buprenorphine/naloxone

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Buprenorphine/{{shy}}naloxone is used for the treatment of opioid use disorder.{{cite web |title=Buprenorphine/Naloxone (Suboxone) |url=https://www.nami.org/About-Mental-Illness/Treatments/Mental-Health-Medications/Types-of-Medication/Buprenorphine/Buprenorphine-Naloxone-(Suboxone) |website=nami.org |publisher=National Alliance on Mental Illness |access-date=12 April 2021}} Long-term outcomes are generally better with use of buprenorphine/{{shy}}naloxone than attempts at stopping opioid use altogether. This includes a lower risk of overdose with medication use. Due to the high binding affinity and low activation at the opioid receptor, cravings and withdrawal for opioids are decreased while preventing a person from getting high and relapsing on another opioid. The combination of the two medications is preferred over buprenorphine alone for maintenance treatment due to the presence of naloxone in the formulation, which is believed to help discourage intravenous use. However, the belief that the addition of naloxone provides this benefit has been called into question, and posters on drug-related online forums have stated that they were able to attain a high by injecting preparations of buprenorphine despite being combined with naloxone.

Buprenorphine/{{shy}}naloxone is effective for treating opioid dependence and serves as a recommended first-line medication according to the U.S. National Institute on Drug Abuse. The medication is an effective maintenance therapy for opioid dependence and has generally similar efficacy to methadone. Both {{nowrap|treatments{{tsp}}{{mdash}}}}{{tsp}}buprenorphine/{{shy}}naloxone and {{nowrap|methadone{{tsp}}{{mdash}}}}{{tsp}}are substantially more effective than abstinence-based treatment. As of October 2023 prescribers no longer need a Drug Addiction Treatment Act (DATA 2000) waiver to prescribe buprenorphine/{{shy}}naloxone for opioid dependence.{{cite web|title=Statutes, Regulations, and Guidelines|url=https://www.samhsa.gov/medication-assisted-treatment/statutes-regulations-guidelines#DATA-2000|url-status=live|website=U.S. Department of Health & Human Services|date=15 June 2015 |archive-url=https://web.archive.org/web/20190603220909/https://www.samhsa.gov/medication-assisted-treatment/statutes-regulations-guidelines |archive-date=2019-06-03 }} All practitioners who have a current DEA registration that includes Schedule III authority, may now prescribe buprenorphine for opioid use disorder in their practice if permitted by applicable state law. The Substance Abuse and Mental Health Services Administration encourages practitioners to treat patients within their practices who require treatment for a substance use disorder. Because it may now be prescribed much more readily out of an office setting (as opposed to methadone, which requires specialized centers), buprenorphine/naloxone allows people more access to this medication and more freedom of administration. It also thus comes with more risks in this vulnerable population. Buprenorphine/{{shy}}naloxone may be recommended for socially stable people who use opioids who cannot retrieve medications from a center daily, who have another condition requiring regular primary care visits, or who have jobs or daily lives that require they maintain all their faculties and cannot take a sedating medication. Buprenorphine/{{shy}}naloxone is also recommended over methadone for people at high risk of methadone toxicity, such as the elderly, those taking high doses of benzodiazepines or other sedating substances, concomitant alcohol use disorder, those with a lower level of opioid tolerance, and those at high risk of prolonged QT interval. It is also helpful to use the medication in combination with psychosocial support and counseling.{{cite book|title=Austria-Codex|editor=Haberfeld, H|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2015|language=de}}

Buprenorphine/naloxone is available in sublingual formulations (that is, products that are dissolved under the tongue). There is no evidence that the tablet formulation is easier to divert and use in ways other than intended by the prescriber compared to the film formulation, or that the tablet formulation has a higher risk for accidental ingestion by children. There are various pharmacokinetic differences between sublingual formulations.{{cite journal | vauthors = Coe MA, Lofwall MR, Walsh SL | title = Buprenorphine Pharmacology Review: Update on Transmucosal and Long-acting Formulations | journal = Journal of Addiction Medicine | volume = 13 | issue = 2 | pages = 93–103 | date = 2019 | pmid = 30531584 | pmc = 7442141 | doi = 10.1097/ADM.0000000000000457 | s2cid = 54478000 }}

Contraindications are severe respiratory or liver impairment and acute alcoholism. There are limited accounts of cross-reactivity with opioids, but there is a possibility.{{cite web|url=https://online.epocrates.com/u/1031672/buprenorphine/Contraindications+Cautions|title=Suboxone Contraindications|access-date=2017-10-30}} Serious central nervous system (CNS) and respiratory depression may also occur with concurrent use of CNS depressants, ingesting alcohol, or other CNS-depressing factors while on buprenorphine/{{shy}}naloxone.

