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Dental considerations for patients taking weight-loss medications Mark Donaldson, Jason H. Goodchild and Jane Ziegler JADA 2014;145(1):70-74 10.14219/jada.2013.3 The following resources related to this article are available online at jada.ada.org (this information is current as of June 28, 2014): Updated information and services including high-resolution figures, can be found in the online version of this article at: http://jada.ada.org/content/145/1/70
This article cites 32 articles, 10 of which can be accessed free: http://jada.ada.org/content/145/1/70/#BIBL Information about obtaining reprints of this article or about permission to reproduce this article in whole or in part can be found at: http://www.ada.org/990.aspx
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ORIGINAL CONTRIBUTIONS
NUTRITION
Dental considerations for patients taking weight-loss medications Mark Donaldson, BSP, PharmD, FASHP, FACHE; Jason H. Goodchild, DMD; Jane Ziegler, DCN, RD, LDN
A
ccording to Demaria,1 the Centers for Disease Control and Prevention National Center for Health Statistics2 and the World Health Organization,3 17 percent of children and more than one-third of adults in the United States are obese (Table 1). Although diet and lifestyle interventions are indicated as first-line therapies for the prevention and treatment of obesity,4-6 patients are not always successful in achieving their goals by using lifestyle modifications alone. This outcome has led to the burgeoning growth of the dietary supplement and weight-loss medication markets.7,8 As patients are turning to pharmacological interventions more often to reach their weight-loss goals, diet-drug, dietary supplement–drug and drug-drug interactions are becoming more prevalent and need to be considered in the treatment of patients.9,10 As Americans live longer, have greater numbers of chronic conditions and take more medications (including those to manage obesity), hospitalizations for adverse drug events are likely to increase.11 Oral health care professionals (OHCPs) in cliniDr. Donaldson is director of pharmacy services, Kalispell Regional Medical Center, Mont.; a clinical professor, Skaggs School of Pharmacy, University of Montana, Missoula; and a clinical assistant professor, School of Dentistry, Oregon Health & Sciences University, Portland. Address correspondence to Dr. Donaldson at 310 Sunnyview Lane, Kalispell, Mont. 59901, e-mail [email protected]. Dr. Goodchild is a clinical associate professor, Department of Oral Medicine, University of Pennsylvania School of Dental Medicine, Philadelphia, and in private practice in Havertown, Pa. Dr. Ziegler is an assistant professor, Department of Nutritional Sciences, Rutgers School of Health Related Professions, Rutgers, The State University of New Jersey, Newark, and an adjunct assistant professor, Diagnostic Sciences, Rutgers School of Dental Medicine, Rutgers, The State University of New Jersey.
abstract Background. In this article, the authors examine prescription weight-loss medications and related dental considerations for oral health care professionals (OHCPs). The authors focus on the most common prescription weight-loss drugs and their potential interactions with medications frequently used in dental practice, and they include recommendations for modification in patient care. Methods. The authors reviewed the literature regarding interactions between weight-loss drugs and medications commonly used in dentistry, including patient-treatment considerations. They also address the interactions of greatest clinical concern that have a high-quality evidence-based foundation in either randomized controlled clinical trials or meta-analyses. Conclusions. Dental treatment can be performed and medications commonly used in dentistry can be administered safely to patients taking orlistat, an inhibitor of fat absorption. The same may not be true, however, for other weight-loss medications that modify the central nervous system neurotransmission of norepinephrine, dopamine or serotonin. OHCPs should be aware of the potential theoretical and pharmacokinetic risks relative to the actual clinical and reported risks for hypertension and cardiotoxicity in particular. Practical Implications. Recognition and avoidance of potential weight-loss drug interactions, especially those with medications commonly used in dentistry, can help clinicians optimize patient treatment while emphasizing patient safety. Key Words. Obesity; dentistry; weight-loss medications; drugs. JADA 2014;145(1):70-74. doi:10.14219/jada.2013.3
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ORIGINAL CONTRIBUTIONS
cal practice need to be aware of potential interactions between medications used to manage obesity and medications commonly used in dentistry. In this article, we examine prescription weight-loss medications and dental practice considerations, with a focus on medications frequently used in dental practice. Weight-Loss Medications and Drugs Used in Dental Practice
TABLE 1
U.S. data for obesity and being overweight and for body mass index (BMI) classification.* PREVALENCE OF BEING OVERWEIGHT AND OF OBESITY AMONG ADULTS AND CHILDREN† 33 Percent of Adults Are Overweight
BMI-RELATED CLASSIFICATION ‡
BMI ≥ 25.0 and < 30.0 kilograms per square meter
35.6 Percent of Adults Are Obese
BMI ≥ 30.0 kg/m2
6.0 Percent of Adults Are Morbidly Obese
BMI ≥ 40.0 kg/m2
17 Percent of Children Are Obese
BMI for age and sex ≥ 95th percentile
* Sources: Demaria,1 Fryar and colleagues2 and World Health Organization.3 † Target BMI is 18.5 to less than 25.0 kg/m2. ‡ A BMI of 35.0 kg/m2 or higher with a comorbidity is considered morbid obesity. Comorbidities include hypertension, type 2 diabetes mellitus, dyslipidemia, sleep apnea, coronary heart disease, stroke, osteoarthritis, reduced fertility and certain cancers.
