bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term safety, tolerability, and efficacy of OROS® hydromorphone in patients with chronic pain
Authors: Wallace, MD Mark , Moulin, MD Dwight E. , Rauck, MD Richard L. , Khanna, PhD Sarita , Tudor, PhD Iulia Cristina , Skowronski, MD Roman , Thipphawong, MD John
Published: February 2018

Objective: To assess the safety and efficacy of long-term repeated dosing of OROS® hydromorphone in chronic pain patients.Design: This multicenter, open-label extension trial enrolled patients from three short-term OROS® hydromorphone trials.Setting: Fifty-six centers in the United States and Canada.Patients: Adults with chronic cancer pain or chronic nonmalignant pain who were receiving stable doses of OROS® hydromorphone (≥8 mg/day). Three hundred and eighty-eight patients were enrolled, 106 patients completed at least 12 months of therapy.Interventions: OROS® hydromorphone (individualized doses) was administered once daily.Main outcome measures: Safety and efficacy (Brief Pain Inventory and patient and investigator global evaluations) were assessed at monthly visits.Results: The median duration of extended OROS® hydromorphone therapy was 274 days. The median daily dose of study medication was 32.0 mg at extension-study baseline, 40.0 mg at month 3, and 48.0 mg at months 6, 9, and 12, respectively. The most frequently reported adverse events were nausea (n = 93, 24.0 percent) and constipation (n = 75, 19.3 percent). The analgesic effects of OROS® hydromorphone, assessed using the Brief Pain Inventory, were maintained throughout the extension. At 12 months, 72.4 percent of patients and 75.9 percent of investigators rated overall treatment as good, very good, or excellent.Conclusions: Once-daily OROS® hydromorphone is an osmotically driven, controlled-release preparation that may be particularly well suited to long-term use, because it provides consistent plasma concentrations and sustained around-the-clock analgesia. In this study, the benefits of OROS® hydromorphone attained in short-term studies were maintained in the long-term when daily administration was continued.
Opioid-induced constipation negatively impacts pain management, productivity, and health-related quality of life: Findings from the National Health and Wellness Survey
Authors: Bell, MHA Timothy , Annunziata, MA Kathy , Leslie, MD, MBA John B.
Published: February 2018

Objective: To characterize the impact of opioidinduced constipation (OIC) on healthcare resource use, work productivity, and health-related quality of life (HRQOL) in patients receiving chronic opioid therapy.Design: Data were collected via Internet questionnaires during the international National Health and Wellness Survey (NHWS) 2004 from individuals aged ≥18 years who reported taking opioids for ≥6 months. Healthcare resource utilization, Work Productivity, and Activity Impairment, and Short-Form 8 (SF-8) questionnaire responses were compared between those who did or did not report OIC.Results: Data were available from 2,430 individuals receiving opioids, of whom 359 reported OIC. Participants with OIC reported significantly more physician visits (mean difference 3.84 visits; p < 0.05) and alternative care provider visits (mean difference 1.73 visits; p < 0.05) over the previous 6 months than those without OIC; however, no significant differences in emergency room visits or number of days of hospitalization were observed. Respondents with OIC also reported significantly greater time missed from work, impairment while working, overall work impairment, and activity impairment (p < 0.05 for all comparisons). HRQOL scores were significantly lower in the OIC group than those without OIC on both the physical and mental components of the SF-8 questionnaire (p < 0.05 for both comparisons).Conclusions: The survey results reflect a negative impact of OIC on individuals’ HRQOL and on society in terms of healthcare resource use and work productivity beyond that imposed by patients’ pain conditions. These findings indicate a need for effective treatment for opioid-induced constipation in patients receiving chronic opioid therapy.
Opioid-induced bowel dysfunction in cancer-related pain: Causes, consequences, and a novel approach for its management
Authors: Holzer, PhD Peter , Ahmedzai, BSc, MBChB, FRCP Sam H. , Niederle, MD Norbert , Leyendecker, PhD Petra , Hopp, MD Michael , Bosse, Statistics (Diploma) Björn , Spohr, PhD Ingrid , Reimer, MD Karen
Published: February 2018

Opioids are the mainstay of management for patients with cancer-related pain. Although the analgesic efficacy of opioid therapy is well documented, the recent European Pain in Cancer survey demonstrated that the management of moderate-to-severe pain in patients with cancer is far from optimal. Bowel dysfunction, and importantly constipation, is a common side effect and has a significant impact on the patient’s morbidity and quality of life. Nonpharmacological strategies and laxatives are often not effective in the management of opioid-induced constipation (OIC), making it necessary to search for new strategies for the treatment of opioid-induced bowel dysfunction. One promising strategy is the prevention of OIC with peripherally acting opioid antagonists that specifically target the underlying cause of this condition, without affecting centrally mediated analgesia. In recent studies, the novel combination of prolonged-release oral oxycodone and prolonged-release oral naloxone provided effective analgesia with improved bowel function in patients suffering from severe cancer-related and noncancer-related pain. The combination has the potential to improve the quality of pain management significantly in these patients.
Dexmedetomidine as a novel therapeutic for postoperative pain in a patient treated with buprenorphine
Authors: Brummett, MD Chad M. , Trivedi, DO Kavita A. , Dubovoy, MD Anna V. , Berland, MD Daniel W.
Published: February 2018

