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ADVERSE DRUG REACTIONS IN THE OROFACIAL REGION

Eastman Dental Institute for Oral Health Care Sciences, University College, University of London, 256 Gray’s Inn Road, London WC1X 8LD, UK;

J.-V. Bagan

Valencia University and Hospital, General Universitario de Valencia, Avenida 3 Cruces, 46014 Valencia, Spain

^* corresponding author, scully.c{at}eastman.ucl.ac.uk

Abstract

Introduction

Drug-related Disorders of the Salivary Glands

(1) DRUG-RELATED XEROSTOMIA

(a) Antidepressants

(b) Antipsychotics

(c) Antihistamines

(d) Muscarinic receptor antagonists used to treat overactive bladder

(e) Alpha receptor antagonists used to treat overactive bladder

(f) Diuretics

(g) Antihypertensives

(h) Appetite suppressants

(i) Decongestants and ''cold cures''

(j) Bronchodilators

(k) Skeletal muscle relaxants

(l) Antimigraine drugs

(m) Opioids, benzodiazepines, hypnotics, and drugs of abuse

(n) H2 receptor antagonists and proton-pump inhibitors

(o) Cytotoxic drugs

(p) Retinoids

(q) Anti-HIV drugs

(r) Cytokines

(2) DRUG-RELATED SALIVARY GLAND SWELLING

(3) DRUG-RELATED SALIVARY GLAND PAIN

(4) DRUG-RELATED HYPERSALIVATION

(5) DISCOLORATION OF SALIVA

Drug-related Disorders of Taste

Drug-related Mucosal Disorders

(1) ORAL ULCERATION

(a) Drug-related oral burns

(b) Drug-related aphthous-like ulceration

(c) Fixed drug eruptions

(d) Drug-related mucositis

(e) Drug-related neoplasms and potentially malignant lesions

(f) Drug-related pemphigoid-like reactions and other bullous disorders

(g) Drug-related pemphigus

(h) Drug-related erythema multiforme

(i) Drug-related toxic epidermal necrolysis

(j) Drug-related lupus-like disorders

(2) DRUG-RELATED WHITE LESIONS

(a) Burns (see above) (b) Lichenoid eruptions

(c) Lupoid reactions (see above) (d) Candidosis

(e) Papillomas

(f) Hairy leukoplakia

(g) Leukoplakia

Drug-related Mucosal Pigmentation

(1) DRUG-RELATED SUPERFICIAL TRANSIENT DISCOLORATION

(2) DRUG-RELATED INTRINSIC PIGMENTATION

Drug-related Swellings

(1) DRUG-RELATED GINGIVAL ENLARGEMENT

(2) DRUG-RELATED LIP AND MUCOSAL SWELLING

Drug-related Cheilitis

Drug-related Neuropathies

(1) DRUG-RELATED TRIGEMINAL NEUROPATHIES

(2) DRUG-RELATED INVOLUNTARY FACIAL MOVEMENTS

(3) DRUG-RELATED OROFACIAL PAIN AND ORAL DYSESTHESIA

Drug-related Oral Malodor (Halitosis)

Drug-related Tooth Discoloration

Summary

REFERENCES

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Key words. Oral, drugs, adverse reactions, salivary, mucosa, ulcers, taste

Introduction

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A wide spectrum of drugs can sometimes give rise to numerous adverse oral manifestations, particularly dry mouth, taste disturbances, oral mucosal ulceration, and/or swelling. A review of the 200 most frequently prescribed drugs (in the USA in 1992) showed the most frequent oral adverse drug reactions (ADRs) to be dry mouth (80.5%), dysgeusia (47.5%), and stomatitis (33.9%) (Smith and Burtner, 1994). However, few randomized double-blind controlled studies have been conducted, and therefore most of the evidence available at the present time is of low level, originating only from case reports, small series, or non-peer-reviewed reports of adverse drug reactions.

This paper reviews the literature based on a MEDLINE search to April, 2003, and highlights the more common and significant adverse oral consequences of drug therapy. When relevant, it provides sources of other suitable reports: It does not include details on the oral side-effects of foodstuffs, tobacco, alcohol, or recreational drugs, or the adverse effects of drugs upon the dentition.

Drug-related Disorders of the Salivary Glands

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    (1) DRUG-RELATED XEROSTOMIA
Dry mouth has a variety of possible causes (Scully, 2003) (Table 1). Common habits such as tobacco smoking, alcohol use (including in mouthwashes), and the consumption of beverages containing caffeine (coffee, some soft drinks) can cause some oral dryness. Drugs are the most common cause of reduced salivation (Table 1, Fig. 1) (Scully, 2003). The drugs most commonly implicated include: alpha receptor antagonists for treatment of urinary retention; amphetamines; anticholinergics; antidepressants (serotonin agonists, or noradrenaline and/or serotonin re-uptake blockers); antihistamines; antihypertensive agents; antimigraine agents; antipsychotics such as phenothiazines; appetite suppressants; atropinics; benzodiazepines, hypnotics, opioids, and drugs of abuse; bronchodilators; cytokines; cytotoxics; decongestants and ‘cold cures’; diuretics; histamine H2 antagonists and proton pump inhibitors; muscarinic receptor antagonists for the treatment of overactive bladder; opiates; protease inhibitors; radioiodine; retinoids; and skeletal muscle relaxants (Scully, 2003).

