting with environmental factors may increase the susceptibility to drug-induced smell and taste disturbances. Loss in taste perception is more frequent in older individuals and is exacerbated by some drugs, diseases, and exposure to toxic chemicals.

Because systematic evidence for olfactory drug effects from controlled studies is sparse, a cross-sectional approach based on bioinformatics, knowledge discovery, and data mining has enabled drug-related information from humans with underlying molecular drug targets (16). For example, this approach has shown that antagonistic targeting of the adrenoceptor alpha 1A gene by several unrelated medications is associated with a significantly higher olfactory score.

Studies conducted on healthy volunteers involving a topical application of tricyclic antidepressants show that they can block responses to a wide range of taste stimuli. The differential suppression of other tastes by tricyclic antidepressants at the level of the taste receptors may contribute to the clinical reports of dysgeusia and hypogeusia.

Olfactory deficits are well documented in patients with extrapyramidal disorders. A study has shown that olfactory deficits may be drug induced in patients with primary affective disorders who develop extrapyramidal movement disorders following neuroleptic therapy (14).

Antithyroid thioamide affects the sense of smell and taste by binding to the Bowman glands in the olfactory mucosa and causes extensive lesion in the olfactory mucosa. The association of clindamycin and taste disorders seems to be independent from age, gender, and infections, and a case report suggests a role for clindamycin concentrations excreted in body fluids like saliva (06). Results of an experimental study show that lipopolysaccharide-induced inflammation in the rat olfactory system inhibits taste progenitor cell proliferation and interferes with taste cell renewal (05). Possible mechanisms to explain the effect of drugs on taste and smell are listed in Table 3.

Table 3. Pathomechanisms of Drug-Induced Disturbances of Smell and Taste

Depletion of vitamins and minerals
	• Zinc depletion: captopril, enalapril, diuretics • Copper depletion: penicillamine • Vitamin A inhibition: cholesterol-lowering drugs
Disturbances of sensory receptors
	• Ion channel disturbances
		- sodium channels: amiloride, spironolactone, lithium - calcium channels: calcium channel blockers (eg, nifedipine)
	• Inhibition of sensory receptor turnover: clarithromycin, chlorhexidine • Reduction of permeability of taste cell membrane: amphotericin B • Disruption of the integrity of lipids in the receptor cell membranes: clofibrates • Inhibition of protein synthesis: aminoglycoside antibiotics • Inhibition of cDNA synthesis: penicillins • Inhibition of ATP-dependent reactions: aspirin • Inhibition of cAMP (adenosine 3’,5’-cyclic monophosphate): metolazone, dipyridamole • Catecholamine alterations: anorexiants, beta blockers • Inhibition of cytochrome P450: quinoline antibiotics, terbinafine, antihistaminics • Olfactory receptor injury: nasal decongestants • Glossitis inhibiting receptor cell turnover: antineoplastic drugs
Interference with axonal transport: colchicine
Inhibition of receptor-coupled “off” events: antivirals, retinoids, antiepileptics, antipsychotics
Inhibition of receptor-coupled “on” events (action potentials): antiarrhythmics, antihypoglycemics
Prostaglandin inhibition: nonsteroidal anti-inflammatory drugs
Hypothyroidism-induced cytotoxic effects: antithyroid drugs

Epidemiology

• The estimated incidence of taste and smell alterations induced by drugs in the clinical practice ranges between 2% and 5%.

The true incidence of drug-induced taste and smell disturbances is difficult to determine because of the infrequency of reporting. The estimated incidence of taste and smell alterations induced by drugs in the clinical practice ranges between 2% and 5%. Of the 150,000 cases recorded in the pharmacovigilance centers in France, only 68 (0.05% of cases) reported olfactory complications related to drugs (22). Frequency of taste disturbance with some commonly used, well-known drugs has been recorded. The number of patients who experience a bad or bitter taste after sumatriptan is 5% (03). Old age and polypharmacy are risk factors for drug-induced taste disturbances. Evaluation of an Italian database of 52,166 spontaneous adverse drug reactions reported revealed 182 cases (approximately 0.3%) of drug-induced taste and smell alterations that were sometimes unexpected and often persistent complaints of patients during pharmacological treatments (30).

In a survey of cancer patients receiving chemotherapy, 55% complained of a gustatory disorder, and 19% complained of an olfactory disorder; occurrences of olfactory disorder were significantly greater in patients who had gustatory disorder than in patients who did not (26).

In an analysis of the drug-induced taste disorders in the Dutch Pharmacist’s database, 17% were listed as dysgeusia and 3.7% as hypogeusia (23). They occur in all drug categories but predominantly in antineoplastic and immunomodulating agents, antiinfectives for systemic use, and those for neurologic disorders.

Prevention

	• Avoid the use of drugs known to induce such disturbances in patients with diseases that make them susceptible to smell and taste disorders.
	• Good nutritional support with zinc supplementation.

