Five reasons to not prescribe opioids

Around one in five Australians experience chronic pain. This is a complex condition to manage, with varied aetiology, pathology and presentation. Multimodal strategies are key, using a combination of different treatment modes to address the biological, social and psychological factors that contribute to the development of chronic pain.

Non-pharmacological strategies are an essential part of management. Medicines have a limited role in managing chronic pain, with guidelines recommending them only as an adjunct to non-pharmacological options. However, despite a lack of evidence to support long-term efficacy, the number of prescriptions for opioids continues to rise in Australia.

There are five key reasons not to prescribe opioids, and to consider deprescribing at every visit.

Adverse events

There is an increased risk of adverse events with extended opioid use: around 80% of people taking opioids long term will experience an adverse event. Most common are constipation, nausea and somnolence, but more serious adverse events can occur.

Limited evidence

Opioids have a limited role in chronic pain management because of a lack of evidence for their long-term benefit.

Central sensitisation

Central sensitisation and tolerance can occur within 4 weeks, limiting the viability of opioids as a clinical intervention.

Risk of abuse

There is a risk of abuse, misuse and addiction. People using opioids long term can develop an opioid-use disorder or exhibit drug-seeking behaviour.

Comorbidities

Co-existing conditions complicate management with opioids: major depression is the most common, and psychotropic medicines can interact with opioids to cause excessive sedation and respiratory depression.

The latest education program from NPS MedicineWise focuses on management of chronic non-cancer pain and is designed to help health professionals consolidate their knowledge on chronic pain management. The program is underpinned by evidence, current guidelines and best practice, and attracts continuing professional development points. To access the program, visit http://www.nps.org.au/chronic-pain.

Cancer nanomedicine: challenges and opportunities

Nanotechnology holds enormous promise for personalised cancer medicine — translation is the key

Medicine is on the cusp of a revolution. Personalised, precision medicine — designed and tailored at a molecular level for an individual’s own physiological make-up — will become an inevitable reality in the 21st century. As with all paradigm shifts in medicine, this will be driven by new science and technology, and the technology of the 21st century is nanotechnology.

Nanomedicine is a rapidly evolving paradigm where nanoscience and nanotechnology are applied to medicine. The science underpinning nanotechnology is that some materials, when reduced from everyday, bulk scales down to nanoscales (billionths of a metre; smaller than the size of a typical virus), exhibit dramatically different physical properties. Harnessing and customising these unique nanoscale properties offer unique advantages to health and medicine for two reasons. First, many key molecules involved in biochemical processes responsible for regulating biological function have nanometre (nm) sizes (eg, a glucose molecule is about 1 nm), so nanoscale probes offer a means for molecular-based interrogation and intervention strategies. Second, because of their size, nanoprobes offer a relatively discreet, non-invasive strategy for disease detection and targeted therapy (although the immune system inevitably catches up).1

An important example of how nanoscale properties can be harnessed for medical applications is magnetic resonance imaging. Here, image contrast is enhanced using magnetic nanoparticles, usually based on gadolinium or iron oxide, which exhibit strong magnetism only when reduced to scales of 20 nm or less.2

Nanoparticles: size matters when it comes to targeting tumours

In cancer nanomedicine, a wide range of nanoparticles continue to be developed for better tumour-targeted delivery of therapeutics (chemotherapy and radiotherapy). These include liposome-, polymer- and micelle-based nanoparticles for encapsulated delivery, and metallic nanoparticles (eg, gold), which have been investigated for targeted radiotherapy.1–3 There are two types of tumour-targeting approaches with nanoparticles: passive and active. Passive targeting relies on tumour vasculature, which has larger endothelial gap junctions compared with healthy tissue. Nanoparticles greater than 8 nm can pass through these gaps to reach tumour cells. An enhanced permeability and retention effect results from the combination of larger gap junctions and defective lymphatic drainage, particularly around fast-growing tumours, facilitating preferential accumulation and prolonged retention in the tumour tissue.1 In active targeting, however, nanoparticles are conjugated with targeting agents, such as antibodies, that are specific to proteins highly expressed by certain tumours (eg, human epidermal growth factor receptor 1 in non-small cell lung cancer).3

Challenges: clinical translation

Despite ongoing progress in basic and preclinical cancer nanomedicine research, arguably the single most important challenge is clinical translation.4 However, most of the many different nanoplatforms developed for cancer therapy have not progressed past Phase II clinical trials.1 Very few have achieved United States Food and Drug Administration approval (eg, liposome-encapsulated doxorubicin and daunorubicin for breast and ovarian cancers, and Kaposi sarcoma). New efforts are focusing on the potential to extend the capabilities of other therapeutic and imaging nanoplatforms developed and approved for non-cancer indications. For example, ferumoxytol is an iron oxide nanoparticle used for treating anaemia and it is also a magnetic resonance imaging contrast-enhancing agent.5 Nanotheranostics — the use of nanoplatforms combining targeted therapy and diagnostic imaging functionality — is a rapidly growing trend.

Why is bench-to-bedside so challenging for cancer nanomedicine? The problems are many. Key difficulties include controlling nanoparticle size and preventing nanoparticle aggregation in vivo, which are critical for clearance by the kidney or liver. Biocompatibility, blood circulation time and the ability to elude the immune system long enough to release a therapeutic cargo, are similarly difficult to clinically validate. Additional practical challenges that need to be overcome for clinical translation include tumour cell specificity, cellular uptake and localisation, and controlled release and functionality of the cancer therapeutic.3

Opportunities: clinical translation

The challenges presented by clinical translation could equally be viewed as opportunities. This is the approach taken by the European Foundation for Clinical Nanomedicine (https://www.clinam.org). Similarly, the US National Cancer Institute (NCI) integrates translational and basic science research in its Alliance for Nanotechnology in Cancer (http://nano.cancer.gov). Launched in 2004, the Alliance held a strategic workshop in 2013, the outcomes of which highlighted several recommendations for future opportunities in cancer nanotechnology.6 These include supporting the development of new techniques and clinical translation in parallel; supporting a stronger focus on developing active targeting strategies; and giving a high priority to imaging probes and lower priority to developing in-vitro nano-enabled techniques. The NCI report also highlighted the importance of interdisciplinary collaboration — bringing together clinical and basic science researchers from diverse backgrounds is the key to creating unique opportunities for genuine breakthrough discoveries in cancer nanomedicine.

A new era in the treatment of multiple sclerosis

Multiple sclerosis (MS) is an immune-mediated disorder of the central nervous system.1 Untreated MS results in significant disability during the prime of life for many with the disease.2 The aetiology of MS remains to be fully elucidated, but the Epstein-Barr virus,3 relative vitamin D deficiency4 and smoking5 have been identified as environmental risk factors that interact with the more than 100 genetic loci associated with susceptibility for the disease.6,7

The past 20 years has seen considerable progress in understanding the pathophysiology and advancing the treatment of MS.8 A number of moderately effective and, more recently, highly effective therapies have been licensed and funded in Australia and other parts of the world. We have recently reviewed in the Journal of Clinical Neuroscience the practicalities of using these therapies and their place in the treatment of individual patients in the Australian and New Zealand context.9–11 The purpose of this article is to highlight some recent developments in MS treatment, with a particular emphasis on the wider implications of the newer agents for health care providers.

