On April 4, 2016 guest bloggers Drs. Jacqueline Pratt Cleary and Joseph Gottwald (a student at the time) posted Buprenorphine, so misunderstood with, as you likely predicted, the old Dr. Pepper parody in tow. That blog focused on the newest buprenorphine dosage form approved by the FDA specifically for the management of chronic pain, Belbuca. This is a buccal dosage form which by definition is absorbed through the cheek. Included in that blog was a smattering on Butrans Transdermal which contains the same drug for delivery through the skin.
I am bothered by the fact that many patients in dire need of buprenorphine to treat pain are unable to obtain either Belbuca or Butrans. Like it or not, a capitalistic healthcare system dictates which patients can and cannot obtain these drugs based on cost (instead of what’s best) in many ways similar to socialistic model. Nevertheless, many, if not most, primary care providers have never heard of Belbuca or Butrans. And those clinicians that do know of these products sometimes find themselves fighting with insurance carriers in order for patients to receive these drugs for a reasonable copay.
Hundreds of emails to me have followed the release of these products, from desperate patients who have legitimate pain syndromes with comorbid opioid abuse disorder and in whom there is no desire and in fact an aversion to taking a pure opioid. But, insurance carriers in general couldn’t care less and would rather see these patients using more abusable drugs such as morphine, oxycodone, or hydrocodone in their generic non-abuse deterrent formulations because these formulations are cheap. And, the insurance carriers’ goal is to minimize expense and maximize profit. But to be fair, pharmaceutical manufacturers are also in business to make money. Notwithstanding, we all hope there is an altruistic side to both such that the patient’s best interest is considered.
Here’s a snippet from one of those e-mails from a football player who was injured and became addicted to opioids:
Dr. Fudin, I have legitimate pain. I make a little money but not much and my health insurance was cancelled in February. I purchased health insurance privately but my doctor refuses to send in the prior-authorization request because he said the insurance won’t pay for my medication unless I agree to work towards lowering the amount I take and see a psychiatrist. My visit and the Suboxone RX all together come to $480. Traveling there by train is another $70 all tolled it is $550. I have been paying for my prescription for 5 months and the collateral damage is tremendous. I understand that Suboxone is prescribed for addiction treatment. Thing is I get a lot of pain relief. I take 8mg/2mg, two to three times a day. It manages my pain and it is a miracle. I do not want to stop but I can’t afford it. I do not know what to do. NSAIDS and Acetaminophen seem to work synergistically with Suboxone. I am a good man who works every day and I want to just continue doing what I am doing but I can’t and I don’t understand why. This seems crazy to me.
I started looking for solutions. I read that there is a drug called Belbuca that is actually FDA approved and indicated for pain. I don’t know if it is prescribed because I can’t find anybody who has ever heard of it. My doctor hasn’t and my pharmacist hasn’t. What bothers me about this more than anything is that if I was looking for a RX for Percocet 10/325 or Lorcet 10/650, there isn’t a problem financially. BUT, that is not an option for me so, if you can, I need help. Please advise?
As the axiom goes, “HOUSTON, WE HAVE A PROBLEM!”
This is not to say that either manufacturer is or has encouraged the use of their products in higher risk patients – in fact it is just the opposite. Both companies have responsibly made it crystal clear in their professional package inserts and to their sales staff that these drugs by FDA regulation and approved indications carry the same risk warnings as pure opioids.
So, I engaged my current Pharmacy Pain Resident Dr. Erica Wegrzyn and Dr. Mena Raouf to summarize some of the attributes of buprenorphine use in the pain arena and to clarify why this country is missing out on a big opportunity that could help patients with the dual diagnosis of opioid abuse disorder in whom non-opioids are either minimally useful or not an option for other medical reasons. Here’s what they had to say…
Buprenorphine is a semi-synthetic opioid sharing opioid chemistry to other dehydroxylated phenanthrene opioids including drugs ranging from pure opiods such as oxycodone to the weak opioid dextromethorphan and receptor blocker naloxone.1 Despite its common use in treatment of opioid dependence, buprenorphine is an effective opioid analgesic that is 25-100 times more potent than morphine.2
But, buprenorphine is underutilized in pain management. It carries a stigma as an agent for substance abuse disorder; however, it was originally introduced to the market for treatment of pain.3 Buprenorphine was approved in 1978 as an injection for treating severe pain followed by the introduction of the sublingual tablets in Europe in 1982.1 It was not until the drug treatment act (DATA) of 2000 that buprenorphine was approved by the food and drug administration (FDA) for opioid dependence followed by the introduction of Suboxone in 2002, containing buprenorphine co-formulated with naloxone.4
Key distinguishing pharmacokinetic properties of buprenorphine include:
- Partial mu-agonist: buprenorphine binds to the mu receptor and activates it to a lesser extent compared to pure opioid agonists.1
