Jeffrey Fudin, PharmD, DAIPM, FCCP, FASHP
Jeffrey Fudin, PharmD, DAIPM, FCCP, FASHP
Dr. Jeff Fudin graduated from Albany College of Pharmacy & Health Sciences with a BS and PharmD. He is a Diplomate to the Academy of Integrative Pain Management, a Fellow to ACCP and ASHP, and a member of several other professional organizations. He is President and Director, Scientific and Clinical Affairs for Remitigate, LLC (remitigate.com), a software platform for interpreting urine drug screens (Urintel) and risk for opioid-induced respiratory depression (Naloxotel). Dr. Fudin is a section editor for Pain Medicine and serves on the editorial board for Practical Pain Management. He practices as a clinical pharmacy specialist (WOC) and director of PGY-2 pharmacy pain residency programs at the Stratton Veterans Administration Medical Center in Albany, New York and has academic affiliations with Western New England University and Albany Colleges of Pharmacy.

A Brief Review of Buprenorphine Products

MARCH 22, 2016
Endo Pharmaceuticals recently announced the availability of Belbuca, the first buccal formulation of buprenorphine approved by the FDA for the treatment of pain.
 
Currently, Belbuca is the only formulation of buprenorphine that can be delivered by dissolving a film that is placed on the inner lining of the cheek for the treatment of chronic pain.1 This article will review the development of various buprenorphine dosage forms, as well as their unique pharmaceutical properties and use in the treatment of pain.
 
Buprenorphine was developed by UK-based Reckitt & Colman Products and released in the United Kingdom in 1978. That same year, a clinical study determined that buprenorphine could be helpful in reducing cravings of pure opioids in patients with an opioid abuse disorder.2 Then, a separate study published in 1982 demonstrated that buprenorphine offered excellent analgesia with a blunted abuse liability.3 
 
Buprenorphine is approved in the Unites States to treat opioid abuse disorder and moderate to severe chronic pain.4 It is a dehydroxylated phenanthrene similar in chemical structure to oxycodone, hydromorphone, oxymorphone, and several other opioids. However, buprenorphine’s mechanism of action of is quite different from the others’.
 
Buprenorphine is a partial agonist at the mu-opioid receptors and an antagonist at the kappa receptors.5,6 Mu-opioid receptor activity produces the analgesic effects of buprenorphine, while a strong affinity for the kappa receptors render them inactive.6,7
 
Because of this unique pharmacology, buprenorphine provides analgesia at therapeutic doses but also has a suggested “ceiling effect” on respiratory depression. As the dosage increases, activity that buprenorphine exhibits as a partial agonist plateaus regardless of subsequent increases.8,9
 
Opioids block the carbon dioxide feedback loop that is used to stimulate the brainstem to increase respiratory rate. The higher the dose, the more effect an opioid has on the feedback loop. 
 
Because of its “ceiling effect” at the opioid receptor, buprenorphine has a much lower likelihood of respiratory depression.10 A clinical study later discovered in 1988 that naloxone reversal of buprenorphine failed to precipitate abstinence and abrupt withdrawal in animals and humans, producing only mild withdrawal effects.11
 
Prior to the recent release of Belbuca, several formulations of buprenorphine were already available: a parenteral formulation (Buprenex), transmucosal film formulated in conjunction with naloxone (Bunavail, Suboxone, Zubsolv), sublingual tablet (Subutex), and transdermal patch (Butrans).
 
Buprenex
Buprenex was released in 1985 in the United States as an injectable formulation of buprenorphine.12 It is intended for intravenous (IV) or intramuscular (IM) administration and contains 0.3 mg of buprenorphine per mL.12 
 
The IV formulation should be delivered slowly over at least 2 minutes. Peak effects of analgesia are observed 1 hour after injection, with initial effects occurring 15 minutes after injection and persisting 6 hours or longer. The elimination half-life ranged from 1.2 to 7.2 hours in pharmacokinetic studies, with an average of 2.2 hours after IV administration.13
 
Buprenex is approved for the relief of moderate to severe pain. This formulation is also used off-label for the treatment of opioid withdrawal in heroin-dependent hospitalized patients.14
 
The most common adverse events seen after the use of this product were nausea, dizziness, sweating, hypotension, headache, vomiting, nausea, vomiting, hypoventilation, and miosis, while sedation was the most prevalent. No dosage adjustments are recommended for renal or hepatic impairment.

