Medicines Q&As

Hypersalivation – what drug treatment options are available?

Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at https://www.sps.nhs.uk/articles/about-ukmi-medicines-
qas/
Date prepared: 3rd April 2017

Background

This is the first of a series of five Q&A documents to address the drug treatment of hypersalivation.
Links to the others are included in the ‘Answer’ section below.

Hypersalivation is the excessive production of saliva and may result in involuntary loss of saliva from
the mouth, i.e. drooling or sialorrhoea (1,2). The pathophysiology of sialorrhoea is often not clear and
in some cases, particularly neurological disorders such as cerebral palsy or Parkinson’s disease, it is
thought to be due to a poor swallowing mechanism and an inadequate rate of swallowing rather than
increased saliva production (2-5).

First-line management of drooling should be directed at the cause, which may be multifactorial and
patient-specific. Often this will require a multidisciplinary team approach, using a combination of
treatments (2,3,6). Several options are available, including practical aids, speech therapy, behaviour
therapy, physiotherapy, radiotherapy, surgery and medication (2-5). Each option has varying degrees
of acceptability and success (7).

Drug therapy is aimed at decreasing the volume of saliva without addressing impaired swallowing (8).
Salivation is primarily mediated by parasympathetic innervation of the salivary glands and historically,
a range of drugs with antimuscarinic actions has been used in an attempt to control hypersalivation
(2-4). Blockade of cholinergic muscarinic receptors reduces salivary volume, but a lack of selectivity
may result in widespread and undesirable central and peripheral effects, including drowsiness,
restlessness, irritability, urinary retention, constipation, and flushing (3,8).

Hypersalivation may occur as an adverse effect of drug treatment, e.g. clozapine. A specific UKMi
Q&A document addresses the subject of drug-induced hypersalivation: Drug-induced hypersalivation
– what treatment options are available?

Answer
There are various drug treatments (see below), which have been used in the management of
hypersalivation, and some are discussed in more detail in additional UKMi Q&A documents. The
majority are not licensed in the UK for this indication. However, one brand of glycopyrronium oral
solution (Sialanar®) is licensed for “the treatment of severe sialorrhoea (chronic pathological drooling)
in children and adolescents aged 3 years and older with chronic neurological disorders” (9).
Procyclidine (injection, tablets and oral solution) and trihexyphenidyl hydrochloride (tablets) are
licensed for the treatment of the symptoms of Parkinson’s disease, which include excessive salivation,
or sialorrhoea/drooling (10-13).

1. Antimuscarinic Drugs

 Amitriptyline
 Atropine
 Benzatropine* (benztropine)
 Glycopyrronium bromide (glycopyrrolate)
 Hyoscine (scopolamine) hydrobromide
 Ipratropium bromide
 Procyclidine
 Trihexyphenidyl hydrochloride (benzhexol hydrochloride)

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2. Botulinum Toxins

3. Other drugs
Anti-reflux medications (e.g. ranitidine and cisapride*)
Modafinil
Piracetam
Rotigotine

* Drugs that are no longer marketed in the UK.

There are few, if any, good quality studies (e.g. randomised controlled trials) to compare the different
therapeutic options available for the management of sialorrhoea (4). For further discussion on the
weaknesses in evidence refer to the ‘Limitations’ section below.

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 (14). 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.

A Cochrane review examining interventions for drooling in children with cerebral palsy identified six
trials eligible for inclusion, four using botulinum toxin A, and two using the pharmacological
interventions, benzatropine or glycopyrronium (15). However the reviewers were unable to reach a
conclusion on the effectiveness or safety of the treatments, and insufficient evidence was found to
inform clinical practice for the management of drooling in this patient group.

A more recent review of management of drooling in children concluded that evidence for interventions
was limited, but possible drug therapies may include transdermal hyoscine, oral glycopyrronium or
salivary gland botulinum toxin injections (3). The review found that evidence of efficacy remains
limited to small, short-term studies, despite the long-term nature of treatment, and that treatments
were associated with adverse effects, with little data on long-term safety. A recommendation was
made to ensure careful discussion of treatment decisions, and follow-up of patients to assess efficacy
and adverse effects.

A UK survey of 23 neurologists with a special interest in motor neuron disease identified the most
popular first-line treatments for sialorrhoea in their patients as: hyoscine hydrobromide patches (65%
of clinicians), amitriptyline (52%), carbocisteine (30%) and atropine eye drops topically to the tongue
(26%) (16). Second-line preferences were: oral glycopyrronium (43%), botulinum toxin (39%),
carbocisteine (35%), amitriptyline (30%) and subcutaneous glycopyrronium (26%). The authors noted
the variation in treatment strategies, and suggested this reflected the lack of evidence based
guidelines.

