Opioids and benzodiazepines are frequently prescribed medications that carry a high risk of dependency and are commonly misused. Long-term use of these agents is associated with significant harm to the individual such as exacerbating the patient’s original symptoms, increasing mortality, and negatively impacting the community by contributing to road trauma. This paper will begin by outlining the regulation of drugs of dependence in Australia and defining misuse, dependency, and associated harms. The evidence for use of these drug classes will then be presented, with reference to best practice guidelines. Finally, the discrepancy between guidelines and prescribing behaviours will be highlighted with reference to specific challenges associated with drugs of dependency. It will be emphasised that doctors, especially the newer generations, have a responsibility to own the problems of drug misuse, and to impact individuals and the community through advocacy and evidence-based clinical governance. It will be shown that whilst opioids and benzodiazepines are effective short-term medicines, there is little support for long-term prescribing. If we are to turn the tide on drug dependency and misuse, change is needed in modern prescribing behaviours to achieve the best long-term outcomes for patients.

The problem

The most commonly misused prescription drugs in Australia are opioids and benzodiazepines, including z-drugs (zolpidem, zopiclone, and zalephon), which are non-benzodiazepines that act on the same receptors [1-3]. Access to these drugs is restricted by the Australian Therapeutic Goods Association Drug Schedule, which determines availability for public consumption [4]. Drugs of dependency include all Schedule 8 drugs (controlled drugs, such as opioids) and some Schedule 4 drugs (prescription only medicines, such as benzodiazepines) [5]. Such restrictions are regularly reviewed and subject to change. For example, alprazolam, a potent benzodiazepine with high toxicity [6], was made Schedule 8 in early 2014 due to a rise in illicit use [7], and there is current debate about the appropriateness of Schedule 4 for codeine, because of increasing codeine-related deaths [8,9].

Drug misuse is an important umbrella term to define in relation to the problems associated with drugs of dependency. Five main categories, that are not mutually exclusive, emerge in the literature:

1. Overuse: Higher dose or dose frequency than prescribed; often due to tolerance and self-adjusted dosing over long-term use [3].
2. Abuse: Overuse with the goal of intoxication [3].
3. Prolonged use: An emerging problem involving continued therapy to achieve a sense of normality. Such individuals have been termed the “hidden population” [2-3]. Similarly, the term “accidental addicts” has emerged in popular media, referring to individuals who become dependent on pharmaceuticals with continued use. Prescribers must be hypervigilant for these patients as they are often of high socioeconomic status and highly functional, in contrast to traditional drug-seeking stereotypes [10].
4. Substance use disorder: This is a formal diagnosis in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) based on eleven symptomatology criteria across four categories (impaired control, social impairment, risky use and pharmacology) [11]. For diagnosis, use must cause clinically significant distress or impairment and occur within a twelve-month period [11].
5. Dependency: A syndrome in which an individual has: (i) a strong drive to use a substance; (ii) difficulty regulating their use; (iii) tolerance; and (iv) withdrawal symptoms on cessation [12].

Opioids and benzodiazepines are included on the World Health Organization list of essential medicines [13], indicated primarily in pain or palliative care (opioids), and anxiety disorders, seizures, acute insomnia, and alcohol withdrawal (benzodiazepines) [3].  Availability of opioids and benzodiazepines has been steadily increasing in recent decades. The number of opioid-dispensing episodes increased from 500,000 to 7.5 million from 1992 to 2012 [14]. Harrison and colleagues evaluated 4666 encounters with general practitioners (GPs) between 2010 and 2011 in which opioids were prescribed or supplied [15]. They found that 3.5% of opioids were prescribed for cancer pain, 43.9% were prescribed for chronic non-cancer pain, with the remainder being prescribed for indications classified as non-chronic [15]. For benzodiazepines, approximately 7 million scripts are written annually [16]. The 2013 National Drug Strategy Household Survey found that 3.3% of people aged 14 or over had used analgesics and 1.6% had used tranquillisers or sleeping pills over the past year for non-medical purposes, with both increasing over each three-yearly iteration of the survey since 2001 [17]. With problematic usage and availability of these drugs in the community (through either personal prescription or diversion), the harm associated with misuse has become increasingly apparent. There is a great degree of harm caused by opioid and benzodiazepine misuse to the individual and community (Table 1).

Table 1: Harms to the individual and community associated with opioid and benzodiazepine misuse

Harms	Opioids	Benzodiazepines
Individual	High risk of dependence [18] and misuse [2]	Extremely habit forming: tolerance and dependence can occur in 2-4 weeks [31-33]
	Physiological effects Constipation [19] Biliary dyskinesia [19] Cognitive impairment [19] Increased risk of death [20]/overdose (including inadvertent childhood ingestion) [2] Sleep apnoea [21] Sexual and endocrine dysfunction [22] Immunosuppression [23] Opioid-induced hyperalgesia [24] Osteoporosis/increased fracture risk [2] Dental caries and necrosis secondary to xerostomia [2] Impaired cognition [2]	Physiological effects Insomnia [7] Anxiety [7] Depression [34] Poor memory and concentration [35] Excessive / daytime sedation [36] Risk of ataxia and falls, disinhibition and amnestic effects [36] Cognitive impairment [37]/decline and dementia [38] Increased mortality with long term use [39]
	Codeine: gastric bleeding [25], severe metabolic imbalances [26-28], and risk of death [8]	Z-drugs: potentially dangerous complex sleep behaviours [16]
	Harms with intravenous abuse:  blood clots, amputation, and serious soft tissue injuries [29,30]	Harms with intravenous abuse:  blood clots, amputation, and serious soft tissue injuries [29,30]
Community	Diversion [40] Low levels of organised crime [41] Driving impairment and motor vehicle accidents [42,43] Doctor shopping affecting GPs [3]	Diversion [7] Low levels of organised crime [41] Driving impairment and motor vehicle accidents [42,43] Doctor shopping impacting GPs [3] Criminal activity through precipitating aggression and disinhibition [41]

Opioids and benzodiazepines are highly habit-forming and potentially destructive to the individual and society. Physiological side effects of long-term use of both drug classes significantly reduce quality of life and contribute to personal suffering through symptoms such as constipation and balance derangement contributing to falls. Further, opioids and benzodiazepines are both associated with increased mortality. This is through means such as deliberate overdose, accidental overdose, and motor vehicle accidents secondary to impaired driving ability [2,42,43]. In Victoria, overdose deaths involving prescription drugs outnumber deaths from road trauma [44], and alcohol and drug helplines receive nearly threefold more calls regarding prescription opioids than heroin [45]. Importantly, an Australian study investigating 320 oxycodone related deaths reported that 52% were due to unintentional overdose, 20% were deliberate self-harm, and the remainder either awaiting coronial enquiry or with indeterminable intent [46]. Victorian coronial data indicate that benzodiazepines are at least contributory in 48.8% of all drug-related deaths [47]. As such, long-term opioid and benzodiazepine use is associated with a very real increase in mortality, not only in people with the intent to self-harm. Overall, opioids and benzodiazepines carry a high risk of dependence, cause a wide range of physiological harms including increased mortality, and they negatively affect the community through diversion and contributing to motor vehicle accidents.

The evidence

Current evidence supports short-term use of both opioids and benzodiazepines for appropriate indications (for example, less than 90 days and one month, respectively). These drugs are effective when used properly and should be available for people who need them. Long-term use, however, is not supported by evidence for the indications for short-term use. Both classes of medications are known to be highly addictive and associated with poor long-term outcomes if use is not time limited. Notably, recent studies suggest that psychobehavioural interventions are at least equivalent to, or more effective than, pharmacotherapy for pain, anxiety, and insomnia [48-50].

Opioids have convincing evidence supporting their use in acute pain [51], cancer pain [52], palliative care, [53] and addiction [54]. Most of the controversy in opioid prescribing relates to use in chronic non-cancer pain, with reviews suggesting little short-term efficacy [55], and tolerance and opioid-induced hyperalgesia occurring with prolonged use [56]. Furthermore, a Cochrane Database review showed no clear gains in pain and functional outcomes when opioids were used long-term [57], and another study found no significant correlations between opioid dose adjustment and clinical pain scores over time [58]. In line with the biopsychosocial conceptualisation of chronic non-cancer pain, multimodal approaches using non-pharmacological strategies such as exercise and psychological interventions have been shown to be superior to monomodal regimens in terms of long-term impact [59]. Cognitive behavioural therapy (CBT) is recommended as first line psychosocial treatment for chronic, non-cancer pain [60]. A Cochrane review in 2012 found that CBT conferred significant improvement in pain, disability, mood, and catastrophising in comparison to wait-list controls [61]. Effect sizes were small to moderate and the only sustained impacts were seen on mood.

Short acting benzodiazepines and z-drugs are effective at managing acute insomnia [62], generalised anxiety disorder, social anxiety, and panic disorder [63]. Dependency can be rapid (for example, within 2 to 4 weeks) [64] and increased mortality has been associated with long-term use [39]. Unfortunately, randomised controlled trials for long-term use are of inadequate duration (approximately 3 months), and lack representative clinical samples [16]. Reassuringly, however, it has been shown that the majority of patients on benzodiazepine therapy for sleep and anxiety do not increase their doses over time [65]. Moreover, a recent three year follow-up study of users of benzodiazepines and z-drugs found less than 1% of patients developed problems with excessive use, which predominated in patients with a significant drug and alcohol history and increased with duration of therapy [66]. This suggests that careful evaluation of patients to identify those at risk of excessive use is important, and that monitoring and cessation plans at first prescription may be protective for this population. Of note, this paper did not assess experience of adverse effects or harms associated with long-term use of benzodiazepines. Instead, it focussed on excessive use only, defined as more than two daily doses over a three month period.

Insomnia treatment is generally recommended to proceed in a stepwise fashion, with initial management emphasising basic sleep hygiene education and stimulus control, with the latter supported by randomised controlled trial evidence for long-term efficacy [67]. If insomnia persists, more involved behavioural interventions, either with or without medications, should be offered. CBT combines sleep hygiene education, stimulus control, and progressive muscle relaxation into a cognitive therapy framework to address insomnia. A recent meta-analysis of randomised controlled trials has shown lasting benefits for establishing sleep, wake times, and sleep efficiency [68]. However, total sleep time was not significantly increased and the patient samples excluded those with medical and psychological comorbidities. As such, the magnitude of the effects needs to be interpreted with caution. CBT is recommended as first line treatment for insomnia by the Royal Australian College of General Practitioners (RACGP) and the British Association for Pharmacology [69] on the basis of previous systematic reviews, which have included randomised controlled trials and patients with medical and psychiatric comorbidities and shown reliable and sustained improvements on sleep parameters [70]. Similarly, in the treatment of anxiety disorders, CBT is supported by meta-analysis of randomised controlled trials [71] and is recommended as first line therapy, either as monotherapy or in combination with antidepressant medication [72].

Current guidelines are in line with the evidence base for long-term prescribing of opioids and benzodiazepines in Australia. The RACGP published two comprehensive documents in 2015 about prescribing drugs of dependency (with particular reference to benzodiazepines) that summarise best evidence, provide concrete guidance and examples of difficult consultations, and ways in which they can be safely and effectively negotiated [5,16]. For opioid prescribing in chronic, non-cancer pain, the Hunter Integrated Pain Service provides additional evidence-based guidelines [19]. An overview of the key prescribing guidelines can be extracted from these documents (Table 2).

Table 2: Summary of guidance for opioid and benzodiazepine prescribing from Australian evidence-based guidelines

Guideline	Authors	Summary of recommendations
Prescribing drugs of dependence in general practice, part A – clinical governance framework* [5]	RACGP	Maintain and develop skills in chronic pain, mental health, drugs of dependency (DOD) and optimise non-pharmacological interventions Inform patients DOD should be prescribed from one practice, one GP and dispensed from one pharmacy In complex cases or if situations deteriorate, be prepared to utilise specialist support Prescribing for drug dependent patients must be based on comprehensive assessment and an authority must be sought when prescribing a Schedule 8 drug Patients have the right to respectful care that promotes their dignity, privacy, and safety Provide patients with information about the purpose, realistic expectations, options, and benefits and risks Develop respectful, non-judgemental, and clear responses to inappropriate requests for DOD
Prescribing drugs of dependence, part B – benzodiazepines[16]	RACGP	Prescription of benzodiazepines (BZDs) should be with the lowest dose and shortest possible timeframe, continual monitoring, and careful consideration of risks and benefits Discuss with patients the potential for dependence, withdrawal, misuse, and known harmful effects such as falls, cognitive decline, and motor vehicle accidents Avoid prescribing to patients with comorbid alcohol or substance use disorders (these patients are more vulnerable to major harms) Use beyond four weeks should be uncommon, if no alternatives are available, long-term use must be supervised with regular attempts at reduction For insomnia, first line should be non-pharmacological (e.g. CBT) and BZDs/Z-drugs only given on an individual basis, with short-term, intermittent dosing For anxiety disorders, first line therapy should include CBT; SSRI/SNRI are suitable first line pharmacological treatments BZD use in anxiety disorders is mostly limited to severe or treatment resistant cases Short term BZD use as occasional adjunctive therapy may be effective at reducing symptoms in the first few days to weeks of SSRI/SNRI therapy BZD discontinuation can be achieved with minimal interventions (such as GP advice/advisory letters), strong therapeutic alliance and psychological therapies
Reconsidering opioid therapy: a Hunter New England perspective [19]	Hunter Integrated Pain Service	Opioid therapy is indicated for acute pain; cancer pain, palliative care; opioid dependency/addiction – NOT chronic, non-cancer pain Multidimensional pain assessment is recommended for all types of pain A drug and alcohol history, use of the risk assessment tools to gauge the risk of opioid misuse and contact with the Australian Prescription Shopping Information service is recommended Opioid therapy for acute pain: Should be time limited and coordinated between hospital and primary care Can usually be ceased within one week of surgery or injury if possible, and weaned and ceased within 90 days in complex cases A daily oral morphine equivalent dose of 100 mg should not be exceeded in primary care A treatment agreement explaining potential benefits, adverse effects, and duration of therapy should be used, with pain and functional outcomes measured Review therapy regularly with the “four A’s”: Analgesia, Activity, Adverse effects, and Aberrant behaviour Should be prescribed with ongoing non-pharmacological supportive care and a focus on evidence-based self-management strategies Involvement of a pain medicine specialist and multidisciplinary pain management team may be helpful Opioid naïve patients prescribed opioids and patients on long term opioids and BZDs should not drive

*These guidelines also provide recommendations for clinical governance and general practice systems of care not summarised here.

The need for evidence-based prescribing behaviours

Evidence does not support long-term therapy with opioids and benzodiazepines. This has been known for some years, yet the problem has only grown. Future generations of practitioners need to engender practice in accordance with guidelines, enhance utilisation of alternative, non-pharmacological interventions, and strive for better patient outcomes.

Consultations that involve the consideration of drugs of dependence present significant challenges to the GP, and usually involve complex and vulnerable patients. GPs report complicating factors such as time pressure, concerns about patient autonomy, patient-centred care and preserving the doctor-patient relationship [73-75]. Studies have shown that GPs have some ambivalence towards prescribing benzodiazepines and may lack consistency in their approach [73]. There is also referral to the notion of the “deserving patient” in the literature, whereby doctors ask themselves whether the patient deserves a prescription rather than whether they should write one [76]. Indeed, it has been reported that some GPs will provide benzodiazepines even when they do not believe it will help, giving reasons such as: having no realistic alternatives; assumptions about the patients’ expectations; problems in saying no; and succumbing to pressure [16]. Importantly, research indicates that many doctors assume that patients want prescriptions or would resist attempts at withdrawal whilst, in fact, patients report wanting explanations and discussion [73,77].

Inevitably, there is often a discrepancy between clinical guidelines and practice. There is some disagreement in the literature regarding the usefulness and clinical impact of best practice guidelines, with some findings demonstrating improved and more consistent management [78,79], whilst others show minimal impacts [80]. Recent studies are suggesting that GPs perceive clinical practice guidelines with a positive attitude [81], but that there are inconsistencies regarding which components are followed [82]. Research into the appropriate prescribing of antibiotics suggests that inappropriate prescribing is more likely to occur in high-volume practices and by those who have been in practice longer [83]. As such, to improve concordance with guidelines, it will be important for junior doctors to emerge into the workplace as proponents of evidence-based prescribing. They should take advantage of their training period, where case loads are lower, to ingrain safe prescribing habits and good clinical governance into their practice. Obviously, there is more to appropriate prescribing than simply following guidelines. There is an art to handling challenging consultations, conveying evidence in a meaningful way, inspiring trust in your patient, and establishing a collaborative management plan, which may or may not meet the patient’s original expectations. In light of this, there are some additional consultation techniques that may facilitate safe prescribing for junior doctors (Table 3).

Table 3: Practical advice for managing patients and drugs of dependency

Areas of Development	Strategies
Professional Knowledge	Engage in continuing medical education for drug dependence and safe prescribing Develop skills in cognitive behavioural strategies and structured problem solving [84,85] Familiarise with typical patient requests and responses from examples [5,16]
Consultation Skills   Time spent in early consultations will save time long-term	Encourage non-pharmacological measures Assess risk/benefits of any drug prescribed Make collaborative decision making for prescribing and non-prescribing [5] Prescribe only for supported indications Prescribe with plan for reduction [5] Be honest and explore issues [5] Involve the patient’s supports [5] Monitor use and look for signs of dependency (review ‘five As’) [5] Identify problem use and refer to specialist services [5] Provide written management plan and fact sheets [5] Seek advice if unsure
Resources	Withdrawal scales for alcohol [86], opioids [87], and benzodiazepines [88] Therapeutic Guidelines for withdrawal management Opioid risk tool [89] Specialist drug and alcohol services NPS MedicineWise Key Points for managing chronic pain [90] The patient’s pharmacist [91] Local support groups Medicare Australia prescription shopping information service (ph. 1800 631 181) [2]

Junior doctors and emerging medical professionals have the power to be agents of change in the evidence-based management of conditions such as chronic, non-cancer pain; anxiety; and insomnia. Doctors in training are often the most up-to-date on evidence-based guidelines in these areas, with greater emphasis on non-pharmacological management and multidisciplinary collaboration in undergraduate and postgraduate programs than in generations past. In addition, medical school curriculums have been modified to promote highly developed communication skills in graduates that are crucial to the ability to inspire motivational change in patients. As highlighted in Table 3, doctors can up-skill by developing their professional knowledge and consulting skills, and engaging with the wealth of resources available to them. Continuing medical education is paramount and skills in cognitive behavioural strategies such as goal setting and structured problem solving, mindfulness strategies, and motivational interviewing are vital to being an effective clinician. In addition, the RACGP provides examples of consultations and scripted responses to common questions such as “I need something to help me sleep” or “I want medication”, which are helpful for the emerging practitioner whilst they are still building clinical experience [16]. In the consulting room, the junior doctor can advocate evidence-based, non-pharmacological approaches; conduct appropriate risk assessment for dependence; and prescribe appropriately with reduction plans already in place. The ‘five As’ of pain medicine (Analgesia, Activity, Adverse effects, Aberrant behaviour, and Affect) provide a useful framework for assessing risk of dependence [5].

It is best practice to seek advice when there is suspicion of problematic use, and link patients in with specialist services. Managing patients who are substance dependent is highly challenging. Leveraging support organisations, specialist alcohol and drug services, community pharmacists, and prescription tracking services provides greater likelihood of positive patient outcomes. Furthermore, it will protect the primary medical professional from burnout.

In order to improve patient outcomes, doctors need to begin raising patient awareness of the likelihood and seriousness of adverse effects of these medications, and enthusiastically advocate and facilitate evidence-based treatments. Moreover, the right treatments need to be provided for the right indications. This is, after all, at the heart of patient-centred care, rather than allowing motivated and vulnerable patients to choose their own treatment.

Conclusion

While current prescribing behaviours are understandable because of patient expectations and time pressure, particularly limiting the opportunity for patient education, this is an area that will need to be addressed in the current generation of training doctors. Guidelines to assist in this have been provided in this paper along with some practical strategies that can be implemented to drive the changes necessary to improve patients’ long-term outcomes. Whilst opioids and benzodiazepines are drugs of dependency, neither the doctor nor the patient should depend on these drugs to treat a long-term problem that can be resolved, or at least managed, with other effective evidence-based treatments.

Acknowledgements

None.

Conflicts of interest

None declared.