The development of medications to treat obesity focused more on efficacy (weight loss) and less on safety until postmarketing surveillance revealed cases in which patients had been harmed by use of the drugs.12,13 Perhaps the most notable of these cases relating to clinical dentistry involved the fenfluramine-phentermine (fen-phen) combination, which was associated with valvular heart disease and required affected patients to receive antibiotic prophylaxis before undergoing invasive procedures.14,15 (The updated American Heart Association guidelines for the prevention of infective endocarditis published in 2007 no longer recommend this practice.16) Case reports such as these have led to the withdrawal of many weight-loss drugs, including fen-phen, from the market, and only recently have new agents been approved for use in the United States (Figure).17-19 Table 219 lists the currently available weight-loss medications, according to mechanisms of action. Inhibitor of fat absorption. Orlistat. Unlike other weight-loss medications, orlistat is a reversible inhibitor of gastric and pancreatic lipases; it inhibits absorption of dietary fats by up to 30 percent.20 In a 2007 literature review, Friedlander and colleagues21 found that there were few dental concerns for patients taking orlistat other than a 2 to 4 percent increase in gingivitis. Investigators in two recently published cases, however, reported that orlistat caused aphthous ulcerations.22 Orlistat may enhance the anticoagulant effect of warfarin and present a clinical challenge if a patient is taking both medications concurrently.23,24 Practitioners should check the patients’ international normalized ratio (INR) to ensure that it is not outside the target range (typically 2.0-3.5) before proceeding with dental treatment.25 Because routine laboratory monitoring for patients taking warfarin is common, if they are routinely compliant with their medication regimen and their INRs typically are stable and have been measured during the week preceding treatment, rechecking their INRs may not be required. If an INR is needed, OHCPs may choose to have the patient obtain an INR through a laboratory
blood draw, or, to facilitate a more timely result, OHCPs may choose to use a simple point-of-care test that can be performed in the office.26 Beyond these considerations, dental treatment and medications that are used commonly in dentistry can be administered safely to patients taking orlistat. Modifiers of central nervous system neurotransmission of norepinephrine, dopamine or serotonin. OHCPs should be concerned about patients who are taking weight-loss medications that modify the central nervous system neurotransmission of norepinephrine, dopamine or serotonin. These medications include phentermine, diethylpropion, benzphetamine, phendimetrazine, the phentermine and topiramate combination, and lorcaserin. Phentermine. Since 1959, phentermine has helped reduce appetite by means of stimulating of the hypothalamus to release norepinephrine.19 The key adverse reactions related to phentermine use and dental treatment include reduced salivary flow (normal salivary flow resumes after the patient stops taking the medication) and unpleasant taste.27 Amphetamine derivatives such as phentermine may enhance the sympathomimetic response of epinephrine and levonordefrin in local anesthetic carpules leading to increased blood pressure and cardiotoxicity, especially in patients with a diagnosed cardiac condition.28 Although this drug interaction may be theoretical, OHCPs should be aware of its potential clinical effect and closely monitor patients for increased blood pressure and heart rate during concomitant use of the drugs. Appropriate physiological monitoring of the patient and awareness of maximum recommended doses of local anesthetics can help ensure patient safety.27 ABBREVIATION KEY. BMI: Body mass index. FDA: Food and Drug Administration. INR: International normalized ratio. OHCP: Oral health care professional.
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1900
1920
1930
1959
1992
1997
1999
2006
2012
Before the 1900s, thyroid preparations were used for weight loss
Dinitrophenol discovered to increase energy expenditure by targeting the basal metabolic rate
First amphetamine introduced
FDA approval of phentermine as an appetitie suppressant
Off-label use of fenfluramine-phentermine (fen-phen) combination
FDA approval of sibutramine
FDA approval of orlistat
European approval of rimonabant
FDA approval of lorcaserin and phentermine and topiramate (Qsymia)
ORIGINAL CONTRIBUTIONS
Figure. Timeline of some of the main classes of antiobesity drugs that have been introduced to the market.17-19 FDA: Food and Drug Administration. Qsymia is manufactured by Vivus, Mountain View, Calif.
TABLE 2
Currently available weight-loss medications, according to mechanisms of action.* GENERIC NAME (BRAND NAME)
MECHANISM OF ACTION
Orlistat (Alli [over the counter], GlaxoSmithKline, Philadelphia; Xenical, Genentech, South San Francisco, Calif.)
Inhibitor of fat absorption
Phentermine (Adipex-P, Gate Pharmaceuticals, North Wales, Pa.; Ionamin, UCB, Smyrna, Ga.; Suprenza, Akrimax Pharmaceuticals, Cranford, N.J.)
