Sublingual Buprenorphine Tablets Research Articles

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.

A Case of Dependence on the Combination Use of Sublingual Buprenorphine, Scopolamine, and Promethazine

Objectives To report the case of a patient, who were an ex-heroin-addict, developed addiction to the prescribed sublingual buprenorphine tablets, scopolamine and promethazine injection. Methods Clinical case description. Results Throughout the abuse of the drugs mentioned above with mental (eg, craving, euphoric, loss of control) and physical symptoms (eg, tolerance, withdrawal symptoms) appeared that fulfill the DSM-IV or ICD-10 criteria for dependence on psychoactive substance. However, the dependence was regarded not to be induced by buprenorphine itself because the patient reported an intense euphoria effect with these 3 drugs, whereas little sense of high was experienced if he only used buprenorphine. Moreover, the case study reports the short-term and long-term consequences of the combination of the 3 medications. Conclusions This case confirms that in the treatment of heroin addiction, some drug with a low abuse potential combined with other injectable scopolamine and promethazine may maximize risks of patient to develop a dependence on these medications, a number of the significant health harms, and long-lasting neuropsychologic impairment. The danger of coabuse of buprenorphine scopolamine and promethazine is highlighted.

Efficacy and Safety of Transdermal Buprenorphine: A Randomized, Placebo-Controlled Trial in 289 Patients with Severe Cancer Pain

Strong opioids are recommended for treating severe cancer pain in the advanced stages of the disease. Few data are available concerning the efficacy of buprenorphine in cancer pain. We compared transdermal buprenorphine 70 μg/h (BUP TDS) to placebo in an enriched design study. Opioid-tolerant patients with cancer pain requiring strong opioids in the dose range of 90–150 mg/d oral morphine equivalents entered a two-week run-in phase, during which they were converted to BUP TDS. Patients who could be stabilized on BUP TDS were randomized to BUP TDS or placebo patch for a two-week maintenance phase. Rescue medication (buprenorphine sublingual tablets 0.2 mg) was allowed as required. Response was defined as a mean pain intensity of <5 (0–10 scale) and a mean daily buprenorphine sublingual tablet intake of ≤2 tablets during the maintenance phase. Of 289 patients who entered the run-in phase, 100 discontinued treatment due to lack of efficacy or adverse events; 189 patients continued treatment in the maintenance phase (94 BUP TDS, 95 placebo), of whom 31 discontinued treatment (7 BUP TDS, 24 placebo). A significant difference in the number of treatment responders was observed: 70 BUP TDS (74.5%, 65.7–83.3) vs. 47 placebo (50%, 39.9–60.1) ( P = 0.0003). This result was supported by a lower daily pain intensity, lower intake of buprenorphine sublingual tablets and fewer dropouts in the BUP TDS group. The incidence of adverse events was slightly higher for BUP TDS. In conclusion, BUP TDS 70 μg/h is an efficacious and safe treatment for patients with severe cancer pain.

Long-term management of chronic pain with transdermal buprenorphine: A multicenter, open-label, follow-up study in patients from three short-term clinical trials

