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After 10 years of heroin dependence, Mr. T, age 36, calls your office and says, “I want to get off heroin.” For 8 months, he’s been using IV heroin 2 to 3 times daily. He says he has tried methadone treatment but found daily dosing cumbersome.
He found your office number on the Substance Abuse and Mental Health Services Administration Web site, which lists physicians qualified to prescribe buprenorphine for opiate detoxification. He has heard about “bup” on the street and wants to know if he is eligible and what he can expect from treatment.
Like Mr. T, 1 million Americans are addicted to opiates.1 As qualified physicians gain experience with using buprenorphine, this agent could revolutionize how opiate-dependent patients are routinely treated. Instead of receiving methadone only in specialized clinics, they can now choose to be treated in physicians’ offices.
Several obstacles, however, are preventing widespread buprenorphine use:
- Too few physicians are trained to offer this office-based treatment.
- Many of the 2,000 doctors who are trained remain uncertain about using buprenorphine.
This article is intended to help overcome obstacles to opiate-dependence treatment by familiarizing psychiatrists—whether trained or not in using buprenorphine—with evidence of this agent’s efficacy and its advantages compared with other treatments.
Efficacy and obstacles
Buprenorphine is a partial opioid agonist that binds to the mu receptor (Box 1).2-5 It is a controlled substance (schedule-III narcotic). Outpatient trials have shown that buprenorphine is more effective than placebo and as effective as methadone for opiate detoxification.6-10
In one of the largest trials, 326 opiate-dependent outpatients were randomly assigned to buprenorphine, buprenorphine/naloxone combination, or placebo for 4 weeks. Both buprenorphine forms were more effective than placebo, as measured by clean urine samples and patient reports of reduced opiate cravings.7
In maintenance treatment, buprenorphine has been shown to be more effective than placebo and as effective as methadone, 60 mg/d, in preventing relapse. In a randomized comparison study, 220 opiate-dependent patients received levomethadyl acetate (LAAM), 75 to 115 mg three times a week; buprenorphine, 16 to 32 mg three times a week; high-dose methadone (60 to 100 mg/d); or low-dose methadone (20 mg/d). Subjects reported using opiates 20 to 30 times in the week before study enrollment. After 17 weeks, treatment retention rates were 58% for buprenorphine, 73% for high-dose methadone, and 20% for low-dose methadone. At the same point, urine samples were negative for opiate use in 40% of patients receiving buprenorphine compared with 39% of those receiving high-dose methadone.10
Buprenorphine is a partial opioid agonist derived from thebaine, an anodyne alkaloid from opium. It binds tightly to the muopiate receptor and produces expected opiate effects such as analgesia and mild euphoria.2 Its partial agonist properties create a ceiling effect and thus a lower likelihood of overdose than with opioid agonists.3
Pharmacokinetics
Buprenorphine has low bioavailability, but its 24- to 60-hour half-life allows once-daily dosing. Because common urine drug screens cannot detect buprenorphine, its use does not cause positive tests for opiates or morphine. Overdose risk is minimal when taken sublingually, with no respiratory depression reported in clinical trials.3,4 The drug is metabolized by the cytochrome P-450 3A4 isoenzyme system and demethylated to norbuprenorphine, which is not significantly bioactive.
Side effects
Nausea, fatigue, constipation, and occasional dysphoria
Abuse potential
Euphoria is less likely with buprenorphine than with opioid agonists because of buprenorphine’s ceiling effects. Theoretically, buprenorphine can be abused by being crushed and injected. The buprenorphine/naloxone combination, if taken parenterally, precipitates opiate withdrawal and thus is preferred for most patients with opioid dependence.
Buprenorphine may be fatal when abused, especially in combination with CNS depressants such as alcohol or high-dose benzodiazepines. However, buprenorphine’s mortality risk remains lower than that of methadone.5
Special precautions
Buprenorphine may precipitate opiate withdrawal during induction when an opioid agonist remains bound to the opiate receptor. Buprenorphine will displace the opiate from the receptor, creating an imbalance in opiate binding that the body interprets as opiate withdrawal.2
To avoid withdrawal, tell the patient not to start buprenorphine until mild withdrawal symptoms occur. In case of withdrawal, tell the patient to continue taking buprenorphine until symptoms are relieved. Adjunctive medications such as benzodiazepines, antiemetics, and antidiarrheals also can be given to control symptoms.
Table
Buprenorphine: A typical dosing strategy
| Phase | Dosage* | Comment |
|---|---|---|
| Induction | Maximum dosage is 32 mg/d; 12 to 24 mg/d typically controls withdrawal symptoms | |
| Day 1 | 4 mg bid (total 8 mg) | |
| Day 2 | 12 mg qd | |
| Day 3 | 16 mg qd | |
| Maintenance | 16 to 24 mg/d is average stabilization dosage | Consider severity of withdrawal symptoms and duration of addiction when deciding when to begin discontinuation |
| Discontinuation | Taper dosage by 2 to 4 mg every 3 to 5 days, then discontinue | Most patients remain on final 2 mg/d at least 1 week; consider alternate-day dosing for patients who experience side effects when attempting to reduce from 2 mg/d to 0 mg/d |
| * Buprenorphine/naloxone is preferred formulation | ||
Slow adoption. Opiate-dependence treatments such as methadone are prescribed in highly regulated environments, which is one reason only 25% of opiate addicts in the United States ever receive treatment.1 Unfortunately, little has changed in the 20 months since the FDA approved buprenorphine for office-based detoxification and maintenance treatment of opiate dependence. More than 2,000 physicians have been trained to use buprenorphine, yet only 20% of them report prescribing it.11
Reasons for this slow introduction include:
- difficulty in obtaining the medication
- lack of appropriate support staff and facilities
- uncertainty about prescribing the medication, despite special training.
Availability. When buprenorphine came to market in late 2003, most commercial pharmacies were not stocking it and it had to be special-ordered. As a result, patients receiving prescriptions had to wait 2 to 3 days for their first dose—a substantial deterrent to prescribing or taking this type of medication. Also, some private physicians and clinics do not keep buprenorphine samples to dispense on-site.
More pharmacies are stocking the medication now, but it remains the physician’s responsibility to ensure that a supply can be dispensed the day it is prescribed.
Support staff and facilities. To prescribe buprenorphine effectively, the physician needs resources for urine testing, physical exams, lab testing, and storing and dispensing buprenorphine. An integrated treatment clinic for opiate-dependent patients, complete with nursing and administrative staff, is ideal. If this support is not available, however, clinicians in private practice can safely prescribe buprenorphine from the office.
Uncertainty. Physicians often adopt new prescription products without hesitation, but buprenorphine’s administration and patient population are unusual. Even some physicians who have taken the special training course remain anxious about using this agent because it may precipitate opiate withdrawal. Also, the training requirement creates a sense that specialist-level knowledge is needed to safely prescribe buprenorphine.