Modifiers of central nervous system neurotransmission of norepinephrine, dopamine or serotonin
Diethylpropion (Tenuate, Sanofi Aventis, Forest Park, Ga.) Benzphetamine (Regimex, WraSer Pharmaceuticals, Ridgeland, Miss.; Didrex, Pfizer, New York City) Phendimetrazine (Bontril, Mallinckrodt Pharmaceuticals, Hazelwood, Mo.) Phentermine and Topiramate (Qsymia, Vivus, Mountain View, Calif.) Lorcaserin (Belviq, Eisai, Woodcliff Lake, N.J.) * Source: Ioannides-Demos and colleagues.19
Diethylpropion, benzphetamine and phendimetrazine. Diethylpropion, benzphetamine and phendimetrazine also are sympathomimetic amines that have pharmacological properties similar to the amphetamines. Their mechanism of action in reducing appetite appears to be secondary to stimulating the hypothalamus to release norepinephrine. OHCPs should take the same precautions regarding blood pressure, heart rate management and local anesthetic use for patients taking these drugs as they do for patients taking phentermine. The key adverse reactions related to dentistry include reduced salivary flow (normal salivary flow resumes when the patient discontinues use) and metallic taste.29 Phentermine and topiramate. This combination of phentermine (described previously) and topiramate (available as an antiseizure drug) is formulated as a controlled-release pill that is taken once daily.30 Although the mechanism of action of topiramate for obesity is not clear, investigators believe that it causes appetite suppression through a combination of g-aminobutyric acid receptor activity, modulation of voltage-gated sodium channels, inhibition of excitatory glutamate receptors and inhibition of carbonic anhydrase.30 The dental considerations for phentermine we described above apply to patients taking the phentermine and topiramate combination because the phentermine
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ORIGINAL CONTRIBUTIONS
component can enhance the sympathomimetic response of vasopressors in local anesthetic carpules, leading to increased blood pressure levels and cardiotoxicity.28 OHCPs should monitor patients closely for increased blood pressure and heart rate levels during concomitant use of the drugs and be aware of the maximum recommended doses of local anesthetic to help ensure patient safety.27 In addition, patients taking this combination may experience paresthesia (4-20 percent of patients), dysgeusia (metallic taste; 1-9 percent of patients) and dry mouth (≤ 19 percent of patients).29-32 Concurrent use of sedatives (for example, benzodiazepines) with phentermine and topiramate combination may potentiate central nervous system depression and should be avoided without medical consultation.29,30 Compared with a placebo, this combination has been found to cause an increase in resting heart rate, and although the clinical significance of this effect is unclear, regular monitoring of the patient’s heart rate and blood pressure is recommended, especially with the use of a local anesthetic containing a vasoconstrictor.29 The phentermine and topiramate combination is teratogenic, and there is an increased risk of developing birth defects (cleft lip with or without cleft palate) associated with first-trimester exposure to the drug.33,34 Lorcaserin. The U.S. Food and Drug Administration approved lorcaserin in 2012 for long-term weight management. Investigators believe that it activates serotonin 5-HT2C receptors, which stimulate neurons in the arcuate nucleus of the hypothalamus to produce proopiomelanocortin.35 This activation leads to increased a-melanocyte–stimulating hormone release at melanocortin-4 receptors, resulting in satiety and decreased food intake.35-37 Although fenfluramine was shown to activate the serotonin subreceptor 5-HT2B, which resulted in serotonin-associated cardiac valvular insufficiency and its subsequent removal from the market,14 lorcaserin preferentially activates a different serotonin subreceptor (5-HT2C). Clinical trial data to date support the finding that valvulopathy is not associated with activation of the 5-HT2C receptor.35 To our knowledge, there are no published reports documenting considerations for OHCPs to keep in mind or special precautions required for dental treatment, sedation or the use of local anesthesia with or without a vasoconstrictor for patients taking lorcaserin. Lorcaserin is, however, a moderate CYP2D6 inhibitor, which may diminish the therapeutic effect of codeine; CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine.35,38 Because codeine and other opioid-based analgesics are not firstline drugs for acute dental pain (which typically is due to inflammation), this potential interaction may be of little concern to OHCPs. For OHCPs who routinely use opioidbased analgesics, however, the use of a combination
product that contains a synthetic opioid such as oxycodone or hydrocodone may help them avoid this potential interaction and should be considered. The combination of acetaminophen with a nonsteroidal anti-inflammatory agent such as ibuprofen is a potential alternative regimen that can be used to avoid having patients receive opioidcontaining analgesics and may be a more appropriate treatment course for patients taking lorcaserin.39 Conclusions
Patients using orlistat may safely receive medications commonly used in dentistry and may safely undergo dental treatment. The same, however, cannot be said for patients using weight-loss medications that modify the central nervous system neurotransmission of norepinephrine, dopamine or serotonin. OHCPs should be aware of the potential for hypertension and cardiotoxicity in these patients and closely monitor the patients’ blood pressure and pulse, especially when using local anesthetics with a vasoconstrictor. Practitioners should stay up-to-date with the literature as new weight-loss medications become available to avoid interactions with drugs commonly used in dentistry. n Disclosure. None of the authors reported any disclosures. Nutrition is published in collaboration with the Nutrition Research Scientific Group of the International Association for Dental Research. 1. Demaria AN. The multiple challenges of obesity. J Am Coll Cardiol 2013;61(7):784-786. 2. Fryar CD, Carroll MD, Ogden CL. Prevalence of Overweight, Obesity, and Extreme Obesity Among Adults: United States, Trends 1960-1962 Through 2009-2010. Hyattsville, Md.: National Center for Health Statistics; 2012:1-8. 3. World Health Organization. Obesity and Overweight. www.who.int/ mediacentre/factsheets/fs311/en/index.html. Accessed June 18, 2013. 4. Kushner RF. Clinical assessment and management of adult obesity. Circulation 2012;126(24):2870-2877. 5. Gidding SS, Lichtenstein AH, Faith MS, et al. Implementing American Heart Association pediatric and adult nutrition guidelines: a scientific statement from the American Heart Association Nutrition Committee of the Council on Nutrition, Physical Activity and Metabolism, Council on Cardiovascular Disease in the Young, Council on Arteriosclerosis, Thrombosis and Vascular Biology, Council on Cardiovascular Nursing, Council on Epidemiology and Prevention, and Council for High Blood Pressure Research. Circulation 2009;119(8):1161-1175. 6. National Heart, Lung, and Blood Institute. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: the Evidence Report. www.nhlbi.nih.gov/guidelines/obesity/ob_gdlns. htm. Accessed May 28, 2013. 7. Swinburn BA, Sacks G, Hall KD, et al. The global obesity pandemic: shaped by global drivers and local environments. Lancet 2011;378(9793): 804-814. 8. Nutrition Business Journal. NBJ’s Supplement Business Report 2012: Executive Summary. New York City: Penton Media; 2012:23-24. http:// newhope360.com/site-files/newhope360.com/files/uploads/2013/04/TOC_ SUMM120928.supp%20report%20FINAL%20standard.pdf. Accessed Nov. 22, 2013. 9. Donaldson M, Touger-Decker R. Dietary supplement interactions with medications used commonly in dentistry. JADA 2013;144(7):787-794. 10. Bray GA, Ryan DH. Medical therapy for the patient with obesity. Circulation 2012;125(13):1695-1703. 11. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med 2011;365(21):2002-2012. 12. Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A. Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials (published correction appears in Lancet 2008;371[9612]:558). Lancet
JADA 145(1) http://jada.ada.org January 2014 73 Copyright © 2014 American Dental Association. All Rights Reserved.
