Buprenorphine/Naloxone Toxicity

First developed by Reckitt and Coleman (now Reckitt Benckiser Pharmaceuticals; Richmond, Va), buprenorphine hydrochloride was initially marketed as an opioid analgesic under the trade name Temgesic 0.2 mg sublingual tablets. It was also marketed as Buprenex in a 0.3 mg/mL injectable solution.

In 2002, the FDA approved a high-dose formulation of buprenorphine as Suboxone in 2 mg and 8 mg doses (with 0.5 mg and 2 mg naloxone, respectively) and Subutex, a buprenorphine product with no active additives, also in 2 mg and 8 mg doses for sublingual administration. Buprenorphine/naloxone preparations are currently available in a range of doses and in tablets and sublingual and buccal films. For example, one Zubsolv 5.7/1.14 mg sublingual tablet provides buprenorphine equivalent to one Suboxone 8/2 mg sublingual film. 

The Drug Addiction Treatment Act of 2000 (DATA 2000) expanded the options available for the treatment of opioid dependence in the United States by allowing for private physicians to prescribe Schedule III, IV, and V drugs for the treatment of opioid dependence. Prior to this legislation, the only option was treatment through licensed methadone clinics.

The goal of DATA 2000 is to create opportunities for more comprehensive care of the opioid-dependent individual. Opening up private treatment options diminishes the stigma associated with opioid addiction and allows opioid addiction treatment to become mainstream. Finally, opening up additional treatment options for opioid dependence may diminish the demand for heroin and other illicit sources of opioids, which may have a substantial impact on health care costs and other social outcomes.[2]

 

Mechanism of action

Buprenorphine is a semisynthetic analogue of the opiate alkaloid thebaine, which is found to a somewhat lesser extent than morphine and codeine in poppy resin or opium. Buprenorphine acts at the mu opiate receptor but does not activate it to the same degree as morphine or other full agonist compounds, such as methadone or hydromorphone; thus, it is called a partial agonist.

Buprenorphine has a high affinity for the mu receptors and can displace other opioid compounds from those receptors, such as morphine and methadone. The clinical effects seen with buprenorphine/naloxone administration or ingestion are significantly prolonged compared with the plasma-half life of buprenorphine or naloxone individually as well as other opioid analgesics. This is due to the slow association-dissociation kinetics of buprenorphine at the mu receptors. The half-life of biophase equilibration for buprenorphine at the mu receptor is 173 minutes.[7]

Buprenorphine is 25-50 times as potent as morphine. A 0.4-mg dose of buprenorphine may produce as much analgesia as a 10-mg dose of morphine given intramuscularly.[8]  However, this is tempered by the "partial agonist" activity of buprenorphine in that with increasing doses of buprenorphine a maximum effect, or ceiling effect, is seen.

The intrinsic activity of buprenorphine with regard to receptor activation has been found to be 0.67 with regard to respiratory depression, where a value of 1.0 indicates full agonistic activity.[7] This is illustrated by the graph below that shows pCO2 levels (used as a measure of respiratory depression) increase to a certain point and then level off. This "leveling off" of effect despite increasing dose is referred to as a "ceiling effect," also illustrated in the image below.

This contrasts with the effects of full agonists, where with increasing dose, an increasing response is seen, as illustrated in the graph below.

Some clinical effects, such as respiratory depression (as monitored by partial pressure of CO2 levels), more consistently appear to exhibit this ceiling effect, while others such as analgesia may follow a more typical dose-response curve.

Buprenorphine has a high affinity for the mu receptor and, because of its partial agonist activity, it may precipitate an abstinence syndrome if administered to patients who are dependent on full mu receptor agonists (eg, morphine, methadone, heroin). In one study, buprenorphine antagonized the respiratory depression produced by fentanyl as well as naloxone, without completely reversing the analgesic effects.[9]

Although (as demonstrated above) there appears to be a ceiling effect in regard to the respiratory depression seen with buprenorphine, certain vulnerable populations, such as young children or infants and individuals with chronic obstructive pulmonary disease (COPD), may be susceptible to significant respiratory depression after exposure to buprenorphine.[6, 10, 11]

Although variable, both subjective and objective effects after buprenorphine administration may be slower in onset, slower to peak effect, and last longer when compared with morphine's effects. For example, peak pupillary constriction occurs about 6 hours after intramuscular injection, whereas maximal respiratory depression is observed at about 3 hours.[8] Plasma levels of buprenorphine may not parallel other clinical effects either.

