- Email: [email protected]
Restless legs syndrome
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Restless legs syndrome Manifestations, treatment and dental implications Arthur H. Friedlander, DDS; Michael E. Mahler, MD; John A. Yagiela, DDS, PhD
Restless legs syndrome (RLS) is a neurological disorder that produces uncomfortable sensations (described as being like “bugs under the skin” or “cola in the veins”) in the legs when an affected person is awake and at rest (sitting or lying down).1 These unpleasant feelings occur deep within the calves; however, unlike cramps, there is an absence of muscle knotting and localized pain. These unpleasant feelings develop most often during the evening or at night, and the affected person can relieve them by voluntarily moving the legs by walking (these people are known as “night
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Background. The authors reviewed the clinical features, epidemiology, pathogenesis and risk facN C tors, medical management, dental findings and U A ING EDU 1 dental management of patients with restless legs syn- R TICLE drome (RLS). Types of Studies Reviewed. The authors conducted a MEDLINE search for the years 2000 through 2004 using the key terms “restless legs syndrome,” “epidemiology,” “pathophysiology,” “treatment” and “dentistry.” They selected articles published in English in peer-reviewed journals for further review, and they gave preference to articles reporting randomized controlled trials. Conclusions. RLS is a neurological disorder that is characterized by unpleasant sensations in the legs that occur at rest, especially at bedtime. These symptoms cause an irresistible urge to get out of bed and move the legs to relieve the discomfort, thereby delaying sleep onset and resulting in fatigue and dysphoria the next day. Clinical Implications. The prevalence of dental disease may be extensive in patients with RLS because of diminished salivary flow resulting from the medications used to treat RLS. Patient education, saliva substitutes and anticaries agents are indicated. Special precautions must be taken when prescribing or administering sedative-hypnotic agents that are likely to have adverse reactions with the medications used to treat RLS. Key Words. Neurological movement disorders; dentistry; restless legs syndrome. JADA 2006;137:755-61. I
CLINICAL FEATURES
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ABSTRACT CON
here is a paucity of information in the dental literature about restless legs syndrome, a relatively recently recognized syndrome that affects mainly older people, an ever-growing segment of the American population. To gain a better understanding of the syndrome and its potential relationship to dentistry, we conducted a MEDLINE search for the years 2000 through 2004 using the key terms “restless legs syndrome,” “epidemiology,” “pathophysiology,” “treatment” and “dentistry.” We selected articles published in English in peer-reviewed journals for further review. We gave preference to articles reporting randomized controlled trials.
Dr. Friedlander is associate chief of staff and the director of Graduate Medical Education, VA Greater Los Angeles Healthcare System, the director of Quality Assurance, Hospital Dental Service, University of California Los Angeles Medical Center, and a professor of Oral and Maxillofacial Surgery, University of California Los Angeles School of Dentistry. Address reprint requests to Dr. Friedlander at VA Greater Los Angeles Healthcare System, 11301 Wilshire Blvd., Los Angeles, Calif. 90073, e-mail “arthur. [email protected]”. Dr. Mahler is the director, Quality Improvement, VA Greater Los Angeles Healthcare System, an attending neurologist, Neurobehavior Clinic, VA Greater Los Angeles Healthcare System, and a clinical professor of Neurology, David Geffen School of Medicine, University of California Los Angeles. Dr. Yagiela is a professor and the chair, Diagnostic and Surgical Sciences, University of California Los Angeles School of Dentistry, and a professor of Anesthesiology, David Geffen School of Medicine, University of California Los Angeles.
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walkers”), rubbing the legs, stretching the legs or simply standing. These aberrant sensations and the irresistible need to move the legs in the evening hours make riding in an airplane or sitting still in a movie theater difficult.1 When they occur at bedtime (within 15-30 minutes of reclining in bed), they often delay sleep onset, limit the total number of hours slept and, thereby, adversely affect the person’s energy level, mood and ability to concentrate the next day.2 RLS symptoms may occur simultaneously in other body parts—frequently in the arms—and less commonly in other areas such as the trunk and genitals.3 Patients have reported that symptoms decrease when they engage in challenging mental tasks such as playing chess.4 The clinical course of RLS is variable, but it typically is chronic and often is progressive. The diagnosis of RLS is based on patient complaint, the results of comprehensive medical and family histories, and normal physical and neurological examinations. Occasionally, RLS may develop secondary to pre-existing conditions such as iron deficiency anemia, end-stage renal disease and the last trimester of pregnancy.5 There are many other reported causes of secondary RLS, including those involving diabetes and neuropathy, but none have been documented clearly. Each of the established secondary forms of RLS almost always resolves when the underlying condition is treated (for example, administration of oral iron supplements, hemodialysis or renal transplantation, or childbirth).6 Approximately 85 percent of people with primary RLS exhibit involuntary, periodic leg movements lasting from 0.5 to five seconds when asleep. These movements consist of extension of the big toe in combination with partial flexion of the ankle, knee and sometimes the hip at regular intervals (typically about 20-40 seconds) during nonrapid eye movement sleep. These movements almost always are identified initially by the person’s bed partner and may be confirmed by polysomnography.7 The diagnostic process also demands that other disorders that have a movement component similar to RLS be ruled out. People with akathisia— a side effect of typical neuroleptic medications— often develop feelings of restlessness in their legs and may tap their feet, walk in place or pace. Constant pacing also commonly is seen in agitated patients who have major depressive disor756
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ders and those who have Alzheimer’s disease or experience other forms of dementia. EPIDEMIOLOGY
In the past, frequent misdiagnosis and poor recognition of RLS hampered epidemiologic studies. It now is known that approximately 10 percent of the adult North American white population of Northern and Western European origin have symptoms of primary RLS on a weekly basis and 6 percent have primary symptoms on a twice weekly basis.8,9 African and Asian populations appear to be less affected.10,11 The prevalence and severity of RLS increase with age.2 In one survey, 3 percent of participants aged 18 to 29 years reported having restless legs on five or more nights per month compared with 10 percent of those aged 30 to 70 years and 19 percent of those 80 years or older.12 Men and women appear to be affected equally in middleaged populations, but women in the older age groups are more likely to have RLS than are older men. For the majority of people with RLS, the symptoms are mild and cause little inconvenience. Approximately 1 to 2 percent of the general population, however, have frequent (> 15 times per month) severe symptoms that impair their sleep, thereby compromising their moods and work and recreational activities.13,14 PATHOGENESIS AND RISK FACTORS
