Endo Pharmaceuticals recently announced the availability of Belbuca, the first buccal formulation of buprenorphine FDA approved for pain. Belbuca is the first and currently the only formulation of buprenorphine that can be delivered by dissolving a film which is placed on the inner lining of the cheek carrying an indication for chronic pain. On the surface, this might look like just another one of those pharmaceutical gimmicks that puts a flashy new formulation on the market to rehash an already available medication. So what’s the big deal?
Like the old Dr. Pepper jingle goes, buprenorphine is “so misunderstood“. But, here to clarify it for you are guest bloggers Joseph Gottwald and Dr. Jacqueline Pratt Cleary.
First, let’s start with some context. Buprenorphine didn’t get its start as a treatment for pain. Rather, it was initially thought to be helpful for reducing cravings for patients that have an opioid abuse disorder. Buprenorphine is a partial agonist at the mu-opioid receptor (responsible for opioid’s euphoric effects) and as such leads to a less robust euphoric response…voila – less abuse potential! Not long after, researchers discovered buprenorphine has some excellent analgesic qualities as well. The safety profile of buprenorphine presents an additional benefit compared to traditional full agonist opioids, as buprenorphine has a “ceiling effect.” This dramatically reduces the risk of opioid-induced respiratory depression – the common causative factor of opioid overdose-related death due to the partial agonist activity. Opioids block the carbon dioxide feedback loop that is used to stimulate the respiratory center in the brainstem to increase respiratory rate. Generally, the higher the dose, the more profound inhibition of this feedback loop. With buprenorphine, however, this effect seems to reach a plateau which is consistent with what is understood about the effects of partial agonists. Therefore, we have an opioid medication with reduced abuse and respiratory depression potential that also has analgesic properties. Given these properties, buprenorphine may serve a unique niche for patients with legitimate chronic pain requiring opioids who are otherwise not candidates for full agonists due to safety, abuse, or other concerns. Let’s review what is currently available:
Prior to the recent release of Belbuca, several formulations of buprenorphine were already available: sublingual tablet (Subutex), transmucosal film (Suboxone), transdermal patch (Butrans), and a parenteral formulation (Buprenex).
Buprenex was released in 1985 and is intended for IV or IM administration. It is approved for the relief of moderate to severe pain is typically reserved for use in the inpatient setting.
Subutex is a sublingual tablet containing buprenorphine that is approved for the treatment of opioid dependence. Although this formulation has been successfully used off-label for the treatment of chronic pain, it is important to note that the manufacturer recommends against the use of Subutex for pain due to reports of death in opioid-naïve patients after receiving 2mg sublingual tablets. Some other challenges with this formulation are concerns for intolerance (many reports of nausea) as well as variable bioavailability.
Suboxone is a transmucosal film product intended to be dissolved under the tongue that combines buprenorphine and naloxone in one formulation. Like Subutex, Suboxone is only approved for the treatment of opioid dependence. The formulation of buprenorphine with naloxone carries some clinical controversy. The initial rationale was this combination included naloxone to act as an abuse deterrent. If the product was to be crushed, injected, or snorted the theory was that the naloxone would antagonize the opioids effects. However, this theory has several flaws. First, buprenorphine has a much higher binding affinity for the mu-opioid receptor than naloxone. Secondly, not only is buprenorphine more strongly bound to its activity site, it has a longer elimination half-life than naloxone. Buprenorphine is not only binding stronger, it is hanging around its site of activity longer. So the presence or absence of naloxone here would in general provide the same result.
Fast forward to the new release of Belbuca. Both Butrans and Belbuca have FDA approval for the management of “pain requiring around-the-clock, long-term opioid treatment not adequately controlled with alternatives,” the new standard labeling required on all extended-release opioids indicated for chronic pain. Additionally, both allow for short-acting full agonist opioids during titration periods.
