Drug Hypersensitivity Associated with Dental TreatmentsABSTRACT
Objective: To characterize drug hypersensitivity associated with dental treatments.
Material and Methods: Data from 5,302 dental patients extracted from the Faculty of Dental Medicine were used to investigate drug use history, drug hypersensitivity, and associations with oral health outcomes. The chi-square test was used, and values of p ≤ 0.05 were considered statistically significant.
Results: The frequency of patients’ self-reported drug hypersensitivity was 26.42% (n = 1,401). The highest frequencies were for opioid/narcotic analgesics (20.84%, n = 292), antibiotics (18.13%, n = 961), and non-steroidal anti-inflammatory drugs (10.46%, n = 141). Most of the patients (68.65%, n = 3,640) reported using medications, mostly for cardiovascular disease (43.1%, n = 1,569), for psychiatric/neurological disorders (39.75%, n = 1,447), drugs that affect the endocrine system (32.55%, n= 1,185), and drugs for pain (24.92%, n = 907). Higher drug hypersensitivity frequencies were associated with older White female subjects (p<0.0001). Associations were also identified between drug hypersensitivity and history of the following dental procedures: tooth extractions (p=0.003), root canal treatment (p=0.0004), prosthodontic treatments (p<0.0001), and orthodontic treatments (p=0.007).
Conclusion: A high frequency of self-reported drug hypersensitivity in dental patients was found, with a higher occurrence in older White women and those with a history of more extensive and invasive dental care.
Keywords: Drug hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Drug Reactions; Adverse; Dental Care
Introduction
Drug hypersensitivity (DH) is defined as an undesirable effect resulting from drug use that may or may not involve the immune system [1]. Previous studies suggested that these events affect about 5 to 25% of the population and are influenced by factors such as sex, age, ethnicity, and history of drug use [2-4].
Diagnosis of DH, in general, involves laboratory tests, dermatological tests, drug provocation tests, and predictive analysis using pharmaco-genetic biomarkers, which are not as frequently conducted. Major clinical events are characterized by immediate reactions, including airway obstruction, hypotension, diarrhea, rash, pruritus, and commonly followed by small pustules, fever, fatigue, nausea, and abdominal pain [5]. This represents the greatest challenge when initiating drug therapy, which may also worsen the patient’s health status who is often already weakened by the health problem motivating the search for care.
Dental treatment often involves the use of drugs to help restore the patient's health, to control trans and postoperative pain, or even to alleviate anxiety associated with treatment. Local anesthetics, analgesics, anti-inflammatory agents, antibiotics, and sedatives are frequently used [6,7]. However, to the best of our knowledge previous studies have never characterized demographic and risk factors related to dental prescription and DH. Thus, there is a need for more studies that elucidate these factors.
Our study characterizes DH occurrences in dental practice with the ultimate goal of contributing to future predictability analyses for the occurrence of new events. Further, we provide dental patient characteristics associated with drug hypersensitivity and we believe that our results will support future studies aiming to implement effective and safer dental treatment plans.
Material and Methods
Data Collection and Ethical Clearance
Medical and dental histories were obtained through the Dental Registry and DNA Repository project of the School of Dental Medicine, University of Pittsburgh, United States. The total cohort consisted of 6,690 subjects. After excluding individuals with incomplete data, 5,302 subjects were included in the analysis. The project was approved by the University of Pittsburgh Institutional Review Board.
Demographic data (age, sex, ethnicity, and education), oral health information history (experiences with dental procedures), drugs used, and self-reported drug hypersensitivity were collected. Figure 1 illustrates the main variables included.
To analyze the drugs used, categorization was performed considering the most used drugs. For therapeutic purposes, the following categories were generated: drugs for psychiatric or neurological disorders, drugs for allergies, drugs for pain control, drugs for birth control, drugs for cardiovascular diseases, antimicrobials (antibiotics, antivirals and antifungals), drugs for gastric diseases (acid inhibitors), drugs that affect the endocrine system (steroidal and non-steroidal anti-inflammatory drugs, hormones, and drugs to treat diabetes), vitamins and supplements, as well as others drugs.