Pharmacokinetics[8, 12]

To understand the clinical effects of the combined buprenorphine/naloxone preparation, one must consider the pharmacokinetic and pharmacodynamic properties of the constituents individually and then the effects of these two chemicals coadministered. Clinical effects will vary substantially among different routes of administration (sublingual, intravenous, or intramuscular). Individual patient characteristics will dramatically influence the clinical presentation as well. Opioid-naive patients—in particular, those in vulnerable populations, such as infants or toddlers—may experience effects very similar to those of a full opioid agonist, while an individual who is physically dependent on a full opioid agonist may experience an abstinence (withdrawal) syndrome.

Absorption

Naloxone has negligible absorption after sublingual or oral administration, whereas buprenorphine is well absorbed by most routes of administration. The buprenorphine/naloxone preparation was formulated for sublingual administration. After sublingual administration, concentrations of buprenorphine in the blood peak at 1-2 hours. Peak pharmacologic effects occur within 100 minutes after sublingual administration. Sublingual maintenance therapy of 8 mg/day resulted in plasma buprenorphine concentrations of 1-8 ng/mL. One Zubsolv 5.7/1.14 mg SL tablet provides equivalent buprenorphine exposure and 12% lower naloxone exposure to one Suboxone 8/2 mg SL film.

Bioavailability

Buprenorphine has approximately 30% bioavailability with sublingual administration. Buprenorphine has better bioavailability after sublingual absorption compared with oral ingestion due to extensive first-pass hepatic metabolism. The time to peak concentration (Tmax) after oral or sublingual buprenorphine administration is poorly characterized; however, one source states a Tmax of 120 minutes. Another study of single, high-dose buprenorphine administration (as Suboxone or Subutex 2/0.5 mg or 8/2 mg tabs) reported Cmax values from 1.6-6.4 ng/mL and Tmax values from 0.5-3 h.[13]

Distribution

The volume of distribution of buprenorphine after Suboxone administration is 2.5 L/kg.

Protein binding

Buprenorphine is approximately 96% protein bound, primarily to alpha and beta globulin.[12]

Metabolism

Buprenorphine undergoes N-dealkylation by CYP3A4 to norbuprenorphine, which is pharmacologically active. Both the metabolite, norbuprenorphine, and the parent compound, buprenorphine, are subject to glucuronidation. Buprenorphine is primarily eliminated in the feces as free drug; however, low concentrations are also eliminated via the urine. Buprenorphine and metabolites are postulated to undergo enterohepatic recirculation.[13]

Half-life

While the half-life of buprenorphine in the plasma has been reported to be approximately 3 hours, this bears little relationship to the duration of clinical effects. Because of buprenorphine's prolonged half-life of association-dissociation from the mu receptors (173 min) and prolonged half-life of elimination (26 h with a range of 9-99 h) as well as the high lipophilicity of buprenorphine and the potency of the active metabolite, norbuprenorphine, the clinical effects may persist for far longer than predicated by plasma half-life of buprenorphine alone.[10, 14]

Drug interactions

Buprenorphine/naloxone may interact with other opioid analgesics, while the individual constituents may interact with one another. One must take into consideration the properties of opioids at the mu receptors in order to understand or anticipate potential drug interactions. Buprenorphine has a high affinity, is a partial agonist, and has a slow dissociation from the mu receptors. Buprenorphine may displace other opioids, including full agonists such as methadone or morphine, from the mu receptor, precipitating withdrawal in opioid-dependent individuals. Buprenorphine and naloxone may compete for mu receptor binding in a dose-dependent manner.

Clinical effects may vary based on route of administration. If buprenorphine/naloxone is taken as intended, via the sublingual route, the naloxone has negligible absorption and thus negligible interaction with buprenorphine at the mu receptor. If injected intravenously, naloxone may compete for mu receptor binding with buprenorphine. Buprenorphine/naloxone was initially formulated as a combination product to deter intravenous abuse of buprenorphine[4] ; however, as can be seen from various epidemiologic studies, intravenous abuse does occur.[1, 3, 15]

From 2004 to 2008, the number of prescriptions for Suboxone increased from 225,014 to 3,154,795 and the number of prescriptions for Subutex increased from 42,211 to 263,878.[16] In 2020, the American Association of Poison Control Centers (AAPCC) reported 2948 single exposures to buprenorphine/naloxone; the majority (57%) were unintentional.[17]  