Methods

This review represents the consensus reached by experts in MS treatment from across Australia and New Zealand. Our findings are based on a critical review of pivotal Phase III clinical trials, and of Cochrane reviews and other systematic reviews of particular themes. Recommendations are made according to the National Health and Medical Research Council levels of evidence scale.12

The current landscape of MS therapy

The choice of therapy for a person with MS will depend on the phase and clinical activity of the disease, individual patient considerations, and the practicalities of drug administration. Appendix 1 summarises data on the dose, route of administration, efficacy, practicalities of use and adverse effect profiles of the 13 MS therapies that are currently licensed in Australia or New Zealand, have completed Phase III clinical trials, or for which a Cochrane meta-analysis is available. The various therapies have differing levels of efficacy, but the impact of even the most effective agents over the short-to-medium term on disease progression and brain atrophy is modest. Conversion to or continuation of progressive disease can still occur while using the most effective therapies, although evidence of new inflammatory disease activity, such as clinical relapses and new lesions identified by magnetic resonance imaging (MRI), may have been almost completely abolished.13

The two agents with the greatest efficacy are both administered as intravenous infusions. Each is associated with significant risks, either in the form of progressive multifocal leukoencephalopathy (PML) for natalizumab,14 or the development of other autoimmune diseases, most commonly Graves’ disease, with alemtuzumab.15

The safety of the long-established injectable therapies (ß- interferons and glatiramer acetate) has been confirmed over two decades of use, but these medications have minor side effects and require self-administered subcutaneous or intramuscular injections.16,17 Their efficacy in preventing relapses is modest, but their longer-term benefit in reducing rates of secondary progression is encouraging.16 Preparations of these two agents that require less frequent administration may improve their tolerability.18,19

The oral agents fingolimod and dimethyl fumarate have intermediate efficacy, appear to be safe, and are well tolerated; they have relatively minor adverse effects that need to be monitored and managed.20,21

The efficacy of the oral agent teriflunomide appears to lie somewhere between that of the other two orally administered drugs and the injectable therapies (ß-interferons and glatiramer acetate), and its safety profile is also reassuring.22

Practicalities

Disease-modifying therapy should be considered in any patient with a first episode of demyelination where supporting evidence in the form of MRI and cerebrospinal fluid (CSF) findings strongly support a diagnosis of MS, or when relapsing-remitting MS has been diagnosed. Those patients who elect not to commence treatment — because of personal preference or because they regard the disease course as mild — should be carefully monitored for evidence of further disease activity, to ensure that this decision can be reviewed when necessary.

While a start-slow-and-escalate approach has generally been advocated for patients with mild to moderate relapsing-remitting MS, most studies have highlighted the need to commence therapy early. There is insufficient evidence to support the concept of induction therapy (the use of higher-efficacy therapy initially followed by lower-efficacy therapy) for MS; optimal disease control generally requires continuation of an effective therapy.11 Evidence of further disease activity (clinical or MRI findings) is generally regarded as indicating that escalation of therapy or a switch to an alternative should be considered.11 The significance of new lesions in the first 6 months of therapy is uncertain, as they may reflect events that occurred before treatment started or a delay in response to treatment. For this reason, many neurologists advocate a repeat “baseline” MRI 6 months after commencing any new therapy.

There is currently little evidence for the utility of combination therapies, although relevant studies are being undertaken.10 While concerns have been expressed about washout periods and the avoidance of overlaps when switching between therapeutic agents, no specific problems have been identified, with one exception: when treatment with natalizumab is initiated, there is an increased risk of PML in patients who are John Cunningham (JC) virus antibody-positive and have been exposed to immunosuppressive therapy.23

It is recommended that all MS therapies be withdrawn in women planning to become pregnant. There is, however, a risk that disease activity may re-emerge, particularly if there are delays in conceiving. This leads to difficult decisions about whether treatment should continue until it has been confirmed that the woman is pregnant, and whether therapy should be discontinued during the pregnancy itself.11 The latter decision will often be guided by recent disease activity and any previous experience of MS attacks during pregnancy. The safest options for young women of childbearing age are glatiramer acetate and dimethyl fumarate (pregnancy category B1), while fingolimod (category D) and teriflunomide (category X) are the riskiest options. Pregnancy itself, particularly the second and third trimesters, is associated with a reduced risk of relapse, but this is balanced by an increased risk of disease activity in the first three months post-partum.24,25

All current treatments for MS have some minor side effects and several of the more potent agents are associated with specific risks that need to be managed.11 These adverse effects and the recommended management strategies are summarised in Appendix 2. Three particular problems that need attention will be discussed here.

Progressive multifocal leukoencephalopathy

PML is caused by infection of the brain with the JC virus; it typically develops in the setting of immune deficiency or immunosuppressive therapy. PML has been extensively documented in patients with MS treated with natalizumab,14 and there have been case reports associated with dimethyl fumarate26 and fingolimod.27 Lymphopenia was not present in two of the cases of PML with dimethyl fumarate and fingolimod, but further data are needed; caution is warranted when using these drugs in any patients who are JC virus antibody-positive. The JC virus is carried by 40%–50% of the general population, and carrier status can be tested with the Stratify JCV antibody test (Focus Diagnostics). After 4 years of exposure to natalizumab, patients who are positive for JC virus antibody have a 1 in 200 risk of developing PML; in patients who are JC virus antibody-negative, the risk is estimated to be less than 1 in 10 000.23 The principal presenting symptoms are subacute onset hemiparesis, dysphasia, cognitive decline and seizures.14 The onset of symptoms can be subtle, and may be further obscured by cognitive or dysphasic symptoms. If these or any other unexplained neurological signs develop in a patient taking natalizumab, they should be immediately referred to their neurologist, their treatment suspended, and urgent MRI and lumbar puncture assessments requested. The presence of JC virus DNA in the CSF should be tested by polymerase chain reaction (PCR), even when the results of serological testing for JC virus antibody are negative.

Autoimmune disease

Autoimmune thyroid disease (30%), idiopathic thrombocytopenic purpura (~ 1%), and, more rarely, anti-glomerular basement membrane (GBM) antibody glomerulonephritis can develop between 1 and 5 years after commencing treatment with alemtuzumab.15 Continual vigilance for the symptoms of these complications is required and, perhaps more importantly, regular laboratory testing, including full blood counts each month for at least 5 years. If detected early, these conditions respond to standard therapies, but they can emerge quite precipitately and should be treated urgently by physicians with relevant expertise.15

Lymphopenia and deranged liver function test results

Almost all of the available therapies have been associated to varying degrees with lymphopenia or liver function derangement. These effects are likely to be part of the mechanisms of action for fingolimod, dimethyl fumarate, teriflunomide and alemtuzumab. Repeat testing and possibly the cessation of therapy are appropriate if significant deviations from normal values (Common Terminology Criteria for Adverse Events [version 3.0; CTCAE], grade 3: lymphocyte count < 0.5 × 109/L, or greater than fivefold elevation of hepatic enzyme levels) or a persistent trend away from normal values do not resolve spontaneously. Therapy should be stopped immediately if a higher degree of abnormality (CTCAE, grade 4: lymphocyte count < 0.2 × 109/L, or greater than 20-fold elevation of hepatic enzyme levels) is detected. In either situation, concomitant medications and the patient’s medical background (recent infections, alcohol misuse, fatty liver disease) should be reviewed carefully before long-term decisions are made.

