Accepted Manuscript Risk Management Strategies For Reducing Oral Adverse Drug Events Ann Eshenaur Spolarich, RDH, PhD PII:
S1532-3382(14)00073-6
DOI:
10.1016/j.jebdp.2014.04.009
Reference:
YMED 960
To appear in:
The Journal of Evidence-Based Dental Practice
Please cite this article as: Spolarich AE, Risk Management Strategies For Reducing Oral Adverse Drug Events, The Journal of Evidence-Based Dental Practice (2014), doi: 10.1016/j.jebdp.2014.04.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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RISK MANAGEMENT STRATEGIES FOR REDUCING ORAL ADVERSE DRUG EVENTS
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Ann Eshenaur Spolarich, RDH, PhD Clinical Associate Professor, Division of Dental Public Health and Pediatric Dentistry; and Associate Director, National Center for Dental Hygiene Research & Practice Ostrow School of Dentistry of USC 925 West 34th Street, Room 4338 Los Angeles, CA 90089-0641 Telephone: 480-575-6630 Fax: 480-629-5859 Email: [email protected]
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ABSTRACT Declarative title: Oral adverse drug effects negatively impact oral health, comfort and function.
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Background: Patients treated in the oral healthcare environment take multiple medications, many of which cause oral complications. Dental professionals are
challenged with making recommendations to prevent or minimize drug-induced oral
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disease risks, while reducing symptoms to improve oral health quality of life.
Methods: This paper presents a critical analysis of current evidence regarding
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common oral adverse drug events, and reviews existing clinical practice guidelines based upon findings from published systematic reviews.
Results: There is a lack of sufficient, high quality evidence to support most recommendations for interventions to relieve signs and symptoms of drug-induced oral
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adverse events. Existing recommendations are largely based on data obtained from observational studies and case reports, and from randomized controlled clinical trials with significant design flaws and potential reporting bias. Outcome measures,
or lacking.
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especially those related to symptom relief and long-range benefits, are either insufficient
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Conclusions: Oral adverse drug effects are a common problem, and additional data is needed to support best practices for product recommendations to improve oral health in medicated patients.
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LEVEL OF EVIDENCE: Level 2 Limited-quality patient-oriented evidence STRENGTH OF RECOMMENDATION GRADE: B Inconsistent or limited-quality patient-oriented evidence
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INTRODUCTION
Patients seen in the oral health care environment often take multiple medications, which cause side effects that impact oral health, comfort and function. Dental
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professionals are expected to make recommendations for product interventions to
prevent and/or reduce symptoms and to improve oral health quality of life. This paper
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examines current scientific evidence and existing clinical practice guidelines to support best practices to minimize risks associated with oral adverse drug events.
Alterations in Saliva
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Hyposalivation and perception of dry mouth (xerostomia) are well-documented adverse drug effects. Decreased salivation is frequently observed with anticholinergic medications, as well as with sympathomimetics, sedative hyponotics, opiates,
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antihistamines and muscle relaxants. 1 Drugs that cause dry mouth by decreasing salivary flow are listed in Table 1. Xerostomia also occurs without changes in salivary
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flow rate, notably with psychological conditions such as anxiety and depression, and following use of inhaled medications. More than 500 medications are associated with adverse effects on the salivary glands, and these mechanisms have been described elsewhere. 1
Drug-induced salivary changes alter normal oral homeostasis, resulting in increased risk for bacterial, fungal and viral infections. Decreased production of salivary mucins
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decreases mucosal protection, contributing to risk for abrasion and trauma from foods, dental restorations and prosthetics, and oral hygiene devices. Loss of lubrication and mucosal integrity contributes to pain and discomfort from ulceration and inflammation.
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Patients may experience difficulty with normal oral function, especially eating, swallowing and speaking.
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Interventions for Xerostomia
A wide range of commercial products are marketed for the relief of dry mouth.
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Clinicians can choose from both pharmacologic and non-pharmacologic interventions to help patients manage their symptoms. Dental professionals frequently recommend use of over-the-counter (OTC) salivary replacement therapies that contain carboxymethylcellulose to simulate the viscosity of natural saliva. These products
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provide only temporary relief from xerostomia. Many products also contain glycerin as a humectant and coating agent for lubrication, and some contain sugar alcohols for caries protection. All are alcohol-free and sugar-free. These products are affordable, but
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compliance may be problematic due to the limited duration of improvement of symptoms, taste, viscosity and inconvenience of frequent dosing.
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Parasympathomimetic drugs (e.g. pilocarpine, cevimeline) stimulate salivary flow, and are approved for use in patients who have undergone radiation therapy and for those with Sjögren’s syndrome. Because these drugs are taken systemically, there are risks for side effects, drug interactions and contraindications which limits their widespread applicability. A small systematic review of 3 randomized controlled clinical trials (RCTs) found that pilocarpine was more effective than placebo, and was at least
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as effective as salivary substitute for subjects with radiation-induced xerostomia. However, only half of participants responded positively to the intervention, and dosedependent side effects and the delayed time to onset of relief limited compliance and
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utility of this intervention. There is a lack of evidence to support using pilocarpine and other parasympathomimetics for this population. 2
Acupuncture and electrostimulation have also been studied as non-pharmacologic
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interventions in subjects with a history of radiation therapy or Sjögren’s syndrome. Most studies utilized small sample sizes, and outcome measures on relief of dry mouth
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symptoms were either missing or limited. Long-range effects on salivary production and symptom relief have not been studied. 3 One small RCT with 61 subjects with medication-induced xerostomia demonstrated that use of a sonic toothbrush improved salivary flow as compared to a manual toothbrush, and after 3 years, follow-up survey
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results showed that 98.2% of subjects reported enhanced salivary flow, and 92.7% indicated that they would continue to use the brush to increase salivary flow. Despite the small sample size and high bias potential, these findings add to the growing
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evidence base that supports the benefits of and compliance with sonic toothbrushing.4 There are numerous RCTs that have examined efficacy of salivary stimulants and
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salivary substitutes against one another and against a placebo. However, many studies are at high risk for bias due to their commercial nature, and measures and outcomes vary considerably across trials. 5 A systematic review examining the efficacy of topical interventions for treatment of dry mouth symptoms found that there is a lack of strong evidence to support any particular topical therapy for this indication. 5 For salivary substitutes, oxygenated
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glycerol triester spray appears to be more effective for relief of symptoms compared to an electrolyte spray, as measured by patient-reported relief using a visual analog scale. Some weak evidence supports that chewing gum is beneficial in patients with some
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residual salivary function, although it is not known how chewing gum compares to use of salivary substitutes. Additional research is necessary to identify which topical
intervention is best for relief of symptoms. More studies are needed to determine
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improved oral function, and client compliance.
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efficacy of different interventions for long-range benefits, such as symptom relief,
Drug-Induced Salivary Hypofunction and Caries Risk
Salivary hypofunction leads to diminished oral clearance, allowing prolonged exposure to oral sugars required for bacterial metabolism by cariogenic flora.
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Diminished salivary buffering agents lower pH of the residual saliva, oral cavity and dental biofilm. Increased adherence of acid-producing bacteria to the teeth coupled with the drop in oral pH decreases acid-resistance of the tooth structure, promoting
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formation of both coronal and root caries.
