From the clinic to the street: the changing role of benzodiazepines in the Scottish overdose epidemic.

Drug-related deaths in Scotland increased for seven years in a row between 2014 and 2020 consolidating Scotland's place at the top of the United Kingdom and European drug-related mortality charts. One of the defining features of this recent and rapid rise has been the role of benzodiazepines which are now involved in two-thirds of all cases. Policy decisions over four decades have contributed to the supply and demand drivers of this unique element of the Scottish overdose crisis. An illicit market once populated by diverted prescription medications is now dominated by a toxic supply of NPS-type benzodiazepines or so-called 'street benzos' which have increased the risk environment for people who use drugs. In response, Scotland needs to urgently expand its harm reduction infrastructure and implement safer supply, drug testing and drug consumption rooms. Such a response should be made in parallel to addressing the socioeconomic inequalities which are fuelling an epidemic of global significance.

Methadone replacement therapy: tried, tested, effective?

Methadone prescription is a controversial topic. While many believe that it is an effective treatment for opiate dependency, others argue that it is not successful in reducing either the addiction or even injecting behaviour. In this debate, Dr Robertson makes the case that methadone has been well tested, is cheap and acceptable to the patient and results in visible improvement. Dr Daniels argues that methadone treatment is philosophically ill-conceived, ethically dubious, and costly. He also highlights evidence that the treatment is potentially harmful to both patients and those in contact with them.

Cannabis and the lung.

The use of cannabis is embedded within many societies, mostly used by the young and widely perceived to be safe. Increasing concern regarding the potential for cannabis to cause mental health effects has dominated cannabis research and the potential adverse respiratory effects have received relatively little attention. Studies on cannabis are challenging and subject to confounding by concomitant use of tobacco and other social factors, and while many of the studies referred to in this review are beset by the difficulties inherent in undertaking epidemiological research of the effects of cannabis, there is an emerging concern among many chest physicians who would suggest that habitual smoking of cannabis may contribute to the development of chronic obstructive pulmonary disease, pneumothorax and respiratory infections, including tuberculosis. Special attention should be given to the risk of lung cancer, particularly as biological plausibility may precede epidemiology.

Mismatched human leukocyte antigen alleles protect against heterosexual HIV transmission.

Genetic variation at the human leukocyte antigen (HLA) loci has been shown to be an important risk factor for progression to HIV disease, but its significance in infection is less well understood. We have investigated its role in HIV transmission in a cohort of individuals at risk for heterosexual infection. Analysis of over 80 individuals revealed that that the degree of concordance at HLA A, B, and DR loci differs significantly between transmitting and nontransmitting couples at risk for heterosexual HIV transmission (p <.02), suggesting that allogeneic immune responses may confer a degree of protection against HIV infection. Analysis of the frequencies of specific alleles at the A, B, and DR loci revealed a significantly higher frequency of HLA DR5 among exposed uninfected individuals, relative to population controls.

The analysis of methadone in nail clippings from patients in a methadone-maintenance program.

This study offers an analytical scheme for methadone in fingernail clippings. Nail specimens (0.18-16.33 mg) were collected from 30 consenting adults participating in a methadone-maintenance program along with questionnaires regarding their drug-use histories. The nail clippings were stored in plastic bags and transferred to the laboratory for analysis. They were decontaminated by sonication for 15-min intervals successively in 0.1% sodium dodecyl sulfate, water (three times), and methanol (three times). The methanolic washes were collected and screened for methadone by enzyme immunoassay (EIA). Three washes were found sufficient to provide EIA negative results. The decontaminated nail clippings were hydrolyzed in 1M NaOH. Aliquots of the hydrolysates were screened for methadone by EIA and confirmed by gas chromatography-mass spectrometry (GC-MS). The mean methadone concentrations in fingernail clippings determined by EIA and GC-MS were 32.8 and 26.9 ng/mg, respectively. Hydrolysates of the equivalent of 10 mg of blank nail clippings were spiked with known concentrations of methadone and analyzed by the developed procedures in order to determine extraction recoveries and limits of detection of the two techniques. Based on our results, fingernails appear to be a potentially useful biological specimen for the analysis of methadone and the monitoring of patient compliance to methadone-maintenance programs.

