Low-dose Transdermal Buprenorphine Research Articles

Lost cost savings to the NHS in England due to the delayed entry of multiple generic low-dose transdermal buprenorphine: a case scenario analysis

ObjectiveOriginator pharmaceutical companies prolonging the patent of a medicine prevents rivals’ entry to the market and competition. As the entry of generic alternatives usually results in price reduction, any delay...

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Transdermal Buprenorphine, Opioid Rotation to Sublingual Buprenorphine, and the Avoidance of Precipitated Withdrawal

Buprenorphine is an opioid, used in the United States and abroad for both analgesia and addiction, with unique opioid receptor binding properties. There are several pharmacological features of buprenorphine that make it an emerging option for the long-term treatment of chronic pain-its respiratory suppression ceiling effect, its efficacy in neuropathic pain and hyperalgesic states, and its decreased suppression of the immune and endocrine systems compared with other long-acting opioids. Previous studies have shown that high-dose sublingual buprenorphine is an effective treatment of chronic pain patients not responding to other opioids. Guidelines for the introduction of sublingual buprenorphine, termed buprenorphine induction, include an opioid-free "withdrawal" period of 12-48 hours to avoid an anticipated and accelerated opioid withdrawal, a syndrome described in this article as precipitated withdrawal. The requirement of a period of opioid abstinence before buprenorphine use may present a significant barrier to its adoption for chronic pain. We present a case series of a novel method of sublingual buprenorphine introduction without an induction period, using the recently Food and Drug Administration-approved low-dose transdermal buprenorphine (Butrans; Purdue Pharma L.P.) as a bridge medication. In these cases, buprenorphine was started in opioid-dependent chronic noncancer pain patients who had taken short-acting opioid medications within hours of the initiation of the rotation. This method avoids the painful abstinence period and did not result in precipitated withdrawal or other significant adverse effects.

Use of the Low-Dose Buprenorphine Patch: A Response

Dear Editor: As the NDA holder and distributor of Butrans® (buprenorphine) Transdermal System, Purdue Pharma L.P. works to ensure the dissemination of accurate and complete information regarding our products. Purdue commends the Journal of Palliative Medicine on its commitment to end-of-life care and patients with intractable pain; however, we are writing to notify you of misinformation published in Fast Fact #268, “Low-Dose Buprenorphine Patch for Pain.” While the review was well written and informative, there are several statements about Butrans (i.e., low-dose buprenorphine patch) that warrant correction or clarification. Listed below by section of the article and article statement in quotes is a summary of significant misinformation that can lead to safety concerns and/or the improper use of Butrans. • Background: ∘ In addition to being approved for use in treatment of opioid addiction, buprenorphine is approved, as an injectable, for relief of moderate to severe pain, as referenced in the Equianalgesic Ratios section. The U.S. approval for this pain indication predates approval for use in addiction treatment by over 20 years (12/29/1981).1 • Pharmacology: ∘ Buprenorphine is described as providing “analgesia with decreased incidence of sedation, euphoria, and respiratory depression compared to other opioids.” There are no head-to-head studies evaluating these outcomes with Butrans in comparison to other opioids. Although buprenorphine is considered a partial agonist at mu opioid receptors, it can be expected to produce pharmacological effects similar to those of full mu-agonists, especially at the buprenorphine doses delivered by Butrans.2 Therefore, sedation, euphoria, and respiratory depression can occur. In fact, respiratory depression is the primary risk of Butrans.3 • Using the low-dose buprenorphine patch: ∘ This section states, “The U.S. formulation of the buprenorphine transdermal system is recommended for opioid tolerant patients requiring up to 80 mg/day of oral morphine equivalents.” The use of Butrans is not limited to opioid-tolerant patients. Butrans has been studied and is approved for use in opioid-naive patients or in opioid-experienced patients requiring up to 80 mg/day of oral morphine equivalents.3–5 ∘ Butrans is described as being “available in strengths of 5, 10, and 20 mcg/hour.” Butrans 15 mcg/hour was approved in July 2013 and Butrans is now available in four dosage strengths.3 We understand that the reason for this omission is because the new strength became available after the writing of this article. ∘ Withdrawal symptoms are described as “symptoms tend to be milder than with other long-acting opioids.” Although this has been demonstrated with other buprenorphine formulations, clinical studies comparing withdrawal symptoms with Butrans to other long-acting opioids have not been conducted. When a patient no longer requires therapy with Butrans, a gradual downward titration of the dose every seven days to prevent signs and symptoms of withdrawal in the physically dependent patient is recommended. Butrans should not be abruptly discontinued.3 ∘ The article states, “Use of more than one patch at a time is not recommended due to risk of QT prolongation.” Although applying more than one patch at a time is not recommended, it is important to clarify that QTc interval prolongation is not dependent on the number of patches worn, but rather on the buprenorphine dose delivered. The maximum dose of Butrans is 20 mcg/hour due to the risk of QTc interval prolongation (which was detected at a dose of 40 mcg/hour).3 • Clinical applications: ∘ This section states, “Other advantages of buprenorphine include a decreased risk of respiratory depression.” While this effect may have been demonstrated with other buprenorphine products, it has not been demonstrated with Butrans. Respiratory depression is the primary risk of Butrans.3 • Summary: ∘ The article concludes by stating, “The low-dose transdermal buprenorphine patch is effective for mild to moderate chronic pain, both malignant and nonmalignant.” Butrans is not recommended for use in treating mild chronic pain. Butrans is indicated for the management of moderate to severe chronic pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time.3 ∘ The low-dose buprenorphine patch is described as being “a reasonable second- or third-line option in patients with low opioid requirements who experience intolerable side effects with other opioids.” Categorizing Butrans as an option for patients only with low opioid requirements misrepresents the patient population for which Butrans is approved. Butrans is approved for use in opioid-naive patients as the first opioid analgesic, as well as in opioid-experienced patients requiring up to 80 mg/day of oral morphine equivalents.3–5 This article provides clinicians with a concise overview of the low-dose buprenorphine patch. We would appreciate a correction that accurately presents the product information in order for clinicians to have the necessary information to use Butrans safely and effectively.

