How Effective Is Buprenorphine for Pain?

A buprenorphine transdermal patch for chronic pain that cannot be controlled by non-opioid analgesics.

Drug name of buprenorphine transdermal patch :

[General name] buprenorphine transdermal patch

[Commodity name] Ruo Siben

Warnings for buprenorphine transdermal patches :

This product may be abused and may cause life-threatening respiratory depression and accidental exposure.
Possibility of abuse This product contains buprenorphine, which is an opioid receptor agonist. It belongs to the nationally administered psychotropic drug. Its abuse tendency is similar to other psychotropic drugs. Before prescribing a patient, assess the risk of opioid abuse or addiction, the patient or his family has a history of drug abuse (including drugs or alcohol or alcohol abuse or addiction), or opioids in patients with mental illness (such as major depression) The risk of substance abuse increases. During the treatment period, regularly monitor all patients receiving this product for signs of misuse, abuse and addiction [see [Precautions]].
Life-threatening respiratory depression During the treatment of this product, respiratory depression may occur even at the recommended dose rather than misuse or abuse, including fatal cases [see [Cautions]]. Doctors who have knowledge about powerful opioids for the treatment of chronic pain are required to prescribe this product. Correct administration and dose titration are the basic principles. Respiratory depression needs to be monitored during treatment, especially after starting treatment or increasing doses of this product.
Accidental exposure Accidental exposure to this product, especially children, can lead to overdose of buprenorphine [see [Precautions]].

Buprenorphine transdermal patch ingredients:

The main ingredient of this product is the chemical name of buprenorphine: (2S) -2- [17- (cyclopropylmethyl> -4,5-epoxy-3-hydroxy-6, 14-bridge ethylene- 14- Morphine-7 -yl] -3,3-dimethylbutane-2-ol Molecular formula: C ₂₉ H ₄₁ N0 ₄
Molecular weight: 467.6

Buprenorphine transdermal patch properties:

This product is a light brown patch with rounded corners and an aluminum protective pad. The center is the drug store. The back is printed with the blue name, specifications and release rate.
5mg: This product is a light brown transdermal patch with square and rounded corners. Labeled 'Norspan 5g / h'.
10mg: This product is a light brown transdermal patch with rectangular and rounded corners. Labeled 'Norspan 10 g / h'.
20mg: This product is a light brown transdermal patch with square and rounded corners. Marked 'Norspan20g / h'.

Indications for buprenorphine transdermal patch :

For non-opioid analgesics for chronic pain that cannot be controlled.

Buprenorphine transdermal patch specifications:

(1) 5mg (6.5cm²).
Rated release rate: 5 micrograms of buprenorphine per hour (for a total of 7 days).
(2) 10mg (12.5cm²).
Rated release rate; 10 micrograms of buprenorphine per hour (for a total of 7 days).
(3) 20mg (25cm²)
Rated release rate: 20 micrograms of buprenorphine per hour (for a total of 7 days).

Buprenorphine transdermal patch usage dosage:

Each buprenorphine transdermal patch is used for 7 days.
Buprenorphine transdermal patches are not suitable for the treatment of acute pain.
Patients 18 years and older:
The initial dose should be the lowest buprenorphine transdermal patch dose (5 g / h buprenorphine transdermal patch). The patient's previous history of opioid use should be considered, as well as the patient's current general and disease status.
Dose adjustment:
During the initiation of buprenorphine transdermal patch treatment and dose adjustment, patients should use short-acting supplemental analgesics at generally recommended doses until the analgesic effect of buprenorphine transdermal patch is achieved.
The dose cannot be increased 3 days before the dose used reaches maximum effectiveness. Subsequent dose increases should be based on the need for complementary painkillers and the patient's response to the analgesic effect of the patch.
When the dose is increased, it can be replaced with a larger patch, or another patch can be used in combination at different sites to achieve the desired dose. No matter what dosage of buprenorphine transdermal patch, it is recommended to use a maximum of two patches at a time. Do not use new patches on the same area for the next 3-4 weeks.
The patient's use should be carefully and regularly monitored to achieve the best dose and the best treatment cycle.
Opioid Conversion:
Buprenorphine transdermal patches can be used as alternative treatments for other opioids. Such patients should start with the lowest dose (5 g / h buprenorphine transdermal patch) and continue to take short-acting supplemental analgesics as needed during dose adjustment.
Renal insufficiency:
Patients with renal insufficiency do not need special dose adjustments.
Liver damage:
Buprenorphine is metabolized by the liver. Its intensity and duration of action may be affected in patients with liver damage. Therefore, the use of buprenorphine transdermal patches in patients with liver damage should be carefully monitored.
Patients with severe liver damage may experience buprenorphine accumulation during the treatment of buprenorphine transdermal patches, and replacement therapy should be considered. Patients must use caution if they must use the patch.
Application area:
The buprenorphine transdermal patch should be used on the outer skin of the upper arm, the upper front of the chest, the upper back, or the side of the chest without allergic intact skin. Do not use it on any skin with large scars. Buprenorphine transdermal patches should be used on areas of the skin with little or no hair. If this is not possible, use scissors to cut the hair away, but do not use a shaver to remove the hair.
If the area of use must be cleaned, use only clean water. Do not use soap, alcohol, oil, lotion or scrubbing equipment. The skin must be dry before applying the patch. It must be used immediately after opening the seal. After removing the protective layer, apply the palm of your hand to squeeze the transdermal patch for about 30 seconds to ensure complete contact, especially at the edges. If the edge of the patch comes off, stick it with tape at the corresponding location.
The patch should be used continuously for 7 days.
Bath tubs, showers, or swimming should not affect the use of the patch. If the patch comes off, use a new patch.
usage time:
Under no circumstances should transdermal buprenorphine be used for longer than necessary. If long-term application of buprenorphine transdermal patches is necessary based on the condition and severity, the patient must be carefully and regularly monitored (if necessary, intermittently) to determine whether the patient needs to continue using it.
Withdrawal:
After the buprenorphine transdermal patch is removed, the serum drug concentration of buprenorphine gradually decreases, so its analgesic effect can be maintained for a certain period of time. This should be taken into account when using buprenorphine transdermal patches followed by other opioids. As a general rule, no other opioid should be used within 24 hours after removing the buprenorphine transdermal patch. There is limited data on starting doses of other opioids after discontinuation of removal of patches.
Patient with fever or external heat:
After using buprenorphine transdermal patches, patients should avoid heating the use site, such as heating pads, electric blankets, heating lamps, saunas, hot baths, heated water beds, etc., because heat can make buprenorphine Increased absorption. When treating patients with fever, it should be noted that fever may increase absorption, leading to increased blood levels of buprenorphine, thereby increasing the risk of opioid reactions.
Use and processing instructions:
Do not use if packaging is damaged.
Post-processing:
When changing the patch, remove the used patch, fold the adhesive layer inward, and keep it out of the reach of children.

Adverse reactions of buprenorphine transdermal patch :

