Specific cautions regarding the use of methadone and buprenorphine
Intoxicated or sedated patients
Methadone and buprenorphine should not be given to patients showing signs of intoxication or sedation, due to the risk of sedative overdose. The risks of methadone and buprenorphine use in opioid-dependent patients who are frequently intoxicated with sedatives such as alcohol and benzodiazepines, needs to be balanced against the benefits of treatment.
Severe hepatic/renal dysfunctions
The metabolism and elimination of methadone and buprenorphine may be affected by either hepatic or renal dysfunction in which case the dose or dosing frequency should be adjusted accordingly.
Respiratory insufficiency
In patients with respiratory insufficiency, methadone and buprenorphine may reduce the respiratory drive.
Psychosis
In patients with active psychosis the risks and benefits of methadone and buprenorphine need to be carefully considered.
Methadone maintenance treatment
Induction
The initial daily dose of methadone should depend on the level of neuroadaptation to opioids. It should generally not be more than 20 mg, except in cases of higher tolerance to opioids, and even then should not be more than 30 mg. For people with low or uncertain levels of tolerance to opioids, the initial daily dose should be 10–15 mg. Caution should be exercised with initial methadone doses more than 20 mg daily. Observing patients 2–3 hours after their dose enables the best assessment of the degree of tolerance to opioids. If patients have significant opioid withdrawal symptoms 2–3 hours after their dose of methadone, then they should be given an additional 5–10 mg methadone and a corresponding increase in their next daily dose. If patients are sedated after their dose of methadone, then the next daily dose should be reduced (and the patient monitored until they are no longer sedated, or treated for overdose, if necessary).
Patients should be observed each day prior to dosing. Patients who are sedated or intoxicated should not be given further doses methadone until the sedation has abated.
Precautions for commencing methadone include: high-risk polydrug use, mental illness, low levels of neuroadaptation to opioids (i.e. recent incarceration), and significant concomitant medical problems.
Stabilization
Once patients are taking opioid agonist maintenance treatment without intoxication or significant withdrawal symptoms, the aim is to titrate the methadone dose to its most effective level. The daily dose of methadone should then be increased by 5–10 mg every few days, as needed, to reduce cravings for opioids, and illicit opioid use. The dose should not be increased by more than 20 mg per week.
Patients should be reviewed prior to each dose increase.
The average effective dose of methadone is 60–120 mg.
Switching from buprenorphine to methadone
Commence methadone 24 hours after the last dose of buprenorphine. From buprenorphine doses of 8 mg daily and above, commence with 30 mg methadone daily. From buprenorphine doses of 4-8 mg daily, commence with 20-30 mg methadone daily. With buprenorphine doses below 4 mg daily, commence with less than 20 mg methadone daily.
Missed methadone doses
If one of two doses are missed the patient can be maintained on the same methadone dose.
If three doses are missed the next methadone dose should be reduced by 25% to adjust for the possible reduction in tolerance. If it is well tolerated, doses can return to previous dose levels. If four doses are missed the next dose should be reduced by 50% to adjust for the potential reduction in tolerance. If the dose is well tolerated doses can be increased over several days to previous levels. If more than four doses are missed, patients should resume induction from baseline.
Frequency of doses
Methadone can be administered daily for most patients. In approximately 30% of patients, methadone does not produce effects that are evenly sustained over 24 hours. This can also occur in pregnancy and when methadone is used in combination with medications that increase its metabolism. In such cases methadone can be administered twice a day, dividing the dose in two. When it is too difficult to pick up the medication twice a day, or when take-home doses are not suitable, then buprenorphine should be considered. Increasing the dose of methadone will increase the duration of action to some extent, but the main determinant is the rate of metabolism of methadone.
