Considerations for Perioperative Opioid Analgesic Stewardship in Australia: A Focus on Tapentadol

Abstract

Opioid-related harm remains a serious public health issue in Australia, where there is a strong focus on judicious use of opioids to optimize postoperative patient outcomes. The risks associated with preoperative opioid use (worsened postoperative pain, surgical outcomes, increased length of stay and financial costs) must be balanced with the risks of sub-optimal post-surgical pain management (development of chronic pain, persistent postsurgical opioid use and opioid dependence). In addition to significantly lower rates of gastrointestinal adverse effects (nausea, vomiting, constipation), tapendatol (vs oxycodone) is less likely to cause excessive sedation and opioid-induced ventilatory impairment, may be associated with less withdrawal symptoms of mild to moderate intensity and significantly lower odds of 3-month persistent postoperative opioid use in certain patient populations. Studies included in this review were phase III/meta-analyses, referenced in Australian clinical guidelines and/or published ≤5 years), except for cost–effectiveness analyses, where all known, relevant published analyses were included.

Plain language summary

Patient harms from medicines related to morphine, which is part of a group of pain-relieving drugs called opioids, is a serious public health issue in Australia, as such, there is a strong focus on the cautious use of these medicines. Using opioids before surgery is associated with risks such as worse pain after surgery and longer hospital stays, however, when pain after surgery is not managed sufficiently, this can result in long-term pain and therefore the need to use these medicines for longer than recommended. Tapentadol is an opioid that has less stomach/gut side effects, causes less sleepiness, is less likely to cause serious breathing impairment, may have less symptoms when stopping the medication and less chance of long-term (more than 3 months) use compared with a more commonly used opioid (oxycodone).

Keywords::

• analgesic stewardship
• opioid
• perioperative
• tapentadol

Practice points

Prescription opioids are commonly used in Australia, as such opioid-related harm remains a serious public health issue

• Australia’s government has taken actions, in the form of regulatory changes, a National Opioid Analgesics Stewardship program and clinical care standard, to minimise the risk of opioid analgesic-related harms.

• Chronic pain sufferers continue to report a significant negative impact on their quality of life following reforms to opioid analgesics, and Australian healthcare professionals view opioid ‘deprescribing’ as challenging.

The challenge to balance the benefits of prescribing opioid analgesics with minimising the possibility of harms continues

• The goal for ‘Perioperative opioid stewardship’ should be the judicious use of opioids for the management of post-surgical pain and optimal postoperative patient outcomes, rather than opioid avoidance, to ensure that the risks of both over- and under-utilization of these agents are carefully considered and balanced.

• The most important potential significant harms related to the use of opioids in acute pain management, outlined in the ANZCA/FPM PS41(G) Position statement on acute pain management 2022 includes Opioid-Induced Ventilatory Impairment (OIVI), Persistent Post-operative Opioid Use (PPOU) and opioid misuse and diversion.

• The body of evidence increasingly supports an association between the use of opioids pre-operatively and worsened postoperative pain, non-optimal surgical outcomes, increased length of stay, and higher financial costs. However, sub-optimal post-surgical pain management has been shown to be associated with the development of chronic pain, PPOU and opioid dependence.

• As outlined in the Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine ‘Acute Pain Management: Scientific Evidence’ (5th Edition), a systematic review of all relevant randomised controlled trials concluded that tapentadol has similar efficacy to conventional opioids, however, is associated with significantly reduced rates of GI adverse effects (nausea, vomiting, constipation).

• The current body of evidence supports that, compared with oxycodone at equianalgesic doses, tapentadol is less likely to cause excessive sedation and OIVI, is associated with a low frequency of opioid withdrawal symptoms and significantly lower odds of 3-month PPOU in patients that receive modified release opioids at discharge, and those undergoing orthopaedic surgery.

Opioid-related harm & regulatory reforms in Australia

Opioid class drugs bind to opioid receptors in the brain, which function to control pain and reward [1]. Opioids have long been considered an effective therapeutic option for the treatment of pain, and are considered the standard of care for the management of severe pain [2]. The use of prescription opioids is common in Australia; In 2016-2017 more than 15 million prescription opioids were dispensed to 3.1 million people [3]. Opioid-related harm and mortality remains a serious public health issue internationally and in Australia. The most recent instalment of the Penington Institute’s ‘Australia’s Annual Overdose Report’, illustrates almost three-times the number of unintentional drug-induced deaths involving opioids since 2006, with opioids contributing to 51.7% (n = 856) of unintentional drug-induced deaths in 2020 [4].

