Skip to Content

Buprenorphine Hydrochloride


Class: Opiate Partial Agonists
VA Class: CN101
Chemical Name: 6,14-Ethenomorphinan-7-methanol, 17 - (cyclopropylmethyl) - α - (1,1 - dimethylethyl) - 4,5 - epoxy - 18,19 - dihydro - 3 - hydroxy - 6 - methoxy - α - methyl - , [5α,7α,(S)]
Molecular Formula: C29H41NO4C29H41NO4•HCl
CAS Number: 52485-79-7
Brands: Buprenex, Butrans, Suboxone, Subutex


Special Alerts:

[Posted 03/22/2016]

AUDIENCE: Family Practice, Psychiatry, Pain Management, Nursing, Endocrinology

ISSUE: FDA is warning about several safety issues with the entire class of opioid pain medicines. See the for a complete listing. These safety risks are potentially harmful interactions with numerous other medications, problems with the adrenal glands, and decreased sex hormone levels. We are requiring changes to the labels of all opioid drugs to warn about these risks.

BACKGROUND: Opioids are powerful prescription medicines that can help manage pain when other treatments and medicines are not able to provide enough pain relief (see List of Opioid Medicines in the ). However, opioids also carry serious risks, including of misuse and abuse, addiction, overdose, and death.

Prescription opioids are divided into two main categories – immediate-release (IR) products, usually intended for use every 4 to 6 hours; and extended release/long acting (ER/LA) products, intended to be taken once or twice a day, depending on the individual product and patient.

See the for additional information, including a listing of opioids, serotonergic medicines, and a data summary.


Serotonin syndrome:

Health care professionals should discontinue opioid treatment and/or use of the other medicine if serotonin syndrome is suspected.

Adrenal insufficiency:

Health care professionals should perform diagnostic testing if adrenal insufficiency is suspected. If diagnosed, treat with corticosteroids and wean the patient off of the opioid, if appropriate. If the opioid can be discontinued, follow-up assessment of adrenal function should be performed to determine if treatment with corticosteroids can be discontinued.

Decreased sex hormone levels:

Health care professionals should conduct laboratory evaluation in patients presenting with such signs or symptoms.

For more information visit the FDA website at: and .


FDA approved a REMS for buprenorphine to ensure that the benefits outweigh the risk. (See REMS: Butrans and REMS: Suboxone, under Dosage and Administration.) The REMS may apply to one or more preparations of buprenorphine and may consist of the following: medication guide, elements to assure safe use, and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center ().


  • Transdermal Systems
  • Indicated for management of moderate to severe chronic pain requiring continuous, around-the-clock opiate analgesia for an extended period.213

  • Potential for abuse of buprenorphine is similar to that of other opiates.213 Clinicians should consider abuse potential when prescribing or dispensing buprenorphine transdermal systems in situations where they are concerned about an increased risk of misuse, abuse, or diversion.213 Individuals at risk for opiate abuse include those with a personal or family history of substance abuse (e.g., alcohol or drug abuse or addiction) or psychiatric disorders (e.g., major depression).213 Assess patient for abuse or addiction potential before prescribing opiates; monitor for misuse, abuse, and addiction during therapy.213

  • Risk of QT interval prolongation; do not exceed a dosage of 20 mcg/hour of transdermal buprenorphine.213 (See Cardiac Effects under Cautions.)

  • Do not expose the transdermal application site or surrounding area to direct external heat sources; temperature-dependent increases in buprenorphine release from the system may result in overdosage and death.213 (See Patients with Fever or Exposure to High Temperatures under Cautions.)


Analgesic; opiate partial agonist.1 2 3 4 6 7 10 11 202 213 214

Uses for Buprenorphine Hydrochloride

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.


Used parenterally for relief of moderate to severe pain1 2 3 4 124 183 185 such as that associated with acute and chronic medical disorders including cancer,31 65 71 99 134 143 trigeminal neuralgia,47 accidental trauma,73 ureteral calculi,98 and MI.4 71 150

Used parenterally for management of postoperative pain in patients who have undergone various types of surgery, including neurologic,138 cardiovascular (e.g., CABG, valve replacement),4 66 71 185 cesarean section,28 71 82 110 gynecologic,28 60 69 71 80 124 149 151 177 abdominal (e.g., cholecystectomy, bowel resection),28 32 44 54 64 69 71 73 76 103 145 151 184 185 urologic,28 124 185 general (e.g., head and neck, breast),53 60 151 and orthopedic (e.g., total hip replacement, spinal fusion).23 26 32 83 92 145 185

Used transdermally for management of moderate to severe chronic pain in patients requiring continuous opiate administration for an extended period.213

Has been used parenterally for preoperative sedation and analgesia35 58 60 127 140 148 and as an adjunct to surgical anesthesia.24 49 58 60 62 71 121 135 142 149 192

Do not use sublingual formulations for analgesia.214 Fatal overdosage reported with such use in opiate-naive individuals.214

Opiate Dependence

Used sublingually for treatment of opiate dependence in an office-based outpatient setting (designated an orphan drug by FDA for this use); used alone and in fixed combination with naloxone.201 202 214

Buprenorphine alone is preferred for the initial (i.e., induction) phase of treatment, administered under the supervision of the prescribing physician in the office setting.202 203 Following induction, buprenorphine in fixed combination with naloxone is preferred for maintenance treatment when use includes unsupervised administration.202 214 Administration of buprenorphine without naloxone in an unsupervised setting should be limited to patients who cannot tolerate naloxone.202

Safety and efficacy of transdermal buprenorphine for treatment of opiate dependence not established.213

Buprenorphine Hydrochloride Dosage and Administration


  • REMS: Butrans
  • FDA has approved a REMS for buprenorphine transdermal systems (Butrans).215 (See REMS.)

  • The REMS requires that a medication guide be provided to the patient each time this formulation is dispensed and outlines a plan to ensure training is provided to clinicians who prescribe this formulation.215

  • Retraining will occur every 2 years, or sooner if the training materials require substantial revision.215 Submission of the training confirmation form does not affect the clinician’s ability to prescribe the drug.215

  • REMS: Suboxone
  • FDA has approved a REMS for sublingually dissolving strips containing buprenorphine in fixed combination with naloxone (Suboxone).216 (See REMS.)

  • The REMS requires that a medication guide be provided to the patient each time this formulation is dispensed and outlines steps to ensure documentation of safe use conditions and proper monitoring for each patient receiving the formulation.216

  • REMS communications are directed to physicians certified under the Drug Addiction Treatment Act (DATA) of 2000 and to pharmacists.216 (See Restricted Distribution Program under Administration.)

  • REMS requirement does not apply when the sublingually dissolving strips are dispensed to patients admitted to an opiate treatment program.216

  • Opiate Dependence
  • To avoid precipitating withdrawal, give the first dose of buprenorphine when clear, objective signs of opiate withdrawal are evident.202 214 In individuals using heroin or other short-acting opiates, administer the first dose ≥4 hours after the last use of the opiate; however, it is preferable to initiate buprenorphine when early signs of opiate withdrawal appear.202

  • Withdrawal symptoms can occur during buprenorphine induction in patients being transferred from methadone maintenance; withdrawal symptoms appear to be more likely in those receiving higher methadone dosages (>30 mg daily) and when the first dose of buprenorphine is given shortly after the last methadone dose.202


Administer by IM or IV injection for relief of pain.1 2 3 Administer transdermally for management of chronic pain only.213 Administer sublingually as a single agent or in fixed combination with naloxone for management of opiate dependence.202 214

Also administered by continuous IV infusion,32 33 34 by IM103 or IV76 79 injection using a patient-controlled infusion device, and by epidural injection for pain relief.23 24 25 26 28 29 30 31 50 78 92 192

For drug compatibility information, see Compatibility under Stability.

Sublingual Administration

Administer as a single daily dose.202 214

Sublingual Tablets

Place tablets under the tongue and allow to dissolve; swallowing the tablets reduces bioavailability.202 Drinking warm fluids prior to administration may aid dissolution.204

For doses requiring >2 tablets, all the tablets may be placed under the tongue at once.202 Alternatively, patients may place 2 tablets under the tongue at a time if they are unable to place >2 tablets comfortably.202

To ensure consistent bioavailability, patients should adhere to the same manner of dosing with continued use.202

Sublingually Dissolving Strips

Place up to 2 strips under the tongue (on either side near the base of the tongue) in a way that minimizes overlapping, and allow to dissolve; patient should not talk while the strip is dissolving, chew the strip, or swallow the strip; these activities may alter absorption.214 219 Drinking water prior to administration may aid dissolution.214 219

For doses requiring >2 strips, place additional strip(s) under the tongue after the first 2 strips have completely dissolved.219

IV Injection

Rate of Administration

Administer over ≥2 minutes.1 2 3

Continuous IV Infusion


Dilute to a concentration of 15 mcg/mL in 0.9% sodium chloride.32

Rate of Administration

Administer via a controlled-infusion device.32

Epidural Injection


Has been diluted to a concentration of 6–30 mcg/mL in 0.9% sodium chloride.23 24 25 26 28 29 30 31 78 92 192

Transdermal Administration

To expose the adhesive surface of the system, peel off and discard the protective-liner covering just prior to application.213

Apply the transdermal system to a dry, intact, nonirritated, hairless or nearly hairless surface on the upper chest, upper back, side of chest, or upper outer arm by firmly pressing the system by hand for 15 seconds with the adhesive side touching the skin and ensuring that contact is complete, particularly around the edges.213 220

Clip, not shave, hair at the application site prior to application if needed.213

Only water should be used if the site must be cleaned before transdermal application;213 do not use soaps, oils, lotions, alcohol, or abrasive devices that could alter absorption of the drug.213 220

Do not use transdermal system if the seal of the package is broken or if the system is altered in any way (e.g., cut, damaged).213

Each transdermal system is intended to be worn continuously for 7 days; apply subsequent systems to a different site after removal of the previous system.213 220 At least 21 days should elapse before reusing any single application site.213

If a system should inadvertently come off during the period of use, apply a new system to a different skin site and leave in place for 7 days.213 220 The edges of the system may be taped in place with first-aid tape if the patient experiences difficulty with system adhesion.213 If adhesion problems persist, an adhesive film dressing (e.g., Bioclusive, Tegaderm) may be applied over the system.220 221

Restricted Distribution Program

The Drug Addiction Treatment Act (DATA) of 2000 allows qualifying physicians to prescribe and dispense opiates in schedules III, IV, and V of the Federal Controlled Substances Act that have been approved by FDA for detoxification or maintenance treatment of opiate dependence.205 Prior to passage of this law, opiate dependence treatment could be provided only at specially registered clinics.203 Under DATA 2000, prescription use of buprenorphine and buprenorphine/naloxone fixed combination in the treatment of opiate dependence is limited to physicians who meet certain requirements and have notified the Secretary of the US Department of Health and Human Services of their intent to prescribe these preparations for this indication.202

Pharmacists may utilize the DATA physician locator (at ) or contact 866-287-2728 or to verify whether a physician is in compliance with the provisions of DATA.203 225


Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as buprenorphine (transdermal systems) and buprenorphine hydrochloride (injection and sublingual tablets); dosage expressed in terms of buprenorphine.1 2 213

Also available as fixed combination of buprenorphine hydrochloride and naloxone hydrochloride (sublingual tablets, sublingually dissolving strips); dosage generally expressed in terms of the buprenorphine content.202 214

Pediatric Patients


Adjust dosage according to the severity of pain, physical status of the patient, and other drugs that the patient is receiving.1 2

IV or IM

Children 2–12 years of age: 2–6 mcg/kg every 4–6 hours; however, longer dosing intervals (e.g., every 6–8 hours) may be sufficient.1 Do not use a fixed around-the-clock dosing interval until an adequate dosing interval has been established by clinical observation of the patient.1

Children ≥13 years of age: 0.3 mg given at intervals of up to every 6 hours as necessary.1 2 3 Repeat initial dose (up to 0.3 mg) once in 30–60 minutes, if needed.1

Exercise particular caution with IV administration, especially with initial doses.1

Decrease dosage by approximately 50% in patients who are at increased risk of respiratory depression.1 (See Respiratory Depression under Cautions.)