Do gender differences in CD4 cell counts matter?

OBJECTIVE: To examine the effect of gender on disease progression and whether gender differences in CD4 lymphocyte counts persisted for the entire course from HIV seroconversion until (death from) AIDS. METHODS: CD4 lymphocyte counts were modelled in 221 female and 443 male seroconverters following seroconversion, backwards from AIDS and backwards from death using regression analysis for repeated measurements. RESULTS: In the period before use of highly active antiretroviral therapy (HAART), progression to AIDS and to death were marginally slower in women than in men as assessed by proportional hazards analysis. Women seroconverted for HIV, developed AIDS and died at higher CD4 cell counts than men (women: 815, 146 and 44 x 10(6) cells/l, respectively; men: 727, 49 and 22 x 10(6) cells/l, respectively), although differences were only statistically significant at AIDS onset. Declines in CD4 lymphocyte counts were not significantly affected by gender and absolute differences between men and women were stable, with exception for the trajectory close to AIDS when the decline became steeper for men than women. CONCLUSION: These gender differences in CD4 lymphocyte counts suggest a delay of initiation of therapy in women compared with men (our model predicted that women reach the threshold of starting HAART at about 12 months later than men). If this delay unfavourably influences progression, treatment guidelines should be revised so that women can benefit equally from HAART.

Effect of chemokine receptor mutations on heterosexual human immunodeficiency virus transmission.

To assess the effect of mutations at the CCR-2 and CCR-5 loci on heterosexual human immunodeficiency virus (HIV) transmission, 144 persons heterosexually exposed to HIV (infected and uninfected [EU]) and 57 HIV-positive index partners were genotyped. A significantly higher frequency of 64I heterozygotes at CCR-2 was observed in HIV-positive than in EU women (P=.02, relative risk=1.6). The allele frequency of 64I in women was 8% in HIV-positive contacts and 1% in EUs (P<.02). At CCR-5, no difference in the frequency of Delta32 was seen between groups, and the CCR-5 genotypes did not differ in accumulated "at-risk" exposure in EUs. Combining the analysis of the Delta32 and 64I mutations in index partners suggested an additive effect on transmission (P=.10). Thus heterozygosity for 64I at CCR-2 acts as a risk factor for HIV infection of women after heterosexual contact but heterozygosity for Delta32 at CCR-5 has no detectable effect.

Geographical variation in disease progression in HIV-1 seroconverted injecting drug users in Europe?

BACKGROUND: Human immunodeficiency virus (HIV) disease progression might vary by geographical region due to differences in the spectrum of HIV-related illnesses and (access to) health care. Therefore, the effect of geographical region, next to the effect of other potential cofactors, on disease progression in 664 injecting drug users (IDU) with documented HIV seroconversion from eight cohorts in Europe was studied. METHODS: Kaplan-Meier methods and Cox proportional hazards analysis were performed to assess the effect of geographical region, other sociodemographics, drug use and repeated HIV exposure on progression from HIV seroconversion to immunosuppression, AIDS and death with AIDS. We considered the confounding effect of study-design related factors (e.g. setting of follow-up), and accounted for pre-AIDS death from natural causes by imputing when each endpoint would have occurred, had they not died without AIDS. RESULTS: Estimates of progression to AIDS and death with AIDS were substantially faster after taking pre-AIDS mortality into account. Median incubation time from seroconversion to the first CD4 count < 200 cells/microliter was 7.7 years (95% CI: 7.1-8.3) and to AIDS 10.4 years (95% CI: 9.8-infinity). The 10-year survival was 70.3% (95% CI: 62.8-76.6). The relative hazards (RH) of AIDS for IDU from central and southern Europe compared with IDU from northern Europe was 1.9 (95% CI: 1.2-3.0) and 1.2 (95% CI: 0.6-2.3), respectively, before, and 1.5 (95% CI: 0.7-3.2) and 1.1 (95% CI: 0.6-2.3) after taking differences in study-design related factors into account. Accounting for these factors, the RH of death with AIDS was 0.9 (95% CI: 0.3-2.5) for central and 1.2 (95% CI: 0.4-3.4) for southern Europe compared with northern Europe. For the first CD4 count < 200 cells/microliter these figures were 0.8 (95% CI: 0.5-1.4) and 0.8 (95% CI: 0.5-1.4). Age at seroconversion was the strongest predictor of disease progression. No statistically significant differences in disease progression were found by gender, foreign nationality, drug use and potential repeated HIV exposure. CONCLUSIONS: We found no evidence for regional variability in HIV disease progression among European IDU. Future studies evaluating geographical differences should consider the confounding effect of study-design related factors and differential non-AIDS mortality. As age is an important determinant of disease progression, it should be considered in recommending treatment.

