Download QA53_7_Hypersalivationalternatives

Medicines Q&As
Q&A 53.7
Hypersalivation – what are the treatment alternatives to
glycopyrronium and hyoscine?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: 25th June 2015
Background
There are three separate Q&A documents to accompany this one which are all concerned with non
drug-induced hypersalivation. They are as follows:
No.50: Hypersalivation – what drug treatment options are available? (basic guidance on choosing
between options)
No.51: Hypersalivation – can hyoscine hydrobromide be used to treat it? (summary of evidence)
No.52: Hypersalivation – can glycopyrronium be used to treat it? (summary of evidence)
This Q&A document is concerned with outlining possible alternatives to hyoscine hydrobromide and
glycopyrronium in the treatment of non drug-induced hypersalivation where these drugs are not
suitable, not tolerated, ineffective or unavailable.
Answer
The following drugs have been used, but none of them are licensed for the treatment of
hypersalivation:
Antimuscarinic Drugs
(1) Amitriptyline. There are no published reports of the use of amitriptyline in the management of
hypersalivation. It has been used anecdotally, but its sedative properties may limit its use to patients
experiencing hypersalivation at night.
(2) Atropine. In the NICE full Clinical Guideline on the management of Parkinson’s disease,
sublingual 1% atropine ophthalmic solution twice daily is one option suggested for the treatment of
hypersalivation (1).
A small randomised double-blind, cross-over placebo-controlled trial which evaluated the
effectiveness of sublingual atropine sulfate drops for the management of hypersalivation failed to
demonstrate any significant benefits (2). Twenty-two patients with advanced tumours of the upper
digestive tract were randomised to receive either atropine sulfate two drops (500 microgram) every 6
hours sublingually for 48 hours or placebo, with a 48 hour washout period before cross-over.
Limitations of this study include a small sample size, its short duration, reliance on subjective outcome
measures, and a high placebo effect.
One small non-comparative study has investigated the use of sublingual atropine for the treatment of
hypersalivation in 7 patients with parkinsonism (3). Each patient received one drop of atropine eye
drop solution (containing 500 micrograms of drug from a 1% w/v solution) sublingually twice a day
and objective and subjective measurements were made at baseline, following the first dose of
atropine and after one week. One patient withdrew because of delirium (concurrent with a urinary
infection) and two patients experienced worsening of hallucinations (pre-existing active hallucinosis
was concealed by both patients). No other side effects were reported. Participants demonstrated
statistically significant reductions in saliva production both subjectively and objectively.
Available through NICE Evidence Search at www.evidence.nhs.uk
1
Medicines Q&As
A more recent case report describes the use of sublingual atropine for the treatment of
hypersalivation in a 14-year old boy with metachromatic leukodystrophy (MLD) (4). Ophthalmic
atropine 0.5% was given as one drop (250 microgram) sublingually every six hours as needed. The
patient’s family and nurses noticed a significant improvement in symptoms within 24 hours with a
perceived onset of action of 15-30 minutes and a duration of action of approximately four hours. No
obvious adverse effects were observed.
The authors of the non-comparative study suggest that the advantages of sublingually administered
atropine include its availability as eye drops, low cost and reversibility (3). However, some patients
may have difficulty manipulating the dropper to ensure proper dosing and there is the potential for
accidental overdose with drops. The exact dose of sublingual atropine has not been established (3,4)
and atropine should not be used in patients with cognitive impairment, dementia and hallucinations
(3). Further studies are required to determine if, and under what circumstances, sublingual atropine is
effective for the management of hypersalivation (4).
(3) Benzatropine. Twenty-seven developmentally disabled patients with severe drooling were treated
with oral benzatropine and efficacy was compared with placebo in a double-blind crossover trial (5).
Following a one-week baseline assessment, patients received either placebo or benzatropine for 2
weeks with a 1-week washout before crossover. The initial benzatropine dose was 500 microgram to
2mg daily, depending on the patient’s age and weight, as a single daily dose. This was increased at
1-2 day intervals until no or infrequent drooling occurred, to a maximum dose of 6mg daily. The dose
was reduced if adverse effects or excessive dryness was present. In the second week, patients were
maintained on their optimal titrated dose. 20 patients completed the study (age range 4-44 years).
The seven patients who did not complete the study (including three patients who withdrew because of
adverse effects) were not included in the final results. Between 50% and 70% of patients treated with
benzatropine showed improvement.