Circumcision-related Pain

Children 9 months to 9 years of age undergoing circumcision: Initial dosage of 3 mcg/kg as an adjunct to surgical anesthesia, followed by additional 3-mcg/kg doses as necessary to provide analgesia postoperatively, has been used.27



Adjust dosage according to the severity of pain, physical status of the patient, and other drugs that the patient is receiving.1 2

IV or IM

0.3 mg given at intervals of up to every 6 hours as necessary.1 2 3 Repeat initial dose (up to 0.3 mg) once in 30–60 minutes, if needed.1 A dosing interval longer than 6 hours may be adequate in some patients.71 72 97 99

It may be necessary to administer single doses of up to 0.6 mg, but the manufacturer recommends that such relatively high doses only be administered IM and only to adults who are not at increased risk of respiratory depression.1

A regimen including an initial dose of 0.3 mg followed by another 0.3-mg dose repeated in 3 hours is as effective as a single 0.6-mg dose in relieving postoperative pain.129

Exercise particular caution with IV administration, especially with initial doses.1

Decrease dosage by approximately 50% in patients who are at increased risk of respiratory depression.1 (See Respiratory Depression under Cautions.)

Continuous IV Infusion

Dosages of 25–250 mcg/hour have been used for the management of postoperative pain.33 34

Epidural Injection

Dosages of 0.15–0.3 mg have been administered in the management of severe, chronic pain (e.g., in terminally ill patients) as frequently as every 6 hours, up to a mean total daily dosage of 0.86 mg (range: 0.15–7.2 mg).31

60 mcg as a single dose, up to a mean total dose of 180 mcg administered over a 48-hour period, has been used for the management of postoperative pain.23

Supplement to Surgical Anesthesia
Epidural Injection

Dosage of 0.3 mg has been used as a supplement to surgical anesthesia with a local anesthetic.24 192

Chronic Pain

When selecting the initial transdermal dose, consider the dose, potency, and characteristics of previous opiate regimens and the reliability of the potency estimate used to calculate an equivalent buprenorphine dosage; the patient’s degree of tolerance to adverse effects; the patient’s age and medical status; type and severity of pain; concurrent therapy; the acceptable balance between efficacy and adverse effects; and the patient’s risk factors for abuse, addiction, or diversion.213 Fatal overdosage possible with the first transdermal dose if the dose is overestimated.213

Manufacturer considers the following dosage recommendations to be suggested approaches to the individual management of each patient.213

Opiate-naive patients: Initiate with buprenorphine 5 mcg/hour.213

Patients previously receiving <30 mg daily of morphine sulfate (or equivalent): Initiate with buprenorphine 5 mcg/hour.213

Patients previously receiving 30–80 mg daily of morphine sulfate (or equivalent): Taper current opiate regimen for up to 7 days to a total 24-hour dosage of ≤30 mg of morphine sulfate (or equivalent) and initiate with buprenorphine 10 mcg/hour.213

Titration: Increase at minimum intervals of 72 hours to a level providing adequate analgesia and acceptable adverse effects, taking into account patient’s requirement for supplemental short-acting analgesics.213 Maximum transdermal dosage is 20 mcg/hour (see Cardiac Effects under Cautions).213

Discontinuance: Periodically reassess need for continued around-the-clock opiate therapy.213 When discontinuing therapy, taper dosage to prevent manifestations of withdrawal.213 Consider use of a short-acting opiate during tapering process.213

Opiate Dependence

Initially, buprenorphine 8 mg on day 1 and 16 mg on day 2.202 From day 3 onward, administer buprenorphine in fixed combination with naloxone at the same buprenorphine dose as on day 2.202

To avoid precipitating withdrawal, give the first dose when objective and clear signs of opiate withdrawal are evident.202 214

Manufacturer recommends that an adequate maintenance dosage, titrated to clinical effectiveness, be achieved as rapidly as possible to prevent undue opiate withdrawal symptoms.202


Target dosage of buprenorphine in fixed combination with naloxone is 16 mg daily; however, dosages as low as 12 mg daily may be effective in some patients.202 214 Adjust dosage in increments/decrements of 2 or 4 mg daily to a dosage that suppresses opiate withdrawal symptoms and ensures that the patient continues treatment.202 214

Usual dosage: 4–24 mg daily depending on the individual patient.202 214

If switching between buprenorphine/naloxone sublingual tablets and sublingually dissolving strips, continue same dosage.214 However, not all doses and dose combinations are bioequivalent; monitor for efficacy and tolerability and adjust dosage if needed.214 (See Bioavailability under Pharmacokinetics.)


The decision to discontinue therapy after a period of maintenance or brief stabilization should be made as part of a comprehensive treatment plan.202 214 Both gradual and abrupt discontinuance have been used; the best method for tapering dosage at the end of treatment has not been established.202 214

Prescribing Limits

Pediatric Patients

IV or IM

Children 2–12 years of age: Manufacturer states that there is insufficient evidence to recommend doses >6 mcg/kg or administration of a repeat dose within 30–60 minutes of the initial dose.1



There are insufficient clinical data to recommend single doses >0.6 mg for long-term use.1 2

Chronic Pain

Maximum 20 mcg/hour (see Cardiac Effects under Cautions).213

Special Populations

Hepatic Impairment

Chronic Pain

Mild to moderate hepatic impairment: Initiate at 5 mcg/hour; titrate dosage to an effective, tolerable level under close supervision.213

Severe hepatic impairment: Transdermal buprenorphine not studied in this population; consider an alternative analgesic regimen that allows for greater dosing flexibility.213

Opiate Dependence

Adjust dosage and monitor for manifestations of opiate withdrawal.202 214 Although both buprenorphine and naloxone are extensively metabolized, not known whether both drugs are affected to the same degree by hepatic impairment; increased concentrations of both drugs expected in patients with moderate or severe hepatic impairment.214

Renal Impairment

No specific dosage recommendations at this time.1 202 213 214

Geriatric Patients


Reduce parenteral dosage by approximately 50%.1

While specific transdermal dosage adjustments are not necessary based on age, use caution to ensure safe use.213 (See Geriatric Use under Cautions.)

Opiate Dependence

Select sublingual dosage with caution, usually starting at the low end of the dosage range, because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.214

Cautions for Buprenorphine Hydrochloride


  • Known hypersensitivity to buprenorphine or any ingredient (e.g., naloxone) in the formulation.1 2 202 213 214

  • Transdermal Buprenorphine
  • Paralytic ileus (diagnosed or suspected).213

  • Substantial respiratory depression or severe bronchial asthma.213

  • Management of acute, short-term, postoperative, mild, or intermittent pain.213



Respiratory Depression

The major toxicity associated with buprenorphine.1 2 4 18 28 33 39 44 48 58 59 62 64 71 73 75 76 84 89 93 95 97 184 185 213

Occurs more frequently in geriatric or debilitated patients, in those with conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation, or when given concomitantly with drugs that depress respiration.213

May occur especially with IV administration.202 214 Deaths have occurred when buprenorphine (usually in conjunction with a benzodiazepine) was misused via IV injection by opiate abusers.202 214 Deaths also have occurred when used with other depressants (e.g., alcohol, other opiates).202 214

Use with extreme caution in patients with pulmonary impairment or compromised respiratory function (e.g., those with COPD, cor pulmonale, decreased respiratory reserve [e.g., asthma, severe obesity, sleep apnea, myxedema, substantial kyphoscoliosis, CNS depression], hypoxia, hypercapnia, preexisting respiratory depression) and in those receiving other respiratory depressant drugs concomitantly.1 2 3 4 202 213 214

Naloxone1 2 3 4 9 21 40 64 71 84 and doxapram1 2 3 9 18 21 59 70 71 76 84 185 may be only partially effective in reversing buprenorphine-induced respiratory depression; use of assisted or controlled respiration may be necessary and should be considered the principal method of management.1 2 3 4 20 46 83

CNS Depression

May cause somnolence, dizziness, alterations in judgment, or alteration in level of consciousness, including coma.1 202 213 214 Use with caution in comatose patients or in patients with CNS depression.1

May impair mental alertness and/or physical coordination needed to perform potentially hazardous activities such as driving or operating machinery; warn patient about possible adverse CNS effects of opiate agonists.1 202 213 214

Concurrent use of other CNS depressants may potentiate CNS depression.1 202 213 214 (See Specific Drugs under Interactions.)

Hepatic Effects

Cytolytic hepatitis and hepatitis with jaundice reported in individuals receiving buprenorphine for opiate dependence.202 213 214

Other serious adverse hepatic events (e.g., hepatic failure, hepatic necrosis, hepatorenal syndrome, hepatic encephalopathy) reported.202 213 214 Some individuals had risk factors for such adverse events (i.e., preexisting hepatic enzyme abnormalities, HBV or HCV infection, concomitant use of potentially hepatotoxic drugs, ongoing illicit use of injectable drugs), but the possibility exists that buprenorphine had a causative or contributory role.202 213 214

Evaluate liver function prior to initiation of buprenorphine for the management of opiate dependence and periodically during treatment.202 214 Evaluate liver function prior to initiation of transdermal buprenorphine for analgesia and periodically during treatment in patients at increased risk of hepatotoxicity (e.g., history of excessive alcohol use, IV drug abuse, or liver disease).213 Evaluate carefully in the event of an adverse hepatic event.202 213 214

Cardiac Effects

QT-interval prolongation observed with transdermal dosage of 40 mcg/hour in healthy adults; do not exceed dosage of 20 mcg/hour.213

Take potential QT-interval prolongation into account when considering transdermal buprenorphine in patients with hypokalemia or clinically unstable cardiac disease (e.g., unstable atrial fibrillation, symptomatic bradycardia, unstable CHF, active myocardial ischemia).213

Avoid use of transdermal buprenorphine in patients with a personal or family (i.e., immediate family member) history of long QT syndrome and in patients who are receiving class IA (e.g., disopyramide, procainamide, quinidine) or class III (e.g., amiodarone, dofetilide, sotalol) antiarrhythmic agents.213

Hypotensive Effects

May cause severe hypotension, especially in patients whose ability to maintain their BP is compromised by depleted blood volume or concomitant drugs (e.g., phenothiazines).213 Use with caution in patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and BP.213

May produce orthostatic hypotension in ambulatory patients.202 213 214

Dependence and Abuse

Possible psychologic dependence to buprenorphine’s opiate agonist activity.1 12 112 Limited physical dependence may occur41 85 86 107 108 109 111 112 147 infrequently;1 2 4 74 178 tolerance to the drug’s opiate agonist activity develops rarely,107 109 171 178 if at all.84 96 123

Potential for abuse exists (see Boxed Warning).213 214

Clinicians should consider abuse potential when prescribing or dispensing buprenorphine in situations where they are concerned about an increased risk of misuse, abuse, or diversion.213 However, concerns about abuse, addiction, and diversion should not prevent the proper management of pain.213