Recommendations

Recommendations for the treatment of MS are summarised in the Box. Key concepts that have emerged include the importance of confidently establishing the diagnosis of MS early, with a view to considering therapy as soon as possible. Monitoring for and managing side effects is important from the perspective of maintaining compliance. Monitoring disease activity by regular clinical reviews and MRI scans during therapy is important, particularly over the first 1–2 years, with a relatively low threshold for escalating therapy in the event of new disease activity. In the case of interferon therapy, clinical relapses and radiological disease activity during the first year of therapy clearly identify patients who will develop more severe disease in subsequent years.28

All current MS treatments are envisaged as long-term therapies or, in the case of alemtuzumab, as requiring sustained monitoring after two or more courses of intravenous infusions. This gives rise to at least two significant problems. The first is maintaining compliance, which can become a significant challenge after several years of therapy, particularly, perhaps counterintuitively, in patients who remain healthy. The second is the need for ongoing monitoring. Several agents require intermittent haematological and liver function tests. Natalizumab therapy requires 6-monthly JC virus antibody testing in seronegative cases to ensure that the patient remains seronegative. Further, it is important to remain vigilant to potential late complications with some of the newer therapies. For patients treated with alemtuzumab, regular monitoring of haematological, renal and thyroid function parameters for at least 5 years and possibly longer is necessary.

Conclusions

We are in an exciting era for the treatment of MS. A number of effective therapies are available with a spectrum of efficacy and tolerability profiles that require careful tailoring to individual patients’ needs, and we must weigh the pros and cons of the route and frequency of administration, together with the perceived potential benefits and risks for the individual patient. General practitioners and specialist physicians need to be aware of the potential complications and specific features of MS therapies, particularly in rural and remote settings where rapid access to specialist neurological services may not be available. Some complications (eg, anti-GBM antibody disease) are better treated by specialist physicians other than neurologists.

While considerable improvements in the treatment of the early inflammatory phase of MS have been achieved, the efficacy of these approaches in progressive disease has been disappointing, even with the more effective therapies.13 Considerable effort is currently being invested in the investigation of the pathophysiology of progressive disease and of potential therapeutic targets by the International Progressive MS Alliance (in which Australian and New Zealand neurologists are participating).

It is evident that the indications for therapy in Appendix 1 and the recommendations listed in the Box are not entirely consistent with one another, and that there is an urgent need for the current restrictions on prescribing MS therapies to be adjusted in the light of new evidence. This will entail a rationalisation of the indications, which would assist neurologists to prescribe the most effective therapies at the appropriate time and in the appropriate setting for the patient, thereby improving their cost-effectiveness.

1
Recommendations for the therapy of multiple sclerosis*

Recommendation

NHMRC Level of evidence

1. In patients presenting with a clinically isolated syndrome, treatment with an injectable disease-modifying therapy should be considered.

2. Patients with active relapsing-remitting disease (2 relapses in 2 years) should be offered ß-interferon, glatiramer acetate, natalizumab, fingolimod, teriflunomide, dimethyl fumarate or alemtuzumab.

3. Clinical progress should be monitored every 3–12 months, with repeat MRI after 3–12 months in the first instance and then every 12 months or less frequently, depending on the response to therapy. Clinical relapses or new MRI lesions should prompt consideration of escalation in therapy to fingolimod, dimethyl fumarate, natalizumab or alemtuzumab.

II-2

4. Where prognostic indicators in relapsing-remitting disease are poor from the outset, therapy with fingolimod, dimethyl fumarate, natalizumab or alemtuzumab should be considered.

5. In very rapidly progressive multiple sclerosis, or where disease fails to respond to standard therapies, the use of immunosuppressive therapy (mitoxantrone/cyclophosphamide), rituximab, autologous haematopoietic stem cell therapy or combination therapy should be considered carefully.

II-2

6. Where the level of disability becomes severe or disease continues to progress, therapy should be discontinued.

III

7. In clinical settings where requirements for government funding of approved therapies are not satisfied for technical reasons, and a significant inflammatory disease burden is suspected or standard therapies are contraindicated, the use of traditional immunosuppressive therapies (azathioprine/mycophenolate) should be considered after discussion of the potential benefits and risks with the patient.

II-1

MRI = magnetic resonance imaging. NHMRC = National Health and Medical Research Council.
*Adapted with permission from Broadley et al 2014.11

Precision medicine: are we there?

Implementation of precision medicine requires a multidisciplinary and systematic approach

In his State of the Union address on 20 January 2015, United States President Barack Obama announced a new initiative in precision medicine, which aims to give “access to the personalised information we need to keep ourselves and our families healthier”.1 So, what is precision medicine? Previously referred to as personalised medicine, it can be defined as the correlation of innate and external factors at an individual level, to better understand the pattern of disease and its impact on the individual, and thus to tailor prevention, intervention and treatment. Precision medicine thus combines genomic and epigenomic data with environmental exposure and lifestyle factors. It has the potential not only to improve health outcomes but to save money by better targeting health interventions to those individuals most likely to benefit.

This research initiative in the US will provide funding through the National Institutes of Health and other partners, initially to cancer medicine. The longer term hope is to create better understanding of genomics, molecular biology and bioinformatics in a bid to improve health for all, not only people suffering with cancer.2

Genetics, the study of heredity, investigates the structure and function of a single gene. We are currently in transition from genetics to genomics, the study of all of an individual’s genes, their molecular structure and function, and their interrelationships and architecture. We are thus refocusing from the utility of single genes in monogenic disorders to the potential of genomics in many complex disorders.

Sequencing of the whole human genome, all 3.3 billion base pairs, has become cheaper, quicker and easier. In the 100 000 Genomes Project, Genomics England is sequencing the whole genome of 100 000 individuals with common cancers or rare inherited diseases, to facilitate the incorporation of genomic medicine into the National Health Service (http://www.genomicsengland.co.uk/the-100 000-genomes-project). Similarly, in the Melbourne Genomics Health Alliance, seven health and research organisations are working in partnership to incorporate genomics into health care and assess the health economics argument for genomics (http://www.melbournegenomics.org.au). This has been initiated with pilot projects in areas such as epilepsy, rare childhood diseases and colon cancer.

While genomics might underpin precision medicine, it is only part of the picture. The bioinformatic capacity to analyse the data will allow interpretation of the pinpoint accuracy of current genetic technology. The impetus needs to shift from technology to informatics in clinical practice and improving health outcomes. Benefits to patients will only occur when their clinical details can be linked to their specific genomic data and their treatment altered accordingly.

Implementation of precision medicine will require convergence of disciplines, involving not only clinicians and scientists, but also mathematicians, engineers and philosophers — rather than the siloed approach of previous decades. Governments internationally are now recognising the importance of this convergence.1,3 In Australia, we have much preliminary data already. The University of Melbourne and Cancer Council Victoria host PEDIGREE (Pathology, Epidemiology, DNA, Informatics & Genetics: a Research Enabling Enterprise) (http://www.cancervic.org.au/research/epidemiology/pedigree). PEDIGREE is a resource of 100 000 people, 20 000 families with cancer, 1 million biospecimens, data, researchers and community representatives, evolving through collaboration over two decades to enable studies of the genetic and environmental factors associated with the risk and prognosis of some of the common cancers that affect Australians. The aim is to develop risk management strategies which can be applied at a population level to those who have a genetic predisposition to these cancers and ultimately prevent the cancers from developing.

