Nicholas Lintzeris

Supervised injectable heroin or injectable methadone versus optimised oral methadone as treatment for chronic heroin addicts in England after persistent failure in orthodox treatment (RIOTT): a randomised trial

BACKGROUND Some heroin addicts persistently fail to benefit from conventional treatments. We aimed to compare the effectiveness of supervised injectable treatment with medicinal heroin (diamorphine or diacetylmorphine) or supervised injectable methadone versus optimised oral methadone for chronic heroin addiction. METHODS In this multisite, open-label, randomised controlled trial, we enrolled chronic heroin addicts who were receiving conventional oral treatment (>or=6 months), but continued to inject street heroin regularly (>or=50% of days in preceding 3 months). Randomisation by minimisation was used to assign patients to receive supervised injectable methadone, supervised injectable heroin, or optimised oral methadone. Treatment was provided for 26 weeks in three supervised injecting clinics in England. Primary outcome was 50% or more of negative specimens for street heroin on weekly urinalysis during weeks 14-26. Primary analysis was by intention to treat; data were adjusted for centre, regular crack use at baseline, and treatment with optimised oral methadone at baseline. Percentages were calculated with Rubins rules and were then used to estimate numbers of patients in the multiple imputed samples. This study is registered, ISRCTN01338071. FINDINGS Of 301 patients screened, 127 were enrolled and randomly allocated to receive injectable methadone (n=42 patients), injectable heroin (n=43), or oral methadone (n=42); all patients were included in the primary analysis. At 26 weeks, 80% (n=101) patients remained in assigned treatment: 81% (n=34) on injectable methadone, 88% (n=38) on injectable heroin, and 69% (n=29) on oral methadone. Patients on injectable heroin were significantly more likely to have achieved the primary outcome (72% [n=31]) than were those on oral methadone (27% [n=11], OR 7.42, 95% CI 2.69-20.46, p<0.0001; adjusted: 66% [n=28] vs 19% [n=8], 8.17, 2.88-23.16, p<0.0001), with number needed to treat of 2.17 (95% CI 1.60-3.97). For injectable methadone (39% [n=16]; adjusted: 30% [n=14]) versus oral methadone, the difference was not significant (OR 1.74, 95% CI 0.66-4.60, p=0.264; adjusted: 1.79, 0.67-4.82, p=0.249). For injectable heroin versus injectable methadone, a significant difference was recorded (4.26, 1.63-11.14, p=0.003; adjusted: 4.57, 1.71-12.19, p=0.002), but the study was not powered for this comparison. Differences were evident within the first 6 weeks of treatment. INTERPRETATION Treatment with supervised injectable heroin leads to significantly lower use of street heroin than does supervised injectable methadone or optimised oral methadone. UK Government proposals should be rolled out to support the positive response that can be achieved with heroin maintenance treatment for previously unresponsive chronic heroin addicts. FUNDING Community Fund (Big Lottery) Research section, through Action on Addiction.

Nabiximols as an Agonist Replacement Therapy During Cannabis Withdrawal: A Randomized Clinical Trial

IMPORTANCE There are no medications approved for treating cannabis dependence or withdrawal. The cannabis extract nabiximols (Sativex), developed as a multiple sclerosis treatment, offers a potential agonist medication for cannabis withdrawal. OBJECTIVE To evaluate the safety and efficacy of nabiximols in treating cannabis withdrawal. DESIGN, SETTING, AND PARTICIPANTS A 2-site, double-blind randomized clinical inpatient trial with a 28-day follow-up was conducted in New South Wales, Australia. Participants included 51 DSM-IV-TR cannabis-dependent treatment seekers. INTERVENTIONS A 6-day regimen of nabiximols (maximum daily dose, 86.4 mg of Δ9-tetrahydrocannabinol and 80 mg of cannabidiol) or placebo with standardized psychosocial interventions during a 9-day admission. MAIN OUTCOMES AND MEASURES Severity of cannabis withdrawal and cravings (Cannabis Withdrawal Scale), retention in withdrawal treatment, and adverse events. Secondary outcomes include postwithdrawal cannabis use, health outcomes, and psychosocial outcomes. RESULTS Nabiximols treatment significantly reduced the overall severity of cannabis withdrawal relative to placebo (F8,377.97 = 2.39; P = .01), including effects on withdrawal-related irritability, depression, and cannabis cravings. Nabiximols had a more limited, but still positive, therapeutic benefit on sleep disturbance, anxiety, appetite loss, physical symptoms, and restlessness. Nabiximols patients remained in treatment longer during medication use (unadjusted hazard ratio, 3.66 [95% CI, 1.18-11.37]; P = .02), with 2.84 the number needed to treat to achieve successful retention in treatment. Participants could not reliably differentiate between nabiximols and placebo treatment (χ21 = 0.79; P = .67), and those receiving nabiximols did not report greater intoxication (F1,6 = 0.22; P = .97). The number (F1,50 = 0.3; P = .59) and severity (F1,50 = 2.69; P = .10) of adverse events did not differ significantly between groups. Both groups showed reduced cannabis use at follow-up, with no advantage of nabiximols over placebo for self-reported cannabis use (F1,48 = 0.29; P = .75), cannabis-related problems (F1,49 = 2.33; P = .14), or cannabis dependence (F1,50 < 0.01; P = .89). CONCLUSIONS AND RELEVANCE In a treatment-seeking cohort, nabiximols attenuated cannabis withdrawal symptoms and improved patient retention in treatment. However, placebo was as effective as nabiximols in promoting long-term reductions in cannabis use following medication cessation. The data support further evaluation of nabiximols for management of cannabis dependence and withdrawal in treatment-seeking populations. TRIAL REGISTRATION anzctr.org.au Identifier: ACTRN12611000398909.

