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. 2022 Nov 28;17(11):e0276867. doi: 10.1371/journal.pone.0276867

Opioid and gabapentinoid prescriptions in England from 2015 to 2020

Yixue Xia 1, Patrice Forget 1,2,3,*
Editor: Vijayaprakash Suppiah4
PMCID: PMC9704625  PMID: 36441772

Abstract

Purpose

Concerns gradually arose about misuse of gabapentinoids (gabapentin and pregabalin), especially when used in combination with opioids. Because it can be a driver of usage, trends in prescribing habits may be interesting to analyse. The aim of this study is to examine the evolution of prescriptions of opioids and gabapentinoids in England from 2015 to 2020 at a regional level.

Methods

This study included data from April 2015 to February 2020, focusing on prescribing data, extracted the OpenPrescribing database. We described the evolution of the prescriptions of opioids and gabapentinoids and calculated their ratios for each month. We used Analyses of Variance (ANOVAs) to compare data between and within regions (over time).

Results

During this period, opioid prescriptions remained stable (from -3.3% to +2.2%/year) and increased for gabapentinoids generally (from +1.5% to +2.2%). The ratio between gabapentinoid to opioid prescriptions increased by more than 20% in 2020 compared to 2015, variably between regions (F(6,406) = [120.2]; P<0.001; LSD Test: P<0.001; ANOVA for repeated measures: P<0.05). In 2019, a decline in the ratio occurred in all regions, but only persisting in the London commissioning region in 2020 (-14.4% in comparison with 2018, 95%CI: -12.8 to -16.3).

Conclusions

Gabapentinoids are increasingly prescribed in England. The ratio of gabapentinoid to opioid prescriptions in England increased from 2015 to 2020. The reclassification of gabapentinoids as controlled drugs, in 2019, may have been associated with a significant reduction, although larger prescribers may have been less influenced.

Background

Opioid analgesics include alkaloids extracted from opium and synthetic analogues that interact with specific central receptors. Usually, opioids are prescribed to relieve acute pain or pain at the end of life [1]. But little evidence supports a lasting effect on chronic pain. However, the use of opioids is not completely safe. Adverse effects of opioids are related to various factors, such as individual differences, dosage, and drug interactions, which are not specific to drug type and route of administration [2].

Gabapentinoids include pregabalin and gabapentin, both of which were initially cleared for seizures. With opioid use disorder becoming an international public health problem, doctors and patients are looking for alternatives. As a result, more prescriptions for gabapentinoids may have been issued. Even if largely uncertain, it was hypothesised by some that gabapentinoids may help reduce opioids, prevent opioid tolerance, improve the quality of opioid analgesic therapy, and treat anxiety [3]. However, these hypotheses have been, at least partially, rejected [4, 5]. Moreover, in high doses, patients may experience euphoria with gabapentinoids, and withdrawal after abruptly stopping use, including seizures [5–7]. In recent years, the gabapentinoid use disorder has developed rapidly and has gradually become a recognized problem around the world. In patients with substance use disorders, especially those involving opioid use, the abuse may even be more serious [8] and the United Kingdom (UK) classified it as a controlled substance in April 2019 [9]. Additionally, the combined use of gabapentinoids and opioids appears to be associated with specific risks. In patients being prescribed opioids and gabapentinoids concomitantly, there is a substantial increase in the risk of opioid-related death [10, 11]. This concomitant use has been accused of being responsible of differences in opioid-related death rates, between different parts of the UK [12]. A similar debate occurred regarding the concomitant use of benzodiazepines and gabapentinoids [13]. Co-prescribing of benzodiazepines is well described, but there is little description of the co-evolution of the prescribing of opioids and gabapentinoids, except for a recent publication in Scotland [10]. This highlights the need to study regional and national differences.

The aim of this study is to examine the evolution of prescriptions of opioids and gabapentinoids in England from 2015 to 2020 at a regional level.

Methods

This report is written according to the Strengthening Reporting in Observational Studies (STROBE) guidelines.

Data sources and preparation

We focused on monthly practice -level data in England from April 2015 to March 2020 and aggregated it at a regional level. In each National Health Service (NHS) Primary Care prescribing organization in the UK, the prescribing data set monthly published by NHS Digital counts for each different drug and dose, describing the number of prescriptions and the total cost. These data come from institutions such as community pharmacies and contain all drugs that have been assigned.

We extracted prescription information from the open OpenPrescribing database for analysis [15]. OpenPrescribing is an online service launched in 2016. Prescribing information is sourced from NHS Digital publishing NHS Business Services Administration monthly and annual prescription data sets and static prescribing trend reports. All data is grouped by drug name and any name available in multiple formulas is combined. OpenPrescribing collects information coming from the following sources: Medications codes and names are also from the NHS Business Service Authority’s Information Portal. Clinical Commissioning Groups (CCGs) and practice prescribing settings, are from NHS Digital’s data downloads (epraccur.csv), used under the terms of the Open Government Licence. CCG names and codes and CCG geographic boundaries are from the Office for National Statistics (ONS) (www.ons.gov.uk). Practice locations are based on data from NHS Digital/ONS.

Data extraction and classification

We extracted prescription data (opioid analgesics, section 4.7.2 of the formularium) (for a full list, see https://openprescribing.net/bnf/040702/; pregabalin, code 0408010AE; and gabapentin, code 0408010G0) as.csv files. All orders (from April 2015 to February 2020) were compiled according to different regions of England. Capital expenditure was counted per year, covering the annual total of pregabalin and gabapentin prescriptions across all NHS England regional teams.