Nail analysis for drugs of abuse: extraction and determination of cannabis in fingernails by RIA and GC-MS.

Fingernail clippings were evaluated as analytical specimens for the detection and quantitation of cannabinoids. Specimens were obtained from consenting adults attending a drug clinic, along with information concerning the drugs which they had used over the previous six months. Methods for the surface decontamination and extraction of the specimens were evaluated. Detergent, water, and methanol washes followed by alkaline hydrolysis and liquid-liquid extraction were selected for use in the study. Extracts were analyzed by radioimmunoassay (RIA) and gas chromatography-mass spectrometry (GC-MS) to detect and quantitate cannabinoids present in fingernail clippings. Positive RIA results were obtained from specimens from six known cannabis users. The mean cannabinoid concentration in fingernail clippings determined by RIA was 1.03 ng/mg. Using GC-MS, the mean delta9-tetrahydrocannabinol concentration in fingernail clippings from a further 14 known cannabis users was 1.44 ng/mg. Using GC-MS, the average 11-nor-delta9-tetrahydrocannabinol-9-carboxylic acid concentration in fingernail clippings from three known cannabis users extracted in acidic pH was 19.85 ng/mg. Based on these results, fingernails are potentially useful biological specimens for the detection of past cannabis use in cases of medicolegal interest.

Characteristics of patients less than 45 years of age compared with older patients undergoing coronary artery bypass grafting.

BACKGROUND: Coronary artery disease (CAD) was not recognized as common among young patients until the study by Yater in 1948. Subsequent studies further elucidated the nature of the disease, which had become more apparent in the younger groups. HYPOTHESIS: The study was undertaken to determine the prevalence of risk factors and severity of coronary disease among young patients aged < or = 45 years undergoing coronary artery bypass grafting (CABG) compared with older patients. METHODS: In all, 112 young patients aged < or = 45 years (Group 1) and 798 older patients aged > 45 years (Group 2) were analyzed for trends to hypertension, smoking, diabetes, family history of heart disease, hypercholesterolemia, obesity, and history of previous myocardial infarction (MI). The severity of disease was examined in terms of number of diseased vessels, vessel size, number of grafts performed, performance of endarterectomies, and left ventricular function. RESULTS: Group 1 had a higher incidence of positive family history (68.5 vs. 51.2%, p < 0.05), and lower incidences of hypertension (62.7 vs. 81.5%, p < 0.05), obesity (42.9 vs. 83.9%, p < 0.05), and history of previous MI (54.5 vs. 94.6%, p < 0.05). Group 2 had a higher incidence of left main disease (22.6 vs. 11.4%, p < 0.05). The distribution of the affected vessels of the young patients was most commonly the left anterior descending (90.4%) followed by the right coronary (79.8%) and circumflex arteries (69.2%). Group 2 had more grafts per patient (3.82 vs. 3.37, p < 0.05). The size of the diseased vessels measured intraoperatively was similar (1.56 vs. 1.58 mm, p = NS) in both groups. Endarterectomy was performed almost three times more often in Group 1 patients (8.2 vs. 3.0%, p < 0.05). Operative mortality was less in Group 1 mean (1.8 vs. 6.3%, p < 0.05). Group 2 had a greater mean left ventricular ejection fraction (53.8 vs. 49.7%, p < 0.05). CONCLUSION: Compared with the older population, patients < or = 45 years of age who underwent CABG had (1) a higher incidence of positive family history of CAD, (2) a higher likelihood of requiring an endarterectomy, and (3) lower operative mortality rate despite a slightly poorer ventricular function.

Changes in opiate treatment during attendance at a community drug service--findings from a clinical audit.

