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bup’ed or duped? is buprenorphine for everyone? p
By Timothy J. Atkinson PhArMD, BCPS, CPE / Jeffrey Fudin PhArMD, FCCP, FAShP, FFSMB
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Buprenorphine prescribing and availability for chronic pain and opioid use disorder (OUd) has seen considerable growth over the past decade, directly corresponding to the reduction in opioid manufacturing and decreased emphasis on traditional opioid prescribing for chronic pain. According to the Centers for Disease Control and Prevention, opioid prescribing decreased to its lowest level in over 14 years in 2019 with 46.7 opioid prescriptions per 100 persons compared to 72.4 per 100 persons in 2006.1 In 2020, the Drug Enforcement Administration reported that total domestic opioid production had decreased by 53% since 2016 with an additional decrease of at least 10% proposed for 2021.2 From 2009 to 2018, the number of individuals receiving buprenorphine for OUd more than doubled from 1.97 to 4.43 per 1000 persons.3 The largest increase was seen in the 35 to 44 age group, which increased from 2.41 to 8.34 per 1000 persons, and the only decrease was the youngest group of 15 to 24 year olds, which decreased from 1.76 to 1.40 per 1000 persons despite significant efforts to expand access to treatment across all age groups.3 Among these efforts was CaRa, or the Comprehensive Addiction and Recovery Act of 2016, that expanded buprenorphine prescribing for OUd to nurse practitioners and physician assistants. A review evaluating the early impact of this change indicated that from 2017 to 2018, buprenorphine prescribing increased by 9.1% nationally overall: 79.6% of that increase directly linked to prescribing from nurse practitioners and physicians assistants.4
towards further expansion of buprenorphine treatment is certain with the Department of Health & Human Services Inter-Agency Taskforce Report on Pain Management Best Practices recommending increased access to buprenorphine for both chronic pain and OUD. 5 It specifically encourages payers to provide coverage and reimbursement for buprenorphine treatment and recommends primary use of buprenorphine rather than use only after failure of standard mu agonist opioids such as hydrocodone or fentanyl when opioid therapy is implemented.5 Notably, there is no incentive or mandate requiring third party payers to support this recommendation. Improving provider expertise, familiarity, and experience with buprenorphine’s unique pharmacology and pharmacokinetics has never been more critical. The societal stigma surrounding medications for OUD (MOUD) is considerable, and the decreased availability of opioids for chronic pain combined with increased emphasis on identification and treatment of OUD has had some unintended consequences and created ethical dilemmas worthy of discussion.
Buprenorphine History
Buprenorphine was first introduced in Europe in 1978 as an injection for the treatment of moderate to severe pain, followed by release of Temgesic® (buprenorphine) 0.2 mg and 0.4 mg sublingual (Sl) tablets for pain in 1982.6 In the United States, Buprenex® (buprenorphine injection) was approved in 1981 for management of pain severe enough to require an opioid analgesic, but it was not until 2002 that Sl buprenorphine was approved in the US for the treatment of OUD as Suboxone® (buprenorphine/ naloxone), which is available in much higher doses common for opioid agonist treatment for OUD. 7 The early release and acceptance of Sl buprenorphine for pain in Europe but not the US has likely furthered the stigma and misconception that buprenorphine is not effective for pain. The disparity between buprenorphine availability for pain worldwide and in the US continues today with buprenorphine transdermal patches (Table 1). Buprenorphine patches ranging from 5 mcg/hour to 20 mcg/hour are available in the US, but in Europe strengths available include 35 mcg/hour to 70 mcg/ hour allowing buprenorphine to take a more prominent role in pain management.8,9 The dose disparity between
Table 1. FDA Approved Buprenorphine Formulations Available in the United States
Opioid Use Disorder
Suboxone® (buprenorphine/naloxone) Sl tab/film*
Subutex® (buprenorphine/naloxone) Sl tab/film*
Zubsolv® (buprenorphine/naloxone) Sl tab
Bunavail® (buprenorphine/naloxone) buccal film
Sublocade® (buprenorphine) SQ monthly injection
Brixadi® (buprenorphine) SQ weekly or monthly injection
Pain
Buprenex® (buprenorphine) IV/IM injection*
Butrans® (buprenorphine) weekly patch
Belbuca® (buprenorphine) buccal film
*Available as generic formulation. Sl=sublingual; IV=intravenous; IM=intramuscular; SQ=subcutaneous.