Buprenorphine is a partial agonist/antagonist used for the outpatient management of pain and addiction. It avidly binds to the opioid receptors and has a long and varied half-life. Its effects can impair the efficacy of opioids used for postoperative pain. The authors present a case of a patient managed with buprenorphine as an outpatient who presented for revision spine surgery and had significant postoperative pain that was successfully treated with hydromorphone and dexmedetomidine. This is the first reported use of dexmedetomidine for postoperative pain in a patient treated with buprenorphine.
Relationship between rate of infusion and reinforcing strength of oxycodone in humans
Authors: Comer, PhD Sandra D. , Ashworth, MD Judy B. , Sullivan, MD, PhD Maria A. , Vosburg, PhD Suzanne K. , Saccone, BS Phillip A. , Foltin, PhD Richard W.
Published: February 2018

The rate of drug delivery to the central nervous system is believed to be an important predictor of the reinforcing strength of a drug. However, only a few studies have directly examined the relationship between drug-taking behavior and rate of drug administration. The purpose of the present experiment was to determine whether manipulating the infusion rate of a fixed dose of opioid alters its reinforcing effectiveness in humans. Twelve heroin-dependent participants (11 male, one female) completed the 2.5-week inpatient study. During test days, participants received $20 and a dose of drug (0 or 40 mg oxycodone administered intravenously over 2, 15, 30, 60, or 90 minutes) in random order during a morning sample session. Participants then worked for the sampled dose and/or money amount during an afternoon choice session by making finger presses on a computer mouse. Under these conditions, 40 mg oxycodone served as a reinforcer only when it was delivered over 2 and 15 minutes. Subjective ratings of drug liking, good effect, and high were similar to the self-administration results. Peak plasma levels of oxycodone generally occurred at the end of each infusion, eg, 2 minutes for the 2-minute infusion duration. Extended-release opioid medications are commonly prescribed for treating pain. The present results provide empirical support for the development of extended-release opioid medications that are difficult to convert into more rapid-acting forms. Specifically, these “abuse-deterrent formulations” could prevent patients from tampering with their medications to enhance their euphoric and reinforcing effects.
Overcoming obstacles to implementing methadone maintenance therapy for prisoners: Implications for policy and practice
Authors: McKenzie, MPH Michelle , Nunn, MS, ScD Amy , Zaller, PhD Nickolas D. , Bazazi, BA Alexander R. , Rich, MD, MPH Josiah D.
Published: February 2018

More than 2.4 million people are currently incarcerated in the United States, many as a result of drugrelated offenses. In addition, more than 200,000 active heroin addicts pass through the correctional system annually. New evidence suggests that both providing prisoners with referrals for community-based methadone programs and providing methadone prior to release reduces recidivism and adverse health and social consequences associated with drug use. This article reports the programmatic challenges associated with initiating methadone treatment in the Rhode Island correctional system. Significant obstacles to implementing methadone treatment include: stigma associated with pharmacological treatment, misconceptions regarding the nature of opioid addiction, logistics of control and storage of methadone, increased work load for nursing staff, and general safety and control concerns. The authors discuss strategies to address these barriers and conclude that providing methadone prior to inmate release is a feasible intervention with the potential to mitigate drugrelated health and social harms.
Chronic opioid therapy issues associated with opioid abuse potential
Authors: Smith, MD Howard S. , Kirsh, PhD Kenneth L. , Passik, PhD Steven D.
Published: February 2018

Chronic opioid therapy continues to be an important “mainstream” option for the relief of pain, despite continued debate over the efficacy and safety of utilizing opioids with chronic noncancer populations. With this increase in utilization for medical purposes, the authors have also experienced a troubling rise in the abuse and diversion of prescription opioids. Providers should note this relationship and always perform due diligence when assessing whether a patient with chronic noncancer pain is an appropriate candidate for opioid therapy based on potential risk factors. Because of the relative shortage of board-certified pain practitioners in the United States, much of the practice of pain management falls on primary care providers, who might feel uncomfortable or overwhelmed when facing these issues. To this end, a set of guidelines are discussed to promote an approach to chronic noncancer pain utilizing “universal precautions” principles. In addition, several risk tools are evaluated, including the Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R), the Opioid Risk Tool (ORT), and the Pain Assessment and Documentation Tool (PADT). Finally, discussion is presented regarding what practices seen in opioid prescribing can be considered “in-or-out” of the mainstream box.
Meta-analysis of the effect of extended-release epidural morphine versus intravenous patient-controlled analgesia on respiratory depression
Authors: Sumida, MD Shawn , Lesley, BS Maggie R. , Hanna, MD Marie N. , Murphy, MD Jamie D. , Kumar, MD Kanupriya , Wu, MD Christopher L.
Published: February 2018