Serious adverse reactions of buprenorphine transdermal patches are similar to those observed in clinical use of other opioid analgesics, such as respiratory depression (especially when used with other central nervous system inhibitors) and hypotension.
The following adverse reactions have been observed: very common (1 / 10), common (1 / 100, <1/10), uncommon (1 / 1000, <1/100), rare (1 / 10) 10,000, <1/1000), very rare (<1 / 10,000), unknown (the incidence cannot be deduced from known information).
immune system:
Uncommon: high blood pressure.
Very rare: allergic reactions, allergic reactions.
Metabolism and nutrition:
Common: loss of appetite.
Uncommon: Dehydration.
spirit:
Common: confusion, depression, insomnia, nervousness.
Uncommon: Sleep disorders, hyperactivity, agitation, loss of self-esteem, euphoria, unstable emotions, anxiety, hallucinations, nightmares
Rare: mental disorders, decreased sexual desire.
Very rare: drug dependence, emotional instability.
nervous system:
Very common: headache, dizziness, drowsiness.
Common: Paresthesia.
Uncommon: Sedation, taste disorders, dysarthria, dull feeling, memory impairment, migraine, syncope, tremor, ataxia, impaired attention.
Rare: balance disorders, language disorders.
Very rare: involuntary muscle contraction.
Eye:
Rare: dry eye, blurred vision.
Very rare: visual impairment, eyelid edema, pupil dilation.
Ears and lost:
Uncommon: tinnitus, dizziness.
Very rare: earache.
heart:
Uncommon: angina, palpitations, tachycardia.
Blood vessels:
Common: Vasodilation.
Uncommon: hypotension, circulatory failure, hypertension, flushing.
Respiration, chest, mediastinum:
Common: Dyspnea.
Uncommon: exacerbation of asthma, cough, hypoxia, rhinitis, wheezing, hyperventilation, snoring
Rare: respiratory depression, respiratory failure.
Gastrointestinal tract:
Very common: constipation, dry mouth, nausea, and vomiting.
Common: abdominal pain, diarrhea, indigestion.
Uncommon: flatulence.
Rare: diverticulitis, difficulty swallowing, and intestinal obstruction.
Hepatobiliary:
Rare: biliary colic.
Skin and subcutaneous tissue:
Very common: itching, erythema.
Common: rash, sweating, rash.
Rare: dry skin, facial edema, hives.
Very rare: pustules, vesicles.
Musculoskeletal and connective tissue:
Uncommon: myalgia spasm, myalgia, muscle weakness, muscle spasm.
Kidney and urinary system:
Uncommon: urinary retention, dysuria.
Reproductive system and breast:
Rare: erectile dysfunction, sexual dysfunction.
Whole body and administration site:
Very common: itching at the site of administration, reaction at the site of administration.
Common: fatigue, weakness, pain, peripheral edema, erythema at the site of administration, rash at the site of administration, chest pain.
Uncommon: fatigue, flu-like symptoms, fever, abnormal muscle tone (rigidity), general weakness, edema, withdrawal symptoms.
Rare: Allergic inflammation at the site of administration.
an examination:
Uncommon: Increased alanine aminotransferase and weight loss.
Injuries, poisoning and surgical complications:
Uncommon: accidental injury, fall.
In some cases, a delayed local allergic reaction with significant signs of inflammation. These patients should discontinue buprenorphine transdermal patches.
The risk of physical dependence of buprenorphine is low. Withdrawal of buprenorphine is unlikely to cause withdrawal symptoms. This may be due to the very slow separation of buprenorphine from the opioid receptor and its gradual decrease in plasma concentration (usually more than 30 hours after removal of the last patch). However, after long-term use of buprenorphine transdermal patches, the withdrawal symptoms similar to those of opioids cannot be completely ruled out. These symptoms include agitation, anxiety, tension, insomnia, hyperkinesia, tremors, and gastrointestinal disorders.

Buprenorphine transdermal patches contraindications:

Buprenorphine transdermal patches are contraindicated in the following cases:
Patients known to be allergic to the active ingredient buprenorphine or any other excipient;
Opioid dependent patients and alternative therapies for narcotics;
Patients with severely impaired respiratory centres and functions or who may have this condition;
For patients who are using a monoamine oxidase inhibitor or have used a monoamine oxidase inhibitor within the first two weeks;
Patients with muscle weakness;
Patients with tremor delirium.

Note for buprenorphine transdermal patch :