Transdermal buprenorphine is available in Europe for the treatment of moderate to severe chronic pain. It has been evaluated at doses of 35, 52.5, and 70 microg/h for the management of moderate to severe chronic cancer and noncancer pain in 3 randomized, double-blind, placebo-controlled trials, each of limited duration (approximately 14 days each). Long-term data are essential to determining the performance of an analgesic in the management of chronic pain. The purpose of this follow-up study was to obtain data on the efficacy and tolerability of long-term treatment with transdermal buprenorphine in cancer and noncancer patients with chronic persistent pain of moderate to severe intensity. This was an open-label, uncontrolled, follow-up study in patients from the 3 previous clinical trials who elected to continue treatment with transdermal buprenorphine 35 microg/h and sublingual buprenorphine tablets (0.2 mg) as needed for breakthrough pain. The patch was to be changed every 72 hours throughout the patient's course of pain therapy. At visits every 2 weeks for the first 4 weeks and every 4 weeks for the remainder of study participation, patients evaluated their pain relief retrospectively on a 4-point verbal rating scale. They also rated the ease of patch handling using a 3-point verbal rating scale. Patterns of dose escalation and dose stability were monitored over time. Adherence to therapy was determined based on the number of patients who complied with the dosing schedule. Adverse events were documented by type, intensity, location (systemic or local), and relationship to study medication. Two hundred thirty-nine patients were included in this follow-up study (120 women, 119 men; 100% white; mean [SD] age, 58 [11.3] years; mean weight, 70.8 [14.7] kg). One hundred thirty-four had cancer-related pain and 105 had pain of noncancerous origin. The mean duration of participation was 7.5 months, and 37 (15.5%) patients participated for >12 months. Maximum study participation was 3.4 years in cancer patients and 5.7 years in noncancer patients. One hundred eighty-eight (78.7%) patients were considered adherent to therapy. The majority (65.9%) of patients managed their pain with the patchalone or took no more than 1 additional sublingual tablet daily for breakthrough pain. At least satisfactory pain relief was reported by 215 (90.0%) patients, and the buprenorphine patch was generally well tolerated. The most common systemic adverse drug reactions were nausea (9.2%), dizziness (4.6%), vomiting (4.2%), constipation (3.8%), and tiredness (2.9%), whereas the most common local adverse drug reactions were erythema (12.1%), pruritus (10.5%), and exanthema (8.8%). Transdermal buprenorphine was generally well tolerated and effective for the long-term treatment of chronic cancer or noncancer pain in these patients who had previously received buprenorphine in 3 short-term clinical trials.

Pharmacokinetics and Pharmacodynamics of Multiple Sublingual Buprenorphine Tablets in Dose‐Escalation Trials

In this investigation, the pharmacokinetic and pharmacodynamic properties were determined of multiple doses of sublingual tablets containing either buprenorphine alone or buprenorphine and naloxone. Subjects were experienced opiate users who received escalating doses (4-24 mg) of buprenorphine either alone or in combination with naloxone. Peak concentration (Cmax) and area under the concentration-time curves (AUCs) increased for both buprenorphine and naloxone with escalating doses. Significant differences were found across the range of doses administered for dose-adjusted Cmax for both tablet formulations and for the dose-adjusted AUCs for the buprenorphine-naloxone tablets. For both formulations, the maximal buprenorphine-induced decreases in respiratory rate and pupil diameter did not vary significantly across doses. Several of the subjective effects of buprenorphine did not increase as the dose of buprenorphine administered was increased. These findings are consistent with the ceiling effect associated with the partial agonist actions of buprenorphine. They also indicate a lack of dose proportionality for buprenorphine sublingual tablets, at least during the times at which levels of this agent are highest.

Methadone versus buprenorphine in pregnant addicts: a double‐blind, double‐dummy comparison study

To evaluate the efficacy and safety of methadone versus buprenorphine treatment in pregnant opioid-dependent women. Randomized, double-dummy, double-blind, flexible-dosing comparison study. Addiction Clinic at the Medical University of Vienna, Austria. Eighteen women were assigned randomly to receive either methadone (n = 9) or buprenorphine (n = 9) during weeks 24-29 of pregnancy. After dropouts, data were available from 14 cases (six in the methadone and eight in the buprenorphine group). Sublingual buprenorphine tablets (8-24 mg/day) or oral methadone solution (40-100 mg/day), with matched placebos. Mothers: retention in treatment, urine toxicology and nicotine use. Neonates: Routine birth data, neonatal abstinence syndrome (NAS) in severity and duration. There was somewhat greater retention in the buprenorphine group but significantly lowered use of additional opioids in the methadone group (P = 0.047).Neonates: There was earlier onset of NAS in neonates born to the methadone (mean 60 hours) than to the buprenorphine groups (mean 72 hours after last medication); 43% did not require NAS-treatment with short treatment duration in both groups (mean 5 days). This preliminary study had limited power to detect differences but the trends observed suggest this kind of research is practicable and that further studies are warranted.

