Abstinence v. maintenance

Abstinence-based treatments comprise the majority of treatment options for substance misuse, with the prominent exception of opioid dependence. Detoxification is the process of reducing and stopping the use of addictive substances such as alcohol, often with some form of medical assistance (e.g. a prescription for benzodiazepines over 7–10 days). Stimulants (such as cocaine and amphetamine) do not require any prescribed medication to assist detoxification although, in practice, hypnotics or other sedative medication are often provided for a short time.

Subsequent editions of the UK Department of Health’s clinical guidelines for substance misuse have oscillated between abstinence and maintenance treatment, with the prevailing emphasis (HM Government 2010) currently in favour of abstinence. This illustrates the cyclical nature of the debate and possibly the preference of incumbent governments.

Maintenance treatment is only recommended for opioid dependence. Methadone (or buprenorphine or lofexidine) may be used in short-term opioid detoxification (over 7–28 days). Alternatively, a maintenance prescription may be used whereby provision of a substitute drug (historically this has been methadone) continues over months or years with no requirement stop. (The term ‘methadone maintenance’ is often subsumed under the title ‘harm reduction’, which also includes other measures such as needle exchanges.)

There is overwhelming evidence that long-term maintenance treatment is consistently superior to detoxification (and other ‘abstinence-based treatments’) in the treatment of opioid dependence. For example, a report from British Columbia of over 25 000 methadone treatment episodes showed that in only 1 in 40 episodes did the individual achieve a successful ‘recovery’ – abstinence from prescribed methadone with no treatment reentry within 18 months. The authors concluded that, ‘the [vast] majority of patients attempting to taper from methadone maintenance treatment will not succeed’ (**Reference Nosyk, Sun and EvansNosyk 2012). There are multiple comparable research reports (**Reference Amato, Minozzi and DavoliAmato 2011). Fewer than 10% of patients dependent on prescribed opioids were able to achieve abstinence for 3 months after a 4-week taper using buprenorphine–naloxone (**Reference Weiss, Potter and FiellinWeiss 2011). Almost identical results were sensationally reported from the UK in the press 6 years ago (Reference EastonEaston 2008). By contrast, around half of patients who are maintained on methadone can almost completely abstain from heroin (**Reference Gossop, Marsden and StewartGossop 2001; **Reference Hubbard, Craddock and AndersonHubbard 2003).

Regardless of the scientific evidence, the political battle between abstinence and harm reduction continues to rage. For example, in 2010 the newly elected UK government announced that substance misuse services should follow a ‘recovery’ model (HM Government 2010). Patients on opioid substitution therapy are ‘encouraged’ to reduce and stop all addictive drugs, including prescribed methadone, although there is no time limit suggested for this process. This illustrates the barriers to adoption of evidence-based practice.

Misuse of prescribed opioids

Misuse of opioids that were prescribed for pain (Table 1) was not a recognised problem 20 years ago. Indeed, the prevailing view was that ‘strong’ opioids such as morphine should be used more liberally, especially in acute settings. In practice, these agents were used primarily for severe acute pain in hospitals or for cancer pain in the community (**Reference Freynhagen, Geisslinger and SchugFreynhagen 2013). There has been a significant increase in prescribing of high-potency opioids for non-cancer pain in recent decades, driven partly by aggressive marketing of these products (**Reference Freynhagen, Geisslinger and SchugFreynhagen 2013). Illicit prescription opioids have become the second most common illicit substance of misuse after cannabis (**Reference Weiss, Potter and FiellinWeiss 2011). In the USA in 2009, the use of a prescription opioid for non-medical reasons was 20 times more common than the use of heroin (**Reference Weiss, Potter and FiellinWeiss 2011). There are now more deaths in the USA from prescription opioids than from heroin, and deaths from overdose following diversion and misuse of these products is the second leading cause of accidental death. In 2010, 5.1 million people over 12 years of age in the USA reported that they had used prescription opioids non-medically in the previous month (1.7% of the entire population) (Substance Abuse and Mental Health Services Administration 2011).

TABLE 1 Relative potency (compared with morphine) and half-life of common prescribed opioids that are misused (oral formulation unless otherwise stated)

Estimates suggest that 4% of all opioid doses prescribed in the USA are resold on the black market (**Reference Katz, Birnbaum and CastorKatz 2010). The overall societal cost of prescribed opioid misuse in the USA in 2007 was estimated at almost $56 billion (US$ in 2009) (**Reference Birnbaum, White and SchillerBirnbaum 2011). Furthermore, there has been an 8% increase in patients seeking help for prescribed analgesic dependency in the UK over the past few years, with 154 deaths from tramadol (compared with 486 for methadone) in 2010–2011 (**Reference Ghodse, Corkery and SchifanoGhodse 2011; Reference StannardStannard 2013).

