Opioid prescribing in out-of-hours primary care in Flanders and the Netherlands: A retrospective cross-sectional study.

BACKGROUND: Increased opioid prescribing has raised concern, as the benefits of pain relief not always outweigh the risks. Acute and chronic pain is often treated in a primary care out-of-hours (OOH) setting. This setting may be a driver of opioid use but the extent to which opioids are prescribed OOH is unknown. We aimed to investigate weak and strong opioid prescribing at OOH primary care services (PCS) in Flanders (Northern, Dutch-speaking part of Belgium) and the Netherlands between 2015 and 2019.
METHODS: We performed a retrospective cross sectional study using data from routine electronic health records of OOH-PCSs in Flanders and the Netherlands (2015-2019). Our primary outcome was the opioid prescribing rate per 1000 OOH-contacts per year, in total and for strong (morphine, hydromorphone, oxycodone, oxycodone and naloxone, fentanyl, tapentadol, and buprenorphine and weak opioids (codeine combinations and tramadol and combinations) and type of opioids separately.
RESULTS: Opioids were prescriped in approximately 2.5% of OOH-contacts in both Flanders and the Netherlands. In Flanders, OOH opioid prescribing went from 2.4% in 2015 to 2.1% in 2017 and then increased to 2.3% in 2019. In the Netherlands, opioid prescribing increased from 1.9% of OOH-contacts in 2015 to 2.4% in 2017 and slightly decreased thereafter to 2.1% of OOH-contacts. In 2019, in Flanders, strong opioids were prescribed in 8% of the OOH-contacts with an opioid prescription. In the Netherlands a strong opioid was prescribed in 57% of these OOH-contacts. Two thirds of strong opioids prescriptions in Flanders OOH were issued for patients over 75, in the Netherlands one third was prescribed to this age group.
CONCLUSION: We observed large differences in strong opioid prescribing at OOH-PCSs between Flanders and the Netherlands that are likely to be caused by differences in accessibility of secondary care, and possibly existing opioid prescribing habits. Measures to ensure judicious and evidence-based opioid prescribing need to be tailored to the organisation of the healthcare system.

Introduction

In Western countries opioid prescribing has increased rapidly over the past decades [1-3], mainly caused by an increase in opioid prescribing to treat chronic pain not related to cancer [4,5]. While short-term use of opioids is relatively safe, the use for chronic pain not related to cancer is problematic in the absence of evidence that the benefits outweigh the risk of developing opioid dependence, opioid use disorder, overdose and death [6-10].

The escalation in opioid prescribing in the United States of America (USA) and Canada, is accompanied by an increase in opioid-related hospitalization, mortality and number of patients in addiction care and has raised global concern [11]. In European countries, such as Belgium and the Netherlands, the use and misuse of prescription opioids also increased, but not to the same extent [3,12,13]. In Belgium, the number of prescription opioid sales increased with 6.8% between 2013 and 2019 with the highest increases reported for oxycodone and tramadol [14]. In the Netherlands the number of prescription opioid users nearly doubled between 2007 and 2017, from 4,100 users per 100,000 inhabitants to 7,500 per 100,000 inhabitants [12,15] with a four-fold increase in the number of oxycodone users.

In several European countries like the UK, Flanders (the Northern, Dutch speaking part of Belgium) and the Netherlands, out-of-hours primary care services (OOH-PCS) provide acute primary care during evenings, nights and weekends when the patient’s own primary care provider is unavailable. Problems commonly presented at the primary care OOH setting include trauma, such as laceration and cuts, infections, such as upper respiratory infections or gastroenteritis, and abdominal pain [16]. Thus, like in other acute care settings, relief of acute pain and acute exacerbations of chronic pain [17] are essential activities of the primary OOH health care providers. Moreover, from previous studies in the acute care setting of emergency departments it is known that opioid prescribing in this acute setting may lead to persistent and high risk opioid use in up to 17% of patients starting with an opioid [18,19]. It is therefore important to investigate the extent of opioid prescribing in the primary care OOH setting.

In the current study we assess opioid prescribing in the primary care OOH setting in the neighbouring regions/countries, Flanders and the Netherlands. Both regions have concerns about the increasing national trends in opioid prescribing. However, the embedding of acute primary care in the health system differs. The scales of the OOH-PCSs in Flanders and the Netherlands are similar, but access to primary and secondary health care is organized differently. In Flanders, both the OOH-PCS and secondary (emergency) care are accessible without referral, whereas Dutch GPs (also in the OOH setting) have a gate keeper role for secondary and tertiary care, and patients are expected to contact the OOH-PCS by phone where triage is done prior to follow-up [16]. These differences in the organization of acute primary care may lead to differences in patient groups who consult the OOH-PCS [16] and thus also to differences in opioid prescribing.

The primary goal of this study is to study the prescribing of weak and strong opioids at the OOH-PCS between 2015 and 2019 in Flanders and the Netherlands. Additionally, this study explores which opioids were prescribed most frequently by GPs in OOH-PCSs in both regions.

Methods

Design and population

We performed a retrospective cross sectional study using routinely recorded electronic health records data of OOH-PCSs over the period 1 January 2015 to 31 December 2019 for Flanders and the Netherlands. In Flanders, data was acquired from iCAREdata [20,21], which comprises 5 to 9 OOH-PCSs over this five-year-period, covering more than 10% of Flanders’ population. In the Netherlands, we used data collected in the Nivel Primary Care Database (Nivel-PCD, [22]). A database containing electronic health records data from 20 to 27 Dutch OOH-PCSs with a joint catchment area of more than half of the Dutch population (Table 1). The population in the catchment area of Nivel-PCD OOH-PCSs is representative for patient age and sex of the Dutch population. This is also the case in Flanders. Due to the extensive distribution over the whole of Flanders, a representative sample considering age and gender is available.