The National Institute for Health and Care Excellence (NICE) full Clinical Guideline on the
management of Parkinson’s disease includes a section on sialorrhoea. Suggested treatment
measures include sublingual 1% atropine ophthalmic solution twice daily and injection of salivary
glands with botulinum toxin A (17). A NICE Clinical Knowledge Summary also suggests botulinum
toxin A, as well as hyoscine hydrobromide patches as specialist treatment options for excessive
salivation associated with Parkinson’s disease (18).

A NICE Clinical Knowledge Summary covering the management of oral problems in palliative care
includes a section on excessive salivation (19). Specialist advice is recommended, with little data
available to guide drug or dosage recommendations. Suggested drug treatments are based on expert
opinion, and include hyoscine hydrobromide (oral, sublingual or transdermal) or amitriptyline.

The BNF for Children suggests oral glycopyrronium or oral/transdermal hyoscine hydrombromide as
options for hypersalivation in palliative care and in children unable to control posture or with abnormal
swallowing reflex (3,20).

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Three Q&A documents have been prepared about non drug-induced hypersalivation, which look at
the evidence behind various treatment options in more detail. These are:

Glycopyrronium: Hypersalivation – can glycopyrronium be used to treat it?

Hyoscine Hydrobromide: Hypersalivation – can hyoscine hydrobromide be used to treat it?

Other antimuscarinic drugs, Botulinum Toxin and Other Drugs: Hypersalivation – what are the
treatment alternatives to glycopyrronium and hyoscine?

The choice of drug should be based on its pharmacological and adverse effect profile as well as the
limited results of available published studies (4). Selection of a particular compound should be based
on individual response and side effects (21). Clearly, larger randomised controlled trials are required
before the place of each of these drugs in the management of hypersalivation can be established.

Summary

 Hypersalivation is the excessive production of saliva and may result in drooling or sialorrhoea.
 Drooling is not always due to hypersalivation, and may be due to poor swallowing mechanism
and an inadequate rate of swallowing. Nonetheless, drug therapy for drooling is aimed at
reducing the volume of saliva.
 Evidence to support efficacy and safety of drug therapy in hypersalivation is limited. Drugs
with antimuscarinic actions, particularly hyoscine hydrobromide and glycopyrronium, are most
commonly used. Botulinum toxins are another option, as well as a selection of other drugs.
 Most drugs are unlicensed for this indication in the UK, although glycopyrronium oral solution
(Sialanar®) is licensed for the treatment of sialorrhoea in children with neurological disorders,
and procyclidine and trihexyphenidyl are licensed for excessive salivation or drooling
associated with Parkinson’s disease.
 Good quality comparative studies are lacking, so prescribers should consider evidence for
effectiveness, potential side effects and available routes of administration when choosing
between treatments. Specialist advice may be required, with little data available to guide drug
or dosage recommendations.
 The various treatment options and evidence are discussed in more detail in other UKMi Q&As
(links provided in this Q&A), and another Q&A discusses treatments for drug-induced
hypersalivation.

Limitations
 To date there are no large randomised controlled trials for any drug to treat hypersalivation, so
the amount of published evidence is limited. Few comparative studies are available. The
evidence for the 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 hypersalivation.

References
1. National Institute for Health and Care Excellence (NICE). Evidence Summary: unlicensed or off-label
medicine. ESUOM15: Hypersalivation: oral glycopyrronium bromide. 2nd July 2013. Available at
http://www.nice.org.uk/advice/esuom15/chapter/Key-points-from-the-evidence
2. Bavikatte G, Lin Sit P, Hassoon A. Management of drooling of saliva. BJMP 2012; 5(1): 507-512
3. Anon. Challenges in managing drooling in children. DTB 2015; 53(6): 66-68
4. Tscheng DZ. Sialorrhea – therapeutic drug options. Ann Pharmacother 2002;36:1785-1790.
5. Hill F, Miller N, Walsh RA, Mockler D, McDowell R, Walshe M. Botulinum toxin for drooling in
Parkinson’s disease (Protocol). Cochrane Database of Systematic Reviews 2016, Issue 10. Art.