Bunavail, Suboxone, and Zubsolv
The buprenorphine transmucosal film is formulated in conjunction with naloxone. This medication is indicated for the treatment of opioid dependence and is used for heroin or other opioid dependency, both for induction and maintenance therapy.15 
 
Although the pharmacokinetics among these 3 products are similar to the sublingual formulations, bioequivalence is variable. Bunavail and Zubsolv are also only indicated for maintenance therapy following induction by Suboxone. Table 1 illustrates the comparable doses available for these 3 products.15
 
Table 1: Available Doses of Buprenorphine/Naloxone Combination Products*
Suboxone SL Tablet Suboxone SL Film Zubzolv SL Tablet Bunavail Buccal Film
2 mg / 0.5 mg 2 mg / 0.5 mg 1.4 mg / 0.36 mg ---------------
4 mg / 1 mg 4 mg / 1 mg ---------------- 2.1 mg / 0.3 mg
8 mg / 2 mg 8 mg / 2 mg 5.7 mg / 1.4 mg 4.2 mg / 0.7 mg
12 mg / 3 mg 8 / 2 mg + TWO 2 mg / 0.5 mg films --------------- 6.3 mg / 1 mg

*(buprenorphine dose/naloxone dose)
 
The film should be taken whole and placed under the tongue until it completely dissolves. US labeling has no limitations in patients with renal impairment, but it suggests using caution in hepatically impaired patients.15 Canadian labeling of the same products has limitations for both renal and hepatic impairment.16 Headache, withdrawal syndrome, pain, and diaphoresis were among the most reported adverse events following the use of Suboxone.15
 
The formulation of buprenorphine with naloxone carries some clinical controversy. The initial rationale was that this combination would be abuse-deterrent if it would be crushed, injected, or snorted. However, this theory has several flaws.
 
First, buprenorphine has a much higher binding affinity for the mu-opioid receptor than naloxone. Second, buprenorphine is not only more strongly bound to its activity site, but also has a longer elimination half-life than naloxone. The half-life of buprenorphine is between 24 to 42 hours, depending on the patient, while the half-life of naloxone is only 2 to 12 hours.17 Therefore, buprenorphine binds to the mu-receptor longer and also remains at the receptor site 4 to 12 times longer than naloxone.18,19

Subutex
Subutex is a sublingual tablet formulation of buprenorphine approved for the treatment of opioid dependence, with a particular focus on the induction phase of treatment. It has also been used off-label successfully for the treatment of chronic pain for which long-term full opioid agonists are not tolerated or appropriate.20,21
 
It is important to note that the manufacturer recommends against the use of Subutex for the treatment of pain because of reports of death in opioid-naïve patients after receiving 2 mg sublingual tablets. Therefore, caution should be taken when selecting the drug for this purpose, particularly for the opioid-naïve population.
 
The tablet should be placed under the tongue and allowed to fully dissolve, as swallowing will reduce bioavailability and is not recommended. A clinical study determined that the bioavailability of Subutex is 29% +/- 10% when compared with an IV buprenorphine formulation.22 Dosages of 2 mg and 8 mg are available, and a dose-related response has been noted up to single doses of 32 mg.
 
Elimination half-life for Subutex ranges from 31 to 35 hours in the plasma. Plasma levels of buprenorphine were found to be higher in those with moderate to severe hepatic impairment, and dose adjustments are recommended for those with severe hepatic impairment.23

Butrans
Butrans is a buprenorphine transdermal patch indicated for the management of pain requiring around-the-clock, long-term opioid treatment that is not adequately controlled with alternatives. Dosages of 5 mcg/hr, 7.5 mcg/hr, 10 mcg/hr, 15 mcg/hr, and 20 mcg/hr are available, but only the 5 mcg/hr dose is recommended for opioid-naïve patients.
 
The manufacturer recommends discontinuing all around-the-clock opioids at the initiation of Butrans, but it does allow the use of short-acting opioids during titration periods. For patients receiving 30 mg to 80 mg oral morphine equivalent daily dose (MEDD), it is recommended to taper the dose to no more than 30 mg MEDD to reduce the risk of opioid withdrawal and inadequate pain control upon conversion to Butrans.24
 
The recommended initial dose selection is based on the MEDD that the patient is currently receiving, as those receiving <30 mg and 30 to 80 mg of MEDD should be initiated on the 5 mcg/hr and 10mcg/hr patch, respectively.24 Of note, a patient can apply up to 2 patches simultaneously during dose titrations, but it is important to apply both patches at the same time at 2 separate, adjacent application sites.
 
