A Comparative Study of The Efficacy and Safety of Different Pharmacological Forms of Cholinolytics And Botulinum Therapy at Sialorrhea In Patients with Amyotrophic Lateral Sclerosis

G.N Levitsky ^1,2, AS Levitsky ³, A G Sanadze  ^4
1Nina Levitskaya Russian Charity ALS Foundation, Moscow,
² Gleb Levitsky clinic, Moscow
³ Private Psychiatrist, Narcologist and Psychotherapist, Moscow
⁴ Myasthenia Center, Moscow
*Corresponding author: Gleb Levitsky, Nina Levitskaya Russian Charity ALS Foundation, Moscow
Citation: Gleb Levitsky (2022) A Comparative Study of The Efficacy and Safety of Different Pharmacological Forms of Cholinolytics And Botulinum Therapy at Sialorrhea In Patients with Amyotrophic Lateral Sclerosis 1(1)
Copyright: ©2022 Gleb Levitsky, This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Received:03 June 2022|Accepted:10 July 2022|Published:25 July 2022
Keywords: botulinum therapy, sialorrhea, amyotrophic lateral sclerosis, dysphagia, dysarthria frontotemporal dementia

ABSTRACT

Efficiency and safety of botulinum therapy (250U Dysport + Amitriptyline 25 mg/d and 500U Dysport) and different pharmacological forms of cholinolytics (Atropini sulfatis drops separately or with Ipratropium bromide (later Atrovent) solution for oral hygiene, Amitriptiline 25 mg/d separately or with Atrovent and Atropine, Scopoderm plaster and Buscopan 40 mg/d) were assessed in 70 patients with amyotrophic lateral sclerosis with bulbar impairment and consequential entry to different study groups. Objective assessment was made by gravimetry of saliva before, 3 days after (for Dysport) and 3 months later for all patient/drug groups. Montreal Cog and Frontotemporal Dysfunction Score were estimated in parallel. The cholinolytic cocktail of Atropine, Atrovent and Amitriptiline had no significant influence on Sialorea(2,09±1,3 и 1,24±0,84 ml/5 min;p=0,083), but had a reversible negative effect of cognitive functions(23,1±2,4, 18,1±1,4* и 21±2,1 degrees;p<0.05). Being administered separately those drugs showed neither significant influence on sialorea, nor on cognitive function, as well as selective peripheral cholinolytic Buscopan (1,79±1,26 и 0,87±0,57 ml/5 min p=0.061). Scopoderm plaster significantly decreased Sialorea(2,14±1,2 и 0,63±0,25 ml/5 min; p=0,03), but significantly and reversibly decreased cognitive performance(25,9±1,9, 17,3±2,1* и 23,3±1,9 degrees; p=0,03). The combination of Dysport 250U and Amitriptiline 25 mg significantly decreased Sialorea (2,45±1,39 и 1,19±0,99 ml/5 min;р=0,048) with neither effect of cognition, nor on speech. 500 U Dysport significantly decreased Sialorea (2,69±0,76 и 1,37±0,42 ml/5 min;р=0,02) in both dysarthric amd anarthric patients, but speeded up anarthria in the former (82±22 и 36±6 days, р=0,019), so is safe in such dose only in bulbar ALS patients with anarthria.

Introduction

Sialorrhea at amyotrophic lateral sclerosis (ALS) develops approximately in 50-67% of cases according to the data of different authors (1,2). Sialorrhea in ALS is caused by disturbance of automatic swallowing of saliva. It is important to treat this condition because: 1) aspiration with saliva is possible (and aspiration pneumonia is fatal in 50% of cases); 2) worsening of dysphagia and dysarthria at uncontrolled sialorrhea can occur (“unclear speech”, inflammatory changes in the oral cavity); 3) appearance of a person with leaking saliva is associated in people with dementia, however, only 5% of ALS patients suffer from frontotemporal dementia with approximately 20% of ALS patients being diagnosed with progressing frontotemporal dysfunction, and, consequently, the understanding of this aspect by the majority of patients with preserved cognitive functions decreases their quality of life and self-esteem causing additional anxiety and depression (3.4). It is necessary to note that it is more correct to consider not sialorrhea at ALS, but the syndrome of oral hypersecretion (SOH), as the liquid leaking from the ALS patient’s mouth contains, apart from saliva, tracheal bronchial secretions, expectoration of which also becomes abnormal (3).

