MedsScan Issue 4, 2023

These reviews provide updates on the international literature on therapeutics. Expert pharmacy practitioners — via SHPA’s Specialty Practice Groups — scan major peer-reviewed journals in areas relevant to Australian pharmacy practice and present precis on major clinical trials, important pharmacoepidemiology studies and pharmacoeconomic research, and other updates relevant to practice. Interested readers are encouraged to explore the original publications in greater detail.


MedsScan editor for #SHPAClinTrials: June Challen

Opportunities and challenges of Artificial Intelligence applied to clinical trials

Clinical trials remain the gold standard for drug development. While this process is essential, it is also slow, expensive and unpredictable. Pharmaceutical research and development teams are looking at streamlining clinical research by leveraging the power of artificial intelligence (AI) in clinical trials to save time and money. This paper identifies the opportunities, challenges and potential implications of AI in clinical trials. Askin et al., performed a search in relevant databases and websites, between 7–14 October 2021, identifying publications addressing the use of AI and Machine Learning in clinical trials over the previous 5 years in the United States and Europe.

A total of 48 publications were reviewed based on the research activity where AI was applied: pre-clinical research, design, recruitment, conduct, and analysis, with recruitment being identified as a key area of interest. Opportunities for AI tools to perform automated eligibility analysis, matching potential participants to trials and simplify trial searching capabilities are discussed as well as the use of AI-based sensors and other wearable devices to improve patient monitoring. Statistical analysis and the issues of missing data and missing visits represent another opportunity for the use of AI.

Of interest to clinical trial pharmacists is the discussion as to how AI could potentially offer improved methods to monitor and confirm adherence to investigational medication. A video capture device with a built in AI algorithm can be employed to confirm medicine has been taken. In summary, Askin et al., conclude that the use of AI in clinical trials whilst being relatively recent, is evolving very rapidly.  However, they acknowledge that appropriate regulatory and ethical guidance is required to ensure that the integration of AI into clinical research protects participants.

Askin S, Burkhalter D, Calado G, El Dakrouni S. Artificial intelligence applied to clinical trials: opportunities and challenges. Health Technol 2023; 13: 203–13.

Can the efficiency of clinical pharmacology studies be improved?

Acknowledging that drug development is expensive and that Phase 1 studies provide critical information that is needed for future development, Polasek at al., list and discuss 10 suggestions that they believe the industry should take to improve the efficiency of Phase 1 studies (and perhaps decrease costs). The authors argue that the design of Phase 1 studies could be smarter and that streamlined protocols should be encouraged in clinical pharmacology studies, suggesting ways that protocols could be shortened with the overriding issue of maintaining participant safety being a focus. 

In Phase 1, single ascending dose studies, use of placebos and participant blinding are questioned as being insufficiently justified from a scientific perspective. Participant cohorts in such Phase 1 studies are typically small and the authors argue that they are therefore underpowered to indicate significant differences in effects between active and placebo groups. The article suggests that open-label study designs without placebo controls should become the standard for clinical pharmacology studies unless adequately justified. Another suggestion discusses increasing participant diversity as a possible method of increasing the enrolment rate.  Suggestions include increasing the upper age limits to allow the participation of healthy older adults (e.g. up to 65–70 years of age), recruiting underrepresented groups (e.g. those in rural locations) and increasing upper weight limits to reflect heavier populations.

Ensuring data derived from these studies are high quality, rather than just high quantity and the suggestion of closer collaboration between sponsors and investigators are some of the other propositions that are made.

Polasek TM, Schuck V. Improving the efficiency of clinical pharmacology studies. Clin Pharmacol Drug Dev 2023; 12: 771–4.

Do all placebo interventions control for the placebo effect?

The double-blind, placebo-controlled trial is the benchmark for clinical trials when determining whether an active treatment is effective. Stanhope et al., argue that the results of such studies are only valid if appropriate placebo controls are used.  

To ensure that a placebo controls for the placebo effect of a treatment intervention, it must have no effect on the outcomes of interest. In this article, the authors discuss issues with placebo controls. Use of placebos that have a potential therapeutic effect are discussed as well as the capacity of placebos to have a negative effect. They must also be indistinguishable from the intervention. The article also discusses the use of an open label placebo, where the study participant is informed of the inert status of the intervention.

Acknowledging acceptance of the possibility that some studies may not be able to effectively control for the placebo effect, Stanhope et al., argue that the best evidence may not come from placebo-controlled studies.

Stanhope J, Salter S, Weinstein P. “A wolf in sheep’s clothing”: when so-called placebo interventions are not what they seem. MJA 2023; 218: 244–6.

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MedsScan editors for #SHPACritCare: Lucy Arno and Grainne Hughes

Safety and effectiveness of apixaban in patients with atrial fibrillation and severe chronic kidney disease

Special contributor: Lidia Zec

There is limited guidance for apixaban dosing in severe chronic kidney disease.  Australian dosing guidelines, which follow the US guidelines, recommend dose adjustment based on weight, creatinine and age. Unlike Australia’s Therapeutic Goods Administration (TGA), the US Food and Drug Administration (FDA) does not contraindicate apixaban with creatine clearance (CrCl) between 15–25 mL/min, however there is minimal data to inform dosing in this population, as these patients were excluded from trials. The dose adjustment being based on weight, creatinine and age means that some US patients with CrCl below 25 mL/min receive the full 5 mg twice daily (bd) dose. This varies from European guidelines which recommend 2.5 mg bd when CrCl is between 15–30 mL/min and contraindicate use if CrCl<15 mL/min.  This study aimed to evaluate the risks of bleeding and stroke/systemic embolism associated with the different apixaban doses in this population and, as a secondary outcome, the risk of death. 

This was a retrospective cohort study of patients with atrial fibrillation (AF) and non-dialysis dependant chronic kidney disease (CKD) stage 4/5 in the US, who commenced apixaban between January 2013 and December 2021.  Risks of bleeding and stroke/systemic embolism were compared by apixaban dose and adjusted for relevant baseline characteristics. 

Of the 4313 included patients, 1705 (40%) received 5 mg and 2608 (60%) received 2.5 mg. The analysis indicated that 5 mg apixaban was associated with a higher bleeding risk compared with 2.5 mg (weighted hazard ratio of 1.63, 95% confidence interval [CI] 1.04–2.54). The risk of stroke/systemic embolism and death did not differ by dose (weighted hazard ratio of 1.01, 95% CI 0.59–1.73 and 1.03, 95% CI 0.77–1.38 respectively). 

The authors concluded that apixaban 5 mg was associated with a 1.6 times higher risk of bleeding than 2.5 mg, with no difference in the risk of stroke/systemic embolism and death in patients with AF and CKD stage 4/5.  They suggest the 2.5 mg bd dose is a more appropriate choice in this population without reducing effectiveness. Further evidence is required, and pharmacists should continue to be cautious with apixaban in renal disease and consider dose reduction in this population. This study highlights the need for ongoing review of dosing recommendations in renal impairment and reminds pharmacists to give consideration to the source of recommendations listed in dosing references.