Expert reviews do not support the long-term prescription of opioids, especially at high doses, for many forms of non-cancer pain (**Reference Noble, Treadwell and TregearNoble 2010). For example, a Cochrane review in 2009 of 10 randomised trials of opioids for osteoarthritis showed that most opioids conferred minimal benefit (**Reference Nüesch, Rutjes and HusniNüesch 2009). Up to 1 in 3 patients who are prescribed opioids for chronic pain show signs of misuse or dependence, especially those with a history of substance use disorder (**Reference Boscarino, Rukstalis and HoffmanBoscarino 2011).

An instrument has been developed (**Reference Webster and WebsterWebster 2005) that might help minimise the misuse of prescribed opioids. Called the Opioid Risk Tool, it involves simple precautions such as drug testing, prescribing contracts specifying the duration of prescription and non-response criteria, objective measures of improvement, regular review, frequent dispensing of small quantities, use of a single prescriber and a single, named pharmacy. However, the principal advice from published guidelines is that opioids should be stopped if they do not help at reasonable doses.

A randomised trial has been reported involving 653 treatment-seeking out-patients dependent on prescription opioids who were prescribed a buprenorphine–naloxone combination to achieve abstinence. Only 6.6% of patients became abstinent from prescription opioids in phase 1 of the trial, a 1-month buprenorphine–naloxone taper plus 2-month follow-up. Those who relapsed were admitted to phase 2. These patients received 3 months of buprenorphine–naloxone stabilisation, followed by a 1-month taper and 2-month follow-up. Almost 50% achieved a successful outcome 2 months after the gradual taper (patients received a substitute prescription for 4 months). (For information, patients were randomised to medication only or medication plus counselling sessions, although the results showed the counselling strategy provided no additional benefit). The trial showed excellent results using a substitute prescription for a modest time rather than rapid detoxification. However, these patients were all in receipt of prescribed opioids rather than using illicit drugs. They were also required to express a desire to come off their prescription in order to take part in the trial. They were therefore likely to have better social functioning and greater motivation than many patients dependent on illicit heroin (**Reference Weiss, Potter and FiellinWeiss 2011).

Cardiac arrhythmias and methadone

Methadone is postulated to produce QT prolongation at high doses and in those with pre-existing cardiac disease. This is elegantly demonstrated in a large study of antidepressants in which methadone was included to demonstrate assay sensitivity. QT prolongation was dose-dependent even at modest doses of methadone (10–50 mg daily; **Reference Castro, Clements and MurphyCastro 2013). QT prolongation (typically over 450 ms in men and 470 ms in women) is thought to predispose to more serious, life-threatening arrhythmias such as torsades de pointes and ventricular fibrillation. However, the rate of serious cardiac events is uncertain in opioid-dependent patients. It is estimated that serious electrocardiogram (ECG) abnormalities affect 2–5% of these patients, while less serious abnormalities affect 10–30%. Patients in methadone treatment are at risk of sudden death as a result of other cardiovascular risk factors, especially smoking, endocarditis and stimulant misuse. Other risk factors for ECG abnormalities include the patient’s age, duration of methadone treatment, previous cardiovascular disease (including hypertension), male gender and concurrent medication (especially drugs that alter potassium balance). Hence, it is not possible to estimate the number, if any, of cardiac deaths that may be caused by methadone.

An expert panel of cardiologists recommended routinely asking patients about symptoms of syncope (such as faints and blackouts). The same panel also recommended that ECGs should be performed annually on all patients who are prescribed methadone, especially those on higher doses (perhaps arbitrarily taken to be doses more than 100 mg) (**Reference Krantz, Martin and StimmelKrantz 2009). Unfortunately, a significant proportion of these ECGs are abnormal (estimated at between 25 and 50%). Furthermore, an independent Cochrane review failed to find support for routine screening for cardiac arrhythmias in all patients on methadone (**Reference Pani, Trogu and MaremmaniPani 2013). Hence, it remains debatable whether annual ECG screening is justified for all patients on methadone or just those who are at high cardiac risk (such as those on daily methadone doses exceeding 100 mg; Department of Health 2007).

Deaths from diverted methadone

Deaths from methadone have been a recurrent problem – around half are caused by diverted prescribed methadone bought on the black market. In England in the 1990s, methadone was responsible for more deaths than illicit heroin. Subsequently, strict recommendations were introduced concerning supervised consumption of methadone, where patients take the drug under direct observation, usually by a pharmacist (Department of Health (England) 2007).

Despite variation in the practice of supervised consumption (**Reference Holland, Maskrey and SwiftHolland 2014), it has reduced the number of deaths by about fourfold (**Reference Strang, Hall and HickmanStrang 2010). In 2011, the National Programme on Substance Abuse Deaths at St George’s, University of London analysed the 1883 drug-related deaths in the UK (**Reference Ghodse, Corkery and ClaridgeGhodse 2012). It reported that 455 (37%) involved heroin/morphine (including 136 (11%) where no other substance was implicated). By contrast, there were 308 deaths (25%) involving methadone (including 87 (7%) with no other substance). Only 131 of the 308 people whose deaths were methadone-related were in receipt of a methadone prescription at the time of death; 177 (58%) presumably obtained methadone from illicit sources. In Scotland methadone was implicated in more than 237 deaths, compared with 221 deaths from heroin/morphine (National Records of Scotland 2013).