Objective: Extended-release epidural morphine (EREM) is a single-dose, extended-release epidural morphine formulation intended to provide postoperative pain relief over a 48-hour period. There have been a few randomized controlled trials investigating the use and safety of EREM versus intravenous patient-controlled analgesia with opioids (IV-PCA); however, the adverse event of respiratory depression of this treatment is unclear. The authors have undertaken a meta-analysis to examine this issue.Methods: A systematic literature search of the National Library of Medicine’s PubMed database was conducted for terms related to EREM. Only randomized controlled trials, in the English language, assessing the rates of respiratory depression of EREM to IV-PCA were included for analysis. Data on pertinent study characteristics and relevant outcomes were extracted from accepted articles. Meta-analysis was performed using the Review Manager 4.2.7 (The Cochrane Collaboration, 2004). A random effects model was used.Results: The authors’ literature search yielded three articles which met all inclusion criteria. All studied doses of EREM were evaluated. Pooled estimates (odds ratio) were made for rates of adverse events of respiratory depression. Use of EREM was associated with significantly higher odds of respiratory depression compared to IV-PCA (odds ratio = 5.74; 95% confidence interval: 1.08, 30.54, p = 0.04). Even when examining only Food and Drug Administration approved dosages for EREM, the use of EREM was associated with significantly higher odds of respiratory depression when compared with IV-PCA (odds ratio = 5.80; 95% confidence interval: 1.05, 31.93, p = 0.04).Conclusions: Although perioperative single-dose epidural EREM (versus IV-PCA) was effective for postoperative pain relief for up to 48 hours, it is associated with significantly higher odds of respiratory depression. Further examination of the issue of respiratory depression of epidural EREM may be warranted.
The analgesic potential of cannabinoids
Authors: Elikottil, MBBS Jaseena , Gupta, MD Pankaj , Gupta, PhD Kalpna
Published: February 2018

Historically and anecdotally cannabinoids have been used as analgesic agents. In recent years, there has been an escalating interest in developing cannabis-derived medications to treat severe pain. This review provides an overview of the history of cannabis use in medicine, cannabinoid signaling pathways, and current data from preclinical as well as clinical studies on using cannabinoids as potential analgesic agents. Clinical and experimental studies show that cannabis-derived compounds act as antiemetic, appetite modulating, and analgesic agents. However, the efficacy of individual products is variable and dependent upon the route of administration. As opioids are the only therapy for severe pain, analgesic ability of cannabinoids may provide a much-needed alternative to opioids. Moreover, cannabinoids act synergistically with opioids and act as opioid sparing agents, allowing lower doses and fewer side effects from chronic opioid therapy. Thus, rational use of cannabis-based medications deserves serious consideration to alleviate the suffering of patients due to severe pain.
Use of an algorithm applied to urine drug screening to assess adherence to an OxyContin® regimen
Authors: Couto, PharmD, MBA Joseph E. , Webster, MD, FACPM, FASAM Lynn , Romney, MS, JD, MPH Martha C. , Leider, MD, MBA Harry L. , Linden, DrPH, MS Ariel
Published: February 2018

Objective: This study examined the ability of an algorithm applied to urine drug levels of oxycodone in healthy adult volunteers to differentiate among low, medium, and high doses of OxyContin®.Participants and interventions: Thirty-six healthy volunteers were randomized to receive 80, 160, or 240 mg of daily OxyContin® to steady state while under a naltrexone blockade. During days 3 and 4 of the study, urine samples of all participants were collected, and oxycodone levels detected in the urine were obtained using a liquid chromatography-mass spectrometry (LC-MS-MS) assay.Outcome measures: The concordance was calculated for raw and adjusted LC-MS-MS urine oxycodone values within each study participant between their third and fourth day values. Also, an analysis of medians was calculated for each of the dosage groupings using Bonett-Price confidence intervals for both raw and adjusted LC-MS-MS values.Results: The concordance correlation coefficient for the raw LC-MS-MS values between days 3 and 4 was 0.689 (95% confidence intervals = 0.515, 0.864), whereas the concordance correlation coefficient for the LC-MS-MS values using the algorithm (ie, normalized values) was 0.882 (95% confidence intervals = 0.808, 0.956). Because of greater variability in the raw values, some overlap was observed in the confidence intervals of the various OxyContin® doses, whereas no overlap was observed in the normalized confidence intervals regardless of the application of a Bonferroni adjustment.Conclusions: In contrast to raw LC-MS-MS values, an algorithm that normalizes oxycodone urine drug levels for pH, specific gravity, and lean body mass discriminates well among all three of the daily doses of OxyContin® tested (80, 160, and 240 mg), even with correcting for multiple analyses.
Methylnaltrexone potentiates body weight and fat reduction with leptin
Authors: Yuan, MD, PhD Chun-Su , Sun, PhD Shi , Attele, MD Anoja , Wang, PhD Chong-Zhi , Tong, BS Robin , Israel, MD Robert J.
Published: February 2018

Objective: Leptin increases energy expenditure by enhancing systemic and brown adipose metabolism. In a neonatal rat model, retroperitoneal fat pad weight decreased significantly in leptin-treated animals, which reduced body weight. As opioids increase feeding, opioid antagonists may decrease food intake and body weight. However, interactions between leptin and the activity of peripheral opioids on body weight and fat accumulation have not been investigated. In this study, the authors evaluated the effects of naloxone (a nonselective opioid antagonist) and methylnaltrexone (a peripherally acting opioid antagonist) on the action of leptin in neonatal rats.Results: Compared with control, the weight gain of pups given a single daily intraperitoneal injection of leptin 0.5 mg/kg, leptin 0.5 mg/kg plus naloxone 0.3 mg/kg, or leptin 0.5 mg/kg plus methylnaltrexone 3.0 mg/kg for 8 consecutive days was significantly reduced (all p < 0.01). Naloxone or methylnaltrexone significantly potentiated leptin’s effect on body weight (p < 0.05 or p < 0.01, respectively). After coadministration of leptin plus naloxone or leptin plus methylnaltrexone, weight reduction in the right retroperitoneal fat pads was also significant compared with the reduction after leptin alone (p < 0.05 or p < 0.01, respectively).Conclusions: The data suggest the existence of a peripheral opioid-related mechanism in leptinactive modulation of body weight.
Bioequivalence and safety of a novel fentanyl transdermal matrix system compared with a transdermal reservoir system
Authors: Moore, MS Kenneth Todd , Adams, MS Holly D. , Natarajan, PhD Jaya , Ariyawansa, MS Jay , Richards, MD Henry M.
Published: February 2018

