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Medicines Q&As
Q&A 50.8
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 www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: 25th June 2015 (partial revision November 3rd 2015)
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 at relevant points in the text below.
Hypersalivation is also known as drooling or sialorrhoea. The pathophysiology of sialorrhoea is not
clear although in some cases (e.g. cerebral palsy) it is thought to be due to a poor swallowing
mechanism and an inadequate rate of swallowing rather than increased saliva production (1).
First-line management of drooling should be directed at the cause, which may be multifactorial and
patient-specific (2). Several options are available, including practical aids, speech therapy,
physiotherapy, surgery and medication. Each option has varying degrees of acceptability and
success (3).
Drug therapy is aimed at decreasing the volume of saliva without addressing impaired swallowing (4).
Salivation is primarily mediated by parasympathetic innervation of the salivary glands (1) and
historically, a range of drugs with antimuscarinic actions has been used in an attempt to control
hypersalivation. 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 (4).
Hypersalivation may occur as an adverse effect of drug treatment, for example, clozapine. A specific
Q&A document addresses the subject of drug-induced hypersalivation - No.54: Drug-induced
hypersalivation – what treatment options are available? The treatment options for clozapine-induced
hypersalivation in particular have been the subject of several review articles (5,6,7,8).
There are various drug treatments (see below), which have been used in the management of
hypersalivation; some are discussed in more detail in three additional Q&A documents. None of the
following drugs are licensed in the UK for the treatment of hypersalivation:
1. Antimuscarinic Drugs
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Amitriptyline
Atropine
Benzatropine
Trihexyphenidyl hydrochloride (benzhexol hydrochloride)
Glycopyrronium bromide (glycopyrrolate): oral, nebulized and subcutaneous
Hyoscine hydrobromide (scopolamine hydrobromide): oral, topical, subcutaneous and
nebulized
2. Beta-Blockers
3. Botulinum Toxin
4. Other drugs
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
Answer
There are no randomised double-blind studies that compare the different therapeutic options available
for the management of sialorrhoea (1). 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 (9). 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 (10).
The choice of drug should be based on its pharmacological and adverse effect profile as well as the
limited results of available published studies (1). Selection of a particular compound should be based
on individual response and side effects (11). Clearly, larger randomised controlled trials are required
before the place of each of these drugs in the management of hypersalivation can be established.
The 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 (12).
Three Q&A documents have been prepared about non drug-induced hypersalivation, which look at
the evidence behind various treatment options in more detail. An outline of their content is given
below:
Hyoscine Hydrobromide (see separate Q&A 51 for more detailed information)
Three small, short-term studies have investigated the use of transdermal hyoscine patches for the
management of hypersalivation in adults and children (2,13,14). Transdermal hyoscine patches offer
several advantages over other treatments including ease of administration, maintenance of steady
state concentrations and a low incidence of systemic side effects compared with other
anticholinergics (15). Hyoscine patches may be particularly useful for patients with intractable
swallowing difficulties (e.g. head and neck cancers) who may have problems with drooling or choking
owing to the normal production of saliva. Hyoscine hydrobromide can also be given by non-topical
routes but there is less evidence to support this.
Glycopyrronium (see separate Q&A 52 for more detailed information)
Glycopyrronium (glycopyrrolate) is slower in onset and produces less tachycardia than atropine or
hyoscine (16). Benefits of using glycopyrronium include its long duration of action and its inability to
cross the blood-brain barrier thus reducing central adverse effects (e.g. sedation, restlessness) (17).
However, the published data available are mainly limited to the use of oral glycopyrronium in children
and young adults with neurodevelopmental disabilities (4,17-21). In one small study in adult patients
with Parkinson’s disease, 39% responded to treatment with oral glycopyrronium (22). The authors of a
NICE Evidence Summary: unlicensed or off-label medicine document, which evaluated the three
published randomised controlled trials (RCTs) (4,20,22), concluded that there is moderate evidence that
oral glycopyrronium bromide reduces hypersalivation or drooling, but these RCTs do not provide
evidence for the efficacy or safety of long-term use of oral glycopyrronium bromide for treating adults,
children and young people with hypersalivation. Further larger RCTs are required (23).
