Amlodipine-Induced Gingival Overgrowth: A Health Justice Issue

Open AccessPublished:November 14, 2021DOI:https://doi.org/10.1016/j.nurpra.2021.10.014

      Highlights

      • Amlodipine is prescribed over 70 million times a year in the United States.
      • Gingival overgrowth is an underappreciated side effect of amlodipine and is more common in patients with poor dental hygiene.
      • Unchecked, gingival overgrowth can lead to pain, tooth loss, financial hardship, and psychosocial suffering.
      • Black/African American patients specifically face a triple threat of higher rates of hypertension and its complications, fewer choices for first-line treatment, and high rates of poverty limiting access to dental care.
      • Simple steps can be taken to avoid this adverse effect, including educating patients about this possible outcome, emphasizing the importance of good oral hygiene, and taking baseline photographs of gums.

      Abstract

      Hypertension is a leading cause of death and disability in the United States and worldwide. As primary care clinicians, nurse practitioners help patients control their blood pressure through lifestyle coaching and medication. Among the first-line medications for hypertension are calcium channel blockers, such as amlodipine. In the US, over 70 million prescriptions for amlodipine are written annually. Here we present a case report of a significant adverse event due to the use of amlodipine—gingival overgrowth. We review the pathophysiology, prevalence, and clinical management of gingival overgrowth. We also expand the understanding of this phenomenon by exploring the serious health justice implications of this adverse effect. Unchecked, gingival overgrowth can lead to tooth movement and eventual loss. Dental changes also cause pain, financial hardship, and psychosocial damage. Patients in poverty are at much greater risk for this adverse outcome due to limited access to dental care. Black patients specifically face a triple threat with higher rates of hypertension and its complications, guidelines that limit therapeutic options for first-line treatment, and high rates of poverty limiting access to dental care.

      Keywords

      Case Presentation

      A 52-year-old with hypertension, left ventricular hypertrophy, prediabetes, chronic right shoulder pain, and a body mass index of 32 presented to his primary care clinic for a blood pressure check. His medications included amlodipine 10 mg daily, lisinopril 40 mg daily, and hydrochlorothiazide 25 mg daily. He had been on this regimen for the past 7 years. He did not use any supplements or over-the-counter medication on a regular basis. He had no history of hospitalization or surgery. His father died of an unknown type of cancer at age 78. His mother had a history of hypertension and died of an unknown cause at age 72. He had 3 adult siblings: a sister who died of end-stage renal disease, a brother with type 2 diabetes, and a brother who had a stroke at age 59. Of his 3 adult children, 2 had hypertension. He was born in New York and had moved to San Francisco at the age of 6. He identified as a Black. He had completed high school and worked as a stay-at-home father, picking up work detailing cars when possible. He lived with his wife, a medical assistant; their 5-year-old daughter; and his wife’s adult daughter. The patient had never used tobacco, rarely used alcohol, and consumed 1 g of cannabis a day. He had a remote history of cocaine use.
      He reported that his teeth had been straightened with braces when he was in his teens. A few years after starting amlodipine, he noticed his teeth had started to move, although he did not connect these events. He had no history of oral surgery or gum trauma. He stated that he had not been to the dentist for years. He attributed his lack of dental care to a fear of the dentist, stemming from the orthodontic treatment he received as a teen. He also reported variable income that at times would make him ineligible for a medical/dental insurance subsidy but would not be sufficient to allow him to afford to buy health insurance. The patient did not have fevers; weight loss; headaches; vision changes; changes to voice or taste; difficulty swallowing; cough; chest pain; shortness of breath at rest, with exertion, or with lying flat; abdominal pain; problems with urination or bowel movements; muscle pain or weakness; rashes; nonhealing wounds; changes to hair, skin, or nails; or lower leg swelling.
      His blood pressure was 160/100 mm Hg. The rest of the vital signs were within normal limits. On physical examination, his gum tissue was firm, pink, moist, and overgrown, displacing most teeth (Figure). There were no abnormal findings on the heart and lung examinations. Recent laboratory data included the following: potassium = 3.6 mmol/L (3.5-5.1 mmol/L), blood urea nitrogen = 18 mg/dL (7-24 mg/dL), and creatinine = 1.05 mg/dL (0.7-1.4 mg/dL). A recent complete blood count with differential was within normal limits.
      Figure thumbnail gr1
      FigureA photograph of the patient presenting for routine primary care. The patient provided written permission for the use of the photograph.

