Clinical & Policy Updates:
SMMGP Clinical Update February-March 2012
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Adjunctive counseling during brief and extended buprenorphine-naloxone treatment for prescription opioid dependence: a 2-phase randomized controlled trial
Weiss RD, Potter JS, Fiellin DA, Byrne M, Connery HS, Dickinson W, et al. Arch. Gen. Psychiatry. 2011 Dec.;68(12):1238-1246
This paper set out to investigate the role of buprenorphine-naloxone and counselling in the management of prescription opioid management. They started with 653 people in outpatient clinics across ten sites in the USA. They didn't completely exclude people with chronic pain - but those requiring ongoing pain management with opioids were excluded, as were those with a "major pain event" in the past 6 months.
The methodology was rather complex. In phase 1 participants were randomised into two different groups: standard medical management +/- intense counselling. The standard medical management regime in phase 1 consisted of a brief period of 1-2 weeks on buprenorphine-naloxone, followed by a 3-4 weeks taper. Follow up continued until week 12 when those who had been been successful were discharged. This was deemed to have happened if they had used on no more than 4 days per month and had two negative urine tests. Those that weren't successful entered phase 2 and were again randomised to two groups: standard medical management +/- intense counselling. However, in phase 2 the standard medical management group were treated for longer - 12 weeks with buprenorphine-naloxone. After 12 weeks those who were successful were tapered down to zero by week 16. They were followed up until week 24.
The results show that only 6.6% (43 out of 653) of patients had successful outcomes during phase 1. However, in phase 2, at week 12, 49.2% (177 out of 360) attained successful outcomes. After week 12 the buprenorphine-naloxone was then tapered down to zero.
The outcomes at week 24 showed that just 8.6% (31 out of 360) were regarded as being successful. At no point in the study were there any significant differences between the counselling groups. Chronic pain didn't have any effect on opioid use outcomes. A history of ever using heroin was associated with lower phase 2 success rates.
Prescription drug addiction: the treatment challenge
Holmes D. The Lancet. 2012 Jan. 7;379(9810):17-18.
This Lancet editorial sets out the scale of the prescription opioid problem. The numbers are eye-watering. Global statistics have suggested a decline in the markets for cocaine, heroin and cannabis. Alongside this there has been a striking increase in the misuse of synthetic opioids. Figures from the USA show a mammoth 430% increase in the rate of treatment admissions for the misuse of prescriptions opioids over the period 1999 to 2009. The state of Florida uses 80% of the world's supply of oxycodone and the problem of prescription opioid misuse has been described by the US Center for Disease Control and Prevention as an epidemic.
SMMGP comment: The Weiss paper is an important study. It's a rare beast when a study from another journal triggers an editorial in the Lancet - but this is the first published randomised controlled trial addressing an issue that is escalating rapidly. One of the key aspects of prescription-opioid abuse has been the almost total absence of specific medical evidence to guide treatment. There has been speculation that the outcomes in prescription-opioid dependence may be better - as a group they tend to be better educated, have shorter periods of dependence with fewer social issues, and there is less injecting drug use. The Weiss paper pours cold water on that suggestion - the outcomes are poor. As many clinicians could have told him, managing this group of patients has unique and significant challenges. In the Lancet editorial Weiss expresses his view that
"many such patients don't want to stop using opioids, but just want to reduce their dose". He also draws attention to the high likelihood of the co-existent chronic pain in this group.
With these challenges in mind it is worth thinking further about the outcomes from this paper. It showed that the intensity of counselling made absolutely no difference but people tended to do well while on buprenorphine-naloxone. There were 360 individuals in this study who went through two buprenorphine-naloxone inductions and detoxifications. Almost half of them remained abstinent after 8 weeks while still on medication but just 31 of them were abstinent from opioids in week 24 - as Weiss states the likelihood of relapse was "overwhelmingly high". The authors' final shot is to ask the question: what length of buprenorphine-naloxone treatment is needed? The answer to this may be that there is no answer- when it comes to recovery, the decision has to rest with the individual.
