A Multicenter Maintenance Study of Oral Pilocarpine Tablets for Radiation-Induced Xerostomia
A Multicenter Maintenance Study of Oral Pilocarpine Tablets for Radiation-Induced Xerostomia
Xerostomia, or oral dryness, results from salivary gland dysfunction. Underlying causes include chronic diseases, such as Sjögren's syndrome, sarcoidosis, and diabetes. Drugs, such as antidepressants, anticholinergics, and antihypertensives, also may result in xerostomia, as can chronic graft-vs-host disease, and use of certain chemotherapeutic agents. Radiation therapy to the head and neck region is particularly detrimental to salivary function, with the majority of patients suffering long-term xerostomia.
Loss of the normal amount and consistency of saliva frequently leads to enhanced formation of caries, recurrent candidiasis, and chronic oral pain and burning. Xerostomia also has a profound impact on patients' quality of life. Persistent dryness impairs the ability to speak, chew, and swallow, and necessitates frequent sips of liquids. Taste is impaired, and sleep is often interrupted. Patients complain of difficulty wearing dentures. Current management with artificial saliva, sialogogues, and fluoride treatment is inadequate.
Pilocarpine hydrochloride, a cholinergic parasympathomimetic agent that primarily affects muscarinic receptors, has been shown to increase saliva and improve functioning with acceptable side effects [1-7]. Its effectiveness and acceptability, however, have mainly been demonstrated for brief periods of use. The goal of this trial was to assess the efficacy and safety of long-term pilocarpine hydrochloride use for the treatment of radiation-induced xerostomia.
Patients were eligible for the study if they had participated in a prior study of oral pilocarpine (fixed-dose, dose-titration, or dose-ranging study). To be eligible for the current study, patients had to have head and neck cancer and be 18 years or older. They must have received at least 4,000 cGy of radiation to the head and neck region at least 4 months prior to study entry and also have significant xerostomia of at least 4 months' duration, presence of at least one parotid gland, and at least some residual salivary gland function, as documented at the end of the prior study. If patients were of childbearing potential, a negative pregnancy test was required. All patients signed an informed consent form.
Patients were ineligible for the study if they had a life expectancy of less than 6 months, cancer treatment was anticipated during this study, or they had used drugs that could result in a dry mouth (eg, anticholinergics, tricyclic antidepressants, antihistamines, beta blockers), ophthalmic pilocarpine, or any investigational agent within 30 days.
The study was a multicenter, maintenance trial, and there was open-label distribution of the study drug, pilocarpine hydrochloride tablets. The starting dose for all patients was 5.0 mg tid. Investigators had the prerogative to adjust doses to between 2.5 and 10.0 mg tid or bid to achieve maximum efficacy with acceptable side effects. The duration of the study was 36 months.
Efficacy of oral pilocarpine for radiation-induced xerostomia was assessed by subjective measures.
At study entry and each visit, patients were asked to judge their own condition, as measured by three forms of subjective assessment:
Part One--First, patients were asked five questions related to functioning during the 3 days prior to the visit. They scored their condition from one extreme to the other using a visual analog scale (VAS), which was converted to an absolute number ranging from 0 to 100 (where 0 represents worse and 100, better). The following questions were asked:
- During the last 3 days, your mouth or tongue was: very dry to not dry.
- During the daytime hours of the last 3 days, the feeling of your mouth and tongue was: extremely uncomfortable to comfortable.
- During the last 3 nights due to dryness of your mouth and tongue, how difficult was it to sleep (very difficult to easy)?
- During the last 3 days due to dryness, how difficult was it to speak without drinking liquids (very difficult to easy)?
- During the last 3 days due to dryness, how difficult was it to chew and swallow food (very difficult to easy)?
Baseline assessment upon entry to the prior study was compared to data from the last evaluable visit using the two-group paired t-test.
Part Two--In the next portion of the subjective evaluation, patients were asked the following questions related to their condition immediately before and after taking medication during the last 3 days prior to their visit:
- Were your mouth and tongue more comfortable?
- Were your mouth and tongue less dry?
- Was it easier to speak without drinking?
Part Three--Finally, patients were asked to rank their present condition of xerostomia from worse to better (using a VAS), as compared with their condition at the beginning of the study. Patients were asked whether their use of oral comfort agents or activities was decreased, unchanged, or increased since the start of study.