Objectives: Fentanyl is a potent synthetic opioid used for the management of chronic pain. A newer transdermal matrix system was developed and compared with a reservoir system used in the United States.Setting: An open-label, single-center, randomized, two-period crossover study was conducted to evaluate the bioequivalence of the transdermal matrix system to the transdermal reservoir system. Seventy-four subjects completed treatment with both the reservoir system (100 μg/h) and the matrix system (100 μg/h), each applied for 72 hours. After application of the first system, subjects completed a 9-day washout and then crossed over to receive the other system for another 72 hours.Main outcome measure: Blood samples for the determination of serum fentanyl concentrations were taken in each treatment period for up to 120 hours following application.Results: The ratios of geometric means for maximum fentanyl concentration (Cmax) and area under the concentration-time curve (AUClast and AUC∞ ) were 106 percent, 110 percent, and 110 percent, respectively. The 90% confidence intervals for the ratios of the geometric means were contained within the bioequivalence criteria of 80-125 percent. The matrix system adhered well to skin. Systemic and topical safety profiles were comparable between treatments.Conclusions: The transdermal fentanyl matrix system adhered well, was well tolerated, and produced systemic exposures of fentanyl that were bioequivalent to the reservoir system.
The endocrine effects of long-term oral opioid therapy: A case report and review of the literature
Authors: Elliott, MD Jennifer A. , Horton, DO Erica , Fibuch, MD Eugene E.
Published: February 2018

The negative effects of long-term opioid administration on the body’s endocrine system have been known for decades.1,2 These effects have been observed and studied with the use of intrathecal opioids and in heroin addicts.3-9 However, they have also been noted to occur with the use of oral opioids, especially in those patients who require chronic opioids for the management of nonmalignant and cancer-associated pain.2,10-13 Epidemiologic data in recent years suggest that up to five million men with chronic nonmalignant pain suffer from opioid-induced androgen deficiency (OPIAD) in the United States.14 Therefore, it is important to understand the physiologic impact of chronic opioid administration in patients. In view of the increasing use of opioids for chronic pain, we must anticipate the potential occurrence of hypogonadism during chronic opioid therapy and monitor patients accordingly. If symptoms of endocrine dysfunction are recognized during chronic opioid therapy, appropriate evaluation, treatment, and follow-up should be instituted. This article describes a case report of a patient who suffered from a clinically significant testosterone deficiency and osteoporosis related to the use of long-term oral opioids for chronic nonmalignant pain. It also includes a review of the existing literature regarding OPIAD and provides recommendations regarding the evaluation and management of OPIAD.
Ultra-rapid opiate detoxification using dexmedetomidine under general anesthesia
Authors: Nasr, MD Dalia Abdelhamid Mohamed , Omran, MD Hani Abdelfattah Said Ahmed , Hakim, MD Sameh Michel , Mansour, MD Waleed Ahmed Abdelrahman
Published: February 2018

Background: In this study, ultra-rapid detoxification using dexmedetomidine under general anesthesia (GA) has been evaluated in preventing the withdrawal symptoms in patients addicted to opioids.Methods: Sixty male patients who were addicted to opioids were assigned to one of the two groups, in which anesthesia was induced and maintained using propofol infusion: group D = treated with dexmedetomidine during anesthesia and for 6 days after recovery from anesthesia; group C = control group treated after recovery from anesthesia with oral dose of lefoxidine 0.2 mg three times daily. Hemodynamic changes and withdrawal symptoms were assessed using Objective Opiate Withdrawal Scale (OOWS) during anesthesia and both the Objective Opiate Withdrawal Scale (OOWS) and Subjective Opiate Withdrawal Scale (SOWS) after recovery from anesthesia. Patient satisfaction was assessed using 101-point verbal rating scale.Results: Hemodynamic data showed that there were statistically significant increases in heart rate and systolic blood pressure during anesthesia in control group. Control group had significantly higher OOWS score on the following 3 days than the dexmedetomidine group, with no significant changes between the two groups from the fourth day till the sixth day except for muscle twitches in the control group on the sixth day (Cd6). Control group had significantly higher SOWS score on the following 4 days than the dexmedetomidine group, with no significant changes between the two groups on the fifth and sixth days except for yawning, nausea, and muscle twitches in control group on the fifth and sixth days (Cd5, Cd6). Patient satisfaction was significantly greater in dexmedetomidine group than in control group.Conclusions: Dexmedetomidine had shown to decrease markedly the withdrawal symptoms when used during ultra-rapid opiate detoxification under GA, and the patients in this group were more satisfied.
Methadone use in children and young adults at a cancer center: A retrospective study
Authors: Anghelescu, MD Doralina L. , Faughnan, RN Lane G. , Hankins, RN Gisele M. , Ward, PharmD Deborah A. , Oakes, RN, CNS Linda L.
Published: February 2018