Drug-induced smell and taste disturbances can be minimized by avoiding the use of drugs known to induce such disturbances in patients with diseases that make them susceptible to smell and taste disorders. Good nutritional support with zinc supplementation may reduce the possibility of the onset of drug-induced smell and taste disorders. Good oral hygiene coupled with prevention of dry mouth may reduce the incidence of taste disturbances. Once a patient shows signs of such disturbance, an early discontinuation of the offending drug may prevent complete loss or irreversible distortion of smell or taste.

Differential diagnosis

Confusing conditions

Drug-induced olfactory and taste disturbances should be differentiated from those associated with aging and several diseases. Age-related loss of smell, presbyosmia, may occur with normal aging, neurodegenerative disorders associated with aging, or as adverse effect of medications. Taste can also diminish with aging and loss of smell also contributes to impairment of taste.

Conditions that affect taste are shown in Table 4. Both non-neurologic and neurologic disorders can affect smell, and these are shown in Table 5 and Table 6, respectively. Drug-induced olfactory disorders are usually bilateral, whereas unilateral anosmia is usually due to head injury or other syndromes unrelated to drug use. Smell and taste disorders frequently coexist, and patients with loss of smell have impairment of taste sensation as well. Perceived taste disturbance might be an interaction of various health factors such as illness and mental condition and is difficult to differentiate from drug-induced taste disturbances. Exposure to low levels of toxins in the air over long periods can lead to transient olfactory disorders or even anosmia. Occupational exposure may account for a significant part of "idiopathic" smell disorders, ie, the 10% to 25% of all olfactory problems within the general population. Olfactory disorders have been reported in workers chronically exposed to metals such as cadmium, chromium, manganese, arsenic, mercury, and organic lead and to other chemicals such as acrylates, styrene, and solvent mixtures. A clue to the cause may be obtained by a careful, detailed history.

Table 4. Conditions That Affect Taste

• Bell palsy • Cancer • Depression • Diabetes mellitus • Guillain-Barré syndrome • HIV infection • Hyperaldosteronism • Hypothyroidism • Meningitis • Migraine headaches • Multiple sclerosis • Parkinson disease • Perceived taste disturbance • Periodontal disease (gingivitis and periodontitis) • Pernicious anemia • Prosthodontic devices • Radiation therapy • Xerostomia (dry mouth) • Zinc deficiency

Table 5. Non-Neurologic Systemic and Local Disorders that Can Cause Hyposmia or Anosmia

	• Local disorders • Allergic rhinitis • Atrophic rhinitis • Burning mouth syndrome • Chronic sinusitis • Cleft palate • Deviated nasal septum and septoplasty • Nasal polyposis • Neoplasms of the nose and nasal sinuses • Paget disease involving facial and maxillomandibular region • Viral rhinitis
Systemic disorders
	• Adrenal disorders • Aging • Cancer • Diabetes mellitus • Hepatic disease • HIV infection • Hypothyroidism • Kallmann syndrome (anosmia, hypogonadism) • Malnutrition, zinc deficiency • Organic solvent exposure • Renal disease • Sjögren syndrome

Table 6. Neurologic and Psychiatric Disorders Associated with Smell Disturbances

• Alzheimer disease • Congenital anosmia • Depression • Down syndrome • Epilepsy: olfactory hallucinations • Head injury • Huntington chorea • Korsakoff psychosis • NeuroCOVID • Parkinson disease • Pick disease • Schizophrenia • Shy-Drager syndrome • Tumors of the anterior cranial fossa

Hyposmia is a common symptom in Parkinson disease and is 1 of the nonmotor symptoms considered in the differentiation of idiopathic Parkinson disease from drug-induced parkinsonism in early stages. One study showed significantly higher scores of taste and smell disorders in Parkinson disease than in drug-induced parkinsonism (12). Preclinical manifestations of idiopathic Parkinson disease, particularly nonmotor symptoms, can be used to distinguish it from drug-induced parkinsonism (19). However, there are some limitations of this approach, such as the occurrence of similar nonmotor symptoms in neurodegenerative disorders other than Parkinson disease and hyposmia in psychiatric patients prior to use of antipsychotic drug therapy. Dopamine transporter single-photon emission computed tomography, which can accurately detect the presynaptic dopaminergic deficit, has some use in the differentiation of Parkinson disease from drug-induced parkinsonism, but it has limitations, and the accuracy is unknown (02).

Anosmia is an early sign of COVID-19 when the olfactory nerve is involved and from where the virus infection can further invade the brain.

Associated or underlying disorders

Associated and underlying disorders are covered under Differential diagnosis.

Diagnostic workup

	• History and general physical examination
	• Special examination of taste and smell
	• Olfactory evoked potentials
	• Brain imaging
	• Biopsy of the olfactory neuroepithelium

Diagnostic workup of a patient with smell or taste impairment proves extensive because the complaints are subjective, thus, making objective assessment difficult. The 4 important components of a clinical evaluation of a patient with smell and taste disturbance include:

History. This is the most important step because the history provides the etiologic clue (eg, the offending drug).

Physical examination. This includes examination of the ear, nose, and throat as well as neurologic examination.

