Effect of pilocarpine hydrochloride on salivary production in previously irradiated head and neck cancer patients

MOSQUEDA-TAYLOR A, LUNA-ORTIZ K, IRIGOYEN-CAMACHO ME, DÍAZ- FRANCO MA, COLL-MUÑOZ AM. EFFECT OF PILOCARPINE HYDROCHLORIDE ON SALIVARY PRODUCTION IN PREVIOUSLY IRRADIATED HEAD AND NECK CANCER PATIENTS. MED ORAL 2004;9:204-11.

SUMMARY 

Objective: To study the effects of pilocarpine hydrochloride on whole salivary gland production in Mexican patients affected by hyposalivation secondary to radiotherapy of the head and neck region.
Study design: With previous written informed consent, 20 patients affected by hyposalivation secondary to head and neck radiation therapy (> 40Gy) were evaluated through the whole saliva test (WST) before, during and after ten weeks of treatment with pilocarpine hydrochloride (5 mg t.i.d.). Hyposalivation-related symptomatology was assessed before and at every week by means of a questionnaire with an ordinal scale ranging from 0-10. Salivary production values recorded at the end of the study and those obtained before treatment were compared by means of Student´s t test. A paired Wilcoxon test was used to compare the differences in the oral symptoms, such as oral dryness, soreness, ability for speaking and swallowing before and after treatment.
Results: Initial WST had a mean salivary production of 0.8 cm (s.d. 0.7), with a range from 0 to 2.9 cm). After ten weeks of treatment salivary production increased to a mean of 2.24 cm (s.d. 0.7), with a range from 1.2 to 4.0 cm. There was a salivary flow increase of 64.5% (p<0.001). In addition, there were significant improvements in oral dryness, mouth comfort, ability to speak and ability to swallow (p<0.01). Adverse effects were usually minimal and they did not cause withdraw from the study in any case.
Conclusions: Administration of 5-mg pilocarpine hydrochloride tablets three times daily significantly improved salivary production and clinical symptomatology secondary to radiation-induced hyposalivation with minimal side-effects. In addition, this study showed that WST is a fast, technically simple and highly reliable method to study salivary production in prospective studies.

Key words: Pilocarpine, radiation, xerostomia, salivary glands, head and neck cancer.

INTRODUCCIÓN 

Head and neck cancer is one of the major oncological problems due to its high mortality rate and because of the sequels of its treatment. Radiotherapy is an important therapeutic alternative in many of the lesions that develop in this anatomical region, used either as a single resource or combined with other therapeutic modalities; however, the effects of radiation not only affect to malignant cells, but it is also absorbed by oral and perioral tissues, particularly those with a high cellular turnover, including the salivary glands (1).

Radiation-induced damage to the salivary glands leads to a significant decrease in salivary gland production, which produces xerostomia and diverse complications derived from the reduced amount of saliva; therefore, during last years numerous studies have been directed towards the development of therapeutic measures that reduce or revert salivary gland hypofunction (2-7) and to objectively record salivary production (8), and for these reasons the aim of this work is to study the effect of pilocarpine hydrochloride on whole saliva production in Mexican patients affected by hyposalivation secondary to radiotherapy of the head and neck region.

PATIENS AND METHODS

The studied population included 20 patients who had undergone radiotherapy for head and neck cancer and finished it at least 45 days before enrollment in this study. All patients were recruited consecutively during follow-up visits in the Head and Neck Service at the Instituto Nacional de Cancerologia in Mexico City. In each case demographic data, WST, oral symptomatology associated to hyposalivation, vital signs, oncological diagnosis, radiation dose employed, physical examination, presence of diseases not related to the oncological problem and type and dose of medication used to control them were recorded before entry to this study.

Inclusion criteria were: patients aged between 18 and 80 years old with a positive history of malignant neoplasm in the oral cavity, major salivary glands, oropharynx, hypopharynx, nasopharynx or lymphoid tissues, which had been submitted to radiotherapy to the salivary gland region in a dose of 40 Gy or more, whose systemic and ophthalmologic evaluations excluded pathologic conditions that contraindicated the use of pilocarpine HCl, all of which signed the written informed consent to participate in the study.

Exclusion criteria included: confirmed history of Sjögren´s syndrome, concomitant use of medications that either stimulated or depressed the salivary gland production and the existence of diseases and conditions in which the use of pilocarpine HCl is contraindicated, such as bronchial asthma, chronic bronchitis, chronic obstructive pulmonary disease, acute iritis, glaucoma, antecedents of ophthalmic surgery, angina, uncontrolled hypertension, pregnancy, lack of effective contraception methods in childbearing age women and in those cases with a positive history of hypersensitivity to pilocarpine.

A 5 mg pilocarpine HCl tablet (Lemery, S.A. de C.V., Mexico) was administered with water three times a day, 30 to 60 min. before meals (15 mg/day). At baseline and at every weekly checkup until study completion (ten weeks) the following aspects were recorded: present dose and effects of pilocarpine HCl, vital signs (blood pressure, pulse, respiratory frequency, temperature and weight), side-effects associated to pilocarpine, oral symptomatology and WST results. According to therapeutic response and the occurrence of side effects, the dose of pilocarpine HCl was adjusted or maintained weekly.

