Tools
Buprenorphine and Naloxone
Indications
FDA-Approved Indications
Buprenorphine and naloxone (buprenorphine-naloxone) combination is Food and Drug Administration (FDA)–approved for detoxification from opioids and maintenance therapy for opioid use disorder.[1] The Drug Addiction Treatment Act made it legal for clinicians to prescribe Schedule III drugs, such as buprenorphine-naloxone, for the treatment of opioid use disorder.[2][3] Buprenorphine-naloxone was the first medication approved for outpatient treatment of opioid use disorder by the Drug Addiction and Treatment Act (2000).[1][3] The sublingual tablet was FDA-approved to treat opioid use disorder in 2002.[1]
Opioid use disorder is defined by a strong motivation to obtain and use opioids in the face of significant detrimental effects on an individual’s health, professional life, and relationships.[2] Buprenorphine-naloxone is a partial agonist used for substitution therapy, wherein the drug is prescribed to decrease craving and the frequency of use of full mu receptor agonists (eg, heroin, fentanyl).[3][4] Substitution therapy decreases the intensity of euphoria from opioid agonism and reduces the incidence of adverse effects. Buprenorphine-naloxone is associated with greater retention in drug treatment programs, a lower frequency of relapse, and less opioid-related overdose than placebo.[5]
Alpha-2 agonists are also used to treat opioid use disorder. Buprenorphine-naloxone is associated with greater suppression of symptoms of opioid withdrawal than the α-2 agonists clonidine and lofexidine.[6] Patients prescribed buprenorphine-naloxone remain in treatment for a longer duration of time, and the adverse effects of treatment appear to be less intense with buprenorphine-naloxone compared to α-2 agonists.[6][7] Additionally, treatment success, defined as urine samples that are free of illicit opioids, is higher in patients on buprenorphine-naloxone than clonidine.[8]
Methadone is another FDA-approved medication for detoxification and maintenance treatment of opioid use disorder. When compared with methadone, buprenorphine-naloxone has a superior safety profile, enabling at-home adherence. This is a significant advantage over methadone, which requires daily administration in a specially approved clinic. Accordingly, buprenorphine-naloxone is preferred for patients who do not live near a methadone clinic or who have transportation challenges. An additional advantage of buprenorphine-naloxone is the duration of the induction period. Buprenorphine-naloxone can be titrated to a maintenance dose over a few days. Methadone induction requires weeks to months to reach the maintenance dose.
Methadone is a full mu receptor agonist with a long duration of action. Methadone has a narrower therapeutic index and is more likely to cause respiratory depression.[9] Buprenorphine-naloxone appears to have a similar capacity to diminish symptoms of opioid withdrawal, is associated with a similar incidence of adverse effects, and is noninferior to methadone for preventing relapse.[6][10][11][12] As a partial mu-opioid receptor agonist, buprenorphine is associated with less feelings of euphoria than methadone, which may contribute to a lower abuse rate. However, some patients experience greater suppression of cravings on methadone than buprenorphine-naloxone due to full mu receptor agonism.[12] According to the CDC 2022 guidelines, a clinical trial indicated no discernible disparity between buprenorphine-naloxone and methadone concerning study retention, pain, functional outcomes, or self-reported adverse effects.[13] The decision regarding buprenorphine-naloxone versus methadone for opioid use disorder treatment should account for the patient’s medications, the likelihood of drug-drug interactions, the presence of cardiac conduction defects such as prolonged QT syndrome, and patient preference.[1]
Off-Label Uses
Buprenorphine-naloxone is used off-label to treat chronic pain. While buprenorphine has a ceiling effect for respiratory depression, a ceiling effect does not appear to exist for analgesia.[14][15] Additionally, buprenorphine is associated with a lower risk of diversion and physical dependence than commonly prescribed opioids due to the partial agonism effect at the mu receptor.[16][17]
Buprenorphine-naloxone is used off-label to treat acute pain in the perioperative period. The duration of analgesia from buprenorphine is 6 to 8 hours; however, it is administered once per day when prescribed for substitution therapy. Accordingly, when used for acute pain management, there may be an advantage to dividing the daily dose into 3 or 4 smaller aliquots for daily administration.[2]
Buprenorphine is used off-label to treat methadone-induced respiratory depression in the emergency room. In 1 study comparing buprenorphine and titrated doses of naloxone, buprenorphine was associated with a higher frequency of arousal to normal consciousness, a lower incidence of recurrence of respiratory depression, and a lower severity of opioid withdrawal symptoms.[18]
Mechanism of Action
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Mechanism of Action
Buprenorphine-naloxone is an effective and commonly prescribed combination medication created to treat opioid use disorder.