Statistical analysis

After compiling the prescriptions data (opioids and gabapentinoids), we calculated the ratios of gabapentinoid (gabapentin and pregabalin) to opioid prescriptions. We displayed these using a line graph with their 95% confidence intervals, calculated for each month, on a rolling year.

The prescription ratios were analysed, after checking the distribution normality using graphical methods, using a one-way Analysis of Variance (ANOVA) to compare prescription counts, and ratios between gabapentinoid and opioid prescriptions, between the different regions, and ANOVAs for repeated measures to compare each region over time. IBM SPSS (SPSS Statistics for Windows, version 25 (SPSS Inc., Chicago, Ill., USA) was used for all the comparison. A P-value <0.05 was considered statistically significant.

Ethics approval

This study does not require patient consent or ethical approval as the data used is publicly available, anonymous and aggregated at source.

Results

Evolution of opioid prescription in England

Between April 2015 and February 2020, the number of opioid prescriptions in regions of England generally remained stable, ranging from -3.3% to +2.2% of change every year (Fig 1, Table 1).

Fig 1. Number of prescriptions for opioid analgesics in each region of England.

Fig 1

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Table 1. Mean monthly prescription count (averaged on the yearly basis) for opioids and gabapentinoids, and their ratio (with 95% confidence intervals– 95%CI–calculated, for each month, on a rolling year) in each region of England.

Prescriptions East of England  South West London Midlands  North East, Yorkshire North West South East
(monthly average)
2015 Opioids 209813 216462 136637 360289 457997 314235 255071
Gabapentinoids 99462 87962 88537 160010 185128 157301 112926
Gabapentinoid/Opioid ratio (95%CI) 0.474 (0.493 to 0.461) 0.406 (0.419 to 0.393) 0.648 (0.671 to 0.625) 0.444 (0.460 to 0.428) 0.404 (0.416 to 0.392) 0.500 (0.518 to 0.483) 0.443 (0.460 to 0.425)
2016 Opioids 211687 220083 137142 366760 468079 317519 256319
Gabapentinoids 111169 98127 100452 177724 206198 174201 125536
Gabapentinoid/Opioid ratio (95%CI) 0.525 (0.540 to 0.515) 0.446 (0.455 to 0.436) 0.732 (0.750 to 0.714) 0.484 (0.497 to 0.472) 0.440 (0.449 to 0.431) 0.548 (0.562 to 0.535) 0.489 (0.503 to 0.476)
2017 Opioids 210213 218992 135921 367791 472951 315138 253914
Gabapentinoids 123264 109317 113120 197516 229733 192258 139521
Gabapentinoid/Opioid ratio (95%CI) 0.586 (0.596 to 0.581) 0.499 (0.504 to 0.494) 0.832 (0.849 to 0.815) 0.537 (0.545 to 0.528) 0.486 (0.491 to 0.480) 0.610 (0.618 to 0.602) 0.549 (0.559 to 0.540)
2018 Opioids 204679 213758 132149 364751 466631 309167 245890
Gabapentinoids 132826 115943 123193 215541 247176 206896 149142
Gabapentinoid/Opioid ratio (95%CI) 0.649 (0.654 to 0.647) 0.542 (0.545 to 0.540) 0.932 (0.952 to 0.913) 0.591 (0.595 to 0.586) 0.530 (0.532 to 0.528) 0.669 (0.674 to 0.664) 0.607 (0.612 to 0.601)
2019 Opioids 201538 211603 133725 369234 461972 309545 242288
Gabapentinoids 138967 117964 109657 229790 251415 215364 156517
Gabapentinoid/Opioid ratio (95%CI) 0.690 (0.692 to 0.688) 0.557 (0.559 to 0.556) 0.821 (0.824 to 0.817) 0.622 (0.625 to 0.619) 0.544 (0.545 to 0.543) 0.695 (0.698 to 0.693) 0.646 (0.648 to 0.644)
2020 Opioids 199369 210202 135237 370295 461678 308719 241610
Gabapentinoids 142270 120299 107617 241681 255145 222747 162378
Gabapentinoid/Opioid ratio (95%CI) 0.710 (0.711 to 0.710) 0.570 (0.570 to 0.570) 0.797 (0.797 to 0.796) 0.651 (0.651 to 0.650) 0.553 (0.553 to 0.552) 0.720 (0.720 to 0.720) 0.669 (0.669 to 0.668)
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Evolution of gabapentinoid prescription in England

From April 2015 to February 2020, the number of prescriptions of gabapentin and pregabalin in England continuously increased, ranging from +1.5% to 11.9% every year (Fig 2, Table 1).

Fig 2. Number of prescriptions for gabapentin and pregabalin in each region of England.

Fig 2

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In early 2019, all regions simultaneously showed a decline, but only persistent in the London commissioning region, falling and remaining 12.3% lower than before.

Evolution of the ratio between gabapentinoid and opioid prescription in England, between and within regions

To study conjointly the evolution of gabapentinoid and opioid prescription, we calculated the ratio of gabapentin and pregabalin to opioids. A one-way ANOVA was performed to compare the ratios and showed statistically significant difference between regions (F(6,406) = [120.2]; P<0.001; LSD Test: P<0.001).

Between April 2015 and February 2020, the evolution of the ratio increased overall, with each region experiencing an increase of more than 20% in 2020 compared to 2015 (P<0.05) (Fig 3, Table 1). In 2019, the decrease in gabapentinoid prescriptions was associated with a variably distributed decline in the ratio between gabapentinoid and opioid prescriptions, significant in all regions (ANOVA for repeated measures within regions: P<0.001) but only persisting in the London commissioning region in 2020 (-14.4% in comparison with 2018; 95%CI: -12.8 to -16.3). Costs were explored while considering all prescriptions as a whole, even if a pharmaco-economic study is beyond the purpose of this work. Costs linked to prescriptions increased rapidly from 2015 to 2019, and the London commissioning region increased the most.

