Professional Drug Information > Buprenorphine Hydrochloride

Buprenorphine (Systemic)

VA CLASSIFICATION
Primary: CN101
Secondary: CN206


Note: Controlled substance classification

Note: Controlled substance classification—

U.S.—Schedule V
Commonly used brand name(s): Buprenex.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Analgesic—

anesthesia adjunct—
Note: Buprenorphine is an opioid agonist/antagonist analgesic.



Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Pain (treatment)—Indicated for the treatment of moderate to severe pain ^{{01} {02} {03} {04} {16} {17} {18} {19} {20} {21} {23} {24} {26} {33}}.

[Anesthesia, general, adjunct]^{04}{07}{25}; or
[Anesthesia, local, adjunct]^{41}—Buprenorphine is used as an opioid analgesic adjunct to general and local anesthesia.

—Prior to administration of buprenorphine, its antagonist activity and its high affinity for, and slow rate of dissociation from, receptor binding sites must be considered. Buprenorphine may precipitate withdrawal symptoms if administered to a patient physically dependent on an opioid analgesic. ^{{01} {03} {04} {05} {07} {08} {10} {13}} Also, buprenorphine may temporarily reduce or block the effects of subsequently administered opioid analgesics ^{{02} {04} {07} {32}}. In addition, buprenorphine-induced respiratory depression or other adverse effects may be difficult to reverse ^{{04} {05} {07} {08} {21} {36}}.

—Buprenorphine (unlike pentazocine, which has cardiovascular effects that tend to increase cardiac work) ^{38} may be administered to patients with angina pectoris or compromised cardiac function, following cardiac or cardiovascular surgery, and to relieve pain due to acute myocardial infarction. ^{{02} {04} {07} {09} {22} {31}}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    504.11 ^{40}

pKa—
    8.42 and 9.92 ^{42}


Other characteristics
    Weakly acidic ^{{01} {02}}; highly lipophilic ^{{01} {02} {05} {08}}

Mechanism of action/Effect:


Analgesic:

Opioid analgesics bind with stereospecific receptors at many sites within the central nervous system (CNS) to alter processes affecting both the perception of pain and the emotional response to pain. Precise sites and mechanisms of action have not been fully determined, but may partially involve alterations in release of various neurotransmitters from afferent nerves sensitive to painful stimuli. ^{38}

It has been proposed that there are multiple subtypes of opioid receptors, each mediating various therapeutic and/or side effects of opioid drugs. The actions of an opioid analgesic may therefore depend upon its binding affinity for each type of receptor and whether it acts as a full agonist or a partial agonist or is inactive at each type of receptor. At least two of these types of receptors (mu and kappa) mediate analgesia. ^{38} Mu receptors are widely distributed throughout the CNS, especially in the limbic system (frontal cortex, temporal cortex, amygdala, and hippocampus), thalamus, striatum, hypothalamus, and midbrain as well as laminae I, II, IV, and V of the dorsal horn in the spinal cord. Kappa receptors are localized primarily in the spinal cord and in the cerebral cortex. A third type of receptor (sigma) may not mediate analgesia; actions at this receptor may produce the subjective and psychotomimetic effects characteristic of most opioids having mixed agonist/antagonist activity. ^{38} Buprenorphine may act primarily as a partial agonist at the mu receptor ^{{01} {02} {06} {07} {08} {10}}; it may also have some agonist activity at the kappa receptor ^{08}. Buprenorphine has little if any activity at the sigma receptor ^{{06} {07}}.



Antagonist:

Buprenorphine may displace mu-receptor opioid agonists from their receptor binding sites and competitively inhibit their actions. Because buprenorphine has high affinity for the mu receptor, but less intrinsic activity at this receptor than morphine or other potent mu-receptor agonists, ^{{02} {06} {07}} it may precipitate withdrawal symptoms in physically dependent patients who are chronically receiving these agonists ^{{01} {05} {07} {08}}. However, because of its partial agonist activity, buprenorphine may attenuate spontaneous withdrawal symptoms caused by abrupt discontinuation of opioid agonists ^{{07} {08} {13}}. Also, buprenorphine dissociates from the mu receptor very slowly ^{{01} {02} {06} {07} {08}} and may reduce or block the effects of subsequently administered mu-receptor agonists ^{{02} {04} {05} {21} {32}}. In some animal studies, the antagonist activity of buprenorphine was comparable to that of naloxone ^{{01} {02}}. One study indicates that buprenorphine may also have some antagonist activity at the kappa receptor ^{12}.



