With the recent FDA approval of a buprenorphine extended release injection, it seemed like a perfect opportunity to discuss practical issues with this new dosage form and how it could change the way buprenorphine is prescribed and administered to patients requiring long-term buprenorphine for the FDA indication of opioid use disorder. According to the professional package insert, “Sublocade is indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a transmucosal buprenorphine-containing product, followed by dose adjustment for a minimum of 7 days. It should be used as part of a complete treatment plan that includes counseling and psychosocial support.”
The applicability and questions in my mind have far broader implications. Here to briefly review those implications is Ms. Caroline Breen, a student pharmacist soon to graduate as a doctor of pharmacy.
Sublocade is the first once-monthly extended release buprenorphine injection that was recently approved by the FDA for moderate to severe opioid use disorder. It is approved for adult patients who have been stable on trans-mucosal buprenorphine (8 to 24 mg equivalent daily) for at least seven days.1
Buprenorphine is a partial agonist at the mu-opioid receptors, and also an antagonist at the kappa receptors. The activity at the mu-opioid receptors is responsible for buprenorphine’s analgesic effect. By blunting the drug-liking or the pleasure effect, it provides its positive benefit in opioid use disorder. Buprenorphine also has utility as a potent analgesic and could be especially beneficial for pain patients requiring long-term opioid therapy. In fact, once it is decided to place a patient on opioids chronically, buprenorphine is the safest most logical first step prior to a full agonist. Unfortunately, that is unlikely to occur in a profit-driven medical system. Moreover, if a patient requires long-term opioid therapy for pain and there is a history of opioid abuse or taking extra doses, a once monthly injection could help foster compliance. Buprenorphine’s partial agonism results in a “ceiling effect” on CO2 accumulation and resultant respiratory depression. All opioids inhibit the carbon dioxide feedback loop that stimulates the brainstem to increase respiratory rate. With most opioids, increasing the dose results in greater inhibition of this feedback loop. Buprenorphine however, reaches a point where increases in dose do not result in more inhibition to the feedback loop. Thus, it is a safer alternative for patients at risk for respiratory depression. Various buprenorphine products are currently approved for either opioid use disorder or pain, but at lower doses in pain. No product is FDA approved for both. 2,3 These products were reviewed in a Pharmacy Times review by Dr. Fudin and colleagues approximately two years ago.
Sublocade delivers a sustained plasma level of buprenorphine with the once monthly injections. Currently, the recommended dosing regimen is 300mg monthly injection for the first two months, followed by the maintenance dose of 100mg monthly. If a patient is not showing enough clinical effect, the maintenance dose can be increased to 300mg monthly. After receiving Sublocade 300mg, the average steady state concentration was 6.54ng/mL, and with 100mg the average steady state concentration was 3.21ng/mL. According to the Sublocade Clinical trial, the reduction of illicit opioid use disorder was associated with plasma concentrations of 2-3ng/mL and mu-opioid receptor occupancy of ≥ 70%.3,4
Serum concentrations with transdermal buprenorphine (Butrans) 10mcg/hr (240mcg per day) with multiple doses were 0.224 ng/mL. 5 Buccal buprenorphine(Belbuca) dosed at the same 240mcg per days dose (as 120mcg every 12 hours) resulted in serum concentrations of 0.364 ng/mL +/-0.125.6 With sublingual buprenorphine/naloxone(Suboxone) 8/2mg, serum concentrations of buprenorphine were 3.37 ng/mL +/-1.8.7
In the United States, the max dose of transdermal buprenorphine is 20mcg/hr. It is capped here due to possible QTc prolongation, as studies of 40mcg/hr resulted in clinically significant increases in QTc.5 However, Suboxone and other formulations used for opioid use disorder are approved for dosing much higher than those approved for pain. In Europe, transdermal buprenorphine is available in 35, 52.5, and 70mcg/hr patches to be changed every 4 days.8
Sublocade comes with a warning to avoid use in patients with possible risk for prolonged QT interval or cardiac disease due to a phase 3 trial in which 7 of the 404 patients experienced an increase in QTc more than 60 ms, with one of these patients reaching a QTc of more than 500 ms. It is noted that these findings were sporadic and transient, and no patient experienced an arrhythmia.3
The ability to use a once monthly injection administered by a healthcare provider could benefit many patients. It would be particularly helpful in patients who are at risk for diverting substances, since the healthcare provider is the one injecting the substance. This also means the patient would be required to have monthly visits with a healthcare provider in order to receive their medication, and the provider would be able to ensure steady serum concentration. Currently, Belbuca(buccal buprenorphine) and Butrans(transdermal buprenorphine) are approved for use in pain management. Using Sublocade for pain would allow patients who are unable to use Butrans or Belbuca to continue to experience the benefits of buprenorphine, and the compliance would presumably be better. Additionally, patients sometimes experience irritation at the application site of Butrans or even a full allergic response to the adhesive. With Belbuca, some patients are unable to use the buccal films if they do not have in-tact healthy oral mucosa or the manual dexterity to insert the patch on the buccal area as directed. An inability to produce enough saliva can also interfere with the absorption of the buccal film formulation. Sublocade gives these patients another alternative option should buprenorphine continue to be the best option for their treatment. Patients would be able to manage their chronic pain without worrying about taking a tablet daily, inserting a buccal film twice daily, or changing a patch weekly. It would allow providers to ensure steady serum concentrations and give patients a safer treatment option. It allows the same benefits as it does with the treatment of opioid use disorder, so why not allow those with chronic pain to reap these benefits?