buprenorphine formulations in the US and in Europe has contributed to increased off-label use for pain with formulations designed and approved for OUD.
Pharmacology
There are several reasons why buprenorphine is thought to reduce risk when deployed to treat pain or OUD, but it begins with its unique pharmacology. Buprenorphine is a thebaine derivative and dehydroxylated phenanthrene with a core structure similar to morphine, hydrocodone, and oxycodone.10 The additions to the core structure are extensive, resulting in a large and bulky molecule significantly impacting binding kinetics including slow receptor association and incomplete and/or delayed dissociation from opioid receptors.11Table 2 summarizes opioid receptors and their functions when activated, along with their associated potential adverse effects.12,13 Buprenorphine is classified as a partial agonist with high binding affinity at mu-opioid receptors, full antagonist with high binding affinity at kappa and delta opioid receptors, and a partial agonist with low binding affinity at the opioid receptor-like-1 opioid receptor.13 It has a very high partition coefficient and a higher mu-opioid receptor binding affinity compared to all other traditional opioids, the former of which correlates directly to rapid passage through the blood-brain barrier. Both partition coefficient and high binding affinity create challenges in the acute pain setting when buprenorphine needs to be overcome by a traditional opioid agonist.14,15 Buprenorphine’s opioid receptor interactions are valuable for MOUD because, while it competes with other opioids to bind to mu-opioid receptors, its dissociation halflife of 166 minutes and 50% binding after 1 hour combined with its high affinity for the receptor make it nearly impossible to dislodge once bound. Therefore, the goal of MOUD is to saturate opioid receptors to prevent activation and possible overdose with opioid use. Complete receptor saturation occurs between 16 to 24 mg/day of Sl buprenorphine.16 Buprenorphine has demonstrated ability to block the effects of morphine for nearly 30 hours after administration, and opioid reversal agents such as naloxone are unpredictable with required concentrations for reversal as high as 40 times higher than required for similar opioids such as fentanyl.17-19 (For more on binding affinity, see Table 3.) Buprenorphine’s classification as a partial agonist is being challenged because it functions as a full opioid agonist throughout the therapeutic range for pain.23,24 There is a ceiling effect on respiratory depression within the therapeutic range, but analgesic effects plateau at higher doses commonly utilized for OUD. 23,24 Buprenorphine activates the opioid receptor-like-1 that attenuates analgesic effects but also the rewarding effects of opioids, and may explain the improved central nervous system clarity and tolerability of buprenorphine.24 Buprenorphine is unique in that it stimulates sufficient G-protein (guanine nucleotide-binding proteins) signaling while limiting beta arrestin recruitment, which has been associated with opioid-induced respiratory depression and abuse. The balance between G-protein and beta arrestin signaling may determine the extent of analgesia vs adverse effects.13
Pharmacokinetics
Buprenorphine has poor oral absorption which is why formulations emphasize Sl, buccal, transdermal, or intravenous administration.10 Buprenorphine undergoes hepatic metabolism via the CyP450 system predominantly through 3a4 to its active metabolite norbuprenorphine although CyP2C8 plays a minor role.24 Plasma concentrations of the major buprenorphine metabolites include norbuprenorphine, buprenorphine-3-glucuronide, and norbuprenorphine-3-glucuronide, which approximate
Opioid Receptor
Mu
Delta
Kappa Table 2. Pharmacologic Activity of Opioid Receptors12,13