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With a concerning number of individuals with serious health conditions favouring homeopathic medicines over conventional treatment, Australia’s National Health and Medical Research Council (NHMRC) recently declared that homeopathy was not efficacious for treating any health condition.  Given homeopathy has existed  since the 18^th century as an alternative medical approach to treatment, the declaration naturally sparked tension with leading homeopathic authoritative bodies and practicing homeopaths.  This article aims to review the laws and regulations underpinning homeopathy and its preparations in Australia, and critically appraises the opinions of major organisations for and against the use of homeopathic medicines in treating serious health conditions.  It provides a brief overview of how clinicians can address the issue of using homeopathic remedies as an alternative to mainstream medicine with patients.  Despite the positions of two leading homeopathic authoritative bodies, the Australian Homeopathy Association and Complementary Medicines Australia, against the NHMRC declaration; there is strong evidence to suggest the need for stricter industry regulations of homeopathic practice and preparations in Australia so as to maximise the health and safety of consumers.  There is also strong scientific evidence to suggest that homeopathic remedies are unlikely to have clinical effects beyond placebo.  Given this, it is up to clinicians to educate their patients and provide them with all the relevant information to not only maximise their health outcomes but also facilitate well-informed decision making regarding homeopathy.

Introduction

Homeopathy, a branch of complementary and alternative medicine founded in the 18^th century, is commonly used in Australia and worldwide on a regular basis as a form of treatment for a number of health conditions.  It is based on two principles: 1) minute doses of substances that mimic illness or symptoms in healthy individuals can be used to treat the same illnesses or symptoms in those who are unwell; and 2) highly diluted preparations retain “memory” of original substances. In March 2015, the National Health and Medical Research Council (NHMRC), Australia’s peak medical research organisation, declared that homeopathy was not efficacious for treating any health condition [1], sparking tension with practicing homeopaths.  The investigation was prompted after a concerning number of individuals with serious health conditions put their health at risk or delayed evidence-based treatment by favouring homeopathic medicines [2]. The NHMRC undertook a systematic review, overseen by their Homeopathy Working Committee (HWC) in which only controlled studies were considered i.e. those that compared a group of people who received homeopathic treatment with a similar group of people who did not receive homeopathic treatment [2]. Following this major systematic review, the latest NHMRC Strategic Plan 2013-15 has responded by broadening its aim to facilitate informed decision-making by Australians regarding their healthcare and the use of non-evidence based treatment [3]. The declaration by the NHMRC has sparked tension with leading homeopathic authoritative bodies. This article aims to review the laws and regulations underpinning homeopathy and its preparations in Australia. It critically appraises the opinions of major organisations for and against the use of homeopathic medicines for treating serious health conditions through evidence and case studies. Lastly, a brief overview of how clinicians can address the issue of using homeopathic remedies as an alternative to mainstream medicine with patients is provided.

Basic principles of homeopathy

Homeopathy, first articulated by a German physician in the 18^th century, Dr Samuel Hahnemann (1755-1843), refers to a unique scientific system of medicine based on the principle of similarity (“like cures like”) [4,5]. Hahnemann describes this principle as a reactive process whereby giving minute doses of a substance thought capable of inducing a series of symptoms in healthy individuals can be used to cure the same symptoms in those suffering (“similia similibus curantur”) [4,5]. Derived from the Greek words hόmoios meaning similar and pathos meaning suffering, disease; the aim of this “simile-based” therapy is to restore health using a “holistic” approach by individually tailoring homeopathic remedies to enhance the individual’s natural healing processes and strengthen their body’s ability to fight against susceptibility of disease [6,7].

The phenomenon underpinning homeopathy as described by Hahnemann was that for homeopathic substances, the higher the dilution, the higher the potency [8]. In Britain, for example, two common preparations are sold over-the-counter: 6C and 30C dilutions. The 30C dilutions are significantly more dilute than the 6C (1 in 100³⁰ vs. 1 in 100⁶ respectively), with the former considered to be more potent [4]. To explain this phenomenon, Hahnemann described that when the preparation is vigorously shaken between each dilution, the energy or essence of a substance is transferred to a solvent, a process called “potentiation” and “succession”, whereby a “memory” of the initial substance is retained in the solution [2,5]. This process is how the purported therapeutic effect is achieved [8]. The most common dilution factor is 10⁶⁰, which can vary depending on the constituents and strengths [5]. Homeopathy is thus a form of therapy based on similarity and dilutions that considers the person as a whole so as to enhance the body’s natural healing processes against various health conditions. However, it is important to highlight here that due to the extensive dilution, standard scientific theory would attest that the final homeopathic preparation is statistically unlikely to contain a single molecule of the original active ingredient [9,10].

Laws and regulations underpinning homoeopathy and homeopathic preparations in Australia

Originally, homeopathy was a self-regulated industry in Australia controlled by individual-state based organisations [11]. In 1997, these organisations merged to form what is known today as the Australian Homeopathy Association (AHA), which is the only national association of professional homeopaths in Australia that maintains the Australian Register of Homeopaths (AROH) [11,12].

Currently, to acquire a private health fund rebate for their services, homeopathic practitioners must be registered with AROH [13]. The AROH guidelines for registration necessitate that all registered practitioners have either passed a competency test for those who have not studied a homeopathic course accredited by AROH or have attained a three-year Advanced Diploma Course at a recognised institution; hold a current first aid certificate; maintain annual professional indemnity insurance; and undergo regular continuing professional development requirements [14]. Furthermore, homeopaths must abide by the AHA Code of Conduct as endorsed by the National Council, which requires them to refer patients with serious illnesses back to medical practitioners for evidence-based treatment [15].

The Australian national regulatory framework for homeopathic practice and its preparations is not as strict as some may anticipate. Homeopathic preparations are seldom registered with the Therapeutic Goods Administration (TGA), the national regulatory organisation that ensures the safety and quality of various therapeutic goods [16]. Those that qualify for registration are homeopathic preparations of no more than 1000-fold dilution, or contain apparent quantities of animal or human ingredients [17]. Most, however, either have undetectable amounts of the “active” ingredient or are too diluted.  Such preparations are thus deemed exempt from the TGA good manufacturing practice requirements, circumventing the rigorous testing for safety and efficacy by TGA that other drugs must undergo [17]. This, in turn, raises the question regarding the safety and efficacy of homeopathic treatment.

On the Australian Register of Therapeutic Goods, complementary medicines including homeopathic preparations can either be “registered” or “listed” depending on the level of risk that the medicines carry [17]. As “registered” medicines carry a high level of risk, they must undergo rigorous and detailed assessment and regulation of all relevant randomised controlled trials so as to provide comprehensive quality, safety, and efficacious data [17]. In contrast, “listed” medicines are not evaluated by TGA as they are of low risk, however, the products must have proven safety, quality, and efficacy as per legislative requirements [17]. Currently, no homeopathic preparations are registered and those listed and claiming to be efficacious must be labelled with the disclaimer “contains homeopathic ingredients without approved therapeutic indications” [17].

The AHA website provides a list of homeopathic medicine suppliers, which is publicly available, with most being sold through health food shops and pharmacies [18]. Such preparations are commercially manufactured and made available to homeopathic practitioners by three Australian suppliers: Pharmaceutical Plant Company, Martin & Pleasance homeopathy lab, and Brauer [18]. In addition, the AHA stress that each homeopathic practitioner has their own unique approach to making custom prescriptions [6], however, no centralised body exists to regulate such practice in Australia [5].

Opinions, the evidence, and case studies

Since the NHMRC declared homeopathy to be ineffective in treating any health condition, a number of disputes have been made by major organisations in favour of homeopathy.  Australia’s two peak industry organisations, Complementary Medicines Australia (CMA) and the AHA, both argue in their letters to the NHRMC that the position was prejudiced based on a draft position statement leaked in 2012 stating “it is unethical for health practitioners to treat patients using homeopathy, for the reason that homeopathy (as a medicine or procedure) has been shown not to be efficacious [19,20].” Furthermore, both the CMA and AHA highlight serious concerns regarding the prelude to and instigation of the work of the NHMRC’s HWC as well as the conduct of the review itself to finalise their conclusion on the use of homeopathy. Several grave issues were raised in both letters with five common key flaws cited: (1) no explanation was provided as to why level 1 evidence including randomised control trials were excluded from the review; (2) the database search used was not broad enough to capture complementary medicine and homeopathic specific content, and excluded non-human and non-English studies; (3) no homeopathic expert was appointed in the NHMRC Review Panel; (4) prior to publication, the concerns raised over the methodology and selective use of data by research contractor(s) engaged for the HWC review were abandoned for unknown reasons; and (5) no justification was provided as to why only systematic reviews were used [19,20]. Other serious accusations made by the AHA in their response letter to the NHMRC involved the blatant bias of the NHMRC evident by: the leakage of their draft position statement in April 2011 and early release of the HWC Draft Review regarding homeopathy to the media; no discussion of prophylactic homeopathy i.e. preventative healthcare; and no reference to the cost-effectiveness, safety, and quality of homeopathic medicines [19].

Despite the NHMRC findings being strongly disputed, they are further supported by positions taken by a number of large and respected organisations.  For example, in 2009, the World Health Organization (WHO) advised against the use of homeopathic medicines for various serious diseases following significant concerns being raised by major health authorities, pharmaceutical industries, and consumers regarding its safety and quality [21]. They reported the clinical effects were compatible with placebo effects [21]. Similarly, in Australia, the Australian Medical Association (AMA) further supports the NHMRC findings by stating in their position statement released in 2012 that there is “limited efficacy evidence” regarding most complementary medicines, thereby posing a risk to patient health [22]. More recently, in May 2015, the Royal College of General Practitioner’s (RACGPs) strongly advocated in their position statement against general practitioner’s prescribing homeopathic medicines, and pharmacists against supporting or recommending it, given the lack of evidence regarding its efficacy [23]. This is particularly pertinent to conventional vaccines given the recent case between the Australian Competition and Consumer Commission (ACCC) vs. Homeopathy Plus! Australia Pty Ltd.  The Federal Court found Homeopathy Plus! Australia Pty Ltd guilty of contravening the Australian Consumer Law by engaging in misleading and deceptive conduct through claiming that homeopathic remedies were a proven, safe, and effective alternative to the conventional vaccine against whooping cough [24].

The positions of the NHMRC, WHO, AMA, and the RACGPs regarding homeopathy is further supported by Cochrane reviews, which provide high-quality evidence with minimal bias [25]. Of the twelve homeopathy Cochrane reviews available in the database, only seven address homeopathic remedies directly and were related to the following conditions: irritable bowel syndrome [26], attention deficit/hyperactivity disorder or hyperkinetic disorder [27], chronic asthma [28], dementia [29], induction of labour [30], cancer [31], and influenza [32]. Given most of these reviews were authored by homeopaths, bias against homeopathy is unlikely [26-32]. The overarching conclusions from these reviews fail to reveal compelling evidence regarding the efficacy of homeopathic remedies [26-32]. For example, Mathie, Frye and Fisher show that there is “no significant difference between the effects of homeopathic Oscillococcinum® and placebo in prevention of influenza-like illness: risk ratio (RR) = 0.48, 95% confidence interval (CI) 0.17-1.34, p-value = 0.16 [31].” The key reasons given for this failure to provide compelling evidence relate to low quality or unclear data, and lack of replicability, suggesting homeopathic remedies are unlikely to have clinical effects beyond placebo [26-32].

Sadly, the ACCC vs. Homeopathy Plus! Australia Pty Ltd is not the only case that has made headlines in Australia in recent years.  An article in the Journal of Law and Medicine coincided with the NHMRC report regarding the number of deaths attributable to favouring homeopathy over conventional medical treatment in recent years [33]. One such case was that of Jessica Ainscough, who passed away earlier this year after losing her battle with a rare form of cancer – epithelioid sarcoma – after rejecting conventional treatment in favour of alternative therapies [34]. Although doctors recognise Ms. Ainscough’s right to choose her own cancer treatments and understand why she refused the disfiguring surgery to save her life, they fear her message may influence others to reject conventional treatments that could ultimately save their lives [35]. Another near death case was that of an eight-month-old boy whose mother was charged with “reckless grievous bodily harm and failure to provide for a child causing danger to death” after ceasing conventional medical and dermatological treatment for her son’s eczema as advised by her naturopath (an umbrella term that includes homeopathy) [36]. The “all-liquid treatment plan” left the boy severely malnourished and consequently, he  now suffers from developmental issues [37]. This case is rather similar to that of R vs. Sam in 2009, where the parents of a nine-month-old girl were convicted of manslaughter by criminal negligence after favouring homeopathic treatment over conventional medical treatment for their daughter’s eczema.  The girl died from septicaemia after her eczema became infected [36,37].

How clinicians can make a difference

As the aim of the latest NHMRC Strategic Plain 2013-15 is to assist Australians in making informed decisions regarding their healthcare, the NHMRC published a resource in April 2014 “Talking with patients about Complementary Medicine – a Resource for Clinicians” [38]. This was developed to facilitate discussion between clinicians and their patients regarding their use of complementary medicines so patients can make well-informed decisions about their healthcare options [38]. Available through the NHMRC website, this resource provides background information on complementary medicines and its regulation in Australia as well as suggestions on how clinicians can initiate discussion with patients regarding its evidence, reliability, effectiveness, and potential risks [38]. For example, to initiate discussion, clinicians can ask their patients if “they have tried anything else to help with their problem” [38]. Such discussion is imperative as many patients fail to disclose they are taking complementary medicines, which in itself may lead to adverse outcomes.  The resource also provides further additional information, resources, and links to help clinicians in providing patients with all relevant information so he/she can make a truly autonomous well-informed decision as per the AMA Code of Ethics [38,39].

Conclusion

Significant repercussions have followed the major review and final position statement by the NHMRC HWC regarding the efficacy of homeopathic remedies in treating health conditions.  Despite the defensive position of the AHA and CMA, there is strong evidence to suggest that there is a need for stricter industry regulations for homeopathic practice and preparations.  Furthermore, given that the efficacy of homeopathic remedies for treating any health condition is unlikely, it is now up to clinicians to provide and ensure that their patients have all the relevant information so they can make a well-informed decisions regarding their health.  With a concerning number of individuals with serious health conditions favouring homeopathic medicines over conventional treatment, collaboration between leading regulatory bodies, clinicians and patients is vital in maximising patient safety and health outcomes.

Acknowledgements

None.

Conflicts of interest

None declared.

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The last 50 years have ushered in an era of rapid technological development in the domain of joint replacement surgery and subsequently improved the lives of millions, both in terms of alleviation of pain and functional restoration. In spite of this technical progress, periprosthetic joint infection remains a barrier in achieving entirely successful outcomes for all joint replacement surgery patients. Once a periprosthetic joint infection has been diagnosed, there exists a vast array of adjuvant treatment modalities. A combination of clinical signs, laboratory and microbiological tests, histopathology, and imaging studies are required to meaningfully diagnose a periprosthetic joint infection, but the increasing incidence of morbid obesity, diabetes, and the rise of the ‘metabolic syndrome’ has been associated with a perceived increase, amongst clinicians, in the rate of periprosthetic joint infections. Indeed, the rising prevalence of this complication demands considerable clinical acumen from the orthopaedic surgeon. It has become increasingly challenging to treat patients who develop infections in the setting of total joint replacement. Surgical options include single or serial washouts vs. single stage or multi-stage exchange procedures, but the utilisation of adjuvant broad-spectrum intravenous antibiotics with myriad systemic side effects is required for adequate treatment. Furthermore, the emerging and proven value of the multidisciplinary team brings together orthopaedic surgeons and infectious disease physicians to act in the best interests of their patients by limiting the considerable morbidity associated with periprosthetic joint infections.

Introduction

Since the developments of Charnley in the 1960s, [1-4] joint replacement surgery has revolutionised the treatment of joint pain, most commonly due to osteoarthritis, and served to restore function and productivity in an increasingly afflicted population. [5] Despite these technical and surgical advances, periprosthetic infections have been an important barrier in achieving successful joint replacement surgery in some patients. [6] In the context of an ageing population, surgeries such as this are becoming evermore prevalent, and hence the frequent review of its process is warranted to achieve the best possible patient outcomes. There are several aspects of arthroplasty that need to be taken into account. Given that prevention is always better than cure, surgical sterility and asepsis is by far the most important factor in preventing periprosthetic infections and maintaining the efficacy of joint replacement surgery as a therapeutic modality. [3] Contributing to this are the various adjuvant treatments included in current perioperative protocols widely used by modern orthopaedic surgeons. However, despite the multitude of additional precautions, it is revealed that infection rates persist at one to four percent in most modern facilities. [6,7] Various patient factors such as obesity and diabetes have also been implicated in the development of periprosthetic joint infections. In considering the contributing factors, an evaluation will also be made of the current treatment options and outcomes for patients in terms of quality of life and economic burden on the healthcare system. Infections of orthopaedic prostheses prove to be a considerably disastrous event for both patients and surgeons, and hence warrant close review of the options available and their value to patient management.

Current perioperative protocols

Perioperative protocols now include a multitude of adjuvant treatments that are very much part of the modern orthopaedic surgeon’s armamentarium. Regimes including perioperative antibiotic therapy, the use of ‘space suits’ by surgeons and theatre nurses, double gloving, antiseptic-coated skin adhesives, adherence to sterile surgical practices, and the utilisation of antibiotic-impregnated bone cement are just some of a number of steps taken to reduce the likelihood of superficial and deep wound infections, [8-11] which in the setting of an artificial prosthesis can lead to limb, and occasionally, life-threatening complications. [12]

These methods have a sound theoretical and clinical basis, [8] and are well-accepted in the orthopaedic surgical community as a means of preventing multiple surgeries to salvage or revise infected prosthetic joints and the toxicity of protracted, high-dose intravenous antibiotic therapy. Despite these measures, a review of the available literature reveals an infection rate of between one and four percent in most modern hospitals [6,7]; importantly, these figures are expressed to patients prior to joint replacement surgery as part of the process of informed consent, as an act of best practice. Although the use of antibiotics has a clear clinical benefit in the setting of periprosthetic infection, it is difficult to discern how useful the other approaches are in helping to reduce infection in joint replacement surgery. [9,13,14]

Basic microbiology of joint infections

Evaluation of microorganisms associated with perioperative infections demonstrate the existence of a wide range of Gram-positive and negative bacteria and fungi that may cause infection. [15] However, there is an overwhelming association between Gram-positive bacteria and perioperative infections, particularly Staphylococcus spp., compared to any other known causative organism. [15-17] There is particular concern for the growing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) associated with perioperative infections.  [16,17] Staphylococcal spp. has also been associated with higher risk of re-infection and persistence of infection in the setting of arthroplasty. [16] Propionibacterium acnes is also reported to be of growing concern, especially in the context of shoulder surgery, for reasons yet to be clearly delineated. [15,18,19]

Patient factors: obesity, diabetes and immunosuppression

Obesity

Obesity is fast becoming an epidemic for the Australian healthcare system. Not only has high body mass index (BMI) been implicated in the increased number of total joint replacements, owing largely to accelerated osteoarthritis (OA), but obesity as a health condition in itself complicates arthroplasty surgery and deleteriously impacts patients’ functional outcomes. Australia has one of the highest rates of obesity in the world, with a quarter of the population being classified as obese, and the incidence is increasing, with 34% of the population predicted to be obese in 2015. [20] Furthermore, because obesity is a risk factor for OA due to increased mechanical joint loading, the proportion of those presenting for joint replacement surgery is even greater and is also set to increase in the short to medium-term. Obesity is associated with a number of co-morbidities such as heart disease, hypertension, diabetes, and the ‘metabolic syndrome’, the latter two of which complicate surgery and independently increase the risk of periprosthetic infection.

There is, however, a degree of ambiguity in the orthopaedic literature, with arguments for and against obesity in itself being an independent risk factor for periprosthetic infection. One centre’s study demonstrated that morbid obesity, or a BMI of > 40, increases the risk of deep prosthetic infection by eight to nine times; however, obesity and a BMI of 30-39, increased the risk by two to three times. [21,22] These rates are also related to the anatomical site of the joint replacement itself. With regards to the knee, only the relationship between morbid obesity and prosthetic infections was found to be statistically significant. [22,23] Addressing the issue of surgery for obese patients is one of the modern-day challenges for orthopaedic surgeons and much work remains to be done in developing a clear framework for addressing this clinical problem.

Diabetes

Diabetes mellitus and hyperglycemia have been indicated as risk factors for various complications in orthopedic surgery, including surgical site infections, pneumonia, prolonged hospital admissions, stroke, and deep vein thrombosis. [24-27] This increased risk is often attributed to the common co-morbidities that exist in diabetic patients, which are of a particular vasculopathic nature. [24] However, it appears that a direct correlation between diabetes mellitus and incidence of periprosthetic joint infection is yet to be clearly delineated. One study has demonstrated an important distinction between controlled and uncontrolled metabolic syndrome (defined as diabetes, dyslipidemia, hypertension, and obesity) and risk of periprosthetic joint infection; however, when compared to healthy patients, both groups appeared to yield non-significant results. [28] Another study investigating rates of infection after total joint arthroplasty has found up to 11.4 times higher incidence of infection in diabetes mellitus patients compared to non-diabetic patients in total hip arthroplasty and 2.6 times higher in total knee replacement. [29] Contrary to this, it was found that the blood glucose level (BGL), measured by HbA1c readings pre- and post-operatively, were not significantly associated with infection risk. [30] Hence, it appears that BGL alone is not an adequate indicator of perioperative infection risk, though it remains an important risk factor for other complications, such as length of stay, in orthopaedic surgery. [30] Therefore, the evidence to support the direct relationship between diabetes mellitus as an independent risk factor for periprosthetic joint infections remains an area requiring further research.