Fig 3. Ratio between gabapentinoid and opioid prescriptions in each region of England.

Fig 3

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The faded lines represent 95% confidence intervals calculated, for each month, on a rolling year.

Discussion

Prescription changes

This study describes the regional evolution in opioid and gabapentinoid prescriptions in England. The number of opioid prescriptions in various regions has essentially stabilized over time (ranging from -3.3% to +2.2%). Meanwhile, prescriptions of gabapentin and pregabalin increased between 2015 and 2020 (ranging from +1.5% to 11.9% every year). Additionally, we found that prescriptions for gabapentin and pregabalin declined in most areas by early 2019, after which the rate of prescription growth declined significantly but remained lower in 2020 only in the London commissioning region (by 12.3%).

In order to study the co-evolution of the prescriptions of gabapentinoids and opioids, we looked at the ratios between gabapentinoids and opioids. From 2015 to the end of 2018, there was a marked increase in all regions, especially in the London commissioning region. At the beginning of 2019, the ratio of the different regions fell, after which the growth rate remained at a low level, but only significantly lower in the London commissioning (-14.4%; 95%CI:-12.8 to -16.3).

Implications in terms of societal impact and national policy

As the public became aware of the potential risk of opioid use disorder, medical staff began to reconsider pain management and seek more appropriate medication prescriptions, including non-opioid pain relievers [4, 5]. Among other things to reduce opioid dependence, gabapentin and pregabalin have been gradually introduced. Between 2007 and 2017, the proportion of patients receiving primary opioid analgesics in combination with prescriptions of gabapentinoids or opioid analgesics in combination with prescriptions of benzodiazepines in primary care may have tripled approximately [16]. In some series, 20 to 25% of patients who started treatment with gabapentinoids were prescribed opioids [17]. If the goal were to partially prevent opioid tolerance and improve the quality of treatment, especially for neuropathic pain, this effect could have been achieved at the cost of increased side effects, and, at best, uncertain [14, 8–20]. In the treatment of non-neuropathic pain, the use of gabapentinoids in combination with opioid analgesics may reduce short-term opioid use and short-term pain levels, but compared to placebo, the incidence of drug-related adverse reactions is higher [21–23].

Although gabapentinoids were initially identified as unlikely to be abused, in recent years gabapentinoids use disorders has gradually become a public health problem that cannot be ignored [3, 8, 10, 11, 16]. In 2016, the UK’s Advisory Council on the Misuse of Drugs recommended that pregabalin and gabapentin be controlled under the Misuse of Drugs Act 1971 as Class C substances and listed under the Misuse of Drugs Regulations 2001 as Schedule 3 [9]. In the UK, controlled drugs are divided into classes A, B and C, depending on potential harms. Class C drugs are considered the least harmful. Schedule 3 implies specific requirements for the prescribing, dispensing, recording and safe storage of certain drugs, such as certain benzodiazepines. In April 2019, pregabalin and gabapentin were classified as Class C substances and listed as additional substances under the Misuse of Drugs Regulations 2001 [24]. The reclassification decision is based on risk of gabapentinoid misuse, abuse and diversion [9]. The decision appears to be linked to the drop in prescriptions of gabapentin and pregabalin in early 2019 we observed in this study.

It was important for all of us to study these regional differences. A multi-regional analysis was essential to consider as some regions may have more or less success in limiting drug-related problems. Although the reasons for the variability observed (in the present study) are uncertain and beyond our analyses, these data open the way to the development and discussion of different strategies. The observed patterns may also warrant future work aimed at better explaining determinants and outcomes, especially those that are modifiable. Importantly, due to the data we had, only prescriptions from England (but dispensed in the UK), were analysed. It would make sense to supplement these analyses by data from other nations and countries and, at least in the UK, to study the effect of other major guidelines, such as the National Institute for Health and Care Excellence (NICE) guidelines on chronic pain, published in 2021 [25].

Limitations

Despite the large amount of data representing the entire national prescription rate in England, this work has its limitations. The use of OpenPrescribing data implies that inherent limitations must be considered. These data analyses include primary care only and are not weighted by quantity or strength of items prescribed [15]. This is especially important given the change in gabapentinoid controlled drug scheduling during the study period, limiting the maximum number of days for each prescription. Most importantly, the data has been aggregated, excluding any analysis (and interpretation) at the patient level. This means that the ratios between gabapentinoid and opioid prescriptions have been observed at the regional level and cannot be automatically extrapolated to the patient level. In other words, it cannot be asserted that these data can be considered as a surrogate for the concomitant use of opioids and gabapentinoids. Prescribing patterns may have been different, depending on the practice or over time and it is not possible to describe what proportion of patients are prescribed both these drugs, as this is not available within the data. Importantly, comparisons between regions (for prescriptions numbers) are very difficult to interpret because the number of inhabitants is different too. However, the differences observed and the variability of the ratio were consistently observed and deserve to be underlined, particularly seeing their implications at a Public Health level.

Conclusions

In England, the number of opioid prescriptions remained stable over the study period (2015 to 2020), but gabapentinoid prescriptions increased. The increase in the ratio between both suggests that gabapentinoids have not replaced opioids in the therapeutic armamentarium.

