SMMGP - Substance Misuse Management Good Practice

Substance Misuse Management Good Practice

Supporting good practice in drug and alcohol treatment

Clinical & Policy Updates:
SMMGP Clinical Update #43 - December 2014

Compiled by Dr Euan Lawson

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Papers & Reports

Time limiting opioid substitution therapy
Advisory Council on the Misuse of Drugs, November 2014

Available at:

This is a short report commissioned in June 2014 by the then Minister of State for Crime Prevention, Norman Baker MP. The ACMD's Recovery Committee were asked to report on:

Here is their response:

"The overall conclusion of this report is that the evidence does not support the case for imposing a blanket time limit on OST treatment for heroin users and this approach is not advised by the ACMD. As evidence strongly suggests that time limiting OST would result in the majority relapsing into heroin use and may have significant unintended consequences including increasing: drug-driven crime (and national crime statistics); heroin overdose death rates; and, the spread of blood-borne viruses including hepatitis and HIV."

Commentary: That's all clear then. It won't be the first time that the government has ignored the evidence when it comes to the ACMD but there is no excuse for doctors and other prescribers to ignore it. The ACMD comment that: "Those implementing this approach [time-liming OST] could also face medico-legal challenges." I have no idea how doctors who have been time-limiting OST in recent years can defend their position - there has been no sudden shift in the evidence on which to base such a policy. The benefits of OST have always been demonstrable and, yet, time-limiting has clearly been happening in the UK - Russia doesn't have a monopoly when it comes to providing scandalously inadequate care for opiate dependent users.

The ACMD also make the point that OST is only one part of treatment - again, no argument there, and it is vitally important that psychosocial interventions are ingrained in services. A position that isn't made easier by commissioners who salami slice treatment provision and divorce psychosocial interventions from prescribing. It's challenging to see the rationale behind this approach - there is certainly no evidence for it of which I'm aware and it can hobble treatment services. The ACMD also reviewed the evidence that people were 'parked' on methadone. They point out that the evidence suggests that in reality, for most people, OST is episodic and only a minority (10-15%) have been in continuous OST for more than 5 years. They sum it up:

"The 'being parked' analogy may be not be correct: most people get out of the car and walk away."

I'd put this down as one of the most important papers I've read this year. We need to push back against methadone denialists and we can't let ideology rule clinical practice: there is no place for time-limiting OST.

Patient Safety Alert: Risk of distress and death from inappropriate doses of naloxone in patients on long-term opioid/opiate treatment
NHS England 20 November 2014

Available at:

NHS England report that they have received details of three patient safety incidents in which they state that there was a "failure to follow the BNF guidance". Two of these incidents resulted in death. They suggest that:

"Doses used in acute opioid/opiate overdose may NOT be appropriate for the management of opioid/opiate-induced respiratory depression and sedation in those receiving palliative care and in chronic opioid/opiate use."

Commentary: Many of you will have received the Patient Safety Alert (PSA) and it is, at first glance, somewhat puzzling. We need to look back at the origin of the alert to unpick this.

It stems from a medico-legal report produced after the death of a patient who had advanced cancer and severe coronary artery disease. It was a palliative care scenario and there was concern about respiratory depression. Naloxone was administered in a large bolus with little monitoring and no consideration of the potential consequences for pain management. There was no apparent effect on the respiratory depression but the patient was left in severe pain - distressing and known to be deleterious in cardiac conditions. There are documented side effects of naloxone, particularly in the elderly, which include tachycardia, arrhythmia, bradycardia and cardiac arrest. Death followed and expert testimony suggested the use of naloxone was an important factor.

The full report is available at and explicitly states at the start that the circumstances in this case are not the same as in non-therapeutic overdose. The Patient Safety Alert is largely about naloxone dosage when opiates are being used to manage pain in cancer and there is concern about respiratory depression. In those circumstances, great caution needs to be exercised when using naloxone in the elderly and with cardiac disease. It emphasises the point that almost no medication can be assumed to be harmless - but it is unfortunate that this Patient Safety Alert could give the impression that naloxone shouldn't be used in community non-therapeutic overdose. That's not the background to this at all.