臨床における薬学の展開―１５年の軌跡―

In this review, we outline the new developments in pharmaceutical practice, education and research achieved by the Department of Pharmacy of the University of Tokyo Hospital in the 15 years from 1990 to 2004.In pharmaceutical practice, we created 1) a computer-aided total dispensing system linked to a system for the efficient examination of prescriptions, a parallel dispensing system for countable and uncountable drugs incorporating several automatic dispensing support devices, and a drug usage consultation system for outpatients using Drug Information Sheets, Drug Information Cards and leaflets, and 2) a total dispensing system for injectable drugs including those for intravenous hyperalimentation (IVH) for inpatients and home parenteral nutrition (HPN).In the area of new dosage forms, we developed several original non-commercial, high level medications designed to improve the QOL of patients, such as buprenorphine sublingual tablets and suppositories and retinoic acid aqueous gel ointment. We also started providing consultation to patients in wards and support for raising the quality of medical treatment, and created a drug information system for medical staff and patients. Other achievements were the development of a therapeutic drug monitoring system (TDM) for organ transplantation and a total clinical research trial management system based on new GCP.In the area of education, we created a pharmaceutical education program for bed-side training (BST) for undergraduate students of the Faculty of Medicine and a training program on pharmaceutical practice for undergraduate students of the Faculty of Pharmaceutical Sciences. We also developed a practical training program for newly graduated trainee pharmacists and a continuing education program for post-graduate pharmacists.In the area of clinical research, we review the following four major projects : 1) Drug interactions between the new quinolone antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs), 2) PK/PD analysis of QT prolongation induced by drugs for non-cardiovascular diseases, 3) Quantitative evaluation of pharmacological effects and adverse effects of β-blocking agents based on the receptor occupancy theory, and 4) Clinical research on genotyping of drug metabolizing enzymes for the purpose of creating tailor-made treatments.

A double-blind, double-dummy, randomized, prospective pilot study of the partial Mu opiate agonist, buprenorphine, for acute detoxification from heroin

The optimum dose of buprenorphine for acute inpatient heroin detoxification has not been determined. This randomized, double-blind, double-dummy, pilot study compares two buprenorphine sublingual tablet dosing schedules to oral clonidine. Heroin users ( N = 30) who met DSM-IV criteria for opioid dependence and achieved a Clinical Opiate Withdrawal Scale (COWS) score of 13 (moderate withdrawal), were randomized to receive higher dose buprenorphine (HD, 8-8-8-4-2 mg/day on days 1–5), lower dose buprenorphine (LD, 2-4-8-4-2 mg/day on days 1–5), or clonidine (C, 0.2-0.3-0.3-0.2-0.1 mg QID on days 1–5). COWS scores were obtained QID. Twenty-four hours after randomization, the percentages of subjects who achieved suppression of withdrawal, as defined by four consecutive COWS scores <12, were: C = 11%, LD = 40%, and HD = 60%. Generalized estimating equation regression models, controlling for baseline COWS and time, indicated that COWS scores over the course of 5 days were lower in both LD and HD compared to C ( χ 2(2) = 13.28, P = 0.001). Similar analyses examining scores over time on the Adjective Rating Scale for Withdrawal (ARSW) and on a Visual Analog Scale of Opiate Craving (VAS) indicated an overall treatment effect on the VAS accounted for by a significant difference between HD and C, but no overall treatment effect on the ARSW. There were no discontinuations due to treatment-related adverse events. Both HD and LD regimens are safe and efficacious treatment for opioid detoxification, but HD demonstrated superiority to C on a greater number of measures.