In most cases, RLS is a primary disorder of unknown cause. However, RLS appears to run in families with an autosomal dominant inheritance pattern, especially in families of people with early-onset RLS.15,16 This genetic association is substantiated further by a study of monozygotic twins in which 10 of 12 twin pairs were concordant for RLS symptoms.17 Although the underlying cause of primary RLS is not understood fully, it is hypothesized by researchers such as Earley and colleagues18 to arise from low iron stores in the brain that result in inadequate activity of the neurotransmitter dopamine. This pathogenesis is supported by magnetic resonance imaging studies that found decreased amounts of iron in the substantia nigra of patients with RLS when compared with iron levels in control patients.18 An immunohistochemical study of the brains of patients with RLS at autopsy likewise suggested decreased amounts of iron in the substantia nigra.19 This decrement in iron can lead to a paucity of dopamine because
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iron is an important cofactor for tyrosine hydroxylase, the rate-limiting enzyme controlling the synthesis of dopamine. The hypothesis is substantiated further by the facts that RLS symptoms reach maximum severity at night when circadian dopamine plasma concentrations are at their lowest, the exquisite responsiveness of RLS symptoms to dopamine agents, and the exacerbation of symptoms by dopamine antagonist drugs that cross the blood-brain barrier.20 MEDICAL MANAGEMENT
Initial management of RLS consists of educating patients about lifestyle practices known to exacerbate the syndrome. Clinicians should discourage patients from using alcohol, tobacco and food products containing caffeine, as well as working shifts or engaging in strenuous physical activity close to bedtime. Medications known to worsen RLS should be changed to drugs that do not cause such adverse affects. Drugs that should be avoided are the antidepressants fluoxetine, paroxetine, sertraline and mirtazapine; the neuroleptics olanzapine and risperidone; lithium; and beta-adrenergic blockers.21 If these strategies fail to ameliorate RLS symptoms that are affecting the patient’s quality of life adversely, the patient’s physician often will mandate pharmacological therapy. Treatment is based on the use of four major classes of medications (dopaminergic agents, sedative-hypnotic agents, opioids and anticonvulsant agents). Most clinicians begin therapy for RLS using a dopaminergic agent.22 Levodopa, generally formulated with carbidopa (an inhibitor of the decarboxylase enzyme that inactivates levodopa to dopamine in the peripheral circulation, thus increasing the amount of levodopa available to cross the blood-brain barrier and enter the central nervous system [CNS]), often is used on an intermittent basis by people having periodic bouts of RLS. Once levodopa enters the brain and is transformed into dopamine, it improves both the sensory and motor deficits of the disorder. However, augmentation (a tendency for symptoms to develop earlier in the day and with increased intensity) occurs frequently with this agent. If augmentation occurs, the clinician usually prescribes another medication for the patient. Dopamine agonists (bromocriptine, cabergoline, pergolide mesylate, pramipexole and ropinirole) are drugs that stimulate dopamine receptors
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directly. They are used most commonly for people who are demonstrating augmentation, as well as for people who are having daily RLS symptoms. Augmentation is less common (20-30 percent) with these longer-acting drugs than with the levodopa-containing preparations, which have shorter half-lives.23 Clinicians prescribe these five agents in small doses to treat RLS and in high doses to treat Parkinson’s disease. Sedative-hypnotic agents are effective because they enhance sleep continuity rather than suppress movement. Clonazepam, the best-studied of this type of RLS medication, has a long duration of action and may result in nocturnal unsteadiness and drowsiness with associated falls or injuries, as well as cognitive impairment. Because of these adverse affects, intermediate-acting sedative-hypnotic agents (such as temazepam) and short-acting agents (such as triazolam, zolpidem and zaleplon) also are recommended. Long-term maintenance treatment with sedativehypnotic agents is limited by tolerance in many patients, but abuse appears to be low in patients with RLS.24 Natural opiates (codeine) and synthetic opioids (oxycodone and propoxyphene) are effective in lessening paresthesia and dysesthesia, motor restlessness and sleep disturbances. Although many clinicians are uncomfortable prescribing opioids over the long term for patients who have RLS to treat symptoms for which there is no biological measure, they acknowledge that these agents have long-term benefits and show little evidence of tolerance or addiction in patients.24 Another treatment for RLS includes the anticonvulsant agents gabapentin and carbamazepine. Gabapentin appears to be particularly useful for RLS symptoms that are characterized as painful. A recent double-blind study in which gabapentin was compared with a placebo showed reduced symptoms on all rating scales, reduced periodic leg movements during sleep and consequent improvement in sleep quality.25 The study also found that patients whose symptoms included pain received the greatest benefit from the drug. DENTAL CONSIDERATIONS
Dentists should schedule patients with RLS for early-morning appointments, because at that time these patients usually are bothered least by their symptoms.25 However, sustained periods of passive rest, such as sitting in a dental chair for a
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TABLE
Adverse orofacial reactions to medications used to treat restless legs syndrome.* ADVERSE REACTION†
MEDICATION Xerostomia
Sialorrhea
Sialadenitis Dysgeusia Stomatitis
Bromocriptine mesylate (Parlodel, Novartis, East Hanover, N.J.)
+
+
0
+
0
Cabergoline (Dostinex, Pfizer, New York City)
+
0
0
0
0
Levodopa (Larodopa, Roche Pharmaceuticals, Nutley, N.J.)
+
+
0
+
0
Levodopa and carbidopa (Sinemet, DuPont, Wilmington, Del.)
+
+
0
+
0
Pergolide mesylate (Permax, Elan Pharmaceuticals, San Diego)
+
0
+
+
+
Pramipexole (Mirapex, Boehringer Ingelheim Pharmaceuticals, Ridgefield, Conn.)
+
+
0
+
0
Ropinirole (Requip, GlaxoSmithKline, Pittsburgh)
+
+
0
0
0
Clonazepam (Klonopin, Roche)
+
+
0
0
0
Temazepam (Restoril, Mallinckrodt Pharmaceuticals, St. Louis)
+
+
0
+
0
Triazolam (Halcion, Pfizer)
+
+
0
+
0
Zaleplon (Sonata, Wyeth-Ayerst, Philadelphia)
+
+
0
+
0
Zolpidem (Ambien, Sanofi-aventis, Bridgewater, N.J.
+
+
0
+
0
Codeine (Codeine Phosphate, Lilly, Indianapolis)
+
0
0
0
0
Oxycodone (Percodan, Endo Pharmaceuticals, Chadds Ford, Pa.)
+
0
0
0
0
Propoxyphene (Darvon, Lilly)
0
0
0
0
0
Carbamazepine (Tegretol, Novartis)
+
0
0
0
+
Gabapentin (Neurontin, Pfizer)
+
+
+
+
+
Dopaminergic Agents
Sedative-Hypnotic Agents
Opioids
Anticonvulsant Agents
* Sources: Physicians’ Desk Reference,27 McEvoy28 and Wynn and colleagues.29 † +: Yes; 0: no.
prolonged period, still may be problematic for some people with RLS. Dentists should consult with the patients’ physicians to discuss the appropriateness of supplementing the therapeutic regimen with an additional and properly timed dose of medication for prolonged dental appointments.26 In the table, we present the findings of our review of the U.S. Food and Drug Administration medication package inserts that accompany some of the medications used in treating RLS and of our analysis of the current medical literature identifying adverse orofacial reactions that may occur.27-29 Some of these drugs also may interact 758
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adversely with dental therapeutic agents. Researchers have implicated medications from all four classes of drugs used to treat RLS in causing alterations in salivary gland function. A modest number of patients have reported having xerostomia; the problem is most acute in patients of advanced age.29 Some of the dopaminergic medications, all of the sedative-hypnotic agents and the anticonvulsant carbamazepine have been found to cause sialorrhea but in lesser numbers of people than those affected with xerostomia. Salivary flow changes also may cause dysgeusia, which has been reported by some patients who were taking dopaminergic medications, sedative-
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TABLE (CONT.)