Reducing dosage and stopping treatment
The decision to discontinue therapy with methadone should be made as part of a comprehensive treatment plan. Evidence suggests that it is associated with a risk of relapse to illicit opioid use and patients should be informed of these risks. Research is lacking on factors predicting successful withdrawal from agonist maintenance, however these may include a brief drug-use history prior to opioid agonist maintenance, no previous treatments prior to opioid agonist treatment, current employment, stable accommodation, cessation of illicit opioid use, cessation of other drug use (including cannabis), and a positive change of social and physical environment since starting treatment.
The daily dose can be generally reduced by up to 2.5 to 5 mg per week without severe opioid withdrawal symptoms. Patients should be reviewed frequently during dose reductions and adjustments to the dose made in accordance with clinical need.
Methadone for opioid detoxification
Commence with 10-20 mg methadone daily, according to the severity of dependence and degree of tolerance to opioids. Reduce the daily methadone dose by 1–2 mg per day. Patients will continue to experience mild opioid withdrawal symptoms in the week after methadone is ceased.
Buprenorphine maintenance treatment
Induction
An adequate maintenance dose, titrated to clinical effectiveness, should be achieved as rapidly as possible to prevent undue opioid withdrawal symptoms due to inadequate dosage.
Prior to induction, consideration should be given to the nature of opioids being used (i.e. long or short-acting), the time since last opioid use, and the degree or level of opioid dependence (i.e. opioid tolerance).
Patients taking street heroin (or other short-acting opioids). When treatment starts, the dose of buprenorphine should be taken at least six hours after the patient last used opioids, or when the early signs of withdrawal appear. The recommended starting dose is 4 mg buprenorphine on day 1, with a possible additional 4 mg depending on the individual patient's requirement.
Patients on methadone. Before starting treatment with buprenorphine, the maintenance dose of methadone should be reduced to 30 mg/day. The first dose of buprenorphine should be taken at least 24 hours after the patient last used methadone. The initial 4 mg buprenorphine induction dose should ideally be administered when withdrawal signs are evident.
Precautions for commencing buprenorphine include: high-risk polydrug use, mental illness, low levels of neuroadaptation to opioids (i.e. recent incarceration), and significant concomitant medical problems.
Stabilization
The dose of buprenorphine should be increased progressively according to the clinical effect in the individual patient. It is recommended to use 8–24 mg daily, the daily dose should not exceed 32 mg. The dosage is adjusted according to reassessments of the clinical and psychological status of the patient.
Less than daily dosing with buprenorphine
After a satisfactory period of stabilization has been achieved the frequency of dosing may be decreased to dosing every other day at twice the individually titrated daily dose. For example, a patient stabilized to receive a daily dose of 8 mg may be given 16 mg on alternate days, with no medication on the intervening days. However, the dose given on any one day should not exceed 32 mg.
In some patients, after a satisfactory period of stabilization has been achieved, the frequency of dosing may be decreased to three times a week (for example on Monday, Wednesday and Friday). The dose on Monday and Wednesday should be twice the individually titrated daily dose, and the dose on Friday should be three times the individually titrated daily dose, with no medication on the intervening days. However, the dose given on any one day should not exceed 32 mg.
Transfer to methadone
Commence methadone 24 hours after the last dose of buprenorphine. From buprenorphine doses of 8 mg daily and above, commence with 30 mg methadone daily. From buprenorphine doses of 4–8 mg daily, commence with 20–30 mg methadone daily. With buprenorphine doses below 4 mg daily, commence with less than 20mg methadone daily.
Reducing dosage and stopping treatment
The decision to discontinue therapy with buprenorphine should be made as part of a comprehensive treatment plan. Studies suggest that it is associated with a risk of relapse to illicit opioid use and patients should be informed of these risks. Research is lacking on factors predicting successful withdrawal from opioid agonist maintenance; however, these factors may include a brief drug-use history before opioid agonist maintenance, no previous treatments before opioid agonist treatment, current employment, stable accommodation, cessation of illicit opioid use, cessation of other drug use (including cannabis), and a positive change of social and physical environment since starting treatment.