Buprenorphine in the Treatment of Opiate Dependence: Its Pharmacology and Social Context of Use in the U.S.

Buprenorphine's physiological effects are produced when it attaches to specific opiate receptors that are designated mu, kappa, or delta. Buprenorphine, a partial agonist at the mu receptor and an antagonist at the kappa receptor, produces typical morphine-like effects at low doses. At higher doses, it produces opiate effects that are less than those of full opiate agonists. Knowledge of the physiological effects of opiate receptors and the way they interact with opiate agonists, partial opiate agonists, and opiate antagonists is fundamental to understanding the safety and efficacy of buprenorphine in treatment of pain and opiate addiction. Knowledge of the historical and social context of opiate agonist treatment of opiate dependence is fundamental to understanding how nonpharmacological factors may limit the clinical adoption and utility of a safe and effective medication in treatment of opiate dependence. This article reviews, the pharmacology of sublingual buprenorphine and the historical context of opiate agonist therapy; delineates classes of opiate receptors and their interaction with opiate agonists, partial agonists, and antagonists; and describes the commercially available pharmaceutical formulations of buprenorphine. It focuses on sublingual buprenorphine tablets, Subutex® and Suboxone®, the FDA-approved formulations of buprenorphine for treatment of opiate dependence. Sublingual buprenorphine, and the combination of sublingual buprenorphine/naloxone, have unique pharmacological properties that make them a logical first-line intervention in the treatment of opioid dependence.

Buprenorphine dosing regime for inpatient heroin withdrawal: a symptom-triggered dose titration study

The study aimed to identify the range of buprenorphine doses required to comfortably alleviate symptoms in patients undergoing inpatient heroin withdrawal using a symptom-triggered titration dosing regime, and to identify the patient characteristics that impact upon the buprenorphine dose requirements. The study was conducted in two Australian inpatient withdrawal units, recruiting 63 dependent, injecting heroin users with no recent methadone treatment, dependence on other drugs, or other active medical or psychiatric conditions. In a single (patient) blinded case series, placebo or 2 mg sublingual buprenorphine tablets was administered four times a day according to severity of withdrawal (assessed with Subjective Opiate Withdrawal Scale). Up to 16 mg buprenorphine was available over the first 4 days of the admission, up to 8 mg on day 5, and placebo continued until day 6. Thirty-two subjects completed the dosing regime, with mean (±S.D.) daily doses of 3.8±2.8 on day 1, 5.8±3.2 on day 2, 4.8±3.3 on day 3, 2.3±2.6 on day 4, 0.8±1.3 on day 5, and a total dose of 17.4±9.7. Higher buprenorphine doses were required by those patients with more severe psychosocial dysfunction, women, those with more frequent heroin use, and those with more severe dependence on heroin at intake. A dosing regime using sublingual buprenorphine tablets for short inpatient heroin withdrawal is proposed.

Analgesic efficacy and tolerability of transdermal buprenorphine in patients with inadequately controlled chronic pain related to cancer and other disorders: A multicenter, randomized, double-blind, placebo-controlled trial

