DRUG EVALUATION

Drugs49(l): 143-155,1995

0012-6667/95/0001-0143/$.13.0010 © Adis International Limited. All rights reserved.

Oral Pilocarpine: A Review of its Pharmacological Properties and Clinical Potential in Xerostomia Lynda R. Wiseman and Diana Faulds Adis International Limited, Auckland, New Zealand Various sections of the manuscript reviewed by: WB. Bowen, Department of Dental Research, University of Rochester, Rochester, New York, USA; J. Ekstrom, Department of Pharmacology, Goteborg University, Goteborg, Sweden; J.B. Epstein, Division of Dentistry, Cancer Control Agency of British Columbia, Vancouver, British Columbia, Canada; U.G. Friis, Department of Pharmacology, University of Odense, Odense, Denmark; T. Hara, Department of Child Neurology, Tottori University School of Medicine, Yonago City, Japan; H. Joensuu, Department of Oncology and Radiotherapy, University of Turku Central Hospital, Turku, Finland; J.T. Johnson, Division of Head and Neck Oncology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh Pennsylvania, USA; EG. Leveque, Department of Otolaryngology, Harper Hospital, 'Detroit, Michigan, USA; T. Nederfors, Department of Hospital Dentistry, Central Hospital, Halmstad, Sweden; S. Shiozawa, Department of Medicine, Kobe University School of Medicine, Kobe, Japan; D. Zegarelli, Columbia Presbyterian Medical Center, New York, New York, USA.

Contents Summary , , , , , , , , , , , 1, Overview of Xerostomia , , , 2, Pharmacological Properties 2.1 Stimulation of Salivary Secretion 2,2 Other Effects on the Oral Cavity 2,3 Pharmacokinetic Properties, 3, Clinical Potential , , 4, Tolerability Profile , , , , , , , , , , 5, Dosage and Administration , , , , 6, Place of Oral Pilocarpine in the Therapy of Xerostomia ,

143 146 146 148

150 150 150 152

153 153

Summary 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 lO-fold higher than after placebo, and no evidence oftolerance 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

Wiseman & Faulds

144

(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 lOmg 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 ofxerostomia, increasing salivary flow and reducing symptom severity to a significantly greater extent than placebo. Further clinical trials should evaluate the potential beneficial effects ofpilocarpine 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 Sjogren'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 lO-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 41Ilg/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 lOmg dose 3 times daily, respectively.

© Adis International Limited. All rights reserved.

Drugs 49 (l) 1995

Oral Pilocarpine: A Review

145

Clinical Potential

The clinical efficacy of pilocarpine as a salivary stimulant has been investigated in patients with salivary gland dysfunction (predominantly Sjogren's syndrome) or radiation-induced xerostomia in double-blind placebo-controlled studies. Pilocarpine S to lOmg 3 times daily was effective in stimulating salivary secretion and improving symptoms ofxerostomia, 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 Smg 3 times daily (S4%) than in those receiving placebo (2S%). 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 Smg, and 27 of3l patients showed symptom improvement after 1 months' treatment with pilocarpine Smg 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 Smg 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 6S% of patients treated with pilocarpine Smg 3 times daily and in 80% of patients treated with the lOmg 3 times daily dosage in a large multicentre study. S.S 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 Smg 3 times daily is recommended for the initial treatment of xerostomia. This may be titrated up to lOmg 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

© Adis International Limited. All rights reserved.

Drugs 49 (1) 1995

Wiseman & Faulds

146

asthma, chronic bronchitis, chronic obstructive pulmonary disease or cardiovascular disease, or when coadministering the drug with ~-adrenergic antagonists or drugs with parasympathomimetic or anticholinergic effects.

1. Overview of Xerostomia Xerostomia (oral dryness) is caused by a lack of normal salivary secretion, through either a reduction in salivary flow or alteration of salivary composition. Saliva production and secretion is vital for the maintenance of oral health and function; thus, complications arising from hyposalivation, such as increased dental caries, difficulty in swallowing, chewing and speaking, and an increased incidence of oral infection, can lead to severe oral disease, nutritional deficiencies and an overall decline in quality of life (for reviews see Navazesh and Ship[1]; Sreebny and Valdini[2]; Toth et al.[3]; Ferguson et al.[4]). Radiation therapy for head and neck cancer causes salivary gland damage in the majority of patients and is an important cause of xerostomia.l 5-8] The severity of hyposalivation depends on the radiation treatment field size, duration of therapy, radiation dose, and the amount of salivary tissue involved. [9, 10] As few as 2 to 3 doses of 225 cGy (225 rad) may cause reversible injury to the parenchyma of the salivary gland, while total doses >6000 cGy cause permanent changes (i.e. fibrosis and secretory hypofunction).[8,1l] Salivary gland hypofunction may also be associated with a variety of systemic disorders, particularly Sjogren's syndrome (an autoimmune disorTable I. Treatment options for relief of the symptoms of xerostomia Salivary stimulants

Mechanical stimulants

Bethanechol chloride

Chewing gum

Bromhexine Citric and malic acids Lemon and glycerine Liquid paraffin

Saliva substitutes

Neostigmine

Synthetic saliva containing carboxymethylcellulose, or mucin with sorbitol and salts containing carboxymethylcellulose

Nicotinic acid Pilocarpine Potassium iodide Sulfarlem

© Adis International Limited. All rights reserved.

