Download Drug induced hypersalivation

Medicines Q&As
Q&A 54.8
Drug-induced hypersalivation - what 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 3rd November 2015)
Background
Hypersalivation, which may manifest as drooling (sialorrhoea), can be caused by medication. This
Q&A summarises published studies or case reports concerning the pharmacological treatment of
drug-induced hypersalivation, although none of the treatments described below are licensed for this
condition. The licensed use of antimuscarinic drugs (e.g. glycopyrronium bromide) as premedicants to
dry bronchial and salivary secretions peri-operatively is not included in this Q&A.
Table 1 lists treatments for clozapine-induced hypersalivation. Table 2 lists treatments for
hypersalivation caused by other drugs.
Answer
Clozapine-Induced Hypersalivation
Many antipsychotics can cause hypersalivation, but it affects around 30% of patients taking clozapine
(reported range 10-80%) (1,2,3). It usually develops early in treatment, is often more prominent at
night, and may reduce compliance (1,2,3,4). The exact mechanism of clozapine-induced
hypersalivation is unknown (2,3,5).
If clozapine dose reduction (in appropriate patients) has not alleviated symptoms and an alternative
antipsychotic is not an option, various pharmacological interventions have been used to manage
hypersalivation (see Table 1 for treatment options). Non-pharmacological strategies (e.g. sugarless
chewing gum) have been recommended first-line but they are often ineffective (2,6,7).
A Cochrane Review to determine the clinical effects of pharmacological interventions (including
traditional Chinese medicines) for clozapine-induced hypersalivation identified 15 trials. The authors
concluded that “There are currently insufficient data to confidently inform clinical practice” and that
“These trials, however, are invaluable guides for current and future study design”. They add that
“Current practice outside of well designed randomised trials should be clearly justified” (8).
Table 1 – Drug Interventions for Clozapine-Induced Hypersalivation.
Intervention
Antimuscarinics
Amitriptyline oral
Report Descriptions
[ref]
Dose of Intervention
(a) Case reports (n=4)
[9]
(b) Case report [10]
(a) 75-100mg per day.
Outcome and notes when
used in clozapine patients
Marked improvement.
(b) 25mg at night.
Beware additive side effects
(e.g. fits, hypotension)
[10,11].
Available through NICE Evidence Search at www.evidence.nhs.uk
1
Medicines Q&As
Table 1 (continued)
Intervention
Atropine eye
drops 1%
sublingually
Report Descriptions
[ref]
(a) Case report [12]
(b) Case reports (n=3)
[6]
(c) Case report [13]
(d) Case report
(atropine solution 1%
sublingually)[14]
Dose of Intervention
(a) 1-2 drops in the
morning.
(b) 1 drop at night (plus
top-up overnight dose
of 1 drop in water prn
(n=1)).
(c) 2 drops bd.
(d) 1 drop up to three
times a day for 7 days
plus oral hyoscine
hydrobromide (reduced
from 900
microgram/day to 300
microgram at bedtime).
Outcome and notes when
used in clozapine patients
(a) Resolution.
(b) “Immediate relief”.
(c) Resolution.
(d) Resolution. Sialorrhea did
not recur following
discontinuation of atropine by
the patient after 7 days.
Fast relief [6] but may not be
sustained [15]; dropper can be
hard to use with risk of
accidental overdose [15].
Beware additive anticholinergic
side effects [13] and bitter
taste [16].
Benzatropine
oral*
(a) Retrospective chart
review (n=60; 15 pts in
each of 4 groups) [17]
(b) Case report [18]
Biperiden oral*
(a) Randomised,
double-blind crossover
trial vs.
glycopyrronium
(n=13)[19]
(b) Case report [20]
(a) Benzatropine 1mg
bd vs. terazosin 2mg
nocte vs. both
treatments together vs.
no treatment.
(b) 2mg per day plus
chewing gum.
(a) At 12 weeks, combination
gave 100% satisfactory
response vs 67% for
benzatropine alone and 93%
for terazosin alone.
(b) Improved.
