Abstract
Rates of opioid misuse and opioid use disorder have been increasing in recent years. Buprenorphine has emerged as an appealing medication for its use not only as treatment for opioid use disorder, but also as an opioid for chronic pain that has a ceiling effect on risks associated with opioid therapy. As other opioid prescribing decreases, buprenorphine prescribing continues to increase. As a result, it is imperative to understand the safety and efficacy of its use in special populations. This review article will explore the safety and efficacy of buprenorphine when used in subjects with hepatic and renal impairment, the elderly, and pregnant women. While manufacturer labeling for buprenorphine products may caution against their use in these populations, further examination of available data indicates that buprenorphine can be used safely and effectively for both chronic pain and/or opioid use disorder in all four of these populations.
Key Indexing Terms
Introduction
In the past decade, concern regarding the appropriate use of opioids in the U.S. has been steadily increasing. In 2016, the controversial CDC Guideline for Prescribing Opioids for Chronic Pain made several strong recommendations for aggressively minimizing opioid prescribing, and decreased prescribing patterns have been observed.
1
Subsequently, the DEA announced in 2017 a mandatory 25% reduction in manufacturer production of all opioids.2
The number of opioid prescriptions nationwide in 2020 had decreased by 44.4% since 2011.Drug Enforcement Administration. "Established aggregate production quotas for schedule I and II controlled substances and assessment of annual needs for the list I chemicals ephedrine, pseudoephedrine, and phenylpropanolamine for 2017." Federal Register 2016-23988 (July 22, 2016). 81 FR 69079. P. 69079-69083. Accessed December 9, 2021.
3
However, drug overdoses have been steadily increasing in the last ten years despite this reduction in prescribing, with synthetic opioids other than methadone providing the highest number of drug overdose deaths.3
As a result, scrutiny has shifted in more recent years from prescription opioids to illicit synthetic opioids, such as fentanyl and its analogues. The increased prevalence of opioid misuse and opioid use disorder (OUD) has created a demand for information regarding medication-assisted therapy (MAT) options for OUD, such as buprenorphine. While traditional opioid prescribing continues to decrease, buprenorphine prescribing has steadily increased over the past few years.3
Furthermore, not only is buprenorphine available in many formulations for OUD treatment, it is also utilized for chronic pain and has recently emerged as a preferred treatment option to decrease risk in providing opioid therapy for chronic pain.4
This also makes buprenorphine an appealing option for pain management as prescribers seek to mitigate safety risks with traditional opioids. As buprenorphine use for both OUD and pain continues to expand and guidelines for both disease states recommend its use, it is essential to understand how this medication should be safely and effectively used in a variety of populations.Buprenorphine
Buprenorphine is a partial mu-opioid agonist, a delta- & kappa-opioid antagonist, and a full opioid-receptor-like 1 (ORL1) agonist that was first developed in the 1970s and studied as an analgesic agent for postoperative pain.
5
However, in 1978, a clinical study proposed that buprenorphine could be useful for treating traditional opioid addiction based on its long-acting activity and potential to help reduce opioid cravings.6
This article also discussed the reduced abuse potential of buprenorphine. Today, buprenorphine is FDA-approved for and used in the treatment of moderate to severe chronic pain and/or OUD. Due to poor oral bioavailability, buprenorphine is administered sublingually (SL), buccally, transdermally, or via intramuscular (IM) or intravenous (IV) injection; available dosage formulations are outlined in Table 1.TABLE 1Buprenorphine formulations.
| Brand Name | Formulation | Contains naloxone | Range of Approved Dosage Strengths (mg) |
|---|---|---|---|
| PAIN | |||
| Belbuca 7 | Buccal film | No | 0.075-0.9 |
| Buprenex 8 | Intravenous injection | No | 0.3 |
| Butrans 9 | Transdermal patch | No | 0.005–0.02 (per hour) |
| OUD | |||
| Bunavail 10 | Buccal film | Yes | 2.1-6.3 |
| Sublocade 11 | Subcutaneous injection | No | 100-300 |
| Suboxone 12 ,13 | Sublingual tablet/film | Yes | 2-12 |
| Subutex 14 | Sublingual tablet | No | 2-8 |
| Zubsolv 15 | Sublingual tablet | Yes | 0.7-11.4 |
Buprenorphine has a unique mechanism of action at opioid receptors. Though it is not a full mu-opioid receptor agonist, buprenorphine has a high binding capacity and high affinity at all opioid receptors, to the extent that it can displace other full opioid agonists.