Treatment requirements
For clinicians. The Drug Addiction Treatment Act of 2000 allows physicians to apply for a waiver from the Controlled Substances Act to prescribe buprenorphine for detoxification. A waiver is not required to prescribe buprenorphine for pain.12
To qualify for the waiver, physicians must be board-certified in addiction psychiatry or have completed a buprenorphine training course. Training is offered online and as a 1-day conference by the American Society of Addiction Medicine, American Academy of Addiction Psychiatry, American Medical Association, and American Psychiatric Association.
For patients. Like Mr. T, opiate users who ask about buprenorphine will want to know what to expect from treatment. To be eligible for buprenorphine treatment, a patient must:
- meet criteria for opiate dependence
- commit to keeping regular appointments—at least 3 times a week for the first 2 weeks then usually once weekly until detoxification is complete
- undergo random urine testing
- participate in psychosocial treatments.
So far, patients’ awareness of buprenorphine is highly variable. Asking an opiate user who presents for treatment what he or she knows about buprenorphine can be a useful screening tool. Highly motivated patients will have read about buprenorphine on the Internet, where they probably obtained your office phone number.
When a patient is accepted into treatment, detoxification with buprenorphine includes three phases: induction, stabilization/mainte-nance, and discontinuation.13 After stabilization, some patients remain in maintenance indefinitely and choose not to discontinue buprenorphine. The choice of who to discontinue and who to maintain on buprenorphine is a clinical decision made by the patient and practitioner. Success rates of detoxification with buprenorphine are similar to rates achieved with methadone and clonidine, although most studies have been conducted during buprenorphine maintenance.5
Case continued: Surprised to feel ‘normal’
Mr. T qualified for buprenorphine and came to the office feeling fairly ill. During withdrawal, his usual first symptom is rhinorrhea, followed by malaise, myalgia, restlessness, and intense cravings. His score of 24 on the Clinical Opiate Withdrawal Scale (COWS), indicated moderate withdrawal.
He felt better but not completely well 1 hour after taking buprenorphine/naloxone, 4 mg. He was given a 4-mg tablet to take at home 2 hours later. The next day his COWS score was 8, indicating mild withdrawal. He said he was surprised at how “normal” he was feeling.
Induction: Getting started
Buprenorphine induction is usually done during mild to moderate opiate withdrawal. Starting buprenorphine too soon—while the patient is relatively comfortable—may precipitate withdrawal because the agent will rapidly displace opiate bound to the receptors. In most cases, the first dose is given in the office so that the patient’s response can be monitored.
Two formulations. Buprenorphine comes alone (in 2- or 8-mg tablets) or in combination with naloxone (in 2 mg/0.5 mg and 8 mg/2 mg tablets). Both forms are given sublingually. Contrary to popular belief, IM buprenorphine is not approved for treating opiate addiction.
Naloxone is not absorbed in sublingual form and serves only to deter IV diversion of buprenorphine. Induction with buprenorphine alone is reserved for patients with documented allergy to naloxone or who are being detoxified from long-acting opiates such as methadone.
Dosing strategies are identical for both formulations. The usual starting dosage is 4 mg once daily, with a maximum dosage of 32 mg/d (Table). Withdrawal symptoms are typically controlled with 12 to 24 mg/d.14
If the patient is in active opiate withdrawal, the starting dose usually relieves symptoms in 30 to 45 minutes. If not, a second 4-mg dose can be given. Most patients do not require >8 mg the first day, but some may require 16 to 24 mg to suppress withdrawal symptoms.15
Some clinicians—such as solo practitioners who lack the resources of an outpatient clinic—prefer to have the patient take the first dose at home. Patients are instructed to take the first dose after withdrawal symptoms begin and to repeat the dose in 1 hour if symptoms persist. Thus, patients titrate their own dosages, but the clinician must be immediately available to handle complications. Induction continues until withdrawal symptoms are controlled.
The next day, patients return for evaluation. An objective scale such as the 11-item COWS can quantify withdrawal symptom severity.16 For each symptom—heart rate, nausea, diaphoresis, or restlessness—the COWS assigns a number corresponding to its severity. A total score >25 indicates moderately severe withdrawal.
After withdrawal symptoms are controlled, follow-up visits are scheduled every 2 to 3 days the first week and then weekly. Some physicians maintain daily contact with patients via e-mail or telephone to track symptoms.
Case continued: Steady improvement
By day 3, Mr. T gradually increased his buprenorphine/naloxone dosage to 16 mg once daily. He continued that dosage for 10 days before his next visit. At that point, he was slightly anxious but physically comfortable. He came into the office on days 2, 5, and 10 and his COWS scores decreased each time.
Stabilization and maintenance
When withdrawal symptoms are stabilized, patients begin maintenance therapy at the dosage that stabilized their symptoms. During maintenance therapy, the average buprenorphine dosage is 16 to 24 mg/d. Because of its long half-life, buprenorphine can be taken once daily, though some patients prefer twice-daily dosing for psychological comfort. Several studies comparing buprenorphine with methadone have found that buprenorphine, 8 to 16 mg/d, is similar in effect to approximately 60 mg/d of methadone.5
During the maintenance phase, it is important to have a policy for patients who relapse to substance abuse while taking buprenorphine (Box 2). During buprenorphine maintenance treatment, the estimated relapse rate to opiate use (chance of one positive test for opiates) ranges from 20% to 60%, compared with a relapse rate of 80% to 90% seen with placebo during clinical trials.5
Case continued: Time to taper?
After taking buprenorphine 2 months, Mr. T wants to taper off. He has been seen weekly and receives individual psychotherapy and group counseling. All urine drug screens have been negative for opiates.
With the psychiatrist’s observation, Mr. T. begins to taper his dosage of 16 mg/d by 4 mg a week. He is comfortable when he reaches 4 mg/d, but notices increased anxiety and general achiness when he reduces buprenorphine to 2 mg/d. He elects to remain at 4 mg/d for another 2 months.
Discontinuation
After the patient has reached a stable dose of buprenorphine, the clinician and patient together consider two treatment options:
- sustain the dose as maintenance therapy
- or taper and discontinue buprenorphine.
Screening
Screen patients for alcohol or benzodiazepine use, which may trigger symptoms similar to opiate withdrawal (buprenorphine does not treat withdrawal from these substances)
Induction
Worsening symptoms with buprenorphine indicate that withdrawal was precipitated; repeat buprenorphine dosing until symptoms are relieved (do not exceed 24 mg the first day)
Tell patients:
- to wait as long as possible before taking the first dose to reduce risk of precipitating withdrawal
- not to swallow the sublingual tablet, as this inactivates the medication
- the tablet can take 5 minutes or more to dissolve under the tongue
Maintenance
Set a policy for patients who relapse to substance use while taking buprenorphine. Consequences may include immediate buprenorphine cessation, transfer to methadone treatment, re-induction of buprenorphine, or referral to an inpatient substance abuse treatment center
Tracking
Log how many of your patients are taking buprenorphine; you may not treat more than 30 at a time
Patients who have had multiple relapses and endured severe opiate withdrawal might consider remaining on buprenorphine for several months before tapering. Mild opiate withdrawal may occur if buprenorphine is tapered too rapidly, though this is not as severe or distressing as a full agonist withdrawal.