Table 1

Description of the OOH-databases in Flanders and the Netherlands.

	Flanders (iCARE database)						The Netherlands (Nivel Primary Care Database)
		2015	2016	2017	2018	2019	2015	2016	2017	2018	2019
Number of OOH-PCSs#		5	7	7	7	9	20	24	27	23	23
Population number*		803,809	1,124,449	1,131,191	1,124,046	1,604,329	8,236,133	10,757,942	11,259,938	9,057,552	10,549,980
Number of contacts**		56,350	80,492	81,898	88,672	130,621	2,108,919	2,703,643	2,770,026	2,308,766	2,656,910
Number of contacts per 1000 inhabitants in catchment area		70.1	71.6	72.4	78.9	81.4	256.1	251.3	246.0	254.9	251.8

# For NL: Number of OOH-PCS cooperations.

*FL has a total population of almost 7 million inhabitants; NL has a total population of approximately 17 million inhabitants.

**In Flanders, OOH care includes consultations and visits during weekends, in the Netherlands, OOH-care includes telephone consultations, consultations and visits during working day evenings, and weekends (numbers for the Netherlands when excluding contacts during evenings and nights on working days and telephone contacts: 806,919, 1,022,721, 1,023,728, 815,414, 906,621).

Description of the data

We extracted patient age, sex, health problem (ICPC code, International Classification of Primary Care), contact date, contact type (face-to face consultation/home visit), and opioid prescriptions (ATC-code, Anatomic Therapeutic Classification) from the electronic health records of the OOH-PCS. We included the following opioids:

strong opioids: morphine (N02AA01, N02AA51), hydromorphone (N02AA03), oxycodone (N02AA05), oxycodone and naloxone (N02AA55), fentanyl (N02AB03), tapentadol (N02AX06), buprenorphine (N02AE01)

weak opioids: codeine combinations (N02BE51, N02AA59, N02AJ06), tramadol (N02AX02), tramadol combinations (N02AJ13, N02AX52))

other opioids: nicomorphine (N02AA04), pethidine (N02AB02), dextromoramide (N02AC01), piritramide (N02AC03)

To improve the comparability of the Flemish and Dutch dataset, we performed an additional analysis in which we excluded the following contacts: (i) telephone contacts in the Netherlands as these are not available in the Flemish system, (ii) contacts on weekdays in the Netherlands. Dutch OOH-PCSs are also open on evenings and nights of weekdays, while Flemish OOH-PCS are not. Therefore, in this additional analysis, for both regions, we only used data from the weekends (19 p.m. on Fridays until 7 a.m. on Mondays).

Data analysis

To assessopioid prescribing over 2015–2019 at the OOH-PCS, we calculated the number of OOH-PCS contacts during which an opioid was prescribed per 1000 OOH-PCS contacts per year. We did this for all opioids combined, and for strong and weak opioids separately. Contacts in which both types of opioids were prescribed were included in both groups. We also assessed the distribution of specific types of opioids, such as morphine and oxycodone, in Flemish and Dutch OOH-PCSs per year. We determined the most common diagnoses for which an opioid was prescribed. Contacts with a missing ICPC code were included in the analyses (0% for Flanders and 5% for the Netherlands).

Ethical approval

Flanders: iCAREdata received approvals concerning patients participation and opt-out options from the Sectoral Committee of Social Security and Health of the Privacy Commission (Beraadslaging_AG_094_2014 and Beraadslaging_AG_094_2014bis) and from the Ethics Committee of the Antwerp Academic Hospital (Approval 13/34/330, dd 02/09/2013). Data were pseudonymized and did not comprise any directly identifying personal information such as names, addresses and citizen service number.

The Netherlands: The use of personal data for research purposes in the Netherlands is regulated under the Dutch Medical Treatment Contracts Act (WGBO). The WGBO stipulates that explicit consent is not required if a) requesting consent is not reasonably possible (if for example the patient is deceased) or- if b) the request for permission cannot reasonably be expected from the caregiver. The latter can refer to situations in which too great effort an effort is needed from health care providers to, or when asking for permission would lead to a selective response. However, data collection should take place taking into account all possible organizational and technical measures needed. In addition the Medical Research Involving Human Subjects Act (WMO), stipulates that approval by one of the national medical ethical committees is required only if the research involves humans subjected to actions or if rules of behavior are imposed on them. This is not the case in our study. OOH-PCSs that participate in Nivel-PCD are contractually obliged to: (i) inform their patients about their participation in Nivel-PCD and (ii) to inform patients about the option to opt-out for inclusion of their data in the database. Data were pseudonymized before leaving the health care organization’s premises and did not comprise any directly identifying personal information such as names, addresses and citizen service number [23]. Neither obtaining informed consent from patients nor approval by a medical ethics committee is obligatory for observational studies containing no directly identifiable data (Dutch Civil Law, Article 7: 458). The study was approved according to the governance code of Nivel-PCD under number: NZR-00319.034, and all legally required technical and organizational measures were applied to avoid real life identification of subjects.

Results

Between 2015 and 2019, approximately 1.9 to 2.5% of OOH contacts resulted in an opioid prescription. Fig 1 and S1A (the Netherlands) and S1B (Flanders) Table show the changes in total, weak and strong opioid prescribing over time. In Flanders, the number of contacts with an opioid prescription decreased from 24.1 per 1000 OOH contacts in 2015 to 20.6 per 1000 OOH contacts in 2017 (relative decrease of 14.5%) and increased thereafter to 23.5 per 1000 OOH contacts in 2019. In the Netherlands, opioid prescribing increased from 19.8 per 1000 OOH contacts in 2015 to 24.5 per 1000 OOH contacts in 2017 (relative increase of 23.7%), and decreased thereafter to 21.4 per 1000 OOH contacts in 2019. S1B Table shows the same numbers for the Netherlands when excluding weekday and telephone contacts, comparable to OOH-care in Flanders. The relative changes over the years are similar, but the opioid prescribing rate is somewhat higher (ranging between 21.7 and 28.0).