Objective: To augment the literature on methadone applications in pediatric oncology, the authors reviewed the use of methadone at a pediatric cancer center over a 5-year period.Design and setting: Forty-one patients received methadone for inpatient or outpatient pain management. The authors retrospectively reviewed their demographic characteristics, diagnoses, type of pain (nociceptive, neuropathic, or mixed) and causes of pain, and the indications, dose regimens, adverse effects, and outcomes of methadone treatment.Results: There were four types of clinical uses for methadone in 41 patients (10 patients had two): nociceptive pain unresponsive to other opioids (17 patients, 33.3 percent), neuropathic pain (20 patients, 39.2 percent), facilitation of weaning from opioids (11 patients, 21.6 percent), and end-of-life pain management (3 patients, 5.9 percent). The mean age of the 24 males (58.5 percent) and 17 females (41.5 percent) at the start of treatment was 15.7 years (range, 0.6-23 years). The most common diagnoses were leukemia (n = 10, 24.4 percent), osteosarcoma (n= 7, 17.0 percent), and rhabdomyosarcoma (n = 5, 12.2 percent). The causes of pain were bone marrow transplant (n = 13, 31.7 percent), amputation (n = 6, 14.6 percent), chemotherapy (n = 5, 12.2 percent), tumor (n = 5, 12.2 percent), limb-sparing surgery (n = 4, 9.8 percent), and other (n = 8, 19.5 percent). Efficacy was assessed at the end (or after 6 months) of methadone treatment. For many patients (43.1 percent), methadone showed efficacy in achieving the purpose for which it was prescribed, including reduction of nociceptive or neuropathic pain and prevention of opioid withdrawal. Sedation was the most common side effect (24.4 percent).Conclusions: Methadone was effective for pediatric patients with neuropathic pain or nociceptive pain unresponsive to other opioids, and it effectively prevented opioid withdrawal.
Characteristics of a nontreatment-seeking sample of over-the-counter codeine users: Implications for intervention and prevention
Authors: Nielsen, BPharm, BPharmSc (Hons), PhD Suzanne , Cameron, BA, BSW, MPhil (Social Science Research) Jacqui , Lee, BSc (Hons), GradCertEd (Tertiary), PhD, MAPS Nicole
Published: February 2018

Objectives: Recently, there has been considerable policy and public interest in the availability of over-the-counter (OTC) codeine. Case reports demonstrating severe harm from OTC codeine have been published. However, few studies have examined how people use these products and who develops dependence. The aim of this study was to better understand who develops problematic use of OTC codeine.Design and setting: The authors conducted a web-based survey with people who self-reported OTC codeine use. Eight hundred participants completed the survey that examined codeine use and dependence, pain, and general physical and mental health.Results: Codeine-dependent people differed from nondependent codeine users on a range of characteristics. They were younger, had lower levels of employment and education, and were more likely to report family history of substance dependence. They were more likely to have taken well above recommended doses of OTC codeine and have taken codeine for considerably longer periods of time than recommended. Codeine-dependent people in this study differed markedly from other populations of opioid-dependent people recruited to research in Australia and were more similar to the general population, suggesting that a web-based survey may have reached an under-researched population of opioid-dependent people.Conclusions: How best to use these findings to identify at-risk OTC codeine users requires consideration. Approaches aimed at reducing harm from prescription opioids may be difficult to implement in pharmacy settings. Implications for pharmacists and other health professionals are discussed.
Potency ratio of hydromorphone and diacetylmorphine in substitution treatment for long-term opioid dependency
Authors: Oviedo-Joekes, PhD Eugenia , Marsh, MD David C. , Guh, MSc Daphne , Brissette, MD Suzanne , Schechter, MD, PhD Martin T.
Published: February 2018

Background: Data on conversion ratios for switching opioids in substitution treatment are limited.Methods: Data were obtained from a randomized controlled trial among long-term opioid-dependent patients conducted in Vancouver and Montreal, Canada. Patients received diacetylmorphine (n 115) or hydromorphone (n 25) on a double-blind basis, on a 1:3 potency ratio with individually adjusted dosage, both injectable.Results: Average daily dosages of hydromorphone and diacetylmorphine prescribed were 212.6 mg and 454.0 mg, respectively; potency ratio was 1:2.0-2.2 at different dose ranges.Conclusions: Studies using hydromorphone as a diacetylmorphine equivalent should consider the ratio found in this study to achieve equipotency and maintain the blinding.
Time to include buprenorphine-naloxone combination in the WHO model list of essential medicines
Authors: Balhara, MBBS, MD, DNB, MNAMS Yatan Pal Singh
Published: February 2018

No abstract
The misuse of prescription pain medication and borderline personality symptomatology
Authors: Sansone, MD Randy A. , Watts, MD Daron A. , Wiederman, PhD Michael W.
Published: February 2018