Xu Y, Chang AR, Inker LA, McAdams-DeMarco M, Grams ME, Shin JI.  Associations of apixaban dose with safety and effectiveness outcomes in patients with atrial fibrillation and severe chronic kidney disease. Circulation 2023; 148: 1145–54.

The use of reflective practice sessions as a way to provide emotional support within an intensive care unit pharmacy during the COVID-19 pandemic

Special Contributor: Ashlei Mornement

In recent years, staff wellbeing has become a focal point for healthcare organisations. This has been highlighted during the COVID-19 pandemic, where emotional support of pharmacy staff working at the front line was paramount. Reflective practice sessions were trialled as a wellbeing strategy for intensive care unit (ICU) pharmacists working at a London hospital at the start of the pandemic. After nine sessions were held, participants were invited to answer an online survey.

This survey was designed to explore participants experiences of attending the sessions including their outcomes and impact, in a personal and professional manner. Thematical analysis was performed to identify themes from survey responses. Seven participants responded to the survey from which four themes were identified. The theme of permission highlighted the need for approval to be sought to attend the sessions. The theme of containing a safe space referred to how participants felt the sessions created a safe space to discuss challenging topics. The theme of connectedness identified that participants felt sharing experiences with colleagues improved their trust and support between themselves. The theme of emotional experience identified participants concerns for themselves and their loved ones.

This article has identified participants’ perceptions surrounding the use of reflective practice sessions during the COVID-19 pandemic. In current practice, reflective practice sessions could be a wellbeing strategy utilised by pharmacy teams.

Fowlis N, Barnett N, Banks S, Jubraj B. A qualitative evaluation of weekly reflective practice sessions for the intensive care unit pharmacy team during the COVID-19 pandemic. Eur J Pharm 2022 [online ahead of print].

The role of acetazolamide in heart failure with fluid overload

Special Contributor: Negin Nasseh

Fluid overload has been shown to increase mortality in critically ill patients. Approximately 50% of ICU patients require pharmacological diuresis, and a vast majority of these patients receive furosemide.

This study aimed to determine whether acetazolamide as an adjunct to furosemide in patients with decompensated heart failure and resultant volume overload achieved better diuresis by day 3 of therapy. This multi-centre, randomised, parallel group, double blind, placebo controlled clinical trial, recruited 519 patients between November 2018 and January 2022, who were admitted to hospital with clinical signs of fluid overload, and acute decompensated heart failure with a raised B natriuretic Peptide (BNP) level.

Participants were randomised to receive, in addition to intravenous (IV) furosemide, either 500 mg IV acetazolamide daily, or placebo. A higher rate of successful decongestion was shown at day 3 in the group receiving acetazolamide (42.2% vs 30.5%; risk ratio [RR] 1.46, p < 0.001), with an exploratory analysis showing that this continued through to hospital discharge. The acetazolamide group had a minor decrease in length of stay in hospital (8.8 days vs 9.9 days, p < 0.02), and no statistically significant difference was found between groups for all-cause mortality or rate of adverse events. 

This trial demonstrates that acetazolamide has a role as an adjunctive therapy to loop diuretics, namely furosemide, when treating volume overload in patients with acute decompensated heart failure.

Mullens W, Dauw J, Martens P, Verbrugge FH, Nijst P, Meekers E, et al. Acetazolamide in acute decompensated heart failure with volume overload. N Engl J Med 2022; 387: 1185–95.

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MedsScan editor for #SHPAEmergMed: Amy Thomson

Trauma and tranexamic acid: the Pre-hospital Antifibrinolytics for Traumatic Coagulopathy and Hemorrhage (PATCH-Trauma) trial

Special contributor: Jill Upton

Prehospital tranexamic acid for severe trauma (PATCH) was an international, multi-centre, double blind, randomised placebo-controlled trial that considered if, in advanced trauma systems, pre-hospital administration of tranexamic acid (TXA) increases the rate of survival with a favourable neurological outcome in trauma patients with suspected trauma-induced coagulopathy (TIC). Adults (n = 1310) were randomly assigned to receive TXA or placebo, given as a pre-hospital 1 g intravenous (IV) bolus dose within 3 h of injury, followed by a 1 g infusion over 8 h in hospital.

The primary outcome was survival with a favourable functional outcome at 6 months after injury, defined as 5 or more on the Glasgow Outcome Scale-Extended which ranges from 1 (death) to 8 (no injury-related problems). Secondary outcomes included death from any cause within 28 days and 6 months of injury. Despite reduced early mortality with treatment, favourable functional outcomes at 6 months were similar in both groups (53.7% with TXA and 53.5% with placebo, risk ratio [RR] 1.00, 95% confidence interval [CI] 0.9–1.12, P = 0.95). At 28 days after trauma, 17.3.% of the TXA group and 21.8% of the placebo group had died. There was no significant difference between groups in terms of deaths at 6 months or in the number of adverse events including vascular occlusive events.  

Consistent with existing trials, PATCH showed that TXA improves short-term mortality and has a good safety profile. However, unlike previous trials PATCH also considered functional outcome and found that while TXA improves chances of survival it has no effect on risk of surviving with severe neurological impairment.

PATCH-Trauma Investigators and ANZICS Clinical Trial Group; Gruen RL, Mitra B, Bernard SA, McArthur CJ, Burns B, Gantner DC, et al. Prehospital tranexamic acid for severe trauma. N Engl J Med 2023; 389: 127–36.

Pharmacist-led sepsis alert response in the emergency department

Special contributor: Jill Upton

Early identification and management of patients with suspected sepsis is crucial because patient outcomes have been shown to be closely linked to timely administration of antibiotics and implementation of a sepsis bundle of care. The Surviving Sepsis Campaign guidelines recommend starting broad-spectrum antimicrobials within 60 minutes.1 This pre-post interventional study analysed data in an Australian emergency department to assess the impact of the implementation of a sepsis alert response system that included an emergency medicine pharmacist. It compared a group of 80 patients presenting to the emergency department with septic shock requiring intensive care unit admission before implementation of the intervention to a group of 104 patients after implementation.

Pre-implementation antimicrobials were administered to patients within 60 mins, 26.3% of the time. This improved post-implementation to 81.7% and the proportion of patients who received other components of the sepsis bundle of care within 60 mins also improved significantly including initiating IV fluids, measuring serum lactate and obtaining blood cultures (odds ratio [OR] 12.6, 95% CI 6.2–25.4, P < 0.001).

The study demonstrated the benefits of an upfront multidisciplinary approach that includes emergency medicine pharmacists to treat patients presenting to the emergency department with suspected sepsis.


  1. Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Crit Care Med 2021; 49: e1063–e1143.

Roman CP, Dooley M, Nevill A, Szmidel M, McGloughlin S, Luckhoff C, et al. Introduction of an emergency medicine pharmacist-led sepsis alert response system in the emergency department: a cohort study. Emerg Med Australas 2023; 35: 564–71.

The greens kids don’t need

An increasing number of jurisdictions across the world have legalised cannabis, including it’s sale in food products as ‘edibles’. Jurisdictions that have legalised recreational cannabis have seen an increased availability within households and a parallel increase in rates of cannabis related paediatric intoxication. Severe effects (such as reduced level of consciousness, respiratory depression and cardiotoxic effects) from cannabis exposure are relatively common in children. Cohen et al., conducted a prospective cohort study of all paediatrics patients presenting to participating hospitals in the United States, Canada and Israel over a 3-year period to 2020 to help define risk factors to predict severe outcomes.