And here’s a thought…
For those patients receiving a once monthly injection for opioid use disorder or for pain that live in remote areas requiring 1-2 hours of driving, why not allow community pharmacists to inject the product so that a STABLE patient only has to visit the buprenorphine prescriber once every 3-6 months? Certainly, the pharmacist could evaluate patients and provide feedback to the prescriber. Wouldn’t that help promote buprenorphine use in patients that truly need it? We know that pharmacists are perfectly capable of giving injections in the community setting and counseling patients – but perhaps it is another case of Nobody Knows as seen in an earlier post.
In closing, we must remember that with any extended release receptor blocker, treating pain post-operatively can become quite a challenge, requiring a team approach to assure adequate pain relief and a safe environment prior to and following surgery, especially for patients with an underlying opioid use disorder that may be prone to relapse in the absence of buprenorphine. For a review and important considerations when treating perioperative pain for both elective and emergent surgery, see references 9 and 10 below with provided hyperlinks.
Questions and comments are always welcome!
GUEST BLOGGER Caroline Breen is a 2018 PharmD Candidate at Western New England University College of Pharmacy. She just completed an advanced practice rotation with the multidisciplinary pain team at the Stratton VA Medical Center in Albany NY under the mentorship of Drs. Erica Wegrzyn and Jeffrey Fudin. After graduation, she plans to continue her career as a community pharmacist.
- FDA Approves SUBLOCADE (Buprenorphine Extended-Release), the First and Only Once-Monthly Injectable Buprenorphine Formulation to Treat Moderate to Severe Opioid Use Disorder [Internet]. Indivior UK Limited; 2017 [cited 2018 Feb 5]. Available from: http://www.indivior.com/wp-content/uploads/2017/11/SUBLOCADE-FDA-Approval-Press-Release.pdf
- Cleary JP, Gottwald J. A brief review of buprenorphine products [Internet]. Pharmacy & Healthcare Communications, LLC; 2016 [cited 2018 Feb 5]. Available from: http://www.pharmacytimes.com/contributor/jeffrey-fudin/2016/03/a-brief-review-of-buprenorphine-products
- Sublocade [package insert]. North Chesterfield(VA): Indivor; 2017. Available from: http://indivior.com/wp-content/uploads/2017/11/SUBLOCADE-Prescribing-Information.pdf
- Nasser AF, Greenwald MK, Vince B, et al. Sustained-release buprenorphine (RBP-6000) blocks the effects of opioid challenge with hydromorphone in subjects with opioid use disorder. J Clin Psychopharmacol. 2016 Feb; 36(1): 18–26.
- Butrans [package insert]. Stamforc(CT): Purdue Pharma L.P.; 2014. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021306s015s019lbl.pdf
- Belbuca [package insert]. Malver(PA): Endo Pharmaceuticals;2015. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207932s000lbl.pdf
- Buprenorphine and naloxone. In: Lexi-Drugs [database on the Internet]. Hudson (OH): Lexi-Comp, Inc.; 2018 [cited 2018 Feb 5].
- Transtec 35, 52.5 and 70 micrograms transdermal patch [Internet]. Cambridge: Napp Pharmaceuticals Limited; 2015 [cited 2018 Feb 5]. Available from: https://www.medicines.org.uk/emc/medicine/8839
- Bettinger JJ, Fudin J, Argoff C. Buprenorphine and Surgery: What’s the Protocol? In Kean N, 2nd ed., Opioid Prescribing and Monitoring—How to Combat Opioid Abuse and Misuse Responsibly. Chap. 6. Pg. 73-78. Pub. Vertical Health, LLC. September 2017.
- Fudin J, Srivastava A, Atkinson TJ, Fudin HR. Opioids for Surgery or Acute Pain in Patients on Chronic Buprenorphine. In Aronoff G, ed., Medication Management of Chronic Pain: What you Need to Know. Publication pending, Trafford Publishing, 2017. Book purchase is available HERE.