Background: Buprenorphine is a potent opioid analgesic that is available in sublingual and parenteral formulations. A new formulation, buprenorphine transdermal delivery system (TDS), has been developed. Objective: The aim of this study was to compare the analgesic efficacy and tolerability of the 3 available dosages of buprenorphine TDS (35.0, 52.5, and 70.0 μg/h) with placebo. Methods: This was a randomized, double-blind, placebo-controlled, multicenter study. Patients with chronic, severe pain related to cancer or other diseases and inadequately controlled with weak opioids were randomized to receive buprenorphine TDS 35.0, 52.5, or 70.0 μg/h or placebo patch for up to 15 days. A new patch was applied every 72 hours, for a total of 5 patches. All patients were permitted rescue analgesia with sublingual buprenorphine tablets (0.2 mg) as required for breakthrough pain. Results: A total of 157 patients (86 women, 71 men; mean [SD] age, 58.7 [11.8] years) were initially enrolled in the study. Buprenorphine TDS was associated with significantly higher response rates than was placebo at the 35.0- and 52.5-μg/h dosages (36.6% and 47.5%, respectively, vs 16.2%; P=0.032 and P=0.003, respectively) and a numerically higher response rate at 70.0 μg/h (33.3%), although this difference did not reach statistical significance. Patients treated with buprenorphine TDS experienced a 56.7% reduction in use of sublingual rescue analgesic during the study compared with an 8% reduction with the placebo patch. A total of 43.5% of patients treated with buprenorphine TDS reported good or complete pain relief compared with 32.4% in the placebo group. Pain intensity decreased in a dose-dependent manner with buprenorphine TDS, and the duration of sleep uninterrupted by pain was improved by the end of the study. More than three fourths (78.8%) of patients in the placebo and buprenorphine TDS groups reported at least 1 adverse event (AE) during the study. The most common AEs were central nervous system and gastrointestinal symptoms. The majority of treatment-related AEs were mild or moderate in intensity and were typical of those occurring at the beginning of therapy with a strong opioid. Conclusions: Buprenorphine TDS was shown to be an effective analgesic against chronic, severe pain in this study population. Patients treated with this new formulation of buprenorphine showed improved duration of sleep and reduced need for additional oral analgesics.

Intravenous use of prescribed sublingual buprenorphine tablets by drug users receiving maintenance therapy in France

Background: In 1996, sublingual buprenorphine was authorized for prescription in France for maintenance therapy (MT). MT should facilitate the rehabilitation of opioid-dependent drug users and reduce the risks associated with injection. However, misuse and side effects have been reported. Objectives: To assess the frequency of buprenorphine injection in 404 subjects on buprenorphine MT and to determine the factors associated with the injection of buprenorphine. Methods: A cross-sectional survey was used to collect data from subjects on buprenorphine MT seeking treatment from health care networks, specialized structures, a prison and a hostel in three different regions of France (1998–1999). Information was collected by trained interviewers using a structured questionnaire. Results: About half (46.5%) of the subjects on MT (188/404) had ever injected buprenorphine; 67.2% of this subgroup had since used both injected and sublingual buprenorphine. Variables associated with buprenorphine injection were having injected a substance other than buprenorphine (odds ratio (OR): 13.18; 95% CI: 5.36–32.42), cannabis use (OR: 2.34; 95% CI: 1.51–3.63) and having a source of income other than a salary (OR: 1.58; 95% CI: 1.02–2.45) and heroin use (OR: 0.23; 95% CI: 0.09–0.61). Conclusions: To decrease buprenorphine injection, prescribers of buprenorphine should participate in networks with specialized centers, and social and professional rehabilitation programs should be implemented for subjects on buprenorphine MT.

Buprenorphine prescription by general practitioners in a French region

Since 1996 French general practitioners (GPs) may prescribe sublingual buprenorphine tablets as maintenance treatment for opiate dependence. The computerised data management of the main French health reimbursement system now allows surveillance of the use of this drug, and how it is prescribed. The purpose of this study is to determine the profile of maintained patients, prescribed doses, associated psychotropic treatments and how practitioners prescribe these treatments. This study analyses the 11186 buprenorphine prescriptions electronically transmitted for reimbursement between September and December 1999 in a specific French region. It was found that the 2078 treated patients consumed a mean of 11.5 mg of buprenorphine per day and 12% of them procured prescriptions from more than two prescribers. 43% of maintained patients had an associated benzodiazepine prescription, mainly flunitrazepam, often on the same prescription form. 61% of patients had regular follow-up, others had occasional consultations (21%) and another 18% had deviant maintenance treatment (more than two prescribers or more than 20 mg per day of daily buprenorphine dose). Benzodiazepine consumption was much higher in the ‘deviant group’ (71.4%). 85% of buprenorphine prescriptions were made by GPs. 21% of GPs prescribed buprenorphine and 61% of those had only one or two maintained patients. Buprenorphine prescription by French GPs is a procedure with no particular requirements, allowing many patients to easily access maintenance treatments. However, a high risk of abuse exists, which demands extensive investigation and evaluation of these practices.

