The goal of induction is to safely suppress opioid withdrawal as rapidly as possible with adequate doses of SUBOXONE (buprenorphine HCl/naloxone HCI dihydrate) or SUBUTEX (buprenorphine HCl) sublingual tablets.

The same induction procedures are applicable for medical withdrawal (ie, detoxification) or initiating SUBOXONE or SUBUTEX maintenance.

Because buprenorphine (the primary active ingredient of SUBOXONE and SUBUTEX) is a partial mu-opioid agonist with a maximal effect less than that of a full mu-opioid agonist (eg, morphine, methadone, heroin), the induction regimen can be more aggressive. The risk of serious adverse effects such as an overdose or treatment dropout is greater if a patient is undertreated with buprenorphine and continues to self-medicate withdrawal symptoms with opioids, alcohol, or other sedative-hypnotics, in particular benzodiazepines.

Note: The preferred medication for a patient to use at home is SUBOXONE.

Note: Throughout this guidance, the dosage refers to the buprenorphine content of the tablets. The ratio of buprenorphine to naloxone in SUBOXONE is 4:1. Naloxone is present in SUBOXONE to deter the abuse of buprenorphine by injection.

1. Induction from short-acting opioids (eg, morphine, oxycodone, hydrocodone, heroin)
Instruct patients on how to take a sublingual tablet and provide patient information about induction.

Administer a patient's first dose (4 mg) of SUBOXONE or SUBUTEX sublingual tablets after moderate opioid withdrawal symptoms have developed. Consider the use of an opioid withdrawal scale for patient assessment (eg, Clinical Opiate Withdrawal Scale [COWS]). Remind the patient that opioid withdrawal symptoms are usually alleviated in 20 to 40 minutes following the first dose of buprenorphine.

If possible, observe the patient for 1 to 2 hours. Dispense or prescribe a second dose of 4 mg of SUBOXONE or SUBUTEX if no precipitated withdrawal is observed. The usual first-day dose is 8 mg. Clinicians have reported prescribing a third dose (2-4 mg) to be taken later in the evening if needed for withdrawal symptoms.

Assess the patient's response to the first day's dosing. If opioid withdrawal symptoms were fully suppressed and the patient is feeling no withdrawal between doses, then keep the dose at the first day's total dose; otherwise increase the dose by 2 or 4 mg on day 2.

Assess the patient's response to the second day's dosing. If opioid withdrawal symptoms are fully suppressed and the patient is feeling no withdrawal between doses, then keep the dose at the second day's dose; otherwise increase the dose by 2 or 4 mg SUBOXONE on day 3.

After 3 days, once the patient is stable, or after a target dose of 16 mg SUBOXONE or greater is achieved, continue at that dose for 3 to 7 days until steady-state levels are achieved before increasing the dose further.

Doses should be decreased by 2 mg at a time if the patient experiences intoxication (not withdrawal effects).

Note: The goal is to induce treatment smoothly and suppress withdrawal as completely and rapidly as possible. Failure to do so may cause the patient to use opioids, alcohol, benzodiazepines, or other medications to alleviate opioid withdrawal symptoms, or it may lead to early treatment dropout.

2. Induction from long-acting opioids (eg, OxyContin*, MS Contin*, methadone)
It is generally not recommended that stable methadone patients transfer to SUBOXONE or SUBUTEX sublingual tablets. However, patients may request to transfer from methadone to SUBOXONE or SUBUTEX for many different reasons.

For example, individual responses to methadone are variable, including the occurrence of side effects and drug interactions. Some patients are reluctant to be on effective methadone doses and may prefer to be maintained on SUBOXONE in a private office setting. A limiting factor for many patients considering maintenance treatment is the problem of dependence on the maintenance opioid. The pharmacologic properties of SUBOXONE or SUBUTEX, including slow dissociation from mu-opioid receptors and apparent mild withdrawal syndrome, may be perceived as a benefit by the patient. It is recommended that the physician review the risks/benefits of transferring from methadone to SUBOXONE or SUBUTEX with the patient well in advance of the transition and provide the patient with realistic expectations during the transition.

Step 1: Preparation
The care of patients being treated in an opioid treatment program should be coordinated with the program until the last day of methadone dosing at the program. Instruct the patient on how to take a sublingual tablet and provide the patient information about induction. Patients transferring from methadone or other long-acting opioids to SUBOXONE or SUBUTEX may experience discomfort for several days and dysphoria for up to 2 weeks. It is critical that your patient is prepared for this.

Step 2: Long-acting opioid dose adjustments
As a practical matter, it may be very difficult for some patients maintained on methadone or who are dependent on other long-acting opioids to reduce their dose. Splitting the dose may be helpful.

Transfer from long-acting opioids to SUBOXONE or SUBUTEX is best achieved if the patient's equivalent methadone dose is first reduced to 30 mg/day or less where possible (normal transfer).

Transfers are possible between a more than 30 to 60 mg/day of an equivalent methadone dose (high-dose transfer), although dose reduction to 30 mg/day or less followed by a normal transfer is preferred.

Patients on a more than 60 mg/day methadone-equivalent dose should have their dose reduced to a 60 mg/day or less methadone-equivalent dose before attempting a high-dose transfer.

Transfers from a more than 60 mg/day methadone-equivalent dose to SUBOXONE or SUBUTEX are not generally recommended. There have been anecdotal reports of patients being transferred from methadone or other long-acting opioids to a short-acting opioid and then transitioned to SUBOXONE. However, this may be allowable for only 3 days given federal regulations (21 CFR 1306.07).

