Clinical & Policy Updates:
SMMGP Clinical Update April-May 2013
Compiled by Dr Euan Lawson
|Download the PDF version of this Update here! (PDF*, 369K)|
Extended-release methylphenidate for treatment of amphetamine/methamphetamine dependence: a randomized, double-blind, placebo-controlled trial
Miles SW, Sheridan J, Russell B, et al. Addiction 2013. Published online ahead of print: doi:10.1111/add.12109
This 22-week study set in Finland and New Zealand wanted to assess how effective methylphenidate was as a substitution therapy. The participants were aged from 16-65 and met the DSM-IV criteria for amphetamine/methamphetamine dependence. The medication used was extended-release methylphenidate (Concerta®) and doses were titrated up to a maximum of 54mg daily. Exclusions included: dependence on any other substances; pregnancy; significant physical disease; and evaluation that suggested a significant risk of suicide or violence.
The primary outcome was the presence of amphetamine/methamphetamine in twice-weekly urine samples. Secondary outcomes included treatment adherence, alterations in craving scores, and self-reported use. In total there were 39 people randomised to methylphenidate and 39 to placebo. The results showed that there was no statistically significant difference in the primary outcome. They used an intention-to-treat analysis (based on 78 participants) but the overall retention was low with only 27 people actually completing the trial. The attrition in the placebo group was significantly worse: in the intervention group 17 out of 39 completed the trial yet in the placebo group it was just 10 out of 39. There was no difference in the self-completed craving scores between the groups either. In terms of adverse events there was no difference between the two arms of the study. There were no issues raised because of any violent behaviour or diversion of the medications.
Commentary: Overall, this study couldn't show any benefit in using extended-release methylphenidate to treat dependence to the stimulants amphetamine or methamphetamine. This study had a high drop out rate and it had climbed up to 72% by 22 weeks. There were a number of quite stringent requirements that had to be met for people to stay in the study. Over a 22-week period that will take its toll but the authors felt there was little option given the abuse potential and the regulatory limits imposed on them. It puts the mockers on the chances of this study being the definitive answer to the question of whether methylphenidate could be effective. That's particularly the case given that the placebo group suffered significantly more losses - something seems to have been keeping the intervention group in treatment. It could just be chance alone but unless future studies can allow a little more leeway in the strictness of the participant requirements these studies will have the same problems and it will be tough to draw definitive conclusions.
Forced withdrawal from methadone maintenance therapy in criminal justice settings: A critical treatment barrier in the United States
Fu JJ, Zaller ND, Yokell MA, et al. J Subst Abuse Treat 2013;44:502-5
This study surveyed a cross-sectional sample of 215 individuals at two inpatient medication-assisted detoxification facilities in the USA. The authors reported that in the USA many inmates have their methadone maintenance therapy stopped and they are forced to withdraw when they to go to prison. The aim of the survey was to assess whether this policy had a deterrent effect for people in the community. The majority (70%) reported that it was a factor and they would, given the option, rather withdraw from heroin than methadone. Just under half (47%) reported that their concern about being forced to withdraw from methadone deterred them from accessing treatment in the community.
Commentary: The main driver for this study was the concern that methadone is being reduced and stopped when people are incarcerated. This study emphasises that it is not simply an issue for prison services - the impact reaches beyond the prison gates and it is an issue for clinicians in the UK. The USA is a more extreme example but it has certainly been happening in prisons in the UK to a limited extent. This is mostly as a consequence of policymakers sniffing the wind in 2010 and thinking they could second-guess forthcoming recovery policies. The recent report from John Strang's Recovery-Orientated Drug Treatment Group makes it clear that blanket policies of reduction aren't appropriate. Most UK doctors have a sound appreciation of the evidence base and have done what they can to avoid reducing methadone in prisons against the individual's will. Ultimately, it would be difficult to stand before a coroner or the GMC and defend forced withdrawals.
Patients receiving opioid maintenance treatment in primary care: successful chronic hepatitis C care in a real world setting
Seidenberg A, Rosemann T, Senn O. BMC Infect Dis 2013;13:9
This was a retrospective patient record analysis of 85 patients with chronic hepatitis C. They had all received opiate substitution therapy (OST) for more than three months in a single-handed general practice in Zurich from 2002 to 2008. Treatment was a combination of pegylated interferon and ribavirin. All the treatments were given in the practice and were coordinated and supervised by the GP.
The results showed that in 35 out of 85 (41.2%) patients anti-viral therapy was started. The median duration of OST was 55 months compared to the group without therapy where it was 24 months. Even after controlling for confounding OST duration was a significant determinant of treatment uptake. Sustained virological response (SVR) was achieved in 25 out of those 35 patients (71%).
