Posted February 2009

Introduction

The information in this appendix conveys the experience of clinicians who currently use buprenorphine and is designed to impart strategies that may be useful to primary care clinicians who treat HIV-infected patients. Given the lack of published data, the recommendations are based on the opinion and experience of the substance use guidelines panel.

Because of its improved safety profile, federal regulations permit trained, registered clinicians to prescribe buprenorphine for the treatment of opioid dependence in general office-based settings. Patients’ ability to receive treatment for opioid dependence in a general primary care setting, and to pick up their medication in their pharmacy, may be appealing to individuals who do not want to receive methadone treatment or who have received methadone treatment in the past and are interested in a different treatment modality. Therefore, clinicians treating opioid-dependent patients are encouraged to register as buprenorphine prescribers (see Table 1 for requirements and Table 2 for available formulations).

Role of Nurse Practitioners and Physician Assistants

Nurse practitioners and physician assistants involved in buprenorphine treatment should attend the full 8-hour training.

Nurse practitioners (NPs) and physician assistants (PAs) cannot write prescriptions for buprenorphine. However, with on-site MD collaboration/ supervision, some practices use NPs and PAs to manage every other aspect of buprenorphine treatment.

Patient Selection

Any person meeting criteria for opioid dependence is a candidate for buprenorphine treatment (see Table A for criteria for substance dependence).
Methadone and buprenorphine are both first-line treatment options for opioid dependence. Further research is needed to determine the factors that may make one option preferable over the other for certain patients. Clinicians should be knowledgeable about both options and should educate opioid-dependent patients about each. Decisions should be individualized for each patient and guided by patient preference. A patient information sheet about use of buprenorphine is available from the New York State Department of Health AIDS Institute.

Specific Patient Groups:

• Heroin Users and Dependent Prescription Opioid Users:
  Both heroin users and prescription opioid users who are not actively being treated for pain may benefit from buprenorphine treatment.
• Polysubstance users:
  Patients who use other drugs in addition to opioids can still be considered candidates for buprenorphine treatment (see Polydrug Use).
• Homeless patients:
  The efficacy of office-based buprenorphine treatment in homeless patients has been shown to be comparable to treatment efficacy in stably housed patients.¹
• Adolescents:
  Data evaluating buprenorphine treatment in adolescents are limited; however, buprenorphine has been shown to be a viable option for opioid dependence treatment in adolescents. Many methadone clinics are not accessible to adolescents because United States Department of Health and Human Services (USDHHS) regulations for the use of methadone in adolescents require that adolescents have two documented failures of drug-free detoxification before they may be considered for methadone maintenance. Early treatment of opioid dependence, before medical and psychological sequelae develop, may be beneficial. More studies are needed to compare the efficacy of buprenorphine treatment with other treatment modalities in this population.

Contraindications

Opiate-Managed Pain

Patients who need ongoing opioid-based pain management or who heavily misuse benzodiazepines should not be considered for buprenorphine treatment.

Pregnancy

The FDA considers pregnancy a contraindication for buprenorphine use. There are little data on safety or efficacy of buprenorphine use during pregnancy.² Some clinicians use it as an alternative to methadone or heroin use. If buprenorphine is prescribed during pregnancy, the buprenorphine monopreparation (Subutex) should be used (see Table 2).

Precautions

Use caution and carefully consider whether to use buprenorphine in patients who are misusing benzodiazepines or alcohol.

Benzodiazepine use is not a contraindication for buprenorphine use; many patients are prescribed both medications. However, the few fatalities that have been associated with buprenorphine use have been in patients who were misusing benzodiazepines, most often by injection, or benzodiazepines plus alcohol. Clinicians must weigh the benefits of reducing heroin use with the potential for fatal misuse in patients who use benzodiazepines and alcohol.

Table 3: Contraindications and Precautions for Prescribing Buprenorphine

Contraindications: Patients who have a need for ongoing opioid-based pain management or who heavily misuse benzodiazepines should not be considered for buprenorphine treatment The FDA considers pregnancy a contraindication for buprenorphine use. There are little data on safety or efficacy of buprenorphine use during pregnancy.2 Some clinicians use it as an alternative to methadone or heroin use.a Precautions: Clinicians should carefully consider whether to use buprenorphine in the following groups: Patients who are misusing benzodiazepines or alcohol Patients with current suicidal or homicidal ideation, or history of serious suicide attemptsb Patients with hepatic impairmentb

a If buprenorphine is prescribed during pregnancy, the buprenorphine monopreparation (Subutex) should be used. b Clinicians should weigh the risk of continued need for illicit drugs against risk of suicide or hepatic impairment.