It is intuitive that a precise therapy, based on the biology of disease, would lead to more effective treatment. And it is intuitive that even if the precise therapy is expensive, the elimination of waste will lead to longer-term cost savings. But to ensure that this is the case, clinical trials must occur in parallel with economic modelling and a robust economic argument must be made to justify the use of precision medicine. Initial support for precision medicine has come through a few effective targeted treatments for cancer. The best known of these are trastuzumab, a monoclonal antibody therapy for HER2-positive breast cancer, and imatinib, a tyrosine kinase inhibitor, for the treatment of chronic myeloid leukaemia. Ward has cautioned that, apart from a few well known exemplars, little has changed in the treatment of cancer and that the “[s]ubstantive benefits of personalised medicine continue to elude us”.3 In the short term, it is the primary objective of the Obama initiative to tackle this problem.1

As a practical example of precision medicine, pharmacogenomics — the use of an individual’s genome to optimise medication prescribing — has promising early outcomes. The dictum to reduce medication errors and harm using the six “rights” — the right drug and right dose for the right person via the right route at the right time with the right documentation — should now expand to include a seventh, the right genotype. An integrated electronic medical record and a pre-emptive pharmacogenomic approach will facilitate this knowledge in advance of the need to use the medication. For example, in individuals of Han Chinese descent, the HLA-B*1502 genotype will predispose an individual taking the antiepileptic drug carbamazepine to severe, life-threatening Stevens–Johnson syndrome.4 It is simple and inexpensive to test individuals of this ethnicity for this allele before commencing carbamazepine. Pharmacogenomics will become more important over time, particularly in areas such as aged mental health, where polypharmacy in frail people complicates a number of comorbidities. Pharmacogenomics will assist in optimising drug selection for an individual, reducing adverse events and also the time lost when drugs are not effective.

To bring precision medicine into practice through genomics, we need a systematic approach. Australia will need to develop genomic literacy in the workforce through a combination of dedicated specialists (clinical geneticists and genetic counsellors), while upskilling all health professionals. In parallel, we require a workforce of genomic diagnosticians and clinical bioinformaticians to receive and translate genomic research discoveries for clinical use.

Precision medicine will be built on a foundation of evidence ranging from population studies to individualised approaches such as single-patient studies, where clinical trials are targeted to the disease process and the individual genotype.

Precision medicine initiatives raise a range of new ethical issues. Until now, most genetic tests have focused on the single gene under investigation, with recent expansion to small gene panels, specific for the clinical question. However, the genome can be sequenced in its entirety once, and then reinterrogated at multiple occasions over an individual’s lifetime. The large amount of data thus generated can be stored and used indefinitely. The issue of unintended findings has been debated for some time. Genomic data may inform individuals about susceptibility to one or many medical conditions which had not been anticipated by their personal or family history. The American College of Medical Genetics has issued a list of actionable genes, defined as genes for which information about mutations, even if found inadvertently, should be returned to the individuals who carry them.5 In the Australian context, in 2014, the National Health and Medical Research Council released a discussion document on the principles for the translation of “omics”-based tests from discovery to health care.6

While uncertainty is not a new concept in health care, the scale of the current uncertainty associated with the interpretation of genomic data is unprecedented. Without correct interpretation, clinical action based on a DNA sequence variation of uncertain significance is potentially harmful. Unless a sequence variation is classified as pathogenic, no clinical utility can be afforded to such a change. This relates to care of the patient, as well as implications for predictive testing and risk management in family members, and the facilitation of reproductive options, all of which need genetic and genomic certainty. Human research ethics and clinical ethics committees will need to be informed and equipped to deal with these issues as more findings from genomic studies are applied to clinical practice. Informed consent for participation warrants consideration in all quarters. It is imperative to gain and retain public trust.

Precision medicine offers a new dimension in prevention, diagnosis and treatment of human disease, one to be embraced and encouraged. In Australia, we have the potential to contribute to the worldwide knowledge base through our genomic capacity and mature research cohorts. The collection of robust, accessible and linked genotype–phenotype datasets, along with lifestyle and environmental data, will help us to realise the potential of precision medicine for the benefit of our communities.

Febuxostat-associated rhabdomyolysis in chronic renal failure

Clinical record

A 68-year-old man of European descent presented to our emergency department with rhabdomyolysis and acute-on-chronic kidney disease. He had a history of stage 3 chronic kidney disease (CKD3) — based on 17 tests in the year before this admission, his estimated glomerular filtration rate (eGFR) was 35 ± 7 mL/min/1.73m2 (CKD3: eGFR = 30–59 mL/min/1.73m2), his serum creatinine concentration was 179 ± 42 µmol/L (reference interval [RI], 60–120 µmol/L) — and of polyarticular tophaceous gout, type 1 diabetes mellitus, hypertension, ischaemic heart disease (coronary artery bypass grafting in 1998) and peripheral vascular disease.

His gout, diagnosed 13 years before this presentation, had been treated with allopurinol and then colchicine. Both, however, caused anaphylactic reactions. He had had multiple short courses of prednisolone to treat acute attacks on a background of naproxen. A month before this presentation, naproxen was withdrawn and treatment with a new hypouricaemic drug, febuxostat(40 mg daily) initiated. This drug was obtained through the Special Access Scheme of the Therapeutic Goods Administration. Two doses of febuxostat were withheld 12 days before this admission when he was admitted to hospital for 8 days with Haemophilus influenzae pneumonia and acute-on-chronic kidney disease, with his serum creatinine concentration peaking at 245 µmol/L. He was treated with intravenous ceftriaxone and azithromycin for 5 days, after which his renal function values had returned to baseline levels. He was discharged home and prescribed oral amoxicillin, which was to be continued for 5 days.

When he presented to our emergency department, the man was lethargic, oliguric, dehydrated and with acute-on-chronic kidney disease (serum creatinine concentration, 669 µmol/L; eGFR, 7 mL/min/1.73m2), but he was haemodynamically stable. There were no symptoms suggesting infection, and he was afebrile. Elevated serum creatine kinase activity (48 200 U/L; RI, 20–200 U/L) and the presence of myoglobin in his urine were consistent with rhabdomyolysis. The man was hyperkalaemic (potassium, 6 mmol/L; RI, 3.5–5.0 mmol/L) with tall T waves in his electrocardiogram; this responded to oral resonium and nebulised salbutamol. His serum creatinine concentration continued to rise despite intravenous hydration, peaking 48 hours after admission at 833 µmol/L (eGFR, 6 mL/min/1.73m2). His bicarbonate levels declined from 22 mmol/L to 15 mmol/L (RI, 24–31 mmol/L), reflecting worsening metabolic acidosis.

At the time of his admission, he was taking (in addition to febuxostat) aspirin (100 mg daily), simvastatin (40 mg daily), gemfibrozil (600 mg twice daily), frusemide (40 mg daily), metoprolol (100 mg twice daily), moxonidine (200 mg twice daily), insulin and omeprazole (20 mg daily).

Febuxostat was considered to be the likely dominant precipitating factor and was withdrawn, as were simvastatin and gemfibrozil; he had used these two medications for 12 years, but febuxostat had only recently been prescribed. Further, application of the Naranjo adverse drug reaction (ADR) probability scale1 indicated that febuxostat possibly caused rhabdomyolysis in our patient.

