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J Dent Res 83(5): 393-397, 2004
© 2004 International and American Associations for Dental Research

RESEARCH REPORT
Clinical

Oral Pilocarpine for Treatment of Opioid-induced Oral Dryness in Healthy Adults

B. Götrick1,*, S. Åkerman2, D. Ericson3, R. Torstenson4, and G. Tobin5

1 Department of Hospital Dentistry and
4 Hospital Pharmacy, Malmö University Hospital, SE-205 02 Malmö, Sweden;
2 Department of Oral Diagnostics and
3 Department of Cariology, Faculty of Odontology, Malmö University, SE-205 06 Malmö, Sweden; and
5 Department of Pharmacology, Göteborg University, Box 431, SE-405 30 Göteborg, Sweden;

* corresponding author, bengt.gotrick{at}skane.se


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Pilocarpine induces a profuse flow of saliva when administered orally, but effects on drug-induced oral dryness have not been examined. The aim of this trial was to investigate if pilocarpine increases production of saliva in individuals suffering from dry mouth due to treatment with opioids. Sixty-five individuals were enrolled in a randomized, double-blind, placebo-controlled trial. The subjects received tramadol (50 mg t.d.s.) to induce oral dryness, and were thereafter assigned to one of three groups. Secretion rate of saliva was measured before and after tramadol, and after the oral administration of pilocarpine (5 mg), placebo, or no treatment. Baseline characteristics did not differ among the groups (mean ± SEM: 0.37 ± 0.06 mL/min), and tramadol lowered the secretion at the same level in all groups (0.15 ± 0.02 mL/min). Pilocarpine increased the flow above that observed with placebo (0.66 ± 0.19 vs. 0.15 ± 0.02 mL/min). Thus, pilocarpine re-establishes the flow of saliva in the state of tramadol-induced oral dryness.

KEY WORDS: pilocarpine • oral dryness • randomized controlled trial • drug-induced xerostomia


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Normal salivation is an essential requirement for oral health due to its important contributions to oral defense mechanisms, and impaired secretion of saliva may lead to dental caries and mucosal deterioration (Mandel and Wotman, 1976; Mandel, 1980). Oral dryness may be caused by diseases such as Sjögren’s syndrome and radiation therapy to the head and neck region and is also one of the most frequently occurring adverse effects of pharmacotherapy (Bahn, 1972; Grad et al., 1985; Sreebny and Schwartz, 1997). Secretion of saliva is almost entirely dependent on nerve-mediated mechanisms, and parasympathetic impulses activating glandular muscarinic receptors are the principal stimulus for fluid secretion in salivary glands (Garrett, 1987). Xerogenic drugs may exert conspicuous inhibitory potency by interfering with neuronal transmission, both centrally and peripherally. This may occur by interference with central pathways or by blockade of muscarinic or adrenergic receptors in the glands (Sreebny and Schwartz, 1997).

Pilocarpine hydrochloride is a parasympathomimetic agent that binds unselectively to muscarinic receptors and exerts a broad spectrum of pharmacological effects, including stimulation of salivary, sweat, and lachrymal glands (Brown and Taylor, 2001). Several double-blind, placebo-controlled trials have demonstrated significant increases in salivary secretion during the administration of oral pilocarpine to patients with radiation-induced xerostomia (Greenspan and Daniels, 1987; Johnson et al., 1993; LeVeque et al., 1993; Rieke et al., 1995; Jacobs and van der Pas, 1996) and to patients with xerostomia due to Sjögren’s syndrome (Fox et al., 1991; Vivino et al., 1999). Pilocarpine (Salagen®) tablets are currently used both for the treatment of radiation-induced dry mouth and in patients with Sjögren’s syndrome dry mouth or dry eyes. In a recent study, pilocarpine was shown to cause relief of xerostomia in morphine-treated cancer patients within 24 hrs, but no quantitative estimation was performed (Mercadante et al., 2000). We undertook the present study to establish whether the oral administration of pilocarpine re-establishes salivary secretion during drug-induced oral dryness. It involved a double-blind, placebo-controlled, parallel-group study to determine the efficacy of pilocarpine treatment in healthy volunteers pre-treated with tramadol. Tramadol has low affinity for opioid receptors but also exerts its effect by direct modulation of central mono-aminergic pathways and has adverse effects similar to those of other opioids, including oral dryness (Lee et al., 1993; Lewis and Han, 1997). Since tramadol has been reported to reduce salivary secretion in less than 10% of treated patients (Lee et al., 1993), and the present study aimed at examining pilocarpine treatment of drug-induced hyposalivation, a reduction of the flow of saliva of less than 40% was taken as an exclusion criterion.