SMMGP are running a Special Interest Training Day - Addiction to Medicines on Thursday 10th May 2012 in Cardiff (the day before the RCGP 17th National Conference) which will cover issues related to problematic use of over-the-counter (OTC) medications, benzodiazepines and other prescribed medication misuse. See the Courses & Events section for more details.
Trazodone for sleep disturbance during methadone maintenance: a double-blind, placebo-controlled trial
Stein MD, Kurth ME, Sharkey KM, Anderson BJ, Corso RP, Millman RP. Drug Alcohol Depend. 2012 Jan. 1;120(1-3):65-73
This study looked at sleep disturbance among those on methadone maintenance therapy (MMT). More than three-quarters of people on MMT report sleep complaints. The authors note that this is not just subjective - it has been backed up by polysomnographic studies showing abnormalities such as decreased REM and slow wave sleep. Trazodone is the second more commonly prescribed medication for treatment of insomnia in the United States. This is an off-label use - and it's currently not licensed in the UK for this purpose either.
They recruited 137 people who had been on methadone for at least one month who were having sleep problems. They measured this with the Pittsburgh Sleep Quality Index (PSQI) and they had to score six or more to be included. Participants were randomly allocated to 50mg trazodone capsules or placebo. Participants took 1-3 capsules as needed at bedtime. The researchers measured sleep objectively during two sleep study nights. The PSQI was used to assess sleep quality.
The results showed that the there was no effect of trazodone on mean PSQI scores during the 6-month follow-up period. In addition, trazodone didn't significantly change illicit drug use one way or another, and it didn't have any effect on the objective measures used in the sleep studies.
Hypnotics' association with mortality or cancer: a matched cohort study
Kripke DF, Langer RD, Kline LE. BMJ Open. 2012 Jan. 4;2(1):e000850-e000850
This American study addressed the issue of hypnotic prescribing. It is estimated that 6-10% of the US adults took a hypnotic drug for poor sleep in 2010. They took 10,529 patients who received hypnotic prescriptions and 23,676 matched controls with no hypnotic scripts. They then followed them for an average of 2.5 years between January 2002 and January 2007.
They computed hazard ratios (HRs) for death after various adjustments for confounders. The results showed that patients prescribed any hypnotics had substantially elevated hazards of dying. They looked at this according to number of doses given per year. Those given 0.4-18 doses/year had a hazard ratio of death of 3.6 (95% CI 2.92 to 4.44); those given 18-132 doses had a hazard ratio of 4.43 and those given >132 doses had a hazard ratio of death of 5.32. They did separate analyses for all the main hynotics (including z-drugs) and found the elevated hazard ratios still held. They also found that hypnotic use in the group taking >132 doses per year was associated with a significant elevation of incident cancer (HR 1.35). They also found the results held when analysing each cormorbidity - indicating that death and cancer associated with hypnotics does not seem to be attributable to pre-existing disease.
SMMGP comment: The BMJ Open paper is not without its flaws - the lack of information about whether people had depression or other psychological illnesses is a particular weakness. However, it did go a long way to excluding a lot of potential confounders. And of course, there will quite rightly be much jumping up and down and shouting about cause and effect: association is not causation after all. However, this is one more piece of evidence that should make doctors pause and think before prescribing.
Sleep is a recurrent theme in consultations for those with substance misuse issues. The first paper investigated a treatment option and the authors claim this to be the first randomised, placebo-controlled trial testing a sleep medication for opioid dependent persons. The results of the study showed no objective or subjective changes in sleep at all with trazodone.
One can't help but feel that whatever the answer to sleep problems might be, it's not convincingly more prescribing. However, it seems that neither patients nor doctors will be easily persuaded of this. It may be that we need to address a lot of other issues - such as the astonishing high rates of smoking, caffeine use and other drugs that can interfere with sleep need to be addressed before we reach for the prescription pad.
Increased incidence of QT interval prolongation in a population receiving lower doses of methadone maintenance therapy
Roy AK, McCarthy C, Kiernan G, McGorrian C, Keenan E, Mahon NG, et al. Addiction. 2012 Feb. 28
The aim of this paper was to investigate the frequency of QTc prolongation in those on methadone maintenance therapy (MMT). It was conducted in a specialist inner-city drug treatment clinic in Ireland between July 2008 to January 2009. In total they recruited 180 patients who were stable on methadone. They all underwent 12-lead ECGs with QTc analysis as well as urine testing for opiates, benzodiazepines and cocaine. ECGs were carried out prior to methadone dosing - making them effectively "trough" ECGs.