Tapering recommendations. To taper buprenorphine, reduce by 2 to 4 mg every 3 to 5 days until the patient is taking 2 mg/d. Most patients remain on this dosage at least 1 week and then discontinue. Those who experience side effects when dropping from 2 mg to 0 mg can take 2 mg every other day for 1 week and then discontinue.
After patients are tapered completely off buprenorphine, encourage them to follow up with the treating physician for at least another month. Opiate withdrawal symptoms have been reported to linger 2 to 3 weeks after the last dose of buprenorphine, but these symptoms—usually anxiety or insomnia—tend to be self-limiting.5
Case continued: Time to taper?
Mr. T has been free from heroin use for 4 months and has returned to work. He is rebuilding his life and continues with psychotherapy. He follows up at the buprenorphine clinic monthly for medication management. At each visit, he repeats the COWS test and undergoes a urine drug screen and vital signs check.
Related resources
- Substance Abuse and Mental Health Services Administration. Physician locator for buprenorphine providers.
- American Academy of Addiction Psychiatry. Information about buprenorphine training course. www.aaap.org/buprenorphine/buprenorphine.html
- Buprenorphine manufacturer’s Web site. Answers to frequently-asked questions. www.suboxone.com
Drug brand names
- Buprenorphine • Subutex
- Buprenorphine/naloxone • Suboxone
- Buprenorphine (IM) • Buprenex
- Clonidine • Catapres
1. Vastag B. In-office opiate treatment, “not a panacea:” physicians slow to embrace therapeutic option. JAMA 2003;290:731-5.
2. Marquet P. Pharmacology of high-dose buprenorphine. In: Kintz P, Marquet P (eds). Buprenorphine therapy of opiate addiction. Totowa, NJ: Humana Press, 2002;69-82.
3. Boyd J, Randell T, Luurila H, Kuisma M. Serious overdoses involving buprenorphine in Helsinki. Acta Anaesthesiol Scand 2003;47:1031-3.
4. Johnson RE, Cone EJ, Henningfield JE, Fudala PJ. Use of buprenorphine in the treatment of opiate addiction. Clin Pharmacol Ther 1989;46:335-43.
5. Johnson RE, Strain EC, Amass L. Buprenorphine: how to use it right. Drug Alcohol Depend 2003;70:S59-S77.
6. Breen CL, Harris SJ, Lintzeris N, et al. Cessation of methadone maintenance treatment using buprenorphine: transfer from methadone to buprenorphine and subsequent buprenorphine reductions. Drug Alcohol Depend 2003;71:49-55.
7. Fudala PJ, Bridge PT, Herbert S, et al. Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone. N Engl J Med 2003;349:949-58.
8. Ling W, Wesson DR. Clinical efficacy of buprenorphine: comparisons to methadone and placebo. Drug Alcohol Depend 2003;70:S49-S57.
9. Gibson AE, Doran CM, Bell JR, et al. A comparison of buprenorphine treatment in clinic and primary care settings; a randomised trial. Med J Aust 2003;179:38-42.
10. Johnson RE, Chutuape MA, Strain EC, et al. A comparison of levomethadyl acetate, buprenorphine and methadone for opioid dependence. N Engl J Med 2000;343:1290-7.
11. Bivol S. National poll of physicians on barriers to widespread buprenorphine use. Boston University School of Public Health, Join Together 2003;1-7.
12. Clark HW. Office-based practice and opioid-use disorders. N Engl J Med 2003;349:928-30.
13. Ling W, Smith D. Buprenorphine: blending practice and research. J Subst Abuse Treat 2002;23:87-92.
14. Fiellin DA, Pantalon MV, Pakes JP, et al. Treatment of heroin dependence with buprenorphine in primary care. Am J Drug Alcohol Abuse 2002;28:231-41.
15. Greenwald MK, Schuh KJ, Stine SM. Transferring methadone-maintained outpatients to the buprenorphine sublingual tablet: a preliminary study. Am J Addict 2003;12:365-74.
16. Wesson DR, Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs 2003;35:253-9.
After 10 years of heroin dependence, Mr. T, age 36, calls your office and says, “I want to get off heroin.” For 8 months, he’s been using IV heroin 2 to 3 times daily. He says he has tried methadone treatment but found daily dosing cumbersome.
He found your office number on the Substance Abuse and Mental Health Services Administration Web site, which lists physicians qualified to prescribe buprenorphine for opiate detoxification. He has heard about “bup” on the street and wants to know if he is eligible and what he can expect from treatment.
Like Mr. T, 1 million Americans are addicted to opiates.1 As qualified physicians gain experience with using buprenorphine, this agent could revolutionize how opiate-dependent patients are routinely treated. Instead of receiving methadone only in specialized clinics, they can now choose to be treated in physicians’ offices.
Several obstacles, however, are preventing widespread buprenorphine use:
- Too few physicians are trained to offer this office-based treatment.
- Many of the 2,000 doctors who are trained remain uncertain about using buprenorphine.
This article is intended to help overcome obstacles to opiate-dependence treatment by familiarizing psychiatrists—whether trained or not in using buprenorphine—with evidence of this agent’s efficacy and its advantages compared with other treatments.
Efficacy and obstacles
Buprenorphine is a partial opioid agonist that binds to the mu receptor (Box 1).2-5 It is a controlled substance (schedule-III narcotic). Outpatient trials have shown that buprenorphine is more effective than placebo and as effective as methadone for opiate detoxification.6-10
In one of the largest trials, 326 opiate-dependent outpatients were randomly assigned to buprenorphine, buprenorphine/naloxone combination, or placebo for 4 weeks. Both buprenorphine forms were more effective than placebo, as measured by clean urine samples and patient reports of reduced opiate cravings.7
In maintenance treatment, buprenorphine has been shown to be more effective than placebo and as effective as methadone, 60 mg/d, in preventing relapse. In a randomized comparison study, 220 opiate-dependent patients received levomethadyl acetate (LAAM), 75 to 115 mg three times a week; buprenorphine, 16 to 32 mg three times a week; high-dose methadone (60 to 100 mg/d); or low-dose methadone (20 mg/d). Subjects reported using opiates 20 to 30 times in the week before study enrollment. After 17 weeks, treatment retention rates were 58% for buprenorphine, 73% for high-dose methadone, and 20% for low-dose methadone. At the same point, urine samples were negative for opiate use in 40% of patients receiving buprenorphine compared with 39% of those receiving high-dose methadone.10
Buprenorphine is a partial opioid agonist derived from thebaine, an anodyne alkaloid from opium. It binds tightly to the muopiate receptor and produces expected opiate effects such as analgesia and mild euphoria.2 Its partial agonist properties create a ceiling effect and thus a lower likelihood of overdose than with opioid agonists.3
Pharmacokinetics
Buprenorphine has low bioavailability, but its 24- to 60-hour half-life allows once-daily dosing. Because common urine drug screens cannot detect buprenorphine, its use does not cause positive tests for opiates or morphine. Overdose risk is minimal when taken sublingually, with no respiratory depression reported in clinical trials.3,4 The drug is metabolized by the cytochrome P-450 3A4 isoenzyme system and demethylated to norbuprenorphine, which is not significantly bioactive.