Butrans patches should be left on for 7 days prior to removal. The dose can be titrated to a maximum of 20 mcg/hr, but doses above this have been shown to cause QT prolongation. This recommendation is based on a study cited in the prescribing information, which states that the 10 mcg/hr dose resulted in no clinically meaningful effect on mean QTcF, whereas a 40 mcg/hr dose resulted in a maximum mean QTcF prolongation of 9.2 ms across the study period.24
 
Dose adjustments should not be made until at least 72 hours of use at the same strength, as it takes 72 hours to achieve steady state concentrations. Time to peak concentration and elimination half-life are 60 hours and 26 hours, respectively.

Belbuca
Belbuca is the newest formulation of buprenorphine available as a buccal film and indicated for the management of pain requiring around-the-clock, long-term opioid treatment not adequately controlled with alternatives. This reflects the new standard labeling required of all extended-release opioids indicated for chronic pain.25
 
There are a wide variety of dosages available, including 75 mcg, 150 mcg, 300 mcg, 450 mcg, 600 mcg, 750 mcg, and 900 mcg. Belbuca offers a wider dosage variation range compared to Butrans, but it requires more frequent dosing. Doses up to 450 mcg every 12 hours were studied in opioid-naïve patients, while doses >450 mcg every 12 hours should be reserved for patients previously taking long-term opioid treatments.
 
As with Butrans, it is recommended to discontinue around-the-clock opioids prior to initiating Belbuca and to taper patients on >30mg MEDD to 30 mg MEDD prior to initiation. Short-acting opioids may be used during titration periods, as well.
 
The bioavailability of Belbuca is 45% to 65%, which is an improvement compared with other mucosally absorbed buprenorphine products. Table 2 illustrates a bioavailability comparison of all of the buprenorphine products previously discussed. 
 
Table 2: Buprenorphine Product Bioavailability
Product Bioavailability (%)
Belbuca (buccal) 45-65%
Butrans (patch) 15%
Subutex (SL)
Suboxone/Bunavail/Zubsolv
29 +/- 10%

The manufacturer provides dose recommendations for patients receiving up to 160 mg MEDD, in which those receiving <30mg, 30 mg to 89mg, and 90 mg to 160 mg MEDD prior to any tapers are recommended to receive doses of 75 mcg every 12 to 24 hours, 150 mcg every 12 hours, and 300 mcg every 12 hours, respectively.
 
Belbuca is designed to adhere to the buccal mucosa and fully dissolve within 30 minutes. Elimination half-life and time to peak concentration are 27.6 hours and 2.5 to 3 hours, respectively.
 
It is important to avoid manipulating the formulation with the tongue, chewing, or swallowing the film, as this may cause lower-than-expected bioavailability because of the first pass effect on buprenorphine when it is taken orally.26 
 
The maximum recommended dose for Belbuca is 900 mcg every 12 hours, presumably because of the potential for QT prolongation. Doses in this range resulted in QTcF values between 450 msec to 480 msec for 2% of patients.26 
 
It is important to recognize that there are many frequently used medications with known effects on the QT interval, such as fluoroquinolone antibiotics, tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and atypical antipsychotics.
 
A single-dose, double-blind, placebo-controlled crossover study evaluated naltrexone-corrected QT prolongation with buprenorphine and naltrexone compared to moxifloxacin. The largest mean QTcF prolongation for 3 mg buccal buprenorphine plus 50 mg naltrexone and moxifloxacin 400 mg were 5.8 ms and 12.0 to 12.4 ms, respectively.27
 
In another meta-analysis studying the magnitude of QT prolongation with SSRIs versus placebo and SSRIs versus TCAs, SSRIs were associated with a 6.10 ms QTc increase. TCAs were associated with an additional 7.05 ms QTc increase compared with SSRIs. Of note, citalopram and escitalopram were the SSRIs with the most notable QT prolongation, with QTc change versus placebo of +10.58ms and +7.27ms, respectively.28
 
In another study of various antipsychotic medications conducted by Pfizer at the request of the FDA, mean QT prolongation from baseline (corrected using the Bazett formula) for ziprasidone 160 mg/day, risperidone 16 mg/day, olanzapine 20 mg/day, quetiapine 750 mg/day, thioridazine 300 mg/day, and haloperidol 15 mg/day were +20.3 ms, 11.6 ms, 6.8 ms, 14.5 ms, 35.6 ms, and 4.7 ms, respectively.29 Figure 1 compiles these data points along with information on QT prolongation from the Butrans and Belbuca prescribing information.
 