Fig 1

Opioid prescribing in out-of-hours primary care in the Netherlands (upper panel) and Flanders (lower panel) between 2015 and 2019, number of contacts with an opioid prescription per 1000 OOH-contacts.

OOH-PCS = out-of-hours primary care service.

Prescription rates for strong opioids in OOH care decreased from 2.1 per 1000 contacts in 2015 to 1.3 in 2018 and increased to 1.8 per 1000 contacts in 2019 (14.3% relative decrease between 2015 and 2019). In the Netherlands, strong opioid prescribing increased from 9.7 to 13.3 per 1000 contacts between 2015 and 2017 (37.1% increase) and slightly decreased thereafter to 12.3 per 1000 contacts in 2019.

Type of opioid prescribed

Fig 2 and S1A Table show the specific types of opioids prescribed in OOH-PCSs in Flanders and the Netherlands. In Flanders, fentanyl, morphine and oxycodone were the most frequently prescribed strong opioids (in 2019 0.3, 0.9 and 0.6 per 1000 contacts respectively). In the Netherlands, morphine and oxycodone were the most commonly prescribed strong opioids over time (in 2019 6.9 and 4.5 per 1000 contacts). In Flanders, tramadol is the most frequently prescribed weak opioid (11.4 per 1000 contacts in 2019), but the prescribing of tramadol combinations and codeine combinations is also substantial, as illustrated by Fig 2 (4.8 and 3.7 per 1000 contacts in 2019). Tramadol was the most frequently prescribed weak opioid in the Netherlands (approximately 80% of all weak opioid prescriptions, 7.8 per 1000 contacts in 2019).

Fig 2

Distribution of type of opioid prescribed in out-of-hours primary care, separately for strong (upper panel) and weak opioids (lower panel) in Flanders and the Netherlands.

The figure does not reflect the relative proportions in prescribing of weak and strong opioids over time (see Fig 1).

Diagnoses for which opioids were prescribed

There was high concordance in both countries on the top-10 diagnoses recorded with a prescription for weak opioids (S2 Table). This list included mostly back-pain and other locomotor system pain, as well as, at lower frequencies, dental pain and stomach pain. These also topped the list of diagnoses recorded with strong opioids, along with dyspnea. In the Netherlands bile duct problems and kidney stones also ranked in the top 10 of diagnoses recorded with strong opioids.

Characteristics of patients with an opioid prescription

Table 2 shows the patient characteristics of patients with an OOH opioid prescription. More than half the patients with an opioid (either strong or weak) was female, both in Flanders and the Netherlands. The age distribution of patients with weak opioids was comparable between Flanders and the Netherlands. However, the age distribution of strong opioid users differs between the countries. Strong opioids were mainly prescribed to patients aged 75 or older in Flanders (64% vs 30% in the Netherlands). The sex and age distribution of patients with an opioid prescription OOH did not change during the study period (S3 Table).

Table 2

Age and sex distribution of patients with an opioid prescription at the out-of-hours service, in Flanders and the Netherlands in 2019.

	All opioids		Weak opioids		Strong opioids
	FL	NL	FL	NL	FL	NL
Total
Sex (% females)	58.2	56.4	58.1	58.2	60.0	55.2
Age category (%)
0–14    15–24    25–44    45–64    65–74    75+	0.26.032.733.69.917.6	0.15.326.032.413.722.4	0.26.534.935.29.513.7	0.27.832.834.511.713.1	007.013.515.264.3	0.13.320.630.615.330.1

Discussion

In this study, we analysed the weak and strong opioid prescribing in OOH-PCSs in both Flanders and the Netherlands between the years 2015 and 2019. In Flanders we observed a slight decrease in OOH opioid prescribing between 2015 and 2019, with the lowest prescription rates in 2017. This trend was present for both weak and strong opioids. For the Netherlands, we observed an increase in OOH opioid prescribing between 2015 and 2017, and a decrease in 2018 and 2019. The increase between 2015 and 2017 was driven by increased prescribing of strong opioids, while weak opioids prescribing remained stable. These changes (both the increase and the decrease thereafter) are consistent with the opioid prescribing trends in the Netherlands in the non-acute primary care setting [15]. The observed decrease in opioid prescribing is likely the result of increased attention since the end of 2017 for the steep rise in and risks of opioid prescribing. In the Netherlands, more than half of all opioids prescribed at the OOH-PCS were strong opioids, which was also comparable to figures in non-acute primary care [15,24].

Prescribing of strong opioids

We observed a marked difference in prescribing of weak and strong opioids between Flanders and the Netherlands. This may be explained by differences in the OOH-setting resulting in a different patient population. This suggests that OOH-PCSs in the Netherlands, which have a gate keeping role, are consulted for more severe cases than OOH-PCSs in Flanders, where secondary care, but also the OOH-PCS, is directly accessible. Furthermore, in the Netherlands patients are expected to contact the OOH-PCS by phone, when formal triage is done, after which follow-up is done on telephone, at a consultation, or in a home visit. This is corroborated by the difference in diagnoses that opioids are prescribed for during OOH. While kidney stones were the main reason for prescribing strong opioids in OOH-PCS in the Netherlands, this diagnosis was not among the top-10 diagnoses with strong opioids prescribed in OOH care in Flanders. It seems likely that patients suffering from kidney stones directly consulted the hospital emergency department in Flanders.