(a) Biperiden 2mg twice
daily vs.
glycopyrronium 1mg
twice daily.
(a) At 4 weeks, hypersalivation
significantly improved vs.
baseline, but less than
glycopyrronium. Cognitive
function reduced.
(b) Hypersalivation eliminated.
(b) Uptitrated to 6mg
per day.
* Not licensed in the UK. Specific products may be imported, or may be available from UK ‘specials’ manufacturers.
Available through NICE Evidence Search at www.evidence.nhs.uk
2
Medicines Q&As
Table 1 (continued)
Intervention
Glycopyrronium
oral#
Report Descriptions
[ref]
(a) Randomised,
double-blind crossover
trial vs. biperiden
(n=13)[19]
(b) Case report [21]
(c) Case series (n=3)
(aged 13-16) [22]
Dose of Intervention
(a) See biperiden
above.
(b) 500 micrograms bd,
increased to 2mg bd
over 10 days.
(c) Dose uptitrated to
2-4mg bd in 2 patients
and from 1mg tds to
2mg tds to 2mg bd in 1
patient.
(d) Case report [23]
(e) Case reports (n=4)
[24]
(d) 1mg at bedtime.
(e) 1mg twice daily
(n=3) increased to 2mg
tds (n=1).
Hyoscine
butylbromide
Case series (n=5) [26]
Hyoscine butylbromide
30-60mg/day (route of
administration not
stated).
Hyoscine
hydrobromide
patch/oral
(a) Case reports (n=4)
[16]
(b) Case report [27]
(a) Patch (dose not
given).
(b) Patch 1.5mg every
72hrs.
(c) 300 microgram
tablet nocte increased
to tds if necessary,
sucked & swallowed.
(c) Anecdotal [3,4]
Ipratropium
bromide nasal
spray 0.03%
(a) Randomised,
double-blind, placebocontrolled, crossover
trial (n=20) [28]
(b) Non-comparative
study (n=10) for 6
months [5]
(c) Retrospective noncomparative study
(n=9) [29]
(d) Case series (n=10)
[15]. Pts failed on sublingual atropine drops
(a) 2 puffs sublingually
at bedtime.
(b) One puff to each
nostril at bedtime.
(c) 2 puffs sublingually
nocte increasing to tds
if necessary;
0.06% strength 2 puffs
up to tds if 0.03%
failed.
(d) 2 puffs sublingually
nocte (n=8) or bd
(n=2).
Outcome and notes when
used in clozapine patients
(a) At 4 weeks, hypersalivation
significantly improved vs.
baseline and vs. biperiden.
Cognitive function unchanged.
(b) Hypersalivation significantly
reduced. Constipation
worsened at higher dose.
(c) Marked reduction in saliva
flow (n=2). Hypersalivation
resolved (n=1). Extensive
constipation observed (n=1).
Dry mouth (n=1) which
resolved on dose reduction.
(d) Hypersalivation reduced.
(e) Improvement (n=2)
including in one patient failing
other treatments.
Hypersalivation resolved
(n=1). Outcome unknown
(n=1).
Objective symptom
improvement at 4 weeks.
Abdominal air pockets
detected at higher dose (n=1).
Monitoring for side-effects
recommended.
(a) Improvement, including pts
failing other treatments.
(b) Persistent improvement.
(c) Widely used in practice
(e.g. Kwells). Beware
cognitive impairment,
drowsiness, worsening of
constipation.
(a) Ipratropium no better than
placebo after 2 weeks.
(b) 7 improved. 2 withdrew
[Dry nose/bleeding (n=1) and
ineffectiveness (n=1)].
(c) Seven patients improved, 2
did not. Effect lasted 2-8
hours.
(d) Reduction or resolution.
Easier to use than atropine
eye drops.
# Glycopyrronium oral solution (Cuvposa®) is licensed in the US (to reduce chronic severe drooling in patients aged 3-16 years
with neurological conditions associated with problem drooling) [25]. It is not currently available in the UK.