When used for treatment of opiate dependence, clinical monitoring must be appropriate to patient’s level of stability.214 Do not authorize multiple refills during early stages of treatment or without appropriate follow-up visits.214

Withdrawal Effects

Sublingual administration of buprenorphine/naloxone fixed combination may cause withdrawal symptoms in individuals who are physically dependent on opiates if the fixed combination is administered before the agonist effects of the opiate have subsided.202 214

Marked and intense opiate withdrawal symptoms are likely if buprenorphine/naloxone fixed combination is misused via parenteral injection by individuals who are physically dependent on opiates.202 214

Buprenorphine may occasionally precipitate mild to moderate signs and symptoms of withdrawal in some patients physically dependent on opiates (because of the drug’s antagonist activity).1 2 87 100 112 183 202 Signs and symptoms of mild withdrawal may also appear following discontinuance of prolonged therapy with buprenorphine alone.4 71 84 100 112

Head Injury and Increased Intracranial Pressure

Respiratory depressant effects of buprenorphine (with CO2 retention and secondary elevation of CSF pressure) may be exaggerated in the presence of head injury, other intracranial lesions, or preexisting increase in intracranial pressure.1 213 214

Buprenorphine produces effects (e.g., pupillary changes) that may obscure neurologic signs of further increase in intracranial pressure in patients with head injuries.1 213 214

Use with caution in patients with head injury, other intracranial lesions, or preexisting elevation in intracranial pressure.1

Dermatologic Effects

Application site reactions (e.g., pruritus, erythema, rash) reported with transdermal administration;213 severe reactions (e.g., burning, discharge, vesicles) reported rarely.213 Reported days to months following initiation of therapy.213

Patients with Fever or Exposure to High Temperatures

Drug absorption from buprenorphine transdermal systems depends in part on the temperature of the skin and increases with increasing temperature.213

Monitor patients who develop a fever or whose core body temperature increases following strenuous exercise for manifestations of opiate toxicity and adjust dosage accordingly.213

Exposure of the application site or surrounding area to direct external heat sources (e.g., heating pads, electric blankets, heat or tanning lamps, saunas, hot tubs, hot baths, heated water beds, prolonged direct sunlight, hot water) may increase percutaneous absorption of buprenorphine; potential for overdosage and death.213 220 Avoid such exposure.213 220


May lower seizure threshold and aggravate seizure disorders or induce seizures in some clinical settings.213 Use with caution in patients with a history of seizure disorders.213

Sensitivity Reactions

Hypersensitivity Reactions

Acute and chronic hypersensitivity reactions reported.202 213 Rash,202 213 214 urticaria,202 213 214 and pruritus202 213 214 are most common;202 213 214 bronchospasm,202 213 214 angioedema,202 213 214 and anaphylactic shock202 213 214 also have occurred.202 213 214 (See Contraindications.)

General Precautions

Pancreatic and Biliary Disease

May increase pressure within the common bile duct and cause spasm of sphincter of Oddi.1 2 21 40 52 54 202 213 214

Use with caution in patients with dysfunction of the biliary tract,1 2 202 213 214 including acute pancreatitis,213 and those undergoing biliary tract surgery.54

Acute Abdominal Conditions

May obscure the diagnosis and/or clinical course of patients with acute abdominal conditions.202 213 214

Use with caution in patients at risk of ileus.213


Use with caution in patients with hypothyroidism.202 213 214

Addison’s Disease

Use with caution in patients with Addison’s disease.202 213 214

Prostatic Hypertrophy or Urethral Stricture

Use with caution in patients with prostatic hypertrophy or urethral stricture.202 213 214

Other Special Risk Patients

Use with caution in debilitated patients and in those with toxic psychoses, acute alcoholism, or delirium tremens.1 202 213 214

Fixed-combination Preparation

When buprenorphine is used in fixed combination with naloxone, consider the cautions, precautions, and contraindications associated with naloxone.202 214

Accidental Exposure

May cause severe or fatal respiratory depression in children accidentally exposed to the drug; store out of reach of children and promptly destroy unused dosage units.214 220


Concomitant use with certain drugs is not recommended or requires particular caution.202 213 214 (See Interactions: Specific Drugs.)

Specific Populations


Category C.1 202 213 214

Safety and efficacy during labor and delivery not established.1 2 213

Opiate withdrawal symptoms (e.g., hypertonia, tremor, agitation, myoclonus) reported in neonates after maternal use of buprenorphine or buprenorphine/naloxone for opiate dependence during pregnancy.202 214 Seizures, apnea, and bradycardia reported rarely.202 214 Onset of symptoms may occur on days 1–8 of life (usually day 1).202 214 Neonates whose mothers received transdermal buprenorphine during gestation also may be at risk; monitor closely for withdrawal signs.213


Distributed into milk.1 202 213 214 Women should not breast-feed infants while receiving buprenorphine.1 202 213 214

Pediatric Use

Safety and efficacy of parenteral buprenorphine as an analgesic not established in children <2 years of age.1 2 Has been used parenterally as a supplement to surgical anesthesia27 and as an analgesic in the management of postoperative pain1 27 and severe chronic pain (e.g., in terminally ill patients)94 in a limited number of children 9 months to 18 years of age.1 27 94

Safety and efficacy of transdermal buprenorphine for analgesia not established in patients <18 years of age.213

Safety and efficacy of buprenorphine and buprenorphine/naloxone sublingual tablets not established for the management of opiate dependence in children <16 years of age;202 safety and efficacy of buprenorphine/naloxone sublingually dissolving strips not established in children.214

Geriatric Use

Use with caution.1 202

Reduce parenteral dosage.1 (See Geriatric Patients under Dosage and Administration.)

Insufficient experience with sublingual formulations in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; select dosage with caution.214

Constipation and urinary retention occurred more frequently in geriatric individuals than in younger adults receiving transdermal buprenorphine.213 While specific transdermal dosage adjustments are not necessary based on age, use caution to ensure safe use.213

Hepatic Impairment

Metabolized in the liver; therefore, activity of the drug may be increased and/or prolonged in patients with hepatic impairment.1 2 Use with caution in patients with severe hepatic impairment.1 2 202 213 (See Hepatic Impairment under Dosage.)

When used for the treatment of opiate dependence in patients with hepatic impairment, adjust dosage and observe the patient for potential withdrawal symptoms.202 214

Close supervision required when used transdermally for the treatment of chronic pain in patients with mild to moderate hepatic impairment.213 Consider use of alternative analgesic with greater dosing flexibility in patients with severe hepatic impairment.213

Renal Impairment

Use with caution in patients with severe renal impairment.1 2 202 213

Common Adverse Effects

Parenteral injection: Sedation (e.g., drowsiness),1 2 3 9 40 44 48 51 53 65 67 69 71 72 75 79 83 95 96 98 110 183 184 185 dizziness,1 2 3 4 9 44 71 99 183 185 vertigo,1 2 3 nausea.1 2 3 4 40 44 49 51 53 67 71 76 79 83 93 105 183 184 185 192

Sublingually dissolving strips: Oral hypoesthesia, glossodynia, oral mucosal erythema, headache, nausea, vomiting, hyperHIDrosis, constipation, manifestations of withdrawal, insomnia, pain, peripheral edema.214 Adverse effects of sublingual tablets generally are similar.214

Transdermal system: Nausea, headache, application site reactions (pruritus, erythema, rash), dizziness, constipation, somnolence, vomiting, dry mouth.213

Interactions for Buprenorphine Hydrochloride

Metabolized principally by CYP3A4.1 202 213 214 Buprenorphine and norbuprenorphine are conjugated by uridine diphosphate-glucuronosyltransferase (UGT) isoenzymes, mainly by UGT 1A1 and 2B7 and by UGT 1A3, respectively.213

Buprenorphine inhibits CYP2D6 and CYP3A4 in vitro; norbuprenorphine is a moderate CYP2D6 inhibitor.214

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased plasma buprenorphine concentrations).1 202 Closely monitor buprenorphine dosage; adjust dosage of one or both drugs if necessary.1 202 214 Pharmacokinetics of transdermally administered buprenorphine not expected to be affected by concomitant CYP3A4 inhibitors.213

CYP3A4 inducers: Potential pharmacokinetic interaction (decreased plasma buprenorphine concentrations).1 202 213 214 Closely monitor patient; adjust buprenorphine dosage if necessary.1 202 213 214

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP2D6 or CYP3A4: Manufacturer of transdermal buprenorphine states that interactions are unlikely.214

Drugs Affecting Hepatic Blood Flow

Drugs that reduce hepatic blood flow may decrease the rate of hepatic elimination of buprenorphine.1 2 4 116 213 Use with caution; reduce dosage of at least one of the drugs.1 186 189

Drugs that Prolong QT Interval

Potential pharmacodynamic interaction (increased risk of QT-interval prolongation).213 (See Cardiac Effects under Cautions.)

Specific Drugs




Anesthetics, local (e.g., bupivacaine, mepivacaine)

Possible potentiation of anesthetic effect24 92 and more rapid onset and prolonged duration of analgesia24

Antiarrhythmic agents, class IA or III (e.g., amiodarone, disopyramide, dofetilide, procainamide, quinidine, sotalol)

Increased risk of QT-interval prolongation reported with transdermal buprenorphine213

Avoid concomitant use with transdermal buprenorphine213

Anticoagulants, (phenprocoumon, no longer commercially available)

Possible purpuric response1 2

Anticonvulsants (carbamazepine, phenobarbital, phenytoin)

Possible decrease in plasma buprenorphine concentrations1 202 213 214

Monitor closely; adjust buprenorphine dosage, if necessary1 202 213 214

Antifungals, azoles (e.g., ketoconazole)

Ketoconazole: Increased plasma buprenorphine concentrations reported with sublingual buprenorphine;1 202 interaction not observed with transdermal buprenorphine213

Monitor closely; adjust dosage of one or both drugs, if necessary1 202 214

Benzodiazepines (e.g., diazepam, lorazepam)

Reports of death or coma when buprenorphine was misused (e.g., self-injection of crushed tablets) via IV injection with benzodiazepines by drug abusers202 213 214

May alter usual ceiling on buprenorphine-induced respiratory depression, making buprenorphine’s respiratory-depressant effects appear similar to those of full opiate agonists213 214

Respiratory and cardiovascular collapse reported in several patients receiving usual doses of IV buprenorphine and oral diazepam concomitantly1 2 59

Bradycardia, respiratory depression, and prolonged drowsiness reported following IV buprenorphine administration during surgery in a patient who had received oral lorazepam preoperatively36

Use with caution202 213 214

CNS depressants (e.g., opiate agonists, tranquilizers, general anesthetics, sedatives/hypnotics, alcohol)

Possible potentiation of CNS depression; deaths reported1 2 3 35 37 42 59 60 64 202 213 214

Use with caution; reduce dosage of at least one of the drugs1 2 3 202 213 214

Avoid alcohol use213 219


Concomitant administration has produced satisfactory analgesia (during and after surgery60 and also in a terminally ill patient with severe, chronic pain that was previously unresponsive to buprenorphine alone37 )


Concomitant administration produced satisfactory analgesia of prolonged duration with minimal respiratory depression; patient was aroused quickly and easily following surgery70


Potential for increased and/or prolonged activity of buprenorphine secondary to reduced hepatic elimination of the drug1 2 4 116 186 191 213

Use with caution; reduce dosage of at least one of the drugs1 186 189

HIV protease inhibitors (atazanavir, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir)