Adverse orofacial reactions to medications used to treat restless legs syndrome.* ADVERSE REACTION† Gingivitis
0
Glossitis Tongue Edema
0
Coated Tongue
Bruxism
Miscellaneous
0
Facial pallor, blepharospasm, nasal congestion, headache, dizziness Toothache, rhinitis, throat irritation, periorbital edema Glossodynia, trismus, dark saliva, pigmentation of teeth, dysphagia, involuntary mouth/tongue movement Glossodynia, trismus, dark saliva, pigmentation of teeth, dysphagia Facial edema, headache, neck pain, periodontal abscess, jaw pain, moniliasis, dysphagia, dental caries, involuntary mouth/tongue movement Falling asleep in dental chair (secondary to sedation), pharyngitis, sinusitis, involuntary mouth/tongue movement, dysphagia Falling asleep in dental chair (secondary to sedation), toothache, headache, pharyngitis, tinnitus
0 0
0 0
0 +
0 0
0
+
0
0 0
0 + +
0 +
+
0
0 0
0
0
0
0 0
+
+
+
0 0
+
0
0
0
Sinusitis, rhinitis, pyrosis, toothache, jaw pain
0
Blurred vision
0
Nausea, vomiting
+
Headache, nausea, oral ulcers
0
Headache, dizziness, sinusitis, rhinitis, dysphagia
0 0
Nausea, vomiting, constricted pupils, suppression of cough reflex Nausea, vomiting
0
Dizziness, lightheadedness, nausea, vomiting, headache
0
Erythema multiforme, carbohydrate craving, tinnitus
0
Dry throat, oral ulcers, rhinitis, bleeding gingivae
+ 0
0
+ 0
0
0
+ 0
+
+
+ 0
0
0
0 0
0
0
0 0
0
0
0 0
0
0
0 0
0
+
0 0
+
+
0
hypnotic agents and anticonvulsant agents.30 Patient education and the maintenance of good oral hygiene are paramount for people who are experiencing xerostomia, given its association with the development of dental caries and periodontal disease. Dentists should prescribe artificial saliva for patients and give them instruction in proper toothbrushing and flossing methods that maximize dental plaque removal. We also recommend that patients receive a clinical examination and oral prophylaxis every three months, as well as receive a fluoride gel with a fluoride concentration of at least 1 percent. A critical review linked the use of levodopacontaining and other dopaminergic drugs used to treat RLS with an increasing severity of
bruxism.31 Confounding this issue is the fact that approximately 15 percent of people with untreated RLS also report severe bruxism.32 The mechanisms underlying these relationships require further study. Therefore, dentists should closely examine the dentition of all patients with RLS for evidence of bruxism, and should institute appropriate interventions for patients with excessive loss of tooth structure. These interventions include consulting with the patients’ physicians to discuss changing the medication to one not associated with causing bruxism or, if necessary, fabricating a prosthetic appliance to protect the dentition. Pergolide mesylate is an ergot-derived dopamine agonist used in low doses to treat RLS and
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in much higher doses to treat Parkinson’s disease. Both treatment regimens, however, cause some patients to develop stiff, fibrotic heart valve leaflets that are unable to close completely, which can result in regurgitation and a predisposition to endocarditis.33 These lesions probably develop because pergolide mesylate stimulates the serotonin 5-HT2B receptor, which is expressed in the fibroblasts of heart valves, thereby inducing fibrosis.34 Horvath and colleagues35 reported the occurrence of similar lesions with long-term use of cabergoline and bromocriptine but so far only in high-dose regimens like those used in the treatment of Parkinson’s disease. A patient with a history of long-term pergolide mesylate usage who requires invasive dental procedures should undergo an evaluation of the structure and function of his or her heart by a physician, preferably a cardiologist. The physician should be asked to comment on the patient’s susceptibility to endocarditis. Initially, the physician will confirm the patient’s medical history and perform a comprehensive physical examination and obtain necessary laboratory tests. The physician will auscultate the patient’s heart for abnormal sounds such as murmurs and evaluate an echocardiogram for the heart’s chamber size, the valve function and any aberrant blood flow patterns related to the valves. Patients who have developed valvular heart disease to the extent that they meet the American Heart Association’s (AHA’s) criteria for the risk of developing endocarditis will need to follow the AHA-recommended antibiotic prophylaxis regimen for invasive dental procedures involving the oral soft tissues.36 Patients who are not allergic to penicillin should recieve 2 grams of amoxicillin one hour before the procedure. Patients who are allergic to penicillin should receive clindamycin, cefadroxil or clarithromycin one hour before the procedure. Furthermore, because endocarditis may occur despite appropriate prophylaxis, dentists must warn these patients to report back to the office if they develop an unexplained fever, night chills, weakness, myalgia, arthralgia, lethargy or malaise after treatment.37-40 Chronic administration of opioids may be associated with the development of tolerance—a reduced drug effect and the need for higher doses of medication to produce the same effect. The development of tolerance often requires clinicians to prescribe larger doses of opioid analgesics (or, preferably, a course of nonsteroidal anti760
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inflammatory drugs) to obtain adequate postoperative dental pain relief. Clinicians must be cautious when prescribing increasing dosages of opioids, because of those drugs’ CNS-depressant effects.41 Similarly, when prescribing antianxiety and sedative-hypnotic drugs for patients undergoing dental procedures, clinicians must consider their additive CNS-depressant effects. Chronic administration of the anticonvulsant carbamazepine has been associated with the development of leukopenia, thrombocytopenia, anemia and pancytopenia on rare occasions. Concurrent administration of propoxyphene, erythromycin or clarithromycin decreases the rate of carbamazepine metabolism, thereby increasing the risk of toxicity, which may manifest as unstable blood pressure, hepatitis, or adverse neurological and sensory effects. Long-term concurrent administration of carbamazepine and acetaminophen increases the risk of developing hepatic toxicity. When prescribing antianxiety or sedative-hypnotic drugs and opioid analgesics for dental procedures in patients who are receiving either carbamazepine or gabapentin, clinicians must take into account the additive CNS-depressant qualities of the dental therapeutic agents.42 Clonazepam may produce a coated (black hairy) tongue. Concurrent administration of erythromycin or clarithromycin with triazolam decreases the rate of triazolam’s rate of metabolism, thereby increasing the risk of toxicity.43 Clinicians need to be cautious when prescribing antianxiety or sedative-hypnotic agents and opioid analgesics for dental procedures for patients who are receiving concurrently any sedative-hypnotic drug for RLS, owing to the increased potential for respiratory depression and sedation. CONCLUSION
