Stefan Müller-Lissner, Gabrio Bassotti, Benoit Coffin, Asbjørn Mohr Drewes, Harald Breivik, Elon Eisenberg, Anton Emmanuel, Françoise Laroche, Winfried Meissner, Bart Morlion
Objective: To formulate timely evidence-based guidelines for the management of opioid-induced bowel dysfunction.
Setting: Constipation is a major untoward effect of opioids. Increasing prescription of opioids has correlated to increased incidence of opioid-induced constipation. However, the inhibitory effects of opioids are not confined to the colon, but also affect higher segments of the gastrointestinal tract, leading to the coining of the term "opioid-induced bowel dysfunction."
Methods: A literature search was conducted using Medline, EMBASE, and EMBASE Classic, and the Cochrane Central Register of Controlled Trials. Predefined search terms and inclusion/exclusion criteria were used to identify and categorize relevant papers. A series of statements were formulated and justified by a comment, then labeled with the degree of agreement and their level of evidence as judged by the Strength of Recommendation Taxonomy (SORT) system.
Results: From a list of 10,832 potentially relevant studies, 33 citations were identified for review. Screening the reference lists of the pertinent papers identified additional publications. Current definitions, prevalence, and mechanism of opioid-induced bowel dysfunction were reviewed, and a treatment algorithm and statements regarding patient management were developed to provide guidance on clinical best practice in the management of patients with opioid-induced constipation and opioid-induced bowel dysfunction.
Conclusions: In recent years, more insight has been gained in the pathophysiology of this "entity"; new treatment approaches have been developed, but guidelines on clinical best practice are still lacking. Current knowledge is insufficient regarding management of the opioid side effects on the upper gastrointestinal tract, but recommendations can be derived from what we know at present.
目的针对阿片类药物引起的肠道功能紊乱,及时制定循证管理指南:便秘是阿片类药物的主要不良反应。阿片类药物处方量的增加与阿片类药物引起的便秘发生率增加有关。然而,阿片类药物的抑制作用并不局限于结肠,还会影响胃肠道的更高部位,因此被称为 "阿片类药物引起的肠道功能紊乱":使用 Medline、EMBASE、EMBASE Classic 和 Cochrane Central Register of Controlled Trials 进行文献检索。使用预定义的检索词和纳入/排除标准对相关论文进行识别和分类。然后,根据推荐强度分类法(SORT)系统的判断,制定了一系列声明并通过评论加以说明,然后标注同意程度及其证据级别:从 10,832 项可能相关的研究中,确定了 33 项引文供审查。对相关论文的参考文献目录进行筛选后,还发现了其他出版物。对阿片类药物引起的肠道功能紊乱的当前定义、发病率和机制进行了回顾,并制定了治疗算法和患者管理声明,为阿片类药物引起的便秘和阿片类药物引起的肠道功能紊乱患者的临床最佳治疗方法提供指导:结论:近年来,人们对这一 "实体 "的病理生理学有了更深入的了解;开发了新的治疗方法,但仍缺乏临床最佳实践指南。目前关于阿片类药物对上消化道副作用的管理知识还不够充分,但可以从我们目前所知的知识中得出一些建议。
{"title":"Opioid-Induced Constipation and Bowel Dysfunction: A Clinical Guideline.","authors":"Stefan Müller-Lissner, Gabrio Bassotti, Benoit Coffin, Asbjørn Mohr Drewes, Harald Breivik, Elon Eisenberg, Anton Emmanuel, Françoise Laroche, Winfried Meissner, Bart Morlion","doi":"10.1093/pm/pnw255","DOIUrl":"10.1093/pm/pnw255","url":null,"abstract":"<p><strong>Objective: </strong>To formulate timely evidence-based guidelines for the management of opioid-induced bowel dysfunction.</p><p><strong>Setting: </strong>Constipation is a major untoward effect of opioids. Increasing prescription of opioids has correlated to increased incidence of opioid-induced constipation. However, the inhibitory effects of opioids are not confined to the colon, but also affect higher segments of the gastrointestinal tract, leading to the coining of the term \"opioid-induced bowel dysfunction.\"</p><p><strong>Methods: </strong>A literature search was conducted using Medline, EMBASE, and EMBASE Classic, and the Cochrane Central Register of Controlled Trials. Predefined search terms and inclusion/exclusion criteria were used to identify and categorize relevant papers. A series of statements were formulated and justified by a comment, then labeled with the degree of agreement and their level of evidence as judged by the Strength of Recommendation Taxonomy (SORT) system.</p><p><strong>Results: </strong>From a list of 10,832 potentially relevant studies, 33 citations were identified for review. Screening the reference lists of the pertinent papers identified additional publications. Current definitions, prevalence, and mechanism of opioid-induced bowel dysfunction were reviewed, and a treatment algorithm and statements regarding patient management were developed to provide guidance on clinical best practice in the management of patients with opioid-induced constipation and opioid-induced bowel dysfunction.</p><p><strong>Conclusions: </strong>In recent years, more insight has been gained in the pathophysiology of this \"entity\"; new treatment approaches have been developed, but guidelines on clinical best practice are still lacking. Current knowledge is insufficient regarding management of the opioid side effects on the upper gastrointestinal tract, but recommendations can be derived from what we know at present.