The decision to reclassify gabapentinoids as drugs at risk of misuse, abuse, and diversion appears to be linked (at least initially) to a decline in gabapentin and pregabalin prescriptions.

Supporting information

S1 Checklist. STROBE statement—checklist of items that should be included in reports of cohort studies.

(DOC)

Click here for additional data file. (85KB, doc)

Abbreviations

ANOVA

Analysis of Variance

CCG

Clinical Commissioning Group

GP

General Practitioner

NHS

National Health Service

SD

Standard deviation

STROBE

Strengthening Reporting in Observational Studies

Data Availability

Data are freely available on www.openprescribing.net and www.ons.gov.uk. Please find here the respective URLs: https://openprescribing.net/analyse/#org=regional_team&numIds=4.7,0408010G0AA,0408010AEAA&denom=nothing&selectedTab=summaryhttps://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/datasets/deathsregisteredinenglandandwalesseriesdrreferencetables.

Funding Statement

The author(s) received no specific funding for this work.

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Decision Letter 0

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PONE-D-22-15405Opioid and gabapentinoid prescriptions in England from 2015 to 2020.PLOS ONE

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Reviewer #1: This is an interesting subject, and worthy of further study.

However there are several issues which ideally need to be addressed before publication:

-The data from OpenPrescribing uses items. Although this may be acceptable, there is no mention of the limitations of this method, i.e. that it doesn't take into account quantity or strength of the items prescribed. This is particularly important given the change to the CD scheduling of gabapentinoids during the study period, limiting the maximum number of days which can be prescribed.

- I think it would be further helpful to more clearly describe the changes to the CD scheduling, and the effect it may have. The statement "The newly promulgated management plan likely influenced prescriptions rate" is unclear - I'm not aware of any management plans being put in place nationally. I'm assuming it relates to move to schedule 3, but this is not mentioned. As a side-note, i'm assuming the "Drug Abuse Act 1971" actually refers to the "Misuse of Drugs Act 1971", and the same for the Misuse of Drugs Regulations 2001.

- It is unclear from the text what the findings represent, due to the limitations of data. There is discussion in the introduction about the safety of the co-prescribed opioids and gabapentinoids. However it is not possible to describe what proportion of patients are prescribed both these drugs, as this is not available within the data. The limitations section on this should be strengthened.

- It would be helpful to see some discussion of demographic differences between regions, otherwise it's not clear why the authors have undertaken the analysis at regional level.

- It would be helpful to see further discussion about possible reasons for the change in ratio, e.g. due to changes in national guidance for other analgesic options.

- This statement is unclear: "about 1% of the general population is in a situation of drug abuse, a proportion that could reach 40% of people who receive prescriptions." This suggests that only 2.5% of patients receive prescriptions. Is this actually referring to patients receiving opioid or gabapentinoid prescriptions? Also, the research referenced does not appear to be a systematic review as described in the authors' text, but a relatively small study based in Appalachian Kentucky, and therefore clarification is needed, particularly given the ability to use this data in a very specific area with known drug abuse problems in the USA with relation to England, which has very different models of care.

- There are some points in the text where ideally the authors should revise the language in order to improve readability. In particular the conclusion should be reviewed for language.

Reviewer #2: Thank you for the opportunity to review this retrospective analysis of prescribing trends of opioids and gabapentinoids over time, in the UK. Please find some suggestions for improvements and/or clarifications.

Abstract: please provide more information about the data sources, and the analysis. There are no statistical results included in the abstract and no test of trend etc.. This should be included.

Please make sure the key points match the findings of the study

Introduction:

-Statement about the dangerous combination use of opioids and gabapentionoids should be stronger in my opinion with reference to at least 3 studies that point to increased mortality from the combo (e.g., refer to the 2 observational studies by Juulink et al; there are others).

-Please mention and reference risk of seizure from stopping abruptly

-Why was data presented as a ratio of opioids to gabapentinoids?

-Did the authors consider looking at opioid doses? Same question for gabapentin vs pregabalin. Why simply look at dispensations? These can change depending on whether prescriptions are for 1,2,4, 6 weeks etc…

- Any consideration to doing a time series analysis of this data?

- I see that costs are mentioned qualitatively in the results but not quantitatively. I also don’t see this in the methods. Should this be added?

-At times I see mention of prescriptions for individual classes and other times I see this reported as a ratio. This needs to be clarified and unified.

-Addiction should be replaced with “use disorder”

-Caution against mentioning that gabapentinoids have been introduced to reduce opioid dependence as this is a hypothesis, only and has not been demonstrated to my knowledge.

-consider reviewing this reference for peri-operative lack of effect: https://pubs.asahq.org/anesthesiology/article/133/2/265/109137/Perioperative-Use-of-Gabapentinoids-for-the#

- Readers who are not from the UK will not know that the management plan is. It is mentioned in a couple of places but it isn’t clear what it consists of and how it is relevant.

- issue with the first sentence on page 11

- I see many pivotal studies addressing the lack of efficacy and the harms of gabapentinoids are missing from the references. Gingras et al., Verret et al., works by Juurink, RCTs showing no effect but increased risk of adverse events that were published in JAMA, NEJM etc…the references could be more robust for this study

- I like the figures but the statistical analysis plan is not that clear to be and the analysis is also not well described or robust. How about at time series analysis? And how about including some measure of the size of the population and the dose vs dispensations. Also not clear whether a ratio was calculated and where that is presented graphically and why it was done.