Atazanavir (with or without ritonavir): Increased plasma buprenorphine and norbuprenorphine concentrations and excessive opiate effects reported with sublingual buprenorphine;213 214 possible decreased atazanavir concentrations when used without low-dose ritonavir224

Indinavir, saquinavir: Possible increased buprenorphine concentrations202

Lopinavir/ritonavir, nelfinavir, ritonavir: Interaction not observed214

Ritonavir-boosted atazanavir: Monitor closely; adjust buprenorphine dosage, if necessary1 202

Atazanavir (without ritonavir): Concomitant use not recommended224

Indinavir, saquinavir: Monitor closely; reduce buprenorphine dosage, if necessary202

Macrolide antibiotics (e.g., erythromycin)

Possible increased plasma buprenorphine concentrations1 202 214

Monitor closely; adjust dosage of one or both drugs, if necessary1 202 214

MAO inhibitors

Possible additive effect or potentiation of CNS depression1 2 3 213

Use with caution;1 2 3 manufacturer recommends allowing 14 days to elapse following discontinuance of MAO inhibitor and initiation of transdermal buprenorphine213


In patients who received a single, high dose of buprenorphine before undergoing cholecystectomy with balanced anesthesia and experienced pain in the immediate postoperative phase, addition of naloxone resulted in adequate analgesia, possibly by counteracting dominant antagonistic effects of buprenorphine58 148

Nonnucleoside reverse transcriptase inhibitors (NNRTIs; efavirenz, delavirdine)

Pharmacokinetic interaction does not result in substantial pharmacodynamic effects213 214

In patients receiving chronic buprenorphine therapy who begin NNRTI therapy, monitor buprenorphine dosage214

Nucleoside reverse transcriptase inhibitors (NRTIs)

Interaction not considered likely213 214


Possible severe hypotension213


Possible decrease in plasma buprenorphine concentrations1 202 213

Monitor closely; adjust buprenorphine dosage, if necessary1 202 213 214

Skeletal muscle relaxants

Potential for enhanced neuromuscular blocking action and increased respiratory depression213

Use with caution213

Buprenorphine Hydrochloride Pharmacokinetics



Approximately 40–90% absorbed following IM administration.116 118 Approximately 55% (range: 15–95%) absorbed following sublingual administration.118 119 Following oral administration, buprenorphine undergoes extensive first-pass metabolism in the GI mucosa and liver.122 131 Absolute bioavailability of about 15% following transdermal administration.213

Following IV administration of a single dose, mean peak plasma concentrations4 116 occurred within 2 minutes.4 116 118 Following IM administration of a dose 3 hours after an initial IV dose, mean peak plasma concentrations occurred within 2–5 minutes.4 9 116 118 Peak plasma concentrations occur about 1.5–1.7 hours after sublingual administration as a dissolving strip.214

Approximately 10 minutes after administration, plasma buprenorphine concentrations are similar following IV or IM injection.4 9 116 118

Pharmacokinetics of the sublingually dissolving strips and sublingual tablets are similar, but not all doses and dose combinations are bioequivalent.214 Bioavailability of sublingually dissolving films is potentially greater than that of sublingual tablets.214

Buprenorphine is quantifiable in plasma about 17 hours after application of a 10-mcg/hour transdermal system; steady-state concentrations attained by day 3 of treatment.213

Application of heat to a 10-mcg/hour transdermal system increased blood buprenorphine concentrations by 26–55%; concentrations returned to normal within 5 hours after removal of heat source.213


Following parenteral administration of single doses in postoperative patients,1 2 3 9 16 21 42 48 71 72 80 82 96 97 98 121 123 124 127 128 the onset of analgesia usually occurs within 10–30 minutes.1 2 3 9 16 17 96 123 124 128 185 Peak analgesia usually occurs within 60 minutes1 71 80 96 128 185 but may occur within 15 minutes in some patients.71


Analgesia generally persists for 6 hours following single IM or IV doses,1 2 3 16 21 71 72 82 96 121 124 185 but has persisted for 4–10 hours following single IM doses1 2 3 16 21 71 72 82 96 97 98 123 124 127 184 and 2–24 hours following single IV doses.42 48 71 80 121 152



Rapidly (within several minutes) distributes into CSF following IV administration;3 63 117 120 CSF concentrations appear to be approximately 15–25% of concurrent plasma concentrations.117 213

Crosses the placenta in rats;71 not known whether buprenorphine crosses the placenta in humans.3

Distributes into human milk.1 2 3 4 213

Plasma Protein Binding

Approximately 96%4 15 71 213 214 (mainly α- and β-globulins;4 71 213 214 does not appear to bind substantially to albumin).4



Almost completely metabolized in the liver,1 2 3 21 116 principally by N-dealkylation (mediated by CYP3A4)202 213 214 to form norbuprenorphine,3 4 71 113 114 115 118 122 125 202 213 214 which may have weak analgesic activity.122 213 Buprenorphine and norbuprenorphine undergo conjugation with glucuronic acid3 71 118 122 125 213 214 (mediated mainly by UGT 1A1 and 2B7 and by UGT 1A3, respectively).213

Elimination Route

Eliminated principally in feces (about 69%)3 4 113 202 214 via biliary excretion4 113 and also in urine (about 30%)114 122 170 202 214 as unchanged drug and metabolites.


Biphasic or triphasic;114 116 118 terminal elimination half-life is approximately 2.2 hours (range: 1.2–7.2 hours) following IV administration,1 2 4 21 40 118 119 and mean plasma elimination half-life is 37 or 24–42 hours following sublingual administration of tablets or dissolving strips, respectively.202 214 Following transdermal administration, the terminal elimination half-life is approximately 26 hours.213

Limited data suggest clearance may be higher in children than in adults.1

Special Populations

Renal impairment does not substantially alter buprenorphine pharmacokinetics, although concentrations of norbuprenorphine and buprenorphine-3-glucuronide may be increased.214 218

Hemodialysis does not substantially alter plasma concentrations of transdermally administered buprenorphine.213

In a limited number of patients with mild or moderate hepatic impairment (Child-Pugh class A or B), buprenorphine exposure was similar to that in patients with normal hepatic function; effect of severe hepatic impairment (Child-Pugh class C) on pharmacokinetics not determined.213

In healthy geriatric adults, pharmacokinetic profile of transdermal buprenorphine generally is similar to that in younger adults.213




Sublingually Dissolving Strips

25°C (may be exposed to 15–30°C).214

Sublingual Tablets

25°C (may be exposed to 15–30°C).202



<40°C; protect from prolonged exposure to light.1


Transdermal System

25°C (may be exposed to 15–30°C).213


For information on systemic interactions resulting from concomitant use, see Interactions.


Drug Compatibility
Admixture CompatibilityHID


Bupivacaine HCl

Glycopyrrolate with haloperidol lactate



Floxacillin sodium

Y-site CompatibilityHID


Allopurinol sodium



Cefepime HCl

Cisatracurium besylate



Etoposide phosphate


Gemcitabine HCl

Granisetron HCl


Melphalan HCl


Pemetrexed disodium

Piperacillin sodium–tazobactam sodium


Remifentanil HCl



Vinorelbine tartrate


Amphotericin B cholesteryl sulfate complex

Doxorubicin HCl liposome injection


  • Exhibits analgesic1 2 71 112 129 and opiate antagonist activities.1 2 4 8 71 74 86 111 112 148 Acts as a partial agonist at μ-opiate receptors8 10 112 147 160 173 175 178 189 194 202 213 214 in the CNS8 160 and peripheral tissues,8 an antagonist at κ-opiate receptors, and an agonist at δ-opiate receptors.202 213 214

  • Binds slowly with4 10 169 and dissociates slowly from the μ-receptor;1 2 3 4 8 10 169 178 179 may account for the prolonged duration of analgesia1 2 3 4 157 179 and possibly in part for the limited physical dependence potential observed.1 2 3 4 8 10 157 178

  • Single sublingual doses of buprenorphine produce physiologic and subjective effects that are similar to those produced by equivalent doses of the buprenorphine/naloxone fixed combination.202

  • Produces dose-related analgesia;4 67 118 128 129 appears to result from a high affinity of buprenorphine for μ- and possibly κ-opiate receptors in the CNS.1 2 8 10 112 117 147 160 173 176 178

  • Opiate agonist and antagonist activities appear to be dose related.160 163 165 At doses of ≤1 mg sub-Q, buprenorphine has a potent analgesic effect;71 160 163 165 at doses >1 mg sub-Q, the opiate agonist activity decreases and the opiate antagonist activity predominates.71 160 163 165 Following IM administration, opiate antagonist activity occurs principally at doses >0.8 mg.1 2 71 160 163

  • Usual parenteral doses potentially may depress respiration to the same degree as 10 mg of parenteral morphine sulfate;1 2 4 71 however, onset of buprenorphine-induced respiration depression is slower than that induced by morphine and appears to be more prolonged.71

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Provide manufacturer’s patient information (medication guide) to the patient each time buprenorphine transdermal system or buprenorphine/naloxone sublingually dissolving strips are dispensed.213 214 215 216 (See REMS: Butrans and REMS: Suboxone, under Dosage and Administration.)

  • Importance of instructing patients in proper techniques for administering the sublingually dissolving strips and transdermal systems.213 214

  • Importance of informing patients that buprenorphine is a drug of abuse.213 214 Instruct patients to keep in a secure place to prevent theft or misuse.213 214 Risk of severe or fatal respiratory depression if misused or used in individuals for whom the drug was not prescribed.213 214

  • Importance of warning patients and/or their caregivers to keep buprenorphine preparations out of the reach of children and pets and to safely dispose of used or unneeded dosage units.213 214

  • Importance of warning patients receiving buprenorphine for the treatment of opiate dependence of the potential danger (e.g., serious overdosage, death) associated with concomitant self-administration of benzodiazepines or other CNS depressants.202 214 (See Cautions.) Importance of not drinking alcohol and of avoiding sleep aids and CNS depressants unless prescribed.213

  • Importance of patients or caregivers informing clinicians in the event of emergency that the patient is receiving buprenorphine or buprenorphine/naloxone and is dependent on opiates.202 214

  • Importance of taking the drug exactly as prescribed; do not exceed the recommended dosage.1 2 213 214

  • Potential for buprenorphine to impair mental alertness or physical coordination; avoid driving or operating machinery until effects on individual are known.1 202 213 214

  • Risk of withdrawal symptoms following abrupt discontinuance; importance of consulting clinician prior to discontinuing the drug.213 214

  • Risk of orthostatic hypotension in ambulatory patients.202 214

  • Importance of informing clinicians if patient has a history of serious skin reactions to adhesives prior to initiating therapy with transdermal buprenorphine.213 Importance of promptly contacting a clinician if symptoms of a serious allergic reaction occur.213 220

  • Patients receiving transdermal buprenorphine should avoid exposing application site to external heat sources (e.g., heating pads, electric blankets, heat lamps, saunas, hot tubs, heated water bed) because of risk of increased buprenorphine exposure, overdosage, and death.213

  • Importance of informing clinician of any breakthrough pain or adverse effects that occur during analgesic therapy, so that therapy may be adjusted based on individual patient requirements.213

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and alcohol consumption, as well as any concomitant illnesses.1 202 213 214

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1 202 213 214

  • Importance of advising patients of other important precautionary information.1 202 213 214 (See Cautions.)


Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule III (C-III) drug.202 206 213 214

Under the Drug Addiction Treatment Act (DATA) of 2000, use of buprenorphine hydrochloride and buprenorphine hydrochloride in fixed combination with naloxone hydrochloride for the treatment of opiate dependence is restricted to physicians who meet certain qualifying requirements and have notified the Secretary of the US Department of Health and Human Services of their intention to prescribe these preparations for this indication.202 (See Restricted Distribution Program under Dosage and Administration.)



Dosage Forms


Brand Names



Transdermal System

5 mcg/hour (5 mg/6.25 cm2)

Butrans ( C-III)

Purdue Pharma

10 mcg/hour (10 mg/12.5 cm2)

Butrans ( C-III)

Purdue Pharma

20 mcg/hour (20 mg/25 cm2)

Butrans ( C-III)

Purdue Pharma

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Buprenorphine Hydrochloride


Dosage Forms


Brand Names




0.3 mg (of buprenorphine) per mL*

Buprenex ( C-III)

Reckitt Benckiser

Buprenorphine Hydrochloride Injection ( C-III)



2 mg (of buprenorphine)

Subutex ( C-III)

Reckitt Benckiser

8 mg (of buprenorphine)

Subutex ( C-III)

Reckitt Benckiser

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Buprenorphine Hydrochloride Combinations


Dosage Forms


Brand Names



Strips, sublingually dissolving

2 mg (of buprenorphine) with Naloxone Hydrochloride 0.5 mg (of naloxone)

Suboxone ( C-III)

Reckitt Benckiser

8 mg (of buprenorphine) with Naloxone Hydrochloride 2 mg (of naloxone)

Suboxone ( C-III)

Reckitt Benckiser


2 mg (of buprenorphine) with Naloxone Hydrochloride 0.5 mg (of naloxone)*

Buprenorphine Hydrochloride and Naloxone Hydrochloride Sublingual Tablets (C-III)

8 mg (of buprenorphine) with Naloxone Hydrochloride 2 mg (of naloxone)*

Buprenorphine Hydrochloride and Naloxone Hydrochloride Sublingual Tablets (C-III)

AHFS DI Essentials. © Copyright, 2004-2016, Selected Revisions March 24, 2016. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.


1. Reckitt Benckiser Pharmaceuticals. Buprenex (buprenorphine hydrochloride) injection prescribing information. Richmond, VA; 2005 Apr.

2. Norwich Eaton Pharmaceuticals, Inc. Buprenex compatibility chart. Norwich, NY; 1986.

3. Norwich Eaton Pharmaceuticals, Inc. Buprenex: background data for review by pharmacy and therapeutic committees. Norwich, NY; 1985 May.

4. Norwich Eaton Pharmaceuticals, Inc. Buprenex product monograph. Norwich, NY; 1985 Jul.

5. Reynolds JEF, ed. Martindale: the extra pharmacopeia. 28th ed. London: The Pharmaceutical Press; 1982:1002-3.

6. Windholz M, ed. The Merck index. 10th ed. Rahway, NJ: Merck & Co, Inc. 1983:207.

7. Jaffe JH, Martin WR. Opioid analgesics and antagonists. In: Gilman AG, Goodman L, Rall TW et al, eds. Goodman and Gilman’s the pharmacological basis of therapeutics. 7th ed. New York: Macmillan Publishing Company; 1985:491-531.

8. Lewis JW. Buprenorphine. Drug Alcohol Depend. 1985; 14:363-72. [PubMed 2986930]

9. Alon E. Clinical pharmacology and toxicology of analgesic drugs: buprenorphine—recent information. Prog Anesthesiol. 1983; 3:305-9.

10. Budd K. Buprenorphine. Clin Anaesthesiol. 1983; 1:147-52.

11. Jasinski DR. Human pharmacology of narcotic antagonists. Br J Clin Pharmacol. 1979; 7(Suppl):287-90S. [IDIS 97800] [PubMed 371652]

12. Cowan A, Lewis JW, MacFarlane IR. Agonist and antagonist properties of buprenorphine, a new antinociceptive agent. Br J Pharmacol. 1977; 60:537-45. [PubMed 409448]

13. Devaux C, Schoepffler P, Gauthier-Lafaye JP. Side-effects of mixed agonist-antagonist analgesics used in sequential anaesthesia. Br J Clin Pharmacol. 1979; 7(Suppl):323-6S.

14. Jacob JJC, Michaud GM, Tremblay EC. Mixed agonist-antagonist opiates and physical dependence. Br J Clin Pharmacol. 1979; 7(Suppl):291-6S.

15. Garrett ER, Chandran VR. Pharmacokinetics of morphine and its surrogates VI: bioanalysis, solvolysis kinetics, solubility, pKa values, and protein binding of buprenorphine. J Pharm Sci. 1985; 74:515-24. [IDIS 200020] [PubMed 4020627]

16. Rolly G, Versichelen L. Buprenorphine as postoperative analgesic. Acta Anaesthesiol Belg. 1976; 27:183-6. [PubMed 801582]

17. Cowan A, Doxey JC, Harry EJR. The animal pharmacology of buprenorphine, an oripavine analgesic agent. Br J Pharmacol. 1977; 60:547-54. [PubMed 409449]

18. Orwin JM. The effect of doxapram on buprenorphine induced respiratory depression. Acta Anaesthesiol Belg. 1977; 28:93-105. [PubMed 337748]

19. Anon. Sublingual buprenorphine. Drug Ther Bull. 1982; 20:74-6. [PubMed 7140531]

20. Henry J, Volans G. ABC of poisoning. Analgesics: opioids. BMJ. 1984; 289:990-3. [IDIS 191703] [PubMed 6435753]

21. Zola EM, McLeod DC. Comparative effects and analgesic efficacy of the agonist-antagonist opioids. Drug Intell Clin Pharm. 1983; 17:411-7. [IDIS 171471] [PubMed 6861632]

22. Banks CD. Overdosage of buprenorphine: case report. N Z Med J. 1979; 89:255-6. [IDIS 122734] [PubMed 286917]

23. Murphy DF, MacGrath P, Stritch N. Postoperative analgesia in hip surgery: a controlled comparison of epidural buprenorphine with intramuscular morphine. Anaesthesia. 1984; 39:181-3. [PubMed 6703273]

24. Louis C, Freye E, Hartung E et al. Buprenorphin in der periduralen Leitungsanasthesie: eine vergleichende Untersuchung mit und ohne Bupivacain. Anasth Intensivther Notfallmed. 1982; 17:341-4. [PubMed 7158741]

25. Zenz M, Piepenbrock S, Hübner B et al. Peridurale Analgesie mit Buprenorphin und Morphin bei postoperativen Schmerzen. (German; with English abstract.) Anasth Intensivther Notfallmed. 1981; 16:333-9.

26. Murphy DF, MacEvilly M. Pain relief with epidural buprenorphine after spinal fusion: a comparison with intramuscular morphine. Acta Anaesthesiol Scand. 1984; 28:144-6. [PubMed 6730874]

27. May AE, Wandless J, James RH. Analgesia for circumcision in children: a comparison of caudal bupivacaine and intramuscular buprenorphine. Acta Anaesthesiol Scand. 1982; 26:331-3. [PubMed 7124308]

28. Murchison DJ, Davis FM, Gibbs JM et al. Epidural buprenorphine. Anaesth Intensive Care. 1984; 12:179. [PubMed 6476361]

29. Murphy DF, Cahill J, Fitzpatrick G et al. Epidural buprenorphine for postoperative pain relief. Anesth Analg. 1985; 64:456-7. [IDIS 197704] [PubMed 3985394]

30. Cahill J, Murphy D, O’Brien D et al. Epidural buprenorphine for pain relief after major abdominal surgery: a controlled comparison with epidural morphine. Anaesthesia. 1983; 38:760-4. [PubMed 6349411]

31. Zenz M, Piepenbrock S, Tryba M. Epidural opiates: long-term experiences in cancer pain. Klin Wochenschr. 1985; 63:225-9. [PubMed 3990166]

32. Fry ENS. Postoperative analgesia: a technique using continuous intravenous infusion of buprenorphine. Anaesthesia. 1984; 39:1134-5. [PubMed 6507832]

33. Fry ENS. Buprenorphine for postoperative analgesia. BMJ. 1982; 285:1427.

34. Fry ENS. Improved pain relief after thoracotomy. BMJ. 1981; 283:1185.

35. Green DW. Buprenorphine, benzodiazepines and respiratory depression. Anaesthesia. 1984; 39:287-8. [PubMed 6703303]

36. Forrest AL. Buprenorphine and lorazepam. Anaesthesia. 1983; 38:598. [PubMed 6135366]

37. Bach V, Carl P, Ravlo O et al. Extradural droperidol potentiates extradural opioids. Br J Anaesth. 1985; 57:238. [IDIS 197593] [PubMed 3970805]

38. Ueland PM, Kvalheim G, Lonning PE et al. Determination of warfarin in human plasma by high performance liquid chromatography and photodiode array detector. Ther Drug Monit. 1985; 7:329-35. [IDIS 204728] [PubMed 4049474]

39. Klose R, Ehrhart A, Jung R. Der Einfluss von Buprenorphin und Tramadol auf die CO2-Antwort in der unmittelbar postoperativen Phase nach Allgemeinanasthesie (German; with English abstract.) Anasth Intensivther Notfallmed. 1982; 17:29-34.

40. Gourlay GK, Cousins MJ. Strong analgesics in severe pain. Drugs. 1984; 28:79-91. [IDIS 186819] [PubMed 6146508]

41. Benos J. Ein Fall von sekundarer Buprenorphin (Temgesic)-abhangigkeit. Nervenarzt. 1983; 54:259-61. [PubMed 6866170]

42. Robertson DH, Laing AW. Intravenous buprenorphine (Temgesic): use following fentanyl analgesic anaesthesia. Clin Trials J. 1980; 17:51-5.

43. Twycross RG. Morphine and diamorphine in the terminally ill patient. Acta Anaesthesiol Scand. 1982; 74(Suppl):128-34.

44. Bradley JP. A comparison of morphine and buprenorphine for analgesia after abdominal surgery. Anaesth Intensive Care. 1984; 12:303-10. [PubMed 6393818]

45. Scott DHT, Arthur GR, Scott DB. Haemodynamic changes following buprenorphine and morphine. Anaesthesia. 1980; 35:957-61. [PubMed 7004250]

46. McQuay HJ, Bullingham RES, Bennett MRD et al. Delayed respiratory depression: a case report and a new hypothesis. Acta Anaesthesiol Belg. 1979; 30(Suppl):245-7. [PubMed 547663]

47. Cathelin M, Vignes R, Viars P. La buprénorphine et la morphine chez l’homme conscient: comparaison des effets secondaires. (French; with English abstract.) Anesth Analg Reanim. 1980; 37:283-93.

48. Piepenbrock S, Zenz M, Gorus R et al. Buprenorphin und Pentazocin zur postoperativen Analgesie: eine Doppelblindstudie nach Baucheingriffen. (German; with English abstract.) Anaesthesist. 1983; 32:601-9.

49. Abrahamsson J, Niemand D, Olsson AK et al. Buprenorphin (Temgesic) als peroperatives Analgetikum: eine multizentrische Studie. (German; with English abstract.) Anaesthesist. 1983; 32:75-9.

50. Zinck B, Fritz KW. Atemdepression nach epiduraler Opiat-Analgesie mit Buprenorphin-Hydrochlorid? (German; with English abstract.) Anasth Intensivther Notfallmed. 1982; 17:345-7.