In Flanders tramadol/paracetamol combinations were often prescribed, in spite of the weak scientific evidence for their use [25,26] and their absence from the guidelines [27,28]. This may be related to the reimbursement status of paracetamol in Belgium. Paracetamol-only products are only reimbursed in Belgium for chronic use after additional administrative hurdles that prelude its use in acute pain [14]. A similar situation holds for the codeine/paracetamol combination products, which could explain their lower share in the OOH-PCSs in Flanders. In marked contrast, tramadol/paracetamol combinations are routinely reimbursed and frequently prescribed. Furthermore, substantial amounts of fentanyl were prescribed in Flemish OOH-PCSs. These are not indicated for acute pain relief or as first choice opioid in case a strong opoid is indicated. However, it is difficult to assess the validity of these OOH prescriptions as they may be an extension of an existing treatment with transdermal fentanyl. In that case it however remains questionable whether these people require OOH-care to obtain a prescription for a chronic condition.

In the Dutch OOH-PCS setting morphine was the most commonly prescribed strong opioid, followed by oxycodone. This differed from trends in opioid prescribing in general practices, where oxycodone is the most commonly prescribed strong opioid [12,15]. During OOH Dutch GPs hardly prescribe fentanyl, whereas in non-acute general practice, fentanyl was prescribed as often as morphine [12,15]. This difference in type of opioid may be explained by a difference in health problems that are encountered during OOH compared to non-acute general practice. Kidney stones were the most common diagnosis for which Dutch GPs prescribed a strong opioid during OOH. To quickly relieve acute severe pain, patients with kidney stones are injected with morphine.

Opioid prescribing for locomotor system problems

Both in Flanders and in the Netherlands, strong opioids were prescribed for back pain and related locomotor system problems. Strong opioids are not intended for chronic use in these type of health problems [29]. However, from the available data, we could not deduct the amount or dosage of prescribed opioids and whether they were initiated at the OOH-PCS or were already used chronically.

Age distribution of patients with an opioid

In Flanders, strong opioids were mainly prescribed to older adults, while in the Netherlands, these were also often prescribed to middle-aged adults. This may be explained by the difference in access to secondary care and presented health problems at the OOH-PCS in the two regions [16]. In general, it is advised to be cautious when prescribing weak opioids to older adults, as it may cause mental confusion [30]. Use of strong opioids leads to an increased fall risk, which is related to mortality in older adults [31].

Study strengths and limitations

The strength of this study is that we rely on large datasets derived from routinely recorded electronic health records to assess opioids prescribing in OOH primary care over a period of five years in two adjacent but different regions/countries, Flanders and the Netherlands. This study, however, also has a number of limitations. First, we did not have precise information on the amount and duration of opioids that were prescribed. Both amount and duration are related to risks for patients [32] and are therefore important indicators of the quality of opioid prescribing. Second, for analysis of the indications for opioid prescription we depended on diagnosis recording by the GP. Third, we did not assess whether opioid prescribing was the start of chronic and potentially problematic opioid use. Last, we did not statistically test whether changes in opioid prescribing over time were significant.

Implications of the study findings

In approximately 2 to 2.5% of all OOH-PCS contacts an opioid was prescribed in both Flanders and the Netherlands. There are no signs of a strong increase in opioid prescribing at OOH-PCSs in Flanders and the Netherlands over the years. Nevertheless, we did observe a marked difference between Flanders and the Netherlands in the prescribing of strong opioids, that are likely caused by differences in the accessibility of secondary care. This implies that the development of measures to stimulate appropriate (strong) opioid prescribing should take into account the organisation of the health care system. Further study on the appropriateness of these prescriptions is needed to determine whether opioid prescriptions in the OOH-PCS are a driver of problematic opioid use.

Conclusion

In this first database study of out-of-hours primary care opioid prescribing we did not observe a large increase in OOH-PCS opioid prescribing between 2015 and 2019 in Flanders, nor in the Netherlands. We did observe large differences in strong opioid prescribing between the two neighbouring regions that are likely to be caused by differences in accessibility of secondary care, and possibly existing opioid prescribing habits. Measures to control opioid prescribing should thus be developed taking into account the organisation of the health care system.

Number of contacts with at least one opioid prescription at the OOH-PCS per 1000 OOH-PCS contacts in 2015–2019 in the Netherlands and in the weekend at the OOH-PCS per 1000 OOH-PCS weekend-contacts in 2015–2019 in Flanders and the Netherlands.

(DOCX)

Click here for additional data file.

Top 10 diagnoses of OOH contacts with > = 1 opioid prescription in Flanders and the Netherlands in 2018.

(DOCX)

Click here for additional data file.

Sex and age distribution of patients with an opioid prescription at the OOH-PCS, in Flanders and the Netherlands in 2015–2019.

(DOCX)

Click here for additional data file.

2 Dec 2021

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Reviewer #1: The authors present a retrospective observational study examining data from routine electronic health records (EMRs) of patients in the Flanders and the Netherlands from 2015 to 2019. They analyzed the number of contacts in which GPs prescribed an opioid and the type of opioids that were prescribed. The opioid crisis in the United States has increased concerns about appropriate opioid prescribing and the significance of clearly defining the benefits and risks of utilizing opioid analgesics in patients suffering from pain. Evaluating real-world prescribing patterns can provide better insight into the creation of national guidelines.

The manuscript is engaging, timely, impactful, and interesting. The described manuscript format is appropriate, and there are ethical issues noted. The manuscript is referenced and structured correctly, and the results support the conclusions. The authors described the study's limitations which might question the generalizability of the data and therefore should suggest that further studies are needed.