**********

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Reviewer #1: Yes: Richard Croker

Reviewer #2: No

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PLoS One. 2022 Nov 28;17(11):e0276867. doi: 10.1371/journal.pone.0276867.r002

Author response to Decision Letter 0

30 Jul 2022

Dear Editor, dear Reviewers,

Thank you for the kind and constructive comments. You will find here a revised version of our work. We hope that this will encounter all your concerns. We remain, of course, open to any other suggestion.

Kind regards,

Patrice Forget and Yixue Xia

Reviewer #1: This is an interesting subject, and worthy of further study.

Answer: Thank your for this encouraging comment.

Reviewer #1: However there are several issues which ideally need to be addressed before publication:

The data from OpenPrescribing uses items. Although this may be acceptable, there is no mention of the limitations of this method, i.e. that it doesn't take into account quantity or strength of the items prescribed. This is particularly important given the change to the CD scheduling of gabapentinoids during the study period, limiting the maximum number of days which can be prescribed.

Answer: The reviewer is obviously right, and we agree that it wasn't well detailed. We have now further detailed the limitations (discussion) section as follows: The use of OpenPrescribing data implies that inherent limitations must be considered. These data analyses include primary care only and are not weighted by quantity or strength of items prescribed. This is especially important given the change in gabapentinoid controlled drug scheduling during the study period, limiting the maximum number of days for each prescription.

Reviewer #1: I think it would be further helpful to more clearly describe the changes to the CD scheduling, and the effect it may have. The statement "The newly promulgated management plan likely influenced prescriptions rate" is unclear - I'm not aware of any management plans being put in place nationally. I'm assuming it relates to move to schedule 3, but this is not mentioned. As a side-note, i'm assuming the "Drug Abuse Act 1971" actually refers to the "Misuse of Drugs Act 1971", and the same for the Misuse of Drugs Regulations 2001.

Answer: Thank you for spotting these sources of confusion. We agree this is unclear, especially for the non-UK reader. We have now rephrased and clarified this paragraph as follows: In 2016, the UK's Advisory Council on the Misuse of Drugs recommended that pregabalin and gabapentin be controlled under the Misuse of Drugs Act 1971 as Class C substances and listed under the Misuse of Drugs Regulations 2001 as Schedule 3. In the UK, controlled drugs are divided into classes A, B and C, depending on potential harms. Class C drugs are considered the least harmful. Schedule 3 implies specific requirements for the prescribing, dispensing, recording and safe storage of certain drugs, such as certain benzodiazepines. In April 2019, pregabalin and gabapentin were classified as Class C substances and listed as additional substances under the Misuse of Drugs Regulations 2001 (20). The reclassification decision is based on risk of gabapentinoid misuse, abuse and diversion. The plan could be closely linked to the drop in prescriptions of gabapentin and pregabalin in early 2019.

Reviewer #1: It is unclear from the text what the findings represent, due to the limitations of data. There is discussion in the introduction about the safety of the co-prescribed opioids and gabapentinoids. However it is not possible to describe what proportion of patients are prescribed both these drugs, as this is not available within the data. The limitations section on this should be strengthened.

Answer: We agree with this point. We have accordingly modified the following paragraph: Prescribing patterns may have been different, depending on the practice or over time and it is not possible to describe what proportion of patients are prescribed both these drugs, as this is not available within the data. /…/ However, the differences observed and the variability of the ratio were consistently observed and deserve to be underlined, particularly seeing their implications at a Public Health level.

Reviewer #1: It would be helpful to see some discussion of demographic differences between regions, otherwise it's not clear why the authors have undertaken the analysis at regional level.

Answer: This is right, even if beyond our analyses. We tried not to be too speculative and mentioned regional/national differences at the end of the introduction, to introduce it from the first section. We also added in the discussion: It was important for all of us to study these regional differences. A multi-regional analysis was essential to consider as some regions may have more or less success in limiting drug-related problems. Although the reasons for the variability observed (in the present study) are uncertain and beyond our analyses, these data open the way to the development and discussion of different strategies. The observed patterns may also warrant future work aimed at better explaining determinants and outcomes, especially those that are modifiable.

Reviewer #1: It would be helpful to see further discussion about possible reasons for the change in ratio, e.g. due to changes in national guidance for other analgesic options.

Answer: To complement the answer to the previous question, we have also added the following sentence: Importantly, due to the data we had, only prescriptions from England (but dispensed in the UK), were analysed. It would make sense to supplement these analyses by data from other nations and countries and, at least in the UK, to study the effect of other major guidelines, such as the National Institute for Health and Care Excellence (NICE) guidelines on chronic pain, published in 2021 (20).

Reviewer #1: This statement is unclear: "about 1% of the general population is in a situation of drug abuse, a proportion that could reach 40% of people who receive prescriptions." This suggests that only 2.5% of patients receive prescriptions. Is this actually referring to patients receiving opioid or gabapentinoid prescriptions? Also, the research referenced does not appear to be a systematic review as described in the authors' text, but a relatively small study based in Appalachian Kentucky, and therefore clarification is needed, particularly given the ability to use this data in a very specific area with known drug abuse problems in the USA with relation to England, which has very different models of care.

Answer: The reviewer is correct, and we have chosen to remove the sentence, as even weaker statements could still be misinterpreted, as this cannot be generalized in any way.

Reviewer #1: There are some points in the text where ideally the authors should revise the language in order to improve readability. In particular the conclusion should be reviewed for language.

Answer: We have completely revised the text for typos. We rewrote the conclusion as follows: Gabapentinoids are increasingly prescribed in England. The number of opioid prescriptions remained stable over the study period (2015 to 2020), but the increase in the ratio suggests that gabapentinoids have not replaced opioids in the therapeutic armamentarium. The decision to reclassify gabapentinoids as drugs at risk of misuse, abuse, and diversion appears to be linked (at least initially) to a decline in gabapentin and pregabalin prescriptions.