      Amlodipine-Induced Gingival Overgrowth

      Amlodipine-induced gingival overgrowth (AIGO) is characterized by an increase in the volume of connective tissue matrix in the gingiva.
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      In vitro, gingival fibroblasts produce more collagen when exposed to amlodipine.
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      Calcium channel blockers (CCBs), such as amlodipine, are also known to downregulate the degradation of connective tissue fibers; collagenase is essential to connective tissue breakdown, and calcium is essential to collagenase activation. By blocking cytoplasmic uptake of calcium, CCBs disrupt the tissue breakdown pathway.
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      The incidence and severity of nifedipine-induced gingival overgrowth.
      The diagnosis of AIGO is usually based on the patient’s comorbidities, symptom constellation, medication profile, physical examination, and laboratory findings. A definitive diagnosis can be made with histology showing cell overgrowth in the absence of dysplasia or other abnormal findings.
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      Amlodipine-induced gingival enlargement: a case report.

       Prevalence

      AIGO may be more common than clinician- and patient-facing reference tools suggest. When prescribing medications, clinicians rely on drug reference tools like Lexicomp and Physician’s Desk Reference that provide up-to-date information on dosing, adverse effects, and monitoring parameters. According to these resources, the incidence of gingival overgrowth (GO) in patients taking dihydropyridine CCBs is less than 10% for nifedipine and less than 1% for amlodipine and felodipine (Lexicomp and Physician’s Desk Reference). Patient-facing resources like Drugs.com and WebMD do not mention GO, even among rare adverse effects.
      However, a review of the recent literature suggests that the prevalence of AIGO may be more than 1%. In the last 4 years alone, there have been over 17 published case studies describing AIGO.
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      Different treatment modalities for drug induced gingival overgrowth: a case series.
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      Appalling adverse effects of amlodipine in a chronic kidney disease patient: a case of drug-induced gingival overgrowth.
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      Amlodipine-induced gingival hyperplasia.
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      A rare case of accelerated gingival overgrowth with high dose amlodipine therapy.
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      • Shome S.
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      In addition to case reports, research also indicates that the prevalence of AIGO may be greater than 1%. Some studies suggest that the prevalence of AIGO is only slightly more common than drug reference guides suggest (ie, < 1%). For example, a retrospective study of over 500 patients in a Nepalese health system found that 2.5% of the patients taking amlodipine developed gingival overgrowth.
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      Amlodipine induced gingival overgrowth in patients at a tertiary level hospital of Nepal.
      Likewise, a retrospective study of about 100 patients in India found a 3.4% prevalence of AIGO.
      • Tejnani A.
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      • et al.
      Incidence of amlodipine-induced gingival overgrowth in the rural population of Loni.
      However, other research points to a much higher rate of AIGO. A 2015 Indian study by Gopal et al
      • Gopal V.
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      • Chainani-Wu N.
      Amlodipine-induced gingival overgrowth with unusual presentation as a gingival mass and rapid regression after dose reduction.
      examined the gums of 133 patients who had been taking amlodipine for at least 3 months. These researchers found evidence of gingival overgrowth in 31.4% of patients. They noted that the duration or dose of medication did not affect overgrowth. The data also showed that baseline gingivitis was more common among those with AIGO. Another study from India looked at the gums of 100 patients taking amlodipine for blood pressure control. These investigators found gingival overgrowth in 61.8% of patients.
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      • Rajan P.B.
      Amlodipine-induced gingival overgrowth.
      They too did not note a correlation between AIGO and the dose or the duration of amlodipine use. A 2020 convenience sample of 130 Turkish patients with hypertension found a 32% prevalence of AIGO.
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      Finally, a retrospective study of 100 Nigerian patients found a 37% prevalence of AIGO.
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      • Bello B.T.
      Effect of calcium channel blockers on gingival tissues in hypertensive patients in Lagos, Nigeria: a pilot study.
      A meta-review of 13 articles of original research, including all but the most recent study mentioned previously, found the prevalence of AIGO to be 26.7%.
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      There are significant limitations to the body of literature on AIGO. To date, there have been no prospective cohort or randomized controlled trials investigating this particular adverse event. Additionally, the preponderance of the evidence from these convenience samples and retrospective analyses is from developing countries where access to dental care is limited, thus confounding the data.

