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NKTR-181, a new molecular entity, mu-opioid receptor agonist with an inherently slow rate of central nervous system (CNS) entry, was designed to provide analgesia while reducing abuse potential. This phase 3, enriched-enrollment, randomized-withdrawal trial evaluated the analgesic efficacy, safety, and tolerability of NKTR-181 in patients with chronic low-back pain (CLBP). Adults with moderate-to-severe CLBP refractory to nonopioid analgesics achieving an analgesic NKTR-181 dosage (100-400 mg twice daily) during the open-label titration period were randomized to continued NKTR-181 treatment, double-blind, or switched to placebo. The study was conducted at 55 sites in the United States. Of 1189 patients exposed to NKTR-181 during the titration period, 610 were randomized to NKTR-181 100 to 400 mg every 12 hours or placebo for 12 weeks. The primary outcome measure was change in weekly pain score (scale, 0-10) at 12 weeks from randomization baseline. Secondary outcome measures included responder rates defined by ≥30% and ≥50% improvement in pain score from screening to 12 weeks. Among 610 randomized patients, the mean pain score decreased from 6.73 to 2.32 during open-label titration. After randomization, the least-squares mean change in pain score was +0.92 for NKTR-181 vs +1.46 for placebo (P = 0.002). The ≥30%-improvement responder rate of NKTR-181 vs placebo was 71.2% vs 57.1% (P < 0.001), and the ≥50%-improvement responder rate was 51.1% vs 37.9% (P = 0.001). NKTR-181 was well tolerated with a low incidence (<3%) of CNS-related adverse events during the randomized treatment phase. In patients with moderate-to-severe CLBP, NKTR-181 demonstrated significant analgesic efficacy and a favorable safety/tolerability profile, with a low incidence of CNS adverse events.

Objectives: Two epidemics in the United States are related: opioid drug injection and hepatitis C virus (HCV) infection. This study quantifies the relationship between illicit/prescription drug misuse and HCV infection in 3 population generations: baby boomers (born 1945-1965, inclusive), pre-baby boomers, and post-baby boomers., Methods: This retrospective study included prescription drug consistency (March-December 2015) and HCV (2011-2015) patient test results performed at a large national clinical reference laboratory. HCV positivity, drug use consistency/inconsistency with prescribed drug information, type of inconsistent use, and inconsistent use of individual drug classes were assessed., Results: This study evaluated 39,231 prescription drug monitoring and HCV sets of test results from 18,410 patients. Of these patients, 25.1% tested positive for HCV and 57.3% demonstrated drug test results that were inconsistent with the prescribed medication(s). The types of drug test inconsistency differed substantially between HCV-positive and -negative patients, particularly testing positive for both non-prescribed drugs and prescribed drugs. Specimens from HCV-positive baby boomer and post-baby boomers demonstrated non-prescribed use of opioids and many other drug classes more often than from HCV-negative patients., Conclusions: The rates of inconsistent drug test results and types of drugs misused suggest that HCV-positive patients are more likely than HCV-negative patients to display high-risk behavior, even beyond opioid use. This difference is most pronounced in the post-baby boomer generation. Healthcare professionals should consider these patterns and how they differ by generation when monitoring for both prescription and illicit drugs, the results of which can impact treatment decisions including prescribing analgesics.