In the healthy human organism, about 2.5 l of saliva is excreted and approximately 600 automatic acts of its swallowing take place daily. Normal values of salivation according to the data of gravimetry of saliva in a healthy person are 0.5-1.5 ml/5 minutes. It is believed that at ALS it is necessary to decrease sialorrhea even at the normal value of salivation because of the risk of aspiration with saliva (1,3,5).

At ALS, prophylactic, pharmacological, surgical, mechanical and radiotherapeutic approaches to the treatment of sialorrhea are possible. Preventive methods include maintaining of the vertical head position, sanation of the oral cavity with antiseptic solutions, exercises for strengthening of the orbicular muscle of the mouth, withdrawal of anticholinesterase drugs as well as decrease of consumption of cultured milk products by the patient (3). Pharmacological methods include: 1) administration of cholinolytics: а) with central and peripheral cholinolytic effect – eye drops with Atropine sulfate orally, oral rinsing with Ipratropium bromide (Atrovent), Amitriptyline orally, application of Scopoderm plasters (Novartis), administration of neuroleptics in the form of drops (for example, risperidone and Periciazine (Neuleptil), б) administration of Buscopan – a drug without central cholinolytic effect); 3) application of the cytostatic agent fluorouracil on salivary glands; 4) subcutaneous injections of botulinic toxin (4, 6-8). Mechanical methods include sanation of oral cavity using a portable electric aspirator. Surgical methods include unilateral tympanotomy, removal of one and more salivary glands, laser intraductal coagulation of salivary gland excretory ducts, transposition or bilateral intraoral ligation of salivary gland excretory ducts (with efficacy being discussed) as well as introduction of botulinic toxin (Dysport, 40U) directly in salivary glands under the control of ultrasound examination, which helps to improve the quality of life of ALS patients (8, 9). Radiotherapy is represented by the method of single irradiation of salivary glands at the dose of 6-7 Gray, the interval of procedure repetition is not established (5). These methods presumably can be combined, with the exception of botulinum therapy and irradiation, as X-rays destroy botulinic toxin.

ALS is a progressive neurodegenerative disease characterized by increase of the salivation degree at intensification of bulbar syndrome as well as low compliance of patients (8.10). Possibly, this is the reason for the small number of clinical trials of treatment methods for sialorrhea being mostly open and comparative. It has been demonstrated that cholinolytics are effective only in 70% of ALS patients, in other cases alternative treatment methods are indicated (7).

No clinical trials of Amitriptyline in the aspect of influencing sialorrhea at ALS have been performed, however, the International Treatment Standard for ALS of the American Academy of Neurologists (2002) contains a C-level recommendation (expert opinion) for this drug (11). The later version of this document (2009) also contains a C-level recommendation for the drug Scopoderm (Novartis) (12). The clinical trial of subcutaneous injections of Dysport at the dose of 250U revealed efficacy and safety of the drug under the control of gravimetry and radioisotopic scintigraphy of parotid salivary glands during a month, at that the response of patients using the analogue-visual scale, the number of applications of a handkerchief per hour before and after the treatment also assessed (6). The clinical study of Dysport introduced at the dose of 250U in the parotid salivary glands under the control of ultrasound examination demonstrated efficacy and safety of the drug for 3 months, at the same time, in the earlier work of other authors it was reported that introduction of Dysport in glands without the ultrasound control caused complication in a number of ALS patients in the form of cellulitis of the mandibular area and calculous sialoadenitis (9, 13).

In the previous work of the author of this article (G.N.L.) in 2006, efficacy and safety of Dysport at the dose of 250U 3 days after injections, efficacy of Amitriptyline at the dose of 25-37.5 mg before night sleep for 2-3 weeks of therapy in presence of adverse effects in the majority of patients, as well as efficacy and good tolerability of the combination of Dysport at the dose of 250U and Amitriptyline at the dose of 12.5 mg before night sleep with evaluation using gravimetry and radioisotopic scintigraphy of salivary glands before and one month after the treatment commencement were demonstrated in a small group of patients with bulbar onset of ALS (14). However, the long-term efficacy and safety of this treatment were not assessed.