   MATERIALS & METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
Sixty-five students (37 females, 28 males) at the Faculty of Odontology, Malmö University, were enrolled in the study. The students, who participated voluntarily (mean age ± SEM, 23 ± 0.5 yrs), were divided into three groups according to the randomizing list produced at the Hospital Pharmacy. Any student who was pregnant, suffering from ongoing disease, taking medications, or having previously received radiotherapy of the neck and head region was excluded from the study. Six subjects were eliminated for these reasons at enrollment. Subjects in whom the tramadol treatment reduced salivary secretion by less than 40% were also excluded after the study had been concluded.

Study Design and Assessment
The amount of unstimulated saliva secreted at rest was measured according to a standard method (Gutman and Ben-Aryeh, 1974; Osterberg et al., 1984) that involved the collection of samples for 5 min at 15-minute intervals over 2 hrs. Subjects were not allowed to eat or drink during this two-hour period, or for the preceding hour. During collection periods, the subjects were seated and relaxed and leaned slightly forward so that saliva accumulated sublingually in the mouth. It was then allowed to drop passively into a small plastic beaker, held directly beneath the lower lip. After determination of the basal secretory rate (baseline, day 1) and the subsequent administration of tramadol (50 mg 3x/day over days 2 and 3), the subjects were randomly assigned to one of three groups: one given no further treatment (Control group), one given pilocarpine (5 mg tablet by oral intake; Pilocarpine group), and the other given a placebo (Placebo group; Fig. 1Go). Random assignment was computer-generated, with a block size of six, and beakers, which were number-connected to the coding, either empty or containing a capsule, were given to the participants consecutively. Tramadol was administered orally at 7 a.m., 1:30 p.m., and 9 p.m. on day 2 and at 7 a.m. and 1:30 p.m. on day 3, since we hoped to achieve a steady-state concentration of the drug by the afternoon on day 3. We measured the quantity of secreted unstimulated saliva for 3 consecutive five-minute periods to determine the effect of tramadol. The Pilocarpine and Placebo group participants were then given a capsule containing either pilocarpine or placebo (double-blind) together with enough water for swallowing (the Control group was supplied with the same volume of water). After 15 min, saliva was collected by the same procedure for saliva collection as on day 1. After the test, a subjective assessment of efficacy and adverse effects was made by questionnaire on day 3, before and after pilocarpine or placebo treatment. Questions were presented as three-point categorical questions (increase in, no change, or decrease in salivary secretion; and no, moderate, or severe adverse effect).



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  		Figure 1. Mean flow rates of unstimulated whole saliva in the pilocarpine group ({blacksquare} ; n = 17), placebo group (• ; n = 17), and control group ({circ} ; n = 14) before (baseline, day 1), after the tramadol regime (50 mg x 5; dryness, day 3) and after pilocarpine/placebo treatment (5 mg x 1; treatment, day 3) or no further treatment (control). Tablet containing pilocarpine/placebo was administered on day 3 at –15 min (arrow). Values are mean ± SEM.

 
Drugs
All drugs were given in capsules which had been prepared at the Hospital Pharmacy, Malmö University Hospital, Sweden. The drugs used were tramadol hydrochloride (Tramadol GEA®, GEA Farmaceutisk Fabrik AB, Helsingborg, Sweden), pilocarpine hydrochloride (Pilocarpine hydrochloridum Ph Eur 5 mg, Lactosum monohydricum Ph Eur 145 mg in Capsulae gelatinosae No. 4 ACL, Hospital Pharmacy, Malmö University Hospital, Sweden), and placebo (Lactosum monohydricum Ph Eur 150 mg in Capsulae gelatinosae No. 4 ACL.; ex tempore; Hospital Pharmacy, Malmö University Hospital). The dosages of tramadol (50 mg 3x/day P.O.) and pilocarpine (5 mg P.O.) were the lowest recommended by the manufacturers according to the Summary of Product Characteristics.

Calculations
A pilot study was performed including six subjects for power analysis of a three-group study design. We needed to recruit 45 participants to achieve a 90% power to detect an increase in unstimulated whole saliva from a dry mouth level (0.15 mL per min) to the level of average secretion for healthy individuals (0.35 mL per min), with a two-sided test and a type I error of 5%. We allowed for screening failures and dropout during the study by increasing the number of subjects needed in each treatment group from 15 to 20. Assessment was based on per protocol analysis and statistical significance determined by one-way analysis of variance (ANOVA) followed by the Bonferroni multiple-comparison test. P values of 0.05 or less were regarded as statistically significant. Values are presented as means ± SEM.

