Drug-Induced Hypersalivation - What Treatment Options Are Available?

Drug-Induced Hypersalivation - What Treatment Options Are Available?

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

Date prepared: 22nd May 2017

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.

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%) (1-3). It usually develops early in treatment, is often more prominent at night, and may reduce compliance (1-4). 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 / Report Descriptions [ref] / Dose of Intervention / Outcome and notes when used in clozapine patients
Antimuscarinics
Amitriptyline oral / (a) Case reports (n=4) [9]
(b) Case report [10]
(c) Case report [11] / (a) 75-100mg per day.
(b) 25mg at night.
(c) 10mg at night / Marked, rapid improvement.
Beware additive side effects (e.g. fits, hypotension) [10,12].
Atropine eye drops 1%sublingually / (a) Case report [13]
(b) Case reports (n=3) [6]
(c) Case report [14]
(d) Case report (atropine solution 1% sublingually)[15] / (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). / (a) Resolution.
(b) “Immediate relief”.
(c) Resolution.
(d) Resolution. Sialorrhoea did not recur following discontinuation of atropine by the patient after 7 days.
Fast relief [6] but may not be sustained [16]; dropper can be hard to use with risk of accidental overdose [16]. Beware additive anticholinergic side effects [14] and bitter taste [17].
Benzatropine oral* / (a) Retrospective chart review (n=60; 15 pts in each of 4 groups) [18]
(b) Case report [19] / (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.
Biperiden oral* / (a) Randomised, double-blind crossover trial vs. glycopyrronium (n=13)[20]
(b) Case report [21] / (a) Biperiden 2mg twice daily vs. glycopyrronium 1mg twice daily.
(b) Uptitrated to 6mg per day. / (a) At 4 weeks, hypersalivation significantly improved vs. baseline, but less than glycopyrronium. Cognitive function reduced.
(b) Hypersalivation eliminated.
Glycopyrronium oral / (a) Randomised, double-blind crossover trial vs. biperiden (n=13)[20]
(b) Case report [22]
(c) Case series (n=3) (aged 13-16) [23]
(d) Case report [24]
(e) Case reports (n=4) [25]
(f) Randomised, double-blind, placebo-controlled trial with extended open-label phase [26] / (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) 1mg at bedtime.
(e) 1mg twice daily (n=3) increased to 2mg tds (n=1).
(f) 1mg at night, increased to 2mg if desired / (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).
(f) Of 10 patients who entered open-label phase, 3 experienced clinically relevant improvement, and 4 experienced some improvement.
Hyoscine butylbromide / Case series (n=5) [27] / Hyoscine butylbromide 30-60mg/day (route of administration not stated). / Objective symptom improvement at 4 weeks. Abdominal air pockets detected at higher dose (n=1). Monitoring for side-effects recommended.
Hyoscine hydrobromide patch/oral / (a) Case reports (n=4) [17]
(b) Case report [28]
(c) Anecdotal [3,4] / (a) Patch (dose not given).
(b) Patch 1.5mg every 72hrs.
(c) 300 microgram tablet nocte increased to tds if necessary, sucked & swallowed. / (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.
Ipratropium bromide nasal spray 0.03% / (a) Randomised, double-blind, placebo-controlled, crossover trial (n=20) [29]
(b) Non-comparative study (n=10) for 6 months [5]
(c) Retrospective non-comparative study (n=9) [30]
(d) Case series (n=10) [16]. Pts failed on sub-lingual 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). / (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.
Oxybutynin oral / Case report [31] / Oxybutynin 5mg daily titrated to 10mg every morning and 5mg nocte then reduced to 5mg bd according to response. / Marked improvement.
Pirenzepine oral* / (a) Randomised, double-blind placebo-controlled cross-over trial (20 Asian patients) [32]
(b) Case reports (n=120) [33]