One hundred and thirty-eight patients were enrolled with a median age of 14 years (interquartile range [IQR] = 3.7–16.0). For analysis the cohort was split into children (n = 60, <10 years) and adolescents (n = 78, >10 years). Ninety-five percent (n = 57) of children were intoxicated unintentionally (100% by ingestion). The primary outcome occurred in 58% (n = 32) which was a severe outcome requiring intensive care unit admission or causing death. In the multivariable logistic regression analysis, polysubstance ingestion (adjusted OR 16.3, 95% CI 4.6–58.3; P < 0.001)) and cannabis edibles ingestion (adjusted OR 5.5, 95% CI 1.9–15.9, P = 0.001) were strong independent predictors of severe outcome.

In the adolescent group, 5 (6.4%) of the exposures were unintentional and 20 had severe outcomes. Of these 20, 16 patients were intubated, of which 5 were exposed to cannabis only (4 were exposed by inhalation and were intubated for either acute respiratory distress syndrome [n = 3] or seizures [n = 1] and one was from ingesting ‘edibles’). All children 10 years and younger ingested edibles. Children are at much higher risk of severe cannabis intoxication compared to adolescents and adults.

In Australia, cannabis contained in ‘edibles’ is not approved for use, however black-market cannabis edibles such as gummies have been detected. Clinicians should have a high index of suspicion for severe outcomes in children under 10 years old who have been found eating cannabis gummies or other edibles such as baked goods.

Cohen N, Mathew M, Brent J, Wax P, Davis AL, Obilom C, et al. Severe outcomes following pediatric cannabis intoxication: a prospective cohort study of an international toxicology surveillance registry. Clin Toxicol (Phila) 2023; 61: 591–8.

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MedsScan editor for #SHPAGenMed: Gail Edwards

Hydrocortisone in severe community-acquired pneumonia

Special Contributor: Khadeeja Rawther

Community Acquired Pneumonia (CAP) is a serious health issue responsible for hospitalisations and mortality. This multi-centre phase 3, double blind, randomised controlled trial investigated if administration of intravenous (IV) hydrocortisone reduced mortality in Intensive Care Units (ICU) patients with severe CAP. Patients were randomised to receive hydrocortisone (n = 400) or placebo (n = 395) in addition to standard therapy including antibiotics and supportive care. Those randomised to the treatment arm received a continuous intravenous infusion of hydrocortisone 200 mg per day which was gradually tapered at either 8 or 14 days. The primary outcome was death from any cause by day 28 with multiple secondary outcomes including death by any cause at day 90, and requirement for mechanical ventilation.

Death occurred in 6.2% (n = 25) of patients in the hydrocortisone group, compared to 11.9% (n = 47) of patients in the placebo group by day 28 (P = 0.006). Mortality at day 90 was 9.3% (n = 36) in the hydrocortisone group compared to 14.7% (n = 57) in the placebo group. Patients who received hydrocortisone had a lower rate of endotracheal intubation (18.0% vs. 29.5%). The hydrocortisone group did not have an increased risk of hospital-acquired infections or gastrointestinal bleeding. However, an increased insulin requirement was evident in the hydrocortisone group, which was as expected with the adverse effect profile.

Administration of hydrocortisone to ICU admitted patients with severe CAP resulted in a lower risk of death. Future research should explore if this data can be extrapolated to intermittent dosing and the potential reversibility of hyperglycaemia, neuropsychological and neuromuscular adverse effects of corticosteroids.

Dequin PF, Meziani F, Quenot JP, Kamel T, Ricard J-D, Badie J, et al. Hydrocortisone in severe community-acquired pneumonia. N Engl J Med 2023; 388: 1931–41.

Phase 2 trial of baxdrostat for treatment-resistant hypertension

Special Contributor: Ann Louise Slee

Aldosterone antagonists such as spironolactone are often prescribed in refractory hypertension but their use can be limited by side effects. Baxdrostat works by inhibiting aldosterone synthase, the enzyme responsible for the synthesis of aldosterone.

BrigHTN was a multicentre, placebo-controlled, double blind randomised trial to study the safety and efficacy of baxdrostat in treatment resistant hypertension. Patients were randomised to receive 0.5 mg (n = 69), 1 mg (n = 69), 2 mg (n = 67) of baxdrostat or placebo (n = 69) daily. The primary outcome was the change in systolic blood pressure measured at twelve weeks. Two hundred and forty-eight patients completed the study with the most common reasons for discontinuation being consent withdrawal (n = 7) and loss to follow up (n = 8). Analysis was based on an intention to treat approach.

Baxdrostat was associated with dose dependent changes in the mean systolic blood pressure, with the differences compared to placebo of -11 mmHg in the 2 mg group (P < 0.001) and -8.1 mmHg in the 1 mg group (P = 0.003). There was no significant difference in the 0.5 mg baxdrostat group. A total of 232 adverse events occurred in 120 patients, with 62% deemed mild and 89% deemed not related to baxdrostat. Adverse events that occurred in 5% or more of patients were urinary tract infections, hyperkalaemia, headache and fatigue.

Results open a new perspective for management of treatment resistant hypertension. While results show baxdrostat reduced blood pressure, further research is needed. Comparative studies as well as studies beyond 12 weeks are warranted to assess benefits and risks.

Freeman MW, Halvorson Y-D, Marshall W, Pater M, Isaacsohn J, Pearce C, et al. Phase 2 trial for treatment resistant hypertension. N Engl J Med 2023; 388: 395–405.

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MedsScan editor for #SHPAOncHaem: Hayley Vasileff

Adherence to recommended treatment timeframes associated with improved breast cancer outcomes

Special contributor: Emily Shi

Breast cancer stands as the second leading cause of cancer-related mortality among Australian women, however 33–52% of women diagnosed with early breast cancer do not receive timely treatment. In 2020, Cancer Australia updated its treatment guidelines for early-stage breast cancer, offering recommendations for six treatment intervals drawing on expert consensus. This population-based cohort study followed a large cohort of women identified from the Queensland Cancer Register, aged 20–79 years from diagnoses of early-breast cancer (1 March 2010–30 June 2013) to 31 December 2020.

The study found that women who received timely treatment according to the recommended intervals had better breast cancer-specific survival rates compared to those who did not adhere to the guidelines. Specifically, longer intervals in diagnosis to surgery, surgery to chemotherapy and chemotherapy to radiotherapy were associated with poorer survival outcomes. The study also identified factors associated with longer treatment intervals, including the type of screening facility, time of year treatment was undertaken and family history of breast or ovarian cancer.

The findings of this paper provide support for the 2020 treatment guidelines and recommended timeframes for early breast cancer treatment; however one should take into account other potential factors contributing to treatment delays, beyond those highlighted in the paper, including considerations of tolerability and patient comorbidities. Determining whether treatment delays directly lead to poorer outcomes, or if the treatment delays are a consequence of patients facing more severe disease, can be challenging to ascertain.