We would like to thank the reviewer, and especially because the constructive comments reassure us that much can still be done to improve knowledge on this subject.

---

Reviewer #2: Thank you for the opportunity to review this retrospective analysis of prescribing trends of opioids and gabapentinoids over time, in the UK. Please find some suggestions for improvements and/or clarifications.

Abstract: please provide more information about the data sources, and the analysis. There are no statistical results included in the abstract and no test of trend etc.. This should be included.

Answer: This is correct. We have tried to complete is but to keep is brief as well. Here is the new abstract version:

Results: During this period, opioid prescriptions remained stable (from -3.3% to +2.2%/year) and increased for gabapentinoids generally (from +1.5% to +2.2%). The ratio between opioid to gabapentinoid prescriptions increased by more than 20% in 2020 compared to 2015, variably between regions (F(6,406)=[120.2]; P<0.001; LSD Test: P<0.001; ANOVA for repeated measures: P<0.05). In 2019, a decline in the ratio occurred in all regions, but only persisting in the London commissioning region in 2020 (-14.4% in comparison with 2018, 95%CI:-12.8 to -16.3).

Conclusions: Gabapentinoids are increasingly prescribed in England. The ratio of gabapentinoid to opioid prescriptions in England increased from 2015 to 2020. The reclassification of gabapentinoids as controlled drugs, in 2019, may have been associated with a significant reduction, although larger prescribers may have been less influenced.

Reviewer #2: Please make sure the key points match the findings of the study

Answer: We checked the first three points to highlight, if required by the editor, and rewrote the last point as follows: In early 2019, the reclassification of gabapentinoids as controlled drugs may have been associated with a significant reduction, although larger prescribers may have been less influenced.

Reviewer #2: Introduction: Statement about the dangerous combination use of opioids and gabapentionoids should be stronger in my opinion with reference to at least 3 studies that point to increased mortality from the combo (e.g., refer to the 2 observational studies by Juulink et al; there are others).

Answer: We thank the reviewer for the suggestions, making it possible to highlight regional differences possibly linked to concomitant prescriptions of opioids and gabapentinoids. We have rewritten the paragraph as follows:

Additionally, the combined use of gabapentinoids and opioids appears to be associated with specific risks. In patients being prescribed opioids and gabapentinoids concomitantly, there is a substantial increase in the risk of opioid-related death (7,8). This concomitant use has been accused of being responsible of differences in opioid-related death rates in different parts of the UK (9).

References

8. Gomes T, Juurlink DN, Antoniou T, Mamdani MM, Paterson JM, van den Brink W. Gabapentin, opioids, and the risk of opioid-related death: A population-based nested case-control study. PLoS Med. 2017 Oct 3;14(10):e1002396.

9. Macleod J, Steer C, Tilling K, Cornish R, Marsden J, Millar T, Strang J, Hickman M. Prescription of benzodiazepines, z-drugs, and gabapentinoids and mortality risk in people receiving opioid agonist treatment: Observational study based on the UK Clinical Practice Research Datalink and Office for National Statistics death records. PLoS Med. 2019 Nov 26;16(11):e1002965.

9. van Amsterdam J, van den Brink W, Pierce M. Explaining the Differences in Opioid Overdose Deaths between Scotland and England/Wales: Implications for European Opioid Policies. Eur Addict Res. 2021;27(6):399-412.

Reviewer #2: Please mention and reference risk of seizure from stopping abruptly

Answer: This has been described indeed. Now, the introduction contains the following sentence:

Even if largely uncertain, it was hypothesised by some that gabapentinoids may help reduce opioids, prevent opioid tolerance, improve the quality of opioid analgesic therapy, and treat anxiety (3). However, these hypotheses have been, at least partially, rejected (4). Moreover, in high doses, patients may experience euphoria with gabapentinoids, and withdrawal after abruptly stopping use, including seizures (5,6).

References

4. Verret M, Lauzier F, Zarychanski R, Perron C, Savard X, Pinard AM, Leblanc G, Cossi MJ, Neveu X, Turgeon AF; Canadian Perioperative Anesthesia Clinical Trials (PACT) Group. Perioperative Use of Gabapentinoids for the Management of Postoperative Acute Pain: A Systematic Review and Meta-analysis. Anesthesiology. 2020 Aug;133(2):265-279.

5. Goodman CW, Brett AS. Gabapentin and Pregabalin for Pain - Is Increased Prescribing a Cause for Concern? N Engl J Med. 2017 Aug 3;377(5):411-414.

6. Schifano F, D'Offizi S, Piccione M, Corazza O, Deluca P, Davey Z, Di Melchiorre G, Di Furia L, Farré M, Flesland L, Mannonen M, Majava A, Pagani S, Peltoniemi T, Siemann H, Skutle A, Torrens M, Pezzolesi C, van der Kreeft P, Scherbaum N. Is there a recreational misuse potential for pregabalin? Analysis of anecdotal online reports in comparison with related gabapentin and clonazepam data. Psychother Psychosom. 2011;80(2):118-22.

4. Mersfelder TL, Nichols WH. Gabapentin: Abuse, Dependence, and Withdrawal. Ann Pharmacother. 2016 Mar;50(3):229-33.

Reviewer #2: Why was data presented as a ratio of opioids to gabapentinoids?