View larger version (87K): [in this window] [in a new window]   Figure 1. Drug-induced xerostomia.

Dry mouth is a common complaint in patients treated for hypertensive, psychiatric, or urinary problems (Streckfus, 1995) and in the elderly (Vissink et al., 1992; Loesche et al., 1995), mainly as a consequence of the large number of drugs used (Fox, 1998; Närhi et al., 1999) and polypharmacy (Loesche et al., 1995; Nederfors, 1996; Fox, 1998). For example, 63% of hospitalized patients and 57% of outpatients complained of dry mouth, and in all patients, the use of psychiatric drugs was the main cause (Pajukoski et al., 2001).

Age and medication seem to play a more important role in individuals with objective evidence of hyposalivation, while female gender and psychological factors are important in individuals with subjective oral dryness (Bergdahl and Bergdahl, 2000).

Hypnotics are also commonly used by the elderly, and most users report ADRs, mainly dry mouth (30%) (Wishart et al., 1981; Busto et al., 2001). In the elderly using non-prescription products—most frequently, dimenhydrinate (21%), acetaminophen (paracetamol) (19%), diphenhydramine (15%), alcohol (13%), and herbal products (11%)—mild ADRs were reported by 75%, the most common complaint being dry mouth (Sproule et al., 1999).

In a large survey of 3311 evaluatable questionnaires, 21.3% of men and 27.3% of women reported dry mouth, with women statistically reporting higher prevalence of dry mouth than men (Nederfors, 1996). Dry mouth was significantly age-related, and there was a strong co-morbidity between reported prevalence of dry mouth and ongoing pharmacotherapy. Unstimulated salivary flow rates were lower among older persons who were female or taking antidepressants, and higher among smokers or people who were taking hypolipidemic drugs (Thomson et al., 2000). It is clear that medication is a better predictor of risk status for dry mouth than either age or gender (Field et al., 2001).

Even in elderly patients with advanced cancer, dry mouth was the fourth most common symptom (78% of patients), but the usual cause was drug treatment, and there was an association with the number of drugs prescribed (Davies et al., 2001). That is not to say that disease can always be excluded as a cause of dry mouth; for example, saliva secretion is more affected by xerogenic drugs and autonomic nervous dysfunction in patients with non-insulin-dependent diabetes than in non-diabetic controls (Meurman et al., 1998).

Furthermore, the cause for which the drug is being taken may also be important. For example, patients with anxiety or depressive conditions may complain of dry mouth even in the absence of drug therapy or evidence of reduced salivary flow. It is thus important to recognize that some patients complaining of a drug-related dry mouth have no evidence of a reduced salivary flow or a salivary disorder, and there may then be a psychogenic reason for the complaint.

Several different mechanisms account for drug-related dry mouth, but an anticholinergic action underlies many: The M3-muscarinic receptors (M3R) mediate parasympathetic cholinergic neurotransmission to salivary (and lacrimal) glands, but other receptors may also be involved (Kawaguchi and Yamagishi, 1995).

    (a) Antidepressants
Early antidepressant medications such as tricyclic antidepressants (TCAs) unfortunately also blocked histaminic, cholinergic, and alpha1-adrenergic receptor sites, causing ADRs such as dry mouth. Men and women may differ in their pharmacokinetic responses to TCAs, in several autonomic indices, and in various adrenergic receptor-mediated responses. Emerging evidence also suggests that women, relative to men, may have a lower rate of brain serotonin synthesis and a greater sensitivity to the depressant effects of tryptophan depletion (Pomara et al., 2001). Finally, the ultrarapid metabolizer phenotype of the enzyme cytochrome P4502D6 (Laine et al., 2001) may be a cause of non-responsiveness to antidepressant drug therapy, and the subsequent prescribing of high doses of antidepressants to such patients leads to an increased risk for ADRs; however, normalization of the metabolic status of ultrarapid metabolizers by the inhibition of cytochrome activity, such as with paroxetine, could offer a solution (Laine et al., 2001).

Newer antidepressants are essentially serotonin (5-hydroxytryptamine: 5HT) agonists, or block re-uptake of noradrenaline (norepinephrine) and/or serotonin. Members of the newer generation of antidepressants—including the selective serotonin re-uptake inhibitors (SSRIs) and multiple-receptor antidepressants (such as venlafaxine, mirtazapine, bupropion, trazodone, and nefazodone)—target one or more specific brain receptor sites without, in most cases, activating unwanted sites such as histamine and acetylcholine (Feighner, 1999; Feighner and Overo, 1999). The SSRI produce no significant changes in salivation (Hunter and Wilson, 1995), but dry mouth may still be seen (e.g., fluoxetine) (Ellingrod and Perry, 1994; Shrivastava et al., 1994; Hunter and Wilson, 1995; Davis and Faulds, 1996; Boyd et al., 1997; Ravindran et al., 1997; Trindade et al., 1998). However, some SSRIs, such as paroxetine, appear to result in less dry mouth than seen with TCAs (Ravindran et al., 1997). Citalopram, the most selective SSRI, is well-tolerated (Feighner and Overo, 1999). Venlafaxine, a mixed-re-uptake inhibitor, may produce dry mouth (Gelenberg et al., 2000). The incidence of ADRs in recipients of venlafaxine XR is similar to that in patients receiving treatment with well-established SSRIs (Wellington and Perry, 2001). Duloxetine hydrochloride, a dual-re-uptake inhibitor of serotonin and norepinephrine, also can produce dry mouth (Detke et al., 2002), as can mianserin, a mainly post-synaptic serotonin 2A agonist (Dolberg et al., 2002). Nefazodone, which has moderate serotonin selective re-uptake blocking properties and direct 5-HT2 antagonism, can produce dry mouth in 19% vs. 13% in placebo (Lader, 1996). Reboxetine, a selective norepinephrine re-uptake inhibitor (selective NRI), causes less dry mouth than TCAs, though it produces dry mouth more frequently than placebo (36% vs. 16%) (Schatzberg, 2000; Versiani et al., 2002). Mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA), can also induce dry mouth (Anttila and Leinonen, 2001).

