Clinical & Policy Updates:
SMMGP Clinical Update October-November 2011
|Download the PDF version of this Update here! (PDF*, 300K)|
Changes in methadone maintenance therapy during and after pregnancy
Albright B, de la Torre L, Skipper B, Price S, Abbott P, Rayburn W. Journal of Substance Abuse Treatment 2011. Published online ahead of print.
This study in the USA was a retrospective case series that looked at 139 consecutive cases of women who began methadone therapy before 26 weeks of pregnancy. The aim of the study was to try to better understand and anticipate changes in daily methadone dosing during pregnancy.
As the pregnancies progressed the methadone dose increased in 86% of women. It decreased in about 7% and remained the same in around 8%. The mean increase in dose was 24mg with a 95% confidence interval from 20-28mg. In 85% of cases the dose of methadone remained within 10mg of the dose at delivery at the sixth week postpartum.
SMMGP comment: Physiological changes in pregnancy such as increases in maternal weight, intravascular volume and renal elimination occur in the second and third trimesters. The findings of this study fit with this strong physiological rationale for increases in dose of methadone during pregnancy. This is useful to bear in mind when it comes to talking to pregnant women - and advising them early that most people will need dose increases.
When it comes to the management of opiate substitution therapy in pregnancy it was worth bearing in mind some of the findings from the MOTHER study published in the NEJM in December 2010 and discussed in the December 2010 SMMGP Clinical Update. This showed that there was no difference in maternal opiate use between methadone and buprenorphine; however, buprenorphine was superior to methadone in two primary outcomes looking at neonatal abstinence syndrome. Some might argue that buprenorphine is marginally first choice to treat opiate dependent women in pregnancy but there was a greater dropout in the buprenorphine group.
However, the gap is narrow and methadone remains an appropriate choice; this paper helps provide useful guidance to tailor methadone doses as needed.
We would also highly recommend the new third edition of Drugscope's book "The Essential Guide to Problem Substance Use During Pregnancy" which is now available to buy.
Benzodiazepines revisited - will we ever learn?
Lader M. Addiction 2011. Published online ahead of print
This is a long descriptive review derived from the Okey Lecture delivered by Professor Malcolm Lader at the Institute of Psychiatry, King's College London, in November 2010.
Amongst many topics in this wide-ranging review Lader considers some of the issues around withdrawal. He states that withdrawal symptoms from the benzodiazepines (BZDs) can occur after 4-6 weeks of use but only in around 15-30% of patients. It has been shown that high levels of neuroticism, lower educational level and lower quality of life are associated with higher levels of distress during withdrawal. He also discusses some of the different patterns of withdrawal symptoms that can occur - some may experience a gradual decrease over 50 weeks, some may note an initial increase in severity at the start of tapering whereas others may experience symptoms that are delayed for four weeks after tapering doses.
There is evidence that minimal interventions can be helpful - a simple letter from GPs resulted in considerable discontinuation with 60% remaining abstinent in one study in the Netherlands. There are little objective data on the optimal rate of benzodiazepine withdrawal and it is clear that it will vary from patient to patient. Lader cites his own 2009 paper on reducing benzodiazepines in primary care that recommends withdrawal be conducted over an 8-12 week period and completed in less than six months. He also suggests flexible schedules that allowed for slowing down. Group therapy may help and CBT may be a useful adjunct to prevent relapse.
There has been heated debate around the topic of maintenance treatment with a slow-onset, long acting benzodiazepine in those who have not managed to withdraw successfully from high doses. This has been criticised for going beyond the evidence base and the problem of cognitive and memory impairments represent a significant limitation.