16
Its partial agonist activity at the mu-opioid receptor and full agonist activity at ORL1 contribute towards analgesic effects, while its antagonist activity at the delta- and kappa-receptors results in a reduced risk of adverse effects.17
It is thought that molecular signaling downstream from mu-opioid receptor activation, such as G protein coupled receptors and beta arrestin recruitment, may also contribute to both analgesia and reduction of opioid-related adverse effects.18
Furthermore, buprenorphine exhibits a “ceiling effect” with regards to its risk of respiratory depression; a plateau in risk is observed with escalating doses.19
Pharmacokinetic data, however, showed that plasma concentrations of buprenorphine were linearly related to dose despite the plateau effect physiologically.19
These characteristics make it a very appealing medication for the treatment of both pain and OUD. However, there are concerns regarding the use of buprenorphine in special populations, such as patients with organ impairment, the elderly, and pregnant women. The purpose of this review article is to examine the available literature on buprenorphine use and evaluate the safety and efficacy of its use in these populations.Hepatic Impairment
The metabolism of buprenorphine is primarily hepatic; subsequently, there has been extensive concern and research on its use in hepatic impairment. Buprenorphine undergoes both phase I and phase II metabolism, with the parent drug predominantly metabolized by CYP3A4 to the subsequent active but weaker metabolite, norbuprenorphine Both buprenorphine and norbuprenorphine then undergo phase II glucuronidation to produce buprenorphine-3-glucuronide (B3G) and norbuprenorphine-3-glucuronide (N3G).
20
Buprenorphine is primarily eliminated via the fecal-biliary route, with roughly a quarter of the parent drug excreted as its conjugated metabolites in the urine.20
In general, hepatic impairment affects phase I reactions more than phase II reactions, where CYP3A metabolism has been shown to be reduced by 30-50%.21
FDA-approved drug labeling for buprenorphine products all advise caution with use in hepatic impairment; however, the rationale varies between dosage formulations. In buprenorphine/naloxone combination products, pharmacokinetic studies have shown that moderate and severe hepatic impairment (defined as Child-Pugh Class B and C, respectively) can significantly increase the total and peak exposure of naloxone to a greater extent than buprenorphine.
10
,12
,13
,15
This has raised concern for precipitated withdrawal. Labeling for both combination sublingual tablets recommend against the use of these products in severe hepatic impairment, due to the observation that total and peak exposures increase more for naloxone than buprenorphine from administration of a single 2 mg sublingual (SL) buprenorphine/naloxone tablet. 22
This trial concluded that combination products should be avoided in severe hepatic impairment, but that they may be used in patients with moderate hepatic impairment who have been established on buprenorphine monotherapy treatment.22
However, these conclusions were made based on the serum concentrations of an agent with very low bioavailability, and they did not correlate with increased adverse effects or withdrawal effects due to naloxone.The transdermal buprenorphine package insert recommends against use in severe hepatic impairment, as this has not been studied and there may be concern for accumulation with a weekly dosing regimen.
9
The buccal buprenorphine package insert recommends a dose reduction in severe hepatic impairment, but not in mild or moderate hepatic impairment.7
Despite pharmacokinetic concerns regarding buprenorphine use in hepatic impairment, should there be a concern for buprenorphine accumulation producing clinically significant effects? This can be answered by examining studies that have assessed the effect of concomitant administration of CYP3A4 inducers or inhibitors and buprenorphine.
Inducer Studies
McCance-Katz et al.
23
evaluated the use of sublingual buprenorphine/naloxone with efavirenz (EFV), a moderate CYP3A4 inducer.23
Because an enzyme inducer accelerates drug metabolism, concomitant use of EFV with buprenorphine would be expected to quickly convert the parent drug into norbuprenorphine, resulting in potential withdrawal symptoms. Pharmacokinetic studies demonstrated that EFV significantly reduced the buprenorphine and norbuprenorphine serum concentrations. The daily area under the curve (AUC24), or the total amount of drug absorbed per day and peak (Cmax) concentration were reduced. AUC24 correlates with adverse effects, while Cmax correlates with efficacy. However, despite a reduction in Cmax and theoretically, efficacy, no participants showed evidence of opioid withdrawal symptoms or cognitive defects after coadministration, evaluated with the Objective Opiate Withdrawal Scale (OOWS) and the Mini-Mental State Examination (MMSE), respectively. Additionally, there were no significant changes in adverse effects or renal clearance of buprenorphine after EFV administration.23
In the same year, the authors also evaluated the effects of rifabutin, a moderate CYP3A4 inducer, and rifampin, a strong CYP3A4 inducer, when administered with subilngual buprenorphine/naloxone.
