6.1. Diagnosis and assessment of opioid dependence
Assessment includes establishing a relationship between the patient and the treatment staff, based on the free exchange of information. Initially, patients may wish to share only information required to start the treatment process. However, as trust develops between the patient and staff, more information may be shared, and treatment staff will be better able to tailor responses to the individual patient.
Determining the physical, psychological and social health-care needs of the patient is an important part of assessment. Assessment should also include factors that may influence drug use, such as past treatment experiences, living conditions, legal issues, occupational situation, and social and cultural factors.
The clinician should take a substance use history to assess:
which psychoactive substances have been used in the past, and which are currently being used
the pattern of use for each substance, including information on the quantity and frequency of use
drug induced health and social problems
previous responses to treatment and other interventions
whether the criteria for harmful use or
dependence are met
how the patient views their substance use
the factors that have contributed, and continue to contribute, to the patient's use of psychoactive substances
the short, medium and long-term goals of the patient, and what has brought the patient to the treatment facility on this occasion.
Clinicians should differentiate between substance dependence and nondependent harmful substance use, because these categories have significant implications for the appropriate treatment strategy.
On examination of the patient, the degree of intoxication or withdrawal should be interpreted in combination with the stated time of last use.1 If there is a history of injection, the injection sites should be visible and consistent with the stated history (usually both recent and old injection marks will be visible).
6.1.1. URINE DRUG SCREENING
Where available and affordable, urine (or other biological sample) drug screening should be routinely conducted at the start of treatment, and should indicate recent opioid use if the person is to be eligible for treatment. When the cost of urine testing is an issue, urine testing should be used at least when a recent history of opioid use cannot be verified by other means (e.g. evidence of opioid withdrawal or intoxication). A negative urine drug screen combined with absence of withdrawal symptoms excludes current neuroadaptation to opioids; however, it does not exclude dependence on opioids in the past 12 months. Thus, dependence should not be diagnosed on urine drug screening alone, but a negative urine drug screen in the absence withdrawal symptoms should prompt caution in the use of opioids and other sedative medication.
Urine testing is also useful, in combination with the history, to identify other substances that have recently been consumed.
Entry into appropriate treatment programmes should not be delayed by waiting for the result of urine drug screening, unless the other findings in the assessment raise concern about the diagnosis.
Naloxone challenge testing should not be used routinely to confirm the presence of current neuroadaptation, because it can induce significant withdrawal effects. The same information can normally be gathered from the patient's history, examination of the person and interpretation of urine drug test results. Provided the patient is informed of the risk of adverse effects, naloxone challenge testing can be used as an alternative to urine drug screening, to confirm the absence of current neuroadaptation (e.g. when considering giving an opioid antagonist to start maintenance treatment). In this situation, an accidental positive reaction is likely to be significantly milder than the reaction that occurs when the test is used to confirm current neuroadaptation.
6.1.2. TESTING FOR INFECTIOUS DISEASES
Voluntary testing for HIV, hepatitis C and common infectious diseases should be offered as part of an individual assessment, accompanied by counselling before and after the test. In areas of high prevalence of HIV, patients should be strongly encouraged to undergo HIV testing. Serology testing and vaccination for hepatitis B is also recommended. As discussed above (Section 5.6), in some circumstances it may be more effective to vaccinate before testing for hepatitis B, and to use accelerated vaccination schedules.
TB and sexually transmitted diseases should also be considered during assessment.
Pregnancy testing should be offered to all women, particularly those contemplating opioid withdrawal, because it may influence the choice of treatment.
6.1.3. IDENTIFYING THE PATIENT
In some circumstances, it may be necessary to confirm the identity of the patient, particularly if treatment with controlled medicines is anticipated. Where patients do not have formal identification, it is advisable to take a photograph and include it in the record signed by the treating clinician, so that the patient can be identified in that clinic. The identity of the patient should be kept private and should not be released without patient consent. When collecting and recording information, the capacity of the service to keep that information private should be discussed with the patient.
6.1.4. COMPLETING THE ASSESSMENT
Sometimes it is not possible to complete the initial assessment in one day; for example, the patient may be intoxicated, in withdrawal or in crisis. In such cases, it may be necessary to make a plan based on the initial assessment, which will then evolve in response to a more comprehensive assessment and the person's response to initial treatment.
6.1.4. DIAGNOSTIC CRITERIA
A diagnosis of opioid dependence has important prognostic and treatment implications. Once opioid dependent, the patient has a significant risk of suffering serious health consequences or of dying from behaviours related to their dependence on opioids.
The International Classification of Diseases, 10th edition (ICD-10) defines opioid dependence as “a cluster of physiological, behavioural, and cognitive phenomena in which the use of opioids takes on a much higher priority for a given individual than other behaviours that once had greater value”. A central characteristic of the dependence syndrome is the desire (often strong, sometimes overpowering) to take opioids, which may or may not have been medically prescribed. Once a person is opioid dependent, returning to substance use after a period of abstinence leads to a more rapid reappearance of other features of the syndrome than occurs with nondependent individuals [104].
The ICD-10 diagnostic criteria for opioid dependence are:
Narrowing of the personal repertoire of patterns of opioid use has also been described as a characteristic feature of dependence.
Opioid dependence does not develop without a period of regular use, although regular use alone is not sufficient to induce dependence.
A definite diagnosis of dependence should usually be made only if three or more of the diagnostic criteria have been experienced or exhibited at some time during the previous year.
6.1.5. MAKING THE DIAGNOSIS
Opioid dependence is essentially diagnosed on the basis of the history provided by the patient. Patients can sometimes be motivated to either overstate or understate their substance use; therefore, it is usually necessary to corroborate the patient history with the results of the physical examination and investigations, and sometime with the history reported by significant others, to be confident of the diagnosis. While any health-care worker can make a provisional diagnosis of opioid dependence provided that they have had appropriate training, the diagnosis should be confirmed by medical staff before opioid agonist treatment is provided.
Injection sites
Examination of injection sites can provide useful information on the timing and duration of injecting drug use. Recent injection marks are small and red, and are sometimes inflamed or surrounded by slight bruising. Old injection sites are generally not inflamed, but sometimes show pigmentation changes (either lighter or darker), and the skin may have atrophied, giving a sunken impression. A combination of recent and old injection sites would normally be seen in an opioid-dependent patient with current neuroadaptation. Many sites can be used for injection, although the cubital fossa (the area on the inside of the elbow joint) and the groin are the most common.
Interpretation of urine drug screens
Urine drug screens provide evidence of recent drug use; this information can contribute to the assessment. The precise interpretation of a test result will depend on the specific commercial test or reagents used. Generally speaking, a positive test for the opioid class of drugs indicates the use of illicit or prescription opioids in the last few days. However, positive reactions can also be caused by large amounts of poppy seeds. Many commercial opioid drug screens do not recognise buprenorphine, but this situation is changing; therefore, it is best to check with the laboratory. Some tests, such as gas-chromatography and mass spectrometry (GCMS), can determine the specific opioid. Heroin is broken down to 6-monoacetylmorphine (6-MAM), then to morphine and then to codeine; thus, the presence of 6-MAM is usually specific for heroin use in the last 24 hours. Morphine, with or without small amounts of codeine, can indicate either heroin or morphine use in the last few days. Small amounts of morphine in the presence of large amounts of codeine can suggest intake of high doses of codeine, since codeine can also be metabolized to morphine although most is metabolized via a different pathway.
Degree of opioid intoxication and withdrawal
Features of opioid intoxication include drooping eyelids and constricted pupils, sedation, reduced respiratory rate, head nodding, and itching and scratching (due to histamine release).
Features of opioid withdrawal include yawning, anxiety, muscle aches, abdominal cramps, headache, dilated pupils, difficulty sleeping, vomiting, diarrhoea, piloerection (gooseflesh), agitation, myoclonic jerks, restlessness, delirium, seizures and elevated respiratory rate, blood pressure and pulse. Annex 10 provides useful scales for assessing the severity of opioid withdrawal.
6.2. Choice of treatment approach
Should agonist maintenance therapy (i.e. methadone or buprenorphine maintenance) be used in preference to withdrawal and oral antagonist therapy (naltrexone) or withdrawal alone?
Efficacy
Methadone versus withdrawal
The recently updated Cochrane review [105] of methadone maintenance therapy versus no opioid replacement therapy identified three randomized controlled trials (RCTs) that compared methadone with opioid withdrawal followed by placebo [106, 107, 108]. These studies show that, compared to opioid withdrawal or placebo, methadone maintenance treatment dramatically reduces levels of illicit opioid use (relative risk [RR] 0.32; 95% confidence interval [CI] 0.23 to 0.44, high quality evidence) and increases retention in treatment (RR 3.05; 95%CI 1.75 to 5.35). Observational studies demonstrate that the mortality rate in methadone treatment is approximately one third the rate out of treatment (RR 0.37; 95%CI 0.29 to 0.48, low-quality evidence).
Methadone appears to reduce the risk of HIV injection by approximately 50% (RR 0.45, 95%CI 0.35 to 0.59, moderate-quality evidence) and there is a similar reduction in seroconversion rates (RR 0.36, 95%CI 0.19 to 0.66, low-quality evidence) compared to withdrawal or no treatment. No studies were found that compare methadone with naltrexone treatment.
Buprenorphine versus withdrawal or placebo
The Cochrane review of buprenorphine identified one study comparing buprenorphine with placebo [109], and one study comparing 1 mg per day with higher doses [110]. Compared to placebo (including 1 mg dose as placebo), buprenorphine leads to a dose-responsive reduction in heroin use and improved retention in treatment. A dose of 16 mg buprenorphine results in higher rates of retention in treatment (RR 1.52, 95%CI 1.23 to 1.88) and less morphine-positive urines (standardized mean difference (SMD) −0.65, 95%CI −0.86 to −0.44) than placebo.
Naltrexone versus placebo
The Cochrane review of naltrexone for prevention of relapse in opioid dependence identified 6 studies, with a total of 249 patients [170]. In detoxified patients, naltrexone was more effective than placebo in reducing heroin use (RR 0.72, 95%CI 0.58 to 0.90, low-quality evidence), but did not affect retention in treatment (RR 1.08, 95%CI 0.74 to 1.57) or relapse at follow-up post treatment (RR 0.94, 95%CI 0.67 to 1.34).
Safety
Methadone maintenance is associated with an increase in mortality during the first two weeks of treatment compared to pretreatment levels, due to respiratory depression [111]. After that time, there is a reduction in mortality that remains until treatment stops. Most patients will resume opioid use at some stage, and the reduction in tolerance associated with the completion of opioid withdrawal can increase the risk of opioid overdose.
Pharmacology studies suggest that buprenorphine probably has less risk of overdose than methadone, but fatal overdoses of buprenorphine combined with other sedatives can still occur.
