Buprenorphine/naloxone

Buprenorphine/naloxone Uses, Dosage, Side Effects, Food Interaction and all others data.

Buprenorphine exerts its analgesic effect via high affinity binding to the μ-opioid receptors in the CNS. It displays partial μ-opioid agonist activity and weak kappa antagonist activity.

Buprenorphine interacts predominately with the opioid mu-receptor. These mu-binding sites are discretely distributed in the human brain, spinal cord, and other tissues. In clinical settings, buprenorphine exerts its principal pharmacologic effects on the central nervous system. Its primary actions of therapeutic value are analgesia and sedation. In addition to analgesia, alterations in mood, euphoria and dysphoria, and drowsiness commonly occur. Buprenorphine depresses the respiratory centers, depresses the cough reflex, and constricts the pupils.

Dependence

Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt discontinuation or rapid taper. The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset. Buprenorphine can be abused in a manner similar to other opioids. This should be considered when prescribing or dispensing buprenorphine in situations when the clinician is concerned about an increased risk of misuse, abuse, or diversion.

Naloxone is a pure opioid antagonist that acts competitively at opioid receptors. While the mechanism of action of naloxone is not fully understood, the preponderance of evidence suggests that naloxone antagonizes the opioid effects by competing for the same receptor sites, especially the opioid mu receptor. Recently, naloxone has been shown to bind all three opioid receptors (mu, kappa and gamma) but the strongest binding is to the mu receptor.

Naloxone is an opioid receptor antagonist indicated in the reversal of opioid overdoses. Naloxone has a shorter duration of action than opioids and multiple doses may be required. The therapeutic window of naloxone is wide, as it has no effect if a patient has not taken opioids. Patients treated with naloxone may experience opioid withdrawal and a person administering naloxone should be aware that reversal of opioid overdoses may not resolve all the symptoms a patient is experiencing if other drugs are involved.

Buprenorphine/naloxone
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Buprenorphine/naloxone
Generic	buprenorphine + naloxone
Type
Therapeutic Class
Manufacturer
Available Country	United States
Last Updated:	September 19, 2023 at 7:00 am

Uses

Buprenorphine is used for Moderate to severe pain, Anaesth premed, Opioid dependence, Anaesth premed, Perioperative analgesia

Naloxone is used for the complete or partial reversal of opioid depression, including respiratory depression, induced by natural and synthetic opioids, including propoxyphene, methadone and certain mixed agonist-antagonist analgesics: nalbuphine, pentazocine, butorphanol, and cyclazocine. Naloxone is also used for diagnosis of suspected or known acute opioid overdosage. Naloxone may be useful as an adjunctive agent to increase blood pressure in the management of septic shock

Buprenorphine/naloxone is also used to associated treatment for these conditions: Opioid Dependence, Severe Pain, Moderate PainOpioid Dependence, Opioid Overdose, Pruritus, Respiratory Depression, Septic Shock, Severe Pain, Moderate Pain, Suspected Opioid Overdose

How Buprenorphine/naloxone works

Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor. It demonstrates a high affinity for the mu-opioid receptor but has lower intrinsic activity compared to other full mu-opioid agonists such as heroin, oxycodone, or methadone. This means that buprenorphine preferentially binds the opioid receptor and displaces lower affinity opioids without activating the receptor to a comparable degree. Clinically, this results in a slow onset of action and a clinical phenomenon known as the "ceiling effect" where once a certain dose is reached buprenorphine's effects plateau. This effect can be beneficial, however, as dose-related side effects such as respiratory depression, sedation, and intoxication also plateau at around 32mg, resulting in a lower risk of overdose compared to methadone and other full agonist opioids. It also means that opioid-dependent patients do not experience sedation or euphoria at the same rate that they might experience with more potent opioids, improving quality of life for patients with severe pain and reducing the reinforcing effects of opioids which can lead to drug-seeking behaviours.

Buprenorphine's high affinity, but low intrinsic activity for the mu-opioid receptor also means that if it is started in opioid-dependent individuals, it will displace the other opioids without creating an equal opioid effect and cause a phenomenon known as "precipitated withdrawal" which is characterized by a rapid and intense onset of withdrawal symptoms (i.e. anxiety, restlessness, gastrointestinal distress, diaphoresis, intense drug cravings, and tachycardia). Individuals must therefore be in a state of mild to moderate withdrawal before starting therapy with buprenorphine.