Commencing in October 2019, the Therapeutic Goods Association (TGA), Australia’s government authority responsible for regulating medicines, commenced implementing opioid reforms to reduce patient harms while allowing sustained access to these medications, where medically necessary. These reforms, which took effect from 1 June 2020, coinciding with the COVID-19 pandemic and the commencement of a national implementation of Real-Time Prescription Monitoring (RTPM) programs, saw tightening of therapeutic indications of opioid medications, the inclusion of boxed warnings and class statements and the requirement for smaller pack sizes [5]. In parallel to this, the TGA engaged the Australian Commission on Safety and Quality in HealthCare (‘the Commission’) in April 2020 to develop a framework for a National Opioid Analgesic Stewardship program, inclusive of a clinical care standard. Opioid stewardship has been defined as “coordinated interventions designed to improve, monitor, and evaluate the use of opioids in order to support and protect human health” (ISMP, Canada) [6]. Together, the TGA’s regulatory changes, the Commission’s National Opioid Analgesics Stewardship program and Clinical Care Standard all aim to minimise the risk of opioid analgesic-related harms in Australia [7].

An ensuing consumer survey was conducted by Pain Australia in 2020, to assess chronic pain sufferers were impacted by these opioid reforms. Notwithstanding the intention to minimise harms, the results of the survey highlighted the lack of a co-ordinated approach to support the significant reforms and the lack of accessible and affordable options for the management of chronic pain. The themes identified in this survey determined that the reforms [8]:

• Created an additional layer of complexity;

• Led to loss in function and autonomy;

• Perpetrated stigma and isolation; and

• Significantly impacted mental health.

A subsequent Pain Australia survey conducted from December 2021 to February 2022 once again demonstrated that overwhelmingly, consumers felt the reforms had had a significant negative impact on their quality of life, reporting [9]:

• Lack of access to alternative support and treatment in place of medication;

• Difficulties in accessing medication for chronic pain;

• Increased GP and health professional visits resulting in increased costs to consumers

• Feelings of stigma and judgement;

• Decreased quality of life;

• Greater feelings of distress and anxiety significantly impacting mental health; and

• Need for greater information, awareness and education of health professionals and consumers about the reforms and alternative treatments and support.

A local qualitative study of Australian healthcare professionals found that physicians view opioid ‘deprescribing’ as challenging. This study not only confirms challenges for both patients and physicians alike in relation to opioid therapy management, but also highlights the importance of prospective opioid deprescribing guidelines, inclusive of patient psychosocial factors and behavioural change techniques [10]. The University of Sydney recently published an Evidence-Based Clinical Practice Guideline for Deprescribing Opioid Analgesics, to guide General Practitioners on when, how and in whom to deprescribe opioids. The Guideline combines evidence-based recommendations and consensus-based recommendations, to guide clinical decision making in relation to tapering and cessation of opioids in pain management [11]. Taken together, the statistics on opioid-related harms and the consumer response to opioid reforms in Australia emphasize the importance of “Perioperative opioid stewardship” – the judicious use of opioids for post-operative pain management and optimal postoperative patient outcomes – rather than ‘opioid avoidance’, to ensure that the risks of both over- and under-utilization of these agents are carefully considered and balanced [12].

Analgesic stewardship as a holistic peri-operative pain management approach

Surgery is an essential part of healthcare; however, it is directly related to pain development and opioid use. Notably, sub-optimal post-surgical pain management has been shown to be associated with the development of chronic pain, persistent post-surgical opioid use (PPOU) and opioid dependence [12]. In 2020-21, the number of elective surgery admissions from waiting lists in Australia was 9.6% higher than in the previous year, most likely due to the restrictions in place for certain elective surgeries in response to COVID-19, emphasising the high proportion of Australians that are likely to be facing lengthy pre-operative periods of pain management [13].