Objective: Efficacy and safety of naloxegol, a peripherally acting µ-opioid receptor antagonist that significantly reduces opioid-induced constipation (OIC), were assessed for patient subgroups defined post hoc by baseline maintenance opioid characteristics., Design: Post hoc, pooled analysis of data from two 12-week, randomized, double-blind, placebo-controlled, phase 3 studies., Setting: Two hundred fifty-seven outpatient centers in the United States and Europe., Patients: Patients with noncancer pain and OIC., Interventions: Naloxegol (12.5 or 25 mg daily) or placebo., Main Outcomes Measures: The primary efficacy endpoint was the proportion of patients meeting response criteria at 12 weeks: at least three spontaneous bowel movements (SBMs)/wk and an increase from baseline of at least one SBM for ≥9 of 12 weeks and ≥3 of the last 4 weeks. No adjustments were made for multiplicity; all p values are descriptive., Results: This analysis included 1,337 patients. Increases in the proportion of patients who achieved response at 12 weeks were observed with naloxegol 25 mg versus placebo in patients taking maintenance oxycodone, hydrocodone, morphine, or fentanyl (p ≤ 0.038); patients taking either ≥120 or <120 morphine-equivalent units at baseline (p ≤ 0.032); and patients treated with their current opioid for >6 months (p ≤ 0.035). Efficacy results were less robust with naloxegol 12.5 mg versus placebo. Adverse event incidences were generally comparable across treatment groups, regardless of opioid dose or duration of therapy but were numerically higher with some specific baseline opioids., Conclusion: In this post hoc, exploratory analysis, naloxegol 25 mg showed similar efficacy in treating OIC regardless of maintenance opioid type, dose, or duration of opioid use at baseline.

Objectives: Recently, more than 63% of the 52,404 drug overdose deaths in the United States involved heroin and opioid pain medications. More than 30% of opioid-related deaths also involved benzodiazepines. Previous studies examining the extent of concurrent opioid and benzodiazepine use have relied on prescription data. To gain fuller insight into the extent of the concurrent use problem, we analyzed opioid and benzodiazepine prescription patterns in the context of drug testing results., Methods: All specimens from patients that were prescribed at least 1 drug and were tested for both opioids and benzodiazepines by a national reference laboratory were included. This resulted in an analytical set of 231,228 sets of test results from 144,535 patients with diverse demographic factors being tested in a variety of health care settings., Results: Laboratory test results indicated concurrent use of opioids and benzodiazepines in over 25% of patients. In 52% of test results with evidence of concurrent use, 1 drug class was prescribed and the other was non-prescribed. Nearly 1 in 5 specimens (19%) testing positive for prescribed opioids also tested positive for non-prescribed benzodiazepines. Over 15% of specimens with prescribed benzodiazepines also demonstrated non-prescribed opioid use., Conclusions: The extent of concurrent use of benzodiazepines and opioids, particularly non-prescribed use, suggests the need for more effective clinician assessment and intervention. The results support the Centers for Disease Control and Prevention opioid prescribing guidelines that drug testing occur before and periodically throughout opioid use and suggest that this testing should be extended to patients prescribed benzodiazepines as well.

Background: Extended-release (ER) opioid analgesics are commonly used to provide safe and effective pain relief to treat pain severe enough to require around-the-clock, long-term dosing. These ER opioid formulations usually contain more drug per dosage unit than immediate-release (IR) agents, and therefore bring with them challenges related to both opioid abuse and misuse, often through manipulation of the dosage form. Oxycodone DETERx ® (Xtampza ® ER, Collegium Pharmaceutical, Inc.) is a novel abuse-deterrent, ER formulation developed to deter common methods of manipulation. In addition to having abuse-deterrent properties, oxycodone DETERx was developed to provide alternative modes of administration for patients with chronic pain and difficulty swallowing., Scope: Using published articles, abstracts, and prescribing information, data supporting the use of oxycodone DETERx are reviewed., Findings: Oxycodone DETERx was effective at reducing chronic pain in patients enrolled in a pivotal clinical trial, and had a tolerability profile expected of opioids. In addition to administration of the intact capsule, oxycodone DETERx can also be administered by sprinkling directly into the mouth from a dosing cup, onto soft foods, or through nasogastric or gastrostomy tubes, thus providing flexible dosing options for patients who have difficulty swallowing. In vitro studies demonstrated the reduced ability of oxycodone DETERx to be manipulated by common techniques used by abusers to defeat the ER characteristics or prepare the formulation for injection. Pharmacokinetic studies demonstrated that the ER characteristics of oxycodone DETERx are maintained if chewed or crushed. As a result, oxycodone DETERx is currently the only ER-formulated opioid without a boxed warning against crushing or chewing. Human abuse-potential studies conducted in a population of recreational opioid users demonstrated lower drug-liking scores for oxycodone DETERx administered intranasally and orally when compared with IR oxycodone., Funding: Collegium Pharmaceutical, Inc.