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ORIGINAL CONTRIBUTIONS 2007;370(9600):1706-1713. 13. Glazer G. Long-term pharmacotherapy of obesity 2000: a review of efficacy and safety. Arch Intern Med 2001;161(15):1814-1824. 14. Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine-phentermine (published correction appears in N Engl J Med 1997;337[24]:1783). N Engl J Med 1997;337(9):581-588. 15. Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis: recommendations by the American Heart Association. JAMA 1997;277(22):1794-1801. 16. Wilson W, Taubert KA, Gewitz M, et al; American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee; American Heart Association Council on Cardiovascular Disease in the Young; American Heart Association Council on Clinical Cardiology; American Heart Association Council on Cardiovascular Surgery and Anesthesia; Quality of Care and Outcomes Research Interdisciplinary Working Group. Prevention of infective endocarditis: guidelines from the American Heart Association—a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group (published correction appears in Circulation 2007;116(15):e376-377). Circulation 2007;116(15):1736-1754. 17. Astrup A. Is cardiometabolic risk improved by weight-loss drugs? Lancet 2010;376(9741):567-568. 18. Powell AG, Apovian CM, Aronne LJ. New drug targets for the treatment of obesity. Clin Pharmacol Ther 2011;90(1):40-51. 19. Ioannides-Demos LL, Piccenna L, McNeil JJ. Pharmacotherapies for obesity: past, current, and future therapies. J Obes 2011;2011:179674. 20. Drent ML, van der Veen EA. Lipase inhibition: a novel concept in the treatment of obesity. Int J Obes Relat Metab Disord 1993;17(4):241-244. 21. Friedlander AH, Weinreb J, Friedlander I, Yagiela JA. Metabolic syndrome: pathogenesis, medical care and dental implications. JADA 2007;138(2):179-187. 22. Sheikh-Taha M, Ghosn S, Zeitoun A. Oral aphthous ulcers associated with orlistat. Am J Health Syst Pharm 2012;69(17):1462, 1464. 23. Zhi J, Melia AT, Guerciolini R, et al. The effect of orlistat on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers. J Clin Pharmacol 1996;36(7):659-666. 24. MacWalter RS, Fraser HW, Armstrong KM. Orlistat enhances warfarin effect. Ann Pharmacother 2003;37(4):510-512. 25. Aframian DJ, Lalla RV, Peterson DE. Management of dental patients taking common hemostasis-altering medications. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103(suppl):S45.e1-S45.e11.
26. Donaldson M, Sullivan J, Norbeck A. Comparison of International Normalized Ratios provided by two point-of-care devices and laboratory-based venipuncture in a pharmacist-managed anticoagulation clinic. Am J Health Syst Pharm 2010;67(19):1616-1622. 27. Yagiela JA. Local anesthetics. In: Yagiela JA, Dowd FJ, Johnson BS, Mariotti AJ, Neidle EA, eds. Pharmacology and Therapeutics for Dentistry. 6th ed. St. Louis: Mosby Elsevier; 2011:246-265. 28. Becker DE. Basic and clinical pharmacology of autonomic drugs. Anesth Prog 2012;59(4):59-168. 29. Derosa G, Maffioli P. Anti-obesity drugs: a review about their effects and their safety. Expert Opin Drug Saf 2012;11(3):459-471. 30. Qsymia. Full prescribing information. Mountain View, Calif.: Vivus; 2012. www.qsymia.com/pdf/prescribing-information.pdf. Accessed Oct. 28, 2013. 31. Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlledrelease, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial (published correction appears in Lancet 2011;377[9776]:1494). Lancet 2011;377(9774):1341-1352. 32. Allison DB, Gadde KM, Garvey WT, et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring) 2012;20(2):330-342. 33. Margulis AV, Mitchell AA, Gilboa SM, et al; National Birth Defects Prevention Study. Use of topiramate in pregnancy and risk of oral clefts. Am J Obstet Gynecol 2012;207(5):405.e1-405.e7. 34. Colman E, Golden J, Roberts M, Egan A, Weaver J, Rosebraugh C. The FDA’s assessment of two drugs for chronic weight management. N Engl J Med 2012;367(17):1577-1579. 35. Belviq. Full product information. Zofingen, Switzerland: Arena Pharmaceuticals; 2012. http://us.eisai.com/package_inserts/BelviqPI.pdf. Accessed Oct. 28, 2013. 36. Hurren KM, Berlie HD. Lorcaserin: an investigational serotonin 2C agonist for weight loss. Am J Health Syst Pharm 2011;68(21):2029-2037. 37. Smith SR, Weissman NJ, Anderson CM, et al; Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) Study Group. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med 2010;363(3):245-256. 38. Bjornsson TD, Callaghan JT, Einolf HJ, et al; Pharmaceutical Research and Manufacturers of America Drug Metabolism/Clinical Pharmacology Technical Working Groups. The conduct of in vitro and in vivo drug-drug interaction studies: a PhRMA Perspective. J Clin Pharmacol 2003;43(5):443-469. 39. Donaldson M, Goodchild JH. Appropriate analgesic prescribing for the general dentist. Gen Dent 2010;58(4):291-297.
