Buprenorphine: Where do we stand?

Author: David Cisewski, MD (@PainProfiles – EM Resident Physician, Icahn School of Medicine at Mount Sinai) // Edited by: Cynthia Santos, MD (Assistant Professor, Emergency Medicine / Medical Toxicology / Addiction Medicine, Rutgers NJMS), Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital), and Brit Long, MD (@long_brit)

Over the last month there has been an uptrend in the news regarding buprenorphine use.  The news, however, has been a mixture of both positive press and negative press for this opioid addiction medication, leaving many confused as to where we currently stand.  The article will serve as an overview of buprenorphine, where it fits in our current opioid crisis, how we’re using in the emergency setting, and what we can anticipate as its role in the months and years to come.

What is buprenorphine?

Buprenorphine is a mu-opioid receptor partial agonist that was first developed in 1978 (Reckitt & Colman Products, UK) to assist in treating chronic pain conditions while reducing overall cravings for pure (full agonist) opioids in individuals suffering from opioid use disorder. Buprenorphine is currently approved in the United States for the use of opioid abuse disorder and in the treatment of moderate/severe chronic pain where it has been shown to be a safe and effective method of reducing opioid use.

What is the mechanism of action of buprenorphine and how does it differ from other opioids?

Buprenorphine is a partial agonist of mu-opioid receptors as well as a weak antagonist at the kappa receptors (Wakhlu, 2009).  The partial agonist effects indicate a  ‘ceiling effect’ to the intrinsic activity of buprenorphine above which no further benefit is received from higher concentrations. Similar to other opioids, buprenorphine fulfills the craving for opioids and suppresses the symptoms of opioid withdrawal, but it is this ‘ceiling effect’ that results in a lower likelihood of symptomatic respiratory depression, less euphoria, and a lower potential for abuse compared to other full agonist opioids (Walsh, 1994). By cutting cravings, patients are able to focus on the counseling and therapy that will allow them to achieve sustained addiction remission.

Compared to morphine, buprenorphine is approximately 25-100x as potent (Khanna, 2015). Buprenorphine also has a higher affinity but a lower intrinsic activity compared to morphine, fentanyl, and methadone (Khanna, 2015).  The higher binding affinity and slower dissociation rate of buprenorphine compared to other opioids results in a long duration of action (Tzschentke, 2002).  These three qualities – high potency, increased binding affinity, lower intrinsic activity – are what make buprenorphine a favorable candidate for opioid dependence treatment.  Note that because of this higher affinity compared to other opioids, it can precipitate withdrawal symptoms when given to individuals currently intoxicated with other opioids which are displaced by buprenorphine (Hammig, 2016).

How is buprenorphine absorbed, metabolized, and excreted?

Buprenorphine can be absorbed across the gastrointestinal mucosa; however, it undergoes extensive first-pass metabolism making this a suboptimal route (Welsh, 2005).  Buprenorphine is only approximately one-fourth when given via the buccal route and one-half via the sublingual route (Kuhlman, 1996; Davis, 2012). Buprenorphine has been found to be effectively absorbed via the sublingual route making this the optimal route of administration.

Following absorption, buprenorphine is metabolized via glucuronidation by the liver CYP3A4 enzyme to inactive metabolites. These metabolites along with parent compound are eliminated predominantly in the feces, with approximately 10-30% excreted in urine (Cone, 1984).  Buprenorphine should be used cautiously with CYP3A4 competing substrates and inhibitors such as statins, amiodarone, haloperidol, macrolides, azole antifungals (fluconazole, ketoconazole), calcium channel blockers, grapefruit juice (bergamottin), methylprednisolone, and protease inhibitors.  However, at therapeutic doses buprenorphine and its metabolites do not inhibit cytochromes and can safely be used with few drug interactions (Zhang, 2003).  As a result of the predominant stool excretion smaller effect of liver cirrhosis on hepatic glucuronidation, buprenorphine is considered a safe opioid alternative in renal and liver failure patients (Tegeder, 1999; Davis, 2012).

Is buprenorphine safe during pregnancy?

A 2016 meta-analysis comparing methadone and buprenorphine use during pregnancy found no difference between the groups with respect to congenital malformations. Additionally, the overall incidence of congenital anomalies were similar to what would be expected in the general population, suggesting both are safe during pregnancy. Buprenorphine offers the added benefit of use in an outpatient basis without the need for daily visits to an opioid treatment program (versus methadone).  A 2017 ACOG opinion statement supported the use of buprenorphine during pregnancy for opioid use disorder.