Rheumatoid arthritis

Rheumatoid arthritis (RA) patients are not only at higher likelihood of requiring joint arthroplasty, but also have an innate immunosuppressed profile due to their management regimes. There is a paucity of recent literature that discusses the relationship between perioperative infections and RA. Of the available most recent data, RA patients have been indicated as being at higher risk of complications when compared to OA patients, another prominent group undergoing joint arthroplasty. RA is also reportedly associated with higher length of hospital stay, cost of hospitalisation, and need for blood product transfusion compared to OA patients. [31] Other studies have found that RA is associated with a higher incidence of prosthesis infection compared to matched OA controls. [32]

Interestingly, contrary to previous studies, a study comparing RA and ‘non-RA’ patient sequelae after total shoulder arthroplasty found that RA patients actually had lower length and less complex stays in hospital post-surgery, and that RA patients were more often routinely discharged home with fewer complications. [33] It has been suggested that the advent of newer RA treatments, such as disease-modifying antirheumatic drugs (DMARDs) and anti-tumour necrosis factor (anti-TNF) inhibitors may contribute to this altered risk for perioperative complications in RA patients. [32]

A further recent study has attempted to compare DMARDs with newer biological agents such as infliximab and rituximab, amongst many others, and their risk association need for total joint arthroplasty and associated periprosthetic infection risk. [34] It appears that the use of biological agents was associated with a higher and earlier, need for joint replacement when compared to DMARDs; however, it was also noted this may be attributed to the fact that patients using biological agents tend to have more aggressive RA. [34] Moreover, it appears that although biological agents tend to require less revision surgeries, there is no significant difference in the rate of joint infection between the two treatment regimens. [34]

Solid organ transplant patients

Solid organ transplant patients are becoming increasingly common as total joint arthroplasty candidates. This is due to the increased rate of solid organ transplants, but reasons for total joint arthroplasty in this group are not much different to otherwise healthy individuals and include osteonecrosis of the femoral head for total hip arthroplasty (THA), and osteoarthritis. [35-37] It has been postulated in the past that this group of patients may be more susceptible to periprosthetic infection due to their use of immunomodulators such as tacrolimus, mycophenolic acid, and corticosteroids such as prednisone. [38] Joint replacement surgery in this patient group has traditionally involved the prophylactic use of antibiotics, presumably for this reason, although the use of perioperative intravenous antibiotics for all patients has become standard practice in orthopaedic surgery. [35-38]

Most recent studies are largely retrospective when observing the rate of perioperative infection, as well as other complications in this highly select patient group. However, contrary to what may be presumed, the most recent literature suggests that patients undergoing THA still have low rates of periprosthetic joint infection as a perioperative complication, despite the nature of the transplant undertaken and the subsequent immunosuppression regime. [36-38] In some studies, the periprosthetic infection rate in the transplant patient group following THA was zero. [37,38] Other cases observed only one wound infection amongst the 55 THAs performed in various solid organ transplant patients. [36] However, the situation appears to be different for this patient group in regards to total knee arthroplasties (TKA). Two studies consistently report the rate of periprosthetic infection as being higher in TKA compared to THA. [36,37]

Another study observing only TKA reported an infection rate of 4 out of the 24 (17.3%) TKAs performed on various solid organ transplant patients. Contrary to these numbers, there have been reports of no statistically significant difference between TKA and THA, with both yielding no increased periprosthetic infection risk. [38] Given all of this recent evidence, it appears that we are yet unable to discern whether there is any true significance between solid organ transplant subgroups and their relative risk of periprosthetic infection in total joint arthroplasty. The conclusion may perhaps be drawn, that it is relatively safer to perform total hip replacements in this patient group compared to total knee replacements. However, one must be cognisant of the fact that most of these studies are retrospective analyses of specific patient cases with relatively small statistical power.

HIV patients

Patients with human immunodeficiency virus (HIV) are also becoming increasingly common candidates for total joint arthroplasty, perhaps owing to the improved efficacy of antiretroviral treatments available to the community and increased longevity of these patients in general. [39] One study reported that HIV patients undergoing joint replacement tend to be younger than matched controls and also yielded non-significant results in its investigation of whether this immunocompromised group will experience higher rates of periprosthetic infection. [40] This suggests periprosthetic infection rates in the HIV population are not as striking as they used to be in the context of total joint arthroplasty. [40] This has been attributed to the advent of more effective antiretrovirals and their increased uptake in this patient population, as well as more effective intravenous drug user (IVDU) education producing a lower bacteraemia risk to seed infection. [40] Other similar studies appear to reflect those previously found in producing either none, [41] or very low rates (one hip in 41 THAs) [39] of periprosthetic infection for total knee or hip arthroplasties in HIV patients.

Recognising perioperative joint infections

It must be borne in mind that recognising infection after total joint replacement remains clinically difficult. A combination of clinical signs, laboratory and microbiological tests, histopathology, and imaging studies are required to meaningfully suggest a prosthetic infection. [42] More important, is the ability to predict and diagnose the early stages of a prosthetic joint infection as prompt intervention and management has the best chance of salvaging the prosthesis and preserving optimal joint function. [9] Given that plain radiographs have low sensitivity and low specificity for detecting early infections, the efficacy of new imaging techniques involving scintigraphy, positron emission tomography, and computerised tomography imaging is currently under investigation, but remains contentious. [9] What is becoming clear is the fact that treatment of orthopaedic infections is no longer solely in the domain of the orthopaedic surgeon. Modern multidisciplinary care now demands a team approach between surgeons and infectious diseases specialists; the need for an evidence-based approach should take priority when managing both superficial and deep infections.

Treatments: antibiotic therapy & surgical revision

Infections of joint replacement components and other implantable orthopaedic hardware are some of the most disastrous events in clinical orthopaedics, especially in terms of patient outcomes, and often considerable and prolonged resource expenditure. Not only is the ordeal of having a prosthetic infection protracted with an increased risk of recurrent infections, there are also a wide range of possibly devastating outcomes, including sepsis and limb amputation. [12] The financial burden is also significant, with the cost of successfully treating an infected joint replacement conservatively placed at approximately $50,000 for early interventions and $100,000 for late interventions. [6] In revising joint replacements for infection, several important questions arise, namely, “Should failed total joints be revised in single or multi-stage operations?” and “What should be done in those situations where bone loss is considerable and metallic structural augmentation is required to restore anatomy?” These and other questions demand attention.

It has become an increasing challenge to treat patients who develop infections in the setting of total joint replacement. Literature is scarce in regards to accepted modes of treatment, particularly with hip, knee, and shoulder prostheses, and moreover, few publications specifically outline the most effective therapeutic regimes. [13] It is problematic for treating teams to appreciate what best clinical practice may be; indeed, the removal and revision of the prosthesis as a single or two-staged procedure is often the fallback position for orthopaedic surgeons. [7,13] The evidence suggests that this approach is one of a number of potential options. At the other end of the spectrum, reports of high rates of successful salvage of prosthesis in situ are also achievable with aggressive debridement and targeted antibiotic therapy alone. [14,43] However, the prevalence of resistant bacteria should be borne in mind and appropriate consultation with an infectious diseases physician is also wise. Moreover, there are other strategies such as MRSA screening and other prophylactic practices that increase the success of an arthroplasty, the discussion of which is beyond the scope of this article.

Patient outcomes & quality of life issues

Of the available treatment outcomes, it appears the most long-standing debate still appears to be between one-stage and two-stage revisions, in terms of surgical interventions. For patients that are unfit for surgery, long-term suppressive antibiotic therapy seems to be a viable option, though the ideal regimen is yet to be delineated. [44] Two-stage revision also appears to be accepted as a ‘gold-standard’ for the management of periprosthetic infections. [45-48] The most recent literature remains rather mixed about the efficacy of one-stage over two-stage revisions in hip and knee arthroplasties. Of the most recent studies, some yield better success rates [45,49] and patient-rated outcomes for one-stage revision [45] or lower than expected success rates for two-stage revision [50]; while others are in support of two-stage revision. [48] Nonetheless, it appears that the success rate of one-stage over two-stage or vice versa is by a small difference in percentage, suggesting perhaps that these methods are quite comparable. Other than the previously noted study, it appears that there are few other available studies that present measurable patient outcomes, aside from the success rate of the treatment method.

It has also been found that patient transfers during the two-stage revision period may negatively impact on its success rate due to various possible reasons. [47] Perhaps as an alternative to either one-stage or two-stage revision alone, a Singaporean hospital has introduced its findings based on a periprosthetic joint infection protocol that reflects progression from incision and drainage (washouts) to two-stage revision depending on patient outcome for the management of MRSA infections. [51] It reports one third of its patients being successfully treated by first-line washouts alone and an 88% success rate in the remaining patients who underwent two-stage revision as second-line treatment. In consideration of new or alternative methods to manage periprosthetic joint infection, one group found that irrigation and debridement may hold promise as a treatment method alone, with a success rate of 55.1% in their study, given its association with lower morbidity, tissue fibrosis, and better functional outcomes when compared to two-stage revision. [46] However, this study also found that successful treatment with single or serial washouts is significantly more likely to fail if conducted after 5 days of symptom onset or clinical detection. [46] Related to this discussion, it was found that pulse lavage to remove biofilm has variable efficacy and is largely dependent on prosthesis material (cobalt chrome vs. polymethyl methacrylate vs. polyethylene) and reaffirms that it alone is not adequate in the management of periprosthetic infection, but must be combined with suppressive antibiotic therapy and/or meticulous debridement for optimal results. [52]

Conclusion

It has become an increasing challenge to treat patients who develop infections in the setting of total joint arthroplasty. The surgical options of single or serial washouts with or without debridement vs. single-stage or multi-stage exchange procedures are all reasonable options, but there is no clear, uniform consensus in the literature that favours one approach over the others. The utilisation of broad-spectrum intravenous antibiotics with myriad systemic side effects is required for adequate treatment and is considered best practice. The value of the multidisciplinary team consisting of the orthopaedic surgeon and the infectious disease physician is brought to bear when these patients are at their most vulnerable. Ultimately, it falls upon the treating clinician to act in the best interests of their patients by limiting the substantial morbidity and impact on quality of life associated with periprosthetic joint infections.

Conflicts of interest

None declared.

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What would society be, so that in his last years a man might still be a man? The answer is simple: he would always have to have been treated as a man. By the fate it allots to its members who can no longer work, society gives itself away.

-Simone de Beauvoir, The Coming of Age (1972)

Currently our elderly are enduring the harsh rationing of medical care. Their age rather than their capacities and needs is directing the treatment, or the lack thereof, that they receive in hospital. As a student walking the wards, I’ve heard clinicians exiting the room of a grey-haired, frail grandmother saying, “What kind of life is that?”, “What’s the point in transfusing her?”, “Treatment is futile, she should be palliated.” All of these phrases and the derivations of them grate on me. I am not a proponent of over-treating, over-testing, and needless infliction of pain against a patient’s wishes. However, when I hear these utterings I wonder whether the elderly patient’s interests are at heart. I wonder if the fact that they are an octogenarian influences the doctor’s view of futility. Futile for whom? Is the treatment futile because it is evident that it won’t cure the patient? Is a cure even what we are looking for in multi-morbid geriatric patients? What if it buys more time for the patient and their family? What if that patient and their family think a few extra days or weeks are exactly what they need to say goodbyes? Surely that is not futile.

Futility can be subjective. We attempt to deny this fact. Doctors are not obliged to give treatment that they consider to be futile. However, prognostication is inexact. It is extremely difficult to determine when treatment is futile for an elderly patient with another infective exacerbation of their chronic obstructive pulmonary disease. No one can tell if this will be the infection that literally knocks the wind right out of them or if they will respond to antibiotics, nebulisers and fluids as they have before and return home. Nothing we have in our vast medical arsenal can precisely determine when a person will die. Therefore, the concept of withholding futile treatment is benevolent in intention but may be treacherous in practicality.

Knowing this, it is important that doctors present the options and possibilities to the patient and their family. This is not something that can be done with speed in the chaos of a morning ward round. It takes time, careful consideration, and discussion of uncertainty. It requires looking at the patient as a whole, identifying their wishes, fears and goals [1] and their family’s desires for them. It is a process that acknowledges that medical treatment extends to an understanding of both the social and psychological needs, not just the medical history and vital signs. It is a deviation from the traditional medical approach, which makes us uncomfortable. But it is undoubtedly the approach that patients need and deserve, especially as they enter the final years, months and days of their life.

In relatively recent times a new medical discourse has emerged. It is peppered with words like “advance care directive”, “not for resuscitation”, and “end-of-life planning”. These concepts are admirable.  [2] They are a step towards ensuring that appropriate treatment is given to elderly patients. They are a systematised way of elucidating the patient’s desires for the end of their life in the event that they are not able to communicate these intentions independently. They can give another degree of certainty that doctors are doing the right thing by the patient when caring for those who are very ill and elderly. They attempt to ensure that patient autonomy is upheld even in their final days. It has been shown by randomised trials that this end-of-life planning, when done thoroughly and correctly, results in increased patient and medical team satisfaction. [3 ] However, when done poorly they have the capacity to collapse into a paper storm of inadequately completed forms, unchecked tick-boxes and a flurry of confusion.

The danger with this contemporary discourse and ever-evolving multitude of forms is that they become a veil for sanctioned ageism in our hospitals. [2] They pretend to address the patient as a whole but have the potential to bolster the fiscal constraints placed on hospitals that indirectly promote limitation of treatment according to age. They may even deny the elderly the empathy that other younger patients with better chances of full recovery receive without question. They are supposed to empower the patient but can instead circumvent the need for physicians and surgeons to learn how to have iterative meaningful conversations with the elderly and their families about their medical care. [2] There is a danger that these forms emerge as yet another mechanism for denial of deserved medical attention. They support the tired cry to create a “sustainable” medical system by discretely refusing the most vulnerable people in hospitals adequate medical consideration and thus further cement the lowly position of our elderly in our health care system. [2] Most worryingly, they delay the important recognition that we are failing our elderly and that our approach needs to change.

Part of the reason I believe that we avoid real discussions with elderly patients with complex health requirements is because it requires us to see ourselves in these osteoporotic, hard-of-hearing folk. [2,4] Too often we separate ourselves from them. We label them as “acopics” on “social visits”. We fail to see the aged as depicting our own destination in life. Perhaps we do this because recognising the elderly as related to us requires us to confront our mortality and contemplate our own ageing and death which is understandably uncomfortable. We don’t want to become them so we run from them as if avoiding the elderly will make us immune to ageing.

I hear doctors and students joke, in tutorials and at the end of a ward round, “I never want to get that way, I hope I die suddenly at 75”. They click their fingers to emphasis the swiftness with which they wish to depart the earth. They all want to spare their inner light from the ravages of time. They playfully ask their colleagues to just titrate morphine up to toxic doses if they have a stroke or become demented. They talk about growing old as if it is a fate worse than death. In doing so, they devalue the elderly that populate the busy wards. [3] Our grandparents become the least worthy of treatment because the implication is that they, as a collective, have nothing to contribute anymore. [4] They have lost their social worth. These phrases perpetuate ageism and they erect barriers which shut out the elderly from an impartial medical system. These jovial remarks are said without any consideration of the fact that they too will grow old. Most probably, they will grow older than the grey-haired people they walk past on the wards because that is the way our demography is headed, largely thanks to modern medicine. By “othering” the elderly, by failing to see the individual behind the date of birth, the connection is never made between doctor and patient, and austerity of care creeps in.

The other reason I believe we relegate the elderly to the medical scrap heap is because they challenge our medical capacities. They sit uncomfortably outside the modus operandi we learn at medical school. In the current hospital system, doctors approach patients with a view to compartmentalise them and break them down into discrete systems and then further into isolated organs within those systems. This method is neat and tidy. It is an efficient method that seeks to unravel dense biological complexities into manageable medical and surgical problems. It is goal-oriented and treatment-focused and on many occasions it makes patients better. However, the flaws in the system present themselves when the geriatric patient arrives in the emergency department. These patients can’t be dissected and deconstructed so easily and consequently they challenge our method. They test our Sherlockian reasoning and routinely disprove our beloved Occam’s razor theory that each and every patient can be summarised with a unifying diagnosis. They stand in the lesser known Hickam’s dictum camp that states that, “Patients can have as many diseases as they damn well please”. [4] This is daunting for us in the medical world. It signals longer assessment times, more complex diagnostics, less reliability in old-faithful heuristics and the possibility that the patient’s problems won’t be neatly tied up at the conclusion of the consult. The elderly are often perceived as a potential threat to our diagnostic and management skills simply because it feels strange to settle with a management plan where a medical cure and resolution is not the endpoint. We perceive this as some sort of failure on our part or a compromise of our identity, [1] but really it is an indication that we, as a group, are not equipped to deal adequately with the elderly patients that are populating our hospitals. It is an indication that we are failing them and that a cultural shift needs to occur within the medical fraternity.

Atul Gawande, the famous American surgeon responsible for the now commonly used “surgical checklist”, describes the inevitable population change occurring in developed nations in his latest book Being Mortal. [1] Traditionally, our demography has been pyramidal in configuration. The broad base of the population is occupied by those under the age of five and the small pointed apex accommodates a much smaller number of those over 80 years of age. However, with the passing of time and the impressive acceleration of modern medicine the shadow this traditional pyramid casts has begun to change shape. Gawande describes it as a “rectangularisation” [1] of the population, whereby the over-80-year-olds are increasing to be greater in proportion with the under-five-year-olds. [1] In essence, people are living longer and the elderly now represent a greater proportion of our society. I believe this new longevity of humanity is exciting as it presents an abundance of new possibilities; however, not all people see it that way. The growth of the elderly is often viewed with the gaze of a miserly economist, where the elderly are seen as a huge financial burden and  are simply mopping up valuable health dollars. Whatever your view, it doesn’t really matter as the growth of the elderly is not reversible. It is happening and we as a medical community must shift to accommodate it and work with it, not against it. As such, the medical treatment of the elderly can no longer be the job of the specialised geriatricians alone. In fact, the number of training geriatricians is amongst the lowest of all the specialties in this time of their greatest demand. [1] This means that we all have a role to play in the care of the elderly in our hospitals. We must use the knowledge that we have to the benefit of our elderly and ensure that the medical treatment they receive supports their individuality and healthy ageing.

Unquestionably this will require a seismic cultural shift amongst doctors. It will require doctors to have that prickly confrontation with their own mortality and to acknowledge the limitations of their skills in this area. It will require openness to learning new skills and a reordering of priorities of treatment in some cases. It will involve an abandonment of the inertia that medical traditions and systems have created in favour of necessary innovation for the future. This seems a daunting task to embark on, but without change we will undoubtedly find ourselves living in a society that displeases us, a society that is fraught with injustice and inequity. The changes we make now must ensure that in the future our society is one that Simone de Beauvoir [5] describes, where a man in his last years might still be a man. [5] Where the vulnerable, those unable to work and those who are grey and tired are protected and their humanity is respected and upheld.

Conflicts of Interest

None declared

References

[1] Gawande A. Being Mortal: Medicine and what matters in the end. New York: Metropolitan Books, Henry Holt and Company; 2014.

[2] Hitchcock K. Dear Life: On caring for the elderly. Quarterly Essay. Issue 57, Australia: Penguin Books; 2015.

[3] Detering K, Hancock AD, Reade MC, Silvester W. The impact of advance care planning on end of life care in elderly patients: randomised controlled trial. BMJ. 2010;340:c1345. DOI: 10.1136

[4] Montgomery K. How Doctors Think: Clinical Judgment and the Practice of Medicine. Oxford: Oxford University Press; 2006.

[5]De Beauvoir S.  The Coming of Age. New York: G.P. Putnam & Sons; 1972.

[6] Hitchcock K. Little White Slips, Australia: Pan Macmillan Australia; 2009.