Fig. 1. Chemical structure of pilocarpine.

der that affects salivary and lacrimal function).[12,13] Many drugs, including antihypertensives and antidepressants, anorexigenic drugs, antihistamines, antipsychotics, antispasmodics, decongestants, diuretics and tranquilisers can cause dry mouth through their anticholinergic/antiadrenergic properties.l 14-16 ] Xerostomia may also occur in states of dehydration, including diabetes, excessive use of diuretics, or neurosis.l 4] Therapeutic options are largely palliative, as reversal of the primary cause is often not possible. Treatment is aimed initially at restoring the flow of saliva using mechanical (chewing gum) and taste stimulants or systemic salivary gland stimulants (sialogogues). If this fails, artificial saliva substitutes and mouth wetting agents may be used, although the majority provide only short term relief of symptoms, and cause irritation of oral tissues during long term use (table I).

2. Pharmacological Properties The salivary stimulant pilocarpine (fig. 1) is a naturally occurring alkaloid derived from the leaves of South American plants of the genus Pilocarpus. It is a cholinergic agonist which has diaphoretic, miotic and central nervous system effects and has been most widely used as a topical treatment for both open-angle and angle-closure glaucoma. Pilocarpine is available as both a tablet and capsule formulation as well as a liquid-based preparation. The latter, however, has inherent instability and degradation problems V 7-19] The drug exerts a broad spectrum of pharmacological effects with predominant muscarinic acDrugs 49 (1) 1995

Oral Pilocarpine: A Review

147

Table II. Randomised double-blind placebo-controlled (P) studies demonstrating the clinical efficacy of oral pilocarpine (PC) in improving salivary gland flow and relieving symptoms of xerostomia caused by either radiation therapy of the head and neck or salivary gland dysfunction Reference

No. of patients

Diagnosis (mean duration of xerostomia)

Fox et al[28]a

6

Inflammatory exocrinopathy [4y]b

Fox et al. [29]a

39

Greenspan & Daniels[27]a

12

Johnson et al[8]

191

Treatment regimen (mg)

Effect on salivary flow rate

Improvement in symptoms of xerostomia

PC 5 ode

pc: whole salivary and parotid salivary flow rates increased P: similar to baseline.

PC: reduction in oral dryness and increased salivation in 6/6 patients. P: no change.

PC: unstimulated major salivary gland flow rate increased in 26/39 patients P: similar to baseline.

PC: 27/31 d patients responded. Salivation increased within 2 to 3h of drug administration and oral dryness, speaking, chewing and swallowing improved after 1mo.

pc: significant increase in

PC: 9/12 patients with marked or moderate improvement P: 2/12 patients.

Px2d

Sjogren's syndrome

PC 5 tide

(n=21); radiation-induced xerostomia (n = 12); idiopathic salivary gland dysfunction (n = 6) [~ 1y]

Px1mo

Severe radiation-induced xerostomia [6mo]

PC 5 or 7.5 tid e orqid Px3mo

Radiation-induced xerostomia [4mo]

PC 5 (n = 71) or 10 (n = 57) tide P (n = 63)

X

5mo

x3mo

Leveque et al.[32]

162

Radiation-induced xerostomia [4moj

PC 2.5,5 or 10 tide (n = 75)e

Schulleret al.[30]

14

Radiation-induced xerostomia [21 mol

PC 3 tid (n = 5) P (n = 9) x3mo

Valdezet al.[33]

9

Patients with head and neck cancer at risk of developing xerostomia during radiation therapy

mean stimulated whole salivary and parotid salivary flow rate after 90d vs P (p < 0.05 and p < 0.005, respectively). PC: % of patients with increased whole and parotid salivary flow rates significantly higher vs P after 4 and 8w of treatment (p < 0.05), but not after 12w.

PC: significant increase in whole and parotid salivary flow P (n = 87) x 3mo rates after 1st dose and after 12w vs P (p < 0.05). PC: increased whole salivary flow rate after 6w in 3/5 patients vs 2/9 in the P group.

e PC 5 qid ( n = 4) PC: smaller radiation-induced P (n = 5) reduction in stimulated whole salivary flow rate vs P. x3mo

a

Crossover study.

b

2 patients had Sicca syndrome and 4 had chronic nonspecific sialadenitis.

c

Tablet or capsule formulation.