Buprenorphine treatment of pregnant opioid-dependent women: maternal and neonatal outcomes

This open-label prospective study examined maternal and neonatal safety and efficacy outcome measures during and following prenatal buprenorphine exposure. Three opioid-dependent pregnant women received 8 or 12 mg sublingual buprenorphine tablets daily for 15–16 weeks prior to delivery. Results showed that buprenorphine in combination with comprehensive prenatal care was safe and effective in these women. Prenatal exposure to buprenorphine resulted in normal birth outcomes, a mean of 4.33 days (minimum possible=4) hospitalization, and a ‘relatively mild’ neonatal abstinence syndrome comprised primarily of tremors (disturbed), hyperactive moro and shortened sleep after feeding. The infants required no pharmacological treatment. Onset of neonatal abstinence signs occurred within the first 12 h after birth, peaked by 72 h and returned to below pre-12 h levels by 120 h. It is concluded that buprenorphine has potential utility for the treatment of pregnant opioid-dependent women.

Double-blind randomized trial of buprenorphine and methadone in opiate dependence

This study compared the safety and efficacy of sublingual buprenorphine tablets with oral methadone in a population of opioid-dependent individuals in a double-blind, randomized, 6-week trial using a flexible dosing procedure. Fifty-eight patients seeking treatment for opioid dependence were recruited in three outpatient facilities and randomly assigned to substitution with buprenorphine or methadone. The retention rate was significantly better in the methadone maintained group (90 vs. 56%; P<0.001). Subjects completing the study in both the treatment groups had similar proportions of opioid positive urine samples (buprenorphine 62%; methadone 59%) and positive urine specimens, as well as mean heroin craving scores decreased significantly over time ( P=0.035 and P<0.001). The proportion of cocaine-positive toxicology results did not differ between groups. At week six mean stabilization doses were 10.5 mg per day for the sublingual buprenorphine tablet, and 69.8 mg per day for methadone, respectively. Patient performance during maintenance was similar in both the groups. The high attrition rate in the buprenorphine group during the induction phase might reflect inadequate induction doses. Thus, buprenorphine is a viable alternative for methadone in short-term maintenance treatment for heroin dependence if treatment induction is done with adequate dosages.

ブプレノルフィン舌下錠の調製と臨床効果

We tried to improve buprenorphine (BN) sublingual tablets (previous tablets) prepared previously [Yakuzaigaku, 46: 134-139 (1986)] by focusing on shortening the disintegration time because the disintegration of these tablets sublingually in man is quite long (7-9 minutes). Five different tablets (100mg) containing 100μg of BN were prepared, and the qualitative characteristics, pharmacokinetic behavior and clinical effect of BN were compared with the previous tablets. In the quality tests, one of the new tablets comprising 78.1 mg of 0.128% BN powder, 19.9 mg of lactose, 1 mg of magnesium stearate and 1 mg of powdered acacia per tablet was superior to the other products in terms of both disintegration and dissolution. The mean sublingual disintegration times fos the placebo of the new tablet in five healthy volunteers and five patients were 3.0 and 3.6 minutes, respectively, values which were significantly shorter than those (7.5 and 6.5 minutes) for the previous tablet. The plasma concentration of BN or analgesic effect arising after sublingual administratation of the new tablet in one healthy volunteer and two patients were closely comparable with those following sublingual administration of the previous tablet. The new tablet is biologically and pharmacologically equivalent to the previous one and is superior to the previous tablet in terms of disintegration characteristics.