Reviewer #2: Thank you for the opportunity to review this retrospective cross-sectional study that examines out-of-hours primary care opioid prescribing in the Netherlands and Flanders. The paper examines an often overlooked source of opioid prescriptions and utilizes two data sources that provide sufficient generalizability for their study areas. The scope is somewhat limited to health systems and countries that have similar models, but that is true of many studies and is hardly a criticism. I think the strength of the study is in their comprehensive data source and straight forward design. I do think the attempts to compare the two regions came up short; there weren't any statistical analyses comparing the two regions. However the authors do an admirable job of explaining why the regions differ in the rates/types of opioid prescribed, interpreting the results within the context of the local environment, and provide the non-European reader (Me) an understanding of the healthcare environment in those two countries/regions. I strongly question the decision to remove the weekday visits from the Netherlands analysis. I can appreciated that this was done to provide a more direct comparison between the two regions. But since there were no analyses done, you've just removed a large number of contacts (visits?) (2 million per year!!!!) and severely biases your study. I would think that by including these visits the reader would gain a much more complete understanding of the role of OOH-PCSs in opioid prescribing, which I believe to be the true benefit of the study (not the regional comparison). In the event that you want to statistically compare the regions, these can be removed.

Specific Comments:

Abstract

Background, Page 2, line 37-38: delete "that differ in the way..." as it is very confusing to read and is not necessary for the abstract

Methods: need to provide more info- study is a retrospective cross sectional study; what is the primary outcome (mean yearly rate of opioid prescriptions per 1000 visits); what are strong v weak opioids; define GP. Also, if you aren't doing a statistical analyses of the yearly rate, you shouldn't use the term "trend". I think it would be very easy to do a piece-wise linear regression using 2017 as a midpoint.

Results, Page 2, line 44-48: Would rewrite the description of the opioid prescribing rates in Flanders to read more like the Netherlands description (rates went from xx to y between 2015 - 2017 and then increased to zzz in 2019.

Page 2, line 48-49: "...OOH-contacts concerning an opioid prescription". I'm assuming that you mean that strong opioids were prescribed 8% of the time WHERE an opioid was prescribed. I would just clarify as it is a little confusing as written.

Conclusion, Page 2, line 55-56: I would rewrite this to something of the effect of "Measures to ensure judicious and evidenced-based prescribing of opioids need to be tailored to the local healthcare system organization".

Introduction

Page 3, line 64: "...benefits outweigh the risk of developing opioid dependence, opioid use disorder, overdose..."

Page 3, line 74-75: "Acute and chronic pain..." this line is out of place in context with the preceding paragraph

Page 3, line 76: I would provide the "definition" of Flanders earlier in the manuscript

Page 3, line 82-84: I would provide an actual number describing the risk of persistent opioid use after prescription (could use Shah A, Hayes CJ, Martin BC. Characteristics of Initial Prescription Episodes and Likelihood of Long-Term Opioid Use - United States, 2006-2015. MMWR Morb Mortal Wkly Rep. 2017;66(10):265-269)

Page 3, line 91: "...with each 80 to 160 GPs" Is this the number of GPs per OOH?

Page 3-4, line 90-106: This explanation of the differences in the care models of the Netherlands and Flanders is excellent and completely necessary to interpret the findings of the study. However it needs to be condensed and moved to the discussion. You can introduce a very brief explanation in the intro to justify why you are comparing the two regions, but the bulk of the description should be reserved for the discussion

Methods

Page 4, line 113: I would think this is a retrospective cross sectional study

Page 4, line 116 and line 121: Does iCAREdata cover 10% or 66% of the Flemish population?

Page 6, line 146-148: I think it is unwise to exclude these data. The comparison between the regions seems like a secondary aim. You are excluding 2 million contacts per year...that's a lot. I would strongly encourage you to include these visits in your yearly descriptions and in the event you go back and perform a statistical analyses comparing the regions, you can then remove them. Trying to describe this very narrow subset of weekend contacts that result in an prescription is just not nearly as helpful.

Page 6, line 150: ALL means need to have 95% CI

Results

All values that represent mean need 95% CI. And please be consistent with the number of significant figures you are using.

Page 6, line 171-172: Would re-write first sentence "Between 2015-2019, XXX (2.5%) OOH-contacts resulted in an opioid prescription (Figure 1, Table S1)"

Page 6-7, line 173-177: I am not following your % decrease calculation; going from 24 --> 21% is an absolute reduction of 3%. 1-(21/24) = 12.5% relative reduction. If my math is incorrect please let me know

Page 7, line 178-179: I would continue to present the mean (with 95% CI) values instead of switching to range.

Page 7, line 188: Give % for each opioid

Discussion

I would encourage you to include some discussion on how these results compare to other studies that describe opioid prescribing, particularly those that examine sources of opioid prescribing. Listed are references that I am familiar with as a US-based provider (Temporal Trends in Opioid Prescribing Practices in Children, Adolescents, and Younger Adults in the US From 2006 to 2018, JAMA Pediatr

. 2021 Oct 1;175(10):1043-1052. doi: 10.1001/jamapediatrics.2021.1832. Opioid Prescribing to US Children and Young Adults in 2019, Pediatrics

. 2021 Sep;148(3):e2021051539. doi: 10.1542/peds.2021-051539. Epub 2021 Aug 16. Variation in Adult Outpatient Opioid Prescription Dispensing by Age and Sex — United States, 2008–2018, MMWR Morb Mortal Wkly Rep. 2020 Mar 20;69(11):298-302. doi: 10.15585/mmwr.mm6911a5.).

Page 8, line 217-218: "Overall we did...nor in the Netherlands." Were you expecting to see a large increase? Was that your hypothesis? Seems odd to state this here, would delete.

Page 8, line 223-225: Are you saying that the overall trend of decreasing opioid prescribing is secondary to the increased knowledge of the dangers of opioids?