Induction

Offer in-office or home induction as options and discuss the advantages and disadvantages of each with the patient (see Table 4).

Induction may take place either in the office or at the patient’s home. Table 4 outlines the advantages and disadvantages of each approach. When the patient opts for home induction, the patient and clinician need to establish a communication plan beforehand to ensure that both the patient and clinician can be easily reached. Buprenorphine/naloxone is a relatively safe medication for home induction; the greatest risk is precipitated withdrawal. Home induction has been described in several publications,^1,3 and anecdotally it is offered by many practitioners.⁴ Some practices may also wish to do in-office induction and DOT for the first several days.

Table 4: Home Induction vs In-Office Induction: Advantages and Disadvantages

Type of Induction Advantages   Disadvantages Home Induction Less office time Patient can plan for withdrawal outside of clinic hours Communication mishaps Precipitated withdrawal may be harder to manage In-Office Induction Assurance that the patient initiates the medication Closer management of stabilization Managing office logistics, e.g., where to have the patient wait, particularly while waiting for the first dose Patient’s timing of withdrawal more constrained

Prior to induction:

• Instruct patients about how the induction will take place (see Table B for an example of a patient information sheet)
• Obtain an initial history and perform a physical examination as indicated
• Inform patients that they need to be in moderate withdrawal before buprenorphine induction [see Table C for the Clinical Opiate Withdrawal Scale (COWS)]

Follow-up after induction:

• Phone call within 24 hours
• Follow-up visit within 1 week
• Weekly to monthly evaluation, as needed, for refill/follow-up and preventive health care

Further guidance on induction can also be found in the SAMHSA/CSAT TIP 40: Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction.

Methadone to Buprenorphine Transfer

If patients are transferring from methadone to buprenorphine, consider the following for each patient:

• If methadone is tapered to a lower dose to facilitate methadone-to-buprenorphine transfer, there may be a risk of relapse and/or instability, including the potential for non-adherence to HIV-related medications. Clinicians should work with patients who are stable on methadone to carefully weigh the risks and benefits of changing opioid pharmacotherapies.
• Methadone programs can coordinate multiple services, which may benefit some patients, according to individual patient needs.
• Some patients may prefer and/or benefit from the structure offered by a methadone program.

Stabilization

Because of the ceiling effect of buprenorphine, the maximum recommended buprenorphine dose is 32 mg.

The correct dose may be selected in the first 1 or 2 days during the induction for many patients. Buprenorphine has a ceiling effect, which means that the agonist effect increases with the dose but plateaus at a moderate dosage. Most patients stabilize on a daily dose of 12 to 24 mg. Because of the ceiling effect, the maximum suggested dose is 32 mg. Some patients are comfortable on as little as 2 to 4 mg/day.

Clinicians may need to encourage patients to increase the dose to one which not only alleviates withdrawal but also extinguishes opioid craving. Some patients prefer to wait until they feel the need for the medication; however, many clinicians recommend the establishment of a routine dose in order to move away from the fluctuating nature of heroin addiction.

Maintenance

The frequency of follow-up visits should be individualized and discussed with the patient, but is generally not less often than monthly.

At each visit, the provider should ask about cravings and intervening use of opioids to assess whether the dose of buprenorphine is adequate for the patient.

Key Point:

The goal of maintenance is to reduce or extinguish the craving for opioids.

Treatment Agreement

A treatment agreement can be useful to establish trust, boundaries, and an acceptable process in the substance use treatment aspect of the provider-patient relationship. Treatment agreements should assume the development of a trusting relationship and outline some of the potential problems that may be encountered, such as medicating acute pain and the danger of mixing buprenorphine with benzodiazepines. The patient information form in Table B may be sufficient if signed by the patient. Both the clinician and the patient should retain a copy.

Urine Toxicology

Urine toxicology for monitoring the use of illicit drugs during therapy is recommended but not required by regulation.

Clinicians should explain to patients that urine toxicology is a tool that is in place to help optimize the care of the patient. When choosing to obtain urine toxicology, clinicians should decide which substances to test for based on whether and how the results will change care. The conventional urine test does not assess for buprenorphine, and therefore cannot be used to monitor for adherence to the buprenorphine regimen. Of note, buprenorphine itself can cause an initial positive result for opioids on some urine drug screens even when other opioids are not being used. If the clinician wishes to test for the presence of buprenorphine, a kit may be obtained from Clinical Laboratory Improvement Amendments of (CLIA).

