Randomised Comparison of a Novel Buprenorphine Oral Lyophilisate versus Existing Buprenorphine Sublingual Tablets in Opioid-Dependent Patients: A First-in-Patient Phase II Randomised Open Label Safety Study.

AIMS: To test the safety of new buprenorphine oral lyophilisate wafer ("bup-lyo") versus standard sub-lingual buprenorphine ("bup-SL"). DESIGN: Randomised (2:1) open-label study; opioid-dependent subjects; subsequent partial cross-over. SETTINGS: Specialised clinical trials facility and addictions treatment facility. PARTICIPANTS: Opioid-dependent subjects (n = 36) commencing buprenorphine maintenance (personalised dose-titration) including patients co-using alcohol, cocaine and benzodiazepines (below thresholds). MEASUREMENTS: Respiratory function (respiratory rate, pulse-oximetry); medication hold and dose adequacy; opiate withdrawal signs and symptoms; tablet disintegration times; treatment retention. Pharmacokinetics (PK) for plasma buprenorphine and norbuprenorphine (n = 11). FINDINGS: Oral lyophilised buprenorphine ("bup-lyo") completely dissolved within 2 min for 58 vs. 5% for "bup-SL." Dose titration resulted in similar maintenance dosing (10.8 vs. 9.6 mg). There were no significant between-group differences in opiate-withdrawal phenomena, craving, adequacy of "hold," respiratory function. No serious adverse events (AEs), nor "severe" AEs, although more AEs and Treatment-Emergent AEs with "bup-lyo" (mostly "mild"). PK found greater bioavailability of buprenorphine with "bup-lyo" (but not norbuprenorphine). CONCLUSIONS: Orally disintegrating buprenorphine oral lyophilisate wafer disintegrated rapidly. No increased respiratory depression was found and clinically no difference between medications was observed. PK found substantially increased bioavailability of buprenorphine (but not of nor-buprenorphine) with "bup-lyo" relative to "bup-SL." In supervised dosing contexts, rapidly disintegrating formulations may enable wider buprenorphine prescribing.

Evaluation of strategies to control Fab light chain dimer during mammalian expression and purification: A universal one-step process for purification of correctly assembled Fab.

Fabs are an important class of antibody fragment as both research reagents and therapeutic agents. There are a plethora of methods described for their recombinant expression and purification. However, these do not address the issue of excessive light chain production that forms light chain dimers nor do they describe a universal purification strategy. Light chain dimer impurities and the absence of a universal Fab purification strategy present persistent challenges for biotechnology applications using Fabs, particularly around the need for bespoke purification strategies. This study describes methods to address light chain dimer formation during Fab expression and identifies a novel CH 1 affinity resin as a simple and efficient one-step purification for correctly assembled Fab.

Pharmacological treatments for drug misuse and dependence.

INTRODUCTION: Substance misuse disorder (DSM-5) remains a major health challenge. Harm reduction is the initial treatment goal, by reducing or eliminating non-prescribed drug use. Eventual abstinence is the ultimate harm reduction goal. However the scope for evidence-based pharmacological interventions remains limited. AREAS COVERED: The paper takes a pragmatic clinical approach to existing and developing pharmacotherapies for substance misuse. Dependence may be characterised as a cycle with three stages: binge/intoxication, withdrawal/negative affect and preoccupation/anticipation (craving). Each of these stages may be the focus of pharmacotherapeutic intervention, and current literature is discussed which is of relevance to the practising clinician. Dependence on opiates, stimulants, cannabis and prescribed medications including benzodiazepines and the current treatments are addressed. EXPERT OPINION: Possible pharmacotherapies of the future include anti-craving medications, which are still incompletely understood. Other developments include ultra-long-acting formulations, some of which have already been produced and are being studied or are in early clinical practice. A completely new line of investigation has been drug 'vaccines', whereby the body is stimulated to produce antibodies to, for example, cocaine and nicotine. Despite a number of evidence-based strategies for the treatment of substance misuse disorder, the range of licensed pharmacological treatment choices nevertheless remains narrow.

Predicting biopsychosocial outcomes for heroin users in primary care treatment: a prospective longitudinal cohort study.