Treatment with naltrexone may increase the risk of sedative overdose in the period following the cessation of naltrexone. Some accelerated opioid withdrawal techniques that are used to start patients on naltrexone – in particular the use of antagonists in combination with heavy sedation – also appear to increase the risk of fatal complications.
A significant proportion of patients in opioid agonist therapy develop adverse effects (see Section 6.5). Methadone leads to a slight increase in the QT interval (i.e. the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle), possibly resulting in a slightly increased chance of life-threatening cardiac arrhythmias, although it is difficult to make a precise estimate of any increased risk. Buprenorphine and naltrexone do not prolong the QT interval.
Contraindications to the use of opioid agonist maintenance treatment, and precautions for use of the treatment, include decompensated liver disease (such as with jaundice and ascites) – because in this context opioids may precipitate hepatic encephalopathy – and acute asthma and other causes of respiratory insufficiency.
Precautions for both opioid agonist treatment and opioid detoxification include high-risk polydrug use, mental illness, low levels of neuroadaptation to opioids (e.g. in recent incarceration, because many people who are incarcerated do not use opioids with the frequency required to maintain their levels of tolerance to opioids) and significant concomitant medical problems.
Precautions to the use of opioid withdrawal over agonist maintenance therapy include pregnancy (because withdrawal can lead to miscarriage), and serious acute physical or psychiatric conditions (because withdrawal may worsen or complicate management of the underlying conditions).
Cost effectiveness
In a recent study of opioid substitution therapy in different countries [112], resource-use and cost data relating to methadone and buprenorphine maintenance treatment were collected in selected WHO member states (Indonesia, Iran, Lithuania and Poland).
The total monthly cost of providing long-term methadone and buprenorphine maintenance treatment (including an initial induction phase) ranged from as little as US$26–36 in Indonesia and the Islamic Republic of Iran (approximately US$1/day) to US$296 in Poland (approximately US$10/day). This provides an indicative range within which to locate the expected investment needed to provide methadone maintenance treatment to a service user in a low or middle-income country. In high-income countries, costs for methadone and buprenorphine maintenance treatment are generally estimated to be US$5000 per year, or US$15 per day [113].
Estimation of the cost of providing medication is not an adequate basis for budgetary planning, because it may represent only a fraction of total service costs (e.g. <20% in the Islamic Republic of Iran). Studies in Australia, Canada, the United States and United Kingdom have estimated the impact of treatment on total health-care costs, social security costs, lost productivity and crime. Thus, these studies estimate the economic “return on investment” in opioid-dependence treatment [62, 114]. They show that treatment of opioid dependence pays for itself, because savings in social costs are greater than the expenditure in treatment. It is difficult to extrapolate the results of these studies to lower income countries.
Estimates of cost effectiveness in high income countries countries have found that both methadone and buprenorphine maintenance are cost effective, being well below accepted thresholds for cost–benefit analysis of treatment [115, 116].
The cost of a “one off” episode of opioid withdrawal varies significantly between settings; it depends on the method of withdrawal, the length of treatment, the medication used and staff resources.
Because of differences between maintenance and withdrawal, it is difficult to estimate the long-term cost implications of choosing between:
opioid agonist maintenance treatment, which is low intensity and long term, and has a low relapse rate
opioid withdrawal, which is high intensity and short term, and has a relatively high relapse rate.
Limitations of the data
No studies were found that directly compared the three different treatment approaches using a randomized design. It may be difficult to investigate this question using RCTs because patients may be reluctant to relinquish their right to choose a treatment modality. The clinical trials that were found compared the decision to attempt opioid withdrawal at one point in time versus methadone maintenance. In practice, an attempted opioid withdrawal that fails is usually followed by repeated attempts until the patient either succeeds, or stops trying to withdraw from opioids. This review found no RCTs comparing repeated attempts at opioid withdrawal with opioid agonist maintenance treatment. Also lacking were studies comparing methadone and buprenorphine maintenance treatment with opioid withdrawal and relapse prevention using naltrexone.
Treatment considerations
In practice, there is often a blurring between opioid agonist maintenance and opioid withdrawal using tapered doses of methadone or buprenorphine. Patients often start with tapering doses of agonist while trying to cease their heroin use, and increase their agonist dose temporarily whenever they relapse.
Benefits of opioid agonist maintenance treatment
The most significant benefit of opioid agonist maintenance treatment is that it has a much lower mortality rate than treatments based on opioid abstinence (the evidence for this effect is stronger for methadone than for buprenorphine). Opioid agonist maintenance treatment results in less heroin use for most patients, and better retention in drug treatment in general.
Undesirable effects and consequences
Many patients find the burden of supervised dosing every day onerous, and some patients experience adverse effects (including opioid withdrawal symptoms between doses) with methadone. Patients on methadone and buprenorphine can still experience opioid effects if they use illicit opioids; although the effects are diminished, they are not blocked completely as they would be with naltrexone. This results in good rates of retention in opioid agonist maintenance treatment, even for those people with ongoing heroin use, but it may delay the progression to long-term abstinence. Travel can be difficult for patients on methadone and buprenorphine if they are required to have their doses supervised. Unsupervised administration results in increased rates of misuse of opioid agonist medication, and diversion to illicit drug markets; also, take-home doses are occasionally consumed by children and opioid-naive adults, with fatal consequences. Cessation of methadone and buprenorphine can result in a withdrawal syndrome that is more prolonged and sometimes more severe than withdrawal from heroin. Also, many patients resume heroin use after cessation of methadone, even after long-term treatment.
Conclusion
For most patients, opioid agonist maintenance treatment will result in better outcomes than attempts at withdrawal, with or without the use of naltrexone after withdrawal. In particular, patients on opioid agonist maintenance treatment are more likely than those not undergoing such treatment to stay alive, not use heroin and be in contact with the treatment system.
Recommendation
For the pharmacological treatment of opioid dependence, clinicians should offer opioid withdrawal, opioid agonist maintenance and opioid antagonist (naltrexone) treatment, but most patients should be advised to use opioid agonist maintenance treatment.
Recommendation
For opioid-dependent patients not commencing opioid agonist maintenance treatment, consider antagonist pharmacotherapy using naltrexone following the completion of opioid withdrawal.
6.3. Opioid agonist maintenance treatment
6.3.1. INDICATIONS FOR OPIOID AGONIST MAINTENANCE TREATMENT
What are the indications for opioid agonist maintenance treatment?
Agonist maintenance treatment is indicated for all patients who are opioid dependent and are able to give informed consent, and for whom there are no specific contraindications. Given the long-term nature of the treatment and the potential for toxicity in the first two weeks, a high degree of certainty of the diagnosis is required before recommending opioid agonist maintenance treatment. If the diagnosis cannot be confirmed by observation of opioid withdrawal, injection sites or confirmation of previous treatment, then treatment should be started carefully and with close monitoring; in this situation, lack of intoxication from opioid agonists will provide direct evidence of opioid tolerance. Staff should be cautious when excluding patients seeking opioid agonist maintenance treatment, because such patients often have poor clinical outcomes if they do not receive treatment [117].
6.3.2. CHOICE OF AGONIST MAINTENANCE TREATMENT
In patients to be treated with agonist maintenance treatment, should preference be given to methadone or buprenorphine?
Efficacy
The Cochrane Collaboration conducted a systematic review and meta-analysis on this topic in 2004 [118] and updated it in 2008 (in press). Ten studies compared methadone and buprenorphine, either using flexible dosing, or doses greater than 6 mg buprenorphine or 50 mg methadone.
Flexible dose buprenorphine versus flexible dose methadone
When using flexible doses, buprenorphine was less likely than methadone to be effective in retaining patients in treatment (6 studies, 837 participants; RR = 0.82, 95%CI: 0.69 to 0.96), but there was no significant difference in heroin use based on results of morphine urinalysis (6 studies, 837 participants; SMD = −0.12, 95%CI: −0.26 to 0.02), or in terms of self-reported heroin use (2 studies, 326 participants; SMD = −0.10, 95%CI: −0.32 to 0.12).
Moderate dose buprenorphine (6–8 mg/day) versus moderate dose methadone (50–80 mg/day)
When using moderate doses, retention in treatment was better with methadone than with buprenorphine (RR = 0.79, 95%CI 0.64 to 0.99, moderate-quality evidence). Also, there was more heroin use with buprenorphine, as shown by morphine positive urines (3 studies, 314 participants: SMD = 0.27, 95%CI 0.05 to 0.50). There was no difference in self-reported heroin use (2 studies, 74 participants; SMD = −0.02, 95%CI −0.48 to 0.45).
Safety data
As a partial agonist, buprenorphine has a better pharmacological safety profile than methadone. Data on safety from randomized trials do not show significant differences between methadone and buprenorphine because of the small sample sizes. The strongest data for improved safety of buprenorphine comes from the widespread introduction of buprenorphine in France in 1995, which was followed by a 79% reduction in opioid overdose mortality [119]. From 1994 to 1998, there were an estimated 1.4 times more deaths related to buprenorphine than to methadone, although 14 times more patients received buprenorphine than methadone [120].
Although deaths have been reported where buprenorphine has been used in combination with other sedatives [121, 122], the rate of buprenorphine-related deaths is estimated at 0.2 per 1000 patient years [123], which is much less than the mortality of untreated heroin dependence [124].
In RCTs, safety data is rarely well collected; however, buprenorphine patients have been found to report more headaches, and methadone patients greater sedation [125]. There is a trend for better psychomotor performance with buprenorphine [126, 127]. When injected, buprenorphine damages veins, and complications of buprenorphine injection are common where buprenorphine is administered to injecting drug users [119, 128]. Methadone appears to prolong the QT interval, and cardiac arrhythmia adverse events have been reported. In clinical trials, the extent to which methadone prolongs the QT interval is minimal; however, there appears to be a small increase in the risk of life-threatening cardiac arrhythmias with methadone that is absent with buprenorphine [129, 130, 131, 132].
Buprenorphine tablets have a high potential for abuse. Wherever buprenorphine has been prescribed to injecting drug users, there has been an associated epidemic of buprenorphine injecting, with patients presenting for treatment using buprenorphine as their first and primary drug of abuse. While some methadone injection occurs, this is rare – particularly when take-home doses are given diluted to 200 ml per dose – and it can be managed by supervised dosing of methadone.
Supervising the dosing of buprenorphine does not completely remove the problem of abuse because it is difficult to adequately supervise the dosing of a sublingual medication that can take up to 15 minutes to dissolve. Injection of diverted buprenorphine can fuel ongoing dependence, transmit bloodborne viruses and result in fatal overdose when the drug is combined with other sedatives. It has also resulted in hepatitis, local and systemic infections, venous and arterial damage, and other injection-related problems.
