Extended-release Opioid Formulations Research Articles

Exploring the use of extended release opioids at shortened dosing intervals in people with chronic pain and high risk medication or substance use.

Background Critical attention to rational opioid prescribing has emerged from the opioid epidemic in North America. Individuals with chronic pain are prescribed extended release opioids in an effort to maintain stable drug levels and for more convenient dosing, though evidence to support improvements in pain or function is lacking. It has been observed that extended release opioid products are used at intervals shorter than recommended by product monographs. The need for shortened intervals has been linked with potential inter-patient variability in pharmacokinetics, among other rationale. Implications of shortened dosing intervals for extended release opioids have not been systematically studied. Objective The aim of this study was to characterize the use of extended release opioid formulations at shortened dosing intervals in a population of patients with chronic pain and high risk for opioid-related harms. Setting This study took place in the Interprofessional Pain and Addiction Recovery Clinic, a specialty ambulatory clinic at the Centre for Addiction and Mental Health in Toronto, Canada for adults with chronic pain and a diagnosis or suspicion of substance use disorder. Method This was a retrospective cross-sectional study. Data were collected from records of patients with assessments completed in the years 2012-2017 (n = 210). Main outcome measure Proportion of patients using extended release opioids at shortened intervals. Results Sixty-one percent of individuals using extended release opioids (n = 78) were using them at shortened intervals. This use was associated with a higher daily morphine equivalent dose (533mg vs 236mg, p < 0.01), use of oxycodone extended release products (50% vs. 27%, p < 0.01), a longer duration of opioid therapy (8.9 vs. 6.8years, p = 0.03) and a diagnosis of chronic neuropathic pain (63% vs. 39%, p < 0.01), with no differences in reported pain intensities, compared with use at standard intervals. Conclusion The use of extended release opioids at shortened intervals was associated with increased daily morphine equivalent doses, thus an increased risk of opioid-related mortality. It is unlikely that of those using extended release opioids, the high proportion of use at shortened intervals is the result of inter-patient differences in metabolism alone. Further study is warranted to explore the underlying drivers and implications for people with chronic pain.

MP29-18 PHARMACEUTICAL PAYMENTS FOR OPIOIDS SIGNIFICANTLY FAVOR EXTENDED-RELEASE MEDICATION AND CORRELATE WITH PHYSICIAN PRESCRIPTIONS

INTRODUCTION AND OBJECTIVES:Extended release opioid formulations were formulated as a means of hopefully reducing abuse and dependence. Still the vast majority of opioid prescriptions written remai...

In Vitro Drug Release After Crushing: Evaluation of Xtampza® ER and Other ER Opioid Formulations.

Background and ObjectiveExtended-release (ER) opioids are associated with high rates of abuse. Recreational opioid users often manipulate ER formulations to achieve a high plasma concentration in a short amount of time, resulting in a more rapid and intense high. Patients may also manipulate ER tablets to facilitate swallowing, without recognizing that manipulation could increase release rate. The goal of this study was to assess the ability of oxycodone DETERx (Xtampza® ER, Collegium Pharmaceutical, Inc., Canton, MA, USA) and other commercially available ER opioid formulations with and without physicochemical abuse-deterrent characteristics to be manipulated by crushing in an in vitro setting.MethodsIn vitro dissolution techniques were used to compare the opioid release from a variety of ER opioid formulations. Dissolution was assessed for intact and crushed dosage forms. Opioid release was quantified using high-performance liquid chromatography.ResultsIntact formulations exhibited drug release rates characteristic of 12- or 24-h dosage forms. After crushing using commonly available household tools, only Xtampza ER maintained ER of opioid.ConclusionsXtampza ER maintained its ER characteristics after crushing, unlike many other commercially available opioid formulations, including some formulated with abuse-deterrent properties. As such, Xtampza ER may be less appealing to abusers and offer a margin of safety for patients who manipulate dosage forms to facilitate swallowing.