Kou K, Aitken JF, Pyke C, Chambers S, Dunn J, Baade PD. Treatment intervals and survival for women diagnosed with early breast cancer in Queensland: the Breast Cancer Outcomes Study, a population-based cohort study. Med J Aust 2023; 219: 409–16.

Partnered Pharmacist Medication Charting expands to cancer services

Special contributor: Shaun O’Connor

Following the successful trials and subsequent rollout of the general medical Partnered Pharmacist Medications Charting (PPMC) model of care across Australia, the evidence base for specialist settings in health services was considered desirable to enhance the case for spread into other units. Cancer services was considered a good candidate due to complexity of medication regimes, the addition of cancer therapy charting and pharmacist involvement already well embedded in clinical units.

A scaling implementation study was carried out across seven sites in Victorian public hospitals. A pre-intervention and implementation comparison was analysed with the primary outcome being proportion of medication charts with at least one medication error. Secondary analyses included patient length of stay (LOS) and evaluating cancer therapy charted by pharmacists.

Of 547 patients who had their medications charted using standard processes, 331 (60.5%) had at least one error compared to 18 (4.3%) of 416 charts using PPMC. The overall patient LOS showed no significant difference between the arms. Of note, cancer therapy was charted by a pharmacist for 42 patients with no errors.

The trial shows significant improvements in medication chart errors supporting the rollout of PPMC into complex specialist medical units beyond general medicine. Cancer therapy that was charted by pharmacists showed no errors which enhances the evidence base for pharmacists to move into specialised roles in cancer services.

Tong EY, Edwards GE, Hua PU, Mitra B, Van Dyk E, Yip G, et al. Implementation of Partnered Pharmacist Medication Charting in haematology and oncology inpatients. J Onc Pharm Prac 2023; [online ahead of print].

DPYD genotype test — a ‘white elephant’?

Special contributor: Thong Wing Chan

Fluoropyrimidine-based treatment is widely used in treating various types of solid tumour. Variants in the DPYD gene are associated with deficiency in diydropyrimidine dehydrogenase (DPD) enzyme and could lead to increased risk of fluoropyrimidine toxicity. Recommended dose modifications for patients with specific DPYD variants are available, however adjusting the intensity of the treatment is not always favourable, or is it? This was a retrospective 3:1 matched pair-survival exploratory analysis with DPYD variant patients who received upfront dose reduction of 25% (for c.2846A>T and c.1236G>A) and 50% (for DPYD*2A and c.1679T>G).

The pooled DPYD analysis showed dose modification in patients with DPYD variants did not negatively impact both progression-free survival (PFS) (hazard ratio [HR] 1.23, 95% confidence interval [CI] 1.0–1.51, P = 0.053) and overall survival (HR 0.95, 95% CI 0.75–1.51, P = 0.698). Notably, a shorter PFS was reported for variant c.1236G>A with dose modification (HR 1.43, 95% CI 1.1–1.86, P = 0.007) and no data on c.1679T>G variant was available due to zero survival. There are over 125 variants in the DPYD gene linked to reduced DPD activity.

In Australia, DPYD genotype testing is usually confined to the four variants studied in this trial. Furthermore, it is not yet reimbursed by Medicare and its lengthy turnaround time could make it less feasible for upfront testing. The outcome of zero survival with 50% dose reduction in patients with the c1679T>G variant adds value to genotype testing for clinicians, who could perhaps consider a non-fluoropyrimidine-based regimen for these patients. In contrast, would genotype testing add value over a clinician’s close monitoring and judgment where a shorter PFS in patients with the c.1236G>A variant who had a 25% dose reduction was shown?

Knikman JE, Wilting TA, Lopez-Yurda M, Henricks LM, Lunenburg CATC, de Man FM, et al. Survival of patients with cancer with DPYD variant alleles and dose-individualized fluoropyrimidine therapy – a matched-pair analysis. J Clin Oncol 2023: JCO2202780 [online ahead of print].

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MedsScan editors for #SHPAPalliative: Vicki Poulier, Jane Lewis and Pascale Dettwiller

Antipsychotic prescribing for agitated delirium at end of life

This is a feasibility study exploring how an algorithm-based treatment can assist palliative care clinicians to better manage terminally ill patients with agitated delirium aligned with the wishes of patients and their families. Prevalence of delirium symptoms is 68–90% in terminally ill cancer patients just before death and alters the quality of life during the last week of life.

The study was conducted in Japan in a 27-bed palliative care unit over an 18-month period. This single-centre, prospective observational study used an opt-out option rather than informed consent. Palliative care clinicians designed the stepwise algorithm to assist in prescribing parenteral antipsychotics, with other delirium management strategies provided as clinically appropriate. Treatment options were: (1) haloperidol only; (2) haloperidol with benzodiazepine; or (3) chlorpromazine/levomepromazine (phenothiazines) if failure of the other two options. Actual doses prescribed were at the discretion of the clinician. Validated tools were used to assess and at Day 0, 1, 3, 7, 14, 21 and 24 hours before death. Treatment goal was defined as no agitation, or acceptable agitation for patients and families.

This study of 164 adult patients with advanced or metastatic cancer demonstrated an adherence to the algorithm of 99%, 94% and 89%, and treatment goals achieved in 66%, 83% and 93% on days 1, 3 and 7 respectively. The survival mean was 8 days from enrolment. Forty-seven percent of patients received treatment (2) at baseline while at day 7, phenothiazines were favoured in 56% of patients. Patient and family preferences were central to decision making, with the aim to balance the  intensity of agitation with maintaining the ability to communicate.

The study concluded that the algorithm may be feasible, effective and safe in managing terminal agitated delirium but that more studies were necessary due to a number of limitations in the design that limited generalisation to other settings. Of note, levomepromazine is only available via Special Access Scheme in Australia which limits its availability in the community.

Imai K, Morita T, Mori M, Kiuchi D, Yokomichi N, Miwa S, et al. Visualizing how to use antipsychotics for agitated delirium in the last days of life. J Pain Symptom Manage 2023; 65: 479–89.

Does paracetamol provide any benefit when added to strong opioids in cancer pain?

Co-administration of paracetamol with opioids demonstrates opioid-sparing effects in moderate to severe acute pain, however in cancer pain, the evidence of benefit remains equivocal.

Intravenous (IV) paracetamol 1 g every 6 h was added to strong opioids for 48 h in patients admitted with acute moderate to severe cancer pain in this randomised, placebo-controlled study in 112 adult in-patients in Chile. The study investigated whether paracetamol improved pain management and reduced total opioid dose and adverse effects. Pain score and opioid use in the previous 24 h was assessed at baseline, 24 h and 48 h.

The mean age of participants was 57.9 years, and more than half had Stage IV cancer (56.8%). The most commonly prescribed opioids prior to admission were tramadol (41.3%) and buprenorphine (26.9%). Over one third of patients were opioid naïve and prescribed strong opioids at the time of admission in accordance with a specified analgesic protocol. Pain intensity and oral morphine equivalent (OME) dose were similar in both arms at baseline. Pain intensity significantly improved at 48 h, but no difference was found overall (82% paracetamol vs 80% placebo, p = 0.81), and there was no difference in total opioid dose or frequency of adverse effects.