Objective: Despite the known high rates of substance misuse among individuals with borderline personality disorder (BPD), little empirical data are available regarding the explicit nature of such misuse with prescribed pain medications–the focus of the present study.Setting: A primary care outpatient setting, with predominantly resident providers, in a midsized mid-western US city.Patients: Consecutive outpatients who currently or have previously been prescribed pain medication (ie, lifetime pain medication exposure) (n = 185).Main outcome measures: Relationships between BPD, according to two measures, and eight author-developed items reflecting prescription pain medication misuse.Results: With the exception of requesting a prescription for pain medication but not having pain (n.s.), all other measures of prescription pain medication misuse were statistically significantly associated with BPD symptoms. There were also some statistically significant interactions between male gender and BPD symptoms in the prediction of pain medication misuse (ie, mixing prescribed pain medications with drugs to get high, using prescribed pain medication for recreational purposes, and selling prescribed pain medications for money). Conclusions: Individuals with BPD are at risk for misusing prescribed pain medications, and this is especially evident regarding particular forms of misuse among men with BPD symptomatology.
Immediate-release tapentadol or oxycodone for treatment of acute postoperative pain after elective arthroscopic shoulder surgery: A randomized, phase IIIb study
Authors: Vorsanger, PhD, MD Gary J. , Klopfer, BS Angela M. , Xiang, PhD Jim , Benson, MS Carmela J. , Moskovitz, MD Bruce L. , Rosenthal, MD Norman R.
Published: February 2018

Objective: Arthroscopic shoulder surgery can result in substantial postoperative pain. This study evaluated the efficacy and safety of tapentadol immediate release (IR) or oxycodone IR in this setting for the treatment of acute pain.Design: Subjects received tapentadol IR 50 or 100 mg or oxycodone IR 5 or 10 mg every 4-6 hours as needed for pain up to 7 days after arthroscopic shoulder surgery. Twice daily, subjects recorded pain intensity from 0 (no pain) to 10 (pain as bad as you can imagine) and pain relief from 0 (none) to 5 (complete). Final assessments included patient and clinician global impression of change and subject satisfaction with treatment. The primary efficacy endpoint was the sum of pain intensity differences (SPID) over 3 days.Results: Of 378 subjects (192 tapentadol IR, 186 oxycodone IR) who took study medication, 312 (158 tapentadol IR, 154 oxycodone IR) had pain intensity ≥4 before the first dose and were evaluated for efficacy. Mean SPID scores over 3 days were 32.1 and 41.1 in the tapentadol IR and oxycodone IR groups, respectively (least-squares mean difference [95% confidence interval], 9.0 [-18.9, 36.9]; p = 0.527). Secondary analyses of pain intensity, pain relief, and subject satisfaction were similar between groups. Subjects and clinicians reported significantly better global impression of change for tapentadol IR. Adverse events were consistent with established safety profiles for IR opioids.Conclusions: Tapentadol IR and oxycodone IR had similar efficacy for pain after arthroscopic shoulder surgery, but subjects and clinicians reported greater overall improvement with tapentadol IR.
Pharmacokinetic evaluation of tapentadol extended-release tablets in healthy subjects
Authors: Zannikos, PhD Peter N. , Smit, PhD Johan W. , Stahlberg, MD Hans-Jürgen , Wenge, PhD Birger , Hillewaert, MSc Vera M. , Etropolski, MD Mila S.
Published: February 2018

Objective: To evaluate serum pharmacokinetics of tapentadol administered to healthy subjects as extended-release (ER) tablets.Design: Seven single-dose studies (five randomized, crossover, bioequivalence studies; a study in Japanese men; and a randomized, crossover, effects-of-food study) and one repeated-dose study.Setting: Clinical research settings in the United States and The Netherlands.Patients or participants: Healthy males and females were enrolled into seven studies; one study enrolled only Japanese males.Interventions: In the bioequivalence studies, subjects first received one polyethylene oxide- or hypromellose-based tapentadol ER tablet (50, 100, 150, 200, or 250 mg; one dose per study), then (after washout) the other formulation (matching dose). In all other studies, subjects received polyethylene oxide-based tapentadol ER tablets. In the repeated-dose study, subjects received one 250 mg tablet, then (after washout) one 250 mg tablet every 12 hours (five doses). In the food-effect study, subjects received one 250 mg tablet within 30 minutes after a high-fat meal or after 10 hours of fasting. In the study in Japanese men, subjects received one 100 mg tablet.Main outcome measures: Maximum tapentadol concentrations (Cmax) were typically observed 5 hours after dosing. Mean terminal half-life values ranged from 4.4 to 5.9 hours. Tapentadol Cmax and AUC values increased proportionally following single ER (polyethylene oxide-based tablets) doses of 50 to 250 mg. Trough tapentadol concentrations increased during repeat dosing until reaching steady-state by the third dose. Serum Cmax and area under the concentration-time curve (AUC) values at steady state were 1.6 and 1.9 times higher relative to singledose administration. Coadministration of the 250 mg dose with a high-fat meal increased Cmax and AUC values by an average of <17 percent.Conclusions: The pharmacokinetics of tapentadol ER are consistent after repeated and single-dose administration. Tapentadol ER may be administered without regard to food intake. No clinically significant differences were observed in the pharmacokinetics of tapentadol between Japanese and Caucasian subjects.
Analyzing the relationship between nonmedical prescription-opioid use and heroin use
Authors: Ruan, MD Xiulu , Wyche, III, MD Melville Q. , Kaye, MD, PhD Alan David
Published: February 2018

No abstract
The emerging therapeutic roles of κ-opioid agonists
Authors: Jones, MD Mark R. , Kaye, MD, PhD Alan David , Kaye, BA Aaron J. , Urman, MD, MBA Richard D.
Published: February 2018

