Oral Side Effects of the Most Commonly Prescribed Drugs in Germany

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This report scores oral side effects of frequently prescribed medications based on package inserts. The presentation and discussion of data from a clinical perspective is commendable.

In order to avoid misleading readers, we recommend making several revisions to this paper.
1. The discrepancy with actual clinical practice, as actual side effects were not examined, should be considered. Of course, side effect reporting itself is biased, but this method is different from reporting side effects observed in prospective trials, so it is necessary to address this discrepancy with clinical practice. As this paper is primarily focused on clinical research, we recommend that the authors state their opinion on how well the data they present reflects clinical practice.
2. The fact that xerostomia and taste disturbance were the main results is consistent with clinical experience. While there is no problem in that this is explained pharmacologically in terms of anticholinergic effects, we recommend that consideration be given to the fact that antibiotics and other drugs can cause dry mouth. Because antibiotics do not have anticholinergic effects, it is necessary to explain the possibility that the effects are not direct on the oral cavity, such as the pathology of the underlying disease for which the antibiotics are used (such as dehydration due to infection) or effects mediated by changes in the intestinal flora.
3. Regarding oral effects, what is needed in the discussion is that the most common scored side effects are not considered: (1) effects on the oral nervous system, (2) exposure to the oral cavity due to drug secretion in saliva, and (3) direct effects of drugs and excipients on the oral cavity. These factors need to be explained, as they have not been considered.
4. Because this is an analysis of commonly prescribed drugs, there are no data or comments on drugs with significant effects on the oral cavity, such as anticancer drugs. However, if possible, explaining that these drugs are not included in this study would help clarify the paper's position as data on everyday clinical practice.
5. In general, there is a lack of information on pharmacological effects and mechanisms, so it would be helpful to readers to include explanations for phenomena that can be explained.
6. As the authors point out, xerostomia can be caused by an actual decrease in saliva secretion or by a mere sensation. Oral discomfort often occurs even in the absence of oral lesions, and changes in central sensory processing are thought to be the underlying mechanism. Including these factors in the discussion would be helpful to readers. It is commendable that the paper draws attention to oral side effects from a clinical perspective, so we recommend that the above comments be taken into consideration and the paper be made more scientific.

Author Response

Dear Reviewer,

 

Thank you for your detailed and helpful advice on our manuscript “Oral side effects of the most commonly prescribed drugs in Germany”. We want to respond to your remarks to the best of our knowledge as follows:

 

Reviewer 1:

 

1. “The discrepancy with actual clinical practice, as actual side effects were not examined, should be considered. Of course, side effect reporting itself is biased, but this method is different from reporting side effects observed in prospective trials, so it is necessary to address this discrepancy with clinical practice. As this paper is primarily focused on clinical research, we recommend that the authors state their opinion on how well the data they present reflects clinical practice.”

 

 

Comment:

Healthcare professionals have a legal obligation to report adverse drug reactions to the drug commission of their respective professional organizations (Drug Commission of the German Medical Association, Drug Commission of Dentists, or Drug Commission of the German Pharmacists). German drug law stipulates that, following the approval of a medicinal product, experience regarding drug safety must be continuously and systematically collected and evaluated. This is one of the tasks of the Federal Institute for Drugs and Medical Devices (BfArM) and the Paul Ehrlich Institute (PEI). Reporting suspected adverse drug reactions is an important component of this process. Due to the nature of this subject the reporting process is always retrospective. Patients, as well as their relatives or representatives, can also report adverse drug reactions at www.nebenwirkungen.bund.de. According to the reporting data of the BfArM of 2023 (https://www.bfarm.de/SharedDocs/Downloads/DE/Arzneimittel/Pharmakovigilanz/Gremien/RoutinesitzungPar63AMG/94Sitzung/pkt-2-1-a.html) most of the ADRs were reported from consumer/patients (44%).In our opinion this figure indicates that the collected data reflect the clinical reality.

 

 

2. “The fact that xerostomia and taste disturbance were the main results is consistent with clinical experience. While there is no problem in that this is explained pharmacologically in terms of anticholinergic effects, we recommend that consideration be given to the fact that antibiotics and other drugs can cause dry mouth. Because antibiotics do not have anticholinergic effects, it is necessary to explain the possibility that the effects are not direct on the oral cavity, such as the pathology of the underlying disease for which the antibiotics are used (such as dehydration due to infection) or effects mediated by changes in the intestinal flora.”