Special examination of taste and smell. Smell acuity reflects the ability to detect and recognize vapors that can be evaluated clinically. The psychophysiologic approach to testing involves measurement of physical parameters such as blood pressure after exposure to odors. Routine testing of taste may not reveal any findings in transient, drug-induced taste disturbances. Electrogustometry (application of weak electrical currents to taste bud areas in the oral cavity) provides a more objective assessment of taste rather than simply testing with salt, bitter, and sweet substances. Abnormal electrogustometry test results were seen in half of patients after chemotherapy for gynecological cancer, with a tendency for the development of hypogeusia in the chorda tympani nerve field and hypergeusia in the greater petrosal nerve field (21).

Laboratory tests. The tests that are used for this purpose are:

Computed tomography of the head. This test is particularly useful for patients with smell disorders. Particular attention is paid to the nasal cavities, anterior cranial fossa, and nasal sinuses. Apart from anatomical abnormalities, neoplasms in these locations should also be ruled out. Further imaging studies, such as MRI, are indicated according to the lesion suspected.

Functional MRI and functional PET. Objective tests for assessing the sense of smell include functional MRI and functional PET.

Electroencephalography and olfactory evoked potentials. These have been used mainly in establishing the sensory function in patients with neurodegenerative disease and for localization of epileptic foci. They have a role in evaluation of a patient in whom the cause of olfactory impairment is not certain. Because of some technical problems, gustatory evoked potentials have not become a routine investigation for taste disorders in humans.

Biopsy of the olfactory neuroepithelium. Biopsy can be obtained by a needle and is generally a safe procedure. Biopsy utility rests in its ability to demonstrate changes that occur in steroid dependent anosmia, posttraumatic anosmia, post-trial olfactory dysfunction, and congenital anosmia.

Differential diagnosis. Drug-induced smell and taste disturbances should be differentiated from other causes, both neurologic and other systemic disorders. For example, patients with traumatic brain injury can present with anosmia. Smell and taste dysfunction are early markers for neurodegenerative diseases such as Alzheimer disease and Parkinson disease, as well as other diseases that involve dopaminergic pathology (08).

Management

	• Treatment is mostly limited to zinc supplementation and the dose reduction of the offending drug or the substitution of the offending drug by another in the same therapeutic category.
	• Treatment with drugs that stimulate cAMP synthesis (theophylline, fluoride, and magnesium) has been used in some cases with good results.

Treatment of smell and taste disturbances is mostly limited to zinc supplementation and the dose reduction of the offending drug or the substitution of the offending drug by another in the same therapeutic category. If the drug-induced disturbances are severe enough to impair the quality of life and the drug is not required for a serious or life-threatening condition, it may be discontinued. Treatment with zinc may correct hyposmia and hypogeusia associated with drug effect. Polaprezinc, a zinc-containing formulation, is commonly used to protect against taste alteration during the course of cancer chemotherapy. In a double-blinded, placebo-controlled randomized clinic trial on patients with chemotherapy-induced alterations in taste or smell, zinc was not found to be effective (17). In a retrospective study of patients treated with polaprezinc for taste alteration due to cancer chemotherapy, there was improvement in 70% of the patients, no change in 25%, and the taste worsened in 5% (18). Multiple regression analysis of the data from this study indicates that in patients who receive high doses of anticancer agents relative to their body surface area and are likely to develop iron deficiency anemia, early administration of zinc-containing formulations may prevent taste alteration.

Treatment with drugs that stimulate cAMP synthesis (theophylline, fluoride, and magnesium) has been used in some cases with good results. An understanding of the complex and multifactorial etiology of taste dysfunction should enable the clinician to institute measures to minimize the impact of smell and taste disturbances in cancer patients on chemotherapy. For example, patients receiving platinum-containing chemotherapy for ovarian cancer may suffer mild olfactory and gustatory impairment, which usually resolves 3 months after completion of therapy. Patients should be informed of this side effect, and symptomatic relief can be provided by additional flavoring of food and a small amount of glutamate (25). Although the underlying mechanisms of chemotherapy-induced smell and taste disturbances have not been elucidated, they are associated with high concentration of salivary Fe and loss of critical salivary immune proteins. Supplementation with lactoferrin, a globular glycoprotein, decreases the concentration of salivary Fe and produces an overall increase of expression of immune proteins while it ameliorates the adverse effects on taste and smell (31). Other treatment options to ameliorate smell and taste disturbances include addition of simulated flavors to food to compensate for losses and to override offending tastes and smells (24).

Outcomes

Early treatment by withdrawing the offending drug provides good chances for recovery of smell and taste. Late cases with damage to the olfactory nerve may not recover.

Special considerations

Pregnancy

Pregnancy has not been reported to affect drug-induced smell or taste disturbances.

Anesthesia

Smell and taste disturbances may result from injury to nerves during infiltration with local anesthetics used during procedures on the teeth or the nose. These may occur as effects of general anesthetics as well.

Future prospects. Drug-induced disorders of smell and taste are usually not considered serious but impair the quality of life. There should be increased awareness of these adverse effects, not only among neurologists, but toxicologists as well. Studies should be conducted to identify drug-induced gustatory system toxicity early in the drug development process, and to stimulate further research at the interface of chemosensory disorders with toxicology (32).