</p>","PeriodicalId":19909,"journal":{"name":"Pain Medicine: The Official Journal of the American Academy of Pain Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5914368/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75621271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dear Editor, We appreciate Crudele and colleagues taking the time to read our publication “Comparing the Effect of Tampering on the Oral Pharmacokinetic Profiles of Two Extended-Release Oxycodone Formulations with Abuse-Deterrent Properties” [1], in which the pharmacokinetic (PK) profiles of manipulated Xtampza extended release (ER) were compared with manipulated reformulated OxyContin. We are grateful to the editors for a chance to respond to their comments. Crudele states that the paper “implies that these PK results are supported by comparative pharmacodynamic (drug liking effects) or human abuse potential study data, when such is not the case.” The study in reference (Gudin et al. 2015) [1] did not collect comparative pharmacodynamic data as the differences of the PK results of the manipulated treatment groups were quite compelling and stand on their own: Crushed Xtampza ER (oxycodone) had a PK profile that was bioequivalent to Xtampza ER taken intact (Figure 1A) [1]. This was in contrast to the crushed OxyContin (oxycodone HCl) profile, which was significantly different than OxyContin taken intact and bioequivalent to crushed immediate-release oxycodone tablets (Figure 1B) [1]. The data presented in the referenced study have been recently duplicated in a second study [2] and are …
尊敬的编辑,我们感谢Crudele和同事花时间阅读我们的出版物“比较篡改对两种具有抗滥用特性的羟考酮缓释制剂的口服药代动力学特征的影响”[1],其中比较了操纵Xtampza缓释(ER)和操纵重新配制的奥施康定的药代动力学(PK)特征。我们非常感谢编辑们给我们一个回复他们评论的机会。Crudele指出,这篇论文“暗示这些PK结果得到了比较药效学(药物喜欢效应)或人类滥用潜力研究数据的支持,而事实并非如此。”参考文献中的研究(Gudin et al. 2015)[1]没有收集比较药效学数据,因为操纵处理组的PK结果差异非常明显,并且是独立的:粉碎的Xtampza ER(羟考酮)的PK谱与完整的Xtampza ER具有生物等效性(图1A)[1]。这与压碎后的奥施康定(盐酸羟考酮)的情况形成对比,后者与压碎后的奥施康定完全不同,与压碎后的羟考酮片具有生物等效性(图1B)[1]。参考研究中提供的数据最近在第二项研究中得到了重复[2],并且是…
{"title":"Response to Crudele et al. Commentary on Gudin et al. “Comparing the Effect of Tampering on the Oral Pharmacokinetic Profiles of Two Extended-Release Oxycodone Formulations with Abuse-Deterrent Properties”","authors":"J. Gudin, E. Kopecky, A. Fleming","doi":"10.1093/pm/pnw279","DOIUrl":"https://doi.org/10.1093/pm/pnw279","url":null,"abstract":"Dear Editor,\u0000\u0000We appreciate Crudele and colleagues taking the time to read our publication “Comparing the Effect of Tampering on the Oral Pharmacokinetic Profiles of Two Extended-Release Oxycodone Formulations with Abuse-Deterrent Properties” [1], in which the pharmacokinetic (PK) profiles of manipulated Xtampza extended release (ER) were compared with manipulated reformulated OxyContin. We are grateful to the editors for a chance to respond to their comments.\u0000\u0000Crudele states that the paper “implies that these PK results are supported by comparative pharmacodynamic (drug liking effects) or human abuse potential study data, when such is not the case.” The study in reference (Gudin et al. 2015) [1] did not collect comparative pharmacodynamic data as the differences of the PK results of the manipulated treatment groups were quite compelling and stand on their own: Crushed Xtampza ER (oxycodone) had a PK profile that was bioequivalent to Xtampza ER taken intact (Figure 1A) [1]. This was in contrast to the crushed OxyContin (oxycodone HCl) profile, which was significantly different than OxyContin taken intact and bioequivalent to crushed immediate-release oxycodone tablets (Figure 1B) [1]. The data presented in the referenced study have been recently duplicated in a second study [2] and are …","PeriodicalId":19909,"journal":{"name":"Pain Medicine: The Official Journal of the American Academy of Pain Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84806544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
It was with great interest that we reviewed the article by Rho et al. “Deconstructing Chronic Low Back pain in the Older Adult-Step by Step Evidence and Expert-Based Recommendations for Evaluation and Treatment. Part VIII: Lateral Hip and Thigh Pain” [1]. We applaud the authors for addressing this common issue of lateral hip pain, and their thoughtfulness and evidence supported discussion regarding the diagnosis of greater trochanteric pain syndrome (GTPS) rather than the commonly used and inaccurate term “greater trochanteric bursitis.” The authors nicely review the literature summarizing that there is a lack of findings on MRI and ultrasound, as well as in histological evidence to support the diagnosis of “bursitis” and/or “tendinitis” in the vast majority of these patients. Additionally, we fully agree with the authors’ noting that there is a lack of inflammatory findings in patients suffering from GTPS and that effective treatment consists of strengthening the weak hip abductors that are often noted in these patients. We have found this to be true in the patients we have treated with GTPS. The authors also note the deficiency of evidence for the use of corticosteroid injections and both the potential systemic side effects and the now well-known toxic effects of corticosteroids to tenocytes, which they note “can potentially contribute to progressive tendinopathy and partial tears.”