Oral symptomatology was assessed by means of a four-questions questionnaire, each one measured with an ordinal scale ranging from 0-10, where zero means absence of symptoms and ten is the higher level of them. This system was employed to evaluate those aspects related to the intensity of xerostomia, such as oral discomfort, perception of humidity and difficulties for speaking and swallowing (Figure 1).

Fig. 1. Questionnaire used to evaluate subjective symptoms *
* Taken of Neidermeier et al, 1998 (2).

 

Salivary production was evaluated through the WST at baseline and at the beginning of every weekly visit, in order to record the resting salivary gland production. WST is a quantitative method developed by Lopez Jornet et al. (8) to measure the whole salivary gland production. It consists on a millimetered 1x17 cm strip of Whatman paper 41 that was introduced in a polyethylene bag, leaving the first five millimeters of the strip out of one end of the bag, which was folded and placed under the tongue to contact the mucosal surface of the floor of the mouth, around the Warthon´s orifice. The patients were sitted, and each subject was instructed to adopt the position known as "coachman position" (the sitting subject lowers his trunk vertically, the back is curved and the head hangs forwards slightly, the hands rest on the knees and the eyes are closed). The paper strip is left on place for five minutes and after done this, the subject opened his/her mouth and the strip was extracted and the wet centimeters read. This test was always carried out in the same clinical space, which was noise-free and in a quiet environment, at least one hour after breakfast, between 9 and 12 a.m.

The results of salivary gland production were expressed in centimeters, obtaining the range, mean and standard deviation (s.d.) for the study group. The amount of saliva that was produced at the end of the study was compared with the values obtained at baseline in each patient, and these data were analyzed through a paired student´s t test. In addition, blood pressure measurements done at baseline and at study completion were compared in the same way. Comparison of oral symptoms was done through a paired Wilcoxon test.

RESULTS

There were 12 women and 8 men. Age ranged form 35 to 85 years (mean 59.5 yr). Mean time interval since last radiation was 25.6 months (s.d. 50.1), with a median of 12 months. Table 1 shows the different types of neoplasms treated in the present series.

Table 1. Distribution of neoplasms according to location and histopathology

WST had a mean baseline value of 0.8 cm (s.d. 0.7) of saliva production (range from 0 to 2.9 cm). At the end of ten weeks of treatment mean salivary production increased to 2.24 cm (s.d. 0.7), with a range from 1.2 to 4.0 cm. There was an increase in salivary production of 64.5%, and the difference between salivary production before and after treatment was statistically significant (p < 0.001), with a mean increase in salivary production of 1.43 cm. In addition, table 2 shows the mean salivary production recorded along the ten weeks of treatment with pilocarpine HCl (1.91 cm), which also confirms this significant increase. Time interval from last radiation to the beginning of treatment did not correlate with salivary production (p > 0.05).

WST - whole saliva test
* P <0.001
Table 2. Mean values and age range, baseline and mean WST obtained along
 ten weeks of treatment with pilocarpine hydrochloride.

 

Oral humidity perception improved in all cases, with a median of 8 at baseline and 3 at the end of the study (p < 0.01). Significant improvement was also achieved in speaking ability. After a median of 7 at baseline, there were no patients who referred difficulties for speaking at the end of the study (p < 0.01). On the other hand, patients also manifested improvement in swallowing, with a median of 8 at the beginning and 3 in the last visit (p < 0.01). Oral discomfort diminished from a median of 6 at baseline to 1 at the end of the study, and at that time more than a half of the patients informed to have no discomfort (p < 0.01).

Adverse effects were usually slight to moderate, and these were absent in three cases (15%); sweating was present in seventeen cases (85%) and this was the only manifestation in 11 cases (55%). Six patients (30%) had other symptoms, such as headache, diarrhea, blurred vision and chills (Table 3); however, it is interesting to note that there were no cases in which treatment had to be interrupted due to these effects. Median blood pressure at baseline was 98.7 (s.d. 14.6), and at the end of the study it was 89.8 (s.d. 6.4) (p>0.05) with no clinical alterations in any case.

Table 3. Frequency and type of adverse effects recorded during 
treatment  with pilocarpine HCl

 

DISCUSSION 

Radiation-induced damage to the salivary glands leads to xerostomia and other complications derived from the reduced salivary flow, such as mucositis, disgeusia, dentin hypersensitivity due to enamel demineralization, caries reactivation, periodontal disease, traumatic ulceration of the mucosa and candidiasis, but it also may favor the occurrence of more severe lesions, such as recurrent suppurative parotitis due to retrograde infection through the excretory salivary gland ducts and osteoradionecrosis (2,9,10). Irreversible damage to the parotid glands is observed from 10 to 20 Gy, when applied in daily doses of 1.8 to 2.0 Gy (2) and therefore all patients included in the present series showed clinical signs of hyposalivation.

