Substances Included Synonyms

Therapeutic Toxic Class

A)

Specific Substances

1) Buprenorphinum
2) RX-6029-M
3) Buprenorphini Hydrochloridum
4) CL-112302
5) NIH-8805
6) UM-952
7) (6R,7R,14S)-17-Cyclopropylmethyl-7,8-dihydro-7- [(1S)-1-hydroxy-1,2,2-trimethylpropyl]-6-O-methyl-6,14- ethano-17-normorphine
8) (2S)-2-[(-)-(5R,6R,7R,14S)-9a-Cyclop ropylmethyl-4,5-epoxy-3-hydroxy-6-methoxy-6,14- ethanomorphinan-7-yl]-3,3-dimethylbutan-2-ol
9) CAS 52485-79-7 (Buprenorphine)
10) CAS 53152-21-9 (Buprenorphine hydrochloride)

1.2.1) MOLECULAR FORMULA
1) BUPRENORPHINE: C29H41NO4
2) BUPRENORPHINE HYDROCHLORIDE: C29H41NO4.HCl

Available Forms Sources

A)

1) Buprenorphine is available as a 0.3 mg/mL solution for injection (Prod Info Buprenex(R), 2001).
2) Buprenorphine and naloxone combination formulation (Suboxone(R)/Reckitt Benckiser) is available as 2 mg/0.5 mg and 8 mg/2 mg sublingual tablets (Prod Info Suboxone(R), 2002).
3) Buprenorphine (Subutex(R)/Reckitt Benckiser) is available as 2 mg and 8 mg sublingual tablets (Prod Info Subutex(R), 2002).
4) Although buprenorphine transdermal system (Transtec(R)) is not available in the US, it is available in other countries (eg; Belgium, UK, Germany, New Zealand) (Evans & Easthope, 2003).
5) A recent open-label trial suggests that IM depot injections of buprenorphine (a novel polymer microcapsule formulation) may be clinically useful. This is not yet available commercially (Sobel et al, 2004).

B)

1) Buprenorphine is a semisynthetic lipophilic opioid derivative of thebaine (Jasinski et al, 1978).

C)

1) Buprenorphine is indicated to control moderate-to-severe pain (Prod Info Buprenex(R), 2001). It is a Schedule III narcotic under the Controlled Substance Act (Prod Info Suboxone(R), 2002; Prod Info Subutex(R), 2002).
2) Buprenorphine/naloxone and buprenorphine sublingual tablets are used to treat opioid dependence (Prod Info Suboxone(R), 2002; Prod Info Subutex(R), 2002).
3) Although buprenorphine transdermal system (Transtec(R)) is not available in the US, it is available in other countries (eg; Belgium, UK, Germany, New Zealand). It is used to treat moderate to severe cancer pain and severe chronic pain unresponsive to nonopioid analgesics (Evans & Easthope, 2003).
4) Buprenorphine has been abused by crushing the tablets and snorting the powder (Strang, 1991).
5) Several authors have reported that intravenous injection of crushed tablets may appear to be a major risk factor for fatalities (Boyd et al, 2003; Kintz, 2002; Kintz, 2001; Tracqui et al, 1998a).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Schedule III prescription medication used for opioid addiction maintenance therapy.
B) PHARMACOLOGY: Partial agonist at the mu-opioid receptor, antagonist at the kappa opioid receptor.
C) TOXICOLOGY: The toxicity is an extension of the pharmacology. Effects include CNS depression, respiratory depression, constipation, and euphoria. Hypotension can occur from mast cell G protein activation and subsequent degranulation of histamine-containing vesicles.
D) EPIDEMIOLOGY: Buprenorphine exposures are common. In adults, severe toxicity may occur from crushing and injecting tablets, but is not common after ingesting buprenorphine alone. Children are at risk for toxicity following ingestion of less than a single tablet. While most deaths are due to overdose, deaths following inadvertent ingestion have occurred.
E) WITH THERAPEUTIC USE

1) Sedation, headache, nausea, vomiting, abdominal pain, constipation, and withdrawal syndrome. At high doses, buprenorphine's agonist effects plateau ("ceiling effect"), limiting the maximum analgesic and respiratory depressant effects. Due to this "ceiling effect," patients who are chronic users/abusers of opioids can experience withdrawal after ingestion of buprenorphine.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE POISONING: Miosis, sedation, and relative bradycardia. Hepatitis is reported rarely.
2) SEVERE POISONING: CNS depression, coma, respiratory depression, and hypotension. Children, in particular, may develop profound, recurrent, or delayed CNS and respiratory depression. In adults, severe effects are generally only seen after crushing and injecting tablets, or after very large ingestions. Acute renal failure is reported rarely.

0.2.20)

A) The buprenorphine/naloxone combination is classified as FDA pregnancy category C. The use of narcotic analgesics, including buprenorphine, during pregnancy is generally associated with fetal adverse effects including neonatal abstinence syndrome (NAS), physical dependence and withdrawal, growth retardation, and, with high doses, neonatal respiratory depression. Due to the lack of adequate well-controlled studies in pregnant women and the potential for NAS, it is recommended that buprenorphine be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus. Buprenorphine is excreted into breast milk; however, the amount received by the infant varies according to the maternal plasma concentration, amount of milk ingested, and extent of first-pass metabolism. Withdrawal symptoms can occur in breastfed infants when the maternal administration of an opioid or breastfeeding is stopped. Because the potential for adverse reactions in the nursing infant exists, it is recommended that breastfeeding or buprenorphine be discontinued upon consideration of the mother's need for treatment.

Laboratory Monitoring

A)

B)

C)

D)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) For patients who have CNS depression without airway compromise or respiratory depression, close monitoring and supplemental oxygen and supportive care is usually all that is required.

B) MANAGEMENT OF SEVERE TOXICITY

1) Supportive care (intravenous crystalloid, supplemental oxygen, and assisted ventilation), may be required. Naloxone can be given for respiratory depression in order to eliminate the need for intubation.

C) DECONTAMINATION

1) PREHOSPITAL: Prehospital decontamination is not recommended because of the potential for CNS depression.
2) HOSPITAL: Administer activated charcoal if the patient can reliably protect their airway.

D) AIRWAY MANAGEMENT

1) Administer oxygen and assist ventilation for respiratory depression. Orotracheal intubation for airway protection should be performed early in cases of obtundation and/or respiratory depression that do not respond to naloxone, or in patients who develop severe acute lung injury.

E) ANTIDOTE

1) Naloxone (adults and children): initial dose 1 mg IV, may repeat. High doses of naloxone (10 to 35 mg in adults) have been used to reverse respiratory depression induced by buprenorphine. The peak effect of naloxone reversal may also be delayed (up to 30 minutes in some cases).

F) DECREASED RESPIRATORY FUNCTION

1) Bag valve mask ventilation and naloxone; endotracheal intubation may be necessary.

G) ACUTE LUNG INJURY

1) Supplemental oxygen; PEEP and mechanical ventilation may be needed.

H) HYPOTENSION

1) Intravenous crystalloid; if hypotension persists, administer dopamine or norepinephrine.

I) ENHANCED ELIMINATION

1) There is no role for enhanced elimination techniques.

J) PATIENT DISPOSITION

1) HOME CRITERIA: There is no role for home management of inadvertent buprenorphine ingestion in children, as significant toxicity has resulted after ingestion of half a tablet.
2) OBSERVATION CRITERIA: Patients with deliberate ingestions or children with any ingestion should be referred to a healthcare facility for observation. All symptomatic patients should be sent to a healthcare facility for observation. All patients should be monitored for a minimum of 12 to 24 hours due to the potential for delayed or recurrent respiratory and CNS depression.
3) ADMISSION CRITERIA: All symptomatic patients should be admitted. Patients with significant persistent CNS depression or those with respiratory depression or hypotension should be admitted to an intensive care setting. Patients requiring multiple doses of naloxone or those who are on a naloxone infusion should be admitted to an intensive care setting.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (coma, severe CNS depression, respiratory failure or severe hypotension), or in whom the diagnosis is not clear.

K) PITFALLS

1) Failure to recognize the potential for delayed toxicity. Buprenorphine can induce opioid withdrawal in chronic opiate users. Response to naloxone is inconsistent; large naloxone doses may be required and maximum reversal effects may be delayed.

L) PHARMACOKINETICS

1) Buprenorphine is rapidly absorbed following oral or sublingual administration. Metabolized extensively by the liver. Volume of distribution is 97 to 187 liters with 96% protein binding. Elimination half life 1.2 to 7.2 hours (IV), 37 hours (SL).

M) DIFFERENTIAL DIAGNOSIS

1) Clonidine overdose, overdose with other opioids, GHB overdose, and overdose from benzodiazepines, sedative-hypnotics, skeletal muscle relaxants, and barbiturates can cause CNS depression and variable degrees of respiratory depression.

0.4.5)

A) OVERVIEW

1) Patients with topical exposure to buprenorphine (transdermal delivery patch) should have the substance removed and the area washed thoroughly with soap and water.

0.4.6)

A) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Range Of Toxicity

A)

B)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

E)

1) Sedation, headache, nausea, vomiting, abdominal pain, constipation, and withdrawal syndrome. At high doses, buprenorphine's agonist effects plateau ("ceiling effect"), limiting the maximum analgesic and respiratory depressant effects. Due to this "ceiling effect," patients who are chronic users/abusers of opioids can experience withdrawal after ingestion of buprenorphine.

F)

1) MILD TO MODERATE POISONING: Miosis, sedation, and relative bradycardia. Hepatitis is reported rarely.
2) SEVERE POISONING: CNS depression, coma, respiratory depression, and hypotension. Children, in particular, may develop profound, recurrent, or delayed CNS and respiratory depression. In adults, severe effects are generally only seen after crushing and injecting tablets, or after very large ingestions. Acute renal failure is reported rarely.

Heent

3.4.3)

A) WITH THERAPEUTIC USE

1) MIOSIS

a) Miosis has been reported in approximately 1% to 5% of patients (n=1133) treated, according to the manufacturer (Prod Info buprenorphine hcl injection, 2004).

B) WITH POISONING/EXPOSURE

1) MIOSIS

a) Miosis may occur following buprenorphine overdose (Swartzentruber et al, 2015; Prod Info SUBUTEX oral tablets, 2010; Magdalan & Merwid-Lad, 2008; Boyd et al, 2003).
b) CASE REPORT: Bilateral miosis occurred in a 4-year-old girl following ingestion of 4 mg of buprenorphine (one-half of an 8 mg tablet). The miosis resolved following gastric decontamination with activated charcoal (Gaulier et al, 2004).
c) CASE SERIES/CHILDREN: According to a retrospective review of buprenorphine overdoses in children younger than 6 years, miosis occurred in 18 of 86 children (21%) (Hayes et al, 2008).
d) CASE SERIES/CHILDREN: According to a retrospective case review of pediatric unintentional buprenorphine/naloxone exposures (n=9), miosis occurred in 6 children (younger than 3 years) following ingestion of buprenorphine/naloxone combination tablets (doses ranging from 0.07 to 0.41 mg/kg) (Pedapati & Bateman, 2011).

Cardiovascular

3.5.2)

A) CARDIOVASCULAR FINDING

1) WITH THERAPEUTIC USE

a) PARENTERAL: Hypotension has been reported in 1% to 5% (n=1133) of patients; hypertension, tachycardia, and bradycardia occur in less than 1% of patients (Prod Info buprenorphine hcl injection, 2004).

1) Intramuscular administration of buprenorphine produces hemodynamic effects similar to those of morphine sulfate in equianalgesic doses (0.3 and 10 mg, respectively). This includes decreases in systolic blood pressure, heart rate, and stroke volume (Heel et al, 1979; Scott et al, 1980). Similar to morphine, cardiovascular depression has not been a significant problem in most patients.

b) SUBLINGUAL: Vasodilation has been reported in 9.3% (n=107) and 3.9% (n=103) of patients following the use of buprenorphine/naloxone and buprenorphine sublingual tablets, respectively (Prod Info SUBUTEX oral tablets, 2010; Fudala et al, 2003).

2) WITH POISONING/EXPOSURE

a) Hypotension may occur following buprenorphine overdose (Henretig & Bassett, 2015; Prod Info SUBUTEX oral tablets, 2010).
b) CASE SERIES/CHILDREN: According to a retrospective review of buprenorphine overdoses involving 86 children younger than 6 years, hypotension occurred in 1 patient (Hayes et al, 2008).

B) MYOCARDIAL INFARCTION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Two hours after nasally insufflating an 8 mg crushed buprenorphine tablet, a 22-year-old man developed chest pain, which resolved spontaneously after 5 minutes. Three weeks later, he developed similar chest pain 2 hours after insufflating another crushed buprenorphine tablet. He presented to hospital with ECG changes suggesting and anterior myocardial infarction. Chest pain and ECG abnormalities resolved. Peak CK was 1296 units with MB of 266 microgram/L. On day 6, coronary angiography revealed normal epicardial coronary arteries with no spasm induced by methylergometrine. Intracoronary ultrasonography revealed a 1 mm circumferential plaque of the LAD. Buprenorphine was detected in blood and urine but cocaine and other opioids were not (Cracowski et al, 1999).