For the "other drugs" category, the following groups were considered: muscle relaxants, laxatives, bronchodilators, anticholesterol medications, anticancer, uric acid reducers, anticoagulants, antispasmodics, antiemetics, drugs for intestinal disorders, glaucoma, smoking cessation, nausea, vomiting, sexual dysfunction, pancreas disease, anemia, liver disease, bone disorders, and urinary disorders.
The self-reported drug hypersensitivity analysis considered the following categories: antibiotics (in general), penicillin, cephalosporin, sulfa drugs, macrolides, others antibiotics, NSAIDs (non-steroidal anti-inflammatory drugs), opioid/narcotic analgesics, local anesthetics, and others drugs (citalopram, promethazine, benzoyl, ketamine, metoclopramide, rufinamide, ranitidine, phenytoin, acetaminophen, lithium, diphenhydramine, lamotrigine, fenofibrate, heparin, haloperidol, sertraline, gabapentin, diltiazem, insulin, metformin, meperidine, terfenadine, atorvastatin, pseudoephedrine, enoxaparin, metoprolol, acetazolamide, loratadine, lisinopril, enalapril, quinidine, primidone, nitrofurantoin, linagliptin, and hydroxyzine.
Data Analysis
The data collected were analyzed using Jamovi software version 1.8 (http://www.jamovi.org). To verify the association between self-reported drug hypersensitivity and experiences with dental procedures, the chi-square test was used. Values of p ≤ 0.005 were considered statistically significant.
Results
Our findings revealed that 26.42% (n=1,401) of the individuals analyzed reported a history of drug hypersensitivity (versus 73.58%; n= 3,901, who reported no hypersensitivity). Regarding antibiotics in general, it was found that 18.13% (n=913) reported hypersensitivity. In relation to the type of drug, the most frequent were opioid/narcotic analgesics (20.84%, n=292), antibiotics (18.13%, n=961), especially penicillin (11.81%, n=626), and non-steroidal anti-inflammatory drugs (10.46%, n=141). Table 1 summarizes the results for self-reported drug hypersensitivity.
Most of the individuals included in the survey were chronic users of some type of drug (68.65%, n=3,640), with higher frequencies for drugs treating cardiovascular disease (43.10%, n=1,569), psychiatric/neurological disorders (39.75%, n=1,447), drugs that affect the endocrine system (32.55%, n=1,185), and drugs for pain (24.92%, n=907) (Table 2).
Our data suggested that White women aged 60 years and over were associated with self-reported drug hypersensitivity (p<0.0001). In addition, a higher self-reported drug hypersensitivity frequency was observed for individuals with a history of dental treatment in the areas of oral surgery, root canal treatment, prosthodontics, and orthodontics) (Table 3).
Association between self-reported drug hypersensitivity and demographic data/oral health history.
Discussion
This study evaluated the self-reported frequency of drug hypersensitivity in dental patients and, therefore, embodies the idea that such events, whether involving an immune response or not, can be characterized as adverse drug events. Data used here refers to the use of drugs prescribed by the dentist or not and involves all classes of available drugs. This may help to explain the high self-reported drug hypersensitivity frequency observed. Similar results were obtained in a prior study performed using medical only electronic health records of 411,543 patients in San Diego County, US [8]. In general, previous studies assessed the occurrence of DH for specific classes of drugs or adverse effects, often with laboratory confirmation [9,10].
High drug hypersensitivity frequencies were observed for antibiotics, especially beta-lactams and sulfa drugs, medications frequently prescribed by dentists, as most oral diseases are of infectious origin. Antibiotics are the most common cause of DH, which can include anaphylaxis, angioedema, orofacial angioedema, and adverse skin reactions such as flushing, itching, and hives [11,12]. The use of sulfonamide antibiotics is also responsible for a high frequency of self-reported DH [13], characterized by cutaneous reactions [14].