The current practice of μ-opioid receptor agonists such as morphine as the primary means of acute and chronic pain relief has several dangerous consequences that limit their effectiveness, including respiratory depression, gastrointestinal motility inhibition, addiction, tolerance, and abuse. Several other opioid receptors, notably the κ-opioid (KOP) receptor, have long been known to play a role in pain relief.Recent discoveries and advancements in laboratory techniques have allowed significant developments of KOP agonists as potential novel therapies for pain relief and other pathological processes. These drugs exhibit none of the classic opioid adverse effects and have displayed pronounced analgesia in several different scenarios. New formulations since 2014 have unveiled increased oral bioavailability, exceptional peripheral versus central selectivity, and a positive safety profile. Continued refinements of established κ-opioid agonist formulations have virtually eliminated the centrally mediated side effects of dysphoria and sedation that limited the applicability of previous KOP agonists. Further research is required to better elucidate the potential of these compounds in pain management, as well as in the mediation or modulation of other complex pathophysiological processes as therapeutic agents.
Attitudes toward the Canadian Guideline for Safe and Effective Use of Opioids for Chronic Non-Cancer Pain: A qualitative study
Authors: Chang, MSc Yaping , Zhu Kan Lun , Florez, MD, MSc Ivan D. , Cho, BHSc Sung Min , Zamir, HBSc Nasim , Toma, BESc Augustin , Mirza, MD Reza Donald , Guyatt, MD, MSc Gordon H. , Buckley, MD Norman , Busse, DC, PhD Jason W.
Published: February 2018

Background: Chronic noncancer pain (CNCP) refers to all pain disorders, not due to cancer, that persist for ≥3 months. The point prevalence of CNCP in the general population of Western countries is between 19 and 33 percent. Opioids are commonly prescribed for CNCP and are associated with both benefits and harms. The Canadian Guideline for Safe and Effective Use of Opioids for CNCP was published in 2010 to provide guidance for optimal opioid prescribing in patients with CNCP.Objectives: To investigate the attitudes toward, and use of, the Canadian Opioids Guideline among pain physicians.Design: A qualitative study using one-on-one, semistructured interviews with 12 pain physicians in Ontario, Canada, and thematic analysis of verbatim transcripts.Results: Major themes that emerged from interviews included: (1) generally positive attitudes toward the 2010 Canadian Opioids Guideline, but limited use—half (six of 12) reported they did not use the guideline in practice; (2) strongly contrasting views regarding the 200 mg/d morphine equivalent watchful dose; (3) recognition of gaps in the guideline, especially recommendations for urine drug screening and pain severity-specific therapy; (4) the guideline is excessively long and the format suboptimal; and (5) improved dissemination and education are needed to enhance guideline uptake.Conclusions: Despite its merits, the Canadian Opioids Guideline suffers from information gaps and from limited uptake, at least in part due to suboptimal format and suboptimal dissemination.
Primary care providers’ prescribing practices of opioid controlled substances
Authors: Shields, MD Lisa B. E. , Nasraty, MD, MMM, CPE Soraya , Bell, MSN, RN, CPN Alisha D. , Vinayakan, MD Anil N. , Gudibanda, MD Raghunath S. , Hester, MD, MBA Steven T. , Honaker, MD, FAAP Joshua T.
Published: February 2018

Objective: Prescription opioid abuse poses a significant public health concern. House Bill 1 (HB1) was enacted in 2012 to address prescription drug abuse in Kentucky. The authors investigated the impact of HB1 on primary care providers’ (PCPs) prescribing practices of Schedule II controlled substances. Design: Retrospective evaluation of PCPs’ prescribing practices in an adult outpatient setting.Methods: A review of the prescribing practices for Schedule II controlled substances written by 149 PCPs. The number of prescriptions for Schedule II controlled substances written by 149 PCPs was compared to the top 10 PCP prescribers. Attention was focused on providers who wrote for oxycontin and/or opana and prescriptions with > 90 pills dispensed.Results: The top 10 PCP prescribers accounted for 38.4 percent of the Schedule II controlled substances and 47.8 percent of the Schedule II controlled substances with > 90 pills dispensed. Of the 60 PCPs who prescribed opana and/or oxycontin, the average number of prescriptions was 14.7 compared to 51.0 for the top 10 PCP prescribers. The average percentage of Schedule II controlled substance prescriptions compared to the total number of prescriptions was 27.9 percent for the top 10 PCP prescribers and 7.05 percent of all PCPs. The average percentage of office visits with Schedule II controlled substance prescriptions compared to total office visits was 24.8 percent for the top 10 PCP prescribers versus 7.7 percent for all PCPs.Conclusions: Further scrutiny is warranted to more closely analyze provider opioid prescribing habits and ensure that the providers at our Institution are prescribing Schedule II controlled substances in compliance with HB1.
A 12-week extension study to assess the safety and tolerability of naloxegol in patients with noncancer pain and opioid-induced constipation
Authors: Webster, MD Lynn , Tummala, MD, MBA, MS Raj , Diva, PhD Ulysses , Lappalainen, MD, PhD Jaakko
Published: February 2018