Mechanism
Buprenorphine is a long-acting opioid that possesses a strong binding coefficient at the mu receptor.[19] A buprenorphine dose of 4 mg per day will bind approximately 50% of mu-opioid receptors, which is sufficient to suppress opioid withdrawal symptoms.[20] A buprenorphine dose of 16 mg will bind approximately 80% of mu-opioid receptors and is sufficient to block the euphoric effects of most abused opioids.[20] Buprenorphine’s slow dissociation kinetics and strong binding affinity can prevent full mu receptor activation by more potent opioids.[3][21] This can prevent opioid-induced respiratory depression and apnea when large doses of full mu receptor agonists, such as fentanyl or heroin, are taken by individuals on buprenorphine-naloxone.[21]
Buprenorphine is a weak antagonist of the opioid kappa and delta receptors, an agonist of the opioid receptor-like-1 protein, and a nociception protein receptor activator.[14][16] Nociception protein receptor activation stimulates breathing, causes bradycardia and hypotension, and has varying effects on pain perception, from antinociception to hyperalgesia, depending upon the level of nervous system activation.[22] Despite a high binding affinity, buprenorphine only partially activates the mu receptor.[14] The combination of buprenorphine’s partial agonism at the mu receptor and nociception protein receptor activation decreases the probability that buprenorphine will cause a critical respiratory event in contrast to full mu receptor activation by opioids such as fentanyl, hydromorphone, oxycodone, and morphine.[21]
Naloxone is a pure opioid receptor antagonist combined with buprenorphine to reduce abuse potential.[3] Naloxone competes and displaces other opioids from the mu, kappa, and delta receptors, diminishing their effects.
Pharmacokinetics
Absorption: Significant interindividual variability is seen with buprenorphine absorption. One study in healthy volunteers found that the bioavailability of sublingually administered buprenorphine was approximately 30%.[23] The coadministration of naloxone with buprenorphine is not associated with reducing buprenorphine bioavailability.[24] The mean time to peak plasma concentration after sublingual buprenorphine is between 40 and 210 minutes.[25] When naloxone is administered sublingually, it has a clinically negligible effect.[26][27] The bioavailability of sublingually administered naloxone is uncertain, but the best evidence is that it is <10%.[24] However, if naloxone is disintegrated via incorporation into a solvent and injected into a vein, naloxone blocks mu receptor activation, precipitating symptoms of opioid withdrawal.[26][28]
Distribution: Buprenorphine has high plasma binding to α- and β-globulins (96%) and a distribution volume significantly greater than adult human physiologic volumes (200 to 300 L).[25] The volume of naloxone distribution after sublingual administration has not been extensively studied. After intravenous (IV) administration, naloxone exhibits weak binding to plasma proteins and has a large volume of distribution (200 L).[29]
Metabolism: Buprenorphine undergoes significant first-pass metabolism (hepatic extraction ratio close to 1) when administered orally, which means a significant proportion of the medication is metabolized in the liver.[3][25] Accordingly, the preferred method of administration is sublingual, bypassing the first-pass effect.[3] The plasma half-life of buprenorphine-naloxone when taken sublingually is 38 hours.[4] Buprenorphine is metabolized primarily by the cytochrome P450 3A4 enzyme.[3] After IV administration, naloxone undergoes rapid hepatic metabolism with a hepatic extraction ratio of 0.8.[30] The elimination half-life of naloxone after IV administration is between 30 minutes and 90 minutes.[29]
Excretion: After sublingual administration, approximately 10% to 30% of buprenorphine and its metabolites are excreted in urine in the conjugated form, with the remainder excreted in feces in the free form.[25] After IV administration, approximately 60% of naloxone and its metabolites are excreted in the urine in the conjugated form.[29] The excretion of naloxone after sublingual administration has not been studied.