Inflammatory reactions during dental treatment are often managed with the use of pharmacological agents. Our results indicated that non-steroidal anti-inflammatory drugs (NSAIDs) are the therapeutic class with the second highest frequency of self-reported drug hypersensitivity. This result is similar to a previous study, with the main manifestations occurring in the respiratory tract, the skin (urticaria), or as a generalized effect (anaphylaxis) [15].
The self-reported frequency of drug hypersensitivity can be explained in part, by higher exposure than expected of the individuals included in the sample to drugs in general. In this study, we observed a high frequency of individuals using drugs for cardiovascular diseases, drugs that affect the endocrine system, drugs for psychiatric/neurological disorders, and for pain control. In general, these people use two or more drugs continuously. The American Heart Association, in conjunction with the National Institutes of Health, indicated that to avoid heart disease, blood pressure, obesity, and high blood cholesterol, lipids must be controlled [16]. Psychiatric disorders and abuse of opioid analgesics occur frequently in the US adult population, which also may explain the data observed in our study [17,18].
Our study indicated a higher frequency of self-reported drug hypersensitivity in White women aged 60 years and older. Similar data have been reported in previous studies [13,19]. To avoid undesirable effects from the use of medications, the identification of high-risk individuals is an important strategy since complications during dental treatment may even result in hospitalizations.
The higher frequency of drug hypersensitivity in women has been reported in other studies [20-22]. Although the role of sex as a factor in provoking drug hypersensitivity is not well understood, pharmacokinetic alterations might predict its higher occurrence in women, who generally present lower body weights and higher fat percentages but are prescribed the same dosages as the ones prescribed to men. Most of the research on this subject was conducted in male subjects, and the aforementioned factors, such as body weight directly affect drug absorption and distribution, which highlights the need for precision medicine efforts in the development of more inclusive clinical pharmacological studies [23].
Older adults tend to be more prone to drug hypersensitivity as well [24]. In addition to using drugs more often, older adults may present physiological changes involving reduced liver and kidney capacity, respectively, for metabolizing and eliminating drugs [25,26]. In addition, decreases in circulating plasma proteins, such as albumin, directly impact drug distribution, promoting exacerbation of pharmacological effects and/or the emergence of adverse effects [16].
In people with a history of dental treatments, our findings revealed a positive association between self-reported drug hypersensitivity and oral surgery (mostly for tooth extractions), root canal treatments, and prosthodontics. Dental procedures performed in these areas are invasive and often require drug therapy. In addition, most of the people treated in prosthodontics clinics are older adults.
Since this is the first report on this subject, our study warrants further investigations to test the hypothesis that the very drugs most often prescribed by dentists promote high frequencies of drug hypersensitivity. However, our results reinforce the need for careful anamnesis and thorough medication history for prior occurrences of drug hypersensitivity. This would favor implementation of a safer and more effective dental treatment plans.
Conclusion
A high frequency of self-reported drug hypersensitivity in dental patients was found, with a higher occurrence in older White women and those with a history of more extensive and invasive dental care.
Data Availability
The data used to support the findings of this study can be made available upon request to the corresponding author.
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Financial SupportThis work was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001.
