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Pharmacology

Digestive system diseases Letters 17 September 2018 Free

Adverse effects of modified release oxycodone/naloxone in patients with moderate to severe liver impairment

To the Editor: Due to the adverse effects of modified release (MR)-oxycodone/naloxone in patients with moderate to severe liver impairment as a result of advanced cirrhosis or with spontaneous or artificially created portosystemic shunts (Box), its use in this patient population is contraindicated.1 In our clinician roles, we have observed both poor analgesic efficacy and opioid withdrawal in such patients, and similar observations are reported in the literature.2,3 There are clear pharmacological and physiological bases for these outcomes. MR-oxycodone/naloxone is an oral combination opioid analgesic. The naloxone component is subject to a significant first-pass metabolism, and bioavailability is less than 2%.4 The benefit of low level oral bioavailability of naloxone is reduced opioid-induced constipation due to antagonism of opioid receptors in the gut while permitting the desired analgesic opioid effects. The recommended dose of MR-oxycodone/naloxone ranges from 2.5/1.25 mg to 80/40 mg twice daily — the upper limit guiding prescribers to avoid further opioid dose escalation.1 In patients with compensated cirrhosis (mild hepatic impairment) (Box), MR-oxycodone/naloxone may cautiously be prescribed.1 Satisfactory analgesia without significant adverse effects has been observed in selected patients with compensated cirrhosis and pain from hepatocellular cancer.5 In moderate to severe liver impairment, the first-pass (hepatic) metabolism of both medications are markedly but disproportionately reduced, thereby increasing the systemic relative exposure to naloxone (Cmax > 5000% of control) compared with oxycodone (Cmax > 200%).1 The mechanisms are hepatocellular dysfunction and spontaneous portosystemic shunting.3 Artificially created surgical or transjugular intrahepatic portosystemic shunts also reduce hepatic extraction. Hepatic infiltration due to malignancy similarly reduces the liver’s ability to metabolise MR-oxycodone/naloxone effectively.2 The relative increase in exposure to naloxone reduces analgesic efficacy through increased antagonism of opioid pain receptors. Escalating doses of MR-oxycodone/naloxone (or other opioid) may not achieve improved analgesia.2 The relatively high systemic naloxone exposure may also induce opioid withdrawal symptoms.3 Switching from MR-oxycodone/naloxone to oxycodone immediate-release in a patient with hepatic impairment contributed to opioid toxicity due to the sudden loss of the high level systemic naloxone exposure.2 In patients with moderate to severe liver impairment due to advanced cirrhosis or with portosystemic shunts, clinicians should be aware of the contraindication of MR-oxycodone/naloxone. Box – Severity of liver impairment in cirrhosis Liver impairment Clinical features of portal hypertension/portosystemic shunting Biochemical signs Mild Early, compensated cirrhosis No ascites or hepatic encephalopathy Albumin ≥ 35 g/L Bilirubin < 34 μmol/L INR < 1.7 Moderate to severe Advanced, decompensated cirrhosis Portosystemic shunting Presence of: Oesophageal/gastric varices Portal vein thrombosis Ascites Hepatic encephalopathy Hepatorenal syndrome TIPSS Surgical portosystemic shunt Albumin < 35 g/L Bilirubin ≥ 34 μmol/L INR ≥ 1.7 INR = international normalised ratio. TIPSS = transjugular intrahepatic portosystemic shunt.

Venessa Pattullo · Gavin G Pattullo · Simone I Strasser

Environmental health Letters 20 August 2018 Free

An era of untreatable gonorrhoea?