Respiratory

3.6.2)

A) HYPOVENTILATION

1) WITH THERAPEUTIC USE

a) Hypoventilation has been reported in 1% to 5% (n=1133) of patients; dyspnea and/or cyanosis was reported in less than 1% of 1133 patients in clinical studies (Prod Info buprenorphine hcl injection, 2004).

B) RHINITIS

1) WITH THERAPEUTIC USE

a) SUBLINGUAL: Rhinitis has been reported in 4.7% (n=107) and 9.7% (n=103) of patients following the use of buprenorphine/naloxone and buprenorphine sublingual tablets, respectively (Prod Info SUBUTEX oral tablets, 2010; Fudala et al, 2003).

C) DECREASED RESPIRATORY FUNCTION

1) WITH THERAPEUTIC USE

a) Respiratory depression has occurred with buprenorphine (Prod Info buprenorphine hcl injection, 2004), as with morphine (buprenorphine 0.3 mg equals morphine 10 mg), and is dose-related (Heel et al, 1979; Orwin et al, 1976). Respiratory depression has not been a clinical problem in most studies. However, depressant effects (and other effects of buprenorphine) were not easily reversed with naloxone, with effects being only partially reversed with high doses of naloxone (Heel et al, 1979).
b) CASE REPORT: Respiratory depression, resulting in cardiopulmonary arrest and death, was reported in an 83-year-old woman receiving buprenorphine for analgesia. The patient received 0.3 mg intravenously every 6 hours for 3 days without sequelae. On day 4 of treatment, the patient was given 2 doses of 0.3 mg intravenously within a period of 60 minutes for severe pain, and subsequently died secondary to cardiopulmonary arrest. This case suggests that lower doses of buprenorphine should be given to the elderly (Fincham, 1989).
c) Severe respiratory depression and pain were reported after administration of a high dose of buprenorphine. These signs were alleviated after naloxone administration (Schmidt et al, 1985).

2) WITH POISONING/EXPOSURE

a) Respiratory depression may occur following buprenorphine overdose (Prod Info SUBUTEX oral tablets, 2010; Boyd et al, 2003).
b) Respiratory depression due to buprenorphine overdose has been primarily due to illicit intravenous injection of crushed sublingual tablets. Evidence at autopsies revealed features of prolonged asphyxiation, including cyanosis, multivisceral congestion, and pulmonary edema (Kintz, 2001).
c) CASE SERIES/CHILDREN: CNS and respiratory depression (in one case, a respiratory rate of 2 per minute was observed) developed in 5 toddlers (age range 16 to 22 months) after ingestion of 8 to 10 mg buprenorphine. Recurrent respiratory depression as long as 18 hours after ingestion developed in one patient (Geib et al, 2006).
d) CASE SERIES/CHILDREN: According to a retrospective review of buprenorphine overdoses in children younger than 6 years, respiratory depression occurred in 6 of 86 children (7%). In 2 of the 6 children (a 4-year-old girl and a 16-month-old boy), respiratory depression was reported 2 and 3 hours postingestion, respectively (Hayes et al, 2008).
e) CASE REPORT: A 71-year-old woman experienced nausea and vomiting and somnolence after applying 4 transdermal 52.5 mcg/hour buprenorphine patches at the same time. Each patch contained 30 mg buprenorphine. Physical examination on admission showed that the patient had miosis, dry mucus membranes, and cyanosis of the lips. Respiratory rate was 8 breaths/minute and her oxygen saturation was 68%. After repeated administration of naloxone 0.8 mg (total of 3 doses IV and 2 doses subcutaneously), the patient completely recovered (Magdalan & Merwid-Lad, 2008).
f) CASE SERIES/CHILDREN: In a retrospective case review of pediatric unintentional buprenorphine/naloxone exposures (n=9), respiratory depression (less than 20 breaths/minute) occurred in 5 children (younger than 3 years) following ingestion of buprenorphine/naloxone combination tablets (doses ranging from 0.07 to 0.32 mg/kg). Hypoxia (O2 saturation less than 90% while sleeping) was reported in 1 patient (Pedapati & Bateman, 2011).
g) CASE REPORT/CHILD: A 23-month-old child presented to the emergency department with vomiting and respiratory depression (respiratory rate of 14 breaths/minute). A single episode of red-orange emesis occurred prior to presentation. Although there was no witnessed ingestion, it was suspected that the patient had ingested his mother's tablets containing 8 mg buprenorphine and 2 mg naloxone, due to the color and smell of the emesis. The patient was lethargic with miotic pupils and an oxygen saturation of 93% on room air. After IV administration of 3 bolus doses of naloxone, followed by a naloxone infusion that was continued for 23 hours (total dose 0.68 mg/kg), the patient recovered with no evidence of CNS or respiratory depression. He was discharged 48 hours post-presentation with continued normal development at his 6-month follow up appointment (Swartzentruber et al, 2015).

D) ACUTE LUNG INJURY

1) WITH THERAPEUTIC USE

a) Noncardiogenic pulmonary edema with respiratory depression is reported in a 21-year-old woman within 90 minutes of a 0.2 mg sublingual dose. An allergic/hypersensitivity reaction was suspected in this case (Thammakumpee & Sumpatanukule, 1994).

Neurologic

3.7.2)

A) CENTRAL NERVOUS SYSTEM DEPRESSION

1) WITH THERAPEUTIC USE

a) PARENTERAL: The most frequent CNS effect is drowsiness and sedation, which occurs in 40% to 75% of patients treated (Heel et al, 1979). The manufacturer has reported sedation in 2/3 of 1133 patients. Dizziness and vertigo occur in about 5% to 10% of patients, while headache was reported in 1% to 5%; confusion, weakness, fatigue, nervousness, depression, slurred speech, euphoria, hallucinations, dysphoria, and paresthesia have been rarely reported (less than 1% of patients) (Prod Info buprenorphine hcl injection, 2004; Harcus et al, 1980; Tigerstedt & Tammisto, 1980; Heel et al, 1979).
b) High doses of opioids or combination opioid agonists/antagonists have been reported to cause a paradoxical pain reaction which resolves upon cessation of the drug. Severe respiratory depression and pain were reported after administration of a high dose of buprenorphine. These signs were alleviated after naloxone administration (Schmidt et al, 1985).

2) WITH POISONING/EXPOSURE

a) Central nervous system depression may occur following buprenorphine overdose (Swartzentruber et al, 2015; Boyd et al, 2003). Sedation may occur following buprenorphine overdose (Prod Info SUBUTEX oral tablets, 2010).
b) The outcome of an overdose ingestion of buprenorphine (35 to 40 tablets of 0.4 mg) was reported in a young male patient. The patient had been taking the drug previously for 10 months. One hour following ingestion, the patient was extremely drowsy and depressed, but oriented and conscious. He experienced no other central nervous system symptoms. He recovered uneventfully. Upon discontinuing the buprenorphine, no withdrawal symptoms were evident (Banks, 1979).
c) CASE SERIES/CHILDREN: CNS and respiratory depression (in one case, a respiratory rate of 2 per minute was observed) developed in 5 toddlers (age range 16 to 22 months) after ingestion of 8 to 10 mg buprenorphine. Recurrent CNS and respiratory depression as long as 18 hours after ingestion developed in one patient (Geib et al, 2006).
d) CASE SERIES/CHILDREN: According to a retrospective review of buprenorphine overdoses in children younger than 6 years, drowsiness or lethargy occurred in 47 of 86 children (55%). In the same review, coma occurred in 2 patients (2%) (Hayes et al, 2008).
e) CASE REPORT: A 71-year-old woman experienced nausea and vomiting and somnolence after applying 4 transdermal 52.5 mcg/hour buprenorphine patches at the same time. Each patch contained 30 mg buprenorphine. Physical examination on admission showed that the patient had miosis, dry mucus membranes, and cyanosis of the lips. Her oxygen saturation was 68%. After repeated administration of naloxone 0.8 mg (total of 3 doses IV and 2 doses subcutaneously), the patient completely recovered (Magdalan & Merwid-Lad, 2008).
f) CASE SERIES/CHILDREN: According to a retrospective case review of pediatric unintentional buprenorphine/naloxone exposures (n=9), drowsiness or lethargy occurred in all 9 children (younger than 3 years) following ingestion of buprenorphine/naloxone combination tablets (doses ranging from 0.07 to 0.41 mg/kg) (Pedapati & Bateman, 2011).
g) CASE REPORT: An 11-year-old boy presented to the emergency department of a community hospital minimally responsive. The patient's vital signs revealed a heart rate of 124 bpm, respiratory rate of 20/minute, blood pressure of 125/75 mmHg, and an oxygen saturation of 98% on non-rebreather mask oxygen supplementation. His Glasgow Coma Scale score was 9 and "bruising" was observed on his extremities. Home medications accessible to the patient included aripiprazole, citalopram, zolpidem, cyclobenzaprine, loratadine, cetirizine, and buprenorphine. Following intubation, the patient was transferred to a children's hospital. Repeat vital sign measurements indicated a heart rate of 124 bpm, respiratory rate of 17/minute on ventilator, blood pressure of 87/48 mmHg, and an O2 sat of 100%. Physical exam noted elbow and knee swelling with bullae and erythematous patches on his face and extremities, referred to as "coma bullae". With supportive care, the patient improved and he was extubated the next day. Comprehensive drug screening was positive for buprenorphine and norbuprenorphine (Henretig & Bassett, 2015).

B) HEADACHE

1) WITH THERAPEUTIC USE

a) SUBLINGUAL: Headache has been reported in 36.4% (n=107) and 29.1% (n=103) of patients following the use of buprenorphine/naloxone and buprenorphine sublingual tablets, respectively (Prod Info SUBUTEX oral tablets, 2010; Fudala et al, 2003).

C) DIZZINESS

1) WITH THERAPEUTIC USE

a) TRANSDERMAL PATCH: Dizziness have been reported following the use of the transdermal patch (Evans & Easthope, 2003).

D) INSOMNIA

1) WITH THERAPEUTIC USE

a) SUBLINGUAL: Insomnia has been reported in 14% (n=107) and 21.4% (n=103) of patients following the use of buprenorphine/naloxone and buprenorphine sublingual tablets, respectively (Prod Info SUBUTEX oral tablets, 2010; Fudala et al, 2003).

E) HALLUCINATIONS

1) WITH THERAPEUTIC USE

a) Central nervous system symptoms of euphoria, hallucinations, dysphoria, and confusion have been reported during therapy, usually in less than 1% of patients (Prod Info buprenorphine hcl injection, 2004; Harcus et al, 1980; Tigerstedt & Tammisto, 1980; Heel et al, 1979).
b) The occurrence of hallucinations has been reported in 5 patients (38 to 58 years of age) following postoperative administration of epidural buprenorphine (total dose, 750 to 1200 mcg). All patients treated received doses of 150 mcg every 6 to 8 hours as required, which is slightly less than the normal postoperative dose. Although parenteral buprenorphine has been associated with a low incidence of hallucinations, these cases suggest that this adverse effect may occur more frequently with the epidural route. The mechanism of these effects is unclear and may involve the high lipid solubility of the drug, resulting in local action at the level of the spinal cord and possibly effects on specific opioid receptors. More investigations are required to support this contention (MacEvilly & O'Carroll, 1989).

F) PSYCHOMOTOR AGITATION

1) WITH POISONING/EXPOSURE

a) CASE SERIES/CHILDREN: According to a retrospective review of buprenorphine overdoses in children younger than 6 years, agitation or irritability occurred in 4 of 86 children (5%) (Hayes et al, 2008).
b) CASE SERIES/CHILDREN: According to a retrospective case review of pediatric unintentional buprenorphine/naloxone exposures (n=9), agitation or irritability occurred in 3 children (younger than 3 years) following ingestion of buprenorphine/naloxone combination tablets (doses ranging from 0.07 to 0.40 mg/kg) (Pedapati & Bateman, 2011).

G) CLOUDED CONSCIOUSNESS

1) WITH POISONING/EXPOSURE

a) CASE SERIES/CHILDREN: According to a retrospective case review of pediatric unintentional buprenorphine/naloxone exposures (n=9), confusion occurred in 3 children (younger than 3 years) following ingestion of buprenorphine/naloxone combination tablets (doses ranging from 0.07 to 0.41 mg/kg) (Pedapati & Bateman, 2011).

H) LEUKOENCEPHALOPATHY

1) WITH POISONING/EXPOSURE

a) CASE REPORT (PEDIATRIC): A 2-year-old child became comatose (Glasgow Coma Scale (GCS) score of 5) with a fever (38.6%), hypertonia, and hyperreflexia after a suspected unintentional ingestion of 2 mg of buprenorphine (one-half of a 4-mg tablet). A brain CT scan without contrast was normal; however, a brain MRI revealed bilateral and symmetrical hypointense signals and hyperintense signals on T1 and T2 weighted images, respectively, with injuries in the white matter of the cerebral hemispheres and the cerebellum. The toxicology screen, obtained on hospital day 4, was positive for buprenorphine. With supportive care, the patient gradually recovered with a GCS score of 15 and a normal EEG, and was subsequently discharged on hospital day 8 (Bellot et al, 2011).
b) CASE REPORT: An 18-year-old man presented to the emergency department comatose with a fever and in respiratory failure, necessitating intubation. Laboratory data indicated leukocytosis and rhabdomyolysis. Serum and urine toxicology screens were positive for benzodiazepines. With supportive care, the patient's condition improved 2 days post-presentation and he was extubated. Five days later, the patient developed spastic quadriparesis, hypertonia, hyperreflexia, and sustained clonus. Brain CT scan and CSF examination were normal; however, a T2 weighted fluid attenuated inversion recovery (FLAIR) MRI of the brain revealed diffuse leukoencephalopathy of the frontal and parietal lobes. Interview of the patient revealed that he had misused benzodiazepines to treat his chronic insomnia and, in addition, he had intravenously injected crushed sublingual buprenorphine tablets into his right external jugular vein on the day of admission.