Common buprenorphine-related adverse effects include headache, constipation, sleep disorders and anxiety. Buprenorphine does not appear to induce significant QT prolongation.
Overall, while buprenorphine itself is likely to be a safer medication, the difficulty of quantifying these benefits and comparing them with the risks of diversion and injection of buprenorphine mean that no conclusions on safety differences can be drawn.
Cost effectiveness
The cost of methadone is approximately US0.5–1.0 cents/mg, or US60 cents to US$1.20 per effective dose (see next section). The cost of delivery and associated treatments varies from US$5000 per annum in well-resourced countries to approximately US$500 per annum in less well-resourced countries.
Buprenorphine costs approximately US10 cents to US$1/mg, or US80 cents to US$8 per minimum recommended dose (see next section). Other costs of treatment are likely to be similar to those for methadone when buprenorphine is supervised.
Methadone is cheaper and more effective than buprenorphine at the doses studied; therefore, it is dominant in cost-effectiveness comparisons in this review.
Limitations of the data
As methadone and buprenorphine are both dose-dependent treatments, adequate comparison depends on doses. Also, because buprenorphine is a partial agonist, it is difficult to directly compare doses with methadone. Pharmacological evidence would suggest that 6–8 mg may not be the optimal buprenorphine dose. Higher doses of buprenorphine will be more effective because they act over a longer time and are more effective in blocking the effects of heroin use. Many studies have not used intention-to-treat analyses, and the patients who drop out of treatment are generally not followed up.
Treatment considerations
Methadone is available in several forms – injectable, oral solution and tablet. The oral solution form is recommended for the treatment of opioid dependence because its administration is more easily supervised; also, take-home medication is less likely to be injected when it is sufficiently diluted (e.g. to 200 mL) when administered.
Buprenorphine is a sublingual tablet most commonly available in sizes of 2 and 8 mg. Because it takes 5–15 minutes to completely dissolve, its ingestion is difficult to supervise. On the positive side, because of its long duration of action, buprenorphine can be administered every second or third day in about two thirds of patients, reducing the need for daily supervision. A formulation of buprenorphine combined with naloxone in a 4:1 ratio is also now available in Australia, Europe and the United States (see Annex 4 for further discussion).
When patients have a history of injecting buprenorphine (either illicitly obtained or prescribed), methadone maintenance should be used in preference to buprenorphine.
Other research and basic research findings
The half-life of methadone is highly variable, and a significant minority of patients will not tolerate 24-hourly methadone without withdrawal symptoms between doses [133]. For many of these patients, buprenorphine may be a better option.
Conclusion
In studies to date, methadone at standard doses has been more effective in retaining people in treatment and reducing heroin use than buprenorphine at standard doses; also, methadone is cheaper. This evidence comes from meta-analyses of well conducted clinical trials (moderate-quality evidence); however, use of higher doses of buprenorphine may produce different results. Although buprenorphine treatment might be expected to be safer than methadone treatment, this has not been confirmed by research. Currently, high-quality methadone provision should be considered the optimal treatment, with buprenorphine reserved for second-line therapy for patients in whom methadone is unwanted, inappropriate or ineffective. Patients who inject buprenorphine should be prescribed methadone in preference to buprenorphine. This conclusion places a high value on treatment outcomes over possible safety differences, because of the high mortality from untreated opioid dependence.
Recommendation
For opioid agonist maintenance treatment, most patients should be advised to use methadone in adequate doses in preference to buprenorphine.
Strength of recommendation – strong
Quality of evidence – high
Remarks – Although the general preference may be for methadone over buprenorphine, some patients may do better with buprenorphine. Reasons for use of buprenorphine may include previous response to buprenorphine or lack of response to methadone, short duration of action of methadone (i.e. withdrawal symptoms between doses), interaction between methadone and other medications taken, specific adverse effects of methadone, treatment availability and patient preference for subjective effects of buprenorphine compared to methadone. Reasons not to use buprenorphine include a history of buprenorphine injection, buprenorphine-specific adverse effects and failure of buprenorphine treatment in the past.
6.3.3. INITIAL DOSES OF OPIOID AGONIST MAINTENANCE TREATMENT
What initial doses of methadone or buprenorphine should be used?
Initial dose of methadone
The initial dose of methadone should be based on a careful assessment of the degree of neuroadaptation of the patient. The first two weeks of methadone treatment is a high-risk period for overdose, because it can be difficult to assess with certainty the level of neuroadaptation. For patients on prescribed opioids, the total daily dose should be converted to an equivalent methadone dose given once daily. For patients using street opioids (e.g. heroin), methadone doses of 20 mg a day will typically be adequate to relieve withdrawal symptoms and retain patients in treatment, while at the same time having a low risk of opioid overdose. Patients with low or uncertain degree of neuroadaptation should start on low doses of methadone and be closely observed. Some patients with high levels of neuroadaptation will experience some discomfort if ceasing heroin and commencing methadone at 20 mg daily. In this group, the use of higher doses (up to 30 mg) to retain patients in treatment and at greater comfort should be balanced against the risk of fatal overdose if the level of neuroadaptation is overestimated. A safer but more labour-intensive strategy is to provide an initial safe dose and review the patient several hours later to assess the response to that dose, adjust the next daily dose and, if necessary, provide a supplementary dose.
Once it has been established that the initial dose is well tolerated, the methadone dose should be gradually increased until the patient is comfortable and not using heroin or other illicit opioids. The rate of increase should be individually assessed, and should generally not be greater than 10 mg every few days.
Recommendation
During methadone induction, the initial daily dose should depend on the level of neuroadaptation; it should generally not be more than 20 mg, and certainly not more than 30mg.
Initial dose of buprenorphine
The risk of overdose during buprenorphine induction is low. In patients with high neuroadaptation to opioids, however, buprenorphine may precipitate withdrawal symptoms initially, and such patients may benefit from lower initial doses (2 mg). In addition, patients should wait until they are experiencing mild opioid withdrawal before taking the first dose of buprenorphine (generally at least 12 hours since last heroin or other short-acting opioids), to reduce the risk of withdrawal symptoms precipitated by buprenorphine. Patients with moderate levels of neuroadaptation will generally tolerate initial doses of 4–8 mg a day.
Once it has been established that the initial dose is well tolerated, the buprenorphine dose can be increased fairly rapidly to a dose that provides stable effects for 24 hours and is clinically effective.
6.3.4. FIXED OR FLEXIBLE DOSING IN AGONIST MAINTENANCE TREATMENT
Should methadone and buprenorphine doses by fixed or individually tailored?
No studies were identified comparing fixed and flexible doses for methadone or buprenorphine maintenance treatment. Flexible dosing schedules are thought to be preferable because of individual differences in absorption and metabolism, and dose-related differences in clinical response. In general, the dose of methadone and buprenorphine should be increased until illicit opioid use ceases. Thereafter, the dose should be reviewed frequently, without allowing patients to become obsessed with minor changes in their dose. The methadone dose should be reviewed more frequently during induction and dose increases, after missed doses and during dose reduction. In general, the patient should be reviewed at least monthly during the maintenance phase of treatment.
6.3.5. MAINTENANCE DOSES OF METHADONE
What maintenance doses of methadone and buprenorphine should be used?
There is moderate-quality evidence that high doses of methadone (>60 mg) result in better retention in treatment and less heroin use than lower doses (<40 mg). Health professionals should prescribe effective doses of methadone and be prepared to increase the dose if patients are still using illicit opioids.
Fixed-dose methadone studies were divided into studies that compared 1–39, 40–59, 60–109 and above 109 mg (patients in this latter category all received 160 mg).
Efficacy
60–109 mg versus 1–39 mg
When compared to doses in the range 1–39 mg, 60–109 mg doses resulted in better retention in treatment (RR 1.36, 95%CI 1.13 to 1.63, high-quality evidence) and had higher rates of opioid abstinence (RR 1.59, 95%CI 1.16 to 2.18, low-quality evidence) and cocaine abstinence (RR 1.81, 95%CI 1.15 to 2.85, moderate-quality evidence).
60–109 mg versus 40–59 mg
When compared to doses in the range 40–59 mg, 60–109 mg doses resulted in better retention in treatment in the long term (RR 1.23, 95%CI 1.05 to 1.45, high-quality evidence), and a non-statistically significant reduction in heroin use (RR 1.51, 95%CI 0.63 to 3.61, low-quality evidence).
40–59 mg versus 1–39 mg
There was no demonstrable difference between medium (40–59 mg) and low doses (1–39 mg) in terms of retention in treatment (RR 1.26, 95%CI 0.91, 1.75, in favour of medium doses, moderate-quality evidence).
Doses above 109mg
When compared to doses in the range 60–109 mg, 160 mg per day did not result in better treatment retention (RR 0.96, 95%CI 0.69 to 1.34, low-quality evidence), although this higher dose resulted in better retention in treatment than doses below 60mg (RR 1.67, 95%CI 1.05 to 2.66).
Non-randomized studies
Numerous non-randomized studies have identified better outcomes for patients on high methadone doses [134, 135, 136, 137, 138, 139].
Safety
High methadone doses may be associated with increased risk of QT prolongation. The precise risk of QT-related adverse effects is difficult to quantity, but it is probably smaller than the benefits of high methadone doses. This is supported by the evidence for lower mortality risk for patients on high methadone doses [140].
Cost effectiveness
No studies were found that compared the cost effectiveness of high and low doses of methadone. In well-resourced countries, the cost of methadone is a small part of the overall cost of treatment, and using high doses is likely to increase the cost-effectiveness of methadone. In less well resourced countries, where the cost of methadone may make up a substantial portion of the costs of treatment, the situation is less clear. However, if heroin use is ongoing at any given methadone dose, increasing the methadone dose is likely to be a cost-effective response.
Limitations of data
The quality of the evidence on this issue is not high. Specifically, there is a lack of research of the impact of methadone doses from RCTs. Although there is a strong association between high methadone doses and good clinical outcomes based on evidence from non-randomized studies, this finding may be biased by patients who respond to methadone staying in treatment longer and on higher doses rather than is the case with those who do not respond.
Treatment considerations
In clinical practice, doses are individually tailored, based on ongoing heroin use, withdrawal symptoms between doses and adverse effects. Pharmacokinetic studies indicate large differences in methadone absorption and metabolism. In this context, trough methadone levels, measured 24 hours after dosing, are likely to be a better measure of the active dose. Some patients are likely to be adequately treated with low doses; others may need doses above the target dose range.
Conclusion
Doses in the range of 60–109 mg are more effective than lower doses. Clinicians should be encouraged to aim for doses in this range in general. Clinicians should encourage patients to use these high doses and not reduce their dose, particularly when they are still using illicit opioids.