74 JADA 145(1) http://jada.ada.org January 2014 Copyright © 2014 American Dental Association. All Rights Reserved.
Dental considerations for patients taking weight-loss medications Mark Donaldson, Jason H. Goodchild and Jane Ziegler JADA 2014;145(1):70-74 10.14219/jada.2013.3 The following resources related to this article are available online at jada.ada.org (this information is current as of June 28, 2014): Updated information and services including high-resolution figures, can be found in the online version of this article at: http://jada.ada.org/content/145/1/70
This article cites 32 articles, 10 of which can be accessed free: http://jada.ada.org/content/145/1/70/#BIBL Information about obtaining reprints of this article or about permission to reproduce this article in whole or in part can be found at: http://www.ada.org/990.aspx
Copyright © 2014 American Dental Association. All rights reserved. Reproduction or republication strictly prohibited without prior written permission of the American Dental Association.
Downloaded from jada.ada.org on June 28, 2014
ORIGINAL CONTRIBUTIONS
NUTRITION
Dental considerations for patients taking weight-loss medications Mark Donaldson, BSP, PharmD, FASHP, FACHE; Jason H. Goodchild, DMD; Jane Ziegler, DCN, RD, LDN
A
ccording to Demaria,1 the Centers for Disease Control and Prevention National Center for Health Statistics2 and the World Health Organization,3 17 percent of children and more than one-third of adults in the United States are obese (Table 1). Although diet and lifestyle interventions are indicated as first-line therapies for the prevention and treatment of obesity,4-6 patients are not always successful in achieving their goals by using lifestyle modifications alone. This outcome has led to the burgeoning growth of the dietary supplement and weight-loss medication markets.7,8 As patients are turning to pharmacological interventions more often to reach their weight-loss goals, diet-drug, dietary supplement–drug and drug-drug interactions are becoming more prevalent and need to be considered in the treatment of patients.9,10 As Americans live longer, have greater numbers of chronic conditions and take more medications (including those to manage obesity), hospitalizations for adverse drug events are likely to increase.11 Oral health care professionals (OHCPs) in cliniDr. Donaldson is director of pharmacy services, Kalispell Regional Medical Center, Mont.; a clinical professor, Skaggs School of Pharmacy, University of Montana, Missoula; and a clinical assistant professor, School of Dentistry, Oregon Health & Sciences University, Portland. Address correspondence to Dr. Donaldson at 310 Sunnyview Lane, Kalispell, Mont. 59901, e-mail [email protected]. Dr. Goodchild is a clinical associate professor, Department of Oral Medicine, University of Pennsylvania School of Dental Medicine, Philadelphia, and in private practice in Havertown, Pa. Dr. Ziegler is an assistant professor, Department of Nutritional Sciences, Rutgers School of Health Related Professions, Rutgers, The State University of New Jersey, Newark, and an adjunct assistant professor, Diagnostic Sciences, Rutgers School of Dental Medicine, Rutgers, The State University of New Jersey.
abstract Background. In this article, the authors examine prescription weight-loss medications and related dental considerations for oral health care professionals (OHCPs). The authors focus on the most common prescription weight-loss drugs and their potential interactions with medications frequently used in dental practice, and they include recommendations for modification in patient care. Methods. The authors reviewed the literature regarding interactions between weight-loss drugs and medications commonly used in dentistry, including patient-treatment considerations. They also address the interactions of greatest clinical concern that have a high-quality evidence-based foundation in either randomized controlled clinical trials or meta-analyses. Conclusions. Dental treatment can be performed and medications commonly used in dentistry can be administered safely to patients taking orlistat, an inhibitor of fat absorption. The same may not be true, however, for other weight-loss medications that modify the central nervous system neurotransmission of norepinephrine, dopamine or serotonin. OHCPs should be aware of the potential theoretical and pharmacokinetic risks relative to the actual clinical and reported risks for hypertension and cardiotoxicity in particular. Practical Implications. Recognition and avoidance of potential weight-loss drug interactions, especially those with medications commonly used in dentistry, can help clinicians optimize patient treatment while emphasizing patient safety. Key Words. Obesity; dentistry; weight-loss medications; drugs. JADA 2014;145(1):70-74. doi:10.14219/jada.2013.3
70 JADA 145(1) http://jada.ada.org January 2014 Copyright © 2014 American Dental Association. All Rights Reserved.
Downloaded from jada.ada.org on June 28, 2014
ORIGINAL CONTRIBUTIONS
cal practice need to be aware of potential interactions between medications used to manage obesity and medications commonly used in dentistry. In this article, we examine prescription weight-loss medications and dental practice considerations, with a focus on medications frequently used in dental practice. Weight-Loss Medications and Drugs Used in Dental Practice
TABLE 1
U.S. data for obesity and being overweight and for body mass index (BMI) classification.* PREVALENCE OF BEING OVERWEIGHT AND OF OBESITY AMONG ADULTS AND CHILDREN† 33 Percent of Adults Are Overweight
BMI-RELATED CLASSIFICATION ‡
BMI ≥ 25.0 and < 30.0 kilograms per square meter
35.6 Percent of Adults Are Obese
BMI ≥ 30.0 kg/m2
6.0 Percent of Adults Are Morbidly Obese
BMI ≥ 40.0 kg/m2
17 Percent of Children Are Obese
BMI for age and sex ≥ 95th percentile
* Sources: Demaria,1 Fryar and colleagues2 and World Health Organization.3 † Target BMI is 18.5 to less than 25.0 kg/m2. ‡ A BMI of 35.0 kg/m2 or higher with a comorbidity is considered morbid obesity. Comorbidities include hypertension, type 2 diabetes mellitus, dyslipidemia, sleep apnea, coronary heart disease, stroke, osteoarthritis, reduced fertility and certain cancers.
