Abstract
Opioids are very addictive drugs because of their powerful effects on reward and pain pathways in the brain. Opioid addiction is currently a worldwide problem and injecting heroin presents serious health risks including death from overdose. The increase in the nonmedical use of prescription opioids and the increase in overdose deaths are worrying trends in North America. There is therefore an increasing need for access to effective treatments. The 2 major drug treatments, methadone and buprenorphine, have proven efficacy but are not necessarily administered in the most effective doses or under optimum conditions. Alternative approaches such as slow-release oral morphine, tincture of opium, and the use of the opioid antagonist naltrexone to maintain abstinence are used seemingly effectively in some countries but have yet to be fully evaluated in randomized controlled trials. Heroin-assisted treatment has proven to be a valuable and effective treatment when administered in specialized clinics but is only appropriate for those who have failed to improve on optimal methadone or buprenorphine maintenance. Recent innovations and substitution treatment as an alternative to incarceration are described. Drug treatment of opioid addiction is most effective when administered as part of a therapeutic program as demonstrated in the initial methadone evaluations and the more recent trials with heroin-assisted treatment.
Introduction
Opioids not only exist naturally as opium, morphine, and codeine derived from opium poppies but also include semisynthetic medicines, such as oxycodone and hydromorphone, as well as synthetic compounds, such as methadone, buprenorphine, and fentanyl. The use of opium is still popular in countries such as Afghanistan, Iran, and Myanmar where it is cheap and readily available, 1 but heroin, which is derived from morphine, is the opioid most often misused in Western countries. 2 Opioids are prescribed for their analgesic effects3,4 but are taken by illicit users principally for their mood-changing euphoric properties which is an indication of their high abuse potential. 5
Heroin binds to opioid receptors in the brain. The receptors are concentrated in areas within the reward pathway, eg, the ventral tegmental area, nucleus accumbens, and cortex, and this accounts for its strong reinforcing effects. Heroin also binds to opioid receptors within the pain pathway, resulting in its analgesic effects. This process affects neurotransmitters, leading to a large increase in the release of dopamine, thought to be due to a decrease in the release of γ-aminobutyric acid. This leads not only to pleasurable feelings but also to the depression of respiration, heart rate, and digestion. 5 Accidental or deliberate consumption of heroin in large quantities (overdose) or combined with other sedative drugs can result in respiratory depression and death. 6
The global number of opioid users (opium, morphine, and heroin) has remained similar at 0.4% of the world population for a number of years and was estimated to be 17 million in 2014. 2 However, the global stability in numbers hides the changes in certain areas. Figures in Asia have shown little change, but in Western and Central Europe where figures have remained stable or declining for the past 20 years, there are currently some signs of a recent increase. Figures from North America have indicated a steady increase over recent years. 2 In contrast, Australia has shown an overall decline since 1998 despite an increase in the nonmedical use of synthetic opioids in the past 5 years. 2
Opioid Dependence
Opioid dependence can be classified into 2 types. Psychological dependence results from the constant seeking for the pleasurable effect. Physical dependence occurs when drug use becomes more frequent and results in withdrawal symptoms when the drug is not taken. Tolerance develops when repeated administration of the same dose of an opioid results in a reduced effect resulting in a need to increase the dose to maintain the desired effect. Although tolerance to opioids is common, it is unlikely to occur with occasional use and differs considerably between individuals. Withdrawal effects occur in dependent users if an opioid is not consumed within a certain period of time and may involve intense feelings of craving. The withdrawal syndrome is characterized as a flu-like illness with muscle aching and gastric disturbance. Symptoms also include restlessness, insomnia, sweating, yawning, sneezing, and dilated pupils which worsen with time and which, if not treated, can last for several days before remitting.
Opioids can be administered via several different routes, eg, orally, inhalation via smoking, intranasal via sniffing or snorting, and intravenous injection. Users usually start with a less harmful route but in a search to intensify the hedonic effects, often progress to injection which is the most harmful route for several reasons. The act of injecting itself can cause local damage to veins especially when it is performed inexpertly. When the equipment is shared or unclean, it presents additional health risks, notably increasing the risk of the acquisition of blood-borne viruses (BBVs) such as Hep-C and human immunodeficiency virus (HIV) which add to the global burden of disease. 7 Because the purity of a drug obtained illegally is unknown, it is also more difficult to control the dose. Intravenous injecting leads to rapid brain penetration of the drug which is a greater risk for both inducing dependence and increasing the risk of overdose. With continued use, physical dependence can develop rapidly. The latest and current edition of the Diagnostic and Statistical Manual of Mental Disorders 8 no longer classifies opioid abuse and dependence separately but includes both under the diagnostic category of Opioid Use Disorder which is then defined according to severity based on the number of diagnostic criteria fulfilled by the individual.