No sufficient information about the safety of sialorrhea therapy with cholinolytic drugs and botulinic toxin is available at present. In the own study, the author of this work demonstrated that Amitriptyline caused adverse effects at the dose of 25 mg a day before night sleep, specifically dry mouth, abnormality of accommodation, constipation, somnolence, urinary retention, at that the decrease of its dose and the combination with a subcutaneous injection of Dysport was effective and safe during one month of therapy (14). Cholinolytics are contraindicated to patients with ALS with concomitant adenoma of the prostate and closed angle glaucoma (7). Negative effects of drugs of botulinic toxin on the function of external respiration and speech in ALS patients are not found in the literature.It is also known that cholinolytic drugs with central and peripheral mechanisms of action can suppress cognitive functions at chronic use (15). The assessment of cognitive functions of ALS patients in the follow up manner during administration and/or withdrawal of cholinolytics has not been previously performed.

There are different opinions relative to the role of pharmacological suppression of cognitive functions at ALS. Some experts consider that it leads to the refusal of patients from aggressive treatment methods, and it indirectly deteriorates the quality of life of their families, and others suppose that it plays a positive role decreasing the degree of expression of anxiety and depression in patients refusing aggressive palliative therapy being in a good sense, but not by the reason of an emotional defect. It is probable that both items are true for certain individual cases as the decision about performance of aggressive palliative therapy at ALS (early tracheostomy, gastrostomy) depends on not only patients themselves, but emotional, physical and material resources of their families (16).

A comparative study of the efficacy and safety of different pharmacological forms of cholinolytics and botulinum therapy for the treatment of sialorrhea at ALS was an objective of this study.

Materials and Methods

The study was performed in Moscow Municipal Ambulatory №144, Moscow Myasthenia Center and Gleb Levitsky clinic with support of Nina Levitskaya Russian Charity ALS Foundation. The study was approved by the Ethical committee of the Centrosoyuz hospital in Moscow.

Seventy ALS patients with bulbar impairment and sialorrhea were assessed (30 men, 40 women, age 39-74 years old, mean age 55±10.9 years old, 55 bulbar onsets, 15 spinal onsets). The diagnosis of ALS was made by the Revised El-Escorial Criteria 1998 with obligatory confirmation by needle electromyography and stimulation electroneuromyography and comparison of results with the Lambert and Airlie House criteria, based on the exclusion of other diseases with similar symptoms by neurovisualization of the central nervous system (17, 18). All patients were informed about prophylactic methods of sialorrhea correction; gravimetry of saliva and assessment of cognitive functions using the Montreal Scale and Scale of frontotemporal dysfunction were performed (19, 20). For gravimetry carrying out, gauze pads were made and weighed using the electronic scales Sartorius CP225D, Germany, with the division value of 0.01 mg. The patients were asked to put 2 pads into the mouth and keep for 5 minutes. After that, the pads were removed and weighed again. The mass of produced saliva was calculated by subtraction of the mass of a dry pad from the mass of the same pad saturated with saliva in ml/5 min (14). The assessment using the Montreal Scale in 7 patients unable to write did not include the graphic test for programming, the test for clock copying and depicting, and in 54 cases of anarthria, the evaluation was conducted with the change of verbal tests (oral counting, repetition of figures, sentences and phonetic activities) by written tests. The assessment on the frontotemporal dysfunction score was performed by interviewing of a relative or a person taking care of the patient and living together with the patient (20). In ALS patients with dysarthria, the terms of anarthria development from the moment of enrollment in the study were calculated, at that, only patients with comparable duration of anarthria were juxtaposed. The case history collection preceded inclusion in the study. Therapy with cholinolytics was not recommended for patients with closed angle glaucoma and/or adenoma of the prostate gland, they were informed about contraindications, at that, botulinic toxin therapy was urgently recommended for them. Ten patients were examined at home by the private psychiatrist A.S. Levitsky.
The study design was sequential, what envisaged testing of several drugs in the same patients, a part f them being lost for the follow up observation due to death, refusal to continue to  participate in the study, technical impossibility of the study performance (patient’s long stay out of town). The interval for the follow up observation was 3 days and 3 months for Dysport and 3 months for other drugs and their combinations.

