Amitriptyline prescribing in public sector healthcare facilities in the Western Cape, South Africa.

BACKGROUND: Inappropriate medication use is a major patient safety concern, especially for the elderly population. Amitriptyline is widely used in primary care in South Africa and a cross-sectional study found that amitriptyline was prescribed potentially inappropriately in 6.5% of elderly patients. An analysis of prescriptions from the Chronic Dispensing Unit in the Western Cape revealed that amitriptyline was one of the most common medicines prescribed without a suitable diagnosis listed on the prescription.
OBJECTIVE: The main objective of the medicine use evaluation (MUE) was to determine whether amitriptyline was prescribed in accordance with recommendations from standard treatment guidelines (STG) and essential medicines lists (EML) endorsed by the National Department of Health, South Africa.
METHODS: A retrospective, cross-sectional, multicentre review of patients' clinical notes was conducted. The study population was selected by systematic random sampling from adult outpatients who were prescribed amitriptyline for longer than three months. Criteria for evaluation included amitriptyline indication and total daily dose prescribed.
RESULTS: Of the sample of 2237 patient medical records reviewed, 1732 (77.4%) included amitriptyline prescriptions that were according to the approved STG indications. For the approved STG indications, amitriptyline was prescribed mainly for osteoarthritis (25.8%), neuropathies (18.5%) and chronic non-cancer pain (17.9%). Major depressive disorders constituted only 8.6% of the patient records reviewed; however, doses were atypically low. The main inappropriate indication for amitriptyline was sleep disorders (16%).
CONCLUSION: This MUE has highlighted the need to improve the use of amitriptyline in specific patient populations, e.g. the elderly and patients with sleeping disorders.

Background

Access to essential medicines is critical in addressing health problems and improving the quality of lives of millions of patients around the world. Medicines form an indispensable component of any healthcare system in the prevention, diagnosis and treatment of diseases and in alleviating disability and functional deficiency. Essential medicines are defined as “medicines that satisfy the priority healthcare needs of the population,” with the concept being that these medicines are intended to be available at all times, in adequate amounts, in appropriate dosage forms, with assured quality and at a price that the individual and country can afford.[1] The World Health Organization (WHO) further states that rational use of medicines require that “patients receive medication appropriate to their clinical needs, in doses that meet their own individual requirements, for an adequate period of time, and at the lowest cost to them and their community”.[2]

Taking the above two concepts into consideration, the prescribing of medicines should generally follow these steps: (a) Determine the diagnosis of the patient; (b) Consider effective and safe treatment options; (c) Select appropriate medicines, which include dose, frequency and duration; (d) Write a clear prescription; (e) Provide patients with the necessary information or counselling; and (f) Follow up to evaluate treatment responses.[3] However, prescribing patterns do not always conform to these ideals, resulting instead in inappropriate and irrational prescribing.[4]

The impact of irrational medicine use can have varying effects on patients and the risk of adverse drug reactions (ADRs) is increased. In older patients the presence of a comorbidity is a strong predictor of repeat admissions for ADRs, especially if they are managed and treated in the community setting.[5] Irrational prescribing can also expose patients to the possibility of developing drug dependence to certain medicines, such as analgesics and tranquillizers.[6] Not only does inappropriate use of medicines have a negative effect on patients, but it also leads to wastage of scarce resources. The WHO estimated that the appropriate use of medicines can result in about 50%–70% cost-efficiency in medicines expenditure.[7]

Inappropriate medication use is a major patient safety concern, especially for the elderly population.[8] In 1987 and 1992, it was reported that between 17.5% and 23.5% of community-dwelling elderly patients in the United States used at least 1 of 20 potential inappropriate medicines.[9] The most frequently prescribed potentially inappropriate medications were diazepam, propoxyphene, dipyridamole, amitriptyline, and chlordiazepoxide; these medicines accounted for 85% of the outpatient visits involving potentially inappropriate medications.[10] A cross-sectional study, including 103 420 patients aged ≥65 years, that was conducted using a database obtained from a pharmaceutical benefit management company in South Africa found that amitriptyline was prescribed potentially inappropriately in 6.5% (n = 36 509) of elderly patients.[11]