In addition to younger age, female sex, smoking, preoperative anxiety and depression, pain catastrophising and preoperative pain, preoperative opioid use has been shown to be a predictor of poorer postoperative pain control in the early postsurgical period [14]. Specifically, the body of evidence increasingly supports an association between preoperative opioid use and higher postoperative pain scores, higher opioid requirements, poorer surgical outcomes, longer length of stay and increased financial costs; as such, preoperative opioid reduction may result in substantial improvements in outcomes [15]. In addition to reducing pre-operative opioid use, consideration of a multimodal enhanced recovery-type protocol can also reduce hospital length of stay, complication rates, postoperative pain severity and opioid requirements [16]. Practical considerations for post-surgical discharge opioid prescribing may include;

• Risk assessment for chronic use and/or misuse, and where required, a plan for suspected opioid abuse, misuse or diversion;

• A multi-modal analgesic regimen, including non-opioid pain medications;

• Choice of opioid based on formulation, method of administration, and efficacy and tolerability profile;

• Providing patient education on risks, storage and safe disposal;

• Limiting the duration of therapy, based on anticipated pain trajectory after discharge, in communication with the patient. Opioid usage the day prior to discharge may be the best predictor of discharge dose and quantity;

• Monitoring of effect and compliance, and considerations for weaning and cessation as appropriate;

• Timely communication to the general practitioner who will manage the patient’s care, or alternatively, development of a plan to assist the patient access healthcare post-discharge.

Guidelines acknowledge that non-pharmacological pain management options are also important in the management of acute pain, however this will not be reviewed in detail here [14]. Notably, in terms of psychological preparation for surgery, procedural information has been demonstrated to have a significant effect on pain, recovery, length of stay and a significant reduction in pain medication [17]. Data from a mixed surgical cohort has also demonstrated that higher patient anxiety, depression, pain behaviours and pain catastrophising result in higher pain trajectories, which in turn result in greater opioid requirements [18]; As such, the importance of clinician communication with patients regarding their procedure, recovery, expectations of pain and multimodal therapies for pain management cannot be underestimated.

Analgesic stewardship should include the consideration of other analgesic and adjuvant medications aside from opioids, for analgesia sufficient to permit patient recovery and functional improvements, as well as the minimisation of analgesia-related harms [16]. Pain score trajectories (i.e. assessment of pain resolution over time), rather than unidimensional pain scores alone, are recommended in assessing patient response to treatment in the immediate postoperative period, and functional assessment scales should be used to assess the extent to which a patient is limited in completing an activity related to the cause of the ‘new’ acute pain [14].

Choice of opioid

Should opioid analgesic therapy be indicated, the minimum quantity of the lowest effective dose of immediate release opioids should be provided, based on the expected duration of severe pain [19]. For the initial prescription in opioid-naive patients, age-based doses are recommended, owing to evidence demonstrating that the dose of opioid required to manage acute pain decreases as patient age increases [14].

Due to the distribution of μ-opioid receptors throughout the body, opioid analgesics may produce a broad spectrum of adverse effects, including dysphoria, euphoria, sedation, constipation, suppression of endocrine systems, cardiovascular disorders, convulsions, nausea, vomiting, opioid-induced hyperalgesia and respiratory depression, which is more completely described by the term Opioid-Induced Ventilatory Impairment (OIVI) [7]. All opioids can lead to dependence, accidental overdose, hospitalisation or death [3], however as opioids remain the basis of systemic analgesia for severe acute pain management [16], the need for better stewardship of opioid analgesic therapies has become evident to ensure that the benefits of prescribing opioid analgesics is balanced to minimise the possibility of harms. The most important potential significant harms related to the use of opioids in acute pain management, as outlined in the Australian and New Zealand College of Anaesthetists/Faculty of Pain Medicine’s (ANZCA/FPM) PS41(G) Position Statement on acute pain management 2022 include [14];

• Opioid-induced ventilatory impairment (OIVI);

• Persistent post-discharge opioid use (PPOU); and

• Opioid misuse and diversion.

This review aims to synopsise the safety data relating to tapentadol, in relation to post-surgical pain management and opioid analgesic stewardship.

Tapentadol, an atypical opioid

While conventional opioids act on μ-opioid receptors, some opioids provide analgesic effects by synergistic mechanisms or via interactions with alternate opioid receptors [16]. Tapentadol exerts analgesic effect through a combination of both μ-opioid receptor agonism (MOR) and noradrenaline reuptake inhibition (NRI) [20]. As a result of the NRI component, there is less reliance on MOR binding with tapentadol compared with conventional opioids to produce analgesia [20–22]. An experimental analysis explored the contribution of the μ-opioid component to tapentadol’s analgesic and adverse effects of in pre-clinical and clinical data [23]. This analysis estimated that the opioid component of tapentadol contributes between 30% and 54% of the effect, as compared with pure MOR agonists with a μ-opioid load of 100% [23]. This data supports the theory that tapentadol provides strong analgesia without being a strong opioid and may explain the differences seen in MOR adverse effects [23].

