Actions of Buprenorphine HCl in details
Pharmacotherapeutic Group: Analgesics, opioids. ATC Code: N02 AE01.
Pharmacology: Pharmacodynamics: Buprenorphine HCl is a partial agonist opioid, acting at the μ-opioid receptor. It also has antagonistic activity at the κ-opioid receptor.
Clinical Studies: The efficacy of Buprenorphine HCl has been evaluated in four 12-week double-blind, controlled clinical trials in opioid-naive and opioid-experienced patients with moderate to severe chronic low back pain or osteoarthritis using pain scores as the primary efficacy variable. Two of these studies, described as follow, demonstrated efficacy in patients with low back pain. One study in low back pain and one study in osteoarthritis did not show a statistically significant pain reduction for either Buprenorphine HCl or the respective active comparators.
12-Week Study in Opioid-Naive Patients with Chronic Low Back Pain: A total of 1,024 patients with chronic low back pain who were suboptimally responsive to their non-opioid therapy entered an open-label, dose-titration period for up to 4 weeks. Patients initiated therapy with 3 days of treatment with Buprenorphine HCl 5 mcg/hr. After 3 days, if adverse events were tolerated, the dose was increased to Buprenorphine HCl 10 mcg/hr. If adverse effects were tolerated but adequate analgesia was not reached, the dose was increased to Buprenorphine HCl 20 mcg/hr for an additional 10-12 days. Patients who achieved adequate analgesia and tolerable adverse effects on Buprenorphine HCl 10 or 20 mcg/hr were then randomized to remain on their titrated dose of Buprenorphine HCl or matching placebo. Fifty-three (53)% of the patients who entered the open-label titration period were able to titrate to a tolerable and effective dose and were randomized into a 12-week, double-blind treatment period. Twenty-three (23)% of patients discontinued due to an adverse event from the open-label titration period and 14% discontinued due to lack of a therapeutic effect. The remaining 10% of patients were dropped due to various administrative reasons.
During the first 7 days of double-blind treatment patients were allowed up to 2 tablets/day of immediate-release oxycodone 5 mg as supplemental analgesia to minimize opioid withdrawal symptoms in patients randomized to placebo. Thereafter, the supplemental analgesia was limited to either acetaminophen 500 mg or ibuprofen 200 mg at a maximum of 4 tablets/day. Sixty-six (66)% of the patients treated with Buprenorphine HCl completed the 12-week treatment compared to 70% of the patients treated with placebo.
Of the 256 patients randomized to Buprenorphine HCl, 9% discontinued due to lack of efficacy and 16% due to adverse events. Of the 283 patients randomized to placebo, 13% discontinued due to lack of efficacy and 7% due to adverse events.
Of the patients who were randomized, the mean pain (SE) NRS scores were 7.2 (0.08) and 7.2 (0.07) at screening and 2.6 (0.08) and 2.6 (0.07) at pre-randomization (beginning of double-blind phase) for the Buprenorphine HCl and placebo groups, respectively.
The score for average pain over the last 24 hrs at the end of the study (week 12/early termination) was statistically significantly lower for patients treated with Buprenorphine HCl compared with patients treated with placebo. The proportion of patients with various degrees of improvement, from screening to study endpoint, is shown in Figure 1.
12-Week Study in Opioid-Experienced Patients with Chronic Low Back Pain: One thousand one hundred and sixty (1,160) patients on chronic opioid therapy (total daily dose 30-80 mg morphine equivalent) entered an open-label, dose-titration period with Buprenorphine HCl for up to 3 weeks, following taper of prior opioids. Patients initiated therapy with Buprenorphine HCl 10 mcg/hr for 3 days. After 3 days, if the patient tolerated the adverse effects, the dose was increased to Buprenorphine HCl 20 mcg/hr for up to 18 days. Patients with adequate analgesia and tolerable adverse effects on Buprenorphine HCl 20 mcg/hr were randomized to remain on Buprenorphine HCl 20 mcg/hr or were switched to a low-dose control (Buprenorphine HCl 5 mcg/hr) or an active control. Fifty-seven (57)% of the patients who entered the open-label titration period were able to titrate to and tolerate the adverse effects of Buprenorphine HCl 20 mcg/hr and were randomized into a 12-week double-blind treatment phase. Twelve (12)% of patients discontinued due to an adverse event and 21% discontinued due to lack of a therapeutic effect during the open-label titration period.
During the double-blind period, patients were permitted to take ibuprofen (200 mg tablets) or acetaminophen (500 mg tablets) every 4 hrs as needed for supplemental analgesia (up to 3,200 mg of ibuprofen and 4 grams of acetaminophen daily). Sixty-seven (67)% of patients treated with Buprenorphine HCl 20 mcg/hr and 58% of patients treated with Buprenorphine HCl 5 mcg/hr completed the 12-week treatment. Of the 219 patients randomized to Buprenorphine HCl 20 mcg/hr, 11% discontinued due to lack of efficacy and 13% due to adverse events. Of the 221 patients randomized to Buprenorphine HCl 5 mcg/hr, 24% discontinued due to lack of efficacy and 6% due to adverse events.