Commentary: This study highlights, again, the enormous potential for primary care to influence a significant area of morbidity and mortality for those who use drugs. The overall treatment rate in this study looks impressive compared with the UK. Treatment rates of around 41% across the board look a very long way off for us. The unique circumstances of this practice may partly explain the high treatment rates - a single-handed GP with a particular focus on the topic is likely to drive for greater participation but it shows what can be achieved. The author notes that the best treatment rates have come when patients have been tested and diagnosed by their own GP - over 21% in one UK study which also found that just 1.6% were referred when the testing was done in a specialist drug and alcohol unit. The increased treatment rates in this study don't seem to have occurred at the expense of treatment success rates either - the overall SVR of 71% is comparable with the standard RCTs.
"It's more about the heroin": injection drug users' response to an overdose warning campaign in a Canadian setting
Kerr T, Small W, Hyshka E, et al. Addiction. Published online first: doi:10.1111/add.12151
This Vancouver study wanted to assess heroin injectors' perceptions and responses to a warning issued by public health officials regarding high-potency heroin and increases in fatal overdoses. They did this by recruiting eighteen active heroin injectors and putting them through semi-structured qualitative interviews.
They found that almost all the participants were aware of the warning. However, their memory of the warning was obscured by social interactions within the drug scene and was focused on heroin quality. In other words, most of the participants were more interested in the fact there was higher quality heroin available and they were actively trying to find it. Many injectors reviewed it as a positive development. There was a small minority who did try to reduce their risk - but they did this through strategies such as buying from their usual dealer as they felt that offered some protection.
Commentary: Anyone involved with substance misuse will be familiar with these types of warnings that appear on a regular basis. They may be emailed around to clinicians and posters will often appear in the premises of community clinics. Typically, as described in this study, they relate to a problem with a particularly strong batch of gear. Telling people about an increased risk due to higher potency drugs would seem like a no-brainer - an entirely sensible and responsible action that must be taken.
This paper demonstrates some interesting unintended consequences. Many clinicians will be familiar with the refrain of some individuals who tell you they are not using because of the low quality of the gear. In some people this seems to be a significant factor and this study suggests that the majority were motivated to use more and seek out a stronger batch of heroin.
So how best do we reduce overdose deaths? There are other areas to address - perhaps we could concentrate on supervised injection facilities. Or we could give out thousands of naloxone kits. In a healthcare system where resources are limited we need good data to establish the best way to reduce overdose deaths.
Take-Home Emergency Naloxone to Prevent Heroin Overdose Deaths after Prison Release: Rationale and Practicalities for the N-ALIVE Randomized Trial
Strang J, Bird SM, Parmar MKB. J Urban Health. Published online first: 1 May 2013. doi:10.1007/s11524-013-9803-1
The N-ALIVE randomised trial started in the UK in May 2012 and the first, preliminary phase, has involved 5,600 prisoners on release. The aim is to see if heroin overdoses occurring after release from prison can be prevented by providing a take-home emergency supply of naloxone. It is thought that as much as 10% of naloxone provided for use in emergencies is used but definitive studies are needed to assess the actual impact on overdose deaths. This study is going to be powered to detect a 30% reduction - there would be an expected 140 deaths among the 28,000 prisoners in the control group and this would be reduced to less than 100 deaths in the intervention group.
Commentary: This study is unusual for the Clinical Update in that it doesn't yet have any results to report. However, topics where the evidence based isn't yet clear still need consideration. The issue of naloxone can be a controversial one and there was considerable discussion of this stirred up at the recent "RCGP 18th National Conference Managing Drug & Alcohol Problems in Primary Care" when one GP suggested that it could be regarded as being negligent to prescribe opiate substitution therapy and not provide naloxone at the same time.
The fact the N-ALIVE study is going ahead emphasises that this is an area where the evidence isn't yet complete and we shouldn't pre-judge the findings. There is a strong moral argument to provide naloxone - and we all want to prevent drug-related deaths. However, deaths due to overdose are, in many cases, complex with poly-drug use being a typical finding. There is also the fact that many people, who are trying hard to leave substances behind, aren't enthusiastic about carrying around a needle and a daily reminder of their problems.
There are other concerns: could providing naloxone encourage riskier behaviour as it is perceived to provide a safety net? The Canadian study discussed above on heroin warnings has already highlighted how unintended consequences can interfere with assumptions.
We can debate it all until the cows come home. The N-ALIVE trial is incredibly important as it will help to flesh out the discussion with some decent scientific evidence.
Opioid addiction agonist therapy and the QT prolongation phenomenon: state of the science and evolving research questions
Wedam EF, Haigney MC. Addiction 2013;108:1015-7
This short report highlights some of the gaps that currently exist around the use of methadone and concerns about QT prolongation. It has been estimated that torsades de pointes (TdP) will be fatal in around 10% of those who develop it. The authors point out that one of the things that we really need to know is whether ECG screening would have any kind of impact. Ideally, a randomised controlled trial would take mortality as its endpoint of mortality. Unfortunately, that would almost certainly require an unfeasibly large study. ECG screening prior to treatment has been resisted due to the concern it will act as a barrier to treatment. The authors recognise that is a barrier that this population can ill afford.