Oral dryness PC 5 or 10mg: 44 and 46% of patients P: 25% of patients (p < 0.05 vs PC) Overall severity PC: 54 and 43% of patients P: 25% of patients (p = 0.01 vs PC) Comfort of mouth and tongue PC: 31 and 37% of patients P: 9.5% of patients (p = 0.001 vs PC). PC: overall condition improved at 8 and 12w for 15 and 30 mg/d (p = 0.015 vs placebo). 7.5 mg/d had little effect. Increased ability to swallow after 6w PC: 3/5 patients P: 3/9 patients Improvement in taste acuity PC: 2/5 patients P: 4/9 patients. Dry mouth when eating PC: 27% of patients P: 84% of patients (p < 0.001 vs PC) Need to sip liquid while eating PC: 37% of patients P: 78% of patients (p < 0.001 vs PC).

d

Only 31 patients completed the protocol and were evaluable for symptom improvement.

e

A total of 75 patients were treated with PC. The dosage was titrated according to response and adverse events. At the end of 12 weeks, the numbers of patients taking the 2.5, 5 and 10mg 3 times daily dosages were 10, 20 and 45, respectively. 2% pilocarpine solution containing 1mg per drop.

Abbreviations and symbols: d = days; h = hours; mo = month(s); od = once daily; qid = 4 times daily; tid = 3 times daily; y = year(s).

© Adis International Limited. All rights reserved.

Drugs 49 (1) 1995

Wiseman & Faulds

148

Parotid gland

r-I---_

Sublingual gland Submaxillary gland

Fig. 2. Location of major salivary glands.

tion. It can increase secretion by the exocrine glands, including the sweat, salivary, lacrimal, gastric, pancreatic and intestinal glands, and the mucous cells of the respiratory tract. In addition, pilocarpine also increases smooth muscle tone and motility in the intestinal and urinary tracts, gallbladder, biliary ducts, and bronchiVo,21J The parasympathomimetic action of pilocarpine mediated by cholinergic muscarinic receptors results in vasodilation and salivary secretion)4J Recent studies in rat sublingual glands indicate that the muscarinic receptors involved in pilocarpineinduced secretion of saliva are of the M3 subtypeJ22J 2.1 Stimulation of Salivary Secretion

The salivary stimulating properties of pilocarpine have been known to Western medicine for more than 100 years, its efficacy in managing patients with xerostomia having been first recognised as early as 1890 (for a review see Ferguson et alJ4]). Studies in both normal volunteers and patients with xerostomia have been conducted since the 1960s and have demonstrated the ability of pilocarpine to stimulate salivary flow and relieve symptoms of oral dryness.l 23 -25 ] In more recent © Adis International Limited, All rights reserved.

placebo-controlled studies in patients with radiation-induced xerostomia or Sjogren's syndrome, pilocarpine has shown superior efficacy in improving xerostomia (table II)J8,26-31] Functional salivary gland parenchyma is necessary for pilocarpine to be effective. While a significant proportion of the salivary glands may be damaged by radiation therapy, it is rare for all the minor and major glands to be totally compromised)34] Salivary gland function may be evaluated by measuring resting and/or stimulated major salivary gland (submandibular, sublingual and parotid glands; fig. 2) flow rates and by salivary gland scintigraphy. [2,9, 10,35] A significant increase in salivary secretion was observed during administration of oral pilocarpine S mg/day for 2 days to 6 patients with Sjogren's syndrome in a double-blind placebo-controlled crossover studyJ28,36] All patients had marked salivary gland disease but had some residual, functionally responsive gland tissue. Parotid and submandibular/sublingual saliva samples were collected immediately before pilocarpine administration, at IS-minute intervals for 1 hour, and then at 2 and 3 hours (fig. 3). The response was rapid, with some patients showing an increase in both parDrugs 49 (1) 1995

Oral Pilocarpine: A Review

149

otid and submandibular/sublingual salivary flow within IS minutes of pilocarpine administration. Maximal flow rates were reached in about 30 to 4S minutes (range IS to 120 minutes) and slowly declined thereafter, returning to baseline levels within about 3 hours. Salivary flow rates following placebo administration remained similar to baseline throughout the study. Mean maximal salivary flow rates after pilocarpine treatment were 2- to lO-fold greater than after placebo. Compared with 2% citrate-stimulated secretions, mean salivary flow rates were higher after pilocarpine (0.24 vs 0.38 mllmin for the parotid gland and 0.27 vs 0.29 ml/min for the submandibular/sublingual glands), although the difference was not statistically significant, and the salivary composition was similar with regard to potassium, sodium and protein levels.[28] Rhodus and Schuh[26] examined the effect of pilocarpine on salivary flow in 18 patients with Sjogren's syndrome. In this single-blind study, patients were randomised to 6 weeks' treatment with either oral pilocarpine Smg 3 times daily (2% solution) or placebo. No appreciable change was found in salivary flow rate in the control group, 8

• Pilocarpine (P)

o Placebo (P)

• Pilocarpine (SM)

o Placebo (SM)

o

15 30 45

60

120

180

Time after pilocarpine administration (min)

Fig. 3. Stimulation of parotid (P) and submandibular/sublingual (SM) salivary gland secretion following treatment of 6 patients with salivary gland hypofunction with oral pilocarpine 5 mg/day or placebo for 2 days.[36] The results shown are the means of 4 days' testing and have been estimated from graphically presented data.