Buprenorphine is commercially available as the brand name product Suboxone which is formulated in a 4:1 fixed-dose combination product along with naloxone, a non-selective competitive opioid receptor antagonist. Combination of an opioid agonist with an opioid antagonist may seem counterintuitive, however this combination with naloxone is intended to reduce the abuse potential of Suboxone, as naloxone is poorly absorbed by the oral route (and has no effect when taken orally), but would reverse the opioid agonist effects of buprenorphine if injected intravenously.

Naloxone is a competitive inhibitor of the µ-opioid receptor. Naloxone antagonizes the action of opioids, reversing their effects. If a patient has not taken opioids, naloxone does not have a significant effect on patients.

Dosage

Buprenorphine/naloxone dosage

Adult:

Oral: Sublingual Moderate to severe pain: 200-400 mcg 6-8 hourly.
IV: Perioperative analgesia: 300-450 mcg via slow inj.
IV/IM: Moderate to severe pain: 300-600 meg 6-8 hourly.
IM: Anesthesia premed: 300 meg.

Severe hepatic Impairment: Dose adjustment needed.

Reversal of central depression from opioid use during surgery:

Adult:100-200 mcg at intervals of 2-3 minute, titrate dose according to response while maintaining analgesia.
Child:5-10 mcg IV at 2-3 min intervals.

Opioid overdosage:

Adult:0.4-2 mg repeated if necessary at 2-3 min intervals. If there is no response after a total of 10 mg has been given, consider the possibility of overdosage with other drugs. Reduce dose for opioid-dependent patients: 0.1-0.2 mg. IM/SC routes may be used (at IV doses) if IV admin is not feasible.
Child:Initially 10 mcg/kg IV followed by 100 mcg/kg IV if necessary. Alternatively, 0.4-0.8 mg IM or SC, repeated as necessary, if IV admin is not feasible.

Opioid-induced depression in neonates due to obstetric analgesia:

Child:10 mcg/kg IV, IM or SC repeated at 2-3 min intervals if necessary or 60 mcg/kg as a single IM dose.

Intravenous:

Reversal of central depression from opioid: Stable in 0.9% sodium chloride and 5% dextrose inj at 4 mcg/ml for 24 hr.
Opioid overdosage: Stable in 0.9% sodium chloride and 5% dextrose ing at 4 mcg/ml for 24 hr.

Parenteral: Stable in 0.9% sodium chloride and 5% dextrose inj at 4 mcg/ml for 24 hr.

Side Effects

Common side effects are CNS depression, including somnolence, dizziness, alterations in judgment and levels of consciousness, including coma; sedation, dizziness, sweating, vertigo, headache; nausea, vomiting, dry mouth, constipation, dyspepsia, abdominal cramps, flatulence, diaphoresis; rash, urticaria, pruritus; miosis, blurred vision, hallucinations and other psychotomimetic effects; hypotension leading to syncope, HTN, tachycardia, bradycardia, ECG abnormalities.

Occur secondarily to reversal (withdrawal) of narcotic analgesia and sedation. Mental depression, apathy, inability to concentrate, sleepiness, irritability, anorexia, nausea, and vomiting in high oral doses during initial treatment of opiate addiction.

Toxicity

Manifestations of acute overdose include pinpoint pupils, sedation, hypotension, respiratory depression and death.

If a patient has not taken opioids, naloxone does not have a significant effect on patients.

The oral LD₅₀ in mice and rats is >1 g/kg. The intraperitoneal LD₅₀ is 80 mg/kg in mice and 239 mg/kg in rats. The subcutaneous LD₅₀ is 286 mg/kg in mice and 500 mg/kg in rats.

Precaution

Patient with pulmonary impairment or compromised respiratory iratory function (e.g. COPD, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, pre-existing respiratory depression). Patient with hypothyroidism, myxedema, adrenocortical insufficiency (e.g. Addison's disease), dysfunction of biliary tract including acute pancreatitis, acute alcoholism, delirium tremens, toxic psychoses, kyphoscoliosis, prostatic hypertrophy or urethral stricture; comatose patients. Patient with CNS depression, history of seizure disorders, head injury, intracranial lesions or conditions in which intracranial pressure may be increased. Patient with personal or family history of QT interval prolongation, hypokalaemia or unstable cardiac disease (e.g. AF, CHF, myocardial ischaemia), particularly in transdermal admin. Hepatic or renal impairment. Pregnancy and lactation.

Patients physically dependent on opioids, or who have received large doses of opioids (acute withdrawal syndrome may be precipitated). Pregnancy and lactation.