Drug-induced dry mouth is a major risk factor for caries. 6 This condition is not age-
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dependent, although it is more likely observed among older adults who typically take a greater number of medications as compared to other age cohorts. However, many children use sympathomimetic drugs, as inhaled drugs for asthma and systemically for attention deficit disorders, among others that can cause dry mouth. Fluoride therapy remains the best intervention for reducing caries risk among these and other high risk patient populations.
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Extensive, strong evidence supports that fluorides are the most efficacious of all available products for remineralization. 6,7 At this time, there is limited, weak evidence to support the value of non-fluoride remineralization therapies as a caries risk reduction
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strategy. 8,9 These products include amorphous calcium phosphate (ACP, licensed from the ADA Foundation). calcium sodium phosphosilicate (NovaMin®) and tricalcium phosphate. There is primarily laboratory data to suggest that these products may be
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effective for remineralization; however, there is no clinical data to support improved efficacy over fluoride alone when any of these products are added to fluoride varnish.8,10
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Phosphorylated proteins, such as milk casein phosphopeptides (CPP) and CPP complexed with ACP (CPP-ACP; Recaldent™) may help with remineralization by bringing ions to the demineralized surface. Additional clinical research is needed to show the caries protective effects of these CPP-ACP products. 8,10
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Dental hygienists often recommend these remineralization products either in place of, or as adjuncts to, both home and in-office fluoride therapies. These recommendations may be based on the purported product effect of raising oral pH, thus
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creating a more favorable oral environment for medicated patients who are at high risk for caries. There is no documented evidence that any of these products improve long-
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term caries outcomes through sustainable, measurable effects on oral pH. Xylitol has been shown to effectively reduce Mutans streptococci in biofilm and saliva, and inhibits maternal to infant transmission. There are many studies that document the benefits of xylitol-containing products to reduce caries risk, although the majority of studies have been conducted on children ranging in age from 6 to 15 years. However, efficacy of different xylitol interventions (e.g. gum, lozenges, mints) remains
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controversial, and some have questioned the quality of published trials. 8,11 Dental hygienists must use caution when extrapolating knowledge from this literature to support use of this intervention among medicated older adults. A new longitudinal
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clinical trial (X-ACT) with 691 subjects has shown that using 1 gram xylitol lozenges 5 times per day did not significantly reduce caries among high risk adults after 33 months of use. 12 However, the authors acknowledge that xylitol should not be discounted as
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beneficial in this population, as additional research is needed to investigate the efficacy of different dosing regimens and delivery methods for this population. For example,
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some older adults may not view chewing gum as a socially-acceptable behavior, and further, this vehicle may not be feasible for edentulous or partially-dentate individuals. Another challenge associated with use of xylitol is that sugar alcohols cannot be
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digested, leading to gastrointestinal distress as a side effect.
Fungal Infections
Patients with persistent drug-induced dry mouth are at risk for recurrent fungal
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infections due to the loss of the natural antifungal properties of saliva. Fungal infections are a common, and frequently recurrent, opportunistic infection caused by Candida
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albicans, leading to symptomatic geographic tongue, mucosal and pharyngeal fungal infections, and angular cheilitis. Figure 1 illustrates a drug-induced fungal infection along the soft palate and oropharynx. The most common medications associated with oral fungal infections include drugs that alter the immune system (e.g. drugs for chemotherapy), broad spectrum antibiotics, and both inhaled and systemic corticosteroids. Drugs associated with oral candidiasis are listed in Table 2. A recent
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systematic review examined the safety and efficacy of various antifungal therapies for at risk populations, including those undergoing treatment causing immunosuppression. 13 Updated clinical practice guidelines for the management of candidiasis have been
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recently published to help clinicians with decision-making while treating at risk
populations.14 Topical antifungals that are not absorbed (e.g. nystatin) are generally safer than systemic antifungals, but compliance is poor with topical antifungal therapy
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due to the need for frequent application (e.g. up to 5 times per day). Newer antifungal drugs (e.g. fluconazole, itraconazole, ketoconazole) are taken systemically, which
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improves convenience and compliance, but pose significant risks for serious drug interactions, toxicities, and risk for promoting resistance of fungal organisms. These adverse drug events limit their use to severe, and/or chronic, mucocutaneous oropharyngeal and esophageal fungal infections, and for other systemic fungal
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infections. 13
Risk reduction strategies for fungal infection are listed in Table 3. Strategies include early recognition and referral for definitive treatment; teaching patients and their
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caregivers to perform daily denture care; and stressing the importance of complying with antifungal therapy. Risk for reinfection occurs with contaminated toothbrushes, lip
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balms and lipsticks, dentures and mouthguards. Risk reduction strategies should be custom-tailored to ensure that dentures, mouthguards and appliances are all treated with antifungal therapy, and to prevent re-infection by disposing of contaminated toothbrushes and cosmetics. To prevent future recurrence in susceptible individuals, dental hygienists can recommend use of either chlorhexidine or essential oil antiseptic mouthrinses, both of
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which have been shown to kill a variety of Candida species. An in-vitro investigation showed that both 0.12% chlorhexidine and essential oil mouthrinse showed comparable antifungal activity against 5 cultured Candida fungal species (C. albicans, C.
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dubliniensis, C. krusei, C. glabrata, C. tropicalis) at commercially available
concentrations. 15 Two clinical studies with subjects presenting with denture stomatitis caused by an overgrowth of Candida albicans and other fungal species in maxillary
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prostheses documented that rinsing with essential oil mouthrinse twice daily was as effective as nystatin oral suspension in reducing clinical palatal inflammation and
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candidiasis. 16,17 Use of an antiseptic mouthrinse is an important preventive strategy for those with chronic drug-induced dry mouth.
Drug-Induced Ulceration and Aphthous Stomatitis
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Aphthous ulcers have a multifactorial etiology, and are frequently observed when dry mouth is associated with loss of lubrication and resultant trauma. Many case reports in the literature document that exposure to certain medications produces aphthous lesions
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as well. Figure 2 illustrates a typical appearance of drug-induced ulceration, where lesions occur in clusters on the labial and/or buccal mucosa.
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Drug-induced ulceration occurs following exposure to cytotoxic drugs used for chemotherapy, as a manifestation of a hypersensitivity reaction, and upon contact with a drug acting as a local irritant, such as that observed with aspirin burn on the mucosa. A case control study revealed drug-induced ulceration occurs with some beta blockers and some nonsteroidal antiinflammatory drugs (NSAIDS). 18 Observational data and case studies document that many other drugs are associated with aphthous ulceration
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and stomatitis, including gold salts used for rheumatoid arthritis, some selective serotonin reuptake inhibitors (SSRIs) used for depression, ACE inhibitors, and drugs that affect the immune system, including the interferons. Drugs that are associated with
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oral ulceration are listed in Table 4.
There are numerous published clinical trials that support the efficacy of topical
corticosteroids to reduce duration and severity of aphthous ulcerations. However,
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clinicians must balance the risk of systemic absorption and related adverse effects associated with the high potency topical agents used intraorally. 19 RCTs have
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examined the effects of a variety of agents to reduce pain and shorten time to healing, including amlexanox paste and cyanoacrylate paste with or without triamcinolone. Evidence on efficacy of these interventions is limited due to study design issues, such as lack of a placebo control group, incomplete blinding, and small sample sizes.