Possibility of abuse This product contains buprenorphine, which is a partial agonist of the mu opioid receptor, and belongs to the nationally administered psychotropic drug. The form of abuse of buprenorphine is similar to other opioid receptor agonists (legal or illegal). Opioid receptor agonists are targeted by drug abusers and drug addicts and are vulnerable to illegal reselling. When prescribing or dispensing this product, if you find that there is an increased risk of misuse, abuse or reselling, the above risks should be taken into account. But concerns about misuse, abuse, and reselling should not prevent proper treatment of pain.
Before prescribing a patient, you need to assess the risk of opioid abuse or addiction. I or my family has a history of drug abuse (including drug or alcohol abuse or addiction) or a patient with a mental illness (such as major depression). The risk of drug abuse increases. Patients at increased risk are still suitable for slow-release opioid therapy; however, monitoring of such patients' signs of misuse, abuse, or addiction should be strengthened. Because such drugs have an addiction risk even in the correct clinical application, all patients receiving opioids should be routinely monitored for signs of misuse, abuse, and addiction.
Misuse or abuse of buprenorphine extracted from buprenorphine transdermal patches by chewing, swallowing, sniffing or injecting it can lead to uncontrolled release of opioids and can lead to significant overdose and death Risk [see [Overdose]].
Life-threatening respiratory depression The main risk of this product is respiratory depression, which, if not diagnosed and treated in a timely manner, can cause respiratory arrest and death. Opioids cause symptoms of respiratory depression as reduced spontaneous breathing and decreased breathing frequency, often accompanied by "sigh" breathing (abnormally long, deep breathing). Carbon dioxide (CO2) retention caused by opioid-induced respiratory depression can aggravate the sedative effects of opioids. According to the clinical manifestations of patients, the control of respiratory depression treatment includes close observation, supportive therapy and the use of opioid antagonists [see [Overdose]].
Severe, life-threatening, or fatal respiratory depression may occur at any time during the treatment of this product, especially during the beginning of treatment or during increased doses. Patients should be closely monitored for respiratory depression during initiation of treatment and dose escalation. Inform patients that they should only be used in accordance with the prescription and not on their own. Store this product out of the reach of children to avoid fatal respiratory depression caused by improper use.
To reduce the risk of respiratory depression, proper dosing and dose titration are basic principles [see [Overdose]]. Patients switching from other opioids to this product may cause fatal overdose if the first dose is too high. Respiratory depression has also been reported with slow-release opioids at the recommended doses and without misuse or abuse.
To further reduce the risk of respiratory depression, the following measures should be considered:
Proper dosing and dose titration are the basic principles. Only medical professionals with knowledge about potent opioids for the treatment of chronic pain can prescribe this product.
This product is contraindicated for patients with respiratory depression and patients with an increased risk of life-threatening respiratory depression [see [Contraindications]].
Accidental exposure Accidental exposure to this product, especially children, can lead to fatal overdose of buprenorphine.
Elderly, cachexia and frail patients Older, cachexia and frail patients are more prone to respiratory depression. Compared with younger and healthy people, this population has poor fat reserves, muscle atrophy, or changes in drug clearance resulting in pharmacokinetics of the drug. Changed. Therefore, such patients should be closely monitored, especially during the beginning of treatment and titration of this product, and when this product is used in combination with other drugs that have respiratory depression.
Medications for patients with chronic lung disease should be monitored in patients with significant chronic obstructive pulmonary disease or pulmonary heart disease, as well as patients with severely reduced respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression, especially at the beginning of treatment and During dose titration, as this type of patients will cause reduced respiratory motility and even apnea even with normal therapeutic doses. If feasible, these patients should be replaced with non-opioid analgesics.
Interactions with alcohol, CNS inhibitors, and illicit drugs If this product is added in the treatment including other CNS inhibitors (such as sedatives, anxiolytics, sleeping pills, antipsychotics, muscle relaxants, other opioids) Can cause hypotension, deep sedation, coma, or respiratory depression. Patients who are being treated with CNS inhibitors should be evaluated with CNS inhibitor cycle and patient response, including the degree of tolerance to CNS inhibitors. In addition, patients should consider whether they are alcoholics or use illicit drugs that can lead to CNS suppression. If starting treatment with this product in patients who are using CNS inhibitors, the initial dose should be lower than the normal dose, and monitor patients for signs of sedation and respiratory depression, and consider reducing the dose of combined CNS inhibitors [see [Drugs interaction].
QTc interval prolongation In a positive control study, the effect of this product on the QTc interval was observed in healthy subjects, and the results showed that this product would not have clinically significant effects at a dose of 10 g / hour; however, At a dose of 40 g / hour (two doses of this product 20 g / hour), the QTc interval was found to be prolonged. In clinical use, apply this to patients with hypokalemia or clinically unstable heart disease (including: unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, or active myocardial ischemia) The product should consider the possibility of the above phenomenon.