RLS has been called the “most common illness you never heard of.”44 Given its association with the aging process and America’s changing demographic pattern, increasing numbers of people seeking dental treatment likely will have RLS. Dentistry, in concert with medicine, has much to offer patients who have RLS. Dentists familiar with the manifestations of the syndrome and its medical management can offer patients the full range of dental treatment options. ■ 1. Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi J. Restless Legs Syndrome Diagnosis and Epidemiology Workshop at the National Institutes of Health; International Restless
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Legs Syndrome Study Group. Restless legs syndrome: diagnostic criteria, special considerations and epidemiology—a report from the Restless Legs Syndrome Diagnosis and Epidemiology Workshop at the National Institutes of Health. Sleep Med 2003;4(2):101-19. 2. Berger K, Luedemann J, Trenkwalder C, John U, Kessler C. Sex and the risk of restless legs syndrome in the general population. Arch Intern Med 2004;164(2):196-202. 3. Hening WA. Subjective and objective criteria in the diagnosis of the restless legs syndrome. Sleep Med 2004;5:285-92. 4. Lesage S, Hening WA. The restless legs syndrome and periodic limb movement disorder: a review of management. Semin Neurol 2004;24:249-59. 5. Manconi M, Govoni V, De Vito A, et al. Pregnancy as a risk factor for restless legs syndrome. Sleep Med 2004;5:305-8. 6. Allen R. Dopamine and iron in the pathophysiology of restless legs syndrome (RLS). Sleep Med 2004;5:385-91. 7. Gosselin N, Lanfranchi P, Michaud M, et al. Age and gender effects on heart rate activation associated with periodic leg movements in patients with restless legs syndrome. Clin Neurophysiol 2003;114: 2188-95. 8. Hening W, Walters AS, Allen RP, Montplaisir J, Myers A, FeriniStrambi L. Impact, diagnosis and treatment of restless legs syndrome (RLS) in a primary care population: the REST (RLS epidemiology, symptoms, and treatment) primary care study. Sleep Med 2004; 5:237-46. 9. Rothdach AJ, Trenkwalder C, Haberstock J, Keil U, Berger K. Prevalence and risk factors of RLS in an elderly population: the MEMO study—memory and morbidity in Augsburg elderly. Neurology 2000;54:1064-8. 10. Tan EK, Seah A, See SJ, Lim E, Wong MC, Koh KK. Restless legs syndrome in an Asian population: a study in Singapore. Mov Disord 2001;16:577-9. 11. Kageyama T, Kabuto M, Nitta H, et al. Prevalences of periodic limb movement-like and restless legs-like symptoms among Japanese adults. Psychiatry Clin Neurosci 2000;54:296-8. 12. Phillips B, Young T, Finn L, Asher K, Hening WA, Purvis C. Epidemiology of restless legs symptoms in adults. Arch Intern Med 2000;160:2137-41. 13. Zucconi M, Ferini-Strambi L. Epidemiology and clinical findings of restless legs syndrome. Sleep Med 2004;5:293-9. 14. Abetz L, Allen R, Follet A, et al. Evaluating the quality of life of patients with restless legs syndrome. Clin Ther 2004;26:925-35. 15. Winkelmann J, Muller-Myhsok B, Wittchen HU, et al. Complex segregation analysis of restless legs syndrome provides evidence for an autosomal dominant mode of inheritance in early age at onset families. Ann Neurol 2002;52:297-302. 16. Chen S, Ondo WG, Rao S, Li L, Chen Q, Wang Q. Genomewide linkage scan identifies a novel susceptibility locus for restless legs syndrome on chromosome 9p. Am J Hum Genet 2004:74:876-85. 17. Ondo WG, Vuong KD, Wang Q. Restless legs syndrome in monozygotic twins: clinical correlates. Neurology 2000;55:1404-6. 18. Earley CJ, Allen RP, Beard JL, Connor JR. Insight into the pathophysiology of restless legs syndrome. J Neurosci Res 2000;62: 623-8. 19. Connor JR, Boyer PJ, Menzies SL, et al. Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome. Neurology 2003;61:304-9. 20. Ferreri F, Rossini PM. Neurophysiological investigations in restless legs syndrome and other disorders of movement during sleep. Sleep Med 2004;5:397-9. 21. Rama AN, Kushida CA. Restless legs syndrome and periodic limb movement disorder. Med Clin North Am 2004;88:653-67. 22. Littner MR, Kushida C, Anderson WM, et al; Standards of Prac-
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tice Committee of the American Academy of Sleep Medicine. Practice parameters for the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. Sleep 2004;27:557-9. 23. Ondo W, Romanyshyn J, Vuong KD, Lai D. Long-term treatment of restless legs syndrome with dopamine agonists. Arch Neurol 2004;61:1393-7. 24. Garcia-Borreguero D, Larrosa O, de la Llave Y, Verger K, Masramon X, Hernandez G. Treatment of restless legs syndrome with gabapentin: a double-blind, cross-over study. Neurology 2002;59 (10):1573-9. 25. Schapira AH. Restless legs syndrome: an update on treatment options. Drugs 2004;64(2):149-58. 26. Silber MH, Ehrenberg BL, Allen RP, et al; Medical Advisory Board of the Restless Legs Syndrome Foundation. An algorithm for management of restless legs syndrome (published correction appears in Mayo Clin Proc 2004;79:1341). Mayo Clin Proc 2004;79:916-22. 27. Physicians’ desk reference. 59th ed. Montvale, N.J.: Medical Economics; 2005. 28. McEvoy GK, ed. AHFS drug information 2005. Bethesda, Md.: American Society of Health-System Pharmacists; 2005. 29. Wynn RL, Meiller TF, Crossley HL, eds. Drug information handbook for dentistry. 9th ed. Hudson, Ohio: Lexi-Comp; 2003. 30. Byrne BE. Oral manifestations of systemic agents. In: Ciancio SG, ed. ADA guide to dental therapeutics. 3rd ed. Chicago: American Dental Association; 2003;504-50. 31. Winocur E, Gavish A, Voikovitch M, Emodi-Perlman A, Eli I. Drugs and bruxism: a critical review. J Orofac Pain 2003;17(2):99-111. 32. Lavigne GJ, Montplaisir JY. Restless legs syndrome and sleep bruxism: prevalence and association among Canadians. Sleep 1994;17:739-43. 33. Flowers CM, Racoosin JA, Lu SL, Beitz JG. The US Food and Drug Administration’s registry of pergolide-associated heart disease. Mayo Clin Proc 2003;78:730-1. 34. Van Camp G, Flamez A, Cosyns B, et al. Treatment of Parkinson’s disease with pergolide and relation to restrictive valvular heart disease. Lancet 2004;363:1179-83. 35. Horvath J, Fross RD, Kleiner-Fisman G, et al. Severe multivalvular heart disease: a new complication of the ergot derivative dopamine agonists. Mov Disord 2004;19:656-62. 36. Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis: recommendations by the American Heart Association. JADA 1997;128:1142-51. 37. Scully C, Roberts G, Shotts R. The mouth in heart disease. Practitioner 2001;245:432-7. 38. Carmona IT, Diz Dios P, Scully C. An update on the controversies in bacterial endocarditis of oral origin. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;93:660-70. 39. Pallasch TJ, Gage TW, Taubert KA. The 1997 prevention of bacterial endocarditis recommendations by the American Heart Association: questions and answers. J Calif Dent Assoc 1999;27:393-9. 40. Mask AG Jr. Medical management of the patient with cardiovascular disease. Periodontol 2000 2000;23(June):136-41. 41. Ganzberg. S. Analgesics: opioids and nonopioids. In: Ciancio SG, ed. ADA guide to dental therapeutics. 3rd ed. Chicago: American Dental Association; 2003:77-103. 42. Ganzberg S. Neurologic drugs. In: Ciancio SG, ed. ADA guide to dental therapeutics. 3rd ed. Chicago: American Dental Association; 2003:366-81. 43. Ganzberg S. Psychoactive drugs. In: Ciancio SG, ed. ADA guide to dental therapeutics. 3rd ed. Chicago: American Dental Association; 2003:382-411. 44. Restless Legs Syndrome Foundation. Available at: “www.rls.org”. Accessed Jan 17., 2005.