BACKGROUND: Opiate substitution treatment for heroin users reduces mortality, illicit drug use, crime, and risk-taking behaviour, and improves physical, mental and social functioning. Few extended studies have been carried out in UK primary care to study factors predicting recovery. AIM: To establish whether primary care opiate substitution treatment is associated with improvements in outcomes over 11 years, in delivering recovery, and to identify predictive factors. DESIGN AND SETTING: A prospective longitudinal cohort study, with repeated measures in the Primary Care Addiction Service, Sheffield, 1999-2011. METHOD: A total of 123 eligible patients were assessed using the Opiate Treatment Index at entry to treatment and at 1, 5, and 11 years. Clinical records were used to assess factors including employment and discharge status. RESULTS: At 11 years, there was a high rate of drug-free discharge (22.0%) and medically-assisted recovery (30.9%), and low mortality (6.5%). Continuous treatment was associated with being discharged drug free (P = 0.005). For those still in treatment, there were highly significant reductions in heroin use and injecting, and significantly improved psychosocial functioning. There were strong positive correlations between mental health, physical health, and social functioning. Patients in employment had significantly better psychological and social functioning (P = 0.017, P = 0.007, respectively). CONCLUSION: Opiate substitution treatment is associated over 11 years with full recovery, drug-free discharge and medically-assisted recovery. There is a strong association between the psychosocial variables, suggesting that intervention in any one of these areas may have extended benefits, by impacting on related variables and employment. The best predictor of a drug-free discharge was continuous uninterrupted treatment.

Can a targeted GP-led clinic improve outcomes for street sex workers who use heroin?

Female street sex workers in the UK are often addicted to heroin, and sex work may be a result of the economic drive to fund this addiction. This study looks at outcomes of a primary care drugs treatment intervention for street sex workers who use heroin, using prescribed maintenance treatment with intensive health and psychosocial support. Thirty-four sex workers entered the study and 100% were retained in the study at 1 year. After 1 year, only 33% of participants were still sex workers. Quality of life had improved significantly and heroin use had reduced.

The effect of time spent in treatment and dropout status on rates of convictions, cautions and imprisonment over 5 years in a primary care-led methadone maintenance service.

BACKGROUND: Methadone maintenance treatment (MMT) in primary care settings is used increasingly as a standard method of delivering treatment for heroin users. It has been shown to reduce criminal activity and incarceration over periods of periods of 12 months or less; however, little is known about the effect of this treatment over longer durations. AIMS: To examine the association between treatment status and rates of convictions and cautions (judicial disposals) over a 5-year period in a cohort of heroin users treated in a general practitioner (GP)-led MMT service. DESIGN: Cohort study. SETTING: The primary care clinic for drug dependence, Sheffield, 1999-2005. PARTICIPANTS: The cohort comprised 108 consecutive patients who were eligible and entered treatment. Ninety were followed-up for the full 5 years. INTERVENTION: The intervention consisted of MMT provided by GPs in a primary care clinic setting. MEASUREMENTS: Criminal conviction and caution rates and time spent in prison, derived from Police National Computer (PNC) criminal records. FINDINGS: The overall reduction in the number of convictions and cautions expected for patients entering MMT in similar primary care settings is 10% for each 6 months retained in treatment. Patients in continuous treatment had the greatest reduction in judicial disposal rates, similar to those who were discharged for positive reasons (e.g. drug free). Patients who had more than one treatment episode over the observation period did no better than those who dropped out of treatment. CONCLUSIONS: MMT delivered in a primary care clinic setting is effective in reducing convictions and cautions and incarceration over an extended period. Continuous treatment is associated with the greatest reductions.

Does methadone maintenance treatment based on the new national guidelines work in a primary care setting?