In order to evaluate the safety of long-term oral pilocarpine use, patients underwent the following at each visit: a physical examination, complete blood count, chemistry panel, and urinalysis. Each subject was scheduled for a clinic visit every 3 months for the first year, and then at 6-month intervals. Each subject was contacted by telephone once a month.
A diary of adverse experiences was kept by each patient and reviewed by the nurse or physician investigator at each visit. An ECG was performed at month 9, and an ophthalmologic examination was performed at month 9 and study's end.
Between November 1990 and December 1991, 265 patients were enrolled in the study from 59 sites. Complete data are available for 261 of these patients, including 185 men and 76 women. Overall, the mean age of these patients was 58 years (Table 1). In their prior study, 150 patients had received active drug and 115, placebo.
Follow-up assessment is based on 265 patients. Of the 129 patients who discontinued the drug, the reasons are as follows: adverse experience (48 patients), lack of efficacy (34), personal reasons or noncompliance (27), and recurrent cancer (20).
Although the trial allowed the investigator to increase or decrease the drug dosage, the majority of patients started with a dose of 5 mg, and 116 patients stayed at that dose throughout the trial (Table 2). Dose was escalated above 5 mg in 128 patients, and had to be reduced in 9 individuals because of side effects.
Subjective Evaluation of Efficacy
When patients' baseline assessments were compared to their last evaluable visit, patients reported a significant improvement in functioning (using the VAS) during the last 3 days prior to their visit (Table 3). Dryness of the mouth and tongue improved from a mean baseline of 23.9 to 42.0 (P less than .01). Comfort of the mouth and tongue improved from 40.9 to 47.6 (P less than .01). Ability to sleep, as related to dryness of the mouth and tongue, changed from 47.9 to 57.1, ease of speaking from 33.8 to 47.1, and ability to eat/drink from 24.4 to 42.8 (P less than .01). There was no evidence of a significant decrease in therapeutic effect over time.
Patients were asked to relate their condition immediately before and after taking medication during the last 3 days prior to their visit. The data from visit 2 are as follows: Of 188 patients, 62% said that their mouth and tongue were more comfortable, 62% stated that their mouth and tongue were less dry, and 58% felt it was easier to speak without drinking (Table 4). Patients were asked how the use of oral comfort agents or activities had changed since the start of study. At their last evaluable visit, 31% stated that the use of oral comfort agents had decreased, 66% felt that use of these agents had not changed, and 3% said that it had increased (N = 214) (data not shown). When patients rated their condition of xerostomia at last study visit compared to their condition at the beginning of the study, the mean patient VAS response was 56.1 (N = 224; Figure 1).
Table 5 lists the type and incidence of adverse experiences. Sweating was the most common side effect. Less frequent, mild to moderate toxicities included flu-like syndrome, urinary frequency, rhinitis, headache, diarrhea, and increased lacrimation. Most side effects lessened within hours after the cessation of therapy. There were no significant toxicities, as measured by the complete blood count, chemistry panel, ECG, urinalysis, or ophthalmic examination.
Radiation therapy is highly successful in the treatment of lymphomas and solid tumors arising in the head and neck region. Unfortunately, the salivary glands often must be included in the radiation field, and patients face life-long xerostomia, which impacts negatively on nutrition, dentition, sleep, speech, and enjoyment of eating. These deleterious effects result from poor or absent salivary flow, as well as changes in the consistency of saliva. Attempts to improve oral function and reduce the high rate of dental caries have included fluoride and antifungal agents as needed. Palliative therapies, such as oral rinses, saliva substitutes, salivary stimulants (hard candy or gum), and frequent sips of water, have proved inadequate.
Oral pilocarpine has been shown to be beneficial in several trials of short-term use [1-7]. In a double-blind, placebo-controlled trial, Fox et al  demonstrated an improvement in salivary flow and a decrease in oral dryness with oral pilocarpine, 5.0 mg bid.1 No severe toxicity was reported. In another double-blind trial, Greenspan and Daniels  noted improved salivary flow and diminished symptoms in 9 of 12 patients treated with oral pilocarpine tablets at a dose of 5.0 to 7.5 mg tid or qid.