During 2008–2010, there were an estimated 1,246 emergency department (ED) visits annually for buprenorphine/naloxone ingestions by children aged < 6 years, compared with an estimated 799 visits annually during 2013–2015. Accounting for prescribing frequency, ED visits for unsupervised buprenorphine/naloxone ingestions declined 65.3%, from an estimated 28.2 ED visits per 100,000 dispensed prescriptions during 2008–2010 to an estimated 9.8 per 100,000 dispensed prescriptions during 2013–2015.[18]

The approximate two-thirds reduction in the rate of ED visits by children for buprenorphine/naloxone ingestions coincided with packaging/formulation changes from tablets in multidose bottles to unit-dose packaged tablets or film strips. A study of poison center calls for pediatric buprenorphine/naloxone exposures also found a significantly lower rate of calls involving film strips in unit-dose packaging, compared with tablets in multidose bottles. Other factors potentially contributing to the rate reduction include increased counseling of patients on safe use and storage and a decline in pediatric medication ingestions overall.ref18}  

In 2020, the AAPCC reported 1143 single exposures in children under 6 years old, which represented 39% of the single exposures reported; 116 single exposures were reported in children ages 6 to 19 years and 1644 sigle exposures were reported in adults.[17]  In one retrospective review of Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS) data, which included 86 children younger than 6 years exposed to Suboxone, 45 (52%) were male and 41 (48%) were female.[6]

The AAPCC reported that in 2020, 71% of buprenorphine exposures were treated in a health care facility. There were 623 cases with moderate effects, 125 with major effects, and two deatha reported.[17]

Pediatric patients represent a particularly vulnerable population with regard to opioid overdoses. The ceiling effects of buprenorphine would suggest minimal toxicity with exposure to buprenorphine or Suboxone; however, literature reports describe serious morbidity associated with some very minimal Suboxone exposures in pediatric patients. Clinical courses were characterized by a need for antidotal therapy (naloxone) and even ventilatory support in some cases.[19]  

A retrospective review of 88 children younger than 7 years (mean age, 24 months) with ingestion of buprenorphine or buprenorphine/naloxone seen at a single pediatric tertiary care center reported 20 patients (23%) received activated charcoal while 48 (55%) were treated with naloxone, and 36 (41%) patients were admitted to the ICU. Observed clinical effects included respiratory depression (83%), oxygen saturation by pulse oximetry (SpO2) <  93% (28%), depressed mental status (80%), miosis (77%), and emesis (45%). The median hospital length of stay was 22 hours and duration of stay was positively associated with estimated exposure dose (P = 0.002).[20]

In another review of buprenorphine-related deaths in France, 20 addicted individuals (19 male, 1 female) were analyzed postmortem. Intravenous injection of crushed tablets, a concomitant intake of psychotropics (especially benzodiazepines), and the high dosage of the buprenorphine formulation available in France were described as the major risk factors for such fatalities.[21]

 

Pertinent history may be obtained from bystanders, family, friends, or emergency medical services. Pill bottles, drug paraphernalia, or eyewitness accounts may assist in the diagnosis. Ingestion time, quantity, and co-ingestants are important aspects of the history and should be ascertained.

The clinical presentation of a patient with buprenorphine/naloxone exposure may differ significantly depending on patient characteristics (eg, whether the patient is opioid naive or vulnerable, opioid tolerant, or opioid dependent), route of administration, co-ingestants, and whether the patient had other opioids in his or her system when buprenorphine/naloxone was ingested..

Pediatric patients, in particular infants or toddlers, may experience profound sedation or respiratory depression after buprenorphine/naloxone exposure despite the purported ceiling effect in regard to respiratory depression. Opioid-dependent patients may present with a precipitated withdrawal syndrome after exposure to buprenorphine/naloxone. Patients with lung disorders, such as chronic obstructive pulmonary disease, may be especially vulnerable to respiratory effects.

In children younger than 6 years, the most common clinical effects include the following:

• Lethargy
• Vomiting
• Miosis
• Respiratory depression
• Agitation
• Coma

In one retrospective review of 86 children younger than 6 years with exposures to buprenorphine, 54 children were found to develop toxicity. The mean time to onset of clinical effect was 64.2 minutes (range, 20 min to 3 h). Fifty-nine percent of the children experienced clinical effects that lasted between 2 and 8 hours, and 26% of children experienced clinical effects of up to 24 hours in duration.[6]  The mean duration of clinical effects in this review is illustrated in the chart below:

Withdrawal syndrome

Administration of buprenorphine may precipitate a withdrawal syndrome in individuals dependent on full opioid agonists such as methadone, morphine, or heroin. Significant withdrawal symptoms are more likely to occur in patients being treated with higher doses of methadone (> 30 mg) and after administration of the first buprenorphine dose in proximity to the last methadone dose.