To evaluate use of methadone and dihydrocodeine prescription in a group of opiate-dependent patients attending a community/general practice drugs project data were recorded at enrollment in 1990 and at the beginning of 1995. Two hundred individuals were included, of whom 85% were receiving a prescription for an opiate and/or a benzodiazepine. There were no major differences between the groups receiving methadone and dihydrocodeine and retention in treatment, death rate and behaviour change was similar in both groups. Trends during the study period included an increase in methadone prescribing and towards longer-acting benzodiazepines. The slightly different effects of dihydrocodeine compared to methadone made it the opiate of choice for many and may indicate a useful addition to the longer-acting methadone. This may make it an alternative to the current experimenting with heroin, dextromoramide (palfium) and injectable methadone for opiate users resistant to control with oral methadone alone.

Pre-AIDS mortality from natural causes associated with HIV disease progression: evidence from the European Seroconverter Study among injecting drug users.

OBJECTIVES: To study differences in pre-AIDS mortality between European cohorts of injecting drug users (IDU) and to evaluate whether pre-AIDS mortality increased with time since HIV seroconversion and decreasing CD4 count. METHODS: The study population consisted of 664 IDU with documented intervals of HIV seroconversion from eight cohort studies. Differences in pre-AIDS mortality were studied between European sites; an evaluation of whether pre-AIDS mortality increased with time since HIV seroconversion and decreasing CD4 count was carried out using Poisson regression. RESULTS: One hundred and seven IDU died, of whom 57 did not have AIDS. Pre-AIDS causes of death were overdose/suicide (49%), natural causes such as bacterial infections/cirrhosis (40%), and unintentional injuries/unknown (11%). Considering pre-AIDS death and AIDS as competing risks, 14.7% were expected to have died without AIDS and 17.3% to have developed AIDS at 7 years from seroconversion. No statistically significant differences in pre-AIDS mortality were found between European regions, men and women, age categories and calendar time periods. Overall pre-AIDS mortality did not increase with time since seroconversion, but did increase with decreasing CD4 count. Evaluating cause-specific mortality, only pre-AIDS mortality from natural causes appeared to be associated with time since seroconversion as well as immunosuppression. For natural causes, the death rate per 100 person-years was 0.13 the first 2 years after seroconversion, 0.73 in years 2-4 [risk relative (RR) to years 0-2, 5.6], 1.83 in years 4-6 (RR, 14.0) and 1.54 for > or = 6 years (RR, 11.7). This rate was 0 for a CD4 cell count > or = 500 x 10(6)/l, 1.06 for 200-500 x 10(6)/l and 4.06 for < 200 x 10(6)/l (RR versus > or = 200 x 10(6)/l, 7.0). In multivariate analysis, both CD4 count and time since seroconversion appeared to be independently associated with death from natural causes; CD4 count appeared to be the strongest predictor (adjusted RR, 5.9). CONCLUSIONS: A high pre-AIDS mortality rate was observed among IDU. No significant differences were observed across European sites. Pre-AIDS mortality from natural causes but not from overdose and suicide was associated with HIV disease progression.

Has the rate of progression to AIDS changed in recent years?

OBJECTIVES: To investigate whether the rate of progression to AIDS has changed over time by testing an effect of the year of seroconversion on AIDS onset (Centers for Disease Control and Prevention 1987 revised classification), next to an effect of the calendar period of follow-up. DESIGN: French multicentre prospective study of 385 homosexual and heterosexual subjects and 231 subjects from a multicentre study of European injecting drug users (IDU), all with a documented date of HIV-1 seroconversion. METHOD: The effect of the year of seroconversion was compared by the log-rank test. Crude and adjusted relative hazard (ARH) were quantified using the Cox model. Calendar period of follow-up was studied separately for sexual exposure group and IDU and treated as a time-dependent variable in a Cox model. RESULTS: In the 616 study subjects the year of seroconversion was not significantly related to AIDS occurrence (n = 108); the ARH was 0.88 [95% confidence interval (CI), 0.56-1.38] for those who seroconverted in 1988-1989, and 1.17 (95% CI, 0.61-2.25) for those who seroconverted after 1989, compared with those who seroconverted before 1988. In the sexual exposure group, a clear trend towards less rapid progression to AIDS was observed in subjects followed in 1991-1992 (ARH, 0.49; 95% CI, 0.24-0.99) and after 1992 (ARH, 0.54; 95% CI; 0.24-1.21), compared with those followed before 1991. This favorable trend was not observed in IDU despite a significant decrease over time of Pneumocystis carinii pneumonia as AIDS-defining illness. Conversely to sexual exposure groups, the frequency of antiretroviral treatment (mainly zidovudine) prescription was still low during the most recent calendar periods in IDU when the CD4 count threshold of 200 x 10(6)/l was reached. CONCLUSIONS: No evidence was found of a change in the rate of progression to AIDS in subjects who seroconverted in recent years. Furthermore, conversely to sexual exposure groups, the lack of favorable trends in IDU users followed in recent years suggest that health-care systems are not always adapted to their lifestyles.