Side effects are similar to those of buprenorphine and other opioids. In addition, naloxone can induce withdrawal symptoms in people who are chemically dependent on opioids. The most common side effects (in order of most to least common) of sublingual tablets include headaches, opioid withdrawal syndrome, pain, nausea, increased sweating, and difficulty sleeping.{{cite web |title=Buprenorphine and Naloxone- buprenorphine hydrochloride and naloxone hydrochloride tablet |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=47236a95-ba0b-4f6a-b406-858cabc726df |website=DailyMed |access-date=30 April 2021 |date=25 March 2021}} The most common side effects seen in film formulations are tongue pain, decreased sensation and redness in the mouth, headache, nausea, vomiting, excessive sweating, constipation, signs and symptoms of opioid withdrawal, sleeping difficulties, pain, and swelling of the extremities.{{cite web | title=Suboxone- buprenorphine hydrochloride, naloxone hydrochloride film, soluble | website=DailyMed | date=31 October 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8a5edcf9-828c-4f97-b671-268ab13a8ecd | access-date=29 September 2020}} Post-approval, the most frequently reported side effects of buprenorphine/naloxone in sublingual strip form (i.e. Suboxone strips) are peripheral edema, stomatitis, glossitis, blistering of the mouth, and mouth ulcers (mouth sores).{{cite web |url=https://www.suboxone.com/pdfs/prescribing-information.pdf |title=Highlights of Prescribing Information |author= |date=2023 |website=suboxone.com |publisher=Indivior UK Limited. |access-date=9 July 2023}}{{cite web |url=https://perks.optum.com/blog/suboxone-side-effects |title=Suboxone side effects: A detailed guide | vauthors = Brewer A | veditors = Weiser P |date=20 April 2023 |website=perks.optum.com |publisher=Optum Perks |access-date=9 July 2023}} Use of buprenorphine/naloxone may also increase the risk of developing certain dental problems (including tooth decay and tooth loss).{{cite journal |vauthors=Etminan M, Rezaeianzadeh R, Kezouh A, Aminzadeh K |title=Association Between Sublingual Buprenorphine-Naloxone Exposure and Dental Disease |journal=JAMA |volume=328 |issue=22 |pages=2269–2271 |date=December 2022 |pmid=36511932 |pmc=9856241 |doi=10.1001/jama.2022.17485}}{{cite journal |vauthors=Barus R, Montastruc F, de Canecaude C, Bagheri H, Sommet A, Lapeyre-Mestre M |title=Sublingual/Buccal buprenorphine and dental problems: a pharmacovigilance study |journal=Expert Opinion on Drug Safety |date=August 2023 |volume=22 |issue=12 |pages=1283–1287 |pmid=37584264 |doi=10.1080/14740338.2023.2247962|s2cid=260923666 }}{{cite web |title=Buprenorphine dissolved in the mouth can cause dental problems |website=U.S. Food and Drug Administration |date=12 January 2022 |url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-dental-problems-buprenorphine-medicines-dissolved-mouth-treat-opioid-use-disorder |access-date=14 November 2023}}

Buprenorphine/naloxone has a milder side effect profile than methadone and limited respiratory effects, due to both agonist/antagonist effects. But buprenorphine/{{shy}}naloxone may be less safe than methadone in people with stable liver disease since it can elevate liver enzymes.{{cite journal | vauthors = Bonhomme J, Shim RS, Gooden R, Tyus D, Rust G | title = Opioid addiction and abuse in primary care practice: a comparison of methadone and buprenorphine as treatment options | journal = Journal of the National Medical Association | volume = 104 | issue = 7–8 | pages = 342–350 | date = 1 January 2012 | pmid = 23092049 | pmc = 4039205 | doi = 10.1016/s0027-9684(15)30175-9 }}