Recommendation
On average, methadone maintenance doses should be in the range of 60–120 mg per day.
6.3.6. MAINTENANCE DOSES OF BUPRENORPHINE
Efficacy
No systematic reviews of the effectiveness of buprenorphine at different doses were found. In randomized trials that have been conducted comparing doses, 6 mg has resulted in less heroin use than 2 mg [141], 8 mg/day has been shown to have better retention than 3 mg per day [142] and 12 mg/day has resulted in less heroin use than 4 mg/day [143]. Two studies examining higher doses have shown a trend (not statistically significant in either study) for 16 mg to be more effective than 8 mg daily [110, 144].
Safety
Buprenorphine dose does not appear to have implications for safety. However, there is a suggestion from one RCT that alanine transaminase (ALT) and aspartate transaminase (AST) levels are more likely to be elevated in patients on higher doses of buprenorphine.
Cost effectiveness
No studies covering cost effectiveness of different doses of buprenorphine were identified in this review. The cost of buprenorphine is a significant component of buprenorphine treatment and, while higher doses are likely to be more effective, the cost effectiveness is not clear.
Limitations of the data
There are few data comparing low doses to those above 6 mg.
Other evidence
High doses of buprenorphine (16– 32 mg) block the additional effects of heroin better than lower doses [145, 146, 147, 148, 149, 150] and last for longer without inducing significant additional sedation.
Conclusion
Although the quality of evidence is low, higher doses are likely to result in better retention and less heroin use than lower doses, with minimal adverse consequences other than cost. On average, doses should be at least 8 mg per day. If patients are continuing to use illicit opioids, consideration should be given to increasing the dose by 4–8 mg, to a limit of 32 mg daily.
Recommendation
Average buprenorphine maintenance doses should be at least 8 mg per day.
6.3.7. SUPERVISION OF DOSING IN OPIOID AGONIST MAINTENANCE TREATMENT
Should opioid agonist maintenance treatment doses be supervised?
There has been very little systematic research on the supervision of dosing in opioid agonist maintenance treatment. All of the clinical trials demonstrating the efficacy and safety of methadone and buprenorphine against placebo or opioid withdrawal have been conducted using supervised administration, as have trials comparing methadone and buprenorphine. Non-supervised administration is used in some countries for buprenorphine treatment, most notably France, and some countries have limited supervision of dosing (such as once a week or less) for stable methadone patients. Diversion occurs with both methadone and buprenorphine if they are unsupervised, although there appears to be much greater diversion and injection of buprenorphine, even when combined with naloxone, than of methadone [151].
This is probably due to multiple factors.
Buprenorphine is an attractive drug for injection because it produces strong effects, even in low doses, resulting in a group of individuals using buprenorphine as their first and main drug of abuse.
The milder withdrawal symptoms with reduced buprenorphine dosing mean that patients can take some of their own buprenorphine and divert the remainder without experiencing strong withdrawal symptoms.
Buprenorphine is difficult to supervise effectively because it is sublingually administered, taking 5-15 minutes to dissolve, wheras methadone is swallowed.
Methadone is difficult to divert when dosing is supervised and when given in diluted form (i.e. 200 mL) for take-home use its injection is rare. It has a long duration of action, making it less attractive to inject regularly. People who do purchase methadone illicitly generally use it for self treatment purposes [152].
The data on diversion and overdose deaths consistently indicate that unsupervised methadone is a hazard, because it results in a substantial number of overdose deaths in people for whom it is not prescribed [153]. Diverted buprenorphine, on the other hand, is less likely to result in death (although deaths have occurred in combination with other sedatives); however, it is likely to be injected. The main problem with buprenorphine diversion is the creation of a group of people primarily dependent on illicit buprenorphine, who are at risk from the problems associated with buprenorphine injection, which can lead to hepatitis C, HIV, endocarditis and local infections. Whether an epidemic of diverted buprenorphine is a net benefit or harm is not easy to ascertain, because it may result in a corresponding drop in heroin use; however, it would not be acceptable in many countries, because it would threaten the viability of the drug treatment system.
These points form the public health argument for supervision of treatment. On the other hand, unsupervised treatment is cheaper to set up and easy to expand. Expansion of treatment is a high priority in many areas where HIV in injecting drug users is a problem and current rates of treatment are low. Rapid expansion of unsupervised buprenorphine is argued to be the most feasible method of meeting the unmet need for treatment in the short term [154]. However, it is not clear whether unsupervised buprenorphine treatment, with its associated problems of buprenorphine injecting, would reduce HIV spread to the extent that has been demonstrated for supervised methadone treatment.
The impact of supervision of treatment on patients themselves must be considered. Opioid dependence implies a lack of control over opioid use; thus, there are strong theoretical reasons why – at the start of treatment at least – supervision of methadone and buprenorphine may be advantageous to the patient. Unfortunately, there is a lack of clinical trial data on this topic. Research has tended to focus on patients who have been in treatment for some time, examining the impact of providing unsupervised treatment to those who meet certain criteria of stability. In this situation, RCTs demonstrate that making unsupervised treatment contingent upon cessation of illicit drug use results in a reduction in illicit opioid use.
On balance, initiating treatment with supervised dosing, assessing response to treatment, and subsequently allowing unsupervised doses to patients who demonstrate stability appears to substantially reduce diversion, probably does not diminish efficacy and is supported by patient groups.
The key elements of “stability” appear to include housing, employment, not being dependent on multiple drugs and ceasing to inject after entering treatment.
It has been argued that because the risk of overdose on buprenorphine is lower then that of methadone, and because unsupervised doses are cheaper to provide and readily accepted by patients, that in places where opioid agonist treatment is not currently available, the greatest public health benefit would occur from the introduction of buprenorphine with unsupervised dosing. It is not possible based on the current data to draw firm conclusions on this proposition. The potential benefits of making treatment more accessible, affordable and possibly more attractive to patients need to be balanced against risk of less effective treatment, creation of an illicit buprenorphine market and potential community antagonism.
Practical considerations
Supervised methadone dosing involves first dispensing methadone liquid into a clean cup, the liquid is then consumed under the direct observation of a nurse, pharmacist or doctor. Talking to patients after they have consumed their methadone is generally adequate to ensure that the dose has been taken.
Buprenorphine supervision is more difficult, because the tablet can easily be sequestered in a corner of the mouth as it takes up to 15 minutes to dissolve. The tablet should be dispensed into a clean container and tipped into the mouth of the patient, under the tongue. Periodic examination should reveal the tablet in various stages of dissolution.
If no longer needed, for whatever reason, unconsumed unsupervised doses should be returned to the place where they were dispensed.
Conclusions
On balance, initiating treatment with supervised dosing, assessing the response to treatment and subsequently allowing unsupervised doses to patients who demonstrate stability appears to substantially reduce diversion, probably does not diminish treatment efficacy and is supported by patient groups. Routine supervision of dosing with methadone or buprenorphine is recommended for all patients unless they have demonstrated that they meet commonly accepted criteria for take-home doses, developed at a regional or national level.
Recommendation
Methadone and buprenorphine doses should be directly supervised in the early phase of treatment.
Recommendation
Take-away doses may be provided for patients when the benefits of reduced frequency of attendance are considered to outweigh the risk of diversion, subject to regular review.
6.3.8. OPTIMAL DURATION OF OPIOID AGONIST TREATMENT
What is the optimal duration of opioid agonist treatment?
There is little research on the optimal duration of opioid agonist treatment. Studies comparing short-term opioid agonist treatment (i.e. weeks to months) to longer term treatment (6–12 months) find better results for longer term treatment. This is consistent with opioid dependence being a longer-term disease. No RCTs comparing longer treatment durations were found. Observational studies indicate that those who remain in long-term opioid agonist therapy are more likely to stay alive than those who do not, and that cessation of opioid agonist maintenance treatment is associated with a risk of relapse to opioid use. Given these findings, these guidelines recommend that opioid agonist treatment should be seen as open ended, and should be continued as long as clinically indicated. Patients and clinical staff should not take lightly the decision to terminate opioid agonist maintenance treatment (e.g. for administrative reasons). Factors predicting successful termination of opioid agonist maintenance treatment are not well described, but are likely to include employment or other meaningful activity, abstinence from opioid and other drug use while taking opioid agonists, and changes in the psychosocial environment after starting opioid agonist treatment.
Practical considerations
The decision to stop opioid substitution therapy can be a difficult one for patients, and they often seek guidance from treatment staff. On the other hand, some patients simply make up their minds that they want to cease opioid agonist treatment. In both situations, patients should be informed of the risks of cessation of the therapy and encouraged to make healthy choices. In patients doing well on opioid substitution therapy, this can also be an occasion to consider the option of more take-home doses as an alternative to cessation of opioid substitution therapy.
6.3.9. USE OF PSYCHOSOCIAL INTERVENTIONS IN MAINTENANCE TREATMENT
Should psychosocial treatments be used in addition to pharmacological maintenance treatments?
Efficacy
A recent Cochrane Collaboration review identified eight RCTs that addressed the issue of whether psychosocial interventions should be used in addition to pharmacological maintenance treatments. Comparing methadone plus psychosocial treatment to methadone alone, the pooled analysis found no difference in treatment retention (RR 0.94, 95%CI 0.85 to 1.02, high-grade evidence); however, heroin use was significantly reduced with the addition of psychosocial treatment (RR 0.69, 95%CI 0.53 to 0.91, high-grade evidence).
Cost effectiveness
Cost effectiveness studies in the United States found that methadone with moderate intensity psychosocial services (1–2 hours per week) are more cost effective than methadone either without psychosocial services or with high intensity services (i.e. several hours a day) [155,156,157].
Limitations of data
Studies have used different techniques, including hypnotherapy, psychotherapy, acceptance and commitment therapy, interpersonal psychotherapy, supportive–expressive psychotherapy, counselling, cognitive behavioural therapy (CBT), contingency management, dialectic behaviour therapy and comprehensive validation therapy. It is difficult to compare these interventions in meta-analyses. Contingency management studies have the most consistently positive findings, regardless of whether vouchers, take-home methadone privileges or prize draw incentives are used. It is not clear whether these interventions can be generalised to settings outside the one in which they were carried out (mainly the United States).
Conclusion
Psychosocial assistance in methadone maintenance can reduce heroin use in methadone maintenance. In the United States, such services are most cost effective if they are of moderate intensity (1–2 hours a week).
Recommendation
Psychosocial support should be offered routinely in association with pharmacological treatment for opioid dependence.
Strength of recommendation – strong
Quality of evidence – high
Remarks – While patients should be offered psychosocial support, they should not be denied agonist maintenance treatment should they refuse such support.