Patients with a long history of QT syndrome or immediate family members of such patients, or are using class IA antiarrhythmic drugs (e.g., quinidine, procainamide, propipamine) or class III antiarrhythmic drugs (e.g., sotal (Lol, amiodarone, dofetilide) should be avoided in patients.
Antihypertensive effect This product can cause severe hypotension, including orthostatic hypotension and syncope in ambulatory patients. Patients with hypovolemic drugs that cause blood pressure instability or who are treated with a certain CNS inhibitor (such as phenothiazines or general anesthetics) increase the risk of hypotension [see [Drug Interactions]]. The above patients should be monitored for signs of hypotension during the initiation of treatment or dose titration of this product.
Use in patients with head injury or elevated intracranial pressure. Patients who are prone to intracranial CO2 retention (such as patients with elevated intracranial pressure or brain tumors) should be monitored for signs of sedation and respiratory depression, especially during treatment initiation. . This product will reduce breathing power, CO2 retention will cause further increase in intracranial pressure. Opioids can also cause unclear clinical course in patients with head injuries.
Patients with impaired consciousness or coma should avoid using this product.
Hepatotoxicity is not observed in chronic pain clinical trials, but other clinical trials and post-marketing adverse event reports have shown cytolytic hepatitis and jaundice in patients receiving sublingual buprenorphine administration Hepatitis cases range from transient asymptomatic elevations of liver transaminase to liver failure, liver necrosis, hepatorenal syndrome, and hepatic encephalopathy. In many cases, patients with liver enzyme abnormalities, hepatitis B or HCV infection, combined use of other potentially hepatotoxic drugs, and injecting drugs in abuse may cause liver toxicity or promote liver toxicity. Patients with an increased risk of hepatotoxicity (such as patients with a history of alcohol abuse, medicinal substance abuse or liver disease) should record baseline liver enzyme levels and be monitored regularly during the treatment of this product.
Rare cases of skin reactions at the site of treatment have been reported. Severe severe skin reactions at the site of treatment with severe inflammatory reactions including "burns", "purulent discharge", and "small blisters" have different onset times. From days to months. Inform patients that if a severe reaction occurs at the site of treatment, they should promptly report and discontinue treatment.
Acute and chronic hypersensitivity cases of buprenorphine have been reported in clinical trials of allergic reactions and post-marketing clinical use. The most common signs and symptoms include rash, urticaria and pruritus. It has been reported to include cases of bronchospasm, angioedema and anaphylactic shock. A history of buprenorphine hypersensitivity is one of the contraindications for this product.
Medications that can increase local temperature Advise patients and their medical staff to avoid exposing the medication site and surrounding skin to direct external heat sources such as heat pads or electric blankets, heating or sun-dampening during the use of transdermal drug delivery systems Sun beds, saunas, hot baths and heated water beds, as this increases the absorption of buprenorphine. Patients are advised to avoid exposing the site and surrounding skin to hot water or prolonged direct exposure to sunlight, which may increase the temperature-dependent release of buprenorphine in the transdermal system and may cause overdose and death.
Patients with fever who use this product for fever or increased body temperature due to overwork due to side effects of opioids should be monitored. If breathing or central nervous system depression occurs, the dose of this product needs to be adjusted.
This product is contraindicated in patients with gastrointestinal disorders using paralytic intestinal obstruction. Other patients with gastrointestinal obstruction should avoid using this product.
The buprenorphine component in this product can cause sphincter spasm in Odi, so patients with biliary diseases including acute pancreatitis should be monitored to avoid worsening symptoms. Opioids may cause elevated serum amylase levels.
The use of buprenorphine in patients with convulsions or epilepsy may worsen seizures in patients with convulsive diseases, and may cause or aggravate seizures in some clinical settings. During the treatment of this product, patients with a history of epilepsy should be monitored to prevent seizures.
Avoiding withdrawal symptoms Like other opioids, long-term use of buprenorphine can cause physical dependence. Withdrawal symptoms include dryness, tearing, rhinorrhea, yawning, sweating, chills, myalgia, and dilated pupils. Significant fluid loss due to vomiting and diarrhea requires intravenous fluids. Withdrawal symptoms (withdrawal syndrome) are usually mild and begin after 2 days and may last up to 2 weeks.
When discontinuing the treatment of this product, the dosage should be gradually reduced [see [Usage and dosage]], and it should not be abruptly discontinued.
Driving and mechanical operations This product can damage nerves and bodies to perform potentially dangerous activities, such as driving or mechanical operations. Even if used as directed by a doctor, it can affect how well patients respond to road safety and their ability to operate machines. Especially at the beginning of treatment and when combined with other substances acting on the central system, such as alcohol, sedatives, sedatives and hypnotics. Warn patients not to drive or operate dangerous machinery unless they are tolerant of the effects of this product and understand how to respond to medications. Doctors should give different advice to different patients. For patients who have used stable doses, general restrictions are not necessary.
If affected, the patient cannot drive or operate the machine for at least 24 hours after the patch is removed at the beginning of the treatment or during the low-to-high dose adjustment phase.
Drugs for the treatment of addiction This product has not been studied in this way and is not approved for the control of addictive diseases.
Athletes use with caution. According to the Anti-Doping Regulations, buprenorphine is a banned substance listed in the doping list, so athletes use this product with caution.