Drug induced QT prolongation: the measurement and assessment of the QT interval in clinical practice
Isbister GK, Page CB. Br J Clin Pharmacol. Published online first: 20 November 2012. doi:10.1111/bcp.12040
This paper gives details on how to measure the QT interval in practice. The fundamental issue is that QT interval varies according to heart rate. This means that the formulae used to calculate the QTc can be inaccurate - they underestimate the QT interval at low heart rates and overestimate at high heart rates. The technique described here doesn't rely on the complicated calculations of correction formulae like Bazett's. Instead it uses a QT nomogram which is a plot of QR against heart rate. The nomogram has a line that suggests people who are at risk of TdP. The QT nomogram has been shown to have a sensitivity of 97% and a specificity of 99%. This compares to a Bazett's QTc of 440ms which has a sensitivity of 99% and a specificity of 67%. If the threshold for Bazett's is raised to 500ms then the sensitivity is 94% and the specificity is 97%.
Commentary: There has been some evidence that the automated QTc churned out by ECG machines is useful enough for screening purposes. It can be prone to errors and if you want to be a little more sophisticated then this offers an alternative to the forbidding process of trying to use the various QTc calculations. One can simply measure the number of small squares from the beginning of the Q wave to the point where the T wave returns to the baseline. (At the normal ECG speed of 25mm/sec one small square is 40ms.) Repeat this in six leads (preferably I, II, aVF, V2, V4 and V6) and take the average. Get the heart rate from the ECG and then use the nomogram to work out whether the current QT interval is safe. If you want to demystify the QT interval then the paper in the British Journal of Clinical Pharmacology is highly recommended.
Image from British Journal of Clinical Pharmacology
Perceived efficacy of e-cigarettes versus nicotine replacement therapy among successful e-cigarette users: a qualitative approach
Barbeau AM, Burda J, Siegel M. Addiction Science & Clinical Practice 2013;8:1-1
This was a qualitative study which used focus groups to explore issues around the use of e-cigarettes, comparison of effectiveness between NRTs and e-cigarettes, barriers to quitting, and reasons for choosing e-cigarettes over other methods. There were 11 participants in the study and all but two of them smoked at least ten cigarettes per day before using e-cigs. They were recruited via an online forum for people interested in the use of e-cigarettes. E-cigarette users are also known as "vapers".
They identified five themes in the focus groups:
- Bio-behavioural feedback. The participants reported that e-cig vaping felt like it was smoking a real cigarette. The feeling of vapour in their throat and exhaling the vapour cloud was important to them.
- Social benefits. This was related to the online community of vapers and they found this support invaluable.
- Hobby elements. This was repeatedly discussed - the techniques of combining devices and juice to get the "perfect vape" was enjoyable to them.
- Personal identity. One of the key factors that the authors suggested was that the individuals were able to redefine themselves as "vapers" rather than "smokers".
- Difference between smoking cessation and nicotine cessation. The vapers didn't necessarily see the use of e-cigs as a means to stopping nicotine completely. They recognised that e-cigs allowed them to quite smoking but they weren't necessarily going to stop e-cigs "in a hurry".
Commentary: One of the papers discussed in the recent Clinical Update workshop at the RCGP conference was the paper by Palmer et al on the prevalence of respiratory diseases in primary care (discussed in the August-September 2012 Clinical Update). The near ubiquity of smoking means that we need to spend more time and effort addressing smoking if we hold any hope of addressing the deep-seated health issues in this population. The people in this study didn't have any other substance misuse issues but there are some lessons here that can be considered. Many people will look at this study and feel some concern that e-cigs will be an end in themselves. That said, there is already some evidence discussed in this paper that people using e-cigs are getting much higher abstinence rates (22-31% at six months have been documented) than seen with other methods. One of the key findings from this study might be the one identified in the "personal identity" theme: e-cigs offer one route for smokers to redefine themselves.
2012 Update in addiction medicine for the generalist
Rastegar DA, Kunins HV, Tetrault JM, et al. Addiction Science & Clinical Practice 2013;8:1-1
This paper was written as a general update on addiction-related medical literature from the years 2010 and 2011. It covers a wide range of topics but is set out in the format of specific clinical questions. It covers questions related to the physical complications of alcohol - such as risk of atrial fibrillation and myocardial infarction. It also addresses a number of questions around pain management, prescription opioid medicine abuse, the use of buprenorphine, and medications for use in alcohol dependence.
Commentary: It is perhaps just a little circular to write about a clinical update paper in the SMMGP Clinical Update. Many of the papers mentioned have been covered in the SMMGP Clinical Update in the past but there is still plenty that is new here. In addition, this paper is published in an open-access journal so it is freely available online to anyone by visiting the BioMed Central webpages. Recommended.