Bupropion hydrochloride, originally developed as an antidepressant, is a selective re-uptake inhibitor of dopamine and norepinephrine which was found to reduce nicotine withdrawal symptoms and the urge to smoke, but commonly produces dry mouth (Zwar and Richmond, 2002). Dry mouth is positively associated with mean bupropion metabolite concentrations, and is inversely related to patient weight (Johnston et al., 2001).

    (b) Antipsychotics
Long-term drug treatment of schizophrenia with conventional phenothiazine antipsychotics such as fluphenazine is commonly associated with dry mouth (Adams and Eisenbruch, 2000).

However, newly developed antipsychotic drugs with more potent and selective antagonistic activity against the dopamine D(2) receptor may not necessarily be associated with a lower incidence of dry mouth. Olanzapine is an atypical antipsychotic which appears to produce dry mouth (Duggan et al., 2000). Significant correlations have been found in in vitro affinities of antipsychotics toward dopamine or other neuronal receptor systems and ADRs: for example, between the K(i) values for dopamine D(1) receptor, alpha (1)-adrenoceptor and histamine H(1) receptor), and the incidence of dry mouth (Sekine et al., 1999). Other atypical antipsychotics—including tiapride (Roger et al., 1998), lithium (Christodoulou et al., 1977; Chacko et al., 1987; Friedlander and Birch, 1990; Tohen et al., 2002), pipamperone dihydrochloride (Potgieter et al., 2002), quetiapine and risperidone (Srisurapanont et al., 2000; Mullen et al., 2001)—may produce dry mouth.

    (c) Antihistamines
The therapeutic effects of most of the older antihistamines were associated with sedating effects on the central nervous system (CNS) and antimuscarinic effects including dry mouth (Gwaltney et al., 1996). Non-sedating antihistamines—most of which are histamine H1 receptor antagonists, such as acrivastine, astemizole, cetirizine, ebastine, fexofenadine, loratadine, mizolastine, and terfenadine, however—are not entirely free from ADRs, though there may be less dry mouth (Mattila and Paakkari, 1999).

    (d) Muscarinic receptor antagonists used to treat overactive bladder
Overactive bladder (OAB)—a chronic, distressing condition characterized by symptoms of urgency (sudden overwhelming urge to urinate) and frequency (urinating more than eight times daily), with or without urge urinary incontinence (sudden involuntary loss of urine)—is treated with muscarinic receptor antagonists, which can lead to troublesome dry mouth.

Dry mouth is a common side-effect seen with immediate-release oxybutynin (Hay-Smith et al., 2002), but a significantly lower proportion of patients taking controlled-release oxybutynin have moderate to severe dry mouth or any dry mouth compared with those taking immediate-release oxybutynin (Versi et al., 2000). Tolterodine, a competitive muscarinic receptor antagonist, produces dry mouth (Jacquetin and Wyndaele, 2001; Layton et al., 2001), though few patients (< 2%) experience severe dry mouth (Zinner et al., 2002), and there is a 23% lower incidence of dry mouth reported with once-daily extended-release tolterodine capsules than with twice-daily immediate-release tablets (Clemett and Jarvis, 2001). Propiverine hydrochloride, a safe and effective antimuscarinic drug as effective as oxybutynin, has a lower severity and incidence of dry mouth (Noguchi et al., 1998; Madersbacher et al., 1999).

    (e) Alpha receptor antagonists used to treat overactive bladder
Tamsulosin, a selective alpha 1A-adrenoreceptor antagonist, produces significantly less dry mouth than terazosin, a less selective alpha antagonist (Lee and Lee, 1997).

    (f) Diuretics
Diuretic agents and psychotropics were the most commonly used xerostomic medications in one study of elderly patients, and were almost equally potent in reducing mean salivary flow rate (Persson et al., 1991). Thiazides may cause dry mouth (McCarron, 1984), but there appear to be few reports showing a relationship between diuretic use and dry mouth. Subjectively, xerostomia was experienced 10 times more frequently after ingestion of furosemide than placebo (Atkinson et al., 1989).

    (g) Antihypertensives
The ganglion blockers and particularly the beta-blockers (beta-adrenoceptor antagonists) may cause dry mouth (Nederfors, 1996) thought to be associated with activation of CNS and salivary gland alpha 2-adrenergic receptors. Such antihypertensive drugs, or sympatholytics (reserpine, methyldopa, and clonidine), are now little used because of such prominent ADRs as dry mouth.