Objectives: To evaluate opioid rescue medication usage and the opioid-sparing effect of low-dose SoluMatrix ® diclofenac developed using SoluMatrix Fine Particle Technology™ in a phase 3 study in patients experiencing pain following bunionectomy surgery., Design: Multicenter, randomized, double-blind, parallel-group study (NCT01462435)., Setting: Four clinical research centers in the United States., Subjects: Four hundred twenty-eight patients aged 18 to 65 years who experienced moderate-to-severe pain following bunionectomy surgery., Methods: Patients were randomized to receive low-dose SoluMatrix diclofenac 35 mg or 18 mg capsules three times daily (35-mg group or 18-mg group), celecoxib 400 mg loading dose followed by 200-mg capsules twice daily (celecoxib 200-mg group), or placebo capsules postsurgery. Patients were permitted to receive opioid-containing rescue medication as needed., Results: Significantly fewer patients who received SoluMatrix diclofenac 35 mg or 18 mg or celecoxib required rescue medication during 0-24 h and >24-48 h postsurgery compared with placebo. Patients in the SoluMatrix diclofenac 35 mg or 18 mg groups or in the celecoxib group used fewer mean rescue medication tablets over 0-24 h and >24-48 h compared with placebo-treated patients. Patients in the SoluMatrix diclofenac 35 mg and 18 mg groups and in the celecoxib group also required rescue medication at later times and at slower rates compared with placebo-treated patients. No serious adverse effects occurred in patients receiving SoluMatrix diclofenac., Conclusions: SoluMatrix diclofenac at two dosage strengths demonstrated an opioid-sparing effect postoperatively in this phase 3 study., Summary: The opioid-sparing effect following low-dose SoluMatrix diclofenac (35 mg or 18 mg three times daily) administration was evaluated in patients experiencing pain following bunionectomy. Significantly fewer patients receiving SoluMatrix diclofenac or celecoxib (400 mg loading, 200 mg twice daily) required rescue medication during 0-24 h and >24-48 h following bunionectomy compared with placebo. No serious adverse events were reported among patients who received SoluMatrix diclofenac. SoluMatrix diclofenac may reduce opioid usage in the postoperative setting in patients with acute pain., (© 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To assess the impact of gabapentin enacarbil on primary and secondary pain endpoints using three data imputation methodologies in a randomized phase II study of adult patients with postherpetic neuralgia., Methods: The primary endpoint was change from baseline to end of maintenance treatment in mean 24-hour average pain intensity score. Secondary endpoints (daytime/nighttime average pain intensity score, daytime/nighttime current pain intensity score, and daytime/nighttime worst pain intensity score) were based on daily electronic diary assessments. Comparisons of each gabapentin enacarbil dose with placebo were performed using three different statistical methodologies: last observation carried forward, baseline observation carried forward, and mixed-effect model for repeated measures., Results: Of the 376 randomized patients, 371 were in the intent-to-treat population (gabapentin enacarbil 1,200 mg, 107; 2,400 mg, 82; 3,600 mg, 87; placebo, 95). For mean 24-hour average pain intensity score, there were statistically significant improvements from baseline to end of maintenance treatment for all gabapentin enacarbil groups vs placebo using the three analysis methods. Significant improvements were also observed for all secondary endpoints with gabapentin enacarbil 1,200 mg using the three analysis methods. Most secondary endpoints also showed improvements following treatment with gabapentin enacarbil 2,400 mg or 3,600 mg compared with placebo., Conclusions: Gabapentin enacarbil (1,200 mg, 2,400 mg, and 3,600 mg) was effective and well tolerated in patients with postherpetic neuralgia compared with placebo, as confirmed by three different and robust statistical methodologies., (© 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Levorphanol is a potent opioid analgesic that was first approved for use in the United States in 1953. Levorphanol is approved for use in moderate to severe pain where an opioid analgesic is appropriate. Levorphanol has a wide range of activities including mu opioid agonism, delta agonism, kappa1 and kappa3 receptor agonism, N-methyl-d-aspartate receptor antagonism and reuptake inhibition of both norepinephrine and serotonin. This multimodal profile might prove effective for pain syndromes that are refractory to other opioid analgesics, such as central and neuropathic pain and opioid-induced hyperalgesia. Levorphanol is well suited as a first-line opioid and can also be used during opioid rotation. It has no known effect on the cardiac QT interval or drug-drug interactions involving hepatic cytochrome P450s enzymes. In these regards, levorphanol may offer a superior safety profile over methadone and other long-acting opioids. Despite its prospective value of multiple mechanisms of action and the potential for treating various types of pain, levorphanol use has been largely supplanted by other recently approved opioids. Its waning use over the years has caused it to be referred to as the "Forgotten Opioid" and resulted in what some consider its underutilization. In fact, levorphanol is relatively unfamiliar to most prescribers. The purpose of this review is to inform practitioners about the attributes of this opioid and reintroduce it to clinicians as an option for treating moderate to severe pain when alternative treatment options are inadequate, not indicated or contraindicated.