Haemodialysis of the patient was commenced, and he had five cycles over the next 11 days. His renal function gradually returned to baseline (Figure). He was discharged on Day 23. Some months later, treatment with benzbromarone was started, a uricosuric drug that was also obtained through the Special Access Scheme. After taking benzbromarone for one-and-a-half months, his plasma urate concentration was 0.26 mmol/L (RI, 0.25–0.50 mmol/L).

Uncontrolled gout is a significant disorder because of the debilitating attacks of acute gout, the ensuing joint damage that causes pain, deformity and loss of function, and the organ damage involved, particularly renal dysfunction. The xanthine oxidase inhibitor allopurinol is an effective medication for reducing plasma urate concentrations to below 0.36 mmol/L, and this effect, if maintained, will almost always eliminate recurrent acute attacks of gout and the risk of joint and organ damage.2–4 As the active form of the drug is cleared exclusively by the kidney, the starting dose needed by patients with impaired renal function is lower.4 Risk of hypersensitivity, manifested as toxic epidermal necrolysis, is an uncommon but significant problem; a macular-papular rash is seen in as many as 2% of patients. These problems may be more common in those with impaired renal function or also using diuretic medications.5

There are alternative approaches for lowering urate levels in patients with hypersensitivity reactions. Uricosuric drugs, such as probenecid, are effective in patients with normal to moderately impaired renal function, but are not effective in those with severe renal impairment.6 Benzbromarone is a more effective uricosuric agent in individuals with renal impairment, but must be imported into Australia under the Special Access Scheme, as it is not registered in this country.7

The availability of a second xanthine oxidase inhibitor, febuxostat, is therefore welcome, especially for patients who do not tolerate allopurinol well. Febuxostat is registered in the United States and Europe, and was recently also registered in Australia (December 2014). The medication is generally well tolerated and dose adjustment is not necessary in patients with mild to moderate renal dysfunction. Liver function abnormalities and cardiovascular thrombotic reactions have been identified by postmarketing studies, but their incidence is very low. Only a few case reports have described hypersensitivity reactions. Cost is an issue, as febuxostat is more expensive than allopurinol, and should therefore not be the agent of first choice.

Rhabdomyolysis is noted as a rare side effect in the product information for febuxostat (following post-marketing experience), but there has only been a single published case report.8 In our patient, a serious additional decline in renal function was marked by substantially elevated creatine kinase activity, suggesting that rhabdomyolysis had caused this decline. It is likely that the concomitant statin and fibrate hypolipidaemic medications (ie, simvastatin and gemfibrozil) that the patient had taken uneventfully for several years contributed to his myositis. Dehydration associated with the patient’s recent pneumonia probably also contributed to renal deterioration.

It is notable that in our case and that of Kang and colleagues,8 patients with chronic kidney disease had been taking statins both before and together with febuxostat. The combination of chronic kidney disease and statin therapy may represent a risk for febuxostat-induced rhabdomyolysis and renal injury.

The options for reducing this patient’s plasma urate levels — a critical goal, given his deteriorating renal function, progressive joint damage, and recurrent and severely painful acute gout — are quite limited. Febuxostat is now clearly contraindicated. Probenecid has limited efficacy when the glomerular filtration rate falls below 30 mL/minute. Benzbromarone, which is more effective than probenecid in patients with impaired renal function, can be obtained in Australia under the Special Access Scheme, and is a reasonable option. However, the patient’s hepatic function would need to be carefully monitored, as the medication was withdrawn from the market in Europe and North America after rare reports of serious hepatic toxicity.7 Recombinant forms of uricase (such as rasburicase, pegloticase) would undoubtedly be effective in reducing urate levels, but repeated use would be prohibitively expensive; further, there is a risk of developing antibodies to pegloticase, which results in reduced efficacy and the possibility of adverse effects.9 Desensitisation to allopurinol, although complex, time-consuming and not without risk, also remains an option.10

Lessons from practice

Options for reducing plasma urate levels to prevent recurrent acute and tophaceous gout are limited, especially in patients with impaired renal function.
Febuxostat is an effective alternative xanthine oxidase inhibitor to allopurinol.
Although the product information for febuxostat indicates that there is no need for dose adjustment in patients with moderate renal impairment, prescribers need to be cautious.
Chronic kidney disease and concomitant statin therapy may represent a risk for febuxostat-induced rhabdomyolysis and subsequent renal injury.

Figure

Time course of serum creatine kinase activity and estimated glomerular filtration rate (eGFR) in our patient. Arrows: Dialysis was undertaken on Days 3, 7, 10, 12 and 15.

State-based legal requirement for Schedule 8 prescriptions: why so complicated?

Inconsistent prescription requirements between Australian states and territories create unnecessary complexity for health professionals

In Australia, medicines defined as Schedule 8 (S8) under the Standard for the Uniform Scheduling of Medicines and Poisons are strictly regulated because of the high risk of misuse and/or physical and psychological dependence associated with them.1 They have to be prescribed, dispensed, documented and destroyed in specific ways that are in compliance with each state and territory’s different drug regulations. S8 medicines are under stricter control than Schedule 4 (S4) medicines (other prescription-only drugs), for which requirements have been standardised between states and territories.2,3

Australia has no central body to regulate the handling of S8 drugs. Although the Therapeutic Goods Administration (TGA) is the national body for the regulation of medicines, each state and territory self-regulates under the general principles established by the TGA and has its own interpretation and legislation regarding S8 drugs, resulting in varied prescribing requirements. The legal requirements for obtaining authority and writing prescriptions for S8 medicines are listed in Box 1 and Box 2: they are often difficult to find and are long and daunting to read.

Impact on practice

The establishment of a national registration agency, the Australian Health Practitioner Regulation Agency (AHPRA), in 2010 meant that Australian health professionals were allowed to freely practise in any state or territory. Greater mobility of health practitioners between jurisdictions has been accompanied by new problems.

First, to the best of our knowledge, prescribers newly relocated to a different state or who practise across more than one jurisdiction have no single, clear resource that documents the slight nuances in each state or territory’s regulations. Legal requirements for prescribing S8 drugs are not accessible in a prescriber-friendly manner. Pharmacists can guide prescribers on the regulations and legality of prescriptions; yet the same confusion applies to pharmacists who move interstate.

Second, travelling patients bringing an S8 prescription interstate might discover that a legal prescription in one state is not legal in another. The dispensing pharmacist would need to contact the medical practitioner in the patient’s home state to find a solution. If this could not be done, treatment would be delayed until a local prescription was obtained from a medical practitioner in the state the patient was visiting.

What can we do?

It may be impractical to unify health care legislation in Australia to eliminate the complexity. However, all states and territories could maintain individual regulations but unify the S8 legal requirements. Given that S4 requirements are standardised between the different states and territories, why are S8 requirements treated differently?

For the moment, resources highlighting state-based S8 requirements for prescribers should be made readily available. A comprehensive quick-reference guide, such as the table we provide here, minimises the ambiguity in legal requirements for health practitioners, and its use may also reduce the amount of time spent by pharmacists and doctors in correcting non-compliant prescriptions.