Amitriptyline is widely used in primary care in South Africa as it is listed as an Essential medicine in South Africa. In the Western Cape, data from the provincial medicine warehouse, the Cape Medical Depot (CMD), indicated an annual consumption of more than 600 000 packs (included 28s, 56s, 84s and 168s) of amitriptyline 10mg or 25mg with an expenditure of R3.5million (US$231 500.00) for the period July 2016 to June 2017.[12] An analysis done on prescriptions at the Chronic Dispensing Unit in the Western Cape revealed that amitriptyline was one of the most common medicines prescribed without a diagnosis listed on the prescription.[13] Thus, concerns for inappropriate prescribing, together with the wide use and potential for adverse effects, led to the Provincial Pharmacy and Therapeutics Committee (PTC) of the Western Cape requesting that a review of the use of amitriptyline be conducted. To our knowledge limited to no data exists on medicine use evaluations for mental health medicines in low to middle income countries (LMICs). Our objective was to establish if amitriptyline is prescribed according to the recommendations set out in the Standard Treatment Guidelines[14, 15] developed by the South African Department of Health.

Method

A retrospective, multicentre review of clinical notes of outpatients was conducted in the public health care sector of the Western Cape. The study population included adult outpatients (≥18 years of age) who received amitriptyline for longer than 3 months during the period 01 April 2016 to 31 July 2017.

The folder review was performed between 27 March 2017 and 31 July 2017. A convenience sample of facilities was selected from health facilities that had at least one fulltime pharmacist and doctor. According to South African legislation, amitriptyline (as a schedule 5 medicine) should be prescribed by a doctor. Facilities with low amitriptyline numbers were excluded. At least 30 folders per facility were selected by random systematic selection and reviewed over a 2 to 4-week period within the study period. The sample size was based on the World Health Organization recommendation of 30 folders per facility [16]. The data was sourced from patients’ clinical records using a data collection tool developed by a multi-disciplinary team that included pharmacists and doctors working in the healthcare facilities. A pilot study was done at one facility to determine ease of use of the data collection tool as well as to determine if the required analysis could be done with the variables collected. Data collected included demographic data (gender and age), diagnosis, medication prescribed, comorbidities and amitriptyline dosages. Information collected was captured onto a predesigned Microsoft® Office Excel (Microsoft, USA) spreadsheet, from where analyses were performed. Descriptive statistics were used to report proportions and percentages of the outcomes. P-values ≤0.05 were considered significant.

The criteria used for evaluation were diagnosis-related. The criteria were determined by using the Standard Treatment Guidelines (STGs) and Essential Medicines List (EML) for Primary Health Care (2014)[14] and Adult Hospital Level (2015)[15]. These guidelines were in use at the time of the review. Table 1 lists the STGs and EML indications for amitriptyline use.

Table 1

Indications for amitriptyline according to Standard Treatment Guidelines[14, 15].

1. Major depressive disorders (MDD) (F32.9)
2. Pain associated with:
Neuropathies (E10.2/E11.2/N08.3)	Rheumatoid arthritis (M05.9/M06.9)	Herpes zoster (B20.3)
Cancer, non-cancer / other (R52.9)	Osteoarthritis (M19.9)	Migraine (G43)

To facilitate data collection, the following non-EML indications were added to the data collection tool: irritable bowel syndrome, anxiety, sleeping disorders and overactive bladder. Diagnoses had to be documented unambiguously (not symptoms) in the medical notes to be accepted. Diagnoses that were not listed on the tool or unclear were included as ‘other non-pain indications’. Folders were reviewed independently and discrepancies were resolved amongst the authors.

A threshold refers to the percentage of charts or records that will meet or exceed the established criteria for the medicine. Ideally, this threshold will be 100 percent, but realistically, a smaller percentage will be more appropriate to account for exceptions to routine medicine prescribing. The threshold was set at 99% as amitriptyline is prescribed predominantly at primary healthcare level. It is expected that 99% of prescriptions should comply with the STG & EML with regards to the diagnosis, dosage and process issues. A deviation of 1% was allowed for exceptions. The threshold was jointly decided upon by a multidisciplinary team.