24
Similar to the aforementioned study, serum concentrations of buprenorphine and norbuprenorphine were significantly reduced by both rifampin and rifabutin. However, 50% of patients in the rifampin group experienced a significant increase in opioid withdrawal symptoms based on change observed in the Clinical Opiate Withdrawal Scale (COWS) after administration. This was not observed in the rifabutin group.24
While this is the first study to show buprenorphine withdrawal symptoms with the induction of CYP3A4, it does have several limitations. The sample size was very small, with only 12 participants in the rifampin group and 9 in the rifabutin group. Additionally, the study period was defined as 15 days; no long-term data is available on this interaction. Further studies are warranted to provide more robust evidence on this interaction.Inhibitor studies
In the same study evaluating efavirenz and buprenorphine, the authors also evaluated the concomitant use of buprenorphine/naloxone and delavirdine (DLV), a CYP3A4 inhibitor. Concomitant use of DLV with buprenorphine would be expected to result in accumulation of the parent drug and a reduced amount of norbuprenorphine, and potentially cause adverse effects consistent with opioid intoxication. Though pharmacokinetic results did reflect increased buprenorphine accumulation and norbuprenorphine clearance with DLV administration, no impaired cognition or withdrawal symptoms were observed. Drowsiness was the only adverse effect that was significantly increased with coadministration of DLV. Again, renal clearance of buprenorphine and its metabolites was not significantly affected.
23
There are two additional studies that have evaluated concomitant use of sublingual buprenorphine/naloxone and multiple antiviral medications that are known CYP3A4 inhibitors. One clinical trial evaluated the effects of coadministration of the protease inhibitors nelfinavir (NFV), ritonavir (RTV), and lopinavir/ritonavir (LPV/R) with buprenorphine.
25
While the administration of each of these protease inhibitors significantly affected buprenorphine and metabolite serum concentrations, none of these pharmacokinetic changes were correlated with any evidence of cognitive deficits or withdrawal symptoms.25
A similar clinical trial was done with atazanavir or atazanavir/ritonavir; the serum concentrations of buprenorphine and all metabolites were increased, but there were no significant changes per OOWS or MMSE scores. A non-significant increase in drowsiness was observed.26
- McCance-Katz E.F.
- Moody D.E.
- Morse G.D.
- et al.
Interaction between buprenorphine and atazanavir or atazanavir/ritonavir.
Drug Alcohol Depend. 2007; 91 (Epub 2007 Jul 23. PMID: 17643869; PMCID: PMC3272856): 269-278https://doi.org/10.1016/j.drugalcdep.2007.06.007
Finally, two placebo-controlled trials studied the use of different dosage formulations of buprenorphine with azole antifungals, potent CYP3A4 inhibitors known to cuase many drug-drug interations. Sublingual buprenorphine administration after five days of voriconazole or posaconazole therapy did result in increased plasma exposure to buprenorphine, though less so with posaconazole than voriconazole.
27
Additionally, most subjects did experience mild to moderate adverse effects; however, these were noted to be transient and did not require treatment. There were also no significant differences in the pharmacological effects of the drug between buprenorphine groups and the placebo group.27
Transdermal buprenorphine was co-administered with ketoconazole and both pharmacokinetic and clinical effects were assessed. There was no significant difference in buprenorphine exposure between patients in the ketoconazole group and patients in the placebo group, and all adverse effects that occurred were known potential effects of buprenorphine use not significantly worsened by ketoconazole administration.28
While it is clear that CYP3A4 inhibitors or inducers can affect the plasma concentrations of buprenorphine, robust evidence is lacking that would indicate changes in levels of parent drug or metabolites are clinically significant. As previously discussed, hepatic impairment disproportionately affects phase I metabolism with CYP enzymes compared to phase II metabolism. Based on the CYP3A4 interaction studies reviewed above, particularly the inhibitor studies, it can be concluded that buprenorphine and norbuprenorphine are quickly shunted through phase II glucuronidation and as a result, changes in phase I metabolism are unlikely to result in accumulation of buprenorphine that would lead to adverse effects.
29
Of note, it is possible that the high affinity and slow dissociation of buprenorphine at opioid receptors reduces the likelihood for adverse effects despite changes in drug plasma concentrations.23
,25
Further studies are still needed to assess the safety of buprenorphine products in severe hepatic impairment.Renal Impairment
Despite the fact that extensive research exists regarding the use of buprenorphine in hepatic impairment, there is minimal existing data evaluating the use of buprenorphine in renal impairment. Because it is well-established that buprenorphine is primarily hepatically metabolized, it is widely assumed that decreased renal function has a negligible effect on plasma buprenorphine levels. Summerfield et al.