Newer centrally acting antihypertensives, with selective agonist effects on the imidazoline I1 brainstem-receptors in the rostral ventromedulla (RVLM), appear to modulate sympathetic activity and blood pressure without affecting salivary flow: Moxonidine and rilmenidine are examples of this new class.

Moxonidine can produce dry mouth, more frequently than placebo (Dickstein et al., 2000) but only in a minority (< 10%), and significantly less than with the older antihypertensives (Schachter, 1999). Rilmenidine produces little dry mouth (Reid, 2001).

ACE inhibitors, which block the ACE enzyme in the renin-angiotensin-aldosterone system, produce dry mouth in about 13% of patients (Mangrella et al., 1998).

    (h) Appetite suppressants
Several appetite suppressants can cause dry mouth, including sibutramine (Richter, 1999; Bray, 2001), fenfluramine plus phentermine (Weintraub et al., 1992), and the herbal Ma Huang and Kola nut supplement (containing ephedrine alkaloids/caffeine) produce dry mouth (Boozer et al., 2002).

    (i) Decongestants and "cold cures"
Decongestants such as pseudoephedrine (Wellington and Jarvis, 2001) and loratadine plus pseudoephedrine sulphate can result in dry mouth (Kaiser et al., 1998).

    (j) Bronchodilators
Anti-asthma drugs can be associated with dry mouth (Thomson et al., 2002). The most common reported ADR after use of the bronchodilator tiotropium is dry mouth (Casaburi et al., 2000).

    (k) Skeletal muscle relaxants
Tizanidine, an alpha 2-adrenoceptor agonist used for the relief of spasticity, can be associated with significant dry mouth (Taricco et al., 2000).

    (l) Antimigraine drugs
Rizatriptan, a serotonin agonist used for the treatment of migraine, can induce dry mouth (Winner et al., 2002).

    (m) Opioids, benzodiazepines, hypnotics, and drugs of abuse
Opioids are well-recognized causes of dry mouth (Bruera et al., 1999), and atropine, hyoscine, and atropinics have long been used to reduce secretions pre-operatively. Dry mouth is the only significant side-effect of transdermal scopolamine (hyoscine) (Gordon et al., 2001). Morphine (Bruera et al., 1999; Zacny, 2001), dihydrocodeine (Freye et al., 2001), and Tramadol (Scott and Perry, 2000) can produce dry mouth.

Benzodiazepines (such as diazepam) (Conti and Pinder, 1979; Elie and Lamontagne, 1984) and zopiclone, a cyclopyrrolone chemically unrelated to benzodiazepines (Wadworth and McTavish, 1993), can produce dry mouth.

Cannabis (Consroe et al., 1986; Grotenhermen, 1999) and Ecstasy (‘XTC’ or ‘E’: 3,4 methylenedioxy-methamphetamine; MDMA) (Peroutka et al., 1988; Milosevic et al., 1999) can produce dry mouth.

    (n) H2 receptor antagonists and proton-pump inhibitors
H2-receptor antagonists produce dry mouth in 41% of recipients (Teare et al., 1995; Kaviani et al., 2001).

    (o) Cytotoxic drugs
Dry mouth can be a consequence of exposure to agents used for chemotherapy of malignant neoplasms, such as retinol (Goodman et al., 1983), or 5-fluorouracil (McCarthy et al., 1998), but this is not invariable (Laine et al., 1992), and there is a paucity of data in this area.

    (p) Retinoids
Systemic retinoids such as etretinate (Wishart et al., 1981), 13 cis-retinoic acid (Hennes et al., 1984), and isotretinoin (Oikarinen et al., 1995) can produce dry mouth.

    (q) Anti-HIV drugs
Didanosine (Dodd et al., 1992; Valentine et al., 1992) and HIV protease inhibitors (Greenwood et al., 1998) can cause dry mouth.

    (r) Cytokines
Alpha interferon therapy for the treatment of chronic hepatitis C infection (Cotler et al., 2000) can cause significant dry mouth. Interleukin-2 (rIL-2), when used, for example, for control of nasopharyngeal carcinoma, can also impair salivation (Chi et al., 2001), and major salivary gland dysfunction has been described in patients with hematological malignancies given interleukin-2-based immunotherapy after autologous stem cell transplantation (Nagler, 1998).

    (2) DRUG-RELATED SALIVARY GLAND SWELLING
Some drugs have been related to salivary gland swelling (Table 2). Painless, usually bilateral, salivary gland enlargement (resembling sialosis) may be an occasional side-effect of phenylbutazone (Cohen and Banks, 1966; Murray-Bruce, 1966; Chimenes, 1971; Herman et al., 1974; Kaufman et al., 1977), oxyphenbutazone (Bosch et al., 1985), or chlorhexidine (Rushton, 1977). The bilateral sialadenitis observed in one adult following naproxen therapy (Knulst et al., 1995) was thought to be allergic in origin, since the affected patient also had a cutaneous rash. A similar mechanism has been proposed to underlie the salivary gland enlargement caused by intravenous radiological contrast media (Gattoni et al., 1991; Ilia et al., 1991). Clozapine, a novel antipsychotic agent, may cause transient salivary gland swelling (Vasile and Steingard, 1995) as well as sialorrhea (see below).