Benzodiazepines, methadone and buprenorphine: interactions and clinical management.

Benzodiazepines (BZDs) are widely used by heroin users not in treatment, and by patients in methadone and buprenorphine (BPN) treatment. This review examines the epidemiology of BZD use by opioid users, and the range of harms that are associated with BZD use in this group, including the association of BZD use with opioid-related mortality. Preclinical and clinical data regarding pharmacokinetic and pharmacodynamic interactions between methadone, buprenorphine, and BZDs are reviewed. An overview of treatment approaches for managing BZD use in this population is presented, including strategies for minimizing abuse and addressing BZD dependence.

The acceptability and feasibility of peer worker support role in community based HCV treatment for injecting drug users

Hepatitis C is the most common blood borne virus in Australia affecting over 200 000 people. Effective treatment for hepatitis C has only become accessible in Australia since the late 1990s, although active injecting drug use (IDU) remained an exclusion criteria for government-funded treatment until 2001. Treatment uptake has been slow, particularly among injecting drug users, the largest affected group. We developed a peer-based integrated model of hepatitis C care at a community drug and alcohol clinic. Clients interested and eligible for hepatitis C treatment had their substance use, mental health and other psychosocial comorbidities co-managed onsite at the clinic prior to and during treatment. In a qualitative preliminary evaluation of the project, nine current patients of the clinic were interviewed, as was the clinic peer worker. A high level of patient acceptability of the peer-based model and an endorsement the integrated model of care was found. This paper describes the acceptability of a peer-based integrated model of hepatitis C care by the clients using the service.

Interactions on mixing diazepam with methadone or buprenorphine in maintenance patients

Abstract: Benzodiazepine use by patients in methadone and buprenorphine substitution treatment is common, despite safety concerns regarding these drug interactions. The relative safety of diazepam use by methadone- or buprenorphine-treated patients has not been systematically examined. This study aimed to examine the effect of single diazepam doses, within normal therapeutic range (doses: 0, 10, and 20 mg), upon physiological, subjective, and performance measures in stable methadone and buprenorphine-treated patients. In a double-blind, randomized crossover design, methadone- or buprenorphine-treated patients were administered their normal opioid dose and either placebo, 10-, or 20-mg diazepam, in balanced order over 3 sessions. Eight methadone- and 8 buprenorphine-prescribed patients with no concurrent benzodiazepine dependence or significant comorbidity were recruited from an outpatient addiction clinic in London. Measures were taken at baseline and for 6 hours after dosing, and included physiological responses (pulse rate, blood pressure, pupil size, respiratory rate, and peripheral pO2), subjective drug effects (Addiction Research Center Inventory subscales, visual analog scales of strength of drug effect, drug-liking, and sedation), and performance measures (simple reaction time, cancellation task, digit symbol substitution task, and balance). The 10- and 20-mg diazepam doses resulted in comparable subjective experiences of greater sedation and strength of drug effects in both patient groups, and had minimal impact on physiological parameters. However, diazepam had greater peak effects on performance measures (simple reaction time, digit symbol substitution task, and cancellation time) in methadone-treated than in buprenorphine-treated patients. Diazepam may significantly alter the response to opioid substitution treatment with methadone or buprenorphine.

The Pain and Opioids IN Treatment study: characteristics of a cohort using opioids to manage chronic non-cancer pain

Abstract There has been a recent increase in public and professional concern about the prescription of strong prescription opioids for pain. Despite this concern, research to date has been limited because of a number of factors such as small sample sizes, exclusion of people with complex comorbidities, and studies of short duration. The Pain and Opioids IN Treatment is a 2-year prospective cohort study of 1500 people prescribed with pharmaceutical opioids for their chronic pain. This article provides an overview of the demographic and clinical characteristics of the cohort using the baseline data of 1514 community-based people across Australia. Participants had been in pain for a period of 10 years and had been on prescription opioids for approximately 4 years. One in 10 was on a daily morphine equivalent dose of ≥200 mg. Employment and income levels were low, and two-thirds of the sample reported that their pain had impacted on their employment status. Approximately 50% screened positive for current moderate-to-severe depression, and 1 in 5 had made a lifetime suicide attempt. There were a number of age-related differences. The younger groups experienced higher levels of pain and pain interference, more mental health and substance use issues, and barriers to treatment, compared with the older group. This study found that the people who have been prescribed strong opioids for chronic pain have very complex demographic and clinical profiles. Major age-related differences in the experiences of pain, coping, mental health, and substance use suggest the necessity of differential approaches to treatment.