Long-term treatment of chronic pain with low-dose 7-day buprenorphine transdermal patch. Observational data from elderly patients of pain relief and quality of life

Six-months analysis of non-interventionally collected observation data of effectiveness of long-term treatment with low-dose 7-day buprenorphine transdermal patch in elderly patients with chronic pain. Analysis of data regarding pain intensity, pain-related impairments of daily life and quality of life documented by 321 pain patients in German primary care (age 72.4 +/- 13.8 years; 67.3% female; musculoskeletal pain 85.4%; mean pain intensity 6.1 +/- 1.2, for 90% > or = 5 NRS11) using standardised self-report instruments (German Pain Questionnaire/German Pain Diary). After initiation with 5/10 microg/h buprenorphine (89.7%/10.3%), treatment was maintained in 57.1/39.1/3.8% patients with stable doses of 5/10/20 microg/h after 6 months. The average pain intensity decreased by 5.1 +/- 1.0 (absolute) to 1.0 +/- 1.0 NRS11 (83.5%), pain-related impairments and burden of pain were reduced by 86.0% and 87.9%, respectively, and pain-related quality of life improved by 97.3% to nearly normalvalues. Pain treatment of elderly persons with 7-day low-dose transdermal buprenorphine patch on a stable dose regimen resulted in fast, effective and sustained pain relief accompanied by marked improvements in daily life participation and quality of life.

Transdermal fentanyl compared to transdermal buprenorphine on descending pain modulation in human experimental models

Transdermal preparation of fentanyl, a μ-receptor agonist, and buprenorphine, a partial μ-receptor agonist and K-receptor antagonist, are used in the treatment of moderate to severe pain. This literature review aimed to compare the effect of these two transdermal patches on descending pain inhibition in human experimental pain models to determine rational treatment guidelines. A Pubmed search was performed using key words transdermal fentanyl and transdermal buprenorphine and 4 randomized double-blind placebo controlled studies were evaluated for levels of evidence. Experimental pain models aimed to induce deep pain, superficial pain, allodynia, and hyperalgesia. Pain stimulus included pressure at the tibial bone, pressure distal to the elbow joint, cutaneous thermal stimulation, cold pressor test, cutaneous electrical stimulation, nerve-growth factor induced muscle soreness, UVB light burn injury, and intradermal capsaicin. Both low dose transdermal buprenorphine and fentanyl provided significant analgesic effect compared to placebo. Buprenorphine and fentanyl showed tissue-differentiated analgesic effects, which may be useful in understanding individual treatment response. Buprenorphine appeared to have a greater effect on bone associated pain and fentanyl appeared to have a greater effect on cold pressure induced pain. Incidences of adverse effects were similar between fentanyl and buprenorphine. However, human experimental pain models were performed in healthy subjects, and may not accurately represent response in chronic pain patients.