Objective: Aims of this consensus panel were to determine (1) an optimal symptom-based method for assessing opioid-induced constipation in clinical practice and (2) a threshold of symptom severity to prompt consideration of prescription therapy., Methods: A multidisciplinary panel of 10 experts with extensive knowledge/experience with opioid-associated adverse events convened to discuss the literature on assessment methods used for opioid-induced constipation and reach consensus on each objective using the nominal group technique., Results: Five validated assessment tools were evaluated: the Patient Assessment of Constipation-Symptoms (PAC-SYM), Patient Assessment of Constipation-Quality of Life (PAC-QOL), Stool Symptom Screener (SSS), Bowel Function Index (BFI), and Bowel Function Diary (BF-Diary). The 3-item BFI and 4-item SSS, both clinician administered, are the shortest tools. In published trials, the BFI and 12-item PAC-SYM are most commonly used. The 11-item BF-Diary is highly relevant in opioid-induced constipation and was developed and validated in accordance with US Food and Drug Administration guidelines. However, the panel believes that the complex scoring for this tool and the SSS, PAC-SYM, and 28-item PAC-QOL may be unfeasible for clinical practice. The BFI is psychometrically validated and responsive to changes in symptom severity; scores range from 0 to 100, with higher scores indicating greater severity and scores >28.8 points indicating constipation., Conclusions: The BFI is a simple assessment tool with a validated threshold of clinically significant constipation. Prescription treatments for opioid-induced constipation should be considered for patients who have a BFI score of ≥30 points and an inadequate response to first-line interventions., (Wiley Periodicals, Inc.)

Objective: Oxycodone DETERx® is an extended-release (ER), microsphere-in-capsule abuse-deterrent-formulation designed to retain its extended-release properties following tampering or misuse (e.g., chewing, crushing). This study assessed the safety and pharmacokinetics of orally administered intact and crushed Oxycodone DETERx® capsules compared with intact and crushed reformulated OxyContin® tablets and crushed immediate-release oxycodone tablets (IR oxycodone)., Methods: This was a randomized, open-label, active-controlled, cross-over study. Healthy subjects received five oxycodone treatments (40 mg) with a standardized high-fat, high-calorie meal: Oxycodone DETERx® (intact or crushed), OxyContin® (intact or crushed), and IR oxycodone (crushed). Blood samples were collected for assessment of oxycodone plasma concentrations., Results: Thirty-eight subjects completed the study. Both crushed and intact Oxycodone DETERx® resulted in lower peak plasma concentrations when compared with IR oxycodone. Crushed Oxycodone DETERx® was bioequivalent to intact Oxycodone DETERx® and exhibited a numerically lower Cmax . Also, median Tmax was unchanged by crushing. In contrast, mean peak plasma oxycodone concentrations for crushed OxyContin® were significantly higher compared with intact OxyContin® and were bioequivalent to IR oxycodone. Median Tmax for crushed OxyContin® was the same as IR oxycodone and 3.25 hours shorter than intact OxyContin®., Conclusions: These data demonstrate that when crushed and taken orally, Oxycodone DETERx® maintains its EXTENDED-release profile, while crushed OxyContin® shows a pharmacokinetic profile similar to an immediate-release product. These results suggest that Oxycodone DETERx® may be less attractive to illicit drug users compared with existing abuse-deterrent-formulations, while providing a safer option for patients who may unknowingly crush their medication such as those who have difficulty swallowing., (Wiley Periodicals, Inc.)