1) Intense rehabilitation was initiated and, 2 weeks later, a repeat MRI revealed greater areas of T2 and FLAIR hyperintensities with new areas of cystic degeneration. The patient was prescribed oral baclofen therapy and was discharged with improvement in his limb spasticity, but not complete resolution (Seet et al, 2005).

Gastrointestinal

3.8.2)

A) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE

1) WITH THERAPEUTIC USE

a) PARENTERAL: Nausea and/or vomiting have been reported frequently during buprenorphine therapy (up to 15% of patients) (Prod Info buprenorphine hcl injection, 2004; Fullerton et al, 1991; Harcus et al, 1980; Tigerstedt & Tammisto, 1980; Heel et al, 1979). In addition, dry mouth (less than 1%), constipation (less than 1%), loss of appetite, dyspepsia, and flatulence have been reported infrequently (Prod Info buprenorphine hcl injection, 2004).
b) SUBLINGUAL: Nausea and vomiting, constipation, and abdominal pain have been reported in 13.6% (n=103), 7.8%, 7.8%, and 11.7% of patients following the use of buprenorphine sublingual tablets, respectively (Prod Info SUBUTEX oral tablets, 2010; Fudala et al, 2003).
c) Buprenorphine may significantly reduce gastric emptying rate. Eight healthy volunteers were given oral acetaminophen 20 mg/kg with buprenorphine 4 mcg/kg and then alone. The buprenorphine significantly reduced the mean peak serum concentration and the area under the plasma concentration-time curve (Adelhoj et al, 1985).
d) TRANSDERMAL PATCH: Constipation, nausea, and vomiting have been reported following the use of the transdermal patch (Evans & Easthope, 2003).

2) WITH POISONING/EXPOSURE

a) CASE SERIES/CHILDREN: According to a retrospective review of buprenorphine overdoses in children younger than 6 years, vomiting occurred in 18 of 86 children (21%) (Hayes et al, 2008).
b) CASE REPORT: A 71-year-old woman experienced nausea and vomiting and somnolence after applying 4 transdermal 52.5 mcg/hr buprenorphine patches at the same time. Each patch contained 30 mg buprenorphine. Physical examination on admission showed that the patient had miosis, dry mucus membranes, and cyanosis of the lips. Her oxygen saturation was 68%. After repeated administration of naloxone 0.8 mg (total of 3 doses IV and 2 doses subcutaneously), the patient completely recovered (Magdalan & Merwid-Lad, 2008).
c) CASE SERIES/CHILDREN: According to a retrospective case review of pediatric unintentional buprenorphine/naloxone exposures (n=9), vomiting occurred in 4 children (younger than 3 years) following ingestion of buprenorphine/naloxone combination tablets (doses ranging from 0.07 to 0.41 mg/kg) (Pedapati & Bateman, 2011).
d) CASE REPORT/CHILD: A 23-month-old child presented to the emergency department with vomiting and respiratory depression (respiratory rate of 14 breaths/minute). A single episode of red-orange emesis occurred prior to presentation. Although there was no witnessed ingestion, it was suspected that the patient had ingested his mother's tablets containing 8 mg buprenorphine and 2 mg naloxone, due to the color and smell of the emesis. The patient was lethargic with miotic pupils and an oxygen saturation of 93% on room air. After IV administration of 3 bolus doses of naloxone, followed by a naloxone infusion that was continued for 23 hours (total dose 0.68 mg/kg), the patient recovered with no evidence of CNS or respiratory depression. He was discharged 48 hours post-presentation with continued normal development at his 6-month follow up appointment (Swartzentruber et al, 2015).

Hepatic

3.9.2)

A) ABNORMAL LIVER FUNCTION

1) WITH THERAPEUTIC USE

a) Cytolytic hepatitis (fibrosing cholestatic hepatitis) with jaundice, asymptomatic rises in hepatic aminotransferases, hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy have been reported (Prod Info SUBUTEX oral tablets, 2010; Auriacombe et al, 2004; Houdret et al, 1999). However, preexistent liver disease or other factors may have been contributory or causal in this population.

B) HEPATORENAL SYNDROME

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Severe hepatitis associated with acute renal failure and anuria have been reported in a patient following the oral ingestion of 112 mg of buprenorphine as sublingual tablets. The buprenorphine and norbuprenorphine plasma levels were 224 ng/mL and 30 ng/mL, respectively. The patient recovered following discontinuation of buprenorphine therapy and hemodialysis treatment (Houdret et al, 1999).

Genitourinary

3.10.2)

A) HEPATORENAL SYNDROME

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Severe hepatitis associated with acute renal failure and anuria have been reported in a patient following the oral ingestion of 112 mg of buprenorphine as sublingual tablets. The buprenorphine and norbuprenorphine plasma levels were 224 ng/mL and 30 ng/mL, respectively. The patient recovered following discontinuation of buprenorphine therapy and hemodialysis treatment (Houdret et al, 1999).

Dermatologic

3.14.2)

A) EXCESSIVE SWEATING

1) WITH THERAPEUTIC USE

a) SUBLINGUAL: Increased sweating has been reported in 14.0% (n=107) and 12.6% (n=103) of patients following the use of buprenorphine/naloxone and buprenorphine sublingual tablets, respectively (Prod Info SUBUTEX oral tablets, 2010; Fudala et al, 2003).
b) PARENTERAL: Increased sweating has been reported in 1% to 5% (n=1133) of patients (Prod Info buprenorphine hcl injection, 2004).

2) WITH POISONING/EXPOSURE

a) CASE SERIES/CHILDREN: In retrospective case review of pediatric unintentional buprenorphine/naloxone exposures (n=9), diaphoresis occurred in 2 children (younger than 3 years) following ingestion of buprenorphine/naloxone combination tablets (doses ranging from 0.18 to 0.29 mg/kg) (Pedapati & Bateman, 2011).

B) ERYTHEMA

1) WITH THERAPEUTIC USE

a) TRANSDERMAL PATCH: Transient erythema and pruritus have been reported following the use of the transdermal patch (Evans & Easthope, 2003).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: An 11-year-old boy presented to the emergency department of a community hospital minimally responsive. The patient's vital signs revealed a heart rate of 124 bpm, respiratory rate of 20/minute, blood pressure of 125/75 mmHg, and an oxygen saturation of 98% on non-rebreather mask oxygen supplementation. His Glasgow Coma Scale score was 9 and "bruising" was observed on his extremities. Home medications accessible to the patient included aripiprazole, citalopram, zolpidem, cyclobenzaprine, loratadine, cetirizine, and buprenorphine. Following intubation, the patient was transferred to a children's hospital. Repeat vital sign measurements indicated a heart rate of 124 bpm, respiratory rate of 17/minute on ventilator, blood pressure of 87/48 mmHg, and an O2 sat of 100%. Physical exam noted elbow and knee swelling with bullae and erythematous patches on his face and extremities, referred to as "coma bullae". With supportive care, the patient improved and he was extubated the next day. Comprehensive drug screening was positive for buprenorphine and norbuprenorphine (Henretig & Bassett, 2015).

C) DERMATITIS

1) WITH POISONING/EXPOSURE

a) LIVEDOID DERMATITIS

1) SUMMARY: Necrotic livedoid dermatitis has been reported in several patients following intra-arterial injections of crushed and solubilized buprenorphine tablets. Papulo-pustular, purpuric and necrotic lesions with cyanosis have been observed in the upper and lower extremities, with reports of an intense burning pain at the injection site. Onset of lesions has ranged from a few hours following injection up to several days later (Wainstein et al, 2015; Del Giudice et al, 2005). In some instances, biopsies of the skin have demonstrated the presence of foreign bodies (eg, magnesium stearate, talc, anhydrous silica, corn starch) that are insoluble excipients of the buprenorphine tablets, and are suggested to be a contributory factor to the livedoid dermatitis (Wainstein et al, 2015; Schneider et al, 2010; Pierre-Alexandre et al, 2007).
2) CASE REPORT: A 34-year-old man, with a history of IV drug abuse, presented with a 1- to 2-day history of rash, pain, and edema in his heels. The rash initially appeared on his left heel and progressed to his right heel symmetrically. Interview of the patient revealed that, prior to onset of signs and symptoms, he had been injecting buprenorphine into his posterior tibial veins. Physical examination indicated a purpuric mottled erythema that blanched, and residual petechiae on his heels and plantar arches. Despite administration of clindamycin empirically, the rash progressed, over the next 3 days, with increased pain and swelling, with no evidence of infection (ie, no fever, no leukocytosis, and negative blood cultures), suggesting a diagnosis of livedoid dermatitis believed to be secondary to buprenorphine injection. With local vasospasm as the suspected mechanism for the dermatitis, a trial of nifedipine was initiated. Over the next 2 days, the patient's signs and symptoms improved and he was discharged with follow-up appointments scheduled; however, he was subsequently lost to follow-up (Wheless et al, 2016).
3) A study was conducted to evaluate the differences in particulates between trade name (Subutex(R)) and generic buprenorphine solutions that could help to explain the cutaneous complications that have been reported following injection of buprenorphine solutions, with livedoid dermatitis occurring primarily following injection of generic buprenorphine solutions. Utilizing the same method of preparation of the buprenorphine solutions that would be used by injected buprenorphine users, the generic and the Subutex(R) tablets were crushed in sterile water, and 6 different solutions were obtained for comparison: non-filtered Subutex (NFS), cotton filtered Subutex (CFS ), sterifilt-filtered Subutex (SFS), non-filtered generic (NFG), cotton-filtered generic (CFG), and sterifilt-filtered generic (SFG). The solutions were then analyzed via laser granulometry, flow cytometry, and scanning electron microscopy. Subutex(R) contained only magnesium stearate as the insoluble excipient and the generic formulation contained 3 insoluble excipients: magnesium stearate, talc, and colloidal anhydrous silica. According to analysis of the solutions via flow cytometry, approximately 76% of the NFG solution contained particles less than 4.2 mcM compared to approximately 56% of the NFS solution which contained particles greater than 4.2 mcM. After filtration, there were a greater number of particles less than 10 mcM in the generic solution compared to the Subutex(R) solution. Particle analysis demonstrated the presence of silica as the predominant non-organic insoluble particle in the majority of CFG solutions (Bouquie et al, 2014).

Musculoskeletal

3.15.2)

A) BACKACHE

1) WITH THERAPEUTIC USE

a) SUBLINGUAL: Back pain has been reported in 3.7% (n=107) and 7.8% (n=103) of patients following the use of buprenorphine/naloxone and buprenorphine sublingual tablets, respectively (Prod Info SUBUTEX oral tablets, 2010; Fudala et al, 2003).

B) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORTS: Two former heroin users presented with pain and weakness of the lower extremities 2 to 3 days after intravenously injecting crushed sublingual buprenorphine tablets into peripheral veins, daily over a 2- to 5-month period. One of the 2 patients also injected into the right femoral vein. Clinical examination of both patients showed weakness of the ankle plantar flexion, foot extension, and eversion and toe extension. Laboratory analyses revealed rhabdomyolysis with creatine kinase levels ranging from 24,918 to greater than 32,000 units/liter (normal, 30 to 350), serum myoglobin levels of 14,840 to 16,500 ng/mL (normal, 16 to 96), leukocytosis of 11 to 16.58 x 10(9)/L (normal 3.20 to 8.90), and C-reactive protein levels of 3.6 to 10.6 mg/dL (normal, 0 to 1). The MRIs of both patients showed muscular abnormalities including diffuse swelling of the right thigh muscles and irregular enhancement of the muscles within the vastus lateralis, adductor magnus, and gluteus maximus. Nerve conduction studies revealed sciatic neuropathy. Both patients recovered with supportive care (Seet & Lim, 2006).

Immunologic

3.19.2)

A) ACUTE ALLERGIC REACTION

1) WITH THERAPEUTIC USE

a) Hypersensitivity phenomena, including hives, rash, pruritus, bronchospasm, angioneurotic edema, and anaphylaxis have been reported in patients following the buprenorphine therapy in some studies and during postmarketing surveillance (Prod Info SUBUTEX oral tablets, 2010).
b) Acute lung injury (noncardiogenic pulmonary edema) with respiratory depression is reported in a 21-year-old woman within 90 minutes of a 0.2 mg sublingual dose. An allergic/hypersensitivity reaction was suspected in this case (Thammakumpee & Sumpatanukule, 1994).

