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 (T_max) after oral or sublingual buprenorphine administration is poorly characterized; however, one source states a T_max 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 C_max values from 1.6-6.4 ng/mL and T_max 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]