Answer: We looked not only at opioid prescriptions and gabapentinoid prescriptions, but also at concomitant use. At the practice and population level, we may have observed different or similar, but simultaneous changes in the prescribing patterns of the two drug classes. These simultaneous changes could have been invisible if they had not been highlighted by ratio analyses. Indeed, we identified in this study differences in ratios, not evident in the prescription data analyzed separately. This is particularly clear when looking at the difference seen in 2019. We have made this clear in various places in the summary and the main text.

Reviewer #2: Did the authors consider looking at opioid doses? Same question for gabapentin vs pregabalin. Why simply look at dispensations? These can change depending on whether prescriptions are for 1,2,4, 6 weeks etc…

Answer: As pointed out by Reviewer #1, OpenPrescribing data analyses are limited by their content. This is why we did not performed these additional analyses. We have not detailed these limitations as follows: The use of OpenPrescribing data implies that inherent limitations must be considered. These data analyses include primary care only and are not weighted by quantity or strength of items prescribed. This is especially important given the change in gabapentinoid controlled drug scheduling during the study period, limiting the maximum number of days for each prescription.

Reviewer #2: Any consideration to doing a time series analysis of this data?

Answer: This is an excellent suggestion. We did not plan to do a time series analysis, and, for this, should hypothesise that these data may have an internal structure (such as autocorrelation, trend or seasonal variation). Of course, this is partly what we did. However, as we think that the main driver might be modifiable (at a prescriber level), we believe descriptive analyses were the most important aspects we were interested in.

Reviewer #2: I see that costs are mentioned qualitatively in the results but not quantitatively. I also don’t see this in the methods. Should this be added?

Answer: We agree that this might be interesting for some, although, in this case, consequences of prescriptions may be important to consider as well. This is why we weren’t convinced by a direct added value of these isolated data. We are, in fact, really afraid that any firm conclusion would be mostly speculative and would weaken the entire work. However, we have precised now that: Costs were explored while considering all prescriptions as a whole, even if a pharmaco-economic study is beyond the purpose of this work.

Reviewer #2: At times I see mention of prescriptions for individual classes and other times I see this reported as a ratio. This needs to be clarified and unified.

Answer: We have checked that the presentation of results is as systematic as possible and corrected it according to the following order; 1. Opioids (absolute); 2. Gabapentinoids; 3. Ratios.

Reviewer #2: Addiction should be replaced with “use disorder”

Answer: Correct. We have also checked and replaced all the places were abuse was to be corrected too.

Reviewer #2: Caution against mentioning that gabapentinoids have been introduced to reduce opioid dependence as this is a hypothesis, only and has not been demonstrated to my knowledge.

Answer: The reviewer is right. We have rephrased it much more cautiously: Even if largely uncertain, it was hypothesised by some that gabapentinoids may help reduce opioids, prevent opioid tolerance, improve the quality of opioid analgesic therapy, and treat anxiety (3).

Reviewer #2: Consider reviewing this reference for peri-operative lack of effect: https://pubs.asahq.org/anesthesiology/article/133/2/265/109137/Perioperative-Use-of-Gabapentinoids-for-the#

Answer: We thank the reviewer for highlighting this work. This well justifies, at least some of our current concerns and the risk of overreliance on gabapentinoids. We have added this reference in the introduction: However, these hypotheses have been, at least partially, rejected (4,5).

4. Verret M, Lauzier F, Zarychanski R, Perron C, Savard X, Pinard AM, Leblanc G, Cossi MJ, Neveu X, Turgeon AF; Canadian Perioperative Anesthesia Clinical Trials (PACT) Group. Perioperative Use of Gabapentinoids for the Management of Postoperative Acute Pain: A Systematic Review and Meta-analysis. Anesthesiology. 2020 Aug;133(2):265-279.

5. Goodman CW, Brett AS. Gabapentin and Pregabalin for Pain - Is Increased Prescribing a Cause for Concern? N Engl J Med. 2017 Aug 3;377(5):411-414.

Reviewer #2: Readers who are not from the UK will not know that the management plan is. It is mentioned in a couple of places but it isn’t clear what it consists of and how it is relevant.

Answer: That's absolutely correct. Throughout the manuscript, and according to the first reviewer, we have reworded and detailed to ensure that it would be clear and relevant for non-UK readers. Among other things, here is an added explanatory paragraph (re)written for discussion:

In 2016, the UK's Advisory Council on the Misuse of Drugs recommended that pregabalin and gabapentin be controlled under the Misuse of Drugs Act 1971 as Class C substances and listed under the Misuse of Drugs Regulations 2001 as Schedule 3. In the UK, controlled drugs are divided into classes A, B and C, depending on potential harms. Class C drugs are considered the least harmful. Schedule 3 implies specific requirements for the prescribing, dispensing, recording and safe storage of certain drugs, such as certain benzodiazepines. In April 2019, pregabalin and gabapentin were classified as Class C substances and listed as additional substances under the Misuse of Drugs Regulations 2001 (19).

Reviewer #2: Issue with the first sentence on page 11

Answer: Thank you. We have corrected the sentence.

Reviewer #2: I see many pivotal studies addressing the lack of efficacy and the harms of gabapentinoids are missing from the references. Gingras et al., Verret et al., works by Juurink, RCTs showing no effect but increased risk of adverse events that were published in JAMA, NEJM etc…the references could be more robust for this study

Answer: Thank you for this suggestion. According to this relevant comment, we tried to identify impactful publications, but without over-referencing. We have added these and hope this will address the reviewer’s concerns.