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Restless legs syndrome Manifestations, treatment and dental implications Arthur H. Friedlander, DDS; Michael E. Mahler, MD; John A. Yagiela, DDS, PhD
Restless legs syndrome (RLS) is a neurological disorder that produces uncomfortable sensations (described as being like “bugs under the skin” or “cola in the veins”) in the legs when an affected person is awake and at rest (sitting or lying down).1 These unpleasant feelings occur deep within the calves; however, unlike cramps, there is an absence of muscle knotting and localized pain. These unpleasant feelings develop most often during the evening or at night, and the affected person can relieve them by voluntarily moving the legs by walking (these people are known as “night
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Background. The authors reviewed the clinical features, epidemiology, pathogenesis and risk facN C tors, medical management, dental findings and U A ING EDU 1 dental management of patients with restless legs syn- R TICLE drome (RLS). Types of Studies Reviewed. The authors conducted a MEDLINE search for the years 2000 through 2004 using the key terms “restless legs syndrome,” “epidemiology,” “pathophysiology,” “treatment” and “dentistry.” They selected articles published in English in peer-reviewed journals for further review, and they gave preference to articles reporting randomized controlled trials. Conclusions. RLS is a neurological disorder that is characterized by unpleasant sensations in the legs that occur at rest, especially at bedtime. These symptoms cause an irresistible urge to get out of bed and move the legs to relieve the discomfort, thereby delaying sleep onset and resulting in fatigue and dysphoria the next day. Clinical Implications. The prevalence of dental disease may be extensive in patients with RLS because of diminished salivary flow resulting from the medications used to treat RLS. Patient education, saliva substitutes and anticaries agents are indicated. Special precautions must be taken when prescribing or administering sedative-hypnotic agents that are likely to have adverse reactions with the medications used to treat RLS. Key Words. Neurological movement disorders; dentistry; restless legs syndrome. JADA 2006;137:755-61. I
CLINICAL FEATURES
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ABSTRACT CON
here is a paucity of information in the dental literature about restless legs syndrome, a relatively recently recognized syndrome that affects mainly older people, an ever-growing segment of the American population. To gain a better understanding of the syndrome and its potential relationship to dentistry, we conducted a MEDLINE search for the years 2000 through 2004 using the key terms “restless legs syndrome,” “epidemiology,” “pathophysiology,” “treatment” and “dentistry.” We selected articles published in English in peer-reviewed journals for further review. We gave preference to articles reporting randomized controlled trials.
Dr. Friedlander is associate chief of staff and the director of Graduate Medical Education, VA Greater Los Angeles Healthcare System, the director of Quality Assurance, Hospital Dental Service, University of California Los Angeles Medical Center, and a professor of Oral and Maxillofacial Surgery, University of California Los Angeles School of Dentistry. Address reprint requests to Dr. Friedlander at VA Greater Los Angeles Healthcare System, 11301 Wilshire Blvd., Los Angeles, Calif. 90073, e-mail “arthur. [email protected]”. Dr. Mahler is the director, Quality Improvement, VA Greater Los Angeles Healthcare System, an attending neurologist, Neurobehavior Clinic, VA Greater Los Angeles Healthcare System, and a clinical professor of Neurology, David Geffen School of Medicine, University of California Los Angeles. Dr. Yagiela is a professor and the chair, Diagnostic and Surgical Sciences, University of California Los Angeles School of Dentistry, and a professor of Anesthesiology, David Geffen School of Medicine, University of California Los Angeles.
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walkers”), rubbing the legs, stretching the legs or simply standing. These aberrant sensations and the irresistible need to move the legs in the evening hours make riding in an airplane or sitting still in a movie theater difficult.1 When they occur at bedtime (within 15-30 minutes of reclining in bed), they often delay sleep onset, limit the total number of hours slept and, thereby, adversely affect the person’s energy level, mood and ability to concentrate the next day.2 RLS symptoms may occur simultaneously in other body parts—frequently in the arms—and less commonly in other areas such as the trunk and genitals.3 Patients have reported that symptoms decrease when they engage in challenging mental tasks such as playing chess.4 The clinical course of RLS is variable, but it typically is chronic and often is progressive. The diagnosis of RLS is based on patient complaint, the results of comprehensive medical and family histories, and normal physical and neurological examinations. Occasionally, RLS may develop secondary to pre-existing conditions such as iron deficiency anemia, end-stage renal disease and the last trimester of pregnancy.5 There are many other reported causes of secondary RLS, including those involving diabetes and neuropathy, but none have been documented clearly. Each of the established secondary forms of RLS almost always resolves when the underlying condition is treated (for example, administration of oral iron supplements, hemodialysis or renal transplantation, or childbirth).6 Approximately 85 percent of people with primary RLS exhibit involuntary, periodic leg movements lasting from 0.5 to five seconds when asleep. These movements consist of extension of the big toe in combination with partial flexion of the ankle, knee and sometimes the hip at regular intervals (typically about 20-40 seconds) during nonrapid eye movement sleep. These movements almost always are identified initially by the person’s bed partner and may be confirmed by polysomnography.7 The diagnostic process also demands that other disorders that have a movement component similar to RLS be ruled out. People with akathisia— a side effect of typical neuroleptic medications— often develop feelings of restlessness in their legs and may tap their feet, walk in place or pace. Constant pacing also commonly is seen in agitated patients who have major depressive disor756
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ders and those who have Alzheimer’s disease or experience other forms of dementia. EPIDEMIOLOGY
In the past, frequent misdiagnosis and poor recognition of RLS hampered epidemiologic studies. It now is known that approximately 10 percent of the adult North American white population of Northern and Western European origin have symptoms of primary RLS on a weekly basis and 6 percent have primary symptoms on a twice weekly basis.8,9 African and Asian populations appear to be less affected.10,11 The prevalence and severity of RLS increase with age.2 In one survey, 3 percent of participants aged 18 to 29 years reported having restless legs on five or more nights per month compared with 10 percent of those aged 30 to 70 years and 19 percent of those 80 years or older.12 Men and women appear to be affected equally in middleaged populations, but women in the older age groups are more likely to have RLS than are older men. For the majority of people with RLS, the symptoms are mild and cause little inconvenience. Approximately 1 to 2 percent of the general population, however, have frequent (> 15 times per month) severe symptoms that impair their sleep, thereby compromising their moods and work and recreational activities.13,14 PATHOGENESIS AND RISK FACTORS