Administration
Available Dosage Forms
FDA-approved formulations of buprenorphine-naloxone include the sublingual tablet, sublingual film, and buccal film.[1][3] The buccal film is no longer available in the United States.
Strength
The ratio of buprenorphine to naloxone in the sublingual film is 4:1, or 4 mg buprenorphine/1 mg naloxone. The sublingual film is available in strengths of 2 mg buprenorphine/0.5 mg naloxone, 4 mg buprenorphine/1 mg naloxone, 8 mg buprenorphine/2 mg naloxone, and 12 mg buprenorphine/3 mg naloxone.
The ratio of buprenorphine to naloxone in the sublingual tablet is approximately 4:1, or 4 mg buprenorphine/1 mg naloxone.[27] The sublingual tablet is available in strengths of 0.7 mg buprenorphine/0.18 mg naloxone, 1.4 mg buprenorphine/0.36 mg naloxone, 2.9 mg buprenorphine/0.71 mg naloxone, 5.7 mg buprenorphine/1.4 mg naloxone, 8.6 mg buprenorphine/2.1 mg naloxone and 11.4 mg buprenorphine/2.9 mg naloxone.
Adult Dose
Before initiating buprenorphine-naloxone, patients with opioid use disorder undergo a period of abstinence and begin to experience mild opioid withdrawal symptoms. For most patients withdrawing from heroin, oxycodone, or fentanyl, a period of 12 hours is sufficient to provoke symptoms of mild withdrawal. Initiation of buprenorphine-naloxone during an inpatient admission may be associated with higher treatment retention.[31] However, buprenorphine-naloxone may be initiated safely at home, in a medical clinic, or in an acute care hospital.[32] There is no limit to the duration of therapy. Some experts believe that indefinite treatment reduces the risk of relapse. Additionally, all-cause mortality is decreased compared to when patients are untreated.[33]
The sublingual film should be placed under the tongue whole without cutting, chewing, or swallowing until complete dissolution occurs.[34] If more than 1 film is being administered simultaneously, place the second film under the other side of the tongue. After buprenorphine-naloxone has dissolved, take a sip of water, swish it around the oropharyngeal cavity, and swallow. The initial dose of buprenorphine-naloxone is typically 2 mg/.5 to 1 mg to 4 mg/0.5 to 1 mg, respectively. If withdrawal symptoms are present, the dose can be increased from 8 mg to 12 mg/2 mg to 3 mg within the first 24 hours.[35] Buprenorphine-naloxone is typically titrated over a few days to the therapeutic dose (8 mg to 32 mg/2 mg to 8 mg, respectively) or the dose necessary to reduce cravings and physiological withdrawal symptoms.[36][37]
Two meta-analyses found that the 16 mg/day to 32 mg/day dose was associated with greater treatment retention and a lower frequency of illicit opioid use compared to lower dosages.[31][38] This may be because higher doses of buprenorphine-naloxone are more effective at suppressing cravings than lower doses.[39][40] However, as per the Substance Abuse and Mental Health Services (SAMHSA), dosages above 24 mg buprenorphine or 24 mg/6 mg buprenorphine/naloxone have no clinical advantage.
The initial dose of sublingual tablets is typically 1.4 mg buprenorphine/0.36 mg naloxone. This dosage is equivalent to 2 mg /0.5 mg in the sublingual film. If withdrawal symptoms are present, the dose may increase to 5.7 mg/1.4 mg (equivalent to sublingual 8 mg/4 mg) within the first 24 hours. Like the buprenorphine-naloxone sublingual film, the tablet form can be titrated to the maintenance dose over a few days.
Specific Patient Populations
Patients with hepatic impairment: Buprenorphine and naloxone undergo significant hepatic metabolism. Increased vigilance for adverse effects is recommended in patients with moderate liver dysfunction (Child-Pugh score of 7 to 9 points). Manufacturers of the sublingual film and tablet recommend avoiding the administration of buprenorphine-naloxone in patients with severe liver dysfunction (Child-Pugh score >9). Acute hepatic necrosis after IV buprenorphine has been reported.[41]
Patients with renal impairment: Manufacturers of the sublingual film and tablet do not recommend dosing adjustments for patients with renal impairment.