Recent developments
A recent development in opioid use disorders relates to the misuse of prescription opioid analgesics such as oxycodone and hydrocodone. In 2014, figures for people with an opioid use disorder related to prescription pain relievers rose to an estimated 1.9 million compared with 586 000 related to heroin in the United States where these medicines are more readily prescribed than in other developed countries. 9 Three possible reasons for this development in North America, ie, both the United States and Canada, have been identified. 10 First, more prescription opioids are dispensed through North American health care systems than any other global region. Second, access is less restricted by regulatory bodies and more reliance is placed on community dispensing. Third, the orientation of the systems themselves is profit-making which results in both increased patient demand and increased use of psychotropic drugs. For example, prescription opioids are often dispensed in unnecessary quantities after dental surgery and remain unused increasing the risk of diversion. 11 Although prescription opioid use might appear less harmful initially, oxycodone and hydromorphone are more easily available than illicit heroin, have similar euphoric properties to heroin, and this can lead to both dependence and abuse resulting in an increased demand for treatment at substance misuse treatment centers and an increased risk of overdose. 12 They have also contributed significantly to the dramatic increase in deaths from opioid overdose in the United States which has quadrupled in the past 15 years in line with the sales of prescription opioids. 13 Prescription opioid misuse has also led to a switch to heroin use both in adolescents 14 and US veterans. 15 Heroin use may also be initiated by sniffing or snorting in young adults, 16 and an increase in intranasal heroin use has been reported recently in the Middle East. 17 With these new developments, there is a need for a variety of both prevention and treatment options. One strategy for prevention was the development of an extended-release formulation of oxycodone in 2010 which has led to a decline in both abuse and diversion over a period of 5 years. 18
Opioid Substitution Treatment
History
In the 1920s, the possession of opioid drugs such as opium and heroin became illegal in the United Kingdom, but morphine and pharmaceutical heroin could still be prescribed by doctors for managing gradual withdrawal (detoxification) or as maintenance treatment to severely dependent patients who were unable to withdraw. 19 This model, often referred to as the “British System,” 20 continued through the 1950s when the number of people affected was comparatively small. However, in the 1960s, it was noted that the incidence of heroin use had increased, and in addition, diversion of prescriptions had begun. Therefore, a specialized clinic system was set up to administer treatment which now included injectable methadone. However, when use was still increasing in the 1970s and a significant amount of imported illicit heroin was identified for the first time, there was a move away from prescribing injectable heroin and an endorsement of oral methadone treatment supported both by the findings from a research study in the United Kingdom 21 and the experiences of methadone maintenance in the United States. 22
In the United States, methadone maintenance treatment was developed in the 1960s 23 and administered at first only to those who were severely dependent on heroin use and had proved resistant to other treatment attempts. High doses were used (80-150 mg) in an attempt to block the euphoric effects of any heroin that might be consumed. This treatment was successful not only in reducing heroin craving and illicit drug use but also in helping the participants to become self-supporting and well-functioning individuals, but this was partly because it was implemented as part of a comprehensive program that included a psychiatric evaluation and gradual reintegration into the community by help with job placement, education, and housing. When it was expanded nationally, methadone maintenance treatment became a more rudimentary administration of substitution treatment which concentrated solely on drug administration without the requisite psychological support and rehabilitation and therefore resulted in less effective results.
Opioid substitution treatment (OST) is now the most common treatment for opioid dependence in Europe 24 with about 50% of opioid users in treatment. It is considered to be the most effective treatment for opioid dependence and thus is recommended worldwide. 25
Methadone substitution was the major treatment for some years in the United States until the licensing of buprenorphine in 1999. Since then, buprenorphine has become the standard alternative treatment for opioid dependence. Methadone and buprenorphine are the only 2 drugs currently licensed and recommended for OST in the United Kingom. 26 However, a newer treatment with restricted availability is pharmaceutical heroin. This is of course fundamentally the same treatment as that used before the introduction of methadone in the United Kingdom but with more restrictions and safety conditions applied. It has been trialed in supervised clinics in several European countries and Canada over the past 15 to 20 years. It is currently available as a treatment in specialized clinics in Switzerland, the Netherlands, and Denmark. In the United Kingdom, despite promising results from the first trial, the cost has meant that it is no longer supported by current government policy. Slow-release oral morphine (SROM) and tincture of opium (OT) are used as substitution treatments in some countries and will be described later.