Ethical considerations

Approval to conduct the study was granted by the Western Cape Pharmacy and Therapeutics Committee, the Western Cape Government Health (WC_201806_021) as well as the University of the Western Cape’s Biomedical Research Ethics Committee (BM18/4/5). For the purpose of the folder review informed consent from patients were not required by the approval committees as this study was retrospective, data was anonymized before analysis and there was no direct patient contact.

Results

Out of 193 health facilities where amitriptyline was prescribed, 102 facilities were excluded due to low amitriptyline numbers (i.e. < 15 prescriptions per week). Thus, out of the 91 facilities, sixty-four facilities (70.3% response rate) contributed to the review of amitriptyline use in the Western Cape. A total of 2237 patient folders were reviewed. These patients received amitriptyline for a period of longer than three months. Metropole facilities, rural facilities and transverse facilities (e.g. tertiary hospitals that serve patients across the province) made up 75%, 17% and 8%, respectively, of the sample. Graph 1 indicates the contribution to the sample by the type of facility. Community Day Centres (CDCs), Community Health Centres (CHCs) and clinics contributed 80% towards the total sample, while hospital outpatients made up 20% of the sample (Fig 1).

Fig 1

Proportion of folders reviewed by facility type.

Demographic information is shown in Table 2. There were two and a half times more females (1639; 73%) than males (597; 27%) receiving amitriptyline. The average age of the patients was 57 years (SD±13.81). Females were on average 2 years older than males, with the average age being 58 years and 56 years, respectively (p<0021).

Table 2

Gender descriptive statistics (n = 2237).

	n	Mean age	Standard deviation	Min age	Max age	Median	Age: CI 95%
Female	1639 (73%)	58	13.31	18	99	57	57.01–58.30
Male	597 (27%)	56	14.99	18	93	56	54.44–56.85
Total	2237* (100%)	57	13.81	18	99	57	56.54–57.69

*One patient with missing gender

For the prescriptions reviewed, 1732 (n = 2237; 77.43%) prescriptions for amitriptyline were according to indications approved in the STGs. Thus, almost a quarter of patients received amitriptyline for indications not listed or approved in the STGs.

As more than one indication was reported for some folder reviews of patients with co-morbidities, a total of 2688 indications for use of amitriptyline were reported in the total sample (n = 2237). The proportion of prescriptions by indication is shown in graph 2 (Fig 2). For the approved STG indications (Table 1), amitriptyline was prescribed mainly for osteoarthritis (25.79%), followed by chronic non-cancer pain (17.88%). Major depressive disorders constituted 8.58%, while all neuropathies combined constituted 18.45% of the patient medical records reviewed. At 16.00%, sleeping disorders made up the highest proportion of patient folder reviews for a Non-STG indication and this also constituted the indication with the third highest proportion of all folders reviewed.

Fig 2

Proportion of prescriptions by indication of use.

Table 3 provides information on sex, age and dose per indication. The most common indication within the female sub-group was osteoarthritis/osteoarthrosis (27.9%) and for males it was neuropathies (25.6%). Elderly patients are prone to side effects of amitriptyline. Amitriptyline increases the risk of urinary retention in males over 55 years old, thus the age sub-groups were split into patients that are ≤55 years and patients above 55 years old. The proportion of patients over 55 years were 54%, 55% and 50% for the total sample, females and males, respectively. Doses were split into ≤50mg and >50mg. Around 95% of the doses prescribed for amitriptyline were ≤ 50mg daily; with 86% of these doses being ≤ 25mg daily. For the STG indications (n = 1732), at least 95% of doses were within guideline recommendations. Doses for the Non-STG indications could not be assessed as there were no clinical practice guidelines in place to use as a reference for these indications.

Table 3

Analysis of sex, age and dose (sub-groups) per indication.