19,20
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Overall, patients gain only moderate benefits related to healing time, and with the exception of corticosteroids, no one product has been shown to be superior to others. 20 Use of antiseptic mouthrinses containing chlorhexidine gluconate, essential oils and
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triclosan have shown reduction in duration and pain, although clinicians must be cautioned that formulations tested in published clinical trials may be different from what
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is commercially available in the United States, and participants may have rinsed more often than recommended twice daily use. 19 One small double-blind RCT supports that use of essential oil mouthrinse (Listerine®) twice daily reduces both duration and pain of aphthous ulcers, which is a simple intervention to recommend to patients with recurrent ulcerations. 21 Over-the-counter topical pain ointments and pastes containing
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benzocaine, and rinsing with liquid diphenhydramine (Benadryl®)combined with a coating agent, such as Maalox®, may also be helpful.
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Drug-Induced Mucositis
Mucositis is an extensive ulceration of the oral mucosal membranes, causing pain, difficulty with eating, speaking and sleeping, and poor quality of life. Mucositis is most
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frequently observed during cancer therapy with radiation and chemotherapy. Figure 3 illustrates the severe inflammation and ulceration associated with chemotherapy-
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induced mucositis. Chemotherapy causes systemic immunosuppression, decreasing the concentration of salivary immunoglobulins, which leads to microbial overgrowth manifesting as mucositis and oral infections. 22
A systematic review reported that 10 interventions showed some benefit for either
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preventing or reducing the severity of mucositis in patients with cancer compared to placebo or no treatment. 23 Two therapies were found to help prevent mucositis. Palifermin (Kepivance®) is a human recombinant keratinocyte growth factor given in a
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series of dosages via IV both before and following myelotoxic conditioning regimens for bone marrow stem cell transplant support. The drug stimulates the growth of cells lining
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the mouth and intestinal tract, but if given during or within 24 hours of chemotherapy, the drug may increase the severity and duration of mucositis. Efficacy is closely related to the timing of chemotherapy. Sucking on ice chips also was found to help prevent mucositis, which is an easy, non-pharmacological intervention for patients to use both at home and in the hospital. 23 Seven other therapies showed varying degrees of benefit in reducing severity of mucositis, and efficacy may be specific to certain forms of cancer
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and type of treatment: additional clinical research is needed. These agents include the coating agent sucralfate, aloe vera, honey, topical antibiotics, granulocyte-colony stimulating factor (G-CSF), the free-radical scavenger amifostine, treatment with lasers
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and IV glutamine. 23
Recently revised clinical practice guidelines based on criteria from the American Society of Clinical Oncology confirm the benefits of palifermin for oral mucositis
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observed with stem cell transplants, as well as for cryotherapy (ice) for chemotherapyinduced mucositis, and amifostine for mucositis from radiation. 24 (Table 5) Further,
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recommendations were made against the use of sucralfate and topical antibiotic lozenges for radiation-induced mucositis, and against systemic glutamine for gastrointestinal tract mucositis. 24 There is either weak or insufficient evidence to recommend use of other topical antimicrobials, including chlorhexidine gluconate and
mucositis. 25
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Lichenoid Drug Reaction
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povidone-iodine, for reducing either chemotherapy-induced or radiation-induced
Lichenoid drug reactions represent a hypersensitivity disorder to circulating antigens
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or to a local irritant, such as a dental material. There are many drugs that cause this reaction (Table 6), but it is most commonly observed with gold salts, ACE inhibitors and NSAIDS.
Figure 4 illustrates that the clinical appearance of the lesion is often indistinguishable from oral lichen planus. It is unknown whether drugs cause this reaction by themselves, or whether they actually initiate latent lichen planus. The best
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intervention to determine the exact nature of this clinical disorder is to discontinue a suspected medication: if the drug is the causative agent, the reaction should disappear. However, this intervention may not be possible if the drug is needed to maintain control
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of a medical condition.
The astute clinician will recognize that the new onset of a lichenoid lesion may be related to initiating use of a new medication. If the causative drug cannot be
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eliminated, an intervention may be needed to assist with patient comfort. Unfortunately at this time, there is insufficient evidence to recommend any intervention as superior for
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managing lichen planus. Best evidence supports use of topical corticosteroids to reduce symptoms, although no studies compared steroids against placebo. Weak evidence supports use of topical aloe vera which may provide some level of pain
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reduction compared to placebo. 26,27
Drug-Induced Taste Alteration
Drugs have the potential to alter taste perception, although these mechanisms are
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not well-understood. It is thought that drugs may alter the concentration of trace metals, or alter receptors involved with taste and smell. Adverse drug reactions that affect taste
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include distortion of taste (dysgeusia), loss of ability to perceive certain taste sensations (hypogeusia), and loss of taste sensation (ageusia). 28 Patients with hyposalivation may experience taste alteration as saliva is necessary to carry tastants (chemicals that stimulate sensory cells in taste buds) to the taste buds. Taste alteration significantly affects quality of life, and can negatively impact food choices and nutritional status. Risk behaviors may be adopted in an attempt to mask or eliminate unpleasant taste
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perception. Dental hygienists should assess patients for excessive mouthwash use, frequent gum chewing, and sucking on candies or mints. Clinical signs and symptoms of these behaviors may include enamel demineralization, new carious lesions, TMJ
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discomfort from chewing gum and soft tissue abnormalities. Unfortunately, taste
alteration will persist for as long as offending drug is taken; discontinuance often results in reversal of the symptom. If it is not feasible to replace the drug with another that
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that contain sugar to reduce risk for caries.
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lacks this side effect, the recommendations should include avoiding candies and mints
Conclusions
Oral adverse drug effects can significantly influence the patient’s oral function, comfort, and quality of life. Known oral drug effects are reported by manufacturers on
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the package insert and in the drug monograph for all OTC and prescription medications. This information is typically organized by body system and located in the gastrointestinal system section within the listing of side effects. All oral health
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professionals should have access to current drug information, preferably using an electronic database that is updated regularly, to assist with oral risk assessment related
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to medication use. Several excellent pharmacology resources are available to support decision-making at the point of care, which are listed in Table 7. Given that drug information changes, it is critical that oral health professionals help patients to adopt behaviors that minimize the impact of oral side effects caused by their medications. Risk management of potential oral complications associated with medication use depends upon wise decision-making when recommending interventions to support
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patient care. Whenever possible, preventive interventions should be selected based upon best available evidence. Additional research is needed to support best practices
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to minimize the oral consequences of medication use.
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SUGGESTED READINGS
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28. Henkin RI. Drug-induced taste and smell disorders. Incidence, mechanisms and management related primarily to treatment of sensory receptor dysfunction. Drug Saf 1994;11:318-77.
Scully C. Drug effects on salivary glands: dry mouth. Oral Dis 2003;9:165-76.