Aim of treatment
Heroin dependence is seen as a chronic relapsing condition, 27 and so to interrupt this cycle/pattern, treatment is necessary to replace the need to acquire heroin. The primary aim of treatment is to stabilize those dependent on heroin and to reduce the health risks of a drug illicitly obtained and unsafely administered and thus the risk of overdose. Heroin itself has a relatively short half-life (3-6 hours) and so requires administration 3 to 4 times a day to avoid unpleasant withdrawal effects. The provision of a longer acting alternative drug will reduce withdrawal effects and is likely to reduce drug-seeking behavior.
Heroin smoking is a popular form of use in some parts of Europe. 28 Despite its detrimental effects on lung function, smoking is less damaging in terms of overdose risk and injection-related harms. Smoked heroin is usually used less frequently (3 or 4 times a week), and the withdrawal syndrome is less severe and of a shorter duration. Consequently, it has been suggested that offering smoking foils instead of syringes may be helpful as a harm reduction strategy, 29 and in August 2014, the UK government approved the issue of free foil by drug treatment providers to individuals as part of a treatment plan. 30 However, in the search for stronger, more immediate effects, users may progress from smoking to injecting. The latter route of administration presents a number of harms to health, the most important of these being accidental overdose which can occur when the individual has not been able to obtain their usual supply of heroin and tolerance has been lost. There was an increase in 21% in opiate deaths due to overdose in the United Kingdom in 2013, but most of these individuals had not been in treatment for at least 6 years. 31 A core aim of treatment is the reduction in drug-related deaths and this requires ready access to effective drug treatment.
A secondary aim is to improve a lifestyle which involves seeking an illegal and highly dependence-inducing drug which incurs not only many health risks but also social risks including being exposed to the risks of entering the illicit drug market. Heroin obtained illicitly is unlikely to be pure and may contain dangerous contaminants, and the act of drug seeking itself exposes the individual to a wider drug-taking culture so that polydrug use becomes more likely, other illicit drugs such as crack cocaine and cannabis being used as well as heroin. It is also common for other sedative prescription drugs such as benzodiazepines to be used with heroin to increase or prolong the effects. During a heroin drought, benzodiazepines have been added to the little heroin which is available or even substituted for it. 32 Combinations of an opioid drug with cocaine, alcohol, a benzodiazepine, or tricyclic antidepressant have been shown to be involved in deaths from overdose. 33
Thus, the short-term aims of successful OST are both to relieve the suffering caused by withdrawal and to reduce the harms incurred by illicit drug use, but the long-term aims are to break the cycle of addictive behavior and prevent relapse, thus integrating the individual back into society. Successful treatment is advantageous not only for the individual but also for the society at large as can be demonstrated by reduced acquisitive crime figures described later.
Adherence to treatment
Adherence or compliance with treatment is an important component in any treatment procedure. However, the consequences of nonadherence to an agreed program of substitution treatment can have dangerous consequences. Nonadherence can take different forms: the treatment may not be collected from the pharmacy or treatment center or it may not be taken as directed. The distance needed to travel to the pharmacy and opening hours can influence the former, but supervised dispensing can overcome the latter. The way a medicine is dispensed can also aid compliance. Once-a-day formulations such as methadone are easier to remember. Adverse reactions such as interference with sleep are likely to reduce adherence.
Good adherence is associated with the patients’ perception of the problem and their view of the treatment offered. An inclusive, well-defined program with flexible dosing and psychological support that is mutually agreed beforehand will aid adherence to it. This was the approach when methadone treatment was first introduced in the United States 23 and is the recommended approach in most clinical guidelines but is not always followed. Thus, when treatment provision is expanded, it can become more perfunctory and less successful than treatment trials would indicate. Barnett et al 34 compared the concordance of substitution programs with clinical practice guidelines and found those that were highly concordant had higher costs but were more effective at reducing illicit heroin use and improving health-related quality of life.
In any treatment, the therapeutic alliance is crucially important. Although this originally referred to the doctor and patient relationship, in fact, it can apply to any health professional, and good key workers can create the conditions to maximize the success of substitution therapy and even recovery.
