Richard Hallinan

Hepatitis C virus prevalence and outcomes among injecting drug users on opioid replacement therapy

Objectives:  To determine hepatitis C virus (HCV) prevalence among injecting drug users (IDUs) receiving opioid replacement therapy in a referred office setting, and assess potential needs for hepatitis C treatment and care.

ABCB1 haplotype and OPRM1 118A > G genotype interaction in methadone maintenance treatment pharmacogenetics

Background: Genetic variability in ABCB1, encoding the P-glycoprotein efflux transporter, has been linked to altered methadone maintenance treatment dose requirements. However, subsequent studies have indicated that additional environmental or genetic factors may confound ABCB1 pharmacogenetics in different methadone maintenance treatment settings. There is evidence that genetic variability in OPRM1, encoding the mu opioid receptor, and ABCB1 may interact to affect morphine response in opposite ways. This study aimed to examine whether a similar gene-gene interaction occurs for methadone in methadone maintenance treatment. Methods: Opioid-dependent subjects (n = 119) maintained on methadone (15–300 mg/day) were genotyped for five single nucleotide polymorphisms of ABCB1 (61A > G; 1199G > A; 1236C > T; 2677G > T; 3435C > T), as well as for the OPRM1 118A > G single nucleotide polymorphism. Subjects’ methadone doses and trough plasma (R)-methadone concentrations (Ctrough) were compared between ABCB1 haplotypes (with and without controlling for OPRM1 genotype), and between OPRM1 genotypes (with and without controlling for ABCB1 haplotype). Results: Among wild-type OPRM1 subjects, an ABCB1 variant haplotype group (subjects with a wild-type and 61A:1199G:1236C:2677T:3435T haplotype combination, or homozygous for the 61A:1199G:1236C:2677T:3435T haplotype) had significantly lower doses (median ± standard deviation 35 ± 5 versus 180 ± 65 mg/day, P < 0.01) and Ctrough (78 ± 22 versus 177 ± 97 ng/mL, P < 0.05) than ABCB1 wild-type subjects. Among subjects with the most common ABCB1 haplotype combination (wild-type with 61A:1199G:1236T:2677T:3435T), the OPRM1 118 A/G genotype was associated with a significantly higher Ctrough than 118 A/A (250 ± 126 versus 108 ± 36 ng/mL, P = 0.016). No ABCB1 haplotype group or OPRM1 genotype was associated with dose or Ctrough without taking into account confounding genetic variability at the other locus. Therefore, two interacting pharmacogenetic determinants of methadone maintenance treatment response were identified, ie, ABCB1, where variants are associated with lower methadone requirements, and OPRM1, where the variant is associated with higher methadone requirements. Conclusion: These opposing pharmacogenetic effects therefore need to be considered in combination when assessing methadone maintenance treatment pharmacogenetics.

Increasing the benefits and reducing the harms of prescription opioid analgesics.

ISSUES Consumption of prescription opioid analgesics (POAs) in Australia has increased steadily in recent years, raising concerns of increasing harms including overdose and dependence, as has occurred in the USA. APPROACH Exposition of the Royal Australasian College of Physicians Prescription Opioid Policy with reference to the published literature, drawing out principles for harm reduction for psychoactive pharmaceutical drugs. KEY FINDINGS Complex professional, patient, regulatory and market factors influence health professionals balancing the benefits and harms of POAs. Owing to the potential for diversion, overlapping markets probably exist for pharmaceutical opioids used for populations with cancer pain, chronic non-cancer pain, and people dependent on pharmaceutical and illicit opioids (including those needing opioid substitution treatment). Attempts to reduce or restrict supply in one area may increase demand in others. There is a need to consider new harm reduction strategies for people with problematic pharmaceutical opioid use. These people are demographically not well characterised, and may be distinct from the more familiar population of injection drug users. IMPLICATIONS Harm reduction is a valid approach for POAs. However, the role of health professionals as gatekeepers of opioid supply, the need to optimise health benefits of POAs, and the likely interplay of complex market forces among populations consuming opioids have no close parallel in harm reduction for other substances. This poses fundamentally different challenges. CONCLUSIONS Reducing inappropriate supply and demand for POAs while maximising their benefits and minimising their harms may improve health outcomes.

Hepatitis C virus incidence among injecting drug users on opioid replacement therapy

Objective: To determine hepatitis C virus (HCV) incidence among injecting drug users (IDUs) receiving opioid replacement therapy (ORT).