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Abdollahi M, Radfar M. A review of drug-induced oral reactions. J Contemp Dent Pract 2003;4:10-31. Scully C, Bagan JV. Adverse drug reactions in the orofacial region. Crit Rev Oral Biol Med 2004;15:221-39. Henkin RI. Drug-induced taste and smell disorders. Incidence, mechanisms and management related primarily to treatment of sensory receptor dysfunction. Drug Saf 1994;11:318-77.
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Figure 1. Drug-induced oral candidiasis affecting the soft palate, uvula and oropharynx. Image courtesy of Dr. Pallavi Parashar
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Figure 2. Drug-induced oral ulcerations typically appear on labial or buccal mucosa as aphthous stomatitis. Image used with permission from VisualDx.
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Figure 3. Chemotherapy-induced mucositis contributes significantly to pain, difficulty with oral function, and poor quality of life. Image used with permission from Sook-Bin Woo, MS, DMD, MMSc and VisualDx.
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Figure 4. Lichenoid drug reaction is often indistinguishable in clinical appearance from oral lichen planus. Image used with permission from Carl Allen, DDS, MSD and VisualDx.
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Table 1. Drugs that cause dry mouth by decreasing salivary flow.
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alpha receptor antagonists amphetamines anticancer drugs (cytotoxic drugs) anticholinergics antidepressants (selective serotonin reuptake inhibitors; norepinephrine/serotonin reuptake inhibitors; tricylics) antihistamines anti-HIV drugs antihypertensives antimigraine drugs antipsychotics appetite suppressants benzodiazepines bronchodilators cytokines (inferons) decongestants diuretics drugs of abuse (cannabis, Ecstasy) H2 receptor blockers muscarinic receptor antagonists opioids proton pump inhibitors retinoids sedatives skeletal muscle relaxants sympathomimetics Adapted from: Scully C. Drug effects on salivary glands: dry mouth. Oral Dis 2003;9:165-76; Abdollahi M, Radfar M. A review of drug-induced oral reactions. J Contemp Dent Pract 2003;4:10-31; Scully C, Bagan JV. Adverse drug reactions in the orofacial region. Crit Rev Oral Biol Med 2004;15:221-39.
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Table 2. Drugs that cause oral candidiasis.
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anticancer drugs antimicrobials (e.g. cephalosporins, ciprofloxacin, clarithromycin, penicillins) corticosteroids griseofulvin immunosuppressants (e.g. cyclosporine, tacrolimus) olanzapine omeprazole oral contraceptives Adapted from: Abdollahi M, Radfar M. A review of drug-induced oral reactions. J Contemp Dent Pract 2003;4:10-31; Scully C, Bagan JV. Adverse drug reactions in the orofacial region. Crit Rev Oral Biol Med 2004;15:221-39.
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Table 3. Risk reduction strategies to prevent and/or minimize oral fungal infections. Therapeutic strategies to reduce risk for treatment failure: Encourage compliance with antifungal therapy
Dispose of contaminated toothbrushes and cosmetics
Treat dentures, mouthguards and appliances with antifungal drugs
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Preventive strategies to reduce risk for recurrence: Use antimicrobial mouthrinses twice daily according to manufacturers’ directions
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Teach patients and their caregivers to perform daily denture care
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Table 4. Drugs associated with causing oral ulceration.
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ACE inhibitors (captopril) alendronate angiotensin II receptor blockers (losartan) anticancer drugs atypical antipsychotics (olanzapine) beta blockers gold salts immunosuppressants (azathioprine, cyclosporine, interferons, mycophenolate, tacrolimus) nonsteroidal antiinflammatory drugs (NSAIDS) protease inhibitors (indinavir) selective serotonin reuptake inhibitors (fluoxetine, sertraline) sulfonamides Adapted from: Abdollahi M, Radfar M. A review of drug-induced oral reactions. J Contemp Dent Pract 2003;4:10-31; Scully C, Bagan JV. Adverse drug reactions in the orofacial region. Crit Rev Oral Biol Med 2004;15:221-39.
Table 5. Evidence-based interventions for managing oral mucositis in patients undergoing cancer therapy. 24
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Intervention Indication palifermin (Kepivance®): human oral mucositis observed with stem cell recombinant keratinocyte growth transplants factor cryotherapy (ice) chemotherapy-induced oral mucositis amifostine radiation-induced oral mucositis Source: Keefe DM, Schubert MM, Elting LS, Sonis ST, Epstein JB, Raber-Durlacher JE, Migliorati CA, McGuire DB, Hutchins RD, Peterson DE; Mucositis Study Section of the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology. Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer 2007;109:820-31.
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allopurinal antiarrhythmics (quinidine, procainamide) antihypertensives (ACE inhibitors, beta blockers, diuretics) antimalarials (chloroquine, hydroxychloroquine, quinidine) carbamazepine lithium metals (gold salts, mercury) metformin methyldopa NSAIDS oral contraceptives penicillins phenothiazines phenytoin protease inhibitors rifampin streptomycin sulfasalazine sulfonamides tetracyclines tolbutamide
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Table 6. Examples of drugs that may cause lichenoid drug reaction.
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Table 7. Resources for dental professionals to support decision-making with medication use at the point of care. Chairside Reference Texts
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Wynn R, Crossley H, Meiller T. Drug Information Handbook for Dentistry, ed. 19. Hudson:OH. Lexi-Comp, Inc., 20132014.
Newland RJ, Meiller T, Wynn R, Crossley H. Oral Soft Tissue Diseases. ed. 6. Hudson:OH. Lexi-Comp, Inc., 2013-2014 Pickett FA, Terezhalmy. Dental Drug Reference with Clinical Implications. ed 2. Baltimore: Lippincott Williams & Wilkins, 2009.
Subscription Electronic Drug Databases Lexicomp® Online™ for Dentistry www.lexi.com
Natural Standard Research Collaboration http://www.naturalstandard.com/
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S1532-3382(14)00073-6
DOI:
10.1016/j.jebdp.2014.04.009
Reference:
YMED 960
To appear in:
The Journal of Evidence-Based Dental Practice
Please cite this article as: Spolarich AE, Risk Management Strategies For Reducing Oral Adverse Drug Events, The Journal of Evidence-Based Dental Practice (2014), doi: 10.1016/j.jebdp.2014.04.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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RISK MANAGEMENT STRATEGIES FOR REDUCING ORAL ADVERSE DRUG EVENTS
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Ann Eshenaur Spolarich, RDH, PhD Clinical Associate Professor, Division of Dental Public Health and Pediatric Dentistry; and Associate Director, National Center for Dental Hygiene Research & Practice Ostrow School of Dentistry of USC 925 West 34th Street, Room 4338 Los Angeles, CA 90089-0641 Telephone: 480-575-6630 Fax: 480-629-5859 Email: [email protected]
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ABSTRACT Declarative title: Oral adverse drug effects negatively impact oral health, comfort and function.
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Background: Patients treated in the oral healthcare environment take multiple medications, many of which cause oral complications. Dental professionals are
challenged with making recommendations to prevent or minimize drug-induced oral
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disease risks, while reducing symptoms to improve oral health quality of life.
Methods: This paper presents a critical analysis of current evidence regarding
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common oral adverse drug events, and reviews existing clinical practice guidelines based upon findings from published systematic reviews.