(362) In vitro assessment of the effects of alcohol on the release rate of extended-release opioid formulations (Hysingla® ER, OxyContin® and Zohydro® ER)

(362) In vitro assessment of the effects of alcohol on the release rate of extended-release opioid formulations (Hysingla® ER, OxyContin® and Zohydro® ER)

Analysis of the Abuse and Diversion of the Buprenorphine Transdermal Delivery System.

Prescription opioid abuse and diversion are major causes of morbidity and mortality in the United States. The buprenorphine transdermal delivery system (BTDS) is indicated for the treatment of moderate to severe chronic pain and provides a continuous dose of 5, 7.5, 10, 15, or 20μg/h buprenorphine for 7days. Quarterly rates of abuse and diversion of BTDS were compared with 4 comparator groups: 1) other buprenorphine products, 2) fentanyl patches, 3) extended-release (ER) opioid tablets/capsules, and 4) ER tramadol. Data were obtained from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) System Poison Center, Drug Diversion, Treatment Programs Combined (Opioid Treatment and Survey of Key Informants' Patients Programs), and College Survey Programs. Rates were calculated using case counts per population and mentions per prescriptions filled. Poisson regression analysis was used to compare mean rates over time across drug groups after allowing for drug group-specific dispersion parameters. Population adjusted abuse rates were low for BTDS in all of the RADARS System programs compared with the other comparator groups. Findings were similar for the prescription adjusted rates, with BTDS reported at the lowest rates in all programs. Route of abuse differed slightly for BTDS and the comparator groups depending on the program. BTDS was abused and diverted at low rates compared with the other opioid groups in 5 programs of the RADARS System using either population-based rates or prescription dispensed rates. Data from the RADARS System show the BTDS is abused and diverted at low rates compared with other opioid groups including other forms of buprenorphine, fentanyl patches, ER opioid formulations, and ER tramadol.

Cigarette smoking and risk of substance use and substance use disorder relapse among adults in recovery

(HAP) of many formulations. These concerns, along with regulatory–authority directives, have led to the development of opioid formulations expected to have abuse-deterrent properties. The attractiveness of opioids for abuse have been quantified using validated measures of subjective pharmacodynamic (PD) effects (e.g., drug liking, drug high), as well as select pharmacokinetic (PK) characteristics of opioids, such aspeakplasmaconcentration (Cmax) and time to achieveCmax expressed as tmax. For example, tampering with opioid formulations (e.g., altering themode of administration) may increase PD effects by increasing Cmax and/or shortening tmax. Given this PK relationship, whichmay foster a drug’s attractiveness for abuse, the Cmax/tmax ratio has been called the abuse quotient (AQ). This investigation examined the putative validity of using AQ as a surrogate clinical measure to characterize the HAP of opioid analgesic formulations. Methods: PK and PD data were retrospectively gathered from a series of randomized, double-blind, controlled clinical trials (RCTs) exploring the HAP of proposed abuse-deterrent extended-release opioid formulations in comparison with control opioid formulations with high abuse potential and, in some cases, placebo. Correlations of AQ, Cmax, and tmax with subjective PD effects influencing drug abuse were assessed within and between RCTs. Results: In all instances, there were statistically significant and high correlations of AQ and PD effects, with higher AQ denoting greater abuse potential. Overall, these associations were stronger for AQ than for Cmax or tmax individually. Conclusions: The AQ appears to be an essential parameter of HAP when developing abuse-deterrent opioid formulations. Further analyses using real-world surveillance data for comparison are recommended. Financial support: Funded internally by PRA Health Sciences, Salt Lake City, UT, USA.

Evaluation of an Extended-Release, Abuse-Deterrent, Microsphere-in-Capsule Analgesic for the Management of Patients with Chronic Pain With Dysphagia (CPD).