			EML INDICATIONS										NON-EML INDICATIONS
Sub-group		Quantity & proportions	Neuropathy	Post-herpetic neuralgia	Herpes Zoster Ophthalmicus	Rheumatoid arthritis	Osteoarthritis / osteoarthrosis	Chronic cancer pain	Other chronic non-cancer pain	Chronic non-specific pain syndrome	Other pain indication, specify	Major depressive disorder	Anxiety disorders	Sleeping disorders	Irritable Bowel Syndrome	Overactive bladder / Enuresis	Any other non-pain indication, specify	No indication noted in patient folder
FEMALES	Females N = 1639	Quantity	244	11	3	87	457	44	291	66	150	148	72	265	36	17	102	170
		% females	14.9%	0.7%	0.2%	5.3%	27.9%	2.7%	17.8%	4.0%	9.2%	9.0%	4.4%	16.2%	2.2%	1.0%	6.2%	10.4%
		% total sample	13.9%	0.5%	0.1%	3.9%	20.4%	2.0%	13.0%	3.0%	6.7%	6.6%	3.2%	11.8%	1.6%	0.8%	4.6%	7.6%
	>55yrs@ n = 909	Quantity	109	9	1	55	333	27	132	37	74	80	32	175	25	15	61	88
		% subgroup*	44.7%	81.8%	33.3%	63.2%	73.0%	61.4%	45.4%	56.1%	49.3%	54.8%	44.4%	66.5%	69.4%	88.2%	59.8%	53.3%
	≤55yrs@ n = 721	Quantity	135	2	2	32	123	17	159	29	76	66	40	88	11	2	41	77
		% subgroup*	55.3%	18.2%	66.7%	36.8%	27.0%	38.6%	54.6%	43.9%	50.7%	45.2%	55.6%	33.5%	30.6%	11.8%	40.2%	46.7%
MALES	Males n = 597	Quantity	153	2	1	15	120	7	109	26	61	44	27	93	10	2	41	54
		% males	25.6%	0.3%	0.2%	2.5%	20.1%	1.2%	18.3%	4.4%	10.2%	7.4%	4.5%	15.6%	1.7%	0.3%	6.9%	9.0%
		% total sample	7.3%	0.1%	0.0%	0.7%	5.4%	0.3%	4.9%	1.2%	2.7%	2.0%	1.2%	4.2%	0.4%	0.1%	1.8%	2.4%
	>55yrs n = 299	Quantity	57	1	0	7	91	7	47	14	32	17	10	59	5	0	23	26
		% subgroup*	37.3%	50.0%	0.0%	46.7%	75.8%	100.0%	43.1%	53.8%	52.5%	38.6%	37.0%	63.4%	50.0%	0.0%	56.1%	48.1%
	≤55yrs n = 298	Quantity	96	1	1	8	29	0	62	12	29	27	17	34	5	2	18	28
		% subgroup*	62.7%	50.0%	100.0%	53.3%	24.2%	0.0%	56.9%	46.2%	47.5%	61.4%	63.0%	36.6%	50.0%	100.0%	43.9%	51.9%
DOSE#	Dose ≤50mg n = 2134	Quantity	383	13	4	97	559	49	378	86	202	171	84	344	45	19	139	216
		% subgroup*	97.0%	100.0%	100.0%	98.0%	97.2%	96.1%	96.9%	95.6%	97.1%	90.0%	86.6%	97.5%	97.8%	100.0%	97.2%	98.2%
	Dose >50mg n = 77	Quantity	12	0	0	2	16	2	12	4	6	19	13	9	1	0	4	4
		% subgroup*	3.0%	0.0%	0.0%	2.0%	2.8%	3.9%	3.1%	4.4%	2.9%	10.0%	13.4%	2.5%	2.2%	0.0%	2.8%	1.8%

*the proportions are per sub-group per indication

# patients with missing doses were not included in the dose sub-group

@ patients with missing ages were not included in the females-age sub-group

Further analysis showed that for males over 55 years, only 9% of patients in this risk group were on doses greater than 25mg daily. For patients that were ≥ 65 years, doses were generally in the lower range, i.e. 87% of the doses were ≤ 25mg daily and another 10% of doses were > 25mg but ≤ 50mg.

Only 1% of the doses were ≥ 125mg daily and these doses were prescribed for indications such as major depressive disorder (MDD), anxiety disorder (Non-STG indication), sleep disorder (Non-STG indication) and osteoarthritis. Although infrequent, high doses (≥125mg daily) of amitriptyline for osteoarthritis were of concern as this was not in line with STG recommendations.

For MDD, 70% of the prescriptions had a dose of ≤ 25mg daily and a further 20% had a dose of 50mg daily. Of these prescriptions, only 41% had another antidepressant or mood stabiliser added, implying that these patients on amitriptyline monotherapy may be sub-optimally managed.

