Buprenorphine was first marketed in the United States in 1985 as a schedule V narcotic analgesic. Initially, the only available buprenorphine product in the United States had been a low-dose (0.3 mg/ml) injectable formulation under the brand name, Buprenex®. Diversion, trafficking and abuse of other buprenorphine products have occurred in Europe and other areas of the world.
In October 2002, the Food and Drug Administration (FDA) approved two buprenorphine products (Suboxone® and Subutex®) for the treatment of narcotic addiction. Both products are high dose (2 mg and 8 mg) sublingual (under the tongue) tablets: Subutex® is a single entity buprenorphine product and Suboxone® is a combination product with buprenorphine and naloxone in a 4:1 ratio, respectively. After reviewing the available data and receiving a schedule III recommendation from the Department of Health and Human Services (DHHS), the DEA placed buprenorphine and all products containing buprenorphine into schedule III in 2002.
Since 2003, diversion, trafficking and abuse of buprenorphine have become more common in the United States. In June 2010, FDA approved an extended release transdermal film containing buprenorphine (Butrans®) for the management of moderate to severe chronic pain in patients requiring a continuous, extended period, around-the-clock opioid analgesic.
Buprenorphine is a semi-synthetic derivative of thebaine, and acts as a partial opioid agonist. Like full agonists, it can produce typical opioid effects and side effects such as euphoria, pain relief, and respiratory depression. Yet unlike full agonists, buprenorphine is constrained by a “ceiling effect” (agonist effects increase linearly with increasing doses until they reach a plateau) thus respiratory depression is rare. Buprenorphine is highly bound to plasma proteins. It is metabolized by the liver via the cytochrome P450 3A4 (CYP 3A4) enzyme system into norbuprenorphine and other metabolites. The half-life of buprenorphine is 24–60 hours. Buprenorphine has poor oral bioavailability and moderate sublingual bioavailability.
Buprenorphine is indicated for the treatment of heroin and other illicit opioid addiction. It may be used both for maintenance and for managing withdrawal, in conjunction with appropriate psychosocial supports.
- Alleviates and prevents withdrawal.
- Blocks the euphoric effects of opioids.
- Reduces the long term craving experienced by many persons with opioid addiction.
Potential side effects are similar to those of other opioids and include nausea, vomiting, and constipation. Cases of liver enzyme elevations have been reported.
- Buprenorphine binds more tightly to opioid receptors than other opioids, thus:
- Buprenorphine precipitates opioid withdrawal syndrome if taken by an opioid dependent person who is not yet in withdrawal.
- Buprenorphine blocks the activity of other opioids, thus barring the use of opioids for pain management.
There are case reports of deaths following the injection of buprenorphine with benzodiazepines. However, when benzodiazepines are taken as directed there is no contraindication.
Data are limited on interactions between buprenorphine and antiretroviral drugs. Studies have found no interaction with zidovudine. Efavirenz has been found to lower buprenorphine levels but with no clinical impact. Protease inhibitors may increase buprenorphine levels via CYP 3A4 inhibition; providers should be alert to the possible need for dose adjustment.
Contraindications to starting buprenorphine include a demonstrated drug allergy, or active sedation or intoxication. Based on a case report, the inactive naloxone component of combined products may build up in patients with moderate to severe hepatic impairment, so buprenorphine mono-product (without naloxone) may be preferred in advanced cirrhosis. The buprenorphine mono-product is commonly used in pregnancy, but pregnancy is not a contraindication to the combined product. There are no other absolute contraindications to buprenorphine use.
The optimal dose to promote recovery and prevent return to use is different for every patient and generally varies between 4 and 32 mg daily (based on the bioavailability of the commonly used buprenorphine or buprenorphine/naloxone sublingual tablets and film). Greater rates of retention in treatment and suppression of illicit opioid use have been found at doses of 16 mg or greater. The maximum dose is generally considered to be 32 mg, although the FDA package insert states that doses higher than 24 mg have not been demonstrated to have a clinical advantage in the treatment of OUD. Some states and settings have imposed regulations on the upper limit of dosing.
