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. 2022 May 20;5(5):CD006981.
doi: 10.1002/14651858.CD006981.pub3.

Treatment for sialorrhea (excessive saliva) in people with motor neuron disease/amyotrophic lateral sclerosis

Eleanor James  1 , Cathy Ellis  2 , Ruth Brassington  3 , Sivakumar Sathasivam  4 , Carolyn A Young  4
Affiliations

Treatment for sialorrhea (excessive saliva) in people with motor neuron disease/amyotrophic lateral sclerosis

Eleanor James et al. Cochrane Database Syst Rev. .

Abstract

Background: Motor neuron disease (MND), also known as amyotrophic lateral sclerosis (ALS), is a progressive neurodegenerative condition that may cause dysphagia, as well as limb weakness, dysarthria, emotional lability, and respiratory failure. Since normal salivary production is 0.5 L to 1.5 L daily, loss of salivary clearance due to dysphagia leads to salivary pooling and sialorrhea, often resulting in distress and inconvenience to people with MND. This is an update of a review first published in 2011.

Objectives: To assess the effects of treatments for sialorrhea in MND, including medications, radiotherapy and surgery.

Search methods: On 27 August 2021, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, AMED, CINAHL, ClinicalTrials.gov and the WHO ICTRP. We checked the bibliographies of the identified randomized trials and contacted trial authors as needed. We contacted known experts in the field to identify further published and unpublished papers.

Selection criteria: We included randomized controlled trials (RCTs) and quasi-RCTs, including cross-over trials, on any intervention for sialorrhea and related symptoms, compared with each other, placebo or no intervention, in people with ALS/MND.

Data collection and analysis: We used standard methodological procedures expected by Cochrane.

Main results: We identified four RCTs involving 110 participants with MND who were described as having intractable sialorrhea or bulbar dysfunction. A well-designed study of botulinum toxin B compared to placebo injected into the parotid and submandibular glands of 20 participants showed that botulinum toxin B may produce participant-reported improvement in sialorrhea, but the confidence interval (CI) was also consistent with no effect. Six of nine participants in the botulinum group and two of nine participants in the placebo group reported improvement (risk ratio (RR) 3.00, 95% CI 0.81 to 11.08; 1 RCT; 18 participants; low-certainty evidence). An objective measure indicated that botulinum toxin B probably reduced saliva production (in mL/5 min) at eight weeks compared to placebo (MD -0.50, 95% CI -1.07 to 0.07; 18 participants, moderate-certainty evidence). Botulinum toxin B may have little to no effect on quality of life, measured on the Schedule for Evaluation of Individual Quality of Life direct weighting scale (SEIQoL-DW; 0-100, higher values indicate better quality of life) (MD -2.50, 95% CI -17.34 to 12.34; 1 RCT; 17 participants; low-certainty evidence). The rate of adverse events may be similar with botulinum toxin B and placebo (20 participants; low-certainty evidence). Trialists did not consider any serious events to be related to treatment. A randomized pilot study of botulinum toxin A or radiotherapy in 20 participants, which was at high risk of bias, provided very low-certainty evidence on the primary outcome of the Drool Rating Scale (DRS; range 8 to 39 points, higher scores indicate worse drooling) at 12 weeks (effect size -4.8, 95% CI -10.59 to 0.92; P = 0.09; 1 RCT; 16 participants). Quality of life was not measured. Evidence for adverse events, measured immediately after treatment (RR 7.00, 95% CI 1.04 to 46.95; 20 participants), and after four weeks (when two people in each group had viscous saliva) was also very uncertain. A phase 2, randomized, placebo-controlled cross-over study of 20 mg dextromethorphan hydrobromide and 10 mg quinidine sulfate (DMQ) found that DMQ may produce a participant-reported improvement in sialorrhea, indicated by a slight improvement (decrease) in mean scores for the primary outcome, the Center for Neurologic Study Bulbar Function Scale (CNS-BFS). Mean total CNS-BFS (range 21 (no symptoms) to 112 (maximum symptoms)) was 53.45 (standard error (SE) 1.07) for the DMQ treatment period and 59.31 (SE 1.10) for the placebo period (mean difference) MD -5.85, 95% CI -8.77 to -2.93) with a slight decrease in the CNS-BFS sialorrhea subscale score (range 7 (no symptoms) to 35 (maximum symptoms)) compared to placebo (MD -1.52, 95% CI -2.52 to -0.52) (1 RCT; 60 participants; moderate-certainty evidence). The trial did not report an objective measure of saliva production or measure quality of life. The study was at an unclear risk of bias. Adverse events were similar to other trials of DMQ, and may occur at a similar rate as placebo (moderate-certainty evidence, 60 participants), with the most common side effects being constipation, diarrhea, nausea, and dizziness. Nausea and diarrhea on DMQ treatment resulted in one withdrawal. A randomized, double-blind, placebo-controlled cross-over study of scopolamine (hyoscine), administered using a skin patch, involved 10 randomized participants, of whom eight provided efficacy data. The participants were unrepresentative of clinic cohorts under routine clinical care as they had feeding tubes and tracheostomy ventilation, and the study was at high risk of bias. The trial provided very low-certainty evidence on sialorrhea in the short term (7 days' treatment, measured on the Amyotrophic Lateral Scelerosis Functional Rating Scale-Revised (ALSFRS-R) saliva item (P = 0.572)), and the amount of saliva production in the short term, as indicated by the weight of a cotton roll (P = 0.674), or daily oral suction volume (P = 0.69). Quality of life was not measured. Adverse events evidence was also very uncertain. One person treated with scopolamine had a dry mouth and one died of aspiration pneumonia considered unrelated to treatment.