Community management of opioid overdose (2014)
Geneva: World Health Organization

Available at:

The WHO point out that an estimated 69,000 people die from opioid overdose each year. In 2010, over 16,000 of them were from an overdose of prescription opioids in the USA. These guidelines make four key recommendations:

  1. People likely to witness an opioid overdose should have access to naloxone and be instructed in its administration.
  2. Naloxone is effective when used intravenously, intramuscularly, subcutaneously and intranasally. The person using it should select the route of administration dependent on circumstances and their skills.
  3. In suspected opioid overdose first responders should focus on airway management, assisting ventilation and administering naloxone.
  4. After successful resuscitation following naloxone, conscious level and breathing should be closely monitored until full recovery has been made.

The WHO report states clearly that the evidence for all four of these recommendations is "very low". In the case of the first recommendation the expert group still made a strong recommendation due to the life-saving nature of the intervention and an apparent absence of harm. They also commented that it is a "feasible intervention, highly valued by those at risk of opioid overdose and those likely to witness an opioid overdose in the community".

Commentary: The figures published in 2014 for overdose deaths in England and Wales are available at the Office for National Statistics website. There were 1,812 deaths registered in England in 2013 and there was a 33% rise in death associated with heroin and opiates compared with 2012. That's a big jump, however, the number of deaths fell for six consecutive years between 2007 and 2012 and so it's a little early to determine if this is a trend. Over 1,800 deaths is, in itself, an argument for any measure that can reduce overdose fatalities but it would be disingenuous to use this as strengthening evidence of the need for naloxone. There is a considerable delay baked into these data - it is only after the coroner's inquest that the deaths get registered so the deaths in 2013 will have occurred many months, or even years, before they get counted.

As regards naloxone, I wouldn't argue with the moral imperative or the expert opinion - it is a powerful narrative that is gaining a lot of traction and can do much to raise awareness of the appalling death toll from opiate overdose. You can access a free e-module, "Naloxone Saves Lives", at the SMMGP website. On the balance of probabilities, naloxone is likely to help address the continuing death toll from overdose, but it is vitally important that it doesn't distract us from the other interventions that have a solid evidence base.

If it turns out that we do have a rising trend of overdose deaths in the UK then this will be underpinned by a complex set of factors. In the past few years I have seen a lot of people who have had their opiate substitution therapy curbed as political pressure has been ratcheted up. It is crucial that interventions such as opiate substitution therapy, alongside appropriate psychosocial interventions, aren't neglected. Any organisation trumpeting its recovery credentials should have its policy regarding OST scrutinised - in terms of the evidence, advocating naloxone or naltrexone while watching opiate substitution therapy being stripped back and limited is indefensible.

Excess mortality among opioid-using patients treated with oral naltrexone in Australia
Degenhardt L, Larney S, Kimber J, Farrell M, Hall W. Drug Alcohol Rev 2014, Oct 10

The overall aim of this study was to estimate the number of deaths in people who were prescribed naltrexone in comparison to the likely outcome if they had received methadone. They were looking at the Australian Special Access Scheme - a mechanism that allows prescription of medications that are not fully registered. Oral naltrexone became registered for the treatment of opioid dependence in 2000 and this study looks at the period 1998-2000.

The results showed that the crude mortality rate for the treatment with oral naltrexone was 4.9 times greater than methadone in Western Australia (95% CI 2.8-8.7) and 3.5 times greater than methadone in New South Wales (95% CI 2.3-5.1). This works out, in the cohort of 1097 patients, as between 25 and 29 additional deaths.