The results showed that the mean QTc was 420.9 +/- 21.1ms with a range of 368 to 495ms. There was no significant association between QTc interval and the presence of cocaine metabolites in the urine. There was no association between methadone dose and QTc interval either. Overall, 8.8% of patients had evidence of prolonged QTc interval (8.3% of men with a QTc =450ms and 0.5% female QTc =470ms). If a level of 450ms is set as the cut-off then overall 11.1% (n=20) had a prolonged QTc interval.
SMMGP comment: The typical incidence of QTc interval prolongation in the normal population is 2.5%. There seems little doubt that this is a further study confirming methadone's effect on the QTc interval. Other studies have shown greater increases on occasions but some of these have had people on relatively larger doses of methadone. In this study the average methadone dose was 81.3mg in males and 74.7mg in females.
The authors make some entirely level-headed comments and suggestions in the discussion. The problem with arrhythmias (including those such as torsades de pointes) is that they are a multivariate issue - there are a number of factors that can increase the risk. Using QT assessment as the sole predictor of arrhythmia completely ignores this basic fact. Perhaps one of the most important factors is congenital long QT syndrome, a condition thought to have a prevalence of around one in 2500 in the population. Enquiring about a personal history of syncope, structural heart disease or arrhythmia, and a family history of unexplained sudden death should be a routine part of the assessment for clinicians. These criteria should probably trigger a pre-treatment ECG but the authors suggest, and it seems entirely reasonable, that it is probably unnecessary (and potentially represents a significant barrier to treatment) to do routine ECGs in all those starting methadone.
The effect of methadone on emotional reactivity
Savvas SM, Somogyi AA, White JM. Addiction. 2011 Nov. 1;107(2):388-392
This study wanted to investigate the effect of methadone on emotional reactivity. They used something called Velten's mood induction procedures to induce elative and depressive emotional reactions in the subjects. They took 21 people on methadone and a further 21 people, to be used as controls, with no history of opioid dependence. Each group was administered the induction procedures at 0 hour and 3 hours (this was to correspond with trough and peak plasma methadone concentrations in the methadone group). They measured emotional reactivity using mood visual analogue scales.
The results showed that at the start the methadone and the control group had similar elation and depression reactivity. However, at 3 hours, the methadone group had significantly decreased reactivity for depression and elation.
SMMGP comment: It is possible that the findings from this study are representative of a general opioid effect and are not methadone-specific. Many clinicians will recognise the "self-medicating" motivation some people have for using heroin to gain relieve from painful past experiences. The findings of this study suggest that methadone does, as many might have suspected, blunt both elative and depressive emotional reactivity. When people talk of that slightly "clouded" view of the world this may be what they are experiencing. For many, with severe distressing emotional issues this may have its own merits but the downsides could be considerable. The authors point out that emotion has a vital role in learning and memory and there is evidence to suggest that emotion suppression is associated with worsened psychopathology.
Do components of current "hardcore smoker" definitions predict quitting behaviour?
Ip DT, Cohen JE, Bondy SJ, Chaiton MO, Selby P, Schwartz R, et al. Addiction. 2012 Jan. 17;107(2):434-440
It has been suggested that we are increasingly seeing a "hardcore" group of smokers who are resistant to quitting. This has been backed up by data suggesting that while there has been a continued reduction in smoking prevalence over several decades the rate of decline has slowed in recent years. This study aimed to explore some of the factors associated with these "hardcore" smokers - the ones it identified for analysis were: high daily cigarette consumption, high nicotine dependence, being a daily smoker, history of long-term smoking, no quit intention and no lifetime quit attempt. The three outcomes that were considered were: continued smoking, not attempting to quit and having an unsuccessful quit attempt or attempts. They recruited 4130 adults smokers in Ontaria, Canada from 2005-08 and followed them for one year. They used a telephone survey to gather the data.