Desired Activity Disadvantages when Activated
Peripheral analgesia, euphoria? Sedation, euphoria, respiratory depression, bradycardia, nausea/vomiting, and decreased gastrointestinal motility
Spinal and supraspinal analgesia Decreased gastrointestinal motility
Spinal analgesia Diuresis and dysphoria
Opioid Receptor-Like-1 Spinal analgesia Sedation
or exceed those of the parent drug. Both glucuronide metabolites of buprenorphine are biologically active at doses relevant to metabolite exposures. Activity of the glucuronides may contribute to the overall pharmacology of buprenorphine.25 Norbuprenorphine quickly undergoes glucuronidation through the UGT1a1 and UGT2b7 gene to improve water solubility for elimination, but studies indicate this conversion occurs rapidly and minimizes potential impact of 3a4 mediated drug interactions.26,27 Buprenorphine has a long terminal half-life of 24 to 42 hours after chronic administration indicating that buprenorphine may continue to have clinically significant effects on treatment for days after it was last administered.7 Buprenorphine is excreted in the urine (30%) and feces (69%).7,27 Since norbuprenorphine has an extremely high affinity for p-glycoprotein, it does not readily pass the blood-brain barrier. It is for this reason that we do not appreciate the full agonist effect of buprenorphine, even though the norbuprenorphine metabolite is present in the blood. Since buprenorphine is administered buccally or sublingually, in the authors’ opinion, it is plausible, if not probable, p-glycoprotein prevents passage back into the gut where mu-receptors would be responsible for opioid-induced constipation.25 marginalization, mistreatment, moral weakness, justification for withholding care, and voluntary or involuntary social isolation.28,29 The stigma associated with long-term opioid therapy for pain is similarly often characterized as weakness, exaggeration, neglect, and negative social reactions, among others.30 The new trend of off-label prescribing of buprenorphine formulations indicated for OUD among pain patients can, unbeknownst to patients, saddle them with the additive stigma of both OUD and pain. If insufficient time and education is allocated to patient education and shared decision making, then the risk of patients feeling “duped” into OUD treatment when they are seeking pain management is very real. Even providers who make it clear they are prescribing buprenorphine for pain should explain further: the formulation is approved for OUD, and other providers reviewing a state’s prescription drug monitoring program are unlikely to understand or believe a patient is receiving treatment for anything other than OUD. This can surely complicate or prevent a patient’s ability to transfer treatment to another pain practice (see Patient Case).
PATIENT CASE
Discussion
In the midst of the opioid overdose epidemic with roughly 130 people dying per day, stigma continues to be a key factor for treatment acceptance despite significant efforts to expand access.28 The stigma against people with substance use disorders has been described as
Mr. Jones is offered buprenorphine/naloxone and informed that his provider is no longer comfortable with his current treatment and no other opioids will be considered. He is told that becoming dependent on these medications is natural. Hearing that this medicine will address his pain, and with a lack of alternatives, he accepts treatment. He is quickly titrated to a moderate dose of buprenorphine/naloxone in divided doses throughout the
Opioids
Buprenorphine
Naltrexone
Fentanyl
Methadone
Naloxone
Morphine
Pentazocine
Range of Ki Value
0.21–1.5
0.4–0.6 (antagonist effects)
0.7–1.9
0.72–5.6
1.0–3.0 (antagonist effects)
1.02–4
3.9–6.9
65–135
Ki value = binding affinity; lower Ki values indicate higher affinity.