Results: There is a lack of sufficient, high quality evidence to support most recommendations for interventions to relieve signs and symptoms of drug-induced oral
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adverse events. Existing recommendations are largely based on data obtained from observational studies and case reports, and from randomized controlled clinical trials with significant design flaws and potential reporting bias. Outcome measures,
or lacking.
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especially those related to symptom relief and long-range benefits, are either insufficient
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Conclusions: Oral adverse drug effects are a common problem, and additional data is needed to support best practices for product recommendations to improve oral health in medicated patients.
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LEVEL OF EVIDENCE: Level 2 Limited-quality patient-oriented evidence STRENGTH OF RECOMMENDATION GRADE: B Inconsistent or limited-quality patient-oriented evidence
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INTRODUCTION
Patients seen in the oral health care environment often take multiple medications, which cause side effects that impact oral health, comfort and function. Dental
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professionals are expected to make recommendations for product interventions to
prevent and/or reduce symptoms and to improve oral health quality of life. This paper
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examines current scientific evidence and existing clinical practice guidelines to support best practices to minimize risks associated with oral adverse drug events.
Alterations in Saliva
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Hyposalivation and perception of dry mouth (xerostomia) are well-documented adverse drug effects. Decreased salivation is frequently observed with anticholinergic medications, as well as with sympathomimetics, sedative hyponotics, opiates,
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antihistamines and muscle relaxants. 1 Drugs that cause dry mouth by decreasing salivary flow are listed in Table 1. Xerostomia also occurs without changes in salivary
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flow rate, notably with psychological conditions such as anxiety and depression, and following use of inhaled medications. More than 500 medications are associated with adverse effects on the salivary glands, and these mechanisms have been described elsewhere. 1
Drug-induced salivary changes alter normal oral homeostasis, resulting in increased risk for bacterial, fungal and viral infections. Decreased production of salivary mucins
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decreases mucosal protection, contributing to risk for abrasion and trauma from foods, dental restorations and prosthetics, and oral hygiene devices. Loss of lubrication and mucosal integrity contributes to pain and discomfort from ulceration and inflammation.
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Patients may experience difficulty with normal oral function, especially eating, swallowing and speaking.
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Interventions for Xerostomia
A wide range of commercial products are marketed for the relief of dry mouth.
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Clinicians can choose from both pharmacologic and non-pharmacologic interventions to help patients manage their symptoms. Dental professionals frequently recommend use of over-the-counter (OTC) salivary replacement therapies that contain carboxymethylcellulose to simulate the viscosity of natural saliva. These products
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provide only temporary relief from xerostomia. Many products also contain glycerin as a humectant and coating agent for lubrication, and some contain sugar alcohols for caries protection. All are alcohol-free and sugar-free. These products are affordable, but
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compliance may be problematic due to the limited duration of improvement of symptoms, taste, viscosity and inconvenience of frequent dosing.
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Parasympathomimetic drugs (e.g. pilocarpine, cevimeline) stimulate salivary flow, and are approved for use in patients who have undergone radiation therapy and for those with Sjögren’s syndrome. Because these drugs are taken systemically, there are risks for side effects, drug interactions and contraindications which limits their widespread applicability. A small systematic review of 3 randomized controlled clinical trials (RCTs) found that pilocarpine was more effective than placebo, and was at least
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as effective as salivary substitute for subjects with radiation-induced xerostomia. However, only half of participants responded positively to the intervention, and dosedependent side effects and the delayed time to onset of relief limited compliance and
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utility of this intervention. There is a lack of evidence to support using pilocarpine and other parasympathomimetics for this population. 2
Acupuncture and electrostimulation have also been studied as non-pharmacologic
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interventions in subjects with a history of radiation therapy or Sjögren’s syndrome. Most studies utilized small sample sizes, and outcome measures on relief of dry mouth
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symptoms were either missing or limited. Long-range effects on salivary production and symptom relief have not been studied. 3 One small RCT with 61 subjects with medication-induced xerostomia demonstrated that use of a sonic toothbrush improved salivary flow as compared to a manual toothbrush, and after 3 years, follow-up survey
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results showed that 98.2% of subjects reported enhanced salivary flow, and 92.7% indicated that they would continue to use the brush to increase salivary flow. Despite the small sample size and high bias potential, these findings add to the growing
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evidence base that supports the benefits of and compliance with sonic toothbrushing.4 There are numerous RCTs that have examined efficacy of salivary stimulants and
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salivary substitutes against one another and against a placebo. However, many studies are at high risk for bias due to their commercial nature, and measures and outcomes vary considerably across trials. 5 A systematic review examining the efficacy of topical interventions for treatment of dry mouth symptoms found that there is a lack of strong evidence to support any particular topical therapy for this indication. 5 For salivary substitutes, oxygenated
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glycerol triester spray appears to be more effective for relief of symptoms compared to an electrolyte spray, as measured by patient-reported relief using a visual analog scale. Some weak evidence supports that chewing gum is beneficial in patients with some
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residual salivary function, although it is not known how chewing gum compares to use of salivary substitutes. Additional research is necessary to identify which topical
intervention is best for relief of symptoms. More studies are needed to determine
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improved oral function, and client compliance.
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efficacy of different interventions for long-range benefits, such as symptom relief,
Drug-Induced Salivary Hypofunction and Caries Risk
Salivary hypofunction leads to diminished oral clearance, allowing prolonged exposure to oral sugars required for bacterial metabolism by cariogenic flora.
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Diminished salivary buffering agents lower pH of the residual saliva, oral cavity and dental biofilm. Increased adherence of acid-producing bacteria to the teeth coupled with the drop in oral pH decreases acid-resistance of the tooth structure, promoting
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formation of both coronal and root caries.
Drug-induced dry mouth is a major risk factor for caries. 6 This condition is not age-
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dependent, although it is more likely observed among older adults who typically take a greater number of medications as compared to other age cohorts. However, many children use sympathomimetic drugs, as inhaled drugs for asthma and systemically for attention deficit disorders, among others that can cause dry mouth. Fluoride therapy remains the best intervention for reducing caries risk among these and other high risk patient populations.