In most cases, RLS is a primary disorder of unknown cause. However, RLS appears to run in families with an autosomal dominant inheritance pattern, especially in families of people with early-onset RLS.15,16 This genetic association is substantiated further by a study of monozygotic twins in which 10 of 12 twin pairs were concordant for RLS symptoms.17 Although the underlying cause of primary RLS is not understood fully, it is hypothesized by researchers such as Earley and colleagues18 to arise from low iron stores in the brain that result in inadequate activity of the neurotransmitter dopamine. This pathogenesis is supported by magnetic resonance imaging studies that found decreased amounts of iron in the substantia nigra of patients with RLS when compared with iron levels in control patients.18 An immunohistochemical study of the brains of patients with RLS at autopsy likewise suggested decreased amounts of iron in the substantia nigra.19 This decrement in iron can lead to a paucity of dopamine because
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iron is an important cofactor for tyrosine hydroxylase, the rate-limiting enzyme controlling the synthesis of dopamine. The hypothesis is substantiated further by the facts that RLS symptoms reach maximum severity at night when circadian dopamine plasma concentrations are at their lowest, the exquisite responsiveness of RLS symptoms to dopamine agents, and the exacerbation of symptoms by dopamine antagonist drugs that cross the blood-brain barrier.20 MEDICAL MANAGEMENT
Initial management of RLS consists of educating patients about lifestyle practices known to exacerbate the syndrome. Clinicians should discourage patients from using alcohol, tobacco and food products containing caffeine, as well as working shifts or engaging in strenuous physical activity close to bedtime. Medications known to worsen RLS should be changed to drugs that do not cause such adverse affects. Drugs that should be avoided are the antidepressants fluoxetine, paroxetine, sertraline and mirtazapine; the neuroleptics olanzapine and risperidone; lithium; and beta-adrenergic blockers.21 If these strategies fail to ameliorate RLS symptoms that are affecting the patient’s quality of life adversely, the patient’s physician often will mandate pharmacological therapy. Treatment is based on the use of four major classes of medications (dopaminergic agents, sedative-hypnotic agents, opioids and anticonvulsant agents). Most clinicians begin therapy for RLS using a dopaminergic agent.22 Levodopa, generally formulated with carbidopa (an inhibitor of the decarboxylase enzyme that inactivates levodopa to dopamine in the peripheral circulation, thus increasing the amount of levodopa available to cross the blood-brain barrier and enter the central nervous system [CNS]), often is used on an intermittent basis by people having periodic bouts of RLS. Once levodopa enters the brain and is transformed into dopamine, it improves both the sensory and motor deficits of the disorder. However, augmentation (a tendency for symptoms to develop earlier in the day and with increased intensity) occurs frequently with this agent. If augmentation occurs, the clinician usually prescribes another medication for the patient. Dopamine agonists (bromocriptine, cabergoline, pergolide mesylate, pramipexole and ropinirole) are drugs that stimulate dopamine receptors
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directly. They are used most commonly for people who are demonstrating augmentation, as well as for people who are having daily RLS symptoms. Augmentation is less common (20-30 percent) with these longer-acting drugs than with the levodopa-containing preparations, which have shorter half-lives.23 Clinicians prescribe these five agents in small doses to treat RLS and in high doses to treat Parkinson’s disease. Sedative-hypnotic agents are effective because they enhance sleep continuity rather than suppress movement. Clonazepam, the best-studied of this type of RLS medication, has a long duration of action and may result in nocturnal unsteadiness and drowsiness with associated falls or injuries, as well as cognitive impairment. Because of these adverse affects, intermediate-acting sedative-hypnotic agents (such as temazepam) and short-acting agents (such as triazolam, zolpidem and zaleplon) also are recommended. Long-term maintenance treatment with sedativehypnotic agents is limited by tolerance in many patients, but abuse appears to be low in patients with RLS.24 Natural opiates (codeine) and synthetic opioids (oxycodone and propoxyphene) are effective in lessening paresthesia and dysesthesia, motor restlessness and sleep disturbances. Although many clinicians are uncomfortable prescribing opioids over the long term for patients who have RLS to treat symptoms for which there is no biological measure, they acknowledge that these agents have long-term benefits and show little evidence of tolerance or addiction in patients.24 Another treatment for RLS includes the anticonvulsant agents gabapentin and carbamazepine. Gabapentin appears to be particularly useful for RLS symptoms that are characterized as painful. A recent double-blind study in which gabapentin was compared with a placebo showed reduced symptoms on all rating scales, reduced periodic leg movements during sleep and consequent improvement in sleep quality.25 The study also found that patients whose symptoms included pain received the greatest benefit from the drug. DENTAL CONSIDERATIONS
Dentists should schedule patients with RLS for early-morning appointments, because at that time these patients usually are bothered least by their symptoms.25 However, sustained periods of passive rest, such as sitting in a dental chair for a
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TABLE
Adverse orofacial reactions to medications used to treat restless legs syndrome.* ADVERSE REACTION†
MEDICATION Xerostomia
Sialorrhea
Sialadenitis Dysgeusia Stomatitis
Bromocriptine mesylate (Parlodel, Novartis, East Hanover, N.J.)
+
+
0
+
0
Cabergoline (Dostinex, Pfizer, New York City)
+
0
0
0
0
Levodopa (Larodopa, Roche Pharmaceuticals, Nutley, N.J.)
+
+
0
+
0
Levodopa and carbidopa (Sinemet, DuPont, Wilmington, Del.)
+
+
0
+
0
Pergolide mesylate (Permax, Elan Pharmaceuticals, San Diego)
+
0
+
+
+
Pramipexole (Mirapex, Boehringer Ingelheim Pharmaceuticals, Ridgefield, Conn.)
+
+
0
+
0
Ropinirole (Requip, GlaxoSmithKline, Pittsburgh)
+
+
0
0
0
Clonazepam (Klonopin, Roche)
+
+
0
0
0
Temazepam (Restoril, Mallinckrodt Pharmaceuticals, St. Louis)
+
+
0
+
0
Triazolam (Halcion, Pfizer)
+
+
0
+
0
Zaleplon (Sonata, Wyeth-Ayerst, Philadelphia)
+
+
0
+
0
Zolpidem (Ambien, Sanofi-aventis, Bridgewater, N.J.
+
+
0
+
0
Codeine (Codeine Phosphate, Lilly, Indianapolis)
+
0
0
0
0
Oxycodone (Percodan, Endo Pharmaceuticals, Chadds Ford, Pa.)
+
0
0
0
0
Propoxyphene (Darvon, Lilly)
0
0
0
0
0
Carbamazepine (Tegretol, Novartis)
+
0
0
0
+
Gabapentin (Neurontin, Pfizer)
+
+
+
+
+
Dopaminergic Agents
Sedative-Hypnotic Agents
Opioids
Anticonvulsant Agents
* Sources: Physicians’ Desk Reference,27 McEvoy28 and Wynn and colleagues.29 † +: Yes; 0: no.
prolonged period, still may be problematic for some people with RLS. Dentists should consult with the patients’ physicians to discuss the appropriateness of supplementing the therapeutic regimen with an additional and properly timed dose of medication for prolonged dental appointments.26 In the table, we present the findings of our review of the U.S. Food and Drug Administration medication package inserts that accompany some of the medications used in treating RLS and of our analysis of the current medical literature identifying adverse orofacial reactions that may occur.27-29 Some of these drugs also may interact 758
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adversely with dental therapeutic agents. Researchers have implicated medications from all four classes of drugs used to treat RLS in causing alterations in salivary gland function. A modest number of patients have reported having xerostomia; the problem is most acute in patients of advanced age.29 Some of the dopaminergic medications, all of the sedative-hypnotic agents and the anticonvulsant carbamazepine have been found to cause sialorrhea but in lesser numbers of people than those affected with xerostomia. Salivary flow changes also may cause dysgeusia, which has been reported by some patients who were taking dopaminergic medications, sedative-
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TABLE (CONT.)