Cannabis and benzodiazepines as determinants of methadone trough plasma concentration variability in maintenance treatment: a transnational study

PurposeTo assess tobacco, alcohol, cannabis and benzodiazepine use in methadone maintenance treatment (MMT) as potential sources of variability in methadone pharmacokinetics.MethodsTrough plasma (R)- and (S)-methadone concentrations were measured on 77 Australian and 74 Swiss MMT patients with no additional medications other than benzodiazepines. Simple and multiple regression analyses were performed for the primary metric, plasma methadone concentration/dose.ResultsCannabis and methadone dose were significantly associated with lower 24-h plasma (R)- and (S)-methadone concentrations/dose. The models containing these variables explained 14–16% and 17–25% of the variation in (R)- and (S)-methadone concentration/dose, respectively. Analysis of 61 patients using only CYP3A4 metabolised benzodiazepines showed this class to be associated with higher (R)-concentration/dose, which is consistent with a potential competitive inhibition of CYP3A4.ConclusionCannabis use and higher methadone doses in MMT could in part be a response to—or a cause of—more rapid methadone clearance. The effects of cannabis and benzodiazepines should be controlled for in future studies on methadone pharmacokinetics in MMT.

Harm reduction, hepatitis C and opioid pharmacotherapy: an opportunity for integrated hepatitis C virus-specific harm reduction

While harm reduction advocates, policy makers and practitioners have a right to be proud of the impact of interventions such as needle and syringe programmes on HIV risk, we can be less sanguine about the ongoing high levels of HCV transmission among injecting drug users (IDUs) and the expanding burden of hepatitis C virus (HCV)-related liver disease. In this Harm Reduction Digest Drs Byrne and Hallinan from the Redfern Clinic and Dr Dore from the National Centre in HIV Epidemiology and Clinical Research offer a model of integrated HCV prevention and treatment services within the setting of opioid pharmacotherapy. In their experience, this common-sense approach provides an opportunity to reduce the burden of HCV and improve overall patient management. They believe that the key elements of a HCV-specific harm reduction model include: regular HCV testing; clinical assessment and determination of need for HCV treatment referral; use of broader HCV treatment inclusion criteria; and flexibility in opioid pharmacotherapy dosing. In an environment when our macro harm reduction interventions seem to have, at best, modest impact on HCV transmission, good clinical practice may be our most effective strategy against the HCV epidemic. This paper provides some practical suggestions as to how this can be done.

Delivery of treatment for hepatitis C virus infection in the primary care setting.

Objectives The aim of this study was to evaluate the feasibility, safety and efficacy of treatment for chronic hepatitis C virus (HCV) infection through a primary care-based model for the delivery of HCV services in New South Wales (NSW), Australia. Participants and methods This observational cohort study recruited participants through seven primary care clinics in NSW, Australia, between November 2010 and June 2013. Patients with HCV genotype 2/3 were treated without specialist review, whereas those with genotype 1 required an initial specialist review. Treatment consisted of pegylated interferon-&agr;-2a/2b and ribavirin. Sustained virological response and adverse events were evaluated. Results Among 41 participants (mean age 44 years, 73% men) initiating treatment with pegylated interferon-&agr;-2a/2b and ribavirin, 90% had injected drugs ever, 16% had injected drugs in the past 30 days and 56% had ever received opioid substitution treatment. HCV genotype 1 and genotype 2/3 occurred in 17% (n=7) and 83% (n=34). Treatment was completed in 83% (34 of 41), with seven discontinuations [adverse event (depression), n=1; patient decision, n=1; lost to follow-up, n=3; virological nonresponse, n=2]. In an intent-to-treat analysis, sustained virological response was 71% overall (29 of 41), 43% in genotype 1 (three of seven) and 76% in genotype 2/3 (26 of 34). Conclusion Initiation of HCV treatment in the primary care setting is an effective alternative for selected patients and may contribute towards increasing access to HCV care.

Constipation and other common symptoms reported by women and men in methadone and buprenorphine maintenance treatment

BACKGROUND Opioid substitution treatment (OST) is often continued long-term and, therefore, opioid-associated symptoms are of interest. Symptoms associated with methadone maintenance treatment (MMT) in men are well described, but there are fewer reports concerning symptoms associated with buprenorphine maintenance treatment (BMT) and very few reports among women. METHOD Recipients of BMT (n=113) and MMT (n=184), non-opioid users (n=105) and opioid users not receiving OST (n=87) completed the Patient Assessment of Constipation (PAC-SYM) and a general symptom checklist. Multivariate analysis included other potential moderators of opioid-associated symptoms. FINDINGS Opioid users reported a higher frequency and severity of symptoms than non-opioid users. Constipation, dry mouth, decreased appetite, sweating and fatigue were highly prevalent in the previous 30days (51-80%). Nausea, itchy skin, trouble urinating, menstrual problems, lightheadedness, blurred vision, heart racing were also common (30-50%). Non-OST opioid users had significantly higher frequency and severity than OST recipients of nausea, vomiting, diarrhoea, decreased appetite, sweating and itchy skin. Sweating was significantly more common in MMT than BMT. Constipation scores were higher in women, otherwise most sex differences were small. Higher PAC-SYM scores were associated with vomiting (OR=1.04) and sweating (OR=1.06). Cannabis use was associated with vomiting (OR=2.19). Constipation (OR=1.07), insomnia (OR=2.5) and depression (OR=2.82) were associated with fatigue. CONCLUSION Men and women receiving OST report similarly high rates of somatic symptoms, though less than opioid users not receiving OST. There were few differences between BMT and MMT. Buprenorphine might be preferred where sweating is problematic. Several modifiable factors were identified.