Duration of Treatment

Duration of treatment should be guided by patient goals, which may change over time.

It is clear from the literature describing methadone experiences that a significant majority of patients who discontinue methadone will relapse to illicit drug use.⁵ The same likely applies to buprenorphine treatment as well. Most long-term opioid-dependent persons with a history of many relapses will require long-term treatment. Among shorter-term users, it is likely that some will need long-term treatment while others will taper and do well without medication.⁶

The goal of treatment, as with many disorders, is not to lead a medication- free life but a high-quality life free of dependence on illicit drugs. As with methadone, some patients will require long-term, sometimes lifelong, buprenorphine treatment.

Key Point:

As with other chronic medical conditions, many patients will require long-term buprenorphine treatment.

Therapeutic Discontinuation

Discuss risks and benefits of tapering and develop a collaborative treatment plan.

Many patients will set the goal for themselves to become medication free. They should be reassured that if they relapse or feel that they will relapse they may return to treatment at any time without being considered “a failure.”

No set protocol for discontinuation of buprenorphine has been established that results in a greater likelihood of long-term abstinence. Many patients can abruptly discontinue buprenorphine with little or no withdrawal. Others may feel more comfortable tapering over a period of time in increments of 2 to 4 mg every few weeks or days.

If the medication does not seem to benefit the patient and cessation is necessary, tapering of the dose rather than abrupt cessation is likely more appropriate. The time period for tapering may depend in part on access to other treatment resources such as methadone maintenance treatment program (MMTP) or residential treatment.

Polydrug Use

Use of multiple drugs is common among patients presenting for treatment of opioid dependence. There is no medical rationale for discontinuing buprenorphine in most patients who are engaged in and receiving benefit from treatment despite continued use of other drugs (see Drug-Drug Interactions). For patients with continued drug use who are not properly participating in treatment and not showing a benefit from treatment, a referral to a higher level of substance use treatment should be offered.

Drug-Drug Interactions

Buprenorphine is metabolized by the CYP450 3A4 enzyme system; therefore, clinicians should be alert to the possibility of interactions with inhibitors, such as azoles, macrolides, non-nucleoside reverse transcriptase inhibitors and protease inhibitors, and inducers, such as phenobarbital, carbamazepine, phenytoin, and rifampicin, although few drug-drug interactions have been reported with buprenorphine use.⁷

Cases of sedation when taken with atazanavir have been reported, with resolution upon lowering the buprenorphine dose. As a potent blocker of opioids, buprenorphine can interfere with pain management.

There is little literature on interactions between buprenorphine and alcohol, cocaine, marijuana, and methamphetamine. Overdose with concomitant benzodiazepine use has occurred, generally by injection of a combination of buprenorphine with benzodiazepines.

For more information, see Drug-Drug Interactions Between ARV Agents, Medications Used in Substance Use Treatment, and Recreational Drugs.

Counseling

Counseling and other support resources should be made available to all patients treated with buprenorphine.

  

 Patients who decline counseling services should be maintained on buprenorphine if otherwise medically appropriate.

Counseling and other psychosocial support is strongly encouraged; services are abundantly available in some parts of New York and sparse in other areas. Support can be in the form of self-help groups, HIV support services, harm reduction centers, and other community resources. Although many studies have shown that counseling is associated with better outcomes, an optimal level of counseling remains unclear.⁸ A national evaluation of buprenorphine by SAMHSA and the American Society of Addiction Medicine found that 40% of patients were not accessing counseling services in the first month of treatment.⁹ Poor access to counseling or refusing to receive counseling is rarely a medical reason for discontinuing the medication, given the likelihood of relapse to illicit opioids. However, as with other medications, if the patient appears to be deriving no benefit from the medication or there is evidence of diversion, the clinician may stop prescribing buprenorphine and refer the patient to other sources of care for opioid dependence. Other sources of care can be found at the New York State Office of Alcoholism and Substance Abuse Services.

Diversion

Be aware of signs of diversion, such as recurring reports of lost medication.

