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Sjögren’s Syndrome (SS) is a chronic, autoimmune, rheumatic disorder characterized by lymphocyte-mediated destruction of exocrine glands and internal organ involvement that occur in association with autoantibody production or as a complication of a preexisting connective tissue disorder. Over time, progressive infiltration of lacrimal and salivary glands by mononuclear cells leads to diminished secretions, with resultant xerostomia (dry mouth) and xerophthalmia (dry eyes) being the most prevalent symptoms.
Morbidity from salivary and lacrimal gland hypofunction results from alteration of mucosal and ocular surfaces and breakdown of the normal host barriers to infection. In addition to significant discomfort from dryness, untreated dry mouth and dry eyes may also lead to complications, including stomatopyrosis (burning mouth), oral ulcers, malnutrition, weight loss, oral candidiasis, bacterial sialoadenitis, sleep disruption, accelerated dental caries, periodontal disease, corneal ulceration or perforation, and bacterial conjunctivitis. Use of currently available treatments, including tear and saliva substitutes, provides transient relief at best and often fails to prevent complications. In addition, patients often find these over-the-counter remedies costly, ineffective, inconvenient, or irritating.
Pilocarpine is a naturally occurring compound derived from the South American shrub Pilocarpus jaborandi. This plant alkaloid is a cholinergic parasympathomimetic agonist that binds to muscarinic-M3 receptors and can cause pharmacological smooth muscle contraction in humans and stimulation of various exocrine glands. Pilocarpine hydrochloride (Salagen) tablets are currently indicated for the treatment of radiation-induced dry mouth. In two previous multicenter, double-blind, placebo-controlled trials, use of pilocarpine tablets provided significant relief to patients with radiation-induced dry mouth. In these two studies, use of pilocarpine tablets significantly improved symptoms of intraoral dryness, oral discomfort, and dysphonia and patients’ global assessment of dry mouth as well as reduced the need for administration of oral comfort agents, such as artificial saliva, water, and hard candy. Patients treated with pilocarpine tablets also demonstrated a statistically significant increase in saliva production, measured as either whole-mouth or parotid salivary flow. It is through this mechanism that cholinergic stimulation of residual-functioning exocrine glandular tissue in patients with SS could potentially alleviate symptoms of dry mouth, dry eyes, or other symptoms associated with SS. Therefore, the present study was undertaken to investigate the efficacy and safety of pilocarpine tablets for the treatment of symptoms associated with dry mouth and dry eyes in patients with SS.
After providing written informed consent, 373 patients with primary or secondary SS and clinically significant dry mouth and dry eyes were randomized to receive 2.5-mg pilocarpine, 5-mg pilocarpine, or placebo tablets 4 times daily for 12 weeks. Symptoms were assessed by questionnaires with visual analog scales or categorical checkboxes. Whole-mouth salivary flow rates were measured.
Saliva is a chemically complex fluid containing several organic and inorganic components, all of which play an essential role in maintaining oral health. Saliva is not only required to preserve the dentition and mucosal surfaces but also to facilitate digestion, phonation, mastication, deglutition, and gustation. Therefore, the oral consequences of salivary gland hypofunction extend beyond those of a dry mouth. Common oral symptoms in SS can also include dysphonia, dysphagia, stomatopyrosis (burning mouth), dysgeusia (altered taste), oral ulcers, and sleep disruption caused by nocturnal fluid ingestion. Attempts to treat these symptoms with replacement therapy using artificial salivas and oral lubricants have been largely unsuccessful, and patient satisfaction and compliance have been low.
For the treatment of symptoms associated with dry eyes in primary and secondary SS, there is a plethora of artificial tear and lubricant preparations available. However, the frequency with which they must be applied suggests the need for novel therapeutic interventions. Ultimately, tear preservation by punctual occlusion or cautery is the last resort to solve this problem. To date, no artificial tear or saliva preparation has successfully duplicated the physicochemical properties of the body’s own fluids well enough to provide a comparable degree of benefit.
The medicinal properties of pilocarpine, including its ability to stimulate salivation, have been recognized for many centuries by the Tupi Indian tribe of northern Brazil, who named this indigenous shrub “jaborandi,” or the “slobber-mouth plant.” In 1888, a British physician described a 65-year-old woman with xerostomia and xerophthalmia who responded symptomatically to treatment with tincture of jaborandi, administered orally and subcutaneously.
The benefit of pilocarpine tablets for treatment of symptoms of dry mouth from various causes, including SS, has been previously suggested in smaller studies and case reports. Data from the present multicenter trial indicate that the use of 5-mg pilocarpine tablets administered 4 times daily (20 mg/d) provides significant symptomatic relief of dry mouth cased by SS and significantly increases saliva production in measurable quantities. Regular use of pilocarpine tablets at this dosage significantly improves other specific symptoms of salivary gland hypofunction in patients with SS, such as oral discomfort, nocturnal fluid ingestion, and the need for saliva substitutes. Some benefit for dysphonia may also occur, as evidenced by the trend toward statistically significant improvement in the 5-mg pilocarpine group for this symptom.
Although the data show that pilocarpine-induced stimulation of salivary flow occurred within 30 minutes of ingestion of the first dose and was maintained through week 12, the onset of subjective benefit for various symptoms took 6 to 12 weeks. Because dry mouth develops rather insidiously in most patients with SS, it is not unreasonable to expect that improvement or reversal of symptoms after treatment would be delayed. This observations suggest that a patient’s symptoms on a given day may reflect not only the quantity of saliva but also the cumulative effect of chronic tissue dehydration. For this reason, it seems that a prolonged treatment course with pilocarpine tablets (e.g., 6-12 weeks) should be recommended to patients to allow sufficient time for symptomatic benefits to occur. In this study, the most dramatic response occurred in patients who took 5-mg pilocarpine tablets 4 times daily. Although salivary flow rates were measured during only the first 90 minutes of the dosing interval, results of previous studies in healthy participants indicate that the pilocarpine effect on flow rates lasts 3 to 5 hours. Optimal therapeutic benefit can therefore be best achieved through a 4-times-daily dosing regimen.
In conclusion, the administration of 5-mg pilocarpine tablets 4 times daily (20 mg/d in divided doses) produced significant benefits for the symptomatic treatment of dryness associated with SS that clearly outweighed adverse effects and risks in this 12-week study. Patients experienced improvement in dryness of the nose, skin, and vagina and the ability to expectorate. Treatment success with pilocarpine will most likely depend on existence of residual exocrine gland function. In SS, this may vary in different organs and cannot always be predicted based on the duration of symptoms. As data from the present study suggest, use of pilocarpine tablets offers a wide range of potential therapeutic effects for patients with SS. Therefore, at the present time, almost any patient with SS with some degree of exocrine gland function could potentially benefit from this treatment depending on therapeutic goals. As with other patient groups with rheumatic conditions, early diagnosis and treatment offer the best hope for a good outcome.
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Frederick B. Vivino, MD; Ibtisam Al-Hashimi, PhD; Zafrulla Khan, DDS; Francis G. LeVeque, DDS; Paul L. Salisbury III, DDS; Tram K. Tran-Johnson, PharmD, PsyD; Charles C. Muscoplat, PhD; Madhu Trivedi, PhD; Barry Goldlust, PhD; Susan C. Gallagher, MS; for the P92-01 Study Group
Source: Archives of Internal Medicine, Volume 159, January 25, 1999.