The results showed that all the "hardcore" components (except for history of long-term smoking and no lifetime quit attempt) did predict those who would make no quit attempt and would continue to smoke. In those who did attempt to stop at least once during the follow-up period the predictors of failure were: high nicotine dependence, high daily cigarette consumption and being a daily smoker. The findings showed that daily heavy smokers with high levels of nicotine dependence are very likely to continue smoking.
SMMGP comment: It is certainly arguable that those in substance misuse services fall into the category of "hardcore" smokers. The findings from this study can be boiled down to a simple message: the best predictor of whether a smoker will continue to smoke is how much they smoke now. Those that have ever attempted to quit are more likely to quit in the future and clinicians could target this group with support and encouragement to try again. Those who have high nicotine dependence may need additional measures and attention - this may mean more intensive support or it may mean additional prescribing. What exactly this would constitute is less clear given this is an area where few, if any, of the available options have enjoyed a great deal of success.
Eating patterns among heroin users: a qualitative study with implications for nutritional interventions
Neale J, Nettleton S, Pickering L, Fischer J. Addiction. 2012 Feb. 8;107(3):635-641
This qualitative study wanted to gain "new insights" into heroin users' eating patterns. They audio-recorded a total of 77 in-depth interviews in community and residential drug services, pharmacies and peer support groups in the south of England. They initially interviewed 40 current or ex-users and then re-interviewed them after 3 months.
They found that heroin user's eating patterns were influenced by many factors. During heroin use they tended to consume quick, convenient, cheap and sweet foods. They ate infrequently and had little interest in food. During periods of cessation, or when in residential services, interest in food, its preparation and eating improved. Initially, weight gain was regarded as a positive thing but anxieties, particularly in women, were then expressed about issues with controlling appetite and becoming overweight. Those with the most dysfunctional eating patterns were women, homeless drug users (limited access to cooking facilities) and those with the most severe addiction (who prioritised accessing drugs over food).
SMMGP comment: This is a neglected area and it has profound implications across a range of health issues. Clinicians need to be prepared to discuss the issue and it may be that routine dietary assessments should be the norm. There are medical conditions such as HIV, alcohol misuse, hepatitis C, and chronic constipation that may merit specific dietary advice and dietary supplements. In addition, many individuals who use heroin may benefit from learning basic life skills on how to shop for and prepare food. As the authors point out food is not just a basic human need - it is also an important social and cultural activity. Like all qualitative studies, it's not possible to generalise too much but this paper does provide, dare I say it, food for thought.
New recreational drugs and the primary care approach to patients who use them
Winstock AR, Mitcheson L. BMJ 2012;344:e288
This is a clinical review of the current approach to the newer drugs that have appeared on the scene in the past few years: ketamine, GHB, mephedrone. The paper split these drugs into three broad groups: gamma-hydroxybutyrate (GHB), gamma-butyl-lactone (GBL) and 1,4-butanediol were put together as they act at the GABA receptors; ketamine, a short-acting dissociative anaesthetic; and newer synthetic stimulants including mephedrone. It provides detail on the modes of action, routes of use and sought after effects. It also covers the signs and symptoms of intoxication, as well as the acute and chronic harms. The paper goes on to outline an approach to finding and assessing users of new recreational drugs.
SMMGP comment: One of the problems with the appearance of new drugs is that it is easy to feel a little disorientated with the chemical names and alphabet soup that seems to surround them. This paper lays out the current issues in clear terms and also gives a simple framework for applying practical measures in general practice. Recommended.
A prospective, randomized, multi-center acceptability and safety study of direct buprenorphine-naloxone induction in heroin-dependent individuals
Amass L. et al.
SMMGP's commentary on the above paper in our previous clinical update drew a response from the manufacturer. In the spirit of open dialogue we provide a summary of their conclusions below:
"It is our belief that the global evidence base supports the existence of misuse and diversion, and it has a significant health impact. Combination therapy is an attempt to address the problem of misuse and diversion and preserve the integrity of buprenorphine and access to treatment. We provide some data to help SMMGP readers make a decision based on the balance of the evidence and current best practice in a global setting when considering the relative merits of buprenorphine/naloxone".
The full response is available to read via the Clinical & Policy Updates section (with the relevant update).