A recent 2017 also found favorability in using buprenorphine to treat newborn infants suffering from neonatal abstinence syndrome after being exposed to opioids in utero (Kraft, 2017).  As compared to oral morphine, infants who received sublingual buprenorphine experienced a nearly 50% drop in days requiring treatment (15 days vs. 28 days), and a one-third hospital stay duration (21 days vs. 33 days) (Kraft, 2017).

What are the different types of buprenorphine?

Though predominantly used as a sublingual film, buprenorphine can also be delivered via transbuccal, transdermal, subdermal (implant), subcutaneous, and parenteral routes (see table).  Several include combination naloxone formulations (eg, suboxone) that prevent an opioid high associated with direct injection.

What are the major side effects of buprenorphine?

The side effect profile of buprenorphine is dependent on the co-consumption of opioids at the time of administration. Individuals with high baseline opioid use or in the midst of an overdose will experience opioid withdrawal, due to buprenorphine’s predominantly antagonistic role. In order to avoid precipitating an opioid withdrawal, buprenorphine should not be given within 24 hours of long-acting opioid use and only once moderate signs of opioid withdrawal are noted (naabt.org). The most prominent side effects are tachycardia, restlessness and agitation,  nausea and vomiting, headache, anxiety, rhinorrhea, muscle/joint aches, goose-flesh skin, and diaphoresis (White, 2018). A full analysis of opioid withdrawal should involve a Clinical Opioid Withdrawal Symptoms (COWS) assessment.

In comparison, individuals using buprenorphine to prevent relapse and suffering from opioid cravings – ie, clean of opioids – will experience the agonistic effects including decreased craving, sedation, miosis, mild respiratory depression (White, 2018).  Unlike other opioids, buprenorphine does not cause spasming of the sphincter of oddi (Cuer, 1989) and results in a much lower incidence of constipation (<5%) than full  mu-agonists (Kress, 2009).

Additionally, buprenorphine is associated with QT prolongation and should be used cautiously with other QT prolonging medications such as fluoroquinolones (moxifloxacin), macrolides, antipsychotics, tricyclic antidepressants, and selective serotonin receptor antagonists (SSRIs). Evidence does show that the QT prolongation in buprenorphine is less than that of methadone, suggesting buprenorphine may be the optimal maintenance therapy in patients with heart conditions (Fareed, 2013; Poole, 2016).

How is buprenorphine typically dosed  to suppress opioid withdrawal?

The goal of both induction and maintenance therapy is to suppress opioid withdrawal as quickly as possible.  Because of the partial agonist effect of buprenorphine, dosing can be relatively aggressive to avoid withdrawal, while still avoiding side effects and intoxication. The following dosing recommendations are based on the Suboxone guide to optimal management of opioid dependence:

1. Administer 4 mg buprenorphine (Suboxone) sublingually allowing 20-40 minutes for withdrawal symptom resolution.

2. Repeat 4 mg dose after 1-2 hours as needed (typical first day doses are 8 mg).

3. After 1-2 hours of  observation, the patient may be discharged if no withdrawal symptoms are observed; consider 2-4 mg home dose for return to home if concern for withdrawal prior to prescription pickup or outpatient follow up.

4. The patient will be assessed on day 2 to see if withdrawal symptoms occurred; if no withdrawal symptoms, day 1 total dosing will become the new daily maintenance dose, otherwise add 2-4 mg daily until withdrawal symptoms subside (typical optimal daily doses will be between 12 mg and 16 mg).

5. Once maintenance dose is achieved, the patient will continue for 3-7 days prior to primary care follow up for reassessment.

6. If patient experiences intoxication, decrease the dose by 2 mg at a time until stable without intoxication.

What is the good press buprenorphine has been getting lately?

A recently published retrospective cohort study in the Annals of Internal medicine (Larochelle, 2018) analyzed the benefits of medications for opioid use disorder by looking at over 17,000 non-cancer related patients seen at 7 centers between 2012-2014 presenting after an opioid overdose.  As compared to naltrexone (opioid-receptor antagonist) which showed no benefit in all-cause or opioid-related mortality compared to no treatment, buprenorphine was associated with decreased all-cause mortality (AHR, 0.63 [CI, 0.46 to 0.87]) and opioid-related mortality (AHR, 0.62 [CI, 0.41 to 0.92]).   What was surprising, however, is that only about 30% of the opioid overdose patients ended up receiving prescriptions for either buprenorphine or methadone in the year that followed the overdose. The conclusion of this study was that buprenorphine (and methadone) should be considered as potential treatment regimens in patients surviving opioid overdoses.

Wait, but hasn’t buprenorphine been getting some negative press as well?