Other actions/effects:

Buprenorphine shares the CNS depressant, respiratory depressant, and hypotensive effects of opioid analgesics ^{{01} {02} {04} {05} {07}}.

Buprenorphine may have less potential for causing habituation or abuse than other strong opioid analgesics ^{{01} {02} {04} {08} {32}}. Studies in animals have indicated that it has less reinforcing efficacy than other opioids ^{{02} {08}}. Also, its slow rate of dissociation from the mu receptor reduces the risk that a severe abstinence syndrome will occur following abrupt withdrawal ^{08}. Studies in opioid addicts have shown that withdrawal effects may not reach maximum intensity ^{{04} {32}} for up to 15 days following abrupt discontinuation. Withdrawal effects are morphine-like, mild to moderate, and may persist for 1 to 2 weeks ^{{05} {07} {08} {32}}. Despite the relatively low risk of habituation, abuse has been reported ^{{08} {29}}; further experience with this medication is necessary before its true abuse potential can be assessed ^{41}.

Although studies in humans have not been done, animal studies have indicated that buprenorphine has potent, prolonged antitussive activity ^{02}.

Absorption:

Intramuscular—Rapid ^{04}; 5 ^{04} to 10 ^{{02} {15}} minutes following intramuscular administration, plasma concentrations are equivalent to those measured 10 minutes following intravenous administration.

Protein binding:

Very high ^{{02} {04} {05} {06}}, primarily to alpha and beta globulin fractions; binding to albumin is not significant. ^{02}

Biotransformation:

Hepatic ^{01}; undergoes extensive enterohepatic circulation ^{{02} {14}}.

Half-life:


Triphasic—Following a dose of 0.3 mg intravenously:

Distribution—2 minutes ^{{02} {15}}

Redistribution—18 minutes ^{15}

Elimination—1.2 to 7.2 hours ^{01}; average 2 to 3 hours. ^{{02} {15}}


Onset of action:


Analgesic:

Intramuscular: About 15 minutes ^{{01} {04}}

Intravenous: More rapid than with intramuscular administration. ^{{01} {04}}



Antagonist:

When used to antagonize effects of fentanyl or sufentanil used in conjunction with nitrous oxide for anesthesia: 15 minutes ^{02}.



Respiratory depressant:

1 to 3 hours following intramuscular administration ^{42}.


Note: Pharmacokinetic studies have demonstrated no apparent relationship between the onset of buprenorphine's activity and its plasma concentration. ^{{04} {15}}


Time to peak concentration:

Intramuscular—2 to 5 minutes ^{{02} {15}}

Intravenous—2 minutes ^{{02} {15}}

Peak plasma concentration

Intravenous—18 nanograms per mL following a 0.3-mg dose ^{{02} {15}}.

Time to peak effect:


Analgesic:

Intramuscular: 1 hour ^{{01} {19}}

Intravenous: Somewhat less than with intramuscular injection ^{01}.



Antagonist:

When used to antagonize effects of fentanyl or sufentanil used in conjunction with nitrous oxide for anesthesia: 1.5 to 2 hours ^{02}.


Duration of action:


Analgesia:


Adults—

Intramuscular or intravenous—Up to 6 hours in most patients ^{{01} {02} {04} {20}}, but 10 hours or longer in some studies ^{{02} {20} {33}}.

Epidural—12 hours following a 0.3-mg dose; 6 hours following a 0.15-mg dose ^{16} (when administered concurrently with a local anesthetic) ^{46}.



Children 2 to 12 years of age—

4 to 5 hours ^{45}




Antagonist:

When used to antagonize effects of fentanyl or sufentanil used in conjunction with nitrous oxide for anesthesia: 4 hours ^{02}.

Following chronic administration of large doses of buprenorphine: In one study in opioid addicts receiving chronic administration of 8 mg per day of buprenorphine subcutaneously, the effects of large doses (up to 120 mg) of subsequently administered morphine were blocked for more than 30 hours following the last dose of buprenorphine ^{{02} {04} {05} {21} {32}}.



