Review of the Pharmacological Properties and Clinical Usefulness of Muscarinic Agonists for Xerostomia in Patients With Sjogren's Syndrome

Hiroshi Yasuda, Hiroshi Niki


Clin Drug Invest. 2002;22(2) 

In This Article

Abstract and Introduction

The anti-xerostomia effects of muscarinic agonists (cholinomimetics) are reviewed. Cevimeline (cevimeline monohydrochloride hemihydrate) is a novel muscarinic agonist that stimulates salivary secretion in animals and humans both with normal salivary gland function and with impaired salivary secretion (xerostomia or oral dryness) as effectively as pilocarpine. Other classic and nonselective muscarinic agonists, such as arecoline, carbachol, muscarine and oxotremorine, as well as acetylcholine, failed to exhibit a sufficient salivation effect even at sublethal doses in animals.

Oral administration of cevimeline 30mg to humans induces a moderate and lasting increase in salivary flow, and the effect is maintained for at least 4 to 6 hours, longer than with pilocarpine. Mean increases in salivary flow rates after cevimeline treatment were 2-fold higher than after placebo, and no evidence of tolerance of the pharmacological effect has been observed during prolonged administration for up to 12 months.

The clinical efficacy of cevimeline in relieving symptoms of xerostomia, including oral dryness and difficulties in chewing, swallowing and speaking, has been demonstrated by placebo-controlled, double-blind, randomised clinical trials in the USA and Japan. In these studies, cevimeline 30mg three times daily increased salivary flow and improved the symptoms of xerostomia in a significantly higher percentage of patients compared with placebo. Some patients receiving cevimeline therapy for xerostomia experienced adverse events such as sweating, gastrointestinal symptoms (nausea, diarrhoea, abdominal pain and vomiting), dizziness and rigors; these effects were related to muscarinic activity and were generally mild and tolerable in comparison with those of pilocarpine.

These findings suggest that muscarinic M3 agonists are suitable for the treatment of xerostomia. Cevimeline in particular has a long-lasting salivation effect with fewer adverse events than pilocarpine, and so is expected to be more useful for the treatment of xerostomia in patients with Sjögren's syndrome, reducing symptom severity and improving their quality of life.

Xerostomia (oral dryness) is caused by a lack of normal salivary secretion. Saliva secretion is vital for maintenance of oral health and function; hyposalivation induces complications such as increased oral mucosa atrophy, oral infection and dental caries, leading to difficulty in swallowing, chewing and speaking, and also to severe oral diseases and an overall decline in quality of life.[1,2] Salivary gland dysfunction is associated with a variety of systemic exocrine disorders, particularly Sjögren's syndrome (an autoimmune disease with salivary and lacrimal dysfunction).[3,4,5] Xerostomia is also induced by radiation therapy for head and neck cancers.[6] There are many patients who experience xerostomia and xerophthalmia (dry eyes), but only artificial saliva and/or tears have been available for temporary relief of these sicca symptoms. In 1998, pilocarpine, a classic muscarinic agonist (cholinomimetic), was approved in some countries, including the USA,[7,8] for improving xerostomia, but its short-acting pharmacological properties and high incidence of adverse effects limit its use.[9]

We have developed a novel muscarinic receptor agonist, cevimeline (Evoxac®; 1 SNI-2011, AF-102B[10]), which acts relatively selectively on salivary glands and induces long-lasting salivary secretion,[11,12,13] a suitable property for improving xerostomia symptoms and oral cavity disorders. Its clinical effectiveness and tolerability have been demonstrated by placebo-controlled, double-blind, randomised clinical studies in patients with Sjögren's syndrome in the USA and Japan.[14,15] This drug was launched in the USA in early 2000 and in Japan in late 2001.

This article reviews the pharmacological profiles and clinical usefulness of the two anti-xerostomia drugs pilocarpine and cevimeline, in comparison with other muscarinic agonists.

1 Use of tradenames is for product identification only and does not imply endorsement.


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