51. Rifat K, Magnin C, Morel D. L’analgésie per et postopératoire a la buprénorphine: effets cardio-circulatoires et respiratoires. (French; with English abstract.) Cah Anesthesiol. 1984; 32:33-6.

52. Pausawasdi S, Kanjanapitak A, Kanjanapanjapol S. The effect of buprenorphine and morphine on intraluminal pressure of the common bile duct. J Med Assoc Thai. 1984; 67:329-33. [PubMed 6491561]

53. Pausawasdi S, Tontisirin O, Bunyaratavej S. A comparison of buprenorphine and morphine for immediate postoperative pain relief in Thai patients. J Med Assoc Thai. 1984; 67:284-9. [PubMed 6481272]

54. Tigerstedt L, Turunen M, Tammisto T et al. The effect of buprenorphine and oxycodone on the intracholedochal passage pressure. Acta Anaesthesiol Scand. 1981; 25:99-102. [PubMed 7324833]

55. Fry ENS. Relief of pain after surgery. Anaesthesia. 1979; 34:549-51. [PubMed 484814]

56. Robbie DS. A trial of sublingual buprenorphine in cancer pain. Br J Clin Pharmacol. 1979; 7(Suppl):315-7S.

57. Ventafridda V, DeConno F, Guarise G et al. Chronic analgesic study on buprenorphine action in cancer pain: comparison with pentazocine. Arzneimittelforschung. 1983; 33:587-90. [PubMed 6683540]

58. Schmidt JF, Chraemmer-Jorgensen B, Pedersen JE et al. Postoperative pain relief with naloxone: severe respiratory depression and pain after high dose buprenorphine. Anaesthesia. 1985; 40:583-6. [PubMed 4025755]

59. Faroqui MH, Cole M, Curran J. Buprenorphine, benzodiazepines and respiratory depression. Anaesthesia. 1983; 38:1002-3. [PubMed 6139041]

60. Green DW, Sinclair JR, Mikhael MS. Buprenorphine versus morphine; a comparison of intra-operative and postoperative analgesia. Anaesthesia. 1985; 40:371-5. [PubMed 3890604]

61. Bethune DW. Haemodynamic effects of buprenorphine after heart surgery. Br Med J. 1979; 1:345. [PubMed 421114]

62. Tashiro C, Aoki Y, Yoshiya I. Buprenorphine-supplemented anesthesia in abdominal surgery. Med J Osaka Univ. 1982; 33:35-40. [PubMed 7155049]

63. Zenz M, Piepenbrock S. Extradural buprenorphine. Br J Anaesth. 1982; 54:1146-7. [PubMed 7126409]

64. Papworth DP. High dose buprenorphine for postoperative analgesia. Anaesthesia. 1983; 38:163. [PubMed 6829887]

65. Ostrowski MJ, Jackson AW. Intra-muscular buprenorphine—clinical experience in its use for relieving pain due to malignant disease. Br J Clin Pract. 1979; 33:286-93. [IDIS 107123] [PubMed 526414]

66. Rosenfeldt FL, Houston B, Thompson D et al. Haemodynamic effects of buprenorphine after heart surgery. Br Med J. 1978; 2:1602-3. [IDIS 89470] [PubMed 728741]

67. Dobkin AB. Buprenorphine hydrochloride: determination of analgesic potency. Can Anaesth Soc J. 1977; 24:186-94. [IDIS 83894] [PubMed 14772]

68. Chakravarty K, Tucker W, Rosen M et al. Comparison of buprenorphine and pethidine given intravenously on demand to relieve postoperative pain. Br Med J. 1979; 2:895-7. [IDIS 103433] [PubMed 391321]

69. Gibbs JM, Johnson H. Comparison of buprenorphine and pethidine for analgesia after abdominal surgery. N Z Med J. 1978; 88:363-6.

70. Fry ENS. Buprenorphine. Lancet. 1980; 2:798.

71. Heel RC, Brogden RN, Speight TM et al. Buprenorphine: a review of its pharmacological properties and therapeutic efficacy. Drugs. 1979; 17:81-110. [IDIS 121541] [PubMed 378645]

72. Dobkin AB, Esposito B, Philbin C. Double-blind evaluation of buprenorphine hydrochloride for post-operative pain. Can Anaesth Soc J. 1977; 24:195-202. [IDIS 83895] [PubMed 321103]

73. Downing JW, Goodwin NM, Hicks J. The respiratory depressive effects of intravenous buprenorphine in patients in an intensive care unit. S Afr Med J. 1979; 55:1023-7. [IDIS 100678] [PubMed 483080]

74. Mello NK, Mendelson JH. Buprenorphine suppresses heroin use by heroin addicts. Science. 1980; 207:657-9. [IDIS 107832] [PubMed 7352279]

75. Hovell BC, Ward AE. Pain relief in the post-operative period: a comparative trial of morphine and a new analgesic buprenorphine. J Int Med Res. 1977; 5:417-21. [PubMed 338392]

76. Gibbs JM, Johnson HD, Davis FM. Patient administration of I.V. buprenorphine for postoperative pain relief using the “Cardiff” demand analgesia apparatus. Br J Anaesth. 1982; 54:279-84. [IDIS 148286] [PubMed 7066127]

77. Cook PJ, James IM, Hobbs KEF et al. Controlled comparison of I.M. morphine and buprenorphine for analgesia after abdominal surgery. Br J Anaesth. 1982; 54:285-90. [IDIS 148287] [PubMed 7039643]

78. Christensen FR, Andersen LW. Adverse reaction to extradural buprenorphine. Br J Anaesth. 1982; 54:476. [IDIS 149559] [PubMed 7066147]

79. Harmer M, Slattery PJ, Rosen M et al. Comparison between buprenorphine and pentazocine given I.V. on demand in the control of postoperative pain. Br J Anaesth. 1983; 55:21-5. [IDIS 167985] [PubMed 6336941]

80. Kamel MM, Geddes IC. A comparison of buprenorphine and pethidine for immediate postoperative pain relief by the I.V. route. Br J Anaesth. 1978; 50:599-602. [IDIS 114456] [PubMed 666936]

81. McQueen EG. New Zealand Committee on Adverse Drug Reactions: seventeenth annual report 1982. N Z Med J. 1983; 96:95-9.

82. Downing JW, Leary WP, White ES. Buprenorphine: a new potent long-acting synthetic analgesic: comparison with morphine. Br J Anaesth. 1977; 49:251-5. [IDIS 84001] [PubMed 334206]

83. McQuay HJ, Bullingham RES, Paterson GMC et al. Clinical effects of buprenorphine during and after operation. Br J Anaesth. 1980; 52:1013-9. [IDIS 124376] [PubMed 7437209]

84. Albert LH. Newer potent analgesics. Ration Drug Ther. 1982; 16:1-6. [IDIS 151039] [PubMed 6124996]

85. Quigley AJ, Bredemeyer DE, Seow SS. A case of buprenorphine abuse. Med J Aust. 1984; 140:425-6. [IDIS 186672] [PubMed 6700515]

86. Wodak AD. Buprenorphine: new wonder drug or new hazard? Med J Aust. 1984; 140:389-90. Editorial. (IDIS 186670)

87. Inturrisi CE. Role of opioid analgesics. Am J Med. 1984; 77:27-37. [IDIS 191144] [PubMed 6486129]

88. Sear JW, Cartwright DP, Alexander JI. Buprenorphine for postoperative analgesia. Br J Anaesth. 1979; 51:71. [IDIS 120376] [PubMed 552286]

89. Orwin JM, Orwin J, Price M. A double blind comparison of buprenorphine and morphine in conscious subjects following administration by the intramuscular route. Acta Anaesthesiol Belg. 1976; 27:171-81. [PubMed 1032070]

90. Holmes AD. Buprenorphine side effects. N Z Med J. 1984; 97:166. [IDIS 184210] [PubMed 6584767]

91. Harper I. Temgesic abuse. N Z Med J. 1983; 96:777. [IDIS 178255] [PubMed 6578447]

92. Lanz E, Simko G, Theiss D et al. Epidural buprenorphine—a double-blind study of postoperative analgesia and side effects. Anesth Analg. 1984; 63:593-8. [IDIS 185994] [PubMed 6375465]

93. Harcus AH, Ward AE, Smith DW. Buprenorphine in postoperative pain: results in 7500 patients. Anaesthesia. 1980; 35:382-6. [PubMed 7435902]

94. Harcus AW, Ward AE, Smith DW. The monitored release of buprenorphine: results in the young. J Int Med Res. 1980; 8:153-5. [PubMed 7371972]

95. Harcus AW, Ward AE, Smith DW. Buprenorphine: experience in an elderly population of 975 patients during a year’s monitored release. Br J Clin Pract. 1980; 34:144-6. [IDIS 117375] [PubMed 7407029]

96. Mok MS, Lippmann M, Steen SN. Multidose/observational, comparative clinical analgetic evaluation of buprenorphine. J Clin Pharmacol. 1981; 21:323-9. [IDIS 137176] [PubMed 7263931]

97. Tigerstedt I, Tammisto T. Double-blind, multiple-dose comparison of buprenorphine and morphine in postoperative pain. Acta Anaesth Scand. 1980; 24:462-8. [PubMed 7018155]

98. Finlay IG, Scott R, McArdle CS. Prospective double-blind comparison of buprenorphine and pethidine in ureteric colic. BMJ. 1982; 284:1830-1. [IDIS 152724] [PubMed 6805715]

99. Kjaer M, Henriksen H, Knudsen J. A comparative study of intramuscular buprenorphine and morphine in the treatment of chronic pain of malignant origin. Br J Clin Pharmacol. 1982; 13:487-92. [IDIS 148516] [PubMed 7066163]

100. Lukas SE, Jasinski DR, Johnson RE. Electroencephalographic and behavioral correlates of buprenorphine administration. Clin Pharmacol Ther. 1984; 36:127-32. [IDIS 187564] [PubMed 6734042]

101. Murray K. Acute urinary retention associated with sublingual buprenorphine. BMJ. 1983; 286:763-4. [IDIS 168081] [PubMed 6402239]

102. Harcus AW, Ward AE, Smith DW. Methodology of monitored release of a new preparation: buprenorphine. Br Med J. 1979; 2:163-5. [IDIS 99867] [PubMed 466334]

103. Harmer M, Slattery PJ, Rosen M et al. Intramuscular on demand analgesia: double blind controlled trial of pethidine, buprenorphine, morphine, and meptazinol. BMJ. 1983; 286:680-2. [IDIS 167978] [PubMed 6402201]

104. Maiche A, Teerenhovi L. Stevens-Johnson syndrome in patients receiving radiation therapy. Lancet. 1985; 2:45. [IDIS 202050] [PubMed 2861495]

105. Blamey SL, Finlay IG, Carter DC et al. Analgesia in acute pancreatitis: comparison of buprenorphine and pethidine. BMJ. 1984; 288:1494-5. [IDIS 186360] [PubMed 6426616]

106. Wang RIH, Johnson RP, Robinson N et al. The study of analgesics following single and repeated doses. J Clin Pharmacol. 1981; 21:121-5. [IDIS 156816] [PubMed 7229117]

107. Mello NK, Mendelson JH, Kuehnle JC. Buprenorphine effects on human heroin self-administration: an operant analysis. J Pharmacol Exp Ther. 1982; 223:30-9. [IDIS 158153] [PubMed 7120124]

108. Brown NM, Strachan JW. Analgesia in acute pancreatitis. BMJ. 1984; 288:1917. [PubMed 6428606]

109. Mello NK, Mendelson JH. Behavioral pharmacology of buprenorphine. Drug Alcohol Depend. 1985; 14:283-303. [PubMed 3888577]

110. Budd K. High dose buprenorphine for postoperative analgesia. Anaesthesia. 1981; 36:900-3. [PubMed 7304894]

111. Jasinski DR, Pevnick JS, Griffith JD. Human pharmacology and abuse potential of the analgesic buprenorphine: a potential agent for treating narcotic addiction. Arch Gen Psychiatry. 1978; 35:501-16. [IDIS 92927] [PubMed 215096]

112. Drug Enforcement Administration. Schedules of controlled substances; rescheduling of buprenorphine from Schedule II to Schedule V of the Controlled Substances Act [Docket No. 83-10]. Fed Regist. 1985; 50:8104-6.