{"title":"Response to: Rho et al. “Deconstructing Chronic Low Back Pain in the Older Adult-Step by Step Evidence and Expert- Based Recommendations for Evaluation and Treatment. Part VIII: Lateral Hip and Thigh Pain”","authors":"G. Malanga","doi":"10.1093/pm/pnw296","DOIUrl":"https://doi.org/10.1093/pm/pnw296","url":null,"abstract":"It was with great interest that we reviewed the article by Rho et al. “Deconstructing Chronic Low Back pain in the Older Adult-Step by Step Evidence and Expert-Based Recommendations for Evaluation and Treatment. Part VIII: Lateral Hip and Thigh Pain” [1]. We applaud the authors for addressing this common issue of lateral hip pain, and their thoughtfulness and evidence supported discussion regarding the diagnosis of greater trochanteric pain syndrome (GTPS) rather than the commonly used and inaccurate term “greater trochanteric bursitis.” The authors nicely review the literature summarizing that there is a lack of findings on MRI and ultrasound, as well as in histological evidence to support the diagnosis of “bursitis” and/or “tendinitis” in the vast majority of these patients. Additionally, we fully agree with the authors’ noting that there is a lack of inflammatory findings in patients suffering from GTPS and that effective treatment consists of strengthening the weak hip abductors that are often noted in these patients. We have found this to be true in the patients we have treated with GTPS. The authors also note the deficiency of evidence for the use of corticosteroid injections and both the potential systemic side effects and the now well-known toxic effects of corticosteroids to tenocytes, which they note “can potentially contribute to progressive tendinopathy and partial tears.”","PeriodicalId":19909,"journal":{"name":"Pain Medicine: The Official Journal of the American Academy of Pain Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86291091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
N. Crudele, J. Giordano, R. Kapil, Amarita S. Randhawa
• "“It is likely that the ability to retain ER features following manipulation will make it less attractive to abusers compared to existing ADFs. . ."” This statement implies that these PK results are supported by comparative pharmacodynamic (drug liking effects) or human abuse potential study data, when such is not the case. • PK profiles of Xtampza ER and OxyContin were examined when ingested with food, "“as this is a common form of administration in the intended patient population.”" This statement is misleading as it suggests Xtampza can be dosed with or without regard to food, when such is not the case. Xtampza ER can only be taken with carefully modulated complete food intake. Failure to follow this stringent procedure, either by physician or patient, will result in variability in the extent of oxycodone absorption and ultimately impact the safety and efficacy of Xtampza ER. • "“Although results of this study showed some minor differences in the PK profile between intact Oxycodone DETERx and intact OxyContin, the two products were bioequivalent on Cmax, AUClast, and AUCinf.”" Authors fail to clarify that Xtampza ER is not bioequivalent to OxyContin in fasting condition. Stated as such, this statement invites the potential for serious dosing errors with OxyContin.
{"title":"In response to Gudin et al. — Comparing the Effect of Tampering on the Oral Pharmacokinetic Profiles of Two Extended-Release Oxycodone Formulations with Abuse-Deterrent Properties","authors":"N. Crudele, J. Giordano, R. Kapil, Amarita S. Randhawa","doi":"10.1093/pm/pnw278","DOIUrl":"https://doi.org/10.1093/pm/pnw278","url":null,"abstract":"• \"“It is likely that the ability to retain ER features following manipulation will make it less attractive to abusers compared to existing ADFs. . .\"” This statement implies that these PK results are supported by comparative pharmacodynamic (drug liking effects) or human abuse potential study data, when such is not the case. • PK profiles of Xtampza ER and OxyContin were examined when ingested with food, \"“as this is a common form of administration in the intended patient population.”\" This statement is misleading as it suggests Xtampza can be dosed with or without regard to food, when such is not the case. Xtampza ER can only be taken with carefully modulated complete food intake. Failure to follow this stringent procedure, either by physician or patient, will result in variability in the extent of oxycodone absorption and ultimately impact the safety and efficacy of Xtampza ER. • \"“Although results of this study showed some minor differences in the PK profile between intact Oxycodone DETERx and intact OxyContin, the two products were bioequivalent on Cmax, AUClast, and AUCinf.”\" Authors fail to clarify that Xtampza ER is not bioequivalent to OxyContin in fasting condition. Stated as such, this statement invites the potential for serious dosing errors with OxyContin.","PeriodicalId":19909,"journal":{"name":"Pain Medicine: The Official Journal of the American Academy of Pain Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74728493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S. Harris, A. Cipriano, S. Colucci, R. Kapil, P. Geoffroy, T. Hopyan, N. Levy‐Cooperman