Adverse drug reactions are common and associated with substantial economic and human costs. Particularly among older adult populations, preventable adverse drug reactions are often caused by drug-drug interactions. All analgesics have side effect profiles and many have known drug-drug interactions. Opioids are recognized as a necessary option for managing moderate-to-severe pain, yet many opioid side effects can be enhanced by metabolic interactions within the liver, involving other drugs, diseases, or genetics., (Copyright © 2012 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)

Prescription opioid analgesics are an essential treatment option for patients with moderate to severe pain. Over the last decade the increased medical use of these agents has contributed to a public health epidemic of abuse, addiction, and overdose-related deaths. These medications remain mainstays in both primary care and pain management practices. As palliative services are incorporated at earlier stages of the disease process and the number of individuals with chronic illness increases, palliative care specialists may encounter an increasing number of patients with opioid abuse and addiction problems. Extended-release (ER) and long-acting (LA) opioid formulations are administered to patients with moderate to severe chronic pain requiring around-the-clock analgesia. Given the large quantity of active ingredient contained within some dosage strengths, this medication class is associated with serious risks when taken improperly. In response to growing reports of abuse and overdose deaths, the US Food and Drug Administration (FDA) announced the need for a risk mitigation strategy for the entire class of medication. The class-wide Risk Evaluation and Mitigation Strategy (REMS) for ER/LA opioids will emphasize prescriber training and patient education to ensure that the therapeutic benefits outweigh the risks of addiction, unintentional overdose, and death. As primary care, pain management, and palliative care clinicians often encounter patients who require ER/LA opioids, an understanding of the suggested requirements and potential impact of this regulation is essential.

Background: The introduction of newly formulated extended release (ER) morphine with sequestered naltrexone (Embeda) has provided another treatment option for moderate to severe persistent pain. Embeda was designed to be an abuse-deterrent opioid formulation. Naltrexone is a centrally acting opioid receptor antagonist that blocks the action of opioid. When taken as directed, insignificant amount of sequestered naltrexone would reach systemic circulation, but upon tampering, the released naltrexone may blunt the euphoria of opioids, and possibly precipitate opioid withdrawal in opioid-dependent patient., Objective: To describe a case report ofa 50-year-old opioid-dependent male who developed acute opioid withdrawal after taking crushed Embeda., Case Report: A 50-year-old male with severe, chronic low back pain due to degenerative disc disease was referred to our clinic for pain management. He was taking ER oxycodone 80 mg tid and Roxicodone 30 mg qid prn, with inadequate pain relief A trial of ER oxymorphone was decided, at 40 mg 1-2 doses bid. The patient returned to the clinic 1 week early, out of his ER oxymorphone. At this time, the decision to switch him to Embeda was made, at 80 mg/3.2 mg, 1-2 doses bid. The patient and his family members were counseled about risk involved with tampering with Embeda. A few hours later, our clinic was informed that the patient was brought to emergency room by ambulance, in severe opioid withdrawal. He was treated with IV fluid, antiemetics, clonidine, and IV hydromorphone. His condition improved and he was discharged home the next morning. Later on, the patient admitted that he took two prescribed Embeda within half an hour, the 1st one whole and the 2nd one crushed. He further admitted that he did so against our medical advice. CONCLUSION. Taking tampered Embeda may precipitate opioid withdrawal in opioid-tolerant patient. To the best of our knowledge, this is the first report of induced opioid withdrawal following consumption of crushed Embeda.