Dengue fever has the highest and fastest-rising morbidity and mortality of any vector-borne viral disease. The growing global impact of dengue is a public health challenge with an economic burden that is currently unmet by licensed vaccines or vector control strategies. Therefore, effective, efficient, safe, and sustainable interventions are a public health priority. However, interventions also must be applicable to tropical and less developed regions where dengue is prevalent. Vector control, the principal method for dengue prevention, is not sustainable because current methodology is expensive and of limited effectiveness. Innovative candidate vaccines, including live-chimeric, live-attenuated, inactivated, subunit, and DNA vaccines, and vector control approaches, such as the release of mosquitoes carrying the dominant-lethal allele or Wolbachia, are in trials.  The most advanced and promising new dengue control measures are the Sanofi Pasteur live-attenuated ChimeriVax vaccine (CYD-TDV) and infection of the Aedes mosquito vector with the endosymbiotic Wolbachia bacteria. While vaccination shows slightly more promise than vector control, in terms of effectiveness and sustainability, integration of both interventions may be more effective than either approach alone.

Relevance to medical students

The rapid pace of development of vaccines for dengue fever will rapidly reduce the over-100-million dengue fever cases and their associated morbidity and mortality within the next few years. A candidate vaccine against dengue viruses called, CYD-TDV, could reach registration and review by the World Health Organization in 2016. If countries do license CYD-TDV, future doctors will need to understand the costs and benefits of vaccination, particularly any undesirable outcomes after vaccination, and whether alternatives exist.

Introduction

There are more than 100 million dengue cases annually and the financial cost of this disease has been estimated to be more than $2 billion in the Americas and $1 billion in South-East Asia each year. [1] The 30-fold increase in the incidence of dengue in the last 50 years has highlighted the failure of existing vector control strategies and the need for new vaccine or vector control approaches. [1] The most advanced of these are the mosquito-infecting bacteria Wolbachia, and Sanofi Pasteur’s chimeric tetravalent dengue vaccine (CYD-TDV). A comparison of their problems and prospects based on effectiveness, efficiency, safety, sustainability, economy, and universality may guide their adoption. While these approaches have been developed in isolation, their combination may help achieve the World Health Organization (WHO) goals of reducing dengue mortality by 50% and morbidity by 25% by 2020. [2]

Vaccinations

Prospects

The ideal dengue fever vaccine would induce a neutralising and balanced response for all four dengue serotypes, provide long-lasting or life-long protection, be safe and stable, balance reactogenicity and immunogenicity, and be cost-effective and context-appropriate.  A more universal vaccine would confer “herd immunity” to the general population by reducing the reservoir of infected individuals and infection transmission. Vaccine candidates should be evaluated in trials spanning different populations and patterns of dengue transmission. [2] Several vaccine types are under development, including live-attenuated, live-chimeric, inactivated, subunit, and DNA vaccines (Table 1). [3] Inactivated and subunit vaccines are safer, in principle, due to a lower risk of reversion to virulence and are under evaluation in pre-clinical or early clinical trials. [4] Several more cost-effective and immunogenic live viral vaccines are under evaluation in late-stage clinical trials. [17]

Table 1: Candidate vaccine approaches.

Vaccine type	Developer	Process	Progress
Live, attenuated chimeric (recombinant)	Acambis / Sanofi Pasteur	Insertion of genes coding for DENV structural proteins into a yellow fever virus (17D) backbone. [5]	Phase III tetravalent – leading candidate [4]
	Centre for Disease Control (CDC) / Inviragen	Insertion of serotype genes into serotype II (DENV2-PDK53) DNA backbone. [6]	Phase II monovalent [7]
	National Institutes of Health (NIH) / University of Maryland	Insertion of serotype II and III genes into safer, more immunogenic serotype I and IV DNA backbone. Live attenuated DENV Delta-30 mutation. [8]	Phase I tetravalent
Live, traditionally attenuated	Walter-Reed Army Institute of Research (WRAIR) / GlaxoSmithKline (GSK)	Attenuation achieved by growing the virus in cultured cells and selecting strains	Phase II tetravalent; technical issues [6]
	Mahidol Institute / Sanofi Pasteur		Phase II tetravalent
Inactivated	GSK	Viruses cultured and killed [9]	Phase I tetravalent
Subunit	Hawaii Biotech	Viral immunogenic envelope is combined with viral non-structural protein antigens to produce recombinant 80% E subunit vaccine [10]	Phase I tetravalent [11]
DNA	WRAIR	Dengue prM-E DNA vaccine incorporating membrane and envelope genes into a plasmid vector [12]	Phase I monovalent

 

The leading vaccine candidate is the tetravalent Sanofi CYD-TDV that recently completed phase III clinical trials. [4] Phase I and II trials have established the vaccine is safe and immunogenic, inducing neutralising antibody responses in 77–100% of recipients receiving three doses of the vaccine. [13] A neutralising immune response is achieved through inserting dengue structural protein genes for the four serotypes onto a yellow fever virus backbone. [14] The multi-centre Phase III efficacy studies have further supported this effectiveness and safety. [17] The vaccine reduces dengue fever incidence by 56% and dengue haemorrhagic fever by 88%. [15] More than 28,000 subjects have been immunised with this vaccine. [16,17] CYD-TDV is based on the safe and effective YF-17D vaccine. [18] Pre-clinical and phase I studies have suggested that the incorporation of four dengue serotypes into the YF-17D RNA backbone has not come at the cost of the vaccine’s stability. [19] The reactogenicity profile is similar to the YF-17D control. [20] A more robust immune response, with no adverse reactions, has been observed post-injection in flavivirus-vaccinated individuals. No cases of dengue-like disease that could arise from reversion of live vaccine strains to virulence were observed in studies on younger subjects. [21] There was a low vaccine viraemia and similar rates of adverse events compared to the YF-17D control. The vaccine’s commercial prospects are still uncertain, but it has a low production cost. [22] Over 20 clinical trials and 20,000 subjects have therefore found the Sanofi vaccine safe and immunogenic. [16]

Problems

The major challenge with the Sanofi Pasteur vaccine has been to induce a balanced immune response against all four dengue virus serotypes (DENV 1-4). The vaccine has needed to elicit protective responses against all four serotypes and not produce sub-neutralising levels of antibody that might enhance subsequent DENV infections. ChimeriVax proved notably inefficient in protecting against DENV-2. [23] The efficacy of ChimeriVax was found to be 61%, 82%, and 90% against DENV-1, DENV-3, and DENV-4, respectively, and only 3.5% against DENV-2 after a single dose and 9.2% against DENV-2 after three doses. [24] Other challenges are the three six-monthly doses of vaccine, which could reduce patient compliance and reduce its utility as a traveller’s vaccine.

Vector control

Prospects

Vector control methods, which seek to eliminate the hosts of disease-transmitting pathogens, need to reduce dengue incidence in an efficient and economical manner without burdening local health infrastructure. While transient control has value in dengue prevention, ideal methods should be sustainable, require minimal reapplication of insecticide, and account for external factors, such as climate change. [15] Safety is paramount and the effects of preventive interventions on health and ecology should be monitored or the strategy may be limited in its use, for example, in the case of the carcinogenic, toxic, and polluting, but highly efficient insecticide, dichlorodiphenyltrichloroethane (DDT). [25] Ultimately, the proposed intervention will need to be based on scientific evidence as well as public and government support. Current chemical, environmental, biological, and genetic vector control methods are not successfully mitigating dengue’s increasing prevalence, geographical distribution, and severity (Table 2). [26] Whether inserting the endosymbiotic Wolbachia bacteria into A. aegypti mosquitoes will be effective in controlling dengue remains to be seen.

Table 2: Candidate vector control approaches

Vector control type	Process	Progress
Chemical [27]	Insecticides, larvicides, pest control	Popular and evidence-based
		Concerns about significant financial and logistical costs, contamination and toxicity and insecticide resistance
Environmental [28]	Eliminating mosquito breeding grounds, screens, water and waste management	Appropriate strategies have the potential to reduce vector transmission and benefit overall health of people and the environment
		Significant infrastructure needed
Biological [29]	Natural predators and pathogens, (for example, Wolbachia)	Successful in local elimination of mosquitoes
		Significant infrastructure needed
Genetic	Release of insects carrying dominant-lethal allele (RIDL), Sterile insect technique (SIT), HE gene, RNAi	Limited field trials and mixed data on effects in reducing target populations in field trials. Large release numbers required

 

Wolbachia promises to be the equivalent of a human “vaccine” for dengue vectors, by inducing a natural biologic resistance to dengue infection in dengue-carrying A. aegypti mosquito populations. Wolbachia occurs naturally in approximately 40% of arthropods and reduces A. aegypti’s ability to respond to viruses, life-span, and reproduction. [30, 31] All three forms of Wolbachia (wAlbB, wMelPop, and wMel), inhibit DENV replication and dissemination within the host mosquito and may block viral transmission. [32, 33] Wolbachia strains can dramatically reduce the lifespan of the female A. aegypti mosquito so that virus transmission may not occur before the insect dies. [34, 35] However, some Wolbachia strains are transmitted from mother to offspring in A. aegypti populations resulting in rapid spread throughout a population. [35] Risk assessments failed to identify significant risks associated with releasing Wolbachia-infected A. aegypti. [36] Safety concerns relate to the possible transfer of Wolbachia to humans by mosquito bites, and to non-target species and mosquito predators. [37] Wolbachia infection rates remain at 100% one year after Wolbachia wMel release in Cairns. [38] This intervention has now received regulatory approval. The success of field trials such as this would allow this innovation to move to countries where dengue is endemic.

Problems

The challenge now remains to make Wolbachia-based vector control strategies more universally applicable and sustainable. Some effects of specific Wolbachia strains on DENV transmission may be inappropriate for certain contexts. For example, wMelPop has a more significant impact on DENV transmission in dengue-endemic settings than wMel due to a stronger DENV transmission-blocking effect. [39] However, the wMelPop strain reduces the fitness of A. aegypti more than wMel, so would require additional Wolbachia mosquito deployment to maintain sufficient levels of Wolbachia-infected vectors to prevent dengue transmission. The sustainability of Wolbachia-based strategies is challenged by the significant financial and operational costs for rearing, releasing and re-establishing Wolbachia-infected mosquito populations. [40] As with insecticides, the evolution of resistance poses a risk. [41] A. aegypti could evolve resistance against particular strains of Wolbachia, similar to the resistance of Drosophila simulans after transinfection with Wolbachia wMelPop. [42] Furthermore, dengue virus strains could develop a means of evading Wolbachia-based transmission blocking. Longer-term, larger-scale trials are needed to assess how Wolbachia can reduce the burden of dengue in a sustainable manner.

Comparisons

Table 3. Overview of promising vaccine and vector control approaches.

	Vaccination – Sanofi Pasteur	Vector control – Wolbachia
Mechanism	1.      Vaccine contains strains against the four dengue virus serotypes 2.      Dendritic cells carry strains to lymph nodes to activate B cell proliferation and antibody production 3.      When bitten by infected mosquitos, antibodies neutralise the virus	1.      Natural arthropod Wolbachia bacteria injected into A. Aegypti eggs 2.      Reduce mosquito reproduction, lifespan and pathogen replication 3.      Wolbachia passed between generations
Efficacy/efficiency	Neutralising and immunogenic; reduces dengue fever by 56% and dengue hemorrhagic fever by 88%; inefficient in tackling DENV-2 in trials	Inhibits DENV replication and dissemination and reduces vector lifespan and reproduction; predicted to reduce transmission by 60–100%
Safety	YF-17D is a safe, stable vaccine backbone; low viraemia, reactogenicity, and adverse events	Minimal safety concerns, such as Wolbachia transfer to humans, non-target species, and mosquito predators
Sustainability	Long-term waning of vaccine-elicited immunity may require boosters	Stable in short-term, but potential for Wolbachia resistance in the long-term
Economy	Low production cost	Large operational and re-establishment costs
Universality	Most useful in tropical regions, rather than as a traveller’s vaccine	Mainly effective in urban centers and tropical regions

 

Vaccination and vector control have the potential to be effective, safe, and sustainable, despite their failure to control dengue to date (Table 3). Two large-scale phase III trials in the Americas and Asia involving 40,000 participants have demonstrated an efficacy of 60.8% for CYD-TDV. [16] However, Wolbachia-based vector control is still at the small-scale trial stage in Australia in order to refine methods with further large-scale trials in Indonesia, Vietnam, and Brazil. Small scale trials have been completed in Vietnam. Licensing of the Sanofi Pasteur vaccine is expected with Australian Pesticides and Veterinary Medicines Authority (AVPMA) approval already achieved in Australia. [4] Licensing of Wolbachia will require further field trials, risk assessment, and time. Both vaccination and Wolbachia involve fixed, front-loaded establishment costs that are significantly lower than traditional vector control methods. The risk of adverse events is increased with the Sanofi Pasteur CYD-TDV vaccine that had an efficacy ranging from 56 to 100% against DENV-1, DENV-3 and DENV-4, but not against DENV-2. It may be that incomplete protection can be achieved through combining vaccine and vector control approaches to reduce DENV-2 transmission.

Combinations

Modelling shows that combining vector control with vaccination could increase intervention effectiveness by reducing vector density and therefore infections. One compartmental model found that an imperfect vaccine could reduce dengue incidence by 57%, ten years post-vaccination, but when combined with other strategies, there was a greater reduction in incidence with a rate of 81%, ten years post-vaccination. [43] Another model demonstrated that less efficacious vaccines should not be applied without concurrently applying vector control approaches. [44] Computer simulations suggest that in areas of high mosquito density, vector control followed by vaccination programs could reduce potential surges in dengue virulence. [45] Vector control and vaccination approaches therefore need context-sensitive and coordinated integration. Applied together, vector control and vaccination interventions could reduce DENV transmission significantly and prove to be cost effective. [46] Vaccines for other diseases have previously been paired with vector control methods with few safety issues, better protection against disease risk, and extended efficacy. [47]

Conclusion

The development of safe, effective, and affordable dengue vaccines and new vector control methods promise to rapidly reduce dengue incidence and therefore morbidity and mortality. The most advanced vaccine candidate has proven safe and protective against three of the four dengue virus serotypes. Of the emerging genetic, biological, and environmental vector control methods, the closest to clinical application is the release of mosquitoes infected with specific strains of Wolbachia that can reduce dengue virus replication, reproduction, and life span. The vaccine shows slightly more promise than the Wolbachia vector control method. History has shown that no single approach is able to control dengue and the future of dengue fever prevention may be integrated immunisation, vector control, and social mobilisation.

Conflict of Interest

None declared.

References

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[2] Guzman M, Halstead S, Artsob H, Buchy P, Farrar J, Gubler D. Dengue: a continuing global threat. Nat Rev Micro. 2010;8(12):S7-S16.

[3] Hombach J, Jane Cardosa M, Sabchareon A, Vaughn D, Barrett A. Scientific consultation on immunological correlates of protection induced by dengue vaccines. Vaccine. 2007;25(21):4130-4139.

[4] Guy B, Barrere B, Malinowski C, Saville M, Teyssou R, Lang J. From research to phase III: Preclinical, industrial and clinical development of the Sanofi Pasteur tetravalent dengue vaccine. Vaccine. 2011;29(42):7229-7241.

[5] Durbin A, Whitehead S. Next-Generation Dengue Vaccines: Novel Strategies Currently Under Development. Viruses. 2011;3(12):1800-1814.

[6] Sun W, Cunningham D, Wasserman S, Perry J, Putnak J, Eckels K. Phase 2 clinical trial of three formulations of tetravalent live-attenuated dengue vaccine in flavivirus-naive adults. Hum Vaccin. 2009;5(1):33-40.

[7] Huang C, Butrapet S, Pierro D, Chang G, Hunt A, Bhamarapravati N. Chimeric Dengue Type 2 (Vaccine Strain PDK-53)/Dengue Type 1 Virus as a Potential Candidate Dengue Type 1 Virus Vaccine. J Virol. 2000;74(7):3020-3028.

[8] Osorio J, Huang C, Kinney R, Stinchcomb D. Development of DENVax: A chimeric dengue-2 PDK-53-based tetravalent vaccine for protection against dengue fever. Vaccine. 2011;29(42):7251-7260.

[9] Halstead S, Deen J. The future of dengue vaccines. Lancet. 2002;360(9341):1243-1245.

[10] Putnak R, Coller B, Voss G, Vaughn D, Clements D, Peters I. An evaluation of dengue type-2 inactivated, recombinant subunit, and live-attenuated vaccine candidates in the rhesus macaque model. Vaccine. 2005;23(35):4442-4452.

[11] Lazo L, Izquierdo A, Suzarte E, Gil L, Valds I, Marcos E. Evaluation in mice of the immunogenicity and protective efficacy of a tetravalent subunit vaccine candidate against dengue virus. Microbiol Immunol. 2014;58(4):219-226.

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[13] Putri D, Sudiro T, Yunita R, Jaya U, Dewi B, Sjatha F. Immunogenicity of a candidate DNA vaccine based on the prM/E genes of a dengue type 2 virus Cosmopolitan genotype. Jpn J Infect Dis. 2015.

[14] White L, Sariol C, Mattocks M, Wahala M. P. B. W, Yingsiwaphat V, Collier M. An Alphavirus Vector-Based Tetravalent Dengue Vaccine Induces a Rapid and Protective Immune Response in Macaques That Differs Qualitatively from Immunity Induced by Live Virus Infection. J Virol. 2013;87(6):3409-3424.

[15] Guy B, Saville M, Lang J. Development of sanofi pasteur tetravalent dengue vaccine. Hum Vaccin. 2010;6(9):696-705.

[16] Capeding M, Tran N, Hadinegoro S, Ismail H, Chotpitayasunondh T, Chua M. Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial. Lancet. 2014;384(9951):1358-1365.

[17] Lang J. Recent progress on sanofi pasteur’s dengue vaccine candidate. J Clin Virol. 2009;46:S20-S24.

[18] Kanesa-thasan N, Sun W, Kim-Ahn G, Van Albert S, Putnak J, King A. Safety and immunogenicity of attenuated dengue virus vaccines (Aventis Pasteur) in human volunteers. Vaccine. 2001;19(23-24):3179-3188.

[19] Bonaldo M, Caufour P, Freire M, Galler R. The yellow fever 17D vaccine virus as a vector for the expression of foreign proteins: development of new live flavivirus vaccines. Instituto Oswaldo Cruz. 2000;95:215-223.

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[21] Guirakhoo F, Kitchener S, Morrison D, Forrat R, McCarthy K, Nichols R. Live Attenuated Chimeric Yellow Fever Dengue Type 2 (ChimeriVax-DEN2) Vaccine: Phase I Clinical Trial for Safety and Immunogenicity: Effect of Yellow Fever Pre-immunity in Induction of Cross Neutralizing Antibody Responses to All. Hum Vaccin.  2006;2(2):60-67.

[22] Guy B, Guirakhoo F, Barban V, Higgs S, Monath T, Lang J. Preclinical and clinical development of YFV 17D-based chimeric vaccines against dengue, West Nile and Japanese encephalitis viruses. Vaccine. 2010;28(3):632-649.

[23] Dayan G, Garbes P, Noriega F, Izoton de Sadovsky A, Rodrigues P, Giuberti C et al. Immunogenicity and Safety of a Recombinant Tetravalent Dengue Vaccine in Children and Adolescents Ages 9-16 Years in Brazil. Am J Trop Med Hyg. 2013;89(6):1058-1065.

[24] Mahoney R, Francis D, Frazatti-Gallina N, Precioso A, Raw I, Watler P. Cost of production of live attenuated dengue vaccines: A case study of the Instituto Butantan, Sao Paulo, Brazil. Vaccine. 2012;30(32):4892-4896.

[25] Halstead S. Dengue vaccine development: a 75% solution? Lancet. 2012;380(9853):1535-1536.

[26] Sabchareon A, Wallace D, Sirivichayakul C, Limkittikul K, Chanthavanich P, Suvannadabba S. Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial. Lancet. 2012;380(9853):1559-1567.

[27] Amarasinghe A, Mahoney R. Estimating potential demand and supply of dengue vaccine in Brazil. Hum Vaccin. 2011;7(7):776-780.

[28] Maguire S, Hardy C. Discourse and Deinstitutionalization: the Decline of DDT. Academy of Management Journal. 2009;52(1):148-178.

[29] Gubler D. Epidemic dengue/dengue hemorrhagic fever as a public health, social and economic problem in the 21st century. Trends in Microbiology. 2002;10(2):100-103.

[30] Maciel-de-Freitas R, Aguiar R, Bruno R, Guimares M, Loureno-de-Oliveira R, Sorgine M. Why do we need alternative tools to control mosquito-borne diseases in Latin America? Instituto Oswaldo Cruz. 2012;107(6):828-829.

[31] Thammapalo S, Meksawi S, Chongsuvivatwong V. Effectiveness of Space Spraying on the Transmission of Dengue/Dengue Hemorrhagic Fever (DF/DHF) in an Urban Area of Southern Thailand. J Trop Med. 2012;2012:1-7.