The authors concluded that paracetamol has no place in moderate to severe cancer pain and has a significant dose burden. Limitations included using IV paracetamol, which requires an inpatient setting and inferring ineffectiveness of oral paracetamol. Other analgesics prescribed were uncontrolled, providing a more real-world scenario. The analgesic protocol for renal impairment included methadone for opioid-naïve patients but fentanyl for prior opioid use, and use of tramadol and buprenorphine all or which may not reflect usual practice in Australia for moderate to severe pain. Pharmacists could determine benefit versus burden experienced by individual patients with moderate to severe cancer pain prescribed regular paracetamol with strong opioids, but also consider whether paracetamol may be indicated in mild to moderate cancer pain where strong opioids may be contraindicated or inappropriate.

Leiva-Vásquez O, Letelier LM, Rojas L, Viviani P, Castellano J, González A, et al. Is acetaminophen beneficial in patients with cancer pain who are on strong opioids? A randomized controlled trial. J Pain Symptom Manage 2023; 66: 183–92.

How do patients dispose of their expired or unused opioid medicines?

Opioids are commonly prescribed to manage symptoms in patients receiving palliative care. Frequent dose titrations or opioid rotations may be required over time to maintain symptom control and may result in unused or expired opioid medicines in the home.

In this Canadian cross-sectional study of adult patients with advanced cancer, those attending their first outpatient palliative care clinic appointment and identified as already taking opioids were asked to complete a 25-question Opioid Safety Survey. The authors primarily investigated if patients disposed of their opioids, the disposal method used and patient characteristics of those who routinely disposed of opioids.

Mean age of the 122 study participants was 64.5 years, with overall mean morphine equivalent daily dose of 88.5 mg. Patients taking neuropathic agents or cannabis were significantly more likely to routinely dispose of opioids (43.4% vs 22.4%, p = 0.025 and 24.5% vs 8.8%, p = 0.038, respectively). Most patients (80.7%) were aware of safe opioid disposal methods, however 52.3% did not routinely dispose of their opioids; the most common reason being possible future need (68.4%). Patients who had to increase their opioid dose over the previous 6 months were significantly less likely to dispose of opioids (odds ratio [OR] 0.38, p = 0.03). A majority of patients (58.6%) received education from their pharmacist or doctor about safe disposal of opioids and these patients were significantly more likely to return to their pharmacist for disposal rather than another disposal method (72% vs 37.5%, p < 0.001).

The authors concluded that those who routinely disposed of opioids were less likely to have responded ‘yes’ to the opioid use disorder survey question, and surmised the reason those taking neuropathic agents or cannabis were more likely to dispose of opioids might be explained by a longer clinical history of prescribed opioids with more healthcare profession interactions and education. Limitations included quality of information available in the patient charts, and the yes/no questions that poorly captured any complexities of data. The authors concluded that further studies are required to understand opioid management in the palliative care context, where safe disposal methods may need to be balanced with ensuring access for future opioid changes required for symptom management.

Lau J, Zimmermann C, Selby P, Furlan AD. Opioid disposal practices of patients with life-limiting cancers in an outpatient palliative care clinic: a cross-sectional study. J Pall Med 2023; 26: 816–25.

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MedsScan editor for #SHPARural: Caitlin Hardman

Thinking differently about recruitment and retention for the rural pharmacy workforce

Special Contributor:  Kelly Beswick

A cross-sectional study of participants across twelve rural communities in Tasmania and Western Victoria was conducted in 2021. This study was to pilot the use of a Pharmacist Community Apgar Questionnaire (PharmCAQ) and its success in determining factors that impact the rural recruitment and retention of pharmacists. The PharmCAQ has 50 factors grouped into 5 categories: geographic, economic and resources, practice and scope of practice, practice environment, and community practice support.

The PharmCAQ was able to identify the most important advantages and challenges for each community involved as well as the top 10 assets that were applicable across the participants. The reputation of the pharmacy, and how it was valued within its community featured most significantly as well as pharmacist autonomy and variety in the work they completed. The most challenging factor to recruit and retain pharmacists related to the geographical location of the community along with ability of the community to also meet the needs of the pharmacist’s family such as availability of schooling and employment opportunities for partners.

The proposed PharmCAQ was found to be statistically reliable, and able “to differentiate high- and low-performing communities”. The authors found that scoring was consistent regardless of setting (community or hospital), or whether the participant was a pharmacist or non-pharmacist, thus demonstrating its potential benefit in a range of settings, and with a range of participants.

Further utilisation of the PharmCAQ in hospital or non-community practice settings could provide a useful way of quantifying attributes of the rural community that can be promoted, and identifying barriers that need resolution.

Terry D, Peck B, Hills D, Bishop J, Kirschbaum M, Obsmiro K, et al. Sustaining rural pharmacy workforce understanding key attributes for enhanced retention and recruitment. Aust J Rural Health 2023; 31: 218–29.

Bridging gaps in rural medication safety with virtual clinical pharmacy services

Special Contributor: Cristen Fleming

In rural and remote Australia, many small hospitals still do not have access to a hospital pharmacist’s specialised skills and medication knowledge, despite the significant health needs of the population and proven benefits for medication safety. This study introduces a model for Virtual Clinical Pharmacy Services (VCPS) to enhance medication safety in underserved areas, addressing healthcare disparities and overcoming challenges of geography and population. The model was developed as part of the implementation of VCPS in eight rural hospitals across rural and remote New South Wales, Australia, in 2020.

The VCPS intervention focused on virtualising core pharmacy activities, such as medication history, reconciliation, medication review, multidisciplinary patient rounding, patient-friendly medication lists, antimicrobial stewardship, and patient education. The research article describes the implementation of the service, including the processes, systems and enablers that were required for a pharmacist to provide virtual clinical services concurrently to multiple small public hospitals.

Collaboration and a structured implementation approach were vital, and at the conclusion of 12 months of research over 7000 pharmacy activities had been undertaken for a cohort of 1306 patients. The study concluded that the VCPS model effectively addressed medication management needs in rural and remote NSW healthcare facilities, and scale-up was planned for all remaining rural hospitals in the region.

For Australian pharmacists, this model serves as an important benchmark, highlighting the value of virtual pharmacy services in rural areas. Health services should consider implementing similar virtual services to enhance medication safety and patient care delivery in underserved or geographically isolated facilities. 

Chambers B, Fleming C, Packer A, Botha L, Hawthorn G, Nott S. Virtual clinical pharmacy services: A model of care to improve medication safety in rural and remote Australian health services. Am J Health Syst Pharm 2022; 79: 1376–84.

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MedsScan editor for #SHPASurgPeriop: Caitlin Mulqueen

Is opioid analgesia required after surgical discharge?

Excessive prescribing of opioid analgesia after surgery has contributed to opioid misuse. Despite this, the value of opioid analgesia in this setting remains uncertain. This systematic review and meta-analysis aimed to assess the impact of opioid analgesia prescribing at surgical discharge on pain intensity and adverse events in comparison to opioid-free analgesia.