Buprenorphine transdermal patch for pregnant and lactating women:

There is no information on pregnant women after using buprenorphine transdermal patches. Animal experiments have shown reproductive toxicity. The potential toxicity for human application is unknown.
At the end of pregnancy, even high doses of buprenorphine for a short period of time can cause respiratory depression in newborns. Long-term use of buprenorphine during the last 3 months of pregnancy may cause withdrawal syndrome in the newborn. Therefore, buprenorphine transdermal patches are contraindicated during pregnancy or in women who plan to become pregnant.
Studies in lactating rats suggest that buprenorphine may inhibit lactation. It was observed that buprenorphine was excreted in rat milk. There is no data on whether buprenorphine is excreted in human milk. Therefore, buprenorphine transdermal patches should be avoided during breastfeeding.

Buprenorphine transdermal patches for children:

Since no studies have been conducted in patients under 18 years of age, buprenorphine transdermal patches are not recommended for patients withdrawal at this age.

Buprenorphine transdermal patch for elderly:

There is no need for dose adjustment for transdermal buprenorphine in elderly patients.

Drug interactions of buprenorphine transdermal patches :

Buprenorphine transdermal patches cannot be used in combination with monoamine oxidase inhibitors (MAOIs). Patients who have used MAOIs in the past two weeks should not use buprenorphine transdermal patches.
Effects of other active substances on the pharmacokinetics of buprenorphine Buprenorphine is mainly metabolized by glycolipidation, and a small part (about 30%) is metabolized by CYP3A4. Combined use with CYP3A4 inhibitors may lead to an increase in plasma concentrations, which in turn enhances the effects of buprenorphine.
A trial of the interaction of buprenorphine with a CYP3A4 inhibitor, ketoconazole, showed that the combination of a buprenorphine transdermal patch with a ketoconazole group and a buprenorphine transdermal patch group The mean peak drug concentration (Cmax) or area under the curve (AUC) of buprenorphine did not show a clinically significant increase.
Interaction tests between buprenorphine and CYP3A4 inducers have not been conducted. The combined use of buprenorphine transdermal patches and enzyme inducers (eg, phenobarbital, carbamazepine, phenytoin, rifampicin) may lead to an increased clearance rate, which in turn reduces the efficacy of the drug.
Certain general anaesthetics (such as halothane) and other drugs that induce a decrease in liver blood flow may reduce the liver's clearance of buprenorphine.
Pharmacodynamic interactions:
Care should be taken when buprenorphine transdermal patches are used in combination with:
Benzodiazepines: May cause central respiratory depression when used in combination with risk of death.
Other central nervous system inhibitors: Other opioid derivatives (for example, analgesics and cough suppressants containing morphine, dexpropoxyphene, codeine, dextromethorphan, or narcotine). Certain antidepressants, sedative H1-receptor antagonists, ethanol, anxiolytics, tranquilizers, clonidine and related substances. Use in combination with these drugs can enhance the inhibitory effect on the central nervous system.
Buprenorphine is a -receptor partial agonist, but buprenorphine can be used as a full -receptor agonist at conventional analgesic dose levels. The exposure of buprenorphine at this dose is approximately equal to or higher than that of a buprenorphine transdermal patch (5, 10, 20 g / h). In the clinical trial of buprenorphine transdermal patch, when the subject changed the -receptor full agonist opioid (the daily dose of morphine up to 90 mg or a drug equivalent to morphine) to Ding During the transdermal patch of buprenorphine, no withdrawal syndrome was found and no opioid withdrawal was reported.