1 Current requirements of Australian states and territories for obtaining authority to prescribe Schedule 8 medicines

State or territory

Required authority

Australian Capital Territory4

Write “Standing short term approval” for treatment of less than 2 months. For treatment of longer than 2 months, write “CHO approval number” followed by approval number from the ACT Chief Health Officer

New South Wales5

From Director-General NSW Health for psychostimulants, alprazolam, methadone, buprenorphine, flunitrazepam and hydromorphone

Northern Territory6

None

Queensland7

None

South Australia8

From SA Minister for Health for more than 2 months of treatment13

Tasmania9

From Tas Secretary for Health for more than 2 months of treatment14,15 (1 month for alprazolam, prior approval for psychostimulants, fentanyl and hydromorphone)

Victoria10,11

May need a Drugs and Poisons Regulation Group permit to prescribe to drug-dependent patients

Western Australia12

From WA Department of Health Chief Executive Officer for more than 2 months of treatment

2 Current legal requirements for prescribing Schedule 8 medicines in each state of Australia

Australian Capital Territory4

New South Wales5

Northern Territory6

Queensland7

South Australia8

Tasmania9

Victoria10,11

Western Australia12

Prescriber

Name

✓

Address

✓

Phone no.

✓

Qualification

✓

Signature

Patient

Name

✓

H (with initials)

✓

Address

✓

Date of birth

✓

Medicine

Name

✓

H (description of the medicine)

✓

H (description of the medicine)

Form

✓

Not specified

✓

Not specified

Strength

✓

Not specified

Quantity

✓

H (in words and figures)

✓ (in words and figures)

H (in words and figures)

✓ (in words and figures)

H (in words and figures)

Direction

✓

No. of repeats

✓

H (in words and figures)

Interval for repeats

✓

Date

✓

Only one S8 drug per prescription*

Multiple items allowed

✓

Not specified

✓

Multiple items allowed

✓

✓ = required. x = not required. H = information that must be written in the doctor’s own handwriting. * Exceptions apply: different forms of the same drug are acceptable.

The crux of the matter: Did the ABC’s Catalyst program change statin use in Australia?

On 24 and 31 October 2013, the Australian Broadcasting Corporation (ABC) aired a two-part special edition of the science journalism series, Catalyst, titled Heart of the matter, that was critical of HMG-CoA reductase inhibitors (“statins”). The program questioned the link between high cholesterol levels and cardiovascular disease, and suggested that the benefits of statins had been overstated and the harms downplayed.1 Nearly 1.5 million Australians are estimated to have viewed each part of the program.2

Statins are recommended nationally and internationally both for primary prevention of cardiovascular events in people at increased risk of cardiovascular disease, and for secondary prevention in those with established cardiovascular disease.3,4 They are the most commonly prescribed medicines in Australia,5 used by over 30% of the population aged 50 years and older.6

Considerable media debate and backlash from the medical community followed the Catalyst program, including criticism for misleading patients.2,7 A National Heart Foundation survey of 1094 patients treated with lipid-modifying medications found that 11% of patients who watched Catalyst reported ceasing to take their cholesterol medicines, an additional 12% stopped taking them but restarted, and 12% reported starting to use “natural remedies”.8 Moreover, a survey by the Australian Capital Territory Government of general practitioners and pharmacists found that 58% reported that some of their patients had stopped taking their statins after the Catalyst program.9 Our purpose in this study was to quantify any changes in the dispensing of statins after the airing of the Catalyst program in October 2013.

Methods

We used dispensing records from the Pharmaceutical Benefits Scheme (PBS) — under which all citizens and permanent residents of Australia are entitled to subsidised access to prescribed medicines — from 1 July 2009 to 30 June 2014 for a 10% random sample of people who were dispensed a PBS-listed medicine. The 10% PBS sample is a standard dataset provided by the Australian Government Department of Human Services for analytical use, and is selected based on the last digit of each individual’s randomly assigned unique identifier. This dataset captures all dispensed PBS-listed medicines attracting a government subsidy, which occurs when the price of the medicine is above the PBS copayment threshold. To protect the privacy of people in this dataset, all dates of dispensing are offset randomly by + 14 or − 14 days; the direction of the offset is the same for all records for each individual.

We restricted our analyses to people for whom we had a complete PBS dispensing history for the entire study period. As many commonly dispensed statins fall below the general copayment threshold ($36.90 at 1 January 2014), but above the concessional copayment threshold ($6.00), we included only long-term concessional beneficiaries (ie, individuals dispensed only medicines attracting a concessional copayment during the 5-year study period). Long-term concessional beneficiaries represent about 51% of all people who are dispensed a statin, and consist of older people, those on a low income and the sick and disabled.

Medicines of interest

We included all doses (including combination products) of PBS-listed statins (atorvastatin, fluvastatin, pravastatin, rosuvastatin and simvastatin) and proton pump inhibitors (PPIs; esomeprazole, lansoprazole, omeprazole, pantoprazole and rabeprazole). PPI dispensing was chosen as the comparator as these medicines are commonly dispensed and are used by a similar population as use statins. In addition, we expected that PPI dispensing would be unlikely to be affected by the Catalyst program.

Measures

We defined discontinuation as the absence of any dispensing for a period of at least three times the number of pills last dispensed (assuming one pill per day) plus a 5-day grace period. Nearly all statin dispensing records (99.5%) were for a 30-day supply; therefore, in most cases, a period of 105 days or more without a statin dispensing record was considered a discontinuation. The date of discontinuation was the date that patients would have been expected to refill their prescriptions plus a 5-day grace period (ie, date of last dispensed statin + 35 days).

We classified individuals into four mutually exclusive risk categories. These were based on medicines dispensed for the treatment of cardiovascular disease (World Health Organization Anatomical Therapeutic Chemical [WHO ATC] codes C [excluding statins and topical agents for treating venous disorders] and B01AC), and diabetes (WHO ATC code A10). These risk categories were: (i) dispensed no other cardiac medicines and no diabetes medicines; (ii) dispensed 1–2 other cardiac medicines and no diabetes medicines; (iii) dispensed ≥ 3 other cardiac medicines and no diabetes medicines; or (iv) dispensed at least one diabetes medicine.

Statistical analysis

We used an interrupted time-series analysis to assess the impact of the Catalyst program on dispensing and discontinuation of statins. The date of the first part of the Catalyst program (24 October 2013) was the change point. For each week, we summed the number of dispensing records and the number of individuals who discontinued for statins and for PPIs, overall and stratified by risk category (statins only). We defined a week as starting on Thursday, the day that Catalyst aired. Data were log-transformed to estimate the percentage change.

PBS dispensing data are highly seasonal;10 once an individual or family’s out-of-pocket PBS expenses exceed the PBS Safety Net threshold for a calendar year, all PBS medicines have a reduced copayment until 31 December of that year. To account for this seasonal variability, as well as long-term trends and autocorrelation, we modelled the time series using an autoregressive integrated moving average (ARIMA) approach, using the Box–Jenkins method11 (Appendix). We created individual ARIMA models for overall dispensing (statins and PPIs), for discontinuation (statins and PPIs), and for dispensing and discontinuation within each risk category (statins only).

We estimated the average number of dispensings of statins per week in Australia (including statins falling below the copayment) in the 3 months before the Catalyst program aired using publicly available aggregated dispensing data.12 These data were used to estimate the impact of the Catalyst program on all statin users, not just people included in the 10% PBS sample.