30
proposed that buprenorphine should be safe in patients with abnormal renal function due to its hepatic metabolism and high systemic clearance.30
They studied the kinetics of buprenorphine in five patients with end stage renal disease (ESRD) and found no significant differences between these patients and controls with normal renal function. Additionally, they did not observe any sedation or respiratory depression in the five patients with ESRD.30
Package inserts for buprenorphine products do not provide any recommendations for dose adjustments in renal impairment or dialysis.7
, 8
, 9
, 10
, 11
, 12
, 13
, 14
, 15
The pharmacokinetics of IV buprenorphine in renal impairment was assessed in two separate studies, with one study evaluating the effects of a single dose, and the other evaluating the effects of multiple doses.
31
A single dose study of nine patients with dialysis-dependent renal failure and six control patients with normal renal function receiving 0.3 mg of IV buprenorphine prior to lower abdominal or body surface surgery showed no significant differences in buprenorphine plasma levels groups up to 24 h after administration.30
Both norbuprenorphine and buprenorphine-3-glucuronide were undetected in plasma samples in both groups. In the multiple dose study, eight patients with renal impairment or failure and twelve patients with normal renal function received a loading dose of 0.6 mg of IV buprenorphine followed by an infusion of buprenorphine 30 mcg/mL administered at up to a rate of 10 mL/h depending on the clinical needs of each patient. Dose-related plasma buprenorphine concentrations were similar between groups; however, levels of both metabolites were increased in patients with renal impairment.31
This may indicate that buprenorphine metabolites are primarily eliminated in the urine, distinct from the elimination of the parent drug. However, in terms of clinical significance, increased levels of these metabolites after continuous infusion in renally impaired patients is unlikely to produce changes in pain control or increased adverse effects; both metabolites are less potent and have lower receptor affinity compared to the parent drug buprenorphine.A study in Europe evaluated transdermal buprenorphine pharmacokinetics in ten patients receiving intermittent hemodialysis (IHD).
32
Transdermal buprenorphine dose ranged from 17.5 mcg/h to 70 mcg/h, and all patients had been receiving therapy for at least one week to ensure steady state was achieved prior to assessment of buprenorphine levels in the blood. Plasma levels of both buprenorphine and norbuprenorphine were measured before and after IHD. There were no significant differences between pre- and post-IHD levels of buprenorphine or norbuprenorphine. These results differ from the aforementioned IV administration study, which reported increased levels of norbuprenorphine after continuous infusion. This may be attributed to the administration of intravenous buprenorphine resulting in higher plasma levels, as opposed to the administration of transdermal buprenorphine resulting in undetectable metabolite levels, as bioavailability of the transdermal formulation is less than 20%.9
Clinically, this would not be expected to cause adverse effects related to drug accumulation as norbuprenorphine is a much weaker active metabolite. Additionally, clinical outcomes showed no difference between pain ratings pre- and post-IHD in this study, and no rescue medications were needed by any of the patients. The authors conclude that transdermal buprenorphine is a safe and effective treatment option for chronic pain patients on IHD, though the small sample size of this study should be taken into account when evaluating the strength of this evidence.32
While available studies evaluating buprenorphine in renal impairment do have limitations related to sample size and study design, the results support what was originally hypothesized over 30 years ago about buprenorphine use in renal impairment in published literature: due to its lack of significant renal metabolism, buprenorphine can be administered in patients with renal impairment or failure with no significant changes in pharmacokinetics or increased incidence of adverse effects. Buprenorphine may be a useful opioid in patients with significant renal impairment whose opioid medication options are limited due to accumulation in renal impairment. However, it is important to consider the bioavailability of buprenorphine products when converting from a full opioid agonist to buprenorphine, as it may be difficult to achieve the same level of pain control with lower bioavailability dosage forms such as transdermal buprenorphine.
Elderly
Though the extent of this article so far has discussed the role of buprenorphine in chronic kidney or liver disease and impairment, changes in renal and hepatic function are often concerns noted in the elderly, regardless of the presence of chronic disease. To fully understand why buprenorphine may be preferred in the geriatric population, however, it is important to understand all of the pharmacokinetic and pharmacodynamic changes that occur with the aging process. Aging can affect anatomy and physiological processes in the gastrointestinal (GI) tract and lungs, as well as in the kidneys and liver. As outlined in Table 2, these age-related physiologic changes have implications for the safety and efficacy of medication administration in this population, as drug metabolism and clearance may be affected and risk for adverse effects can increase.
33
, - Bhutto A.
- Morley J.E.
The clinical significance of gastrointestinal changes with aging.