Side effects
Nausea, fatigue, constipation, and occasional dysphoria
Abuse potential
Euphoria is less likely with buprenorphine than with opioid agonists because of buprenorphine’s ceiling effects. Theoretically, buprenorphine can be abused by being crushed and injected. The buprenorphine/naloxone combination, if taken parenterally, precipitates opiate withdrawal and thus is preferred for most patients with opioid dependence.
Buprenorphine may be fatal when abused, especially in combination with CNS depressants such as alcohol or high-dose benzodiazepines. However, buprenorphine’s mortality risk remains lower than that of methadone.5
Special precautions
Buprenorphine may precipitate opiate withdrawal during induction when an opioid agonist remains bound to the opiate receptor. Buprenorphine will displace the opiate from the receptor, creating an imbalance in opiate binding that the body interprets as opiate withdrawal.2
To avoid withdrawal, tell the patient not to start buprenorphine until mild withdrawal symptoms occur. In case of withdrawal, tell the patient to continue taking buprenorphine until symptoms are relieved. Adjunctive medications such as benzodiazepines, antiemetics, and antidiarrheals also can be given to control symptoms.
Table
Buprenorphine: A typical dosing strategy
| Phase | Dosage* | Comment |
|---|---|---|
| Induction | Maximum dosage is 32 mg/d; 12 to 24 mg/d typically controls withdrawal symptoms | |
| Day 1 | 4 mg bid (total 8 mg) | |
| Day 2 | 12 mg qd | |
| Day 3 | 16 mg qd | |
| Maintenance | 16 to 24 mg/d is average stabilization dosage | Consider severity of withdrawal symptoms and duration of addiction when deciding when to begin discontinuation |
| Discontinuation | Taper dosage by 2 to 4 mg every 3 to 5 days, then discontinue | Most patients remain on final 2 mg/d at least 1 week; consider alternate-day dosing for patients who experience side effects when attempting to reduce from 2 mg/d to 0 mg/d |
| * Buprenorphine/naloxone is preferred formulation | ||
Slow adoption. Opiate-dependence treatments such as methadone are prescribed in highly regulated environments, which is one reason only 25% of opiate addicts in the United States ever receive treatment.1 Unfortunately, little has changed in the 20 months since the FDA approved buprenorphine for office-based detoxification and maintenance treatment of opiate dependence. More than 2,000 physicians have been trained to use buprenorphine, yet only 20% of them report prescribing it.11
Reasons for this slow introduction include:
- difficulty in obtaining the medication
- lack of appropriate support staff and facilities
- uncertainty about prescribing the medication, despite special training.
Availability. When buprenorphine came to market in late 2003, most commercial pharmacies were not stocking it and it had to be special-ordered. As a result, patients receiving prescriptions had to wait 2 to 3 days for their first dose—a substantial deterrent to prescribing or taking this type of medication. Also, some private physicians and clinics do not keep buprenorphine samples to dispense on-site.
More pharmacies are stocking the medication now, but it remains the physician’s responsibility to ensure that a supply can be dispensed the day it is prescribed.
Support staff and facilities. To prescribe buprenorphine effectively, the physician needs resources for urine testing, physical exams, lab testing, and storing and dispensing buprenorphine. An integrated treatment clinic for opiate-dependent patients, complete with nursing and administrative staff, is ideal. If this support is not available, however, clinicians in private practice can safely prescribe buprenorphine from the office.
Uncertainty. Physicians often adopt new prescription products without hesitation, but buprenorphine’s administration and patient population are unusual. Even some physicians who have taken the special training course remain anxious about using this agent because it may precipitate opiate withdrawal. Also, the training requirement creates a sense that specialist-level knowledge is needed to safely prescribe buprenorphine.
Treatment requirements
For clinicians. The Drug Addiction Treatment Act of 2000 allows physicians to apply for a waiver from the Controlled Substances Act to prescribe buprenorphine for detoxification. A waiver is not required to prescribe buprenorphine for pain.12
To qualify for the waiver, physicians must be board-certified in addiction psychiatry or have completed a buprenorphine training course. Training is offered online and as a 1-day conference by the American Society of Addiction Medicine, American Academy of Addiction Psychiatry, American Medical Association, and American Psychiatric Association.
For patients. Like Mr. T, opiate users who ask about buprenorphine will want to know what to expect from treatment. To be eligible for buprenorphine treatment, a patient must:
- meet criteria for opiate dependence
- commit to keeping regular appointments—at least 3 times a week for the first 2 weeks then usually once weekly until detoxification is complete
- undergo random urine testing
- participate in psychosocial treatments.
So far, patients’ awareness of buprenorphine is highly variable. Asking an opiate user who presents for treatment what he or she knows about buprenorphine can be a useful screening tool. Highly motivated patients will have read about buprenorphine on the Internet, where they probably obtained your office phone number.
When a patient is accepted into treatment, detoxification with buprenorphine includes three phases: induction, stabilization/mainte-nance, and discontinuation.13 After stabilization, some patients remain in maintenance indefinitely and choose not to discontinue buprenorphine. The choice of who to discontinue and who to maintain on buprenorphine is a clinical decision made by the patient and practitioner. Success rates of detoxification with buprenorphine are similar to rates achieved with methadone and clonidine, although most studies have been conducted during buprenorphine maintenance.5
Case continued: Surprised to feel ‘normal’
Mr. T qualified for buprenorphine and came to the office feeling fairly ill. During withdrawal, his usual first symptom is rhinorrhea, followed by malaise, myalgia, restlessness, and intense cravings. His score of 24 on the Clinical Opiate Withdrawal Scale (COWS), indicated moderate withdrawal.
He felt better but not completely well 1 hour after taking buprenorphine/naloxone, 4 mg. He was given a 4-mg tablet to take at home 2 hours later. The next day his COWS score was 8, indicating mild withdrawal. He said he was surprised at how “normal” he was feeling.