    (4) DRUG-RELATED HYPERSALIVATION
Anticholinesterases are the main cause of hypersalivation (Table 3). Clozapine, an atypical antipsychotic drug claimed to have superior efficacy and to cause fewer motor adverse effects than typical antipsychotics for people with treatment-resistant schizophrenic patients, can cause hypersalivation (Wahlbeck et al., 2000). This may be ameliorated with atropine eye drops (Comley et al., 2000).

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ACE inhibitors, anti-thyroids, beta-lactam antibiotics, biguanides, chlorhexidine, opiates, and protease inhibitors are particularly implicated. Up to 4% of patients treated with ACE inhibitors may have dysgeusia, although this adverse effect is self-limiting and reversible within a few months, even with continued therapy (Henkin, 1994). Newer therapies—such as the anti-HIV protease inhibitors (Scully and Diz, 2001), therapy with tripotassium dicitrato bismuthate chelate, clarithromycin, and lansoprazole therapy for H. pylori infection (Scott, 1998), terbinafine (Stricker et al., 1996), intravenous pentamidine (Glover et al., 1995), and isotretinoin (Halpern et al., 1996)—may cause some degree of loss of taste or altered taste.

There is preliminary evidence that alpha lipoic acid might improve dysgeusia, at least in idiopathic cases (Femiano et al., 2002), but the condition is best improved by reducing use of the offending drug.

Drug-related Mucosal Disorders

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    (1) ORAL ULCERATION
A wide range of etiologies, from burns to vesiculobullous disorders of various kinds, can result in oral ulceration. Many reports of mouth ulceration following drug use have been from non-specialists, and therefore their description as ‘aphthous’-like or other fairly specific entities can often be questioned, leading to some difficulty in accurately ascribing cause and effect.

    (a) Drug-related oral burns
Oral desquamation or ulceration may follow burns from the accidental ingestion of caustics such as lime (Schier et al., 2002), from the local application of aspirin or toothache preparations, potassium tablets, pancreatic supplements, and other agents such as trichloracetic acid or hydrogen peroxide or from the use of various oral health care products (Kuttan et al., 2001). Sodium lauryl sulfate, present in some oral health care products, particularly dentifrices, may cause mucosal irritation or ulceration (Herlofson and Barkvoll, 1994; Scully et al., 1999; Kuttan et al., 2001). Application of cocaine may produce similar lesions (Parry et al., 1996).

    (b) Drug-related aphthous-like ulceration
Sodium lauryl sulfate may predispose to ulcers similar to aphthous ulceration (Herlofson and Barkvoll, 1994). There are also case reports of aphthous-like ulceration arising following the use of beta-blockers such as labetalol (Pradalier et al., 1982), alendronate (Gonzalez-Moles and Bagan-Sebastian, 2000), captopril (Seedat, 1979; Nicholls et al., 1981; Corone et al., 1987; Montoner et al., 1990), nicorandil (Boulinguez et al., 1997; Reichart, 1997; Agbo-Godeau et al., 1998; Cribier et al., 1998; Desruelles et al., 1998; Roussel et al., 1998; Marquart-Elbaz et al., 1999; Shotts et al., 1999), some non-steroidal anti-inflammatory drugs (NSAIDs) (Siegel and Balciunas, 1991; Healy and Thornhill, 1995), mycophenolate or sirolimus (van Gelder et al., 2003), protease inhibitors (Scully and Diz, 2001), tacrolimus (Hernandez et al., 2001), and sulfonamides, though the exact pathogenic mechanisms are unclear in all of these.

A case-control study has now confirmed the associations of oral ulceration with NSAIDs and beta-blockers (Boulinguez et al., 2000) (Fig. 2).

View larger version (106K): [in this window] [in a new window]   Figure 2. NSAID-induced ulceration.

    (d) Drug-related mucositis
Cytotoxic drugs are very commonly associated with mucositis and ulceration, which arises consistently with many chemotherapy regimens (Table 6), particularly those involving methotrexate, 5-fluorouracil, doxorubicine, melphelan, mercaptopurine, or bleomycin (Femiano et al., 2003). Such reactions can be so severe as to be treatment-limiting on occasion (Bell et al., 2001). Widespread sloughing and ulceration arise within days of commencement of therapy, the associated pain often requiring opioid therapy and/or alteration or cessation of chemotherapy. The ulceration may be a portal of entry for infection and hence a potential cause of septicemia. Drugs such as phenylbutazone that can cause agranulocytosis may also induce oral ulceration (Fig. 3).

View larger version (107K): [in this window] [in a new window]   Figure 3. Phenylbutazone-induced ulceration.

    (e) Drug-related neoplasms and potentially malignant lesions
There is an increased prevalence of dysplastic and malignant lip lesions in immunosuppressed renal-transplant recipients (King et al., 1995) and liver transplant recipients (Haagsma et al., 2001). Oral leukoplakia has progressed rapidly to squamous cell carcinoma in some immunosuppressed patients (Hernandez et al., 2003), and oral squamous cell carcinoma has been reported in immunosuppressed patients without any recorded precursor lesion (Varga and Tyldesley, 1991).