Ethics Considerations
All patients consented verbally and in writing to participate in the study. The Ethics Committee of the University of Lund approved the study as well as the research protocol. The trial was carried out according to the Helsinki Declaration.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Of the 65 participants enrolled, 60 completed the protocol, and 48 of those were the subject of the pilocarpine evaluation. Reasons for elimination included adverse effects of the tramadol treatment (four subjects) and illness (one subject). Adverse effects of tramadol that were reported included dizziness, nausea, and somnolence. In 12 of the subjects, the tramadol-induced reduction in salivary flow was less than 40%, and these subjects were subsequently excluded in accordance with previously defined criteria. The participants generally showed good compliance to the time schedule for tramadol administration. Subjects missed the intake time by more than 1 hr on only 13 of the 300 occasions and never by more than 2 hrs.

Effect of Tramadol Treatment
Tramadol treatment significantly decreased salivary flow rates, roughly halving the rate of secretion (p < 0.01, n = 60). Eighteen subjects felt no discomfort during tramadol treatment; 22 considered it to be acceptable, while 20 found it to be unpleasant. When reported, discomfort was attributable to the well-known adverse effects of tramadol, most frequently somnolence and dizziness. However, the opioid did not have any effect on pilocarpine-induced salivation. In the pilot study, the peak responses to pilocarpine were 1.36 ± 0.35 mL/min and 1.36 ± 0.24 mL/min, before and after tramadol administration, respectively.

Effect of Pilocarpine
Pilocarpine invariably increased the flow of saliva significantly 30 min after intake (Fig 1Go; p < 0.05–0.001). The time period until maximal flow rate was reached varied for the individuals, but generally occurred within 30–90 min. Considering each individual’s maximum, the means of these responses were slightly greater than the maximum of the time-response curve (0.94 ± 0.17 vs. 0.66 ± 0.19 mL/min; TableGo and Fig. 1Go, respectively). The flow subsequently declined slowly during the rest of the 120-minute observation period, but without ever returning to the tramadol level (dryness). In two individuals, however, the flow rate increased steadily over the whole of the observation period. Salivary flow rates following administration of placebo (0.15 ± 0.02 mL/min) remained similar to the tramadol level (0.15 ± 0.02 mL/min) throughout the study, and the responses in the placebo group were similar to the flow rate in the control group (Fig. 1Go). Mean maximal salivary flow rate after pilocarpine treatment was four-fold greater than after placebo and four-fold greater than flow rate after tramadol treatment (dryness). Pilocarpine also increased the flow of saliva above the rate recorded before the administration of tramadol (i.e., baseline; TableGo). None of the participants given pilocarpine found it unpleasant, although two reported sweating.


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  		Table. Mean Flow Rates of Unstimulated Whole Saliva in Pilocarpine Group (n = 17)a
 
Self-assessment of Saliva Production
In the self-assessment of the tramadol efficacy performed for all 60 participants, 48 of the subjects stated that they were aware of a decrease in saliva production, while 12 did not. However, there was no correlation between the experience of xerostomia and reduced flow of saliva (r2 = 0.04; n.s., Fig. 2AGo). Of the 12 individuals excluded from the pilocarpine part of the study, only three said that they did not experience xerostomia. In the corresponding assessment after pilocarpine/placebo treatment, all except one were aware of the increase in the rate of flow of saliva, and there was some correlation between the increase in flow rate and the subjects’ experience (r2 = 0.35; p < 0.001, Fig. 2BGo).



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  		Figure 2. Changes in the flow of saliva (the mean flow rate over the periods; i.e., baseline, dryness, and active treatment periods) vs. the subjects’ own estimations of changes in the flow of saliva after (a) tramadol treatment (dryness level compared with baseline level) in 60 subjects (n = 48 in "Decrement group"; n = 12 in "No change group") and after (b) pilocarpine/placebo treatment (treatment level compared with dryness level) in 34 subjects (n = 5 in "Decrement group"; n = 13 in "No change group"; n = 16 in "Increment group"). Each symbol represents one individual.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The interpretation of clinical studies of sialogenic drugs intended to treat drug-induced oral dryness is usually hampered by a retrospective study design including elderly participants, medicated with more than one drug affecting secretion and suffering from some disease (Nederfors et al., 1997; Närhi et al., 1999). In the present study, we used a model in which oral dryness was produced by tramadol in young individuals. This provided homogenous study groups, which is important in the conduct of clinical trials with a relatively small number of subjects, and may well prove useful in the design of future studies. First, tramadol induced oral dryness in a large number of participants (a reduction by 40% or more in 80% of the subjects). Second, it has a relatively short half-life, and third, it causes few, and then only mild, adverse effects (Lewis and Han, 1997). The potent inhibition of salivary secretion that it produces is underlined by the fact that it gave rise to the sensation of a dry mouth at the lowest recommended analgesic dose. To provoke oral dryness in the healthy participants in the present study, we administered tramadol orally over two days, which reduced the mean flow for all subjects (n = 60) to approximately 0.2 mL per min before the exclusion of "non-dry" participants. However, after exclusion of the low-responders, the mean flow rate was close to the limit for what is generally regarded as hyposalivation (Sreebny, 1992).