Glycopyrronium tablets are now available in the UK, but they are not licensed for the treatment of
hypersalivation (24). One report describes the formulation of an oral preparation for administration via
a PEG tube (25). A 1mg/5ml oral solution of glycopyrronium (Cuvposa®) has been approved for use in
the United States to reduce chronic severe drooling in patients aged 3-16 years with neurological
conditions associated with problem drooling (26). This is not currently available in the UK. No efficacy
data comparing the different oral formulations of glycopyrronium have been published (27). Isolated case
reports have been published describing the use of nebulized or subcutaneous glycopyrronium (28,29).
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
Other Drugs (see separate Q&A 53 for more detailed information)
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 (11). Benzatropine often
produces sedation, or less commonly, dysphoria and restlessness (18). Benzatropine tablets are no
longer available in the UK but can be imported from abroad.
The authors of one small non-comparative study suggest that the advantages of sublingually
administered atropine include its availability as a ready-made solution (eye drops), low cost and
reversibility (30). 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 (30). However, one small randomised placebocontrolled trial which evaluated the effectiveness of sublingual atropine sulfate drops for the
management of hypersalivation failed to demonstrate any significant benefits (31).
Trihexyphenidyl hydrochloride, modafinil, beta-blockers and botulinum toxin have been used in
certain situations with some success.
Summary
A range of pharmacological options are available to treat hypersalivation. Most of them are
antimuscarinic drugs and all are unlicensed in the UK for the treatment of hypersalivation. There are
no randomised controlled comparative studies, so prescribers should consider evidence for
effectiveness, potential side effects and available routes of administration when choosing between
them. The absence of long-term studies means that there is no evidence for continued effectiveness
or safety if used continuously for long periods.
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 for the use of some of these drugs is limited to anecdotal reports
only.
 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 (1) particularly as there is inter-individual variation in saliva
production. No single method of measurement of salivary flow and outcome presentation is
available (9).
 This Q&A has not addressed the management of drug-induced sialorrhoea.
 The majority of the studies are short-term studies so long-term efficacy and safety data are not
available.
References
(1)
Tscheng DZ. Sialorrhea – therapeutic drug options. Ann Pharmacother 2002;36:1785-1790.
(2)
Brodtkorb E, Wyzocka-Bakowska MM, Lillevold PE et al. Transdermal scopolamine in
drooling. Journal of Mental Deficiency Research 1988;32:233-237.
(3)
Zeppetella G. Nebulized scopolamine in the management of oral dribbling: three case
reports. J Pain Symptom Manage 1999;17:293-295.
(4)
Mier RJ, Bachrach SJ, Lakin RC et al. Treatment of sialorrhea with glycopyrrolate: a doubleblind, dose-ranging study. Arch Pediatr Adolesc Med 2000;154:1214-1218.
(5)
Bird AM, Smith TL, Walton AE. Current treatment strategies for clozapine-induced
sialorrhea. Ann Pharmacother 2011;45:667-75.
(6)
Davydov L, Botts SR. Clozapine-induced hypersalivation. Ann Pharmacother 2000;34:662-5.
(7)
Rogers DP, Shramko JK. Therapeutic options in the treatment of clozapine-induced
sialorrhea. Pharmacotherapy 2000;20:1092-1095.
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
(8)
(9)
(10)
(11)
(12)
(13)
(14)
(15)
(16)
(17)
(18)
(19)
(20)
(21)
(22)
(23)
(24)
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(29)
(30)
(31)
Praharaj SK, Arora M, Gandotra S. Clozapine-induced sialorrhea: pathophysiology and
management strategies. Psychopharmacology 2006;185:265-273.
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.
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.