In a study of three children with cerebral palsy (aged 5,9,12 years), treatment with oral benzatropine
significantly improved drooling compared to periods where a placebo was used (6). Each child
received benzatropine 1mg daily for 5 days each week (Monday to Friday), and the daily dose was
increased by 1mg each week until a significant reduction in drooling was achieved (this was a dose of
3mg daily for each child). This dose was continued for a further three weeks followed by a 2-week
washout period. Benzatropine 3mg daily or placebo was then administered in 2-week blocks, with
washout periods at the weekends, for a further 8 weeks. All three children remained on benzatropine
after the completion of the trial although one child subsequently developed unwanted visual side
effects and discontinued treatment. No other side effects were reported during the trial.
Benzatropine tablets are no longer available in the UK but can be imported from abroad.
(4) Trihexyphenidyl Hydrochloride (Benzhexol Hydrochloride). A study of 20 children (aged 3-12
years) with cerebral palsy revealed that trihexyphenidyl improved drooling in 17 recipients (7). One
child showed no difference and two had increased drooling. The trihexyphenidyl dose started at 1mg
twice daily, and increased to 2mg twice daily after 2 weeks if necessary, and then finally to 2mg three
times daily after a further two weeks until satisfactory control or the maximum dose was reached.
Patients were treated for a minimum of 3 months and adverse effects were reported infrequently
despite some patients continuing treatment for up to 2 years (7).
A retrospective chart review was carried out for 101 children (aged 1-18 years) with cerebral palsy,
who received trihexyphenidyl for dystonia (28.7%), sialorrhoea (5.9%) or both (65.4%) (8). The mean
initial dose was 95 microgram/kg/day (range 10-414 microgram/kg/day) as a twice daily dose,
gradually increased at least every 2 weeks by 10-20% according to efficacy and tolerability. The mean
maximum dose was 550 microgram/kg/day (range 30 microgram/kg/day to 3.13 mg/kg/day) given two
or three times a day. Side effects were reported in 69.3% of patients including constipation,
decreased urinary frequency, behavioural changes and excessive dry mouth. Thirty-six patients
(35.6%) discontinued treatment including 8% due to intolerable side effects and 8.9% due to lack of
efficacy. Sialorrhoea was reduced in 60.4% of patients.
Available through NICE Evidence Search at www.evidence.nhs.uk
2
Medicines Q&As
The authors of the retrospective chart review suggest that trihexyphenidyl should be started at a low
dose with a gradual stepwise increase over several weeks to promote tolerability and to account for a
potentially delayed response to treatment (8).
Beta-Blockers
In one small, uncontrolled pilot study, sixteen bulbar amyotrophic lateral sclerosis/motor neuron
disease patients, who were complaining of thick tenacious secretions, were treated with either oral
propranolol 10mg twice daily or oral metoprolol 25mg twice daily (9). They were already taking
maximal anticholinergic medications (hyoscyamine or amitriptyline). The authors hypothesise that, in
these patients, the source of secretions is a combination of serous and mucus outflow from the
salivary glands plus mucus from the nose and lungs, and that selective combination drug therapy
involving anticholinergics and beta-blockers may be necessary. Based on subjective responses, 12
of the 16 patients (75%) reported a significant reduction in their thick secretions within one week. The
other 4 patients noticed no change. Follow-up ranged from 2 to 9 months, with one patient
experiencing a progressive reduction in responsiveness to the treatment after 9 months despite
gradual increases in the beta-blocker dose.
Botulinum Toxin
In the NICE full Clinical Guideline on the management of Parkinson’s disease, injection of salivary
glands with botulinum toxin A is one option suggested for the treatment of hypersalivation (1).
Systematic reviews and meta-analyses of botulinum toxin in the management of hypersalivation have
been published (e.g.10,11). An international consensus statement defining the assessment,
intervention and aftercare of patients with drooling treated with botulinum toxin A is also available
(12). In addition, a large number of individual studies have been published. For further information on
the use of botulinum toxin for the treatment of hypersalivation, a full literature search should be
carried out.
Since the administration of botulinum toxin is invasive and requires specialized expertise to perform
the intervention, patient access to treatment is restricted (3). The effect of repeated injections of
botulinum toxin over time, or the risk of developing antibodies, are not known (13).
Ipratropium Bromide
One randomised, double-blind, placebo-controlled, crossover study investigated the safety, tolerability
and efficacy of ipratropium bromide spray in the management of Parkinson’s disease related
hypersalivation (14). In the study 17 patients were recruited and 15 completed the trial. Patients used
one or two metered doses (sprays) of ipratropium bromide (21 microgram/metered dose) or placebo
sublingually up to four times per day for 2 weeks, with a one week washout before crossover.
Ipratropium bromide had no significant effect on the amount of saliva produced, but was well
tolerated.