Reviewer #2: I like the figures but the statistical analysis plan is not that clear to be and the analysis is also not well described or robust. How about at time series analysis? And how about including some measure of the size of the population and the dose vs dispensations. Also not clear whether a ratio was calculated and where that is presented graphically and why it was done.

Answer: We agree that the statistical analysis part was not clear, and we have also reformatted the results section, both in the main manuscript and the abstract.

To be concise, the reviewer will find here the abstracts results section, but will find many more details in the manuscript: During this period, opioid prescriptions remained stable (from -3.3% to +2.2%/year) and increased for gabapentinoids generally (from +1.5% to +2.2%). The ratio between opioid to gabapentinoid prescriptions increased by more than 20% in 2020 compared to 2015, variably between regions (F(6,406)=[120.2]; P<0.001; LSD Test: P<0.001; ANOVA for repeated measures: P<0.05). In 2019, a decline in the ratio occurred in all regions, but only persisting in the London commissioning region in 2020 (-14.4% in comparison with 2018, 95%CI:-12.8 to -16.3).

As explained above, we appreciate the suggestion of performing a time series analysis. However, not hypothesising that that these data may have an internal structure (such as autocorrelation, trend or seasonal variation), we did not perform it. We hope that the reviewer will find that acceptable, wishing to focus on the descriptive analyses, being the most important aspects to us.

We also have found and corrected an error in the Y axis of the figure 3 (initially presented multiplied by a factor 1000 to simplify the presentation). We apologise for this.

Attachment

Submitted filename: Authors_Response.docx

Click here for additional data file. (26.1KB, docx)

Decision Letter 1

Jorge Enrique Machado-Alba

27 Sep 2022

PONE-D-22-15405R1Opioid and gabapentinoid prescriptions in England from 2015 to 2020.PLOS ONE

Dear Dr. Forget,

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.

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Reviewers' comments:

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Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

**********

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Reviewer #1: Partly

Reviewer #2: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #1: No

Reviewer #2: Yes

**********

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Reviewer #2: Yes

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Reviewer #1: Thank you for the revision to this paper.

However, I still have concerns regarding the basis for the analyses. As stated in my previous review, it is not possible to tell from the prescribing data available at OpenPrescribing.net whether a patient is taking opioids and gabapentinoids concomitantly, and that the limitations should be strengthened. The paper now states "However,

the differences observed and the variability of the ratio were consistently observed and deserve to be underlined, particularly seeing their implications at a Public Health level", and now includes "we described the evolution of the prescriptions of opioids and gabapentinoids, and calculated their ratios (as a surrogate for their concomitant use at a population level) for each month." I do not believe you can use this data to show any sort of surrogate of concomitant taking of opioid and gabapentinoid, for reasons stated above, and therefore this should be revised to remove this suggestion.

Reviewer #2: (No Response)

**********

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: Richard Croker

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.]

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 PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2022 Nov 28;17(11):e0276867. doi: 10.1371/journal.pone.0276867.r004

Author response to Decision Letter 1

27 Sep 2022

Dear Editor, dear Reviewers,

Thank you for the kind and constructive comment. You will find here a revised version of our work. We hope that this will encounter all your concerns. We remain, of course, open to any other suggestion.

Kind regards,

Patrice Forget and Yixue Xia

Reviewer #1: Thank you for the revision to this paper.

However, I still have concerns regarding the basis for the analyses. As stated in my previous review, it is not possible to tell from the prescribing data available at OpenPrescribing.net whether a patient is taking opioids and gabapentinoids concomitantly, and that the limitations should be strengthened.

The paper now states "However, the differences observed and the variability of the ratio were consistently observed and deserve to be underlined, particularly seeing their implications at a Public Health level", and now includes "we described the evolution of the prescriptions of opioids and gabapentinoids, and calculated their ratios (as a surrogate for their concomitant use at a population level) for each month."

I do not believe you can use this data to show any sort of surrogate of concomitant taking of opioid and gabapentinoid, for reasons stated above, and therefore this should be revised to remove this suggestion.

Answer: Thank you for the comment. This is right, and what we may believe is different than what we can state. In other words, we fully agree with the reviewer that this is factually not supported by the data presented and can in no way be taken as certain. Accordingly, we have checked, throughout, and removed any mention of "surrogate" or “concomitant” and strengthened the limitation section as follows:

This means that the ratios between gabapentinoid and opioid prescriptions have been observed at the regional level and cannot be automatically extrapolated to the patient level. In other words, it cannot be asserted that these data can be considered as a surrogate for the concomitant use of opioids and gabapentinoids. Prescribing patterns may have been different, depending on the practice or over time and it is not possible to describe what proportion of patients are prescribed both these drugs, as this is not available within the data.

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Decision Letter 2

Vijayaprakash Suppiah

17 Oct 2022

Opioid and gabapentinoid prescriptions in England from 2015 to 2020.

PONE-D-22-15405R2

Dear Dr. Forget,

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

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Kind regards,

Vijayaprakash Suppiah, PhD

Academic Editor

PLOS ONE

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Reviewer #2: All comments have been addressed

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Reviewer #2: Yes

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Reviewer #2: Yes

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Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Checklist. STROBE statement—checklist of items that should be included in reports of cohort studies.

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    Attachment

    Submitted filename: Authors_Response2.docx

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    Data Availability Statement

    Data are freely available on www.openprescribing.net and www.ons.gov.uk. Please find here the respective URLs: https://openprescribing.net/analyse/#org=regional_team&numIds=4.7,0408010G0AA,0408010AEAA&denom=nothing&selectedTab=summaryhttps://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/datasets/deathsregisteredinenglandandwalesseriesdrreferencetables.

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