Reproductive

3.20.1)

A) The buprenorphine/naloxone combination is classified as FDA pregnancy category C. The use of narcotic analgesics, including buprenorphine, during pregnancy is generally associated with fetal adverse effects including neonatal abstinence syndrome (NAS), physical dependence and withdrawal, growth retardation, and, with high doses, neonatal respiratory depression. Due to the lack of adequate well-controlled studies in pregnant women and the potential for NAS, it is recommended that buprenorphine be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus. Buprenorphine is excreted into breast milk; however, the amount received by the infant varies according to the maternal plasma concentration, amount of milk ingested, and extent of first-pass metabolism. Withdrawal symptoms can occur in breastfed infants when the maternal administration of an opioid or breastfeeding is stopped. Because the potential for adverse reactions in the nursing infant exists, it is recommended that breastfeeding or buprenorphine be discontinued upon consideration of the mother's need for treatment.

3.20.2)

A) HEAD CIRCUMFERENCE

1) A retrospective study that evaluated early growth and developmental outcome of infants with in-utero exposure to high-dose methadone (100 mg or higher per day), low dose-methadone (less than 100 mg/day), and buprenorphine, reported lower head circumference z-scores in infants prenatally exposed to methadone doses greater than 100 mg at 3 to 5 months of age. This finding can have a negative impact on motor skill development during early infancy (Bier et al, 2015).

B) ANIMAL STUDIES

1) RATS, RABBITS: Buprenorphine was not teratogenic in rats and rabbits after the oral administration of 190 and 60 times the human daily sublingual dose on a mg/m(2) basis, respectively, nor was it teratogenic after the subcutaneous administration of doses of approximately 18 and 21 times, respectively, the maximum recommended human dose on an AUC basis, the IM administration of doses approximately 6 and 12 times the human daily sublingual dose, respectively, or the IV administration of doses 1 and 2 times the human daily sublingual dose on a mg/m(2) basis. However, increases in skeletal abnormalities including extrathoracic vertebra and thoracolumbar ribs were seen in rats after the subQ administration of approximately 5 times the maximum recommended human dose on an AUC basis but not after the oral administration of oral doses 194 times the human daily sublingual dose on a mg/m(2) basis (Prod Info PROBUPHINE(R) subdermal implant, 2016).
2) RATS, RABBITS: Teratogenicity was not observed at oral buprenorphine doses up to approximately 150 and 50 times, respectively, the recommended human daily sublingual dose of 16 mg on a mg/m basis. Teratogenicity was also not observed at IM buprenorphine doses in rats and rabbits approximately 20 and 35 times, respectively, the recommended human daily sublingual dose of 16 mg on a mg/m basis (Prod Info SUBOXONE(R) sublingual film, 2014; Prod Info ZUBSOLV(R) sublingual tablets, 2014; Prod Info BUNAVAIL(TM) buccal film, 2014).
3) RATS, RABBITS: Teratogenicity was not observed at IM or subQ buprenorphine doses in rats and rabbits approximately 3 and 6 times the recommended human daily sublingual dose of 16 mg based on surface area, respectively, IV buprenorphine doses approximately 0.5 times and equal to the recommended human dose, respectively, and oral doses approximately 95 and 30 times the recommended human dose, respectively (Prod Info SUBOXONE(R) sublingual film, 2014). There was also no evidence of teratogenicity when rats or rabbits were exposed to transdermal buprenorphine doses of up to one (rats) or four (rabbits) patches every 3 days (approximately 110 times the AUC based on the maximum recommended human dose [MRHD] of 20 mcg/hr) and subQ buprenorphine up to approximately 140 times the AUC based on the MRHD (Prod Info BUTRANS(R) transdermal system patch, 2014).
4) RATS, RABBITS: When rats were administered subQ buprenorphine doses of approximately 0.6 times the recommended human daily dose, significant increases in skeletal abnormalities (eg, extrathoracic vertebrae or ribs) were noted; however, these effects were not observed at oral doses up to 160 mg/kg/day. When rabbits were treated with daily IM doses approximately 6 times and equal to the recommended human dose, respectively, skeletal abnormalities were observed; however, the increase was not clinically significant (Prod Info SUBOXONE(R) sublingual film, 2014).

3.20.3)

A) PREGNANCY CATEGORY

1) Buprenorphine is classified as FDA pregnancy category C (Prod Info BUTRANS(R) transdermal system patch, 2014; Prod Info buprenorphine hcl injection, 2004).
2) Buprenorphine/naloxone is classified as FDA pregnancy category C (Prod Info BUNAVAIL(TM) buccal film, 2014; Prod Info ZUBSOLV(R) sublingual tablets, 2014; Prod Info SUBOXONE(R) sublingual film, 2014).
3) The use of narcotic analgesics, including buprenorphine, during pregnancy is generally associated with fetal adverse effects including neonatal abstinence syndrome (NAS), physical dependence and withdrawal, retardation of growth, and, with high doses, neonatal respiratory depression (Hytinantti et al, 2008; Lee, 1994; Cunningham et al, 1993). Due to the lack of adequate well-controlled studies in pregnant women and the potential for NAS, it is recommended that buprenorphine be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. If buprenorphine is required for a prolonged period in a pregnant woman, monitor the newborn for opioid withdrawal syndrome. Buprenorphine should not be used in women during and immediately before labor; shorter-acting analgesics or other analgesic techniques are more appropriate (Prod Info ZUBSOLV(R) sublingual tablets, 2014; Prod Info BUTRANS(R) transdermal system patch, 2014; Prod Info SUBOXONE(R) sublingual film, 2014; Prod Info buprenorphine hcl injection, 2004). However, the American College of Obstetricians and Gynecologists recommends that buprenorphine treatment be considered for opioid dependence during pregnancy, although methadone therapy is the standard of care (ACOG Committee on Health Care for Underserved Women & American Society of Addiction Medicine, 2012).
4) SUBDERMAL IMPLANT: No adequate and well-controlled studies have examined the use of buprenorphine subdermal implant during pregnancy. However, neonatal opioid withdrawal syndrome reportedly occurred in the offspring of women treated with buprenorphine sublingual tablets during pregnancy (Prod Info PROBUPHINE(R) subdermal implant, 2016).

B) NEONATAL OPIOID WITHDRAWAL SYNDROME

1) Prolonged use of opioids during pregnancy may cause neonatal opioid withdrawal syndrome, a life-threatening syndrome if not recognized and treated. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity, abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Therefore, it is recommended that buprenorphine be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus (Prod Info PROBUPHINE(R) subdermal implant, 2016; Prod Info BELBUCA(TM) buccal film, 2015; Prod Info BUNAVAIL(TM) buccal film, 2014; Prod Info BUTRANS(R) transdermal system patch, 2014)
2) Neonatal withdrawal symptoms have been reported in infants born to mothers who received buprenorphine during pregnancy, usually on the first day after birth (range, day 1 to day 8). Symptoms have included tremor, agitation, myoclonus, and hypertonia. Seizures, apnea, respiratory depression, and bradycardia have also been reported (Prod Info PROBUPHINE(R) subdermal implant, 2016; Prod Info BELBUCA(TM) buccal film, 2015; Prod Info BUTRANS(R) transdermal system patch, 2014; Prod Info BUNAVAIL(TM) buccal film, 2014; Prod Info SUBOXONE(R) sublingual film, 2014; Prod Info ZUBSOLV(R) sublingual tablets, 2014).

C) RESPIRATORY DEPRESSION

1) Neonatal respiratory depression has been reported among infants born to women treated with buprenorphine during labor. Buprenorphine should not be used in women during or immediately before labor; shorter-acting analgesics or other analgesic techniques are more appropriate (Prod Info PROBUPHINE(R) subdermal implant, 2016; Prod Info BELBUCA(TM) buccal film, 2015; Prod Info BUNAVAIL(TM) buccal film, 2014; Prod Info ZUBSOLV(R) sublingual tablets, 2014; Prod Info BUTRANS(R) transdermal system patch, 2014)

D) NEONATAL ABSTINENCE SYNDROME

1) A prospective study of buprenorphine use in 67 pregnancies of 66 women demonstrated lower birth weight, an increased need for neonatal care unit treatment, and a greater incidence of neonatal abstinence syndrome (NAS), morphine replacement therapy, and sudden infant death syndrome (SIDS) compared with the general population (n=57,759). Buprenorphine dose was initiated at 2 to 4 mg/day and increased up to 12 mg/day based on individual need. Buprenorphine dose decreased by a median 2.3 mg/day (range, 8-mg increase to 24-mg decrease/day). Compared with the national register, the incidence of neonatal care unit admission was greater in the study group (91% vs 10.6%) and birth weight was significantly lower (3180 g vs 3512 g; p less than 0.01). NAS and morphine replacement therapy occurred in 51 (76%) and 38 (57%), respectively, of the 67 pregnancies. Two cases of SIDS were reported in the study group (3%) compared with 0.19/1000 live births in the general population yielding a 150 times higher incidence of SIDS in the study group. Both cases of SIDS corresponded to women with compliance problems. The incidences of premature birth, cesarean section, low Apgar scores (6 or lower), and umbilical artery pH less than 7.05 were similar to the national register (Kahila et al, 2007).
2) A double-blind, double-dummy, flexible-dosing, randomized controlled study of 131 pregnant women exposed to buprenorphine or methadone (n=58 and n=73, respectively) did not demonstrate a significant difference in the percentage of neonates requiring neonatal abstinence syndrome (NAS) treatment, peak NAS scores, or neonate head circumference between treatment groups. There was an 89% decrease in the total amount of morphine required to treat NAS in neonates exposed to buprenorphine compared with neonates exposed to methadone. In addition, neonates exposed to buprenorphine spent a mean 43% less time in the hospital than neonates exposed to methadone. The significance of the results did not vary when the analysis was adjusted for selected covariates. An analysis of secondary outcomes revealed that neonates exposed to buprenorphine required an average of 58% less time in the hospital receiving treatment for NAS than neonates exposed to methadone. There were no significant differences between the 2 treatment groups in the incidence of maternal and/or neonatal adverse effects (Jones et al, 2010).
3) In a prospective cohort study of pregnant women enrolled in Norwegian opioid maintenance treatment programs (n=38), neither the incidence of neonatal abstinence syndrome (NAS) nor the duration of NAS treatment was associated with the maternal dose of methadone (n=26) or buprenorphine (n=12). NAS was reported in 58% and 67% of infants following maternal methadone and buprenorphine use, respectively. NAS treatment lasted for a mean 43 and 37 days in the methadone- and buprenorphine-exposed groups, respectively. The maternal daily dose of methadone and buprenorphine (mean 90 mg and 13.3 mg, respectively, before delivery) did not significantly correlate with duration of NAS treatment (p=0.054 and p=0.31, respectively). There were also no significant differences in occurrence (p=0.73) or duration (p=0.64) of NAS treatment between the methadone and buprenorphine groups (Bakstad et al, 2009).
4) In a systematic review of 21 published reports of buprenorphine exposure during pregnancy that included 15 evaluable cohorts (n=309), neonatal abstinence syndrome (NAS) was reported in 193 infants (62%), while 149 required treatment (48%). The review included 14 case reports, 5 prospective studies, and 2 open-label studies. The onset of NAS generally occurred in the first 12 to 48 hours of life, peaked at 72 to 96 hours, and lasted 120 to 168 hours (Johnson et al, 2003).
5) A prospective study of 58 neonates exposed in utero to maternal buprenorphine demonstrated a greater incidence of neonatal abstinence syndrome (NAS) requiring morphine treatment and long-term hospitalization when born to compliant mothers (ie, attended at least 50% of prenatal visits; n=28) compared to noncompliant mothers (n=30). Buprenorphine was started at a median 13.5 weeks of gestation with a median 5-mg buprenorphine dose on the day of delivery. Duration of hospital stay was 28 and 19 days for infants from the compliant and noncompliant groups, respectively (p=0.012). Among the 38 infants requiring morphine, treatment duration was 20 days with a mean age of 2.4 days at morphine initiation and mean initial dose of 0.34 mg/kg/day. Length of morphine treatment was 18 and 10 days for infants from the compliant and noncompliant groups, respectively (p=0.009). A high mean and single high Finnegan score on day 0 correlated with morphine treatment duration (p less than 0.01 and less than 0.05, respectively). High mean Finnegan scores on days 1 and 2 correlated with duration of hospital stay (p less than 0.05). Buprenorphine IV use resulted in a higher single and mean Finnegan score than sublingual use (p=0.003 and 0.002, respectively). At least 1 urine sample from each infant collected on day 0, 1, or 2 was positive for buprenorphine. Urinary norbuprenorphine concentrations on day 1 (n=29) correlated with length of hospital stay (Pearson's correlation, r=0.496; p=0.006) but not with duration of morphine treatment. Intergroup differences in gestational age, birth measurements, and newborn variables were not significant. Upon hospital discharge, the infants were sent home (n=11), placed in foster care (n=19), or sent with their mothers to care facilities (n=28) (Hytinantti et al, 2008).
6) NAS was absent or mild in 12 of 15 neonates born to opioid-dependent women who were maintained on buprenorphine during the latter part of pregnancy (mean treatment period, 12 weeks). During treatment, 91% of the mothers' urine tests were negative for opioids (Fischer et al, 2000).
7) When 13 retrospective cases of buprenorphine exposure in utero were compared with 11 prospective cases, the frequency of neonatal withdrawal syndrome was 63% and 69%, respectively. However, the prospective cases also received medical and psychosocial support and, as a group, showed fewer complications than those reviewed retrospectively. Prematurity, fetal growth retardation, and acute fetal distress occurred with greater frequency in the retrospective group (Jernite et al, 1999).
8) CASE SERIES: Of 34 pregnancies in which the women were treated with buprenorphine for opioid addiction, there were 31 live births, 1 still birth, 1 spontaneous abortion, and 1 voluntary termination of pregnancy. NAS was observed in 13 (41.9%) patients, 8 of whom required opioid treatment. Two of the infants had malformations (premature ductus arteriosus stricture and tragus appendix). Overall, the authors believed that buprenorphine may be a safe option for opioid addiction maintenance therapy during pregnancy; however, further investigations are warranted (Lacroix et al, 2004).
9) CASE SERIES: Eleven of 13 neonates developed NAS after the maternal administration of buprenorphine during pregnancy. Ten of the 11 neonates required treatment. Morphine chlorohydrate 0.5 mg/kg/day was used in 7 cases and showed better results than morphine alone or in combination with diazepam. Seven infants had motor abnormalities (lower-limb hypotonia, jerky movements, and jitteriness) that resolved in 3 to 6 months (Kayemba-Kay's & Laclyde, 2003).
10) CASE REPORT: Buprenorphine was used to prevent withdrawal at 4 months of gestation in a heroin-dependent pregnant woman. After continuing buprenorphine 4 mg/day throughout pregnancy, she gave birth at 39 weeks to an apparently normal female. Approximately 48 hours after birth, the infant developed mild withdrawal syndrome (agitation, sleep disorders, tremor, yawning, noisy breathing, and slight fever) (Marquet et al, 1997).