- Potent kappa antagonist: reduces stress-induced drug seeking behavior. Interestingly kappa receptor selective opioid peptides, dynorphins, normally drive anxiety and stress and increase the desire to take opioids.5,6 Additionally, kappa receptor antagonism has demonstrated antidepressant like activity and currently there are multiple kappa receptor antagonists undergoing phase III trials for depression.7
- Strong binding affinity: buprenorphine binds tightly to the mu receptor competing with other opioids for the binding site.1
- Slow dissociation rate: buprenorphine has a dissociation half-life of 5-6 hours producing a prolonged activity at the receptor level.1
- Elimination half-life: buprenorphine has an elimination half-life of 24 to 42 hours depending on the formulation.1
Aside from its lower abuse potential, there are other niches for buprenorphine’s use in chronic pain management. This was discussed in detail in the previous post mentioned above, Buprenorphine, so misunderstood. Due to its partial agonist profile, buprenorphine has a ceiling effect on CO2 accumulation, meaning its effects on respiratory depression plateaus at higher doses.8 This makes it a good option for patients with underlying respiratory compromise or at high risk for respiratory depression requiring opioid therapy. Additional benefits include a lower incidence of opioid-induced androgen deficiency compared to other opioids and decreased immunosuppressive effects when studied in comparison to morphine and fentanyl.9,10
Many logistical roadblocks exist to prescribing buprenorphine for pain. Current buprenorphine products approved for pain are expensive as they are available as branded, non-generic options only. Some providers have sought to get around this issue by prescribing alternative buprenorphine products that are considered off-label for pain, but more affordable. This practice has also created a dilemma. In July 2016, Tennessee passed an amendment to the Addiction Treatment Act prohibiting the off-label use of buprenorphine products that are indicated for opioid-dependence for pain management.
JF: What problem does that solve Tennessee? Obviously none for the patients that need this drug. A short-sited bean counter may tell you it’s saving money for the state. Maybe…but what’s the cost to the patient victim that is forced by the state to take the least expensive, more dangerous alternatives such as morphine, hydrocodone or oxycodone? Moreover, what’s the cost to society to treat these patients in rehab – or do we just bank on an overdose and death? #bureaucrats versus #ifieverhadabrain
Buprenorphine is used for pain at doses much lower than for treatment of opioid dependence.11 FDA approved formulations for pain include Buprenex® (injection), Butrans® (transdermal), and BelbucaTM (buccal).12-14 Products approved for opioid dependence include Zubsolv® (SL), Suboxone® (SL, Film), and Bunavail® (buccal) and are co-formulated with naloxone. 4, 15,16 A brief overview of different buprenorphine products can be viewed HERE.
In Europe, buprenorphine is approved for pain at much higher doses than in the United States (US).11 The maximum recommended dose for transdermal buprenorphine in the US is 20mcg/hr changed every 7 days due to reports from one study showing a mean QTc prolongation of 9.2 mSecs on 40mcg/hr patch.17However, the starting dose in Europe is 35 mcg/hr patch changed every 4 days and the maximum dose is 140mcg/hr every 4 days.18
The biggest challenge in converting patients from a full opioid agonist to buprenorphine is the potential to induce withdrawal in the initial 1-2 week post initiation in opioid-dependent patients due to buprenorphine’s strong binding affinity displacing the former opioid agonist. Buprenorphine products approved for pain are available in lower doses (in micrograms) whereas products approved for substance abuse are available only in higher doses (in milligrams). Receptor occupancy at the mu-receptor for 2mg, 16mg, and 32mg doses are 24-47%, 85-92%, and 94-98% respectively. 19 In a randomized, double-blind, double-dummy, active controlled analysis of 70 of patients on morphine equivalent dose (MED) ≥ 80mg, patients were assigned to receive buccal buprenorphine at 50% of their MED or full mu-agonist (morphine or oxycodone) at 50% MED.20 Researchers used a 100:1 conversion factor from MED to buccal buprenorphine. Of the 35 patients receiving buccal buprenorphine, one patient experienced opioid withdrawal compared to 2 patients in the full mu-agonist group. There was no statistically significant difference in pain scores between both groups. Overall, the study suggests that switching patients to buccal buprenorphine at 50% of MED dose is comparable in safety and tolerability to reducing a patient to a 50% MED of their current regimen.
Late and Breaking Research
Due to the aforementioned pharmacologic properties and presumed attributes, use of buprenorphine for chronic pain may offer a unique and safer alternative for patients at risk of opioid abuse disorder and for those with diminished pulmonary function that have no other options. A study attempting to examine this was just approved at the Stratton VA Medical Center in Albany NY under the direction of Drs. Fudin and Wegrzyn. This retrospective review is examining the use of Butrans® transdermal patch and BelbucaTM buccal film. Outcomes assessed will include differences between pre-treatment and current pain scores, morphine equivalent daily dose (MEDD) of opioids for breakthrough pain prior to and following initiating buprenorphine, number of visits to the ER or PCP for acute pain flare-ups, and whether or not patients remained or withdrew from therapy and the reasons for discontinuation. Preliminary results of this data are intended for presentation at #PainWeek2016 as a late breaking poster. Drs. Fudin and Wegrzyn hope to see some of you there to shake your hand and answer questions!
