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A review of the safety of buprenorphine in special populations

      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.
      • Dowell Deborah
      • Haegerich Tamara
      • Chou Roger
      CDC guideline for prescribing opioids for chronic pain - United States, 2016.
      Subsequently, the DEA announced in 2017 a mandatory 25% reduction in manufacturer production of all opioids.

      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.

      The number of opioid prescriptions nationwide in 2020 had decreased by 44.4% since 2011.
      2021 Overdose Epidemic Report: Physicians’ Actions to Help End the Nation's Drug-Related Overdose and Death Epidemic - and What Still Needs to be Done.
      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.
      2021 Overdose Epidemic Report: Physicians’ Actions to Help End the Nation's Drug-Related Overdose and Death Epidemic - and What Still Needs to be Done.
      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.
      2021 Overdose Epidemic Report: Physicians’ Actions to Help End the Nation's Drug-Related Overdose and Death Epidemic - and What Still Needs to be Done.
      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.
      U.S. Department of Health and Human Services
      Pain Management Best Practices Inter-Agency Task Force Report: Updates, Gaps, Inconsistencies, and Recommendations.
      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.
      • Rolly G.
      • Versichelen L.
      Buprenorphine as postoperative analgesic.
      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.
      • Jasinski D.R.
      • Pevnick J.S.
      • Griffith J.D.
      Human pharmacology and abuse potential of the analgesic buprenorphine: a potential agent for treating narcotic addiction.
      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 NameFormulationContains naloxoneRange of Approved Dosage Strengths (mg)
      PAIN
       Belbuca
      Belbuca Buccal Film.
      Buccal filmNo0.075-0.9
       Buprenex
      Buprenex Injection.
      Intravenous injectionNo0.3
       Butrans
      Butrans Transdermal Patch.
      Transdermal patchNo0.005–0.02 (per hour)
      OUD
       Bunavail
      Bunavail Buccal Film.
      Buccal filmYes2.1-6.3
       Sublocade
      Sublocade Injection.
      Subcutaneous injectionNo100-300
       Suboxone
      Suboxone Sublingual Film.
      ,
      Suboxone Sublingual Tablet.
      Sublingual tablet/filmYes2-12
       Subutex
      Subutex Sublingual Tablet.
      Sublingual tabletNo2-8
       Zubsolv
      Zubsolv Sublingual Tablet.
      Sublingual tabletYes0.7-11.4
      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.
      • Boas R.A.
      • Villiger J.W.
      Clinical actions of fentanyl and buprenorphine. The significance of receptor binding.
      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.
      • Lutfy K.
      • Cowan A.
      Buprenorphine: a unique drug with complex pharmacology.
      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.
      • Bettinger J.
      • Quevedo H.B.
      • Cleary J.
      Emerging pharmacologic mechanisms of buprenorphine to explain experience of analgesia versus adverse effects.
      Furthermore, buprenorphine exhibits a “ceiling effect” with regards to its risk of respiratory depression; a plateau in risk is observed with escalating doses.
      • Walsh S.L.
      • Preston K.L.
      • Stitzer M.L.
      • Cone E.J.
      • Bigelow G.E.
      Clinical pharmacology of buprenorphine: ceiling effects at high doses.
      Pharmacokinetic data, however, showed that plasma concentrations of buprenorphine were linearly related to dose despite the plateau effect physiologically.
      • Walsh S.L.
      • Preston K.L.
      • Stitzer M.L.
      • Cone E.J.
      • Bigelow G.E.
      Clinical pharmacology of buprenorphine: ceiling effects at high doses.
      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).
      • Cone E.J.
      • Gorodetzky C.W.
      • Yousefnejad D.
      • Buchwald W.F.
      • Johnson R.E.
      The metabolism and excretion of buprenorphine in humans.
      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.
      • Cone E.J.
      • Gorodetzky C.W.
      • Yousefnejad D.
      • Buchwald W.F.
      • Johnson R.E.
      The metabolism and excretion of buprenorphine in humans.
      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%.
      • Rodighiero V.