Respiratory depression:

May persist significantly ^{41} longer than morphine-induced respiratory depression ^{{04} {05}}.


Note: Pharmacokinetic studies have demonstrated no apparent relationship between the duration of buprenorphine's activity and its plasma concentration ^{{04} {15}}. The medication's prolonged duration of action is more likely related to its slow rate of dissociation from receptor binding sites ^{{01} {02} {04} {08} {15}}.


Elimination:
    Primarily biliary/fecal ^{{02} {04} {05} {14}}; about 68% ^{{04} {05} {14}}(range 50 to 71%) ^{02} of an intramuscular dose is eliminated in the feces as unchanged buprenorphine ^{{02} {04} {05} {14}} within 7 days ^{02}. Up to 27% of an intramuscular dose ^{{02} {04} {05} {14}} may be excreted in the urine as conjugated buprenorphine and as a dealkylated metabolite ^{{04} {05} {14}}; little if any unchanged buprenorphine appears in the urine ^{14}. It has been proposed that the medication undergoes extensive enterohepatic circulation ^{{02} {14}} and is excreted into the bile as inactive conjugates, which are subsequently hydrolyzed in the gastrointestinal tract ^{02}.

Note: A study in a limited number of pediatric patients 3 to 5 years of age showed that clearance of buprenorphine in children, although subject to high interpatient variability, may be more rapid than in adults ^{45}.



Precautions to Consider

Carcinogenicity

Studies in animals have not shown that buprenorphine has carcinogenic potential ^{02}.

Mutagenicity

Studies utilizing in vitro and in vivo test systems have shown some evidence of mutagenicity with very high concentrations or doses in some test systems but not in others using similar concentrations or doses ^{02}.

Pregnancy/Reproduction
Fertility—
Reproduction studies with rats have not shown evidence of impaired fertility with subcutaneous or intramuscular administration of 0.05, 0.5, or 5 mg per kg of body weight per day (up to 1000 times the human dose) ^{{01} {02}}.

Pregnancy—
Adequate and well-controlled studies in humans have not been done ^{{01} {02}}.

Studies in rats administered up to 1000 times the human dose intramuscularly or up to 160 times the human dose intravenously showed no evidence of teratogenicity. However, studies in rabbits showed a dose-related trend toward extra rib formation, which was statistically significant with intramuscular administration of 1000 times the human dose. Also, studies in rats showed an increased incidence of postimplantation losses and early fetal deaths with intramuscular administration of 10 or 100, but not 1000, times the human dose per day. A slight increase in postimplantation losses, possibly treatment-related, also occurred in rats receiving up to 160 times the human dose intravenously. In addition, intramuscular administration of 1000 times the human dose per day to rats throughout gestation caused dystocia, a high incidence of neonatal mortality, and a slow growth rate in surviving offspring. ^{{01} {02}}

FDA Pregnancy Category C ^{{01} {02}}.


Labor and delivery—

Safe use of buprenorphine in labor and delivery has not been established ^{01}. However, it has been recommended that the medication not be used during labor because of potential respiratory depressant effects in the neonate, which may be very difficult to reverse ^{{34} {35}}.

Breast-feeding

Although it is not known whether buprenorphine is distributed into human breast milk ^{{01} {02}}, problems in humans have not been documented. Concentrations in the milk of lactating animals have been shown to equal or exceed maternal plasma concentrations ^{02}; it is reasonable to assume that this highly lipophilic medication would be distributed into human breast milk also ^{01}. In addition, animal studies have shown that administration of buprenorphine throughout the periods of gestation and lactation inhibits milk production ^{01}.

Pediatrics

Appropriate studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of buprenorphine in children 2 years of age and older ^{45}.


Geriatrics


Geriatric patients may be more sensitive to the effects, especially the respiratory depressant effects, of opioid analgesics ^{38}, including buprenorphine ^{01}. Also, elderly patients are more likely to have age-related renal function impairment, which may require caution and dosage adjustment in patients receiving buprenorphine. It is recommended that initial dosage for these patients be reduced by one-half. ^{44} However, geriatric patients may also be more sensitive to the analgesic effects of the medication so that lower doses and/or a longer interval between doses may provide sufficient analgesia ^{38}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Other interactions applying to opioid analgesics may apply to buprenorphine also, although documentation is currently not available.