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Extensive, strong evidence supports that fluorides are the most efficacious of all available products for remineralization. 6,7 At this time, there is limited, weak evidence to support the value of non-fluoride remineralization therapies as a caries risk reduction
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strategy. 8,9 These products include amorphous calcium phosphate (ACP, licensed from the ADA Foundation). calcium sodium phosphosilicate (NovaMin®) and tricalcium phosphate. There is primarily laboratory data to suggest that these products may be
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effective for remineralization; however, there is no clinical data to support improved efficacy over fluoride alone when any of these products are added to fluoride varnish.8,10
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Phosphorylated proteins, such as milk casein phosphopeptides (CPP) and CPP complexed with ACP (CPP-ACP; Recaldent™) may help with remineralization by bringing ions to the demineralized surface. Additional clinical research is needed to show the caries protective effects of these CPP-ACP products. 8,10
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Dental hygienists often recommend these remineralization products either in place of, or as adjuncts to, both home and in-office fluoride therapies. These recommendations may be based on the purported product effect of raising oral pH, thus
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creating a more favorable oral environment for medicated patients who are at high risk for caries. There is no documented evidence that any of these products improve long-
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term caries outcomes through sustainable, measurable effects on oral pH. Xylitol has been shown to effectively reduce Mutans streptococci in biofilm and saliva, and inhibits maternal to infant transmission. There are many studies that document the benefits of xylitol-containing products to reduce caries risk, although the majority of studies have been conducted on children ranging in age from 6 to 15 years. However, efficacy of different xylitol interventions (e.g. gum, lozenges, mints) remains
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controversial, and some have questioned the quality of published trials. 8,11 Dental hygienists must use caution when extrapolating knowledge from this literature to support use of this intervention among medicated older adults. A new longitudinal
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clinical trial (X-ACT) with 691 subjects has shown that using 1 gram xylitol lozenges 5 times per day did not significantly reduce caries among high risk adults after 33 months of use. 12 However, the authors acknowledge that xylitol should not be discounted as
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beneficial in this population, as additional research is needed to investigate the efficacy of different dosing regimens and delivery methods for this population. For example,
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some older adults may not view chewing gum as a socially-acceptable behavior, and further, this vehicle may not be feasible for edentulous or partially-dentate individuals. Another challenge associated with use of xylitol is that sugar alcohols cannot be
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digested, leading to gastrointestinal distress as a side effect.
Fungal Infections
Patients with persistent drug-induced dry mouth are at risk for recurrent fungal
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infections due to the loss of the natural antifungal properties of saliva. Fungal infections are a common, and frequently recurrent, opportunistic infection caused by Candida
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albicans, leading to symptomatic geographic tongue, mucosal and pharyngeal fungal infections, and angular cheilitis. Figure 1 illustrates a drug-induced fungal infection along the soft palate and oropharynx. The most common medications associated with oral fungal infections include drugs that alter the immune system (e.g. drugs for chemotherapy), broad spectrum antibiotics, and both inhaled and systemic corticosteroids. Drugs associated with oral candidiasis are listed in Table 2. A recent
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systematic review examined the safety and efficacy of various antifungal therapies for at risk populations, including those undergoing treatment causing immunosuppression. 13 Updated clinical practice guidelines for the management of candidiasis have been
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recently published to help clinicians with decision-making while treating at risk
populations.14 Topical antifungals that are not absorbed (e.g. nystatin) are generally safer than systemic antifungals, but compliance is poor with topical antifungal therapy
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due to the need for frequent application (e.g. up to 5 times per day). Newer antifungal drugs (e.g. fluconazole, itraconazole, ketoconazole) are taken systemically, which
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improves convenience and compliance, but pose significant risks for serious drug interactions, toxicities, and risk for promoting resistance of fungal organisms. These adverse drug events limit their use to severe, and/or chronic, mucocutaneous oropharyngeal and esophageal fungal infections, and for other systemic fungal
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infections. 13
Risk reduction strategies for fungal infection are listed in Table 3. Strategies include early recognition and referral for definitive treatment; teaching patients and their
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caregivers to perform daily denture care; and stressing the importance of complying with antifungal therapy. Risk for reinfection occurs with contaminated toothbrushes, lip
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balms and lipsticks, dentures and mouthguards. Risk reduction strategies should be custom-tailored to ensure that dentures, mouthguards and appliances are all treated with antifungal therapy, and to prevent re-infection by disposing of contaminated toothbrushes and cosmetics. To prevent future recurrence in susceptible individuals, dental hygienists can recommend use of either chlorhexidine or essential oil antiseptic mouthrinses, both of
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which have been shown to kill a variety of Candida species. An in-vitro investigation showed that both 0.12% chlorhexidine and essential oil mouthrinse showed comparable antifungal activity against 5 cultured Candida fungal species (C. albicans, C.
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dubliniensis, C. krusei, C. glabrata, C. tropicalis) at commercially available
concentrations. 15 Two clinical studies with subjects presenting with denture stomatitis caused by an overgrowth of Candida albicans and other fungal species in maxillary
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prostheses documented that rinsing with essential oil mouthrinse twice daily was as effective as nystatin oral suspension in reducing clinical palatal inflammation and
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candidiasis. 16,17 Use of an antiseptic mouthrinse is an important preventive strategy for those with chronic drug-induced dry mouth.
Drug-Induced Ulceration and Aphthous Stomatitis
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Aphthous ulcers have a multifactorial etiology, and are frequently observed when dry mouth is associated with loss of lubrication and resultant trauma. Many case reports in the literature document that exposure to certain medications produces aphthous lesions
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as well. Figure 2 illustrates a typical appearance of drug-induced ulceration, where lesions occur in clusters on the labial and/or buccal mucosa.
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Drug-induced ulceration occurs following exposure to cytotoxic drugs used for chemotherapy, as a manifestation of a hypersensitivity reaction, and upon contact with a drug acting as a local irritant, such as that observed with aspirin burn on the mucosa. A case control study revealed drug-induced ulceration occurs with some beta blockers and some nonsteroidal antiinflammatory drugs (NSAIDS). 18 Observational data and case studies document that many other drugs are associated with aphthous ulceration
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and stomatitis, including gold salts used for rheumatoid arthritis, some selective serotonin reuptake inhibitors (SSRIs) used for depression, ACE inhibitors, and drugs that affect the immune system, including the interferons. Drugs that are associated with
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oral ulceration are listed in Table 4.
There are numerous published clinical trials that support the efficacy of topical
corticosteroids to reduce duration and severity of aphthous ulcerations. However,
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clinicians must balance the risk of systemic absorption and related adverse effects associated with the high potency topical agents used intraorally. 19 RCTs have
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examined the effects of a variety of agents to reduce pain and shorten time to healing, including amlexanox paste and cyanoacrylate paste with or without triamcinolone. Evidence on efficacy of these interventions is limited due to study design issues, such as lack of a placebo control group, incomplete blinding, and small sample sizes.
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Overall, patients gain only moderate benefits related to healing time, and with the exception of corticosteroids, no one product has been shown to be superior to others. 20 Use of antiseptic mouthrinses containing chlorhexidine gluconate, essential oils and
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triclosan have shown reduction in duration and pain, although clinicians must be cautioned that formulations tested in published clinical trials may be different from what
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is commercially available in the United States, and participants may have rinsed more often than recommended twice daily use. 19 One small double-blind RCT supports that use of essential oil mouthrinse (Listerine®) twice daily reduces both duration and pain of aphthous ulcers, which is a simple intervention to recommend to patients with recurrent ulcerations. 21 Over-the-counter topical pain ointments and pastes containing
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benzocaine, and rinsing with liquid diphenhydramine (Benadryl®)combined with a coating agent, such as Maalox®, may also be helpful.