A well-known double-blind trial involving 193 intravenous opioid addicts revealed that 53% of the urine samples after 30 weeks were opioid-positive in those randomised to 80–100 mg methadone, compared with 62% of those receiving 40–50 mg (number needed to treat NNT = 11) (**Reference Strain, Bigelow and LiebsonStrain 1999). However, this trial was performed in a research population who were starting treatment and it involved supervised consumption for all participants over the 30 weeks. A more recent US trial involving 1267 opioid-dependent patients supports many other reports by showing increased retention in treatment over 6 months for patients on methadone doses over 60 mg/day (80% v. 74% for doses ≤60 mg; NNT = 16), while doses over 120 mg had 91% retention (NNT ~6) (**Reference Hser, Saxon and HuangHser 2013). However, it was unclear whether retention in treatment necessarily indicated a better outcome in terms of reduced opioid use, as the trial compared methadone with buprenorphine–naloxone and those that dropped out were not followed up. Unfortunately, in practice many patients will receive take-home doses of methadone after 3–6 months. Dispensing higher doses of methadone for patients to take home is likely to greatly increase the risk to other drug users.

Legal highs

‘Legal highs’ are newly available, synthetic psychoactive substances that are not regulated under current legislation such as the UK Misuse of Drugs Act 1971 (Table 2) (Faculty of Addictions Psychiatry 2014). Briefly, legal highs are taken for their temporary stimulant and euphoric effects in a similar manner to cannabis, ecstasy or ketamine. Side-effects and overdose produce symptoms similar to those of illegal stimulants. A Europe-wide survey in 2011 suggested that 5–10% of young people had taken a legal high in the previous year (compared with 25–50% for cannabis, depending on age) (Gallup Organization 2011). Legal highs are usually bought on the internet or sold by the same dealers as cannabis and ecstasy. There are many hundreds of compounds: examples include ‘meow meow’ (mephedrone), GBL (gammabutyrolactone, an industrial solvent), BZP (benzylpiperazine) and salvia (an extract from the sage plant). The exact content of the illicit tablets or powder is extremely variable and some supplies may have completely different active agents when purchased at different times.

TABLE 2 Examples of legal highs (description and action) and related drugs of misuse

Testing a single psychoactive product to determine whether it is likely to cause harm typically costs around £1 million and takes about 1 year. This is highly onerous given the number of active chemicals used as legal highs. One approach to dealing with this problem is to require manufacturers and distributors to prove that their products pose a low risk of harm before they receive approval (**Reference Winstock and RamseyWinstock 2010). Unfortunately, this is unlikely to be effective when products are ordered internationally on the internet and when they are being imported supposedly as plant food, solvents or industrial chemicals.

Treatment services for legal highs are being developed, although this is a very recent problem. Abstinence-based options are usually offered as for cannabis or stimulants.

Gabapentin and pregabalin

These anticonvulsant drugs are now being widely prescribed for pain, especially for more intractable neuropathic pain, to avoid the risk of dependence associated with opioids. Gabapentin and pregabalin enhance the action of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in a similar manner to benzodiazepines. There are now many reports of misuse of pregabalin and gabapentin, which produce euphoria and intoxication similar to the effects of alcohol (**Reference Schifano, D'Offzi and PiccioneSchifano 2011). This problem is only just emerging and there is no consensus on how it should be managed. However, restrictions are now being placed on the prescribing of pregabalin in the USA (Drug Enforcement Administration 2011).

MCQs

Select the single best option for each question stem

1. 1 Of the following list, the most common cause of avoidable death in the world is:

   1. a tobacco

   2. b alcohol

   3. c heroin

   4. d cocaine

   5. e cannabis.

2. 2 The second most common class of illicit drugs of misuse in the USA in 2011 was:

   1. a cannabis

   2. b cocaine

   3. c prescription opioids

   4. d heroin

   5. e ketamine.

3. 3 Over the past decade, supervised consumption has reduced deaths from methadone overdose by about:

   1. a fourfold

   2. b tenfold

   3. c half

   4. d 10%

   5. e twentyfold.

4. 4 The proportion of the adult populations of the USA and UK estimated to have used benzodiazepines regularly for 12 months or over is:

   1. a 20%

   2. b 0.1%

   3. c 2%

   4. d 40%

   5. e 50%.

5. 5 Regarding ‘legal highs’, testing a single compound to determine whether it is likely to cause harm:

   1. a typically costs £10 000 and takes 1 month

   2. b typically costs £10 00 and takes 6 months

   3. c typically costs £100 000 and takes 6 months

   4. d typically costs £100 000 and takes 1 year

   5. e typically costs £1 000 000 and takes 1 year.

MCQ answers

1

a

2

c

3

a

4

c

5

e