» CNS depression–producing medications, other (See Appendix II ) or
Monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine, and selegiline    (concurrent use may increase the CNS depressant, respiratory depressant, and hypotensive effects of these medications and/or buprenorphine; caution is recommended; ^{{01} {38}} it is recommended that dosage of buprenorphine be reduced by one-half; a reduction in dosage of the other agent may also be required ^{44})


Naltrexone    (although not documented, the possibility must be considered that usual doses of buprenorphine will be ineffective if administered to a patient receiving naltrexone therapy [because naltrexone blocks the therapeutic effects of other potent opioids] and that administration of increased doses of buprenorphine to override naltrexone-induced blockade of opioid receptors may increase the risk of adverse effects)


» Opioid analgesics, other    (if administered prior to another opioid analgesic, buprenorphine may reduce the therapeutic effects of the other opioid ^{{07} {23}};in one study in opioid addicts receiving chronic administration of 8 mg per day of buprenorphine, the effects of large doses [up to 120 mg] of morphine were blocked during buprenorphine therapy and for at least 30 hours following the last dose of buprenorphine)

^{{02}{04}{05}{21}{32}}    (buprenorphine antagonizes the respiratory depressant effects of large doses of previously administered opioids; however, additive respiratory depression may occur if buprenorphine is administered in conjunction with low doses of other opioids ^{{02} {04} {07}})

    (when administered following fentanyl derivative–assisted anesthesia, buprenorphine may reverse the respiratory depressant effects of fentanyl or its derivatives [alfentanil and sufentanil] while providing adequate postoperative analgesia ^{{02} {04} {07}}; however, in one study, administration of 0.3 or 0.45 mg of buprenorphine intramuscularly every 6 hours following opioid-assisted anesthesia with total doses of 0.2 or 0.3 mg of fentanyl or 1.75 or 4 mg of phenoperidine [not available in the U.S.] caused a higher incidence of hypotension, respiratory depression, and CNS depression than equianalgesic doses [10 or 15 mg] of morphine intramuscularly every 6 hours ^{21})

    (buprenorphine may precipitate withdrawal symptoms in physically dependent patients who are chronically receiving potent mu-receptor agonists such as morphine ^{{01} {03} {04} {05} {07} {08} {10}}; however, because of its partial agonist activity, buprenorphine may partially suppress spontaneous withdrawal symptoms caused by abrupt discontinuation of opioid agonists ^{{07} {08} {13}})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Gastric emptying studies    (buprenorphine may delay gastric emptying, thereby invalidating test results)


Hepatobiliary imaging using technetium Tc 99m disofenin    (delivery of technetium Tc 99m disofenin to the small bowel may be prevented because of buprenorphine-induced constriction of the sphincter of Oddi and increased biliary tract pressure; these actions result in delayed visualization and thus resemble obstruction of the common bile duct ^{43})

With physiology/laboratory test values
Amylase, plasma and
Lipase, plasma    (values may be increased because buprenorphine can cause contractions of the sphincter of Oddi ^{38} and increased biliary tract pressure ^{01}; the diagnostic utility of determinations of these enzymes may be compromised for up to 24 hours after medication has been given ^{38})


Cerebrospinal fluid (CSF) pressure    (may be increased ^{01}; effect is secondary to respiratory depression–induced carbon dioxide retention)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist ^{{01} {38}}:
» Diarrhea caused by poisoning, until toxic material has been eliminated from gastrointestinal tract    (may slow elimination of toxic material)


» Respiratory depression, acute    (may be exacerbated)


Risk-benefit should be considered when the following medical problems exist
Abdominal conditions, acute    (diagnosis or clinical course may be obscured)


» Asthma, acute attack or
» Respiratory impairment or disease, chronic    (opioids may decrease respiratory drive and increase airway resistance in these patients; it is recommended that dosage be reduced by one-half, ^{44} unless the patient is being mechanically ventilated)


Cardiac arrhythmias or
Seizures, history of    (may be induced or exacerbated by opioids)


Dependence on opioid analgesics, current    (buprenorphine may precipitate withdrawal symptoms if patient is currently receiving other opioids)