[32] Nam V, Yen N, Duc H, Tu T, Thang V, Le N. Community-Based Control of Aedes aegypti By Using Mesocyclops in Southern Vietnam. Am J Trop Med Hyg. 2012;86(5):850-859.

[33] Mousson L, Zouache K, Arias-Goeta C, Raquin V, Mavingui P, Failloux A. The Native Wolbachia Symbionts Limit Transmission of Dengue Virus in Aedes albopictus. PLoS Negl Trop Dis. 2012;6(12):e1989.

[34] Moreira L, Saig E, Turley A, Ribeiro J, O’Neill S, McGraw E. Human Probing Behavior of Aedes aegypti when Infected with a Life-Shortening Strain of Wolbachia. PLoS Negl Trop Dis. 2009;3(12):e568.

[35] Yeap H, Mee P, Walker T, Weeks A, O’Neill S, Johnson P. Dynamics of the “Popcorn” Wolbachia Infection in Outbred Aedes aegypti Informs Prospects for Mosquito Vector Control. Genetics. 2010;187(2):583-595.

[36] Moreira L, Iturbe-Ormaetxe I, Jeffery J, Lu G, Pyke A, Hedges L. A Wolbachia Symbiont in Aedes aegypti Limits Infection with Dengue, Chikungunya, and Plasmodium. Cell. 2009;139(7):1268-1278.

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[41] Popovici J, Moreira L, Poinsignon A, Iturbe-Ormaetxe I, McNaughton D, O’Neill S. Assessing key safety concerns of a Wolbachia-based strategy to control dengue transmission by Aedes mosquitoes. Instituto Oswaldo Cruz. 2010;105(8):957-964.

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[43] Ferguson N, Hue Kien D, Clapham H, Aguas R, Trung V, Bich Chau T. Modeling the impact on virus transmission of Wolbachia-mediated blocking of dengue virus infection of Aedes aegypti. Sci Trans Med. 2015;7(279):279ra37-279ra37.

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Diseases attributed to tobacco smoking are some of the most prevalent and preventable in the world. Therefore, smoking cessation programs and interventions are crucial components of population health strategies. Currently used interventions and medications have proved effective in aiding patient abstinence from tobacco, yet they are often met with low patient uptake, satisfaction, and compliance. Electronic cigarettes pose a new challenge for clinicians as minimal evidence exists on their safety, health impact and effectiveness as smoking cessation tools.

The evidence to date on electronic cigarettes was reviewed and this guide was developed to assist medical students in providing information and advice to patients about electronic cigarettes. The guide includes information on types of electronic cigarettes, how they work, their health effects, their use in smoking cessation and, current regulation in Australia. The article also includes patient-centred frequently asked questions, with evidence-based answers.

Figure 1: Aerosol from an e-cigarette

Behind the smoke screen

What are e-cigarettes?

Electronic cigarettes, also known as e-cigarettes, e-cigs, personal vaporisers or electronic nicotine delivery systems (ENDS), are battery-operated devices used to simulate the experience of smoking by delivering flavoured nicotine, in the form of an aerosol (Figure 1). Despite the original design dating back to 1963, [1] it was only in 2003 that the Chinese inventor and pharmacist, Hon Lik, was able to  develop the first commercially viable modern e-cigarette. [2]

People use e-cigarettes for many reasons, including: To make it easier to reduce the number of cigarettes you smoke (79.0%), they may be less hazardous to your health (77.2%), they are cheaper than regular cigarettes (61.3%), they are a quitting aid (57.8%), so you can smoke in places where smoking regular cigarettes is banned (57.4%), as an alternative to quitting (48.2%), e-cigarettes taste better than regular cigarettes (18.2%). [3]

What makes up an e-cigarette?

There are various classes of e-cigarette, but all follow a simple design. A lithium ion battery is attached to a heating element known as an “atomiser” which vaporises the e-liquid. The e-liquid, sometimes called “juice”, is traditionally held in a cartridge (the mouth piece) and usually consists of a combination of propylene glycol and glycerine (termed humectants) to produce aerosols that simulate conventional cigarette smoke. [4] Liquid nicotine, water, and/or flavourings are commonly included in e-liquids as well. Some devices have a button designed to activate the atomiser; however, more recent designs work via a pressure sensor that detects airflow when the user sucks on the device. This pressure sensor design emits aerosolised vapour, which the user inhales. This practice is known as ‘vaping’.

What types of e-cigarettes exist?

Currently, three classes of e-cigarettes exist on the market [5]:

Figure 2: A cigalike.

“e-Go’s” comprise the second class. These are larger than cigalikes and have removable tanks that can be refilled with e-liquid (Figure 3).

Figure 3: An e-Go.

Finally, there are modular e-cigarettes (or ‘mods’), which are usually larger than e-Go’s. They have a removable tank and can be customised to the user’s preferences (Figure 4).

Figure 4: A modular e-cigarette, or “mod”.

Why is this important?

E-cigarette devices vary vastly between developers. [6] Users are able to modify their e-cigarette atomisers, circuitry, and battery power to alter vapour production. [7-9] By 2014, there were an estimated 466 brands of e-cigarette with 7764 flavours. [10] Users are also able to select their own e-juice, with 97-99% of users choosing e-liquid containing nicotine. [6, 11] Despite devices on the market delivering less nicotine than conventional combustible cigarettes, [12] many health professionals are concerned about the short and long-term health effects of e-cigarettes. [13]

Demystifying the situation

How safe are e-cigarettes?

Given that e-cigarettes have been available for just under a decade, no long-term studies into their health effects currently exist. However, several short-term studies have been conducted on the health implications of e-liquids, e-cigarette devices, and vapour.

Nicotine

The e-cigarette market is largely unregulated. One study found nicotine amounts in e-liquids varied greatly, with concentrations ranging from 0-34 mg/mL. [14] Of additional concern, further studies found significant discrepancies between ‘label concentration’ of nicotine and ‘actual concentration’, [15] with one reporting that ‘nicotine free’ e-liquids actually contained nicotine. [16] This is of ethical concern given that nicotine is a highly addictive drug [17] likely to influence usage patterns and dependence behaviours. There is a need to assess nicotine dependence in e-cigarette users. [18] One study looked at pharmacokinetic absorption of nicotine by comparing nicotine delivery via e-cigarettes, combustion cigarettes, and nicotine inhalers. It found that e-cigarette absorption rates lay between those of combustion cigarettes and nicotine inhalers, implying that nicotine is absorbed though both buccal (slow, nicotine inhaler) and pulmonary (fast, combustion cigarette) routes. As nicotine dependence is related to absorption rate and exposure, this suggests e-cigarettes users are at risk of dependence. This claim was verified by other studies, which conclusively demonstrated e-cigarette users can achieve nicotine exposure similar to that of combustion cigarette smokers. [19,20]

Propylene glycol and glycerine (humectants)

Propylene glycol and glycerine have not been deemed safe for inhalation [21] because little is known about their long-term impacts on health when inhaled. [22] By-products of heating both propylene glycol (propylene oxide) and glycerine (acrolein) have been found to be potentially carcinogenic and irritating to the respiratory tract. [23] A systematic review of contaminants in e-cigarettes concluded that humectants warrant further investigation given the precautionary nature of threshold limit values (TLVs) for exposures to hydrocarbons with no established toxicity (The TLV of a substance being the level to which it is believed a worker can be exposed, day after day, for a working lifetime without adverse health effects). [24]

Flavours

There are over 7000 flavours of e-liquid as of January 2014. Despite nearly all of these flavourings having been approved for human oral consumption, their safety when heated and inhaled remains questionable. [25] In fact, many flavourings have been shown to be cytotoxic when heated and others resemble known carcinogens. [26] One study found heating cinnamon flavoured e-liquid produced cinnamaldehyde, a highly cytotoxic substance, [27] while another study found balsamic flavour e-cigarettes triggered pro-inflammatory cytokine release in lung epithelium. [28] Furthermore, a recent study looking at 30 e-fluids found that the majority of flavours consisted of aldehydes which are known ‘primary irritants’ of the respiratory mucosa. [29] Manufacturers do not always disclose the exact ingredients in their e-liquids and many compounds are potentially cytotoxic, pro-inflammatory and/or carcinogenic. Thus, the safety of e-liquids cannot be assured. [25,30]

Toxins

In the US, the Food and Drug Administration analysed the vapour of 18 cartridges from two leading e-cigarette manufacturers and confirmed the presence of known and potentially carcinogenic or mutagenic substances. These included diethylene glycol (DEG, an ingredient used in antifreeze that is toxic to humans), tobacco-specific nitrosamines (TSNAs, human carcinogens) and tobacco-specific impurities suspected of being harmful to humans (anabasine, myosmine, and β-nicotyrine). [31] To put these findings into context, the concentration of toxins in e-cigarettes ranged between 9 and 450 times less than those in conventional cigarettes. [19] Secondly, they were found to be at acceptable involuntary work place exposure levels. [24] Furthermore, levels of TSNAs were comparable in toxicity to those of nicotine inhalers or patches, [32] two forms of nicotine replacement therapy (NRT) commonly used in Australia. [33] Lastly, e-cigarettes contain only 0.07-0.2% of the TSNAs present in conventional cigarettes. [34] Of note, in 15 subsequent studies that looked at DEG in e-cigarettes, none was found. [34] 

E-cigarette device

Many chemicals used in e-liquids are considered safe for oral ingestion, yet their health effects when inhaled as vapour remain uncertain. This applies not only to e-liquids but also the e-cigarette device itself. Many e-cigarette devices are highly customisable, with users able to increase voltages, producing greater toxin levels. One study identified arsenic, lead, chromium, cadmium and nickel in trace amounts not harmful to humans, while another found these elements at levels higher than in combustion cigarettes. [36,37] Lerner et al. looked at reactive oxygen species (ROS) generated in e-cigarette vapour and found them similar to those in conventional smoke. They also found metals present at levels six times greater than in conventional cigarette smoke. [38] A recent review noted that small amounts of metals from the devices in the vapour are not likely to pose a serious health risk to users, [24] while other studies found metal levels in e-cigarette vapour to be up to ten times less than those in some inhaled medicines. [39] Given that metals found in e-cigarette vapour are likely a contaminant of the device [6, 40], variability in the e-cigarette manufacturing process and materials requires stricter regulation to prevent harm to consumers.

Effects on health

E-cigarettes appear to be safer than combustion cigarettes, [15] but they should not be considered harm free. [41] A 2014 Cochrane review found no ‘serious’ adverse effects from e-cigarette trials to date, [42] yet another review which included 28 publications found hazards related to e-cigarettes (Table 1). [43].

Table 1. Frequently reported hazards of electronic cigarette smoking [43]

Respiratory system	Upper respiratory tract irritation, dry cough, dryness of the mucus membrane, nose bleeding, release of cytokines and pro-inflammatory mediators, allergic airway inflammation, decreased exhaled nitric oxide (FeNO) synthesis
Nervous system	Headache, dizziness, nervousness, insomnia, sleeplessness
GIT	Nausea, vomiting, dry mouth, mouth or tongue sores/inflammation, black tongue, gum bleeding, gingivitis, gastric burning, constipation
CVS	Palpitation, chest pain
Eye	Irritation, redness and dryness of the eyes, can cause eye damage
Choking hazards	Accidental exposure to high concentrations of e-liquids can cause choking hazards
Malignancy	Change in bronchial gene expression and risk of lung cancer
Miscellaneous	Shortness of breath, shivering etc

Other large studies supported this information. [23,44-46] Research on short-term changes to cardiorespiratory physiology following e-cigarette use included increased airway resistance [25] and slightly elevated blood pressure and heart rate. [47] As the short- and long-term consequences of e-cigarette use are currently unclear, [47] a conservative stance would be to assume vaping as harmful until more evidence becomes available.

Where there’s smoke, there’s fire

 Australian law and e-cigarettes

In Australia there is currently no federal law that specifically addresses the regulation of electronic cigarettes; rather, laws that relate to poisons, tobacco, and therapeutic goods have been applied to e-cigarettes in ways that effectively ban the sale of those containing nicotine. In all Australian states and territories, legislation relating to nicotine falls under the Commonwealth Poisons Standard. [49,50] In all states and territories, the manufacture, sale, personal possession, or use of electronic cigarettes that contain nicotine is unlawful, unless specifically approved, authorised or licenced. [49,50]

Under the Commonwealth Poisons Standard nicotine is considered a Schedule 7 – Dangerous Poison. E-cigarettes containing nicotine could be removed from this category in the future should any device become registered by the Therapeutic Goods Administration (TGA), thus allowing it to be sold lawfully.

There are currently no TGA registered nicotine containing electronic cigarettes [51] and importation, exportation, manufacture and supply is a criminal offence under the Therapeutic Goods Act 1989. [52] It is, however, possible to lawfully import electronic cigarettes containing nicotine from overseas for personal therapeutic use (e.g. as a quitting aid) if one has a medical prescription as this is exempt from TGA registration requirements outlined in the personal importation scheme under the Therapeutic Goods Regulations 1990.

Therefore, it is up to the discretion of the medical practitioner if they provide a prescription for a product not yet approved by the TGA. Given that legislation currently exists to permit medical practitioners to assist individuals in obtaining e-cigarettes, it is imperative we understand both the legal environment at the time and the health consequences.

Stick that in your e-cig and vape it!

E-cigarettes as smoking cessation aids

Figure 5: Quitting tobacco cigarettes through vaping (Image courtesy vaping360.com)

A debate continues as to whether e-cigarettes – with or without nicotine – are able to play a role in smoking cessation (Figure 5). In the absence of large scale clinical trials it is impossible to answer this question definitively. What is clear from smoking statistics worldwide is that more needs to be done regarding smoking cessation. E-cigarettes may be another tool to help achieve a tobacco free future. Thus far, conventional NRT has been rated by most smokers attempting to quit as unappealing [53] despite evidence that NRT increases quit rates by 50-70% compared to placebo. [54] Few trials have been conducted to investigate whether e-cigarettes are effective tools for smoking cessation, but one recent systematic review and meta-analysis found that nicotine containing e-cigarettes were associated with both a significant reduction in the number of combustion cigarettes smoked as well as complete smoking tobacco abstinence. [53] This suggests that e-cigarettes have potential as cessation aids and tobacco harm reduction devices.

E-cigarettes containing nicotine were more successful in helping patients reduce or quit smoking than those without nicotine according to a recent Cochrane review, [42] a finding in-line with conventional NRT vs. placebo studies. The review was unable to compare e-cigarette trials to conventional NRT trials given differences in study designs but commented that on average quit rates using conventional NRT at 12 months were 10%, while e-cigarette use corresponded with quit rates of 20%.

E-cigarettes, unlike conventional NRT products, are not only able to provide smokers with nicotine to satisfy their pharmacological addiction, but by design simulate many of the behaviours that have been psychologically ingrained through long-term smoking. E-cigarettes allow users to inhale and exhale a smoke-like substance. They can handle a device of similar shape to satisfy the oral fixation. Psychological triggers from ‘smoker-friendly venues’ can be relieved by using e-cigarettes, and flavourings can be customised to tobacco or menthol. These factors may prove e-cigarettes a valuable ally in the fight on tobacco. However, there is concern among some health practitioners that e-cigarettes may be a gateway to use of combusted tobacco. [55] If a patient is seeking advice about quitting, it is important to provide them with well tested NRT and medications. These include nicotine delivery preparations for oromucosal (nicotine gum and spray) and transdermal (nicotine patches) routes as well as other drugs including bupropion, varenicline and cytisine medications, [56] with varenicline being the most effective in improving likelihood of quitting. [53]

Questions you may be asked by patients

My partner and I are looking to start a family soon. Is it safe to use electronic cigarettes during pregnancy?

As e-cigarettes lack many of the harmful carcinogens found in regular tobacco cigarettes, consumers might be misled into believing these products are safe. This is of great concern to traditionally high-risk groups, such as pregnant women. In a 2015 review, the author concluded that, based on current evidence, no amount of nicotine is known to be safe during pregnancy. [40] To date, there is no evidence looking specifically at e-cigarette use in pregnant women, however much is known about nicotine exposure in pregnancy. Nicotine is metabolised faster in pregnant women [57] and easily crosses the placental barrier to enter fetal circulation, [40,58] and nicotinic receptors implicated in brain development [59,60] are present in the fetal brain from the first trimester of pregnancy. Many women may seek to use e-cigarettes since conventional NRT in pregnant women has been highly unsuccessful for smoking cessation. [61] Nicotine is considered a Category D drug under Australian pregnancy guidelines (formerly ADEC) and exposure during pregnancy has been found to cause significant health consequences in the fetus and neonate. [62] It is important to inform patients that current evidence suggests nicotine, at any concentration, during pregnancy is not considered safe and all efforts should be made to ensure a nicotine-free pregnancy with effective strategies implemented prior to conception.

My housemates are always using e-cigarettes near me. Can I get sick if I am around them when they use one?

Evidence, especially long-term data, is lacking on the effects of e-cigarettes on bystanders. [13] What is known is e-cigarette vapour contains nicotine and particles that may be inhaled by persons in the vicinity of e-cigarette users. [28] One study found low levels of formaldehyde and nicotine among several other chemicals emitted into the air. It was subsequently concluded that toxins in e-cigarette aerosols were emitted at much lower levels compared with conventional cigarette emissions. [63] A 2014 systematic review [24] compared TLVs to the “worst case” assumptions about both chemical content of aerosols and liquids as well as behaviour of e-cigarette users and concluded “there is no evidence that vaping produces inhalable exposures to contaminants of the aerosol that would warrant health concerns by the standards that are used to ensure safety of workplaces”. Any effect on bystanders from e-cigarette vapour is likely to be much less than combustion cigarettes, a similar conclusion reached by other studies. [39,64] However, some studies have shown serum cotinine levels (the primary metabolite of nicotine) to be increased in non-smokers exposed to e-cigarette vapour, [65,66] though only to levels ten percent of that of second-hand smoke from conventional cigarettes. Even if toxins in vapour are likely to pose little harm to bystanders, the very presence of toxins and nicotine in vapour is inconsistent with the claim most e-cigarette companies make of vapour being ‘just harmless water vapour’.

So I’ve heard e-cigarettes may be unhealthy, but are they dangerous?

There are potential dangers surrounding e-cigarettes arising from their design and engineering. The United States Fire Administration recently compiled a report of over 25 fires or explosions from e-cigarettes, either while being used or charged, many of which resulted in serious burns to individuals and damage to property. [67]

Nicotine in the e-liquid refill packs is considered a potentially lethal poison. [11] If ingested or in direct contact with skin it poses a potential serious health risk, [68] including the potential for overdose in children. [69] There has been at least one known fatality in a toddler from accidental ingestion and overdose of liquid nicotine intended for e-cigarette use. There have been over 3500 liquid nicotine exposure related incidents recorded by the American Association of Poison Control Centres since November 2014. [70]

What are tobacco companies doing about e-cigarettes?

It is worth noting that many tobacco companies have opted to include e-cigarettes in their product portfolio. [6] Thus ethically speaking, it is vital for doctors to understand that by recommending e-cigarettes they may indirectly be supporting the tobacco industry.

Conclusion

E-cigarettes are a growing market and present a novel challenge to clinicians and medical students. Traditional approaches of obtaining pack-year histories or relying on tell-tale signs of smoking such as tar stained fingers or smoke odour will not work for e-cigarette users. We must ask specifically about use of e-cigarettes when taking a smoking history, use terms like ‘vaping’, ask whether the e-juice contains nicotine and if they have customised their devices. We must not become complacent simply because e-cigarettes are currently viewed as the lesser of two evils with regards to impact on health. As medical students, deciding whether or not to endorse e-cigarettes as smoking cessation aids is a complex issue given that proven, safe, and effective treatments currently exist, and those should be used as primary cessation aids. If a patient has used these primary aids and failed to quit, it is worthwhile considering e-cigarettes as an avenue for achieving tobacco abstinence. It is unlikely that the clinicians we encounter in our studies will have a detailed understanding on e-cigarettes and vaping practises; it is therefore up to us to keep abreast of such knowledge to provide patients with quality information and care.

Acknowledgments

The author would like to thank Kelly Mirowska-Allen, a third-year medical student at the University of Melbourne, for assistance in proofreading this article and providing support and advice.

Conflict of interest

None declared.