Objective: Sensory and motor abnormalities are common among patients with complex regional pain syndrome (CRPS). The purpose of the present study was to define and characterize these abnormalities and to develop a hypothesis regarding the area of the central nervous system from which they derive., Design: Data were acquired from study subjects using clinical examination and quantitative assessment of neurological function. Subjects were divided into four groups. CRPS patients were differentiated into two groups based on the presence or absence of sensory deficit on the face to clinical examination. The other two groups were composed of patients with other chronic pain syndromes and normal individuals without chronic pain or disability. Clinical and quantitative data were compared between groups., Patients: One hundred forty-five CRPS patients, 69 patients with other pain conditions, and 26 normal individuals were studied., Results: A high incidence of trigeminal hypoesthesia was observed in CRPS patients. CRPS patients with trigeminal hypoesthesia manifested bilateral deficits of sensory function, with a predominant hemilateral pattern. These patients also manifested bilateral motor weakness with a more prominent hemiparetic pattern. Both sensory and motor deficits were greatest ipsilateral to the painful side of the body. These features differed significantly from those of CRPS patients lacking clinical trigeminal deficit, other pain patients, and normals. A lower cranial nerve abnormality (sternocleidomastoid weakness) and a myelopathic feature (Hoffman's reflex) were more common in CRPS patients with trigeminal hypoesthesia., Conclusions: Nearly half of CRPS patients had abnormalities of spinothalamic, trigeminothalamic, and corticospinal function that may represent dysfunction of the medulla. One-third of the remaining CRPS patients had neuroimaging evidence of spinal cord or brain pathology. The majority of CRPS patients in this study have measurable abnormalities of the sensory and motor systems or neuroimaging evidence of spinal cord or brain dysfunction.

The tryptophan (TRP) depletion paradigm has been employed to investigate mood and behavioral effects of acutely lowering plasma TRP, and presumably brain serotonin (5-hydroxytryptamine [5-HT]) levels through administration of a special diet and/or amino acid drink. Our goal was to test the assumption that a corresponding fall in central levels of TRP and 5-HT (measured by its major metabolite, 5-hydroxyindoleacetic acid [5-HIAA]) occurs during the standard execution of this method in healthy adult subjects. Three males and two females completed the protocol, which included a one-day low-TRP diet and a TRP-free amino acid drink. Lumbar puncture was performed, with placement of an indwelling catheter connected to a peristaltic pump and fraction collector. Cerebrospinal fluid (CSF) was sampled continuously for a 13.5-hour period (before, during, and after the drink), with fractions removed every 15 minutes. Plasma samples were simultaneously obtained. CSF TRP levels and plasma TRP levels were highly correlated, falling a mean of 92% and 85% from baseline, respectively. CSF nadirs were reached several hours after plasma nadirs. CSF 5-HIAA decreased modestly (24% to 40%, mean 31% change from baseline), with lowest concentrations observed 8-12 hours after the amino acid drink. These data suggest that TRP depletion results in substantial declines in central 5-HT turnover.

We conducted a prospective multi-institutional study of nosocomial and community-acquired pneumonias in 1378 patients admitted to the ICUs of six hospitals. We also investigated 1005 of these patients who were intubated and mechanically ventilated for a reason other than pneumonia, the risk of developing pneumonia, and the relationship between the incidence of pneumonia and the length of time during which the patients were mechanically ventilated. A bacteriologic diagnosis was made in 38% of the nosocomial and 21% of the community-acquired pneumonias. The total mortality rate was 40%; 47% of the patients with nosocomial and 17% of the patients with community-acquired pneumonias died. Because it was difficult to make an etiologic diagnosis in two-thirds of the cases, the treatment had to be based on an assumed causative organism.