Abstract Objectives. A once-daily, extended-release hydrocodone bitartrate tablet with abuse-deterrent properties (Hysingla ER [HYD]) is available for the treatment of chronic pain in appropriate patients. This study evaluated the oral abuse potential and pharmacokinetics (PK) of HYD intact, chewed, or milled to fine particles in comparison with hydrocodone solution or placebo. Design. Single-center, double-blind, randomized, five-period, five-treatment crossover study. Subjects. Healthy adult, nondependent, recreational opioid users. Methods. Forty subjects received orally administered treatments of hydrocodone 60 mg solution, HYD 60 mg intact, HYD 60 mg chewed, HYD 60 mg milled to fine particles, or placebo, separated by a five- to seven-day washout. Assessments over 36 hours postdose included subjective measures of drug liking and willingness to take drug again (assessed using visual analog scales [VAS]), pupillometry, PK, and safety measures. Results. Following oral administration, HYD intact, HYD chewed, and HYD fine particles led to significantly lower “at this moment” drug liking compared with hydrocodone solution. HYD intact and chewed were significantly different from hydrocodone solution on overall drug liking, take drug again, and good effects. Pupil constriction, as measured by pupillometry, occurred later with HYD intact and HYD chewed than with hydrocodone solution. Across treatments (hydrocodone solution, HYD fine particles, HYD chewed, and HYD intact, respectively), mean Cmax and rate of absorption (Cmax/Tmax) values decreased, respectively, and median Tmax values increased, respectively. Safety was consistent with the known effects of opioid agonists. Conclusion. HYD demonstrated reduced oral abuse potential compared with hydrocodone solution in healthy adult, nondependent, recreational opioid users.*
抽象的目标。每日一次,缓释双酒石酸氢可酮片具有滥用威慑性能(Hysingla ER [HYD])可用于治疗慢性疼痛的适当患者。本研究评估了HYD的口服滥用潜力和药代动力学(PK),与氢可酮溶液或安慰剂相比,完整的、咀嚼的或磨成细颗粒的HYD。设计。单中心、双盲、随机、五期、五治疗交叉研究。科目。健康成人,非依赖性,娱乐性阿片类药物使用者。方法。40名受试者接受口服治疗:氢可酮60毫克溶液、HYD 60毫克完整、HYD 60毫克咀嚼、HYD 60毫克磨成细颗粒或安慰剂,通过5至7天的洗脱期分开。服药后36小时的评估包括药物喜好和再次服药意愿的主观测量(使用视觉模拟量表[VAS]评估)、瞳孔测量、PK和安全性措施。结果。与氢可酮溶液相比,口服给药后,HYD完整、HYD咀嚼、HYD细颗粒导致“此时”药物喜爱度明显降低。与氢可酮溶液相比,HYD完整组和咀嚼组在整体药物喜好、再服药、效果均有显著性差异。用瞳孔测量法测得,嚼食HYD组瞳孔收缩时间晚于氢可酮组。不同处理(氢可酮溶液处理、HYD细颗粒处理、HYD咀嚼处理和HYD完整处理),平均Cmax和吸收率(Cmax/Tmax)值分别降低,中位数Tmax值分别升高。安全性与阿片类激动剂的已知作用一致。结论。在健康成人、非依赖性、娱乐性阿片类药物使用者中,与氢可酮溶液相比,HYD的口服滥用可能性降低*
{"title":"Oral Abuse Potential, Pharmacokinetics, and Safety of Once-Daily, Single-Entity, Extended-Release Hydrocodone (HYD) in Recreational Opioid Users","authors":"S. Harris, A. Cipriano, S. Colucci, R. Kapil, P. Geoffroy, T. Hopyan, N. Levy‐Cooperman","doi":"10.1093/pm/pnw208","DOIUrl":"https://doi.org/10.1093/pm/pnw208","url":null,"abstract":"Abstract Objectives. A once-daily, extended-release hydrocodone bitartrate tablet with abuse-deterrent properties (Hysingla ER [HYD]) is available for the treatment of chronic pain in appropriate patients. This study evaluated the oral abuse potential and pharmacokinetics (PK) of HYD intact, chewed, or milled to fine particles in comparison with hydrocodone solution or placebo. Design. Single-center, double-blind, randomized, five-period, five-treatment crossover study. Subjects. Healthy adult, nondependent, recreational opioid users. Methods. Forty subjects received orally administered treatments of hydrocodone 60 mg solution, HYD 60 mg intact, HYD 60 mg chewed, HYD 60 mg milled to fine particles, or placebo, separated by a five- to seven-day washout. Assessments over 36 hours postdose included subjective measures of drug liking and willingness to take drug again (assessed using visual analog scales [VAS]), pupillometry, PK, and safety measures. Results. Following oral administration, HYD intact, HYD chewed, and HYD fine particles led to significantly lower “at this moment” drug liking compared with hydrocodone solution. HYD intact and chewed were significantly different from hydrocodone solution on overall drug liking, take drug again, and good effects. Pupil constriction, as measured by pupillometry, occurred later with HYD intact and HYD chewed than with hydrocodone solution. Across treatments (hydrocodone solution, HYD fine particles, HYD chewed, and HYD intact, respectively), mean Cmax and rate of absorption (Cmax/Tmax) values decreased, respectively, and median Tmax values increased, respectively. Safety was consistent with the known effects of opioid agonists. Conclusion. HYD demonstrated reduced oral abuse potential compared with hydrocodone solution in healthy adult, nondependent, recreational opioid users.*","PeriodicalId":19909,"journal":{"name":"Pain Medicine: The Official Journal of the American Academy of Pain Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88297222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Michael D. Smith, L. Webster, J. Lawler, K. Lindhardt, J. Dayno