Commentary: This is a remarkable piece of evidence and the calculation by the authors bears repeating - this study suggests that 25 to 29 people lost their lives as a consequence of being prescribed naltrexone rather than opiate substitution therapy. These are not paltry differences in mortality - that's a massive difference in a modest study and even at the bottom end of the confidence interval the mortality was over twice as high. The authors found that this excess in mortality comes from overdose deaths after stopping oral naltrexone and for various reasons this difference is more likely to represent an underestimate than an overestimate.

The evidence for injectable naltrexone is already flimsy but this study has important implications when it comes to plans for detoxification and prescribing oral naltrexone. It's worth emphasising that the deaths weren't as a consequence of naltrexone per se - they were due to overdose in people who had become opioid-naive. The study is also a little old now with a sample that goes back 14-15 years and it's not clear on the level of psycho-social interventions available to patients at that time to help prevent relapse. It serves as a timely reminder, alongside the ACMD's report on time-liming methadone, that detoxification carries a very high tariff when relapse occurs. At the very least, we need to make sure we are having a full and open conversation with the person planning a detoxification to ensure they are aware of the harms, as well as the benefits, of their chosen treatment.

Sexual Dysfunction Improved in Heroin-Dependent Men after Methadone Maintenance Treatment in Tianjin, China
Zhang M, Zhang H, Shi CX, McGoogan JM, Zhang B, Zhao L, et al. PLoS One 2014, Feb;9(2):e88289

This study was based in China and participants had to have been on methadone for more than one month and had at least one sexual encounter while dependent on heroin in the past two years. They completed a questionnaire on drug use, sexual behaviours, and also a version of the International Index of Erectile Function (IIEF). They also took blood and tested for hormone levels including testosterone.

A total of 293 men were included in the study. The results showed that in people with long-term heroin use there was sexual dysfunction in all five of the IIEF domains - erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction. Sexual dysfunction significantly improved after starting methadone. There was no association between methadone dose or duration of treatment and sexual dysfunction. Plasma testosterone did decline in those on methadone - but low testosterone levels weren't associated with sexual dysfunction.

Commentary: Previous studies covered in the update have shown that there is an association with poor sexual health, methadone maintenance therapy and use of opioids. However, these haven't actually teased out the effect of a transition from heroin dependence to methadone maintenance. Overall, we see physical health improving with methadone maintenance when people get stable but I've certainly met people who regard methadone as having a negative effective on their sexual function. There is some evidence around its effect on testosterone levels but his paper showed that MMT improved sexual function even though it was also associated with testosterone levels that decreased.

The relationship between sugar-containing methadone and dental caries: A systematic review
Tripathee S, Akbar T, Richards D, et al. Health Education Journal 2012, Jul 8;72(4):469-85

The review specifically looked at the consequences of methadone with sugar on dental health. Here's the summary from the authors:

"The current literature shows no robust evidence which links sugar-containing methadone, with dental caries experience. Moreover, it is widely recognized that sugar-content of methadone is only one risk factor within a multi-factorial aetiology of tooth decay."

Commentary: Methadone with sugar typically has about 197mg/ml of sucrose. That means that 50mg will have around 9.85g of sucrose - the equivalent of 2.5 teaspoons of sugar. A can of coke has around six teaspoons so when taken in a single dose the sugar content of methadone isn't going to be the most important factor in that person's dental health.

If you are tilted towards sugar-free methadone then it might be worth bearing in mind the effects of the artificial sweetener. One brand of methadone uses maltitol in a dose of 0.4mg/ml in their methadone. This causes dose-dependent problems with GI side effects and anyone on more than about 70mg methadone may well be suffering from colic, borborygmi and flatulence. Laxative effects may kick in above about 100mg methadone in those sugar-free preparations (which, given the constipating effects of opioids may not be a big problem). Not very pleasant - but not something we necessarily ask about in a consultation either. The other effect shared by all opiates is xerostomia - they dry up the mouth and so anyone on regular opiates is at higher dental risk and needs appropriate dental care. Sugar-free gum may help with the production of saliva.

