Oral Pilocarpine: A Review of its Pharmacological Properties and Clinical Potential in Xerostomia

Abstract

Synopsis

Pilocarpine is a cholinergic agonist which stimulates salivary secretion both in individuals with normal salivary gland function and in those with impaired salivary flow (xerostomia or oral dryness). A rapid increase in salivary flow rate is observed following oral pilocarpine administration and peak levels are maintained for at least 1 to 2 hours. Mean salivary flow rates after administration of pilocarpine are 2- to 10-fold higher than after placebo, and no evidence of tolerance to the pharmacological effects of the drug has been observed during prolonged administration for up to 5 months.

The clinical efficacy of oral pilocarpine in relieving symptoms of xerostomia (resulting from radiation therapy to the head and neck region or salivary gland dysfunction), including oral dryness and difficulty in chewing, swallowing and speaking, has been demonstrated in double-blind placebo-controlled clinical trials. In these studies, pilocarpine 5 to 10mg 3 times daily increased salivary flow and improved symptoms of xerostomia in a significantly higher percentage of patients than did placebo (54 versus 25% in one study).

Preliminary findings indicate that administration of pilocarpine during radiation therapy may reduce the severity of xerostomia; however, this requires further investigation.

The majority of patients receiving oral pilocarpine therapy for xerostomia experience adverse events (most commonly sweating); however, these are generally mild and tolerable in nature.

Thus, pilocarpine is an effective agent for the treatment of xerostomia, increasing salivary flow and reducing symptom severity to a significantly greater extent than placebo. Further clinical trials should evaluate the potential beneficial effects of pilocarpine on the incidence of dental caries and oral candidiasis during prolonged therapy, its prophylactic efficacy during radiation therapy and its efficacy relative to that of other salivary stimulants.

Xerostomia

Xerostomia (oral dryness) is caused by changes in salivary gland function. This may result from radiation therapy to the head and neck region, the use of drugs with anticholinergic/antiadrenergic properties, or systemic disease such as the autoimmune disease Sjögren’s syndrome, which causes structural damage to the glands. The symptoms of xerostomia, which include increased dental caries, difficulty in chewing, swallowing and speaking, and an increased incidence of oral candidiasis, can have a significant effect on quality of life. Treatment options (including salivary stimulants and saliva substitutes) are largely palliative and generally offer only short term relief of symptoms.

Pharmacological Properties

Pilocarpine is a muscarinic cholinergic agonist. Its ability to stimulate salivary secretion in both healthy volunteers and patients with xerostomia has been known to Western medicine for more than a century, with recent studies demonstrating its superior efficacy relative to that of placebo. Salivary flow can be stimulated within 15 minutes of oral pilocarpine administration and peak flow rates maintained for at least 1 to 2 hours in patients with xerostomia. In one study, the mean salivary flow rate was 2- to 10-fold higher after pilocarpine treatment than after placebo, and the drug appeared to increase salivary flow to a greater extent than citrate. No evidence of tolerance to the salivary stimulating properties of pilocarpine was observed during prolonged therapy for 5 months.

While studies in partially desalivated animals have indicated that prolonged administration of pilocarpine may reduce the incidence of caries and oral infection, this remains to be shown in humans.

The pharmacokinetic properties of oral pilocarpine in patients with xerostomia require further study. Peak plasma drug concentrations following 2 days’ oral administration of pilocarpine 5 or 10mg 3 times daily to 30 healthy male volunteers were 15 and 41 μg/L, respectively, and were reached in 1.25 and 0.85 hours, respectively. The rate of absorption was decreased when the drug was taken with food. Pilocarpine was eliminated predominantly in the urine with an elimination half-life of 0.76 and 1.35 hours following administration of a 5 or 10mg dose 3 times daily, respectively.

Clinical Potential

The clinical efficacy of pilocarpine as a salivary stimulant has been investigated in patients with salivary gland dysfunction (predominantly Sjögren’s syndrome) or radiation-induced xerostomia in double-blind placebo-controlled studies. Pilocarpine 5 to 10mg 3 times daily was effective in stimulating salivary secretion and improving symptoms of xerostomia, including dry mouth, difficulty in swallowing, chewing and speaking, in a significantly higher percentage of patients than placebo.

In a large multicentre study (n = 191), the overall severity of xerostomia was reduced in a significantly higher percentage of patients following 12 weeks’ treatment with pilocarpine 5mg 3 times daily (54%) than in those receiving placebo (25%). Pilocarpine treatment was associated with an increased ability to speak without requiring liquids, and a reduced need for oral comfort agents. The percentage of patients with an increase in whole and unstimulated parotid salivary flow rates was also higher in pilocarpine recipients versus placebo.

Unstimulated major salivary gland output was significantly increased in 26 of 39 patients after initial exposure to pilocarpine 5mg, and 27 of 31 patients showed symptom improvement after 1 months’ treatment with pilocarpine 5mg 3 times daily. A global assessment after 6 months of treatment showed 27 of 31 patients to have some symptom improvement (pronounced in 6 patients and moderate in 14) in this study.

Preliminary results of a small double-blind placebo-controlled study indicate that pilocarpine administration during radiation therapy may reduce the severity of xerostomia. Patients treated with pilocarpine 5mg 3 times daily starting the day before radiation therapy had smaller losses in salivary gland function following irradiation than those receiving placebo and reported fewer symptoms of xerostomia.

Tolerability Profile

Pilocarpine has been generally well tolerated in clinical trials. While adverse events were reported by most patients and were usually mild in severity, their incidence and severity were dose-related. Sweating was the most common effect, and occurred in 37 to 65% of patients treated with pilocarpine 5mg 3 times daily and in 80% of patients treated with the 10mg 3 times daily dosage in a large multicentre study. 5.5 and 29% of patients, respectively, withdrew from therapy during the 3-month treatment period because of excessive sweating.

Other events, which were probably related to the cholinergic activity of pilocarpine, included chills, nausea, dizziness, rhinitis, flushing, asthenia, urinary frequency, increased lacrimation, palpitations and gastrointestinal tract disturbance.

No significant effects have been observed on heart rate, blood pressure, or cardiac conductivity during pilocarpine therapy in patients with xerostomia to date; however, this requires further examination, especially in patients with possible complicating medical conditions.

Dosage and Administration

Oral pilocarpine 5mg 3 times daily is recommended for the initial treatment of xerostomia. This may be titrated up to 10mg 3 times daily in patients showing a poor response who tolerate the lower dosage. The lowest dosage that is effective and tolerable should be used for maintenance therapy.

Pilocarpine is contraindicated in patients with uncontrolled asthma, and in patients with acute iritis or narrow-angle glaucoma (unless required before surgery). Caution is advised when administering the drug to patients with controlled asthma, chronic bronchitis, chronic obstructive pulmonary disease or cardiovascular disease, or when coadministering the drug with β-adrenergic antagonists or drugs with parasympathomimetic or anticholinergic effects.