       Risk Factors

      Risk factors for drug-induced gingival overgrowth include poor oral hygiene, male sex, genetic predisposition, and possibly being a middle-aged adult.
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      Amlodipine-induced gingival enlargement: a case report.
      ,
      • Gaur S.
      • Agnihotri R.
      Is dental plaque the only etiological factor in Amlodipine induced gingival overgrowth? A systematic review of evidence.
      Gingivitis due to poor oral hygiene is the most commonly cited modifiable risk factor.
      • Quenel L.
      • Keribin P.
      • Giran G.
      • Tessier M.H.
      • Lesclous P.
      Amlodipine-induced gingival enlargement: a case report.
      Gingivitis triggers the release of cytokines, leading to fibroblast cell proliferation and a subsequent increase in collagen synthesis.
      • Matsuda S.
      • Okanobu A.
      • Hatano S.
      • et al.
      Relationship between periodontal inflammation and calcium channel blockers induced gingival overgrowth—a cross-sectional study in a Japanese population.
      Amlodipine simply amplifies this existing pathway by accelerating matrix buildup and inhibiting matrix breakdown.
      • Livada R.
      • Shiloah J.
      Calcium channel blocker-induced gingival enlargement.
      Studies suggest sex plays a role in the development of AIGO because males are more susceptible than females. CCBs can impact androgen metabolism by converting testosterone into an active metabolite, which appears to induce collagen synthesis or prevent its degradation by targeting certain populations of fibroblasts.
      • Gaur S.
      • Agnihotri R.
      Is dental plaque the only etiological factor in Amlodipine induced gingival overgrowth? A systematic review of evidence.
      In terms of age, gingival overgrowth is most commonly observed in men in their fourth or fifth decade of life. However, it is difficult to be certain that this age group is at higher risk for this complication because the data are skewed. Most patients are started on amlodipine in middle age, so the higher prevalence of AIGO in middle-aged patients could simply be a function of higher rates of antihypertensive medications for these patients.
      • Gaur S.
      • Agnihotri R.
      Is dental plaque the only etiological factor in Amlodipine induced gingival overgrowth? A systematic review of evidence.
      Genetic risk factors include polymorphisms in genes that regulate inflammatory pathways and genes that regulate drug metabolism.
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      For example, patients with AIGO have higher cytosolic concentrations of a protein that blocks apoptosis.
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      • Noyan U.
      • et al.
      The gingival crevicular fluid levels of growth factors in patients with amlodipine-induced gingival overgrowth: a pilot study.
      Apoptosis helps limit inflammation by causing cell lysis; without this intervention, cell cycles are longer, and cells can grow larger. Researchers speculate that a genetic polymorphism may increase expression of this apoptosis-blocking protein. Additionally, studies show higher levels of interleukin 1a (IL-1A) in AIGO gum tissue.
      • Lauritano D.
      • Martinelli M.
      • Baj A.
      • et al.
      Drug-induced gingival hyperplasia: an in vitro study using amlodipine and human gingival fibroblasts.
      IL-1A upregulates cytokine production, driving inflammation. Upregulated production of IL-1A suggests another possible genetic predisposition to AIGO. Finally, Quenel et al
      • Quenel L.
      • Keribin P.
      • Giran G.
      • Tessier M.H.
      • Lesclous P.
      Amlodipine-induced gingival enlargement: a case report.
      reported that amlodipine is metabolized in the liver by the cytochrome P450 pathway. They noted that cytochrome P450 is known to have many polymorphisms and speculate that 1 of the polymorphisms may predispose patients to be responders.
      • Quenel L.
      • Keribin P.
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      • Lesclous P.
      Amlodipine-induced gingival enlargement: a case report.