6.4. Management of opioid withdrawal
Although distressing, the opioid withdrawal syndrome is rarely life threatening; however, pharmacologically assisted management of opioid withdrawal can make withdrawal from opioids more comfortable and more likely to succeed. Given the high rate of relapse, assisted opioid withdrawal is not considered an effective treatment of opioid dependence on its own (see section 6.3).
6.4.1. SIGNS, SEVERITY AND TREATMENT PRINCIPLES
The severity of opioid withdrawal depends on the dose and pharmacological properties of the opioids used, and on the extent of neuroadaptive changes that have taken place in the patient. Drugs with short half-lives will give rise to withdrawal symptoms at an earlier phase than those with long half-lives; the symptoms will also peak and resolve earlier. Untreated heroin or morphine withdrawal typically reaches its peak 36–72 hours after the last dose, and symptoms will have subsided substantially after 5 days. Untreated withdrawal from methadone or other long-acting opiates typically reaches its peak at 4–6 days, and symptoms do not substantially subside for 10–12 days. Untreated buprenorphine withdrawal following the abrupt cessation of long-term buprenorphine treatment emerges within 3–5 days of the last dose, and mild withdrawal features can continue for several weeks.
Opioid antagonists (e.g. naltrexone), which induce rapid changes in receptor activity, can precipitate withdrawal symptoms of greater severity than those normally seen in heroin withdrawal, if administered in close connection with opioid use. Treatment with naltrexone can be started within one week of cessation of short-acting opioids and buprenorphine. By contrast, naltrexone is usually not started until 10–14 days after the cessation of methadone.
The severity of withdrawal is related to the degree and rate of reversal of neuroadaptive changes related to opioid use. The most severe withdrawal occurs with the sudden reversal of significant levels of neuroadaptation; for example, when naltrexone is taken by patients who are taking high doses of methadone.
6.4.2. ASSESSMENT OF OPIOID WITHDRAWAL
When assessing the severity of current opioid withdrawal features, both subjective and objective withdrawal features are relevant. Subjective withdrawal features are a more sensitive measure of opioid withdrawal, but objective signs, when present, are more reliable. For the purpose of dose titration, it is best to place greater emphasis on observable signs rather than subjective symptoms.
Symptoms and signs of opioid withdrawal and assessment of withdrawal severity are listed below – the asterisks indicate withdrawal symptoms that can be quantified by the Subjective Opiate Withdrawal Scale (SOWS):
sweating*
lacrimation (excessive tear formation)*
yawning*
feeling hot and cold*
anorexia and abdominal cramps*
nausea
vomiting and diarrhoea*
tremor
insomnia and restlessness*
generalized aches and pains*
tachycardia
hypertension*
piloerection (gooseflesh)
dilated pupils
increased bowel sounds.
Severity of withdrawal symptoms can also be quantified with the Objective Opioid Withdrawal Scale (OOWS), or with a combined single objective and subjective scale such as the Clinical Opiate Withdrawal Scale (COWS) (Annex 11).
When assessing the patient for planned opioid withdrawal, including admission to a residential detoxification facility or provision of medication to manage withdrawal symptoms, it is important to complete a thorough assessment of the patient (see section 6.1). and, as appropriate, inform the patient of the estimated risks of opioid withdrawal (including the effects of subsequent relapse), as compared to opioid agonist maintenance treatment. Since withdrawal from opioids is associated with higher mortality than opioid agonist maintenance treatment, some indication of the patient's informed consent for opioid detoxification is advised. Precautions for opioid dependence include pregnancy (specifically the first and third trimesters) and current acute comorbid conditions.
6.4.3. CHOICE OF TREATMENTS FOR ASSISTING WITHDRAWAL FROM OPIOIDS
Opioid withdrawal can be managed by controlling the rate of cessation of opioids and by providing medication that relieves symptoms, or by a combination of the two.
This analysis focuses on the three approaches to assisting withdrawal from opioids that have been most widely evaluated: tapered oral methadone, tapered sublingual buprenorphine and tapered oral adrenergic alpha-2 agonists.
There are many other alternative treatments; for example:
shorter acting oral opioids – these are not examined here due to an absence of research on their use and difficulties in enabling supervised administration, should it be required
recently developed transdermal formulations of opioids and adrenergic alpha-2 agonists – these may have a role to play, although research is also limited at this stage
medications to manage specific withdrawal symptoms used in combination with opioids or alpha-2 agonists (e.g. benzodiazepines for anxiety and insomnia, anti-emetics for nausea and vomiting, and paracetamol and non-steroidal anti-inflammatory drugs [NSAIDs] for muscle aches)
Detailed guidance on the use of these medications is beyond the scope of these guidelines.
What treatments should be used to assist withdrawal from opioids?
Efficacy
Methadone versus alpha-2 agonists
In the pooled analysis (7 studies, 577 participants), there was no significant difference between methadone and alpha-2 agonists in treatment completion (RR 1.09, 95%CI 0.90 to 1.32, moderate-quality evidence). There was no difference in rates of relapse at follow-up (intention-to-treat analysis) (RR 1.06: 95%CI 0.55 to 2.02, low-quality evidence).
Methadone versus buprenorphine
In the pooled analysis (2 studies, 63 participants), there was no significant difference in completion of treatment between methadone and buprenorphine (RR 0.88: 95%CI 0.67 to 1.15, low-quality evidence).
Buprenorphine versus alpha-2 agonists
In the pooled analysis (8 studies, 653 participants) comparing buprenorphine to alpha-2 agonists, there were higher completion rates with buprenorphine (RR 1.53, 95%CI 1.18 to 1.99, moderate-quality evidence), lower peak objective withdrawal scores (SMD −0.61, 95%CI −0.86 to −0.36, moderate-quality evidence), and lower overall self reported levels of opioid withdrawal (SMD −0.59, 95%CI −0.79 to −0.39, high-quality evidence).
Safety
Methadone has the greatest risk of over sedation, although this is reduced with the use of lower doses (<20 mg). Buprenorphine, while safer than high doses of methadone, is nonetheless potent even at low doses, and can cause significant respiratory depression when used in combination with other sedatives, including benzodiazepines, alcohol, tricyclic antidepressants, sedating antihistamines and major tranquilizers. A number of deaths have been reported involving the combination of buprenorphine with benzodiazepines and other sedatives. As a partial agonist, buprenorphine can induce precipitated withdrawal if used while heroin is still bound to receptors. This may occur on up to 10% of occasions in which buprenorphine is used for opioid withdrawal. The main adverse effect of buprenorphine is headache. Alpha-2 agonists can cause postural hypotension, which can lead to dizziness and fainting. In overdose, alpha-2 agonists induce profound bradycardia which may require intensive care treatment but is not usually fatal. Lofexidine induces less postural hypotension than clonidine; Cochrane Collaboration reviews of clinical trials detected no difference in safety.
Cost effectiveness
There are limited data to differentiate the cost effectiveness of these medications when used for opioid withdrawal. Buprenorphine and lofexidine are more expensive than methadone. Despite this, an analysis in Australia found outpatient buprenorphine to be more cost effective than outpatient clonidine [158].
Limitations of data
It is difficult to make an assessment of the relative effectiveness of withdrawal treatment from detoxification trials because of variations in practice and because participants often leave withdrawal units on the day of the last dose, before withdrawal symptoms are completed. Data on severity of withdrawal are useful to compare treatments, but are not uniformly collected and are difficult to include in meta-analysis. Furthermore, withdrawal methods vary and few studies use the same techniques.
Treatment considerations, duration of the treatment
All treatments can be used in inpatient and outpatient withdrawal settings. Methadone and buprenorphine can be administered as once-daily supervised doses, to reduce diversion and increase safety (guanfacine can also be administered once daily, although the need for supervised dosing is less with alpha adrenergic agonists). Gradual reduction of methadone and buprenorphine can reduce the severity and increase the length of opioid withdrawal. Such gradual reductions improve treatment retention but reduce the rate of successful completion of withdrawal [159].
Conclusion
Buprenorphine is suitable for once-daily administration; it leads to less severe withdrawal and higher rates of completion than alpha-2 agonists.
Methadone is cheaper than buprenorphine and carries no risk of precipitated withdrawal; it is suitable for use in pregnancy.
Alpha-2 agonists can lead to shorter duration of withdrawal symptoms and shorter time to commencement of naltrexone.
All three medications listed above can be used for opioid withdrawal. Clinical trials clearly show that buprenorphine is more effective than alpha-2 agonists, and clinical experience would suggest that methadone lies somewhere between the two, even though equivalent to both in the Cochrane Collaboration reviews. Choice should depend on the individual situation, capacity to tolerate withdrawal symptoms, timeframe and patient preferences.
Recommendation
For the management of opioid withdrawal, tapered doses of opioid agonists should generally be used, although alpha-2 adrenergic agonists may also be used.
6.4.4. ACCELERATED WITHDRAWAL MANAGEMENT TECHNIQUES
Accelerated withdrawal techniques use opioid antagonists to induce withdrawal and thus complete the process more quickly. Here, the techniques are divided depending on whether they co-administer minimal or heavy sedation. Minimal sedation refers to levels that might commonly be prescribed in the management of opioid withdrawal in outpatient or residential settings, because they have a low risk of inducing respiratory depression. Heavy sedation refers to the administration of either oral or parenteral sedatives or anaesthesia that have a significant risk of inducing respiratory depression. The use of heavy sedation requires intensive monitoring and the capacity to assist respiration, such as would be provided in an intensive care setting.
Should antagonists with minimal sedation be used for opioid withdrawal?
Efficacy
Four studies (394 participants) were found that examined the issue of whether antagonists with minimal sedation should be used for opioid withdrawal. In the pooled analysis, there were no significant differences in rates of completion between different opioid antagonist techniques, (RR 1.26, 95%CI 0.80 to 2.00, moderate-quality evidence). No difference in relapse rates was detected (RR 0.83, 95%CI 0.52 to 1.35, low-quality evidence [160].
Safety
Data from observational studies suggest higher rates of adverse effects with the use of opioid antagonists (RR 3.7, 95%CI 0.65 to 21.32, very low-quality evidence).
Cost effectiveness
Although the use of opioid antagonists adds to the cost of medications for opioid withdrawal, the overall cost effectiveness may be greater than conventional withdrawal treatment if the duration of withdrawal treatment is reduced [158].
Treatment considerations
Naltrexone hydrochloride is available primarily as a solid oral formulation in 25 mg and 50 mg tablets. Naloxone is available as ampoules for injection, at a concentration of 0.4 mg in 1 mL, or as a prefilled syringe.