Buprenorphine transdermal patch overdose:

Clinical symptoms The clinical manifestations of acute overdose of this product are respiratory depression, lethargy developing into snoring and coma, skeletal muscle relaxation, cold skin, pupil contraction, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring and death . In the case of overdose, due to severe hypoxia, significant pupil dilation may occur, rather than dilation of the pupil.
Overdose treatment In the case of overdose, if necessary, a maintenance-open airway should be re-established to assist or control breathing. With other support plus measures (including oxygen inhalation and vasopressor medications) to treat symptoms such as cyclic shock and pulmonary edema, cardiac arrest or arrhythmia will require enhanced life support technology.
Naloxone may not have any reversal effect on the respiratory depression produced by buprenorphine. During the treatment of buprenorphine overdose, the limit of high-dose naloxone is 10 to 35 mg / 70 kg, and the onset of naloxone may be delayed by 30 minutes or more. Doxapram hydrochloride (a respiratory stimulant) can also be used.
Remove this product immediately because it is expected that the duration of your effects will be less than the duration of this product's buprenorphine, and monitor carefully until the patient re-establishes reliable spontaneous breathing. Even during the improvement of symptoms, medical testing is still needed because of the possibility of continued absorption of the prolonged action of buprenorphine from the skin. After removing this product, the average concentration of buprenorphine within 12 hours (range 10 to 24 hours) will be about 50% lower, showing a terminal half-life of 26 hours. There is a long apparent terminal half-life, and patients need to be monitored or treated for at least 24 hours.
In individuals who are physically dependent on opioids, administration of opioid receptor antagonists may enhance symptoms of acute withdrawal. The severity of withdrawal symptoms depends on the degree of psychological dependence and the dose of the antagonist. If it is decided to use opioid receptor antagonists to treat severe respiratory depression symptoms in physically dependent patients, the antagonist should be given carefully at the beginning and the gradually increasing dose should be less than the usual dose of the antagonist.
Buprenorphine acts on -opioid receptors and is a partial opioid agonist. Buprenorphine has an antagonistic effect on x-opioid receptors.
In single- or repeated-dose toxicity tests in rats, rabbits, guinea pigs, dogs, and mini-pigs, buprenorphine transdermal patches have only minor or no systemic adverse events, and all test animals have visible skin Stimulate the response. It has no teratogenic effect on rats and rabbits. However, there are also reports in the literature that buprenorphine-induced rats have experienced perinatal death.
A series of standard genotoxicity test results show that buprenorphine is not genotoxic.
Long-term studies in rats and mice have shown that buprenorphine has no carcinogenic effect on humans.
Existing toxicological data show that none of the additives in the transdermal patch has a carcinogenic effect.

Pharmacology and toxicology of buprenorphine transdermal patch :

Pharmacological classification: Analgesics, opioids buprenorphine acts on -opioid receptors and is a partial opioid agonist. Buprenorphine has an antagonistic effect on x-opioid receptors.
In single- or repeated-dose toxicity tests in rats, rabbits, guinea pigs, dogs, and mini-pigs, buprenorphine transdermal patches have only minor or no systemic adverse events, and all test animals have visible skin Stimulate the response. It has no teratogenic effect on rats and rabbits. However, there are also reports in the literature that buprenorphine-induced rats have experienced perinatal death.
A series of standard genotoxicity test results show that buprenorphine is not genotoxic.
Long-term studies in rats and mice have shown that buprenorphine has no carcinogenic effect on humans.
Existing toxicological data show that none of the additives in the transdermal patch has a sensitizing effect.