Drug abuse or dependence, history of, including acute alcoholism or
Emotional instability or
Suicidal ideation or attempts    (increased risk of opioid abuse)


Gallbladder disease or gallstones    (opioids may cause biliary colic)


Gastrointestinal tract surgery, recent    (opioids may alter gastrointestinal motility)


Head injury or
Increased intracranial pressure, pre-existing or
Intracranial lesions    (risk of respiratory depression and further elevation of cerebrospinal fluid pressure is increased; also, opioids may cause sedation and pupillary changes that may obscure clinical course of head injury)


Hepatic function impairment    (opioids metabolized in liver)


Hypothyroidism    (risk of respiratory depression and prolonged CNS depression is greatly increased)


» Inflammatory bowel disease, severe    (risk of toxic megacolon may be increased, especially with repeated dosing)


Prostatic hypertrophy or obstruction or
Urethral stricture or
Urinary tract surgery, recent    (opioids may cause urinary retention)


Renal function impairment    (buprenorphine metabolites excreted via kidneys; also, may cause urinary retention)


Sensitivity to buprenorphine, history of
Caution is also advised in administration to geriatric or very ill or debilitated patients, who may be more sensitive to the effects, especially the respiratory depressant effects, of buprenorphine.




Side/Adverse Effects

Note: Buprenorphine appears less likely than other opioid agonist/antagonist analgesics to cause the subjective and psychotomimetic effects characteristic of this class of drugs ^{{02} {07} {08}}. These effects may include several or all of the following, occurring as a group: confusion, delusions, feelings of depersonalization or unreality, hallucinations (usually visual), dysphoria, nightmares, and nervousness or anxiety ^{38}. However, several of these effects have been reported individually (incidence < 1%) in patients receiving buprenorphine ^{01}.
Buprenorphine may have less dependence or abuse liability than other potent opioid analgesics ^{{01} {02} {04} {08} {32}}. However, abuse has been reported ^{{08} {29}}.
In some studies, the incidence and/or severity of nausea and vomiting occurring with buprenorphine was greater than that induced by meperidine ^{17} or morphine ^{{18} {24}}.
Epidural administration of buprenorphine may be associated with a lower incidence of adverse effects, such as late respiratory depression, pruritus, and urinary retention, than has been reported with epidural morphine ^{16}. However, early respiratory depression resistant to naloxone therapy has been reported. Also, signs of shock (pallor, cold skin, low blood pressure, and tachycardia) have been reported in a few patients following epidural buprenorphine. Although these signs eventually abated spontaneously, naloxone and other treatments were not effective in reversing them. ^{36}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence 1 to 5% ^{01}
    
Decreased blood pressure
    
respiratory depression, mild (unusually slow breathing)^{42}
Note: Whether buprenorphine's respiratory depressant activity is subject to the same ceiling effect (i.e., the depth of respiratory depression is not increased with higher doses) reported for other opioid agonist/antagonist drugs has not been established in humans ^{{05} {07}}. Studies in animals indicate that such a ceiling effect may occur, but at higher dosage levels than with other opioid agonist/antagonist drugs ^{41}.



Incidence <1% ^{01}
    
CNS effects (confusion, hallucinations, mental depression or other mood or mental changes; psychosis^{45}; ringing or buzzing in ears)
    
conjunctivitis ^{44}(red and/or irritated eyes)
    
dermatitis, allergic (skin rash, hives, or itching)
    
increased blood presssure
    
increased or decreased heart rate
    
paresthesia (pain, numbness, tingling, or burning feeling in hands or feet)
    
respiratory depression, severe (blue color of face, lips, or fingernails; difficult or troubled breathing)^{42}
    
urinary retention (decrease in amount of urine; swelling of face, fingers, hands, feet, or lower legs; weight gain)
    
Wenckebach block



Those indicating need for medical attention only if they continue or are bothersome
Incidence up to 66% ^{01}
    
Drowsiness

Incidence 5 to 10% ^{01}
    
Dizziness or lightheadedness
    
nausea —especially in ambulatory patients

Incidence 1 to 5% ^{01}
    
Headache
    
increased sweating
    
vomiting —especially in ambulatory patients

Incidence <1% ^{01}
    
Blurred vision or any change in vision
    
false sense of well-being
    
general feeling of discomfort or illness
    
pain, redness, or swelling at place of injection
    
slurred speech
    
trembling
    
unusual nervousness
    
unusual tiredness
    
unusual weakness



Those indicating possible withdrawal and the need for medical attention if they occur within 15 days after medication is discontinued
    