      Effects of liver disease on pharmacokinetics.
      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.
      Bunavail Buccal Film.
      ,
      Suboxone Sublingual Film.
      ,
      Suboxone Sublingual Tablet.
      ,
      Zubsolv Sublingual Tablet.
      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.
      • Nasser A.F.
      • Heidbreder C.
      • Liu Y.
      • et al.
      Pharmacokinetics of sublingual buprenorphine and naloxone in subjects with mild to severe hepatic impairment (child-pugh classes A, B, and C), in hepatitis C virus-seropositive subjects, and in healthy volunteers.
      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.
      • Nasser A.F.
      • Heidbreder C.
      • Liu Y.
      • et al.
      Pharmacokinetics of sublingual buprenorphine and naloxone in subjects with mild to severe hepatic impairment (child-pugh classes A, B, and C), in hepatitis C virus-seropositive subjects, and in healthy volunteers.
      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.
      Butrans Transdermal Patch.
      The buccal buprenorphine package insert recommends a dose reduction in severe hepatic impairment, but not in mild or moderate hepatic impairment.
      Belbuca Buccal Film.
      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.
      • McCance-Katz E.F.
      • Moody D.E.
      • Morse G.D.
      • et al.
      Interactions between buprenorphine and antiretrovirals. I. The nonnucleoside reverse-transcriptase inhibitors efavirenz and delavirdine.
      evaluated the use of sublingual buprenorphine/naloxone with efavirenz (EFV), a moderate CYP3A4 inducer.
      • McCance-Katz E.F.
      • Moody D.E.
      • Morse G.D.
      • et al.
      Interactions between buprenorphine and antiretrovirals. I. The nonnucleoside reverse-transcriptase inhibitors efavirenz and delavirdine.
      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.
      • McCance-Katz E.F.
      • Moody D.E.
      • Morse G.D.
      • et al.
      Interactions between buprenorphine and antiretrovirals. I. The nonnucleoside reverse-transcriptase inhibitors efavirenz and delavirdine.
      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.
      • McCance-Katz E.F.
      • Moody D.E.
      • Prathikanti S.
      • Friedland G.
      • Rainey P.M.
      Rifampin, but not rifabutin, may produce opiate withdrawal in buprenorphine-maintained patients.
      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.
      • McCance-Katz E.F.
      • Moody D.E.
      • Prathikanti S.
      • Friedland G.
      • Rainey P.M.
      Rifampin, but not rifabutin, may produce opiate withdrawal in buprenorphine-maintained patients.
      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.
      • McCance-Katz E.F.
      • Moody D.E.
      • Morse G.D.
      • et al.
      Interactions between buprenorphine and antiretrovirals. I. The nonnucleoside reverse-transcriptase inhibitors efavirenz and delavirdine.
      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.
      • McCance-Katz E.F.
      • Moody D.E.
      • Smith P.F.
      • et al.
      Interactions between buprenorphine and antiretrovirals. II. The protease inhibitors nelfinavir, lopinavir/ritonavir, and ritonavir.
      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.
      • McCance-Katz E.F.
      • Moody D.E.
      • Smith P.F.
      • et al.
      Interactions between buprenorphine and antiretrovirals. II. The protease inhibitors nelfinavir, lopinavir/ritonavir, and ritonavir.
      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.
      • McCance-Katz E.F.
      • Moody D.E.
      • Morse G.D.
      • et al.
      Interaction between buprenorphine and atazanavir or atazanavir/ritonavir.
      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.
      • Fihlman M.
      • Hemmila T.
      • Hagelberg N.M.
      • et al.
      Voriconazole more likely than posaconazole increases plasma exposure to sublingual buprenorphine causing a risk of a clinically important interaction.
      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.
      • Fihlman M.
      • Hemmila T.
      • Hagelberg N.M.
      • et al.
      Voriconazole more likely than posaconazole increases plasma exposure to sublingual buprenorphine causing a risk of a clinically important interaction.
      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.
      • Kapil R.P.
      • Cipriano A.
      • Michels G.H.
      • et al.