SMMGP comment: This comprehensive review is highly recommended. The issue of benzodiazepines in practice shows little signs of fading. There has been a decrease in benzodiazepine prescribing over the period 1991 to 2009 but there were still over 10 million prescription items issued in 2009. This reduction is mainly accounted for by a drop in hypnotic BZDs and dispensing of anxiolytic BZDs has mostly been rising. Longer-term hypnotic prescribing of more than 8 weeks has remained fairly steady - accounting for 20% of BZDs. There seems to be little sign of much appetite amongst doctors to stop prescribing these tablets and the internet has provided a new source of unreliable medication for many.
Lader makes the point that he is encountering increasing numbers of cases where GP experts have regarded the unlicensed prescribing (i.e. beyond four weeks) of benzodiazepines as "prima facie" a breach of duty of care until proven otherwise. Dramatically, but not implausibly, he suggests that prescribing patterns of benzodiazepines may ultimately be changed by the legal rather than the medical profession.
Oral tobacco products: Preference and effects among smokers
Hatsukami DK, Jensen J, Anderson A et al. Drug and Alcohol Dependence 2011;118:230-236
The aim of this American study was to explore the preferences for oral tobacco products in the context of a short 2-week cessation trial. The participants went through an initial sampling phase when they got to try out the five different products (General Snus, Camel Snus, Marlboro Snus, Stonewall and Ariva). They then used their preferred product in the treatment phase. They initially assessed 135 individuals and 99 entered the sampling phase. A further 97 went on to the cessation phase. None of the users preferred General Snus but the participants were equally divided among the four other products.
The results showed that Camel Snus seemed to achieve the greatest effect with greater craving relief and satisfaction, reduced use of cigarettes and greater abstinence during the follow-up period compared with the other products. Camel Snus had the highest nicotine content (of the four products selected) at just under 2mg/portion of free nicotine. However, it should be noted General Snus (the product that no one wanted) had the most nicotine at around 3.4mg/portion.
Randomized, placebo-controlled, double-blind trial of Swedish snus for smoking reduction and cessation
Joksić G, Spasojević-Tišma V, Antic R, Nilsson R and Rutqvist LE. Harm Reduction Journal 2011;8:25
This placebo-controlled RCT enrolled 319 healthy smokers aged 20-65 years at two centres in Belgrade, Serbia. They had to have a history of daily smoking for more than one year with an average daily consumption of more than 10 cigarettes in the past month. The majority (81%) had expressed a desire to quit rather than reduce their smoking. The study was conducted over a 48 week period. The main study objective was smoking reduction.
The primary endpoint was defined as a biologically verified reduction of ≥50% in the average number of cigarettes smoked per day during weeks 21-24 compared with baseline. The study also looked at 1-week point prevalence rates of complete smoking cessation at 12, 24, 36 and 48 weeks. The snus used is described as a "low nitrosamine, moist, oral tobacco product with a water content of c. 45-55%, a nicotine content of c. 1% and a pH of c. 8.5". The placebo snus products were apparently identical but did not contain nicotine or tobacco.
The results showed that both groups reduced the number of cigarettes smoked per day. In terms of the primary endpoint the results indicated no difference between the snus groups and placebo. The authors noted that the results for complete cessation showed that those in the snus group were more likely to quit completely; however, while the odds ratios for this varied from 1.9 to 3.4 they were statistically borderline.
SMMGP comment: A lot of the interest in snus and other oral tobacco products stems from the Swedish experience where there is a tradition of oral, smokeless tobacco. Sweden has fewer male smoking-related deaths than in other European countries and it is the only EU country where male smoking prevalence is less than females.
The second study was in Serbia (where there is a smoking prevalence of around 30-40%) to see how oral tobacco would fare in a culture outside of Sweden. The results don't show any clear benefit of snus with all smokers considerable reducing their consumption. There may be some selection bias here with the study recruiting smokers who were highly motivated.
A study looking at oral tobacco products in smokers who don't want to quit may be more revealing - and perhaps more pertinent to a harm reduction approach to smoking. There is a dose-response relationship with cigarettes and the harms, if any, from oral nicotine products are far out-weighed by the harms from normal cigarettes. This study doesn't offer any clear evidence of benefit and, in any case, harm reduction measures - when applied to cigarettes - remain controversial and beyond the pale for many medical professionals.
