Buprenorphine Products Research Articles

Pilot evaluation of a novel unilateral onychectomy model and efficacy of an extended release buprenorphine product

Pilot evaluation of a novel unilateral onychectomy model and efficacy of an extended release buprenorphine product

Lack of adverse effects during a target animal safety trial of extended-release buprenorphine in Fischer 344 rats.

Extended-release buprenorphine is an effective analgesic in laboratory animals, and its safety has been established in mice but not in rats. The authors used a target animal safety trial to evaluate the safety of extended-release buprenorphine in rats. Fischer 344 rats received post-surgical subcutaneous injections of 1.3 mg, 3.9 mg or 6.5 mg buprenorphine per kg body weight (two times, six times or ten times the intended dose, respectively), and their body weight, clinical signs and symptoms, clinical pathology and histopathology were monitored for 4 d. Body weight was not significantly different in rats that received buprenorphine compared with control rats. Signs of nausea-related behavior were observed in 25% of the rats treated with buprenorphine. Clinical pathology results for all rats were normal, and gross and microscopic histopathology examinations identified no substantial abnormalities, suggesting that this behavior was of minor consequence. Other adverse events previously reported to occur with opiate therapy, including weight loss and dermal lesions at drug injection sites, were not observed in this study. The results of this study show that post-surgical administration of an extended-release buprenorphine product is safe in Fischer 344 rats and does not necessarily cause substantial adverse effects, confirming that opiate therapy is a viable choice in laboratory animal medicine.

Trends in the use of buprenorphine by office-based physicians in the United States, 2003-2013.

Despite buprenorphine's promise as a novel therapy for opioid dependence, little is known about its clinical adoption. We characterized trends in ambulatory use of buprenorphine in the United States. Cross-sectional, descriptive analyses of buprenorphine utilization from 2003 to 2013 using the IMS Health National Disease and Therapeutic Index, a nationally representative audit of ambulatory care. The primary unit of analysis was an office visit where buprenorphine was used for opioid dependence (treatment visit). Between 2003 and 2013, there was significant uptake of buprenorphine in ambulatory treatment visits, from 0.16 million [M] (95% confidence interval [CI] 0.10-0.20) visits in 2003 to 2.1M (CI 1.9-2.3M) treatment visits during 2013. Approximately 90% involved the use of brand name combination buprenorphine/naloxone (Suboxone), although this percentage decreased modestly to 80% by the last quarter of 2013. Buprenorphine prescribing increased among all specialties, but the proportion accounted for by primary care physicians increased significantly from 6.0% in 2003 to 63.5% in 2013 and decreased among psychiatrists from 92.2% to 32.8% over the same time period. The use of buprenorphine products to treat opioid dependence has increased significantly in the past 10 years and has shifted to greater use by primary care physicians, indicating a rapidly changing face of opioid maintenance therapy in the United States.

Buprenorphine/naloxone pediatric ingestion: Exposure rates differ between film and tablet formulations

RADARS System Poison Center program case counts and medical outcomes for unintentional exposures to buprenorphine/naloxone tablets and oral film among children aged 0 – 5 years from October 2009 to March 2013 were analyzed. To account for drug availability, rates were standardized using unique recipients of a dispensed drug (URDD) per year-quarter. Negative binomial regression was used to estimate rates and confidence intervals. Average quarterly rates were calculated from 2011/Q2 – 2013/Q1. 1,695 reports of unintentional exposure to sublingual buprenorphine products were analyzed.

Emergency hospitalizations for unsupervised prescription medication ingestions by young children.

Emergency department visits and subsequent hospitalizations of young children after unsupervised ingestions of prescription medications are increasing despite widespread use of child-resistant packaging and caregiver education efforts. Data on the medications implicated in ingestions are limited but could help identify prevention priorities and intervention strategies. We used nationally representative adverse drug event data from the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project and national retail pharmacy prescription data from IMS Health to estimate the frequency and rates of emergency hospitalizations for unsupervised prescription medication ingestions by young children (2007-2011). On the basis of 1513 surveillance cases, 9490 estimated emergency hospitalizations (95% confidence interval: 6420-12,560) occurred annually in the United States for unsupervised prescription medication ingestions among children aged <6 years from 2007 through 2011; 75.4% involved 1- or 2-year old children. Opioids (17.6%) and benzodiazepines (10.1%) were the most commonly implicated medication classes. The most commonly implicated active ingredients were buprenorphine (7.7%) and clonidine (7.4%). The top 12 active ingredients, alone or in combination with others, were implicated in nearly half (45.0%) of hospitalizations. Accounting for the number of unique patients who received dispensed prescriptions, the hospitalization rate for unsupervised ingestion of buprenorphine products was significantly higher than rates for all other commonly implicated medications and 97-fold higher than the rate for oxycodone products (200.1 vs 2.1 hospitalizations per 100,000 unique patients). Focusing unsupervised ingestion prevention efforts on medications with the highest hospitalization rates may efficiently achieve large public health impact.