All analyses were performed in SAS, version 9.3 (SAS Institute Inc), and Stata, version 12 (Statacorp).

The study was approved by the New South Wales Population and Health Services Ethics Committee (2013/11/494) and the Department of Human Services External Request Evaluation Committee.

Results

In our sample, 191 833 people were dispensed a statin from 1 July 2009 to 30 June 2014, with a mean of 26 946 statin dispensings weekly (range, 23 505 to 30 465). The average age of statin users in our study sample in 2013 was 72 years (SD, 12 years), and 55% were women. Thirteen per cent of our study population were dispensed no other cardiac or diabetes medicines, 25% were dispensed 1–2 cardiac medicines and no diabetes medicines, 36% were dispensed ≥ 3 cardiac medicines and no diabetes medicines, and 27% were dispensed diabetes medicines (93% of whom were also dispensed at least one cardiac medicine).

The overall trend in dispensing was relatively stable, with the highest dispensing counts in November and December, and lowest in January and February owing to individuals reaching their safety net threshold and preferentially refilling their prescriptions more frequently at the end of the calendar year. Raw dispensing counts and counts adjusted for seasonal variation are presented in Box 1 (A). Rates of discontinuation follow a similar pattern, with an increase at the beginning of every year Box 1 (B).

Dispensing

The week the Catalyst program was aired, we found a significant sustained change of 2.60% fewer statin dispensings per week (Box 2). Given that there are an average of 538 640 statin dispensings per week in Australia,12 this corresponds to an estimated decrease of 14 005 dispensings per week in the Australian population. Assuming that most users are dispensed statins once a month, the equivalent of 60 897 Australians would be affected.

We found a significant reduction in the rate of statin dispensings in all risk categories (Box 2), with 6.0% fewer statin dispensings per week to people with no evidence of taking other cardiac or diabetes medicines and 1.9% fewer dispensings to those with evidence of taking diabetes medicines.

We also identified a decrease in statin dispensing of 1.96% (95% CI, 1.12%–2.79%; P < 0.001) starting the week of 1 March 2012, which coincided with the publication of a news story about the risk of diabetes and dementia associated with statin use;13 the level of statin dispensing returned to expected levels in March 2013.

We found no significant change in the number of PPIs dispensings in the period following the Catalyst program (0.08%; 95% CI, − 1.53% to 1.71%; P = 0.92).

Discontinuation

The number of people discontinuing their use of statins increased by 28.8% (P < 0.001) in the week that the Catalyst program aired, and this effect decayed by 9% (P < 0.001) per week, returning to average levels after 18 weeks (Box 3). On average, 1.8% of statin users discontinued using statins each month before the Catalyst program aired; thus, following the Catalyst program, an estimated 28 784 additional Australians discontinued their use of statins. A significant increase in discontinuation was observed regardless of the use of other cardiovascular and diabetes medications (Box 3).

In addition, we observed an increase in discontinuation after the 2012 news story,13 peaking at 29.0% (95% CI, 19.1%–39.6%; P < 0.001) and decaying by 8% each week thereafter, lasting 21 weeks.

There was no apparent change in PPI discontinuation following the airing of the Catalyst program.

Discussion

We found significant and sustained changes in statin dispensing following the airing of the Catalyst program — 2.6% fewer statins were dispensed every week (a total of 504 180 fewer dispensings of statins), which equates to 60 897 Australians having been affected up to 30 June 2014, as a result of increased discontinuation, decreased initiation and/or poor adherence. This includes an estimated 28 784 additional people who discontinued their statins.

On average, among all statin users, the number-needed-to-treat over 5 years to prevent one major vascular event such as a myocardial infarction or stroke ranges from 21 (for those with pre-existing coronary heart disease) to 40 (for those without).14 It is unclear how long the change in statin use that we observed is likely to last. If the 60 897 individuals we estimated to have been affected continue to be non-adherent, this could result in between 1522 and 2900 preventable, and potentially fatal, major vascular events. While statins have been shown to reduce cardiovascular events regardless of an individual’s absolute cardiovascular risk,15 national guidelines recommend their use in those who have had a previous cardiovascular event and in those at moderate or high absolute cardiovascular risk.16 There is evidence that, in Australia, statins are both underused in those at high risk and overused in those at low risk.17 Some of the observed reduction in use may result from patients at low absolute risk of cardiovascular disease ceasing therapy.

However, individuals who did and did not concomitantly take cardiovascular and diabetes medications had reduced their use of statins after the Catalyst program aired. This includes individuals likely to be at high cardiovascular risk, such as those with diabetes; the proven and substantial efficacy of statins in this group means they can least afford to discontinue therapy.18,19

Many elements of the Catalyst program’s contents were inconsistent with the recommendations of key medical advice about statins and cardiovascular disease3 and the ABC has since withdrawn the program, primarily on the grounds that it breached their impartiality standards.20 The program was watched by a substantial proportion of the Australian public and is likely to have influenced their beliefs about the risks and benefits of statins and the relationship between high cholesterol and cardiovascular disease. Belief in the effectiveness of medication and the need for treatment are important predictors of adherence to lipid-lowering medications.21 The National Heart Foundation’s survey of users of lipid-modifying agents found that, compared with those who were unaware of the program, those who watched it were more likely to express concerns about taking their cholesterol medicines, and a desire to stop.8

Our study is not the first to show the impact of adverse media reports on prescribed medicine use in Australia. A 2007 television news program about the association between osteonecrosis of the jaw and bisphosphonate use was associated with 29 633 fewer prescriptions.22 Further, our incidental finding of a reduction in statin dispensing in 2012 that coincided with a news story about the risks of diabetes and dementia demonstrates the long-lasting impact of such publicity; statin dispensing only returned to average levels after a year.

The strength of our study lies in the use of a representative sample of all Australians ever dispensed a PBS-subsidised medicine, and the use of a long-term concessional beneficiary population, ensuring complete capture of statin dispensing. Analyses of time-series data can be problematic because of high levels of autocorrelation, underlying trends, and seasonality. While PBS dispensing data are particularly seasonal, the ARIMA approach is well established and ideally suited for dealing with these problems.11,23 Further, although the lack of change in PPI dispensing supports the idea that the changes in statin dispensing were in response to the Catalyst program, we cannot rule out other factors affecting dispensing behaviour during this study period. We also saw no change in non-statin lipid-lowering medicines (data not shown). We also did not know the exact dates of dispensing, as all dates were offset by 2 weeks, but this would be expected to bias our findings towards the null. Lastly, while we categorised individuals based on other cardiovascular and diabetes medicines they were dispensed, it is not possible to know their true level of cardiovascular risk without additional information, such as blood pressure and smoking status, which was not available in our study.

We estimated the change in the use of statins after the airing of the Catalyst program in all Australians who were prescribed statins based on findings in our study sample. However, as the Australian non-concession population is younger, has higher socioeconomic status, and is in better health than the long-term concession population, they probably have a lower risk of cardiovascular events and a higher risk of not adhering to their statin regimen. Consequently, we may have underestimated the population-level impact on dispensing.

As of mid 2014, there is no indication that the change in dispensing after the Catalyst program has abated. Even though the observed effect was relatively small, the prevalence of statin use in Australia and the established efficacy of these drugs14,22 means that a large number of people are affected, and may suffer unnecessary consequences. The changes in statin use occurred despite warnings in the Catalyst program that its content should not be taken as medical advice, and public criticism of the program. The subsequent retraction of the program may counteract some of the apparent negative impact, but this remains to be seen.