Self-reported pain intensity on the first day after surgical discharge, measured using the visual analogue scale, and vomiting up to 30 days after surgical discharge were the primary outcomes. A total of 47 studies, with a combined total of 6607 patients discharged after undergoing an elective, minor or moderate surgical procedure, were included in the review. Prescription of opioid analgesia was not associated with a reduction in pain intensity on the first day after discharge in comparison to opioid-free analgesia (weighted mean difference 0.01 cm, 95% confidence interval [CI] -0.26–0.27, moderate certainty evidence). Prescription of opioid analgesia was associated with an increased risk of vomiting up to 30 days after discharge in comparison to opioid-free analgesia (10.9% vs 1.3%, risk ratio 4.50, 95% CI 1.93–10.51, high certainty evidence). The results of this review support the use of opioid-free analgesia on discharge following elective, minor (e.g. dental or hand procedure) or moderate (e.g. minimally invasive orthopaedic or general surgery) surgical procedures as opioid analgesia does not reduce pain intensity, but it does increase the risk of vomiting.

There were, however, significant limitations associated with this review including the inclusion of studies with a high risk of bias and the analyses of heterogenous populations and interventions. The results of this review are not applicable to major or emergency surgical procedures. It should also be noted that the majority of included studies involved weak opioids, had little regard for non-pharmacological interventions for pain management and rarely considered other factors that can impact a patient’s opioid consumption and duration of use. High quality research is required to confirm, and expand on, the results of this review.

Fiore JF Jr, El-Kefraoui C, Chay MA, Nguyen-Powanda P, Do U, Olleik G, et al. Opioid versus opioid-free analgesia after surgical discharge: a systematic review and meta-analysis of randomised trials. Lancet 2022; 399: 2280–93.  

The impact of intraoperative tranexamic acid on bleeding and cardiovascular outcomes

Perioperative bleeding is a common complication of noncardiac surgery and is associated with increased morbidity and mortality. The incidence and severity of such bleeding may be decreased by the use of tranexamic acid. There is, however, limited data on the use of tranexamic acid in nonorthopaedic and noncardiac surgery.

This international, randomised, controlled trial, across 114 hospitals in 22 countries, aimed to evaluate the effects of tranexamic acid compared to placebo in patients undergoing noncardiac surgery as part of the POISE-3 trial. Composite bleeding outcome (life-threatening bleeding, major bleeding or bleeding into a critical organ) and composite cardiovascular outcome (myocardial injury, nonhaemorrhagic stroke, peripheral arterial thrombosis or symptomatic proximal venous thromboembolism) at 30 days after randomisation were the trial’s primary efficacy outcome and primary safety outcome, respectively.

A total of 9535 patients, 45 years of age or older, undergoing inpatient noncardiac surgery and at increased risk of bleeding and cardiovascular complications were given a 1 g bolus at the start and end of surgery. A composite bleeding outcome event occurred in 9.1% of patients who received tranexamic acid and 11.7% of patients who received placebo (hazard ratio [HR] 0.76, 95% CI 0.67–0.87, p < 0.001). A composite cardiovascular outcome event occurred in 14.2% of patients who received tranexamic acid and 13.9% of patients who received placebo (HR 1.02, 95% CI: 0.92–1.14, p = 0.04).

The results of this trial display a significantly lower incidence of composite bleeding outcomes with tranexamic acid in comparison to placebo. The results also display a small increase in composite cardiovascular outcomes with tranexamic acid in comparison to placebo and noninferiority was not established. It is important to note that the bleeding and cardiovascular risk associated with individual surgeries was not considered. Instead, all noncardiac surgeries performed by various surgical specialties were analysed together. We may start to see this used more broadly to reduce bleeding and the use of blood products in surgery.

Devereaux PJ, Marcucci M, Painter TW, Conen D, Lomivorotov V, Sessler DI, et al. Tranexamic acid in patients undergoing noncardiac surgery. N Engl J Med 2022; 386: 1986–97.  

Investigating the association between perioperative medication use and postoperative delirium

Postoperative delirium is a common complication for older adults, occurring in up to 50% of older adults undergoing major surgery. It can also be associated with postoperative neurocognitive disorder (PND). Research evaluating the association between perioperative medication use and both postoperative delirium and PND is limited.

Consequently, this observational study aimed to investigate three associations in older adults undergoing major elective surgery: (1) preoperative medication use and postoperative delirium, (2) inpatient postoperative medication use and postoperative delirium and (3) inpatient postoperative medication use and cognition one month postoperatively. A total of 560 patients, aged 70 years or older, scheduled to undergo major elective surgery, planned for a minimum 3-day inpatient stay and without a history of dementia were included in the analysis. Whilst an inpatient, 24% of patients developed delirium.

There was no significant association between prehospital benzodiazepine, opioid, beta-blocker or statin use and delirium. Inpatient postoperative use of benzodiazepines was associated with a greater risk of delirium (adjusted hazard ratio 3.23, 95% CI 2.10–4.99). No association between inpatient postoperative medication use and cognition one month postoperatively was identified. The results of this study support avoidance of inpatient benzodiazepines in the postoperative period in order to reduce the risk of postoperative delirium in older adults.

The limitations of this observational study, however, should be noted. The associations identified do not infer causality and the lack of associations identified may be due to inadequate power. The results may not reflect current surgical and perioperative care practices given the study enrolment period of 2010 to 2013 nor reflect all surgical specialties given 81% of included patients underwent orthopaedic surgery. Medication adherence and dose data were also not evaluated. Further research is required to evaluate the impact of perioperative medication use on postoperative delirium and PND. 

Duprey MS, Devlin JW, Griffith JL, Travison TG, Briesacher BA, Jones R, et al. Association between perioperative medication use and postoperative delirium and cognition in older adults undergoing elective noncardiac surgery. Anesth Analg 2022; 134: 1154–63.   

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MedsScan editors for #SHPATechnicians: Tara Clayson-Fisher, Bryan Walker and Debbie Parker

Resilience and the potential of teamwork to transform the pharmacy

In 2022, the Pharmacy Technician Certification Board in the United States conducted a national survey of 20 000 pharmacy technicians and showed that 75% of pharmacy technicians remained in their jobs after the COVID-19 pandemic. Seventy-five per cent remained working, showing pharmacy technicians’ genuine dedication and determination in the workforce. However, 74% of pharmacists feel they do not have enough support, time, or resources to perform their jobs.

Pharmacy professionals should be able to support each other and serve patients. When we support each other, there is less burnout, and patients do not suffer from a lack of quality healthcare from the pharmacy. When there is a teamwork culture, staff turnover is significantly reduced.

This culture of teamwork will be crucial as the ageing of the ‘Baby Boomer’ generation will increase the needs and demands for pharmacy services. Ask these critical questions in determining how to identify how to improve the teamwork on your team:

  1. Does your pharmacy’s culture allow for teamwork? Is there clear communication between all parts of the team in the pharmacy?
  2. Can you identify key players among your team who may be willing to take on additional leadership roles (and be adequately compensated for those extra tasks)?

Allowing the staff to collaborate actively and contribute to improving day-to-day operations will provide the framework and motivation for teamwork to flourish. Staff cooperation helps to improve things and makes the pharmacy more efficient. Recognising the teamwork potential in the pharmacy and involving everyone in the pharmacy to play an active role is essential for the mental wellbeing of the staff, excellent patient care and the pharmacy’s success.