Patients who have chronic pain with dysphagia (difficulty swallowing) (CPD) often have difficulty taking oral medication and, as such, alter their medications by crushing or chewing in an attempt to make it easier to swallow. Such manipulation of currently marketed, extended-release (ER) opioid analgesics can significantly alter the pharmacokinetic (PK) properties of the formulations, resulting in poor treatment outcome or serious adverse events. There is an unmet medical need for oral ER opioid formulations suitable for patients with CPD. The primary objectives of this study were to conduct in vitro studies to evaluate alternate means of administration of a new, extended-release (ER), abuse-deterrent, microsphere-in-capsule formulation of oxycodone for patients with CPD. Specifically, these studies investigated the in vitro equivalence of drug release rates from Oxycodone DETERx® ER intact capsules (control condition) and administration via alternate modes-opening the capsule and sprinkling the microspheres onto soft foods or administration through enteral tubes. Secondary objectives were to compare alternate modes of administration of Oxycodone DETERx® to a commercially available ER-morphine product. Soft food study: Oxycodone DETERx® microspheres were sprinkled onto and mixed with several soft foods (ie, applesauce, vanilla pudding, strawberry jam, yogurt, and vanilla ice cream); the effect of drug contact time (0, 30, and 60 minutes) on drug release was studied. Enteral tube study: Oxycodone DETERx® microspheres were administered through varying sizes of nasogastric (10 and 12 Fr.) tubes and a 16 Fr. gastrostomy tube using 5 different delivery vehicles (ie, water, liquid nutritional feeds [Jevity®, Ensure®], and milk [whole milk and 2% milk]). Drug release rate was characterized using a standard in vitro dissolution methodology; dissolution of intact Oxycodone DETERx® capsules served as the control for both the soft food and enteral tube studies. Oxycodone concentration was measured using a standardized high-performance liquid chromatography (HPLC) assay. Similarity factor (f2) analysis was used to compare similarity of the dissolution profiles of test and control conditions. The mean dissolution profile of Oxycodone DETERx® microspheres sprinkled onto and mixed with each of the soft foods were similar (f2 > 50) to that of the control. Study drug-food contact time did not impact dissolution profiles. The dissolution data obtained from Oxycodone DETERx® microspheres passed through enteral feeding tubes of varying sizes were similar (f2 > 50) to that of the control. Unlike a marketed morphine sulfate ER pellet formulation, Oxycodone DETERx® did not clog any of the studied enteral tubes. A new ER, abuse-deterrent, microsphere-in-capsule formulation of oxycodone can be administered by sprinkling onto soft food without affecting the drug release profile of the formulation. The formulation can also be administered directly via enteral tubes without affecting drug release and without clogging enteral tubes. Oxycodone DETERx® may offer physicians and patients with CPD an alternate treatment option, especially in those patients who have dysphagia or an aversion to swallowing monolithic tablet/capsule formulations and for whom analgesic patches or other opioid formulations are not a viable therapeutic option.

Primary Care Considerations of the Pharmacokinetics and Clinical Use of Extended-Release Opioids in Treating Patients with Chronic Noncancer Pain

Extended–release (ER) opioid analgesics are associated with prolonged analgesia and greater stability in pain relief compared with immediate–release formulations. Due to the pharmacokinetic (PK) characteristics of ER opioids and additional clinical advantages, the use of ER opioids for patients with moderate–to–severe chronic noncancer pain has increased. Primary care physicians are the major prescribers of opioids and require an in–depth understanding of the risks and benefits of opioid treatment in pain management. With appropriate knowledge of PK profiles and clinical outcomes of commonly prescribed ER opioids, primary care physicians can safely and effectively manage this patient population. In addition, the development of ER opioids with abuse–deterrent features marks an important milestone in potentially reducing abuse and may be factored into the clinical decision–making process. This article provides a comprehensive review of the PK and clinical effects of ER opioids and discusses novel ER opioid formulations that may limit abuse potential.