Low‐dose transdermal buprenorphine – long‐term use and co‐medication with other potentially addictive drugs

Recently, low-dose transdermal buprenorphine (LD-TD-BUP) was introduced for treatment of patients with chronic non-malignant pain. The primary aim of this study was to determine the proportion of patients who were prescribed LD-TD-BUP for non-malignant pain who became long-term users. The secondary aim was to determine the proportion of patients who co-medicated with other opioids or benzodiazepines during treatment with LD-TD-BUP. Data were drawn from the Norwegian Prescription Database that covers all prescriptions dispensed at pharmacies to the entire Norwegian population (4.7 million inhabitants). The study population consisted of all patients who were dispensed at least one prescription of LD-TD-BUP from its introduction in November 2005 to 31 December 2008. Patients who were dispensed more than 24 patches (≥ 6 months) were defined as long-term users. Reimbursement codes were used to stratify patients as having cancer pain or non-malignant pain. Among new users of LD-TD-BUP for non-malignant pain (n = 13,451), only 22% became long-term users, while 44% were only dispensed one prescription. Among long-term users who were opioid naive when LD-TD-BUP was initiated, 43% co-medicated with other opioids or benzodiazepines, compared with 82% of those who previously had used opioids. Three years after introduction, 0.4% of the Norwegian population had been dispensed LD-TD-BUP. Only one-fifth had become long-term users. Those who used opioids before the first dispension of LD-TD-BUP co-medicated with other potentially addictive drugs to a much higher degree compared with those who were opioid naive.

A Randomized, Double-Blind, Double-Dummy Comparison of the Efficacy and Tolerability of Low-Dose Transdermal Buprenorphine (BuTrans® Seven-Day Patches) With Buprenorphine Sublingual Tablets (Temgesic®) in Patients With Osteoarthritis Pain

A Randomized, Double-Blind, Double-Dummy Comparison of the Efficacy and Tolerability of Low-Dose Transdermal Buprenorphine (BuTrans® Seven-Day Patches) With Buprenorphine Sublingual Tablets (Temgesic®) in Patients With Osteoarthritis Pain

Long-term low-dose transdermal buprenorphine therapy for chronic noncancer pain

Long-term low-dose transdermal buprenorphine therapy for chronic noncancer pain

A Randomized, Double-Blind, Double-Dummy Comparison of the Efficacy and Tolerability of Low-Dose Transdermal Buprenorphine (BuTrans Seven-Day Patches) With Buprenorphine Sublingual Tablets (Temgesic ) in Patients With Osteoarthritis Pain

Osteoarthritis (OA) is a common cause of chronic pain, particularly in the older population. Modern approaches to the management of OA pain recommend tailoring treatment to the individual. This study examines treatment options for OA pain in the form of low-dose transdermal and sublingual opioid analgesia. The aims of this trial were to compare the efficacy and tolerability of seven-day, low-dose transdermal buprenorphine patches (BuTrans, Napp Pharmaceuticals Limited UK) with sublingual buprenorphine (Temgesic, Schering-Plough Limited UK) in patients with moderate to severe pain caused by OA of the hip(s) and/or knee(s), and to establish analgesic equivalence of the two products. Two hundred forty-six patients with OA pain in the hip(s) and/or knee(s) were enrolled in this randomized, double-blind, parallel-group study; 110 completed the study. Patients were randomized to receive transdermal buprenorphine patches (5, 10, and 20 microg/hour) or sublingual buprenorphine (200 and 400 microg tablets). Their medication was titrated to pain control and they were treated for up to seven weeks. The main outcome measures were pain intensity (primary outcome), sleep disturbance, quality of life, and safety assessments. Patients' Box Scale-11 pain scores decreased between entry and assessment in both treatment groups. During the 28-day assessment period, the estimated mean treatment differences (95% confidence intervals) were 0.00 (-0.68,0.69), -0.11 (-0.85,0.63), and -0.13 (-0.95,0.68), for the morning, midday, and evening scores, respectively. All the confidence intervals were within the prespecified limits for equivalence (-1.5, 1.5). Use of escape medication was low. In both treatment groups, sleep disturbance caused by pain decreased between entry and assessment. Patients' quality of life improved during the study. Significantly fewer patients receiving the transdermal buprenorphine patches reported nausea (P=0.035), dizziness (P=0.026), and vomiting (P=0.039). In conclusion, seven-day, low-dose transdermal buprenorphine patches are as effective as sublingual buprenorphine, with a better tolerability profile.

Introduction of low dose transdermal buprenorphine — did it influence use of potentially addictive drugs in chronic non-malignant pain patients?

Introduction of low dose transdermal buprenorphine — did it influence use of potentially addictive drugs in chronic non-malignant pain patients?