BACKGROUND: General practitioners (GPs) are being encouraged to treat more drug users but there are few studies to demonstrate the effectiveness of primary care treatment. AIM: To determine whether patients retained on methadone maintenance treatment for one year in a modern British primary care setting, with prescribing protocols based on the new national guidelines, can achieve similar harm reduction outcomes to those demonstrated in other settings, using objective outcome measures where available. DESIGN OF STUDY: Longitudinal cohort study. SETTING: The Primary Care Clinic for Drug Dependence, Sheffield. METHOD: The intervention consisted of a methadone maintenance treatment provided by GPs with prescribing protocols based on the 1999 national guidelines. The first 96 eligible consenting patients entering treatment were recruited; 65 completed the study. Outcome measures were current drug use, HIV risk-taking behaviour, social functioning, criminal activity, and mental and physical health, supplemented by urinalysis and criminal record data. RESULTS: Frequency of heroin use was reduced from a mean of 3.02 episodes per day (standard deviation [SD] = 1.73) to a mean of 0.22 episodes per day (SD = 0.54), (chi 2 = 79.48, degrees of freedom [df] = 2, P < 0.001), confirmed by urinalysis. Mean numbers of convictions and cautions were reduced by 62% (z = 3.378, P < 0.001) for all crime. HIV risk-taking behaviour, social functioning, and physical and psychological wellbeing all showed significant improvements. CONCLUSION: Patients retained on methadone maintenance treatment for one year in a primary care setting can achieve improvements on a range of harm reduction outcomes similar to those shown by studies in other, often more highly structured programmes.

Concomitant drugs of misuse and drug using behaviours associated with fatal opiate-related poisonings in Sheffield, UK, 1997-2000.

AIMS: To examine the degree of involvement of concomitant drugs of misuse and other previously identified behavioural risk factors in acute accidental opiate-related poisoning fatalities in Sheffield, 1997-2000. DESIGN: Retrospective analysis of coroners' records. SETTING: Sheffield, UK. PARTICIPANTS: All those who died from an acute accidental opiate-related poisoning in Sheffield between 1 January 1997 and 31 December 2000. MEASUREMENTS: Coronial data were collated under the headings: demographic characteristics, circumstances of death and toxicological findings. FINDINGS: Ninety-four deaths occurred over the study period. The majority of cases were regular users of illicit drugs. Approximately 20% of deaths were preceded by a period of abstinence from drug use, with imprisonment and hospitalization as the most common reasons. Sixty-one per cent of cases had concomitant drugs of misuse detected from toxicology most commonly benzodiazepines and/or alcohol. These were, however, found in relatively small concentrations and opiate blood concentrations were no lower in deaths where multiple substances were involved. Despite evidence to suggest that smoking is the preferred route of heroin administration in this region, the vast majority of cases involved injecting. CONCLUSIONS: Administration of an opiate via intravenous injection was the most consistent factor associated with these deaths over the period of this study. Co-administration of other central nervous system depressants, at least in lower quantities appear to be a feature rather than a risk factor per se in such fatalities.

Methadone maintenance treatment can be provided in a primary care setting without increasing methadone-related mortality: the Sheffield experience 1997-2000.

Methadone maintenance treatment has been shown in many studies to reduce mortality and morbidity among heroin users. However, there has been concern that widespread methadone prescribing will lead conversely to an increase in methadone-related deaths. This study in Sheffield shows no increase in methadone-related mortality over a two-year period, during which 400 untreated patients were recruited into primary care methadone treatment in the city.

Deaths from drugs of abuse in Sheffield 1997-1999: what are the implications for GPs prescribing to heroin addicts?

OBJECTIVE: Our aim was to examine the characteristics of drug abuse deaths in Sheffield between 1997 and 1999 with particular attention on the role of prescribed medication and the impact of increased methadone prescribing. METHODS: Information was made available on all deaths reported to the City of Sheffield Coroner between 1 January 1997 and 31 December 31 1999. These records were searched to identify individuals who died from a 'drug of abuse'-related poisoning. RESULTS: A total of 82 drug of abuse-related deaths occurred in Sheffield during the 3-year period. The number of deaths rose from 16 in 1997 to 34 in 1999 (112%), with the largest increase occurring between 1997 and 1998. The mean age over the period of study was 29.4 years (SD 7.5 years), the overwhelming majority of which were male (92%), single (89%) and unemployed (84%). Heroin on its own or in combination with other drugs was considered to be responsible for death in 70% of all cases. Deaths attributable either wholly or partially to methadone poisoning fell from 37% in 1997 to 18% in 1999. CONCLUSIONS: Given that the proportion of deaths involving methadone over this period fell against a background of increased prescribing, then it would appear that the availability of methadone is not a factor involved in the increase in the number of drug of abuse-related deaths in this study.