© Adis International Limited. All rights reserved,

0,3

•

0.25

~

o Baseline

o After treatment

r--

c

.S-

-*

0.2

CI)

'§ ?;

,g ~

.~

c;;

0,15 r--

0.1

r--

r--

r--

(j)

0,05

o

WUS

PSS

Pilocarpine

PSS

WUS

Placebo

Fig. 4. Effect of 6 weeks' treatment with either pilocarpine 5mg 3 times daily or placebo on whole unstimulated (WUS) or parotid stimulated (PSS) salivary secretion in 18 patients with Sjogren's syndrome,[26] * p < 0,001 vs baseline.

whereas pilocarpine caused a significant increase in both whole unstimulated and stimulated parotid salivary flow rates compared with baseline (fig. 4). Patients with secondary Sjogren's syndrome showed a greater response than those with primary disease. The overall increase in whole unstimulated salivary flow was significantly greater in the pilocarpine treatment group than in the controls (O.lS vs 0.02 ml/min; p < 0.001), as was the increase in parotid salivary flow (0.14 vs 0.009 mllmin; p < 0.001). The salivary response to pilocarpine therapy (Smg 3 times daily for S months) in 39 patients with salivary gland dysfunction resulting from radiation therapy to the head and neck region or Sjogren's syndrome is shown in table III. Compared with baseline, both parotid and submandibular gland salivary outputs were significantly increased 1 and 2 hours after the initial pilocarpine dose, but not after 4 hours. The same time course of salivary response was seen after 30 days' treatment with pilocarpine, and there was no evidence of tolerance' to the salivary stimulating effects of the drug after S months' treatment. The magnitude of response did not differ significantly between the Drugs 49 (1) 1995

Wiseman & Faulds

150

Table III. Major salivary gland flow rates after administration of oral pilocarpine 5mg at 0 hours and again at 5 hours to 39 patients with salivary gland dysfunction[29] Time (hours)

0

Salivary gland output (ml/min) parotid glands

submandibular/sublingual glands

0.014

0.014

0.051*

0.044*

2

0.029*

0.028*

4

0.011

0.018

6

0.048*

0.028*

Symbol: * p < 0.05 versus baseline.

first and fifth months of active drug treatment. Salivary flow rates remained similar to baseline levels during 1 month of treatment with placebo. 2.2 Other Effects on the Oral Cavity

Xerostomia is associated with a significant increase in the incidence of dental caries and oral candidiasis (see Section 1). The efficacy of pilocarpine in reducing dental caries and oral candidiasis in humans remains to be shown; however, animal studies have shown a beneficial effect.l 37 -39 ] Pilocarpine-treated rats with compromised salivary gland function (submandibular/sublingual glands removed but parotid glands left intact), and fed a cariogenic diet, had significantly fewer sulcal caries than animals not receiving prolonged pilocarpine administration.l 38 ] The decreased incidence of caries in pilocarpine-treated animals did not correlate with a lower rate of oral Streptococcus sobrinus infection in this study. However, the incidence of S. sobrinus infection in partially desalivated pilocarpine-treated rats was lower compared with untreated controls in another study.l39] Furthermore, the addition of pilocarpine to the diet caused a reversal of sucrose-induced caries in laboratory rats.[37] Further studies are warranted to determine the long term effects of pilocarpine on the incidence of dental caries and oral infection in patients with xerostomia. © Adis International Lirnited. All rights reserved.

2.3 Pharmacokinetic Properties

Few data are available on the pharmacokinetic properties of oral pilocarpine in humans, particularly in patients with symptoms of xerostomia. Following 2 days' administration of oral pilocarpine 5 or lOmg 3 times daily (at 0800, 1200 and 1800 hours) to 30 healthy male volunteers, mean peak plasma drug concentrations (C max ) of 15 and 411lg/L were reached in 1.25 and 0.85 hours (tmax ), respectively: [40] The respective areas under the plasma drug concentration-time curves (AVC) were 35 and 108 IlgiL • h. The rate of absorption of pilocarpine was decreased when it was taken with food.l 41 ] Mean t max values increased from 0.87 hours in the fasted state to 1.47 hours after administration of pilocarpine 10mg with a high fat meal. The mean C max value decreased slightly from 59.2 to 51.8 Ilg/L after a meal but the difference was not statistically significant. Pilocarpine was excreted predominantly in the urine of healthy volunteers, with a mean elimination half-life of 0.76 hours following 5mg 3 times daily and 1.35 hours following lOmg 3 times daily.l40] The pharmacokinetic properties of pilocarpine 5mg in elderly male volunteers were similar to those observed in healthy young male volunteers, whereas mean Cmax and AVC values were doubled in elderly female volunteers compared with those found in males of both age groups.l42] The pharmacokinetic properties of pilocarpine in patients with renal or hepatic dysfunction have not been described. 3. Clinical Potential