E) ANIMAL STUDIES

1) RABBITS: Buprenorphine administration resulted in statistically significant preimplantation losses at oral doses approximately 2 times the human daily sublingual daily dose on a mg/m(2) basis and statistically significant postimplantation losses at IV doses approximately 0.5 times the human daily sublingual dose on a mg/m(2) basis (Prod Info PROBUPHINE(R) subdermal implant, 2016).
2) RATS: Maternal toxicity, an increase in the number of stillbirths, decreased litter size, and decreased offspring growth were noted when pregnant rats were exposed to one-fourth of one 5-mcg/hr transdermal patch every 3 days or subQ daily doses approximately 10 times that of humans after the administration of one 20-mcg/hr transdermal patch from gestation day 6 to lactation day 21. There was also evidence of maternal toxicity when no adverse effects were noted in the offspring (Prod Info BUTRANS(R) transdermal system patch, 2014).
3) RABBITS: When rabbits were treated with oral and IV buprenorphine doses approximately equal and 0.3 times the recommended human dose, respectively, significant pre- and postimplantation losses, respectively, were reported (Prod Info SUBOXONE(R) sublingual film, 2014).
4) RATS, RABBITS: In rats, dose-related postimplantation losses, evidenced by increased numbers of early resorptions and consequent reductions in number of fetuses, were observed at oral buprenorphine doses approximately 6 times the recommended human daily sublingual dose of 16 mg on a mg/m basis. In rabbits, postimplantation losses were observed at oral buprenorphine doses of 40 mg/kg/day. In both rats and rabbits, IM buprenorphine doses of 30 mg/kg/day caused postimplantation losses (Prod Info SUBOXONE(R) sublingual film, 2014; Prod Info ZUBSOLV(R) sublingual tablets, 2014; Prod Info BUNAVAIL(TM) buccal film, 2014).
5) RATS: Dystocia was observed in pregnant rats treated with IM buprenorphine doses approximately 6 times the recommended human dose. Increased neonatal mortality rates were noted in rats treated with oral, IM, and subQ doses approximately equivalent, 0.6 times, and approximately equivalent to the recommended human dose, respectively. In pregnant rats, oral doses approximately 97 times the recommended human dose resulted in delayed righting reflexes and startle responses in pups (Prod Info PROBUPHINE(R) subdermal implant, 2016).

3.20.4)

A) BREAST MILK

1) Buprenorphine is excreted into breast milk (Prod Info PROBUPHINE(R) subdermal implant, 2016; Prod Info BELBUCA(TM) buccal film, 2015; Prod Info BUNAVAIL(TM) buccal film, 2014; Prod Info ZUBSOLV(R) sublingual tablets, 2014); however, the amount received by the infant varies according to the maternal plasma concentration, amount of milk ingested by the infant, and extent of first-pass metabolism. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid or breastfeeding is stopped. Because the potential for adverse reactions in the nursing infant exists, it is recommended that breastfeeding or buprenorphine be discontinued upon consideration of the mother's need for treatment (Prod Info PROBUPHINE(R) subdermal implant, 2016; Prod Info BELBUCA(TM) buccal film, 2015; Prod Info BUTRANS(R) transdermal system patch, 2014; Prod Info SUBOXONE(R) sublingual film, 2014; Prod Info buprenorphine hcl injection, 2004).
2) An open observational study of 7 opiate-addicted women who became pregnant during a buprenorphine maintenance program revealed that breastfeeding newborns exposed to buprenorphine and norbuprenorphine may be compatible. Urine samples collected from 6 infants were analyzed together with breast milk, blood, and urine samples from their mothers during a 24-hour period 1 week after birth. Low levels of buprenorphine and norbuprenorphine were found in the infants' urine (less than 1.5 nanomole/L). Breast milk AUC varied in buprenorphine from 0.06 to 0.2 mg hour/L and in norbuprenorphine from 0.03 to 0.15 mg hour/L; plasma AUC varied in buprenorphine from 0.03 to 0.1 mg hour/L and in norbuprenorphine from 0.06 to 0.22 mg hour/L. Breastfed infants were exposed to a calculated buprenorphine dose per kilogram of body weight of less than 1%, with an average milk/plasma AUC of 1.7 for buprenorphine and 0.7 for norbuprenorphine. One mother and infant pair had buprenorphine and norbuprenorphine levels drawn at 9 months, and the results showed a drug distribution pattern consistent with earlier findings (Lindemalm et al, 2009).
3) When a nursing mother is treated with buprenorphine, the potential risks to the nursing infant include CNS depression and subsequent decreased weight gain (Schaefer, 2001).
4) One report described 10 mothers administered extradural buprenorphine plus bupivacaine for cesarean delivery at term whose nursing infants ingested significantly less milk per day than the control infants. The mothers received the extradural medications for 3 days following delivery. By day 7, the infants' daily weights as a percentage of birth weight were also decreased (Hirose et al, 1997).
5) Based upon samples from a single mother-child pair, the daily infant ingestion of buprenorphine was only 3.28 mcg from a lactating mother receiving buprenorphine 4 mg daily (Marquet et al, 1997a).
6) If a patient chooses to breastfeed her infant while undergoing buprenorphine treatment, she should be advised of the possible risks to her infant. When administered a single dose as epidural anesthesia during labor, buprenorphine appears to have little effect on breastfeeding or the nursing infant (Schaefer, 2001).

B) ANIMAL STUDIES

1) RATS: During reproduction studies with buprenorphine in rats, an evident lack of milk production resulted in reduced viability and lactation indices (Prod Info PROBUPHINE(R) subdermal implant, 2016; Prod Info SUBOXONE(R) sublingual film, 2014).
2) RATS: Buprenorphine was present in the milk of lactating rats following transdermal or subQ buprenorphine doses in a peri- and postnatal study (Prod Info BUTRANS(R) transdermal system patch, 2014).

3.20.5)

A) ANIMAL STUDIES

1) RATS: The dietary administration of buprenorphine at doses equivalent to approximately 22 times the highest human daily dose on an AUC basis resulted in reduced female conception rates, whereas the dietary administration of approximately 18 times the recommended human daily dose had no adverse effects (Prod Info PROBUPHINE(R) subdermal implant, 2016). Reduced female conception rates occurred with dietary administration of buprenorphine at doses approximately 28 times the recommended human daily dose of 16 mg on a mg/m(2) basis. Impaired fertility was not evident with a dietary dose approximately 6 times the recommended human daily dose of 16 mg on a mg/m(2) basis (Prod Info PROBUPHINE(R) subdermal implant, 2016; Prod Info SUBOXONE(R) sublingual film, 2014). There was also no evidence of impaired fertility when transdermal buprenorphine was administered at a dose of one-fourth of a 5-mcg/hr patch, one 5-mcg/hr patch, or one 20-mcg/hr patch every 3 days in males for 4 weeks prior to mating for a total of 10 weeks and in females for 2 weeks before mating through gestation day 7 (approximately 65 times [females] and 100 times [males] the maximum recommended human dose of 20 mcg/hr) (Prod Info BUTRANS(R) transdermal system patch, 2014).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS52485-79-7 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs, respiratory effort, and mental status.
B) Monitor arterial blood gases, serum electrolytes, and renal function in patients with severe poisoning.
C) Obtain a chest x-ray in patients with clinical evidence of pulmonary edema.
D) Routine urine toxicology opioid assays generally do not detect buprenorphine.

4.1.2)

A) Monitor arterial blood gases, serum electrolytes, and renal function in patients with severe poisoning.
B) OTHER

1) Buprenorphine exhibited extensive tissue distribution, with the highest levels found in the bile. The authors suggest that bile may be the sample of choice for postmortem screening (Tracqui et al, 1998a).

4.1.4)

A) OTHER

1) MONITORING

a) Monitor vital signs, respiratory effort, and mental status.

2) CHEST RADIOGRAPH

a) Obtain a chest x-ray in patients with clinical evidence of pulmonary edema.

Methods

A)

B)

C)

D)

E)

F)

G)

H)

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) All symptomatic patients should be admitted. Patients with significant persistent CNS depression or those with respiratory depression or hypotension should be admitted to an intensive care setting. Patients requiring multiple doses of naloxone or those who are on a naloxone infusion should be admitted to an intensive care setting.

6.3.1.2) HOME CRITERIA/ORAL

A) There is no role for home management of inadvertent buprenorphine ingestion in children, as significant toxicity has resulted after ingestion of half a tablet (Hayes et al, 2008).

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (coma, severe CNS depression, respiratory failure or severe hypotension), or in whom the diagnosis is not clear.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with deliberate ingestions or children with any ingestion should be referred to a healthcare facility for observation. All symptomatic patients should be sent to a healthcare facility for observation. All patients should be monitored for a minimum of 12 to 24 hours due to the potential for delayed or recurrent respiratory and CNS depression.

Monitoring

A)

B)

C)

D)

Oral Exposure

6.5.1)

A) Prehospital decontamination is not recommended because of the potential for CNS depression.

6.5.2)

A) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.3)

A) MONITORING OF PATIENT

1) Monitor vital signs, respiratory effort, and mental status.
2) Monitor arterial blood gases, serum electrolytes, and renal function in patients with severe poisoning.
3) Obtain a chest x-ray in patients with clinical evidence of pulmonary edema.
4) Routine urine toxicology opioid assays generally do not detect buprenorphine.

B) NALOXONE

1) Although the manufacturer has reported that high doses of naloxone hydrochloride, 10 to 35 mg/70 kg may be of limited value in the management of buprenorphine overdose, high doses of naloxone have been used to reverse respiratory depression induced by buprenorphine (Prod Info SUBUTEX oral tablets, 2010; Gal, 1989; Jasinski et al, 1978; Cho et al, 2006).
2) In one study, using healthy volunteers, naloxone 1 milligram intravenously produced minimal effects on respiratory depression induced by buprenorphine 0.3 milligram/70 kilograms intravenously. Doses of 5 milligrams and 10 milligrams intravenously did, however, produce consistent reversal of respiratory depression; more complete reversal was observed with the 10-milligram dose. Reversal effects were not observed during the first 30 minutes post-administration, which is in contrast to reversal effects observed with respiratory depression due to other opioids. Reversal effects were maximal after 3 hours. It is thought that the limited efficacy of naloxone is related to the strong affinity of buprenorphine for the opioid-receptor binding site, and the relative inability of naloxone to displace the drug from these sites (Gal, 1989).
3) In a pediatric series, usual doses of naloxone (0.4 to 0.8 mg) were effective; although several patients required repeated doses of naloxone infusion for recurrent CNS and respiratory depression (Geib et al, 2006).
4) CASE REPORT: A 71-year-old woman required repeated administration of naloxone 0.8 mg (total of 3 doses IV and 2 doses subcutaneously) after developing recurrent somnolence, miosis, and a decrease in oxygen saturation following application of 4 transdermal buprenorphine patches at the same time (Magdalan & Merwid-Lad, 2008).
5) CASE REPORT/CHILD: A 23-month-old child presented to the emergency department with vomiting and respiratory depression following a suspected ingestion of 8 mg/2 mg buprenorphine/naloxone tablets of an unknown amount. The patient was lethargic with miotic pupils and an oxygen saturation of 93% on room air. He was initially given 3 0.4-mg doses of IV naloxone, resulting in increased alertness and respirations. A naloxone infusion was then initiated at a dose of 0.06 mg/hour. Approximately 15 minutes after beginning the infusion, somnolence and bradypnea recurred, necessitating an increase in the infusion to 0.2 mg/hour (0.015 mg/kg). Because of continued somnolence and respiratory depression, the infusion was increased to 0.04 mg/kg/hour for 10 hours, then was tapered to 0.02 mg/kg/hour for 3 hours, then 0.01 mg/kg/ hour for 7 hours. Following a total infusion time of 23 hours, and a total naloxone dose of 0.68 mg/kg, the patient was alert with no evidence of CNS or respiratory depression. He was discharged 48 hours after admission with continued normal development at his 6-month follow-up appointment (Swartzentruber et al, 2015).
6) NALOXONE/SUMMARY

a) Naloxone, a pure opioid antagonist, reverses coma and respiratory depression from all opioids. It has no agonist effects and can safely be employed in a mixed or unknown overdose where it can be diagnostic and therapeutic without risk to the patient.
b) Indicated in patients with mental status and respiratory depression possibly related to opioid overdose (Hoffman et al, 1991).
c) DOSE: The initial dose of naloxone should be low (0.04 to 0.4 mg) with a repeat dosing as needed or dose escalation to 2 mg as indicated due to the risk of opioid withdrawal in an opioid-tolerant individual; if delay in obtaining venous access, may administer subcutaneously, intramuscularly, intranasally, via nebulizer (in a patient with spontaneous respirations) or via an endotracheal tube (Vanden Hoek,TL,et al).
d) Recurrence of opioid toxicity has been reported to occur in approximately 1 out of 3 adult ED opioid overdose cases after a response to naloxone. Recurrences are more likely with long-acting opioids (Watson et al, 1998)

7) NALOXONE DOSE/ADULT

a) INITIAL BOLUS DOSE: Because naloxone can produce opioid withdrawal in an opioid-dependent individual leading to severe agitation and hypertension, the initial dose of naloxone should be low (0.04 to 0.4 mg) with a repeat dosing as needed or dose escalation to 2 mg as indicated (Vanden Hoek,TL,et al).