The above mentioned manifestations may produce severe incapacity in the affected individuals to perform the diverse functions of the oral tissues, such as speak, swallow, perceive flavors and to wear prosthetic apparatus, among others. That is why during the recent years research has been directed towards production of therapeutic measures that diminish or revert irreversible salivary gland hypofunction caused by radiotherapy and other degenerative processes of glandular parenchyma.

Available treatments for alleviating dry mouth sensation and its complications include the continuous moisturizing of the oral mucosa with repeated applications of water or saliva substitutes in the form of liquids, spray or gels, as well as stimulation of the residual glandular parenchyma with chemical agents, chewing or by means of systemically administered cholinergic agents, such as pilocarpine HCl (2-4,11,12).

Pilocarpine is a naturally occurring alkaloid, first isolated in 1875 from the leaves of the South American plants Pilocarpus jaborandi or Pilocarpus microphyllus (6). Farmacologically, pilocarpine HCl is a parasympathomimetic agent that acts as a muscarinic agonist with moderate b-adrenergic activity. This alkaloid produces exocrine gland stimulation in human beings. To date, it is the most widely studied systemic sialogogue, and diverse studies have demonstrated its usefulness in treating hyposalivation due to diverse causes (2,11,13), and for this reason became the first FDA-approved drug for treatment of Sjögren syndrome related xerostomia and other causes of irreversible hyposalivation (5). In addition, there are some studies that reveal that the use of pilocarpine HCl in post-irradiated patients increases salivary gland production and improves the quality of life of the affected individuals (3,6,7). The usual recommended dosage is one or two 5 mg tablets taken three times a day, administered 30 to 60 minutes before meals (15 to 30 mg/day). Sialogogue effect starts usually after 30 min, and it lasts 2-3 hours on average. The most frequent secondary effects are the same that are produced by other cholinergic drugs, such as gastrointestinal upset, sweating, tachycardia, bradycardia, increase in respiratory secretion production, increase in smooth muscle tonicity and blurred vision. Therefore, contraindications are limited to those patients with biliary disease, glaucoma, acute iritis and renal colic. It is also important to evaluate the risk of administering the drug to patients with heart diseases, bronchial asthma, angina, antecedents of myocardial infarction, chronic bronchitis and chronic obstructive pulmonary disease (5). In the present study, adverse affects were mild to moderate in intensity, and they were usually well-tolerated by the patients, none of which had to stop their treatment.

In Mexico, as well as in most countries in America, there was no pilocarpine hydrochloride tablets available for treatment of xerostomia until now; therefore, treatment of this condition and its sequels had been based on the use of general measures directed towards continuous hydration of the oral mucosa with water, repeated applications of glycerin and some other measures that only produces temporal relief, without the protective effects that saliva produces on the hard and soft oral tissues. On the other hand, as the general features of the diverse populations in which pilocarpine HCl is being used to treat hyposalivation differs in some aspects with those found in Latin American population (height, mean weight, nutritional status and other features), it is not known if the dose of medication suggested for those populations are the same for our population. In the present series, only one patient used more than 15 mg/day of this drug, without having improvement after using 25 mg/day, which was considered a case with a more severe damage of the glandular tissue, which may explain the lack of response.

In this and other series (3,13), the percentage of patients that referred to feel better with the use of pilocarpine in terms of moisture perception and the other symptoms that were evaluated was maintained along the treatment, which may be due to gradual changes occurring in the oral mucosa related to the appearance of humidity in a more or less persistent state. Although the symptomatic improvement associated to pilocarpine intake has been consistently observed in this and other series (3,4,6), this correlation is less clear with respect to sialometry results, which may be due, at least partly, to the fact that the techniques used in these studies to measure salivary gland production are similar to those used to determine the salivary gland production in people that produces large volumes of saliva, which do not detect small increases in its production (3). In addition, it has to be considered that those patients that produced larger amounts of saliva before radiotherapy-induced salivary gland destruction do require a higher production in order to perceive a symptomatic relief, while those patients that already had a scant production of saliva before radiotherapy would benefit with smaller increases in salivary production. In this respect, WST is a rapid, technically simple method, that can be used systematically to record salivary gland production in prospective studies and to compare diverse populations to be studied.

In conclusion, the results of the present study confirm a high efficacy of pilocarpine HCl when used as 5 mg tablets three times daily during ten weeks, which produced both objective increase in whole saliva production as well as increasing moisture perception, facilitating swallowing and speaking, and diminishing the frequency of mucosal hydration. In addition, in this work it was observed that a dose of 15 mg/day of pilocarpine HCl has few adverse effects, which were usually mild and well tolerated, and in no case treatment had to be interrupted due to them.

Aknowledgement
The authors wish to express our aknowledgement to Ms Refugio Reyes for her enthusiastic collaboration in recruitment and attention to the patients included in the present series.

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