Body aches
    
diarrhea
    
fast heartbeat
    
gooseflesh
    
increased sweating
    
loss of appetite
    
nausea or vomiting
    
nervousness, restlessness, or irritability
    
runny nose
    
shivering or trembling
    
sneezing
    
stomach cramps
    
trouble in sleeping
    
unexplained fever
    
unusually large pupils of eyes
    
weakness^{38}
    
yawning




Overdose
For specific information on the agents used in the management of buprenorphine overdose, see:
   • Naloxone (Systemic) monograph; and/or
   • Doxapram (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and chronic ^{38}
    
Cold, clammy skin
    
confusion
    
convulsions
    
dizziness, severe
    
drowsiness, severe
    
low blood pressure
    
nervousness or restlessness, severe
    
pinpoint pupils of eyes
    
slow heartbeat
    
slow or troubled breathing
    
unconsciousness
    
weakness, severe


Treatment of overdose
Specific treatment—Use of the opioid antagonist naloxone for buprenorphine-induced respiratory depression ^{{01} {38}}. However, even in doses as high as 16 mg, naloxone may not completely antagonize buprenorphine-induced respiratory depression or other adverse effects ^{{01} {02} {04} {05} {07} {08} {21}}.

The respiratory stimulant doxapram may be administered if naloxone fails to reverse respiratory depression ^{{01} {06}}.

Assisted or controlled ventilation may be necessary despite administration of naloxone and/or doxapram ^{01}.

Monitoring—May include monitoring the respiratory and cardiac status of the patient ^{01}.

May include continual monitoring of the patient so that additional naloxone and/or doxapram may be administered as needed. Administration of these medications by continuous intravenous infusion, with the rate of infusion being adjusted according to patient response, may be preferable to intermittent administration. ^{{06} {38}}

Supportive care—May include establishing adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled respiration using 100% oxygen ^{41} if respiratory depression is severe; if respiratory depression is mild, i.e., a conscious and responsive patient is breathing unusually slowly (but without difficulty) and/or coaching the patient to breathe produces improvement, these measures may not be required.

May include administering intravenous fluids, vasopressors, and other supportive measures as needed ^{{01} {38}}.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Narcotic Analgesics (Systemic—For Pain Relief) and Narcotic Analgesics (Systemic—For Surgery and Obstetrics).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Allergic reaction to buprenorphine, history of





Breast-feeding—Buprenorphine has inhibited milk production in animal studies





Use in the elderly—Lower doses recommended because of increased sensitivity to opioids
Other medications, especially other CNS depression–producing medications and other opioids
Medical problems, especially diarrhea caused by poisoning, respiratory depression or disease (including asthma), and severe inflammatory bowel disease

Proper use of this medication
Proper administration technique (if dispensed for home use)

» Importance of not taking more medication than the amount prescribed because of danger of overdose and habit-forming potential

» Not increasing dose if medication is less effective after a few weeks; checking with physician
Missed dose (if on scheduled dosing): Using as soon as possible; not using if almost time for next dose; not doubling doses

» Proper dosing

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress during long-term therapy

» Avoiding alcohol or other CNS depressants during therapy

» Caution if dizziness, drowsiness, lightheadedness, or false sense of well-being occurs

Caution when getting up suddenly from a lying or sitting position

Lying down if nausea, vomiting, dizziness, or lightheadedness occurs

Caution if any kind of surgery (including dental surgery) or emergency treatment is required

» Checking with physician before discontinuing medication after prolonged use of high doses; gradual dosage reduction may be necessary to avoid withdrawal symptoms

» Suspected overdose: Getting emergency help at once


Side/adverse effects
Signs and symptoms of potential side effects, especially respiratory and/or CNS depression, allergic dermatitis, hallucinations, and overdose


General Dosing Information
Intramuscular administration of 300 mcg (0.3 mg) of buprenorphine provides analgesia equivalent to that produced by intramuscular administration of 10 mg of morphine ^{{08} {19}}.