Curr Opin Clin Nutr Metab Care. 2008; 11 (PMID: 18685464): 651-660https://doi.org/10.1097/MCO.0b013e32830b5d37
34
, 35
, 36
, 37
TABLE 2Age-related physiologic changes and effects on pharmacotherapy.
| Body System | Changes in Elderly | Outcome | Implications for Medication Administration |
|---|---|---|---|
| Gastrointestinal (GI) 30 ,31 | Decreased GI motility | Increased risk of constipation | Increased susceptibility to constipation due to opioid use |
| Decreased gastric secretions | Increased gastric pH | Decreased medication absorption | |
| Hepatic 32 | Decreased hepatic mass | Decreased hepatic metabolism | Decreased phase I metabolism of medications; medications undergoing phase II metabolism less affected |
| Decreased hepatic blood flow | Medications with a high extraction ratio more likely to accumulate | ||
| Renal 33
The clinical significance of gastrointestinal changes with aging. Curr Opin Clin Nutr Metab Care. 2008; 11 (PMID: 18685464): 651-660https://doi.org/10.1097/MCO.0b013e32830b5d37 | Decreased blood flow and glomerular filtration rate | Decreased clearance of water-soluble substances | Water-soluble medications accumulate; increased risk of adverse effects |
| Respiratory 34 | Decreased lung elasticity and increased chest wall rigidity | Increased respiratory difficulty | Increased risk of respiratory depression associated with opioid use |
Additionally, though not specific to a particular organ system, age-related increases in body fat to lean mass ratio, and decreases in total body water and plasma albumin, can have a significant effect on overall drug absorption, bioavailability, and clearance.
36
How is buprenorphine affected by these age-related changes in pharmacokinetics? Buprenorphine is not administered orally due to low oral bioavailability. Its unique routes of administration allow it to bypass the GI tract. Not only does this reduce the risk of changes in drug bioavailability or absorption in the elderly, but it also results in less direct contact with opioid receptors in the GI tract, which may decrease the incidence of GI-related adverse effects compared to other opioids.
38
Transdermal and buccal buprenorphine allow for complete avoidance of the GI opioid receptors, and there is evidence that these formulations result in less constipation compared to other routes of administration of buprenorphine.39
,40
However, constipation is still one of the most common adverse effects noted in pre- and post-marketing studies with buprenorphine products.The effects of renal and hepatic dysfunction on the metabolism and excretion of buprenorphine have already been extensively discussed in this article. To summarize, buprenorphine levels do not appear to significantly increase in renal impairment, nor is there an increase in the incidence of buprenorphine-related adverse effects. Clinical implications of hepatic dysfunction are minimal because buprenorphine primarily undergoes phase II metabolism, which is less affected by organ dysfunction than phase I metabolism. The aforementioned ceiling effect on respiratory depression may also make buprenorphine a safer opioid option in geriatric patients who may already be at an increased risk of this adverse effect.
38
In many clinical studies of buprenorphine products that led to their approval, there was not a significant number of patients over the age of 65 included to determine differences in response compared to younger patients. This is the case for the sublingual forms and the subcutaneous injection formulation of buprenorphine.
11
, 12
, 13
, 14
However, clinical trials for both transdermal and buccal buprenorphine did evaluate the differences between elderly and younger patients.7
,9
In both cases, the incidence of certain buprenorphine-related adverse effects were higher in older subjects. However, no pharmacokinetic differences were noted between the two populations. The manufacturer labeling for all buprenorphine products does not recommend any dosing changes in the geriatric population, but does advise caution with use in the elderly, particularly with dosage formulations that have not been extensively studied in this group of subjects.7
, 8
, 9
, 10
, 11
, 12
, 13
, 14
, 15
Both transdermal and buccal buprenorphine products carry warnings for increased risk of QTc prolongation with use, and it is well established that QTc prolongation risk increases with age at baseline.7
,9
However, the majority of patients in clinical trials for buprenorphine were not elderly, and additional clinical trials evaluating the specific risk of QTc prolongation included a younger population.41
It is important to note that QTc prolongation with transdermal buprenorphine has been shown to be a dose-dependent adverse effect. QTc prolongation was absent at therapeutic transdermal doses of 10 mcg/h, but present at supratherapeutic (based on FDA labeling) doses of 40 mcg/h.41
While there is a lack of data about QTc prolongation with buprenorphine in the geriatric population, the risk is currently shown only at doses above the recommended maximum transdermal dose, at a value unlikely to be significant enough to result in proarrhythmic effects.41
Overall, transdermal buprenorphine has the largest body of evidence for its use in the geriatric population given its effectiveness for pain relief and its safety profile and one-fourth of the total subjects in clinical trials falling into the 65 years or older age category.