1) This dose can also be given intramuscularly or subcutaneously in the absence of intravenous access (Howland & Nelson, 2011; Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008; Maio et al, 1987; Wanger et al, 1998).

b) Larger doses may be needed to reverse opioid effects. Generally, if no response is observed after 8 to 10 milligrams has been administered, the diagnosis of opioid-induced respiratory depression should be questioned (Howland & Nelson, 2011; Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008). Very large doses of naloxone (10 milligrams or more) may be required to reverse the effects of a buprenorphine overdose (Gal, 1989; Jasinski et al, 1978).

1) Single doses of up to 24 milligrams have been given without adverse effect (Evans et al, 1973).

c) REPEAT DOSE: The effective naloxone dose may have to be repeated every 20 to 90 minutes due to the much longer duration of action of the opioid agonist used(Howland & Nelson, 2011).

1) OPIOID DEPENDENT PATIENTS: The goal of naloxone therapy is to reverse respiratory depression without precipitating significant withdrawal. Starting doses of naloxone 0.04 mg IV, or 0.001 mg/kg, have been suggested as appropriate for opioid-dependent patients without severe respiratory depression (Howland & Nelson, 2011). If necessary the dose may be repeated or increased gradually until the desired response is achieved (adequate respirations, ability to protect airway, responds to stimulation but no evidence of withdrawal) (Howland & Nelson, 2011). In the presence of opioid dependence, withdrawal symptoms typically appear within minutes of naloxone administration and subside in about 2 hours. The severity and duration of the withdrawal syndrome are dependant upon the naloxone dose and the degree and type of dependence.(Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008)
2) PRECAUTION should be taken in the presence of a mixed overdose of a sympathomimetic with an opioid. Administration of naloxone may provoke serious sympathomimetic toxicity by removing the protective opioid-mediated CNS depressant effects. Arrhythmogenic effects of naloxone may also be potentiated in the presence of severe hyperkalemia (McCann et al, 2002).

d) NALOXONE DOSE/CHILDREN

1) LESS THAN 5 YEARS OF AGE OR LESS THAN 20 KG: 0.1 mg/kg IV/intraosseous/IM/subcutaneously maximum dose 2 mg; may repeat dose every 2 to 5 minutes until symptoms improve (Kleinman et al, 2010; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008)
2) 5 YEARS OF AGE OR OLDER OR GREATER THAN 20 KG: 2 mg IV/intraosseous/IM/subcutaneouslymay repeat dose every 2 to 5 minutes until symptoms improve (Kleinman et al, 2010; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Krauss & Green, 2006). Although naloxone may be given via the endotracheal tube for pediatric resuscitation, optimal doses are unknown. Some experts have recommended using 2 to 3 times the IV dose (Kleinman et al, 2010)
3) AVOIDANCE OF OPIOID WITHDRAWAL: In cases of known or suspected chronic opioid therapy, a lower dose of 0.01 mg/kg may be considered and titrated to effect to avoid withdrawal: INITIAL DOSE: 0.01 mg/kg body weight given IV. If this does not result in clinical improvement, an additional dose of 0.1 mg/kg body weight may be given. It may be given by the IM or subQ route if the IV route is not available (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008)

e) NALOXONE DOSE/NEONATE

1) The American Academy of Pediatrics recommends a neonatal dose of 0.1 mg/kg IV or intratracheally from birth until age 5 years or 20 kilograms of body weight (AAP, 1989; Kleinman et al, 2010).
2) Smaller doses (10 to 30 mcg/kg IV) have been successful in the setting of exposure via maternal administration of narcotics or administration to neonates in therapeutic doses for anesthesia (Wiener et al, 1977; Welles et al, 1984; Fischer & Cook, 1974; Brice et al, 1979).
3) POTENTIAL OF WITHDRAWAL: The risk of precipitating withdrawal in an addicted neonate should be considered. Withdrawal seizures have been provoked in infants from opioid-abusing mothers when the infants were given naloxone at birth to stimulate breathing (Gibbs et al, 1989).
4) In cases of inadvertent administration of an opioid overdose to a neonate, larger doses may be required. In one case of oral morphine intoxication, 0.16 milligram/kilogram/hour was required for 5 days (Tenenbein, 1984).

f) NALOXONE/ALTERNATE ROUTES

1) If intravenous access cannot be rapidly established, naloxone can be administered via subcutaneous or intramuscular injection, intranasally, or via inhaled nebulization in patients with spontaneous respirations.
2) INTRAMUSCULAR/SUBCUTANEOUS ROUTES: If an intravenous line cannot be secured due to hypoperfusion or lack of adequate veins then naloxone can be administered by other routes.
3) The intramuscular or subcutaneous routes are effective if hypoperfusion is not present (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008). The delay required to establish an IV, offsets the slower rate of subcutaneous absorption (Wanger et al, 1998).
4) Naloxone Evzio(TM) is a hand-held autoinjector intended for the emergency treatment of known or suspected opioid overdose. The autoinjector is equipped with an electronic voice instruction system to assist caregivers with administration. It is available as 0.4 mg/0.4 mL solution for injection in a pre-filled auto-injector (Prod Info EVZIO(TM) injection solution, 2014).
5) INTRANASAL ROUTE: Intranasal naloxone has been shown to be effective in opioid overdose; bioavailability appears similar to the intravenous route (Kelly & Koutsogiannis, 2002). Based on several case series of patients with suspected opiate overdose, the average response time of 3.4 minutes was observed using a formulation of 1 mg/mL/nostril by a mucosal atomization device (Kerr et al, 2009; Kelly & Koutsogiannis, 2002). However, a young adult who intentionally masticated two 25 mcg fentanyl patches and developed agonal respirations (6 breaths per minute), decreased mental status and mitotic pupils did not respond to intranasal naloxone (1 mg in each nostril) administered by paramedics. After 11 minutes, paramedics placed an IV and administered 1 mg of IV naloxone; respirations normalized and mental status improved. Upon admission, 2 additional doses of naloxone 0.4 mg IV were needed. The patient was monitored overnight and discharged the following day without sequelae. Its suggested that intranasal administration can lead to unpredictable absorption (Zuckerman et al, 2014).

a) Narcan(R) nasal spray is supplied as a single 4 mg dose of naloxone hydrochloride in a 0.1 mL intranasal spray (Prod Info NARCAN(R) nasal spray, 2015).
b) FDA DOSING: Initial dose: 1 spray (4 mg) intranasally into 1 nostril. Subsequent doses: Use a new Narcan(R) nasal spray and administer into alternating nostrils. May repeat dose every 2 to 3 minutes. Requirement for repeat dosing is dependent on the amount, type, and route of administration of the opioid being antagonized. Higher or repeat doses may be required for partial agonists or mixed agonist/antagonists (Prod Info NARCAN(R) nasal spray, 2015).
c) AMERICAN HEART ASSOCIATION GUIDELINE DOSING: Usual dose: 2 mg intranasally as soon as possible; may repeat after 4 minutes (Lavonas et al, 2015). Higher doses may be required with atypical opioids (VandenHoek et al, 2010).
d) ABSORPTION: Based on limited data, the absorption rate of intranasal administration is comparable to intravenous administration. The peak plasma concentration of intranasal administration is estimated to be 3 minutes which is similar to the intravenous route (Kerr et al, 2009). In rare cases, nasal absorption may be inhibited by injury, prior use of intranasal drugs, or excessive secretions (Kerr et al, 2009).

6) NEBULIZED ROUTE: DOSE: A suggested dose is 2 mg naloxone with 3 mL of normal saline for suspected opioid overdose in patients with some spontaneous respirations (Weber et al, 2012).
7) ENDOTRACHEAL ROUTE: Endotracheal administration of naloxone can be effective(Tandberg & Abercrombie, 1982), optimum dose unknown but 2 to 3 times the intravenous dose had been recommended by some (Kleinman et al, 2010).

g) NALOXONE/CONTINUOUS INFUSION METHOD

1) A continuous infusion of naloxone may be employed in circumstances of opioid overdose with long acting opioids (Howland & Nelson, 2011; Redfern, 1983).
2) The patient is given an initial dose of IV naloxone to achieve reversal of opioid effects and is then started on a continuous infusion to maintain this state of antagonism.
3) DOSE: Utilize two-thirds of the initial naloxone bolus on an hourly basis (Howland & Nelson, 2011; Mofenson & Caraccio, 1987). For an adult, prepare the dose by multiplying the effective bolus dose by 6.6, and add that amount to 1000 mL and administer at an IV infusion rate of 100 mL/hour (Howland & Nelson, 2011).
4) Dose and duration of action of naloxone therapy varies based on several factors; continuous monitoring should be used to prevent withdrawal induction (Howland & Nelson, 2011).
5) Observe patients for evidence of CNS or respiratory depression for at least 2 hours after discontinuing the infusion (Howland & Nelson, 2011).

h) NALOXONE/PREGNANCY

1) In general, the smallest dose of naloxone required to reverse life threatening opioid effects should be used in pregnant women. Naloxone detoxification of opioid addicts during pregnancy may result in fetal distress, meconium staining and fetal death (Zuspan et al, 1975). When naloxone is used during pregnancy, opioid abstinence may be provoked in utero (Umans & Szeto, 1985).

8) INTRANASAL NALOXONE shows promise, particularly in the prehospital setting of opioid overdose. Data suggests high bioavailability through the nasal mucosa, with onset of action and plasma bioavailability curves which are similar to the intravenous route. Doses of 0.8 to 2 mg of intranasal naloxone were given to 6 patients with heroin overdose. Adequate spontaneous respiration returned within 2 minutes (Kelly & Koutsogiannis, 2002).
9) PRECAUTION

a) Caution should be taken in the presence of a mixed overdose of cocaine with an opioid. Administration of naloxone may provoke serious sympathomimetic toxicity by removing the protective opioid-mediated CNS depressant effects. The arrhythmogenic effects of naloxone may also be potentiated in the presence of a severe hyperkalemia (McCann et al, 2002).

C) NALMEFENE

1) The recommended nalmefene dose for opioid toxicity in a nonopioid dependent patient is 0.5 mg/70 kg slow intravenously, intramuscularly or subcutaneously. This may be followed by a second dose 2 to 5 minutes later. If after following a total dose of 1.5 mg/70 kg, no clinical response has been achieved, it is unlikely that further doses will have an effect. Do not administer more than is required to restore the respiratory rate to normal, in order to minimize the likelihood of cardiovascular stress and precipitated withdrawal syndrome (Prod Info Revex(R), nalmefene, 1998).
2) NALMEFENE COMPARED TO NALOXONE: In a randomized, double-blind study naloxone was compared to nalmefene in patients presenting with impaired consciousness due to suspected opioid overdose. Patients received either 1 mg nalmefene, 2 mg nalmefene or 2 mg naloxone IV every 5 minutes based on clinical need. Patients with suspected opioid dependence were given half doses of study drug. Results showed nalmefene and naloxone to both be efficacious, safe and to yield similar outcomes (Kaplan et al, 1999).
3) Naloxone is recommended as the drug of choice in all opioid overdoses/toxicity based on its short duration of effect, and ease in which it can be titrated.

D) CONTRAINDICATED TREATMENT

1) Nalorphine and levallorphan have agonist and antagonist properties including respiratory depression. They should no longer be used because if it is not an opioid that is being treated, CNS depression may ensue.