Buprenorphine may suppress respiration, especially in geriatric, very ill, or debilitated patients and patients with respiratory problems ^{01}. It is recommended that dosage for these patients be reduced by one-half initially, then adjusted as required and tolerated. However, geriatric patients may also be more sensitive to the analgesic effects of the medication so that lower doses and/or a longer interval between doses may be sufficient to provide effective analgesia. ^{38}

Dosage and dosing intervals should be individualized on the basis of the severity of pain, the condition of the patient, other medications given concurrently, and patient response ^{38}.

Some clinicians recommend that patients in chronic pain due to neoplastic disease receive opioid analgesics on a fixed dosage schedule in order that they remain free of pain rather than on an as needed basis after pain recurs ^{38}.

Concurrent administration of a non-opioid analgesic (such as aspirin or other salicylates, other nonsteroidal anti-inflammatory analgesics, or acetaminophen) with opioid analgesics provides additive analgesia and may permit lower doses of the opioid analgesic to be utilized ^{38}.

Although buprenorphine may have less potential for causing habituation or abuse than other opioid analgesics ^{{01} {02} {04} {08} {32}}, psychological and physical dependence may occur with chronic administration ^{{02} {04} {05} {07} {08}}. An abstinence syndrome may be precipitated when the medication is abruptly discontinued. ^{{02} {04} {05} {07} {08}} Although withdrawal symptoms may not reach maximum intensity ^{{04} {05} {32}} for up to 15 days following discontinuation, if they occur they may persist for 1 to 2 weeks. ^{{05} {07} {08} {32}} Also, abuse has been reported ^{{08} {29}}.

Rapid intravenous injection of most opioid analgesics has caused anaphylactoid reactions, severe respiratory depression, hypotension, peripheral circulatory collapse, and cardiac arrest. Although these effects have not been documented with buprenorphine, the same precautions applying to other opioid analgesics may apply, i.e., administering the medication slowly, with an opioid antagonist and equipment for artificial ventilation available. ^{38} It is recommended that intravenous injections of buprenorphine be administered over at least 2 minutes ^{44}.

Frequent monitoring of the patient's respiratory status is recommended during buprenorphine therapy ^{42} because of the risk of respiratory depression ^{28}.

When an opioid analgesic is administered parenterally, the patient usually should be lying down and should remain recumbent for a period of time to minimize side effects such as hypotension, dizziness, lightheadedness, nausea, and vomiting. If these side effects occur in an ambulatory patient, they may be relieved if the patient lies down. ^{38}

In patients with shock, impaired perfusion may prevent complete absorption following intramuscular injection. Repeated administration may result in overdose due to an excessive amount suddenly being absorbed when circulation is restored. ^{38}

Tolerance to buprenorphine requiring increased dosage to maintain adequate analgesia has not occurred in long-term studies in cancer patients ^{{04} {20} {37}}. However, tolerance has been demonstrated in studies with opioid addicts ^{41}.


Parenteral Dosage Forms

Note: The dosing and strength of the available dosage form are expressed in terms of buprenorphine base (not the hydrochloride salt).


BUPRENORPHINE HYDROCHLORIDE INJECTION

Usual adult and adolescent dose
Analgesic
Intramuscular or slow intravenous, 300 mcg (0.3 mg) (base) every six or more hours as needed ^{01}. An additional dose of up to 300 mcg (0.3 mg) may be administered thirty to sixty minutes following the initial dose, if necessary.


Note: Dosage may be increased to 600 mcg (0.6 mg) ^{{01} {02}}, or the frequency of administration may be increased to every four hours ^{02} if necessary, depending upon the severity of pain and patient response. This larger dose should be administered only via the intramuscular route and only to patients who are not at high risk for opioid toxicity ^{45}. Although doses exceeding 600 mcg (0.6 mg) have been administered in some studies, long-term use of such doses is not recommended because of insufficient data ^{01}.


Usual pediatric dose
Analgesic
Children up to 2 years of age: Dosage has not been established.

Children 2 to 12 years of age: Intramuscular or slow intravenous, 2 to 6 mcg (0.002 to 0.006 mg) (base) per kg of body weight every four to six hours or as needed ^{45}.

Note: Because of interpatient variability in buprenorphine clearance, it is recommended that the appropriate dosing interval for an individual pediatric patient be determined before a fixed-interval dosing regimen is scheduled ^{45}.