As with other chronic physical or mental health conditions, some patients will drop out of treatment. They often wish to be free of the constrictions of attending the clinic and in the case of heroin dependence underestimate the difficulties that will present in remaining drug free. Leaving treatment frequently results in relapse, and the loss of tolerance can lead to accidental overdose. This can result in a pattern of cycling in and out of treatment. 35
Patient attitudes toward OST, and, in particular, concerns about the long-term taking of a medication, may impede treatment entry and adherence, affecting good outcomes. Unfounded concerns about the physical effects of methadone such as dental and muscle problems, as well as fears about the difficulty of withdrawing from methadone have often been reported.36–38
Current Methods of Treatment
There are 2 methods of using drug treatments to treat heroin addiction. Detoxification concentrates on stopping opioid use, and substitution aims to maintain the user on a therapeutic drug.
Detoxification
The aim of detoxification is to take the patient off heroin completely. The most common method of detoxification is the replacement of heroin with methadone and then gradual tapering of the methadone dose over about 3 to 4 weeks. This is usually done under supervision in hospital and followed up using relapse prevention strategies in the community. However, incompletion and relapse were shown to be common on all methods used in withdrawal. 39 Given the chronic relapsing nature of opioid addiction, 40 the lasting effects of detoxification are limited to those with less severe problems of opioid addiction. Those with a longer history and frequent daily usage may be able to detox initially but are highly likely to relapse and then reenter treatment eventually developing a pattern of cycling in and out of treatment. Inpatient treatment is expensive and therefore not cost-effective for those with severe dependence unless they are well-motivated and have stable life circumstances.
Substitution
For a substitution treatment to be successful, it needs not only to suppress withdrawal but also to have an equivalent strength to street heroin. There are currently 2 major substitution therapies, methadone and buprenorphine, and a third, pharmaceutical heroin, which has been trialed and is available to treat specialized cases in some countries.
Methadone
Methadone maintenance or substitution is considered the gold standard pharmacological treatment and is consequently the most commonly used substitution treatment internationally. It is a full opioid agonist, meaning that it binds fully to the μ-opioid receptor and is therefore able to replace heroin and suppress withdrawal symptoms. It is slow to reach its peak plasma level (average = 3 hours) but long-acting with a plasma half-life of 22 to 25 hours which means that although it exerts pleasant and sedating effects, it does not induce an immediate high and it only needs to be administered once a day. It is usually administered as an oral mixture/liquid in the United Kingdom, the intake of which can be supervised easily and which is unsuitable for injecting. Take-home supplies can be supplied in some cases, but it is important to note that methadone can be toxic and life-threatening especially if consumed by children and it also has some abuse potential. Treatment should be started slowly and gradually increased so that it may take some weeks to achieve the necessary dose. Once stabilized on methadone, the individual is free of withdrawal effects and therefore the necessity for drug-seeking behavior with all the consequent associated risks. However, methadone induces its own metabolism and so the dosage may need to be increased during maintenance treatment. An adequate dose is crucial to prevent heroin being used on top. There is a large body of research evidence to support the clinical use of methadone substitution. 41 It has been shown to be especially effective for severe dependence. 42 A recent Cochrane review showed that at low or flexible doses, methadone suppressed illicit drug use and was able to retain more patients in treatment than buprenorphine. 43 At fixed medium and high doses, both methadone and buprenorphine seemed to be equally effective but the authors caution that flexible doses are most often used in clinical practice which indicates the superiority of methadone treatment. It is important to note that inadequate doses are likely to lead to poor compliance and the use of other sedative drugs.
All pharmacological treatments have unwanted effects, and with methadone, the most common effect is respiratory depression after overdose. 44 It is also associated with adverse cardiac effects such as ventricular arrhythmia 45 and QTc prolongation 46 and so caution should be exercised in patients with a family history of cardiac conditions or congestive heart failure. Electrocardiographic monitoring is recommended prior to starting treatment, although the efficacy of this approach has not been thoroughly evaluated. 47 In common with all opioid drugs, methadone has some abuse potential, especially if heroin cannot be obtained. However, this can be minimized by supervised consumption in the clinic or pharmacy to avoid diversion.