Available through NICE Evidence Search at www.evidence.nhs.uk
3
Medicines Q&As
Table 1 (continued)
Intervention
Report Descriptions
[ref]
Case report [30]
Oxybutynin oral
Pirenzepine oral*
Trihexyphenidyl
(benzhexol)
hydrochloride
oral
(a) Randomised,
double-blind placebocontrolled cross-over
trial (20 Asian
patients) [31]
(b) Case reports
(n=120) [32]
(c) Non-comparative
study (n=29) for 3
days [33]
(a) Non-comparative
study (n=14) for 15
days [34]
Oxybutynin 5mg daily
titrated to 10mg every
morning and 5mg nocte
then reduced to 5mg
bd according to
response.
(a) Pirenzepine
25mg/day increased by
25mg/week to
100mg/day for further 5
weeks.
(b) Daily dosages of
25-100mg pirenzepine.
(c) Pirenzepine 50mg
daily.
(b) Case report with 3
month follow-up [35]
(a) 5mg nocte,
gradually increasing to
maximum of 15mg
nocte.
(b) 6mg per day in
divided doses.
(c) Case report [36]
(c) 2mg at night.
Adrenoceptor Agonists
Clonidine
(a) Case series (n=4)
patch/oral
[37]
(b) Case series (n=12)
[38] 4 weeks treatment
Guanfacine* oral
Dose of Intervention
Case report [40]
(a) Patch* 100-200
micrograms per week.
(b) Oral 50 micrograms
nocte increased to 100
micrograms after 2
weeks if ineffective.
1mg in the morning.
Outcome and notes when
used in clozapine patients
Marked improvement.
(a) Pirenzepine no better than
placebo.
(b) Improvement. Mild
diarrhoea observed.
(c) Reduced incidence of
hypersalivation. Serum
clozapine levels elevated in 3
pts and reduced in 1 pt with
concomitant pirenzepine, but
confounding factors also
present.
(a) 11 pts improved; 3 pts did
not.
(b) Marked reduction in
nocturnal hypersalivation and
disappearance of daytime
hypersalivation.
(c) Resolution. Constipation
and tachycardia reported.
May impair cognitive function
[4]. Start with trial of a low
dose before increasing further
[36].
(a) 2 pts showed marked and
sustained improvement. 1 pt
developed tolerance. 1 pt did
not respond.
(b) 11 pts had good or partial
response. 1 pt did not
respond.
Caution: additive hypotension
with clozapine [2]. May cause
depression and may
exacerbate psychosis [11,38].
Tolerance may develop [38].
Avoid abrupt cessation [39].
Improvement.
Avoid abrupt cessation [41].
* Not licensed in the UK. Specific products may be imported, or may be available from UK ‘specials’ manufacturers.
Available through NICE Evidence Search at www.evidence.nhs.uk
4
Medicines Q&As
Table 1 (continued)
Intervention
Report Descriptions
[ref]
Case report [42]. 1
month’s treatment
Lofexidine oral
Dose of Intervention
200 micrograms bd.
Outcome and notes when
used in clozapine patients
Significant improvement.
Avoid long-term use [42] and
abrupt cessation [41]. May
exacerbate psychosis and
depression [4].
Adrenoceptor Antagonists
Terazosin oral
Retrospective chart
review (n=60) [17]
See benzatropine
above.
Beware additive hypotension
[39].
Miscellaneous
Amisulpride oral
Bupropion oral
Moclobemide
oral
Sulpiride oral
(a) Randomised,
double-blind, placebocontrolled, cross-over
study (n=20). 3 wks
active treatment [43]
(b) Open-label
crossover trial vs.
moclobemide (n=53)
[44]
(c) Case report;
patient also on
pirenzepine
throughout [45]
(d) Case report with 3
month follow-up [46]
(e) Case report [47]
(a) Amisulpride
100mg/day titrated up
to 400mg/day over 1
week.
(a) Statistically significant
improvement. Prolactin levels
rose in most patients and may
need monitoring.
b) Amisulpride
400mg/day vs.
moclobemide
300mg/day.