Objective. To compare the relative human abuse potential of intact and manipulated morphine abuse-deterrent, extended-release injection-molded tablets (morphine-ADER-IMT) with that of marketed morphine sulfate ER tablets Methods. This randomized, double-blind, triple-dummy, active- and placebo-controlled, 4-way crossover, single-center study included adult volunteers who were experienced, nondependent, recreational opioid users. Participants were randomized 1:1:1:1 to placebo, morphine-ADER-IMT (60 mg, intact), morphine-ADER-IMT (60 mg, manipulated), and morphine ER (60 mg, manipulated) and received 1 dose of each oral agent in crossover fashion, separated by ≥5 days. Pharmacodynamic and pharmacokinetic endpoints were assessed, including the primary endpoint of peak effect of Drug Liking (Emax) via Drug Liking Visual Analog Scale (VAS) score and the secondary endpoints of time to Emax (TEmax) and mean abuse quotient (AQ; a pharmacokinetic parameter associated with drug liking). Results. Thirty-eight participants completed the study. Median Drug Liking VAS Emax was significantly lower after treatment with manipulated morphine-ADER-IMT (67) compared with manipulated morphine ER (74; P = 0.007). TEmax was significantly shorter after treatment with manipulated morphine ER compared with intact (P < 0.0001) or manipulated (P = 0.004) morphine-ADER-IMT. Mean AQ was lower after treatment with intact (5.7) or manipulated (16.4) morphine-ADER-IMT compared with manipulated morphine ER (45.9). Conclusions. Manipulated morphine-ADER-IMT demonstrated significantly lower Drug Liking Emax compared with manipulated morphine ER when administered orally. Morphine-ADER-IMT would be an important new AD, ER morphine product with lower potential for unintentional misuse by chewing or intentional manipulation for oral abuse than currently available non-AD morphine ER products.
{"title":"Human Abuse Potential of an Abuse-Deterrent (AD), Extended-Release (ER) Morphine Product Candidate (Morphine-ADER Injection-Molded Tablets) versus Extended-Release Morphine Administered Orally in Nondependent Recreational Opioid Users","authors":"Michael D. Smith, L. Webster, J. Lawler, K. Lindhardt, J. Dayno","doi":"10.1093/pm/pnw174","DOIUrl":"https://doi.org/10.1093/pm/pnw174","url":null,"abstract":"Objective. To compare the relative human abuse potential of intact and manipulated morphine abuse-deterrent, extended-release injection-molded tablets (morphine-ADER-IMT) with that of marketed morphine sulfate ER tablets Methods. This randomized, double-blind, triple-dummy, active- and placebo-controlled, 4-way crossover, single-center study included adult volunteers who were experienced, nondependent, recreational opioid users. Participants were randomized 1:1:1:1 to placebo, morphine-ADER-IMT (60 mg, intact), morphine-ADER-IMT (60 mg, manipulated), and morphine ER (60 mg, manipulated) and received 1 dose of each oral agent in crossover fashion, separated by ≥5 days. Pharmacodynamic and pharmacokinetic endpoints were assessed, including the primary endpoint of peak effect of Drug Liking (Emax) via Drug Liking Visual Analog Scale (VAS) score and the secondary endpoints of time to Emax (TEmax) and mean abuse quotient (AQ; a pharmacokinetic parameter associated with drug liking). Results. Thirty-eight participants completed the study. Median Drug Liking VAS Emax was significantly lower after treatment with manipulated morphine-ADER-IMT (67) compared with manipulated morphine ER (74; P = 0.007). TEmax was significantly shorter after treatment with manipulated morphine ER compared with intact (P < 0.0001) or manipulated (P = 0.004) morphine-ADER-IMT. Mean AQ was lower after treatment with intact (5.7) or manipulated (16.4) morphine-ADER-IMT compared with manipulated morphine ER (45.9). Conclusions. Manipulated morphine-ADER-IMT demonstrated significantly lower Drug Liking Emax compared with manipulated morphine ER when administered orally. Morphine-ADER-IMT would be an important new AD, ER morphine product with lower potential for unintentional misuse by chewing or intentional manipulation for oral abuse than currently available non-AD morphine ER products.","PeriodicalId":19909,"journal":{"name":"Pain Medicine: The Official Journal of the American Academy of Pain Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86051712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-06-01Epub Date: 2015-12-14DOI: 10.1093/pm/pnv020
Lynn R Webster, Ernest A Kopecky, Michael D Smith, Alison B Fleming
Objective: Evaluate the human abuse potential (HAP) of an experimental, microsphere-in-capsule formulation of extended-release oxycodone (oxycodone DETERx®) (herein "DETERx").