Table 4 indicates amitriptyline prescribed with other pain modulating medicines. Paracetamol was widely used in combination with amitriptyline, with just under two thirds of the prescriptions having this combination. Furthermore, a third of the prescriptions comprised amitriptyline with tramadol. Amitriptyline on its own was predominantly prescribed for sleep disorders and neuropathies. Amitriptyline with paracetamol only (as only other pain-modulating medicine) was predominantly prescribed for neuropathies, osteoarthritis and other chronic non-cancer pain. For amitriptyline with non-steroidal anti-inflammatory drugs (NSAIDs) only or tramadol only, osteoarthritis and other chronic non-cancer pain were the main indications.

Table 4

Concomitant pain medicine use.

Pain Medicines	Quantity	Percentage
Amitriptyline
Amitriptyline only	690	30.84%
+ Paracetamol
Paracetamol all	1398	62.49%
Paracetamol only	478	21.37%
+Ibuprofen/NSAID
Ibuprofen/NSAID all	466	20.83%
NSAID only	72	3.22%
+Tramadol
Tramadol all	748	33.44%
Tramadol only	60	2.68%

Table 5 compares the thresholds set and results observed for the STG indications, appropriate dosing and clear documentation. Observed results of 77%, 95% and 90% were achieved, respectively. The proportion calculated for ‘appropriate dosing’ was estimated from prescriptions with STG indications only as no recommendation on dosing is provided for Non-STG indications.

Table 5

Thresholds observed according to STG criteria.

Criteria	Thresholds	Observed
Indications	99%	77%
Dosages	99%	95%
Recording of diagnosis information	99%	90%

Discussion

With an unknown proportion of the population that would be adherent to guidelines, a proportion of 50% (i.e. ρ = 0.5) and a confidence interval of 95% were used to calculate the sample size required i.e. 384. In order to expose all facilities that matched our inclusion criteria to the MUE methodology and requiring at least 30 patient medical record reviews per facility, a total of 2237 patient medical records were reviewed; this was well within the calculated sample size. In the Western Cape, the approach for patient care is that, generally, around 85% of patients should receive healthcare at a primary level, around 12% at hospital level and around 3% at a tertiary care level. Furthermore, the indications for amitriptyline, including follow-up after referral from hospital level, falls mainly within the ambit of primary care. Thus, as 80% of the sample was made up from primary care level patients, this indicated a fair representation of the patient distribution.

In South Africa, the Standard Treatment Guidelines and Essential Medicines List (STGs) are evidence-based medicine recommendations aimed to cater for most of the population[14,15]. Adherence to these recommendations is expected from all public sector healthcare facilities to ensure an effective standard of care, safety and equitable access to medicines. As amitriptyline was used predominantly at primary care according to consumption data, adherence to the STGs was expected to be high; and thus, a high threshold (99%) was set for what is considered appropriate prescribing of amitriptyline in the province.

In our review the majority of the ambulatory patients received amitriptyline as per STGs, mainly as an adjunct for pain control in chronic pain conditions. However, almost one quarter of the prescriptions were for indications that are not in line with the STGs and thus, there is room for improvement. Around 16% of the patients were on amitriptyline for sleep disorders and this may suggest a need for appropriate sleep disorder management opportunities within the public sector. According to the STGs, sleep hygiene and stimulus control are the first steps of treatment; and if medication is required, short-term benzodiazepines are the preferred agents to use for the treatment of insomnia. Non-benzodiazepines tend not to be abused in comparison to benzodiazepines, are effective in insomnia and may offer a better safety profile over benzodiazepines. However, the use of amitriptyline for insomnia is regarded as off-label use. Low-dose amitriptyline has been used successfully in patients with insomnia, but is contraindicated in suicidal patients or in those with cardiac risk factors. It is generally recommended that antidepressants be prescribed at therapeutic doses when insomnia coexists with a mood disorder.[17] The STGs, therefore, recommend referral of patients that cannot be managed utilising cognitive behaviour methods or short-term benzodiazepines.