(c) Non-comparative study (n=29) for 3 days [34] / (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. / (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.
Trihexyphenidyl (benzhexol) hydrochloride oral / (a) Non-comparative study (n=14) for 15 days [35]
(b) Case report with 3 month follow-up [36]
(c) Case report [37] / (a) 5mg nocte, gradually increasing to maximum of 15mg nocte.
(b) 6mg per day in divided doses.
(c) 2mg at night. / (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 [37].
Adrenoceptor Agonists
Clonidine patch/oral / (a) Case series (n=4) [38]
(b) Case series (n=12) [39] 4 weeks treatment / (a) Patch* 100-200 micrograms per week.
(b) Oral 50 micrograms nocte increased to 100 micrograms after 2 weeks if ineffective. / (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 [11,39]. Tolerance may develop [39]. Avoid abrupt cessation [40].
Guanfacine oral / Case report [41] / 1mg in the morning. / Improvement.
Avoid abrupt cessation [42].
Lofexidine oral / Case report [43]. 1 month’s treatment / 200 micrograms bd. / Significant improvement.
Avoid long-term use [43] and abrupt cessation [42]. May exacerbate psychosis and depression [4].
Terazosin oral / Retrospective chart review (n=60) [18] / See benzatropine above.
Beware additive hypotension [40].
Miscellaneous
Amisulpride oral / (a) Randomised, double-blind, placebo-controlled, cross-over study (n=20). 3 wks active treatment [44]
(b) Open-label crossover trial vs. moclobemide (n=53) [45]
(c) Case report; patient also on pirenzepine throughout [46]
(d) Case report with 3 month follow-up [47]
(e) Case report [48] / (a) Amisulpride 100mg/day titrated up to 400mg/day over 1 week.
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. / (a) Statistically significant improvement. Prolactin levels rose in most patients and may need monitoring.
(b) At 2 weeks, 39 improved, 1 worsened and 13 unchanged. Less effective than moclobemide.
(c) Enabled reduced pirenzepine dose. Hyper-salivation markedly improved.
(d) Significant improvement in hypersalivation.
(e) Marked improvement in daytime hypersalivation but night-time hypersalivation still present. Constipation and tachycardia reported.
Bupropion oral / Case report with 300 days follow-up [49]. Previous treatment failure with six other drugs / Bupropion 100mg*/day increased to bupropion SR 150mg/day after 18 days. / Marked improvement in daytime hypersalivation but night-time hypersalivation still present.
Clozapine and bupropion lower the seizure threshold [49].
Metoclopramide oral / Double-blind, randomised, placebo- controlled trial (n=58), 3 wks [50] / 10mg/day, titrated up by 10mg/day per week to max 30mg/day / Statistically significant improvement in hypersalivation and drooling severity. 20 subjects (66.7%) treated with metoclopramide reported significant decline or total disappearance of clozapine-associated hypersalivation vs. 8 patients (28.6%) who received placebo (p=0.031). No adverse effects reported.
Moclobemide oral / (a) Non-comparative study (n=14). Treatment for 2 weeks [51]
(b) Open-label crossover trial vs. amisulpride (n=53) [45] / (a) Moclobemide 150mg/day increased to 300mg/day after 1 week if ineffective.
(b) See amisulpride above. / (a) 9 patients improved; 5 did not.
(b) At 2 weeks, 44 improved and 9 unchanged. More effective than amisulpride.
Sulpiride oral / Non-comparative study (n=18) for 21 days [52] / Sulpiride 150-300mg per day. / Hypersalivation reduced in all patients.
Quetiapine oral / Retrospective chart review (n=158) [53] / Bedtime quetiapine dose as required clinically, plus reduction in clozapine dose by about 25%. / Quetiapine was “beneficial in some patients”. Adding benzatropine or terazosin as well resolved hypersalivation in all patients.
Botulinum toxin A injection / Case report [54] / Botulinum toxin 150 units into each parotid gland. / Beneficial response at 2 weeks still apparent at 12 weeks.

* Not licensed in the UK.