To the Editor: We are concerned about the emergence of antibiotic-resistant gonorrhoea in Australia. On 17 April 2018, the Commonwealth’s Chief Medical Officer Brendan Murphy released a statement about two cases of multidrug-resistant gonorrhoea that had recently been detected in Australia1 — at least one of these patients acquired the infection in Southeast Asia. These particular cases were similar to the one recently reported in the United Kingdom,2 where the patient was reported3 as having high level resistance to azithromycin and to ceftriaxone — the cornerstone of treatment. Also notable in that case was treatment failure using spectinomycin, with ongoing detection of the bacterium on throat swab. Treatment with intravenous ertapenem was successful. It should be of concern that gonorrhoea may only have the option of intravenous treatment, but the real problem here is that we may be on the precipice of untreatable gonorrhoea. With almost 750 000 short term resident returns every month,4 and over 200 000 of these being returns from Southeast Asia, the likelihood of repeated introductions is real. In the current context of rising gonorrhoea rates in Australia,5 further importation, transmission and spread of these resistant organisms will add substantial challenges to the disease control, especially in men who have sex with men and in Indigenous Australians. Such spread will incur significant health and health care costs for the sexual and reproductive health of Australians. There is an urgent need for all treating doctors to ensure that swabs for culture are taken for all symptomatic patients, as well as for those with an initial positive polymerase chain reaction result; for travellers to be aware of the risks of having unprotected sex; and for any multidrug-resistant patients and contacts to be referred for expert advice to ensure testing and treatment.

Brett Sutton · Mihaela Ivan

Environmental health Letters 2 April 2018 Free

Tackling antimicrobial resistance globally

To the Editor:Your publication of a review on global approaches to antimicrobial resistance is timely.1 We especially note that antibiotic-resistant pathogens are not limited by borders, have greater impact on disadvantaged communities, and will require coordinated, high level government commitment to minimise their threat.1 In Australia, Indigenous communities bear a disproportionate burden of infectious diseases. This burden arises on a background of overcrowding, poorly built and maintained water and sanitation infrastructure, and colonisation of companion animals by human pathogens. The delivery of biomedically oriented health services leads to frequent use of broad spectrum antibiotics, promoting the development of multiresistant pathogens.2 The prominent multiresistant pathogen methicillin-resistant Staphylococcus aureus first emerged in hospitals, but, in Australia, it was soon identified in remote Indigenous communities.2 Health services have been unable to control its development and spread. As a consequence, community-acquired methicillin-resistant S. aureus is now the dominant strain of this bacterium in Central Australia, where Indigenous people are one-quarter of the population, but bear three-quarters of the S. aureus disease burden in Alice Springs Hospital.3 Primary health care is founded on full community participation and an intersectoral approach, incorporating education, housing and other sectors to complement health services.4 Housing for Indigenous communities remains inadequate, and government responses deficient, particularly in remote regions.5 As a result, even high quality health services have limited impact on Indigenous people’s health and wellbeing. Safe, secure, functioning housing that is appropriate for its occupants is a building block to manage other areas of Indigenous disadvantage.5 The deficit in appropriate housing contributes to bacterial colonisation, infection and development of antimicrobial resistance among Indigenous Australians.2 “Illness is a weapon” was intended as a metaphor for the resistance of Indigenous people to their ongoing colonisation.6 However, the threat of antibiotic resistance evolving through the neglected conditions in which some communities find themselves could make this metaphor more real than was likely intended. The spread of antibiotic-resistant pathogens in Indigenous communities and elsewhere is a global threat, which highlights the need to transform services for Indigenous people using approaches driven by communities and focused on their strengths.