{{further|Opioid withdrawal}}

When taken in excess, buprenorphine/naloxone can produce dysphoric symptoms for non-opioid-dependent/tolerant people because buprenorphine is a partial opioid agonist. The sublingual formulation of the buprenorphine/{{shy}}naloxone combination was designed to reduce the potential to inject the medication in comparison to buprenorphine alone. If the combination is taken sublingually, as directed, the addition of naloxone does not diminish buprenorphine's effects. When an opioid-dependent person dissolves and injects a combination sublingual tablet, it is believed that a withdrawal effect may be triggered because of naloxone's high parenteral bioavailability. However, the efficacy of naloxone in preventing misuse by injection has more recently been brought into question and preparations including naloxone could even be less safe than preparations containing solely buprenorphine. While this mechanism may act to deter intravenous injection, the Suboxone formulation can still produce an opioid agonist "high" if used sublingually by non-dependent persons, leading to opioid dependence.[https://www.ncbi.nlm.nih.gov/books/NBK64245/ Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction]. Treatment Improvement Protocol (TIP) 40. Laura McNicholas. US Department of Health and Human Services.{{cite journal | vauthors = Strain EC, Stoller K, Walsh SL, Bigelow GE | title = Effects of buprenorphine versus buprenorphine/naloxone tablets in non-dependent opioid abusers | journal = Psychopharmacology | volume = 148 | issue = 4 | pages = 374–383 | date = March 2000 | pmid = 10928310 | doi = 10.1007/s002130050066 | s2cid = 10401443 }}

Buprenorphine's sedating/narcotic effect is increased by other sedating substances, such as other opioids, benzodiazepines, first-generation antihistamines, alcohol, and antipsychotics. Opioids and especially benzodiazepines also increase the risk of potentially lethal respiratory depression.

Strong inhibitors of the liver enzyme CYP3A4, such as ketoconazole, moderately increase buprenorphine concentrations; CYP3A4 inducers can theoretically decrease concentrations of buprenorphine.

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File:Buprenorphine is a Partial Agonist at the μ-Opioid Receptor.png

Buprenorphine binds strongly to opioid receptors and acts as a pain-reducing medication in the central nervous system (CNS). It binds to the μ-opioid receptor with high affinity, which produces analgesic effects in the CNS. It is a partial μ-opioid receptor agonist and a weak κ-opioid receptor antagonist. As a partial agonist, buprenorphine binds and activates the opioid receptors, but has only partial efficacy at the receptor relative to a full agonist, even at maximal receptor occupancy. It is thus well-suited to treat opioid dependence, as it produces milder effects on the opioid receptor with lower dependence and habit-forming potential.

Naloxone is a pure opioid antagonist that competes with opioid molecules in the CNS and prevents them from binding to the opioid receptors.{{cite journal | vauthors = Orman JS, Keating GM | title = Buprenorphine/naloxone: a review of its use in the treatment of opioid dependence | journal = Drugs | volume = 69 | issue = 5 | pages = 577–607 | date = 2009 | pmid = 19368419 | doi = 10.2165/00003495-200969050-00006 | s2cid = 209147406 }} Naloxone's binding affinity is highest for the μ-opioid receptor, then the δ-opioid receptor, and lowest for the κ-opioid receptor.{{Cite book|title=Molecular neuropharmacology: a foundation for clinical neuroscience| vauthors = Nestler EJ, Jonathan D, Hyman SE, Malenka RC |date=2009|publisher=McGraw-Hill Medical|isbn=9780071481274|edition=2nd|location=New York|pages=190–191, 287|oclc=273018757}} Naloxone has poor bioavailability, and is rapidly inactivated following oral administration.{{Cite news |url= https://www.drugs.com/monograph/naloxone-hydrochloride.html |title=Naloxone Hydrochloride Monograph for Professionals |work=Drugs.com |access-date=2017-11-28}} When injected, it exerts its full effects.

The principle behind its function as a deterrent is as follows: when taken sublingually as prescribed, buprenorphine's effects at the opioid receptor dominate, while naloxone's effects are negligible due to the low oral absorption. But when someone attempts to misuse the medication via either injection or inhalation, the naloxone is intended to act as an antagonist and either reduce the opioid's euphoric effects or even precipitate withdrawal in those dependent on opioids. This helps reduce the potential for deviating from the prescriber's intended use relative to buprenorphine, though it does not eradicate it.{{cite journal | vauthors = Katz N | title = Abuse-deterrent opioid formulations: are they a pipe dream? | journal = Current Rheumatology Reports | volume = 10 | issue = 1 | pages = 11–18 | date = January 2008 | pmid = 18457606 | doi = 10.1007/s11926-008-0003-z | s2cid = 26827910 }} One reason that naloxone might have limited efficacy as an abuse-deterrent is that buprenorphine binds more tightly to the mu-opioid receptor than naloxone.