Miscellaneous Drugs Inducing Hypersalivation

The authors of a Cochrane Review of anticholinergic medication for non-clozapine neuroleptic-induced hypersalivation in people with schizophrenia were unable to locate any relevant randomised controlled trials (55). They suggest that further research is required to guide practice.

Table 2 - Hypersalivation Caused by Other Medicines with Drug Interventions Used.

Drug causing hypersalivation / Report Details [ref] / Intervention / Outcome
Aripiprazole / Case report [56] / Oral trihexyphenidyl 2mg daily. / Significant reduction in hypersalivation.
Risperidone oral / (a) Case report [57]
(b) Case report [58]
(c) Case report (age 14) [59] / (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. / (a) Rapid and marked improvement.
(b) Full remission of hypersalivation.
(c) Hypersalivation markedly decreased.
Quetiapine / Case report [60] / Oral benzatropine* 1mg twice daily.
Atropine eye drops 0.1% sublingually. / No improvement with benzatropine and atropine so quetiapine discontinued and hypersalivation resolved.
Bethanechol / Case report with 4 mth follow-up [61] / Ipratropium bromide MDI 2 puffs every 6 hrs onto buccal mucosa. / Significant symptomatic improvement.
Irinotecan plus oxaliplatin / Case report [62] / Subcutaneous atropine (no dose given). / Resolution.
Oxaliplatin might potentiate irinotecan’s cholinergic effects [63] so prophylaxis has been given (atropine 250 micrograms subcutaneously) a few minutes before irinotecan [64].
Lithium / Case report [65] / Propantheline bromide 15mg bd. / Satisfactory relief.

*Not licensed in the UK.

Summary

Clozapine-Induced Hypersalivation

There are currently no drug treatments licensed for the management of clozapine-induced hypersalivation. However a number of agents are suggested in the literature. The limited evidence for their efficacy and safety is summarised in this Q&A.

If hypersalivation is troublesome, reduce clozapine dose or use a different antipsychotic if feasible.

There are 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.

The potential for interactions with clozapine should be carefully considered, including additive effects such as hypotension, prolongation of the QT interval, central nervous system effects (e.g. drowsiness, seizures), and antimuscarinic effects.

It should also be considered that some treatments may cause psychiatric side effects (e.g. depression with clonidine, confusion and hallucinations with hyoscine hydrobromide, agitation with trihexyphenidyl).

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”.

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 neuroleptic-induced hypersalivation in people with schizophrenia were unable to locate any relevant randomised controlled trials). They suggest that further research is required to guide practice.

Limitations

To date 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 include 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.

