Quality use of publicly subsidised tapentadol in Australia: a population‐based analysis

Sustained‐release (SR) tapentadol was listed on Australia's Pharmaceutical Benefits Scheme (PBS) in 2014 for chronic severe pain requiring long‐term opioid treatment. Dispensings have increased since listing despite declining trends in other PBS‐listed opioids. Preferential prescribing of SR opioids may increase the risk of dependence and accidental overdose, particularly when used to treat acute pain.


Introduction
Tapentadol is a μ-opioid agonist, moderate noradrenaline reuptake inhibitor (NRI) and weak serotonin reuptake inhibitor.It is less potent than most strong opioids (e.g.2][3][4] Tapentadol has been associated with lower risks of serious adverse events relative to strong conventional opioids, 3,4 although it still poses a risk of misuse, abuse and harm, particularly when used concurrently with other central nervous system depressants. 2The literature also reports a potential risk of serotonin syndrome associated with co-administration of Abbreviations: IR, immediate-release; MAOI, monoamine oxidase inhibitor; OME mg, oral morphine equivalent milligram; PBS, Pharmaceutical Benefits Scheme; SNRI, serotonin and noradrenaline reuptake inhibitor; SR, sustained-release; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant Conflict of interest: S.-A.Pearson and N. L. Pratt are members of the Drug Utilisation Sub Committee of the Pharmaceutical Benefits Advisory Committee.The views expressed in this paper do not represent those of the Committee.All remaining authors have declared no conflicts of interest relevant to the submitted work. ][7] Sustained-release (SR) tapentadol, licensed for relief of chronic moderate to severe pain, was approved for marketing in Australia from February 2013 8 by the Therapeutic Goods Administration and listed for public subsidy on the Pharmaceutical Benefits Scheme (PBS) in June 2014 for the treatment of 'chronic severe pain requiring daily, continuous, long term opioid treatment' (Box 1). 9,10Since its market entry national monthly sales have rapidly increased, with tapentadol accounting for the third largest percentage of total oral morphine equivalents (10.7%) sold in December 2017. 8Most tapentadol sold in Australia is SR, with immediaterelease (IR) accounting for 2.5% of all tapentadol oral morphine equivalents sold in 2017. 8The concern with preferential prescribing of SR opioids more generally is that higher doses, longer duration of action and larger pack sizes may increase the risk of dependence 11 and overdose, 12 particularly when used to treat acute pain. 13he most recent government statistics for PBS-listed tapentadol (SR) demonstrate a steady increase in dispensed prescriptions and new use per quarter since its listing to 2019.This is in direct contrast to the declining trends in the use of all other PBS-listed opioids. 14Quality use of Medicines and Medicines Safety' is Australia's 10th National Health Priority, 15,16 with a strong commitment to reducing harms associated with high-risk medicines (such as opioids).[17][18][19][20] To our knowledge, the quality of use of publicly subsidised tapentadol (SR) has not been assessed in Australia.We therefore examined trends in the annual rates of tapentadol initiation and individual patterns of use from time of initiation to a year after commencing treatment.Specifically, we examined prior, recent use of other opioids, concurrent use of potentially interacting medicines and duration of treatment.

Methods
We conducted a population-level assessment of tapentadol dispensing in Australia.This study adheres to the STROBE reporting guidelines 21 (Table S1).

Setting and data
We used longitudinal dispensing records on subsidised medicines dispensed from community pharmacies, private hospitals and on discharge from public hospitals (in most states) between 1 June 2014 and 31 December 2021 for a 10% random sample of PBS-eligible Australians, described elsewhere 22,23 ('PBS data').Records contain encrypted patient and prescriber identifiers and information on dispensed unit dose strength and pack size; information on the indication for prescribing and the prescribed daily dose is not available.
Prescribed opioids can also be purchased privately, where the patient is responsible for paying the full cost of the medicine.Private dispensings are not captured in the PBS data.Thus, to gain a comprehensive view of the total tapentadol sales (PBS plus private market), we also assessed national sales of tapentadol between June 2014 and December 2021 using data provided by IQVIA (www.iqvia.com;'IQVIA data').IQVIA is a company that collects and maintains a database of sales by pharmaceutical wholesalers and manufacturers to community pharmacies and hospitals.These data comprise the total number of packs sold in each month, regardless of payer (subsidised or private) and represent over 94% of the Australian market. 24,25Individual-level records are not available from IQVIA.
Analysis of the PBS data was approved by the New South Wales Population and Health Services Research Ethics Committee (2019/ETH01776) and the Services Australia External Request Evaluation Committee approved the use of the data (reference RMS2369).Ethics approval was not required for the analysis of the aggregate sales data.