Of the patients who were able to be randomized in the double-blind period, the mean pain (SE) NRS scores were 6.4 (0.08) and 6.5 (0.08) at screening and were 2.8 (0.08) and 2.9 (0.08) at prerandomization (beginning of double-blind period) for the Buprenorphine HCl 5 mcg/hr and Buprenorphine HCl 20 mcg/hr, respectively.
The score for average pain over the last 24 hrs at week 12 was statistically significantly lower for subjects treated with Buprenorphine HCl 20 mcg/hr compared to subjects treated with Buprenorphine HCl 5 mcg/hr. A higher proportion of Buprenorphine HCl 20 mcg/hr patients (49%) had at least a 30% reduction in pain score from screening to study endpoint when compared to Buprenorphine HCl 5 mcg/hr patients (33%). The proportion of patients with various degrees of improvement from screening to study endpoint is shown in Figure 2.
Pharmacokinetics: There is evidence of enterohepatic recirculation.
Studies in non-pregnant and pregnant rats have shown that Buprenorphine HCl passes the blood-brain and placental barriers.
Concentrations in the brain (which contained only unchanged Buprenorphine HCl) after parenteral administration were 2-3 times higher than after oral administration.
After intramuscular or oral administration Buprenorphine HCl apparently accumulates in the foetal gastrointestinal lumen-presumably due to biliary excretion, as enterohepatic circulation has not fully developed.
Each patch provides a steady delivery of Buprenorphine HCl for up to 7 days. Steady state is achieved during the 1st application. After removal of Buprenorphine HCl, Buprenorphine HCl concentrations decline, decreasing approximately 50% in 12 hrs (range 10-24 hrs).
Absorption: Following Buprenorphine HCl transdermal patch application, Buprenorphine HCl diffuses from the patch through the skin. In clinical pharmacology studies, the median time for Buprenorphine HCl 10 mcg/hr transdermal patch to deliver detectable Buprenorphine HCl concentrations (25 picograms/mL) was approximately 17 hrs. Analysis of residual Buprenorphine HCl in patches after 7-day use shows 15% of the original load delivered. A study of bioavailability, relative to intravenous administration, confirms that this amount is systemically absorbed.
Buprenorphine HCl concentrations remain relatively constant during the 7-day patch application.
Application Site: A study in healthy subjects demonstrated that the pharmacokinetic profile of Buprenorphine HCl delivered by Buprenorphine HCl transdermal patch is similar when applied to upper outer arm, upper chest, upper back or the side of the chest (midaxillary line, 5th intercostal space). The absorption varies to some extent depending on the application site and the exposure is at the most approximately 26% higher when applied to the upper back compared to the side of the chest.
In a study of healthy subjects receiving Buprenorphine HCl transdermal patch repeatedly to the same site, an almost doubled exposure was seen with a 14 day rest period. For this reason, rotation of application sites is recommended and a new patch should not be applied to the same skin site for 3-4 weeks.
In a study of healthy subjects, application of a heating pad directly on the transdermal patch caused a transient 26-55% increase in blood concentrations of Buprenorphine HCl. Concentrations returned to normal within 5 hrs after the heat was removed. For this reason, applying direct heat sources eg, hot water bottles, heat pads or electric blankets directly to the patch is not recommended. A heating pad applied to a Buprenorphine HCl transdermal patch site immediately after patch removal did not alter absorption from the skin depot.
Distribution: Buprenorphine HCl is approximately 96% bound to plasma proteins.
Studies of intravenous Buprenorphine HCl have shown a large volume of distribution, implying extensive distribution of Buprenorphine HCl. In a study of intravenous Buprenorphine HCl in healthy subjects, the volume of distribution at steady state was 430 L, reflecting the large volume of distribution and lipophilicity of the active substance.
Following intravenous administration, Buprenorphine HCl and its metabolites are secreted into bile and within several minutes, distributed into the cerebrospinal fluid. Buprenorphine HCl concentrations in the cerebrospinal fluid appear to be approximately 15-25% of concurrent plasma concentrations.
Biotransformation and Elimination: Buprenorphine HCl metabolism in the skin following Buprenorphine HCl transdermal patch application is negligible.