Butrans, a buprenorphine transdermal patch product, is available in dosages ranging from 5mcg/hr to 20mcg/hr. According to the manufacturer, this range could provide adequate analgesia for patients requiring up to 80mg oral morphine equivalent daily dose (MEDD) prior to initiation. Each patch is intended to remain in place for 7 days and takes ~3 days to achieve steady state levels. Currently, the maximum approved dose is limited to 20mcg/hr due to concerns of QT prolongation. This recommendation is based on the study cited in the prescribing information that states the 10mcg/hr dose resulted in no clinically meaningful effect on mean QTcF whereas a 40mcg/hr dose resulted in a maximum mean QTcF prolongation of 9.2ms across the study period. We’ll return to the concept of QT prolongation with buprenorphine shortly.
Belbuca, the newest buccal film formulation of buprenorphine, is available in dosages ranging from 75mcg to 900mcg. The film is intended to be utilized every 12 hours and according to the manufacturer may provide adequate analgesia for patients requiring up to 160mg MEDD prior to initiation. This is a much needed dosage expansion as there are many patients with significant indications for opioid pain who are not candidates for full agonist opioids due to concerns for either abuse or adverse events. Buprenorphine may be a viable alternative if we can provide a dose with adequate analgesia. Again, the dose is limited to 900mcg every 12 hours due to concerns for QT prolongation – doses in the approved range resulted in QTcF values between 450-480ms for 2% of patients.
There is a good deal of discussion regarding QT prolongation here and for good reason – it has the potential to cause serious harm. However, it is also important to place the magnitude of prolongation in the context of other available and widely used drugs that also are known to cause QT prolongation. You can find the details on this data in the linked article below, but here is a figure that provides a comparison of QT prolongation magnitude among a variety of drugs including antipsychotics, antidepressants, antibiotics and buprenorphine. Note that this data is not meant to be used for direct comparisons between the various agents due to differences in study design, QT correction strategies and population variations, but is provided as context for the current landscape of QT prolonging drugs. It is important for pharmacists and providers to recognize that drug-drug interactions, history of cardiac conditions, as well as concomitant use of medications which prolong the QT interval should all be considered during therapy selection.
The introduction of Belbuca allows for on-label use of higher buprenorphine doses but also highlights the need for providers to become familiar with dosage conversion, acute pain management options for patients on chronic buprenorphine therapy, and abuse potential. We didn’t get into the discussion much, but acute pain management in the perioperative setting for those on buprenorphine is discussed more extensively in an article by Fudin et al HERE. Basically, acute pain management becomes much more complicated when you’ve taken up all the available opioid receptors with buprenorphine. Buprenorphine’s unique pharmacology may provide an option for complex pain patients with a history of opioid misuse/abuse, or for those that have any number of comorbid medical risks. The warning for QT prolongation has unfortunately put a limit on several of the dosage forms; however, the provided information and forthcoming studies will hopefully shed some light on this highly debated topic. Each patient should be approached as an individual case and warrants a discussion regarding clinically relevant QT prolongation. Buprenorphine is a much needed compound that pain practitioners should be grateful to have in their armamentarium; however, knowledge and understanding of its properties is a necessity. Now with the release of the new Belbuca products the “ceiling” was raised a little higher.
You can find a detailed version of this article in the Pharmacy Times HERE including references for the above information.
About the guest bloggers:
Joseph Gottwald is a 2016 PharmD candidate at the Albany College of Pharmacy and Health Sciences and will begin medical school after graduation. He has experience as a research assistant in organic synthesis and interest in neuropharmacology. He is currently under the mentorship of Dr. Fudin subsequent to completion of an advanced practice rotation in pain management.
Dr. Pratt Cleary is a PGY2 Pain and Palliative Care Resident at the Stratton VA Medical Center in Albany, New York, under the mentorship of Dr. Jeffrey Fudin. Her research interests include risk stratification prior to and following opioid therapy with emphasis on requisite naloxone qualification for in-home use. She has been a leader in the expansion of the risk index for overdose or serious opioid induced respiratory depression (RIOSORD) tool presenting and educating providers and patients on a national scale. Prior to completion of a PGY1 General Practice Residency at Sentara Healthcare System in Norfolk, Virginia, she earned her BS in Biochemistry at Furman University and her Doctor of Pharmacy at South Carolina College of Pharmacy, MUSC Campus. Dr. Pratt hopes to pursue a career in pharmacy academia upon completion of her PGY2 residency training.