E) ACUTE LUNG INJURY

1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).

F) HYPOTENSIVE EPISODE

1) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

2) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

3) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

G) EXPERIMENTAL THERAPY

1) PRAMIPEXOLE/WITHDRAWAL SYMPTOMS: A 31-year-old man, with sleep apnea believed to be caused by buprenorphine use in combination with clonazepam, experienced withdrawal symptoms of anxiety and leg restlessness after tapering his buprenorphine daily dose of 32 mg. The buprenorphine dose had been slowly tapered from 32 mg to 2 mg over a 3-month period without incident; however, the development of withdrawal symptoms occurred when he tried to taper below 2 mg, and the severity of symptoms prevented him from tapering below 1 mg. His withdrawal symptoms did not improve following clonidine therapy, 0.4 mg daily; pramipexole 0.25 mg was then initiated. Following one dose of pramipexole, the patient reported complete resolution of his withdrawal symptoms. He was able to completely taper off his buprenorphine dose and his sleep apnea subsequently resolved (Makhinson & Gomez-Makhinson, 2014).

Dermal Exposure

6.9.1)

A) DERMAL DECONTAMINATION

1) Patients with topical exposure to buprenorphine (transdermal delivery patch) should have the substance removed and the area washed thoroughly with soap and water.

6.9.2)

A) GENERAL TREATMENT

1) Treatment is SYMPTOMATIC and SUPPORTIVE.

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

A)

1) There is no information regarding the effectiveness of hemodialysis or hemoperfusion for the removal of buprenorphine from plasma. However, these procedures are unlikely to be of benefit due to the high protein binding and relatively large volume of distribution of buprenorphine.

Abstracts

Range Of Toxicity

Summary

A)

B)

Therapeutic Dose

7.2.1)

A) BUPRENORPHINE

1) BUCCAL FILM

a) OPIOID-NAIVE: 75 mcg once or twice daily (every 12 hours) for at least 4 days, then increasing to 150 mcg every 12 hours; may increase in increments of 150 mcg every 12 hours, no more often than every 4 days, up to a MAXIMUM dose of 900 mcg every 12 hours (Prod Info BELBUCA(TM) buccal film, 2015).
b) OPIOID-TOLERANT: If daily opioid dose is less than 30 mg oral morphine sulfate equivalents (MSE), initial buprenorphine buccal film dose is 75 mcg once daily or every 12 hours. If MSE is 30 to 89 mg, initial dose is 150 mcg every 12 hours. If MSE is 90 to 160 mg, initial dose is 300 mcg every 12 hours. Dose may be increased in increments of 150 mcg every 12 hours, no more often than every 4 days, up to a MAXIMUM dose of 900 mcg every 12 hours (Prod Info BELBUCA(TM) buccal film, 2015).

2) INTRADERMAL IMPLANT

a) Insert 4 single-rod implants (each containing 74.2 mg of buprenorphine) subdermally into the inner side of the upper arm; remove after 6 months; may insert 4 new implants into other arm at time of removal; if implants are not inserted on the day of removal, initiate transmucosal buprenorphine at the patient's previous dosage; after implants have been inserted once into each arm, transition back to transmucosal buprenorphine; do not reinsert into previously-used sites or sites other than the upper arm (Prod Info PROBUPHINE(R) subdermal implant, 2016).
b) Expelled implant: Instruct patient to bring implant to office in plastic bag; determine if entire 26 mm implant was expelled, then dispose of properly; may insert replacement implant(s) in same arm, either laterally or medially to the unexpelled implants, or may place in the contralateral arm (Prod Info PROBUPHINE(R) subdermal implant, 2016)

3) PARENTERAL

a) The usual dose is 0.3 mg administered IM or slow IV (over at least 2 minutes) up to every 6 hours as needed (Prod Info buprenorphine hcl injection, 2004).
b) Single doses up to 0.6 mg, administered IM only, may be given depending on the severity of pain and the patient's response (Prod Info buprenorphine hcl injection, 2004).

4) SUBLINGUAL

a) The typical maintenance dose range is 4 to 24 mg once daily sublingually; adjust dosage in 2- to 4-mg increments/decrements to a level that holds patient in treatment and suppresses opioid withdrawal effects (Prod Info SUBUTEX(R) sublingual tablets, 2011).

5) TRANSDERMAL

a) OPIOID-NAIVE PATIENTS: The usual initial dose is 5 mcg/hr transdermally, then titrated based on analgesic requirement and tolerance at a minimum interval of every 72 hr; MAX 20 mcg/hr; patch should be replaced every 7 days (Prod Info Butrans(R) transdermal patch, 2011).
b) OPIOID-TOLERANT PATIENTS: The usual initial dose is 5 mcg/hr in patients who were receiving a total daily morphine dose or equivalent of less than 30 mg and 10 mcg/hr in patients who were receiving a total daily morphine dose between 30 and 80 mg (Prod Info Butrans(R) transdermal patch, 2011).

B) BUPRENORPHINE/NALOXONE

1) BUCCAL FILM

a) The initial dose is based on final induction dose of buprenorphine/naloxone sublingual tablets. For buprenorphine 8 mg/naloxone 2 mg SL tablets, use buprenorphine 4.2 mg/naloxone 0.7 mg buccal film. Apply to buccal mucosa once daily (Prod Info BUNAVAIL(TM) buccal film, 2014).
b) For maintenance, the target dose is buprenorphine 8.4 mg/naloxone 1.4 mg applied to buccal mucosa once daily; adjust dose in increments or decrements of buprenorphine 2.1 mg/naloxone 0.3 mg based on patient response. The usual dose range is buprenorphine 2.1 mg/naloxone 0.3 mg to buprenorphine 12.6 mg/naloxone 2.1 mg per day (MAX dose) (Prod Info BUNAVAIL(TM) buccal film, 2014).

2) BUCCAL OR SUBLINGUAL

a) FILM

1) INITIAL DOSE: Buprenorphine 2 mg/naloxone 0.5 mg or buprenorphine 4 mg/naloxone 1 mg. Titrate in increments of 2 mg or 4 mg of buprenorphine in 2-hour intervals. MAX dose: buprenorphine 8 mg/naloxone 2 mg (Prod Info SUBOXONE(R) sublingual film, buccal film, 2015).
2) TREATMENT DAY 2: Single daily dose up to buprenorphine 16 mg/naloxone 4 mg (Prod Info SUBOXONE(R) sublingual film, buccal film, 2015)
3) MAINTENANCE: The general dose is buprenorphine 4 mg/naloxone 1 mg. Recommended target dose: buprenorphine 16 mg/naloxone 4 mg daily. MAX dose: buprenorphine 24 mg/naloxone 6 mg daily. Adjust dose in increments of 2 mg to 4 mg of buprenorphine to a level that suppresses opioid withdrawal symptoms (Prod Info SUBOXONE(R) sublingual film, buccal film, 2015).

b) TABLETS

1) SUBOXONE(R)

a) The recommended target dose is buprenorphine 16 mg/naloxone 4 mg sublingually once daily; adjust dose in 2 mg/0.5 mg or 4 mg/1 mg increments or decrements to optimal clinical effects; typical dose ranges from buprenorphine 4 mg/naloxone 1 mg to buprenorphine 24 mg/naloxone 6 mg daily (Prod Info SUBOXONE(R) sublingual tablets, 2011).

2) ZUBSOLV(R)

a) INDUCTION: The recommended initial dose is buprenorphine 1.4 mg/naloxone 0.36 mg sublingually. For the remainder of Day 1, dose up to buprenorphine 4.2 mg/naloxone 1.08 mg in divided doses of 1 to 2 tablets at 1.5 to 2 hour intervals. On Day 2, a single daily dose of up to buprenorphine 11.4 mg/naloxone 2.9 mg is recommended (Prod Info ZUBSOLV(R) sublingual tablets, 2015).
b) MAINTENANCE: The recommended target dosage is buprenorphine 11.4 mg/naloxone 2.9 mg in a single daily dose. Adjust in increments/decrements of buprenorphine 1.4 mg/naloxone 0.36 mg or buprenorphine 2.9 mg/naloxone 0.71 mg (Prod Info ZUBSOLV(R) sublingual tablets, 2015).

7.2.2)

A) BUPRENORPHINE

1) BUCCAL FILM

a) Safety and effectiveness have not been established in pediatric patients (Prod Info BELBUCA(TM) buccal film, 2015).

2) INTRADERMAL IMPLANT

a) 16 YEARS OR OLDER: Insert 4 single-rod implants (each containing 74.2 mg of buprenorphine) subdermally into the inner side of the upper arm; remove after 6 months; may insert 4 new implants into other arm at time of removal; if implants are not inserted on the day of removal, initiate transmucosal buprenorphine at the patient's previous dosage; after implants have been inserted once into each arm, transition back to transmucosal buprenorphine; do not reinsert into previously-used sites or sites other than the upper arm (Prod Info PROBUPHINE(R) subdermal implant, 2016)
b) Expelled implant: Instruct patient to bring implant to office in plastic bag; determine if entire 26 mm implant was expelled, then dispose of properly; may insert replacement implant(s) in same arm, either laterally or medially to the unexpelled implants, or may place in the contralateral arm (Prod Info PROBUPHINE(R) subdermal implant, 2016)

3) PARENTERAL

a) 13 YEARS AND OLDER: The usual dose is 0.3 mg administered IM or slow IV (over at least 2 minutes) up to every 6 hours, as needed (Prod Info buprenorphine hcl injection, 2004)
b) 2 TO 12 YEARS: The usual dose is 2 to 6 mcg/kg IM or IV every 4 to 6 hours (Prod Info buprenorphine hcl injection, 2004).

4) SUBLINGUAL

a) The safety and efficacy of buprenorphine sublingual tablets have not been established in pediatric patients (Prod Info SUBUTEX(R) sublingual tablets, 2011).

5) TRANSDERMAL

a) Buprenorphine transdermal patches are not recommended for use in children (Prod Info Butrans(R) transdermal patch, 2011).

B) BUPRENORPHINE/NALOXONE

1) BUCCAL

a) The safety and effectiveness of buccal film have not been established in pediatric patients (Prod Info BUNAVAIL(TM) buccal film, 2014).

2) BUCCAL OR SUBLINGUAL

a) The safety and effectiveness of buprenorphine/naloxone sublingual or buccal film have not been established (Prod Info SUBOXONE(R) sublingual film, buccal film, 2015).

3) SUBLINGUAL

a) The safety and effectiveness of buprenorphine/naloxone sublingual tablet and sublingual film have not been established (Prod Info ZUBSOLV(R) sublingual tablets, 2015; Prod Info SUBOXONE(R) sublingual tablets, 2011).

Minimum Lethal Exposure

A)

Maximum Tolerated Exposure

A)

1) CASE REPORT: Following the intentional ingestion of 40 milligrams buprenorphine, a 35-year-old heroin-dependent man developed severe opioid withdrawal which was precipitated within one hour. In an attempt to alleviate symptoms, the patient took an additional 24 milligrams, with no relief, followed by another 16 or 24 milligrams. The patient was admitted to the hospital 2 days later and put on methadone therapy (Clark et al, 2002).
2) CASE REPORT: Severe hepatitis associated with acute renal failure and anuria have been reported in a patient following the ingestion (oral instead of sublingual) of 112 mg of buprenorphine. The buprenorphine and norbuprenorphine plasma levels were 224 ng/mL and 30 ng/mL, respectively. The patient recovered following the discontinuation of buprenorphine therapy and hemodialysis treatment (Houdret et al, 1999).
3) CASE REPORT: A 71-year-old woman developed nausea and vomiting, somnolence, miosis, and respiratory depression (8 breaths/minute, O2 saturation 68%) after applying 4 transdermal 52.5 mcg/hr buprenorphine patches at the same time. Each patch contained 30 mg buprenorphine. After repeated administration of naloxone 0.8 mg (total of 3 doses IV and 2 doses subcutaneously), the patient completely recovered (Magdalan & Merwid-Lad, 2008).
4) PROSPECTIVE STUDY: A prospective study was conducted to evaluate withdrawal symptoms in patients receiving buprenorphine 72 mg (3-fold the recommended daily dose of 24 mg) orally in an outpatient setting. Nine patients, who were at least 20 years of age, with opioid dependence and a history of opioid use for at least 1 year prior to maintenance treatment, were recruited into the study. Seven of the 9 patients completed the study. Patients were administered 72 mg (9 8-mg tablets) of buprenorphine on day 1 of the study. Blood samples were drawn 2, 24, 48, and 72 hours after ingestion, and opiate withdrawal symptoms were assessed, over a 72-hour period, with objective and subjective opiate withdrawal scales. Mean peak plasma concentrations of buprenorphine and norbuprenorphine (the metabolite) occurred 2 hours post-ingestion as expected and exhibited a gradual decline thereafter. Low withdrawal symptom scores from both the objective and subjective opiate withdrawal scales were reported in all 7 patients, and there were no significant adverse effects reported, indicating that high-dose buprenorphine was well-tolerated; however, further investigation is warranted (Hvittfeldt et al, 2015).