day and reports pain is significantly improved. Several months later, he begins reporting that the medication isn’t as helpful for his pain, and he believes that the pain was better managed on his previous regimen with traditional opioids. His request to make a change is denied and he becomes frustrated with care. It is explained to Mr. Jones that he is not a candidate for traditional opioid therapy because of his OUD diagnosis, which he says is not accurate because he’s never had a problem with opioids and only takes them for pain. He plans to switch his care to another provider, but every practice requires either a letter of good standing or an explanation of the results of the state prescription drug monitoring program query. Ultimately, Mr. Jones is informed by multiple clinics that due to his use of buprenorphine/naloxone he is not considered a candidate for opioid therapy. They offer to refer him to a suboxone clinic but he does not agree to treatment for OUD and is discharged. Mr. Jones now feels that he’s been tricked (duped) into this situation and didn’t realize the full impact of the stigma that surrounded treatment with buprenorphine/naloxone nor that it would render him ineligible for traditional opioid therapy in the eyes of most providers. He decides to taper and discontinue use hoping that abstinence will allow him to start over and receive a second chance from a provider viewing his situation with fresh eyes. However, now he must contend with coming off high dose opioid therapy that is reserved for OUD treatment and he likely underestimates the impact discontinuation of buprenorphine/naloxone will have on his pain.
Unfortunately, situations like the Patient Case are becoming far more common as buprenorphine/ naloxone use is expanded and off-label prescribing for pain increases. Even providers who take time to explain why buprenorphine/naloxone is being selected for pain and discuss all the ramifications of treatment will have patients reconsider after initiating therapy and who feel “duped” when eventually confronted with the societal stigma and few alternative treatment options. The ethical dilemmas described have contributing factors that make these types of clinical conundrums commonplace.
Complex Persistent Opioid Dependence
Buprenorphine’s increased popularity has led many to believe it is a panacea, and expanded use is promoted without apparent appreciation for the potential ramifications as described in the Patient Case. Complex persistent opioid dependence (CPOD) is the grey area where patients may not be ideal candidates to continue opioid therapy but refuse a diagnosis of OUD, making treatment by pain or substance use disorder professionals difficult. In this grey area of high-risk chronic pain management, we find a variety of folks treated with long-term opioid therapy considered high-risk perhaps because of high doses, polydrug risk with benzodiazepine and opioid combinations, personal or family history of substance abuse, or
Product Table 4. Equivalence Based on Bioavailability of Buprenorphine Formulations32
Available Strengths Percent Bioavailability Indication Morphine Eq 30 mg PO
Buprenex® (injectable) 0.3 mg/mL 100% Pain 0.3 mg
Belbuca® (buccal film) 75, 150, 300, 450, 600, 750, 900 mcg 45%-65% Pain
Butrans® (TD patch) 5, 7.5, 10, 15, 20 mcg/hr 15%
Subutex® (Sl tab/film) Suboxone® (Sl tab/film) Bunavail® (buccal film) Zubsolv® (Sl tab) 2/0.5, 4/1, 8/2, 12/3 mg 2.1/0.3, 4.2/0.7, 6.3/1 mg 1.4/0.36, 5.7/1.4 mg 29% ± 10% 29% ± 10% 20% ± 10%
Sublocade® (SQ injectable) 300, 100 mcg na
*Strength unavailable commercially, ½ of lowest available dosage form. TD=transdermal; Sl=sublingual; SQ=subcutaneous; na=not applicable Pain
OUD OUD OUD
OUD 15 mcg/hr
1 mg/0.25 mg* na 0.7/0.18 mg*
na
psychiatric diagnoses that may complicate management and require a higher level of monitoring. Clinicians often provide education on these topics and attempt to initiate change to reduce risk, but what happens when the patient struggles to make the requested changes? When patients are not adherent during a taper, this aberrant behavior is considered misuse and potentially abuse. Lack of progress combined with aberrant behavior allows transition to buprenorphine/naloxone Sl through a diagnosis of CPOD. CPOD is a recent phenomenon promoted as a reasonable expansion of buprenorphine/naloxone use by those focused on the profound benefits and evidence to support use in OUD. 31 For some patients that may be appropriate, but did we allow patients sufficient time to adjust? Did we pause and reassess mental health stability? Provide additional education, and engage in shared decision making to see if the aberrant behavior resolves? Perhaps creating a new term that sounds like opioid dependence will justify expansion of buprenorphine/naloxone use into the grey area of treatment that has long been uncomfortable for patients and providers.