There are small differences in the pharmacokinetics between different sublingual buprenorphine/{{shy}}naloxone products. These differences may require changes in dose when a person switches from one product to another. The buprenorphine/{{shy}}naloxone sublingual film (e.g. trade name Suboxone) achieves higher buprenorphine maximum plasma concentrations (C_max) and area under the curve (AUC, a measure of total drug exposure) than the original buprenorphine/{{shy}}naloxone sublingual tablets at equal doses. For example, at a buprenorphine/{{shy}}naloxone dose of 8 mg/2 mg, the buprenorphine C_max after a single dose of the original tablet formulation is around 3 ng/mL whereas that of the 8 mg/2 mg film formulation is around 3.55 ng/mL. The Zubsolv trade name sublingual tablets have higher buprenorphine bioavailability than the original sublingual tablets, while the Bunavail trade name buccal films have the highest bioavailability. For example, a single dose of Bunavail 4.2 mg/0.7 mg achieves a C_max around 3.41 ng/mL.

{{Main|Buprenorphine#Pharmacokinetics}}

Buprenorphine is metabolized by the liver, primarily via the cytochrome P450 (CYP) isozyme CYP3A4, into norbuprenorphine. The glucuronidation of buprenorphine is primarily carried out by the UDP-glucuronosyltransferases (UGTs) UGT1A1 and UGT2B7, while norbuprenorphine is glucuronidated by UGT1A1 and UGT1A3. These glucuronides are then eliminated mainly through excretion into bile. The elimination half-life of buprenorphine is 20 to 73 hours (mean 37 hours). Due to the mainly hepatic elimination, there is no risk of accumulation in people with kidney problems.{{cite journal | vauthors = Moody DE, Fang WB, Lin SN, Weyant DM, Strom SC, Omiecinski CJ | title = Effect of rifampin and nelfinavir on the metabolism of methadone and buprenorphine in primary cultures of human hepatocytes | journal = Drug Metabolism and Disposition | volume = 37 | issue = 12 | pages = 2323–2329 | date = December 2009 | pmid = 19773542 | pmc = 2784702 | doi = 10.1124/dmd.109.028605 }}

{{Main|Naloxone#Pharmacokinetics}}

Naloxone is extensively inactivated by first-pass metabolism in the liver, meaning that the use of buprenorphine/{{shy}}naloxone as prescribed should not lead to active naloxone in the blood (which, as an opioid antagonist, would reverse the effect of buprenorphine or other opioids).

While the cost of the medication buprenorphine/{{shy}}naloxone is greater than buprenorphine alone, one analysis predicted the overall costs would be less in the United States due to a lower risk of misuse.{{cite book | vauthors = Mauskopf J, Earnshaw SR, Brogan A, Wolowacz S, Brodtkorb TH |title=Budget-Impact Analysis of Health Care Interventions: A Practical Guide |date=2017 |publisher=Springer |isbn=9783319504827 |page=146 |url=https://books.google.com/books?id=jLEvDwAAQBAJ&pg=PA146 }}

Before the Drug Addiction Treatment Act of 2000 (DATA), physicians were not allowed to prescribe narcotics to treat opioid dependence. People with narcotic dependence had to go to registered clinics to receive treatment. With DATA, Suboxone was the first medication approved for office-based treatment for opioid dependence. Suboxone has thus become widely used as a replacement for methadone as it can be prescribed by doctors in their offices, while methadone can only be provided at specialized addiction centers, of which there are a limited number, often making access difficult. Integrating Medication-Assisted Treatment into outpatient primary care practices improves patient access to Suboxone.Kirk JK, et al. (2020). "Launching a Medication-Assisted Treatment in an Outpatient Office-Based Practice." Journal of Primary Care & Community Health. https://doi.org/10.1177/2150132720940723 Some physicians are also leading a movement to begin prescribing it out of the emergency department (ED), as some small studies have shown ED-initiated Suboxone to be effective with people more likely to remain in addiction treatment compared to those either referred to addiction treatment programs or those receiving just a brief intervention in the department.{{cite journal | vauthors = D'Onofrio G, O'Connor PG, Pantalon MV, Chawarski MC, Busch SH, Owens PH, Bernstein SL, Fiellin DA | title = Emergency department-initiated buprenorphine/naloxone treatment for opioid dependence: a randomized clinical trial | journal = JAMA | volume = 313 | issue = 16 | pages = 1636–1644 | date = April 2015 | pmid = 25919527 | pmc = 4527523 | doi = 10.1001/jama.2015.3474 }}{{cite web |url= http://www.chcf.org/~/media/MEDIA%20LIBRARY%20Files/PDF/PDF%20E/PDF%20EDMATOpioidProtocols.pdf |title=Emergency Department Medication-Assisted Treatment of Opioid Addiction| vauthors = Herring A |date=August 2016 | work = California Health Care Foundation |access-date=14 December 2017 }}