Comment:
In a systematic literature search Kiesel and coworkers found more than 500 drugs with an anticholinergic effect (Kiesel EK, Hopf YM, Drey M. An anticholinergic burden score for German prescribers: score development. BMC Geriatr. 2018 Oct 11;18(1):239. doi: 10.1186/s12877-018-0929-6.). 356 drugs were categorised as having no, 104 drugs were scored as weak, 18 as moderate and 29 as having strong anticholinergic effects. According to their newly created drug-based anticholinergic burden score (ACB) only two antibiotics, namely ampicillin and clindamycin, belong to the group with the lowest ACB (Score 1).  Amoxicillin as the most widespread dental antibiotic has no anticholinergic effect (Score 0). Therefore, it can be assumed that the specific relevance of antibiotics for xerostomia is neglectable low. A dry mouth may lead to oral candidiasis, which may also be caused by treatment with antibiotics, immunosuppressants or corticosteroids. There are no reliable data on infections inducing xerostomia or effects on saliva by changes of the intestinal flora.

3. “Regarding oral effects, what is needed in the discussion is that the most common scored side effects are not considered: (1) effects on the oral nervous system, (2) exposure to the oral cavity due to drug secretion in saliva, and (3) direct effects of drugs and excipients on the oral cavity. These factors need to be explained, as they have not been considered.”

Comment:
We mentioned the oral effect “hypesthesia” in Table 1. In our opinion, because of the low share of this ADR (3%) in all categories of oral ADRs a special discussion is not necessary. In a current systematic review only phenytoin, tacrolimus, voriconazole and lamotrigine were drugs suitable for a saliva-based drug monitoring (Nguyen TA, Chen RH, Hawkins BA, Hibbs DE, Kim HY, Wheate NJ, Groundwater PW, Stocker SL, Alffenaar JC. Can we Predict Drug Excretion into Saliva? A Systematic Review and Analysis of Physicochemical Properties. Clin Pharmacokinet. 2024 Aug;63(8):1067-1087. doi: 10.1007/s40262-024-01398-9.). Therefore, saliva secretion of the examined drugs of our study is not predictable and not worth to be discussed. “Stomatitis” as a direct effect on oral mucosa is mentioned several times in the discussion, namely in the context of antibiotic and analgesic side effects.

4. “Because this is an analysis of commonly prescribed drugs, there are no data or comments on drugs with significant effects on the oral cavity, such as anticancer drugs. However, if possible, explaining that these drugs are not included in this study would help clarify the paper's position as data on everyday clinical practice.”

Comment:
In the discussion, we have added an explanatory note, that rarely prescribed medications with relevant oral side effects could not be considered.

5. “In general, there is a lack of information on pharmacological effects and mechanisms, so it would be helpful to readers to include explanations for phenomena that can be explained.”

Comment:
We have implemented additional pharmacological information regarding anticholinergic effects of medications, dysgeusia and angioedema.

6. “As the authors point out, xerostomia can be caused by an actual decrease in saliva secretion or by a mere sensation. Oral discomfort often occurs even in the absence of oral lesions, and changes in central sensory processing are thought to be the underlying mechanism. Including these factors in the discussion would be helpful to readers.”

Comment:
Impairment of taste and smell usually affects sensory function at a molecular level. Therefore, we have addressed this topic in the discussion.

 

We hope that our manuscript will meet your approval and we are looking forward to hearing from you.

 

Sincerely yours,

 

 

 

PD Dr. Dr. F. Halling                          Prof. Dr. Dr. R. Lutz                             PD Dr. Dr. A. Meisgeier

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Hello, dear colleagues!

This article is a relevant and methodologically sound study aimed at a systematic analysis of oral adverse event scores (OSES) for the 100 most frequently prescribed medications in Germany.

Despite its obvious strengths, the manuscript requires correction on the following points.
1. Some of the cited literature, particularly in the sections on general principles of polypharmacy and OSES, is outdated (e.g., Ciancio, 2004; Porter et al., 2004; Gomes & Demoly, 2005).
2. The text is unclear on how exactly the OSES was calculated for the group of medications. It states that it is a "mean score." Clarification is needed: was it calculated as the sum of the OSES scores for all medications in the group, divided by the number of medications? Or by the number of OSES?
3. In the caption to Fig. 5 (p. 10) the word "Oral" is written with a capital letter, while in the text and other figures a lowercase letter is used ("oral Side Effect Score"). It is desirable to standardize.