Objective: To compare the long-term safety and tolerability of naloxegol with placebo in patients with opioid-induced constipation (OIC) and noncancer pain. Design: Twelve-week, multicenter, randomized, double-blind, parallel-group phase 3 extension study (KODIAC-07, NCT01395524).Setting: Clinical investigation centers in the United States.Patients: Adult outpatients (N = 302) with confirmed OIC who had completed a 12-week pivotal phase 3 study (KODIAC-04, NCT01309841).Interventions: Daily oral administration of naloxegol (12.5 and 25 mg) or placebo.Main Outcome Measures: Adverse events (AEs), including treatment-related AEs, serious AEs, and AEs of special interest; changes from baseline to week 12 in pain scores, daily opioid dose, and symptoms and quality-of-life measurements. Results: No important new AEs occurred during this extension study compared with KODIAC-04. AEs occurred more frequently with naloxegol 25 mg (41.2 percent) versus naloxegol 12.5 mg (34.0 percent) and placebo (33.0 percent). Treatment-emergent AEs occurring in >5 percent of patients in either naloxegol group during the treatment period were arthralgia (25 mg; 5.2 percent) and diarrhea (12.5 mg; 5.3 percent); two reported AEs attributable to opioid withdrawal syndrome in naloxegol groups were deemed unrelated to study medication. None of the gastrointestinal serious AEs was adjudicated as bowel perforation; one patient (naloxegol 12.5 mg) had an event adjudicated as a major cardiovascular event and was unrelated to study medication. Pain scores and daily opioid dose were unchanged, and improvements in symptoms and quality-of-life observed in KODIAC-04 were maintained throughout the extension study.Conclusion: Naloxegol was generally safe and well tolerated in this 12-week extension study in patients with noncancer pain and OIC.
Tramadol for maintenance in opioid dependence: A retrospective chart revie
Authors: Sarkar, MD, DNB Siddharth , Lal, MD Rakesh , Varshney, MD Mohit , Balhara, MD, DNB, MNAMS Yatan Pal Singh
Published: February 2018

Background and aims: Tramadol is an opioid agonist which can be potentially used for maintenance treatment of patients with opioid use disorders. This chart review presents the characteristics of individuals with an ICD 10 diagnosis of opioid dependence who were maintained on tramadol for a period of at least 6 months.Methods: Records of patients seeking treatment for opioid dependence from the outpatient clinic of the National Drug Dependence Treatment Centre, Ghaziabad, India were screened. One hundred consecutive patients who received tramadol for more than 6 months were included.Results: The sample comprised exclusively of males and had a mean age of 40.9 years. The median dose of tramadol at initiation and continuation was 300 mg/ day. Sixty-two patients achieved complete abstinence during the course of treatment. Greater age, longer duration of opioid use, and better follow-up adherence were associated with abstinent status. The rates of abstinence were higher among those presenting with natural opioid use as compared to others (prescription opioid use or heroin use).Conclusion: Tramadol can be an alternative medication for harm reduction in select group of patients with opioid dependence. Further research is required to strengthen the evidence base of rational use of tramadol for maintenance treatment of patients with opioid dependence.
Evaluating the abuse potential of opioids and abuse-deterrent opioid formulations: A review of clinical study methodology
Authors: Setnik, PhD Beatrice , Schoedel, PhD Kerri A. , Levy-Cooperman, PhD Naama , Shram, PhD Megan , Pixton, MS Glenn C. , Roland, PharmD, MS Carl L.
Published: February 2018

With the development of opioid abuse-deterrent formulations (ADFs), there is a need to conduct well-designed human abuse potential studies to evaluate the effectiveness of their deterrent properties. Although these types of studies have been conducted for many years, largely to evaluate inherent abuse potential of a molecule and inform drug scheduling, methodological approaches have varied across studies. The focus of this review is to describe current “best practices” and methodological adaptations required to assess abuse-deterrent opioid formulations for regulatory submissions. A literature search was conducted in PubMed® to review methodological approaches (study conduct and analysis) used in opioid human abuse potential studies. Search terms included a combination of “opioid,” “opiate,” “abuse potential,” “abuse liability,” “liking,” AND “pharmacodynamic,” and only studies that evaluated single doses of opioids in healthy, nondependent individuals with or without prior opioid experience were included. Seventy-one human abuse potential studies meeting the prespecified criteria were identified, of which 21 studies evaluated a purported opioid ADF. Based on these studies, key methodological considerations were reviewed and summarized according to participant demographics, study prequalification, comparator and dose selection, route of administration and drug manipulation, study blinding, outcome measures and training, safety, and statistical analyses. The authors recommend careful consideration of key elements (eg, a standardized definition of a “nondependent recreational user”), as applicable, and offer key principles and “best practices” when conducting human abuse potential studies for opioid ADFs. Careful selection of appropriate study conditions is dependent on the type of ADF technology being evaluated.
Insights and issues from FDA Advisory Committee meetings on abuse-deterrent opioids
Authors: Miller, MS Christopher J. , Dart, MD Richard C. , Katz, MD, MS Nathaniel P. , Webster, MD, FACPM, FASAM Lynn R.
Published: February 2018

It is the current policy of the US Food and Drug Administration (FDA) to convene expert Advisory Committees to provide input on key regulatory decisions regarding opioid products, including approval and labeling of opioid abuse-deterrent formulations (ADFs). Advisory Committee meetings on ADF opioids consider whether the laboratory and clinical data submitted by the sponsor are sufficient to support marketing approval and labeling of the product with properties expected to deter abuse by specific routes of abuse (ie, oral, intranasal, intravenous). The FDA has typically followed the approval and labeling recommendations for ADFs reviewed by its Advisory Committees, highlighting the importance of these meetings in the regulatory approval process. This review describes common issues considered by Advisory Committees for ADF opioids as well as insights on how to prepare for these meetings based on recent relevant experience and regulatory decisions.