Thirteen patients received Atropine sulfate in 1% mouth drop solution by 2 drops in each corner of the mouth 3 times a day 15 minutes before food intake (Group A), the follow up assessment was performed for nine from them (22 observations in total, dropout 30%).

Afterwards, 3 months later, I n addition to Atropine drops before meal, washing with the solution of Ipratropium bromide (Atrovent) in dose of 0.25 mg/ml and 5 ml 3 times a day 15 minutes after meal were prescribed for these 9 patients. Atropine drops before meal and Atrovent after meal were administered simultaneously for four new patients, and, thus, Group B was formed (n=13). The follow up assessment was performed for only seven patients from this group (20 observations in total, dropout 46%).

Group C included 20 newly recruited patients with prescription of Amitriptyline in dose of 25 mg before night sleep orally. The follow up assessment was performed for only 15 patients from this group (35 observations in total).

After that, for 15 patients from Group C (Amitriptyline) Atropine and Atrovent were additionally prescribed, and for 7 patients from Group B (Atropine, Atrovent) –Amitriptyline was added, at that 11 more new patients were additionally recruited, for which Atropine, Atrovent and Amitriptyline were prescribed simultaneously, and, thus, Group D was formed (n=33). The follow up assessment was performed for only 17 patients from this group (50 observations in total, dropout 51%). In Group D, the percentage of dropout was connected, mostly, with the refusal from further participation in the trial due to the feeling of inefficiency of the therapy and/or adverse events (including cognitive impairment), however, we managed to persuade 8 patients to re-enter the study due to purchasing Dysport by Nina Levitskaya Russian Charity ALS Foundation - 19 ampules of 500U for continuation of the study.

After signing the Informed Consent, Dysport (dry powder diluted in 2.5 ml of physiological solution for obtaining the concentration of 200U of Dysport per 1 ml) was injected by insulin syringes, where 0.1 ml corresponded to 3.5 scale divisions (20U), if after the traction blood was absent in a syringe (14). In those 8 patients cognitive functions were assessed 3 months after the cholinolytic cocktail withdrawal.

Of the rest 25 “old” patients from Group D, 12 patients, with Atropine and Atrovent withdrawal and preservation of Amitriptyline, received Dysport at the total dose of 250U in the form of subcutaneous injections by 62.5U above the upper (1.5 cm lower the lobe of the ear near the edge of the lower jaw) and lower (1.5 cm from the corner of the lower jaw in the direction of the nose) poles of parotid salivary glands bilaterally. The follow up assessment was performed for only 10 patients. Thus, Group E was formed (Dysport 250U + Amitriptyline 25 mg) (n=12, 22 observations, dropout 16%).

For two newly recruited patients, a woman with closed angle glaucoma and a man with adenoma of the prostate gland suffering from bulbar onset ALS and anarthria, treatment with Dysport 500U was suggested (by 125 U subcutaneously in the projection of the upper and lower poles of parotid glands bilaterally). The same therapy was suggested to 11 patients from Group D with Atropine, Atrovent and Amitriptyline cancelling. Two patients developed dysarthria, and 9 - anarthria. Thus, Group F was formed. The follow up assessment was performed for 11 patients (n=13, 24 observations, dropout 15%), at that, they were subjected (for the third time) to cognitive function assessment at withdrawal of cholinolytic cocktail changed by Dysport. Afterwards, all 11 patients addressed to investigators with the request about repeated injections. Afterwards, seven patients (3-4 months later) purchased an ampule of Dysport on their own and asked to be injected again. Seven follow up observations were added. In two patients with dysarthria, during a month after injections of 500U of Dysport, anarthria developed.
For the two “old” patients from Group D, with Atropine, Amitriptyline and Atrovent withdrawal, Buscopan  was suggested in dose of two 10-mg tablets 2 times a day (in total, 40 mg a day) for 3 months. Their cognitive functions were assessed for the third time at withdrawal of cholinolytics. Besides, additional 18 patients were recruited, for which Buscopan was also prescribed. The follow up assessment was performed in 15 patients. Thus, Group G was formed (n=20, 35 observations, dropout 25%).
For five patients from Group G who refused the follow up observation due to the feeling of therapy inefficiency, Scopoderm ТТS plaster was suggested (Novartis, with release of 0.5-1.5 mg of scopolamine a day, change every 72 hours and placement on the parotid area after hygienic treatment a half an hour before the application). The drug was purchased by Nina Levitskaya Russian Charity ALS Foundation  in the amount of 66 packs containing 5 plasters. This treatment was suggested also for 4 ALS patients received single Dysport in Group F, who could not afford purchasing of Dysport for repeated treatment due to economic reasons. Additionally, two “new” patients were recruited. The dynamic assessment was performed for 7 from these 11 patients. Thus, Group H was formed (Scopoderm, n=11, 18 observations, dropout 36%). In 5 of these 7 patients, cognitive functions were assessed 3 months after the cholinolytic plaster withdrawal.