The use of low dose amitriptyline in major depressive disorders raised concerns for possible inappropriate management of these conditions. Low doses of amitriptyline for treating mood disorders may not only be ineffective but could also produce unwarranted adverse effects in patients. The lifetime prevalence for major depression in South Africa is 9.8%[18]. In a study conducted in the private healthcare sector of South Africa, only 26.2% of patients who received amitriptyline-containing products were compliant[19]. This raises further concerns when taking under dosing, as seen in our study, into consideration. Ineffective treatment of mood disorders has a substantial risk for suicide.

A third of the patients were on tramadol and amitriptyline, concurrently, and this combination can induce constipation, precipitate urinary retention in elderly men, lower the seizure threshold and cause serotonin syndrome. The current STGs do not provide any recommendation on education or precautions on the potential risk of serotonin syndrome. This review highlights the potential risk of serotonin syndrome in this population.

The highest proportion of prescriptions was indicated for osteoarthritis (26%); however, there is limited evidence for recommending amitriptyline therapy for inflammatory arthritis and some evidence of benefit in fibromyalgia, but no evidence of benefit of amitriptyline in osteoarthritis.[20] Also, in a systematic review to determine effectiveness of amitriptyline in musculoskeletal pain and improved functionality, it was concluded that amitriptyline may be effective, but further research is needed to establish efficaciousness and the specific indication(s) for amitriptyline.[21] A Cochrane review is underway, currently, to determine the safety and efficacy of antidepressants for osteoarthritis.[22] Thus, due to safety concerns and a paucity of evidence of efficacy of amitriptyline in osteoarthritis, amitriptyline was not included in the South African Primary Health Care STG for this indication. Preferably, amitriptyline should therefore not be initiated at primary care level for this indication, especially, because of potential cardiotoxicity in patients with co-morbid cardiovascular conditions. Amitriptyline, however, remains listed in the Adult Hospital STG for osteoarthritis as adjunctive therapy for pain control as this is considered standard of care, currently, and there is uncertainty as to whether amitriptyline is not efficacious[15].

The mean age of the sample was 57 (±14) years and older patients often have multiple diseases, especially co-morbid cardiovascular conditions, requiring multiple medicines; this increases the potential for using inappropriate medicines and ultimately results in various adverse effects. In elderly patients there exist concerns with the use of anticholinergic drugs due to potential confusion, constipation, urination problems, blurry vision and low blood pressure. This review highlighted the importance of considering the benefit (effectiveness) versus the risks when prescribing amitriptyline, especially due to the patient groups involved.

Conclusion

This review has highlighted the importance of evaluating patients’ need for amitriptyline when receiving it for chronic use. In these public healthcare facilities, there is a need to improve the use of amitriptyline in specific patient populations, e.g. elderly men, patients with major depressive disorders, patients with sleeping disorders or with co-morbid cardiovascular conditions.

De-identified data set.

(XLSX)

Click here for additional data file.

Transfer Alert

This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present.

14 Jan 2020

PONE-D-19-33673

Amitriptyline prescribing in public sector healthcare facilities in the Western Cape, South Africa

PLOS ONE

Dear Prof Coetzee,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

We would appreciate receiving your revised manuscript by Feb 28 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Vijayaprakash Suppiah, PhD

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements:

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at http://www.plosone.org/attachments/PLOSOne_formatting_sample_main_body.pdf and http://www.plosone.org/attachments/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. We noticed you have some minor occurrence(s) of overlapping text with the following previous publication(s), which needs to be addressed:

https://doi.org/10.1001/jama.286.22.2823

https://doi.org/10.1093/ajhp/56.5.433

http://www.healthconnect-intl.org/IRD_feb13.html

http://dx.doi.org/10.22270/jddt.v9i3.2649

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the Methods section. Further consideration is dependent on these concerns being addressed.

3. In the ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records/samples used in your retrospective study. Specifically, please ensure that you have discussed whether all data/samples were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data/samples from their medical records used in research, please include this information.

4. To comply with PLOS ONE submission guidelines, in your Methods section, please provide additional information regarding your statistical analyses. For more information on PLOS ONE's expectations for statistical reporting, please see https://journals.plos.org/plosone/s/submission-guidelines.#loc-statistical-reporting.

5. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I see that the data may not be free accessible, but I would presume it could be 'washed' of any identifying features?