      Effect of ketoconazole on the pharmacokinetic profile of buprenorphine following administration of a once-weekly buprenorphine transdermal system.
      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.
      • Tegeder I.
      • Lotsch J.
      • Geisslinger G.
      Pharmacokinetics of opioids in liver disease.
      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.
      • McCance-Katz E.F.
      • Moody D.E.
      • Morse G.D.
      • et al.
      Interactions between buprenorphine and antiretrovirals. I. The nonnucleoside reverse-transcriptase inhibitors efavirenz and delavirdine.
      ,
      • McCance-Katz E.F.
      • Moody D.E.
      • Smith P.F.
      • et al.
      Interactions between buprenorphine and antiretrovirals. II. The protease inhibitors nelfinavir, lopinavir/ritonavir, and ritonavir.
      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.
      • Summerfield R.J.
      • Allen M.C.
      • Moore R.A.
      • Sear J.W.
      • McQuay H.J.
      Buprenorphine in end stage renal failure.
      proposed that buprenorphine should be safe in patients with abnormal renal function due to its hepatic metabolism and high systemic clearance.
      • Summerfield R.J.
      • Allen M.C.
      • Moore R.A.
      • Sear J.W.
      • McQuay H.J.
      Buprenorphine in end stage renal failure.
      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.
      • Summerfield R.J.
      • Allen M.C.
      • Moore R.A.
      • Sear J.W.
      • McQuay H.J.
      Buprenorphine in end stage renal failure.
      Package inserts for buprenorphine products do not provide any recommendations for dose adjustments in renal impairment or dialysis.
      Belbuca Buccal Film.
      Buprenex Injection.
      Butrans Transdermal Patch.
      Bunavail Buccal Film.
      Sublocade Injection.
      Suboxone Sublingual Film.
      Suboxone Sublingual Tablet.
      Subutex Sublingual Tablet.
      Zubsolv Sublingual Tablet.
      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.
      • Hand C.W.
      • Sear J.W.
      • Uppington J.
      • Ball M.J.
      • McQuay H.J.
      • Moore R.A.
      Buprenorphine disposition in patients with renal impairment: single and continuous dosing, with special reference to metabolites.
      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.
      • Summerfield R.J.
      • Allen M.C.
      • Moore R.A.
      • Sear J.W.
      • McQuay H.J.
      Buprenorphine in end stage renal failure.
      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.
      • Hand C.W.
      • Sear J.W.
      • Uppington J.
      • Ball M.J.
      • McQuay H.J.
      • Moore R.A.
      Buprenorphine disposition in patients with renal impairment: single and continuous dosing, with special reference to metabolites.
      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).
      • Filitz J.
      • Griessinger N.
      • Reinhard S.
      • Likar R.
      • Schuttler J.
      • Koppert W.
      Effects of intermittent hemodialysis on buprenorphine and norbuprenorphine plasma concentrations in chronic pain patients treated with transdermal buprenorphine.
      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%.
      Butrans Transdermal Patch.
      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.
      • Filitz J.
      • Griessinger N.
      • Reinhard S.
      • Likar R.
      • Schuttler J.
      • Koppert W.
      Effects of intermittent hemodialysis on buprenorphine and norbuprenorphine plasma concentrations in chronic pain patients treated with transdermal buprenorphine.
      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.
      • Bhutto A.
      • Morley J.E.
      The clinical significance of gastrointestinal changes with aging.
      • Blechman M.B.
      • Gelb A.M.
      Aging and gastrointestinal physiology.
      • Mangoni A.A.
      • Jackson S.H.
      Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications.
      • Milton J.C.
      • Hill-Smith I.
      • Jackson S.H.
      Prescribing for older people.
      • Scott-Warren V.
      • Maguire S.
      Physiology of ageing.
      TABLE 2Age-related physiologic changes and effects on pharmacotherapy.
      Body SystemChanges in ElderlyOutcomeImplications for Medication Administration
      Gastrointestinal (GI)
      • Summerfield R.J.
      • Allen M.C.
      • Moore R.A.
      • Sear J.W.