Pilocarpine provided effective relief from symptoms of xerostomia after radiation therapy in the majority of patients with head and neck cancer or in patients with salivary gland disease (predominantly Sjogren's syndrome) in several doubleblind placebo-controlled studies (table II). Patients received tablet or capsule formulations of pilocarpine in all studies with one exception,[30] in which Drugs 49 (1) 1995

Oral Pilocarpine: A Review

a 2% solution of pilocarpine was administered. A combination of objective and subjective parameters, assessed during and after therapy, were used to evaluate the clinical response to treatment. Objective parameters included unstimulated and/or stimulated major salivary gland (submandibular/sublingual and parotid glands) flow rates. Saliva was collected from the parotid gland using a Carlson Crittenden cup[43] placed over the parotid papillae and was collected from the submandibullar/sublingual glands using a micropipette apparatus)8,27,29,32] Subjective parameters included assessment by questionnaires, visual analogue scales and/or patients' diaries of symptom improvement, including oral dryness, mouth comfort, speaking ability, swallowing, chewing and taste acuity. In preliminary crossover studies whole and parotid salivary flow rates were higher during the pilocarpine treatment phase than during placebo, and a greater proportion of patients showed symptom improvement during pilocarpine administration.[27,28] More recent studies involving larger patient numbers have confirmed these findings and shown pilocarpine 5 to 10mg 3 times daily for up to 3 months to be an effective dosage for the relief of symptoms of xerostomia)8,29,32] Two multicentre dose-finding studies compared the efficacy of pilocarpine 2.5, 5 and/or lOmg 3 times daily with that of placebo in patients with xerostomia lasting more than 4 months after radiation therapy for head and neck cancer.[8,32] Results of patient questionnaires on symptom improvement during pilocarpine administration indicated that pilocarpine 15 or 30 mg/day improved symptoms of xerostomia to a similar extent, and was significantly more effective than placebo (table II). The 7.5mg dose, however, had little effect on symptom improvement versus placebo)32] In the intention-to-treat analysis by Johnson et al.,[8] which included a total of 191 patients, 44% (31 of 71) of pilocarpine (15 mg/day) recipients experienced improved oral dryness versus 25 % (16 of 63) of placebo recipients (p < 0.05), and 31 versus 9.5% of patients experienced improved com© Adis International Limited. All rights reserved.

151

fort of the mouth and tongue (p = 0.001), after 12 weeks. An improvement in the overall severity of xerostomia occurred in 54 versus 25% of patients treated with pilocarpine and placebo, respectively (p =0.01). A larger proportion of patients were able to speak without requiring liquids in the pilocarpine treatment groups, and pilocarpine administration was associated with a reduction in the need for oral comfort agents (artificial saliva, water, candy). The number of patients showing a response to pilocarpine therapy increased with treatment duration, the highest response rate occurring at the end of the study period (i.e. after 12 weeks). Interestingly, the time course of maximum improvement in saliva production observed during therapy with pilocarpine did not correlate with the timing of greatest symptom improvement. The percentage of patients showing an increase in whole and unstimulated parotid saliva production was significantly higher after pilocarpine administration than placebo after 4 and 8 weeks of treatment but, in contrast to symptom improvement, the difference was not statistically significant after 12 weeks of treatment. [8] Fox et al.[29] measured the objective and subjective responses during 5 months' treatment with pilocarpine 5mg 3 times daily in 39 patients with severe xerostomia of at least 1 year's duration (table II). Unstimulated major salivary gland output was significantly increased in 26 of 39 patients after initial administration of pilocarpine, with patients observing an improvement in salivation lasting for 2 to 3 hours after drug administration. Salivary output did not increase significantly compared with baseline in any patients during the placebo treatment period (placebo was administered for 1 month at some point between months 2 and 6 of the crossover study period). 27 .of 31 patients reported an improvement in symptoms of xerostomia, including oral dryness, speaking, chewing and swallowing, after 1 month of treatment with pilocarpine. The improvement in oral dryness was judged as pronounced by 6 patients, moderate by 14, minimal by 6, inconsistent by 1 and nonexistent Drugs 49 (1) 1995