Patient and clinician's ratings of improvement in methadone-maintained patients: Differing perspectives?
Trujols J, Siňol N, Iraurgi I, Batlle F, Guàrdia J, Pèrez de los Cobos J. Harm Reduction Journal 2011;8:23
This Spanish study looked at the patient's perspective and compared it to clinicians' ratings when assessing how well treatment had worked. They recruited 110 patients with their respective psychiatrists (n=5) and nurse (n=1). All the participants completed a scale assessing how the patient's condition had changed from the beginning of methadone maintenance therapy. They used the Patient Global Impression of Improvement scale (PGI-I) and the Clinical Global Impression of Improvement Scale (CGI-I).
The results showed that there was only weak concordance between patients and clinicians. There was a slightly better concordance between patients and psychiatrists - this did, in fact, reach statistical significance but as the authors highlight it was still small and didn't reach the recommended minimum effect size.
SMMGP comment: Methadone has been shown to be effective across a range of areas. When it comes to assessing the evidence base there is often a quest for "hard" endpoints - mortality, morbidity, reduced crime rates, negative urine samples etc. There is a crucial point from this study that must be emphasised - although there was poor concordance between clinician and patient this was because the patients' assessments of methadone maintenance were significantly more positive.
There are clearly some valuable lessons from this study for policy makers about developing our systems to get patients and clinicians better aligned. This is an important area to develop in order to maximise benefits from a treatment with >more evidence that just about any other medication. But one of the key findings from this study isn't that methadone only appears to work when assessed from the perspective of the "system". It works for the people taking it too.
Risk of drug-related mortality during periods of transition in methadone maintenance treatment: A cohort study
Cousins G, Teljeur C, Motterlini N, McCowan C, Dimitrov BD, Fahey T. Journal of Substance Abuse Treatment 2011;41:252-260
This Scottish study's aim was to try and identify the periods where there is an elevated risk of drug-related mortality for those taking methadone in primary care. They looked retrospectively at a cohort of 3,162 Scottish drug users between January 1993 and February 2004. Where deaths occurred during treatment or within 3 days of the last methadone prescription they were considered "on-treatment". Any deaths occurring after four or more days were considered "off-treatment".
A total of 64 drug-related deaths were identified. The greatest risk of death was in the first two weeks after treatment. A history of psychiatric admission was associated with an increased risk of death "on-treatment". Co-prescribing of benzodiazepines was also independently associated with a risk of death. Increasing numbers of treatment episodes and urine testing were protective. In conclusion, the study provided evidence that the greatest risk of death is during treatment transition - both into treatment and out of treatment. Treatment initiation and the first 30 days after dropout or discharge were shown to be the most dangerous.
SMMGP comment: This is a useful study - based in primary care in Scotland it will be directly relevant to many substance misuse services in the UK. However, there have been changes in the way services are provided in recent times and some of these deaths go back eighteen years. As the authors point out the first national guidelines probably had little impact until after 2000 and this cohort was well advanced by then. Despite the large size of the cohort (amounting to 14,597 person-years) this study may still be a little underpowered given there were only 64 drug-related deaths. This could mean it has not picked up some potentially significant contributions. Unfortunately, there is no information regarding supervision - the role of which has been emphasised in recent guidelines to reduce risk during induction.
The underlying message for clinicians will be familiar - retention in treatment remains crucial and particular care needs to be taken during methadone inductions and when people leave services, whether planned or not.
Anabolic androgenic steroid use in teens: Prevalence, demographics and perception of effects
Lorang M, Callahan B, Cummins KM, Achar S and Brown SA. Journal of Child & Adolescent Substance Abuse 2011;20:358-369
This study surveyed 4,231 high school students in the USA to get a better idea of prevalence of the use of anabolic-androgenic steroids (AAS). Overall the lifetime use was reasonably low at 1.4% but use was higher in males and those participating in at least one school sport. Half of the high school students believed that steroids improved athletic performance and 38% reported that use improves appearance. It was shown that recreational drug use and frequency of drug use increased risk of steroids.