Post-transplant lymphoproliferative disease (Raut et al., 2000), non-Hodgkin’s or MALT lymphoma (Hsi et al., 2000), usually manifesting as ulceration of the gingivae, fauces, or palate (Bilinska-Pietraszek et al., 2001; Mandel et al., 2001), or, rarely, Kaposi’s sarcoma (Meyers et al., 1976; Qunibi et al., 1988) may be complications of long-term immunosuppressive therapy, and there have even been reports of the resolution of malignancies where immunosuppression has been reduced (Keogh et al., 2002).

    (f) Drug-related pemphigoid-like reactions and other bullous disorders
At least 30 drugs can give rise to conditions resembling bullous or mucous membrane pemphigoid (Vassileva, 1998) (Table 7). These drugs belong to a variety of pharmacological (thiol and non-thiol) and therapeutically targeted groups, including ACE inhibitors, furosemide, NSAIDs, penicillamine, psoralens, sulphonamides, cardioactive agents, and penicillin-related antibiotics. The oral mucosa is frequently affected in drug-induced pemphigoid, particularly penicillamine-induced disease, and can be the only affected mucosal surface, although patients often also have cutaneous lesions (Troy et al., 1981; Shuttleworth et al., 1985; Velthuis et al., 1985; Gall et al., 1986; Rasmussen et al., 1989). Other than the high frequency of oral mucosal lesions, the only other clinically distinguishing features of drug-induced pemphigoid are the younger age of affected patients compared with idiopathic (autoimmune) pemphigoid, and the resolution of disease following withdrawal of the causative agent.

Linear IgA disease (LAD) can be drug-induced, and affected patients have IgA antibodies to bullous-pemphigoid-associated antigen 1 (BPAG or BP1) or other antigens (Palmer et al., 2001). LAD is especially commonly induced by vancomycin (Kuechle et al., 1994), but other drugs such as angiotensin-converting enzyme inhibitors may be involved (Femiano et al., 2003).

    (g) Drug-related pemphigus
Drug-induced pemphigus is not uncommon (Brenner et al., 1997). Traditionally, drugs that are capable of inducing pemphigus are divided into two main groups according to their chemical structure—drugs containing a sulfhydryl radical (thiol drugs or SH drugs) and non-thiol or other drugs, the latter often sharing an active amide group in their molecules (Wolf and Brenner, 1994).

Pemphigus vulgaris may occasionally be associated with drugs with active thiol groups in the molecule (Scully and Challacombe, 2002). Drugs implicated include penicillamine (Wolf et al., 1991; Laskaris and Satriano, 1993; Shapiro et al., 2000), phenol drugs (Goldberg et al., 1999), rifampicin (Gange et al., 1976), diclofenac (Matz et al., 1997), and, rarely, captopril (Korman et al., 1991), other ACE-inhibitors (Kaplan et al., 1992; Ong et al., 2000), and other drugs (Table 8).

The role of diet in the etiology of pemphigus is reviewed elsewhere (Brenner et al., 1998; Tur and Brenner, 1998), but garlic in particular may cause occasional cases of pemphigus (Laskaris and Nicolis, 1980; Korman et al., 1991; Ruocco et al., 1996).

    (h) Drug-related erythema multiforme
A wide range of drugs—especially barbiturates, cephalosporins, NSAIDs, estrogens, phenothiazines, progestogens, protease inhibitors, sulphonamides, sulphonylurea derivatives, and tetracyclines—may give rise to erythema multiforme (Table 9), and it may be clinically impossible to distinguish drug-induced erythema multiforme from disease due to other causes (Roujeau, 1997; Ayangco and Rogers, 2003). The distinction of severe erythema multiforme from toxic epidermal necrolysis is quite unclear.

    (i) Drug-related toxic epidermal necrolysis
Toxic epidermal necrolysis (TEN; Lyell syndrome) is clinically characterized by extensive mucocutaneous epidermolysis preceded by a macular or maculopapular exanthema and enanthema (Lyell, 1979; Rasmussen et al., 1989). Intra-orally, there is widespread painful blistering and ulceration of all mucosal surfaces. Toxic epidermolysis may be associated with antimicrobials (sulphonamides, thiacetazone), analgesics (phenazones). anti-epileptics, allopurinol, chlormezanone, rifampicin, fluconazole, and vancomycin (Ayangco and Rogers, 2003).

    (j) Drug-related lupus-like disorders
Systemic lupus erythematosus (SLE) may be induced by a wide variety of different drugs. Indeed, over 70 agents have been implicated in causing drug-induced lupus (Rich, 1996) (Table 10). The most commonly implicated agents of drug-induced SLE are procainamide and hydralazine, although drugs less commonly associated include chlorpromazine, isoniazid, methyldopa, penicillamine, and quinine, as well as whole groups of drugs such as anticonvulsants, beta-blockers, sulphonamides, and others (Price and Venables, 1995).

    (2) DRUG-RELATED WHITE LESIONS
    (a) Burns (see above)
(b) Lichenoid eruptions
Since the advent of antimalarial therapy, there have been an ever-increasing list and spectrum of drugs that may give rise to mucocutaneous lichen planus (LP)-like eruptions (lichenoid reactions) (McCartan and McCreary, 1997; Scully et al., 1998). However, many of the reports claiming associations have been single case reports, and many of the drugs implicated in cutaneous lichenoid reactions have not been shown to be associated with oral lesions.