Treatment regimens
Dosing regimens used in clinical trials range from a single dose of 50 mg naltrexone daily to a graduated increase of 12.5 mg naltrexone daily. Techniques vary from a single daily dose of naloxone to the use of naloxone infusions. Other than the observation that regimens that use higher initial doses of naltrexone are associated with higher rates of delirium, it is not clear which of these approaches is more effective. Careful and continuous monitoring is necessary during the hours immediately following administration of opioid antagonists, because of the possibility of delirium, vomiting and diarrhoea. To prevent and treat excessive diarrhoea and vomiting, expensive medications, such as ondansetron and octreatide, are often required, combined with intravenous fluid replacement. Opioid antagonist withdrawal techniques should not be undertaken in patients with a history of cardiac disease, psychosis, chronic renal impairment or decompensated liver disease, or current dependence on alcohol, benzodiazepines or stimulants.
Benefits
Use of antagonists may reduce the duration of withdrawal; thus reducing the overall severity of withdrawal and increasing the chances of successful completion. In inpatient settings where the cost of the facility is high compared to the cost of medication, this may result in significant cost savings. This technique facilitates commencement of naltrexone treatment.
Undesirable effects and consequences
Adverse effects of opioid withdrawal treatment may include a higher peak severity of withdrawal symptoms, possibly resulting in dehydration (and resulting complications such as renal failure) and delirium. Complications from excessive sedation used in managing the increase in peak withdrawal severity could include aspiration pneumonia and respiratory depression.
Conclusion
The small number of clinical trials conducted on treatments for opioid withdrawal have used a variety of approaches, making generalization difficult. Results from these trials suggest that antagonist-induced withdrawal techniques increase the severity of opioid withdrawal initially, and may increase the adverse effects of withdrawal. Given the potential for harm, there is not enough evidence of benefit to recommend the routine use of these techniques.
Recommendation
Clinicians should not routinely use the combination of opioid antagonists and minimal sedation in the management of opioid withdrawal.
Should antagonists with heavy sedation or anaesthesia be used for opioid withdrawal?
Opioid withdrawal with opioid antagonists and heavy sedation or anaesthesia is defined as withdrawal that requires monitoring of vital functions such as respiratory rate and oxygen saturation. Such withdrawal usually takes place in intensive care settings.
Efficacy
A recent Cochrane Collaboration review [161] identified RCTs in which ultra-rapid opioid detoxification (UROD) was compared to:
inpatient
opioid withdrawal with clonidine (two studies [
162,
163])
inpatient withdrawal with buprenorphine (one study [
163])
opioid antagonist and minimal sedation techniques (two studies [
164,
165]).
Completion of treatment and commencement of naltrexone
In the pooled analysis, there was no difference in the rates of completion of treatment of naltrexone compared to either clonidine (RR 1.15, 95%CI 0.79 to 1.68, moderate-quality evidence), or buprenorphine (RR 0.82, 95%CI 0.34 to 1.97, low-quality evidence). The use of antagonists and heavy sedation resulted in higher rates of naltrexone commencement than inpatient clonidine withdrawal (RR 3.40: 95%CI 2.32 to 4.98, moderate-quality evidence), but not inpatient buprenorphine withdrawal (RR 0.97: 95%CI 0.88 to 1.07, low-quality evidence).
Relapsed at follow-up
Heavy sedation or anaesthesia made no difference in rates of heroin use at the 6 month follow-up (RR 0.97, 95%CI 0.88 to 1.08, moderate-quality evidence).
Retention in treatment at 12 months
Heavy sedation or anaesthesia made no difference to rates of retention in treatment at 12 months (RR 0.95, 95%CI 0.69 to 1.30, moderate-quality evidence).
Safety
Higher rates of adverse effects were seen with techniques involving heavy sedation or anaesthesia (RR 3.21, 95%CI 1.13 to 9.12, moderate-quality evidence).Potential adverse effects include severe opioid withdrawal resulting in dehydration (and resulting complications such as renal failure) and delirium. Potential complications from excessive sedation include aspiration pneumonia and respiratory depression [166]. Three life-threatening adverse events occurred out of 35 participants in the heavy sedation groups, and none out of 71 participants in the non-heavy sedation groups (RR 14, 95%CI 0.74 to 264, low-quality evidence).
Cost effectiveness
Techniques using heavy sedation and anaesthesia are expensive. In an Australian analysis, these techniques did not offer any cost-effective advantages over techniques using antagonists and minimal sedation [158].
Limitations of data
Studies do not have enough numbers to accurately determine safety data. Variations in technique may result in different patterns of safety and efficacy.
Treatment considerations
At a minimum, techniques involving heavy sedation should be conducted in a setting that is suitable for managing respiratory depression, such as an intensive care or high-dependency unit. A number of patients have died when this technique has been used outside intensive care unit settings [166, 167].
Summary
Compared with use of methadone and alpha-2 adrenergic agonist treatment for opioid detoxification, use of opioid antagonists and heavy sedation may mean that it is possible to start naltrexone earlier. However, use of opioid antagonists and heavy sedation is of little benefit over buprenorphine-assisted withdrawal or use of opioid antagonists with minimal sedation. In addition, the use of opioid antagonists and heavy sedation leads to significantly higher complication rates. Given this balance, techniques combining opioid antagonists and heavy sedation are not recommended.
Recommendation
Clinicians should not use the combination of opioid antagonists with heavy sedation in the management of opioid withdrawal.
6.4.5. TREATMENT SETTING FOR OPIOID WITHDRAWAL
Should withdrawal from opioids be conducted in inpatient or outpatient settings?
Efficacy
A recent Cochrane Collaboration review [168] identified one RCT that directly addressed the issue of whether withdrawal from opioids should be conducted in inpatient or outpatient settings. The review found better rates of completion of treatment for the inpatient group (RR 1.91, 95%CI 1.03 to 3.55, very low-quality evidence). There were no differences in relapse rates between inpatient and outpatient groups (RR 1.07, 95%CI 0.97 to 1.18).
Safety
There were no data to compare the safety of inpatient and outpatient withdrawal. It might be expected that inpatient withdrawal would be safer than outpatient withdrawal, but no data are available on this topic.
Cost effectiveness
Inpatient opioid detoxification is significantly more expensive than outpatient opioid detoxification.
Australian data suggest that outpatient withdrawal with buprenorphine is significantly more cost effective [158].
Limitations of data
The RCT upon which the efficacy data is based has significant flaws; as a result, the grade of evidence is low. It seems that many patients allocated to the inpatient group either refused inpatient treatment or dropped out before opioid withdrawal was arranged.
Treatment considerations
Inpatient treatment is expensive to administer because it generally requires a secure environment, 24-hour nursing care and daily medical care. Patients in opioid withdrawal are generally restless and irritable, and it can be a challenging environment in which to work. Ensuring the health and safety of the staff in residential withdrawal units requires adequate staffing and training levels.
Benefits
Opioid withdrawal in residential facilities has higher rates of success and is probably safer.
Undesirable effects and consequences
Opioid withdrawal in residential facilities is expensive and is inconvenient for many patients.
Conclusion
Inpatient detoxification appears to have higher rates of completion of withdrawal than outpatient detoxification, but there is no demonstrable difference in relapse rates. Data to estimate the relative safety of inpatient and outpatient detoxification are lacking. It is more cost effective to provide most opioid detoxification on an outpatient basis, reserving inpatient opioid detoxification for patients who:
6.4.8. PSYCHOSOCIAL ASSISTANCE IN ADDITION TO PHARMACOLOGICAL ASSISTANCE FOR OPIOID WITHDRAWAL
Is psychosocial assistance plus pharmacological assistance for opioid withdrawal more useful than pharmacological assistance alone?
Efficacy
The pooled results of five RCTs (184 participants) indicate that combined psychosocial and pharmacological assistance results in greater rates of completion of treatment (RR 1.68, 95%CI 1.11 to 2.55, moderate-quality evidence), lower rates of relapse at follow-up (RR 0.41, 95%CI 0.27 to 0.62, moderate-quality evidence), despite a trend towards higher rates of opioid use during detoxification (RR 1.3, 95%CI 0.99 to 1.70, moderate-quality evidence). There were no differences in rates of other substance use during detoxification [169].
Treatment considerations
The types of psychological assistance provided in the studies were contingency management, community reinforcement, psychotherapeutic counselling and family therapy. The data show no clear advantage of one technique over the others, although the evidence (from four studies) is strongest for contingency management approaches combined with methadone or buprenorphine.
Benefits
Psychosocial assistance can:
In addition, psychosocial support can help to educate patients about the sort of withdrawal symptoms they will experience, provide them with useful strategies for minimizing withdrawal and help them to interpret the current withdrawal phenomena. It can also facilitate transfer to post-withdrawal treatment options, and assist with reintegration into society.
Undesirable effects and consequences
There is a theoretical risk that psychosocial interventions to assist people undertaking opioid withdrawal may inadvertently encourage people to continue with opioid detoxification instead of moving to more effective longer term interventions, such as opioid agonist maintenance treatment.
Conclusion
For those who wish to withdraw from opioids, combined psychosocial and pharmacological assistance increases the chance of successfully completing opioid withdrawal. The evidence is strongest for contingency management approaches.
Recommendation
Psychosocial services should be routinely offered in combination with pharmacological treatment of opioid withdrawal.
6.6. Psychosocial interventions
The term “psychosocial support” is used here to refer to a broad range of interventions at a social and psychological level. Interventions at a social level include assistance with basic needs such as food, clothing, accommodation and employment, as well as basic health-care, friendship, community and the pursuit of happiness. Interventions at a psychological level range from unstructured supportive psychotherapy and motivational interviewing techniques, to highly structured psychological techniques. Clinicians and health providers should choose which psychosocial intervention to offer to opioid-dependent patients, based on research evidence, how appropriate a method is to the patient's individual situation, how acceptable it is to the patient, whether trained staff are available, and cultural appropriateness.
6.6.1. PSYCHOLOGICAL INTERVENTIONS
A complete discussion of the range of psychological interventions is beyond the extent of this document; however, two subtypes of therapy dominate the literature – CBT and contingency management.
CBT has become the leading approach in a variety of mental and behavioural disorders including phobias, anxiety and obsessive-compulsive disorders; it can also be effective in depression and eating disorders. CBT in substance dependence is based on the principle that addictions are learned behaviours that can be modified. Cognitive approaches primarily aim to change addictive behaviours by changing faulty cognitions that serve to maintain behaviour, or by promoting positive cognitions or motivation to change behaviour. Commonly used variants are cognitive therapy and motivational-enhancement therapy.
Behavioural approaches aim primarily to modify behaviours underpinned by conditioned learning; that is, by classical and operant conditioning. They include interventions that aim to extinguish classically conditioned responding (e.g. cue exposure and response prevention), or that are based on instrumental conditioning (e.g. community reinforcement or contingency management) – an approach in which positive non-drug taking behaviours are rewarded. Behavioural approaches involving aversive conditioning are historically important, mainly in the alcohol treatment field, but their use has ceased, mainly for ethical reasons. CBT requires training of staff in, for example, clinical psychology.