Following transdermal application, Buprenorphine HCl is eliminated via hepatic metabolism, with subsequent biliary excretion and renal excretion of soluble metabolites. Hepatic metabolism, through CYP3A4 and UGT1A1/1A3 enzymes, results in 2 primary metabolites, norbuprenorphine and Buprenorphine HCl 3-O-glucuronide, respectively. Norbuprenorphine is glucuronidated before elimination. Buprenorphine HCl is also eliminated in the faeces. In a study in post-operative patients, the total elimination of Buprenorphine HCl was shown to be approximately 55 L/hr. Norbuprenorphine is the only known active metabolite of Buprenorphine HCl.
Effect of Buprenorphine HCl on the Pharmacokinetics of Other Active Substances: Based on in vitro studies in human microsomes and hepatocytes, Buprenorphine HCl does not have the potential to inhibit metabolism catalysed by the CYP450 enzymes CYP1A2, CYP2A6 and CYP3A4 at concentrations obtained with use of Buprenorphine HCl 20 mcg/hr transdermal patch. The effect on metabolism catalysed by CYP2C8, CYP2C9 and CYP2C19 has not been studied.
How should I take Buprenorphine HCl?
Follow all directions on your prescription label. Buprenorphine HCl can slow or stop your breathing. Never use Buprenorphine HCl in larger amounts, or for longer than prescribed. Tell your doctor if the medicine seems to stop working as well in relieving your pain.
Buprenorphine HCl may be habit-forming, even at regular doses. Never share this medicine with another person, especially someone with a history of drug abuse or addiction. MISUSE OF NARCOTIC MEDICINE CAN CAUSE ADDICTION, OVERDOSE, OR DEATH, especially in a child or other person using the medicine without a prescription. Selling or giving away Buprenorphine HCl is against the law.
The Buprenorphine HCl sublingual tablet should be placed under the tongue and allowed to dissolve. Do not chew the tablet or swallow it whole. If your doctor has prescribed more than 2 tablets per dose, place the correct number of tablets under your tongue at the same time and allow them to dissolve completely.
While using Buprenorphine HCl, you may need frequent blood tests to check your liver function.
If you need surgery, tell the surgeon ahead of time that you are using Buprenorphine HCl. You may need to stop using the medicine for a short time.
Wear a medical alert tag or carry an ID card stating that you take Buprenorphine HCl. Any medical care provider who treats you should know that you are being treated for narcotic addiction. Make sure your family members know you are using Buprenorphine HCl in case they need to speak for you during an emergency.
Do not stop using Buprenorphine HCl suddenly, or you could have unpleasant withdrawal symptoms. Ask your doctor how to safely stop using Buprenorphine HCl.
Store at room temperature away from moisture and heat.
Keep track of the amount of medicine used from each new bottle. Buprenorphine HCl is a drug of abuse and you should be aware if anyone is using your medicine improperly or without a prescription.
Do not keep leftover Buprenorphine HCl pills. Ask your pharmacist where to locate a drug take-back disposal program. If there is no take-back program, flush any unused pills down the toilet
Never crush or break a Buprenorphine HCl pill to inhale the powder or mix it into a liquid to inject the drug into your vein. This practice has resulted in death with the misuse of Buprenorphine HCl and similar prescription drugs.
Buprenorphine HCl administration
IM: Administer immediate-release injection via deep IM injection.
IV: Administer immediate-release injection slowly, over at least 2 minutes. Administration over 20 to 30 minutes preferred when managing opioid withdrawal in heroin-dependent hospitalized patients (Welsh 2002).
Oral:
Buccal film: Prior to placing the film, moisten inside of cheek with tongue or water. Apply film with a dry finger immediately after removing it from packaging. Place yellow side of film against the inside of the moistened cheek; press and hold the film in place for 5 seconds with finger (film should stay in place after this period). Keep film in place until it dissolves completely (usually within 30 minutes of application). Do not chew, swallow, touch, or move film after placement. Avoid eating or drinking until film dissolves. Do not cut or tear the film. Avoid application to areas of the mouth with any open sores or lesions. To dispose of film; remove foil overwrap from any unused, unneeded films and dispose by flushing down the toilet.
Sublingual tablet: Tablet should be placed under the tongue until dissolved (can take up to 10 minutes to fully dissolve [SAMHSA 2018]); should not be chewed or swallowed (swallowing tablets before dissolved reduces bioavailability). If two or more tablets are needed per dose, all may be placed under the tongue at once, or two at a time. To ensure consistent bioavailability, subsequent doses should always be taken the same way.
Subcutaneous injection: Administer extended-release injection as an abdominal subcutaneous injection only, using only the syringe and safety needle included with product. Do not administer IV or IM. Inject between the transpyloric and transtubercular planes in an area with adequate subcutaneous tissue that is free of skin conditions (eg, nodules, lesions, excessive pigment.) Rotate the injection site between injections. Subsequent precipitation following injection results in a solid depot which will gradually release Buprenorphine HCl. The patient may have a lump for several weeks that will decrease over time; advise not to rub or massage the injection site. In the event the depot from an extended-release injection must be removed, it can be surgically excised under local anesthesia within 14 days of injection. See prescribing information for details. For insertion by health care providers trained in the injection technique and certified through the REMS program.