It is confusing as this sentence just follows your statement that prescribing of strong opioids increased between 2015-2019 so it makes it seem like you are saying the attention being paid to prescribing has lead to increased strong opioid prescribing

Page 9, line 254: Please provide a reference

Page 9-10: Given the high prevalence of tramadol in your sample, I would include some discussion on the recent paper that showed increased mortality with tramadol (Association of Tramadol vs Codeine Prescription Dispensation With Mortality and Other Adverse Clinical Outcomes, JAMA. 2021 Oct 19;326(15):1504-1515. doi: 10.1001/jama.2021.15255.)

Limitations: IF you are going to continue to exclude the weekday contacts in the Netherlands, it needs to be listed in the limitations as this is excluding the majority of contacts from the Netherlands and significantly biases the results. As stated previously, would strongly encourage you to include these results and perform trend analysis.

Tables and Figures

Try to use "." or "," as decimal points...you go back and forth in the supplemental material

Figure 1: Year should be on the X-axis

**********

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4 Feb 2022

We thank the reviewers for their valuable comments that helped us to improve our manuscript. We provide a point-by-point reply below. Numbering of the comments starts at 7, as comment 1 to 6 were comments regarding journal requirements, that were replied to separately.

Reviewer #1:

7.

The authors present a retrospective observational study examining data from routine electronic health records (EMRs) of patients in the Flanders and the Netherlands from 2015 to 2019. They analyzed the number of contacts in which GPs prescribed an opioid and the type of opioids that were prescribed. The opioid crisis in the United States has increased concerns about appropriate opioid prescribing and the significance of clearly defining the benefits and risks of utilizing opioid analgesics in patients suffering from pain. Evaluating real-world prescribing patterns can provide better insight into the creation of national guidelines.

The manuscript is engaging, timely, impactful, and interesting. The described manuscript format is appropriate, and there are ethical issues noted. The manuscript is referenced and structured correctly, and the results support the conclusions. The authors described the study's limitations which might question the generalizability of the data and therefore should suggest that further studies are needed.

Author’s reply: We thank the reviewer for the compliments. We agree with the reviewer that further study is required to shed further light on the appropriateness of opioid prescriptions out-of-hours and whether this is a driver of problematic opioid use. We included a sentence on required further study in the implications section in the discussion of the manuscript: “Further study on the appropriateness of these prescriptions is needed to determine whether opioid prescriptions in the OOH-PCS are a driver of problematic opioid use.”

Reviewer #2:

8.

Thank you for the opportunity to review this retrospective cross-sectional study that examines out-of-hours primary care opioid prescribing in the Netherlands and Flanders. The paper examines an often overlooked source of opioid prescriptions and utilizes two data sources that provide sufficient generalizability for their study areas. The scope is somewhat limited to health systems and countries that have similar models, but that is true of many studies and is hardly a criticism. I think the strength of the study is in their comprehensive data source and straight forward design. I do think the attempts to compare the two regions came up short; there weren't any statistical analyses comparing the two regions. However the authors do an admirable job of explaining why the regions differ in the rates/types of opioid prescribed, interpreting the results within the context of the local environment, and provide the non-European reader (Me) an understanding of the healthcare environment in those two countries/regions. I strongly question the decision to remove the weekday visits from the Netherlands analysis. I can appreciated that this was done to provide a more direct comparison between the two regions. But since there were no analyses done, you've just removed a large number of contacts (visits?) (2 million per year!!!!) and severely biases your study. I would think that by including these visits the reader would gain a much more complete understanding of the role of OOH-PCSs in opioid prescribing, which I believe to be the true benefit of the study (not the regional comparison). In the event that you want to statistically compare the regions, these can be removed.

Author’s reply: we thank the reviewer for the elaborate review and followed the suggestion of the reviewer to provide a complete understanding of the role of OOH-PCSs in opioid prescribing in the Netherlands, by including all contacts. For Flanders it was not necessary to distinct between week and weekend-contacts since the OOH-PCS services are only available for primary care during the weekends and national holidays. We reply to specific comments below.

Specific Comments:

Abstract

9.

Background, Page 2, line 37-38: delete "that differ in the way..." as it is very confusing to read and is not necessary for the abstract

Author’s reply: we removed this from the abstract as suggested.

10.

Methods: need to provide more info- study is a retrospective cross sectional study; what is the primary outcome (mean yearly rate of opioid prescriptions per 1000 visits); what are strong v weak opioids; define GP.

Author’s reply: We indeed used a retrospective cross sectional design and updated this term throughout the manuscript. Furthermore, we updated our methods section (i.e. definitions of strong and weak opioids, an definition of GP) in the abstract according to the reviewer’s suggestions.

11.

Also, if you aren't doing a statistical analyses of the yearly rate, you shouldn't use the term "trend". I think it would be very easy to do a piece-wise linear regression using 2017 as a midpoint.

Author’s reply: As we have only 5 data points (5 years analyzed), we chose not to do a piece wise linear regression analysis. We refer to this in the limitation section of the discussion: “Last, we did not statistically test whether changes in opioid prescribing over time were significant.”. Although we did not statistically test changes over time, we do provide numbers that provide insight in changes in opioid prescribing over time. We believe therefore, we can still talk about trends in opioid prescribing. We adjusted the manuscript to avoid terminology that suggests that we statistically test trends and also avoid the word “trend”.

12.

Results, Page 2, line 44-48: Would rewrite the description of the opioid prescribing rates in Flanders to read more like the Netherlands description (rates went from xx to y between 2015 - 2017 and then increased to zzz in 2019.

Author’s reply: This was changed as suggested into: “In Flanders, OOH opioid prescribing went from 2.4% in 2015 to 2.1% in 2017 and then increased to 2.3% in 2019.”

13.

Page 2, line 48-49: "...OOH-contacts concerning an opioid prescription". I'm assuming that you mean that strong opioids were prescribed 8% of the time WHERE an opioid was prescribed. I would just clarify as it is a little confusing as written.