References

  1. Szabadi E, Tavernor S. Hypo- and hypersalivation induced by psychoactive drugs: Incidence, mechanisms and therapeutic implications. CNS Drugs 1999;11(6):449-466.
  2. Bird AM, Smith TL, Walton AE. Current treatment strategies for clozapine-induced sialorrhea. Ann Pharmacother 2011;45:667-75.
  3. Praharaj SK, Arora M and Gandotra S. Clozapine-induced sialorrhea: pathophysiology and management strategies. Psychopharmacology 2006;185:265-273.
  4. Taylor D, Paton C, Kapur S. The South London and Maudsley NHS Foundation Trust, Oxleas NHS Foundation Trust. The Maudsley Prescribing Guidelines in Psychiatry. 12th Edition. Chichester, Wiley Blackwell; 2015 pp165, 174-176.
  5. Calderon J, Rubin E, Sobota WL. Potential use of ipratropium bromide for the treatment of clozapine-induced hypersalivation: a preliminary report. Int Clin Psychopharmacol 2000;15:49-52.
  6. Antonello C, Tessier P. Clozapine and sialorrhea: A new intervention for this bothersome and potentially dangerous side effect (letter). J Psychiatry Neurosci 1999;24(3):250.
  7. Davydov L, Botts SR. Clozapine-induced hypersalivation. Ann Pharmacother 2000;34:662-665.
  8. Syed R, Au K, Cahill C, Duggan L, He Y, Udu V, Xia J. Pharmacological interventions for clozapine-induced hypersalivation. Cochrane Database of Systematic Reviews 2008, Issue 3. Art. No.: CD005579. DOI: 10.1002/14651858.CD005579.pub2. Accessed 3rd April 2017 via
  9. Copp PJ, Lament R, Tennent TG. Amitriptyline in clozapine-induced sialorrhoea (letter). Br J Psychiatry 1991;159:166.
  10. Praharaj SK, Arora M. Amitriptyline for clozapine-induced nocturnal enuresis and sialorrhoea (letter). Br J Clin Pharmacol 2007;63(1):128-129.
  11. Sinha S, Simlai J, Praharaj SK. Very low dose amitriptyline for clozapine-associated sialorrhea. Current Drug Safety 2016; 11(3): 262-263
  12. Rogers DP, Shramko JK. Therapeutic options in the treatment of clozapine-induced sialorrhea. Pharmacotherapy 2000;20(9):1092-1095.
  13. Comley C, Galletly C, Ash D. Use of atropine eye drops for clozapine induced hypersalivation (letter). Aust N Z J Psychiatry 2000;34:1033-1034.
  14. Sharma A, Ramaswamy S, Dahl E et al. Intraoral application of atropine sulfate ophthalmic solution for clozapine-induced sialorrhea (letter). Ann Pharmacother 2004;38:1538.
  15. Mustafa FA, Khan A, Burke J et al. Sublingual atropine for the treatment of severe and hyoscine-resistant clozapine-induced sialorrhea (letter). Afr J Psychiatry 2013;16:236-242.
  16. Tessier P, Antonello C. Clozapine and sialorrhea: update (letter). J Psychiatry Neurosci 2001;26(3): 253.
  17. McKane JP, Hall C, Akram G. Hyoscine patches in clozapine-induced hypersalivation (letter). Psychiatric Bulletin 2001;25(7):277.
  18. Reinstein MJ, Sirotovskaya LA, Chasanov MA et al. Comparative efficacy and tolerability of benzatropine and terazosin in the treatment of hypersalivation secondary to clozapine. Clinical Drug Investigation 1999;17(2):97-102.
  19. Bourgeois JA, Drexler KG, Hall MJ. Hypersalivation and clozapine (letter). Hospital and Community Psychiatry 1991;42(11):1174
  20. Liang C-S, Ho P-S, Shen L-J et al. Comparison of the efficacy and impact on cognition of glycopyrrolate and biperiden for clozapine-induced sialorrhea in schizophrenic patients: a randomized, double-blind, crossover study. Schizophr Res 2010;119:138-144.
  21. Richardson C, Kelly DL, Conley RR. Biperiden for excessive sweating from clozapine (letter). Am J Psychiatry 2001;158(8):1329-1330.
  22. Duggal HS. Glycopyrrolate for clozapine-induced sialorrhea (letter). Prog Neuro-Psychopharmacol Biol Psychiatry 2007;31:1546-1547.
