ORAL PILOCARPINE FOR RADIATION-INDUCED XEROSTOMIA - INTEGRATED EFFICACY AND SAFETY RESULTS FROM 2 PROSPECTIVE RANDOMIZED CLINICAL-TRIALS

Purpose: Pilocarpine hydrochloride administered in either a fixed-dose or in a dose-titration protocol three times a day for 12 weeks was ev aluated for its abilitly to relieve symptoms of postradiation xerostom ia and to improve saliva production. The studies were randomized, doub le-blind, placebo-controlled, multicenter clinical trials. A total of 369 patients who had received at least 40 Gy of radiation to the head and neck with clinically significant xerostomia were enrolled in the t wo studies. In the dose-titration study, 162 patients were enrolled an d they received a thrice daily regimen of 2.5 mg tablets for first 4 w eeks, 5.0 mg tablets for the second 4 weeks, and 10.0 mg tablets for l ast 4 weeks of a 12-week study. Patients in the titration study were a llowed to down titrate following at least one dose escalation to allev iate bothersome side effects, if any. In the fixed dose study, 207 pat ients received either placebo, 5.0 mg, or 10.0 mg tablets t.i.d. for 1 2 weeks. Methods and Materials: Patients were evaluated for symptomati c relief by responding to questionnaires using visual analog scales an d categorical questions; and, for saliva production by sialometry. Que stionnaires measured relief of intraoral dryness, improvement in overa ll condition (global response), oral discomfort, difficulty in speakin g, chewing and swallowing, denture wearing, and usage of artificial sa liva. Evaluations were conducted at baseline, and weeks 4, 8, and 12. Results: There were statistically significant improvements in salivary flow in pilocarpine treatment groups vs. placebo. There was a signifi cant improvement in the overall ''global'' condition of xerostomia ass ociated with the use of pilocarpine in both studies. In the fixed-dose study, there were significant improvements in oral dryness, mouth com fort, ability to speak, and reduction in the use of oral comfort agent s. The dose-titration study showed improvements in dryness that approa ched significance (p = 0.057) and a decreased use of oral comfort agen ts (p = 0.045). All pilocarpine dosages (2.5, 5.0, and 10.0 mg three t imes a day) were judged to be safe. Adverse experiences were those exp ected for a cholinergic agonist, with the most common being mild to mo derate sweating. The incidence of these events increased by dose. Conc lusion: It is concluded that in these studies pilocarpine produced cli nically significant benefits with acceptable side effects and risks fo r the treatment of symptomatic postradiation xerostomia. The incidence of most adverse events increased with dose. Best results may require continuous treatment for more than 8 weeks with doses greater than 2.5 mg three times a day. A 5.0 mg thrice daily regimen produced the best clinical results when both efficacy and side effects were taken into consideration. There may be some patients who would experience some ad ditional benefit by increasing the dose to 10 mg thrice daily.