Tapentadol has been studied in various post-operative and non-surgical pain conditions [20,24,25], and studies of equianalgesic doses (tapentadol 50 mg vs oxycodone 10 mg) consistently show comparable efficacy [16,20,26]. Two independent systematic review and meta-analyses have been published; Wang et al. 2020, included eight randomized controlled trials (RCTs, n = 3706 patients) in a meta-analysis which compared 50–100 mg tapentadol immediate release (IR) with 5–15 mg oxycodone IR [24]. They found 50 mg of tapentadol IR was associated with less pain control compared with oxycodone IR, however there were no significant differences at higher doses or when a titration strategy reflective of clinical practice was used. It should be noted that the 50 mg efficacy analysis included a study where the active comparator was oxycodone 15 mg, which is not an equianalgesic dose (1 mg oral morphine equivalent for oxycodone = 1.5 mg, for tapentadol = 0.3 mg) [27]. The authors concluded that tapentadol IR can be considered as a first line opioid for acute pain, based on their findings which showed tapentadol IR is as effective as other opioids at higher doses and is associated with fewer gastrointestinal adverse effects [24]. Xiao et al. 2017 included nine RCTs (n = 3961) in the meta-analysis which compared tapentadol IR (50 mg, 75 mg, 100 mg) with 10 mg oxycodone IR [25]. The analysis found that there were no significant differences between any dose of tapentadol IR and oxycodone 10 mg, concluding that all three doses of tapentadol IR could provide comparable efficacy to oxycodone IR 10 mg, with significantly lower incidence of nausea and constipation (tapentadol IR 50 or 75 mg vs oxycodone IR 10 mg; all p < 0.05) [25].

In Australia, only the sustained release (SR) formulation of tapentadol is subsidised by the Australian Pharmaceutical Benefit Schedule (PBS), as such tapentadol IR has a higher cost than traditional IR opioids, such as oxycodone. Despite this, tapentadol IR was found to be a cost-effective alternative to oxycodone IR for the management of post-operative pain after major hip surgeries (reported as an ICER; AU$ per QALM) in a recent Australian cost–effectiveness analysis. Notably, this result was driven by the assumptions made regarding the probability of gastrointestinal (GI) adverse events with oxycodone versus tapentadol and the costs associated with the management of GI events [28]. The findings of this analysis are consistent with previous international cost–effectiveness analyses, including;

• A 2021 Italian cost–effectiveness analysis of tapentadol compared with oxycodone/naloxone, which demonstrated that despite prices of oxycodone/naloxone generic formulations being lower, the costs associated with treatment discontinuation were always higher than those associated with tapentadol [29]; and

• Two cost–effectiveness analyses conducted in the USA; one concluding that the cost of pain medication was offset by reductions in pharmacy and medical costs associated with the treatment of adverse events and opioid switching/discontinuation [30], the other demonstrating that replacing 5% of oxycodone IR with tapentadol IR in a hypothetical cohort of 1500 hospitalized patients would result in a net saving of USD $22,922 after factoring drug cost [31].

Similar cost–effectiveness analyses have been published for tapentadol SR in chronic non-cancer pain, concluding better quality of life outcomes at a lower cost, compared with oxycodone SR [32,33].

Implications for reduced gastrointestinal adverse events with tapentadol versus conventional opioids