Morphine Equivalent Daily Dose Concerns
Patients are often considered for buprenorphine treatment when they have struggled with an opioid taper because the aberrant behaviors that emerge when patients struggle to stabilize on a lower dose of opioids are often interpreted as evidence of OUD. Ironically, the decision to offer them buprenorphine/naloxone in such cases serves to dramatically increase their overall morphine equivalent daily dose far beyond their previous use, further reinforcing physical dependence on opioid therapy. Additionally, this transition may be promoted inadvertently by policies that remove buprenorphine from opioid metrics in population management, analytics in managed care, or other regulatory scrutiny.
Table 4 includes a proposed buprenorphine equivalence based upon bioavailability comparison that correlates to the presumed equianalgesic doses of buprenorphine injection to oral morphine. It is important to understand, however, that no true equivalence of a partial agonist/antagonist to a traditional full agonist can exist because of competitive receptor binding and other variables outside the scope of this commentary. Moreover, while critics may say that equianalgesic conversions were never intended to be applied to OUD, the comparison is useful to demonstrate that buprenorphine formulations routinely utilized for OUD would be extraordinarily high doses of traditional opioid therapy. As an example, 2 mg of Sl buprenorphine would be equivalent to oral morphine 60 mg, but the most common dose of buprenorphine utilized for OUD is 16 mg per day. This proposed equivalence is consistent with methadone dosing for OUD averaging 100 mg daily, which would be between 400 to 1200 mg or oral morphine daily if reversed. Neither of these comparisons is fair because converting back to morphine is not well characterized in equianalgesic studies, and methadone and buprenorphine’s unique pharmacology contribute to their mechanism and increased potency compared to traditional opioids. However, even conservative calculations make it clear that off-label use of buprenorphine formulations designed for OUD represent substantial increases in daily opioid use and it is inconceivable to think this does not contribute to further dependence on opioids.
US vs Europe: Dose Disparity
Off-label use of buprenorphine formulations designed for OUD but prescribed for pain would not be necessary if there were not such a disparity between available strengths. In addition, the long history of available buprenorphine Sl tablets approved for pain in Europe likely contributed to acceptance of buprenorphine’s role in pain management and reduced stigma of treatment for pain or OUD. Today, buprenorphine Sl and transdermal formulations are approved at much higher strengths for pain in Europe than are available in the US, eliminating the need for off-label use and normalizing buprenorphine acceptance as an effective analgesic.
Flexibility of Treatment Setting
Off-label prescribing of buprenorphine for chronic pain is only possible because of the unique approach in the United States to MOUD with office-based opioid treatment (ObOT) made possible through introduction of the Dea X-waiver with the Drug Addiction Treatment Act (DaTa) 2000 legislation. One of the purported advantages to ObOT was reduction in stigma due to the ability to receive care in a generalized medical setting. While this certainly expands access to treatment for OUD to meet an urgent public health need, overlap into off-label use was inevitable with increasing popularity of off-label prescribing of buprenorphine/naloxone for pain or comorbid OUD and pain. Methadone, for example, by regulation cannot be used for the treatment of OUD outside of a facility registered and accredited both nationally with SaMSha and locally with mental health services for that state. One solution is to follow Europe’s example of deregulation and allow all MOUD to be prescribed without special license by any provider in any medical setting with clear benefits for removing underlying stigma of treatment.
Conclusion
With dramatic increases to buprenorphine prescribing and mandatory reductions in opioid manufacturing, it is natural that many patients previously stable on long-term opioid therapy will find themselves in ObOT clinics receiving buprenorphine/naloxone. Emphasizing shared decision making and patient education can assist providers in reducing stigma or patients feeling “duped” into treatment. With any major shift in the treatment paradigm, we must be cognizant of the patient-specific concerns and/ or ethical dilemmas that arise as the unintended consequences.
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