Wiseman & Faulds

152

80

o Placebo o Pilocarpine Smg Pilocarpine 10mg

60 Vi

c: ~ Q)

'0

~ 40 Q)

"c: Q)

"0

'r:; E

20

Sweating

Chi llS

Nausea

Dizziness

Rhinitis

Asthenia

Fig. 5. Incidence of adverse events which were significantly (p < 0.05) increased after pilocarpine therapy [5mg (n = 73) or 10mg (n = 69) 3 times daily] compared with placebo (n = 65) during 3 months' treatment in patients with. radiation-induced xerostomiaJS]

by 4 in a global assessment carried out at the end of the 6-month study period. A small double-blind placebo-controlled study found that patients treated with pilocarpine Smg 3 times daily for 3 months (beginning the day before starting radiation therapy) had a lower incidence of oral symptoms during radiation therapy than placebo recipients.l3 3l Although salivary flow decreased in all 9 patients within the first week of radiation therapy, patients who were treated with pilocarpine had smaller losses in stimulated salivary gland function during this period than placebo recipients. Pilocarpine did not stimulate salivary secretion from glands that were completely irradiated. A large well controlled clinical trial is warranted to determine if the extent of salivary gland damage and resultant severity of xerostomia is reduced when pilocarpine is administered during rather than after radiation therapy.

4. Tolerability Profile Mild and tolerable adverse events are frequently reported during pilocarpine therapy, their incidence being dose-related.[8, 32l © Adis International Limited, All rights reserved,

Sweating was the most common adverse effect reported in clinical trialsJ8,27,29, 32 l In the largest tria1,l 8l sweating occurred in 37% of 73 patients receiving pilocarpine Smg 3 times daily, and in 80% of 69 patients taking the higher dosage of lOmg 3 times daily for 3 months. Excessive sweating was the only reason for withdrawal from treatment in this study by 17% (24 of 142) of patients. Four of 73 patients (S.S%) treated with the lower dosage of pilocarpine and 20 of 69 (29%) treated with the higher dosage stopped treatment. Other investigators reported an incidence of 6S% for sweating in 31 patients treated with pilocarpine Smg 3 times daily for S monthsJ29] However, no patients withdrew from therapy as a result of excessive sweating. Other adverse events primarily related to the cholinergic activity of pilocarpine included chills, nausea, dizziness, rhinitis, flushing, asthenia, urinary frequency, increased lacrimation, palpitations and gastrointestinal tract disturbanceJ8,27,29, 32l The incidence of events reported in the largest study[8 l are summarised in figure S. As pilocarpine is a parasympathomimetic agent, there is some potential for cardiovascular and pulmonary effects. No significant effects on heart rate, Drugs 49 (1) 1995

153

Oral Pilocarpine: A Review

blood pressure, or cardiac conductivity have been observed to date in patients with xerostomia; however, studies were not performed in patients with possible complicating medical conditions such as asthma or patients taking ~-adrenergic antagonistsJ28,29] In addition, the use of pilocarpine in patients with medication-induced xerostomia, such as those with antidepressant-related salivary hypofunction, remains to be studied with regard to potential drug interactions.

5. Dosage and Administration For the treatment of xerostomia, pilocarpine is predominantly administered orally either in tablet or capsule form. It is also available as a 2% solution; however, this is formulation is less stable. The recommended dosage for the initiation of treatment of xerostomia is 5mg 3 times daily.l20] This may be titrated up to lOmg 3 times daily in patients who do not respond adequately to, but are able to 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 when miosis is undesirable, e.g. in acute iritis and narrow-angle glaucoma. However, despite being contraindicated in the latter patients in the general setting, pilocarpine is used routinely in the ophthalmological setting in the acute phase of an angle closure emergency until such time as surgery can be performed. As pilocarpine can increase airway resistance, bronchial smooth muscle tone and bronchial secretions, the drug should be administered with caution in patients with controlled asthma, chronic bronchitis, or chronic obstructive pulmonary disease. Pilocarpine should also be used with caution in patients with cardiovascular disease, as it can cause transient changes in haemodynamics or cardiac rhythm which this patient group may be unable to compensate for. The manufacturer recommends close supervision when administering pilocarpine to patients taking ~-adrenergic antagonists because of the possibility of cardiac conduction disturbances. Co© Adis International Limited. All rights reserved.

administration of pilocarpine with drugs that have parasympathomimetic activity may result in additive pharmacological effects, and pilocarpine may antagonise the effects of anticholinergic agents.