Author’s reply: Indeed, that is what we meant. We adjusted as follows: “In 2019, in Flanders, strong opioids were prescribed in 8% of the OOH-contacts with an opioid prescription.”

14.

Conclusion, Page 2, line 55-56: I would rewrite this to something of the effect of "Measures to ensure judicious and evidenced-based prescribing of opioids need to be tailored to the local healthcare system organization".

Author’s reply: we changed the conclusion of the abstract as suggested into: “Measures to ensure judicious and evidence-based opioid prescribing need to be tailored to the organisation of the healthcare system.”

Introduction

15.

Page 3, line 64: "...benefits outweigh the risk of developing opioid dependence, opioid use disorder, overdose..."

Author’s reply: we changed this as suggested into: “the benefits outweigh the risk of developing opioid dependence, opioid use disorder, overdose and death.”

16.

Page 3, line 74-75: "Acute and chronic pain..." this line is out of place in context with the preceding paragraph

Author’s reply: we removed this sentence from the manuscript. As in the following paragraph we already mention the following: “Thus, like in other acute care settings, relief of acute pain and acute exacerbations of chronic pain are essential activities of the primary OOH health care providers.”

17.

Page 3, line 76: I would provide the "definition" of Flanders earlier in the manuscript

Author’s reply: we left the definition of Flanders at the same position in the text, as it is the first time that Flanders is mentioned in the manuscript. The numbers mentioned in the paragraph before refer to Belgium, not to Flanders only. We added the definition of Flanders to the abstract.

18.

Page 3, line 82-84: I would provide an actual number describing the risk of persistent opioid use after prescription (could use Shah A, Hayes CJ, Martin BC. Characteristics of Initial Prescription Episodes and Likelihood of Long-Term Opioid Use - United States, 2006-2015. MMWR Morb Mortal Wkly Rep. 2017;66(10):265-269)

Author’s reply: thank you for providing this reference. We did not include the reference in the paragraph as it does not refer to long-term opioid use starting in acute care specifically. Therefore, we chose to include an estimate from studies in the acute care setting.

This sentence now reads as follows: “Moreover, from previous studies in the acute care setting of emergency departments it is known that opioid prescribing in this acute setting may lead to persistent and high risk opioid use in up to 17% of patients starting with an opioid.”

19.

Page 3, line 91: "...with each 80 to 160 GPs" Is this the number of GPs per OOH?

Author’s reply: This was indeed the number of GPs per OOH. However, based on the following comment of the reviewer, we removed this part from the introduction and added an adjusted paragraph to the discussion. (see comment 20)

20.

Page 3-4, line 90-106: This explanation of the differences in the care models of the Netherlands and Flanders is excellent and completely necessary to interpret the findings of the study. However it needs to be condensed and moved to the discussion. You can introduce a very brief explanation in the intro to justify why you are comparing the two regions, but the bulk of the description should be reserved for the discussion

Author’s reply: we condensed the paragraph in the introduction and added parts of the original paragraph to the discussion.

The introduction now reads as follows: “The scales of the OOH-PCSs in Flanders and the Netherlands are similar, but access to primary and secondary health care is organized differently. In Flanders, both the OOH-PCS and secondary (emergency) care are accessible without referral, whereas Dutch GPs (also in the OOH setting) have a gate keeper role for secondary and tertiary care, and patients are expected to contact the OOH-PCS by phone where triage is done prior to follow-up [16]. These differences in the organization of acute primary care may lead to differences in patient groups who consult the OOH-PCS [16] and thus also to differences in opioid prescribing.“

Methods

21.

Page 4, line 113: I would think this is a retrospective cross sectional study

Author’s reply: This has been adjusted throughout the manuscript.

22.

Page 4, line 116 and line 121: Does iCAREdata cover 10% or 66% of the Flemish population?

Author’s reply: We apologize for this inconvenience. In this study, we only included data representative for 10% of the Flemish population. During the last years, iCAREdata grew extensively, leading to a population coverage of 66%. However, information is not available for these OOH-PCSs across the entire time horizon of this study. For this reason, the same subset of OOH-PCS was chosen to allow reliable comparison between the years. We revised the manuscript accordingly and removed the sentence in which we mention 66% of the Flemish population from the method section.

23.

Page 6, line 146-148: I think it is unwise to exclude these data. The comparison between the regions seems like a secondary aim. You are excluding 2 million contacts per year...that's a lot. I would strongly encourage you to include these visits in your yearly descriptions and in the event you go back and perform a statistical analyses comparing the regions, you can then remove them. Trying to describe this very narrow subset of weekend contacts that result in an prescription is just not nearly as helpful.

Author’s reply: We followed the reviewers suggestion to repeat the analyses for the Netherlands including all contacts. This is now described in the method section of the manuscript. For comparison, the results excluding weekday and telephone contacts are included as supplementary material. Numbers in the abstract and in the results section were updated, as well as figures and supplementary material. The number of contacts in which an opioid was prescribed, slightly decreased. The changes over the years were similar to the results of the analysis excluding telephone and weekday contacts. Therefore the overall conclusion did not change.

24.

Page 6, line 150: ALL means need to have 95% CI

Author’s reply: we did not calculate means, but proportions and rates based on the entire datasets. We therefore think it is not meaningful to add 95% CIs. We updated terminology in the method section of the manuscript to clarify that we calculate rates and proportions and not means.

Results

25.

And please be consistent with the number of significant figures you are using.

Author’s reply: we checked the whole manuscript and changed the number of significance when inconsistent (1 in the text and 2 in tables).

26.

Page 6, line 171-172: Would re-write first sentence "Between 2015-2019, XXX (2.5%) OOH-contacts resulted in an opioid prescription (Figure 1, Table S1)"

Author’s reply: we changed this sentence as follows: “Between 2015 and 2019, approximately 2.5% of OOH contacts during the weekend resulted in an opioid prescription.”