Rosalie Schultz

Substance‐related disorders Systematic review 12 February 2018 Free

Identifying and treating codeine dependence: a systematic review

Objectives: Codeine dependence is a significant public health problem, motivating the recent rescheduling of codeine in Australia (1 February 2018). To provide information for informing clinical responses, we undertook a systematic review of what is known about identifying and treating codeine dependence. Study design: Articles published in English that described people who were codeine-dependent or a clinical approach to treating people who were codeine-dependent, without restriction on year of publication, were reviewed. Articles not including empirical data were excluded. One researcher screened each abstract; two researchers independently reviewed full text articles. Study quality was assessed, and data were extracted with standardised tools. Data sources: MEDLINE and EMBASE were searched for relevant publications on 22 November 2016. The reference lists of eligible studies were searched to identify further relevant publications. 2150 articles were initially identified, of which 41 were eligible for inclusion in our analysis. Data synthesis: Studies consistently reported specific characteristics associated with codeine dependence, including mental health comorbidity and escalation of codeine use attributed to psychiatric problems. Case reports and series described codeine dependence masked by complications associated with overusing simple analgesics and delayed detection. Ten studies described the treatment of codeine dependence. Three reports identified a role for behavioural therapy; the efficacy of CYP inhibitors in a small open label trial was not confirmed in a randomised controlled trial; four case series/chart reviews described opioid agonist therapy and medicated inpatient withdrawal; two qualitative studies identified barriers related to perceptions of codeine-dependent people and treatment providers, and confirmed positive perceptions and treatment outcomes achieved with opioid agonist treatments. Conclusion: Strategies for identifying problematic codeine use are needed. Identifying codeine dependence in clinical settings is often delayed, contributing to serious morbidity. Commonly described approaches for managing codeine dependence include opioid taper, opioid agonist treatment, and psychological therapies. These approaches are consistent with published evidence for pharmaceutical opioid dependence treatment and with broader frameworks for treating opioid dependence. PROSPERO registration: CRD42016052129.

Suzanne Nielsen · Tim MacDonald · Jacinta L Johnson

17 00749
Substance‐related disorders Letters 15 January 2018 Free

Caution with the forthcoming rescheduling of over-the-counter codeine-containing analgesics

To the Editor: After extensive public consultation, the Therapeutic Goods Administration announced that all over-the-counter codeine preparations, including over-the-counter codeine-containing analgesics (OTC CCAs) will be rescheduled as prescription only in February 2018, citing the substantial risk of drug toxicity from deliberate misuse and the relative lack of efficacy compared with safer products. Codeine is a weak analgesic — even at doses of 60 mg — and the Australian Medicines Handbook notes that “there is no conclusive evidence that products containing 8–15 mg of codeine per tablet with paracetamol, aspirin or ibuprofen have any benefits over these non-opioids alone”.1 Misuse and harm are widespread, with people who are addicted to codeine taking 40 or more tablets a day. In 2016, more than 500 000 Australians aged 14 years or over used OTC CCAs non-medically. Despite more restrictive scheduling in 2010, a Poisons Information Centre described a 17.9% annual increase from 2004–2015 in calls concerning the misuse of ibuprofen–codeine analgesics.2 Moreover, drug clinics describe a 10-year four-fold increase in treatments where codeine was a drug of concern (Box). Prolonged high-dose ibuprofen exposure secondary to codeine addiction may cause bleeding or perforated gastric ulcers; non-steroidal anti-inflammatory drug-induced enteropathy, with diaphragm disease and bowel obstruction; anaemia; protein-losing enteropathy; hypoalbuminaemia; renal tubular acidosis and death. Medical practitioners should consider OTC CCA misuse in patients presenting with non-steroidal anti-inflammatory drug-related or paracetamol-related morbidity, as many patients do not disclose their misuse, therefore creating a failure to recognise the underlying cause of the presenting complaint.4 Apart from the human cost of serious injury and loss of life, there is also the cost of treatment for dependence; the cost of hundreds of hospital admissions, involving avoidable surgery, intensive care and serious morbidity;4,5 and the statistical cost of lives lost.6 Practitioners need to prepare for the forthcoming rescheduling to avoid substituting OTC CCAs with either prescription opioid analgesics or prescribing a codeine–paracetamol product, which may cause paracetamol hepatotoxicity. In addition, practitioners should treat codeine dependence by referral, opioid replacement therapy or medicated withdrawal with follow-up. The unfavourable risk–benefit profile for OTC CCAs means that the planned Australian rescheduling aligns with many other countries to minimise harm. Access to effective analgesics without a prescription is now provided by products with the non-addictive ibuprofen–paracetamol combination, which offer better analgesia than OTC CCAs.7 Box – Treatments provided for own drug use, by principal and additional drug of concern (codeine), from 2003–04 to 2013–143

Stephan A Schug · Malcolm DH Dobbin · Jennifer L Pilgrim

Letter to the Editor1

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