Efficacy and safety of low-dose transdermal buprenorphine patches (5, 10, and 20 μg/h) versus prolonged-release tramadol tablets (75, 100, 150, and 200 mg) in patients with chronic osteoarthritis pain: A 12-week, randomized, open-label, controlled, parallel-group noninferiority study

Objective: This study compared the efficacy and safety of low-dose 7-day buprenorphine patches and prolonged-release tramadol tablets in patients with chronic, moderate to severe osteoarthritis (OA) pain of the hip and/or knee. Methods: Eligible patients were adults with a clinical and radiologic diagnosis of OA of the hip and/or knee and moderate to severe pain, as confirmed by a mean Box Scale 11 (BS-11) score ≥4 while using paracetamol 4000 mg/d for pain during the screening week. Patients were randomized in a 1:1 ratio to receive either low-dose 7-day buprenorphine patches (patch strengths of 5, 10, and 20 μg/h, with a maximum dosage of 20 μg/h) or twice-daily prolonged-release tramadol tablets (tablet strengths of 75, 100, 150, and 200 mg, with a maximum dosage of 400 mg/d) over a 12-week open-label treatment period. Supplementary paracetamol was available as rescue medication throughout the study. The primary end point was the difference in BS-11 scores from baseline to the completion of treatment. Noninferiority was assumed if the treatment difference on the BS-11 scale was −1.5 boxes, indicating a clinically meaningful result. Secondary efficacy variables were rescue medication use, sleep disturbance and quality of sleep, and patients' and investigators' global assessments of pain relief. In addition, patient preference was assessed at the completion visit by asking patients whether, given equal pain relief, they would prefer basic treatment for OA pain with a patch applied once weekly or a tablet taken twice daily. Exploratory variables included investigators' assessments of patients' pain, stiffness, and ability to perform daily activities (Western Ontario and McMaster Universities Osteoarthritis Index); patients' quality of life (EuroQol EQ-5D health states index and EuroQol visual analog scale); and abuse and diversion of study drug. Results: One hundred thirty-four patients (69 receiving 7-day buprenorphine patches and 65 receiving tramadol tablets) were randomized and received ≥1 dose of study medication. A respective 98.6% and 100% of the 2 treatment groups were white, with mean (SD) ages of 64.4 (11.1) and 64.2 (9.3) years. Both treatments were associated with a clinically meaningful reduction in pain from baseline to study completion. The least squares mean change from baseline in BS-11 scores in the 7-day buprenorphine patch and tramadol tablet groups was −2.26 (95% CI, −2.76 to −1.76) and −2.09 (95% CI, −2.61 to −1.58). The efficacy of 7-day buprenorphine patches was noninferior to that of prolonged-release tramadol tablets. The incidence of adverse events (AEs) was comparable in the 2 treatment groups: 226 AEs were reported in 61 patients (88.4%) in the 7-day buprenorphine patch group, and 152 AEs were reported in 51 patients (78.5%) in the tramadol group. Ten patients (14.5%) in the 7-day buprenorphine patch group and 19 (29.2%) in the tramadol tablet group withdrew from the study due to AEs. The most common AEs in the 7-day buprenorphine patch group were nausea (30.4%), constipation (18.8%), and dizziness (15.9%); the most common AEs in the tramadol tablet group were nausea (24.6%), fatigue (18.5%), and pain (12.3%). Most patients (47/67 [70.1%] in the 7-day buprenorphine patch group and 43/61 [70.5%] in the tramadol tablet group) reported that they would prefer a 7-day patch to a twice-daily tablet for future pain treatment. Conclusions: In these patients with chronic, moderate to severe OA pain of the hip and/or knee, 7-day low-dose buprenorphine patches were an effective and well-tolerated analgesic. The buprenorphine patches were noninferior to prolonged-release tramadol tablets. European Union Drug Regulating Authorities Clinical Trials number: 2006-003233-32.

Introduction of low dose transdermal buprenorphine – Did it influence use of potentially addictive drugs in chronic non-malignant pain patients?

The aim was to study the introduction of the new low dose transdermal buprenorphine (LD-TD-BUP) in Norway, particularly with regard to former use and co-medication with other potentially addictive drugs. The nationwide Norwegian Prescription Database contains information on all prescription drugs dispensed to individual non-institutionalised patients, and we may follow all individuals who received LD-TD-BUP (Norspan ®) after marketing on the Norwegian market on 15/11/05. We studied all prescriptions of opioids and other potentially addictive drugs to patients receiving at least two LD-TD-BUP prescriptions during 2004–2006. Poisson regressions were run with concomitant use of addictive drugs (yes, no) as the endpoint. Overall, 1884, non cancer individuals received at least two prescription of LD-TD-BUP. Of these 91.7% received prescriptions of other opioids and 58.6% of them had also been prescribed benzodiazepines/carisoprodol before the prescription of LD-TD-BUP. Of the LD-TD-BUP users who received more than one prescription, 60% co-medicated with at least one other potentially addictive drug, and 24% with at least two. In the multivariate analysis, the variables associated with a higher likelihood of using co-medicated drugs were: previous use of benzodiazepines/carisoprodol relative risk RR = 16.7 (95% CI 10.4–26.9), previous use of opioids RR = 4.0 (1.9–8.7) and younger age 20–40 years RR = 1.9 (1.6–2.3). So far, it is questionable whether the introduction of LD-TD-BUP actually has stabilised opioids consumption or whether it has complicated and increased the consumption of potentially addictive drugs.