      • McQuay H.J.
      Buprenorphine in end stage renal failure.
      ,
      • Hand C.W.
      • Sear J.W.
      • Uppington J.
      • Ball M.J.
      • McQuay H.J.
      • Moore R.A.
      Buprenorphine disposition in patients with renal impairment: single and continuous dosing, with special reference to metabolites.
      Decreased GI motilityIncreased risk of constipationIncreased susceptibility to constipation due to opioid use
      Decreased gastric secretionsIncreased gastric pHDecreased medication absorption
      Hepatic
      • Filitz J.
      • Griessinger N.
      • Reinhard S.
      • Likar R.
      • Schuttler J.
      • Koppert W.
      Effects of intermittent hemodialysis on buprenorphine and norbuprenorphine plasma concentrations in chronic pain patients treated with transdermal buprenorphine.
      Decreased hepatic massDecreased hepatic metabolismDecreased phase I metabolism of medications; medications undergoing phase II metabolism less affected
      Decreased hepatic blood flowMedications with a high extraction ratio more likely to accumulate
      Renal
      • Bhutto A.
      • Morley J.E.
      The clinical significance of gastrointestinal changes with aging.
      Decreased blood flow and glomerular filtration rateDecreased clearance of water-soluble substancesWater-soluble medications accumulate; increased risk of adverse effects
      Respiratory
      • Blechman M.B.
      • Gelb A.M.
      Aging and gastrointestinal physiology.
      Decreased lung elasticity and increased chest wall rigidityIncreased respiratory difficultyIncreased 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.
      • Milton J.C.
      • Hill-Smith I.
      • Jackson S.H.
      Prescribing for older people.
      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.
      • Likar R.
      Transdermal buprenorphine in the management of persistent pain: safety aspects.
      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.
      • Webster L.R.
      • Camilleri M.
      • Finn A.
      Opioid-induced constipation: rationale for the role of norbuprenorphine in buprenorphine-treated individuals.
      ,
      • Griessinger N.
      • Sittl R.
      • Likar R.
      Transdermal buprenorphine in clinical practice–a post-marketing surveillance study in 13,179 patients.
      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.
      • Likar R.
      Transdermal buprenorphine in the management of persistent pain: safety aspects.
      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.
      Sublocade Injection.
      Suboxone Sublingual Film.
      Suboxone Sublingual Tablet.
      Subutex Sublingual Tablet.
      However, clinical trials for both transdermal and buccal buprenorphine did evaluate the differences between elderly and younger patients.
      Belbuca Buccal Film.
      ,
      Butrans Transdermal Patch.
      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.
      Belbuca Buccal Film.
      Buprenex Injection.
      Butrans Transdermal Patch.
      Bunavail Buccal Film.
      Sublocade Injection.
      Suboxone Sublingual Film.
      Suboxone Sublingual Tablet.
      Subutex Sublingual Tablet.
      Zubsolv Sublingual Tablet.
      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.
      Belbuca Buccal Film.
      ,
      Butrans Transdermal Patch.
      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.
      • Harris S.C.
      • Morganroth J.
      • Ripa S.R.
      • Thorn M.D.
      • Colucci S.
      Effects of buprenorphine on QT intervals in healthy subjects: results of 2 randomized positive- and placebo-controlled trials.
      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.
      • Harris S.C.
      • Morganroth J.
      • Ripa S.R.
      • Thorn M.D.
      • Colucci S.
      Effects of buprenorphine on QT intervals in healthy subjects: results of 2 randomized positive- and placebo-controlled trials.
      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.
      • Harris S.C.
      • Morganroth J.
      • Ripa S.R.
      • Thorn M.D.
      • Colucci S.
      Effects of buprenorphine on QT intervals in healthy subjects: results of 2 randomized positive- and placebo-controlled trials.
      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.
      Butrans Transdermal Patch.
      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.
      • Steiner D.
      • Munera C.
      • Hale M.
      • et al.
      Efficacy and safety of buprenorphine transdermal system (BTDS) for chronic moderate to severe low back pain: a randomized, double-blind study.