Medicines of interest
Tapentadol (SR) is available in 28-tablet packs (50, 100, 150, 200 and 250 mg tablet strengths) and is currently the only subsidised formulation available.Tapentadol (IR) 50 mg (10-and 20-tablet packs) is only available on private prescriptions.We quantified national sales of both tapentadol (IR) and (SR) and examined individual-level dispensing patterns of publicly subsidised tapentadol (SR).
To assess prescribing patterns in relation to guidance outlined in the tapentadol (SR) product information 2 about potential interacting medications, we examined

BOX 1 Tapentadol (SR) therapeutic indication
Approved indication 2 Management of severe pain requiring daily, continuous, longterm treatment where other treatment options provide insufficient pain management.
Subsidised indication 9,10 Chronic severe disabling pain requiring daily, continuous, long-term opioid treatment where condition is unresponsive to non-narcotic analgesics.

Use of subsidised tapentadol (SR)
We used the PBS data to assess patterns of use of subsidised tapentadol (SR).

Study population
We defined a new user cohort of PBS-eligible adults aged 18 years and older whose first observed dispensing for tapentadol (SR) occurred between 1 September 2014 and 31 December 2021.As tapentadol was not available on the PBS (and therefore not observable in PBS dispensing claims) prior to June 2014, we considered the first observed dispensing for each individual during the study period as their tapentadol initiation date.We considered the period 1 June to 31 August 2014, the first 3 months after listing, as a washout to allow for the possibility of people switching from private dispensing prior to public subsidy (and hence not new use) and excluded people who had their first dispensing during this period.

Initiation
We calculated the annual initiation of subsidised tapentadol (SR) per 1000 population over the study period, using the Australian Bureau of Statistics Estimated Resident Population 29 (aged 18 years and over) as the denominator.We defined initiation as the first observed dispensing for a person.As the PBS data represented a 10% random sample of eligible Australians, we multiplied the numerator by 10 to estimate national trends.To provide a more granular picture of trends in tapentadol initiation, we also calculated the monthly number of tapentadol initiators in a sensitivity analysis.
To contextualise tapentadol initiations with respect to other opioids, we conducted a second sensitivity analysis whereby we compared the annual initiation (per 1000 population) of tapentadol (SR) and all other opioids from 2015 (first full year of the study period) to 2021.We used a 365-day lookback to ascertain new use of other opioids and multiplied the numerator by 10 to estimate national trends.

Patterns of tapentadol use in the year following initiation
We restricted our cohort to people with a first observed tapentadol (SR) dispensing prior to 31 December 2020.We assessed sex, age (18-44, 45-64, 65-84, 85 years and older), and tablet strength at the time of first dispensing.We examined discontinuation in the 365 days following initiation, defined as a period of at least 90 days without a subsequent tapentadol (SR) dispensing.We used 90 days based on clinical input; tapentadol is sold in 28-tablet packs where tablets cannot be split, and we expected most users intending to continue tapentadol therapy to refill their prescriptions within this time.We measured the number of prescriptions dispensed prior to discontinuation or at the end of the first year of use, whichever was earlier.We calculated treatment duration as the number of days between the first and last dispensing +30 days (accounting for the last prescription prior to discontinuation); for people who did not discontinue within the first year, we set duration as 365 days.
We quantified dispensing of PBS-listed medicines with potential interactions on the same day as, and within ±30 days of, a dispensed tapentadol (SR) prescription and identified prescriptions written by the same practitioner prescribing tapentadol (SR) (i.e. with the same prescriber identifier).
We assessed dispensing of other PBS-listed opioids in the 90 days prior to and 90 days following (and including) tapentadol (SR) initiation.We also identified opioids dispensed on the same day as tapentadol (SR) initiation.