As always, comments are welcome and encouraged!
This post was collaboratively written with Drs. Erica Wegrzyn and Mena Raouf.
Dr. Raouf is a PGY-1 Pharmacy Resident at the VA Tennessee Valley Healthcare System in Nashville TN. He received his Pharm.D. from Albany College of Pharmacy in Health Sciences in Albany, NY with a concentration in nephrology. Dr. Raouf completed an advanced pharmacy practice rotation at the Stratton VA Medical Center under the mentorship of Dr. Fudin, where he developed a strong interest in pain management. Following his PGY-1 residency training, Dr. Raouf hopes to pursue a PGY-2 in Pain Management.
Erica Wegrzyn, B.A., B.S., PharmD is currently completing a PGY-2 Pain and Palliative Care residency at the Stratton VA Medical Center, Albany NY. Dr. Wegrzyn received her PharmD from Western New England University College of Pharmacy, Springfield MA and completed a PGY-1 residency at Maine General Medical Center, Augusta ME. Prior to completing her PharmD, Dr. Wegrzyn also received her bachelors’ degrees in Biochemistry and Music (trombone) from Ithaca College. Dr. Wegrzyn’s initial interest in pain management was sparked by her exposure to Dr. Fudin’s pain practice during her final academic year while completing an advanced practice rotation at the Stratton VA Medical Center. In her new role as a PGY2 Resident she has already had an intense few weeks with three pending publications and is looking forward to some busy clinics starting next week. Dr. Wegrzyn thrilled to return to the Albany area where she is will resume her roles as a volunteer firefighter with Selkirk Fire District and also with “Out of the Pits” pitbull rescue. Dr. Wegrzyn is pictured here with her therapy certified and Selkirk FD resident fire dog, Blue.
- Lutfy K, Cowan A. Buprenorphine: A Unique Drug with Complex Pharmacology. Current neuropharmacology. 2004;2(4):395-402.
- Khanna IK, Pillarisetti S. Buprenorphine – an attractive opioid with underutilized potential in treatment of chronic pain. Journal of Pain Research. 2015;8:859-870.
- Suboxone [package insert]. Richmond, VA: Reckitt Benckiser Pharmaceuticals; September 2015.
- McLaughlin JP, Marton-Popovici M, Chavkin C (2003). Kappa opioid receptor antagonism and prodynorphin gene disruption block stress-induced behavioral responses. J Neurosci23: 5674–5683.
- Melief EJ, Miyatake M, Bruchas MR, Chavkin C (2010). Ligand-directed c-Jun N-terminal kinase activation disrupts opioid receptor signaling. Proc Natl Acad Sci USA107: 11608–11613
- Dahan A. Opioid-induced respiratory effects: new data on buprenorphine. Palliat Med. 2006;20 Suppl 1:s3-8.
- Bliesener N, Albrecht S, Schwager A, Weckbecker K, Lichtermann D, Klingmüller D. Plasma testosterone and sexual function in men receiving buprenorphine maintenance for opioid dependence. J Clin Endocrinol Metab. 2005;90(1):203-6.
- Sacerdote P. Opioids and the immune system. Palliat Med. 2006;20 Suppl 1:s9-15.
- Chen KY, Chen L, Mao J. Buprenorphine-naloxone therapy in pain management. Anesthesiology. 2014 May;120(5):1262-74.
- Subutex [package insert]. Columbus (OH): Roxane Laboratories; February 2015. 24.
- Butrans [package insert]. Stamford (CT): Purdue Pharma; June 2014.
- Belbuca [package insert]. Malvern (PA): Endo Pharmaceuticals; December 2015
- Bunavail [package insert]. BioDelivery BioDelivery Sciences International, Inc. (BDSI), Raleigh, NC
- Zubsolv [package insert]. Orexo. International, Inc. July 2013
- Mercadante S1, Ferrera P, Villari P.Is there a ceiling effect of transdermal buprenorphine? Preliminary data in cancer patients. Support Care Cancer. 2007 Apr;15(4):441-4
- Greenwald MK, Johanson CE, Moody DE et al. Effects of buprenorphine maintenance dose on mu-opioid receptor availability, plasma concentrations, and antagonist blockade in heroin-dependent volunteers. Neuropsychopharmacology. 2003 Nov;28(11):2000-9
- Webster L, Gruener D, Kirby T et al. Evaluation of the Tolerability of Switching Patients on Chronic Full μ-Opioid Agonist Therapy to Buccal Buprenorphine. Pain Med. 2016 Feb 25. pii: pnv110. [Epub ahead of print]