Fox et al  confirmed these findings in a double-blind, placebo-controlled trial using 5.0 mg oral pilocarpine tablets tid for 6 months. Subjective improvement was reported in 27 of 31 patients, and 20 of those exhibited a measurable increase in unstimulated salivary flow. Patients reported sweating, urinary frequency, and increased lacrimation, but serious toxicities were not noted. Valdez et al , in a 3-month trial of oral pilocarpine in patients undergoing radiation, demonstrated a lower incidence of oral xerostomia symptoms in the active-treatment group compared with the placebo group.
Placebo-Controlled Trials of Oral Pilocarpine Tablets
Two large, multicenter, placebo-controlled clinical trials recently evaluated the safety and efficacy of oral pilocarpine hydrochloride tablets [6,7]. Efficacy was most clearly demonstrated in the fixed-dose trial . In this trial, a significantly greater number of pilocarpine-treated patients in both the 5- and 10-mg groups experienced improvements in oral dryness and mouth comfort, as compared with those receiving placebo. With respect to secondary response variables, pilocarpine improved the ability to speak, mouth and tongue comfort, and the need for oral comfort agents. Saliva production increased with pilocarpine, but the volume of saliva did not necessarily correlate with symptomatic relief.
Results of the dose-titration trial  were similar to those seen in the fixed-dose trial. Sensations of oral dryness improved with pilocarpine, particularly at the 5- and 10-mg doses. As in the fixed-dose trial, overall global improvement in the dose-titration trial was significantly better with pilocarpine than with placebo. Also, those receiving pilocarpine used significantly fewer oral comfort agents than did those receiving placebo. At every visit, post-dose salivary production was significantly increased in pilocarpine-treated patients compared with those receiving placebo.
In both studies, adverse reactions associated with pilocarpine were mild and typical of side effects seen with cholinergic agonists. The most common drug-related effect in the large, multicenter trials was sweating, which generally occurred 20 to 60 minutes after dosing and was short lived. Side effects of pilocarpine also appeared to be dose-related.
Maintenance Study of Oral Pilocarpine Tablets
Although the aforementioned trials demonstrated the short-term benefit of oral pilocarpine with acceptable toxicity, it was anticipated that the need for this drug would be lifelong. Thus, the present study was undertaken to evaluate long-term efficacy and safety. We demonstrated that oral pilocarpine hydrochloride is moderately effective in reducing the symptoms of radiation-induced xerostomia, including dryness, oral discomfort, sleep disturbances, difficulty with speech, chewing, and swallowing. When given as a maintenance drug, this effect can be maintained for up to 36 months. A starting dose of 5 mg tid appears to be optimal.
Side effects are tolerable, with sweating being the most common adverse effect. Only 18% of patients discontinued the drug due to adverse experiences. We conclude from this study that oral pilocarpine hydrochloride tablets can be safely used for the relief and long-term management of xerostomia.
1. Fox PC, van der Ven PF, Baum BJ et al: Pilocarpine for the treatment of xerostomia associated with salivary gland dysfunction. Oral Surg Oral Pathol 61:243-248, 1986.
2. Greenspan D, Daniels TE: Effectiveness of pilocarpine in postirradiation xerostomia. Cancer 59:1123-1125, 1987.
3. Fox PC, Atkinson JC, Macynski A, et al: Pilocarpine for treatment of salivary hypofunction-a six month trial (abstract). J Dent Res 68:315, 1989.
4. Valdez IH, Wolff A, Atkinson JC, et al: Use of pilocarpine during head and neck radiation therapy to reduce xerostomia and salivary dysfunction. Cancer 71:1848-1851, 1993.
5. Fox PC, Atkinson JC, Macynski AA, et al: Pilocarpine treatment of salivary gland hypofunction and dry mouth (xerostomia). Arch Intern Med 151:1149-1152, 1991.
6. Johnson JT, Ferretti GA, Nethery WJ, et al: Oral pilocarpine for post-irradiation xerostomia in patients with head and neck cancer. N Engl J Med 329:390-395, 1993.
7. LeVeque FG, Montgomery M, Potter D, et al: A multicenter, randomized, double-blind, placebo-controlled, dose-titration study of oral pilocarpine for treatment of radiation-induced xerostomia in head and neck cancer patients.