As for the manuscript, the only comment I have is that it would be nice to see some of the statistics in a more compelling way. In particular, it is suggested that the big worry is the irrational prescribing for some subsets of the population. If the breakdown of the statistics was made for these populations within a table, some of the concerns/results would come through more clearly. For example, if Graph 2 was split for the elderly and for elderly males and females, that would really help to emphasise the point.

It would also be nice to get a bit more clarity on how the review of medical notes was done. Were there cases that were unclear? How were those addressed? Did each of the authors look through all of the notes to reach agreement, or was that chore split...

Reviewer #2: This is a useful review that uses standard methods . I would encourage publication after minor revisions as very few of these Medicine Use Evaluations are published in Low and Middle Income Countries. The work undertaken in this study could be replicated in many LMICs.

Specific Comments

Abstract The abstract includes the sentence "Amitriptyline is widely used in primary care in South Africa

and a cross-sectional study found that amitriptyline was prescribed potentially

inappropriately in 6.5% of patients." The reference to which this refers is I think reference 11. This was a study of "eldeley" patients. That should be made clear in the abstract.

Background Line 89. I suggest that the equivalent amount in USDollars be provided for the 3.5 million Rand to provide a context for non South African readers.

Methods I would like some more details of the "convenience sample". Clinical notes of outpatients in the public health sector of Western Cape could cover a broad range of facilities. Did the convenience sample of sixty four facilities come from all districts or was it limited to the Cape Town Metro region from which two of the four authors come. How many facilities with low amitryptiline facilities were excluded. What was the retrospective time period for which the records were reviewed?

Table 1 includes mention of Major Depressive Disorders. No abbreviation (MDD) for this term is provided. Later in the text on Lines 190 and 194 the abbreviation is used. I would suggest including the abbreviation the first time it is used.

Results Line 139 mentions that hospitals made up 20% of the sample. I would suggest repeating that only outpatient prescribing records were used. Hospital MUE's can be confused if inpatient and outpatient data are mixed.

Discussion I found the discussion very readable and interesting. One aspect that was not mentioned is how rare it is in LMICs for MUEs to be done for mental health medicines. Antibiotic use is frequently reviewed but mental health medicines are rarely studied. I was surprised at the relatively high rate of use according to guidelines. I was not surprised at the low dosage used for the treatment of depression. This has been reported elsewhere.

Conclusion. This is a useful study which has used robust methods that could be replicated in outer LMIC health systems. For that reason alone this paper should be published. The revisions I have suggested should be seen as clarifications.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Steven F Koch

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

2 Mar 2020

Also see cover letter:

Comments addressed by authors:

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at http://www.plosone.org/attachments/PLOSOne_formatting_sample_main_body.pdf and http://www.plosone.org/attachments/PLOSOne_formatting_sample_title_authors_affiliations.pdf

This was noted and adjusted accordingly. The authors welcome further guidance from the lay-out editorial team.

2. We noticed you have some minor occurrence(s) of overlapping text with the following previous publication(s), which needs to be addressed:

https://doi.org/10.1001/jama.286.22.2823

https://doi.org/10.1093/ajhp/56.5.433

http://www.healthconnect-intl.org/IRD_feb13.html

http://dx.doi.org/10.22270/jddt.v9i3.2649

This was noted as an error and corrected. The article by Rajender et al was cited, while Zhan et al was found to reference the same authors as us, namely Wilcox et al (reference number 9). The last two links are websites that actually reference the World Health Organization documents listed in our reference list.

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the Methods section. Further consideration is dependent on these concerns being addressed.

3. In the ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records/samples used in your retrospective study. Specifically, please ensure that you have discussed whether all data/samples were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data/samples from their medical records used in research, please include this information.

Additional information was provided under the sub-heading “Ethical Considerations”. Informed consent for patients were not required. Patient folders were reviewed retrospectively.

4. To comply with PLOS ONE submission guidelines, in your Methods section, please provide additional information regarding your statistical analyses. For more information on PLOS ONE's expectations for statistical reporting, please see https://journals.plos.org/plosone/s/submission-guidelines.#loc-statistical-reporting.

Noted. The necessary description was added in the method section.

5. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

This was noted. Data will be uploaded as supporting material. Statements updated as required.