Typical signs and symptoms of the opioid withdrawal syndrome include diarrhea, yawning, hypersensitivity to any pain, cramps and aches, pupillary dilation, and sweating. A withdrawal syndrome may develop upon discontinuation of buprenorphine preparations; however, it is significantly less severe and of shorter duration than withdrawal associated with other full opioid receptor agonists.

 

The respiratory effort frequently is impaired in opiate intoxication. Both bradypnea and hypopnea are observed. Rates as slow as 4-6 breaths per minute often are observed with moderate-to-severe intoxication. The body retains the hypoxic drive to breathe but may be overridden by the central nervous system sedative effects of a severe overdose.

Mild peripheral vasodilation may occur and result in orthostatic hypotension. However, persistent or severe hypotension should raise the suspicion of co-ingestants and prompt reevaluation. Cardiovascular effects, as well as other clinical findings (ie, sedation, nausea, vomiting, dizziness, sweating, headache) may be similar to those from full opiate agonists such as morphine.[8]

Opioids prolong gastrointestinal transit times, possibly causing delayed and prolonged absorption. Initial tendencies for nausea and emesis are transient. Pink frothy sputum, dyspnea, hypoxia, and bronchospasm strongly suggest acute lung injury.

Intravenous drug abuse (IVDA) carries an additional list of complications. Cellulitis and abscesses are frequent complications of  IVDA. Staphylococcal or streptococcal bacteria are typical organisms cultured from these infections, but anaerobic bacteria may also be seen.

Hematogenous dissemination of bacteria, commonly to the epidural space, can cause spinal epidural abscess. This also may occur from spread of vertebral osteomyelitis; Staphylococcus aureus is the most common organism causing this type of infection. Gram-negative bacilli may be observed as well.

Osteomyelitis in IVDA is well known; if a patient with long-term IVDA presents with back pain, this diagnosis should be added to the differential.

Site-specific sequelae, such as Horner syndrome from patients injecting into the neck region, may be observed.

Particulate matter poses a threat because of embolic phenomena. Pulmonary emboli and peripheral emboli are two common complications. Thrombi initiated by vessel intimal damage from the needle may lead to similar syndromes. Inadvertent intra-arterial injection is another potential complication, possibly resulting in necrosis of the affected extremity. Intraneural injection may cause transient or permanent neuropathy.

Endocarditis is one of the most serious complications of IVDA. The diagnosis is difficult to make in the ED and requires a high index of suspicion. Although either side of the heart may be affected, the right side, particularly the tricuspid valve, is involved more commonly than the left. Murmurs may be heard. Repeated septic pulmonary emboli may be the only presenting signs. S aureus is commonly the etiologic agent. Left-sided endocarditis can result from a variety of bacterial pathogens, including Escherichia coli or Streptococcus, Klebsiella, or Pseudomonas species. Physical examination findings consistent with endocarditis are observed more frequently in left-sided disease than in right-sided disease.

Necrotizing fasciitis is a life-threatening infection that is characterized by septic necrosis. A dusky, erythematous, tender, confluent rash that spreads rapidly and is associated with fever, chills, tachycardia, tachypnea, and leukocytosis should prompt aggressive resuscitation, aggressive therapy, and surgical consultation.

Pneumonia is common in IVDA. The usual pathogens should be considered, but aspiration should be added in patients who have been unconscious. Tuberculosis should be added to the differential diagnosis early to avoid unnecessary exposure to health care workers and other patients and to ensure timely and adequate treatment.

HIV infection and hepatitis C should be considered in all patients who have a history of IVDA.[22]

Although widely available, drug screens rarely alter clinical management in uncomplicated buprenorphine overdoses. Drug screens are most sensitive when performed on urine. Specific assays for buprenorphine are not routinely available in the emergency department or hospital laboratory.