Camp-Bruno JA, Winsberg BG, Green-Parsons AR et al. Efficacy of benztropine therapy for
drooling. Dev Med Child Neurol 1989;31:309-319.
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.
Lewis DW, Fontana C, Mehallick LK et al. Transdermal scopolamine for reduction of drooling
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Mato A, Limeres J, Tomas I et al. Management of drooling in disabled patients with
scopolamine patches. Br J Clin Pharmacol 2010; 69:684-688.
Dreyfuss P, Vogel D, Walsh N. The use of transdermal scopolamine to control drooling: a
case report. Am J Phys Med Rehabil 1991;70:220-222.
Olsen AK, Sjøgren P. Oral glycopyrrolate alleviates drooling in a patient with tongue cancer.
J Pain Symptom Manage 1999;18:300-302.
Bachrach SJ, Walter RS, Trzcinski K. Use of glycopyrrolate and other anticholinergic
medications for sialorrhea in children with cerebral palsy. Clin Pediatr 1998;37:485-490.
Blasco PA, Stansbury JCK. Glycopyrrolate treatment of chronic drooling. Arch Pediatr
Adolesc Med 1996;150:932-935.
Stern LM. Preliminary study of glycopyrrolate in the management of drooling. J Paediatr
Child Health 1997;33:52-54.
Zeller RS, Lee, H-M, Cavanaugh PF et al. Randomized phase III evaluation of the efficacy
and safety of a novel glycopyrrolate oral solution for the management of chronic severe
drooling in children with cerebral palsy or other neurologic conditions. Therapeutics and
Clinical Risk Management 2012;8:15-23.
Zeller RS, Davidson J, Lee H-M et al. Safety and efficacy of glycopyrrolate oral solution for
management of pathologic drooling in pediatric patients with cerebral palsy and other
neurologic conditions. Therapeutics and Clinical Risk Management 2012;8:25-32.
Arbouw MEL, Movig KLL, Koopmann M et al. Glycopyrrolate for sialorrhea in Parkinson
disease: a randomized, double-blind, crossover trial. Neurology 2010;74:1203-1207.
National Institute for Health and Care Excellence (NICE). Evidence Summary: unlicensed or
off-label medicine. ESUOM15: Hypersalivation: oral glycopyrronium bromide. 2nd July 2013.
Accessed via http://www.nice.org.uk/advice/esuom15/chapter/Key-points-from-the-evidence
on 1st July 2015.
Summary of Product Characteristics Glycopyrronium tablets 1mg and 2mg. Morningside
Healthcare. Accessed via http://www.mhra.gov.uk/spc-pil/index.htm on November 3rd 2015.
Lucas V, Amass C. Use of enteral glycopyrrolate in the management of drooling. Palliat Med
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Cuvposa (glycopyrrolate 1mg/5ml) oral solution. Prescribing Information. Revised May
2013. Accessed via http://www.cuvposa.com/ on 21st July 2015.
Eiland LS. Glycopyrrolate for chronic drooling in children. Clin Ther 2012;34:735-742.
Strutt R, Fardell B, Chye R. Nebulized glycopyrrolate for drooling in a motor neuron patient. J
Pain Symptom Manage 2002;23:2-3.
Cooper-Knock J, Ahmedzai SH, Shaw P. The use of subcutaneous glycopyrrolate in the
management of sialorrhoea and facilitating the use of non-invasive ventilation in amyotrophic
lateral sclerosis. Amyotrophic Lateral Sclerosis 2011;12:464-465.
Hyson HC, Johnson AM, Jog MS. Sublingual atropine for sialorrhea secondary to
parkinsonism: a pilot study. Mov Disord 2002;17:1318-1320.
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Available through NICE Evidence Search at www.evidence.nhs.uk
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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 (date of partial revision 3rd November 2015)
Checked by
Nicola Watts, Lead Clinical Advice Pharmacist (partial revision checked by Samantha Owen) (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 (partial revision checked 10th November 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/)
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 NICE Evidence Search at www.evidence.nhs.uk
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