Available through Specialist Pharmacy Service at www.sps.nhs.uk

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No.: CD012408. DOI: 10.1002/14651858.CD012408. Accessed 30th March 2017 via

http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD012408/full
6. Brodtkorb E, Wyzocka-Bakowska MM, Lillevold PE et al. Transdermal scopolamine in drooling.
Journal of Mental Deficiency Research 1988;32:233-237.
7. Zeppetella G. Nebulized scopolamine in the management of oral dribbling: three case reports. J Pain
Symptom Manage 1999;17:293-295.
8. Mier RJ, Bachrach SJ, Lakin RC et al. Treatment of sialorrhea with glycopyrrolate: a double-blind,
dose-ranging study. Arch Pediatr Adolesc Med 2000;154:1214-1218.
9. Summary of Product Characteristics. Sialanar 320 micrograms/ml Glycopyrronium (400
micrograms/ml Glycopyrronium Bromide) Oral Solution. Proveca Limited. Last updated on eMC
4/1/2017. Accessed 30th March 2017 via http://www.medicines.org.uk/emc/medicine/32715
10. Summary of Product Characteristics. Kemadrin 5mg/ml Solution for injection. Auden Mckenzie
(Pharma Division) Ltd (a subsidiary of Actavis PLC). Last updated on eMC 16/11/2015. Accessed
30th March 2017 via http://www.medicines.org.uk/emc/medicine/31207
11. Summary of Product Characteristics. Kemadrin tablets 5mg. Aspen. Last updated on eMC 2/3/2016.
Accessed 30th March 2017 via http://www.medicines.org.uk/emc/medicine/2171
12. Summary of Product Characteristics. Procyclidine Rosemont 5mg/5ml Oral Solution. Rosemont
Pharmaceuticals Limited. Last updated on eMC 11/7/2016. Accessed 30th March 2017 via
http://www.medicines.org.uk/emc/medicine/8072
13. Summary of Product Characteristics. Trihexyphenidyl 2mg Tablets. Genus Pharmaceuticals. Last
updated on eMC 3/2/2015. Accessed 30th March 2017 via
http://www.medicines.org.uk/emc/medicine/28617
14. 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.
15. 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. Accessed 30th March 2017 via
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008624.pub3/full
16. Hobson EV, McGeachan A, Al-Chalabi A, Chandran S, et al. Management of sialorrhoea in motor
neuron disease: A survey of current UK practice. Amyotrophic Lateral Sclerosis and Frontotemporal
Degeneration 2013; 14(7-8): 521-527
17. National Collaborating Centre for Chronic Conditions. Parkinson’s disease: national clinical
guideline for diagnosis and management in primary and secondary care. London: Royal College
of Physicians, June 2006. Available via https://www.nice.org.uk/guidance/cg35/evidence
18. National Institute for Health and Care Excellence (NICE). Clinical Knowledge Summaries:
Parkinson’s disease. February 2016. Accessed 30th March 2017 via
https://cks.nice.org.uk/parkinsons-disease
19. National Institute for Health and Care Excellence (NICE). Clinical Knowledge Summaries: Palliative
care-oral. Last revised December 2016. Accessed 30th March 2017 via
https://cks.nice.org.uk/palliative-care-oral
20. Paediatric Formulary Committee. BNF for Children Legacy (online) London: BMJ Group,
Pharmaceutical Press, and RCPCH Publications Limited: section 15.1.3. Accessed 30th March 2017
via www.medicinescomplete.com
21. Camp-Bruno JA, Winsberg BG, Green-Parsons AR et al. Efficacy of benzatropine therapy for
drooling. Dev Med Child Neurol 1989;31:309-319.

Quality Assurance
Prepared by
Samantha Owen, Principal Pharmacist Critical Evaluation, Southampton Medicines Advice Service,
University Hospital Southampton NHS Foundation Trust (based on earlier work by Kate Pickett)

Date Prepared
3rd April 2017

Contact: medicinesadvice@uhs.nhs.uk

Checked by
Joshua McKie, Lead Pharmacist Critical Evaluation, Southampton Medicines Advice Service,
University Hospital Southampton NHS Foundation Trust

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Date of check
23rd May 2017

Search strategy:
Medline (via Ovid): exp *SIALORRHEA/dt
Embase (via Ovid): exp HYPERSALIVATION/dm, dt
Drugdex (accessed via https://www.micromedexsolutions.com/)
Electronic Medicines Compendium (accessed via http://www.medicines.org.uk/emc/)
NICE Evidence Search (accessed via www.evidence.nhs.uk)
Cochrane Library (accessed via http://www.cochranelibrary.com/)
NICE (accessed via http://www.nice.org.uk/)
BNF (accessed via www.medicinescomplete.com)

Available through Specialist Pharmacy Service at www.sps.nhs.uk