References
-
[1] Dykewicz MS, Lam JK. Drug hypersensitivity reactions. Med Clin North Am 2020; 104(1):109-128. https://doi.org/10.1016/j.mcna.2019.09.003
» https://doi.org/10.1016/j.mcna.2019.09.003 -
[2] Kvedariene V, Sitkauskiene B, Tamasauskiene L, Rudzeviciene O, Kasiulevicius V, Nekrosyte G, et al. Prevalence of self-reported drug hypersensitivity reactions among Lithuanian children and adults. Allergol Immunopathol 2019; 47(1):32-37. https://doi.org/10.1016/j.aller.2018.05.006
» https://doi.org/10.1016/j.aller.2018.05.006 -
[3] Rubio M, Bousquet P-J, Gomes E, Romano A, Demoly P. Results of drug hypersensitivity evaluations in a large group of children and adults. Clin Exp Allergy 2012; 42(1):123-130. https://doi.org/10.1111/j.1365-2222.2011.03887.x
» https://doi.org/10.1111/j.1365-2222.2011.03887.x -
[4] Sousa-Pinto B, Fonseca JA, Gomes ER. Frequency of self-reported drug allergy: A systematic review and meta-analysis with meta-regression. Ann Allergy Asthma Immunol 2017;119(4):362-373. https://doi.org/10.1016/j.anai.2017.07.009
» https://doi.org/10.1016/j.anai.2017.07.009 -
[5] Böhm R, Proksch E, Schwarz T, Cascorbi I. Drug hypersensitivity: Diagnosis, genetics, and prevention. Dtsch Arztebl Int 2018; 115(1): 29-30. https://doi.org/10.3238/arztebl.2018.0501
» https://doi.org/10.3238/arztebl.2018.0501 -
[6] Becker DE Adverse drug reactions in dental practice. Anesth Prog 2014; 61 (1):26-34. https://doi.org/10.2344/0003-3006-61.1.26
» https://doi.org/10.2344/0003-3006-61.1.26 -
[7] Stein K, Farmer J, Singhal S, Marra F, Sutherland S, Quiñonez C. The use and misuse of antibiotics in dentistry: A scoping review. J Am Dent Assoc 2018; 149(10):869-884. https://doi.org/10.1016/10.1016/j.adaj.2018.05.034
» https://doi.org/10.1016/10.1016/j.adaj.2018.05.034 -
[8] Macy E, Poon K-YT. Self-reported antibiotic allergy incidence and prevalence: Age and sex effects. Am J Med 2009; 122(8):778-e1-7. https://doi.org/10.1016/j.amjmed.2009.01.034
» https://doi.org/10.1016/j.amjmed.2009.01.034 -
[9] Duong TA, Valeyrie-Allanore L, Wolkenstein P, Chosidow O. Severe cutaneous adverse reactions to drugs. Lancet 2017; 390(10106):1996-2011. https://doi.org/10.1016/S0140-6736(16)30378-6
» https://doi.org/10.1016/S0140-6736(16)30378-6 -
[10] Guvenir H, Misirlioglu ED, Capanoglu M, Buyuktiryaki B, Onay ZR, Ginis T, et al.The frequency of nonsteroidal anti-inflammatory drug hypersensitivity in children with asthma. Int Arch Allergy Immunol 2018; 176(1):26-32. https://doi.org/10.1159/000487305
» https://doi.org/10.1159/000487305 -
[11] Khan DA, Banerji A, Bernstein JA, Bilgicer B, Blumenthal K, Castells M, et al. Cephalosporin allergy: Current understanding and future challenges. J Allergy Clin Immunol Pract 2019; 7(7):2105-2114. https://doi.org/10.1016/j.jaip.2019.06.001
» https://doi.org/10.1016/j.jaip.2019.06.001 -
[12] Blumenthal KG, Peter JG, Trubiano JA, Phillips EJ. Antibiotic allergy. Lancet 2019; 393(10167):183-198. https://doi.org/10.1016/S0140-6736(18)32218-9
» https://doi.org/10.1016/S0140-6736(18)32218-9 -
[13] Vardakas KZ, Kalimeris GD, Triarides NA, Falagas ME. An update on adverse drug reactions related to β-Lactam antibiotics. Expert Opin Drug Saf 2018; 17(5):499-508. https://doi.org/10.1080/14740338.2018.1462334
» https://doi.org/10.1080/14740338.2018.1462334 -
[14] Dibbern Jr DA, Montanaro A. Allergies to sulfonamide antibiotics and sulfur-containing drugs. Allergy Asthma Immunol 2008; 100(2):91-101. https://doi.org/10.1016/S1081-1206(10)60415-2