 
Note that these data are not meant to be used for direct comparisons between the various agents because of differences in study design, QT correction strategies, and population variations, but are instead 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, and concomitant use of medications that prolong the QT interval should all be considered during therapy selection.

Final Thoughts
Buprenorphine is a unique analgesic agent that requires a clinician who is familiar with its pharmacokinetic profiles, as well as the benefits and pitfalls with each various dosage formulation available. 
 
Buprenorphine also undergoes extensive metabolism through the CYP3A4 system, so attention must be paid to the potential for significant drug interactions among other medications that are substrates, inhibitors, or inducers of this system. Literature examining the effect of co-administration with CYP3A4 inhibitors/inducers has shown mixed results regarding the clinical relevance of this interaction, but given the potential risk of accumulated opioids, caution is recommended.30-33
 
With the development of Belbuca, a new dosage threshold allows clinicians to use buprenorphine on-label at higher doses if needed. This also means that more providers will need to become familiar with dosage conversion, acute pain management options for patients on chronic buprenorphine therapy, and abuse potential. The previously mentioned “ceiling effect” of buprenorphine limits the risk of opioid-induced respiratory depression and makes a buprenorphine formulation a logical choice for a patient with a history of drug abuse or misuse that has true chronic pain.9,10
 
Although the under-treatment of chronic pain continues to plague patients in our current opioid epidemic, buprenorphine has been prescribed preferably by some clinicians to treat complex patients requiring opioids that have a notable propensity for dose-creeping. Although this is not the intent of any manufacturer and is in fact listed as a contraindication, it may provide the least risky option in patients who cannot receive alternative non-opioid analgesics for any number of comorbid medical risks.

Buprenorphine has various pitfalls, but it also has a unique pharmacologic mechanism and a niche for use in multiple dosage forms and for patients with a history of opioid misuse or abuse. Although the warning for QT prolongation has unfortunately put a limit on several of the dosage forms, the provided information and forthcoming studies will hopefully shed some light on this highly debated topic. This medication allows for unique dosing formulations, distinct pharmacology, and alternative therapy in the setting of chronic pain with a history of abuse. 
 
Buprenorphine is a much-needed compound that pain practitioners should be grateful to have in their armamentarium, but knowledge and understanding of its properties are necessities.  

This article was written collaboratively with Jacqueline Pratt Cleary, PharmD, and Joseph Gottwald, PharmD candidate.
  
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. Fudin. Her research interests include risk stratification prior to and following opioid therapy with emphasis on requisite naloxone qualification for in-home use. 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.

Joseph Gottwald is a 2016 PharmD candidate at the Albany College of Pharmacy and Health Sciences and will begin medical school after graduation. He is currently under the mentorship of Dr. Fudin subsequent to completion of an advanced practice rotation in pain management.
 