Induction: Getting started
Buprenorphine induction is usually done during mild to moderate opiate withdrawal. Starting buprenorphine too soon—while the patient is relatively comfortable—may precipitate withdrawal because the agent will rapidly displace opiate bound to the receptors. In most cases, the first dose is given in the office so that the patient’s response can be monitored.
Two formulations. Buprenorphine comes alone (in 2- or 8-mg tablets) or in combination with naloxone (in 2 mg/0.5 mg and 8 mg/2 mg tablets). Both forms are given sublingually. Contrary to popular belief, IM buprenorphine is not approved for treating opiate addiction.
Naloxone is not absorbed in sublingual form and serves only to deter IV diversion of buprenorphine. Induction with buprenorphine alone is reserved for patients with documented allergy to naloxone or who are being detoxified from long-acting opiates such as methadone.
Dosing strategies are identical for both formulations. The usual starting dosage is 4 mg once daily, with a maximum dosage of 32 mg/d (Table). Withdrawal symptoms are typically controlled with 12 to 24 mg/d.14
If the patient is in active opiate withdrawal, the starting dose usually relieves symptoms in 30 to 45 minutes. If not, a second 4-mg dose can be given. Most patients do not require >8 mg the first day, but some may require 16 to 24 mg to suppress withdrawal symptoms.15
Some clinicians—such as solo practitioners who lack the resources of an outpatient clinic—prefer to have the patient take the first dose at home. Patients are instructed to take the first dose after withdrawal symptoms begin and to repeat the dose in 1 hour if symptoms persist. Thus, patients titrate their own dosages, but the clinician must be immediately available to handle complications. Induction continues until withdrawal symptoms are controlled.
The next day, patients return for evaluation. An objective scale such as the 11-item COWS can quantify withdrawal symptom severity.16 For each symptom—heart rate, nausea, diaphoresis, or restlessness—the COWS assigns a number corresponding to its severity. A total score >25 indicates moderately severe withdrawal.
After withdrawal symptoms are controlled, follow-up visits are scheduled every 2 to 3 days the first week and then weekly. Some physicians maintain daily contact with patients via e-mail or telephone to track symptoms.
Case continued: Steady improvement
By day 3, Mr. T gradually increased his buprenorphine/naloxone dosage to 16 mg once daily. He continued that dosage for 10 days before his next visit. At that point, he was slightly anxious but physically comfortable. He came into the office on days 2, 5, and 10 and his COWS scores decreased each time.
Stabilization and maintenance
When withdrawal symptoms are stabilized, patients begin maintenance therapy at the dosage that stabilized their symptoms. During maintenance therapy, the average buprenorphine dosage is 16 to 24 mg/d. Because of its long half-life, buprenorphine can be taken once daily, though some patients prefer twice-daily dosing for psychological comfort. Several studies comparing buprenorphine with methadone have found that buprenorphine, 8 to 16 mg/d, is similar in effect to approximately 60 mg/d of methadone.5
During the maintenance phase, it is important to have a policy for patients who relapse to substance abuse while taking buprenorphine (Box 2). During buprenorphine maintenance treatment, the estimated relapse rate to opiate use (chance of one positive test for opiates) ranges from 20% to 60%, compared with a relapse rate of 80% to 90% seen with placebo during clinical trials.5
Case continued: Time to taper?
After taking buprenorphine 2 months, Mr. T wants to taper off. He has been seen weekly and receives individual psychotherapy and group counseling. All urine drug screens have been negative for opiates.
With the psychiatrist’s observation, Mr. T. begins to taper his dosage of 16 mg/d by 4 mg a week. He is comfortable when he reaches 4 mg/d, but notices increased anxiety and general achiness when he reduces buprenorphine to 2 mg/d. He elects to remain at 4 mg/d for another 2 months.
Discontinuation
After the patient has reached a stable dose of buprenorphine, the clinician and patient together consider two treatment options:
- sustain the dose as maintenance therapy
- or taper and discontinue buprenorphine.
Screening
Screen patients for alcohol or benzodiazepine use, which may trigger symptoms similar to opiate withdrawal (buprenorphine does not treat withdrawal from these substances)
Induction
Worsening symptoms with buprenorphine indicate that withdrawal was precipitated; repeat buprenorphine dosing until symptoms are relieved (do not exceed 24 mg the first day)
Tell patients:
- to wait as long as possible before taking the first dose to reduce risk of precipitating withdrawal
- not to swallow the sublingual tablet, as this inactivates the medication
- the tablet can take 5 minutes or more to dissolve under the tongue
Maintenance
Set a policy for patients who relapse to substance use while taking buprenorphine. Consequences may include immediate buprenorphine cessation, transfer to methadone treatment, re-induction of buprenorphine, or referral to an inpatient substance abuse treatment center
Tracking
Log how many of your patients are taking buprenorphine; you may not treat more than 30 at a time
Patients who have had multiple relapses and endured severe opiate withdrawal might consider remaining on buprenorphine for several months before tapering. Mild opiate withdrawal may occur if buprenorphine is tapered too rapidly, though this is not as severe or distressing as a full agonist withdrawal.
Tapering recommendations. To taper buprenorphine, reduce by 2 to 4 mg every 3 to 5 days until the patient is taking 2 mg/d. Most patients remain on this dosage at least 1 week and then discontinue. Those who experience side effects when dropping from 2 mg to 0 mg can take 2 mg every other day for 1 week and then discontinue.
After patients are tapered completely off buprenorphine, encourage them to follow up with the treating physician for at least another month. Opiate withdrawal symptoms have been reported to linger 2 to 3 weeks after the last dose of buprenorphine, but these symptoms—usually anxiety or insomnia—tend to be self-limiting.5
Case continued: Time to taper?
Mr. T has been free from heroin use for 4 months and has returned to work. He is rebuilding his life and continues with psychotherapy. He follows up at the buprenorphine clinic monthly for medication management. At each visit, he repeats the COWS test and undergoes a urine drug screen and vital signs check.
Related resources
- Substance Abuse and Mental Health Services Administration. Physician locator for buprenorphine providers.
- American Academy of Addiction Psychiatry. Information about buprenorphine training course. www.aaap.org/buprenorphine/buprenorphine.html
- Buprenorphine manufacturer’s Web site. Answers to frequently-asked questions. www.suboxone.com
Drug brand names
- Buprenorphine • Subutex
- Buprenorphine/naloxone • Suboxone
- Buprenorphine (IM) • Buprenex
- Clonidine • Catapres
After 10 years of heroin dependence, Mr. T, age 36, calls your office and says, “I want to get off heroin.” For 8 months, he’s been using IV heroin 2 to 3 times daily. He says he has tried methadone treatment but found daily dosing cumbersome.