» https://doi.org/10.1016/S1081-1206(10)60415-2 -
[15] Sánchez-Borges M, Caballero-Fonseca F, Capriles-Hulett A, González-Aveledo L. Hypersensitivity reactions to nonsteroidal anti-inflammatory drugs: An update. Pharmaceuticals 2010; 3(1):10-18. https://doi.org/10.3390/ph3010010
» https://doi.org/10.3390/ph3010010 -
[16] Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, et al. Heart disease and stroke statistics-2020 update: A report from the American Heart Association. Circulation 2020; 141(9):e139-596. https://doi.org/10.1161/CIR.0000000000000757
» https://doi.org/10.1161/CIR.0000000000000757 -
[17] Hasin DS, Sarvet AL, Meyers JL, Saha TD, Ruan WJ, Stohl M, et al. Epidemiology of adult DSM-5 major depressive disorder and its specifiers in the United States. JAMA Psychiatry 2018; 75(4):336-346. https://doi.org/10.1001/jamapsychiatry.2017.4602
» https://doi.org/10.1001/jamapsychiatry.2017.4602 -
[18] Vadivelu N, Kai AM, Kodumudi V, Sramcik J, Kaye AD. The opioid crisis: A comprehensive overview. Curr Pain and Headache Rep 2018; 22(3):1-6. https://doi.org/10.1007/s11916-018-0670-z
» https://doi.org/10.1007/s11916-018-0670-z -
[19] Gomes E, Cardoso MF, Praca F, Gomes L, Mariño E, Demoly P. Self-reported drug allergy in a general adult Portuguese population. Clin Exp Allergy 2004; 34(10):1597-1601. https://doi.org/10.1111/j.1365-2222.2004.02070.x
» https://doi.org/10.1111/j.1365-2222.2004.02070.x -
[20] Greil W, Zhang X, Stassen H, Grohmann R, Bridler R, Hasler G, et al. Cutaneous adverse drug reactions to psychotropic drugs and their risk factors - A case-control study. Eur Neuropsychopharmacol 2019; 29(1):111-121. https://doi.org/10.1016/j.euroneuro.2018.10.010
» https://doi.org/10.1016/j.euroneuro.2018.10.010 -
[21] Tharpe N. Adverse drug reactions in women’s health care. J Midwifery Women’s Health 2011; 56(3):205-213. https://doi.org/0.1111/j.1542-2011.2010.00050.x
» https://doi.org/0.1111/j.1542-2011.2010.00050.x - [22] Nakagawa K, Kajiwara A. Female sex as a risk factor for adverse drug reactions. Nihon Rinsho 2015; 73(4):581-585.
-
[23] Zucker I, Prendergast BJ. Sex differences in pharmacokinetics predict adverse drug reactions in women. Biol Sex Differ 2020;11(1):1-14. https://doi.org/10.1186/s13293-020-00308-5
» https://doi.org/10.1186/s13293-020-00308-5 -
[24] Oscanoa TJ, Lizaraso F, Carvajal A. Hospital admissions due to adverse drug reactions in the elderly. A meta-analysis. Eur J Clin Pharmacol 2017; 73(3):759-770. https://doi.org/10.1007/s00228-017-2225-3
» https://doi.org/10.1007/s00228-017-2225-3 -
[25] Dong MH, Bettencourt R, Barrett-Connor E, Loomba R. Alanine aminotransferase decreases with age: The Rancho Bernardo Study. PloS One 2010; 5(12):e14254. https://doi.org/10.1371/journal.pone.0014254
» https://doi.org/10.1371/journal.pone.0014254 -
[26] Waring RH, Harris RM, Mitchell SC. Drug metabolism in the elderly: A multifactorial problem? Maturitas 2017; 100:27-32. https://doi.org/10.1016/j.maturitas.2017.03.004
» https://doi.org/10.1016/j.maturitas.2017.03.004
Edited by
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Academic Editor: Alessandro Leite Cavalcanti
Publication Dates
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Publication in this collection
01 July 2024 -
Date of issue
2024
History
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Received
13 Dec 2022 -
Reviewed
27 Oct 2023 -
Accepted
19 Nov 2023