Non-Analgesic Effects of Opioids: Opioids’ Effects on Sleep (Including Sleep Apnea)

The exact effect of opioid analgesics on sleep is to be determined. Although literature data are sporadically reported, the aim of this review is to summarize the already known effects of such medications on sleep. A variety of effects, both positive and negative, has been suggested, when opioids are used for pain treatment, but in the absence of pain as well. Although often thought to promote restful sleep, the reality is much more complicated. Sleep disturbances and alterations of sleep quantity and quality have been reported. In addition, their sedative effects have been relatively well established and opioids can cause respiration to slow and become irregular, leading to hypercapnia and hypoxia. As a result, their usage has been linked to irregular or ataxic breathing (Biot's breathing) and their use has been associated with both central and obstructive sleep apnea. One could estimate that central apnea is a common complication of such chronic therapy, affecting between 30% and 90% of patients. Thus, sleep disturbances can be induced or deteriorated. On the other hand, extended release opioid formulations have been suggested to improve sleep due to no analgesic gaps and less walking because of breakthrough pain. Furthermore, several reports have shown significantly improved sleep quantity and adequacy, with reduced sleep disturbances. Still, as no prospective trials on the effect of opioid therapy on sleep are available and evidence is scarce, definitive conclusions cannot be drawn. Future studies with their effect on sleep as primary end-point are needed to draw permanent conclusions.

Effects of Alcohol on the Pharmacokinetics of Morphine Sulfate and Naltrexone Hydrochloride Extended Release Capsules

Although contraindicated, coingestion of alcohol and opioids by patients or drug abusers is a major health concern because of dangerous additive and potentially life-threatening sedative and respiratory effects. In addition, alcohol has been shown to disrupt the extended-release characteristics of certain extended-release opioid formulations, releasing a hazardous amount of opioid over a short time period. Morphine sulfate and naltrexone hydrochloride extended release capsules (MS-sNT), which contain naltrexone sequestered in each pellet core, are indicated for management of chronic, moderate to severe pain. Sequestered naltrexone is designed for release upon product tampering (crushing) to potentially mitigate morphine-induced subjective effects. This open-label, single-dose, 4-way crossover, pharmacokinetic drug interaction study compared the relative bioavailability of morphine and naltrexone when MS-sNT is administered (under fasting conditions) with increasing doses of alcohol. Thirty-two healthy, opioid-naive adults were randomized to MS-sNT administered with 240 mL of 4%, 20%, or 40% alcohol or water. No drug interaction was found between morphine in MS-sNT and 4% or 20% alcohol. Administration with 40% alcohol did not affect overall morphine exposure but was associated with a 2-fold increase in C(max) and reduction of t(max) from 9 to 4 hours versus MS-sNT taken with water. Naltrexone sequestering was successful in all treatment arms and not affected by coadministration with alcohol over the dose range tested.

Clinical Strategies for the Primary Health Care Professional to Minimize Prescription Opioid Abuse

Prescription opioid analgesic therapy can be effective in managing chronic noncancer pain in appropriately selected patients. However, the risks and benefits of prescription opioids should be carefully considered when treating this patient population. A dramatic increase in opioid–related morbidity and mortality has been observed in the United States in the past decade. Therefore, health care providers must balance the treatment of chronic pain with the need to minimize the risks of opioid misuse, abuse, addiction, and diversion. Current literature suggests that most patients with chronic pain are managed at the primary care level. However, many of these practitioners are not skilled in risk assessment, stratification, and monitoring. This article reviews strategies and tools that providers may implement to help identify appropriate patients for chronic opioid therapy and recognize signs of drug–related aberrant behaviors and abuse. In addition, the potential role of abuse–deterrent, extended–release opioid formulations to reduce risk in patients and nonmedical users of opioids is introduced. Collectively, these preventative measures may effectively reduce opioid misuse, abuse, and diversion without denying adequate analgesia in appropriate patients.