He found your office number on the Substance Abuse and Mental Health Services Administration Web site, which lists physicians qualified to prescribe buprenorphine for opiate detoxification. He has heard about “bup” on the street and wants to know if he is eligible and what he can expect from treatment.
Like Mr. T, 1 million Americans are addicted to opiates.1 As qualified physicians gain experience with using buprenorphine, this agent could revolutionize how opiate-dependent patients are routinely treated. Instead of receiving methadone only in specialized clinics, they can now choose to be treated in physicians’ offices.
Several obstacles, however, are preventing widespread buprenorphine use:
- Too few physicians are trained to offer this office-based treatment.
- Many of the 2,000 doctors who are trained remain uncertain about using buprenorphine.
This article is intended to help overcome obstacles to opiate-dependence treatment by familiarizing psychiatrists—whether trained or not in using buprenorphine—with evidence of this agent’s efficacy and its advantages compared with other treatments.
Efficacy and obstacles
Buprenorphine is a partial opioid agonist that binds to the mu receptor (Box 1).2-5 It is a controlled substance (schedule-III narcotic). Outpatient trials have shown that buprenorphine is more effective than placebo and as effective as methadone for opiate detoxification.6-10
In one of the largest trials, 326 opiate-dependent outpatients were randomly assigned to buprenorphine, buprenorphine/naloxone combination, or placebo for 4 weeks. Both buprenorphine forms were more effective than placebo, as measured by clean urine samples and patient reports of reduced opiate cravings.7
In maintenance treatment, buprenorphine has been shown to be more effective than placebo and as effective as methadone, 60 mg/d, in preventing relapse. In a randomized comparison study, 220 opiate-dependent patients received levomethadyl acetate (LAAM), 75 to 115 mg three times a week; buprenorphine, 16 to 32 mg three times a week; high-dose methadone (60 to 100 mg/d); or low-dose methadone (20 mg/d). Subjects reported using opiates 20 to 30 times in the week before study enrollment. After 17 weeks, treatment retention rates were 58% for buprenorphine, 73% for high-dose methadone, and 20% for low-dose methadone. At the same point, urine samples were negative for opiate use in 40% of patients receiving buprenorphine compared with 39% of those receiving high-dose methadone.10
Buprenorphine is a partial opioid agonist derived from thebaine, an anodyne alkaloid from opium. It binds tightly to the muopiate receptor and produces expected opiate effects such as analgesia and mild euphoria.2 Its partial agonist properties create a ceiling effect and thus a lower likelihood of overdose than with opioid agonists.3
Pharmacokinetics
Buprenorphine has low bioavailability, but its 24- to 60-hour half-life allows once-daily dosing. Because common urine drug screens cannot detect buprenorphine, its use does not cause positive tests for opiates or morphine. Overdose risk is minimal when taken sublingually, with no respiratory depression reported in clinical trials.3,4 The drug is metabolized by the cytochrome P-450 3A4 isoenzyme system and demethylated to norbuprenorphine, which is not significantly bioactive.
Side effects
Nausea, fatigue, constipation, and occasional dysphoria
Abuse potential
Euphoria is less likely with buprenorphine than with opioid agonists because of buprenorphine’s ceiling effects. Theoretically, buprenorphine can be abused by being crushed and injected. The buprenorphine/naloxone combination, if taken parenterally, precipitates opiate withdrawal and thus is preferred for most patients with opioid dependence.
Buprenorphine may be fatal when abused, especially in combination with CNS depressants such as alcohol or high-dose benzodiazepines. However, buprenorphine’s mortality risk remains lower than that of methadone.5
Special precautions
Buprenorphine may precipitate opiate withdrawal during induction when an opioid agonist remains bound to the opiate receptor. Buprenorphine will displace the opiate from the receptor, creating an imbalance in opiate binding that the body interprets as opiate withdrawal.2
To avoid withdrawal, tell the patient not to start buprenorphine until mild withdrawal symptoms occur. In case of withdrawal, tell the patient to continue taking buprenorphine until symptoms are relieved. Adjunctive medications such as benzodiazepines, antiemetics, and antidiarrheals also can be given to control symptoms.
Table
Buprenorphine: A typical dosing strategy
| Phase | Dosage* | Comment |
|---|---|---|
| Induction | Maximum dosage is 32 mg/d; 12 to 24 mg/d typically controls withdrawal symptoms | |
| Day 1 | 4 mg bid (total 8 mg) | |
| Day 2 | 12 mg qd | |
| Day 3 | 16 mg qd | |
| Maintenance | 16 to 24 mg/d is average stabilization dosage | Consider severity of withdrawal symptoms and duration of addiction when deciding when to begin discontinuation |
| Discontinuation | Taper dosage by 2 to 4 mg every 3 to 5 days, then discontinue | Most patients remain on final 2 mg/d at least 1 week; consider alternate-day dosing for patients who experience side effects when attempting to reduce from 2 mg/d to 0 mg/d |
| * Buprenorphine/naloxone is preferred formulation | ||
Slow adoption. Opiate-dependence treatments such as methadone are prescribed in highly regulated environments, which is one reason only 25% of opiate addicts in the United States ever receive treatment.1 Unfortunately, little has changed in the 20 months since the FDA approved buprenorphine for office-based detoxification and maintenance treatment of opiate dependence. More than 2,000 physicians have been trained to use buprenorphine, yet only 20% of them report prescribing it.11
Reasons for this slow introduction include:
- difficulty in obtaining the medication
- lack of appropriate support staff and facilities
- uncertainty about prescribing the medication, despite special training.
Availability. When buprenorphine came to market in late 2003, most commercial pharmacies were not stocking it and it had to be special-ordered. As a result, patients receiving prescriptions had to wait 2 to 3 days for their first dose—a substantial deterrent to prescribing or taking this type of medication. Also, some private physicians and clinics do not keep buprenorphine samples to dispense on-site.
More pharmacies are stocking the medication now, but it remains the physician’s responsibility to ensure that a supply can be dispensed the day it is prescribed.
Support staff and facilities. To prescribe buprenorphine effectively, the physician needs resources for urine testing, physical exams, lab testing, and storing and dispensing buprenorphine. An integrated treatment clinic for opiate-dependent patients, complete with nursing and administrative staff, is ideal. If this support is not available, however, clinicians in private practice can safely prescribe buprenorphine from the office.
Uncertainty. Physicians often adopt new prescription products without hesitation, but buprenorphine’s administration and patient population are unusual. Even some physicians who have taken the special training course remain anxious about using this agent because it may precipitate opiate withdrawal. Also, the training requirement creates a sense that specialist-level knowledge is needed to safely prescribe buprenorphine.