Strength(s) usually available
U.S.—



Without preservative


300 mcg (0.3 mg) (base) per mL (Rx) [Buprenex (dextrose 5%)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing. Avoid prolonged exposure to light.

Incompatibilities:
Buprenorphine injection is chemically incompatible with diazepam and with lorazepam.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.
   • May be habit-forming.

Note: Controlled substance in the U.S.

Revised: 07/29/1994

References

1. Buprenex package insert (Norwich Eaton—US), Rev 6/85.
   

2. Buprenex product monograph (Norwich Eaton—US), 6/85.
   

3. Temgesic Data Sheet. In: Association of the British Pharmaceutical Industry Data Sheet Compendium. 1985-1986: 1197-8.
   

4. AMA Drug evaluations. 5th ed. Chicago: American Medical Association, April 1983: 85-7.
   

5. Goodman and Gilman's the pharmacological basis of therapeutics. 6th ed. 1980: 528.
   

6. Avery GS. Drug treatment. 2nd ed. 1980: 325-6, 1213.
   

7. Kaplan JA, editor. Cardiac anesthesia. Vol 2. Cardiovascular pharmacology. 1983: 65-9.
   

8. Drug Alcohol Depend 1984; 14: 363-72.
   

9. J Neurochem 1982; 38: 1771-3.
   

10. Br J Clin Pharmacol 1979; 7 (suppl 3): 297S-308S.
    

11. Br J Clin Pharmacol 1982; 13: 665-73.
    

12. Pharmaceutical Res 1985 July; 151-94.
    

13. Clin Pharmacol Ther 1984; 36: 127-32.
    

14. Drug Metab Dispos 1984; 12: 577-81.
    

15. Clin Pharmacol Ther 1980; 28: 667-72.
    

16. Anesth Analg 1984; 63: 593-8.
    

17. Br Med J 1982; 284: 1830-1.
    

18. Br J Clin Pharmaol 1982; 13: 487-92.
    

19. J Clin Pharmacol 1982; 22: 165-72.
    

20. Clin Ther 1982; 5: 61-8.
    

21. Br J Anaesth 1982; 54: 285-90.
    

22. Br Med J 1979; 280: 300-2.
    

23. Anaesthesia 1985; 40: 371-5.
    

24. Anaesthesia 1984; 39: 324-8.
    

25. Br J Anaesth 1985; 57: 271-4.
    

26. Br J Anaesth 1983; 55: 21-5.
    

27. Br Med J 1981; 283: 1185.
    

28. Br Med J 1985.
    

29. Br Med J 1984; 288: 1917.
    

30. Br Med J 1983; 286: 763-4.
    

31. Br Med J 1978; 2(6152): 1602-3.
    

32. Arch Gen Psychiatry 1978; 35: 501-16.
    

33. Br J Anaesth 1978; 50: 605-9.
    

34. Dukes MNG, editor. Meyler's side effects of drugs. An encyclopedia of adverse reactions and interactions. 10th ed. Amsterdam: Elsevier, 1984: 130-1.
    

35. Reynolds JEF, editor. Martindale, the extra pharmacopeia. 28th ed. London: The Pharmaceutical Press, 1982: 1002.
    

36. Dukes MNG, editor. Side effects of drugs annual 8. Amsterdam: Elsevier, 1984: 80.
    

37. Br J Clin Pharmacol 1979; 7(suppl 3): 315S-317S.
    

38. Panel consensus, Opioid (Narcotic) Analgesics (Systemic) monograph draft for USPDI 1986.
    

39. Panel consensus, Doxapram (Systemic) monograph draft for USPDI 1986.
    

40. Fleeger CA, editor. USAN 1994. USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1993: 103.
    

41. Panel consensus draft for USPDI 1986.
    

42. Manufacturer comment.
    

43. Technetium Tc 99m disofenin monograph; reviewer comment.
    

44. Buprenex package insert (Norwich Eaton—US), Rev 11/87, Rec 11/88.
    

45. Buprenex package insert (Reckitt & Colman). In: PDR Physicians' desk reference. 48th ed. 1994. Montvale, NJ: Medical Economics Data Production Company, 1994: 1834-5.
    

46. Panel comment, 5/94.
    

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