Buprenorphine
Buprenorphine is a partial μ-opioid agonist, meaning that at high doses, it only partially activates the μ-opioid receptor and consequently produces less euphoric and sedating effects than full agonists such as heroin and methadone. However, it still alleviates heroin withdrawal effects. It has a plasma half-life of 24 to 36 hours, and so, although it is usually administered once a day, at higher doses, it can be administered every other day and can block the effects of heroin. It is usually administered as a tablet to be taken sublingually which makes supervised dosing more lengthy and difficult.
The advantages of buprenorphine are that it is less toxic and less likely to lead to respiratory depression and therefore safer in overdose than methadone meaning that prescriptions increased rapidly after its introduction in the United Kingdom, 48 but methadone remains the standard treatment to date. In many European countries, buprenorphine is the preferred treatment. In France, it is prescribed by general practitioners and dispensed by local pharmacies and this has led to a reduction in deaths from heroin overdose. 49 The 2 formulations of sublingual tablets containing buprenorphine alone and combined with naloxone are also commonly prescribed as office-based treatment in the United States where a mucoadhesive combination film formulation was also approved in 2010. However, buprenorphine has not been shown to be more effective than methadone and retains fewer patients in treatment than methadone when flexible doses are used. Although this can be overcome using fixed doses above 7 mg/d, buprenorphine is usually administered in flexible doses in clinical practice. 43
A significant drawback of buprenorphine is its high abuse potential 50 leading to illegal trade or diversion. In an attempt to control for this, a combination tablet was developed containing buprenorphine and naloxone, an opioid antagonist which prevents the rewarding effects of the drug if large doses are consumed. However, this action seems to be a reduction rather than a full suppression as all 3 sublingual preparations are misused. Abuse was found to be most common with the single tablet and least with the combination film in this US survey, 50 and prescriptions for the film have increased substantially since its introduction. The tablets can also be converted to a liquid which can be injected. Lavonas et al 50 stated that the number of patients who reported doing this in the 30 days before entering a treatment program amounted to 25.4% of all the reports of buprenorphine abuse. However, in a concurrent survey in Australia, 51 the injection level of all 3 formulations of buprenorphine by patients currently not in treatment was similar when availability was controlled. A recent study which surveyed all Finnish patients in OST 52 obtained a response rate of 60%, 36% of whom reported injecting drugs in the prior 6 months. In both those who injected their own medication (16%) and those who injected illicit OST (33%), this was associated with treatment with the combination tablet at a dose below 9 mg/d, and the latter group also used other illicitly obtained psychotropic drugs. Interesting new developments which have been produced to counter buprenorphine misuse are a sustained release preparation 53 and a subdermal implant with a duration of action of 6 months which has been approved very recently by the US Food and Drug Administration. 54 Both have shown early promising results but require more evaluation. A very recent development is a buprenorphine oral lyophilisate wafer which has been shown to be as effective as the sublingual tablet but which dissolves much more rapidly. 55
It can be concluded that buprenorphine may not be the preferred treatment for many patients, especially those with complex needs. However, it is a valuable option for patients who have a relatively stable life but whose drug use has temporarily got out of control. For them, being able to receive treatment with a less sedating drug which can be prescribed by their family doctor and does not have to be taken every day may enable them to regain control over their drug abuse more quickly.
Medication dose
One of the main aims of maintenance treatment is to keep the blood concentrations of the medication within a narrow range so that the patient experiences minimal intoxication or minimal withdrawal symptoms. 56 Arriving at an optimal dose for each patient will depend on a range of factors including the patient’s severity of addiction, their level of tolerance, the potency of the opioid used, and the method of administration. Research studies and meta-analyses have found that average doses of methadone between 60 and 120 mg daily and average doses of buprenorphine between 12 and 16 mg daily lead to better patient outcomes in terms of reducing their illicit drug use and retaining them in treatment when compared with lower doses.57,58 However, dosing decisions in practice are generally arrived at through discussions between the patient and their doctor, and some patients may opt for being maintained at lower doses, perhaps feeling confident in their ability to change their behavior or that they are more psychologically stable. And while there is little evidence to support routine maintenance dosing at levels of 100 mg per day in the case of methadone, some patients might require these higher doses to prevent lapses into illicit drug use. Thus, the medication dose regimen is best individualized, with the patient and their doctor keeping the medication under constant review, and the doctor explaining why some adjustments may be needed to maintain optimal dosing. 56
Heroin-assisted treatment
Despite the efficacy of opiate agonist therapies, there remain a small number of patients who are resistant to these treatments and fail to improve. 59 Individual characteristics are important, and a minority of users are intolerant or have been shown to metabolize methadone more rapidly so that once-daily administration is inadequate to suppress withdrawal symptoms. 60 Therefore, in recent years, there has been a focus on the prescription of injectable pharmaceutical heroin to these patients in specialized supervised clinics. Often methadone is provided to cover any withdrawal symptoms overnight, which is why it is usually referred to as heroin-assisted treatment (HAT).