Treatment requirements
For clinicians. The Drug Addiction Treatment Act of 2000 allows physicians to apply for a waiver from the Controlled Substances Act to prescribe buprenorphine for detoxification. A waiver is not required to prescribe buprenorphine for pain.12
To qualify for the waiver, physicians must be board-certified in addiction psychiatry or have completed a buprenorphine training course. Training is offered online and as a 1-day conference by the American Society of Addiction Medicine, American Academy of Addiction Psychiatry, American Medical Association, and American Psychiatric Association.
For patients. Like Mr. T, opiate users who ask about buprenorphine will want to know what to expect from treatment. To be eligible for buprenorphine treatment, a patient must:
- meet criteria for opiate dependence
- commit to keeping regular appointments—at least 3 times a week for the first 2 weeks then usually once weekly until detoxification is complete
- undergo random urine testing
- participate in psychosocial treatments.
So far, patients’ awareness of buprenorphine is highly variable. Asking an opiate user who presents for treatment what he or she knows about buprenorphine can be a useful screening tool. Highly motivated patients will have read about buprenorphine on the Internet, where they probably obtained your office phone number.
When a patient is accepted into treatment, detoxification with buprenorphine includes three phases: induction, stabilization/mainte-nance, and discontinuation.13 After stabilization, some patients remain in maintenance indefinitely and choose not to discontinue buprenorphine. The choice of who to discontinue and who to maintain on buprenorphine is a clinical decision made by the patient and practitioner. Success rates of detoxification with buprenorphine are similar to rates achieved with methadone and clonidine, although most studies have been conducted during buprenorphine maintenance.5
Case continued: Surprised to feel ‘normal’
Mr. T qualified for buprenorphine and came to the office feeling fairly ill. During withdrawal, his usual first symptom is rhinorrhea, followed by malaise, myalgia, restlessness, and intense cravings. His score of 24 on the Clinical Opiate Withdrawal Scale (COWS), indicated moderate withdrawal.
He felt better but not completely well 1 hour after taking buprenorphine/naloxone, 4 mg. He was given a 4-mg tablet to take at home 2 hours later. The next day his COWS score was 8, indicating mild withdrawal. He said he was surprised at how “normal” he was feeling.
Induction: Getting started
Buprenorphine induction is usually done during mild to moderate opiate withdrawal. Starting buprenorphine too soon—while the patient is relatively comfortable—may precipitate withdrawal because the agent will rapidly displace opiate bound to the receptors. In most cases, the first dose is given in the office so that the patient’s response can be monitored.
Two formulations. Buprenorphine comes alone (in 2- or 8-mg tablets) or in combination with naloxone (in 2 mg/0.5 mg and 8 mg/2 mg tablets). Both forms are given sublingually. Contrary to popular belief, IM buprenorphine is not approved for treating opiate addiction.
Naloxone is not absorbed in sublingual form and serves only to deter IV diversion of buprenorphine. Induction with buprenorphine alone is reserved for patients with documented allergy to naloxone or who are being detoxified from long-acting opiates such as methadone.
Dosing strategies are identical for both formulations. The usual starting dosage is 4 mg once daily, with a maximum dosage of 32 mg/d (Table). Withdrawal symptoms are typically controlled with 12 to 24 mg/d.14
If the patient is in active opiate withdrawal, the starting dose usually relieves symptoms in 30 to 45 minutes. If not, a second 4-mg dose can be given. Most patients do not require >8 mg the first day, but some may require 16 to 24 mg to suppress withdrawal symptoms.15
Some clinicians—such as solo practitioners who lack the resources of an outpatient clinic—prefer to have the patient take the first dose at home. Patients are instructed to take the first dose after withdrawal symptoms begin and to repeat the dose in 1 hour if symptoms persist. Thus, patients titrate their own dosages, but the clinician must be immediately available to handle complications. Induction continues until withdrawal symptoms are controlled.
The next day, patients return for evaluation. An objective scale such as the 11-item COWS can quantify withdrawal symptom severity.16 For each symptom—heart rate, nausea, diaphoresis, or restlessness—the COWS assigns a number corresponding to its severity. A total score >25 indicates moderately severe withdrawal.
After withdrawal symptoms are controlled, follow-up visits are scheduled every 2 to 3 days the first week and then weekly. Some physicians maintain daily contact with patients via e-mail or telephone to track symptoms.
Case continued: Steady improvement
By day 3, Mr. T gradually increased his buprenorphine/naloxone dosage to 16 mg once daily. He continued that dosage for 10 days before his next visit. At that point, he was slightly anxious but physically comfortable. He came into the office on days 2, 5, and 10 and his COWS scores decreased each time.
Stabilization and maintenance
When withdrawal symptoms are stabilized, patients begin maintenance therapy at the dosage that stabilized their symptoms. During maintenance therapy, the average buprenorphine dosage is 16 to 24 mg/d. Because of its long half-life, buprenorphine can be taken once daily, though some patients prefer twice-daily dosing for psychological comfort. Several studies comparing buprenorphine with methadone have found that buprenorphine, 8 to 16 mg/d, is similar in effect to approximately 60 mg/d of methadone.5
During the maintenance phase, it is important to have a policy for patients who relapse to substance abuse while taking buprenorphine (Box 2). During buprenorphine maintenance treatment, the estimated relapse rate to opiate use (chance of one positive test for opiates) ranges from 20% to 60%, compared with a relapse rate of 80% to 90% seen with placebo during clinical trials.5
Case continued: Time to taper?
After taking buprenorphine 2 months, Mr. T wants to taper off. He has been seen weekly and receives individual psychotherapy and group counseling. All urine drug screens have been negative for opiates.
With the psychiatrist’s observation, Mr. T. begins to taper his dosage of 16 mg/d by 4 mg a week. He is comfortable when he reaches 4 mg/d, but notices increased anxiety and general achiness when he reduces buprenorphine to 2 mg/d. He elects to remain at 4 mg/d for another 2 months.
Discontinuation
After the patient has reached a stable dose of buprenorphine, the clinician and patient together consider two treatment options:
- sustain the dose as maintenance therapy
- or taper and discontinue buprenorphine.
Screening
Screen patients for alcohol or benzodiazepine use, which may trigger symptoms similar to opiate withdrawal (buprenorphine does not treat withdrawal from these substances)
Induction
Worsening symptoms with buprenorphine indicate that withdrawal was precipitated; repeat buprenorphine dosing until symptoms are relieved (do not exceed 24 mg the first day)
Tell patients:
- to wait as long as possible before taking the first dose to reduce risk of precipitating withdrawal
- not to swallow the sublingual tablet, as this inactivates the medication
- the tablet can take 5 minutes or more to dissolve under the tongue
Maintenance
Set a policy for patients who relapse to substance use while taking buprenorphine. Consequences may include immediate buprenorphine cessation, transfer to methadone treatment, re-induction of buprenorphine, or referral to an inpatient substance abuse treatment center
Tracking
Log how many of your patients are taking buprenorphine; you may not treat more than 30 at a time
Patients who have had multiple relapses and endured severe opiate withdrawal might consider remaining on buprenorphine for several months before tapering. Mild opiate withdrawal may occur if buprenorphine is tapered too rapidly, though this is not as severe or distressing as a full agonist withdrawal.