Adverse orofacial reactions to medications used to treat restless legs syndrome.* ADVERSE REACTION† Gingivitis
0
Glossitis Tongue Edema
0
Coated Tongue
Bruxism
Miscellaneous
0
Facial pallor, blepharospasm, nasal congestion, headache, dizziness Toothache, rhinitis, throat irritation, periorbital edema Glossodynia, trismus, dark saliva, pigmentation of teeth, dysphagia, involuntary mouth/tongue movement Glossodynia, trismus, dark saliva, pigmentation of teeth, dysphagia Facial edema, headache, neck pain, periodontal abscess, jaw pain, moniliasis, dysphagia, dental caries, involuntary mouth/tongue movement Falling asleep in dental chair (secondary to sedation), pharyngitis, sinusitis, involuntary mouth/tongue movement, dysphagia Falling asleep in dental chair (secondary to sedation), toothache, headache, pharyngitis, tinnitus
0 0
0 0
0 +
0 0
0
+
0
0 0
0 + +
0 +
+
0
0 0
0
0
0
0 0
+
+
+
0 0
+
0
0
0
Sinusitis, rhinitis, pyrosis, toothache, jaw pain
0
Blurred vision
0
Nausea, vomiting
+
Headache, nausea, oral ulcers
0
Headache, dizziness, sinusitis, rhinitis, dysphagia
0 0
Nausea, vomiting, constricted pupils, suppression of cough reflex Nausea, vomiting
0
Dizziness, lightheadedness, nausea, vomiting, headache
0
Erythema multiforme, carbohydrate craving, tinnitus
0
Dry throat, oral ulcers, rhinitis, bleeding gingivae
+ 0
0
+ 0
0
0
+ 0
+
+
+ 0
0
0
0 0
0
0
0 0
0
0
0 0
0
0
0 0
0
+
0 0
+
+
0
hypnotic agents and anticonvulsant agents.30 Patient education and the maintenance of good oral hygiene are paramount for people who are experiencing xerostomia, given its association with the development of dental caries and periodontal disease. Dentists should prescribe artificial saliva for patients and give them instruction in proper toothbrushing and flossing methods that maximize dental plaque removal. We also recommend that patients receive a clinical examination and oral prophylaxis every three months, as well as receive a fluoride gel with a fluoride concentration of at least 1 percent. A critical review linked the use of levodopacontaining and other dopaminergic drugs used to treat RLS with an increasing severity of
bruxism.31 Confounding this issue is the fact that approximately 15 percent of people with untreated RLS also report severe bruxism.32 The mechanisms underlying these relationships require further study. Therefore, dentists should closely examine the dentition of all patients with RLS for evidence of bruxism, and should institute appropriate interventions for patients with excessive loss of tooth structure. These interventions include consulting with the patients’ physicians to discuss changing the medication to one not associated with causing bruxism or, if necessary, fabricating a prosthetic appliance to protect the dentition. Pergolide mesylate is an ergot-derived dopamine agonist used in low doses to treat RLS and
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in much higher doses to treat Parkinson’s disease. Both treatment regimens, however, cause some patients to develop stiff, fibrotic heart valve leaflets that are unable to close completely, which can result in regurgitation and a predisposition to endocarditis.33 These lesions probably develop because pergolide mesylate stimulates the serotonin 5-HT2B receptor, which is expressed in the fibroblasts of heart valves, thereby inducing fibrosis.34 Horvath and colleagues35 reported the occurrence of similar lesions with long-term use of cabergoline and bromocriptine but so far only in high-dose regimens like those used in the treatment of Parkinson’s disease. A patient with a history of long-term pergolide mesylate usage who requires invasive dental procedures should undergo an evaluation of the structure and function of his or her heart by a physician, preferably a cardiologist. The physician should be asked to comment on the patient’s susceptibility to endocarditis. Initially, the physician will confirm the patient’s medical history and perform a comprehensive physical examination and obtain necessary laboratory tests. The physician will auscultate the patient’s heart for abnormal sounds such as murmurs and evaluate an echocardiogram for the heart’s chamber size, the valve function and any aberrant blood flow patterns related to the valves. Patients who have developed valvular heart disease to the extent that they meet the American Heart Association’s (AHA’s) criteria for the risk of developing endocarditis will need to follow the AHA-recommended antibiotic prophylaxis regimen for invasive dental procedures involving the oral soft tissues.36 Patients who are not allergic to penicillin should recieve 2 grams of amoxicillin one hour before the procedure. Patients who are allergic to penicillin should receive clindamycin, cefadroxil or clarithromycin one hour before the procedure. Furthermore, because endocarditis may occur despite appropriate prophylaxis, dentists must warn these patients to report back to the office if they develop an unexplained fever, night chills, weakness, myalgia, arthralgia, lethargy or malaise after treatment.37-40 Chronic administration of opioids may be associated with the development of tolerance—a reduced drug effect and the need for higher doses of medication to produce the same effect. The development of tolerance often requires clinicians to prescribe larger doses of opioid analgesics (or, preferably, a course of nonsteroidal anti760
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inflammatory drugs) to obtain adequate postoperative dental pain relief. Clinicians must be cautious when prescribing increasing dosages of opioids, because of those drugs’ CNS-depressant effects.41 Similarly, when prescribing antianxiety and sedative-hypnotic drugs for patients undergoing dental procedures, clinicians must consider their additive CNS-depressant effects. Chronic administration of the anticonvulsant carbamazepine has been associated with the development of leukopenia, thrombocytopenia, anemia and pancytopenia on rare occasions. Concurrent administration of propoxyphene, erythromycin or clarithromycin decreases the rate of carbamazepine metabolism, thereby increasing the risk of toxicity, which may manifest as unstable blood pressure, hepatitis, or adverse neurological and sensory effects. Long-term concurrent administration of carbamazepine and acetaminophen increases the risk of developing hepatic toxicity. When prescribing antianxiety or sedative-hypnotic drugs and opioid analgesics for dental procedures in patients who are receiving either carbamazepine or gabapentin, clinicians must take into account the additive CNS-depressant qualities of the dental therapeutic agents.42 Clonazepam may produce a coated (black hairy) tongue. Concurrent administration of erythromycin or clarithromycin with triazolam decreases the rate of triazolam’s rate of metabolism, thereby increasing the risk of toxicity.43 Clinicians need to be cautious when prescribing antianxiety or sedative-hypnotic agents and opioid analgesics for dental procedures for patients who are receiving concurrently any sedative-hypnotic drug for RLS, owing to the increased potential for respiratory depression and sedation. CONCLUSION