There is absolutely no doubt that as a general principle avoiding medication loaded with sugar is a sound one. My view is that it shouldn't be ignored - but it is a massive distraction from the real issues; giving sugar-free methadone and thinking you've done your bit to manage someone's dental health is to miss the point comprehensively.

The cost-effectiveness and public health benefit of nalmefene added to psychosocial support for the reduction of alcohol consumption in alcohol-dependent patients with high/very high drinking risk levels: a Markov model
Laramée P, Brodtkorb TH, Rahhali N, et al. BMJ Open 2014;4(9):e005376

This paper used a modelling process to compare costs and effects over a 5-year period in the NHS in England and Wales. The trials used were ESENSE 1, ESENSE 2 and SENSE. They estimated the number of alcohol-attributable events and then went on to measure the cost per quality-adjusted life year (QALY) gained and number of alcohol-attributable events avoided.

The results showed that nalmefene (in combination with psychosocial support) cost £5204 per QALY gained. This puts it well inside the usual threshold of £20,000 per QALY gained. This could be expressed, in terms that are much easier for the average human to comprehend, as the avoidance of 7,179 alcohol-attributable diseases/injuries and 309 deaths per 100,000 patients over the course of 5 years (compared with psychosocial support on its own).

Commentary: This paper isn't a light and breezy read for the average clinician looking for some guidance on prescribing of nalmefene. The introduction of medications like nalmefene is a change in approach to managing alcohol dependence and problem drinking where we now have harm reduction measures. Or, more accurately, a complementary approach - we're not going to stop trying to do detoxification in a timely and effective fashion, but we could do with some ability to reduce the devastating harms from alcohol.

We should get all the cards out on the table - this study is very much a Lundbeck enterprise (they make nalmefene as Selincro&#reg;). However, cost-effectiveness studies need to be done in order for organisations like NICE to agree to put them in guidelines - these studies aren't going to be done by a third party so it's inevitable that the pharmaceutical industry will feature heavily in these publications.

The overall effects of nalmefene remain quite small - even in this sub-group of high risk drinkers alcohol intake was reduced by an average of less than 2 units per day and heavy drinking days were reduced by an average of around three days. That's not terribly much (and psychosocial interventions were shown to be very effective too) but the whole point about this is that the detrimental effects of alcohol on the individual and communities are so spectacular that even small reductions in intake are likely to translate into big public health benefits. That's what this paper shows. Clinically, the evidence suggests we should be using this - but you'll need to familiarise yourself with the indications to match the treatment given to the sub-groups that were shown to benefit. In the ESENSE studies these were:

Genetic influences on alcohol-related hangover
Slutske WS, Piasecki TM, Nathanson L, Statham DJ, Martin NG. Addiction 2014, Dec;109(12):2027-34

This article assessed the genetic component of hangovers. And, you'll not be surprised to learn, they did a twin study - in this case Australian twins who were grilled on their experience of hangovers.

The factors they assessed included hangover frequency and hangover resistance (being able to drink without getting a hangover). They used data from 4,764 telephone interviews conducted between 2004 and 2007. They found that 94% of the participants had consumed alcohol in the past year. On average the participants had consumed alcohol just over twice per week in the previous year and been intoxicated on 10 days. There was an average of 6.24 hangovers in the past year - men had 8.5 and women had 4.5. Among those who had been drunk at least once in the past year 14.7% were classified as hangover resistant. The twin correlations showed that 43% (95% CI = 22-63%) of the variation in hangover resistance was down to genetic influences.

Commentary: The study itself is a serious piece of science and it's certainly not an easily accessible puff piece aimed at the Christmas BMJ. One might speculate that hangovers are a useful mechanism to limit drinking - and there's no information here on whether those who are "hangover resistant" are more likely to end up with alcohol use problems in the course of their life. The finding of 43% of variation in hangover resistance being attributable to the genes is an impressively high genetic contribution. Perhaps in the future we'll be testing for those genes but a little clinical history taking will tell us the same now. It's all speculation but if you did find yourself just a little worse for wear then you can always blame your parents.