Access to Suboxone can be limited due to varying prior authorization requirements across different insurers. Prior authorization is used by insurance companies to limit certain medications' use by requiring approval before the insurance company will pay for them.{{cite web |title=Preauthorization |url=https://www.healthcare.gov/glossary/preauthorization |website=HealthCare.gov |access-date=September 15, 2018}} This can influence a person's financial access and adherence. Financial access is determined through prior authorization approval, which the prescriber must request before the person can start the medication. The time it takes to have the request approved can delay the person starting the medication. The prior authorization process can also affect adherence because approval is needed for every prescription. This presents the potential for a gap in treatment and withdrawal symptoms as the person waits for approval. Several insurance companies, as well as Medicaid in various states, have removed the use of prior authorization for Suboxone in an attempt to increase access to this treatment.{{cite web |title=Insurance Rules Can Hamper Recovery From Opioid Addiction |url=https://www.npr.org/sections/health-shots/2016/08/05/485554456/insurance-rules-can-hamper-recovery-from-opioid-addiction |website=NPR.org |date=August 5, 2016 |access-date=September 15, 2018}}

In July 2019, the British company Reckitt Benckiser Group (RB Group) and its current/former affiliated entities (notably Indivior, which split from RB Group in 2014) settled with the US Department of Justice (DOJ) regarding the sale and marketing of brand name Suboxone (buprenorphine/{{shy}}naloxone).{{cite news | vauthors = Howard J |title=Drugmaker to pay $1.4 billion in largest US opioid treatment settlement |url= https://www.cnn.com/2019/07/12/health/opioid-lawsuit-reckitt-benckiser-bn/index.html |website=CNN |access-date=13 July 2020}} The non-prosecution agreement involves RB Group paying up to $1.4 billion, the largest settlement payment in U.S. history involving an opioid-class medication. This record was surpassed in October 2020, when Purdue Pharma reached an $8 billion settlement for claims related to injuries and deaths caused by the opioid epidemic, which includes criminal fines, forfeiture, and civil damages.{{cite web|title=Purdue reaches $8B settlement on federal opioid charges—but will it ever pay that amount?|url=https://www.fiercepharma.com/pharma/purdue-reaches-8b-settlement-federal-opioid-charges-but-will-it-ever-pay-amount|access-date=2021-03-19|website=FiercePharma|date=21 October 2020 |language=en}} The 2019 case alleged anti-competitive behavior by RB Group and Indivior surrounding the expiration of their regulatory exclusivity for Suboxone sublingual tablets.{{cite web |title=Reckitt Benckiser Group plc to Pay $50 Million to Consumers, Settling FTC Charges that the Company Illegally Maintained a Monopoly over the Opioid Addiction Treatment Suboxone |url=https://www.ftc.gov/news-events/press-releases/2019/07/reckitt-benckiser-group-plc-pay-50-million-consumers-settling-ftc |website=www.ftc.gov |publisher=Federal Trade Commission |access-date=13 July 2020 |date=11 July 2019}} The DOJ alleged that RB Group and Indivior employed a product hopping scheme (when a firm ceases production of a product upon expiration of regulatory exclusivity in favor of another product that still has regulatory exclusivity in order to prevent generic manufacturer competition) by misrepresenting that the Suboxone sublingual film formulation was safer than the sublingual tablet formulation because "children are less likely to be accidentally exposed to the film product". There was no scientific evidence for that claim.{{cite web |title=Indivior Inc. Indicted for Fraudulently Marketing Prescription Opioid |url=https://www.justice.gov/usao-wdva/pr/indivior-inc-indicted-fraudulently-marketing-prescription-opioid |website=www.justice.gov |publisher=US Department of Justice |access-date=13 July 2020 |date=9 April 2019}} The company also sponsored a complaint to the FDA, expressing concern that buprenorphine/{{shy}}naloxone sublingual tablets (the very product they formerly produced) were unsafe, requesting that applications for regulatory approval of generic products by other pharmaceutical companies (their competitors) be rejected by the US Food and Drug Administration.

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