113. Brewster D, Humphrey MJ, McLeavy MA. Biliary excretion, metabolism and enterohepatic circulation of buprenorphine. Xenobiotica. 1981; 11:189-96. [PubMed 7293215]

114. Blom Y, Bondesson U. Analysis of buprenorphine and its N-dealkylated metabolite in plasma and urine by selected-ion monitoring. J Chromatogr. 1985; 338:89-98. [PubMed 4019659]

115. Bartlett AJ, Lloyd-Jones JG, Rance MJ et al. The radioimmunoassay of buprenorphine. Eur J Clin Pharmacol. 1980; 18:339-45. [IDIS 127216] [PubMed 7439255]

116. Bullingham RES, McQuay HJ, Moore A et al. Buprenorphine kinetics. Clin Pharmacol Ther. 1980; 28:667-72. [IDIS 124019] [PubMed 7438685]

117. Villiger JW, Boas RA, Taylor KM. A radioreceptor assay for opiate drugs in human cerebrospinal fluid and plasma. Life Sci. 1981; 29:229-33. [PubMed 6270490]

118. Bullingham RES, McQuay HJ, Moore RA. Clinical pharmacokinetics of narcotic agonist-antagonist drugs. Clin Pharmacokinet. 1983; 8:332-43. [IDIS 173933] [PubMed 6352139]

119. Bullingham RES, McQuay HJ, Porter EJB et al. Sublingual buprenorphine used postoperatively: ten hour plasma drug concentration analysis. Br J Clin Pharmacol. 1982; 13:665-73. [IDIS 150305] [PubMed 7082534]

120. Boas RA, Taylor KM, Villiger JW et al. Epidural opiate analgesia. N Z Med J. 1982; 95:84.

121. Obel D, Hansen LK, Huttel MS et al. Buprenorphine-supplemented anaesthesia: influence of dose on duration of analgesia after cholecystectomy. Br J Anaesth. 1985; 57:271-4. [IDIS 198695] [PubMed 3978009]

122. Cone EJ, Gorodetzky CW, Yousefnejad D et al. The metabolism and excretion of buprenorphine in humans. Drug Metab Dispos. 1984; 12:577-81. [IDIS 191041] [PubMed 6149907]

123. Rossano C, De Luca LF, Firetto V et al. Activity and tolerability of buprenorphine after parenteral and sublingual administration. Clin Ther. 1982; 5:61-8. [PubMed 7127370]

124. Rolly G, Versichelen L. First experience with a new analgesic drug: buprenorphine. Acta Anaesthesiol Belg. 1976; 27:134-8. [PubMed 1015212]

125. Rance MJ, Shillingford JS. The metabolism of phenolic opiates by rat intestine. Xenobiotica. 1977; 7:529-36. [PubMed 414464]

126. Summerfield RJ, Allen MC, Moore RA et al. Buprenorphine in end stage renal failure. Anaesthesia. 1985; 40:914. [PubMed 4051160]

127. Sear JW, Alexander JI. Comparison of buprenorphine-hyoscine and papaveretum-hyoscine as premedicants for gynaecological surgery. Br J Anaesth. 1983; 55:319-24. [IDIS 169243] [PubMed 6220729]

128. Ouellette RD. Comparison of analgesic activity of buprenorphine hydrochloride and morphine in patients with moderate to severe pain postoperatively. Surg Gynecol Obstet. 1984; 159:201-6. [IDIS 190865] [PubMed 6474320]

129. Watson PJQ, McQuay HJ, Bullingham RES et al. Single-dose comparison of buprenorphine 0.3 and 0.6 mg I.V. given after operation: clinical effects and plasma concentrations. Br J Anaesth. 1982; 54:37-43. [IDIS 146253] [PubMed 7055528]

130. Adriaensen H, Mattelaer B, Vanmeenen H. A long-term open, clinical and pharmacokinetic assessment of sublingual buprenorphine in patients suffering from chronic pain. Acta Anaesthesiol Belg. 1985; 36:33-40. [PubMed 4013631]

131. Rance MJ, Shillingford JS. The role of the gut in the metabolism of strong analgesics. Biochem Pharmacol. 1976; 25:735-41. [PubMed 1275955]

132. Brunk SF, Delle M. Morphine metabolism in man. Clin Pharmacol Ther. 1974; 16:51-7. [PubMed 4843237]

133. Strang J. Abuse of buprenorphine. Lancet. 1985; 2:725. [IDIS 205264] [PubMed 2863704]

134. Foley KM. The treatment of cancer pain. N Engl J Med. 1985; 313:84-95. [IDIS 202084] [PubMed 2582259]

135. Kay B. A double-blind comparison between fentanyl and buprenorphine in analgesic-supplemented anaesthesia. Br J Anaesth. 1980; 52:453-7. [IDIS 115017] [PubMed 6990950]

136. Martin WR, Jasinski DR, Mansky PA. Naltrexone, an antagonist for the treatment of heroin dependence: effects in man. Arch Gen Psychiatry. 1973; 28:784-91. [PubMed 4707988]

137. Mello NK, Mendelson JH, Kuehnle JC et al. Operant analysis of human heroin self-administration and the effects of naltrexone. J Pharmacol Exp Ther. 1981; 216:45-54. [IDIS 130484] [PubMed 7452507]

138. Huse K, Stahl HJ, Kramer M. Veranderungen von Kreislauffunktion, Atmung und des Elektroenzephalogramms nach Buprenorphin. (German; with English abstract.) Prakt Anasth. 1978; 13:489-94.

139. Mello NK, Lukas SE, Mendelson JH. Buprenorphine effects on cigarette smoking. Psychopharmacology. 1985; 86:417-25. [PubMed 3929312]

140. O’sullivan G, Bullingham RES, McQuay HJ et al. A comparison of intramuscular and sublingual buprenorphine, intramuscular morphine and placebo as premedication. Anaesthesia. 1983; 38:977-84. [PubMed 6356971]

141. Coltart DJ, Malcolm AD. Pharmacological and clinical importance of narcotic antagonists and mixed antagonists—use in cardiology. Br J Clin Pharmacol. 1979; 7(Suppl):309-13S.

142. Fry ENS. Continuous narcotic infusions for relief of postoperative pain. Br Med J. 1979; 1:1149.

143. Lamerton RC. Cancer patients dying at home: the last 24 hours. Practitioner. 1979; 223:813-7. [IDIS 109310] [PubMed 94440]

144. Boas RA, Villiger JW, Taylor KM. Sequential analgesia—clinical correlates of opiate receptor dynamics. N Z Med J. 1982; 95:823-4.

145. Ouellette RD. Buprenorphine and morphine efficacy in postoperative pain: a double-blind multiple-dose study. J Clin Pharmacol. 1982; 22:165-72. [IDIS 149511] [PubMed 7047580]

146. Ashton H. Benzodiazepine withdrawal: an unfinished story. BMJ. 1984; 288:1135-40. [IDIS 185025] [PubMed 6143582]

147. Preston KL, Bigelow GE. Pharmacological advances in addiction treatment. Int J Addict. 1985; 20:845-67. [IDIS 208144] [PubMed 2867050]

148. Pedersen JE, Chraemmer-Jorgensen B, Schmidt JF et al. Naloxone—a strong analgesic in combination with high-dose buprenorphine? Br J Anaesth. 1985; 57:1045-6. Letter. (IDIS 207683)

149. Sjovall S. Use of midazolam and buprenorphine in combination anaesthesia. Ann Clin Res. 1983; 15:151-5. [IDIS 209180] [PubMed 6651208]

150. Hayes MJ, Fraser AR, Hampton JR. Randomised trial comparing buprenorphine and diamorphine for chest pain in suspected myocardial infarction. Br Med J. 1979; 2:300-2. [IDIS 100838] [PubMed 383195]

151. Hovell BC. Comparison of buprenorphine, pethidine and pentazocine for the relief of pain after operation. Br J Anaesth. 1977; 49:913-6. [IDIS 93803] [PubMed 334210]

152. Kay B. A double-blind comparison of morphine and buprenorphine in the prevention of pain after operation. Br J Anaesth. 1978; 50:605-8. [IDIS 114457] [PubMed 352372]

153. Emrich HM, Vogt P, Herz A. Possible antidepressive effects of opioids: action of buprenorphine. Ann NY Acad Sci. 1982; 398:108-12. [PubMed 6760767]

154. Emrich HM, Vogt P, Herz A. A possible role of opioids in depression: significant improvement after buprenorphine. Biol Psychiatr. 1981; 5:380-5.

155. Emrich HM, Vogt P, Herz A et al. Antidepressant effects of buprenorphine. Lancet. 1982; 2:709. [IDIS 157385] [PubMed 6126640]

156. Staritz M, Poralla T, Manns M et al. Pentazocine hampers bile flow. Lancet. 1985; 1:573-4. [IDIS 197341] [PubMed 2857916]

157. Dum J, Blasig J, Herz A. Buprenorphine: demonstration of physical dependence liability. Eur J Pharmacol. 1981; 70:293-300. [PubMed 6262095]

158. Moore RA, McQuay HJ, Bullingham RES. Buprenorphine and stress. Lancet. 1980; 2:1084.

159. Kubicki S, Azcona A. Electroencephalographic study of pentazocine and buprenorphine. Acta Anaesthesiol Belg. 1979; 30(Suppl):123-33. [PubMed 547656]

160. Sadée W, Richards ML, Grevel J et al. In vivo characterization of four types of opioid binding sites in rat brain. Life Sci. 1983; 33:187-9. [PubMed 6141486]

161. Villiger JW, Taylor KM. Buprenorphine: characteristics of binding sites in the rat central nervous system. Life Sci. 1981; 29:2699-2708. [PubMed 6276633]

162. Villiger JW. Binding of buprenorphine to opiate receptors: regulation by guanyl nucleotides and metal ions. Neuropharmacology. 1984; 23:373-5. [PubMed 6328350]

163. Dum JE, Herz A. In vivo receptor binding of the opiate partial agonist, buprenorphine, correlated with its agonistic and antagonistic actions. Br J Pharmacol. 1981; 74:627-33. [PubMed 6271322]

164. Mendelson JH, Ellingboe J, Mello NK et al. Buprenorphine effects on plasma luteinizing hormone and prolactin in male heroin addicts. J Pharmacol Exp Ther. 1982; 220:252-5. [IDIS 145318] [PubMed 7057390]

165. Kareti S, Moreton JE, Khazan N. Effects of buprenorphine, a new narcotic agonist-antagonist analgesic on the EEG, power spectrum and behavior of the rat. Neuropharmacology. 1980; 19:195-201. [PubMed 7360334]

166. Moore RA, McQuay HJ, Bullingham RES. Reversal of postoperative hyperglycaemia by buprenorphine. Lancet. 1980; 2:597-8.