Ayers M. Teamwork in the pharmacy. CPhT CONNECT 2023; 3(4): 38–41.

Specialisation: how to retain talented individuals in the pharmacy

Due to the COVID-19 pandemic, many pharmacy technicians left the profession due to workload stress, burnout, lack of resources, being treated badly, poor pay and mental health stress. The overriding question is, what now? If you leave your role as a pharmacy technician, do you need to leave the pharmacy profession altogether? The answer is there are options available. Instead of the pharmacy technician being the master of everything that makes a pharmacy operate, more specialist roles need to be created to retain individuals with talents that pharmacy departments can’t afford to lose.

An example is a controlled substance technician. Even though all pharmacy technicians require general knowledge of controlled substances, this role focuses on specific aspects, such as keeping records of all the transactions in the safe, making prepacks and ordering supplies. More responsibility can be taken on while building on present abilities and improving efficiency.

Other specialised roles include clinical review technician in managed care, pharmacy automation specialist, training and quality coordinator in hospital, supervisor positions such as pharmacy manager (managing workflow in the pharmacy dispensary), auditor positions related to pharmacy supply chain management and asset and loss prevention specialist. Making such specialised roles available aids progress from being a pharmacy technician to more of a professional and career-making role, instead of a step-up position. This is only a partial list. So far, 414 unique career paths have been identified by NPTA (National Pharmacy Technician Association) through member feedback.

The most common skills required are organisation, attention to detail, understanding of medicines, multitasking, product knowledge and leadership. These skills are required of every pharmacy technician to perform their present duties. With the advent of these specialised professional roles, pharmacists will be better positioned to assume more specialised roles without compromising patient safety while promoting teamwork and retention of pharmacy technicians.

Johnston M, Galvan E, Nash A. The great resignation becomes the great opportunity. CPhT CONNECT 2022; 3(3): 18–23.

Progression in the workforce

Creating a career ladder benefits both employees and employers. A career ladder is a progression through defined goals that begin at the base level and move to high-level positions within the specific organisation” The career ladder provides the outline and structure for pharmacy technicians to progress professionally. Retention of quality employees while increasing their knowledge, experience and confidence is one of the positive things that career ladders help create.

Why have a career ladder? Besides helping to promote personal and professional growth, leadership skills and better work culture, it helps empower pharmacy technicians to pursue their careers within their organisation instead of leaving and going elsewhere to move forward. Each level has clearly defined parameters and a path to continue upward and reward hard work.

What incentives can organisations provide? An example is adding a set dollar amount that pharmacy technicians will be provided upon successful advancement for continuing education or special training. Merit pay increases when pharmacy technicians reach specific goals. The merit pay would be in addition to the base salary. A cash bonus for those who have demonstrated commitment and dedication to their job performance and continue to excel and lead year after year. Reimbursement incentives for those who take courses at university in pharmacy. The organisation helps pay for courses, and the employee stays there for a set time to access the reimbursement.

When is the time to implement a career ladder? The time is right now. With ageing populations starting to enter retirement and the results of the pandemic causing shortages in pharmacy technicians, retention of quality staff is a paramount issue.

Keys D. Career ladders: advancement for pharmacy technicians in home infusion. CPhT CONNECT 2023; 4(1): 18–23.

Leadership in the pharmacy

This article discusses how to build the skills necessary for leadership in the pharmacy workforce. To define leadership, the author draws on Tony Robbins who defines leadership as “the ability to inspire a team to achieve a particular goal (…) to influence, inspire and help others become their best selves building their skills and achieving goals along the way”.

What skills are needed to improve leadership? Many ideas can be found online about which skills are needed for leadership. These following skills are those the author drew upon in his personal experiences:

  1. Adroitness to gain trust: How fast can you become trustworthy?
  2. Cogent communication skills: Can you convey your instructions, praise, and objections so the staff can comprehend?
  3. The ability to turn information into action: Can you make an idea into reality with efficient execution?
  4. Active listening: Are you listening to be heard or asking questions to prolong the conversation?
  5. Visionary: Can you see things when they are not there and know where the pharmacy should go?
  6. Adaptability: Can you change your plans abruptly or adjust when rules and regulations changes?

When gaining trust, management must first show trust. Believe in your team, and your team will believe in you. Understand technicians’ work, ask them pertinent questions, and be involved.

Two main parts of communication are the expression and the reception of a thought. “To effectively communicate, we must realise that we are all different in how we perceive the world and use this understanding to guide our communication with others.”

“Without knowledge, action is useless, and knowledge without action is futile”. If you have found a more logical and systematic way to complete a process, find a way to pitch the idea. Get a second opinion from a colleague before bringing it to management. Then, engage in a genuine, sincere, but brief dialogue with management. Try to avoid withholding an idea or process that could alleviate the physical demands of the workplace.

Sometimes, you hear some impractical and/or harmful ideas from your peers. If you reject those ideas by saying, ‘that’s silly’, you will never get that person to engage in anything to help the team again. Listening is an important skill to help technicians solve their problems by leading them to answer their questions. Listening also helps find out what processes might need changing.

Improving leadership is a continuous process. It must be addressed regularly with the avenues of communication always open and with both management and employees able to handle constructive criticism.

Wilson B. Leadership in pharmacy. CPhT CONNECT 2023; 3(4): 13–5.

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MedsScan editors for #SHPATransitionCare: Margaret Jordan, Ahmed Zeidan and Deirdre Criddle

Engaging pharmacists into general practice to improve medicines safety

Special contributor: Elizabeth Manias

The general practice pharmacy model is an innovative means of collaborative care, which provides support to general practitioners (GPs) in medication reconciliation and review, opportunities for shared decision-making with patients and carers and identification of medicines for deprescribing. While this model is established in the United States, Canada, and the United Kingdom, it is still developing in Australia. The aims of the study were to evaluate a general practice pharmacist (GPP) model on optimising medicines management and to explore the perspectives of this model from general practitioners, practice personnel, patients, and carers. This two-phase study comprised a quantitative assessment of deprescribing recommendations of medicines plans and qualitative evaluation of participants’ perspectives of the GPP model of care. Within an Australian metropolitan GP clinic, the GPP identified a median of three medicines recommendations, of which 86% were accepted by GPs and patients. Deprescribing was undertaken in over half (54%) of patient consultations, where opioid medicines, aspirin, complementary medicines, gabapentinoids and proton pump inhibitors were commonly ceased. Interviews with 28 participants indicated the model facilitated the process of identifying and resolving medicines discrepancies and supported the role of GPs in reducing dose and usage of unnecessary medicines. Participants also believed the GPP model helped to identify triggers for deprescribing, especially in patients with complex medicines regimens. The study provides valuable evidence of the value of a GPP model of care in optimising medicines management. Further research is needed to evaluate the model in diverse patient and clinical populations.

Jordan M, Mullan J, Stewart A, Chen TF. A pharmacist integrated into a general practice in Australia: an evolving model of care in medicines optimization. Int J of Pharm Pract 2023 [online ahead of print].