      ,
      • Steiner D.
      • Sitar S.
      • Wen W.
      • et al.
      Efficacy and safety of the seven-day buprenorphine transdermal system in opioid-naïve patients with moderate to severe chronic low back pain: an enriched, randomized, double-blind, placebo-controlled study.
      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.
      • 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.
      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%.
      • Griessinger N.
      • Sittl R.
      • Likar R.
      Transdermal buprenorphine in clinical practice–a post-marketing surveillance study in 13,179 patients.
      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 EvidenceEfficacy OutcomesSafety Outcomes
      Three phase III randomized, controlled clinical trials
      • Likar R.
      Transdermal buprenorphine in the management of persistent pain: safety aspects.
      • Webster L.R.
      • Camilleri M.
      • Finn A.
      Opioid-induced constipation: rationale for the role of norbuprenorphine in buprenorphine-treated individuals.
      • Griessinger N.
      • Sittl R.
      • Likar R.
      Transdermal buprenorphine in clinical practice–a post-marketing surveillance study in 13,179 patients.
      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
      • Scott-Warren V.
      • Maguire S.
      Physiology of ageing.
      80% of patients reported “good” or “very good” pain relief at starting dosesConstipation 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.
      • Likar R.
      Transdermal buprenorphine in the management of persistent pain: safety aspects.
      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.
      • Atkinson T.J.
      • Fudin J.
      • Pandula A.
      • Mirza M.
      Medication pain management in the elderly: unique and underutilized analgesic treatment options.

      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.
      • Patrick S.W.
      • Schumacher R.E.
      • Benneyworth B.D.
      • Krans E.E.
      • McAllister J.M.
      • Davis M.M.
      Neonatal abstinence syndrome and associated health care expenditures: United States, 2000–2009.
      • Patrick S.W.
      • Davis M.M.
      • Lehmann C.U.
      • Cooper W.O.
      Increasing incidence and geographic distribution of neonatal abstinence syndrome: United States 2009 to 2012.
      Virginia Department of Health
      Pregnancy-Associated Deaths from Drug Overdose in Virginia, 1999-2007: A Report from the Virginia Richmond Mortality Review Team.
      Maryland Department of Health and Mental Hygiene
      Maryland Maternal Mortality Review 2016 Annual Report.
      This has prompted the assessment of pharmacotherapy options for OUD in pregnancy.
      Virginia Department of Health
      Pregnancy-Associated Deaths from Drug Overdose in Virginia, 1999-2007: A Report from the Virginia Richmond Mortality Review Team.
      ,
      Maryland Department of Health and Mental Hygiene
      Maryland Maternal Mortality Review 2016 Annual Report.
      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.
      • Jones H.E.
      • Heil S.H.
      • Baewert A.
      • et al.
      Buprenorphine treatment of opioid-dependent pregnant women: a comprehensive review.
      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.
      Opioid Use and Opioid Use Disorder in Pregnancy
      ACOG Committee Opinion Number 711.
      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.
      Opioid Use and Opioid Use Disorder in Pregnancy
      ACOG Committee Opinion Number 711.
      ,
      American Society of Addiction Medicine
      Treating Pregnant People with Opioid Use Disorder. ASAM COVID-19 Task Force Recommendations: Caring for Patients During the COVID-19 Pandemic.
      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.
      • Jones H.E.
      • Heil S.H.
      • Baewert A.
      • et al.
      Buprenorphine treatment of opioid-dependent pregnant women: a comprehensive review.
      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.
      • Jones H.E.
      • Kaltenbach K.
      • Heil S.H.
      • et al.
      Neonatal abstinence syndrome after methadone or buprenorphine exposure.
      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.
      • Jones H.E.
      • Kaltenbach K.
      • Heil S.H.
      • et al.
      Neonatal abstinence syndrome after methadone or buprenorphine exposure.
      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.
      • Jones H.E.
      • Heil S.H.
      • Baewert A.
      • et al.
      Buprenorphine treatment of opioid-dependent pregnant women: a comprehensive review.