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Detection and triage of cervical cancer has undergone commendable advances since the introduction of the Papanicolaou (Pap) smear, Human Papilloma Virus (HPV) detection, and recent implementation of the HPV vaccine. Many Australian females have benefited from these public health advances, however as with many other health trends in Australia, the Indigenous population appears to be lagging behind. This article reviews cervical cancer incidence and mortality as well as its public health management in the Indigenous context. It also reiterates clear issues in the medical record system for identifying Indigenous status in screening and addresses the reasons for disparities in these health trends. In reintroducing the idea of self-collection techniques in the Indigenous context, it is hoped that its ability to overcome privacy and cultural issues associated with traditional Pap smear collection methods and its potential to benefit Indigenous uptake of cervical screening is highlighted. These benefits could be extended to all women who remain averse to the idea of traditional Pap smear collection procedure. This article also explores the possibility of developing a screening method involving the combination of tampon self-collection with ThinPrep and Hybrid Capture II DNA assay technology.

 Cervical cancer screening and prevention in the Indigenous context

Cancer is a growing health issue for Indigenous populations in Australia and it is now being listed alongside cardiovascular disease as a focus for national health strategies to improve Indigenous health. [1] Despite recent trends of decreases in incidence and mortality for cervical cancer in the general population, Indigenous women suffer from higher rates of incidence (21.4 vs. 8.6 per 100,000) and mortality (9.0 vs. 1.9 per 100,000) according to the most recent report on cervical screening from the Australian Institute of Health and Welfare. [1] Reports suggest that Indigenous women also suffer from later detection of cervical cancers, with positive Pap smears on average showing more advanced cellular atypia. [2] It is suggested that incidence and mortality from cervical cancer is highly related to the frequency of screening undergone by the patient. [3] Hence, it is arguable that the best way to address the disparity in cervical cancer between Indigenous and non-Indigenous populations is to encourage screening uptake by Indigenous women.

Participation of Indigenous women in preventative measures regarding cervical cancer (Pap smears and HPV vaccine) is hard to quantify. One difficulty is that Indigenous status is not a mandatory field on pathology requisitions for Pap smears. [4,5] As a result, state and territory registers do not have reliable information to quantify the number of Indigenous women participating in screening programs. [4,6] Data taken from individual Indigenous health services and communities estimate the number of Indigenous women in those communities undergoing Pap smears ranges from 27-63% [4] with other studies report an increasing trend of women in the Northern Territory participating in cervical screening since 1999. [2] Other data has shown positive results for vaccine uptake amongst Indigenous Queensland adolescents in school-based programs as part of the national vaccination strategy. [7] This will benefit future generations of Indigenous women in regards to cervical cancer prevention. However, in considering health prevention strategies that more directly influence immediate cancer rates in Indigenous populations, it is arguably more important to consider the cervical cancer screening issues in women who did not receive the HPV vaccine in their adolescence.

The aforementioned health trends are attributed to complex and multifaceted explanations. Risk factors contributing to higher cervical cancer burden for Indigenous women reportedly may be related to health behaviours (e.g. smoking), other co-morbidities (e.g. diabetes), and sexually transmitted infection. [8] However, in terms of cervical cancer screening, reluctance to either participate in cancer screening, or return for follow up of abnormal results is an especially large contributor to the burden of disease. [9] Cultural barriers between the Indigenous community and the health system are also likely to be heavy contributors. A study of Indigenous women found that they have fearful and fatalistic attitudes toward cancer [9] and there is a heavy social stigma surrounding the topic of cervical cancer as it is a ‘dirty disease’. In fact, other gynecological problems are often ignored as they are associated with a sense of shame. [9]

When considering the prominent cultural barriers for Indigenous women, it can be proposed that the participation in screening amongst this demographic could be improved by implementing more culturally respectful methods of testing, health promotion, and education in communities to encourage uptake of screening methods. The latter part of this solution has been quite effectively implemented in certain areas of Australia through the efficient use of Aboriginal healthcare workers in collaboration with other government public health initiatives. [10] However, it appears we are still strongly limited by the screening technique itself. The most reasonable solution to avoiding the issue of physician-associated collection and invasion of personal privacy for Indigenous women (as with all women) lies in the development of a self-collection protocol. This avenue has been explored in the past by different studies with varying results; but in light of newly developing technology, now may be the time for re-examination.

Methods of self-collection technique

There are many possible methods of self-collection currently being explored, including tampons, dry swabs, and brushes. These aim to pick up sloughed off cervical cells in the vaginal canal for review.  A study by Budge et al. has explored the possibility of a tampon ‘self-collection’ technique to gather cervical cells for pathological review in place of the traditional Pap smear protocol. However, as identified by this study, an inherent problem with the efficacy of using tampon collection technique is that adequate collection of cells for review relies heavily on correct positioning of the tampon within the vaginal canal. [11] Harper et al. have contributed to the development of tampon collection by observing correlations between increased cervicovaginal exposure time and increased efficacy of the self-collection technique, finding comparable efficacy with traditional swab collection techniques. [12] Another study that looked at the efficacy of dry swab collection techniques, similar to tampon collection, observed that it was lacking in ability to pick up endocervical cells for cytological review. [13] It was also found that though self-collected samples provided comparable cytology concordance with physician-collected samples, its low sensitivity and negative predictive value prevents its use as a primary screening tool. [13] Hence there has been a movement to combine self-collection with other innovations to improve its viability as a screening tool for cervical cancer. The study by Budge et al. combined the use of tampon self-collection with ThinPrep technology to preserve the viable cells collected, the efficacy of which is discussed below.

ThinPrep

ThinPrep is proposed to help preserve accuracy where transport and storage issues may otherwise affect sensitivity of testing in a rural setting. [11] ThinPrep is characterized by the usual technique of collection of cells of the transitional zone of the cervix with a brush and the sample is then immediately immersed in a fixating agent to be delivered to a laboratory. [14] The mixture is then centrifuged, filtered, and processed to a mono-layered sample for histological analysis. [14] This method of preparation is said to provide a more easily-analysed sample, free of obscuring factors such as blood and mucous, overlapping cells or air-drying artefacts. [14] As a result, it has been concluded that ThinPrep does have the potential to increase sensitivity of testing if used correctly compared with conventional Pap smear methods. [15] However, Michael et al. suggests the ThinPrep method is not completely fault-proof. There have been cellular changes reported in ThinPrep samples compared to conventional smears. [16] Those cellular changes included smaller appearing cells, and nucleolar and cytoplasmic changes. Despite this, Michael et al. does note that general features of malignancies such as nuclear pleomorphism and membrane irregularities are well-preserved. [16] Currently, it appears that ThinPrep is only approved for use with traditional cervical cell collection methods. The use of ThinPrep with tampon collection remains a research initiative that has definite potential. If further research is conducted to support the efficacy of ThinPrep in better preserving collected samples we may have a very effective means of reducing disparities in quality of service to not only Indigenous, but all rurally located women in Australia.

Hybrid capture collection

Development of Hybrid Capture II (HC2) DNA testing assay sheds light on the possibility of using HPV DNA testing of cervicovaginal samples as new means of triage for the need to screen with cytological review. Putting this into practice would require facilitating the self-collection of samples and analysing them for infection with particular HPV subtypes, for example the HPV genotypes 16 and 18 which are the most strongly associated with development of cervical cancer. [17] Depending on the type of infection, further cytological analysis may be prompted, involving a traditional physician-collected Pap smear (in the absence of a self-collected specimen adequate for cytological review). Incorporating this step of ‘pre-screening’ may encourage women to become more receptive to making contact with the screening process.

Igidbashian et al. have tested the efficacy of combining the self-collection technique and the HC2 assay for detection of cervical cancer risk compared with traditional Pap smears. Their study shows that incorporation of HC2 allows increased sensitivity in detection of HPV infection compared with cytological review. [18] However, it also demonstrated detection of transient HPV infections which may not be relevant for the detection of cervical neoplasia. [18] Despite this, the study does allude to the ability of HPV testing to separate women into high risk and low risk groups of developing of cervical intraepithelial neoplasia (CIN). [18] This is supported by the work of Bulkman et al. which approves of the use of HC2 testing to allow earlier detection of more potentially severe lesions. [19] Cochrane Collaboration has not yet reviewed this matter in particular; but does provide some support for the use of HPV DNA testing via HC2 assay over repeat cytological review in the triage of women with minor cervical cell changes present on an initial cytological review. [21] The prognostic value of HPV testing for cervical carcinomas is also recognised in a study by Lai et al. which notes an association between HPV 18 infection and poorer prognosis of cervical cancer. [22]

There is insufficient research to support or refute the use of HPV DNA testing as a ‘pre-cytological screening’ tool; but it is arguably a worthwhile avenue of research given the current inclusion of HPV DNA testing in many guidelines. Furthermore, there is evidence to support the comparable efficacy of self-collected samples versus physician-collected samples in HPV infection detection as opposed to cytological analysis. [23] Incorporation of HPV DNA testing may power the possibility of self-collection techniques. The use of this in screening methods for cervical cancer has great potential to overcome many of the privacy issues surrounding a physician-conducted cervical swab in conservawomen.

Acceptability of self-collection techniques

Positive results regarding the acceptability of self-collection techniques has been demonstrated by Guan et al. in a study amongst a rural Chinese population [24], whose culture may have conservative elements similar to that seen in the Indigenous women of Australia. The study also suggests that self-collection techniques may be a promising alternative to traditional specimen collection in rural areas where there may be a lack of trained medical practitioners. [24] This idea is supported by findings of Budge et al. in observing many women voiced their approval that the tampon-collection technique was ‘less embarrassing’ and gave them ‘more control over [their] own health’. [11] Both these factors are pertinent indications for the value of developing and using self-collection techniques amongst Indigenous women. However, despite such promising research, previous systematic reviews of self-collection technique suggest there is still insufficient evidence to support their clinical use in place of the traditional methods  This would suggest it may be worthwhile for further research to be invested in this area – the combination of self-collection with ThinPrep and HC2 may be the answer to improving screening rates in rurally located Indigenous women.

Conclusion

Despite successes of previously implemented prevention strategies for cervical cancer in Australia; it is clear that once again, the Indigenous population is lagging behind, with Indigenous women suffering from a greater burden of disease due to cervical cancer compared to non-Indigenous women. This could be attributed to their lower access or uptake of the only current widely available and approved tool: Pap smears. The issues of invasiveness and breach of privacy surrounding Pap smear practice itself stands as a significant barrier between Indigenous women and their uptake of cervical cancer screening. Addressing the possible alternatives to traditional Pap smear collection may be pertinent to successfully overcoming particular cultural barriers to cervical screening. Concepts of tampon-collection technique, incorporation of ThinPrep and Hybrid Capture II assay technology all pose potential improvements in the area of self-collection methods. Successful development of a combined technique with appropriate health promotion could make incredible differences in uptake of cervical screening amongst all the generations of Indigenous women who missed out or may miss out on the HPV vaccine. It may also be helpful to make modifications to the records process for screening tests to mandatorily include Indigenous status of women to gain more reliable data.

Acknowledgements

None.

Conflict of interest

None declared.

Correspondence

D Quach: 93dquach@gmail.com

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The United States is unique among Western countries in setting the minimum legal drinking age at 21 years. The choice of 21 was largely driven by a powerful road-safety lobby group in the 1980s; however a wealth of clinical and epidemiological evidence has subsequently emerged in its favour. A highly-publicised article in the Medical Journal of Australia [1] recently proposed raising the Australian minimum drinking age from 18 to 21, citing both sociological and neurodevelopment arguments.  This essay reviews the three conditions that should be satisfied for such a legislative change to occur, and proposes an alternate license-based model for age regulation as a thought experiment.

Age-21 Laws in the 21^st Century

When prohibition ended in the United States in 1933 with the 21^st Amendment, states were given autonomy to set their own alcohol regulations. This included the minimum legal drinking age. The commonest age chosen was 21 years (in 32 states), followed by 18 years (13 states), 20 years (3 states), and 16 years (in Ohio). [2] 21 was likely favoured because, at the time, this was the age of majority in most US states – the age when an individual was legally considered an adult, the age when they could vote in state elections. [3]

Forty years later, in the midst of the Vietnam War, the issue of drinking age emerged once again into the spotlight. A public campaign argued that it was nonsensical for a man to be conscripted to the army, be sent abroad to fight and die for his country, and yet not legally be permitted to have a drink. One by one, under strong public pressure, the states lowered the drinking age to 18 years. [3] This coincided with changes in the age of majority at a federal level. The 26^th Amendment of 1971 gave 18-20 year-olds the right to vote in the United States – 18 years became the age of adulthood.

However, while voting rights persisted for 18-year-olds, this lowered drinking age lasted but one generation. In 1984, the Reagan administration passed the National Minimum Drinking Age Act, which raised the legal drinking age to 21 again. [4] To expedite the change, the federal government threatened significant infrastructure cuts to any states that did not comply. By 1988, alcohol was banned for under-21s in all 50 states and territories across America. Even Ohio.

The strongest lobby group in support of this raised drinking age was “Mothers Against Drunk Driving” (MADD) – a not-for-profit organisation run by mothers of the victims of alcohol-fuelled driving accidents, many of whom were under the age of 21. [5] MADD claims that this legislation has saved over 25,000 lives since 1988, purely from traffic-related morbidity. [6] Subsequent evidence has confirmed that a 21-year old drinking age has benefits far beyond road safety, reducing the incidence of alcohol dependence [7], alcohol-related violence [8], suicide [9], and risky sexual behaviours amongst youth. [10] More recent neurodevelopmental evidence has bolstered the case, demonstrating that alcohol exposure impairs neuronal maturation in under-21s. [11] Consequently, the US persists in this awkward legislative balance where individuals can vote, drive and enlist in the army at 18, but cannot yet purchase a beer.

This is not unique from an international perspective in that 6 other nations have a 21-year minimum drinking age: Sri Lanka, Indonesia, Kazakhstan, Oman, Pakistan and Palau. [12] In all these cases, the choice of 21 was driven far more by cultural and religious factors than epidemiological evidence. The closest other OECD nation is Japan, with a drinking age of 20. The vast majority of countries have chosen 18 years, in line with the standard age of legal majority. Switzerland, Belgium, Austria, Germany, and the Netherlands have all chosen an age of 16.

Advance Australia where?

Although it is clearly not the mainstream position internationally, public support is growing for a 21 year minimum drinking age in Australia. In 2010, 50.2% of respondents supported such a change, compared to 40.7% in 2004. [13] In a 2014 article in the Medical Journal of Australia, Toumbourou et al. elegantly assembled the case for a 21-year threshold [1]. The article gained significant media attention in May 2014, catapulting the issue of drinking age into the spotlight – not for reasons of youth enfranchisement (as in the Vietnam era), not for reasons of road safety, but with a comprehensive clinical and epidemiological argument behind it. The National Alliance for Action on Alcohol and the Australian Medical Association have added weight to this “age-21” campaign. But is this a realistic option for Australia? In the delicate balancing act between theoretical goals and practical realities, what age is the magic number? Is a single age too simple?

The burden of proof

Any case for age-21 legislation in Australia should demonstrate three key points:

• That alcohol consumption at 18-21 years causes significant negative outcomes
• That age-21 regulations are effective at reducing the alcohol intake of under-21s
• That the benefit of alcohol restriction outweighs the value of preserving 18-21 year olds’ autonomy

The reason point (iii) is necessary is that points (i) and (ii) are likely true for all age groups: restricting alcohol purchase would presumably reduce alcohol consumption and therefore alcohol-related complications irrespective of age. As a society, we have made a policy decision to tolerate alcohol use despite its associated risks in the interests of public autonomy. So the real question here is whether under-21s are disproportionately affected by alcohol-related risks to the point that this autonomy should be overridden and all consumption legally forbidden. Is the 18-21 age group really so vulnerable?

Condition 1 – An age of vulnerability

There is accumulating evidence to suggest that 18-21 year olds are a population at extreme risk from alcohol-related complications based on neurodevelopmental, road-safety, and behavioural data.

1.Neurodevelopmental

Cross-sectional studies have shown that alcohol consumption during adolescence is associated with short- and long-term cognitive impairment, including deficits in information processing, memory, attention and executive function. [11, 14] This is especially true for binge drinking behaviours. [15] Structurally, there appears to be impaired white matter development in the prefrontal cortex and fronto-striatal circuitry, which has been demonstrated with CT [16], fMRI [17] and post-mortem data. [18] However, some critics have argued that these neurobiological variations may be pre-existing features that predispose individuals to alcohol experimentation, rather than the consequence of alcohol abuse. For example, in a recent review article Clark et al. [19] suggest that studies have not sufficiently controlled for confounding psychological variables, such as attention deficits and disruptive behaviours, which are known to be associated with early alcohol experimentation. To clarify the causal links, further longitudinal data is required assessing the baseline neurobiological status of adolescents before their first alcohol exposure.

2. Road Safety

A 2001 meta-analysis of 9 population studies found that raising the minimum legal drinking age from 18 to 21 caused a 12% reduction in overall road-related mortality. [20] This aligns with the data collected by MADD and the National Highway Safety Administration in the United States [6]. However, the question arises whether these improvements in road safety are age-specific. Would raising the drinking age to 25 also cause a 10% drop in accidents among 21-24 year-olds? The argument is that 18-21 year-old drivers are the least experienced, the least responsible, and therefore the most vulnerable to alcohol. However, there is a lack of rigorous data to demonstrate age-specificity. The legal alcohol limits for driving in Australia are somewhat age-dependent, with L- and P- drivers having a zero blood-alcohol tolerance, compared to 0.05% for full-licensees. Does a differential blood alcohol threshold provide adequate protection to account for the clear difference in risk profile between adolescents and older drivers? [21]

3. Risk behaviours

Beyond road-related accidents, there is strong evidence to suggest a broader correlation between alcohol use and risky behaviours. A survey of Australian 17-19 year olds on “Schoolies” showed that 64% had consumed more than 10 drinks on a single occasion, and 18% displayed risky sexual behaviours. [22] A survey of almost 9000 American adolescents 12-21 showed a striking correlation between alcohol excess and physical violence [23]; while Miller et al. argue that early alcohol consumption, especially in the form of binge drinking, may be a precursor of other illicit drug use. [24] Many studies also demonstrate a link between alcohol excess and suicidal behaviours in adolescents, however the causal direction has not been well characterised. [25] These are compelling arguments that demonstrate not only a deleterious effect of alcohol, but also a clear correlation between minimum age legislation and outcome data.

Condition 2 – The power of the law

Despite certain experimental shortfalls, the overarching trend across neurodevelopmental, road safety and behavioural data seems to support this notion of 18-21 year-olds being particularly vulnerable to alcohol. If we accept this to be true, then the second key burden of proof relates to whether an elevated age gap actually does translate into a reduction in early-age alcohol consumption. Some critics argue that higher age restrictions in fact drive alcohol use underground and lead to more dangerous patterns of consumption. [26] In other words, age-21 laws do not allow adolescents to learn safe drinking practices within a family context, instead forcing them to experiment independently, albeit at a later age. However, the data from large-scale European studies comparing adolescent drinking behaviours in the EU and US strongly suggest otherwise. The European School Survey Project on Alcohol and Other Drugs (ESPAD) found that a greater proportion of 10^th-graders in Europe had consumed alcohol within the past 30 days (33% in the US versus 80% in Denmark, 75% in Germany, 64% in France). [26] Furthermore, a higher percentage had been intoxicated before age 13 (8% in the US versus 25% in Denmark, 14% in Germany, 9% in France). Of course, it is difficult to disentangle the effect of legislation in each of these countries from the influence of culture and tradition. However, on the surface it would appear that countries with lower drinking age consistently show earlier exposure to alcohol in adolescence.

New Zealand data have demonstrated that youth several years below the legal drinking age invariably gain access to alcoholic products through older friend circles and siblings [27] – a phenomenon that Tambourou et al. refer to as the “trickle-down” effect. [1] Evidence suggests that an upward shift in the legal drinking age not only reduces the number of 18-21 year olds consuming alcohol, but also significantly reduces the likelihood of 15-18 year olds acquiring it. In summary, the evidence supports the hypothesis that legal restrictions do translate into community practice.

Condition 3: A balancing act

Having satisfied the first two conditions, we arrive at the third and most challenging question: does the negative impact of alcohol amongst under-21s outweigh their personal autonomy as legal adults? Tangled up with this argument is the deeply-ingrained cultural idea that alcohol consumption is a mark of adulthood, a rite of passage. By instituting age-21 laws, the state would not only be removing personal autonomy, but also stamping out cultural aspects of the coming-of-age tradition. Is this fair, is it necessary, is it overly paternalistic? There is some evidence to suggest that raising the minimum legal drinking age causes a ‘reactance phenomenon’ where underage individuals drink more in response to the imposed restrictions. [28] However a large meta-analysis by Wagenaar et al. disputes this finding, demonstrating amongst 33 studies from 1960-2000 a strong inverse relationship between minimum drinking age and alcohol consumption rates. [29]

In spite of these data, there remains the fundamental philosophical issue of whether it is equitable to impose a blanket regulation across all under-21s when the negative statistics are driven by a small minority of excessive alcohol drinkers? Ultimately, these are questions of political philosophy more than clinical data – to what extent should the state protect individuals from themselves? There are no easy answers. This is a situation where public opinion must shape government policy.