Does electrocardiography improve methadone safety

We commend Stringer et al.[1][1] for their excellent summary of the literature on methadone-associated Q-T interval prolongation. However, we question their recommendation to perform routine electrocardiography before and during the course of methadone treatment as a measure to prevent torsade de

Moving the debate forward on prescription opioids

The study by Leong et al. (published in the October 2009 issue of the Internal Medicine Journal) of trends in opioid prescriptions captured by the Health Insurance Commission database accords with other evidence of increasing use of pharmaceutical opioids in Australia, reviewed in the recently released Royal Australasian College of Physicians’ policy. The fundamental question arising from these data is how much of this increased pharmaceutical opioid supply reflects appropriate prescribing and sanctioned use and how much inappropriate prescriber behaviour and problematic use. Total opioid base supply in Australia, which is captured by Treaties and Compliance, has increased enormously between 1991 and 2005. The greatest increases have been in morphine from 1991, when sustained release preparations became available, until about 2001, with a plateau since then, and in oxycodone since 2000, when the sustained release preparation Oxycontin (Purdue Pharma, Stamford, Connecticut, USA) came on the market. Australian oxycodone supply measured in kilograms has been increasing steeply since 2003, and first exceeded morphine supply in 2007. Evidence from the USA demonstrates that there is a strong correlation between therapeutic exposure to opioid analgesics and problematic use, and between total opioid sales and drug poisoning mortality. In the USA, unintentional drug poisoning deaths increased by 68% during 1999–2004, most of this increase being attributed to deaths associated with opioid analgesics. Although Australia would appear to be somewhat behind America in this trend, we are also less well provided with surveillance and monitoring data, having for example no equivalent of the Drug Abuse Warning Network. In Australia, the Office of Chemicals Safety records all S8 import and manufacture, and can track supply down to pharmacy level, but cannot identify individual patients or customers or the indication for prescription. Even Leong et al.’s data set, the most comprehensive available relating to supply to patients, does not include private prescriptions, or prescriptions for which the cost is less than the Pharmaceutical Benefits Schedule (PBS) co-payment. Evidence on harms related to licit and illicit pharmaceutical opioid use is scant, as Leong et al. point out. Some indication of the scale of problematic use, which may include diversion to third parties, comes from the Doctor Shoppers database, which already in 2000 showed 1 in 9 prescriptions for MS Contin 100 mg and 1 in 7 prescriptions for Oxycontin 80 mg were accounted for by identified ‘doctor shoppers’ (defined as people attending 15 or more general practitioners (GPs) annually). Among the difficulties in determining the extent of appropriate and inappropriate prescribing is the lack of consensus, to which Leong et al. allude, on the proper place of opioid treatment in chronic non-malignant pain. Many guidelines exist for the treatment of patients with chronic pain, including the use of opioids, but none is designed for practical use in the busy front line of general practice. The same is true of risk assessment at the front line. Guidelines alone do not necessarily translate into good practice, but they should be part of a comprehensive strategy to reduce the risk associated with opioid prescribing. They need to be simple, generally accepted, and used in constructive processes embedded in professional development, such as audit and feedback. The national prescribing service provides a good model for this. Doctors have a duty of care to provide adequate pain relief to those who need it while minimizing problematic use of opioids by patients and diversion to third parties. However, strong forces discourage the thorough assessment, multidisciplinary care and biopsychological framework that are needed for optimal management of patients with chronic pain. These include the historical predominance of the ‘biomedical model’ in medical practice and, in Australia, Medicare funding arrangements for GPs that favour brief consultations while requiring complex and frustrating paperwork to facilitate patient access even to minimal allied health services. Limited access to pain and addiction physicians in public sector referral centres, and their near nonexistence in private practice in the community, add to the pressures for default to the script pad. Another strong force which may push in the other direction, towards a ‘just say no’ approach, is the lack of real-time access to prescription records of patients, so that GPs and dispensing pharmacists are often flying blind. There may be a range of responses, from philosophical resignation to Internal Medicine Journal 40 (2010) 5–6