As with many medications, diversion of buprenorphine is of concern. However, recent literature has found that the addition of naloxone significantly lowers the desirability of Suboxone for purposes of intoxication.¹⁰ A national evaluation of buprenorphine found that 14% of patients said it was easier or equally easy to sell or buy buprenorphine on the street than methadone or OxyContin^®.¹¹

Overdose

Opioid maintenance is a powerful tool in the prevention of opioid overdoses.¹² The ceiling effect of buprenorphine makes overdose unlikely. Patients are less likely to suffer fatal overdoses with buprenorphine than with methadone.¹³ Injection with benzodiazepines is the cause of 78% to 90% of fatal buprenorphine overdoses. Alcohol is implicated in many opioid overdoses and may be a risk; however, no deaths attributable to buprenorphine and alcohol alone have been reported.

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References

1. Alford DP, La Belle CT, Richardson JM, et al. Treating homeless opioid dependent patients with buprenorphine in an office-based setting. J Gen Intern Med 2007;22:171-176. [Abstract]

2. Jones HE, Martin PR, Heil SH, et al. Treatment of opioid-dependent pregnant women: Clinical and research issues. J Subst Abuse Treat 2008;35:245-259. [Abstract]

3. Lee JD, Grossman E, DiRocco D, et al. Home buprenorphine/naloxone induction in primary care. J Gen Intern Med 2009;24:226-232. [Abstract]

4. Campopiano M. Office-based therapy with buprenorphine. Counter Details, Pennsylvania Medical Society; Dec 2006. [Monograph]

5. Magura S, Rosenblum A. Leaving methadone treatment: Lessons learned, lessons forgotten, lessons ignored. Mt Sinai J Med 2001;68:62-74. [Abstract]

6. Substance Abuse and Mental Health Services Administration. Clinical guidelines for the use of buprenorphine in the treatment of opioid addiction: A Treatment Improvement Protocol (TIP) 40. Rockville, MD: Center for Substance Abuse Treatment, US Department of Health and Human Services; 2004. DHHS Publication SMA 04-3939. Available at: www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat5.chapter.72248

7. Bruce RD, Altice FL, Gourevich MH, et al. Pharmacokinetic drug interactions between opioid agonist therapy and antiretroviral medications: Implications and management for clinical practice. J Acquir Immune Defic Syndr 2006;41:563-572. [Abstract]

8. Fiellin DA, Pantalon MV, Chawarski MC, et al. Counseling plus buprenorphine-naloxone maintenance therapy for opioid dependence. N Engl J Med 2006;355:365-374. [Abstract]

9. Stanton A, McLeod C, Luckey B, et al. Expanding treatment of opioid dependence: Initial physician and patient experiences with the adoption of buprenorphine. American Society of Addiction Medicine; 2006.

10. Alho H, Sinclair D, Vuori E, et al. Abuse liability of buprenorphine-naloxone tablets in untreated IV drug users. Drug Alcohol Depend 2007;88:75-78. [Abstract]

11. SAMHSA Evaluation of the Impact of the DATA Waiver Program: Summary Report; March 2006. [Report]

12. Sporer KA. Strategies for preventing heroin overdose. BMJ 2003;326:442-444.

13. Gibson AE, Degenhardt LJ. Mortality related to pharmacotherapies for opioid dependence: A comparative analysis of coronial records. Drug Alcohol Rev 2007;26:405-410. [Abstract]

Further Reading

Lintzeris N, Mitchell TB, Bond A, et al.  Interactions on mixing diazepam with methadone or buprenorphine in maintenance patients. J Clin Psychopharmacol 2006;26:274-283. [Abstract]

Mintzer IL, Eisenberg M, Terra M, et al. Treating opioid addiction with buprenorphine-naloxone in community-based primary care settings. Ann Fam Med 2007;5:146-150. [Abstract]

Moore BA, Fiellin DA, Barry DT, et al. Primary care office-based buprenorphine treatment: Comparison of heroin and prescription opioid dependent patients. J Gen Intern Med 2007;22:527-530. [Abstract]

New York City Department of Health and Mental Hygiene. Buprenorphine: An Office-Based Treatment for Opioid Dependence. City Health Information 2008;27:25-32. [Newsletter]

Reed LJ, Glasper A, de Wet CJ, et al. Comparison of buprenorphine and methadone in the treatment of opiate withdrawal: Possible advantages of buprenorphine for the treatment of opiate-benzodiazepine codependent patients? J Clin Psychopharmacol 2007;27:188-192. [Abstract]

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Table A: Criteria for Substance Dependence

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Table B: Sample Patient Information Sheet

Table C: Clinical Opiate Withdrawal Scale (COWS)

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