Contingency management rewards or punishes specific types of behaviours using a structured, transparent approach that increases learning of desired behaviours. Most programmes focus on positive behaviours, with reinforcement for the desired behaviour. The elements of a contingency management programme are:
regular monitoring for the presence or absence of the desired behaviour (e.g. regular urine tests);
specified rewards for the desired behaviour (e.g. money, vouchers, take-home methadone doses or lottery tickets);
positive personal feedback from staff for the desired behaviour.
Contingency management can be administered by staff with relatively little training.
Counsellors should be aware of links to available social services or other social resources in the community.
6.6.2. SOCIAL INTERVENTIONS
Vocational training
Vocational training includes a range of programmes designed to help patients find and retain employment. Vocational training can include skills training, sheltered work environments and monitoring of drug use during employment [174, 175, 176].
Housing
Housing services can vary from group accommodation for the homeless to more stable, affordable, long-term accommodation. The importance of housing is such that assistance with housing may be necessary before cessation of drug use can be attempted. While there may be risks in accommodating drug users together in institutional settings, stable accommodation in a drug-free environment is desirable. The strategies adopted will depend on local resources and norms.
Activities
The ability of patients to participate in and enjoy leisure activities of their choice is an important aspect of psychosocial support. Programmes can provide access to a range of healthy leisure activities.
Self-help groups
In the context of opioid dependence, self-help groups are voluntary, small-group structures formed by peers to assist each other in their struggle with opioid dependence. Usually abstinence oriented, they often provide both material assistance and emotional support, and promulgate an ideology or values through which members may attain a greater sense of personal identity [177].
Patients receiving pharmacological treatment should be encouraged to participate in self-help groups. Although there has been little research on this form of treatment, observational studies on 12-step groups (e.g. Narcotics Anonymous) are positive, with strong “in-treatment” effects. This form of therapy is inexpensive and provides important psychosocial support.
Social skills training
Social skills training refers to methods that use the principles of learning theory to promote the acquisition, generalization and durability of skills needed in social and interpersonal situations. Training should take place in the context of real everyday life experiences, not in closed, unrealistic settings.
Traditional healers
Traditional and spiritual healers may have a role in the provision of psychosocial support, if they are culturally acceptable to the patient. Although the assessment of these methods is beyond the scope of this document, clinical staff might wish to explore what options there are for such support with their patients.
6.6.3. PROVISION OF PSYCHOSOCIAL SUPPORT
Staff and volunteers can provide psychosocial support commensurate with their level of expertise. As a minimum, anyone providing psychosocial support to people with opioid dependence should participate in a brief training programme so that they do not put themselves at risk or inadvertently cause harm. Professional staff without specific psychotherapeutic training might be expected to be able to provide supportive psychotherapy or structured therapy based on an appropriate manual after a brief training period (e.g. 1–2 weeks).
6.7. Treatment of overdose
Opioid overdose is identifiable by a combination of signs and symptoms, including pinpoint pupils and respiratory depression. Dilated pupils suggest an alternative diagnosis. Patients with suspected opioid overdose should be treated if the respiratory rate is less than 10 per minute or if they are hypoxic on pulse-oxymetry (oxygen saturation <92%).
Initial treatment of hypoxic patients should include supplemental oxygen and assisted ventilation, as necessary. This would typically include clearing the airway and applying bag and mask ventilation with oxygen.
Naloxone is a non-selective, short-acting opioid receptor antagonist that has a long clinical history of successful use for the treatment of overdose. It is an effective antidote for overdoses of short-acting opiates such as heroin. In managing opioid overdoses, the primary concern should always be respiration and oxygenation. Any respiratory arrest should be managed with assisted ventilation and oxygen while waiting for naloxone to be administered or to take effect. Typically, adequate respiration will resume within 30 seconds of naloxone administration. The ideal dose of naloxone is one that improves ventilation without inducing withdrawal. If in doubt, it is better to err on the side of too high rather than too low a dose. A standard dose for the treatment of suspected heroin overdose is 400 mcg intramuscularly or 800 mcg subcutaneously, repeated 2 minutes later, if necessary. If there is IV access and adequate patient ventilation, small aliquots of 100 mcg can be given in repeated doses until the patient is breathing with a rate of greater than 10 breaths a minute, without inducing opioid withdrawal.
Initial use of doses of naloxone that are too high (>2 mg) can induce severe withdrawal, with the risk of vomiting and aspiration; very high doses (>10 mg) may even be life threatening [178].
Overdoses of long-acting opioids are more difficult to manage. In this situation, the duration of sedation will outlast the effects of naloxone. The safest method of treating long-acting opioid overdose is likely to be ventilation, if available. Although patients can also be managed with repeated boluses of naloxone or naloxone infusions, death can occur if there is unnoticed interruption to the naloxone infusion, or if the patient wakes up and discharges themselves from medical care.
Ideally, patients should be observed for 2 hours after naloxone administration before they are discharged. In practice, this can be difficult to achieve, but it is most important in patients where overdose is suspected to involve long-acting opioids.
In some countries, prefilled naloxone syringes are distributed to patients and family members, in combination with training in resuscitation [78, 79]. Although the use of naloxone by non-medical personnel is not without risks [80, 178], and may even be illegal in some countries, such use may prevent overdoses. Evaluation of such distribution systems has been positive [78,79], and naloxone distribution is likely to be an affordable approach to the prevention of opioid overdose, particularly where inexpensive prefilled syringes are available.
6.8. Special considerations for specific groups and settings
6.8.1. PATIENTS WITH HIV/AIDS, HEPATITIS AND TB
As described in section 5.6.8, opioid agonist treatment enhances adherence to treatment with anti-infective agents in patients with opioid dependence (see section 5.6.8 for a more detailed discussion).
When presented with an active drug user with TB and opioid dependence, the first priority of the treatment service should be to treat the active TB without spreading it further. If opioid dependence treatment can be commenced in a way that does not put other patients at risk, then this is ideal. Otherwise, it may be better to delay treatment until the patient is no longer infectious.
When presented with an active drug user with HIV and opioid dependence, it is simpler to delay antiretroviral treatment until the patient is stabilized on opioid substitution treatment than to attempt to start antiretroviral drugs before opioid substitution treatment. There is no need to delay antibiotic treatments such as co-trimoxazole or isoniazid, if it is indicated.
6.8.2. ADOLESCENTS
Adolescents 12–18 years old present to treatment services with the full range of opioid-dependence severity. Some adolescents may be brought to the clinic by their families, who are concerned about recent drug use that may not have reached the level of dependent use. On the other hand, many adolescents presenting to treatment services come from socially disadvantaged backgrounds, are living on the street and may have more severe dependence than many adult patients. In between these two groups is a third with dysfunctional families. Studies suggest that the earlier that substance use commences, the higher the risk of dependence and adverse health consequences [179].
Working with adolescents requires a sensitivity to the issues pertinent to adolescent health in general, because drug use is often a result of events occurring elsewhere in an adolescent's life. Assessment should be broad and should include medical, psychological, education, family and other aspects of the adolescent's life. Treatment should cover as many aspects of the adolescent's life as possible. Given their special treatment needs, adolescents with opioid dependence often benefit from special health services aimed directly at them.
Treatment approaches should accommodate adolescents, who often have higher levels of risk taking, novelty seeking and responses to peer pressure than older individuals (probably due to incomplete development of brain areas of inhibitory control). Thus, training in self-control, resilience and decision-making should be included in psychosocial interventions. To ensure that treatment is as effective as possible, the treatment programme needs to be individualised and comprehensive, and needs to take into consideration an adolescent's strengths, psychosocial supports, education, legal and medical status and history, and pattern of illicit drug use.
Recent research has provided important information about the clinical profile of opioid-dependent adolescents, and has underscored the high prevalence of comorbid psychiatric disorders among this population. Psychiatric disorders that often accompany opioid dependence include depression, post-traumatic stress disorder, conduct disorder and attention deficit hyperactivity disorder. Some of these disorders (e.g. depressive disorders) are more evident among opioid-dependent female adolescents than among their male counterparts. It is unclear to what extent existing psychiatric disorders lead to “self-medication” with opioids and other drugs among this adolescent population; however, addressing psychiatric comorbidity along with substance use is likely to lead to more effective, comprehensive care.
Adolescents may live with one or more parents, and are likely to still be in the legal custody of one or more parents. Parents may play a central role in the lives of adolescents entering substance abuse treatment, in comparison to adults entering treatment. Adolescents may thus be in need of family counselling, to improve relationships with parents or to help parents learn how to be as supportive as possible of their adolescent while that person is in treatment for their substance use disorder. High levels of parental involvement and low levels of parental detachment protect against opioid use among adolescents.
Experimentation with substance use often starts in adolescence; thus, Addiction. or substance dependence, has frequently been referred to as a developmental disorder. Providing effective interventions early in an adolescent's drug involvement is critical if this progression is to be altered. Early intervention is particularly important in light of emerging research, suggesting that adolescents may progress from substance use to dependence more rapidly than adults. Additionally, substance use among adolescents may interfere with cognitive, social and emotional development [15, 180].
Effective early intervention for opioid-dependent adolescents – combining pharmacotherapy and psychosocial treatment – can help to prevent adolescents from following a substance-using life trajectory, and from transitioning from intranasal or oral to injecting opioid use. Moreover, early psychosocial intervention with young people who have used heroin but who are not yet opioid dependent can help to prevent young people from becoming dependent on opioids.
Should pharmacological treatment for adolescents with opioid dependence differ from that for adults?
No systematic reviews addressing this question were found. Some clinical trials were found that supported the use of agonist pharmacotherapy, both for opioid withdrawal and maintenance. One RCT demonstrated that, compared to clonidine patches, 28-day reducing buprenorphine retained more people in treatment (72% versus 39%), and led to higher rates of induction to naltrexone (61% versus 5%) [181].
The use of agonist pharmacotherapy is still the recommended therapy for adolescent opioid dependence. However, adolescents with a short period of dependence and those living in families may respond to opioid withdrawal with or without naltrexone, and these would be reasonable alternatives. Opioid agonist pharmacotherapy in this population can also be started on an interim or trial basis, and short-term therapy may be all that is required if the response is positive.
A comprehensive treatment programme that addresses this entire clinical profile is more likely to produce better outcomes than a programme that focuses on one clinical problem in isolation.
6.8.3. WOMEN
Women have been found to differ from men in their drug-use patterns, with women using less quantity but advancing more quickly to dependence, and using more prescription sedatives. Women who become opioid dependent are more likely to have less education, fewer financial resources and higher rates of sexual and physical abuse [183]. Often, the needs of women in substance dependence treatment settings are also different. They are more likely to have child-care responsibilities that may limit access to treatment, and they may be reluctant to participate in group psychosocial activities with men. They also report significant rates of sexual harassment by male treatment staff [183].