       Clinical Diagnosis

      Patients with GO may complain of pain with eating, loose or painful teeth, and bleeding of gums during oral hygiene activities.
      • Tungare S.
      • Paranjpe A.G.
      Drug induced gingival overgrowth (DIGO).
      Signs of GO include hypertrophy of gum tissue, widening gaps between teeth, and loose teeth.
      • Renzo G.
      • Dario N.D.
      • Gianfranco G.
      • Gabriele M.
      • Luca T.
      The management of amlodipine-induced gingival overgrowth associated to generalized chronic periodontitis-a case report.
      ,
      • Gopal V.
      • Quo B.C.
      • Chainani-Wu N.
      Amlodipine-induced gingival overgrowth with unusual presentation as a gingival mass and rapid regression after dose reduction.
      Although the gum itself may be enlarged, there should be no pus, tenderness, or redness of the gingiva; these features are suggestive of infection or of a more sinister cause of the overgrowth like cancer.
      • Quenel L.
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      • Giran G.
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      • Lesclous P.
      Amlodipine-induced gingival enlargement: a case report.

       Management

      When encountered with gum overgrowth, prescribers should explore a wide range of possible causes, including other medications, autoimmune disease, and cancer.
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      Amlodipine-induced gingival enlargement: a case report.
      Focal red, tender lesions can be a rare initial presentation of sarcoidosis.
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      Diffuse gingival enlargement with associated cytopenia necessitates the consideration of acute myeloid leukemia.
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      Gum overgrowth with associated fatigue, weight loss, and gastrointestinal symptoms should trigger nurse practitioners (NPs) to consider an atypical presentation of Crohn disease.
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      If there are no concerning signs or symptoms that may indicate serious pathology and if the swelling started any time after the initiation of amlodipine, drug-induced GO should be at the top of the differential. Amlodipine should be immediately discontinued and replaced with a different antihypertensive medication recommended by national guidelines.
      • Quenel L.
      • Keribin P.
      • Giran G.
      • Tessier M.H.
      • Lesclous P.
      Amlodipine-induced gingival enlargement: a case report.
      Amlodipine should also be added to the patient’s list of adverse drug reactions to ensure it is not restarted. If the overgrowth is identified before teeth move and/or become loose, the gum enlargement will likely regress a few months after the discontinuation of amlodipine.
      • Gopal V.
      • Quo B.C.
      • Chainani-Wu N.
      Amlodipine-induced gingival overgrowth with unusual presentation as a gingival mass and rapid regression after dose reduction.
      The patient should be counseled on the importance of oral hygiene and referred to a dental provider for evaluation and routine care.
      • Quenel L.
      • Keribin P.
      • Giran G.
      • Tessier M.H.
      • Lesclous P.
      Amlodipine-induced gingival enlargement: a case report.
      If GO is not recognized until gum overgrowth has caused teeth to move and/or loosen, the offending medication (ie, amlodipine) should still be replaced with a medication from a different class to prevent progression.
      • Quenel L.
      • Keribin P.
      • Giran G.
      • Tessier M.H.
      • Lesclous P.
      Amlodipine-induced gingival enlargement: a case report.
      These patients should also be referred to an oral surgeon; oral surgery providers will consider tooth extraction, gum scaling, and surgical resection of the enlarged tissue.
      • Kumar S.
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      • Srivastava A.
      • Agarwal A.
      Management of amlodipine-induced gingival enlargement–a case report.
      Additional considerations for patients with advanced GO include referral to behavioral health for psychosocial support and for help finding financial resources for needed dental work that is not covered by insurance, including implants, bridges, or dentures if teeth extractions are warranted.