Subjects: There were 39 qualifying subjects (72% male, 85% white, mean age of 27 years) with 36 completing all four Double-blind Treatment Periods.
Methods: The four phases encompassed: 1) Screening; 2) Drug Discrimination; 3) Double-blind Treatment; and 4) Follow-up. Drug Discrimination tests ensured that subjects could distinguish placebo from opioid. The four Double-blind Treatments compared DETERx-administered as either a crushed intranasal (IN) or an intact oral (PO) preparation-with immediate-release oxycodone IN (OXY-IR IN) and with an intact IN and PO placebo DETERx control.
Results: For primary pharmacokinetic (PK) assessments, abuse quotient (Cmax/Tmax) was lower with DETERx IN than DETERx PO; both treatments were substantially lower than OXY-IR IN (6.24, 8.60, and 69.6 ng/mL/h, respectively). For drug liking, the primary subjective pharmacodynamic (PD) endpoint, both DETERx IN and DETERx PO produced significantly lower scores than OXY-IR IN (P ≤ 0.0001 for each); DETERx IN was less liked than DETERx PO (P ≤ 0.05), mirroring the PK relationships. Objectively assessed pupillometry corroborated the more rapid and significantly greater effect of OXY-IR IN than either DETERx IN or DETERx PO (P ≤ 0.007 for each). Overall safety profiles of DETERx and OXY-IR were comparable and both were well tolerated.
Conclusions: Pharmacokinetic and pharmacodynamic outcomes suggest that DETERx IN has relatively low HAP; continued research in larger populations is suggested.
目的:评估缓释羟考酮(羟考酮 DETERx®)(以下简称 "DETERx")实验性微球胶囊制剂的人体滥用潜力(HAP):随机、双盲、双假、阳性和安慰剂对照、单剂量、四阶段、四疗程、交叉研究:受试者共有 39 名合格受试者(72% 为男性,85% 为白人,平均年龄为 27 岁),其中 36 人完成了全部四个双盲治疗期:四个阶段包括1)筛选;2)药物辨别;3)双盲治疗;4)随访。药物鉴别测试确保受试者能够区分安慰剂和阿片类药物。四次双盲治疗将 DETERx(以压碎的鼻内(IN)或完整的口服(PO)制剂给药)与速释羟考酮 IN(OXY-IR IN)以及完整的 IN 和口服安慰剂 DETERx 对照组进行了比较:在主要药代动力学(PK)评估中,DETERx IN 的滥用商数(Cmax/Tmax)低于 DETERx PO;两种疗法的滥用商数(Cmax/Tmax)均大大低于 OXY-IR IN(分别为 6.24、8.60 和 69.6 纳克/毫升/小时)。在药物喜欢度(主要的主观药效学终点)方面,DETERx IN 和 DETERx PO 的得分均显著低于 OXY-IR IN(各 P ≤ 0.0001);DETERx IN 的喜欢度低于 DETERx PO(P ≤ 0.05),反映了 PK 关系。客观评估的瞳孔测量法证实,OXY-IR IN 比 DETERx IN 或 DETERx PO 的作用更迅速且明显更大(P 均≤ 0.007)。DETERx 和 OXY-IR 的总体安全性相当,耐受性良好:结论:药代动力学和药效学结果表明,DETERx IN 的 HAP 相对较低;建议继续在更大的人群中进行研究。
{"title":"A Randomized, Double-Blind, Double-Dummy Study to Evaluate the Intranasal Human Abuse Potential and Pharmacokinetics of a Novel Extended-Release Abuse-Deterrent Formulation of Oxycodone.","authors":"Lynn R Webster, Ernest A Kopecky, Michael D Smith, Alison B Fleming","doi":"10.1093/pm/pnv020","DOIUrl":"10.1093/pm/pnv020","url":null,"abstract":"<p><strong>Objective: </strong>Evaluate the human abuse potential (HAP) of an experimental, microsphere-in-capsule formulation of extended-release oxycodone (oxycodone DETERx®) (herein \"DETERx\").</p><p><strong>Design: </strong>Randomized, double-blind, double-dummy, positive- and placebo-controlled, single-dose, four-phase, four-treatment, crossover study.</p><p><strong>Setting: </strong>Clinical research site.</p><p><strong>Subjects: </strong>There were 39 qualifying subjects (72% male, 85% white, mean age of 27 years) with 36 completing all four Double-blind Treatment Periods.</p><p><strong>Methods: </strong>The four phases encompassed: 1) Screening; 2) Drug Discrimination; 3) Double-blind Treatment; and 4) Follow-up. Drug Discrimination tests ensured that subjects could distinguish placebo from opioid. The four Double-blind Treatments compared DETERx-administered as either a crushed intranasal (IN) or an intact oral (PO) preparation-with immediate-release oxycodone IN (OXY-IR IN) and with an intact IN and PO placebo DETERx control.</p><p><strong>Results: </strong>For primary pharmacokinetic (PK) assessments, abuse quotient (Cmax/Tmax) was lower with DETERx IN than DETERx PO; both treatments were substantially lower than OXY-IR IN (6.24, 8.60, and 69.6 ng/mL/h, respectively). For drug liking, the primary subjective pharmacodynamic (PD) endpoint, both DETERx IN and DETERx PO produced significantly lower scores than OXY-IR IN (P ≤ 0.0001 for each); DETERx IN was less liked than DETERx PO (P ≤ 0.05), mirroring the PK relationships. Objectively assessed pupillometry corroborated the more rapid and significantly greater effect of OXY-IR IN than either DETERx IN or DETERx PO (P ≤ 0.007 for each). Overall safety profiles of DETERx and OXY-IR were comparable and both were well tolerated.</p><p><strong>Conclusions: </strong>Pharmacokinetic and pharmacodynamic outcomes suggest that DETERx IN has relatively low HAP; continued research in larger populations is suggested.</p>","PeriodicalId":19909,"journal":{"name":"Pain Medicine: The Official Journal of the American Academy of Pain Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4894244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90596634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Objective. The increasing incidence of cancer survivorship has shifted treatment of cancer-related pain from short-term analgesia to long-term chronic pain management. As a result, alternatives to oral analgesics, such as intrathecal therapy, may be beneficial for patients with cancer-related pain. The authors review the use of intrathecal therapy in the management of cancer-related pain. Methods. The Medline database was searched for English-language articles that included “ziconotide” or “morphine” AND (“cancer” OR “malignant”) AND “intrathecal” in title or abstract. Available abstracts from scientific congresses in the areas of neuromodulation and oncology were also reviewed. Results. Intrathecal therapy provides pain relief with reduced systemic concerns in patients with cancer-related pain. Patients should undergo multidisciplinary evaluation and, in most cases, drug trialing before intrathecal pump implantation. Morphine, an opioid (µ-opioid receptor antagonist), and ziconotide, a nonopioid (selective N-type calcium channel inhibitor), are both approved for intrathecal analgesia; however, tolerance and safety concerns may deter the use of intrathecal morphine. Ziconotide has also shown efficacy for reduction of cancer-related pain; however, proper dosing and titration must be used to prevent adverse events. There is little information available on use of intrathecal therapies specifically in cancer survivors. Conclusions. Treatment of cancer-related pain has shifted toward chronic pain management strategies, especially among cancer survivors. Intrathecal therapy provides an alternate route of administration of chronic pain medications (e.g., morphine and ziconotide) for cancer patients with and without active disease, although additional research is needed to support effectiveness in cancer survivors.
{"title":"Intrathecal Therapy for Cancer-Related Pain","authors":"B. Bruel, A. Burton","doi":"10.1093/pm/pnw060","DOIUrl":"https://doi.org/10.1093/pm/pnw060","url":null,"abstract":"Objective. The increasing incidence of cancer survivorship has shifted treatment of cancer-related pain from short-term analgesia to long-term chronic pain management. As a result, alternatives to oral analgesics, such as intrathecal therapy, may be beneficial for patients with cancer-related pain. The authors review the use of intrathecal therapy in the management of cancer-related pain. Methods. The Medline database was searched for English-language articles that included “ziconotide” or “morphine” AND (“cancer” OR “malignant”) AND “intrathecal” in title or abstract. Available abstracts from scientific congresses in the areas of neuromodulation and oncology were also reviewed. Results. Intrathecal therapy provides pain relief with reduced systemic concerns in patients with cancer-related pain. Patients should undergo multidisciplinary evaluation and, in most cases, drug trialing before intrathecal pump implantation. Morphine, an opioid (µ-opioid receptor antagonist), and ziconotide, a nonopioid (selective N-type calcium channel inhibitor), are both approved for intrathecal analgesia; however, tolerance and safety concerns may deter the use of intrathecal morphine. Ziconotide has also shown efficacy for reduction of cancer-related pain; however, proper dosing and titration must be used to prevent adverse events. There is little information available on use of intrathecal therapies specifically in cancer survivors. Conclusions. Treatment of cancer-related pain has shifted toward chronic pain management strategies, especially among cancer survivors. Intrathecal therapy provides an alternate route of administration of chronic pain medications (e.g., morphine and ziconotide) for cancer patients with and without active disease, although additional research is needed to support effectiveness in cancer survivors.","PeriodicalId":19909,"journal":{"name":"Pain Medicine: The Official Journal of the American Academy of Pain Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77442637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
L. Webster, D. Gruener, Todd Kirby, Q. Xiang, E. Tzanis, A. Finn
Objective Assess whether patients with chronic pain receiving 80 to 220 mg oral morphine sulfate equivalent of a full μ-opioid agonist could be transitioned to buccal buprenorphine at approximately 50% of their full dose without inducing opioid withdrawal or sacrificing analgesic efficacy. Methods. A randomized, double-blind, double-dummy, active-controlled, two-period crossover study in adult patients receiving around-the-clock full opioid agonist therapy and confirmed to be opioid dependent by naloxone challenge. Study doses were substituted at the time of the regular dose schedule for each patient. The primary endpoint was the proportion of patients with a maximum Clinical Opiate Withdrawal Scale score ≥ 13 (moderate withdrawal) or use of rescue medication. Results. 35 subjects on ≥ 80 mg morphine sulfate equivalent per day were evaluable for opioid withdrawal. One patient during buccal buprenorphine treatment and two during 50% full μ-opioid agonist treatment experienced opioid withdrawal of at least moderate intensity. The mean maximum Clinical Opiate Withdrawal Scale scores were similar, and numerically lower on buccal buprenorphine. There were no significant differences in pain ratings between treatments. The most frequent adverse events with buccal buprenorphine were headache (19%), vomiting (13%), nausea, diarrhea, and drug withdrawal syndrome (each 9%), and with full μ-opioid agonist were headache (16%), drug withdrawal syndrome (13%), and nausea (6%). Conclusions. Chronic pain patients treated with around-the-clock full μ-opioid agonist therapy can be switched to buccal buprenorphine (a partial μ-opioid agonist) at approximately 50% of the full μ-opioid agonist dose without an increased risk of opioid withdrawal or loss of pain control.