The development of medications to treat obesity focused more on efficacy (weight loss) and less on safety until postmarketing surveillance revealed cases in which patients had been harmed by use of the drugs.12,13 Perhaps the most notable of these cases relating to clinical dentistry involved the fenfluramine-phentermine (fen-phen) combination, which was associated with valvular heart disease and required affected patients to receive antibiotic prophylaxis before undergoing invasive procedures.14,15 (The updated American Heart Association guidelines for the prevention of infective endocarditis published in 2007 no longer recommend this practice.16) Case reports such as these have led to the withdrawal of many weight-loss drugs, including fen-phen, from the market, and only recently have new agents been approved for use in the United States (Figure).17-19 Table 219 lists the currently available weight-loss medications, according to mechanisms of action. Inhibitor of fat absorption. Orlistat. Unlike other weight-loss medications, orlistat is a reversible inhibitor of gastric and pancreatic lipases; it inhibits absorption of dietary fats by up to 30 percent.20 In a 2007 literature review, Friedlander and colleagues21 found that there were few dental concerns for patients taking orlistat other than a 2 to 4 percent increase in gingivitis. Investigators in two recently published cases, however, reported that orlistat caused aphthous ulcerations.22 Orlistat may enhance the anticoagulant effect of warfarin and present a clinical challenge if a patient is taking both medications concurrently.23,24 Practitioners should check the patients’ international normalized ratio (INR) to ensure that it is not outside the target range (typically 2.0-3.5) before proceeding with dental treatment.25 Because routine laboratory monitoring for patients taking warfarin is common, if they are routinely compliant with their medication regimen and their INRs typically are stable and have been measured during the week preceding treatment, rechecking their INRs may not be required. If an INR is needed, OHCPs may choose to have the patient obtain an INR through a laboratory
blood draw, or, to facilitate a more timely result, OHCPs may choose to use a simple point-of-care test that can be performed in the office.26 Beyond these considerations, dental treatment and medications that are used commonly in dentistry can be administered safely to patients taking orlistat. Modifiers of central nervous system neurotransmission of norepinephrine, dopamine or serotonin. OHCPs should be concerned about patients who are taking weight-loss medications that modify the central nervous system neurotransmission of norepinephrine, dopamine or serotonin. These medications include phentermine, diethylpropion, benzphetamine, phendimetrazine, the phentermine and topiramate combination, and lorcaserin. Phentermine. Since 1959, phentermine has helped reduce appetite by means of stimulating of the hypothalamus to release norepinephrine.19 The key adverse reactions related to phentermine use and dental treatment include reduced salivary flow (normal salivary flow resumes after the patient stops taking the medication) and unpleasant taste.27 Amphetamine derivatives such as phentermine may enhance the sympathomimetic response of epinephrine and levonordefrin in local anesthetic carpules leading to increased blood pressure and cardiotoxicity, especially in patients with a diagnosed cardiac condition.28 Although this drug interaction may be theoretical, OHCPs should be aware of its potential clinical effect and closely monitor patients for increased blood pressure and heart rate during concomitant use of the drugs. Appropriate physiological monitoring of the patient and awareness of maximum recommended doses of local anesthetics can help ensure patient safety.27 ABBREVIATION KEY. BMI: Body mass index. FDA: Food and Drug Administration. INR: International normalized ratio. OHCP: Oral health care professional.
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1900
1920
1930
1959
1992
1997
1999
2006
2012
Before the 1900s, thyroid preparations were used for weight loss
Dinitrophenol discovered to increase energy expenditure by targeting the basal metabolic rate
First amphetamine introduced
FDA approval of phentermine as an appetitie suppressant
Off-label use of fenfluramine-phentermine (fen-phen) combination
FDA approval of sibutramine
FDA approval of orlistat
European approval of rimonabant
FDA approval of lorcaserin and phentermine and topiramate (Qsymia)
ORIGINAL CONTRIBUTIONS
Figure. Timeline of some of the main classes of antiobesity drugs that have been introduced to the market.17-19 FDA: Food and Drug Administration. Qsymia is manufactured by Vivus, Mountain View, Calif.
TABLE 2
Currently available weight-loss medications, according to mechanisms of action.* GENERIC NAME (BRAND NAME)
MECHANISM OF ACTION
Orlistat (Alli [over the counter], GlaxoSmithKline, Philadelphia; Xenical, Genentech, South San Francisco, Calif.)
Inhibitor of fat absorption
Phentermine (Adipex-P, Gate Pharmaceuticals, North Wales, Pa.; Ionamin, UCB, Smyrna, Ga.; Suprenza, Akrimax Pharmaceuticals, Cranford, N.J.)