Tapering recommendations. To taper buprenorphine, reduce by 2 to 4 mg every 3 to 5 days until the patient is taking 2 mg/d. Most patients remain on this dosage at least 1 week and then discontinue. Those who experience side effects when dropping from 2 mg to 0 mg can take 2 mg every other day for 1 week and then discontinue.
After patients are tapered completely off buprenorphine, encourage them to follow up with the treating physician for at least another month. Opiate withdrawal symptoms have been reported to linger 2 to 3 weeks after the last dose of buprenorphine, but these symptoms—usually anxiety or insomnia—tend to be self-limiting.5
Case continued: Time to taper?
Mr. T has been free from heroin use for 4 months and has returned to work. He is rebuilding his life and continues with psychotherapy. He follows up at the buprenorphine clinic monthly for medication management. At each visit, he repeats the COWS test and undergoes a urine drug screen and vital signs check.
Related resources
- Substance Abuse and Mental Health Services Administration. Physician locator for buprenorphine providers.
- American Academy of Addiction Psychiatry. Information about buprenorphine training course. www.aaap.org/buprenorphine/buprenorphine.html
- Buprenorphine manufacturer’s Web site. Answers to frequently-asked questions. www.suboxone.com
Drug brand names
- Buprenorphine • Subutex
- Buprenorphine/naloxone • Suboxone
- Buprenorphine (IM) • Buprenex
- Clonidine • Catapres
1. Vastag B. In-office opiate treatment, “not a panacea:” physicians slow to embrace therapeutic option. JAMA 2003;290:731-5.
2. Marquet P. Pharmacology of high-dose buprenorphine. In: Kintz P, Marquet P (eds). Buprenorphine therapy of opiate addiction. Totowa, NJ: Humana Press, 2002;69-82.
3. Boyd J, Randell T, Luurila H, Kuisma M. Serious overdoses involving buprenorphine in Helsinki. Acta Anaesthesiol Scand 2003;47:1031-3.
4. Johnson RE, Cone EJ, Henningfield JE, Fudala PJ. Use of buprenorphine in the treatment of opiate addiction. Clin Pharmacol Ther 1989;46:335-43.
5. Johnson RE, Strain EC, Amass L. Buprenorphine: how to use it right. Drug Alcohol Depend 2003;70:S59-S77.
6. Breen CL, Harris SJ, Lintzeris N, et al. Cessation of methadone maintenance treatment using buprenorphine: transfer from methadone to buprenorphine and subsequent buprenorphine reductions. Drug Alcohol Depend 2003;71:49-55.
7. Fudala PJ, Bridge PT, Herbert S, et al. Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone. N Engl J Med 2003;349:949-58.
8. Ling W, Wesson DR. Clinical efficacy of buprenorphine: comparisons to methadone and placebo. Drug Alcohol Depend 2003;70:S49-S57.
9. Gibson AE, Doran CM, Bell JR, et al. A comparison of buprenorphine treatment in clinic and primary care settings; a randomised trial. Med J Aust 2003;179:38-42.
10. Johnson RE, Chutuape MA, Strain EC, et al. A comparison of levomethadyl acetate, buprenorphine and methadone for opioid dependence. N Engl J Med 2000;343:1290-7.
11. Bivol S. National poll of physicians on barriers to widespread buprenorphine use. Boston University School of Public Health, Join Together 2003;1-7.
12. Clark HW. Office-based practice and opioid-use disorders. N Engl J Med 2003;349:928-30.
13. Ling W, Smith D. Buprenorphine: blending practice and research. J Subst Abuse Treat 2002;23:87-92.
14. Fiellin DA, Pantalon MV, Pakes JP, et al. Treatment of heroin dependence with buprenorphine in primary care. Am J Drug Alcohol Abuse 2002;28:231-41.
15. Greenwald MK, Schuh KJ, Stine SM. Transferring methadone-maintained outpatients to the buprenorphine sublingual tablet: a preliminary study. Am J Addict 2003;12:365-74.
16. Wesson DR, Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs 2003;35:253-9.
1. Vastag B. In-office opiate treatment, “not a panacea:” physicians slow to embrace therapeutic option. JAMA 2003;290:731-5.
2. Marquet P. Pharmacology of high-dose buprenorphine. In: Kintz P, Marquet P (eds). Buprenorphine therapy of opiate addiction. Totowa, NJ: Humana Press, 2002;69-82.
3. Boyd J, Randell T, Luurila H, Kuisma M. Serious overdoses involving buprenorphine in Helsinki. Acta Anaesthesiol Scand 2003;47:1031-3.
4. Johnson RE, Cone EJ, Henningfield JE, Fudala PJ. Use of buprenorphine in the treatment of opiate addiction. Clin Pharmacol Ther 1989;46:335-43.
5. Johnson RE, Strain EC, Amass L. Buprenorphine: how to use it right. Drug Alcohol Depend 2003;70:S59-S77.
6. Breen CL, Harris SJ, Lintzeris N, et al. Cessation of methadone maintenance treatment using buprenorphine: transfer from methadone to buprenorphine and subsequent buprenorphine reductions. Drug Alcohol Depend 2003;71:49-55.
7. Fudala PJ, Bridge PT, Herbert S, et al. Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone. N Engl J Med 2003;349:949-58.
8. Ling W, Wesson DR. Clinical efficacy of buprenorphine: comparisons to methadone and placebo. Drug Alcohol Depend 2003;70:S49-S57.
9. Gibson AE, Doran CM, Bell JR, et al. A comparison of buprenorphine treatment in clinic and primary care settings; a randomised trial. Med J Aust 2003;179:38-42.
10. Johnson RE, Chutuape MA, Strain EC, et al. A comparison of levomethadyl acetate, buprenorphine and methadone for opioid dependence. N Engl J Med 2000;343:1290-7.
11. Bivol S. National poll of physicians on barriers to widespread buprenorphine use. Boston University School of Public Health, Join Together 2003;1-7.
12. Clark HW. Office-based practice and opioid-use disorders. N Engl J Med 2003;349:928-30.
13. Ling W, Smith D. Buprenorphine: blending practice and research. J Subst Abuse Treat 2002;23:87-92.
14. Fiellin DA, Pantalon MV, Pakes JP, et al. Treatment of heroin dependence with buprenorphine in primary care. Am J Drug Alcohol Abuse 2002;28:231-41.
15. Greenwald MK, Schuh KJ, Stine SM. Transferring methadone-maintained outpatients to the buprenorphine sublingual tablet: a preliminary study. Am J Addict 2003;12:365-74.
16. Wesson DR, Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs 2003;35:253-9.