      Case Study Outcome

      The patient was advised to immediately stop amlodipine. Although the patient’s blood pressure was above goal, the patient had endorsed poor adherence to the treatment regimen. The patient was given a blood pressure kit with a log, asked to check his blood pressure at home once a day, and encouraged to take his remaining blood pressure medications (lisinopril and hydrochlorothiazide) regularly. He was scheduled to return to the clinic in 2 weeks for a review of his home blood pressure readings and a clinic-based blood pressure reading. The plan was to add spironolactone if his blood pressure remained above the goal of less than 130/80 mm Hg.
      The patient missed the follow-up visit and then soon after lost his health insurance. After a year of no continuous coverage, the patient finally found full-time employment. A few months later, he established care with an outside health system covered by his new employer’s insurance plan. He continues to struggle with loose and disorganized teeth, causing pain, difficulty eating, and psychological injury. He is working with his new health care providers to achieve control of his blood pressure. He is also planning to have all of his teeth extracted within the coming months.

      Discussion

      The most significant risk factor for developing gum overgrowth while taking amlodipine is gingivitis.
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      Amlodipine-induced gingival enlargement: a case report.
      Gingivitis is prevented with a rigorous home dental hygiene routine and regular professional teeth cleaning.
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      Amlodipine-induced gingival enlargement: a case report.
      In the United States, access to professional dental care is inextricably linked to income and insurance coverage.
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      A lack of access to dental care results in more dental decay and fewer dental visits for low-income patients.
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      Patients who opt to pay out of pocket for treatment may resort to predatory financing to pay for dental care. Both provider-based and third-party financing offer loans for dental services with interest varying from 3.45% to 35.99% annual percentage rate.
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      Patients who decide that the cost of dental care is unaffordable face different costs. Patients with untreated dental disease experience increased absenteeism from work due to dental symptoms and face reduced employability due to the stigma associated with poor oral health.
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      Another report concluded that less positive and more negative characteristics are attributed to individuals with greater dental defects.
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      Some individuals internalize this perception; more than 33% low-income adults with abnormal oral health conditions report not smiling with their teeth.
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      When it comes to AIGO, Black patients specifically face a triple risk of higher rates of hypertension, fewer guideline-driven options for first-line treatment, and higher rates of poverty. Black patients are more likely to need medication for blood pressure control because they have higher rates of hypertension than their White counterparts (46% vs 35%).
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      • Wu B.
      • et al.
      Low-income Californians and healthcare. The Henry J. Kaiser Family Foundation and California Health Care Foundation. 2019.
      When treating Black patients for hypertension, NPs rely on national guidelines that advocate for CCBs or thiazide diuretics as first-line therapy.
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      • et al.
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      These guidelines preclude the recommendation of renin-angiotensin-aldosterone system (RAAS) inhibitors as first-line monotherapy based on data from 1 study that found more adverse events when used as monotherapy in Black patients.
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      Some clinicians worry that this recommendation leads to underprescribing of RAAS inhibitors to Black patients who would benefit from them for blood pressure control. The recommendation also leads to CCBs being disproportionately prescribed to Black patients. Finally, Black patients are more likely to have limited access to professional dentistry due to poverty. In 2016, the national median net wealth for White households was $171,000, whereas that of Black households was $17,600, approximately 10% that of White households.
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      Implications for Practice