An individualised system

One key problem is that public policy cannot take into account the diversity of the target population – with 18-21 year olds varying significantly in maturity, family support, and risk-taking behaviour. Given this variability, one might consider a system where alcohol regulations are personally tailored. As a thought experiment, consider the possibility of “alcohol licenses” for individuals. An 18-year-old might be required to pass a written examination on content similar to the current Responsible Service of Alcohol syllabus. There could be a point system, with points lost and licenses potentially revoked for alcohol-related misdemeanours. Perhaps even a provisional license system (like L- and P-plates) restricting the type and quantity of alcohol that could be purchased by youth. This would require a large bureaucratic infrastructure to support it; however it may be one option for creating a smoother pathway from adolescence into responsible alcohol use.

Conclusions

Toumbourou et al. conclude their article with a call-to-action for a multi-level advocacy campaign in support of age-21 regulations. [1] However, perhaps the real value is in the dialogue more than the outcome. Ultimately, drinking age is an arbitrary number that does not perfectly match the maturity levels of all individuals and certainly does not perfectly translate into alcohol consumption patterns. The important point is that society becomes aware of the risk of premature alcohol use, and that this knowledge becomes integrated into family education, peer dynamics, and youth culture. The real goal should be for adolescents to approach alcohol in a mature and sensible fashion. Regardless of where the Australian law ultimately settles, perhaps it takes a high-profile legislative debate in order to bring this conversation into the spotlight.

Acknowledgements

None.

Conflict of interest

None declared.

Correspondence

M Seneviratne: msen5354@uni.sydney.edu.au

References

[1] Toumbourou J, Jones S, Hickie B. Should the legal age for alcohol purchase be raised to 21? Med J Aust, 2014;200(10):568-70.

[2] Miron J, Tetelbaum E. Does the minimum legal drinking age save lives? Economic Inquiry 2009;47(2):317-36.

[3] The law relating to age of majority, the age of marriage and some connected subjects, in Working Paper No. 2. 1977, The Law Reform Commission.

[4] LegalFlip. Why is the Legal Drinking Age 21 in the United States? 2014; Available from: http://www.legalflip.com/Article.aspx?id=20&pageid=84.

[5] DeJong W, Blanchette J. Case closed: research evidence on the positive public health impact of the age 21 minimum legal drinking age in the United States. J Stud Alcohol  Drugs, 2014;Suppl 17:108-15.

[6] Lives saved in 2008 by restraint use and minimum drinking age laws – in National Highway Traffic Safety Administration. June 2009.

[7] Dawson DA, Goldstein RB, Chou SP, RuanW J, Grant BF. Age at first drink and the fi rst incidence of adult-onset DSM-IV alcohol use disorders. Alcoholism: Clin Exp Res 2008;322:149-60.

[8] Hingson R, Heeren T, Zakocs R. Age of drinking onset and involvement in physical fights after drinking. Pediatrics, 2001;108:872-77.

[9] Birckmayer J, Hemenway D. Minimum-age drinking laws and youth suicide, 1970-1990. Am J Public Health Res, 1999;89:1365-68.

[10] Hingson R, Heeren T, Winter MR, Wechsler H. Early age of first drunkenness as a factor in college students’ unplanned and unprotected sex attributable to drinking. Pediatrics, 2003;111:34-41.

[11] Squeglia L, Jacobus J, Tapert SF. The Influence of Substance Use on Adolescent Brain Development. Clin EEG Neurosci, 2009;40(1):31-38.

[12] Hanson GR, Venturelli PJ, Fleckenstein AE. Current statistics and trends in alcohol consumption, in Drugs and Society. 2015, Jones & Bartlett Publishing.

[13] National Drug Strategy Household Survey report, in AIHW Cat. No. PHE 145. 2010, Australian Institute of Health and Welfare.

[14] Hermens D, Lagopoulos J, Tobias-Webb J. Pathways to alcohol-induced brain impairment in young people: a review. Cortex, 2013;49:3-17.

[15] Carlen PL, Fornazzari L, Bennett J, Wikinson DA. Computerized tomographic scan assessment of alcoholic brain damage and its potential reversibility. Alcohol Clin Exp Res 1986;10:226-32.

[16] Agartz I BS, Hamma FJ, Svinhufvud K. Volumetry during acute alcohol withdrawal and abstinence: a descriptive study. Alcohol, 2003;38:71-78.

[17] Krill J, Halliday GM, Svoboda MD, Cartwright H. The cerebral cortex is damaged in chronic alcoholics. Neuroscience, 1997;73:993-98.

[18] Clark DB, Thatcher DL, Tapert SF. Alcohol, psychological dysregulation, and adolescent brain development. Alcoholism: Clin Exp Res, 2008; 32(3):375-385.

[19] Shults R, Elder RW, Sleet DA. Reviews of evidence regarding interventions to reduce alcohol-impaired driving. Am J Prev Med, 2001;21(4)Suppl 1:66-88.

[20] Jonah BA, Dawson NE. Youth and risk: age differences in risky driving, risk perception, and risk utility. Alcohol Drugs and Driving, 1987;3(3):13-29.

[21] Jones S BL, Robinson L. The schoolies experience: the role of expectancies, gender roles and social norms of recent school leavers. Wollongong, NSW: Centre for Health Initiatives, University of Wollongong, 2011.

[22] Swahn MH. Alcohol-consumption behaviors and risk for physical fighting and injuries among adolescent drinkers. Addictive Behaviors, 2004;29(5):959-963.

[23] Miller JW. .Binge drinking and associated health risk behaviors among high school students Pediatrics, 2007;119(1):76-85.

[24] Hallfors DD. Adolescent depression and suicide risk. Am J Prev Med, 2007;27(3):224-231.

[25]    Friese B, Grube JW. Youth drinking rates and problems: a comparison of European countries and the United States Prevention Research Center – Pacific Institute for Research and Evaluation.

[26] Kypri K, Dean J, Kirby S. ‘Think before you buy under-18s drink’: evaluation of a community alcohol intervention. Drug Alcohol Rev, 2004;24:13-20.

[27] Allen DN, Sprenkel DG, Vitale PA. Reactance theory and alcohol consumption laws: further confirmation among collegiate alcohol consumers. J Stud Alcohol, 1994; 55(1).55-67

[28] Wagenaar AC,Toomey TL. Effects of minimum drinking age laws: review and analyses of the literature from 1960 to 2000. J Stud Alcohol Suppl, 2002;(14):206-25.

Substance use disorders are exceedingly complex management issues which result in significant medical and social consequences. Epidemiological studies in the United States and Australia show that more men than women are affected by substance use disorders. However, there is evidence to suggest that women have distinctly different and potentially more hazardous patterns of substance use. These include: a greater tendency to escalate usage, relatively higher rates of relapse, and the telescoping phenomenon (which results in a more rapid progression from the initiation of substance use to drug dependence and adverse medical consequences). Proposed mechanisms for the variable impact of substance use disorders on men and women include biological and gender-based theories which incorporate environmental, psychological and social factors. Studies attribute the biological differences to direct and indirect oestrogen-mediated mechanisms, and the influence of dopamine on structures in the brain including the nucleus accumbens and striatal pathways. Psychosocial variables include psychiatric co-morbidities, family responsibilities, financial issues and perceptions of stigma. The differences in the progression and outcomes of substance use disorders between men and women pose the question as to whether their management can be enhanced by a gender-specific approach. This article outlines the various treatment facilities available in Australia and explores the types of facilities that women tend to use. Gender-specific programs and/or facilities have been shown to be most useful when they support sub-populations of women such as pregnant mothers, mothers with dependent children, and victims of domestic or sexual violence.

Introduction

Both licit and illicit drug use contribute to a significant financial and disease burden in Australia. [1] Currently, epidemiological data suggests that more men are diagnosed with substance use disorders relative to women. [1-7] However, there are sex and gender differences which distinguish patterns of addiction and behavior in both groups. These sex differences have a biological basis, with associations between oestradiol-related central pathways and the propagation of drug seeking behaviours in women relative to men. [2,6,8]

The difference in the prevalence and impact of substance use disorders between genders incorporates environmental, psychological and social factors. Currently, fewer women access drug treatment programs relative to men. [9] This may be representative of the fact that fewer women suffer from substance use disorders, however it may also reflect hindrances towards seeking or accessing treatment. Such barriers towards treatment include increased perceptions of stigma, dependent family members, and financial circumstances. [10-12]

Therefore, although more men are diagnosed with substance use disorders, a different approach towards prevention and treatment may be required for women. A review of the current literature is necessary to question whether an argument can be made to support gender-specific programs to address substance use disorders.

Definitions, epidemiology and gender differences

The term ‘substance use disorder’ as defined in the Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) combines substance abuse and dependence associated with both licit and illicit drugs, which were previously distinguished in DSM-4. [13] Where possible, we refer to substance use disorders based on DSM-5 criteria. However, DSM-4 terminology is retained in order to maintain consistency with previous epidemiologic studies and data.

Differences in epidemiologic data, psychological factors, and clinical management may exist between the various types of substances; however, this article will focus on general principles in order to better understand sex and gender differences associated with substance use disorders and management options.

Licit drug use disorders refer to the legal use of legal drugs. Tobacco and alcohol are the most frequently used drugs – 15% of Australians over the age of 14 were daily smokers in 2010 while 24% were ex-smokers. [1] In 2012, approximately 78% of all Australians aged 14 and over drank alcohol during the year, with 18% drinking at harmful levels. [9]

Illicit substance use disorders, on the other hand, refer to the illegal use of legal drugs or use of illegal drugs. Although relatively uncommon compared to licit drugs, approximately 42% of Australians aged 14 and over reported using illicit drugs in their lifetime, with 15% reporting use in the last 12 months. [9] Cannabis, followed by ecstasy and hallucinogens were the most common illicit drugs used.

There are consistent reports that suggest a higher prevalence of substance abuse in men relative to women. [1-7] This is in keeping with data from the Australian Bureau of Statistics pertaining to Gender Indicators, which showed that men reported higher rates of substance use disorders in the year prior to data collection (7% males relative to 3% females) and throughout their lifetime (35% males relative to 14% females). [7] This is consistent with studies conducted in the United States (US) where, for example, a large survey of over 40,000 adults stated that men are twice as likely (13.8%) than women (7.1%) to address DSM-4 criteria for any drug use disorder.[3]

However, women have distinctly different patterns of drug use, which may be explained by a combination of sex and gender differences. [2,12] For instance, studies show that women tend to escalate drug use (relevant to alcohol, cannabis, opioids and cocaine) relative to men, which contributes to notion of the ‘telescoping phenomenon’. [2,6,12] The term suggests that the development of behavioural, psychological and medical consequences of a substance use disorder occur at a faster rate in women relative to men. [2,12] Notably, despite the use of relatively smaller quantities of drugs within a shorter timeframe, women show greater rates of adverse social and medical consequences. [3] Furthermore, Becker and Hu’s review [2] suggests that once drug addiction has been established, women find it more difficult to quit and are more prone to relapse following periods of abstinence in comparison with men.

Therefore, despite the fact that quantitatively more men may suffer from addiction, the differences in the pattern of drug seeking behaviour, escalation to use disorders, and treatment retention need to be addressed.

Sex differences

Sex differences relevant to drugs of addiction have been evidenced in both animal and human models. [2] Animal studies performed on rodents suggest that females are more likely to self-administer drugs of addiction (in this case cocaine) and have oestradiol-associated mechanisms to further propagate drug seeking mechanisms which are not present in male rodents. [2,6]

Oestrogen-mediated sex differences are evident in most phases of drug abuse including acquisition, maintenance, escalation and relapse. [2,8] Proposed mechanisms for this effect include direct interactions with the striatum and nucleus accumbens to facilitate dopamine release, and indirect interactions via sensitisation of receptors and changes in neuronal excitability. [6,8,14] The alterations in dopamine release act to regulate neurochemical responses and behaviours in favour of addiction, particularly to psychomotor stimulant drugs. [6,14]

Another contributing factor to the sex differences in drug addiction is the effect of the menstrual cycle on motivation behaviours. The impact of the menstrual cycle seems to be variable depending upon the timing of the cycle, hormone concentrations, and type of substance abused. For instance, increased euphoria, desire, and energy are enhanced when using cocaine in the follicular phase relative to the luteal phase. [2] In support of the notion that oestrogen plays a role in the perceived effects of drugs of addiction, the addition of oestradiol during the follicular phase resulted in a self-reported increase in the euphoric effects of dexamphetamine. [2]

Additionally, a review of 13 studies that investigated the impact of the menstrual cycle on smoking cessation suggested that women experience greater tobacco cravings and negative affect responses to tobacco withdrawal during the late luteal phase, where oestrogen and progesterone levels are diminishing. [2] The proposed mechanism for this is that the relatively higher oestrogen levels in the follicular phase may ‘alleviate some of the negative consequences’ associated with quitting smoking. Becker and Hu [2] support this theory by identifying a study that confirms the relationship between oestradiol, positive affect and decreased anxiety.

The variations in drug use and withdrawal symptoms during the menstrual cycle, such as increased euphoria when using cocaine during the follicular phase versus enhanced negative affect responses to tobacco withdrawal during the luteal phase, suggest that fluctuating oestrogen levels can have an impact on subjective experiences of substance use disorders.

It is difficult to truly isolate biological differences from psychosocial issues that may impact on the development and management of substance use disorders. However, there is evidence to support the significance of biological variations on the subjective experiences and outcomes associated with substance use disorders. These include the relationship between oestradiol and addiction behavior in animal studies, variations in drug-related experiences during the menstrual cycle, and the notion (detailed above) that women have a greater tendency to escalate drug use and develop adverse medical/psychological effects as a consequence of substance use disorders. The question remains as to whether the telescoping phenomenon in women requires a different management approach – are there any benefits of targeting women through specific programs or do mixed-gendered programs and facilities suffice?

Psychosocial differences

In addition to the identified biological differences in substance use disorders, psychosocial factors may contribute to variations in addiction behaviours, treatment initiation and outcomes. Such factors include, but are not limited to, psychiatric co-morbidities, dependent family members, financial issues and perceptions of stigma.

Studies suggest that women with substance abuse disorders are more likely to have a prior diagnosis of a psychiatric disorder relative to men, with more women meeting criteria for anxiety, depression, and eating disorders. [3] Potential contributing factors to this difference in mental health outcomes include higher rates of experienced trauma such as sexual abuse and/or intimate partner violence, disrupted family environments, and a perception of over-responsibility (such as caring for a child or other family members) in women relative to men. [3,10,11,15] The correlation between psychiatric disorders with substance use disorders urges the need for more holistic treatment. Specialised services that incorporate mental health into the management of substance use disorders have shown to yield better outcomes with respect to treatment retention and continuity of care. [16]

In addition to psychiatric co-morbidities, previous studies document a greater perception of stigma amongst female substance abusers, whereby women experienced higher levels of guilt, embarrassment and shame relative to males. [11,15,17,18] This has an impact on the willingness to seek and/or continue treatment not only for substance use disorders but other necessary community services. The Network of Alcohol and Other Drug Agencies (NADA) report suggests that women identified having difficulty accessing services such as pre-natal classes and housing support due to perceived stigma, discrimination and fear of judgment from child protection services. [11]

Social factors that hinder management of substance use disorders in women relative to men include: lower education levels and financial income, housing issues, interaction with child protection services, and dependent children and/or other dependent family members. [10-12] Green’s research [10] and NADA’s report [11] suggest that women experience relatively greater difficulty in finding time to attend regular treatment sessions due to family responsibilities and transport issues. The social factors mentioned above, in conjunction with the perception of stigma, act as significant barriers for women to access treatment. These need to be addressed in order to successfully promote women to seek initial treatment while providing necessary support to facilitate long-term management.

Current use of treatment facilities

Briefly, the types of treatment facilities in Australia as outlined by the AIHW’s report include [9]:

• Assessment only, whereby agencies identify the severity of the issue and refer accordingly
• Information and education only
• Support and case management only
• Counseling for individuals and groups through methods such as cognitive behavior therapy
• Withdrawal management (home, in-patient, or out-patient)
• Rehabilitation (residential treatment services, therapeutic communities or community-based rehabilitation)
• Other holistic approaches, which include relapse prevention, living skills classes, safer using, etc.
• Other health services include GP visits, hospital treatment and homelessness services.

In Australia, fewer women (32%) received treatment through alcohol and other drug treatment services relative to men (68%) in 2012-2013, which is consistent with studies conducted in the US where extensive research regarding the impact of gender on substance abuse is conducted. [9] It is unclear whether the reduced proportion of women seeking treatment is solely reflective of the relatively smaller number of women with addiction issues, or also inclusive of the financial and psychosocial factors that can prevent women from seeking treatment. [9]

Studies based in the US allow for the identification of gender differences between the types of facilities used for managing substance abuse disorders. Women are more likely to approach mental health or primary clinics rather than addiction treatment programs or specialty clinics. [3,19] It is proposed that this may be due to the perception that psychological distress and impairment associated in those substance use disorders may be better addressed by directly treating the mental health issue. [19]

There is limited research regarding the impact of this preference on treatment outcomes, however Mojtabai’s study [19] found that this pattern of treatment was less effective when compared to participants who sought help in specialty settings. [10] Management through facilities dedicated to substance use disorders was associated with a relatively reduced likelihood of continued substance use, with fewer participants reporting alcohol and substance use in the past month. [10,19] The study urges for better integration of substance use disorder management in the mental health system, and an efficient referral system across the ‘traditionally separate systems of care’. [19]

Future directions: utility of gender-based programs?

Services that provide comprehensive support by addressing medical, psychiatric and social issues (such as employment or child protection) have been shown to improve attendance, social adjustment and relapse rates in both men and women. [12,20] Previous research suggests that gender does not seem to predict patient retention, treatment completion, or patient prognosis once an individual begins treatment. [12] This seems to contradict the need for gender-specific programs, considering that treatment appears to offer equal benefit to both men and women. However, this needs to be considered in light of the fact that there are differences in the rates of treatment access between men and women, which may be explained in part by the psychosocial factors outlined above.

There is evidence to suggest the benefit of gender-specific programs or facilities in certain contexts. These include programs that focus on female-specific topics such as sexual abuse and body image, residential facilities for women with dependent family, and tailored care for pregnant mothers. [10,21] In 2005, the Drug and Alcohol Services Information System (DASIS) report in the US suggested that 41% of substance abuse treatment facilities that accepted female clients provided additional support programs specifically for women. [22] There are gender specific programs and facilities, including those dedicated to pregnant women, in most Australian states – although they may not be as numerous as those available in the US. For instance, out of 28 Network of Alcohol and Other Drug Agencies services in New South Wales, Australia, 7 provided women-only services. [11]

Gender specific psycho-education sessions on topics specific to women have received positive feedback in a few different studies. [11,16,19] These sessions allow for the discussion of more sensitive issues such as domestic violence, sexual abuse, parenting, weight and body image in a more comfortable scenario. [10,11,21] It is crucial that these programs are flexible and avoid the use of a confrontational style. [16] The presence of dynamic and interpersonal discussion is considered beneficial, and is suggested to occur more often and in an uninterrupted fashion in women-only programs. [16] The importance of self-expression without interruption is highlighted by the fact that unaddressed issues may result in adverse psychological effects. [16] Specific interventions that have been proven to be effective include but are not limited to: parenting skills for mothers on methadone maintenance, relapse prevention for women with post traumatic stress disorder, and relapse prevention for women with marital distress and alcohol dependence. [10,11,12]

Programs specific to women tend to offer facilities that allow for accompanying children (through child care support during clinics and day programs), and may also provide residential facilities for the client and dependent family.  Such facilities have been shown to have better treatment outcomes including longer lengths of stay. [11,12,16] Furthermore, family inclusive practices may have services that aim to repair relationships with children and family members thus enhancing support systems and the quality of the home environment.