Heroin-assisted treatment is not a first-line treatment, but several randomized trials have now been conducted and published in various European countries and Canada on pharmaceutical heroin as a treatment for heroin-dependent users (primarily injectors) who are not responsive to standard maintenance treatment and continue to use heroin in or out of treatment. Switzerland was the first country to introduce a heroin-assisted substitution program in the 1990s, and the results were positive, showing a reduction in illicit drug use and fewer offenses committed after 6 months’ heroin treatment compared with other maintenance treatment. 61 A further evaluation of 1969 patients found that retention in treatment improved with 70% staying in the program for at least a year with improved health and a reduction in criminal behavior. 62 Researchers in the Netherlands conducted 2 multisite randomized controlled trials (RCTs) on inpatients who continued to use heroin while in methadone maintenance treatment.63,64 A novel aspect of this work was that participants were divided into those who injected and those who inhaled heroin as inhalation is a common route of heroin administration in the Netherlands. They were given heroin via their preferred route supplemented with methadone for a year. The results confirmed that prescribed heroin was more effective than methadone maintenance alone. However, a Cochrane review 65 concluded that there was insufficient evidence to recommend treatment with pharmaceutical heroin at that time as the trials differed in too many aspects. However, subsequent studies in Spain, Germany, and Canada have not only confirmed the clinical effects to be superior to oral methadone treatment but also found a reduction in drug-related problems, HIV risk behavior, and illicit heroin use.66–68 These studies compared injectable heroin with oral methadone treatment and estimated street heroin use by self-report, but a later study compared injectable heroin with both injectable methadone and optimized oral methadone and used urinalysis to determine street heroin use. 69 The results confirmed the efficacy of injectable heroin by achieving 50% of negative samples for street heroin between 14 and 26 weeks of treatment. In addition, a follow-up study has shown that these improvements can be maintained for up to 4 years in those who stay in treatment. 70
The exact nature of the trials differs between countries, but taken together, these results confirm the efficacy of HAT for patients with severe heroin dependence who have proved nonresponsive to methadone treatment. Indeed, the assessment of a later Cochrane review 71 was that HAT is a valuable and effective treatment when administered in specialized clinics. However, it should only be considered within the scope of a well-established and functioning treatment system.
Slow-release oral morphine
Slow-release oral morphine was first introduced to treat chronic pain as it provides steady blood levels of morphine over 24 hours, but it has also been used as a substitution treatment for heroin dependence. 72 It was first registered for use as an OST in general practice in Austria in 1998 where dosing is generally supervised 73 and is currently also available in Bulgaria, Austria, Slovenia, Slovakia, and Australia. 74 In some cases, it can provide a valuable alternative treatment for patients who show poor tolerance of standard maintenance medications.75,76 However, few controlled trials have been conducted, and Ferri et al 77 only found 3 RCTs which could be included in their recent review. They concluded that there was insufficient evidence from these to recommend the use of SROM as a maintenance treatment at present. A major drawback is diversion and misuse, and supervised consumption is therefore recommended.
Tincture of opium
In certain regions of the world, eg, Middle East and Asia, conventional opiate agonist treatments are expensive, and OT is a cheaper alternative. In Iran, OT is commonly used as a medicine to treat various health complaints as well as pain and so is viewed positively by the public. 1 Consequently, there has been a growing interest in also employing it as a treatment for heroin addiction. 1 A nationwide program to treat opioid addiction has been implemented in Iran where OT has been used since 2011. 78 Opioid detoxification is the preferred method of treatment, and so, the 3 RCTs which have been completed have used detoxification and there is currently no RCT of maintenance treatment with OT. Nevertheless, OT has become the second most common treatment for opioid dependence after methadone. 1 In early studies, low doses were often used, but a recent study using higher doses has shown OT to be as effective as methadone in opioid withdrawal. 79 A prospective case series examined treatment with OT in 226 male opioid-addicted clients. 78 They were first stabilized on OT, and if they consented to withdraw, their dose was reduced by 10% every 21 days. After 1 year, 16.4% had dropped out, 9.8% had withdrawn successfully, but most (74%) had continued on OT maintenance treatment.