      This case highlights several targets for provider interventions. When starting CCBs, patients should be informed of this rare but serious adverse effect and told to report any teeth or gum changes immediately. If there are signs of overgrowth on examination, the NP should consider the broad array of disease that can drive gum overgrowth. If AIGO is suspected, amlodipine should be replaced immediately with a different class of antihypertensive medication. Amlodipine should be added to the patient’s list of adverse drug reactions so that it is not inadvertently restarted. The patient should also be immediately referred to a dentist or oral surgeon.
      Clinicians working with safety net populations should be particularly vigilant about GO when starting CCBs. Safety net populations have less access to dental care and so are at greater risk for gingivitis, the biggest risk factor for GO. Additionally, safety net populations have limited means to correct gum and tooth deformities due to advanced GO, meaning they may go longer without repair, as happened in this case study. Providers may consider taking yearly photographs of teeth to monitor for early signs of GO, especially in patients without access to dental care.
      For policy makers, there are also several targets for interventions. The Food and Drug Administration regularly recommends specific monitoring guidelines for medications. For example, patients taking the anti-inflammatory medication hydroxychloroquine are advised to get regular eye examinations to monitor for retinal toxicity, an adverse event in 7.5% of users.
      • Yusuf I.
      • Sharma S.
      • Luqmani R.
      • Downes S.
      Hydroxychloroquine retinopathy.
      The Food and Drug Administration could advise yearly dental examinations for patients taking amlodipine. More importantly, policy makers should have an eye toward fixing upstream drivers of health disparities. For example, the expansion of Medicaid to include dental care would catch early cases of GO and lower the incidence of advanced GO. Additionally, drug safety testing subject parameters could include income, specifically patients living below the poverty line. By including economic diversity, adverse effects due to conditions of poverty can be identified.
      The writers of hypertension treatment guidelines should consider noting the overlap of poverty, poor access to dental care, and increased risk for AIGO. Because guidelines specifically recommend CCBs and thiazide diuretics over RAAS inhibitors as initial monotherapy for Black patients without heart failure or chronic kidney disease, it is imperative to highlight the increased prevalence of the major risk factor (the lack of access to dental care) for developing this rare adverse effect. Both clinicians and policy makers should be aware that iatrogenic disease can erode patients’ trust in individual providers and in the health care system in general.
      Finally, the makers of electronic health record systems should integrate medical and dental systems. Without the ability to see each other’s notes, it is nearly impossible for either dental or medical providers to share clinical concerns and treatment plans.

      Next Steps for Research

      The actual rate of AIGO among Americans taking amlodipine is unknown because no recent studies have been conducted in this country. Prospective cohort or randomized controlled trials would help clarify the prevalence and risk factors for AIGO. In addition, researchers could query dental databases to investigate the prevalence of AIGO. Although a preliminary exploration of dental databases reveals problems, medication lists are incomplete, the reason for tooth extraction or gum scaling is often not recorded, and insurance status is omitted.

      Conclusion

      This case report adds another example of AIGO to the literature. It also provides an up-to-date review of the prevalence, pathophysiology, and management of AIGO. Based on recent research, the prevalence of AIGO is likely more than what is reported in resources for prescribers and patients. In some populations, like those without access to dental care, the prevalence may be quite high. This case study adds to the current knowledge by exploring the intersection of poverty and this iatrogenic disease. The poorest patients are at the highest risk for AIGO and suffer the greatest injury due to a lack of access to dental care to prevent and treat this condition. By educating our patients about the risk for AIGO, NPs can prevent this iatrogenic disease and reinforce our trustworthiness as stewards of good health.

      Acknowledgments

      The authors would like to acknowledge several colleagues who provided critical feedback on the paper including Dr. Marjorie Hammer and Dr. Kala Metha. The principal author is also grateful for the mentorship of Dr. Nicholas Nelson, who first identified this phenomenon for her. Most importantly, the authors are grateful for the generosity of the patient featured in this vignette. His willingness to share his private health issue in hopes of preventing this befalling other patients is fundamental to this report.

      Supplementary Data

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      Biography

      P. Suzanne Portnoy, DNP, FNP-C, is the Associate Director of Street Medicine for CommuniCare Health Centers in Yolo County, CA, and can be contacted at [email protected] .
      Shin-Yu Lee, PharmD, BCACP, is the supervisor of Ambulatory Care Clinical Pharmacy Services for San Francisco Health Network in San Francisco, CA, and an assistant clinical professor at the University of California at San Francisco School of Pharmacy in San Francisco.
      Ashley McMullen, MD, is an internal medicine physician at the San Francisco Veterans Administration Medical Center and an assistant professor of medicine at the University of California at San Francisco School of Medicine in San Francisco.
      Vera Qu, BA, is a research assistant at Stanford University in Palo Alto, CA.