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Drug-Induced Mucositis
Mucositis is an extensive ulceration of the oral mucosal membranes, causing pain, difficulty with eating, speaking and sleeping, and poor quality of life. Mucositis is most
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frequently observed during cancer therapy with radiation and chemotherapy. Figure 3 illustrates the severe inflammation and ulceration associated with chemotherapy-
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induced mucositis. Chemotherapy causes systemic immunosuppression, decreasing the concentration of salivary immunoglobulins, which leads to microbial overgrowth manifesting as mucositis and oral infections. 22
A systematic review reported that 10 interventions showed some benefit for either
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preventing or reducing the severity of mucositis in patients with cancer compared to placebo or no treatment. 23 Two therapies were found to help prevent mucositis. Palifermin (Kepivance®) is a human recombinant keratinocyte growth factor given in a
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series of dosages via IV both before and following myelotoxic conditioning regimens for bone marrow stem cell transplant support. The drug stimulates the growth of cells lining
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the mouth and intestinal tract, but if given during or within 24 hours of chemotherapy, the drug may increase the severity and duration of mucositis. Efficacy is closely related to the timing of chemotherapy. Sucking on ice chips also was found to help prevent mucositis, which is an easy, non-pharmacological intervention for patients to use both at home and in the hospital. 23 Seven other therapies showed varying degrees of benefit in reducing severity of mucositis, and efficacy may be specific to certain forms of cancer
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and type of treatment: additional clinical research is needed. These agents include the coating agent sucralfate, aloe vera, honey, topical antibiotics, granulocyte-colony stimulating factor (G-CSF), the free-radical scavenger amifostine, treatment with lasers
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and IV glutamine. 23
Recently revised clinical practice guidelines based on criteria from the American Society of Clinical Oncology confirm the benefits of palifermin for oral mucositis
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observed with stem cell transplants, as well as for cryotherapy (ice) for chemotherapyinduced mucositis, and amifostine for mucositis from radiation. 24 (Table 5) Further,
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recommendations were made against the use of sucralfate and topical antibiotic lozenges for radiation-induced mucositis, and against systemic glutamine for gastrointestinal tract mucositis. 24 There is either weak or insufficient evidence to recommend use of other topical antimicrobials, including chlorhexidine gluconate and
mucositis. 25
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Lichenoid Drug Reaction
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povidone-iodine, for reducing either chemotherapy-induced or radiation-induced
Lichenoid drug reactions represent a hypersensitivity disorder to circulating antigens
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or to a local irritant, such as a dental material. There are many drugs that cause this reaction (Table 6), but it is most commonly observed with gold salts, ACE inhibitors and NSAIDS.
Figure 4 illustrates that the clinical appearance of the lesion is often indistinguishable from oral lichen planus. It is unknown whether drugs cause this reaction by themselves, or whether they actually initiate latent lichen planus. The best
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intervention to determine the exact nature of this clinical disorder is to discontinue a suspected medication: if the drug is the causative agent, the reaction should disappear. However, this intervention may not be possible if the drug is needed to maintain control
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of a medical condition.
The astute clinician will recognize that the new onset of a lichenoid lesion may be related to initiating use of a new medication. If the causative drug cannot be
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eliminated, an intervention may be needed to assist with patient comfort. Unfortunately at this time, there is insufficient evidence to recommend any intervention as superior for
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managing lichen planus. Best evidence supports use of topical corticosteroids to reduce symptoms, although no studies compared steroids against placebo. Weak evidence supports use of topical aloe vera which may provide some level of pain
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reduction compared to placebo. 26,27
Drug-Induced Taste Alteration
Drugs have the potential to alter taste perception, although these mechanisms are
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not well-understood. It is thought that drugs may alter the concentration of trace metals, or alter receptors involved with taste and smell. Adverse drug reactions that affect taste
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include distortion of taste (dysgeusia), loss of ability to perceive certain taste sensations (hypogeusia), and loss of taste sensation (ageusia). 28 Patients with hyposalivation may experience taste alteration as saliva is necessary to carry tastants (chemicals that stimulate sensory cells in taste buds) to the taste buds. Taste alteration significantly affects quality of life, and can negatively impact food choices and nutritional status. Risk behaviors may be adopted in an attempt to mask or eliminate unpleasant taste
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perception. Dental hygienists should assess patients for excessive mouthwash use, frequent gum chewing, and sucking on candies or mints. Clinical signs and symptoms of these behaviors may include enamel demineralization, new carious lesions, TMJ
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discomfort from chewing gum and soft tissue abnormalities. Unfortunately, taste
alteration will persist for as long as offending drug is taken; discontinuance often results in reversal of the symptom. If it is not feasible to replace the drug with another that
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that contain sugar to reduce risk for caries.
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lacks this side effect, the recommendations should include avoiding candies and mints
Conclusions
Oral adverse drug effects can significantly influence the patient’s oral function, comfort, and quality of life. Known oral drug effects are reported by manufacturers on
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the package insert and in the drug monograph for all OTC and prescription medications. This information is typically organized by body system and located in the gastrointestinal system section within the listing of side effects. All oral health
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professionals should have access to current drug information, preferably using an electronic database that is updated regularly, to assist with oral risk assessment related
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to medication use. Several excellent pharmacology resources are available to support decision-making at the point of care, which are listed in Table 7. Given that drug information changes, it is critical that oral health professionals help patients to adopt behaviors that minimize the impact of oral side effects caused by their medications. Risk management of potential oral complications associated with medication use depends upon wise decision-making when recommending interventions to support
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patient care. Whenever possible, preventive interventions should be selected based upon best available evidence. Additional research is needed to support best practices
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to minimize the oral consequences of medication use.
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14. Pappas PG, Kauffman CA, Andes D, Benjamin DK Jr, Calandra TF, Edwards JE Jr, Filler SG, Fisher JF, Kullberg BJ, Ostrosky-Zeichner L, Reboli AC, Rex JH, Walsh TJ, Sobel JD; Infectious Diseases Society of America. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 2009;48:503-35. 15. Meiller TF, Kelley JI, Jabra-Rizk MA, DePaola LG, Baqui AAMA and Falkler WA. In vitro studies of the efficacy of antimicrobials against fungi. Oral Surg Oral Med Oral Path Oral Radio Endod 2001;91:663-670.
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16. DePaola LG, Minah GE, Elias SA, Eastwood GW and Walters RA. Clinical and microbial evaluation of treatment regimens to reduce denture stomatitis. Inter J Prosthet 1990;3(4) 369-374.
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17. DePaola LG, Minah GE, Leupold RL, Faraone KL and Elias SA. The effect of antiseptic mouthrinses on oral microbial flora and denture stomatitis. Clin Prev Dent 1986;8(6):3-8.
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18. Boulinguez S, Bedane C, Bouyssou-Gauthier M, Cornee-Leplat I, Truong E, Bonnetblanc JM. Giant buccal aphthosis caused by nicorandil. Presse Med 1997;26:558-558 19. Scully C. Clinical practice. Aphthous ulceration. N Engl J Med 2006;355:165-72. 20. Porter S, Scully C. Aphthous ulcers (recurrent). Clin Evid 2005;13:1687-1694 21. Meiller TF, Kutcher MJ, Overholser CD, Niehaus C, DePaola LG, Siegel MA. Effect of an antimicrobial mouthrinse on recurrent aphthous ulcerations. Oral Surg Oral Med Oral Pathol 1991;72:425-429 22. Jensen SB, Pedersen AM, Reibel J, Nauntofte B. Xerostomia and hypofunction of
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the salivary glands in cancer therapy. Support Care Cancer. 2003;11:207-225.
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23. Worthington HV, Clarkson JE, Bryan G, Furness S, Glenny AM, Littlewood A, McCabe MG, Meyer S, Khalid T. Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev 2011;4: Art. No.: CD000978. DOI: 10.1002/14651858. CD000978.pub5.