Post-marketing surveillance of buprenorphine-naloxone in Australia: Diversion, injection and adherence with supervised dosing

BACKGROUND These studies compared the diversion and injection of buprenorphine-naloxone (BNX), buprenorphine (BPN) and methadone (MET) in Australia. METHODS Surveys were conducted with regular injecting drug users (IDUs) (2004-2009, N=881-943), opioid substitution treatment (OST) clients (2008, N=440) and authorised OST prescribers (2007, N=291). Key outcome measures include the unsanctioned removal of supervised doses, diversion, injection, motivations, drug liking and street price. Levels of injection among IDUs were adjusted for background availability of medications. Doses not taken as directed by OST clients were adjusted by total number of daily doses dispensed. RESULTS Among regular IDUs, levels of injection were lower for BNX relative to BPN, but comparable to those for MET, adjusting for background availability. Among OST clients, fewer BNX clients (13%) reported recently injecting their medication, than BPN (28%) and MET clients (23%). Fewer MET clients (10%) reported removal of supervised doses, than BPN (35%) and BNX clients (22%). There were no differences in prevalence of recent diversion (28% of all OST clients). Adjusting for the total doses dispensed, more BPN was injected (10%), removed (12%) and diverted (5%), than MET (5%, <1% and 2% respectively) and BNX (5%, 9% and <1% respectively). In 2009, the median street price of BNX was equivalent to that for BPN. CONCLUSIONS BNX was less commonly and less frequently injected than BPN, but both sublingual medications were diverted more than liquid MET.

Implementing Buprenorphine Treatment in Community Settings in Australia: Experiences from the Buprenorphine Implementation Trial

Buprenorphine was registered in Australia as a maintenance and detoxification agent for the management of opioid dependence in November, 2000, and became widely available in August, 2001. This paper provides an overview of key developments in the introduction of buprenorphine treatment in Australia, with an emphasis upon the delivery of services in community-based (primary care) settings. A central study in this work was the Buprenorphine Implementation Trial (BIT), a randomized, controlled trial comparing buprenorphine and methadone maintenance treatment delivered under naturalistic conditions by specialist and community-based service providers (general practitioners and community pharmacists) in 139 subjects across nineteen treatment sites. In addition to conventional patient outcome measures (treatment retention, drug use, psychosocial functioning, and cost effectiveness), the BIT study also involved the development and evaluation of clinical guidelines, training programs for clinicians, and client literature, which are described here. Integration of treatment systems (methadone with buprenorphine, specialist and primary-care programs) and factors thought to be important in the uptake of buprenorphine treatment in Australia since registration are discussed.

Methodology for the Randomised Injecting Opioid Treatment Trial (RIOTT): evaluating injectable methadone and injectable heroin treatment versus optimised oral methadone treatment in the UK.

Whilst unsupervised injectable methadone and diamorphine treatment has been part of the British treatment system for decades, the numbers receiving injectable opioid treatment (IOT) has been steadily diminishing in recent years. In contrast, there has been a recent expansion of supervised injectable diamorphine programs under trial conditions in a number of European and North American cities, although the evidence regarding the safety, efficacy and cost effectiveness of this treatment approach remains equivocal. Recent British clinical guidance indicates that IOT should be a second-line treatment for those patients in high-quality oral methadone treatment who continue to regularly inject heroin, and that treatment be initiated in newly-developed supervised injecting clinics.The Randomised Injectable Opioid Treatment Trial (RIOTT) is a multisite, prospective open-label randomised controlled trial (RCT) examining the role of treatment with injected opioids (methadone and heroin) for the management of heroin dependence in patients not responding to conventional substitution treatment. Specifically, the study examines whether efforts should be made to optimise methadone treatment for such patients (e.g. regular attendance, supervised dosing, high oral doses, access to psychosocial services), or whether such patients should be treated with injected methadone or heroin.Eligible patients (in oral substitution treatment and injecting illicit heroin on a regular basis) are randomised to one of three conditions: (1) optimized oral methadone treatment (Control group); (2) injected methadone treatment; or (3) injected heroin treatment (with access to oral methadone doses). Subjects are followed up for 6-months, with between-group comparisons on an intention-to-treat basis across a range of outcome measures. The primary outcome is the proportion of patients who discontinue regular illicit heroin use (operationalised as providing >50% urine drug screens negative for markers of illicit heroin in months 4 to 6). Secondary outcomes include measures of other drug use, injecting practices, health and psychosocial functioning, criminal activity, patient satisfaction and incremental cost effectiveness. The study aims to recruit 150 subjects, with 50 patients per group, and is to be conducted in supervised injecting clinics across England.

Unplanned pregnancy and contraceptive use in women attending drug treatment services

At an international level, there are calls for a greater focus on women and harm reduction in recognition that female drug users have a unique set of issues that are not routinely assessed in drug treatment programs.