Pregnant patients: Pregnancy is not considered a contraindication to buprenorphine-naloxone therapy.[42] Conversely, untreated opioid use disorder during pregnancy increases the risk for fetal, neonatal, and maternal morbidity.[43] Substitution therapy is recommended for treating opioid use disorder in pregnancy.[44][45] Buprenorphine-naloxone and methadone are both appropriate first-line therapies for opioid use disorder during pregnancy.[46] Substitution therapy does not appear to increase the risk for childhood developmental problems.[47][48] Human studies have not found an association between buprenorphine-naloxone therapy and gestational age at birth or the prevalence of birth defects.[49][50][51]
Buprenorphine-naloxone crosses the placenta and is found in the fetal circulation in women taking a daily dose >4 mg/1 mg. Fetal exposure to naloxone was significantly lower than buprenorphine, with undetectable levels in 45% of infants. Fetal concentrations were highly correlated with maternal drug levels.[52] Infants born to mothers on buprenorphine-naloxone therapy may experience neonatal withdrawal symptoms such as depressed breathing, irritability, tremors, and convulsions after birth.[53] Buprenorphine-naloxone may be associated with less severe neonatal abstinence symptoms, greater odds of full-term birth, greater birth weight, and shorter duration of fetal hospitalization than methadone.[49][54][55]
Breastfeeding patients: Buprenorphine-naloxone is not contraindicated in women who are breastfeeding; however, the drug does enter breast milk. Buprenorphine has poor oral availability. Thus, the quantity of buprenorphine that would be expected to enter the infant’s systemic circulation is low.[56] Insufficient data exists regarding the excretion of naloxone into breast milk, but the limited oral absorption suggests a low likelihood of impacting the breastfed infant.[57][58]
Pediatric patients: There is a lack of data regarding the use of buprenorphine-naloxone in pediatric patients. The decision to use buprenorphine-naloxone to treat opioid use disorder should be based upon risk-benefit analysis and shared decision-making that includes the clinician and, at times, the patient’s family.
Geriatric patients: There is a lack of data regarding the use of buprenorphine-naloxone in geriatric patients. The decision to use buprenorphine-naloxone to treat opioid use disorder should be based upon a risk-benefit analysis that includes consideration of gastrointestinal, neurological, hepatic, renal, cardiac, and dental disease.
Surgical patients: Surgery represents a significant challenge to patients on buprenorphine-naloxone therapy. Patients on buprenorphine-naloxone therapy have increased sensitivity to pain, decreased tolerance of pain, and decreased analgesic effect from opioids, which makes the achievement of adequate postoperative analgesia difficult.[59][60] Patients on buprenorphine-naloxone therapy may worry about inadequate perioperative analgesia, experiencing unfair treatment, and the temptation to relapse upon hospital discharge.[61]
Buprenorphine-naloxone should be discontinued before surgery. The concern is that postoperative analgesia is inadequate because buprenorphine can limit the effectiveness of full opioid agonists, which are commonly used to provide postoperative analgesia. This view is supported by case reports of poor-quality postoperative analgesia in patients maintained on buprenorphine.[62][63] If buprenorphine-naloxone is discontinued the day before surgery, the previous dose can be resumed if the abstinent period is ≤3 days.
While discontinuation of buprenorphine-naloxone can facilitate easier control of postoperative pain, many clinicians now advocate for continuing buprenorphine-naloxone maintenance therapy throughout the perioperative period.[2][64] This strategy avoids anxiety associated with halting buprenorphine-naloxone maintenance therapy, having to rely upon short-acting opioids to treat symptoms of withdrawal, and the difficult transition from full to partial mu receptor agonism after surgery.[2] Several studies have confirmed that buprenorphine therapy may be continued through the postoperative period without compromising short- or long-term pain relief or adversely affecting long-term outcomes.[65][66]
Buprenorphine-naloxone treatment within the normal therapeutic range (16 mg/4 mg) typically leaves about 20% of mu receptors unoccupied.[20] These unoccupied mu receptors are available for full receptor agonism when common perioperative opioids, such as fentanyl and hydromorphone, are administered.[3] Sufentanil may be the preferred opioid in the perioperative period for individuals on buprenorphine-naloxone therapy because it possesses a higher binding affinity than buprenorphine.[67] There is no evidence that treatment of acute pain after surgery with opioids is associated with a higher likelihood of addiction relapse.[68]
Postoperative multimodal analgesia is recommended for all patients on buprenorphine-naloxone. Patients will not exhibit tolerance to nonopioid analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, COX-3 inhibitors, pregabalin, gabapentin, α-2 agonists, local anesthetics, and NMDA receptor antagonists such as ketamine.[2] Regional anesthesia techniques are amongst the most effective methods of treating postoperative pain, and they should be incorporated into the postoperative analgesia plan whenever possible.