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.

EPA-0861 – Patterns of drug misuse on guernsey, british channel islands

Introduction Guernsey is a British Protectorate island (population 65000) in the English Channel. Illicit drugs are difficult to import and expensive people look to alternative substances. Objectives To establish patterns of drug misuse among patients referred for treatment. Methods Case note audit of all referred patients in 2011, cross referenced with sudden unexpected death case review results. Results 198 patients were referred, 80 (40%) for mainly drug dependency. Reported patterns of use tended to follow local availability and polydrug misuse was common. Of the drugs clients, 96% reported misusing prescription only medicines (POMs) and over the counter (OTC) drugs, particularly opiates and benzodiazepines. Buprenorphine products were most commonly misused (26%), followed by benzodiazepines (25%), dihydrocodeine (22%), heroin (11%) and codeine (6%) (more than 1 drug may be reported so totals Conclusions High rates of pharmaceutical drug misuse on Guernsey may reflect the low availability of illicit drugs like heroin and cocaine. This increases demand for addictive POMs and OTCs. Prescribers in isolated communities need to be more cautious when prescribing addictive POMs, particularly fentanyl. Pharmacists may also need to monitor for OTC drug misuse, particularly of codeine-containing medications.

Opioid Abuse and Deterrence: Buprenorphine Products

Abuse of opioid based prescription drugs is an ongoing global health concern that affects millions of individuals worldwide. The economic burden from this abuse has led to the development of treatment programs and the use of methadone maintenance in clinics. Yet, methadone itself has abuse liability and is misused in ways such as crushed for nasal insufflation or dissolved for subsequent intravenous injection. Later, a newer synthetic opioid working as a partial agonist at the mu-opioid receptor, buprenorphine (Subutex®), became available for outpatient use.This new opioid produces restricted euphoria, decreases withdrawal symptoms, and can prevent displacement of buprenorphine should the user decide to take illicit opioids. Due to high risk of abuse, the product was discontinued and now only available as a combination (Suboxone®) with the opioid antagonist naloxone.Users who abuse the combination product by parenteral routes will have euphoric effects cancelled by the presence of naloxone. Such novel dosage forms having additional physical and/or pharmacological barriers can provide a safe and effective option for medication-assisted treatment of opioid addiction with increased access to care.

Diversion and abuse of buprenorphine: Findings from national surveys of treatment patients and physicians

Background Since 2003, buprenorphine has been approved for the treatment of opioid dependence in office-based practice. Diversion and abuse can be a threat to its continued approval under these conditions. Methods As part of a national postmarketing surveillance program, applicants to substance abuse treatment and physicians certified to prescribe buprenorphine were surveyed about their perceptions of buprenorphine/naloxone diversion and abuse. These surveys were supplemented by information from national databases. Availability of buprenorphine/naloxone was measured by number of tablets dispensed. Results Measures of diversion and abuse of buprenorphine/naloxone increased from 2005 to 2009. The results from the applicant survey showed that the perceptions of the extent of diversion and abuse were lower than positive controls, methadone, oxycodone and heroin, but higher than the negative control, amitriptyline. By 2009, 46% of the physicians believed that buprenorphine/naloxone was diverted but 44% believed illegal use was for self-management of withdrawal and 53% believed the source of the medication was substance abuse patients. Other measures from national databases showed similar results. When adjusted for millions of tablets sold per year, slopes for measures of diversion and abuse were reduced. Conclusions The increases in diversion and abuse measures indicate the need to take active attempts to curb diversion and abuse as well as continuous monitoring and surveillance of all buprenorphine products. However, these increases parallel the increased number of tablets sold. Finding a balance of risk/benefit (i.e. diversion and abuse versus expanded treatment) remains a challenge.

