Analgesics, opioids. ATC Code:
Buprenorphine is a partial agonist opioid, acting at the μ-opioid receptor. It also has antagonistic activity at the κ-opioid receptor.
The efficacy of Sovenor 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 Sovenor 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 Sovenor 5 mcg/hr. After 3 days, if adverse events were tolerated, the dose was increased to Sovenor 10 mcg/hr. If adverse effects were tolerated but adequate analgesia was not reached, the dose was increased to Sovenor 20 mcg/hr for an additional 10-12 days. Patients who achieved adequate analgesia and tolerable adverse effects on Sovenor 10 or 20 mcg/hr were then randomized to remain on their titrated dose of Sovenor 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 Sovenor completed the 12-week treatment compared to 70% of the patients treated with placebo.
Of the 256 patients randomized to Sovenor, 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 Sovenor 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 Sovenor 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. (See Figure 1.)
Click on icon to see table/diagram/image
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 Sovenor for up to 3 weeks, following taper of prior opioids. Patients initiated therapy with Sovenor 10 mcg/hr for 3 days. After 3 days, if the patient tolerated the adverse effects, the dose was increased to Sovenor 20 mcg/hr for up to 18 days. Patients with adequate analgesia and tolerable adverse effects on Sovenor 20 mcg/hr were randomized to remain on Sovenor 20 mcg/hr or were switched to a low-dose control (Sovenor 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 Sovenor 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 Sovenor 20 mcg/hr and 58% of patients treated with Sovenor 5 mcg/hr completed the 12-week treatment. Of the 219 patients randomized to Sovenor 20 mcg/hr, 11% discontinued due to lack of efficacy and 13% due to adverse events. Of the 221 patients randomized to Sovenor 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 Sovenor 5 mcg/hr and Sovenor 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 Sovenor 20 mcg/hr compared to subjects treated with Sovenor 5 mcg/hr. A higher proportion of Sovenor 20 mcg/hr patients (49%) had at least a 30% reduction in pain score from screening to study endpoint when compared to Sovenor 5 mcg/hr patients (33%). The proportion of patients with various degrees of improvement from screening to study endpoint is shown in Figure 2. (See Figure 2.)
Click on icon to see table/diagram/image
There is evidence of enterohepatic recirculation.
Studies in non-pregnant and pregnant rats have shown that buprenorphine passes the blood-brain and placental barriers.
Concentrations in the brain (which contained only unchanged buprenorphine) after parenteral administration were 2-3 times higher than after oral administration.
After intramuscular or oral administration buprenorphine 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 for up to 7 days. Steady state is achieved during the 1st application. After removal of Sovenor, buprenorphine concentrations decline, decreasing approximately 50% in 12 hrs (range 10-24 hrs).
Following Sovenor transdermal patch application, buprenorphine diffuses from the patch through the skin. In clinical pharmacology studies, the median time for Sovenor 10 mcg/hr transdermal patch to deliver detectable buprenorphine concentrations (25 picograms/mL) was approximately 17 hrs. Analysis of residual buprenorphine 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 concentrations remain relatively constant during the 7-day patch application.
A study in healthy subjects demonstrated that the pharmacokinetic profile of buprenorphine delivered by Sovenor 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 Sovenor 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. 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 Sovenor transdermal patch site immediately after patch removal did not alter absorption from the skin depot.
Buprenorphine is approximately 96% bound to plasma proteins.
Studies of intravenous buprenorphine have shown a large volume of distribution, implying extensive distribution of buprenorphine. In a study of intravenous buprenorphine 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 and its metabolites are secreted into bile and within several minutes, distributed into the cerebrospinal fluid. Buprenorphine concentrations in the cerebrospinal fluid appear to be approximately 15-25% of concurrent plasma concentrations.
Biotransformation and Elimination:
Buprenorphine metabolism in the skin following Sovenor transdermal patch application is negligible.
Following transdermal application, buprenorphine 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 3-O-glucuronide, respectively. Norbuprenorphine is glucuronidated before elimination. Buprenorphine is also eliminated in the faeces. In a study in post-operative patients, the total elimination of buprenorphine was shown to be approximately 55 L/hr. Norbuprenorphine is the only known active metabolite of buprenorphine.
Effect of Buprenorphine on the Pharmacokinetics of Other Active Substances:
Based on in vitro
studies in human microsomes and hepatocytes, buprenorphine does not have the potential to inhibit metabolism catalysed by the CYP450 enzymes CYP1A2, CYP2A6 and CYP3A4 at concentrations obtained with use of Sovenor 20 mcg/hr transdermal patch. The effect on metabolism catalysed by CYP2C8, CYP2C9 and CYP2C19 has not been studied.