Modifiers of central nervous system neurotransmission of norepinephrine, dopamine or serotonin
Diethylpropion (Tenuate, Sanofi Aventis, Forest Park, Ga.) Benzphetamine (Regimex, WraSer Pharmaceuticals, Ridgeland, Miss.; Didrex, Pfizer, New York City) Phendimetrazine (Bontril, Mallinckrodt Pharmaceuticals, Hazelwood, Mo.) Phentermine and Topiramate (Qsymia, Vivus, Mountain View, Calif.) Lorcaserin (Belviq, Eisai, Woodcliff Lake, N.J.) * Source: Ioannides-Demos and colleagues.19
Diethylpropion, benzphetamine and phendimetrazine. Diethylpropion, benzphetamine and phendimetrazine also are sympathomimetic amines that have pharmacological properties similar to the amphetamines. Their mechanism of action in reducing appetite appears to be secondary to stimulating the hypothalamus to release norepinephrine. OHCPs should take the same precautions regarding blood pressure, heart rate management and local anesthetic use for patients taking these drugs as they do for patients taking phentermine. The key adverse reactions related to dentistry include reduced salivary flow (normal salivary flow resumes when the patient discontinues use) and metallic taste.29 Phentermine and topiramate. This combination of phentermine (described previously) and topiramate (available as an antiseizure drug) is formulated as a controlled-release pill that is taken once daily.30 Although the mechanism of action of topiramate for obesity is not clear, investigators believe that it causes appetite suppression through a combination of g-aminobutyric acid receptor activity, modulation of voltage-gated sodium channels, inhibition of excitatory glutamate receptors and inhibition of carbonic anhydrase.30 The dental considerations for phentermine we described above apply to patients taking the phentermine and topiramate combination because the phentermine
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ORIGINAL CONTRIBUTIONS
component can enhance the sympathomimetic response of vasopressors in local anesthetic carpules, leading to increased blood pressure levels and cardiotoxicity.28 OHCPs should monitor patients closely for increased blood pressure and heart rate levels during concomitant use of the drugs and be aware of the maximum recommended doses of local anesthetic to help ensure patient safety.27 In addition, patients taking this combination may experience paresthesia (4-20 percent of patients), dysgeusia (metallic taste; 1-9 percent of patients) and dry mouth (≤ 19 percent of patients).29-32 Concurrent use of sedatives (for example, benzodiazepines) with phentermine and topiramate combination may potentiate central nervous system depression and should be avoided without medical consultation.29,30 Compared with a placebo, this combination has been found to cause an increase in resting heart rate, and although the clinical significance of this effect is unclear, regular monitoring of the patient’s heart rate and blood pressure is recommended, especially with the use of a local anesthetic containing a vasoconstrictor.29 The phentermine and topiramate combination is teratogenic, and there is an increased risk of developing birth defects (cleft lip with or without cleft palate) associated with first-trimester exposure to the drug.33,34 Lorcaserin. The U.S. Food and Drug Administration approved lorcaserin in 2012 for long-term weight management. Investigators believe that it activates serotonin 5-HT2C receptors, which stimulate neurons in the arcuate nucleus of the hypothalamus to produce proopiomelanocortin.35 This activation leads to increased a-melanocyte–stimulating hormone release at melanocortin-4 receptors, resulting in satiety and decreased food intake.35-37 Although fenfluramine was shown to activate the serotonin subreceptor 5-HT2B, which resulted in serotonin-associated cardiac valvular insufficiency and its subsequent removal from the market,14 lorcaserin preferentially activates a different serotonin subreceptor (5-HT2C). Clinical trial data to date support the finding that valvulopathy is not associated with activation of the 5-HT2C receptor.35 To our knowledge, there are no published reports documenting considerations for OHCPs to keep in mind or special precautions required for dental treatment, sedation or the use of local anesthesia with or without a vasoconstrictor for patients taking lorcaserin. Lorcaserin is, however, a moderate CYP2D6 inhibitor, which may diminish the therapeutic effect of codeine; CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine.35,38 Because codeine and other opioid-based analgesics are not firstline drugs for acute dental pain (which typically is due to inflammation), this potential interaction may be of little concern to OHCPs. For OHCPs who routinely use opioidbased analgesics, however, the use of a combination
product that contains a synthetic opioid such as oxycodone or hydrocodone may help them avoid this potential interaction and should be considered. The combination of acetaminophen with a nonsteroidal anti-inflammatory agent such as ibuprofen is a potential alternative regimen that can be used to avoid having patients receive opioidcontaining analgesics and may be a more appropriate treatment course for patients taking lorcaserin.39 Conclusions
Patients using orlistat may safely receive medications commonly used in dentistry and may safely undergo dental treatment. The same, however, cannot be said for patients using weight-loss medications that modify the central nervous system neurotransmission of norepinephrine, dopamine or serotonin. OHCPs should be aware of the potential for hypertension and cardiotoxicity in these patients and closely monitor the patients’ blood pressure and pulse, especially when using local anesthetics with a vasoconstrictor. Practitioners should stay up-to-date with the literature as new weight-loss medications become available to avoid interactions with drugs commonly used in dentistry. n Disclosure. None of the authors reported any disclosures. Nutrition is published in collaboration with the Nutrition Research Scientific Group of the International Association for Dental Research. 1. Demaria AN. The multiple challenges of obesity. J Am Coll Cardiol 2013;61(7):784-786. 2. Fryar CD, Carroll MD, Ogden CL. Prevalence of Overweight, Obesity, and Extreme Obesity Among Adults: United States, Trends 1960-1962 Through 2009-2010. Hyattsville, Md.: National Center for Health Statistics; 2012:1-8. 3. World Health Organization. Obesity and Overweight. www.who.int/ mediacentre/factsheets/fs311/en/index.html. Accessed June 18, 2013. 4. Kushner RF. Clinical assessment and management of adult obesity. Circulation 2012;126(24):2870-2877. 