Buprenorphine can be dosed one to three times a day. Because of its long-acting properties, it can also be dosed three times a week under observation. Daily dosing may enhance adherence, but taking buprenorphine every six to eight hours provides better pain management for patients with chronic pain. Because buprenorphine is a Schedule III drug, refills can be called in or faxed. Appendix B lists the formulations and dosages available.
Like other opioids commonly abused, buprenorphine is capable of producing significant euphoria. Data from other countries indicate that buprenorphine has been abused by various routes of administration (sublingual, intranasal and injection) and has gained popularity as a heroin substitute and as a primary drug of abuse. Large percentages of the drug abusing populations in some areas of France, Ireland, Scotland, India, Nepal, Bangladesh, Pakistan, and New Zealand have reported abusing buprenorphine by injection and in combination with a benzodiazepine.
How to Start a Patient on Buprenorphine?
Initial Assessment Standard OUD care is moving toward a “medication first” model, where patients are started on medications without extensive assessments, just as patients with psychosis are started on medications to stabilize them before starting behavioral health therapy.
After shared decision making with the patient, a focused assessment can include the following:
- History that establishes diagnosis of OUD using DSM-5 criteria; the frequency, amount, and routes of opioid use; and other drug or alcohol use
- History of drug treatment and discussion of treatment options — that is, buprenorphine vs. methadone vs. naltrexone
- Significant medical and psychiatric history (including suicidality), and active medication list and allergies
- Physical exam that is performed, referred for, or recently recorded, with attention to signs and symptoms of withdrawal or intoxication
- Laboratory testing is not required, but the following should be considered, initially or later in treatment: urine drug testing, pregnancy testing, liver function testing, hepatitis and HIV serologies
- State prescription drug monitoring program database (CURES in California) checked for controlled substances
Managing Withdrawal Symptoms
Patients typically go 12 to 48 hours without other opioids before starting buprenorphine to avoid precipitated withdrawal symptoms. The Clinical Opioid Withdrawal Score (COWS) can help assess the patient’s withdrawal severity.
Medications such as non-opioid analgesics, antihistamines, anti-nausea medications, clonidine, and loperamide can be provided to the patient to increase comfort during the period of withdrawal. Buprenorphine patches can be used for patients with chronic pain diagnoses.
Overdose prevention education and a prescription for naloxone (in case of overdose) should be provided to all patients considering or receiving buprenorphine, in case of return to use. They should be provided again if the patient discontinues medication treatment.
Lab testing for HIV and hepatitis, and immunization and treatment for hepatitis A, B, and C are especially important for patients who have ever injected drugs, as are sterile needles for those at risk of ongoing injection drug use.
Just as many smokers require 30 or more quit attempts before they quit for good, multiple quit attempts may be required before a patient reaches full sobriety. Clinicians should treat a return to use with compassion, as part of the typical course of a chronic relapsing and remitting disease. In no case should patients be dismissed from treatment due to return to use or positive drug screens, nor should they be dismissed from treatment for using other substances (such as THC or methamphetamine); this only puts the patient at risk of overdose or other harm. Buprenorphine is effective for OUD and should not be discontinued only because the patient has other use disorders. Returns to use or ongoing positive urine screens may indicate the patient needs a higher level of care, and clinicians or their staff should develop relationships with opioid treatment programs to facilitate these transfers of care.
- Drug Enforcement Administration; Diversion Control Division Drug & Chemical Evaluation Section: BUPRENORPHINE, December 2019
- Buprenorphine in the Context of HIV—FACT SHEET: AIDS Education and Training centers, August 2005
- Buprenorphine: An Overview for Clinicians; California Health Care Foundation, August 2019
- Buprenorphine: National Drug and Alcohol Research Centre. Updated 2016. Edited by Dr Suzanne Nielsen.