Absence of hepatitis C virus transmission but frequent transmission of HIV-1 from sexual contact with doubly-infected individuals.

Hepatitis C virus (HCV) is transmitted through infected blood and blood products, but evidence of other routes of transmission is less clearly understood. In a study designed to examine human immunodeficiency virus (HIV) transmission, the prevalence of HCV has also been measured. Sixty-one couples were analysed, 30 in which partners were at risk through sexual contact alone, of whom 12 (40%) became infected with HIV and none with HCV. Thirty-one partners were exposed sexually and additionally through intravenous drug use. Of these, 16 (52%) became infected with HIV and 25 (80%) contracted HCV infection. These findings support the evidence of others that HCV is only rarely transmitted by sexual intercourse in heterosexual relationships and that HIV is not a co-factor for HCV transmission.

The molecular epidemiology of human immunodeficiency virus type 1 in six cities in Britain and Ireland.

We have sequenced the p17 coding regions of the gag gene from 211 patients infected either through injecting drug use (IDU) or by sexual intercourse between men from six cities in Scotland, N. England, N. Ireland, and the Republic of Ireland. All sequences were of subtype B. Phylogenetic analysis revealed substantial heterogeneity in the sequences from homosexual men. In contrast, sequence from over 80% of IDUs formed a relatively tight cluster, distinct both from those of published isolates and of the gay men. There was no large-scale clustering of sequences by city in either risk group, although a number of close associations between pairs of individuals were observed. From the known date of the HIV-1 epidemic among IDUs in Edinburgh, the rate of sequence divergence at synonymous sites is estimated to be about 0.8%. On this basis we estimate the date of divergence of the sequences among homosexual men to be about 1975, which may correspond to the origin of the B subtype epidemic.

Cannabis use in the community.

BACKGROUND: The illegal use of cannabis has been increasing in many Western countries for the past two decades. Recently, some interest has been shown in modifying legislation and control. The need for general practitioners to be aware of the short- and long-term consequences of cannabis use is increasing, and more information is required about its effects on behaviour, psychological states and the respiratory and cardiovascular systems. The use of general practice populations to study the prevalence of cannabis use and its damaging effects is less represented in the literature than it should be, considering the extent of cannabis consumption. AIM: A study was carried out in 1995 to determine the prevalence of cannabis use in a general practice population and any associated health problems. As a pilot study, samples of cannabis were obtained for forensic analysis. METHOD AND PATIENTS: Two questionnaires were used. One very short enquiry about the use, if any, of the drug, and a longer one about the effects of its use. Data concerning medical effects were included from patients' case notes. Samples of cannabis were obtained for forensic examination. RESULTS: A very high proportion (61%) of patients surveyed indicated some cannabis use (past or present). Thirty-seven per cent had used it in the previous 12 months. Users could be broadly divided into transitory experimenters, regular users and heavy users. Medical problems included those attributed to associated tobacco smoking, other illegal drug use and psychological problems. Benefits perceived by patients recording use were many. Polydrug use and legislation issues were difficult to separate from the effects of cannabis itself. Chest infections, anxiety and depression, and drug dependence were common diagnoses, and 13 of the 32 females in the study group had evidence of cervical smear abnormalities. CONCLUSIONS: Few serious damaging effects from cannabis use itself were identified, although chest infections and anxiety problems were common. Tobacco damage, associated drug use and criminal or legal issues dominated and obscured the important perceived benefits and the scientific understanding of the effects and side effects of the drug. More research into several identified areas is required.