5. Gidding SS, Lichtenstein AH, Faith MS, et al. Implementing American Heart Association pediatric and adult nutrition guidelines: a scientific statement from the American Heart Association Nutrition Committee of the Council on Nutrition, Physical Activity and Metabolism, Council on Cardiovascular Disease in the Young, Council on Arteriosclerosis, Thrombosis and Vascular Biology, Council on Cardiovascular Nursing, Council on Epidemiology and Prevention, and Council for High Blood Pressure Research. Circulation 2009;119(8):1161-1175. 6. National Heart, Lung, and Blood Institute. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: the Evidence Report. www.nhlbi.nih.gov/guidelines/obesity/ob_gdlns. htm. Accessed May 28, 2013. 7. Swinburn BA, Sacks G, Hall KD, et al. The global obesity pandemic: shaped by global drivers and local environments. Lancet 2011;378(9793): 804-814. 8. Nutrition Business Journal. NBJ’s Supplement Business Report 2012: Executive Summary. New York City: Penton Media; 2012:23-24. http:// newhope360.com/site-files/newhope360.com/files/uploads/2013/04/TOC_ SUMM120928.supp%20report%20FINAL%20standard.pdf. Accessed Nov. 22, 2013. 9. Donaldson M, Touger-Decker R. Dietary supplement interactions with medications used commonly in dentistry. JADA 2013;144(7):787-794. 10. Bray GA, Ryan DH. Medical therapy for the patient with obesity. Circulation 2012;125(13):1695-1703. 11. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med 2011;365(21):2002-2012. 12. Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A. Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials (published correction appears in Lancet 2008;371[9612]:558). Lancet
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ORIGINAL CONTRIBUTIONS 2007;370(9600):1706-1713. 13. Glazer G. Long-term pharmacotherapy of obesity 2000: a review of efficacy and safety. Arch Intern Med 2001;161(15):1814-1824. 14. Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine-phentermine (published correction appears in N Engl J Med 1997;337[24]:1783). N Engl J Med 1997;337(9):581-588. 15. Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis: recommendations by the American Heart Association. JAMA 1997;277(22):1794-1801. 16. Wilson W, Taubert KA, Gewitz M, et al; American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee; American Heart Association Council on Cardiovascular Disease in the Young; American Heart Association Council on Clinical Cardiology; American Heart Association Council on Cardiovascular Surgery and Anesthesia; Quality of Care and Outcomes Research Interdisciplinary Working Group. Prevention of infective endocarditis: guidelines from the American Heart Association—a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group (published correction appears in Circulation 2007;116(15):e376-377). Circulation 2007;116(15):1736-1754. 17. Astrup A. Is cardiometabolic risk improved by weight-loss drugs? Lancet 2010;376(9741):567-568. 18. Powell AG, Apovian CM, Aronne LJ. New drug targets for the treatment of obesity. Clin Pharmacol Ther 2011;90(1):40-51. 19. Ioannides-Demos LL, Piccenna L, McNeil JJ. Pharmacotherapies for obesity: past, current, and future therapies. J Obes 2011;2011:179674. 20. Drent ML, van der Veen EA. Lipase inhibition: a novel concept in the treatment of obesity. Int J Obes Relat Metab Disord 1993;17(4):241-244. 21. Friedlander AH, Weinreb J, Friedlander I, Yagiela JA. Metabolic syndrome: pathogenesis, medical care and dental implications. JADA 2007;138(2):179-187. 22. Sheikh-Taha M, Ghosn S, Zeitoun A. Oral aphthous ulcers associated with orlistat. Am J Health Syst Pharm 2012;69(17):1462, 1464. 23. Zhi J, Melia AT, Guerciolini R, et al. The effect of orlistat on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers. J Clin Pharmacol 1996;36(7):659-666. 24. MacWalter RS, Fraser HW, Armstrong KM. Orlistat enhances warfarin effect. Ann Pharmacother 2003;37(4):510-512. 25. Aframian DJ, Lalla RV, Peterson DE. Management of dental patients taking common hemostasis-altering medications. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103(suppl):S45.e1-S45.e11.
26. Donaldson M, Sullivan J, Norbeck A. Comparison of International Normalized Ratios provided by two point-of-care devices and laboratory-based venipuncture in a pharmacist-managed anticoagulation clinic. Am J Health Syst Pharm 2010;67(19):1616-1622. 27. Yagiela JA. Local anesthetics. In: Yagiela JA, Dowd FJ, Johnson BS, Mariotti AJ, Neidle EA, eds. Pharmacology and Therapeutics for Dentistry. 6th ed. St. Louis: Mosby Elsevier; 2011:246-265. 28. Becker DE. Basic and clinical pharmacology of autonomic drugs. Anesth Prog 2012;59(4):59-168. 29. Derosa G, Maffioli P. Anti-obesity drugs: a review about their effects and their safety. Expert Opin Drug Saf 2012;11(3):459-471. 30. Qsymia. Full prescribing information. Mountain View, Calif.: Vivus; 2012. www.qsymia.com/pdf/prescribing-information.pdf. Accessed Oct. 28, 2013. 31. Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlledrelease, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial (published correction appears in Lancet 2011;377[9776]:1494). Lancet 2011;377(9774):1341-1352. 32. Allison DB, Gadde KM, Garvey WT, et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring) 2012;20(2):330-342. 33. Margulis AV, Mitchell AA, Gilboa SM, et al; National Birth Defects Prevention Study. Use of topiramate in pregnancy and risk of oral clefts. Am J Obstet Gynecol 2012;207(5):405.e1-405.e7. 34. Colman E, Golden J, Roberts M, Egan A, Weaver J, Rosebraugh C. The FDA’s assessment of two drugs for chronic weight management. N Engl J Med 2012;367(17):1577-1579. 35. Belviq. Full product information. Zofingen, Switzerland: Arena Pharmaceuticals; 2012. http://us.eisai.com/package_inserts/BelviqPI.pdf. Accessed Oct. 28, 2013. 36. Hurren KM, Berlie HD. Lorcaserin: an investigational serotonin 2C agonist for weight loss. Am J Health Syst Pharm 2011;68(21):2029-2037. 37. Smith SR, Weissman NJ, Anderson CM, et al; Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) Study Group. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med 2010;363(3):245-256. 38. Bjornsson TD, Callaghan JT, Einolf HJ, et al; Pharmaceutical Research and Manufacturers of America Drug Metabolism/Clinical Pharmacology Technical Working Groups. The conduct of in vitro and in vivo drug-drug interaction studies: a PhRMA Perspective. J Clin Pharmacol 2003;43(5):443-469. 39. Donaldson M, Goodchild JH. Appropriate analgesic prescribing for the general dentist. Gen Dent 2010;58(4):291-297.
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