Salivary glands are activated by sympathetic and parasympathetic efferents originating in primary salivary centers (Strack et al., 1989; Jansen et al., 1992). It is reasonable to expect that xerogenic drugs exert their effects by either of the following mechanisms: (1) blockade of muscarinic or adrenergic receptors in the salivary glands; or (2) inhibition of activity in the primary salivary centers, resulting in a decreased outflow of efferent impulses to the salivary glands. Since activation of muscarinic receptors is by far the most potent natural stimulus for salivation, the parasympathomimetic pilocarpine is well-suited for treatment of oral dryness caused by xerogenic drugs that do not involve muscarinic receptor blockade. Tramadol is apparently such a drug, since it did not affect pilocarpine-induced fluid secretion. Pilocarpine has been the drug of choice for treatment of radiation-induced xerostomia, dry mouth, and dry eyes in patients with Sjögren’s syndrome (Johnson et al., 1993; Vivino et al., 1999). Currently, pilocarpine, but not placebo treatment, effectively and rapidly reversed tramadol-induced oral dryness. The results eliminate any possible placebo effect and indicate that even though drug treatment may vastly hamper secretion, the secretory capacity still remains, and secretion can be re-established with a short latency. The results confirm the assumption made by Mercadante et al.(2000), that a placebo-effect could be neglected.

In the current study, correlation between reductions in salivary flow and the subjects’ reported experience was very weak or absent, whereas there was some correlation between these parameters after pilocarpine. A 50% reduction in salivary flow has been postulated as a limit for patients experiencing xerostomia, although it is not known to what level secretory output must become diminished before oral dysfunction will become clinically significant (Ship et al., 1991). In the present study, some subjects did not experience any change in sensation, even if the flow was reduced by more than 50%, and similarly, some reported a sensation of decrement even though there was a modest increase in flow. Analysis of the data indicates that subjective estimation of a change in flow is of very limited value in the evaluation of xerogenic drugs. This is further underlined by the fact that tramadol induced hyposalivation in 80% of the participants in the present study, which is in marked contrast to what has been reported in the literature (reductions in only 10% of patients; Lee et al., 1993). This difference may be explained by quantification of the flow of saliva in contrast to evaluation by asking subjects about their experienced flow rate. Pilocarpine caused no adverse effects, except that two (out of 17) individuals complained of increased sweating. In previous treatments with pilocarpine, patients have complained of severe nocturnal sweating and therefore discontinued the medication (Wiseman and Faulds, 1995). However, since a beneficial effect was obtained in the present study with a single dose, and after a short latency, it seems likely that schedules for its administration could be devised which would avoid such undesirable effects.

The current study thus shows that oral pilocarpine can re-establish the flow of saliva in pharmacological states of oral dryness, and that low-dose regimes may be sufficient to restore secretion. The effect of pilocarpine treatment on quality of life, the prevention of dental caries, or the composition of the saliva secreted is presently unknown.


   ACKNOWLEDGMENTS
 
We are indebted to Elisabeth Thornqvist for her capable assistance during the conduct of the study. This research was supported by grants from the Public Dental Service, Skåne, the Swedish Dental Society, Ferrings och Svenska Enures Akademin, Stiftelsen Ragnhild och Einar Lundströms Minne, Wilhelm och Martina Lundgrens Vetenskapsfond, and Magnus Bergvall’s Foundation.

Received February 28, 2003; Last revision December 29, 2003; Accepted March 5, 2004


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 ABSTRACT
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 MATERIALS & METHODS
 RESULTS
 DISCUSSION
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Garrett JR (1987). The proper role of nerves in salivary secretion: a review. J Dent Res 66:387–397.[Abstract/Free Full Text]

Grad H, Grushka M, Yanover L (1985). Drug induced xerostomia. The effects and treatment. J Can Dent Assoc 51:296–300.

Greenspan D, Daniels TE (1987). Effectiveness of pilocarpine in postradiation xerostomia. Cancer 59:1123–1125.[ISI][Medline]

Gutman D, Ben-Aryeh H (1974). The influence of age on salivary content and rate of flow. Int J Oral Surg 3:314–317.[ISI][Medline]

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Jansen AS, Ter Horst GJ, Mettenleiter TC, Loewy AD (1992). CNS cell groups projecting to the submandibular parasympathetic preganglionic neurons in the rat: a retrograde transneuronal viral cell body labeling study. Brain Res 572:253–260.[ISI][Medline]

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Lee CR, McTavish D, Sorkin EM (1993). Tramadol. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states. Drugs 46:313–340.[ISI][Medline]

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