Modafinil
In two children (aged 13 and 6 years) with spastic cerebral palsy, treatment with modafinil for
spasticity resulted in a dramatic improvement in drooling (15). In the first case, the modafinil was
gradually increased from 50mg daily to 200mg daily over several months, and drooling stopped,
although irritability developed at this dose. This resolved on discontinuation of treatment and modafinil
was then restarted at 100mg every other day with a view to increasing the dose stepwise back to
150mg in the morning. In the second case, modafinil was started at 25mg in the morning and was
gradually increased to 100mg in the morning over a few months. No side effects are mentioned and it
is reported that the patient stopped drooling.
Ranitidine plus cisapride
A combination of ranitidine and cisapride was used in an attempt to reduce drooling in 9 children with
cerebral palsy and gastro-oesophageal reflux (16). However, this proved ineffective. Cisapride is no
longer marketed in the UK.
Available through NICE Evidence Search at www.evidence.nhs.uk
3
Medicines Q&As
Summary












There are no randomised double-blind studies that compare the different therapeutic options
available for the management of sialorrhoea (17). An in-depth systematic review of the medical
literature investigating the efficacy of anticholinergic drugs to treat drooling in children with
multiple disabilities found that because of the methodological drawbacks within the studies and
the small number of reports, no general conclusion could be reached and a meta-analysis could
not be performed. The authors concluded that there was some evidence that at least three
anticholinergic drugs (benzatropine, glycopyrronium and trihexyphenidyl hydrochloride) are
effective in the treatment of drooling in this patient group. However, it could not be concluded that
one anticholinergic drug was preferable to others (18). More recently, a Cochrane review
examining interventions for drooling in children with cerebral palsy was unable to reach a
conclusion on the effectiveness or safety of either botulinum toxin A, benzatropine or
glycopyrronium. Insufficient evidence was found to inform clinical practice for the management of
drooling in this patient group (19).
The choice of drug should be based on its pharmacological and adverse effect profile as well as
the limited results of the available published studies (17). Selection of a particular compound
should be based on individual response and side effects (5). Clearly, larger randomised
controlled trials are required before the place of each of these drugs in the management of
hypersalivation can be established.
The dose of oral benzatropine, which can be given as a single daily dose, should be titrated
individually for each patient, starting with a low dose and increasing, as indicated, by small weekly
increments until therapeutic benefit is achieved or side effects occur (5). Benzatropine often
produces sedation, or less commonly, dysphoria and restlessness (20). Benzatropine tablets are
no longer available in the UK but can be imported from abroad. Trihexyphenidyl (benzhexol) is an
alternative.
The authors of one small non-comparative study suggest that the advantages of sublingually
administered atropine include its availability as eye drops, low cost and reversibility (3). However,
some patients may have difficulty manipulating the dropper to ensure proper dosing and there is
the potential for accidental overdose with drops. The exact dose of sublingual atropine has not
been established and atropine should not be used in patients with cognitive impairment, dementia
and hallucinations (3). However, one small randomised placebo-controlled trial which evaluated
the effectiveness of sublingual atropine sulfate drops for the management of hypersalivation failed
to demonstrate any significant benefits (2).
There are two case reports of modafinil producing a dramatic improvement in drooling in two
children with spastic cerebral palsy (15).
Beta-blockers may be a useful “add-on” option with antimuscarinic drugs in some patients with
amyotrophic lateral sclerosis/motor neuron disease.
Botulinum toxin injections can be effective in certain circumstances, but require specialist
expertise for administration.
Limitations
There are no major randomised placebo-controlled trials for any drug to treat hypersalivation, so
the amount of published evidence is limited. No randomised double-blind comparative studies
are available. The evidence to support use of some of these drugs is limited to anecdotal reports
only.
The majority of the studies are short-term so long-term efficacy and safety data are not available.
Most of the studies included small numbers of patients.
The majority of the studies rely on subjective outcome measurements since it is difficult to assess
saliva production objectively particularly as there is inter-individual variation in saliva production.
No single method of measurement of salivary flow and outcome presentation is available.
This Q&A has not addressed the management of drug-induced sialorrhoea.
Available through NICE Evidence Search at www.evidence.nhs.uk
4
Medicines Q&As
References
(1)
NICE Full Guideline. Parkinson’s Disease Clinical Guideline 35. 28th June 2006.
Accessed via http://www.nice.org.uk/guidance/cg35/evidence on 1st July 2015.
(2)
De Simone GG, Eisenchlas JH, Junin M et al. Atropine drops for drooling: a randomized
controlled trial. Palliat Med 2006;20:665-671.