9
Three of these were phase III randomized trials evaluating transdermal buprenorphine, two of which demonstrated significantly improved pain scores versus comparators in both opioid-naïve and opioid-tolerant patients in chronic low back pain, and the third of which showed almost a 50% reduction in pain scores in patients with hip or knee osteoarthritis.42
,43
In the trial with osteoarthritis patients, transdermal buprenorphine was compared to sublingual buprenorphine, and while both formulations showed similar effectiveness, the transdermal formulation demonstrated a more favorable adverse effect profile.44
In particular, there was significantly less nausea, dizziness, and vomiting in the transdermal buprenorphine group. While this trial did not show a significant reduction in constipation in the transdermal buprenorphine group, a post-marketing study in Europe in which half of the patients on transdermal buprenorphine were over the age of 70 reported that constipation occurred at a remarkably low rate of 1%.- James I.
- O'Brien C.
- McDonald C.
- et al.
A randomized, doubleblind, double-dummy comparison of the efficacy and tolerability of low-dose transdermal buprenorphine (BuTrans SevenDay Patches) with buprenorphine sublingual tablets (Temgesics) in patients with osteoarthritis pain.
J Pain Symptom Manag. 2010; 40: 266-278
40
This study also found that 80% of the patients reported very good or good pain relief at low doses; only 18% of patients required a dose increase from the starting dose of 35 mcg/h during the study. Available doses of transdermal buprenorphine are different in Europe than the U.S., with dosage formulations of 35 mcg/h, 52.5 mcg/h, and 70 mcg/h. While a low rate of adverse effects using these higher doses is promising for safe use in the elderly, the efficacy results may not be generalizable to the American population, as doses of transdermal buprenorphine available in the U.S. are much lower. Table 3 summarizes this evidence for transdermal buprenorphine use in the elderly.TABLE 3Evidence for transdermal buprenorphine in the elderly.
| Body of Evidence | Efficacy Outcomes | Safety Outcomes |
|---|---|---|
| Three phase III randomized, controlled clinical trials 38 , 39 , 40 | Significantly lower pain scores compared to placebo in opioid-experienced and opioid-naive patients with low back pain Nearly a 50% reduction in pain scores in patients with osteoarthritis, with similar efficacy to sublingual buprenorphine | Transdermal buprenorphine more well-tolerated compared to sublingual buprenorphine |
| One post-marketing clinical trial 37 | 80% of patients reported “good” or “very good” pain relief at starting doses | Constipation occurring in just 1% of patients over the age of 70 |
The physiologic consequences of the aging process can complicate medication administration in elderly patients. Each aspect of pharmacokinetics can be affected, so careful consideration of how drug efficacy and safety may change is paramount. Additionally, organ dysfunction and decline can pre-dispose this population to an increased risk of adverse effects. While caution should be exercised with any opioid medication in the geriatric population, buprenorphine's unique mechanism of action and routes of administration make it the favorable opioid option for elderly patients. It is minimally affected by organ dysfunction, and at baseline has reduced incidence of adverse effects that elderly patients have an increased risk for, such as respiratory depression and GI upset.
38
In particular, transdermal buprenorphine has demonstrated efficacy in several common pain conditions in elderly patients, and has robust evidence supporting its favorable adverse effect profile compared to other opioids and even other formulations of buprenorphine. The transdermal patch also has the additional benefit of being applied once every seven days, which may improve compliance for patients in which polypharmacy is often a concern.45
Pregnancy
Finally, the discussion of buprenorphine use in pregnancy is a unique one. In this population, there are safety and efficacy concerns not only for the mother, but also for the fetus and neonate as well. Additionally, while buprenorphine is recommended for both OUD and chronic pain treatment in other populations, guideline recommendations for pregnant women focus on buprenorphine use for the treatment of OUD, where benefits have been shown to outweigh risks of use. Traditional and illicit opioid misuse and dependence in the pregnant population has continued to increase in recent years, along with rates of neonatal abstinence syndrome (NAS), a postnatal withdrawal syndrome caused by maternal opioid use.
46
, 47
, 48
, 49
This has prompted the assessment of pharmacotherapy options for OUD in pregnancy.48
,49
Pharmacotherapy may help to address risks of untreated OUD during pregnancy; these risks include maternal illness or death and several neonatal risks such as poor fetal growth, preterm birth, stillbirth, birth defects, and NAS.50
Buprenorphine use in pregnancy has been studied in the literature for its role in opioid use disorder treatment rather than pain treatment. Due to known risks of fetal harm associated with all opioids during pregnancy, this class of medications is not recommended for pain management in pregnant women.