Author Response

Dear Reviewer,

 

Thank you for your detailed and helpful advice on our manuscript “Oral side effects of the most commonly prescribed drugs in Germany”. We want to respond to your remarks to the best of our knowledge as follows:

 

Reviewer 2:

1. “Some of the cited literature, particularly in the sections on general principles of polypharmacy and OSES, is outdated (e.g., Ciancio, 2004; Porter et al., 2004; Gomes & Demoly, 2005).”

Comment:
We have removed the outdated literature and replaced it by more current studies.

2. “The text is unclear on how exactly the OSES was calculated for the group of medications. It states that it is a "mean score." Clarification is needed: was it calculated as the sum of the OSES scores for all medications in the group, divided by the number of medications? Or by the number of OSES?”

Comment:
We have made a clarification how we calculated the “oral side effect score” (OSES). The new version is as follows:“We assigned scores to the different categories according to their clinical relevance: Four points were awarded for 'very common', three for 'common', two for 'uncommon' and one for 'rare'. The sum of all scores for each drug was defined as “oral side effect score” (OSES). In the case of medication classes, we attributed all drugs to their ATC-groups according to the Anatomical Therapeutic Chemical classification (ATC), summarized all scores of the drugs belonging to this medication class and calculated the mean score for each ATC-group. The ten individual medications with the highest associated OSES were identified.”

3. In the caption to Fig. 5 (p. 10) the word "Oral" is written with a capital letter, while in the text and other figures a lowercase letter is used ("oral Side Effect Score"). It is desirable to standardize.

Comment: Captions were standardized.

 

 

We hope that our manuscript will meet your approval and we are looking forward to hearing from you.

 

Sincerely yours,

 

 

 

PD Dr. Dr. F. Halling                          Prof. Dr. Dr. R. Lutz                             PD Dr. Dr. A. Meisgeier

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

Dear Authors,

certain categories contain drugs with very different mechanisms and possible adverse effects. For example, antihypertensives should be further divided, as well as the antidiabetics and antibiotics. Calcium Channel Blockers have a distinct effect, that of gingival enlargement, which is not attributed to other drugs from the same overall category. Also, the time frame should be taken into account. How long is a drug administered, and in which dosage? Do you have such data , ideally presented in a table?

Author Response

Dear Reviewer,

 

Thank you for your detailed and helpful advice on our manuscript “Oral side effects of the most commonly prescribed drugs in Germany”. We want to respond to your remarks to the best of our knowledge as follows:

 

Reviewer 3:

1. “Certain categories contain drugs with very different mechanisms and possible adverse effects. For example, antihypertensives should be further divided, as well as the antidiabetics and antibiotics. Calcium Channel Blockers have a distinct effect, that of gingival enlargement, which is not attributed to other drugs from the same overall category. “

Comment:

Referring to your note we have inserted the following passus into the discussion:
“When we look in detail at the three medication groups with the highest number of oral ADRs (Tab. 2), there are only two medications each with strikingly high OSES: in the case of analgesics gabapentin and pregabalin, regarding antibiotics azithromycin and amoxicillin and referring to antihypertensives enalapril and ramipril. Therefore, higher OSES seem not to be a “group-effect” typical for a special medication class but obviously depend mainly on the active ingredient of the drugs. Some impressive dental side effects like calcium channel blocker-induced gingival enlargement are not mentioned as an ADR, because in total the occurrence of these effects is very low (Glick et al., 2020).“

2. “Also, the time frame should be taken into account. How long is a drug administered, and in which dosage? Do you have such data, ideally presented in a table?”

Comment:

This analysis is retrospective. The database “PharMaAnalyst” does not provide these data.

 

 

We hope that our manuscript will meet your approval and we are looking forward to hearing from you.

 

Sincerely yours,

 

 

 

PD Dr. Dr. F. Halling                          Prof. Dr. Dr. R. Lutz                             PD Dr. Dr. A. Meisgeier

Author Response File: Author Response.pdf

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

Dear authors,

it is better now.