Interaction

Plasma-buprenorphine concentrations may be affected when co-administered with drugs that induce or inhibit CYP3A4 isoenzyme. Enhanced depressant effects of other CNS depressants, other opiate agonists, anaesth, antihistamines, muscle relaxants, tranquilisers (e.g. phenothiazines), sedatives and hypnotics (e.g. benzodiazepines). Increased and/or prolonged activity with drugs that may reduce hepatic blood flow (e.g. halothane). Receiving class IA (e.g. quinidine, procainamide) or class III (e.g. sotalol, amiodarone) antiarrhythmic agents with transdermal buprenorphine may increase the risk of QT interval prolongation.

Decreased effect of opioid analgesics.

Volume of Distribution

Buprenorphine is highly lipophilic, and therefore extensively distributed, with rapid penetration through the blood-brain barrier. The estimated volume of distribution is 188 - 335 L when given intravenously. It is able to cross into the placenta and breast milk.

The volume of distribution of naloxone is 200 L. Naloxone distributes into tissues rapidly. It can also cross the placenta and blood-brain barrier.

Elimination Route

Bioavailablity of buprenorphine/naloxone is very high following intravenous or subcutaneous administration, lower by the sublingual or buccal route, and very low when administered by the oral route. It is therefore provided as a sublingual tablet that is absorbed from the oral mucosa directly into systemic circulation.

Clinical pharmacokinetic studies found that there was wide inter-patient variability in the sublingual absorption of buprenorphine and naloxone, but within subjects the variability was low. Both Cmax and AUC of buprenorphine increased in a linear fashion with the increase in dose (in the range of 4 to 16 mg), although the increase was not directly dose-proportional. Buprenorphine combination with naloxone (2mg/0.5mg) provided in sublingual tablets demonstrated a Cmax of 0.780 ng/mL with a Tmax of 1.50 hr and AUC of 7.651 ng.hr/mL.

Coadministration with naloxone does not effect the pharmacokinetics of buprenorphine.

An intranasal dose of naloxone is 42-47% bioavailable. An 8 mg dose of nasal naloxone reaches a C_max of 12.3-12.8 ng/mL, with a T_max of 0.25 hours, and an AUC of 16.7-19.0 h*ng/mL. A 0.4 mg intramuscular dose reaches a C_max of 0.876-0.910 ng/mL, with a T_max of 0.25 hours, and an AUC of 1.94-1.95 h*ng/mL. A 2 mg intravenous dose reaches a C_max of 26.2 ng/mL with an AUC of 12.8 h*ng/mL.

Half Life

Buprenorphine demonstrates slow dissociation kinetics (~166 min), which contributes to its long duration of action and allows for once-daily or even every-second-day dosing. In clinical trial studies, the half-life of sublingually administered buprenorphine/naloxone 2mg/0.5mg was found to be 30.75 hours.

The mean half life of naloxone hydrochloride is 1.8-2.7 hours intranasally, 1.4 hours intramuscularly, and 1.2 hours intravenously. In neonates, the mean half life is 3.1 ± 0.5 hours.

Clearance

Clearance may be higher in children than in adults. Plasma clearance rate, IV administration, anaesthetized patients = 901.2 ± 39.7 mL/min; Plasma clearance rate, IV administration, healthy subjects = 1042 - 1280 mL/min.

The clearance of naloxone is 2500 L/day.

Elimination Route

Buprenorphine, like morphine and other phenolic opioid analgesics, is metabolized by the liver and its clearance is related to hepatic blood flow. It is primarily eliminated via feces (as free forms of buprenorphine and norbuprenorphine) while 10 - 30% of the dose is excreted in urine (as conjugated forms of buprenorphine and norbuprenorphine).

The overall mean elimination half-life of buprenorphine in plasma ranges from 31 to 42 hours, although the levels are very low 10 hours after dosing (majority of AUC of buprenorphine is captured within 10 hours), indicating that the effective half-life may be shorter.

After oral or intravenous administration, naloxone is 25-40% eliminated in the urine within 6 hours, 50% in 24 hours, and 60-70% in 72 hours. The metabolites naloxone-3-glucuronide, noroxymorphone, and naloxol are all detected in the urine.

Pregnancy & Breastfeeding use

Pregnancy Category C. Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.

Contraindication

Transdermal: Patient with known or suspected paralytic ileus, substantial respiratory depression or severe bronchial asthma. Management of acute, intermittent, mild, or short-term (including post-op) pain. Concomitant admin of IV buprenorphine and oral diazepam. Concurrent use or w/in 14 days of discontinuation of MAOIs.