(c) Amisulpride up to
600mg daily with
clozapine dose
reduction.
(d) Amisulpride
50mg/day.
(e) Amisulpride
50mg/day increased
over 2 weeks to
150mg/day.
(b) At 2 weeks, 39 improved,
1 worsened and 13
unchanged. Less effective
than moclobemide.
(c) Enabled reduced
pirenzepine dose. Hypersalivation markedly improved.
Case report with 300
days follow-up [48].
Previous treatment
failure with six other
drugs
Bupropion 100mg*/day
increased to bupropion
SR 150mg/day after 18
days.
(a) Non-comparative
study (n=14).
Treatment for 2 weeks
[49]
(b) Open-label
crossover trial vs.
amisulpride (n=53)
[44]
Non-comparative
study (n=18) for 21
days [50]
(a) Moclobemide
150mg/day increased
to 300mg/day after 1
week if ineffective.
(b) See amisulpride
above.
Sulpiride 150-300mg
per day.
(d) Significant improvement in
hypersalivation.
(e) Marked improvement in
daytime hypersalivation but
night-time hypersalivation still
present. Constipation and
tachycardia reported.
Marked improvement in
daytime hypersalivation but
night-time hypersalivation still
present.
Clozapine and bupropion
lower the seizure threshold
[48].
(a) 9 patients improved; 5 did
not.
(b) At 2 weeks, 44 improved
and 9 unchanged. More
effective than amisulpride.
Hypersalivation reduced in all
patients.
* Not licensed in the UK. Specific products may be imported, or may be available from UK ‘specials’ manufacturers.
Available through NICE Evidence Search at www.evidence.nhs.uk
5
Medicines Q&As
Table 1 (continued)
Intervention
Report Descriptions
[ref]
Retrospective chart
review (n=158) [51]
Quetiapine oral
Botulinum toxin A
injection
Case report [52]
Dose of Intervention
Bedtime quetiapine
dose as required
clinically, plus reduction
in clozapine dose by
about 25%.
Botulinum toxin 150
units into each parotid
gland.
Outcome and notes when
used in clozapine patients
Quetiapine was “beneficial in
some patients”. Adding
benzatropine or terazosin as
well resolved hypersalivation
in all patients.
Beneficial response at 2
weeks still apparent at 12
weeks.
* Not licensed in the UK. Specific products may be imported, or may be available from UK ‘specials’ manufacturers.
Miscellaneous Drugs Inducing Hypersalivation
The authors of a Cochrane Review of anticholinergic medication for non-clozapine neurolepticinduced hypersalivation in people with schizophrenia were unable to locate any relevant randomised
controlled trials (53). They suggest that further research is required to guide practice.
Table 2 - Hypersalivation Caused by Other Medicines with Drug Interventions Used.
Drug causing
hypersalivation
Aripiprazole
Report Details
[ref]
Case report [54]
Risperidone oral
(a) Case report
[55]
(b) Case report
[56]
(c) Case report
(age 14) [57]
Quetiapine
Case report [58]
Bethanechol
Case report with
4 mth follow-up
[59]
Intervention
Oral trihexyphenidyl 2mg
daily.
(a) Oral clonidine
100micrograms nocte,
increased to 100 micrograms
bd over 3 days.
(b) Single dose of IM
biperiden* (dose not stated)
followed by oral biperiden*
2mg daily.
(c) Diphenhydramine
25mg/day increased to
50mg/day in 1 week (route of
administration not stated) plus
chewing gum.
Oral benzatropine* 1mg twice
daily.
Atropine eye drops 0.1%
sublingually.
Ipratropium bromide MDI 2
puffs every 6 hrs onto buccal
mucosa.
Outcome
Significant reduction in
hypersalivation.
(a) Rapid and marked
improvement.
(b) Full remission of
hypersalivation.
(c) Hypersalivation markedly
decreased.
No improvement with
benzatropine and atropine
so quetiapine discontinued
and hypersalivation
resolved.
Significant symptomatic
improvement.