In total, 233 paired gravimetric evaluations with salivation assessment from 466 parotid glands in 70 patients with ALS and bulbar impairment were performed. The total number of group members was 89. At the same time, in total, 125 procedures of paired cognitive functions assessment by Montreal Cog test and Frontotemporal dysfunction Score were carried out. In two patients who received Dysport without cholinolytics before or after, the assessment of cognitive functions was not performed. In 15 patients in whome cholinolytic cocktail and Scopoderm were withdrawn, assessment of cognitive functions was performed for the third time. The rate of anarthria development from the moment of inclusion in the study was assessed in 12 patients from groups B and C, finally entered Group D and in 5 patients from Group H as well as in 12 patients from Group E (Dysport 250U + Amitriptyline) (29 observations in total) and compared in time in 2 patients from Group F (Dysport 500U + dysarthria).

Statistical processing was performed using Statistica 5 software. Student’s t-criterion and Mann-Whitney U-criterion were used, differences were regarded statistically significant at p<0.05.
Results

The original degree of sialorrhea was comparable in all groups and, on the average, exceeded normal values in each group. Initially, cognitive functions, on the average, were slightly decreased. The results of treatment in groups А (Atropine), B (Atropine+ Atrovent), C (Amitriptyline), D (Atropine+Atrovent + Amitriptyline), E (Dysport 250U +Amitriptyline), F (Dysport 500U), G (Buscopan ) and H (Scopoderm) with comparative analysis of gravimetry and cognitive tests before and after the treatment are represented in Table 1. Table 2 displays results of the analysis of cognitive functions after withdrawal of cholinolytics.

Table 1. Results of gin therapeutic groups of ALS patients received sialorrhea treatment.

Table 2. The follow up of cognitive functions of patients at withdrawal of cholinolytics Abbreviations: s –scores; р<0.05, **р=0.05-0.1

The Table 1 shows that treatment with Atropine drops or combination of Atropine and Atrovent mouth-washing did not lead to desired effect on  sialorrhea, and did not change cognitive functions. Treatment by Amitriptyline decreased sialorrhea and caused impairment of cognitive functions at the level of a trend. The cholinolytic cocktail of Atropine, Atrovent and Amitriptyline lead to sialorrhea decrease at the level of a trend with the result being statistically significant, but, at the same time, with reversible worsening of cognitive functions. The illustration of regression of cognitive impairments at withdrawal of cholinolytics in ALS by the Montreal Cog Scale was reported in our previous work (21). Scopoderm reliably decreased sialorrhea and caused statistically significant and reversible decrease of cognitive functions. Buscopan decreased sialorrhea at the level of a trend and did not influence cognitive functions. Dysport at the dose of 250U in the combination with Amitriptyline reliably decreased sialorrhea, similar to Dysport at the dose of 500U. At the same time, it is necessary to note statistically significant differences in time of anarthria ensuing in two patients from the group of Dysport 500U, who received the drug during a state of  dysarthria, and in patients who were administered cholinolytics and comparable with the previous ones in anarthria ensuing(82±22 and 36±6, р=0.019).