Pharmacokinetics of buprenorphine transdermal patch :

There is evidence that buprenorphine can be absorbed through the enterohepatic circulation.
The experimental results of non-pregnant rats and pregnant rats show that buprenorphine can cross the blood-brain barrier and placental barrier. By parenteral administration, the concentration of the drug in the animal's brain (containing only the original form of buprenorphine) is 2 to 3 times that of the oral medication. After intramuscular injection or oral buprenorphine, buprenorphine has a significant accumulation in the gastrointestinal tract of the fetus, which is presumed to be related to bile excretion. The reason is that the fetal enterohepatic circulation has not yet fully matured.
Each patch can release buprenorphine stably for 7 days. Steady state can be reached after the first application. After the buprenorphine transdermal patch was removed, the concentration of buprenorphine decreased to about 50% within 12 hours (10 to 24 hours).
absorb:
After using a buprenorphine transdermal patch, buprenorphine diffuses from the patch site through the skin. Clinical pharmacological studies have shown that the median time to detect buprenorphine (25 pg / mL) after using "buprenorphine transdermal patch 10 g / h" is about 17 hours. A 7-day post-distribution analysis of residual buprenorphine in the patch showed that the drug release was 15% of the initial load. The results of the bioavailability test (relative to intravenous administration) showed that the amount was absorbed throughout the body. During the 7-day discount period, the blood concentration of buprenorphine remained almost the same.
Application area:
A healthy volunteer trial showed the pharmacokinetics of buprenorphine after a transdermal patch of buprenorphine was applied to the outside of the upper arm, above the chest, above the back, or on the thorax (midaxillary line, fifth intercostal space). Basically the same. There is a certain correlation between drug absorption and the application site.Among them, the buprenorphine transdermal patch applied over the back has the largest difference in exposure compared with the thoracic side, the former is about 26% higher than the latter.
Trials of repeated application of buprenorphine transdermal patches on the same site by healthy volunteers have shown that the drug exposure level has almost doubled compared to the 14-day intermittent group. Therefore, it is recommended that the patch be changed during use Apply the site. Do not use a new patch on the area where this product has been applied for the next 3 to 4 weeks.
In a healthy subject trial, when a heating pad was applied to the transdermal patch, the blood concentration of buprenorphine showed a transient increase (increased by 26-55%). Within 5 hours of removing the heating pad, the blood concentration returned to normal levels. To do this: It is not recommended to apply a heat source (such as a thermos, heating pad or electric blanket) directly to the patch. If the patch is applied immediately after the patch is peeled off, it will not affect the transdermal absorption.
distributed:
The binding rate of buprenorphine to plasma proteins was approximately 96%.
The results of intravenous injection of buprenorphine show that the drug has a high distribution volume, suggesting that buprenorphine is widely distributed in the body. The concentration of buprenorphine in healthy volunteer cerebrospinal fluid is about 15-25% of the plasma concentration at the same time point.
Biotransformation and elimination:
With buprenorphine transdermal patches, the metabolism of buprenorphine in the skin is negligible. After applying the transdermal patch, buprenorphine is eliminated by metabolism in the liver, and then soluble metabolites are excreted through the bile and kidney. The CYP3A4 and UGT1A1 / 1A3 enzyme molecules in the liver are involved in the metabolism of buprenorphine and generate two main metabolites, norbuprenorphine and buprenorphine 3-O-glucuronide. Norbuprenorphine is glycated before elimination. Buprenorphine is also cleared via stool. A trial in postoperative patients showed that the overall clearance of buprenorphine was about 55 L / h.
Norbuprenorphine is currently the only known active metabolite of buprenorphine.
Effects of Buprenorphine on Pharmacokinetics of Other Sexually Active Substances:
In vitro tests of human microsomes and hepatocytes showed that buprenorphine did not have a metabolic reaction catalyzed by the CYP450 enzymes CYP1A2, CYP2A6, CYP3A4 under the concentration conditions of 20 g / h of buprenorphine transdermal patch Inhibition. No trials have been conducted on the effects of metabolic reactions catalyzed by CYP2C8, CYP2C9, and CYP2C19.