Step 3: Stop long-acting opioid dosing
Normal Transfer (from methadone-equivalent dose ≤30 mg):

At least 24 hours should elapse after the last long-acting opioid dose. The initial dose of SUBOXONE or SUBUTEX should be administered when moderate signs (see COWS) of withdrawal are evident.

• High-dose transfer (from methadone-equivalent doses ranging from 30 to 60 mg):
• No SUBOXONE or SUBUTEX sublingual tablets should be given after the last methadone or long-acting opioid dose until the patient experiences maximal withdrawal discomfort (at least 48-96 hours after last dose). Earlier dosing with SUBOXONE or SUBUTEX is highly likely to precipitate withdrawal.
• Be prepared to administer limited amounts of withdrawal medication (eg, clonidine, loperamide, sleep aid, NSAID, etc) for symptomatic relief.
• High-dose transfer patients need careful monitoring and dose titration according to the response of the patient. If withdrawal symptoms have not worsened or have improved within 2 to 4 hours after the first dose of SUBOXONE or SUBUTEX, an additional 4-mg dose of SUBOXONE or SUBUTEX is recommended. Clinicians have reported prescribing a third dose (2-4 mg) to be taken later in the evening if needed for withdrawal symptoms.

Step 4: Select initial SUBOXONE or SUBUTEX dose
Note: The dosing of SUBOXONE or SUBUTEX depends on the patient's existing dose of long-acting opioid (labeled as the methadone-equivalent dose in the following table).

3. Dose adjustment/stabilization following induction

• You should aim to have reached a suitable maintenance dose of SUBOXONE or SUBUTEX within 1 to 2 weeks.
• It takes from 3 to 7 days for steady-state blood levels to be achieved.
• After the patient is stabilized (2-3 days), once-a-day dosing should be possible.
• Doses should be titrated according to regular review of the following clinical signs/symptoms:
• Intoxication, withdrawal, and cravings over the past 24 hours
• Additional drug use and the patient's reason for use of illicit street drugs or prescription opioids
• Side effects or other adverse events
• Adherence to dosing regimen
• Patient's expressed satisfaction

Adjustments to the SUBOXONE or SUBUTEX dose of sublingual tablets should be made:

• At 3- to 7-day intervals
• In 2- to 4-mg increases or 2-mg decreases if the patient experiences intoxication (not withdrawal effects)
• It is believed that most patients can be stabilized on a dose between 12 mg and 16 mg; however, due to patient variability, each patient should be dosed to clinical effect. There is no maximum recommended dose; however, doses greater than 32 mg are not generally needed.
• It is important to warn patients of the dangers of misusing benzodiazepines when taking SUBOXONE or SUBUTEX. Overdose deaths have occurred when buprenorphine and benzodiazepines were concomitantly abused via the parenteral route.^1-6 On at least one occasion, a buprenorphine overdose has been associated with oral benzodiazepine ingestion.⁷ Only 2 buprenorphine alone overdose deaths have been reported; in both cases, death was due to Mendelson's syndrome (ie, asphyxiation due to aspirating vomitus).⁴

As with all opioids, patients should be warned of the dangers of the self-administration of benzodiazepines when taking SUBOXONE.

4. Dose reduction/medical withdrawal following maintenance
Significant withdrawal symptoms are unusual during gradual SUBOXONE or SUBUTEX sublingual tablets dose taper.

• The rate of dose reduction should be determined in collaboration with the patient.
• Prepare the patient for possible feelings of less energy, lower appetite, irritability, difficulty sleeping, etc. It is the duty of the physician to prepare patients for these effects in order to maximize their chance of a successful treatment outcome. However, these effects are transitory and should last only a few days.
• Realistic goals for reduction should be established.
• Generally, the more gradual the reduction, the better the outcome.
• Your patients should expect to experience some withdrawal discomfort once they reach low doses or stop taking SUBOXONE or SUBUTEX completely.
• Slow down or stop the dose reductions if:
• Your patient starts to reuse opioids
• Your patient's physical, psychological, or social well-being begins to deteriorate

Examples of dose reduction rates and schedules are shown below:

5. Induction onto naltrexone
To avoid precipitated withdrawal, it is generally recommended that naltrexone be initiated 3 to 5 days after the last dose of SUBOXONE or SUBUTEX sublingual tablets following dose taper.

Prior to administering the initial dose of naltrexone, patients should receive a naloxone challenge (although not referenced in the literature, current best practice is that the initial dose of naloxone should be 1.0 mg followed every 15 minutes with an additional 1-mg dose until a cumulative dose of 4 mg naloxone is administered within 1 hour or until withdrawal signs and symptoms are observed) similar to that recommended following cessation of a full mu-opioid agonist, if they have been maintained on a chronic dose of SUBOXONE or SUBUTEX for a period greater than 7 days.⁷

6. Transfer to methadone
In a number of clinical trials, study participants were transferred to methadone at the completion of the trial or during the trial if the subject was not controlled by buprenorphine. There were no reported difficulties in transferring subjects directly from SUBOXONE or SUBUTEX to methadone. The patient should be transferred to 30 to 40 mg of methadone and the dose titrated to clinical effect. The first daily dose can be split to assess the patient's response and then the daily dose adjusted according to their response.