167. Rolandi E, Marabini A, Franceschini R et al. Changes in pituitary secretion induced by an agonist-antagonist opioid drug, buprenorphine. Acta Endocrinol. 1983; 104:257-60. [PubMed 6415992]

168. Mendelson JH, Ellingboe J, Kuehnle JC et al. Heroin and naltrexone effects on pituitary-gonadal hormones in man: interaction of steroid feedback effects, tolerance and supersensitivity. J Pharmacol Exp Ther. 1979; 214:503-6.

169. Boas RA, Villiger JW. Clinical actions of fentanyl and buprenorphine: the significance of receptor binding. Br J Anaesth. 1985; 57:192-6. [PubMed 2982388]

170. Cone EJ, Gorodetzky CW, Yousefnejad D et al. 63Ni electron-capture gas chromatographic assay for buprenorphine and metabolites in human urine and feces. J Chromatogr. 1985; 337:291-300. [PubMed 3838755]

171. Edwards IR. Medicine Adverse Reactions Committee: eighteenth annual report, 1983. N Z Med J. 1984; 97:729-32. [IDIS 195531] [PubMed 6239993]

172. Arroyo JL, Ponz L, Carrascosa F et al. Effects of extradural analgesia with etidocaine and opioids on endocrine function. Br J Anaesth. 1982; 54:240P.

173. Budd K. The use of partial antagonist analgesics in the treatment of acute and chronic pain. Can Anaesth Soc J. 1985; 32:399-401.

174. Clifford JM, Hoare RC. The photographic measurement of miosis in volunteers after i.v. buprenorphine and its relation to other pharmacologic effects. Br J Clin Pharmacol. 1982; 14:621P.

175. Sadée W, Rosenbaum JS, Herz A. Buprenorphine: differential interaction with opiate receptor subtypes in vivo. J Pharmacol Exp Ther. 1982; 223:157-62.

176. Tyers MB. A classification of opiate receptors that mediate antinociception in animals. Br J Pharmacol. 1980; 69:503-12. [PubMed 6249436]

177. Dodson ME, Hussain A, Matheson H. A study comparing intravenous buprenorphine, morphine and pentazocine in post-operative pain relief. In: Harcus AW, Smith R, Whittle B, eds. Pain: new perspectives in measurement and management. New York: Churchill Livingstone; 1978:181-6.

178. Lewis JW, Rance MJ, Sanger DJ. The pharmacology and abuse potential of buprenorphine: a new antagonist analgesic. In: Mello NK, ed. Advances in substance abuse. Greenwich, CT: JAI Press Inc; 1983; 3:103-54.

179. Hambrook JM, Rance MJ. The interaction of buprenorphine with the opiate receptor: lipophilicity as a determining factor in drug-receptor kinetics. In: Kosterlitz HW, ed. Opiates and endogenous opioid peptides. Amsterdam: Elsevier/North Holland Biomedical Press; 1976:295-301.

180. Martin WR. Pharmacology of opioids. Pharmacol Rev. 1984; 35:283-323.

181. The United States Pharmacopeia, 21st rev, and The national formulary, 16th ed. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1986(Suppl 4):2257-82.

182. USP DI: 1987 drug information for the health care provider. Johnson KW, ed. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1986; I:466-70.

183. Wallenstein SL, Kaiko RF, Rogers AG et al. Crossover trials in clinical analgesic assays: studies of buprenorphine and morphine. Pharmacotherapy. 1986; 6:228-35. [IDIS 394439] [PubMed 3540873]

184. Carl P, Crawford ME, Madsen NBB et al. Pain relief after major abdominal surgery: a double-blind controlled comparison of sublingual buprenorphine, intramuscular buprenorphine, and intramuscular meperidine. Anesth Analg. 1987; 66:142-6. [IDIS 226263] [PubMed 3544957]

185. Ouellette RD, Mok MS, Gilbert MS et al. Comparison of buprenorphine and morphine: a multicenter, multidose study in patients with severe postoperative pain. Contemp Surg. 1986; 28:55-64.

186. Eastwood CJ Jr (Norwich Eaton Pharmaceuticals, Inc): Personal communication; 1987.

187. Bretschneider H. Osmolalities of commercially supplied drugs often used in anesthesia. Anesth Analg. 1987; 66:361-2. [IDIS 229703] [PubMed 3565802]

188. Cone EJ, Gorodetzky CW, Darwin WD et al. Stability of the 6,14-endo-ethanotetrahydrooripavine analgesics: acid-catalyzed rearrangement of buprenorphine. J Pharm Sci. 1984; 73:243-6. [IDIS 182053] [PubMed 6707893]

189. Richards ML, Sadée W. Buprenorphine is an antagonist at the κ opioid receptor. Pharm Res. 1985; 2:178-81. [PubMed 24272810]

190. Lukas SE, Brady IV, Griffiths RR. Comparison of opioid self-injection and disruption of schedule-controlled performance in the baboon. J Pharmacol Exp Ther. 1986; 238:924-31. [PubMed 3746670]

191. Reviewers’ comments (personal observations); 1987.

192. Knape JTA. Early respiratory depression resistant to naloxone following epidural buprenorphine. Anesthesiology. 1986; 64:382-4. [IDIS 212887] [PubMed 3954137]

193. Doxey JC, Everitt JE, Frank LW et al. A comparison of the effect of buprenorphine and morphine on the blood gases of conscious rats. Br J Pharmacol. 1982; 75:118P.

194. Buprenorphine. In: WHO Expert Committee on Drug Dependence. 25th report. Technical report series 775. sandoz: World Health Organization; 1989:21-4.

195. Johnson RE, Cone EJ, Henningfield JE et al. Use of buprenorphine in the treatment of opiate addiction. I. Physiologic and behavioral effects during a rapid dose induction. Clin Pharmacol Ther. 1989; 46:335-43. [IDIS 259079] [PubMed 2776393]

196. Bickel WK, Stitzer ML, Bigelow GE et al. A clinical trial of buprenorphine: comparison with methadone in the detoxification of heroin addicts. Clin Pharmacol Ther. 1988; 43:72-8. [IDIS 237879] [PubMed 3275523]

197. Kosten TR, Krystal JH, Charney DS et al. Rapid detoxification from opioid dependence. Am J Psychiatry. 1989; 146:10. [PubMed 2643353]

198. Sakol MS, Stark C, Sykes R. Buprenorphine and temazepam abuse by drug takers in Glasgow—an increase. Br J Addict. 1989; 84:439-41. [PubMed 2566343]

199. O’Connor JJ, Moloney E, Travers R et al. Buprenorphine abuse among opiate addicts. Br J Addict. 1988; 83:1085-7. [PubMed 3265643]

200. Johnson RE, Jaffe JH, Fudala PJ. A controlled trial of buprenorphine treatment for opioid dependence. JAMA. 1992; 267:2750-5. [IDIS 296725] [PubMed 1578593]

201. Food and Drug Administration. Orphan designation pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to June 28, 1996. Rockville, MD; 1996 Jul.

202. Reckitt Benckiser Pharmaceuticals, Inc. Suboxone (buprenorphine hydrochloride and naloxone hydrochloride dihydrate) sublingual tablets and Subutex (buprenorphine hydrochloride) sublingual tablets prescribing information. Richmond, VA; 2006 Sep.

203. Reckitt Benckiser Pharmaceuticals, Inc. Information for Pharmacists: Suboxone (buprenorphine hydrochloride/naloxone hydrochloride dihydrate, sublingual tablets) and Subutex (buprenorphine hydrochloride, sublingual tablets).

204. Raisch DW, Fye CL, Boardman KD et al. Opioid dependence treatment, including buprenorphine/naloxone. Ann Pharmacother. 2002; 36:312-21. [IDIS 476846] [PubMed 11847954]

205. Boatwright DE. Buprenorphine and addiction: challenges for the pharmacist. J Am Pharm Assoc. 2002; 42:432-8.

206. Drug Enforcement Administration (DEA), Department of Justice. Schedules of controlled substances: rescheduling of buprenorphine from schedule V to schedule III—final rule. Fed Regist. 2002; 67:62354-70. [PubMed 12369590]

207. Fiellin DA, O’Connor PG. New federal initiatives to enhance the medical treatment of opioid dependence. Ann Intern Med. 2002; 137: 688-92.

208. O’Connor PG, Fiellin DA. Pharmacologic treatment of heroin-dependent patients. Ann Intern Med. 2000; 133:40-54. [IDIS 449519] [PubMed 10877739]

209. Ling W, Charuvastra C, Collins JF et al. Buprenorphine maintenance treatment of opiate dependence: a multicenter, randomized clinical trial. Addiction. 1998; 93:475-86. [PubMed 9684386]

210. Johnson RE, Chutuape MA, Strain EC et al. A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N Engl J Med. 2000; 343:1290-7. [IDIS 454761] [PubMed 11058673]

213. Purdue Pharma. Butrans (buprenorphine) transdermal system for transdermal administration prescribing information. Stamford, CT; 2011 Jun.

214. Reckitt Benckiser Pharmaceuticals. Suboxone (buprenorphine and naloxone) sublingual film prescribing information. Richmond, VA; 2010 Aug.

215. Purdue Pharma. Butrans (buprenorphine) transdermal system: Risk Evaluation and Mitigation Strategy (REMS). Stamford, CT; 2010 Jun 30.

216. Reckitt Benckiser Pharmaceuticals. Suboxone (buprenorphine and naloxone) sublingual film: Risk Evaluation and Mitigation Strategy (REMS). Richmond, VA; 2010 Aug.

217. Drug Enforcement Administration. Authority for practitioners to dispense or prescribe approved naracotic controlled substances for maintenance or detoxification treatment. 21 CFR Parts 1301 and 1306. Final rule. [Docket No. DEA-202F] Fed Regist. 2005; 70:36338-44.

218. Hand CW, Sear JW, Uppington J et al. Buprenorphine disposition in patients with renal impairment: single and continuous dosing, with special reference to metabolites. Br J Anaesth. 1990; 64:276-82. [PubMed 2328175]

219. Reckitt Benckiser Pharmaceuticals. Medication guide: Suboxone (buprenorphine and naloxone) sublingual film. Richmond, VA; 2010 Sep.

220. Purdue Pharma. Medication Guide: Butrans (buprenorphine) transdermal system. Stamford, CT; 2010 Jun.

221. Purdue Pharma. Prescribing Butrans (buprenorphine) transdermal system: a training guide for healthcare providers. Stamford, CT; 2010.

222. Drug Enforcement Administration. Changes to patient limitation for dispensing or prescribing approved narcotic controlled substance for maintenance or detoxification treatment by qualified individual practitioners. 21 CFR Part 1301. Final rule. [Docket No. DEA-275F] Fed Regist. 2008; 73:29685-88.

223. Steiner D, Munera C, Hale M et al. Efficacy and Safety of Buprenorphine Transdermal System (BTDS) for Chronic Moderate to Severe Low Back Pain: A Randomized, Double-Blind Study. J Pain. 2011; :. [PubMed 21807566]

224. Bristol-Myers. Reyataz (atazanavir sulfate) capsules prescribing information. Princeton, NJ; 2011 Feb.

225. US Department of Health and Human Services, Substance Abuse and Mental Health Services Administration. Frequently asked questions about buprenorphine and the Drug Addiction Treatment Act 2000 (DATA 2000). From SAMHSA website. Accessed 2011 Nov 4.

HID. Trissel LA. Handbook on injectable drugs. 16th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2011:222-225.