Subsidised versus private tapentadol
To assess the market share of SR versus IR tapentadol, we used the IQVIA data to calculate the total number of packs of tapentadol sold in each month, stratified by formulation, between June 2014 and December 2021.As a result of legal requirements around storage and monitoring of opioids, these data closely approximate the complete capture of all prescription tapentadol sales in Australia. 8,24We also calculated the total monthly oral morphine equivalent milligrams (OME mgs) sold, by formulation, as (tablet strength * quantity dispensed * 0.4). 30o assess the proportion of total tapentadol (SR) sales attributable to the PBS, we first estimated national subsidised sales from the PBS data by summing total monthly dispensings of tapentadol (SR) between June 2014 and December 2021, by packs and OME mgs, and multiplying by 10.We then calculated the ratio of subsidised dispensings to total tapentadol (SR) sales (calculated from the IQVIA data as above) in each month, expressed as a percentage.
All analyses were conducted with SAS version 9.4 (Cary, NC, USA).

Results
Use of subsidised tapentadol (SR)

Initiation
Initiation of tapentadol (SR) increased from 0.8/1000 population in 2014, peaking at 7.5/1000 population in 2019 before declining to 5.3/1000 in 2021 (Fig. 1).There was a notable decrease in initiations from April 2020 to June 2020, with the number of monthly initiators through to the end of 2021 remaining consistently lower than those observed in 2018 and 2019 (Fig. S1).In contrast to tapentadol (SR), initiation of all other opioids declined steadily (Fig. S2).
In the 90 days preceding their first tapentadol (SR) dispensing, nearly half of all new users (28 976; 45.4%) were dispensed another PBS-listed opioid (Table 2).More than half of those with recent opioid exposure (i.e. in the prior 90 days; 15 286 (52.8%)) continued tapentadol beyond the initial dispensing, whereas two-thirds of new users without recent opioid exposure (23 264; 66.9%) received one dispensing only.
Nearly a quarter of new users (15 071; 23.6%) were dispensed another opioid on the same day as their initial tapentadol (SR) dispensing (Table 2).Use of nontapentadol opioids after tapentadol (SR) initiation was more common among people with recent opioid exposure: two-thirds of people with recent opioid exposure (19 033; 65.7%) were dispensed another non-tapentadol opioid in the 90 days following tapentadol initiation, compared to just over one-third (12 915; 37.1%) of people without recent opioid exposure.Oxycodone IR was the most common other opioid dispensed in both groups.Nearly a quarter of all new users (14 708; 23.1%) received only a single dispensing of tapentadol (SR) and no other opioids in the 3 months either before or after initiation (Fig. S3).
Most tapentadol (SR) sold in Australia was subsidised by the PBS (Fig. 3).There was a sustained drop in the proportion of sales attributable to the PBS from June 2020 onwards, with a corresponding increase in private sales.On average, 69.1% of all tapentadol (SR) packs (86.6% OME mgs) sold each month were PBS subsidised prior to June 2020, dropping to 63.9% (82.9% OME mgs) afterwards (Figs.S5 (packs) and S6 (OME mgs)).

Discussion
In our nationally representative sample of Australians, we observed an increase in tapentadol (SR) initiation following its public subsidy until 2019, after which the number of people initiating tapentadol declined.Most tapentadol sold in Australia is publicly subsidised; however, we found evidence of a shift to the private market from June 2020 onwards.More than half of new users only received a single tapentadol dispensing.Concurrent use of potentially interacting medicines, which increases the potential for medicine-related harms, was common; many of these medicines were