27.

Page 6-7, line 173-177: I am not following your % decrease calculation; going from 24 --> 21% is an absolute reduction of 3%. 1-(21/24) = 12.5% relative reduction. If my math is incorrect please let me know

Author’s reply: We recalculated all relative reductions mentioned in the results section and changed where incorrect.

28.

Page 7, line 178-179: I would continue to present the mean (with 95% CI) values instead of switching to range.

Author’s reply: As explained in the reply to comment 24, we did not calculate means, but rates. For consistency in the presentation of results, we changed this paragraph as follows: “Prescription rates for strong opioids in OOH care decreased from 2.1 per 1000 contacts in 2015 to 1.3 in 2018 and increased to 1.8 per 1000 contacts in 2019 (14.3% relative decrease between 2015 and 2019). In the Netherlands, strong opioid prescribing increased from 9.7 to 13.3 per 1000 contacts between 2015 and 2017 (37.1 % increase) and slightly decreased thereafter to 12.3 per 1000 contacts in 2019.”

29.

Page 7, line 188: Give % for each opioid

Author’s reply: This was now added for the year 2019. We would also like to refer to figure 2 in which the distribution of opioids is illustrated for each year and opioid group (strong vs weak).

Discussion

30.

I would encourage you to include some discussion on how these results compare to other studies that describe opioid prescribing, particularly those that examine sources of opioid prescribing. Listed are references that I am familiar with as a US-based provider (Temporal Trends in Opioid Prescribing Practices in Children, Adolescents, and Younger Adults in the US From 2006 to 2018, JAMA Pediatr

. 2021 Oct 1;175(10):1043-1052. doi: 10.1001/jamapediatrics.2021.1832. Opioid Prescribing to US Children and Young Adults in 2019, Pediatrics

. 2021 Sep;148(3):e2021051539. doi: 10.1542/peds.2021-051539. Epub 2021 Aug 16. Variation in Adult Outpatient Opioid Prescription Dispensing by Age and Sex — United States, 2008–2018, MMWR Morb Mortal Wkly Rep. 2020 Mar 20;69(11):298-302. doi: 10.15585/mmwr.mm6911a5.).

Author’s reply: Comparison is difficult due to differences in setting (e.g. different patients contacting different settings, such as day time general practice, OOH services and emergency departments), health systems (gate keeper system, versus system with direct accessibility of secondary care) and the severity of the “opioid pandemic” (Western European countries versus US for example). Therefore, other than the comparison that was already mentioned (within the Netherlands), we chose to not add further comparison.

31.

Page 8, line 217-218: "Overall we did...nor in the Netherlands." Were you expecting to see a large increase? Was that your hypothesis? Seems odd to state this here, would delete.

Author’s reply: We indeed did not mention a hypothesis considering the direction of expected change in our manuscript. We thus deleted this sentence from the manuscript.

32.

Page 8, line 223-225: Are you saying that the overall trend of decreasing opioid prescribing is secondary to the increased knowledge of the dangers of opioids? It is confusing as this sentence just follows your statement that prescribing of strong opioids increased between 2015-2019 so it makes it seem like you are saying the attention being paid to prescribing has led to increased strong opioid prescribing.

Author’s reply: We meant to say that both the increase in strong opioid prescribing and the decrease in opioid prescribing from 2017 on, were consistent with opioid prescribing in the non acute primary care setting. Furthermore, the decrease is likely the result of increased attention for the risks of opioid prescribing from the end of 2017 on. We clarified this in the manuscript as follows: “The increase between 2015 and 2017 was driven by increased prescribing of strong opioids, while weak opioids prescribing remained stable. These changes (both the increase and the decrease thereafter) are consistent with the opioid prescribing trends in the Netherlands in the non-acute primary care setting [15]. The observed decrease in opioid prescribing is likely the result of increased attention since the end of 2017 for the steep rise in and risks of opioid prescribing.”

33.

Page 9, line 254: Please provide a reference

Author’s reply: we added a reference to this sentence.

34.

Page 9-10: Given the high prevalence of tramadol in your sample, I would include some discussion on the recent paper that showed increased mortality with tramadol (Association of Tramadol vs Codeine Prescription Dispensation With Mortality and Other Adverse Clinical Outcomes, JAMA. 2021 Oct 19;326(15):1504-1515. doi: 10.1001/jama.2021.15255.)

Author’s reply: The high tramadol prevalence is indeed notable. However, we did not include this reference in our manuscript, as tramadol users in the study suggested by the reviewer are compared with codeine users and in another study with NSAID users. In Flanders and the Netherlands, these patient groups differ greatly, where e.g. codeine is hardly used as pain medication, whereas tramadol is. Higher mortality for tramadol than codeine users could be expected.

35.

Limitations: IF you are going to continue to exclude the weekday contacts in the Netherlands, it needs to be listed in the limitations as this is excluding the majority of contacts from the Netherlands and significantly biases the results. As stated previously, would strongly encourage you to include these results and perform trend analysis.

Author’s reply: We followed the reviewer’s suggestion and included all contacts for the Netherlands (see reply to comment 23).

Tables and Figures

36.

Try to use "." or "," as decimal points...you go back and forth in the supplemental material

Author’s reply: All decimal comma’s in supplementary table 2 were changes into “.”

37.

Figure 1: Year should be on the X-axis

Author’s reply: We amended the figure and put year on the X-axis.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

28 Feb 2022

Opioid prescribing in out-of-hours primary care in Flanders and the Netherlands: a retrospective cross-sectional study

PONE-D-21-33076R1

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30 Mar 2022

PONE-D-21-33076R1

Opioid prescribing in out-of-hours primary care in Flanders and the Netherlands: a retrospective cross-sectional study

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