General practice pharmacists in Australia: why do they leave?

Special contributor: Bianca Heron

General Practice offers alternative career options for pharmacists within Australia, with work encompassing patient contact, collaboration with GPs and utilisation of clinical skills.  High turnover is reported with one in five pharmacists leaving general practice in Australia recorded.1 

This exploratory study aimed to review factors that contribute to pharmacists leaving general practice in Australia. Fourteen pharmacists were identified via the Primary Health Network across 11 general practices in the Australian Capital Territory. Pharmacists that left general practice within 12 months of commencement were recruited for interviews. Interview questions were informed by the literature and pre-tested on pharmacists prior to use in the study. Thematic analysis was undertaken on the responses of those recruited. 

Characteristics of pharmacists who left general practice (n = 5) were compared to those who remained (n = 9). Of those who remained in general practice, higher rates of accreditation for medication reviews were noted (57% vs 20%). Mentoring was also provided across both groups: 60% in those who left compared to 67% for those who remained. The median time spent in general practice for those that left was 8 months (range 3–10). Of the five who left, two moved to community pharmacy, two to government roles, and one to an aged care facility. Four key themes were identified by researchers from the interviews of the pharmacists that left. These were: (i) job satisfaction, which was influenced by underutilisation and part time hours; (ii) the challenges of the new role which included poor utilisation; (iii) poor role definition; and (iv) professional relationships, influenced by tensions when taking on roles previously completed by others. Of interest, none of the five pharmacists mentioned salary.

Despite the study’s limitations of small sample size and recruitment from one jurisdiction, it does highlight important considerations for other jurisdictions with pharmacists in general practice. The importance of clear role descriptions that are understood within the team and greater retention strategies are important. Whilst mentoring was evident in both groups, the need for early and accessible mentoring with low costs was highlighted. Medication review accreditation equips pharmacists to interact with GPs, and the higher rates of accreditation in those who remained may indicate an area for further review/investment. A larger study across multiple sites would be important to determine if the results found were applicable across all areas of general practice pharmacists working in Australia.

  1. Benson H, Sabater-Hernández D, Benrimoj SI, Williams KA. Piloting the integration of non-dispensing pharmacists in the Australian general practice setting: a process evaluation. Int J Integr Care 2018; 18: 4.

Deeks LS, Kosari S, Peterson GM, Sudeshika T, Naunton M. Factors contributing to pharmacists leaving employment in general practice in Australia: an exploratory study. Int J Pharm Pract 2023; 31: 438–41.

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MedsScan editor for #SHPAWomenNewborn: Kate Luttrell

Oral relugolix combination therapy versus placebo in patients with endometriosis associated pain

Guest contributor: Tamara Lebedevs

Background: Endometriosis is a debilitating reproductive condition characterised by the growth of endometrial-like tissue outside of the uterus, affecting 1 in 9 Australian women. Symptoms include dysmenorrhoea, deep dyspareunia, chronic pelvic pain and infertility. The condition affects individuals physically and mentally and has a significant socioeconomic burden on their families and the wider community.

Endometriosis-associated pain is managed by analgesics, surgical removal or drugs that cause ovarian suppression. However, symptoms recur within 5 years following surgery in 40–50% of women and existing drug treatments are often ineffective and/or have unpleasant side effects. Gonadotropin-releasing hormone (GnRH) agonists are effective for pain control, but their use can cause significant reduction in bone mineral density, limiting use to short term only, similarly with GnRH antagonists.

Aim: Relugolix — an oral GnRH receptor antagonist, combined with estradiol and a progestin — was evaluated for treatment of endometriosis-associated pain.

Method: SPIRIT 1 and 2 were replicate, phase 3, multicentre, randomised, double-blind placebo-controlled trials delivered across 219 research centres in 6 continents. Participants with surgically confirmed endometriosis and moderate (or more severe) dysmenorrhoea with associated non-menstrual pain were randomised in a 1:1:1 ratio to either 24 weeks of treatment with relugolix combination, placebo or to a delayed relugolix arm (12 weeks of relugolix in monotherapy followed by 12 weeks of combination therapy). The use of the ‘delayed’ arm permitted investigation of the impact of hypo-estrogenism on efficacy, tolerability and bone mineral density.1

In total, 638 and 623 participants were randomized to SPIRIT 1 and 2, respectively, with similarities in each arm with regard to age, body mass index and ethnicity.

Results: At 6 months, significantly more patients had a reduction in dysmenorrhoea in response to relugolix combination therapy than they did to placebo (158 [75%] of 212 patients vs 57 (27%) of 212 patients [SPIRIT 1] and 155 [75%] of 206 patients vs 62 [30%] of 204 patients [SPIRIT 2]) and significantly more patients had a reduction in non-menstrual pelvic pain in response to relugolix combination therapy than they did to placebo (124 [58%] of 212 patients vs 84 [40%] of 212 patients [SPIRIT 1] and 136 [66%] of 206 patients vs 87 [43%] of 204 patients [SPIRIT 2]). Most women on relugolix combination therapy reported no bleeding or infrequent bleeding during the study and fewer women required opioid and non-opioid analgesics than women who received placebo. The incidence of adverse events, both serious and non-serious, was similar among relugolix combination treatment and placebo groups (151 [71%] of 212 vs 140 [66%] of 212 [SPIRIT 1] and 166 [81%] vs 153 [75%] of 204 [SPIRIT 2]) with the most common symptoms being headache and nasopharyngitis followed by hot flushes.

These two trials demonstrate that once daily relugolix (an oral GnRH antagonist) in combination with estradiol and norethisterone acetate is effective for moderate to severe pain from endometriosis.

Key limitations: Further research is needed to determine its effectiveness in comparison with currently available treatments. Ethnic diversity was not reflected in the patient cohort and there was a lack of detail regarding subtype of endometriosis. Another limitation was the 24-week treatment duration. As most women with endometriosis require treatment beyond 6 months, longer-term data are required on sustained effectiveness and safety, especially with regard to bone mineral density. However, the long-term therapeutic effects are being further assessed in an 80-week, long-term extension study, which will provide up to 2 years of benefit and risk information for relugolix combination therapy.

Impact on practice: The combination product (Ryeqo) is approved by the Therapeutics Goods Administration (TGA) in Australia for treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age and currently the medical sponsor has a TGA application to include the indication for treatment of moderate to severe pain associated with endometriosis.2

This oral therapy has the potential to address the unmet clinical need for long-term medical treatment for endometriosis, reducing the need for opioid use or repeated surgical treatment.


  1. Department of Error. Erratum. Lancet 2022; 400 (10353): 660.
  2. Therapeutic Goods Administration. RYEQO 40/1/0.5 Gedeon Richter Australia Pty Ltd. Canberra: Commonwealth of Australia; 2023. Available from <>. Accessed 6 November 2023.

Giudice LC, As-Sanie S, Arjona Ferreira JC, Becker CM, Abrao MS, Lessey BA, et al. Once daily oral relugolix combination therapy versus placebo in patients with endometriosis-associated pain: two replicate phase 3, randomised, double-blind, studies (SPIRIT 1 and 2). Lancet 2022;399 (10343): 2267–79.

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