Pregnant women with substance use disorders can be at high risk of numerous medical and social issues affecting their mental and physical health, which in turn impacts upon their risk of obstetric complications and the subsequent health of their baby. Pregnant women are more likely to: be of younger age, have previously given birth, have limited social supports (including limited financial stability) and have a concomitant psychiatric diagnosis. Such populations require a multitude of coordinated services and can significantly benefit from residential services, which allow for increased social support for themselves and dependent family. [11] Programs dedicated to pregnant and perinatal women have demonstrated significantly improved patient engagement and pregnancy outcomes. [12,23,24] Specific intervention programs that have yielded beneficial results for expecting mothers include alcohol interventions for pregnant women, contingency management to increase abstinence in pregnant women, and comprehensive service models for pregnant women such as access to prenatal care. [11] The benefit of customised care was highlighted by a study which recorded higher infant birth weights (2934 grams vs. 2539 grams) and a smaller proportion of neonatal intensive care admissions (10% vs. 26%) when comparing cocaine-dependent mothers who received twice-weekly addiction counseling with those who did not. [23]

In addition to gender-specific treatment, future directions may include a transition to more gender-sensitive services. [10] Suggested strategies include: matching therapist and client gender, mixed-gender group sessions concurrently led by both male and female leaders, and gender-specific treatment information or content. [10] The results of client and therapist gender matching are unclear. Some studies suggest that clients reported a sense of greater empathy resulting in longer treatment durations and lower rates of relapse, whilst other showed no difference in outcomes. [10]

Conclusion

There are documented sex differences with respect to substance use disorders through direct and indirect oestrogen-mediated mechanisms, the dopamine influence on nucleus accumbens and striatal pathways, and variable impacts of the menstrual cycle. These occur in addition to gender differences, which incorporate psychosocial variables such as psychiatric disorders, family environment, domestic violence, and social stigma. Currently, men experience higher rates of substance abuse relative to women; however, women are more likely to escalate drug use and suffer from biological and/or psychological consequences at lower doses and shorter durations of drug use. Additionally, women are less likely to enter treatment relative to men.

Studies provide inconclusive results regarding the benefits of gender-specific programs over those that have a gender-mix. However, there may be a need to support sub-populations of women including pregnant mothers, mothers with dependent children, and victims of domestic or sexual violence. Therefore, future directions include the need to increase awareness regarding substance use disorders, facilitate treatment for women in general, provide ongoing support to relevant subgroups, and consider a more gender-sensitive approach during management of substance use disorders.

Acknowledgements

The author wishes to acknowledge Dr. Christine Phillips and Dr. Elizabeth Sturgiss for their support and feedback.

Conflicts of Interest

None declared

Correspondence

A Jain: arunimajain12@gmail.com

References

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[3] Back SE CR, Brady T. Substance Abuse in Women: Does Gender Matter [Internet] 2006. [updated 2006, cited 2015 March 12]; Available from: http://www.psychiatrictimes.com/substance-use-disorder/substance-abuse-women-does-gender-matter.

[4] Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, Wittchen HU, Kendler KS. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Arch Gen Psychiatry. 1994;51:8-19.

[5] Conway KP, Compton W, Stinson FS, Grant BF. Lifetime comorbidity of DSM-IV mood and anxiety disorders and specific drug use disorders: results from the national epidemiologic survey on alcohol and related conditions. J Clin Psychiatry. 2006;67:247-57.

[6] Roth ME, Cosgrove KP, Carroll ME. Sex differences in the vulnerability to drug abuse: a review of preclinical studies. Neuroscience & Biobehavioral Reviews. 2004;28(6):533-46.

[7] Australian Bureau of Statistics. Mental Health: Key Series 2013 [Internet]. 2013 [cited 2015 March 12]; Available from: http://www.abs.gov.au/ausstats/abs@.nsf/Lookup/4125.0main+features3150Jan%202013.

[8] Carroll ME, Lynch WJ, Roth ME, Morgan AD, Cosgrove KP. Sex and estrogen influence drug abuse. Trends in Pharmacological Sciences. 2004;25(5):273-9.

[9] Australian Insitute of Health and Welfare. Alcohol and other drug treatment services in Australia 2012-13. Drug Treatment Series. Canberra: AIHW; 2014.

[10] Green C. Gender and use of substance abuse treatment services. [cited 2015 April 22]; Available from: http://pubs.niaaa.nih.gov/publications/arh291/55-62.htm

[11] Jenner L, Lee N, Cameron J, Harney A. Women’s alcohol and other drug services development program: needs analysis final report. Network of Alcohol and other Drug Agencies; 2014.

[12] Greenfield SF, Brooks AJ, Gordon SM, Green CA, Kropp F, McHugh RK, et al. Substance abuse treatment entry, retention, and outcome in women: a review of the literature. Drug Alcohol Dependence. 2007;86(1):1-21.

[13] American Psychiatric Association. Substance-related and addictive disorders [Internet]. 2013 [updated 2013; cited 2015 March 12];  Available from: http://www.dsm5.org/Documents/Substance%20Use%20Disorder%20Fact%20Sheet.pdf.

[14] Becker JB. Gender Differences in Dopaminergic Function in Striatum and Nucleus Accumbens. Pharmacology Biochemistry and Behavior. 1999;64(4):803-12.

[15] Nelson-Zlupko L KE, Dore MM. Gender differences in drug addiction and treatment: implications for social work intervention with substance-abusing women. Social work. 1995;40(1):45-54.

[16] Claus RE, Orwin RG, Kissin W, Krupski A, Campbell K, Stark K. Does gender-specific substance abuse treatment for women promote continuity of care? Journal of Substance Abuse Treatment. 2007;32(1):27-39.

[17] Brady KT, Randall CL. Gender differences in substance use disorders. The Psychiatric clinics of North America. 1999;22(2):241-52.

[18] Shimmin C. Understanding stigma through a gender lens. Canadian Women’s Health Network. 2009;11(2):14-7

[19] Mojtabai R. Use of specialty substance abuse and mental health services in adults with substance use disorders in the community. Drug and Alcohol Dependence. 2005;78(3):345-54.

[20] Marsh JC, Cao D, D’Aunno, T. Gender differences in the impact of comprehensive services in substance abuse treatment. Journal of Substance Abuse Treatment. 2004;27:289-300.

[21] Lindsay AR, Warren CS, Velasquez SC, Lu M. A gender-specific approach to improving substance abuse treatment for women: the healthy steps to freedom program. Journal of Substance Abuse Treatment. 2012;43(1):61-9.

[22] Center for Substance Abuse Treatment. Addressing the specific needs of women. Rockville:Drug and Alcohol Services Information System; 2009.

[23] McLellan TA Lewis DC, O’Brien CP, Kleber HD. Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. JAMA. 2000;284(13):1689-95

[24] Morris M, Seibold C. Drugs and having babies: An exploration of how a specialist clinic meets the needs of chemically dependent pregnant women. Midwifery. 2012;28:163-72.

The gender imbalance in ADHD

Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent neuropsychiatric condition placing a considerable burden of disease on our population. ADHD primarily manifests in childhood with symptoms of inattention, hyperactivity and/or impulsivity that affect normal function. [1] Though ADHD affects both children and adults, current literature has focused greatly on the disorder in children and this paper will focus mainly on the paediatric population. Australian statistics reported ADHD as the leading mental and behavioural condition amongst children 0-14 years of age, accounting for 12% of children with a disability in 2004. [2] Furthermore, the diagnosis of ADHD in paediatric consultations has increased in frequency to almost 18% of the referred population. [3] Unfortunately, the prevalence of ADHD has been difficult to assess due to its heterogeneous nature and dependence on diagnostic criteria and classification. [4] Despite these obstacles, the reported demographic of ADHD has illustrated a skewed gender distribution towards males worldwide, creating a scope for exploring the gender differences in ADHD. [5-7] Current research has focused on theories supporting changing diagnostic criteria, phenotypic differences and biological differences to explain this gender difference in the prevalence of ADHD. However, to better understand this gender distribution, it is important to understand the terminology utilised in ADHD and how this has influenced current prevalence estimates for the disorder.

Definition of ADHD

The terminology and criteria surrounding ADHD have undergone significant revision over time. On the whole, it should be emphasised that normal childhood development displays active, impulsive and inattentive behavior and diagnosing ADHD should be based on a comprehensive subjective and objective assessment of the individual. [1] The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM) provides specific criteria for diagnosing ADHD, but is also a prime example of the changing definition of the disorder. [1] ADHD was initially defined as a hyperkinetic reaction of childhood in the DSM-II, followed by Attention Deficit Disorder, with or without hyperactivity, in DSM-III, and finally ADHD with subtypes presented in DSM-IV. [8] The DSM-V now defines ADHD as pattern of inattention and/or hyperactivity-impulsivity that is persistent, interferes with development, has symptoms presenting in two or more settings, and directly impacts on the individual’s functional capabilities. [9] The core symptoms of inattention and hyperactivity-impulsivity each contain their own set of symptoms, of which six or more must be present in children and five or more in adults for at least 6 months prior to assessment. [9] The DSM-V has also reframed subtypes of ADHD from the DSM-IV to presentations including combined presentation, predominantly inattentive presentation and predominantly hyperactivity-impulsivity presentation. This evolving terminology has been implicated in many studies attempting to explain the differing prevalence of ADHD across the world, which, in turn, influences the gender distribution of ADHD.

Prevalence of ADHD

ADHD is a heterogeneous disorder with symptoms requiring both temporal and spatial conditions and the lack of definite diagnostic tools has prevented an accurate representation of the disorder worldwide. [4,8,10] Firstly, there are variations in methodology, including the diagnostic criteria used and evaluation of clinical impairment. [4] For example, studies may illustrate increased rates of childhood ADHD classified using the DSM-IV criteria but decreased rates in those who undergo further assessment, suggesting diagnostic inaccuracy. [10] Furthermore, a recent community-based study in America illustrated increasing prevalence estimates with the new DSM-V criteria for age of onset and symptom count, but decreasing prevalence with the new criteria requiring a degree of impairment due to the disorder, based on changing case definitions of ADHD. [8] Overall, there are strengths to having accepted diagnostic criteria in the DSM, however the lack of tools to identify and quantify these symptoms continues to be an obstacle in current prevalence estimates for ADHD.

In addition, the population sample (e.g. community or clinic) contributes greatly to varying prevalence estimates. [4] For example, an Australian study based on participants identified in a parental-reported survey illustrated an ADHD prevalence of 13.6% with a male: female prevalence ratio of 2:1. [6] Conversely, an Australian clinical study showed a greater gender difference with a male to female ratio of 4:1. [3] This illustrates a well-recognised pattern in the prevalence of ADHD where male to female ratios are higher in referred populations than in community-based samples. [4,7,11] The main explanation for this evident gender distribution between the population samples has widely been accepted as referral bias, whereby a myriad of factors has resulted in a greater number of males reaching clinics for diagnosis and management of ADHD. [11] There have been many factors found contributing to this referral bias including phenotypic differences, recognition of comorbidities and symptom reporting amongst the ADHD patient population. [11] Overall, the skewed gender distribution in ADHD prevalence is influenced by both methodology and population variables and these need to be carefully considered when analysing the role of gender in ADHD.

Phenotypic differences in ADHD

ADHD presents with a myriad of manifestations that share the underlying characteristics of inattention and/or hyperactivity. In general, the main differences in symptom recognition for ADHD differs with males being more likely to be recognised for externalising symptoms in contrast to females exhibiting internalising features. [5,7,12] These symptoms can be further described as males more likely to present with disruptive behaviours that correspond to the hyperactive-impulsive core symptoms whereas females are more likely to present with symptoms correlating to inattention. [6,7,10,12] Multiple studies have also shown that females are more likely to exhibit physiological anxiety, whereas males were reported for rule breaking and risk taking actions. [6,12] Females were also more likely to present with somatic complaints, which have been considered a marker for anxiety proneness across the literature. [7,12]

Furthermore, the recent inclusion of ADHD subtypes has added to the gender differences in ADHD, where females are found more likely to be diagnosed with predominantly inattentive ADHD whereas males are more commonly diagnosed with predominantly hyperactivity-impulsivity or combined presentations. [12,13] This, in turn, has consequences on the aforementioned referral bias, where females who are identified to have symptoms of ADHD were not considered impaired if exhibiting inattenttive ADHD, but considered severely impaired when exhibiting hyperactive-impulsive ADHD. [11,13] Another implication of these subtypes is the tendency for hyperactive and/or impulsive behaviour to lessen over time whereas inattentive behaviour tends to persist. [1] This, in turn, may lead to more males being recognised for their ADHD in childhood due to an increased tendency to express hyperactive/impulsive behaviour and for female patients to be under-recognised. [13] Phenotypic differences in ADHD play an important role in ascertaining the gender distribution of this disoder as these differences may result in referral bias and therefore account for the greater number of males recognised with the disorder. [11,13]

Comorbidities in ADHD

Comorbidity in childhood psychiatry is an expected phenomenon, with ADHD commonly presenting with common concurrent neuropsychiatric conditions. [14] For example, disruptive behavioural disorders such as oppositional defiant disorder have a high rate of comorbidity with ADHD, sharing particular symptoms with the hyperactive or impulsive subtype. [14] Similarly, anxiety disorders are also commonly diagnosed in patients with ADHD, usually with a more severe and distinctly inattentive clinical presentation. [15] Furthermore, these childhood psychiatric disorders appear to illustrate a similar gender distribution to that of ADHD, with disorders such as autism spectrum disorder being widely accepted to have a male predominance in childhood. [16] However, reports of comorbidity in ADHD is subject to the same limitations of referral bias, phenotypic differences and diagnostic criteria that influence the prevalence and gender distribution across childhood psychiatry. [14]

Furthermore, both males and females have been found more likely to have comorbid ADHD, in comparison to a solitary diagnosis of ADHD [17] Some studies have shown parents and teachers to report more difficulties with oppositional behaviours, social difficulties, depression and anxiety in females, compared to their male counterparts. [12] However others have illustrated an equal increase in presentation of comorbid conditions in the hyperactivity-impulsivity subtypes, with the gender difference being higher levels of comorbidity for females in the inattentive subtype through comorbid social and generalised anxiety disorders. [17] Another study found the only statistically significant gender difference to be a higher rate of substance use disorders in females with ADHD, particularly in early adolescence. [13] Overall, comorbidity in ADHD is an important consideration in studying the prevalence of the disease and how the gender distribution of these disorders can influence the gender distribution of ADHD.

Symptom reporting in ADHD

Firstly, many studies have commented on symptoms reported by patients, parents, teachers and clinicians – all of which provide different criteria for diagnosis of ADHD. Studies have shown self-reported symptoms to be highest in the clinical setting, whereas community-based research focuses heavily on parent- and teacher-reported symptoms. [12] A review of variations in ADHD prevalence mentioned that multiple studies have shown different rates of symptom reporting between parent and teacher. [4] Teachers’ contributions are substantial as they can provide daily observations of patients in comparison to unaffected individuals of the same age, environment and developmental level. [4] Parents are also valuable as they provide a change in an individual’s behaviour over time. However, both groups lend themselves to symptom recognition biased towards hyperactivity and impulsivity, as these tend to be more disruptive in both the school and home environment. This results in under-recognition of internalising symptoms such as depression and inattention, which, in turn, influence the rates of symptom reporting for ADHD. [4,12]

Furthermore, the culture surrounding ADHD has resulted in it being considered a male disorder. [5,10] This has multiple implications, from a greater tendency to recognise symptoms in the community to specialist referral for ADHD symptoms, with the social and cultural constructs of ADHD making males more likely to be subject to symptom reporting. [7,10] The lower prevalence rates have also been attributed to the higher likelihood of referral for disruptive behaviour, more commonly seen in the hyperactivity-impulsivity presentation or combined presentation of ADHD [11]. This, in itself, creates a skewed gender distribution as these have been illustrated at higher rates in the male population. [5] On average, there are more similarities than differences in the symptomatology of ADHD across genders, and symptoms are not sex-specific, but rather show trends as discussed above. [5,13] However, it is important to be aware of the gender differences when applied to ADHD subtypes, comorbid psychological conditions and the sources of symptom reporting for accurate diagnosis and management of ADHD in our population.

Biological Differences in ADHD

Biological factors have also been shown to influence gender differences in ADHD prevalence in our population. However, the majority of research conducted in this field has been underpowered due to the disproportionate number of males diagnosed with the disease, and the lack of drive to characterise any prospective sex differences. [18] A recent review discussed the evidence for neurogenetic and endocrine mechanisms, where differences in chromosomal composition, sex-linked genes and early exposure to hormones can interact to affect the manifestation of ADHD between sexes. [19] For example, there is an inherent sex difference in the male-limited expression of the Y chromosome and the presence of only one X chromosome, which leads to the presence of different genes and mutations that may influence neurodevelopment and susceptibility to ADHD between genders. [19]

Furthermore, there is increasing research into the anatomy and physiology of the neurological aspects of ADHD. This has illustrated a complex network of brain regions that are structurally modified to produce a developmental deviation in response to immature cortical under-arousal. [18] This has also produced gender differences whereby electroencephalography (EEG) studies have shown different patterns between males and females, and further differentiation between ADHD subtypes. [20] Overall, the current literature has emphasised a need for more focused research on the biological differences in ADHD to better characterise the profile of ADHD in males and females.

Management of ADHD

The implications of gender differences on the diagnosis and identification of ADHD have been discussed, however it is important to also consider the impact of gender on the management of ADHD. Pharmacological management in the form of stimulant medication has recently been gaining traction in current treatment practices for ADHD. [3,21] In general, current trends have shown that males with ADHD are more likely to receive pharmacotherapy and psychotherapy than females. [13] For example, in Western Australia, the prescription rates for stimulant medication were greater in males than females. [22] NSW Public Health illustrated a similar pattern, with males four times more likely to be on stimulant medication than females, though there has been an increase in the prescription patterns for females over the last two decades. [23] These statistics elucidate gender differences in practitioner trends and management of ADHD, however further investigation would be required to explain these trends in correlation to the disease recognition and prevalence as discussed earlier. In addition, it is also important to consider the possibility of gender differences in the treatment response for ADHD, though a recent population-based study has shown the response was favourable and did not differ between genders. [24]

In addition to pharmacological management, there is an increased role of behavioural intervention in the management of ADHD. Behavioural therapy represents a collection of specific interventions that modify the physical and social environment in order to change behaviour. [21] These interventions can be delivered through parental, classroom or peer interventions that reward desired behavioural traits and discourage undesirable behaviours through techniques such as planned ignoring, appropriate consequences and/or punishment. [21] When considering individual behavioural intervention in ADHD management, females are said to benefit from management of comorbid conditions such as mood and/or anxiety disorders that may exacerbate the expression of ADHD in combination with pharmacotherapy. [25] Mixed-gender treatment is another option for behavioural intervention in ADHD, which involves group-based behavioural interventions with both male and female patients. However, studies have shown gender differences to influence this management strategy as the mixed-gender setting may suppress treatment effect in females and fail to address gender-specific social impairments. [26] A recent American study investigated the effects of single- versus mixed-gender treatment for adolescent females and found females were more likely to benefit from single-gender treatment with more assertiveness, self-management and compliance. [26] Conversely, males exhibited lower levels of physical and relational aggression and better self-management and compliance in the mixed-gender setting. [26] Overall, behavioural intervention is important in the management of ADHD and needs to account for gender differences in disease presentation and response to treatment.

Future directions in ADHD

ADHD is rapidly gaining awareness for its burden of disease in our paediatric population. However, current literature has lacked focus in characterising important epidemiological trends in ADHD, such as the distribution between genders. Firstly, most of the discussion above has been based on studies using the DSM-IV criteria for diagnosis and therefore further studies based on the DSM-V criteria may again alter the gender prevalence of the disorder. Secondly, study design needs to account for population sample bias, especially between community- and clinic-based samples, in order to better estimate the disease and gender prevalence across the world. Studies also need to be designed with the aim of defining the phenotypic differences and the direct impact of these on symptom reporting in order to tailor future practice and better recognise ADHD throughout the population. The same should apply to biological differences and response to management, both pharmacological and behavioural as the main examples, for more effective clinical practice. It should also be noted this discussion focused mainly on paediatric ADHD, however current literature has seen rapid growth in research into adults with ADHD, though it is limited with regards to the gender distribution in these populations. Similar to the evidence discussed above, it is reasonable to expect the gender ratios in ADHD prevalence to be similarly affected by referral or identification bias, poorly defined diagnostic criteria and biological differences. [27] On the whole, the consensus across current literature is a need for further investigation that can better define the prevalence of ADHD in our population and the influence, if any, of gender.

Conclusion

ADHD is an increasing burden of psychiatric disease for our paediatric population with a reported greater prevalence amongst male patients. The skewed gender distribution of the disorder has been widely varied due to differing diagnostic criteria, terminology and research methodology. The differences found illustrated variation in disease presentation and psychological comorbidities, as well as biological differences that may account for the variation in disease presentation between genders. Furthermore, there were differences in reporting of ADHD symptomatology between patient, parent, teacher and clinician as well as differing trends in management that may influence the recognition and treatment of ADHD across our population. Overall, these differences warrant further research to better understand ADHD and characterise the disease profiles between males and females for increased accuracy in identification, diagnosis and treatment in our population.

Acknowledgements

Many thanks to Associate Professor Christine Phillips for introducing students to the social foundations of medicine and promoting discussion on a gender perspective.

Conflicts of interest

None declared.

Correspondence

M Bokil: bokil.mug@gmail.com

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