51
However, despite these risks, untreated substance use disorder can lead to a variety of medical complications and psychosocial problems for both mother and child. For these reasons, opioid agonist pharmacotherapy is still recommended as the standard of care for pregnant women with OUD to reduce the risk of relapse, which can lead to worse outcomes such as overdose, human immunodeficiency virus (HIV) and hepatitis C infections, and death.51
,52
Historically, methadone has been the standard of care for opioid dependence pharmacotherapy during pregnancy. This is based on evidence that maintenance methadone treatment increases duration of abstinence and avoidance of associated risk behaviors and decreases fetal illicit drug exposure and NAS.
50
Research assessing buprenorphine use for opioid dependence in pregnant patients has increased in recent years given emerging evidence for its safe and effective use, and limited access to methadone for patients in certain geographical areas.Most of the data directly comparing buprenorphine to methadone in the pregnant population is derived from the MOTHER trial.
53
While there was no significant difference in rates of NAS between the two treatment groups, buprenorphine use resulted in reduced severity of NAS, reduced morphine doses required for treatment of NAS, and shortened duration of infant hospital stay.53
It is important to note that rates of discontinuation were higher in the buprenorphine group. Two other small RCTs also compared methadone with buprenorphine with nonsignificant results between groups.50
More recent systematic reviews show nonsignificant trends favoring buprenorphine for reduction of the risk of abnormal fetal heart rate and motor activity as well.50
Looking at the available evidence as a whole, buprenorphine and methadone produce similar maternal outcomes, while buprenorphine may reduce certain fetal and neonatal risks associated with the use of these medications during pregnancy.54
However, no evidence currently exists to warrant a recommendation of either methadone or buprenorphine over the other for opioid use disorder treatment in pregnancy. The Substance Abuse and Mental Health Services Association (SAMHSA) guidelines recommend either opioid agonist for the treatment of OUD.55
Package insert labeling for all buprenorphine products advises caution with the use of buprenorphine in pregnant patients due to the risk for NAS, and advises that risks vs. benefits of use for opioid dependence treatment must be weighed.
7
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, 11
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To date, low quality studies have not shown that there is an increased risk of major malformations at birth specifically related to buprenorphine use for opioid dependence.56
The package inserts of buprenorphine/naloxone combination products state that there are no adequate safety studies assessing the use of Suboxone in pregnant patients. Historically, there has been concern for naloxone precipitating fetal withdrawal and resulting in poor neonatal outcomes. However, three studies in the past decade have retrospectively assessed use of the combination product for opioid use disorder in pregnant patients, evaluating both maternal and neonatal outcomes, as summarized in Table 4. Debelak et al.- Lind J.N.
- Interrante J.D.
- Ailes E.C.
- et al.
Maternal use of opioids during pregnancy and congenital malformations: a systematic review.
Pediatrics. 2017; 139 (and also Jumah et al)e20164131https://doi.org/10.1542/peds.2016-4131
57
found that in 10 patients that had used buprenorphine/naloxone, there were no significant adverse maternal or neonatal outcomes.57
When Wiegand et al.58
compared buprenorphine/naloxone to methadone for opioid use disorder treatment in pregnancy, infants born to mothers taking buprenorphine/naloxone had less incidence of NAS and shorter hospital stays.58
A third retrospective study compared the use of buprenorphine/naloxone to opioid and no-opioid exposure groups. No difference was found in the occurrence of the primary neonatal outcomes between the buprenorphine/naloxone and no-opioid exposure groups. Additionally, pregnant women taking buprenorphine/naloxone had higher birth weight babies and less exposure to marijuana during pregnancy compared to women exposed to other opioids.59
Based on current evidence, buprenorphine/naloxone does not increase maternal or neonatal risk in pregnancy compared to buprenorphine monotherapy; in fact, the SAMHSA guidelines recommend advising pregnant women that research has not shown an increased risk of birth defects associated with opioid agonists for the treatment of OUD.- Jumah N.A.
- Edwards C.
- Balfour-Boehm J.
- et al.
Observational study of the safety of buprenorphine+naloxone in pregnancy in a rural and remote population.
BMJ Open. 2016; 6 (PMID: 27799240; PMCID: PMC5093362)e011774https://doi.org/10.1136/bmjopen-2016-011774
55
TABLE 4Retrospective studies assessing combination buprenorphine/naloxone in pregnancy.
| Study | Findings |
|---|---|
| Debelak et al. 53 | No significant adverse maternal or neonatal outcomes in ten patients that had used buprenorphine/naloxone during pregnancy |
| Wiegand et al. 54 | Less incidence of NAS and shorter hospital stays in infants born to mothers who took buprenorphine/naloxone |
| Jumah et al. 55 | No difference in neonatal outcomes between buprenorphine/naloxone and no-opioid exposure groups of pregnant women Higher birth weights and less maternal exposure to marijuana during pregnancy in mothers taking buprenorphine/naloxone compared to mothers taking other opioids |
Buprenorphine use in lactation is not discussed extensively in this review, given sparse available data. There are two case reports that calculated buprenorphine exposure through breastmilk to be minimal, with one report observing no clinical effects in infants after exposure to buprenorphine in breastmilk.