Confirmation of buprenorphine exposure is feasible with drug-specific radioimmunoassay, gas or liquid chromatography with mass spectroscopy, or enzyme-linked immunosorbent assay (ELISA). Quantification of buprenorphine, and its metabolite norbuprenorphine, may be performed in reference laboratories, but results likely will not return in sufficient time to impact clinical decision making.[11]

In patients with moderate-to-severe toxicity, performing the following baseline studies is appropriate:

• Complete blood cell count
• Comprehensive metabolic panel
• Creatine kinase level
• Arterial blood gas determination

Obtain chest radiographs if acute lung injury is suspected or if aspiration has possibly occurred.

An electrocardiogram should be obtained on all patients with intentional overdose to rule out effects of possible cardioactive co-ingestants (eg, tricyclic antidepressants [TCAs], Na/K/Ca/β-channel blockers).

 

Stabilize all acute life-threatening conditions. Ensure a patent airway. Intubate if necessary (eg, to manage respiratory depression). Establish an intravenous (IV) line.

Obtain information about the overdose or exposure, including the following:

• Number of tablets or films
• Dosage
• Last date the prescription was filled (the bottles should be brought to the hospital if possible)
• Check blood glucose levels with a fingerstick, or administer a bolus of dextrose if bedside testing is not available.
• Administration of high-dose naloxone may be indicated if the patient has altered mental status (stupor or coma) and/or depressed respiration.

Naloxone may have variable efficacy in reversing the clinical effects of buprenorphine/naloxone ingestion or overdose. Naloxone has been reported to prevent the clinical effects of buprenorphine if administered prior to buprenorphine; however, it has been reported to be less effective at reversing clinical effects (eg, sedation, respiratory depression) once they are manifest. Despite those data, naloxone has demonstrated efficacy in the treatment of respiratory depression and sedation in pediatric patients inadvertently exposed to buprenorphine/naloxone.[11, 6, 10]

Treatment of patients with buprenorphine/naloxone exposure includes mainly supportive therapies such as management of the airway, breathing, and circulation (ABCs). Oxygenation, administration of intravenous fluids, and monitoring may be necessary. Despite the purported safety of buprenorphine/naloxone compared with full opioid analgesics, coma and significant respiratory depression can occur. Resuscitative maneuvers (eg, intubation) should be performed as needed. 

For patients with acute lung injury, care is supportive and the condition typically improves within 24-48 hours. Diuretics or mannitol are not useful and may cause intravascular volume depletion or worsen hypotension.

Any symptomatic patient with buprenorphine/naloxone exposure will need prolonged monitoring until symptoms have been absent for at least 8 hours; this is necessary to avoid recurrence, particularly after naloxone administration. Subtle signs and symptoms from buprenorphine/naloxone exposure may be difficult to detect in pediatric patients and some experts recommend even longer periods of observation, up to 24 hours, to ensure patient safety. Patients' respiratory and cardiovascular status should be monitored throughout.

An asymptomatic patient, in particular, an infant or child, should be monitored for 6-8 hours. If no signs of respiratory depression, nausea, or vomiting or decreased level of consciousness develop, the patient should be safe for discharge or psychiatric evaluation.

Treatment with naloxone

Relatively low doses of naloxone (eg, 0.4-2 mg) will have no effect on buprenorphine-induced respiratory depression in most instances. Higher doses (2.5-10 mg) of naloxone cause only partial reversal of the respiratory effects of buprenorphine.

Patients may need multiple repeat doses of naloxone after buprenorphine/naloxone exposure because the half-life of naloxone (33 minutes, in healthy adults) is significantly shorter than that of buprenorphine.[7] Most sources describe the duration of naloxone effect as ranging from 60 minutes to 4 hours,[10]  while the clinical effects of buprenorphine may persist for extended durations because of slow dissociation from opioid receptors. Recrudescence of symptoms after initial naloxone administration has been reported.[11]

After naloxone administration, pediatric patients, in particular, should be observed either overnight or for at least 8 hours while being monitored for any return of symptoms. Some authors advocate monitoring even asymptomatic pediatric patients for 24 hours due to concern for delayed respiratory depression;[11] however, it appears that patients who are truly asymptomatic, and do not require initial naloxone antidotal therapy or other supportive care, do not have spontaneous delayed toxicity. Careful initial assessment is important to discern subtle clinical effects.

Providers need to consider that the emergency department or hospital setting can provide a high degree of stimulation that may artificially facilitate "alertness". Once this degree of stimulation has diminished, the patient may then become susceptible to the respiratory and CNS depressant effects of the buprenorphine preparation.