The possible association of drugs with lichenoid reactions was noted when quinacrine and mepacrine, used as antimalarials during World War II, were seen to cause lichenoid lesions. Apart from these drugs, gold was probably the most common agent recognized as initiating a lichenoid reaction (Penneys et al., 1974). Gold salts can cause a range of mucocutaneous lesions (Hakala et al., 1986) of which oral lichenoid lesions may be the first (Brown et al., 1993; Laeijendecker and van Joost, 1994).

The drugs now most commonly implicated in lichenoid reactions are the non-steroidal anti-inflammatory drugs and the angiotensin-converting enzyme inhibitors (Potts et al., 1987; Firth and Reade, 1989; Robertson and Wray, 1992; Van Dis and Parks, 1995). Lichenoid reactions also may follow the use of HIV protease inhibitors (Scully and Diz, 2001), antihypertensive agents, antimalarials, phenothiazines, sulphonamides, tetracyclines, thiazide diuretics, and many others (Table 11) (Dinsdale and Walker, 1966; Roberts and Marks, 1981; Chau et al., 1984; Hogan et al., 1985; Colvard et al., 1986; Markitziu et al., 1986;Torrelo et al., 1990), but the list of drugs implicated lengthens almost weekly and, interestingly, includes several agents which have also been used in the therapy of lichen planus, particularly dapsone (Downham, 1978), levamisole (Kirby et al., 1980), tetracycline (Mahboob and Haroon, 1998), and interferon (see below). Occasionally, there are lichenoid reactions to multiple drugs (Wiesenfeld et al., 1982).

The exact pathogenic mechanism by which drugs may cause LP-like disease are not known. Some of the agents implicated (e.g., penicillamine, captopril, and gold sodium thionalate) are thiol-like and hence implicated in pemphigus-like disease (see below). However, in LP, quite different immunological mechanisms are involved. It is likely that Grinspan’s syndrome simply represents a drug-induced disorder (Lamey et al., 1990), and drug therapy may occasionally account for the co-occurrence of LP with lupus erythematosus or bullous-like disease (Flageul et al., 1986). Clinical identification of lichenoid drug reactions has been based largely on subjective criteria: There does seem to be sometimes a tendency for these oral lesions to be unilateral (Lamey et al., 1995a) and erosive (Potts et al., 1987), but these features are by no means invariable. Histology may help; lichenoid lesions may have a more diffuse lymphocytic infiltrate and contain eosinophils and plasma cells, and there may be more colloid bodies than in classic LP, but there are no specific features (Van der Haute et al., 1989), and immunostaining is usually non-contributory, though basal cell cytoplasmic antibodies may be found (Lamey et al., 1995b), but this has not been confirmed (Ingafou et al., 1997) and surely occurs less reliably than in cutaneous drug reactions (van Joost, 1974; McQueen and Behan, 1982; Gibson et al., 1986).

The most reliable means to diagnose lichenoid reactions is if the reaction remits with drug withdrawal and returns on rechallenge, but frequently this is not possible because of the need to ensure patient safety.

Dental restorative materials may also be associated with lichenoid lesions. Most patients with OLP have no evidence of any association with dental restorative materials (Hietanen et al., 1987). However, contact with or proximity to restorations involving amalgams or other materials causes some lichenoid reactions—that is, lesions that clinically and histologically resemble LP closely, but have an identifiable etiology (Lind et al., 1986; Bolewska et al., 1990). These reactions are presumably due to allergic or toxic reactions to compounds released or generated, the Koebner phenomenon, or possibly due to plaque accumulated on the surfaces of the restorations (Holmstrup, 1991).

Some of these oral lesions may improve after substitution of the amalgam by other materials (Finne et al., 1982; Jolly et al., 1986; Lind et al., 1986; Bolewska et al., 1990; Jameson et al., 1990; Skoglund and Egelrud, 1991; Laine et al., 1992; Bircher et al., 1993; Ostman et al., 1994; Henriksson et al., 1995; Smart et al., 1995; Bratel et al., 1996; Ibbotson et al., 1996), though this is often not the case with gingival lesions (Henriksson et al., 1995).

Significant reactions to mercuric salts on skin-testing may be seen in some patients with OLP (Finne et al., 1982; Eversole and Ringer, 1984; Mobacken et al., 1984; James et al., 1987; Ostman et al., 1994), though others have not found this (Hietanen et al., 1987). Finne et al.(1982) demonstrated mercury sensitivity by patch-testing in 62% of 29 patients with OLP and only 3.2% of a control group, and in a few patients their oral lesions regressed on removal of the amalgams (Finne et al., 1982). Reactions to mercuric chloride have been reported (Skoglund and Egelrud, 1991; Smart et al., 1995). These findings have been supported, and recently in studies by Skoglund and co-workers (Ostman et al., 1994), a patch-test positivity against mercury was found in 39.6% of 48 patients. Of those who had a positive patch test to mercury, 94.7% showed regression of lesions after removal of amalgams, but even 82.6% of those who showed no reaction to mercury on patch-testing also showed regression after removal of amalgams. Epicutaneous patch tests are of little prognostic value (Ostman et al., 1994; Ibbotson et al., 1996). Oral mucosal lesions of lichenoid character might not be associated with allergy to mercury, but with mechanical or galvanic insults; their interpretation calls for intra-oral patch-testing (Axéll et al., 1986).