6. Place of Oral Pilocarpine in the Therapy of Xerostomia Xerostomia resulting from salivary gland hypofunction is common in patients undergoing radiotherapy for head and neck cancer, but may also occur in patients with systemic disorders such as Sjogren's syndrome and following therapy with several different drug classes, in particular antihypertensives and antidepressants. While there are numerous salivary stimulants currently available, the efficacy of many of these agents has not been clearly demonstrated in published clinical trials. Pilocarpine stimulated salivary secretion in a significantly greater number of patients than did placebo in double-blind clinical trials. Symptoms associated with xerostomia, including oral dryness and difficulty in chewing, swallowing and speaking, were significantly improved and the need for oral comfort agents was reduced. The majority of studies were conducted in patients with radiation-induced xerostomia; however, responses to pilocarpine therapy have also been observed in patients with Sjogren's syndrome. The finding that pilocarpine administration during radiation therapy resulted in a smaller reduction in salivary flow and a lower incidence of oral symptoms during radiation therapy compared with placebo suggests that pilocarpine prophylaxis may be beneficial compared with rescue treatment in reducing the severity of xerostomia; however, this requires confirmation in large well controlled comparative trials. The clinical efficacy of pilocarpine relative to that of other salivary stimulants such as bromhexine and sulfarlem (anethole trithione) as well as bethanechol hydrochloride, potassium iodide and neostigmine remains to be determined, as does the optimal treatment regimen using different drug combinations. Drugs 49 (l) 1995

Wiseman & Faulds

154

As xerostomia is likely to persist life-long, the efficacy of pilocarpine in stimulating salivary production during prolonged therapy is important, and this aspect requires further investigation. Animal studies have indicated that prolonged therapy with pilocarpine reduces the incidence of dental caries and oral infection; however, such benefits remain to be shown in humans. Thus, pilocarpine has demonstrated superior efficacy to that of placebo in reducing the severity of xerostomia resulting from radiation therapy to the head and neck region or Sjogren's syndrome in studies of up to 6 months' duration. While further investigation is necessary to determine its prophylactic efficacy, its long term efficacy in decreasing the incidence of dental caries and oral candidiasis and its efficacy relative to that of other salivary stimulants, the current body of evidence is sufficient to conclude that oral pilocarpine offers an effective and welcome alternative to the limited, and in many cases poorly studied, therapeutic options for the management of patients with xerostomia.

References 1. Navazesh M, Ship II. Xerostomia: diagnosis and treatment. Am J Otolaryngol1983; 4: 283-92 2. Sreebny LM, Valdini A. Xerostomia: a neglected symptom. Arch Intern Med 1987; 147: 1333-7 3. Toth BB, Martin JW, Fleming n. Oral complications associated with cancer therapy. J Clin Periodontol 1990; 17: 508-15 4. Fergnson MM. Pilocarpine and other cholinergic drugs in the management of salivary gland dysfunction. Oral Surg Oral Med Oral Patho11993; 75: 186-91 5. Frank RM, Herdly J, Philippe E. Acquired dental defects and salivary gland lesions after irradiation for carcinoma. J Am Dent Assoc 1953; 70: 868-83 6. Karmiol M, Walsh RF. Dental caries after radiotherapy of the oral regions. J Am Dent Assoc 1975; 91: 838-45 7. Dreizen S, Brown LR, Handler S, et al. Radiation-induced xerostomia in cancer patients: effect on salivary and serum electrolytes. Cancer 1976; 38: 273-8 8. 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 1993; 329: 390-5 9. Vissink A, Panders AK, s-Gravenmade EJ, et al. The causes and consequences of hyposalivation. Ear Nose Throat J. 1988; 67: 166-76 10. Valdez JH, Atkinson JC, Ship JA, et al. Major salivary gland function in patients with radiation-induced xerostomia: flow rates and sialochemistry. Radiation Oncology BioI Phys 1993; 25: 41-7

© Adis International Lirnited. All rights reserved.