The daily dose of buprenorphine can generally be reduced by up to 4–8 mg per week without severe opioid withdrawal symptoms. Patients should be reviewed frequently during dose reductions and adjustments to the dose made in accordance with clinical need.
Alpha 2 adrenergic agonists for opioid detoxification
Alpha adrenergic agonists can cause significant hypotension and bradycardia and should not be the treatment of choice for the management of opioid withdrawal in elderly patients and patients with coronary insufficiency, ischaemic heart disease, bradycardia, cerebrovascular disease, pregnancy and breastfeeding. It is recommended to monitor the pulse and blood pressure when using clonidine, and to withhold or reduce the dose if the patient experiences symptoms of reduced circulation (e.g. dizziness on standing) or if the pulse or the blood pressure become too low (e.g. pulse less than 50 bpm, blood pressure less than 90/60 mmHg).
Clonidine
In the management of opioid withdrawal, clonidine is generally administered in doses of up to 100–300 mcg, three or four times daily, up to a maximum of 10–17 mcg/kg/day, reducing after the first two days and finishing by day 4 or 5. In an inpatient or residential setting, the initial dose should be in the range of 1–2 mcg/kg, with subsequent doses adjusted accordingly.
In outpatient settings, where blood pressure is not being monitored, lower doses should be used, with maximum daily doses of 450–900 mcg, according to the patient's weight and severity of opioid withdrawal.
Lofexidine
Initially the dose is 0.4–0.6 mg twice daily, increasing as necessary and tolerated to a maximum of 2.4 mg daily, in 2–4 divided doses. Treatment should be for 7–10 days, followed by a gradual withdrawal of 2–4 days.
Guanfacine
Initially the dose should be 0.25 to 0.5 mg per day, increased as necessary and tolerated to 1–2 mg daily (in 1–4 divided doses) for 3–5 days then tapering over 2–3 days.
Other treatments for opioid withdrawal
Many different medications can be used in combination with alpha-2 agonists to manage specific symptoms of opioid withdrawal (e.g. benzodiazepines for anxiety and insomnia, anti-emetics for nausea and vomiting, and paracetamol and non-steroidal anti-infammatory drugs [NSAIDs] for muscle aches). Detailed guidance on the use of these medications is beyond the scope of these guidelines.
Patients with diarrhoea, vomiting and excessive sweating can become significantly dehydrated and occasionally aggressive fluid replacement may be required.
Naltrexone treatment
Induction phase
Naltrexone commences after detoxification and after the patient has been free of opioids for 7 days (for short-acting opioids) or 10 days (for methadone). This should be verified at least by a negative urine drug screen and also by a negative naloxone challenge test, if in doubt. The standard maintenance dose is 50 mg orally per day. If patients experience gastrointestinal side effects, these may be helped by reducing the dose to 25 mg naltrexone for a few days.
Maintenance phase
If patients use heroin on a day that they have taken naltrexone, they can continue to take naltrexone the next day.
If a patient misses a day of naltrexone and takes heroin or other opioids, they should either recommence naltrexone at the earliest opportunity or wait 7 days and recommence as per normal induction. If they recommence naltrexone straight away they will experience a reduced withdrawal syndrome. To predict the severity of the withdrawal syndrome, patients can be given a naloxone challenge. Alpha-2 adrenergic agonists can be used to manage the withdrawal symptoms that occur.
If a patient misses more than one day of naltrexone and takes heroin or other opioids, they may experience severe opioid withdrawal upon naltrexone recommencement and patients should be advised to wait 7 days or alternatively to consider opioid agonist maintenance therapy.
There is no good evidence on the optimal duration of treatment. It is recommended that this be individually determined according to the specific clinical situation.
Naltrexone can be ceased without a withdrawal syndrome. Commencing opioid agonist maintenance therapy from naltrexone should proceed with great caution because the tolerance to opioids will be very low.