Quality use of tapentadol in Australia
prescribed by the same practitioner and dispensed on the same day as tapentadol.
The decline in tapentadol initiations in the second quarter of 2020 likely reflects the impact of the COVID-19 pandemic, 31 although changes to opioid prescribing policies and regulations introduced in June 2020 [18][19][20] may have also contributed to the sustained drop in initiations seen through 2021.
In Australia, tapentadol (SR) is the only publicly subsidised tapentadol formulation, indicated for the treatment of chronic moderate to severe pain requiring daily, long-term opioid therapy. 2,9,10The high prevalence of single dispensings of tapentadol (SR) is unexpected given the indication of chronic pain.There are several plausible explanations; single dispensings may represent discontinued tapentadol because of adverse effects or use for acute or subacute pain.We found that 55% of new tapentadol (SR) users had no other opioid exposure in the prior 3 months, so if these single dispensings represent use for chronic pain, they are in a relatively opioid-naïve population.In addition, some Australian hospitals have reported frequent use of tapentadol (SR) for acute postsurgical pain which may continue for short periods following discharge. 32A single dispensing may also indicate episodic use of tapentadol, a common treatment approach for opioids used in cases of chronic pain. 33Nonetheless, our findings align with a contemporary study of opioid prescribing in general practices in Victoria, Australia, which found that nearly half of all patients prescribed opioids only received a single prescription, although this study included all people prescribed opioids, not just people with chronic pain. 34ur findings indicated possible concurrent use of tapentadol and medicines with potential interactions.Dispensing of gabapentinoids, benzodiazepines and antidepressants within ±30 days of tapentadol was common, occurring among a quarter to more than a tenth of new users, respectively, and mostly prescribed by the same practitioner.This may signify poorly controlled chronic pain or reflect non-narcotic pain management prior to tapentadol initiation.35,36 Co-administration of tapentadol and other serotonergic agents might cause serotonin syndrome, and concurrent use is cautioned. 2,5,6Concurrent dispensing with MAOIwhich are contraindicatedoccurred but was much lower among new users of tapentadol than in the general population (<0.2% vs 1.0% respectively). 37It is therefore possible that some of the single tapentadol dispensings may reflect interaction-related adverse events and subsequent tapentadol discontinuation among patients concurrently exposed to tapentadol (SR) and other medicines.
Our findings are pertinent considering the current policy interest in quality use of medicines. 15][20] We found a decrease in monthly pack sales of subsidised tapentadol (SR) from June 2020 onwards while overall sales continued to increase, suggesting a shift to the private market; the timing corresponds to increased restrictions in PBS subsidy of opioid dispensing.Indeed, Koch et al. 39 found that many people likely switched to the Quality use of tapentadol in Australia private market to access opioids following PBS prescribing restrictions introduced in June 2020, suggesting that recent policy changes may have had minimal effect on overall opioid use in Australia.Other approaches may be warranted; our results highlight the potential importance of prescriber-level interventions to reduce the concurrent prescribing of sedating medicines and strengthen concordance with best practice guidelines.
Our study has important limitations.As the available data did not have information on indication, further research is needed to ascertain prescribing associated with cancer pain or following acute injury or surgery.Furthermore, the data used in this study only capture subsidised medicines; given many analgesic medicines (e.g.non-steroidal anti-inflammatory drugs) are available without a prescription or purchased privately, we were also not able to ascertain exposure to non-narcotic analgesic therapy for pain management.The data only represent prescriptions dispensed; actual consumption is unknown.We also did not have individual-level information on privately dispensed medicines (including IR tapentadol); misclassification of initiation is therefore possible for people with private tapentadol dispensings.Private opioid prescriptions have been shown to account for approximately 12-17% of the Australian market, [40][41][42] although we found this to be higher for tapentadol (nearly 40% of packs and 22% of OME mgs sold in December 2021).However, our analysis demonstrated that the majority of tapentadol sold in Australia is subsidised; it is therefore unlikely misclassification impacts all initiations.Nonetheless, the ratio of private versus subsidised opioid sales is changing, 39 underscoring the importance of having visibility on both sectors of the market into the future.
The study period included the COVID-19 pandemic.Restrictions on hospital services and changes to health service delivery models in Australia 43,44 resulted in significant increases in prescribing of antidepressants 37 and dental medicines (including opioids). 45Delays to surgery likely reduced initiation of opioids for postsurgical pain but may have led to corresponding increases in opioid use for chronic pain relief as waiting periods grew longer.Although new use of subsidised tapentadol (SR) declined during the pandemic period, the full extent of the impact of these public health measures on opioid prescribing more generally is not yet known.

Conclusion
Our study provides a contemporary assessment of tapentadol (SR) initiation, characteristics of new users and dispensing of interacting medicines with tapentadol (SR) in Australia following its listing for public subsidy.Although most tapentadol sold in Australia has been subsidised, the market is still evolving and there is evidence of a shift towards private sales following PBS restrictions.We have identified patterns of dispensing indicating tapentadol (SR) is generally used for short duration, with more than half of new users receiving a single dispensing and suggesting concurrent dispensing with potentially interacting medicines is common.

Table 1
Patterns of tapentadol utilisation and characteristics of new users (≥18 years), September 2014 to December 2020

Table 2
Patterns of tapentadol and other opioid use among people ≥18 years initiating tapentadol, September 2014 to December 2020 PBS subsidised opioid exposure 90 days prior to tapentadol initiation †Suppositories, oral liquids.‡Only includes buprenorphine and methadone for pain; does not include use of these medicines for treatment of opioid dependence.PBS, Pharmaceutical Benefits Scheme.