Adverse Effects
Adverse Drug Reactions
The most common adverse effects attributed to buprenorphine-naloxone administration are caused by buprenorphine’s ability to uncouple and displace opioids with greater mu receptor agonism, which may precipitate withdrawal symptoms.[28] Buprenorphine has a strong binding coefficient at the mu receptor but causes low mu receptor activation. When buprenorphine is administered to a patient experiencing a euphoric effect from a full mu agonist, such as fentanyl, the level of mu receptor agonism will decrease precipitating symptoms of opioid withdrawal. Symptoms of opioid withdrawal syndrome include pain, irritability, rhinorrhea, nausea, vomiting, abdominal cramping, myalgia, tachycardia, and diaphoresis.[69] Though opioid withdrawal syndrome is distressing, it has a low association with mortality.
As an opioid, buprenorphine is also associated with adverse effects from direct mu receptor agonism. These include headache, drowsiness, dizziness, constipation, cognitive impairment, and respiratory depression. The frequency of these adverse effects increases with increasing dose.[70] Most patients on maintenance therapy buprenorphine-naloxone develop tolerance to the adverse effects of drowsiness, dizziness, sedation, and respiratory depression. However, constipation and miosis are usually still present after months of therapy.[71][72]
Several case reports describe the development of dental caries, tooth erosion, and tooth decay after initiating buprenorphine-naloxone therapy.[73][74] The mechanism by which buprenorphine-naloxone causes dental damage is uncertain, but it is hypothesized to be associated with the acidity of the dissolved drug.[73][75] The sublingual film form of buprenorphine-naloxone is associated with hypoesthesia, or numbness, in the area of film dissolution. This is usually temporary and short-lived.
Opioid-induced hyperalgesia refers to the condition where exposure to prescribed opioids leads to hyperalgesia and allodynia.[76][77] In 2023, the FDA emphasized the requirement for a new warning regarding opioid-induced hyperalgesia. This phenomenon can potentially arise with prolonged use and higher doses.
Drug-Drug Interactions
Buprenorphine-naloxone should be administered cautiously in patients prescribed central nervous system depressants such as alcohol, muscle relaxants, and benzodiazepines. Administration of buprenorphine with benzodiazepines is associated with acute respiratory deterioration.[3][78][79][80]
Buprenorphine-naloxone therapy may prolong the corrected QT interval (QTc). Patients taking QT-prolonging medications such as antipsychotics, antidepressants, antiarrhythmics, macrolide antibiotics, fluoroquinolone antibiotics, or ondansetron should be monitored with an electrocardiogram during the induction period.
Buprenorphine-naloxone undergoes significant hepatic metabolism by the cytochrome P450 3A4 enzyme. Dose adjustment may be required for patients taking medications with substantial inhibition of the cytochrome 3A4 enzyme, including macrolide antibiotics, ketoconazole, and protease inhibitors, as these can prolong the duration of action.[4]
Administration of buprenorphine-naloxone with medications possessing anticholinergic properties such as benztropine, oxybutynin, diphenhydramine, scopolamine, antipsychotics, and tricyclic antidepressants can increase the risk for urinary retention and constipation.[81][82]
The coadministration of MAO inhibitors such as phenelzine, tranylcypromine, and linezolid with opioids, including buprenorphine, may result in serotonin syndrome.[83] Buprenorphine-naloxone is not advised in patients currently taking MAO inhibitors or within 14 days after discontinuing such treatment.