RLS has been called the “most common illness you never heard of.”44 Given its association with the aging process and America’s changing demographic pattern, increasing numbers of people seeking dental treatment likely will have RLS. Dentistry, in concert with medicine, has much to offer patients who have RLS. Dentists familiar with the manifestations of the syndrome and its medical management can offer patients the full range of dental treatment options. ■ 1. Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi J. Restless Legs Syndrome Diagnosis and Epidemiology Workshop at the National Institutes of Health; International Restless
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Legs Syndrome Study Group. Restless legs syndrome: diagnostic criteria, special considerations and epidemiology—a report from the Restless Legs Syndrome Diagnosis and Epidemiology Workshop at the National Institutes of Health. Sleep Med 2003;4(2):101-19. 2. Berger K, Luedemann J, Trenkwalder C, John U, Kessler C. Sex and the risk of restless legs syndrome in the general population. Arch Intern Med 2004;164(2):196-202. 3. Hening WA. Subjective and objective criteria in the diagnosis of the restless legs syndrome. Sleep Med 2004;5:285-92. 4. Lesage S, Hening WA. The restless legs syndrome and periodic limb movement disorder: a review of management. Semin Neurol 2004;24:249-59. 5. Manconi M, Govoni V, De Vito A, et al. Pregnancy as a risk factor for restless legs syndrome. Sleep Med 2004;5:305-8. 6. Allen R. Dopamine and iron in the pathophysiology of restless legs syndrome (RLS). Sleep Med 2004;5:385-91. 7. Gosselin N, Lanfranchi P, Michaud M, et al. Age and gender effects on heart rate activation associated with periodic leg movements in patients with restless legs syndrome. Clin Neurophysiol 2003;114: 2188-95. 8. Hening W, Walters AS, Allen RP, Montplaisir J, Myers A, FeriniStrambi L. Impact, diagnosis and treatment of restless legs syndrome (RLS) in a primary care population: the REST (RLS epidemiology, symptoms, and treatment) primary care study. Sleep Med 2004; 5:237-46. 9. Rothdach AJ, Trenkwalder C, Haberstock J, Keil U, Berger K. Prevalence and risk factors of RLS in an elderly population: the MEMO study—memory and morbidity in Augsburg elderly. Neurology 2000;54:1064-8. 10. Tan EK, Seah A, See SJ, Lim E, Wong MC, Koh KK. Restless legs syndrome in an Asian population: a study in Singapore. Mov Disord 2001;16:577-9. 11. Kageyama T, Kabuto M, Nitta H, et al. Prevalences of periodic limb movement-like and restless legs-like symptoms among Japanese adults. Psychiatry Clin Neurosci 2000;54:296-8. 12. Phillips B, Young T, Finn L, Asher K, Hening WA, Purvis C. Epidemiology of restless legs symptoms in adults. Arch Intern Med 2000;160:2137-41. 13. Zucconi M, Ferini-Strambi L. Epidemiology and clinical findings of restless legs syndrome. Sleep Med 2004;5:293-9. 14. Abetz L, Allen R, Follet A, et al. Evaluating the quality of life of patients with restless legs syndrome. Clin Ther 2004;26:925-35. 15. Winkelmann J, Muller-Myhsok B, Wittchen HU, et al. Complex segregation analysis of restless legs syndrome provides evidence for an autosomal dominant mode of inheritance in early age at onset families. Ann Neurol 2002;52:297-302. 16. Chen S, Ondo WG, Rao S, Li L, Chen Q, Wang Q. Genomewide linkage scan identifies a novel susceptibility locus for restless legs syndrome on chromosome 9p. Am J Hum Genet 2004:74:876-85. 17. Ondo WG, Vuong KD, Wang Q. Restless legs syndrome in monozygotic twins: clinical correlates. Neurology 2000;55:1404-6. 18. Earley CJ, Allen RP, Beard JL, Connor JR. Insight into the pathophysiology of restless legs syndrome. J Neurosci Res 2000;62: 623-8. 19. Connor JR, Boyer PJ, Menzies SL, et al. Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome. Neurology 2003;61:304-9. 20. Ferreri F, Rossini PM. Neurophysiological investigations in restless legs syndrome and other disorders of movement during sleep. Sleep Med 2004;5:397-9. 21. Rama AN, Kushida CA. Restless legs syndrome and periodic limb movement disorder. Med Clin North Am 2004;88:653-67. 22. Littner MR, Kushida C, Anderson WM, et al; Standards of Prac-
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tice Committee of the American Academy of Sleep Medicine. Practice parameters for the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. Sleep 2004;27:557-9. 23. Ondo W, Romanyshyn J, Vuong KD, Lai D. Long-term treatment of restless legs syndrome with dopamine agonists. Arch Neurol 2004;61:1393-7. 24. Garcia-Borreguero D, Larrosa O, de la Llave Y, Verger K, Masramon X, Hernandez G. Treatment of restless legs syndrome with gabapentin: a double-blind, cross-over study. Neurology 2002;59 (10):1573-9. 25. Schapira AH. Restless legs syndrome: an update on treatment options. Drugs 2004;64(2):149-58. 26. Silber MH, Ehrenberg BL, Allen RP, et al; Medical Advisory Board of the Restless Legs Syndrome Foundation. An algorithm for management of restless legs syndrome (published correction appears in Mayo Clin Proc 2004;79:1341). Mayo Clin Proc 2004;79:916-22. 27. Physicians’ desk reference. 59th ed. Montvale, N.J.: Medical Economics; 2005. 28. McEvoy GK, ed. AHFS drug information 2005. Bethesda, Md.: American Society of Health-System Pharmacists; 2005. 29. Wynn RL, Meiller TF, Crossley HL, eds. Drug information handbook for dentistry. 9th ed. Hudson, Ohio: Lexi-Comp; 2003. 30. Byrne BE. Oral manifestations of systemic agents. In: Ciancio SG, ed. ADA guide to dental therapeutics. 3rd ed. Chicago: American Dental Association; 2003;504-50. 31. Winocur E, Gavish A, Voikovitch M, Emodi-Perlman A, Eli I. Drugs and bruxism: a critical review. J Orofac Pain 2003;17(2):99-111. 32. Lavigne GJ, Montplaisir JY. Restless legs syndrome and sleep bruxism: prevalence and association among Canadians. Sleep 1994;17:739-43. 33. Flowers CM, Racoosin JA, Lu SL, Beitz JG. The US Food and Drug Administration’s registry of pergolide-associated heart disease. Mayo Clin Proc 2003;78:730-1. 34. Van Camp G, Flamez A, Cosyns B, et al. Treatment of Parkinson’s disease with pergolide and relation to restrictive valvular heart disease. Lancet 2004;363:1179-83. 35. Horvath J, Fross RD, Kleiner-Fisman G, et al. Severe multivalvular heart disease: a new complication of the ergot derivative dopamine agonists. Mov Disord 2004;19:656-62. 36. Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis: recommendations by the American Heart Association. JADA 1997;128:1142-51. 37. Scully C, Roberts G, Shotts R. The mouth in heart disease. Practitioner 2001;245:432-7. 38. Carmona IT, Diz Dios P, Scully C. An update on the controversies in bacterial endocarditis of oral origin. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;93:660-70. 39. Pallasch TJ, Gage TW, Taubert KA. The 1997 prevention of bacterial endocarditis recommendations by the American Heart Association: questions and answers. J Calif Dent Assoc 1999;27:393-9. 40. Mask AG Jr. Medical management of the patient with cardiovascular disease. Periodontol 2000 2000;23(June):136-41. 41. Ganzberg. S. Analgesics: opioids and nonopioids. In: Ciancio SG, ed. ADA guide to dental therapeutics. 3rd ed. Chicago: American Dental Association; 2003:77-103. 42. Ganzberg S. Neurologic drugs. In: Ciancio SG, ed. ADA guide to dental therapeutics. 3rd ed. Chicago: American Dental Association; 2003:366-81. 43. Ganzberg S. Psychoactive drugs. In: Ciancio SG, ed. ADA guide to dental therapeutics. 3rd ed. Chicago: American Dental Association; 2003:382-411. 44. Restless Legs Syndrome Foundation. Available at: “www.rls.org”. Accessed Jan 17., 2005.
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