Opioid Antagonist Therapy
Naltrexone
Naltrexone is an opioid antagonist which, when taken regularly, blocks both the analgesic and rewarding effects of opioids completely. In the United Kingdom, naltrexone is only licensed for use orally, but depot and implantable slow-release formulations are used in other countries. 80 Naltrexone can be used to maintain abstinence in patients who have already detoxified. However, typically most dependent opiate users find it difficult to be compliant with naltrexone treatment and stop using it to return to their drug use. Less than a third of patients were retained in treatment in a meta-analysis of 13 relevant studies identified for a Cochrane review. The review concluded there was no good evidence currently available that naltrexone improved treatment retention or abstinence rates. 81 Naltrexone may be helpful for those patients who have a high motivation to abstain, particularly those like ex-prisoners whose drug use is closely monitored and face sanctions if they resume their drug use. A randomized, multisite effectiveness trial of extended-release injection naltrexone versus community-based treatment as usual found that naltrexone provided a modest protective effect against relapse among patients with some criminal justice involvement. 82
Naloxone
Naloxone is an opioid antagonist which reverses the effects of opioid overdoses. As stated previously, it is already added to one formulation of buprenorphine to block the rewarding effects of higher doses and the consequent risk of overdose. However, if administered quickly enough, it can reverse the effects of methadone and other opioid overdoses. In an attempt to minimize risk of accidental overdose, a kit containing naloxone has been given to users or their families. This take-home provision of naloxone has now been implemented in more than 15 countries, and a recent review found it to reduce overdose deaths with a low rate of adverse effects. 83 Naloxone is usually administered by injection which requires some training, but recently an intranasal version has been developed.
Treatment as an Alternative to Incarceration
People with heroin dependence often resort to acquisitive crime such as shoplifting and burglary to finance their drug use.84,85 Opioid substitution treatment programs have been found to have an ameliorating effect on such criminal behavior. In England, the National Treatment Outcome Research Study (NTORS) that followed patients in drug treatment more than 5 years found that after the first year in treatment, the number of self-reported crimes was reduced to one third of intake levels, and criminal involvement was reduced by about half. 86 Similar findings emerged from a meta-analysis of 28 relevant, mainly US studies with offending rates reduced by a third across the studies. 87 With such strong evidence for the benefits of treatment in reducing criminal behavior and its economic consequences, a range of initiatives have been introduced into the criminal justice system with the intention of making treatment an effective alternative to incarceration for heroin-dependent offenders. In the United Kingdom, Drug Treatment and Testing Orders (DTTOs) were introduced in 1998 with DTTOs offering rapid access to specific treatment programs. An evaluation showed that this approach was effective. It showed a marked reduction in not only drug use, particularly of crack cocaine, but also in unsafe injecting behavior and offending behavior. In addition, those who remained in the program showed increased progression on all these measures. 88 Even the individuals who left the program because their court orders were revoked still showed decreased drug use and acquisitive crime at the 1-year follow-up compared with before sentencing. The Drug Interventions Programme (DIP) was introduced in 2003 to build on this approach and in particular to bring together multiple agencies to tackle the problems of dependent drug use and associated crime. This was not restricted to the community but was also used in prisons. In 2005, a new Community Order or a Suspended Sentence Order which included a Drug Rehabilitation Requirement (DRR) was introduced. It comprises structured treatment and regular drug testing and was designed to be a more flexible replacement to the previous orders so that drug users with a minor criminal history could access short-term drug treatment before their drug-taking and associated offending potentially escalated. Those with more problematic drug use and serious offending had to conform to more conditions and requirements. 89 The treatment rather than punishment approach has resulted in a decrease in drug-related offenses. 90 But if incarcerated, heroin-dependent offenders have found OST programs to be beneficial. Where they have been available in prisons, they have reduced drug use, injecting and sharing injecting equipment, and they have consistently been found to promote treatment entry and retention after release from prison. 91 In the United States, where access to OST can be difficult for offenders who are dependent on heroin, 80 naltrexone has been used not only to help those offenders maintain abstinence after detoxification but also to reduce criminal acts. 82 Thus, both opioid substitution and antagonist therapies can provide economic and social benefits for society by reducing crime.