At the same time the Annals of IM research was published, Post, et al released research data in the American Academy of Pediatrics following the investigation of buprenorphine exposures among the pediatric population (<19 years old) (Post, 2018).  Data collected from the US poison control center between 2007-2016 found that over 11,000 children had been exposed to buprenorphine, the majority of which were unintentional uses in children under 6 years old.  Especially concerning was that suspected suicide was the second most common reason for overdose among adolescents, highlighting the fact that even safe packaging and limited access may necessitate mental health screening among this population.  This research set off a call for concern regarding buprenorphine use and the potential danger among the opioid-naive pediatric population.

If it’s potentially dangerous to the pediatric population, is pharmacotherapy necessary for opioid use disorder? Couldn’t opioid abusers benefit from therapy alone?

It is important to note that behavioral interventions are not cure-alls and has shown limited success rates when not combined with a multimodal medication-assisted treatment (MAT) plan involving buprenorphine (or methadone) as part of an opioid maintenance therapy (OMT).  Medications such as buprenorphine and methadone are an essential part of the integral treatment of opioid use disorder.

This all seems like primary care management – is there a role of buprenorphine in the ED?

Not surprisingly, the ED is the first place many of the opioid abusers are seen following either an overdose or opioid withdrawal.  Many of emergency medicine experts have argued strongly for the initiation of buprenorphine therapy starting in the ED with close follow up with outpatient addiction clinics or primary care physician that could further initiate a comprehensive treatment regimen.  Reuben Strayer, MD (@emupdates), a long-time advocate for the effective management of opioid use/misuse in the emergency setting recently stated that there are many ways to treat opioid withdrawal, but that buprenorphine should be considered the drug of choice.

Dr. Gale D’Onofrio, chair of the emergency department at Yale University has also been a focal advocate for addressing opioid abuse/withdrawal with buprenorphine in the emergency setting.  A 2017 study by D’Onofrio, et al found that buprenorphine treatment initiated in the emergency department was associated with increased engagement in addiction treatment and reduced illicit opioid use during the 2-month interval when buprenorphine was continued in primary care (though found to have no significant differences in illicit opioid use at 6 or 12 months).  During an interview with Yale News Dr. D’Onofrio stated,

“The ED visit is an ideal opportunity to identify patients with opioid use disorder and initiate treatment and direct referral, similar to best practices for other diseases, such as high blood pressure and diabetes”

What about treating opioid overdose with buprenorphine?

Throughout the FOAM community, it has also been hypothesized that the use of buprenorphine may (paradoxically) be the optimal medication used in heroin/opioid overdose as the antagonist effect (among high concentrations of opioid agonists) will predominate, resulting in reduced sedation and respiratory depression without sending the patient spiraling into an acute opioid withdrawal often seen with naloxone use.  More research is needed to evaluate the safety and efficacy of this use.

What has been the societal response to buprenorphine use for opioid abuse disorder?

While many drug abuse counselors and healthcare providers have subscribed to and promoted the therapeutic effects of buprenorphine, there remains a large percentage of the population who still view the drug as a glorified opioid – a substitution of one addiction for another  – which has stigmatized the use of the drug in many communities.  A recently published NY Times article covering the challenges faced by Dr. Nicole Gestala, a primary care doctor in Iowa focused on using buprenorphine as a means of managing opioid addiction, only to be faced by big pharma price tags, insurance company pushback and strict federal prescribing requirements.  The general sentiment is that it’s easier and cheaper to prescribe percocet or hydrocodone than it is to prescribe therapeutic buprenorphine.

Yet other communities have openly embraced buprenorphine use in combating the opioid epidemic. San Francisco mayor Mark Ferrell announced in May, 2018 that he would be funding an opioid-addiction team to supply buprenorphine to over 250 homeless heroin users throughout the Bay area.  As mayor Ferrell quoted to the San Francisco Chronicle,

“Drug abuse is rampant on our streets, and the recipe of waiting for addicts to come into a clinic voluntarily is not working. Plain and simple. So we’re going to take a different approach.”

A further win could come in the anticipated price drop as buprenorphine patents expire.  Last month the FDA approved the first generic version of suboxone. This not only make this an affordable treatment medication that can be readily available across the nation, it sends the signal that we are recognizing the therapeutic benefit of buprenorphine and the need for its widespread availability.

What about all the Vivitrol advertisements I see on the subway?  Isn’t this the treatment of choice for opioid abuse?