Subdermal implant: For insertion under local anesthesia by health care providers trained in the insertion and removal procedure through the REMS program. See prescribing information for details.
Transdermal patch: Apply patch to intact, nonirritated skin only. Apply to a hairless or nearly hairless skin site. If hairless site is not available, do not shave skin; hair at application site should be clipped. Prior to application, if the site must be cleaned, clean with clear water and allow to dry completely; do not use soaps, alcohol, oils, lotions, or abrasives due to potential for increased skin absorption. Do not use any patch that has been damaged, cut or manipulated in any way. Remove patch from protective pouch immediately before application. Remove the protective backing, and apply the sticky side of the patch to one of eight possible application sites (upper outer arm, upper chest, upper back or the side of the chest [each site on either side of the body]). Up to 2 patches may be applied at the same time adjacent to one another at the same application site. Firmly press patch in place and hold for ~15 seconds. Change patch every 7 days. Rotate patch application sites whenever a patch is replaced or added; wait ≥21 days before reapplying another patch to the same skin site. Avoid exposing application site to external heat sources (eg, heating pad, electric blanket, heat lamp, hot tub). Incidental exposure to water while bathing or showering is acceptable based on experience during clinical studies. If there is difficulty with patch adhesion, the edges of the system may be taped in place with first-aid tape. If ineffective, the system may be covered with waterproof or semipermeable adhesive dressings suitable for 7 days of wear. If the patch falls off during the 7-day dosing interval, dispose of the patch and apply a new patch to a different skin site. Dispose of patches using the Patch-Disposal Unit or by folding the adhesive sides of the patch together and then flushing down the toilet. In Canada, disposal via a pharmacy take back program is recommended; trash disposal is not advised.
Buprenorphine HCl pharmacology
Buprenorphine HCl (Buprenorphine HCl) is a parenteral opioid analgesic with 0.3mg Buprenorphine HCl (Buprenorphine HCl) being approximately equivalent to 10 mg morphine sulfate in analgesic and respiratory depressant effects in adults. Pharmacological effects occur as soon as 15 minutes after intramuscular injection and persist for 6 hours or longer. Peak pharmacologic effects usually are observed at 1 hour. When used intravenously, the times to onset and peak effect are shortened.
The limits of sensitivity of available analytical methodology precluded demonstration of bioequivalence between intramuscular and intravenous routes of administration. In postoperative adults, pharmacokinetic studies have shown elimination half-lives ranging from 1.2-7.2 hours (mean 2.2 hours) after intravenous administration of 0.3mg of Buprenorphine HCl. A single, ten-patient, pharmacokinetic study of doses of 3µg/kg in children (age 5-7 years) showed a high inter-patient variability, but suggests that the clearance of the drug may be higher in children than in adults. This is supported by at least one repeat- dose study in postoperative pain that showed an optimal inter-dose interval of 4-5 hours in pediatric patients as opposed to the recommended 6-8 hours in adults.
Buprenorphine HCl, in common with morphine and other phenolic opioid analgesics, is metabolized by the liver and its clearance is related to hepatic blood flow. Studies in patients anesthetized with 0.5% halothane have shown that this anesthetic decreases hepatic blood flow by about 30%.
Mechanism of Analgesic Action: Buprenorphine HCl (Buprenorphine HCl) exerts its analgesic effect via high affinity binding to u subclass opiate receptors in the central nervous system. Although Buprenorphine HCl (Buprenorphine HCl) may be classified as a partial agonist, under the conditions of recommended use it behaves very much like classical u agonists such as morphine. One unusual property of Buprenorphine HCl (Buprenorphine HCl) observed in in vitro studies is its very slow rate of dissociation from its receptor. This could account for its longer duration of action than morphine, the unpredictability of its reversal by opioid antagonists, and its low level of manifest physical dependence.
Narcotic Antagonist Activity: Buprenorphine HCl demonstrates narcotic antagonist activity and has been shown to be equipotent with naloxone as an antagonist of morphine in the mouse tail flick test.
Cardiovascular Effects: Buprenorphine HCl (Buprenorphine HCl) may cause a decrease or, rarely, an increase in pulse rate and blood pressure in some patients.
Effects on Respiration: Under usual conditions of use in adults, both Buprenorphine HCl (Buprenorphine HCl) and morphine show similar dose-related respiratory depressant effects. At adult therapeutic doses, Buprenorphine HCl (0.3mg Buprenorphine HCl) can decrease respiratory rate in an equivalent manner to an equianalgesic dose of morphine (10mg).
References
- DailyMed. "BUPRENORPHINE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
- EPA DSStox. "Buprenorphine: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
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