The Australian and New Zealand College of Anaesthetists (ANZCA) and Faculty of Pain Medicine (FPM) ‘Acute Pain Management: Scientific Evidence’ (5th Edition), state that postsurgical patients who experienced an opioid-related adverse effect had a 55% longer hospital length of stay (LOS), 47% higher costs, 36% increased risk of readmission and 3.4-times higher risk of inpatient mortality [16]. In a recent Australian retrospective cohort study of surgical patients who received at least one dose of opioid analgesics (n = 17,886), 1814 patients (10.2%) experienced any opioid-related adverse event (ORADE), the most prevalent being gastrointestinal ORADEs (54.7%) [34]. In this study, compared with patients who did not experience an ORADE, those who did had three-times the rate of having a longer LOS (eate ratio [RR] 3.00, 95% CI 2.97–3.04) [34]. A recent systematic review of 16 retrospective US observational studies of hospitalised patients demonstrated that in the majority of studies analysed, ORADEs were associated with increased hospital length of stay, 30-day readmission, in-patient mortality, and higher hospital costs (USD $1,698–$21,176)/decreased hospital revenue (USD $418–$3,076 per day) [35]. As outlined previously and in the ANZCA/FPM ‘Acute Pain Management: Scientific Evidence’ (5th Edition), tapentadol has significantly reduced rates of GI adverse effects (nausea, vomiting, constipation) versus oxycodone [20,24,25,30,31,36–39]. The difference in GI adverse event rates between tapentadol and oxycodone may be partially owing to the opioid receptor binding affinity of tapentadol, which is 10- to 20-fold lower than receptor binding affinity of oxycodone [40]. This was demonstrated in a randomised, double-blind, placebo-controlled study with 21 healthy male participants, where tapentadol SR 50 mg BD was compared with oxycodone SR 10 mg BD for its effect on GI transit times and colonic motility, using an ambulatory 3D-Transit system. The study demonstrated that tapentadol SR induced fewer GI effects and affected GI motility less than dosing with oxycodone in equianalgesic doses with 14 days of dosing in healthy volunteers [40].

Opioid-induced ventilatory impairment

Opioid-induced ventilatory impairment (OIVI) can occur in any patient treated with opioids, even in the absence of identifiable risk factors that are predictive of an increased risk of OIVI. However, there have been some patient risk factors identified, including older age, female gender, sleep disordered breathing, obesity, renal impairment, pulmonary disease (in particular chronic obstructive pulmonary disease), cardiac disease, diabetes, hypertension, neurologic disease, two or more comorbidities, genetic variations in opioid metabolism and opioid-tolerant patients [14]. Modifiable risk factors include; the administration of more than one opioid, sustained release opioids, sedatives and sedating analgesic adjuvants, and opioid dose in opioid-naive patients [6]. As excessive sedation almost always occurs concurrently with significant OIVI, regular assessment of sedation levels with a sedation score in all acute pain patients receiving an opioid may be considered a more reliable clinical indicator of early OIVI, as compared with a decreased respiratory rate [6]. Although typically the highest risk for OIVI is within 24 h of surgery, education regarding the significance of excessive sedation should be provided to all patients, and their carers when opioids are prescribed on discharge [6,14].

The assessment of OIVI in clinical trials is challenging, and the incidence in the acute setting is not clear due to publications commonly referring to substitute measures (i.e., respiratory rate and oxygen saturation) [14]. A 2021 review of case reports, clinical trials and data reported to the National Poison Data System (NPDS) found that tapentadol does appear to affect respiratory drive, although concludes that this aspect of tapentadol has not been well investigated [41]. A small cross-over study in 15 healthy volunteers compared the respiratory impact of tapentadol (100 and 150 mg) with oxycodone 20 mg; All three treatments produced significant and long-lasting respiratory depression [42]. Tapentadol 100 mg (equianalgesic to 20 mg oxycodone) [27], but not 150 mg, had a modest respiratory advantage over oxycodone 20 mg [42]. Currently, Australian guidelines acknowledge that tapentadol is less likely to cause excessive sedation and OIVI versus oxycodone [43].

Persistent post-operative opioid use

Persistent post-operative opioid use (PPOU) among patients naive to opioids pre-operatively is typically defined as continuing opioid use in the period ≥90 days post-surgery, with studies demonstrating that up to 25% of patients continue taking an opioid for some years after discharge [14].

Pre-existing chronic opioid use is one of the strongest predictors of PPOU, as such, opioid weaning pre-operatively could be of benefit [14]. Opioid withdrawal symptoms can include abdominal cramping, muscle aches and pain, insomnia, dysphoria, anxiety, restlessness, nausea and vomiting, diarrhoea, rhinorrhoea/sneezing, trembling, yawning, epiphora and piloerection [44]. Phase II, phase III and long-term safety trials from 15 weeks’ up to 2 years have demonstrated that the majority of patients experienced no opioid withdrawal after abrupt discontinuation of tapentadol, with the remainder experiencing mild-moderate withdrawal symptoms as measured by Clinical Opioid Withdrawal Scale (COWS) and Subjective Opioid Withdrawal Scale (SOWS) assessments [45–50].