(3)
Hyson HC, Johnson AM, Jog MS. Sublingual atropine for sialorrhea secondary to
parkinsonism: a pilot study. Mov Disord 2002;17:1318-1320.
(4)
Rapoport A. Sublingual atropine drops for the treatment of pediatric sialorrhea. J Pain
Symptom Manage 2010;40:783-788.
(5)
Camp-Bruno JA, Winsberg BG, Green-Parsons AR et al. Efficacy of benztropine therapy
for drooling. Dev Med Child Neurol 1989;31:309-319.
(6)
Owen SE, Stern LM. Management of drooling in cerebral palsy: three single case studies.
Int J Rehabil Res 1992;15:166-169.
(7)
Reddihough D, Johnson H, Staples M et al. Use of benzhexol hydrochloride to control
drooling of children with cerebral palsy. Dev Med Child Neurol 1990;32:985-989.
(8)
Carranza-del Rio J, Clegg NJ, Moore A et al. Use of trihexyphenidyl in children with
cerebral palsy. Pediatr Neurol 2011;44:202-206.
(9)
Newall AR. Orser R, Hunt M. The control of oral secretions in bulbar ALS/MND. J Neurol
Sci 1996;139(suppl):43-44.
(10)
Rodwell K, Edwards P, Ware RS et al. Salivary gland botulinum toxin injections for
drooling in children with cerebral palsy and neurodevelopmental disability: a systematic
review. Dev Med Child Neurol 2012;54:977-987.
(11)
Vashishta R, Nguyen SA, White DR et al. Botulinum toxin for the treatment of sialorrhea:
a meta-analysis. Otolaryngology – Head and Neck Surgery 2013;148(2):191-196.
(12)
Reddihough D, Erasmus CE, Johnson H et al. Botulinum toxin assessment, intervention
and aftercare for paediatric and adult drooling: international consensus statement.
European Journal of Neurology 2010;17(Suppl 2):109-121.
(13)
Meningaud J-P, Pitak-Arnnop P, Chikhani L, Bertrand J-C. Drooling of saliva: a review of
the etiology and management options. Oral Surg Oral Med Oral Pathol Oral Radiol Endod
2006;101:48-57.
(14)
Thomsen TR, Galpern WR, Asante A et al. Ipratropium bromide spray as treatment of
sialorrhea in Parkinson’s disease. Mov Disord 2007;22:2268-2273.
(15)
Hurst D, Cedrone N. Modafinil for drooling in cerebral palsy. J Child Neurol 2006;21:112114.
(16)
Heine RG, Catto-Smith AG, Reddihough DS. Effect of antireflux medication on salivary
drooling in children with cerebral palsy. Dev Med Child Neurol 1996;38:1030-1036.
(17)
Tscheng DZ. Sialorrhea – therapeutic drug options. Ann Pharmacother 2002;36:17851790.
(18)
Jongerius PH, van Tiel P, van Limbeek J et al. A systematic review for evidence of
efficacy of anticholinergic drugs to treat drooling. Arch Dis Child 2003;88:911-914.
(19)
Walshe M, Smith M, Pennington L. Interventions for drooling in children with cerebral
palsy. Cochrane Database of Systematic Reviews 2012, Issue 11. Art. No.: CD008624. DOI:
10.1002/14651858.CD008624.pub3.
(20)
Blasco PA, Stansbury JCK. Glycopyrrolate treatment of chronic drooling. Arch Pediatr
Adolesc Med 1996;150:932-935.
Available through NICE Evidence Search at www.evidence.nhs.uk
5
Medicines Q&As
Quality Assurance
Prepared by
Kate Pickett, Lead Pharmacist – Formulary and Medicines Q&As, Southampton Medicines Advice
Service, University Hospital Southampton NHS Foundation Trust
Date Prepared
25th June 2015
Checked by
Nicola Watts, Lead Clinical Advice Pharmacist (based on the Q&A originally checked by Simon Wills,
Sandra Hicks and Sue Gough), Southampton Medicines Advice Service, University Hospital
Southampton NHS Foundation Trust
Date of check
6th October 2015
Search strategy:
Medline (Ovid Online): exp *SIALORRHEA/dt (limited to human and English language)
Embase (NICE Evidence): exp HYPERSALIVATION/dt (limited to human and English language and
years 1998-2015)
Drugdex (accessed via https://www.micromedexsolutions.com/)
Cochrane Library (accessed via http://www.cochranelibrary.com/)
NICE Evidence Search (accessed via www.evidence.nhs.uk)
NICE (accessed via http://www.nice.org.uk/)
BNF (accessed via www.medicinescomplete.com)
Available through NICE Evidence Search at www.evidence.nhs.uk
6