Access to Treatment
Despite the proven advantages of OST outlined above, there are still a number of users who have difficulty accessing this treatment due to a number of factors such as a limited supply of treatment facilities creating long waiting lists, high thresholds for starting treatment such as length of heroin abuse, intolerance of any other drug abuse, required attempts at detoxification, an inability to pay for treatment, and complex insurance schemes. Treatment is free in the United Kingdom, and the harm reduction approach 92 adopted from the late 1980s greatly improved access to treatment. It aimed to reduce the health, social, and economic harms associated with drug use to both individuals and society. The focus was principally on the reduction in both the spread of BBVs such as HIV and Hep-B and Hep-C and of drug-related deaths. Needle exchange facilities were increased across the country and expanded to include readily available local pharmacy schemes to reduce the sharing of injecting equipment and the consequent risks. Local drug clinics were increased to provide OST and offer support and encouragement to enable users to adopt safer injecting practices or even to stop injecting. They also provided access to testing and treatment for BBVs. The incidence of BBVs in injecting drug users in Glasgow was found to be high but decreased in the period after the introduction of needle exchange programs in the city. 93 There is still a need for a more person-centered approach so that individuals feel involved in both the aim and process of treatment. The situation in other countries can be very different. For example, as outlined earlier, the United States is in the middle of a prescription opioid overdose epidemic, but in a recent study of treatment use, most of the participants had not received any treatment. 94 Volkow has identified a need to decrease inappropriate access to prescription opioids, to educate people about overdose prevention, and to improve access to treatment within a complex health care system. 80
Is Medication Enough?
Guidelines on maintenance therapy are very clear that regular counseling, psychosocial therapy, and social interventions for patients are essential elements of an effective treatment program.25,95 But a recent meta-analysis of relevant research studies found that the value of adding such structured interventions to standard maintenance therapy is not apparent. 96 The review found 35 trials for its review, predominantly from the United States. In these trials, patients were randomly allocated to substitute prescribing with and without extra therapy, the therapies being largely those that encourage behavior change such as cognitive behavioral therapy and contingency management. Overall, the review found that adding structured psychosocial interventions to standard treatment did not lead to additional benefits in terms of abstinence from drug use or retention in the treatment program. 96 However, the reviewers comment that the therapy was generally described as counseling, and it was unclear whether this was the same over all trials and so there was a need for more trials in which structured approaches could be evaluated. Since this review, other RCTs have been conducted97–99 which have not changed this conclusion. A recent review of 27 studies 100 reported that including psychosocial interventions was generally beneficial, but this review has some limitations which have been highlighted in a commentary by Schwartz. 101 There may well be some people who would benefit from extra therapy and it is often the psychologically unstable that are excluded from research trials. 102 Family and couples therapy have also been found to be beneficial for some patients. But in light of the compelling evidence for the effectiveness of maintenance therapy, the psychologically and socially disadvantaged people coming into treatment are likely to benefit from an optimized basic maintenance service, long term with adequate medication doses, and where a therapeutic alliance can be developed. Through such a therapeutic relationship, UK guidelines see the possibility of developing the patient’s “social capital,” by helping them to find employment and housing, as important for achieving good outcomes. 95
Conclusions
Effective treatment of opioid addiction is important not only for addicted individuals but also for the society in which they live. Drug seeking for an illicit drug results in antisocial behavior, and injecting drug use increases the global burden of infectious diseases. Access to treatment and the provision of effective treatment strategies is essential, and the earlier the intervention in the addiction process, the more effective it can be. Unfortunately, treatment in the early stages is often difficult to obtain as resources are aimed at more severe cases. However, as with physical illnesses, prevention strategies are crucial in reducing the incidence of heroin addiction. Reducing inappropriate access to prescription opioids is imperative for the health and well-being of young people. There has been a growth in promising new formulations of both buprenorphine and naloxone which might encourage more people into treatment as well as improving retention. New drug treatments with novel actions would not only increase the number of effective pharmacological options available but also could radicalize the field. However, pharmacotherapy alone can never be the complete answer. There is a need for other adjunct therapies. In particular, ensuring that staff are properly trained in the correct administration of current treatments and that these are implemented according to clinical practice guidelines is a priority. Currently, there is an emphasis on individualized treatments. This highlights a need for more research to explore individual treatment strategies so that it becomes easier to determine which individuals respond to which treatments and the most effective approach for each person.
Footnotes
Funding:
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests:
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Author Contributions
AJB wrote the first draft of the manuscript and JW reviewed and added to the manuscript.