11. Eneroth CM, Henrikson CO, Jackobsson pA. Effects of fractionated radiotherapy on salivary gland function. Cancer 1972; 30: 1147-53 12. Diagnosis of Sjogren's syndrome. Lancet 1992; 340: 150 13. Bjerrum K, Prause JU. Primary Sjogren's syndrome: a subjective description of the disease. Clin Exp Rheumatol 1990; 8: 283-8 14. Pilocarpine used to stimulate normal saliva production. J Am Dent Assoc 1985; 111: 310 15. Butt GM. Drug-induced xerostomia. J Can Dent Assoc 1991; 57: 391-3 16. Sreebny LM, Schwartz SS. Reference guide to drugs and dry mouth. Gerontology 1986; 5: 75-99 17. Kreienbaum MA, Page DP. Stability of pilocarpine hydrochloride and pilocarpine nitrate ophthalmic solutions submitted by US hospitals. Am J Hosp Pharm 1986; 43: 109-17 18. Gibbs IS, Tuckerman MM. Formulation of a stable pilocarpine hydrochloride solution. J Pharm Sci 1974; 63: 276-9 19. Neville GA, Hasan FB, Smith ICP. Quantitative analysis of degradation products in pilocarpine hydrochloride opthalmic formulations. J Pharm Sci 1976; 65: 638-42 20. MOl Pharma. Salagen (pilocarpine hydrochloride): treatment for radiation-induced xerostomia in head and neck cancer patients. Minneapolis, USA. 21. Oral pilocarpine for xerostomia. Med Lett Drugs Ther 1994 August; 36: 76 22. Iwabuchi Y, Masuhara T. Subtypes of the muscarine receptors that are involved in pilocarpine-induced secretion of saliva from rat sublingual glands. Asia Pac J Pharmacol 1992 Dec; 7: 271-6 23. Mandel JD, Katz R, Zengo A, et al. The effect of pharmacologic agents on salivary secretion and composition in man. I. Pilocarpine, atropine and anticholinesterases. J Oral Ther Pharmaco11967; 4: 192-9 24. Mandel JD, Katz RL. Effect of pilocarpine and a beta adrenergic blocking agent on human saliva. Pharmacol Ther Dent 1971; 1: 71-82 25. Prutting J. Pilocarpine nitrate and psychostimulants. JAMA 1965; 193: 236-7 26. Rhodus NL, Schuh MJ. Effects of pilocarpine on salivary flow in patients with Sjogren's syndrome. Oral Surg Oral Med Oral Patho11991; 72: 545-9 27. Greenspan D, Daniels TE. Effectiveness of pilocarpine in postradiation xerostomia. Cancer 1987; 59: 1123-5 28. Fox PC, van der Ven PF, Baum BJ, et al. Pilocarpine for the treatment of xerostomia associated with salivary gland dysfunction. Oral Surg Oral Med Oral Pathol 1986; 61: 243-8 29. Fox PC, Atkinson JC, Macynski AA, et al. Pilocarpine treatment of salivary gland hypofunction and dry mouth (xerostomia). Arch Intern Med 1991; 151: 1149-52 30. Schuller DE, Stevens P, Clausen KP, et al. Treatment of radiation side effects with oral pilocarpine. J Surg Oncol 1989; 42: 272-6 31. Vivino FB, Hermann GA, Huang CH, et al. Preliminary study of pilocarpine tablets in Sjogren's syndrome [abstract no. 296]. Arthritis Rheum 1994 September; 37 (9) Suppl.: S208 32. 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. J Clin Oncol 1993; ,11: 1124-31 33. Valdez JH, Wolff A, Atkinson JC, et al. Use of pilocarpine during head and neck radiation therapy to reduce xerostomia and salivary dysfunction. Cancer 1993; 71: 1848-51

Drugs 49 (1) 1995

Oral Pilocarpine: A Review

34. Greenspan D. Oral complications of cancer therapies. Management of salivary dysfunction. NCI Monograph 1990; 9: 159-61 35. Kohn WG, Ship JA, Atkinson JC, et al. Salivary gland99 "'J'Cscintigraphy: a grading scale and correlation with major salivary gland flow rates. J Oral Pathol Med 1992; 21: 70-4 36. Fox Pc. Systemic therapy of salivary gland hypofunction. J Dent Res 1987; 66 Spec: 689-92 37. Leach SA, Connell R. Reversal of fissure caries in the albino rat by stimulating salivary flow with pilocarpine. Caries Res 1990; 24: 127-9 38. O'Connell AC, Pearson SK, Bowen WHo Pilocarpine alters caries development in partially desalivated rats. J Dent Res 1994; 73: 637-43 39. Ortiz GC, Pearson SK, Bowen WHo Influence of pilocarpine, propranolol, and atropine on susceptibility to infection [abstract 186]. J Dent Res 1992; 71: 129 40. Hunt.TL. A double-blind, placebo-controlled, multiple-dose, tolerance and pharmacokinetic study of oral pilocarpine hydrochloride (HCI) in healthy male subjects. MGI Pharma

© Adis Internationallirnited. All rights reserved.

155

(Minneapolis) data on file. MGI 647.83.CR91-03; Dec 24, 1991. 41. Hunt TL. The effect of a high fat meal on the bioavailability of oral pilocarpine hydrochloride (HCI) in healthy, male subjects. MGI Pharma (Minneapolis) data on file. MGI 647.83.CR91-02; Dec 27, 1991. 42. Hunt TL. A single-dose, pharmacokinetic study of oral pilocarpine hydrochloride (HCI) (5mg) in elderly subjects. MGI Pharma (Minneapolis) data on file. MGI 647.83.CR91-05; Jan 3, 1992. 43. Carlson AV, Crittenden AL. The relationship of ptyalin concentration to the diet and to the rate of secretion of saliva. Am J Physiol 1910; 26: 169-77

Correspondence: Lynda R. Wiseman, Adis International Limited,41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand.

Drugs 49 (l) 1995