Several patient-related and modifiable risk factors for PPOU beyond pre-operative opioid use have been identified, including; psychological comorbidities (anxiety, depression, catastrophic thinking, and post-traumatic stress disorder), preoperative use of benzodiazepines, antidepressants, tobacco, alcohol and substance use disorders, pre-existing chronic pain, lower age, female sex, socioeconomic factors, unrealistic patient expectations, reliance on unidimensional pain scores for assessment and opioid titration, pain and opioid dose trajectories that are not decreasing, excessive opioid analgesia, sustained release opioid use, excessive unnecessary repeat opioid prescriptions and insufficient deprescribing guidance [14]. There are inconsistent data regarding the risk of PPOU relating to certain types of surgical procedures and initial postoperative opioid type.

A recent Australian retrospective observational study of administrative data from hospital and community pharmacies compared the rates of PPOU between oxycodone and tapentadol in 122,836 surgical patients who were discharged from one of four private hospital sites between 2016 and 2021, to seek to understand whether the opioid type prescribed post-operatively has an impact on longer-term outcomes [51]. The study found that, after controlling for sociodemographic characteristics, co-morbidities and other established risk factors, orthopaedic surgery patients (n = 19,832) discharged on tapentadol IR had lower odds of PPOU at 3-months compared with those discharged on oxycodone IR (opioid naive: OR: 0.51, 95% CI: 0.31,0.83, opioid experienced: OR: 0.63, 95% CI: 0.45, 0.9) [52]. For all surgical specialties combined and after controlling for covariates, tapentadol SR ± IR was associated with significantly lower odds of 3-month PPOU than oxycodone SR ± IR, in both patients who were opioid naive (OR: 0.81,95%CI:0.69,0.94) and in patients who were opioid experienced (OR: 0.81, 95%CI: 0.71,0.93). The findings indicate lower odds of patients developing PPOU with tapentadol compared with oxycodone in patients that received modified release opioids at discharge, and those undergoing orthopaedic surgery, consistent with previous studies indicating that opioid type may be relevant to PPOU rates [52]. Although in Australia there are clear recommendations against sustained release opioids in this setting, the study findings have implications for patients with higher analgesic requirements, whereby the use of atypical opioids such as tapentadol may reduce rates of PPOU in these patients.

Potential for abuse

As with all opioids, tapentadol has the potential for abuse. As such, for all patients receiving opioids:

• The risk of opioid misuse should be assessed;

• Patient/carer education on the potential risks for unintended, long-term use, misuse and addiction should be provided; and

• Patients should be regularly monitored for signs of misuse and abuse [14].

Strategies to reduce the risk of abuse include prescribing the drug in the smallest quantity required and providing guidance on the safe storage and proper disposal of any unused drug [20]. There are a number of publications examining tapentadol abuse in Australia and internationally, however this is not the subject of this review.

Conclusion

Opioids continue to form an integral part of the armamentarium for severe pain management, with opioid analgesic stewardship initiatives aiming to ensure their judicious use to reduce patient harms. When an opioid is clinically indicated, tapentadol is an atypical opioid that demonstrates similar efficacy to conventional opioids, however when compared with oxycodone at equianalgesic dosing, tapentadol is associated with significantly reduced rates of GI adverse effects, may be less likely to cause OIVI and is associated with significantly lower odds of 3-month PPOU in certain patient populations.

Future perspective

With opioids as the basis of systemic analgesia for severe acute pain management, the requirement to balance pain management and minimise opioid analgesic-related harms continues to be a challenge. The expansion of analgesic stewardship programs and post-surgical enhanced recovery protocols in Australia, in addition to evolving data for patient and treatment risk factors for OIVI and PPOU will continue to inform best-practice opioid prescribing to optimize postoperative patient outcomes.

Acknowledgments

S Jin (manuscript review) and C Morgan (manuscript review and approval).

Financial & competing interests disclosure

SC Ternel (Lebret) is a paid employee of CSL-Seqirus Australia. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

SC Ternel (Lebret) is a paid employee of CSL-Seqirus Australia. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.