Discussion

For the first time, this study revealed inefficiency of such forms of cholinolytics as Atropine drops, the combination of Atropine drops before meal with Atrovent mouth-washing after meal as well as Amitriptyline, and a trend of cognitive functions impairment in the Amitriptyline group was shown. The combination of Atropine, Atrovent and Amitriptyline decreases sialorrhea only at the level of a trend, but, at the same time, significantly suppressed cognitive functions, with the effect, however, being reversible after the cocktail withdrawal. Thus, a negative relation “efficacy-safety” for cholinolytics with central activity for the therapy of sialorrhea at ALS was demonstrated for the first time. During the study, the percentage of patients who received the effect from cholinolytics was not 70%, but only 10% (only Group H, Scopoderm) (7). Assessment of efficacy and safety was based on objective tests, with results obtained using devices (gravimetry) and medical experience (assessment by scales), suggesting that assessment of treatment by cholinolytics using the visual-analogous scale or the number

of applications of a handkerchief per hour can be not objective due to possible changes of cognitive functions (15). It is necessary to note that in some patients with impaired cognitive functions treated with the cholinolytic cocktail,  elements of drug dependency were revealed. It means that they were prone to more frequent use of drugs, i.e. overdosing, what make us conclude about the lack of safety in  treatment of ALS patients by the cholinolytic cocktail without constant medical control. In general, the decrease of cognitive functions represents a chronic complication of unknown significance, but, the risk of cholinolytic delirium in cases of overdosing can be higher, since 15.3% of ALS patients are predisposed to drug abuse, including drugs for sialorrhea, according to the data of our earlier study of situational psychological impairments at ALS (21). Scopoderm has become the only cholinolytic demonstrated reliable efficacy of sialorrhea correction, which also reliably, but reversibly, suppressed cognitive functions , that was confirmed by Odachi et al. (4). As it has been mentioned earlier, there is no single opinion about a positive or negative role of drug-related decrease of cognitive functions at ALS– in some cases it can calm patients, in other it hampers making decisions about the use of aggressive palliative therapy methods (16, 22). The combination of Dysport 250U and Amitriptyline 25 mg is effective for sialorrhea correction and safe, without decrease of cognitive functions and acceleration of anarthria. Buscopan, cholinolytic without  central effect, is safe in terms of cognitive functions, but it is not effective enough for the control of sialorrhea in ALS. Previously, the efficacy and safety of Dysport at the dose of 250U in 3 days and 1 month was showed, however the long-term efficacy is doubtful taking in account the progressing character of the disease, including increase of SOH and dysphagia (3).Unfortunately, within the frames of complicated design of this study, we have failed to increase the observational group for Dysport 250U without cholinolytics taking in account a former retrospective group due to economic restrictions (5, 6). We have also demonstrated that Dysport in dose of 500U is not safe in ALS patients with dysarthria, because they can quicker progress to anarthria. Dysport in dose of 500U is safe only in ALS patients with anarthria, in whom it effectively and reliably decreases sialorrhea for 3 months.

The study  demonstrates availability of conservative treatment of sialorrhea in ALS capable to decrease salivation effectively,  that, as in the case with Scopoderm, influences cognitive functions, or, as in the case with Dysport or its combination with Amitriptyline, does not influence cognitive functions. It allows physicians to avoid surgical methods of treatment, which can cause complications undesirable in such a severe disease (13). Despite carrying out a large number of tests in general, the total population of patients (number of observations) was divided in several small groups, and in some cases, test results were deficient in the statistical power. Confirmation of results on separate drugs in a larger population of patients seems to be reasonable (Dysport, Amitriptyline, Scopoderm, Buscopan). Undoubtedly, the results of this work could have been influenced by not only such factor as a sample size, but, at the same time, the presence of SOH component not corrected by the administered drugs, lack of patients compliance as well as difference in the degree of manifestation and rate of progression of dysphagia, which was not assessed in this work (5). It would be also interesting to investigate the efficacy and safety of irradiation of salivary glands at ALS and compare new data with the results of pharmacological therapy (5,7).

The authors declare no conflict of interests

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