Contraindications
Box Warning
Buprenorphine-naloxone carries a box warning that it contains an opioid that can be misused, leading to addiction and death. Administration of buprenorphine-naloxone is associated with fatal respiratory depression.[79] The risk is increased when buprenorphine-naloxone is used with benzodiazepines and other sedating medications, including alcohol.[79][80] Buprenorphine-naloxone should be stored in a location not accessible to children, as fatal respiratory depression has been reported.[84] Buprenorphine-naloxone should not be administered to individuals with known hypersensitivity to any ingredient. Severe hypersensitivity, including anaphylaxis and angioedema, is an absolute contraindication to buprenorphine-naloxone therapy.
Warnings and Precautions
There are several relative contraindications to the initiation of buprenorphine-naloxone therapy. Pulmonary and gastrointestinal contraindications include respiratory depression, status asthmaticus, acute bronchospasm, cor pulmonate, mechanical bowel obstruction, and ileus.[4] Patients with cirrhosis or liver failure require slow titration during the induction period with the recognition that maintenance dose requirements may be lower in this population. Buprenorphine treatment is generally linked to low rates of serum enzyme elevations, comparable to or less than those observed with methadone, even in populations with coexisting chronic liver diseases. However, acute liver injury has been reported within weeks to months of initiating buprenorphine following misuse via IV administration of sublingual tablets. This injury typically displays hepatocellular patterns without immune-allergic features and occurs mainly in patients with concurrent chronic hepatitis C. The mechanism is dose-dependent direct toxicity. Reported cases range from mild to severe hepatitis, occasionally resulting in fatalities. Some patients resumed buprenorphine use without recurrence, including those with a history of IV misuse.[41]
Relative neurologic contraindications include altered mental status from acute alcohol intoxication, sedative-hypnotics, benzodiazepines, and psychosis from drugs of abuse.[79][80][85] Buprenorphine-naloxone is also relatively contraindicated after traumatic brain injury because of its association with respiratory acidosis and increased intracranial pressure. Additionally, the effects of buprenorphine-naloxone, including miosis and depressed mental status, may obscure patient evaluation after traumatic brain injury. Lastly, buprenorphine-naloxone is relatively contraindicated after loss of sympathetic tone, including high spinal cord injury or neuraxial anesthesia, because it can worsen hypotension.
Adrenal insufficiency, including Addison disease, is a relative contraindication to buprenorphine-naloxone therapy. Chronic buprenorphine-naloxone therapy may worsen adrenal function, leading to symptoms of fatigue, weakness, abdominal pain, anorexia, hypotension, and hyponatremia.[86][87]
Monitoring
All patients undergoing buprenorphine-naloxone induction should have frequent office visits to promote treatment compliance and facilitate early detection of diversion. These visits may include drug testing and medication dose adjustments.[35] During this vulnerable period, patients should be monitored for signs and symptoms of opioid withdrawal syndrome and severe pain.
Although pregnancy is not considered a contraindication to buprenorphine-naloxone therapy, β-human chorionic gonadotropin (hCG) testing is recommended before initiating therapy. Some clinicians prefer buprenorphine over buprenorphine-naloxone in pregnant women. Buprenorphine-naloxone therapy is associated with hypogonadism.[88][89][90] Accordingly, it is recommended to assess for evidence of adrenal insufficiency before initiating therapy.
Buprenorphine-naloxone is associated with dental decay.[73][74] Regular, frequent dental appointments are recommended for patients who are on buprenorphine-naloxone maintenance therapy.[91][92]
The correlation between buprenorphine-naloxone and hepatitis is unknown. Patients with preexisting liver dysfunction appear to be at increased risk of hepatitis.[93] Regular alanine transaminase and aspartate transaminase enzyme levels are recommended during the induction period and periodically during maintenance therapy for patients with preexisting liver dysfunction or those at high risk for liver dysfunction like alcohol use disorder.
Buprenorphine-naloxone therapy may prolong the QTc. Patients with long QT syndrome, hypokalemia, hypomagnesemia, or those prescribed QT-prolonging medications should undergo an electrocardiogram during the induction period.