B)

1) CASE SERIES: CNS and respiratory depression (in one case, a respiratory rate of 2 per minute was observed) developed in 5 toddlers (age range 16 to 22 months) after ingestion of 8 to 10 mg buprenorphine. Recurrent respiratory depression as long as 18 hours after ingestion developed in one patient (Geib et al, 2006).
2) CASE REPORT: A 9-month-old developed miotic pupils, lethargy and respiratory depression after ingesting buprenorphine 8 mg/naloxone 2 mg. Effects reversed only after 5 mg naloxone IV. Mental status returned to normal 43 hours after ingestion (Cho et al, 2006).
3) CASE REPORT: Restlessness and bilateral miosis were reported in a 4-year-old child approximately 15 minutes after she ingested 4 mg of buprenorphine (one-half of an 8-mg tablet). She received activated charcoal, was observed for 24 hours, and never developed respiratory or CNS depression (Gaulier et al, 2004).
4) CASE SERIES: According to a retrospective review of buprenorphine overdoses involving children less than 6 years of age, Ingestion of 4 mg (one-half of a single 8 mg tablet; 0.215 mg/kg) caused CNS and respiratory depression in a 20-month-old boy, and ingestion of up to 24 mg of buprenorphine in a 2-year-old boy resulted in coma and respiratory depression. In the same review, a 20-month-old boy ingested 12 mg of buprenorphine and subsequently developed cyanosis, respiratory depression, and lethargy (Hayes et al, 2008).
5) CASE SERIES/CHILDREN: According to a retrospective case review of pediatric unintentional buprenorphine/naloxone exposures (n=9), drowsiness/lethargy, respiratory depression, agitation/irritability, vomiting, miosis, diaphoresis, and confusion occurred in children less than 3 years of age following ingestion of buprenorphine/naloxone tablets, at doses ranging from 0.07 to 0.41 mg/kg (Pedapati & Bateman, 2011).
6) CASE REPORT: A 2-year-old child became comatose (Glasgow Coma Scale (GCS) score of 5) with a fever (38.6%), hypertonia, and hyperreflexia after a suspected unintentional ingestion of 2 mg of buprenorphine (one-half of a 4-mg tablet). A brain CT scan without contrast was normal; however, a brain MRI revealed bilateral and symmetrical hypointense signals and hyperintense signals on T1 and T2 weighted images, respectively, with injuries in the white matter of the cerebral hemispheres and the cerebellum. The toxicology screen, obtained on hospital day 4, was positive for buprenorphine. With supportive care, the patient gradually recovered with a GCS score of 15 and a normal EEG, and was subsequently discharged on hospital day 8 (Bellot et al, 2011).

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) Following sublingual administration of 0.4 mg buprenorphine, plasma concentrations were 0.07, 0.28, 0.51, and 0.74 ng/mL at 20 minutes, 1 hour, 2 hours, and 150 minutes, respectively. This suggests a delay in absorption with sublingual administration. Plasma levels were similar to those following intramuscular and intravenous administration at 80 minutes. Average peak levels were achieved in 150 minutes (Bullingham et al, 1981).
2) AREA UNDER THE CURVE: After sublingual doses of fixed-dose buprenorphine/naloxone (Suboxone(TM)) 4/1 mg, 8/2 mg, and 16/4 mg, AUC(0-48) values of buprenorphine were approximately 13, 20 and 35 ng x hr/mL, respectively. In this study, the AUC(0-48) of buprenorphine was about 33 ng x hr/mL after a single sublingual 16-mg dose of buprenorphine alone (Subutex(TM)) (Prod Info SUBUTEX oral tablets, 2010).
3) Following the use of a single transdermal patch (35 mcg/hour), the following values were obtained: the time to minimum therapeutic concentration (100 pg/mL) 21 hours; area under the plasma concentration-time curve 20228 pg x hour/mL (Evans & Easthope, 2003).

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) Ingestion of 4 mg of buprenorphine (one-half of an 8-mg tablet) by a 4-year-old child resulted in serum buprenorphine and norbuprenorphine concentrations of 0.64 and 7.7 mcg/L, respectively, and 173 and 419 mcg/L, respectively, in the urine (Gaulier et al, 2004).
2) The post-mortem femoral blood concentrations, of buprenorphine and norbuprenorphine in a 14-year-old boy, who ingested an unknown amount of buprenorphine, were 1.1 ng/mL and 0.2 ng/mL, respectively (Kintz et al, 2003).
3) CASE REPORT: Fatal intoxication following self-administration of a massive dose of buprenorphine (Subutex(R) sublingual tablets) has been reported. The following post mortem tissue concentrations were obtained (Gaulier et al, 2000):

a) BLOOD: Buprenorphine 3.3 mg/L; Norbuprenorphine 0.4 mg/L
b) URINE: Buprenorphine 3.4 mg/L; Norbuprenorphine 0.6 mg/L
c) BILE: Buprenorphine 2035 mg/L; Norbuprenorphine 536 mg/L
d) BRAIN: Buprenorphine 6.4 mcg/g; Norbuprenorphine 3.9 mcg/g

4) CASE SERIES: In a case series of 20 fatalities involving high-dose, sublingual buprenorphine tablets, the following levels were obtained (Tracqui et al, 1998a):

1) AVERAGE POSTMORTEM CONCENTRATIONS
2) Buprenorphine 1.1 to 29.0 ng/mL (mean 8.4 ng/mL); norbuprenorphine 0.2 to 12.6 ng/mL (mean 2.6 ng/mL)
3) Myocardium - Buprenorphine 6.0 ng/g
4) Kidney - Buprenorphine 35.0 ng/g
5) Brain - Buprenorphine 45.5 ng/g
6) Liver - Buprenorphine 80.0 ng/g
7) Bile - Buprenorphine 575 to 72,650 ng/mL; norbuprenorphine, 41 to 30,000 ng/mL
8) Hair - Buprenorphine 6 to 597 ng/g (mean 137 ng/g); norbuprenorphine nondetected

5) In the same case series, buprenorphine exhibited extensive tissue distribution, with the highest levels found in the bile. The authors suggested that bile may be the sample of choice for postmortem screening (Tracqui et al, 1998a).
6) CASE SERIES: In two series of 29 acute poisoning cases (20 fatal), involving high-dose sublingual buprenorphine tablets as substitution therapy, the following blood levels were obtained: nonfatal cases - 1.0 to 2.3 ng/mL, mean 1.4 ng/mL; fatal cases - 1.1 to 29.0 ng/mL, mean 8.4 ng/mL (Tracqui et al, 1998).

a) In addition to buprenorphine, almost all patients used psychotropic medications, especially benzodiazepines. Buprenorphine tablets were crushed and injected intravenously by 18 of these patients (Tracqui et al, 1998) .

7) CASE SERIES: In two series of 39 and 78 fatalities involving buprenorphine, the following postmortem levels were reported (Kintz, 2001):

a) Buprenorphine blood levels 0.5 to 51.0 ng/mL (mean 10.2 ng/mL); 0.1 to 76 ng/mL (mean 12.6 ng/mL)
b) Norbuprenorphine blood levels 0.2 to 47.1 ng/mL (mean 8.2 ng/mL); less than 0.1 to 65 ng/mL (mean 10.6 ng/mL)
c) Buprenorphine hair levels: 10 to 1080 pg/mg

8) CASE SERIES: In a case series of 13 fatalities involving buprenorphine as a substitution treatment for heroin-dependent patients, the following blood levels were obtained: buprenorphine 0.3 to 7.7 ng/mL (mean 3.5 ng/mL); norbuprenorphine 0.3 to 16.2 ng/mL (mean 2.9 ng/mL) (Kintz, 2002).
9) CASE REPORTS: Three individuals (ranging in age from 17 years to 35 years) were found dead, suspected of having nasally insufflated unknown amounts of crushed buprenorphine sublingual tablets, as well as consuming alcohol. Postmortem buprenorphine blood concentrations ranged from 6.1 ng/mL to 15.4 ng/mL (Ferrant et al, 2011).

Workplace Standards

A)

1) Not Listed

B)

1) Not Listed

C)

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

D)

1) Not Listed

Toxicity Information

7.7.1)

A) LD50- (INTRAPERITONEAL)MOUSE:

1) 90 mg/kg (RTECS, 2003)

B) LD50- (ORAL)MOUSE:

1) 260 mg/kg (RTECS, 2003)

C) LD50- (INTRAPERITONEAL)RAT:

1) 197 mg/kg (RTECS, 2003)

Pharmacology Toxicology

Pharmacologic Mechanism

A)

B)

C)

D)

E)

F)

G)

1) In nondependent subjects, sublingual use of buprenorphine/naloxone in doses of up to 16/4 milligrams (mg) has produced typical agonist effects similar to 16-mg sublingual buprenorphine alone (Johnson & McCagh, 2000; Prod Info SUBUTEX oral tablets, 2010).
2) One study demonstrated that 16 mg of the tablet formulation of buprenorphine significantly decreased intravenous heroin self-administration, relative to 8 mg buprenorphine (Comer et al, 2001).
3) Buprenorphine has been given as alternate-day dosing, with twice the daily maintenance dose every other day (Amass et al, 1994) or triple the daily maintenance dose every third day or quadruple the daily maintenance dose every fourth day (Petry et al, 2000).
4) One meta-analysis reported that subjects receiving buprenorphine 8 to 12 mg/day were 1.26 times more likely to discontinue treatment and 8.3% more likely to have a positive urinalysis for opiates than subjects receiving methadone 50 to 80 mg/day (Barnett et al, 2001).
5) One randomized, double-blind, placebo-controlled trial reported that buprenorphine/naloxone combination and buprenorphine alone (sublingual tablets) are safe and effective in reducing the use of opiates and the craving for opioids among opioid-dependent persons in office-based setting (Fudala et al, 2003). In another randomized study, low-dose methadone was less effective than levomethadyl acetate, buprenorphine and high-dose methadone in reducing the use of illicit opioids (Johnson et al, 2000).

Toxicologic Mechanism

A)

1) At high doses its agonist effects plateau ("ceiling effect") limiting the maximal analgesic effect and respiratory depression. This ceiling effect confers a high safety profile clinically, a low level of physical dependence, and only mild withdrawal symptoms on cessation after prolonged administration.

a) In a double-blind, randomized, placebo-controlled study, the respiratory effects of intravenous buprenorphine and fentanyl were compared in humans and rats. Healthy volunteers were given either buprenorphine doses 0.7, 1.4, 4.3 and 8.6 mcg/kg (n=20) or fentanyl doses 1.1, 2.1, 2.9, 4.3 and 7.1 mcg/kg (n=21) or placebo (n=7). These doses were infused intravenously over 90 seconds and measurements of minute ventilation at a fixed end-tidal PCO2 of 7 kPa were obtained for 7 hours. In fentanyl group, a dose-dependent depression of minute ventilation with apnea at doses equal to or greater than 2.9 mcg/kg was observed. Buprenorphine produced depression of minute ventilation which levelled off at doses equal to or greater than 3.0 mcg/kg to about 50% of baseline (Dahan et al, 2005).

1) Rats were given either buprenorphine doses 0, 100, 300, 1000 and 3000 mcg/kg or fentanyl 0, 50, 68 and 90 mcg/kg infused intravenously over 20 minutes. Arterial PCO2 was measured 5, 10, 15 and 20 minutes after the start of fentanyl infusion and 30, 150, 270 and 390 minutes after the start of buprenorphine infusion. Fentanyl showed a linear effect on arterial PCO2, with maximum respiratory depression at 20 minutes (maximum PaCO2 8.0 kPa). However, irrespective of the time at which measurements were obtained, the relationship of arterial PCO2 and buprenorphine was non-linear, with a ceiling effect at doses greater than 1.4 mcg/kg. In rodents, the ceiling in respiratory effect occurs at a much lower dose (0.1 mg/kg) than the ceiling in analgesic effect (1.0 mg/kg), which indicates the relative safety of buprenorphine combined with its ability to produce effective analgesia in these animals. Overall, these data confirmed a ceiling effect of buprenorphine but not fentanyl with respect to respiratory depression (Dahan et al, 2005).

2) Respiratory depression due to buprenorphine overdose has been primarily due to illicit intravenous injection of crushed sublingual tablets. Evidence at autopsies revealed features of prolonged asphyxiation, including cyanosis, multivisceral congestion, and pulmonary edema (Kintz, 2001).
3) Respiratory depressant effects of buprenorphine, however, are similar to morphine when given in equianalgesic doses (0.3 and 10 mg intramuscular (IM), respectively). Respiratory depression is dose-related when the drug is given in therapeutic doses and peak respiratory depressant effects are slower in onset after buprenorphine (IM) than morphine. Similarly, duration of depressant effects appear to be longer (Heel et al, 1979; Baster et al, 1977; Baster et al, 1976).

B)

Physicochemical

Physical Characteristics

A)

B)

Ph

A)

Molecular Weight

A)

B)

Animal Toxicology

References

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BUPRENORPHINE

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Dermatologic

Musculoskeletal

Immunologic

Reproductive

Carcinogenicity

Monitoring Parameters Levels

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Dermal Exposure

Enhanced Elimination

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Toxicity Information

Pharmacologic Mechanism

Toxicologic Mechanism

Physical Characteristics

Ph

Molecular Weight

General Bibliography