  23. Robb AS, Lee RH, Cooper EB et al. Glycopyrrolate for treatment of clozapine-induced sialorrhea in three adolescents. J Child Adolesc Psychopharmacol 2008;18(1):99-107.
  24. Praharaj SK, Munoli RN, Sharma PSVN. Low-dose glycopyrrolate for clozapine-associated sialorrhea (letter). J Clin Psychopharmacol 2014;34(3):392.
  25. Blissit KT, Tillery E, Latham C et al. Glycopyrrolate for treatment of clozapine-induced sialorrhea in adults. Am J Health-Syst Pharm 2014;71:1282-1287.
  26. Colen-De Koning JCA, Man WH, Wilting I, et al. The effect of glycopyrronium bromide on nocturnal clozapineinduced sialorrhoea in psychiatric patients. Pharmaceutisch Weekblad 2015; 150(43):219-222
  27. Takeuchi I, Suzuki T, Kishi T et al. Effect of scopolamine butylbromide on clozapine-induced hypersalivation in schizophrenic patients: a case series. Clinical Psychopharmacology and Neuroscience 2015;13(1):109-112.
  28. Gaftanyuk O, Trestman RL. Scopolamine patch for clozapine-induced sialorrhea (letter). Psychiatr Serv 2004;55(3):318.
  29. Sockalingam S, Shammi C, Remington G. Treatment of clozapine-induced hypersalivation with ipratropium bromide: a randomized, double-blind, placebo-controlled crossover study. J Clin Psychiatry 2009;70(8):1114-1119.
  30. Freudenreich O, Beebe M, Goff DC. Clozapine-induced sialorrhea treated with sublingual ipratropium spray: A case series (letter). J Clin Psychopharmacol 2004;24(1):98-100
  31. Leung JG, Puri NV, Jacobson MJ. Immediate-release oxybutynin for the treatment of clozapine-induced sialorrhea. Ann Pharmacother 2011;45:e45
  32. Bai Y-M, Lin C-C, Chen J-Y et al. Therapeutic effect of pirenzepine for clozapine-induced hypersalivation: A randomized, double-blind, placebo-controlled, cross-over study. J Clin Psychopharmacol 2001;21(6):608-611
  33. Fritze J, Elliger T. Pirenzepine for clozapine-induced hypersalivation (letter). Lancet 1995;346:1034
  34. Schneider B, Weigmann H, Hiemke C et al. Reduction of clozapine-induced hypersalivation by pirenzepine is safe. Pharmacopsychiatry 2004;37:43-45
  35. Spivak B, Adlersberg S, Rosen L et al. Trihexyphenidyl treatment of clozapine-induced hypersalivation. Int Clin Psychopharmacol 1997;12:213-215
  36. Aggarwal A, Garg A, Jiloha R. Trihexyphenidyl (benzhexol) in clozapine-induced nocturnal enuresis and sialorrhea (letter). Indian J Med Sci 2009;63(10):470
  37. Praharaj SK, Sarkhel S, Khanande RV et al. Complete resolution of clozapine-induced sialorrhea with low dose trihexyphenidyl. Psychopharmacol Bull 2010;43(4):73-75
  38. Grabowski J. Clonidine treatment of clozapine-induced hypersalivation (letter). J Clin Psychopharmacol 1992;12(1):69-70
  39. Praharaj SK, Verma P, Roy D et al. Is clonidine useful for treatment of clozapine-induced sialorrhea? J Psychopharmacol 2005;19(4):426-428
  40. Joint Formulary Committee. British National Formulary (online). London: BMJ Group and Pharmaceutical Press. Accessed 3rd May 2017 via
  41. Webber MA, Szwast SJ, Steadman TM et al. Guanfacine treatment of clozapine-induced sialorrhea (letter). J Clin Psychopharmacol 2004;24(6):675-676
  42. Anon. Guanfacine treatment of clozapine-induced sialorrhea. Primary Psychiatry 2005;12(2):23-24
  43. Corrigan FM, MacDonald S, Reynolds GP. Clozapine-induced hypersalivation and the alpha2 adrenoceptor (letter). Br J Psychiatry 1995;167:412
  44. Kreinin A, Novitski D, Weizman A. Amisulpride treatment of clozapine-induced hypersalivation in schizophrenia patients: a randomized, double-blind, placebo-controlled cross-over study. Int Clin Psychopharmacol 2006;21:99-103
  45. Kreinin A, Miodownik C, Sokolik S et al. Amisulpride versus moclobemide in treatment of clozapine-induced hypersalivation. The World Journal of Biological Psychiatry 2011;12:620-626