{"title":"Evaluation of the Tolerability of Switching Patients on Chronic Full μ-Opioid Agonist Therapy to Buccal Buprenorphine","authors":"L. Webster, D. Gruener, Todd Kirby, Q. Xiang, E. Tzanis, A. Finn","doi":"10.1093/pm/pnv110","DOIUrl":"https://doi.org/10.1093/pm/pnv110","url":null,"abstract":"Objective Assess whether patients with chronic pain receiving 80 to 220 mg oral morphine sulfate equivalent of a full μ-opioid agonist could be transitioned to buccal buprenorphine at approximately 50% of their full dose without inducing opioid withdrawal or sacrificing analgesic efficacy. Methods. A randomized, double-blind, double-dummy, active-controlled, two-period crossover study in adult patients receiving around-the-clock full opioid agonist therapy and confirmed to be opioid dependent by naloxone challenge. Study doses were substituted at the time of the regular dose schedule for each patient. The primary endpoint was the proportion of patients with a maximum Clinical Opiate Withdrawal Scale score ≥ 13 (moderate withdrawal) or use of rescue medication. Results. 35 subjects on ≥ 80 mg morphine sulfate equivalent per day were evaluable for opioid withdrawal. One patient during buccal buprenorphine treatment and two during 50% full μ-opioid agonist treatment experienced opioid withdrawal of at least moderate intensity. The mean maximum Clinical Opiate Withdrawal Scale scores were similar, and numerically lower on buccal buprenorphine. There were no significant differences in pain ratings between treatments. The most frequent adverse events with buccal buprenorphine were headache (19%), vomiting (13%), nausea, diarrhea, and drug withdrawal syndrome (each 9%), and with full μ-opioid agonist were headache (16%), drug withdrawal syndrome (13%), and nausea (6%). Conclusions. Chronic pain patients treated with around-the-clock full μ-opioid agonist therapy can be switched to buccal buprenorphine (a partial μ-opioid agonist) at approximately 50% of the full μ-opioid agonist dose without an increased risk of opioid withdrawal or loss of pain control.","PeriodicalId":19909,"journal":{"name":"Pain Medicine: The Official Journal of the American Academy of Pain Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82468132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dear Editor, The recognition of needle entry into an epidural space is a pivotal moment in cervical, thoracic, or lumbar epidural injections. Its significance cannot be overestimated. Regardless of how experienced you are, realizing that you are approaching an epidural space makes your heart beat faster. The safety of the procedure and its success rate depends upon proper and reliable identification of the needle entering into the epidural space. Recent advances in our understanding of fluoroscopic guidance allow pain practitioners to safely place the needle close to the ventral interlaminar line (VILL) [1–4]. However, recognition of the needle exiting the ligamentum flavum and entering into the epidural space was until now performed with the art of the loss of resistance technique (LORT). To rely upon LORT, a practitioner has to master his tactile sensation of change in resistance to the level of …
{"title":"Contrast Spread Technique: Evolution","authors":"Y. Perper","doi":"10.1093/pm/pnv100","DOIUrl":"https://doi.org/10.1093/pm/pnv100","url":null,"abstract":"Dear Editor,\u0000\u0000The recognition of needle entry into an epidural space is a pivotal moment in cervical, thoracic, or lumbar epidural injections. Its significance cannot be overestimated. Regardless of how experienced you are, realizing that you are approaching an epidural space makes your heart beat faster. The safety of the procedure and its success rate depends upon proper and reliable identification of the needle entering into the epidural space. Recent advances in our understanding of fluoroscopic guidance allow pain practitioners to safely place the needle close to the ventral interlaminar line (VILL) [1–4]. However, recognition of the needle exiting the ligamentum flavum and entering into the epidural space was until now performed with the art of the loss of resistance technique (LORT). To rely upon LORT, a practitioner has to master his tactile sensation of change in resistance to the level of …","PeriodicalId":19909,"journal":{"name":"Pain Medicine: The Official Journal of the American Academy of Pain Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80492108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}