References
1. Endo International plc. Endo announces launch of BELBUCA™ (buprenorphine) buccal film for chronic pain management. http://www.newswire.ca/news-releases/endo-announces-launch-of-belbuca-buprenorphine-buccal-film-for-chronic-pain-management-569634871.html. Published February 22, 2016. Accessed March 2, 2016.
2. Jasinski DR, Pevnick JS, Griffith JD. Human pharmacology and abuse potential of the analgesic buprenorphine. Arch Gen Psychiatry. 1978;35:501-516.
3. Lewis J. The antagonist analgesic concept. The Dependence Phenomenon. Lancaster, England: MTP Press,1982.
4. Blaine JD. (ed.). Buprenorphine: an alternative treatment for opioid dependence. National Institute on Drug Abuse Research Monograph 121.1992.
5. Fudin J. Chemical classes of opioids. PainDr.com. http://paindr.com/wp-content/uploads/2012/05/Opioid-Chemistry-09-2011.pdf. Published September 2011. Accessed March 21, 2016.
6. Hardman JG, Gilman AG, Limbird LE. Opioid analgesics. Goodman and Gilman’s: The Pharmacological Basis of Therapeutics. (10th ed.). New York: McGraw-Hill, 2011.
7. US Department of Health and Human Services. KAP Keys for Physicians: Based on TIP 40, Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. [Rockville, MD]: U.S. Dept. of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for Substance Abuse Treatment, 2005.
8. Walsh SL, Preston KL, Stitzer ML, Cone EJ, Bigelow GE. Clinical pharmacology of buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther. 1994;55:569–580.
9. Mercadante S, Ferrera P, Villari P. Is there a ceiling effect of transdermal buprenorphine? Preliminary data in cancer patients. Support Care Cancer. 2007;15:441–444.
10. Teater D. The psychological and physical side effects of pain medications. http://safety.nsc.org/sideeffects. Accessed March 16, 2016.
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12. Norwich Eaton Pharmaceuticals, Inc. Buprenex product monograph. Norwich, NY: The Corporation, 1985.
13. Kuhlman JJ Jr, Lalani S, Magluilo J Jr, et al. Human pharmacokinetics of intravenous, sublingual and buccal buprenorphine. J Anal Toxicol. 1996;20(6):369-378.
14. Welsh CJ, Suman M, Cohen A, et al. The use of intravenous buprenorphine for the treatment of opioid withdrawal in medically ill hospitalized patients. Am J Addict. 2002;11(2):135-40.
15. Suboxone (buprenorphine/naloxone) [prescribing information]. Richmond, VA: Reckitt Benckiser Pharmaceuticals; September 2015.
16. BUNAVAIL (buprenorphine and naloxone) buccal film, CIII [prescribing information online]. BioDelivery BioDelivery Sciences International, Inc. (BDSI), Raleigh, NC. bdsi.com/siteres.aspx?resid=5a738443-a797-41cd-a39a-a8deb2a4a585. Published June 23, 2014. Accessed March 16, 2016.
17. Suboxone (buprenorphine/naloxone) [Canadian product monograph]. United Kingdom: Indivior UK Limited; August 2015.
18. Boas RA, Villiger JW. Clinical actions of fentanyl and buprenorphine. The significance of receptor binding. Br J Anaesth. 1985;57:192-196. 
19. Buprenorphine HCl/Naloxone HCl Sublingual Tablets [prescribing information]. Elizabeth, NJ: Actavis Elizabeth; February 2013.
20. Malinoff HL, Barkin RL, Wilson G. Sublingual buprenorphine is effective in the treatment of chronic pain syndrome. Am J Ther. 2005 Sep-Oct;12(5):379-84.
21. Mendelson J, Upton RA, Everhart ET, Jacob P 3rd, Jones RT.  Bioavailability of sublingual buprenorphine. J Clin Pharmacol. 1997 Jan;37(1):31-37.
22. Daitch D, Daitch J, Novinson D, et al. Conversion from high-dose full-opioid agonists to sublingual buprenorphine reduces pain scores and improves quality of life for chronic pain patients. Pain Med. 2014 Dec;15(12):2087-2094.
23. Subutex [prescribing information]. Columbus (OH): Roxane Laboratories; February 2015.
24. Butrans [prescribing information]. Stamford (CT): Purdue Pharma; June 2014.
25. Barlas S. FDA requires new labeling for some opioids. P T. 2013 Nov;38(11):644.
26. Belbuca [prescribing information]. Malvern (PA): Endo Pharmaceuticals; December 2015.
27. Darpo B, Zhou M, Bai SA, Ferber G, Xiang Q, Finn A. Differentiating the effect of an opioid agonist on cardiac repolarization from mu-receptor-mediated, indirect effects on the QT interval: a randomized, 3-way crossover study in healthy subjects. Clin Ther. 2016 Feb;38(2):315-326.
28. Beach SR, Kostis WJ, Celano CM, et al. Meta-analysis of SSRI-associated QTc prolongation. J Clin Psychiatry. 2014 May;75(5):e441-e449.
29. FDA Briefing Document for Zeldox Capsules (Ziprasidone). New York, Pfizer Inc, July 18, 2000, p 116.
30. Moro C, Taino R, Mandala M, Labianca R. Buprenorphine-induced acute respiratory depression during ifosfamide-based chemotherapy. Ann Oncol. 2006:17(9):1466-1467.
31. Kapil RP, Cipriano A, Michels GH, et al. Effect of ketoconazole on the pharmacokinetic profile of buprenorphine following administration of a once-weekly buprenorphine transdermal system. Clin Drug Investig. 2012 Sep 1;32(9):583-592.
32. McCance-Katz EF, Moody DE, Morse GD, et al. Interaction between buprenorphine and atazanavir or atazanavir/ritonavir. Drug Alcohol Depend. 2007 Dec 1;91(2-3):269-278.
33. Vergara-Rodriguez P, Tozzi MJ, Botsko M, et al. Hepatic safety and lack of antiretroviral interactions with buprenorphine/naloxone in HIV-infected opioid-dependent patients. J Acquir Immune Defic Syndr. 2011 Mar 1;56 Suppl 1:S62-S67.

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