      More recent systematic reviews show nonsignificant trends favoring buprenorphine for reduction of the risk of abnormal fetal heart rate and motor activity as well.
      • Jones H.E.
      • Heil S.H.
      • Baewert A.
      • et al.
      Buprenorphine treatment of opioid-dependent pregnant women: a comprehensive review.
      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.
      • Jones H.E.
      • Finnegan L.P.
      • Kaltenbach K.
      Methadone and buprenorphine for the management of opioid dependence in pregnancy.
      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.
      Substance Abuse and Mental Health Services Administration
      Clinical Guidance for Treating Pregnant and Parenting Women With Opioid Use Disorder and Their Infants.
      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.
      Belbuca Buccal Film.
      Buprenex Injection.
      Butrans Transdermal Patch.
      Bunavail Buccal Film.
      Sublocade Injection.
      Suboxone Sublingual Film.
      Suboxone Sublingual Tablet.
      Subutex Sublingual Tablet.
      Zubsolv Sublingual Tablet.
      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.
      • Lind J.N.
      • Interrante J.D.
      • Ailes E.C.
      • et al.
      Maternal use of opioids during pregnancy and congenital malformations: a systematic review.
      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.
      • Debelak K.
      • Morrone W.R.
      • O'Grady K.E.
      • Jones H.E.
      Buprenorphine + naloxone in the treatment of opioid dependence during pregnancy-initial patient care and outcome data.
      found that in 10 patients that had used buprenorphine/naloxone, there were no significant adverse maternal or neonatal outcomes.
      • Debelak K.
      • Morrone W.R.
      • O'Grady K.E.
      • Jones H.E.
      Buprenorphine + naloxone in the treatment of opioid dependence during pregnancy-initial patient care and outcome data.
      When Wiegand et al.
      • Wiegand S.L.
      • Stringer E.M.
      • Stuebe A.M.
      • Jones H.
      • Seashore C.
      • Thorp J.
      Buprenorphine and naloxone compared with methadone treatment in pregnancy.
      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.
      • Wiegand S.L.
      • Stringer E.M.
      • Stuebe A.M.
      • Jones H.
      • Seashore C.
      • Thorp J.
      Buprenorphine and naloxone compared with methadone treatment in pregnancy.
      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.
      • 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.
      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.
      Substance Abuse and Mental Health Services Administration
      Clinical Guidance for Treating Pregnant and Parenting Women With Opioid Use Disorder and Their Infants.
      TABLE 4Retrospective studies assessing combination buprenorphine/naloxone in pregnancy.
      StudyFindings
      Debelak et al.
      • Jones H.E.
      • Kaltenbach K.
      • Heil S.H.
      • et al.
      Neonatal abstinence syndrome after methadone or buprenorphine exposure.
      No significant adverse maternal or neonatal outcomes in ten patients that had used buprenorphine/naloxone during pregnancy
      Wiegand et al.
      • Jones H.E.
      • Finnegan L.P.
      • Kaltenbach K.
      Methadone and buprenorphine for the management of opioid dependence in pregnancy.
      Less incidence of NAS and shorter hospital stays in infants born to mothers who took buprenorphine/naloxone
      Jumah et al.
      Substance Abuse and Mental Health Services Administration
      Clinical Guidance for Treating Pregnant and Parenting Women With Opioid Use Disorder and Their Infants.
      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.
      • Lindemalm S.
      • Nydert P.
      • Svensson J.O.
      • et al.
      Transfer of buprenorphine into breastmilk and calculation of infant drug dose.
      ,
      • Ilett K.F.
      • Hackett L.P.
      • Gower S.
      • et al.
      Estimated dose exposure of the neonate to buprenorphine and its metabolite norbuprenorphine via breastmilk during maternal buprenorphine substitution treatment.
      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.
      Opioid Use and Opioid Use Disorder in Pregnancy
      ACOG Committee Opinion Number 711.
      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.
      • Feghali M.
      • Venkataramanan R.
      • Caritis S.
      Pharmacokinetics of drugs in pregnancy.
      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 PopulationRecommendations
      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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