Data are lacking on the relative efficacy of gender-specific services for women. To retain women, services may need to provide either individual or female-only group counselling, cater for people with small children (e.g. provide child-care facilities), and have measures to guard against sexual harassment of female patients by male staff.
6.8.4. PREGNANCY AND BREASTFEEDING
For women who are pregnant or breastfeeding, opioid agonist maintenance with methadone is seen as the most appropriate treatment, taking into consideration effects on the fetus, neonatal abstinence syndrome, and impacts on antenatal care and parenting of young children. Opioid-dependent women not in treatment should be encouraged to start opioid agonist maintenance treatment with methadone or buprenorphine. Pregnant women who are taking opioid agonist maintenance treatment should be encouraged not to cease it while they are pregnant. Although many women want to cease using opioids when they find out they are pregnant, opioid withdrawal is a high-risk option because a relapse to heroin use will affect the capacity to care for the child. In addition, severe opioid withdrawal symptoms may induce a spontaneous abortion in the first trimester of pregnancy, or premature labour in the third trimester. Relapse to heroin use during pregnancy can also result in poorer obstetric outcomes. Opioid agonist maintenance is thought to have minimal long-term developmental impacts on children when compared to the risk of maternal heroin use and resulting harms.
Methadone is preferred over buprenorphine because of the longer experience of the safety of methadone in pregnancy compared to buprenorphine, despite the fact that early research with buprenorphine suggests that its use may result in less neonatal abstinence syndrome than occurs with the use of methadone. If women are being successfully treated with buprenorphine, then the benefit of staying with a treatment that is working should also be taken into consideration.
In the second and third trimester, methadone doses may need to be increased, due to increased metabolism and circulating blood volume. Splitting the dose into two 12-hour doses may produce more adequate opioid replacement in this period. After birth, the dose of methadone may also need to be adjusted as some of these changes reverse.
Although methadone and buprenorphine are detectable in breast milk, the levels are low and are not thought to significantly affect the infant. Breastfeeding, on the other hand, has many benefits, including mother–infant bonding, nutrition and prevention of childhood illness. Opioid-dependent mothers should be encouraged to breastfeed, with the possible exception of HIV-positive mothers or those using alcohol or cocaine and amphetamine type drugs; in such cases, specific advice should be sought.
Untreated neonatal abstinence syndrome can cause considerable distress to infants and, in rare cases, can cause seizures. Cochrane Collaboration reviews indicate that opioids and barbiturates are more effective than placebo or benzodiazepines, with opioids probably more effective than barbiturates.
Recommendation
Opioid agonist maintenance treatment should be used for the treatment of opioid dependence in pregnancy.
Recommendation
Methadone maintenance should be used in pregnancy in preference to buprenorphine maintenance for the treatment of opioid dependence; although there is less evidence about the safety of buprenorphine, it might also be offered.
6.8.5. OPIUM USERS
People dependent on opium who are suffering harm as a result can be treated with opioid agonist maintenance treatment, consistent with the approach for dependence on other opioids. Two trials have demonstrated the effectiveness of buprenorphine in this population [184, 185].
It is important to ensure that opium smokers meet criteria for opium dependence beyond simple tolerance and withdrawal. If unclear, it may be wise for opium smokers to attempt withdrawal first before commencing opioid agonist maintenance treatment.
6.8.6. DRIVING AND OPERATING MACHINERY
Opioid intoxication can occur during induction onto methadone or buprenorphine. Patients should be advised not to drive while sedated. As patients will not know what effect their first few methadone and buprenorphine doses will have on them, they should be advised not to plan to drive at this time.
6.8.7. PSYCHIATRIC COMORBIDITY WITH OPIOID DEPENDENCE
Psychiatric comorbidity with opioid dependence is common; in particular, depression, anxiety, personality and post-traumatic stress disorders should be specifically looked for early in treatment and on a regular basis thereafter. As with medical comorbidity, there is likely to be a greater uptake of treatment if the treatment can be provided by the same medical practitioner or at the same facility in an integrated service. Failing that, strong links with other services should be established to facilitate referral and to establish the framework for joint involvement; such a framework should include clarification about prescribing of psychoactive medication and about giving the patient a consistent therapeutic message.
6.8.8. POLYSUBSTANCE DEPENDENCE
Annex 12 lists the acute and chronic interactions of opioids, alcohol, benzodiazepines, stimulants and cannabis.
In the treatment of polysubstance dependence, opioid agonist maintenance treatment can be started for the opioid dependence component, in an inpatient facility if necessary, while the person is simultaneously withdrawn from alcohol, benzodiazepines and stimulants.
For withdrawal from high doses of benzodiazepines, gradual withdrawal may be necessary. If benzodiazepines are to be given to outpatients on opioid agonist maintenance treatment, this should be done carefully, because there is little evidence to support the long-term use of these drugs and they increase the risk of sedative overdose. If gradually reducing doses of benzodiazepines are prescribed to facilitate the safe withdrawal from benzodiazepines, the prescription should be from a single practitioner, and the dispensing should occur with administration of the dose of methadone, if possible. Patients should be discouraged from withdrawing from opioid agonist maintenance before ceasing benzodiazepines.
6.9. Management of pain in patients with opioid dependence
6.9.1. ACUTE PAIN
Pain in patients with opioid dependence is often exacerbated by the lowering of the pain threshold that tolerance to opioids can induce. Opioid-dependent patients are more resistant to pain management with opioids, due either to their tolerance to opioids or to blocking effects of medications used to treat opioid dependence, including buprenorphine and naltrexone. Patients with opioid dependence have a right to adequate pain relief; however, some patients will try to manipulate the health system to obtain opioids. Measures that can be taken to minimize this include:
Clinical assessment should be used to distinguish between opioid withdrawal and opioid intoxication. Opioids should be titrated to pain response, with close assessment of the clinical features of withdrawal and intoxication, to determine appropriate dose levels.
Patients not on agonist maintenance treatment
For patients using illicit opioids without opioid agonist maintenance treatment, starting opioid agonist maintenance treatment with methadone allows for combined management of opioid dependence and pain. Inadequate analgesia often contributes to patients self-administering illicit opioids.
Patients on antagonist medication (naltrexone)
Patients on naltrexone will not respond to opioid analgesics in a regular manner. For mild Pain. non-opioid analgesics (e.g. paracetamol and NSAIDs) should be used. Patients taking naltrexone will not benefit from opioid-containing medicines such as cough, cold and antidiarrhoeal preparations. In an emergency, pain management may consist of regional analgesia; conscious sedation with non-opioids such as benzodiazepines or ketamine; and use of non-opioid techniques of general anaesthesia. For elective surgery pain management in hospital, naltrexone should be discontinued at least 72 hours before elective surgery (including dental surgery), if it is anticipated that opioid analgesia may be required. The treating surgeon or doctor should be informed that the patient has been taking naltrexone. The patient should then be abstinent from opioids for three to seven days – depending on the duration of the opioid use and the half-life of the opioid – before resuming naltrexone treatment. If in doubt, a naloxone challenge test can be administered to determine whether naltrexone can be recommenced without inducing opioid withdrawal.
Patients on partial agonists (buprenorphine)
Because of the high affinity of buprenorphine for the opioid receptor, patients treated with buprenorphine may need higher effective opioid activity to manage acute pain. The high affinity opioid agonist fentanyl may be more effective than other opioids in this situation. For mild Pain. increasing the dose of buprenorphine or addition of weak opioids (e.g. tramadol) may be effective, although such approaches have not been systematically investigated.
For treatment of acute pain not responding to these measures, the options are to:
cease buprenorphine and use full
opioid agonists, such as methadone or morphine, then switch back to buprenorphine when pain resolves
continue buprenorphine with the use of high doses of opioids but, as the blocking effect of buprenorphine reduces over time, take care to avoid overdose if buprenorphine is ceased while high doses of opioids are continued
continue buprenorphine and use non-
opioid analgesia such a ketamine infusion; or employ the judicious adjunctive use of clonidine or benzodiazepines.
Patients on full agonist (methadone)
For mild or acute Pain. consider non-opioid analgesics (e.g. paracetamol). Where parenteral analgesics are required, the NSAID ketorolac should be considered. For elective surgery, pain management in hospital is recommended. Patients on methadone who are experiencing acute pain in hospital often receive inadequate doses of opioids for their pain. For patients in methadone maintenance treatment, the same analgesic techniques should be used in the same way as for other patients; such techniques include the use of injectable and patient-controlled analgesia. Because of their tolerance of opioids, patients taking methadone will require larger doses of opioid analgesia for adequate pain relief.
Partial agonists, such as buprenorphine, should be avoided because they may precipitate withdrawal symptoms. There is evidence of cross-tolerance between methadone and anaesthetic agents; thus, patients on methadone may require higher doses of anaesthetic agents in the event of dental or surgical procedures. Patients needing methadone for ongoing management of chronic pain benefit from a comprehensive management plan. Specialist advice should be sought regarding such patients.
6.9.2. CHRONIC PAIN
The recent escalation in the use of opioids for chronic pain in some parts of the world [186] suggests a significant overlap between treatment of chronic pain and dependence on prescription opioids. This document does not attempt to address the use of opioids in the management of chronic pain; however, patients with chronic pain and patterns of use of their prescribed opioids that fit the criteria for dependence (i.e. more than just tolerance and withdrawal), are often referred (or refer themselves) to opioid-dependence treatment facilities. Typically, they present with problems such as injecting their prescribed opioids, taking rapidly escalating doses of opioids and taking opioids in greater quantities than prescribed (resulting in intoxication or overdose); they may also present with other features that raise suspicions of misuse, which they may deny. In the management of such patients, the first step could be to determine that there has been a comprehensive assessment of the cause of the Pain. both physical and psychological, with any physical cause found being treated. For patients not on opioid agonist maintenance treatment, the next step would be to provide supervised methadone or buprenorphine in place of unsupervised opioids, to provide stable opioid effects and eliminate cycles of withdrawal and intoxication. For pain persisting despite adequate opioid agonist maintenance treatment, opioid rotation should be considered.
In some cases, it could be that the opioid treatment is no longer useful, either because it is being abused or because it is suspected that pain is being exacerbated by opioid-induced hyperalgaesia [187]. Opioid withdrawal may be considered as an approach to reverse opioid-induced hyperalgaesia, although it may risk relapse to illicitly obtained opioids.
Measures that can be taken to prevent the abuse of prescription opioids include systems that encourage all opioid analgesia to be provided by one doctor, a graded approach to supervision of dosing, prescription of formulations less liable to abuse (e.g. liquid methadone formulations) and careful patient selection.