1 Weekly unadjusted and seasonally adjusted (A) dispensing counts and (B) number of people discontinuing use of statins and proton pump inhibitors (PPIs), 1 July 2009 to 30 June 2014

2 Autoregressive integrated moving average (ARIMA) modelling results* of the impact of the Catalyst program on statin dispensing

Population

Mean weekly dispensings 12 weeks before Catalyst

Weekly change in number of dispensings

% (95% CI)

Overall

27 536

− 2.60 (− 3.77 to − 1.40)

< 0.001

No cardiac or diabetes medicines

2 549

− 6.03 (− 8.28 to − 3.73)

< 0.001

1–2 cardiac medicines and no diabetes medicines

6 602

− 2.77 (− 4.54 to − 1.06)

0.002

≥ 3 cardiac medicines and no diabetes medicines

10 252

− 2.40 (− 3.34 to − 1.46)

< 0.001

Diabetes medicines

8 133

− 1.94 (− 3.45 to − 0.42)

0.01

* ARIMA specification, (3,1,1)(3,1,1)52.

3 Autoregressive integrated moving average (ARIMA) modelling results of the impact of the Catalyst program on the number of people who discontinued their use of statins

Population

Mean weekly number of discontinuers 12 weeks before Catalyst

Peak change in discontinuation

Weekly
decay

Duration of effect*

Time to peak

% (95% CI)

Overall†

576

0 weeks

28.8% (15.4% to 43.7%)

< 0.001

18 weeks

No cardiac or diabetes medicines†

0 weeks

72.2% (27.3% to 133.0%)

< 0.001

16%

16 weeks

1–2 cardiac medicines and no diabetes medicines†

143

0 weeks

58.4% (28.6% to 95.1%)

< 0.001

12%

20 weeks

≥ 3 cardiac medicines and no diabetes medicines‡

186

1 week

30.5% (11.1% to 53.3%)

0.001

13%

14 weeks

Diabetes medicines†

161

2 weeks

38.6% (13.3% to 69.6%)

0.002

40%

5 weeks

* The impact was considered to have ended when it decayed to ≤ 5%. † ARIMA specification, (0,1,1)(0,1,1)52. ‡ ARIMA specification, (0,1,2)(0,1,2)52.

Knowing when to stop antibiotic therapy

To the Editor: The recent article by Gilbert usefully drew attention to the the harms that can arise from unnecessarily long courses of antibiotics.1 It was of particular interest that she highlighted the misconception that resistance will emerge if a course of treatment is not completed.

Australian health professionals commonly advise patients verbally to complete antibiotic courses, and professional guidance for pharmacists specifically recommends annotating dispensing labels with the words “until all used” or “until all taken”.2 This recommendation appears to be widely implemented based on our analysis of de-identified dispensing records collected as part of the PROMISe III trial.3

This dataset contains over 11 000 dispensings for the two most widely prescribed antibiotics in Australia, cephalexin and amoxycillin.4 Dispensing directions included a reference to completing the course in 87.9% and 91.7% of prescriptions for these two drugs, respectively.

The impact of advice to complete antibiotic courses is likely to be magnified in Australia by two further system factors, namely the poor alignment of pack sizes with clinically appropriate course durations and the widespread practice of prescribing antibiotics with repeat prescriptions.5

A significant change in both professional practice and the arrangements under the Pharmaceutical Benefits Scheme will therefore be necessary if we are to avoid perpetuating current habits, which may be contrary to efforts now being made to improve antimicrobial stewardship.

AMA proposes pharmacy and GP team to improve patient care

The AMA has provided the Federal Government with their proposal to integrate non—dispensing pharmacists as a key part of the general practice health care team.

According to AMA President, A/Prof Brian Owler, the ‘Pharmacist in General Practice Incentive Program (PGPIP)’ would create greater efficiencies for general practices, better care for patients, new career opportunities for pharmacists, and significant Budget savings across the whole health system.

“Under this program, pharmacists within general practice would assist with things such as medication management, providing patient education on their medications, and supporting GP prescribing with advice on medication interactions and newly available medications,” A/Prof Owler said.

“Evidence shows that the AMA plan would reduce fragmentation of patient care, improve prescribing and use of medicines, reduce hospital admissions from adverse drug events (ADE), and deliver better health outcomes for patients.”

The proposal is backed by an independent analysis from the highly respected Deloitte Access Economics, which shows that the AMA proposal delivers a benefit-cost ratio of 1.56, which means that every $1 invested in the program generates $1.56 in savings to the health system.

Deloitte Access Economics estimates that, if 3,100 general practices took up the PGPIP, it would cost the Federal Government $969.5 million over four years. However, this would be more than offset through broader savings to the health system in the following areas:

hospital savings of $1.266 billion – due to reduced number of hospital admissions following a severe ADE;
PBS savings of $180.6 million – due to the reduced number of prescriptions from better prescribing and medication compliance;
individual patient savings of $49.8 million – reduced co-payments for medical consultations and medicines; and.
MBS savings of $18.1 million – due to reduced number of GP attendances following a moderate or severe ADE.

The AMA has developed this model in consultation with the Pharmaceutical Society of Australia (PSA), and it has the full backing of the PSA.

The AMA proposal for the Pharmacist in General Practice Incentive Program (PGPIP), including the Deloitte Access Economics analysis, is at https://ama.com.au/article/general-practice-pharmacists-improving-patient-care

Proton pump inhibitors: too much of a good thing?

Proton pump inhibitors (PPIs) are a mainstay in the management of acid peptic disorders; they are highly effective at relieving symptoms and are generally well tolerated. However, there is growing international concern about their increasing use. Long-term use is only recommended in specific clinical situations, yet data indicate that this accounts for the majority of total use and large numbers of PPI users do not actually have a clear indication for therapy (http://www.nps.org.au/publications/health-professional/medicinewise-news/2015/proton-pump-inhibitors).

A big problem is that once people are on a PPI, therapy is often not stepped down appropriately. Up to 30% of patients may be able to stop PPI therapy after the initial course of therapy without experiencing symptoms, but a step-down approach is not necessarily part of their ongoing management. Overuse of PPIs may increase risks of adverse effects and incur unnecessary costs for both taxpayers and individuals.

While PPIs are generally considered safe, there are reports (mostly from observational studies) about more serious, albeit rare, adverse events associated with their use, including enteric infections, pneumonia, fractures and acute interstitial nephritis. While reports are insufficient to establish a causal relationship, they may warrant consideration, especially against a backdrop of significant overprescribing of PPIs.

In the past decade, at least two PPIs have featured annually in the top 10 most prescribed Pharmaceutical Benefits Scheme (PBS)-subsidised medicines and, in the 2013–14 financial year, over 19 million prescriptions were issued, most of these for managing gastro-oesophageal reflux disease. The most commonly prescribed PPI in 2013–14 incurred a cost of over $200 million to the PBS.

NPS MedicineWise has recently published a suite of free resources (http://www.nps.org.au/heartburn-and-reflux) to support quality use of PPIs, including a symptomatic management pad for use with patients, and a clinical e-audit and interactive online case study (Continuing Professional Development points available).