60
,61
The American College of Obstetrics and Gynecology (ACOG) enncourages breastfeeding in women stable on buprenorphine or methadone for OUD unless there is a contraindication to breastfeeding such as illicit drug use or HIV infection.51
However, this also takes into consideration the more general benefits of breastfeeding, such as providing attachment and immunity.Overall, buprenorphine may reduce the risk of adverse neonatal outcomes compared to methadone in the treatment of opioid use disorder in pregnant patients. However, no randomized-controlled trials exist that show significantly reduced occurrence of maternal, fetal, or neonatal adverse outcomes with buprenorphine compared to methadone. When pharmacotherapy is warranted for opioid use disorder in pregnant mothers, both options can be considered and the choice can be made based on patient-specific factors. Well-designed trials are needed to further establish clinical significance of these findings from the direct comparison of both medications. Additionally, close monitoring and follow-up of these patients is required, as pharmacokinetic changes in pregnancy such as increased volume of distribution and decreased protein binding may affect patient response to dose and warrant dosing changes.
62
Neither medication has been studied for pain management in the pregnant population. Due to the numerous alternative pharmacotherapy options for pain that pose significantly less risks than opioids, neither buprenorphine nor methadone are recommended for the treatment of pain in pregnancy. Non-pharmacologic and non-opioid interventions are preferred for pain management in pregnancy. Though these risks are still present in pregnant patients receiving buprenorphine or methadone for opioid use disorder treatment, health outcomes are improved in pregnant women receiving medication assisted therapy compared to untreated pregnant women or women using traditional or illicit opioids. Additionally, pharmacologic options for the treatment of withdrawal symptoms only in OUD do not reduce the risk of relapse and are therefore not a sufficient alternative. Ultimately, if used for the management of opioid use disorder, these benefits of opioid use in pregnancy outweigh the potential risks, and other pharmacotherapy options are not able to provide benefits that outweigh the risks. The same cannot be said for opioid use for pain management in pregnant patients.Conclusions
The special populations discussed in this review are at increased risk due to potentially serious adverse outcomes resulting in unique treatment challenges without a robust repository of evidence-based studies. In addition, patients with pain and/or OUD have additional limitations and restrictions to available pharmacotherapy options. Buprenorphine's unique mechanism of action makes it highly effective for managing pain and OUD, but reduces the risk of common opioid-related adverse effects such as sedation and respiratory depression. Buprenorphine also has multiple non-oral routes of administration that reduce the incidence of side effects that may occur if absorbed directly through the GI tract. Buprenorphine can potentially be used effectively and safely in patients with liver or kidney disease, pregnancy, and elderly patients in individualized clinical situations, making it an appealing choice for use in special populations. Recommendations for its use are summarized in Table 5. Buprenorphine's recent elevation to preferred use in both pain and OUD populations creates a significant educational need for providers to approach treatment with increased confidence and competency.
TABLE 5Summary of recommendations for buprenorphine use in special populations.
| Special Population | Recommendations |
|---|---|
| Hepatic Impairment | • Buprenorphine is primarily glucuronidated; metabolism less affected in hepatic impairment • Interaction studies indicate that buprenorphine can be used safely in mild and moderate hepatic impairment • Recommend hepatic function monitoring |
| Renal Impairment | • Buprenorphine can be used safely in renal dysfunction • No evidence of accumulation leading to opioid-related adverse effects |
| Elderly | • Buprenorphine can be used with caution in the elderly • Transdermal buprenorphine shown to be safe and effective in the elderly and can improve adherence |
| Pregnancy & Lactation | • Buprenorphine is a first-line agent for the treatment of OUD in pregnancy • Avoid buprenorphine (and all opioids) in pregnancy for pain management • Recommend continuing buprenorphine for OUD during lactation if no contraindications to breastfeeding |
Author Contributions
Both authors were involved in content development, outlines of the manuscript, editing and re-writing processes, and assisting with responses to reviewers.
Declaration of Competing Interest
The author has no financial or other conflicts of interest to disclose.
Acknowledgement
There was no source of funding used for the writing of this review article.
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Article info
Publication history
Published online: July 14, 2022
Accepted:
June 29,
2022
Received:
January 25,
2022
Identification
Copyright
© 2022 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.