  46. Croissant B, Hermann D, Olbrich R. Reduction of side effects by combining clozapine with amisulpiride: case report and short review of clozapine-induced hypersalivation. A case report. Pharmacopsychiatry 2005;38:38-39
  47. Praharaj SK, Sarkar S, Sinha VK. Amisulpride treatment for clozapine-induced sialorrhea (letter). J Clin Psychopharmacol 2009;29(2):189-190
  48. Praharaj SK, Ray P, Gandotra S. Amisulpride improved debilitating clozapine-induced sialorrhea. American Journal of Therapeutics 2011;18(3):e84-e85
  49. Stern RG, Bellucci D, Cursi-Vogel N et al. Clozapine-induced sialorrhea alleviated by bupropion – a case report (letter). Prog Neuropsychopharmacol Biol Psychiatry 2009;33:1578-1580
  50. Kreinin A, Miodownik C, Mirkin V, et al. Double-blind, randomized, placebo-controlled trial of metoclopramide for hypersalivation associated with clozapine. J Clin Psychopharmacol 2016; 36(3):200-205
  51. Kreinin A, Miodownik C, Libov I et al. Moclobemide treatment of clozapine-induced hypersalivation: pilot open study. Clin Neuropharmacol 2009;32(3):151-153
  52. Kreinin A, Epshtein S, Sheinkman A et al. Sulpiride addition for the treatment of clozapine-induced hypersalivation: preliminary study. Israel Journal of Psychiatry and Related Sciences 2005;42(1):61-63
  53. Reinstein MJ, Sonnenberg JG, Mohan SC et al. Use of quetiapine to manage patients who experienced adverse effects with clozapine. Clinical Drug Investigation 2003;23(1):63-67
  54. Kahl KG, Hagenah J, Zapf S et al. Botulinum toxin as an effective treatment of clozapine-induced hypersalivation (letter). Psychopharmacology 2004;173:229-230
  55. Essali A, Rihawi A, Altujjar M, Alhafez B, Tarboush A, Alhaj Hasan N. Anticholinergic medication for non-clozapine neuroleptic-induced hypersalivation in people with schizophrenia. Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.: CD009546. DOI: 10.1002/14651858.CD009546.pub2. Accessed 3rd April 2017 via
  56. Praharaj SK, Jana AK, Sinha VK. Aripiprazole-induced sialorrhea (letter). Prog Neuropsychopharmacol Biol Psychiatry 2009;33:384-385
  57. Gajwani P, Franco-Bronson K, Tesar GE. Risperidone-induced sialorrhea (letter). Psychosomatics 2001;42(3):276
  58. Panagiotidis PT, Fountoulakis KN, Siamouli M et al. Risperidone-induced sialorrhea responsive to biperiden treatment. Schizophr Res 2007;93:410-411
  59. Usta MG, Tufan AE, Cüceloğlu EA. Diphenhydramine use in the treatment of risperidone-induced sialorrhea (letter). J Child Adolesc Psychopharmacol 2012;22(3):254-255
  60. Allen S, Hoffer Z, Mathews M. Quetiapine-induced hypersalivation (letter). Primary Care Companion Journal of Clinical Psychiatry 2007;9(3):233
  61. Kunwar AR, Doufekias E, Nihalani N et al. Ipratropium bromide for treatment of bethanechol-induced sialorrhea (letter). Ann Pharmacother 2003;37:1343
  62. Valencak J, Raderer M, Kornek GV et al. Irinotecan-related cholinergic syndrome induced by coadministration of oxaliplatin (letter). J Natl Cancer Inst 1998;90(2):160
  63. Dodds HM, Bishop JF, Rivory LP. More about: Irinotecan-related cholinergic syndrome induced by coadministration of oxaliplatin (letter). Journal of the National Cancer Institute 1999;91(1):91-92
  64. Cvitkovic E, Marty M, Wasserman E et al. Re: Irinotecan-related cholinergic syndrome induced by coadministration of oxaliplatin (letter). Journal of the National Cancer Institute 1998;90(13):1016-7
  65. Donaldson SR. Sialorrhea as a side effect of lithium: a case report. Am J Psychiatry 1982;139(10):1350-1351

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).

Top View