Some literature reports resistance or difficulty reversing clinical effects of buprenorphine with naloxone.[23] However, clinical trial simulations have demonstrated that complete reversal of respiratory depression by naloxone is feasible. Specifically, complete reversal of low-dose buprenorphine-induced respiratory depression may be achieved with a continuous infusion of naloxone at doses of naloxone from 2-4 mg/70 kg/hour.[7] Additional experiments with incremental doses of buprenorphine and naloxone describe an optimal reversal of respiratory depression with doses of naloxone that would fit a bell-shaped curve with both low- and high-dose naloxone being less effective. The optimal dose for a 0.2 and 0.4 mg exposure of buprenorphine is reported to be from 2-4 mg/70 kg by weight.[24]

If administered in single-dose increments, high doses of naloxone (up to 10 mg) may be needed to reverse the clinical effects of buprenorphine. If naloxone does not reverse clinical effects, it is imperative that supportive ventilatory care continues.

Decontamination

Gastrointestinal decontamination has no role after isolated sublingual buprenorphine/naloxone exposure. The risks of administration of activated charcoal to the patient with altered mental status far outweigh any possible benefit of administration. Patients with protected airway (eg, endotracheal intubation, normal mental status), who were recently exposed to toxic co-ingestants, may receive charcoal after thorough clinical consideration of risks and benefits.

Case reports

In one report, a 2-year-old boy was found with one tablet of buprenorphine/naloxone (8 mg buprenorphine/2 mg naloxone) in his mouth. The tablet was described as "partly dissolved". The child experienced sedation (but was arousable), nausea, and vomiting. Naloxone was not administered. The patient was ambulatory at 5 hours postingestion and discharged to home 6 1/2 hours post exposure asymptomatic and stable.[10]

In a report of 5 children exposed to buprenorphine/naloxone, the exposure produced a classic opioid toxidrome of respiratory depression (including apnea), CNS depression, and miosis. Four out of 5 children received naloxone, including multiple doses and prolonged, continuous, intravenous infusions, which successfully reversed the respiratory and CNS depression. One child was intubated and mechanically ventilated. The authors of this report caution about the potential for delayed onset of CNS and respiratory depression after buprenorphine exposure.[11]

In another case, a 28-month-old boy was found with a buprenorphine/naloxone (8 mg buprenorphine/2 mg naloxone) tablet in his mouth. The tablet was noted to be moist but intact. At 1.5 hours from time of discovery, the child was found to have a depressed level of consciousness and bradypnea (slow and shallow breathing). CNS and respiratory depression were significantly reversed with 0.2 mg of naloxone administered intramuscularly; however, the child needed 2 additional doses of naloxone, administered intramuscularly (both 0.2 mg) due to persistence of symptoms. The child was discharged asymptomatic, after being monitored in the pediatric intensive care unit overnight (approximately 24 hours).[25]

The prescribing physician should be notified in all cases of exposure to buprenorphine/naloxone. Patients with an intentional exposure should be evaluated by a psychiatrist after the intoxication has resolved, to determine whether they need inpatient psychiatric care. All pediatric exposures should be referred for assessment by the Department of Health and Human Services (DHHS).

Consult a regional poison control center certified by the American Association of Poison Control Centers (AAPCC) at (800) 222-1222, a medical toxicologist certified by the American College of Medical Toxicology, or a clinical toxicologist certified by the American Board of Applied Toxicology.

Although substantially decreased, ED visits for pediatric ingestions of buprenorphine/naloxone were not eliminated after widespread adoption of unit-dose, child-resistant packaging. One explanation might be that some patients using buprenorphine/naloxone for medication-assisted treatment divide doses rather than consuming the entire unit, leaving unused partial doses accessible to children. In addition, the proportion of buprenorphine/naloxone prescriptions dispensed in unit-dose packaging began to decline at the end of 2013, reflecting the introduction of generic buprenorphine/naloxone tablets packaged in multidose bottles. As prescribing increases, and if multidose bottles again become the predominant form of packaging, parents who are enrolled in buprenorphine treatment will need to be educated how to store medication safely and how to prevent drug exposure to children at home.[18]

Some literature reports resistance or difficulty reversing clinical effects of buprenorphine with naloxone.[23] Repeat administration of high doses of naloxone may be needed. If naloxone does not reverse clinical effects, it is imperative that supportive care continues.

Class Summary

This agent is used to reverse the toxic effects of narcotics.

Naloxone (Narcan)

Prevents or reverses opioid effects (hypotension, respiratory depression, sedation), possibly by displacing opiates from their receptors.