There may also be occasional reactions to gold restorations (Conklin and Blasberg, 1987), although this has not been substantiated. There is also a report of OLP in relation to cobalt in a restoration (Torresani et al., 1994).

Composite restorations have also been implicated in oral lichenoid reactions (Lind and Hurlen, 1988), and so the wholesale replacement of amalgams as a possible treatment is not necessarily warranted.

    (c) Lupoid reactions (see above)
(d) Candidosis
Pseudomembranous candidosis arises secondary to therapy with broad-spectrum antibiotics (Scully et al., 1994), corticosteroids (both systemic and inhaler preparations), and other immunosuppressive regimens (e.g., ciclosporin) and cytotoxic therapies (Table 12). More rarely, mucormycosis and aspergillosis may cause thrush-like areas or other lesions in patients on long-term immunosuppressive therapies (Dreizen et al., 1992; Scully, 1992; Seymour et al., 1997).

    (f) Hairy leukoplakia
Oral hairy leukoplakia, usually affecting the dorsum and lateral borders of the tongue and floor of mouth, may be a consequence of Epstein-Barr virus infection, associated with therapy with corticosteroids (topical and systemic), ciclosporin, or other long-term immunosuppressive regimens (Triantos et al., 1997).

    (g) Leukoplakia
Tobacco and alcohol use are important risk factors for leukoplakia (Pindborg et al., 1980; Sciubba, 1995) and oral epithelial dysplasia (Jaber et al., 1998). An increased frequency of lesions with epithelial dysplasia of the lips (but not oral mucosa) has been observed in some but not all iatrogenically immunosuppressed patients (King et al., 1995; Seymour et al., 1997).

Sanguinarine, the principal alkaloid of the bloodroot plant (Sanguinaria canadensis), which is used in some mouthwashes and dentifrices for its anti-plaque activity, may be associated with the development of oral leukoplakia (Damm et al., 1999; Allen et al., 2001; Mascarenhas et al., 2001, 2002).

Drug-related Mucosal Pigmentation

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    (1) DRUG-RELATED SUPERFICIAL TRANSIENT DISCOLORATION
Superficial transient discoloration of the dorsum of the tongue and other soft tissues and teeth may be of various colors, typically yellowish or brown, and may be caused by some foods and beverages (such as coffee and tea), some habits (such as tobacco, betel, and crack cocaine use) (Mirbod and Ahing, 2000), and some drugs (such as iron salts, bismuth, chlorhexidine, or antibiotics), especially if these also induce xerostomia (such as psychotropic agents) (Ramadan, 1969; Suzuki et al., 1983; Ogunwande, 1989; Heymann, 2000) (Table 13). When such discoloration noticeably affects the posterior dorsum of the tongue, and the filiform papillae are excessively long and stained dark brown or black, the term ‘black hairy tongue’ is used, but this is less common than other superficial discolorations.

    (2) DRUG-RELATED INTRINSIC PIGMENTATION
Localized areas of pigmentation of the mucosa may be due to amalgam, while gingival pigmentation can arise secondary to the gold or metal alloys of crowns (Kedici et al., 1995). Heavy metal salts were previously reported to cause pigmentation, particularly of the gingival margin (Tables 13, 14).

Minocycline has increasingly been reported to cause widespread blue, blue-grey, or brown pigmentation of the gingivae and mucosae. While much of this pigmentation may reflect discoloration of the underlying bone and roots of teeth, there is also inherent pigmentation of the oral mucosa, including the tongue (Meyerson et al., 1995; Westbury and Najera, 1997).

Oral contraceptives may, albeit rarely, cause melanotic pigmentation (Hertz et al., 1980), as can cyclophosphamide, busulphan, and ACTH (Scully and Porter, 1997). In HIV disease, drug-induced melanotic pigmentation may arise following therapy with clofazimine zidovudine and/or ketoconazole, the pigmentation being variably diffuse or macular-like (Ficarra et al., 1990; Porter et al., 1990).

Kaposi’s sarcoma of the mouth is a rare complication of immunosuppression, manifesting as a blue, red, or purple macule, papule, nodule, or area of ulceration, typically on the palate or gingivae, but able to affect other oral mucosal sites (see above).

Drug-related Swellings

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    (1) DRUG-RELATED GINGIVAL ENLARGEMENT
Gingival enlargement is a well-described oral side-effect of drug therapy (Marshall and Bartold, 1998) (Table 15). The drugs most commonly implicated in causing this enlargement are phenytoin (Seymour and Jacobs, 1992), ciclosporin (Seymour and Jacobs, 1992a), and the calcium-channel-blockers nifedipine (Fattore et al., 1991), diltiazem (Bowman et al., 1988), verapamil (Pernu et al., 1989), and amlodipine (Ellis et al., 1993). Patients receiving therapy with both ciclosporin and calcium-channel-blockers (e.g., post-cardiac or -renal allograft recipients) may be sometimes, but not always, particularly liable to drug-induced gingival enlargement.

Rarely, Kaposi’s sarcoma (Qunibi et al., 1988) or squamous cell carcinoma (Varga and Tyldesley, 1991) may arise within areas of ciclosporin-induced gingival enlargement.

Other drugs that have been occasionally reported to cause gingival enlargement include erythromycin (