5. Review Comments to the Author

Reviewer #1: I see that the data may not be free accessible, but I would presume it could be 'washed' of any identifying features?

Data will be made available as supporting information.

As for the manuscript, the only comment I have is that it would be nice to see some of the statistics in a more compelling way. In particular, it is suggested that the big worry is the irrational prescribing for some subsets of the population. If the breakdown of the statistics was made for these populations within a table, some of the concerns/results would come through more clearly. For example, if Graph 2 was split for the elderly and for elderly males and females, that would really help to emphasise the point.

For the purpose of the review we have complied with the request and provided a table (Table 3) containing the split. It should be noted that the numbers are then smaller and might not be as compelling. Our aim was not to answer our questions in this way, but rather to give a broad overview of use in a specific population. We welcome further comments and recommendations.

It would also be nice to get a bit more clarity on how the review of medical notes was done. Were there cases that were unclear? How were those addressed? Did each of the authors look through all of the notes to reach agreement, or was that chore split...

Addressed in the reviewed manuscript. Folders were reviewed independently and discrepancies were discussed with the main authors.

Reviewer #2: This is a useful review that uses standard methods . I would encourage publication after minor revisions as very few of these Medicine Use Evaluations are published in Low and Middle Income Countries. The work undertaken in this study could be replicated in many LMICs.

Specific Comments

Abstract The abstract includes the sentence "Amitriptyline is widely used in primary care in South Africa and a cross-sectional study found that amitriptyline was prescribed potentially

inappropriately in 6.5% of patients." The reference to which this refers is I think reference 11. This was a study of "eldeley" patients. That should be made clear in the abstract.

Background Line 89.

Noted and corrected in the reviewed manuscript.

I suggest that the equivalent amount in USDollars be provided for the 3.5 million Rand to provide a context for non South African readers.

This was noted and corrected.

Methods I would like some more details of the "convenience sample". Clinical notes of outpatients in the public health sector of Western Cape could cover a broad range of facilities. Did the convenience sample of sixty four facilities come from all districts or was it limited to the Cape Town Metro region from which two of the four authors come. How many facilities with low amitryptiline facilities were excluded. What was the retrospective time period for which the records were reviewed?

We described the distribution of health facilities better and provided a breakdown of rural vs. urban facilities. Please see the amended text.

Table 1 includes mention of Major Depressive Disorders. No abbreviation (MDD) for this term is provided. Later in the text on Lines 190 and 194 the abbreviation is used. I would suggest including the abbreviation the first time it is used.

This was corrected at first mention. Major Depressive Disorders were written in full.

Results Line 139 mentions that hospitals made up 20% of the sample. I would suggest repeating that only outpatient prescribing records were used. Hospital MUE's can be confused if inpatient and outpatient data are mixed.

This was corrected to clearly describe outpatient use only. Inpatients were not part of the study.

Discussion I found the discussion very readable and interesting. One aspect that was not mentioned is how rare it is in LMICs for MUEs to be done for mental health medicines. Antibiotic use is frequently reviewed but mental health medicines are rarely studied. I was surprised at the relatively high rate of use according to guidelines. I was not surprised at the low dosage used for the treatment of depression. This has been reported elsewhere.

We note the above comment. Adding a comment on the rarity of utilization reviews done in LMIC were added in the background.

30 Mar 2020

Amitriptyline prescribing in public sector healthcare facilities in the Western Cape, South Africa

PONE-D-19-33673R1

Dear Dr. Coetzee,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

With kind regards,

Vijayaprakash Suppiah, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I only had rather minor comments the first time through, as did the other reviewer. In my view, the comments have been adequately addressed.

Reviewer #2: All reviewer comments have been addressed. I believe that this is a useful article to be published as there are very few MUE's of Mental health topics in LMICs.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Prof Steven F. Koch

Reviewer #2: Yes: Richard Laing

6 Apr 2020

PONE-D-19-33673R1

Amitriptyline prescribing in public sector healthcare facilities in the Western Cape, South Africa

Dear Dr. Coetzee:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

For any other questions or concerns, please email plosone@plos.org.

Thank you for submitting your work to PLOS ONE.

With kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Vijayaprakash Suppiah

Academic Editor

PLOS ONE