Vivitrol (aka, naltrexone) is a pure opioid-receptor antagonist initially approved by the FDA in 2006 for alcohol abuse but was expanded in 2010 to opioid abuse.  This approval came after an often questioned Russian study found benefit in its use among patients suffering from opioid abuse (full coverage of story can be found here).  In comparison to buprenorphine, naltrexone is taken once a month for opioid abuse disorder. Unlike buprenorphine which cuts craving and offers mild opioid effects, naltrexone is the equivalent of quitting cold turkey, resulting in the full effect of opioid withdrawal.  The idea is that even with relapses during periods of extreme opioid withdrawal, the patient would not experience the ‘high’ as long as naltrexone was on board to block the opioid receptors.  In theory this works but as one can easily imagine this could lead to incredibly debilitating pain and suffering and a reduced quality of life in individuals fighting an opioid addiction.

Additionally, as compared to the mildly reinforcing effects of buprenorphine which promote continued compliance, naltrexone offers no incentive for medication adherence, resulting in poor compliance. Naltrexone can also result in overdose and death following relapse when users return to previously high doses of opioids during periods of built up tolerance that become lost during periods of complete sobriety.  Vivitrol is widely viewed as the non-opioid treatment alternative to buprenorphine, particularly among those who argue buprenorphine is just another opioid adding ‘fuel to the epidemic fire’.

Can anyone prescribe buprenorphine?

The short answer is no – only physicians with a special “X” number issued by the DEA (ie, DEA-X) can prescribe buprenorphine.  Under the Drug Addiction Treatment Act of 2000 (DATA 2000), physicians who meet certain qualifications can treat opioid dependency with narcotic medications (ex, buprenorphine) approved by the FDA. To qualify, physicians (also NPs, PAs) must complete an 8-hour course and complete an application to obtain a waiver (DEAX waiver). This waiver entitles the applicant to prescribe buprenorphine to up to 30 patients.  In order to treat over 30 patients, the physician can then apply to SAMSHA (Substance Abuse and Mental Health Services Administration) which will allow treatment of up to 100 patients.  Once a physician has prescribed buprenorphine to 100 patients (for at least one year), they can apply to increase their patient limits to 275 under new federal regulations

For physicians/NPs/PAs interested in offering this treatment, they can get started here: Get Waivered!

Where do lawmakers stand with the market battle between buprenorphine and naltrexone?

Currently, the house is divided among the two rivaling medications and involves a deeply-tangled web of interconnections among lobbyists, big pharma, and opposing republican and democratic representatives.  Under current legislation, physician prescribers of buprenorphine require specialty training that allows for a limited 30 patient prescriptions the first year following initial certification (see above).  A controversial House bill sponsored by Rep. Paul Tonko (N.Y.) would not only increase those prescription caps, but would also allow nurse practitioners and physician assistants to continue prescribing the drug.  This bill has received continued opposition, and many of whom have hypothesized is fueled by the influence of Alkermes, the drug company that manufactures Vivitrol. An extensive rundown on the house bills proposed to combat the opioid crisis can be found here.

In this month’s EMA ‘Reflections of a Skeptic’ (July, 2018), Dr. Jerry Hoffman discussed what he referred to as the  abomination of an opioid-free ED.  In his always-eloquent reflection Dr. Hoffman reminds the listener that addiction is a psychosocial dysfunction of an individual with a disease and just as we treat all other disease processes we have a responsibility to treat opioid use disorder and provide safe, legal therapeutic alternatives for the patient in search of help. Dr. Hoffman further emphasizes that we as emergency physicians should be focusing less on “catching” people expressing drug-seeking behavior and more on identifying these patients with ‘treatment-seeking’ behavior for an underlying opioid-abuse disease process for whom we may be their last resort.  Buprenorphine is a medication designed, researched, and effectively used to assist in opioid-abuse recovery in these individuals and should be considered an optimal tool in every emergency physician’s armamentarium.

Additional Reading:

• The National Alliance of Advocates for Buprenorphine Treatment – a great one-stop source for buprenorphine education (org)
• Annals of Internal Medicine – Medication for Opioid Use Disorder After Nonfatal Opioid Overdose and Association With Mortality: A Cohort Study
• NIH – Methadone and buprenorphine reduce risk of death after opioid overdose
• Annals of Pediatrics – Buprenorphine Exposures Among Children and Adolescents Reported to US Poison Control Centers
• Clinical Pain Advisor – Switching From Buprenorphine-Naltrexone to XR-Naltrexone as Effective as XR-Naltrexone
• Cochrane Review, 2014 – Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence
• EP Monthly – RX Pad: Reducing Relapses Through Opioid Maintenance Therapy
• EP Monthly – How Emergency Physicians Can Face the Twin Epidemics of Opioid Abuse & Chronic Pain
• NY Times – When an Iowa Family Doctor Takes On the Opioid Epidemic