* Not licensed in the UK. Specific products may be imported, or may be available from UK ‘specials’ manufacturers.
Available through NICE Evidence Search at www.evidence.nhs.uk
6
Medicines Q&As
Table 2 (continued)
Drug causing
hypersalivation
Irinotecan plus
oxaliplatin
Lithium
Report Details
[ref]
Case report [60]
Case report [63]
Intervention
Subcutaneous atropine (no
dose given).
Propantheline bromide 15mg
bd.
Outcome
Resolution.
Oxaliplatin might potentiate
irinotecan’s cholinergic
effects [61] so prophylaxis
has been given (atropine
250 micrograms
subcutaneously) a few
minutes before irinotecan
[62].
Satisfactory relief.
* Not licensed in the UK. Specific products may be imported, or may be available from UK ‘specials’ manufacturers.
Summary
Clozapine-Induced Hypersalivation




There are currently no drug treatments licensed for the management of clozapine-induced
hypersalivation.
If hypersalivation is troublesome, reduce clozapine dose or use a different antipsychotic if
feasible.
There is very limited comparative efficacy data to support the choice of one treatment for
clozapine-induced hypersalivation over another. In practice the potential risks and benefits of
each option should be considered on an individual basis. Some options have specific risks:
a) Some agents may have additive hypotensive effects with clozapine (e.g. amitriptyline,
terazosin, clonidine, lofexidine). Blood pressure should be monitored in these patients.
b) Some may cause drowsiness (e.g. hyoscine, benzatropine, amitriptyline).
c) Some may cause psychiatric side effects (e.g. depression with clonidine, agitation with
trihexyphenidyl).
d) Antimuscarinic agents will have additive side effects with clozapine so patients should be
observed for worsening of these side effects e.g. constipation (64). Cognitive function may
also be impaired. Pirenzepine, glycopyrronium and ipratropium are believed to have little CNS
penetration. Peripherally, anticholinergics can impair the gag reflex, compromising swallowing
and increasing the risk of aspiration (27).
e) Amitriptyline with clozapine may increase the risk of convulsions.
f) Amisulpride with clozapine may cause hyperprolactinaemia.
The authors of a Cochrane Review concluded that “There are currently insufficient data to
confidently inform clinical practice” and that “Current practice outside of well designed randomised
trials should be clearly justified” (8).
Miscellaneous Drugs Inducing Hypersalivation

Information on the treatment of hypersalivation induced by other drugs is limited to case reports
and management needs to be considered on an individual basis.

The authors of a Cochrane Review of anticholinergic medication for non-clozapine neurolepticinduced hypersalivation in people with schizophrenia were unable to locate any relevant
randomised controlled trials (53). They suggest that further research is required to guide practice.
Available through NICE Evidence Search at www.evidence.nhs.uk
7
Medicines Q&As
Limitations
 There are no major randomised placebo-controlled trials for any drug to treat drug-induced
hypersalivation, so the amount of published evidence is limited. 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 data are not available.
 Most of the studies included small numbers of patients or are case reports.
 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 “standard” method of measurement of salivary flow and outcome presentation is
available.
 None of the drugs investigated are licensed for the management of drug-induced hypersalivation.
The licensed use of antimuscarinic drugs (e.g. glycopyrronium bromide) as premedicants to dry
bronchial and salivary secretions peri-operatively is not included in this Q&A.
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10
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
13th October 2015 (date 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)
 Embase (NICE Evidence): exp*HYPERSALIVATION/si (limited to human and English
language)
 Drugdex (accessed via http://www.micromedexsolutions.com/micromedex2/librarian)
 Electronic Medicines Compendium (accessed via http://www.medicines.org.uk/emc/)
 Cochrane library (accessed via http://www.cochranelibrary.com/)
 NICE Evidence Search (accessed via https://www.evidence.nhs.uk/)
 BNF (accessed via www.medicinescomplete.com )
 NICE (accessed via http://www.nice.org.uk/)
Available through NICE Evidence Search at www.evidence.nhs.uk
11