Buprenorphine/Naloxone Toxicity

Updated: Dec 29, 2015
  • Author: Timothy J Wiegand, MD; Chief Editor: Asim Tarabar, MD  more...
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Overview

Background

Buprenorphine, a schedule III partial mu receptor agonist, was approved by the US Food and Drug Administration (FDA) for the treatment of opioid dependence on October 8, 2002. Suboxone and Zubsolv are the trade names for preparations containing buprenorphine and naloxone in a 4:1 ratio. These products were developed as a maintenance treatment for opioid dependence and combined with naloxone to prevent IV drug abuse. 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 Food and Drug Administration 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 sublingualadministration. One Zubsolv 5.7/1.14 mg SL tablet provides equivalent buprenorphine to one Suboxone 8/2 mg.

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 opioid addiction treatment becomes mainstream. Finally, by opening up additional treatment options for opioid dependence, the demand for heroin and other illicit sources of opioids may be diminished with substantial impact on health care cost and other social outcomes. Currently, a maximum of 30 opioid-dependent patients can be treated per physician group, with the ability to increase that number to 100 after a trial period of 1 year. [1]

Buprenorphine is a partial agonist at the mu opioid receptor and an antagonist at the kappa receptor. It has very high affinity and low intrinsic activity at the mu receptor and will displace morphine, diacetylmorphine, methadone, or other opioid full agonists from the receptor. Its partial agonist effects imbue buprenorphine with several clinically desirable pharmacologic properties, including lower abuse potential; lower level of physical dependence (less severe withdrawal syndrome); a ceiling effect, with respect to clinical effects, at higher doses; and greater safety in overdose compared with opioid full agonists.

Naloxone has negligible bioavailability via the sublingual or oral routes and does not accumulate to clinically significant concentrations when administered in this manner. Naloxone was added to buprenorphine in an effort to deter intravenous abuse of this preparation. [2, 1, 3] {ref37| [4, 5]

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Pathophysiology

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 the receptor such as morphine and methadone. The clinical effects seen with Suboxone administration or ingestion are significantly prolonged compared to the plasma-half life of buprenorphine or naloxone individually as well as to 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. [6]

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; [7] however, this is tempered by the "partial agonist" activity of buprenorphine in that as doses of buprenorphine are increased 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. [6] 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.

Dose/response (pCO2) with buprenorphine. Dose/response (pCO2) with buprenorphine.

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

Pharmacologic effects comparing a full agonist, mo Pharmacologic effects comparing a full agonist, morphine, to a partial agonist, buprenorphine.

Some clinical effects, such as respiratory depression (as monitored by pCO2 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. [8]

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. [9, 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. [7] Plasma levels of buprenorphine may not parallel other clinical effects either.

Pharmacokinetics  [7, 12]

In considering the clinical effects of the combined buprenorphine/naloxone preparation, Suboxone, 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, and, in particular, vulnerable populations, such as infants or toddlers, may experience effects very similar to a full opioid agonist, while an individual who is physically dependent on a full opioid agonist may experience an abstinence (withdrawal) syndrome after administration of the Suboxone preparation.

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.

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 long-beyond those predicated by plasma half-life of buprenorphine alone. [10, 14]

Dosing

Buprenorphine is typically available in a 0.3-mg/mL solution for intramuscular injection (as buprenorphine HCl) to treat moderate or severe pain. Naloxone intravenous/intramuscular solution is available in 0.4 or 2 mg vials for reversal of opioid effects or treatment of opioid overdose. The combined preparation, Suboxone, is available in 2/0.5 or 8/2 mg tablets to be administered sublingually for treatment of opioid dependence. Subutex (buprenorphine alone) is also available as 2 and 8 mg tablets for sublingual administration.

The typically recommended sublingual daily dose is 16-24 mg/day. Initiation of Suboxone (OBOT) therapy is typically with an 8/2 mg (8 mg buprenorphine/2 mg naloxone) Suboxone tab. Doses may be divided throughout the day for more consistent analgesic activity. After initiation of Suboxone therapy, the daily dose is titrated to effect, which is absence of withdrawal symptoms and opioid craving. Zubsolv is absorbed more completely and quickly than Suboxone. Zubsolv 5.7/1.4 mg provides equivalent buprenorphine exposure as Suboxone 8/2 mg.

Zubsolv conversion dose for patients ending induction and beginning maintenance is as follows:

  • 8 mg buprenorphine = 5.7/1.4 mg Zubsolv
  • 12 mg buprenorphine = 8.5/2.12 mg Zubsolv
  • 16 mg buprenorphine = 11.4/2.8 mg Zubsolv

Drug interactions

The Suboxone preparation may interact with other opioid analgesics while the individual constituents (buprenorphine and naloxone) 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 then based on route of administration. If taken as intended, via the sublingual route, 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. Suboxone was initially formulated as a combination product to deter intravenous abuse of buprenorphine; however, as can be seen from various epidemiologic studies, intravenous abuse does continue to occur with Suboxone . [2, 3, 15]

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Epidemiology

Frequency

United States

Between 2003 and 2004, the number of buprenorphine-containing tablets distributed from US pharmacies increased 7-fold. [11] In 2014, the American Association of Poison Control Centers reported 2,137 single exposures. [16] Recent increases in the incidence of opioid abuse and dependence as well as increases in the number of patients individual OBOT providers may treat lead to continued increases in Suboxone exposure. [1]

Mortality/Morbidity

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 with clinical courses characterized by a need for antidotal therapy (naloxone) and even ventilatory support in some cases. [17]

One retrospective review of 86 children younger than 6 years (45 males and 41 females; mean age, 2.06 +/- 0.86 years) with ingestion of buprenorphine is described as follows: [9]

All cases described were unintentional: 34 cases of 2/0.5 mg Suboxone tab (2 mg buprenorphine and 0.5 mg naloxone), 32 cases of 8/2 mg Suboxone tab (8 mg buprenorphine and 2 mg naloxone), 11 with Subutex (buprenorphine alone preparation), and 10 with unspecified formulations of buprenorphine.

Sixty-four patients (74%) were managed in a health care facility, and 22 patients (26%) were managed at home.

Clinical effects in one series of pediatric Suboxone exposures were as follows: [9]

  • 37% remained asymptomatic
  • Symptomatic children presented with the following symptoms:
    • Lethargy (55%)
    • Vomiting (21%)
    • Miosis (21%)
    • Respiratory depression (7%)
    • Agitation (5%)
    • Coma (3%)
  • Children younger than 2 years are more likely to experience clinical effects, and 5 of 6 severe effects occurred in children younger than 2 years of age.

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. [18]

Sex

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. [9]

Demographics from a retrospective review of 86 chi Demographics from a retrospective review of 86 children exposed to buprenorphine.

Age

While ceiling effects would suggest that toxicity from buprenorphine exposures would be minimal, literature reports include serious effects in pediatric patients including the need for antidotal therapy (naloxone) due to respiratory depression and even the need for ventilatory support. A retrospective review of 86 pediatric exposures is discussed above under the Mortality/Morbidity section. [9, 11, 19, 10]

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