Anabolic steroids and male infertility: a comprehensive review
Leme de Souza G and Hallak J. BJU International 2011. Published online ahead of print.
This paper provides a brief overview of the impacts of anabolic-androgenic steroids (AAS) and their effect on male reproductive functions. The most common is that males presenting with infertility may have low quality semen - low or absent sperm counts with abnormalities in sperm motility and morphology. These can persist for longer periods but usually there is spontaneous recovery 4-12 months after discontinuation. There is evidence that there can be a persistent state of hypogonadism due to negative feedback from androgens on the hypothalamic-pituitary axis.
SMMGP comment: The government have recently published their response to the Advisory Committee on the Misuse of Drugs (ACMD) recommendations on anabolic steroids. The ACMD recommended a UK national survey, particularly one that considered sub-groups such as children and young people to get a better national profile of use to target interventions. They accepted most of the ACMD recommendations but unfortunately not this one so the scale of the issue in the UK remains difficult to grasp.
The government accepted the ACMD's recommendation regarding importation and they plan to legislate to make it illegal to import steroids unless they are actually in one's personal possession. While it is difficult to support the importation of substances where quality control, contamination, etc may be an issue this will need to be watched carefully - steroid users will continue to use and they may turn to local steroid "factories" which may be just as, if not more, risky.
The impact of needle and syringe provision and opiate substitution therapy on the incidence of hepatitis C virus in injecting drug users: pooling of UK evidence
Turner KME, Hutchinson S, Vickerman P et al. Addiction 2011;206:1978-1988
This study was a meta-analysis that looked at a total of 2986 injecting drug users in the UK who were surveyed over the period 2001-9. These came from six studies in the UK. Two studies made a direct assessment of the incidence of HCV by retesting injectors after one year and the other four studies used a test to identify those that had been newly infected. The primary outcome considered was new HCV infection and the secondary outcomes were based on self-reports of whether there had been any needle sharing in the past month and the number of injections in the last month.
Access to either opiate substitution therapy (OST) or a needle and syringe programme (NSP) halved the risk of HCV infection. The results showed that full harm reduction (defined as being on OST plus high NSP coverage) reduced the odds of new HCV infection by nearly 80%. NSP was regarded as high coverage if sufficient sterile injecting equipment could be obtained for each injection. It also reduced self-reported needle sharing by 48% and mean injecting frequency by just under 21 injections per month.
The cost-effectiveness of HCV antiviral treatment for injecting drug user populations
Martin NK, Vickerman P, Miners A et al. Hepatology 2011. Published online ahead of print.
This study used a mathematical model to assess the impact of providing treatment for injecting drug users compared with treating ex/non-IDUs or no treatment at all. The results showed that at HCV prevalence rates of 20% and 40% treatment of IDUs is clearly the most cost-effective policy option. At HCV prevalence rates of 60% treatment of ex/non-IDUs is slightly more cost-effective. The results also showed that the cost-effectiveness of HCV treatment in IDUs held good even if considerable lower treatment success rates were achieved.
SMMGP comment: There are three strands to consider in the management of HCV infection - opiate substitution therapy, needle and syringe programmes and treatment. All three are covered in these two papers. The infectivity of HCV is much greater than in HIV. The virus survives longer in syringes and is easier to transmit through any sharing. This means partial NSP isn't sufficient to hold back ongoing infection. We need better and comprehensive coverage.
The message is clear. Clinicians need to support those who want opiate substitution therapy (and clearly there are benefits in this which go beyond HCV), we need to support the expansion and continuation of needle exchanges and, probably most importantly, we need to get more IDUs into treatment. As the meerkat would say "It's simples!"