Authors' conclusions: There is some low-certainty or moderate-certainty evidence for the use of botulinum toxin B injections to salivary glands and moderate-certainty evidence for the use of oral dextromethorphan with quinidine (DMQ) for the treatment of sialorrhea in MND. Evidence on radiotherapy versus botulinum toxin A injections, and scopolamine patches is too uncertain for any conclusions to be drawn. Further research is required on treatments for sialorrhea. Data are needed on the problem of sialorrhea in MND and its measurement, both by participant self-report measures and objective tests. These will allow the development of better RCTs.

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Conflict of interest statement

Dr E James: none

Dr C Ellis: none.

Dr R Brassington: none. She is Managing Editor of Cochrane Neuromuscular. She joined the author team before peer review and was not thereafter involved in editorial assessment.

Dr S Sathasivam: received consultancy fees from UCB Pharma regarding research in myasthenia gravis. He has received a fee from Argenx to write a review on Real World Evidence of Myasthenia Gravis treatment. UCB Pharma and Argenx do not manufacture interventions currently of interest for the treatment of sialorrhea in MND. Dr Sathasivam has received consultancy fees from Merz for help in developing a protocol to manage sialorrhoea.

Prof CA Young has lectured at commercially‐sponsored meetings and participated in advisory boards funded by pharmaceutical companies, though never on sialorrhea in MND. She has grants on quality of life in MND funded by the Motor Neurone Disease Association, on quality of life in MS funded by the Multiple Sclerosis Society and pharmaceutical companies, and on quality of life in stroke funded by the NIHR grants; employer paid for multicenter trial work on taurousodeoxycholic acid sponsored by Irccs Istituto Nazionale Tumori‐Fondazione Pascale, tirasemtiv sponsored by Cytokinetics and ODM‐109 sponsored by Orion. Consultancy fees: Merck, Wellcome Trust, Roche, Teva, Novartis, Med Day, GW Pharmaceuticals and Actelion. Payment for lectures: Novartis, Merck, Sanofi Genzyme, Roche, Cytokinetics, MS Academy, and Teva. Travel/accommodation/meeting expense reimbursement: Biogen, Roche, and Teva. Reports on patient care for health service ombudsman. Unpaid work for patient charities: Darby Rimmer Foundation and My Name'5 Doddie. Payments direct to employer from various companies and educational providers for various teaching, reports, and meetings (no personal records).

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study. Green = low risk of bias; yellow = unclear risk of bias; red = high risk of bias ; blank = not applicable
1.1
1.1. Analysis
Comparison 1: Botulinum toxin injection versus placebo, Outcome 1: Number of participants reporting improvement
1.2
1.2. Analysis
Comparison 1: Botulinum toxin injection versus placebo, Outcome 2: Volume of saliva mL in 5 min (final values)
1.3
1.3. Analysis
Comparison 1: Botulinum toxin injection versus placebo, Outcome 3: SEIQOL‐DW (0‐100) (final values)
2.1
2.1. Analysis
Comparison 2: Radiotherapy versus botulinum toxin, Outcome 1: Adverse events
3.1
3.1. Analysis
Comparison 3: Dextromethorphan and quinidine sulfate combination (DMQ) versus placebo, Outcome 1: CNS‐BFS score
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References

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