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24. Keefe DM, Schubert MM, Elting LS, Sonis ST, Epstein JB, Raber-Durlacher JE, Migliorati CA, McGuire DB, Hutchins RD, Peterson DE; Mucositis Study Section of the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology. Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer 2007;109:820-31.
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25. Barasch A, Elad S, Altman A, Damato K, Epstein J. Antimicrobials, mucosal coating agents, anesthetics, analgesics, and nutritional supplements for alimentary tract mucositis. Support Care Cancer 2006;14:528-32. 26. Thongprasom K, Carrozzo M, Furness S, Lodi G. Interventions for treating oral lichen planus. Cochrane Database Syst Rev 2011;7:CD001168. DOI: 10.1002/14651858.CD001168.pub2. 27. Keenan AV, Ferraiolo D. Insufficient evidence for effectiveness of any treatment for oral lichen planus. Evid Based Dent 2011;12:85-6.
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SUGGESTED READINGS
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28. Henkin RI. Drug-induced taste and smell disorders. Incidence, mechanisms and management related primarily to treatment of sensory receptor dysfunction. Drug Saf 1994;11:318-77.
Scully C. Drug effects on salivary glands: dry mouth. Oral Dis 2003;9:165-76.
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Abdollahi M, Radfar M. A review of drug-induced oral reactions. J Contemp Dent Pract 2003;4:10-31. Scully C, Bagan JV. Adverse drug reactions in the orofacial region. Crit Rev Oral Biol Med 2004;15:221-39. Henkin RI. Drug-induced taste and smell disorders. Incidence, mechanisms and management related primarily to treatment of sensory receptor dysfunction. Drug Saf 1994;11:318-77.
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Figure 1. Drug-induced oral candidiasis affecting the soft palate, uvula and oropharynx. Image courtesy of Dr. Pallavi Parashar
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Figure 2. Drug-induced oral ulcerations typically appear on labial or buccal mucosa as aphthous stomatitis. Image used with permission from VisualDx.
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Figure 3. Chemotherapy-induced mucositis contributes significantly to pain, difficulty with oral function, and poor quality of life. Image used with permission from Sook-Bin Woo, MS, DMD, MMSc and VisualDx.
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Figure 4. Lichenoid drug reaction is often indistinguishable in clinical appearance from oral lichen planus. Image used with permission from Carl Allen, DDS, MSD and VisualDx.
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Table 1. Drugs that cause dry mouth by decreasing salivary flow.
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alpha receptor antagonists amphetamines anticancer drugs (cytotoxic drugs) anticholinergics antidepressants (selective serotonin reuptake inhibitors; norepinephrine/serotonin reuptake inhibitors; tricylics) antihistamines anti-HIV drugs antihypertensives antimigraine drugs antipsychotics appetite suppressants benzodiazepines bronchodilators cytokines (inferons) decongestants diuretics drugs of abuse (cannabis, Ecstasy) H2 receptor blockers muscarinic receptor antagonists opioids proton pump inhibitors retinoids sedatives skeletal muscle relaxants sympathomimetics Adapted from: Scully C. Drug effects on salivary glands: dry mouth. Oral Dis 2003;9:165-76; Abdollahi M, Radfar M. A review of drug-induced oral reactions. J Contemp Dent Pract 2003;4:10-31; Scully C, Bagan JV. Adverse drug reactions in the orofacial region. Crit Rev Oral Biol Med 2004;15:221-39.
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Table 2. Drugs that cause oral candidiasis.
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anticancer drugs antimicrobials (e.g. cephalosporins, ciprofloxacin, clarithromycin, penicillins) corticosteroids griseofulvin immunosuppressants (e.g. cyclosporine, tacrolimus) olanzapine omeprazole oral contraceptives Adapted from: Abdollahi M, Radfar M. A review of drug-induced oral reactions. J Contemp Dent Pract 2003;4:10-31; Scully C, Bagan JV. Adverse drug reactions in the orofacial region. Crit Rev Oral Biol Med 2004;15:221-39.
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Table 3. Risk reduction strategies to prevent and/or minimize oral fungal infections. Therapeutic strategies to reduce risk for treatment failure: Encourage compliance with antifungal therapy
Dispose of contaminated toothbrushes and cosmetics
Treat dentures, mouthguards and appliances with antifungal drugs
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Preventive strategies to reduce risk for recurrence: Use antimicrobial mouthrinses twice daily according to manufacturers’ directions
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Teach patients and their caregivers to perform daily denture care
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Table 4. Drugs associated with causing oral ulceration.
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ACE inhibitors (captopril) alendronate angiotensin II receptor blockers (losartan) anticancer drugs atypical antipsychotics (olanzapine) beta blockers gold salts immunosuppressants (azathioprine, cyclosporine, interferons, mycophenolate, tacrolimus) nonsteroidal antiinflammatory drugs (NSAIDS) protease inhibitors (indinavir) selective serotonin reuptake inhibitors (fluoxetine, sertraline) sulfonamides Adapted from: Abdollahi M, Radfar M. A review of drug-induced oral reactions. J Contemp Dent Pract 2003;4:10-31; Scully C, Bagan JV. Adverse drug reactions in the orofacial region. Crit Rev Oral Biol Med 2004;15:221-39.
Table 5. Evidence-based interventions for managing oral mucositis in patients undergoing cancer therapy. 24
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Intervention Indication palifermin (Kepivance®): human oral mucositis observed with stem cell recombinant keratinocyte growth transplants factor cryotherapy (ice) chemotherapy-induced oral mucositis amifostine radiation-induced oral mucositis Source: Keefe DM, Schubert MM, Elting LS, Sonis ST, Epstein JB, Raber-Durlacher JE, Migliorati CA, McGuire DB, Hutchins RD, Peterson DE; Mucositis Study Section of the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology. Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer 2007;109:820-31.
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allopurinal antiarrhythmics (quinidine, procainamide) antihypertensives (ACE inhibitors, beta blockers, diuretics) antimalarials (chloroquine, hydroxychloroquine, quinidine) carbamazepine lithium metals (gold salts, mercury) metformin methyldopa NSAIDS oral contraceptives penicillins phenothiazines phenytoin protease inhibitors rifampin streptomycin sulfasalazine sulfonamides tetracyclines tolbutamide
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Table 6. Examples of drugs that may cause lichenoid drug reaction.
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Table 7. Resources for dental professionals to support decision-making with medication use at the point of care. Chairside Reference Texts
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Wynn R, Crossley H, Meiller T. Drug Information Handbook for Dentistry, ed. 19. Hudson:OH. Lexi-Comp, Inc., 20132014.
Newland RJ, Meiller T, Wynn R, Crossley H. Oral Soft Tissue Diseases. ed. 6. Hudson:OH. Lexi-Comp, Inc., 2013-2014 Pickett FA, Terezhalmy. Dental Drug Reference with Clinical Implications. ed 2. Baltimore: Lippincott Williams & Wilkins, 2009.
Subscription Electronic Drug Databases Lexicomp® Online™ for Dentistry www.lexi.com
Natural Standard Research Collaboration http://www.naturalstandard.com/
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