Patients are at high risk for relapse and opioid-related overdose after halting buprenorphine-naloxone therapy. All-cause mortality and mortality due to opioid overdose increases immediately after cessation of buprenorphine-naloxone therapy.[3][94] The proportion of mu receptors available for full receptor agonists, such as fentanyl and heroin, increases after buprenorphine-naloxone therapy ceases. During this vulnerable period, an opioid dose that was previously tolerated may precipitate critical respiratory depression. Follow-up is recommended after halting therapy to monitor for depression, anxiety, and drug-seeking behavior.[35]
Toxicity
Signs and Symptoms of Overdose
Buprenorphine overdose typically presents with miosis (eye pupillary constriction), depressed consciousness, and respiratory depression—which, if severe, can result in death.[95] Buprenorphine-naloxone is associated with a much lower likelihood of severe respiratory depression than full mu receptor agonists, such as fentanyl and heroin. Dose-effect studies have found there is a ceiling effect regarding the degree of respiratory depression that buprenorphine can cause.[3][19] This protective ceiling effect is attenuated when buprenorphine is co-administered with benzodiazepines.[1][79][80]
Management of Overdose
The treatment for opioid-induced respiratory depression is naloxone and ventilatory support. Patients, caregivers, and members of the social support system should be counseled on recognizing and treating respiratory depression. In the hospital setting, the authors have successfully administered 40 mcg of naloxone every 1 to 2 minutes until respiratory and central nervous system depression abates. Administering naloxone in this manner will decrease the severity of opioid withdrawal symptoms. Naloxone is also available in a prefilled syringe for intramuscular injection and as an over-the-counter nasal spray.[96] Due to the short duration of action, patients may require repeated doses or the initiation of a naloxone infusion. The combination medication buprenorphine-naloxone is not an appropriate treatment for opioid-induced respiratory depression.
Enhancing Healthcare Team Outcomes
Opioid use disorder is a significant public health problem. Buprenorphine-naloxone is one of the most effective medications to treat opioid use disorder. Coordination of effective interprofessional team communication is essential for patients to safely initiate therapy, decrease harm, reduce the risk of relapse, and ensure care is provided.
Social workers, mental health therapists, and psychiatrists serve an instrumental role in identifying patients who may benefit from buprenorphine-naloxone therapy. After therapy has begun, social workers, therapists, and psychiatrists are essential components of the safety net required to monitor for diversion, medication toxicity, withdrawal symptoms, dosing compliance, and concurrent psychiatric disorders.
According to section 1262 of the Consolidated Appropriations Act of 2023, all clinicians with Drug Enforcement Administration (DEA) authority for schedule III medications can prescribe buprenorphine-naloxone. Many state nurse practitioners and physician assistants may prescribe buprenorphine-naloxone to increase access. Although the prescription of buprenorphine for opioid use disorder requires the clinician to obtain a waiver from Substance Abuse and Mental Health Services (SAMHSA), buprenorphine for chronic pain does not require a waiver.[13] A study utilized a quasi-experimental design to assess a new 4-hour Medication-Assisted Treatment training program tailored for primary care clinicians as an addition to the standard 8-hour SAMHSA DATA 2000 waiver training.
Evaluating 183 participants, pretraining and posttraining assessments revealed notable improvements in clinicians' confidence and competence in implementing medication-assisted treatment, indicating the potential efficacy of the supplemental training. Further research to confirm these findings and explore broader policy implications is recommended for wider adoption.[97] These clinicians are ultimately responsible for ethical considerations like determining who should be treated, ensuring that the patient understands the adverse effects and the benefits of treatment, and obtaining informed consent.
Pharmacists are essential for assessing drug-drug interactions and providing guidance on the initial dose, maintenance dose, and required dosing adjustments due to changes in organ system function and comorbidities. Nurses are often the first to field patient questions about the dosing regimen and patient concerns related to adverse effects. Laboratory technicians and medical assistants reduce the risk of adverse effects through their role in monitoring organ function. In cases of severe overdose, individuals should be hospitalized in the medical intensive care unit, necessitating supervision by critical care clinicians.
Successful treatment of opioid use disorder requires interprofessional care coordination.[98] Each team member must draw upon their unique experiences, knowledge, and skills to create a care plan that minimizes adverse drug reactions, enhances safety, and increases the likelihood of treatment retention. By leveraging a multidisciplinary approach, personalized care plans can be crafted for patients, mitigating the adverse effects of buprenorphine-naloxone and potentially enhancing the overall quality of life for individuals undergoing treatment.
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