Buprenorphine transdermal system has REMS

Prdue Pharma LP on July 1 announced that its new buprenorphine transdermal system, Butrans, received marketing approval from FDA and has a risk evaluation and mitigation strategy (REMS). Butrans appears to be the first buprenorphine product to have an approved REMS. FDA’s online list of approved REMS programs, updated on June 30, showed no entry for a buprenorphine product. According to the product’s labeling, the buprenorphine transdermal system is intended for use in the management of moderate to severe chronic pain in patients who require round-the-clock therapy with an opioid analgesic for an extended period of time. Each patch is intended to be worn for seven days. One of the eight contraindications to use of the product is postoperative pain. Although buprenorphine injection has been used in the treatment of postoperative pain, the labeling for the transdermal system states that the product must not be used for that purpose. Purdue Pharma said the REMS includes a medication guide, elements to assure safe use, also known as ETASU, and a timetable for the company to submit assessments on the REMS. One feature of the ETASU is the training of health care providers.

Med Check

Med Check

A retrospective evaluation of patients switched from buprenorphine (subutex) to the buprenorphine/naloxone combination (suboxone)

BackgroundIn Finland, buprenorphine (Subutex) is the most abused opioid. In order to curb this problem, many treatment centres transferred ("forced transfer") their buprenorphine patients to the buprenorphine plus naloxone (Suboxone) combination product in late 2003.MethodsData from a retrospective study involving five different treatment centers, examining the effects of switching patients to Suboxone, were gathered from 64 opioid-dependent patients who had undergone the medication transfer.ResultsMost patients (90.6%) switched to Suboxone at the same dose of buprenorphine that they had been receiving as Subutex (average 22 mg). The majority of these patients (71.9%) were maintained at the same dose of Suboxone throughout the 4-week study period. During the first 4 weeks, 50% of the patients reported adverse events and at the four month time point, 26.6% reported adverse events. However, due to adverse events one patient only discontinued treatment with Suboxone during the 4-week study period, and five during the four month follow-up period. Of the 26 patients in the follow-up period, Suboxone was misused intravenously once each by 4 patients and twice by 1 patient. These 5 patients all reported that injecting Suboxone was like injecting "nothing" with any euphoria, or that it was a bad experience.ConclusionWe conclude that when patients are transferred from high doses (> 22 mg) of buprenorphine to the combination product, dose adjustments may be necessary especially in the later phase of the treatment. We recommend that a transfer from Subutex to Suboxone should be carefully discussed and planned in advance with the patients and after the transfer adverse events should be regularly monitored. With regard of buprenorphine IV abuse, the combination product seems to have a less abuse potential than buprenorphine alone.

Relationship between therapeutic use and abuse of opioid analgesics in rural, suburban, and urban locations in the United States

The goal of these studies was to determine the relationship between prescribed use of opioid analgesics and their non-medically related use (abuse) at a regional level across the country. To gather information about prescription drug abuse, we asked 233 drug abuse treatment specialists to provide us Quarterly reports on the number of cases of prescription opioid analgesic abusers who used opioid analgesics to get high in the past 30 days. We found that there was a very strong correlation between therapeutic exposure to opioid analgesics, as measured by prescriptions filled, and their abuse. There were, however, geographical loci that represented outliers in which abuse was disproportionately high relative to therapeutic use (>95th percentile), most of which were in very small urban, suburban, and rural areas. The rank order of abuse shows that buprenorphine products, extended release (ER) oxycodone and methadone are the most intensely abused prescription opioid analgesics, with hydrocodone the least abused, when the data are corrected for degree of exposure, i.e., cases/1000 persons filling a prescription. If, on the other hand, one uses the number of cases/100 000 population, hydrocodone ranked as high as ER oxycodone and all other drugs grouped together at very low levels of abuse. Since the latter conclusion ignores therapeutic exposure, we conclude that the rate of abuse of highly efficacious opioid analgesics is best expressed as cases of abuse/1000 persons filling a prescription, which yields the best possible estimate of the risk-benefit ratio of these drugs.

Buprenorphine Products for the Pharmacologic Management of Opioid Addiction: Why Shouldn't Advanced Practice Nurses Prescribe?

This paper describes the current legislative authority that permits office-based prescribing of buprenorphine products for the pharmacological treatment of opioid addiction by physicians with certain qualifications. It outlines ways prescribers can improve the quality of care, ensure safety, prevent diversion and abuse of the medications, and improve treatment outcomes. It advances the concept of enabling advanced practice nurses with prescriptive authority (nurse practitioners) to prescribe buprenorphine products for the treatment of opioid addiction, so as to improve access to this treatment and reduce the treatment capacity gap.

Accessing opiate dependence treatment medications: buprenorphine products in an office-based setting

Accessing opiate dependence treatment medications: buprenorphine products in an office-based setting