Shorter drug testing intervals are associated with improved drug misuse rates.

OBJECTIVE: The Centers for Disease Control and Prevention (CDC) recommend that clinicians prescribing opioids for chronic pain should consider at least annual urine drug testing (UDT). We evaluated whether shorter intervals for repeat UDT are associated with decreased rates of drug misuse. DESIGN: Retrospective analysis of deidentified serial UDT and matched prescribing data. SETTING: We analyzed Quest Diagnostics 2016-2017 UDT results from new patients being monitored for prescription drug adherence, in nonsubstance use disorder (SUD) treatment environments. MAIN OUTCOME MEASURES: Drug misuse was defined as the absence of a prescribed substance or the presence of a nonprescribed substance. Patients with ≥3 sets of the UDT results were included. RESULTS: UDT results from 49,601 patients (148,803 specimens) were tested. Declines in misuse between the first and second UDT were highest for those tested at the shortest intervals: approximately weekly, 19 percent; monthly, 15 percent; bimonthly, 12 percent; quarterly, 9 percent; semiannually, 3 percent; misuse rates increased by 1 percent for patients tested annually. Declines in misuse were more pronounced for opioids than other drug groups. Substantial declines in positivity were noted for heroin (32 percent) and nonprescribed fentanyl (10 percent). Declines in misuse between the second and third UDT followed a similar pattern. CONCLUSIONS: UDT intervals of ≤ quarterly were associated with marked declines, but testing annually or semiannually was not associated with consistent decreases. Our findings suggest that clinical strategies that include serial testing conducted quarterly or sooner may be instrumental in decreasing drug misuse. Testing more frequently than "at least once annually" should be considered by clinicians monitoring potential drug misuse.

Utility of lidocaine as a topical analgesic and improvements in patch delivery systems.

Interest in and use of topical analgesics has been increasing, presumably due to their potential utility for relief of acute and chronic pain. Topically applied agents with analgesic properties can target peripheral nociceptive pathways while minimizing absorption into the plasma that leads to potential systemic adverse effects.Clinical trials have found 5% lidocaine patches to be effective and well tolerated for the treatment of post-herpetic neuralgia (PHN) with a minimal risk of toxicity or drug-drug interactions. With this patch formulation, the penetration of lidocaine into the skin produces an analgesic effect without producing a complete sensory block. Use of topical lidocaine is supported by clinical practice guidelines, including first-line treatment by the American Academy of Neurology (guidelines retired 2018), the European Federation of Neurological Societies and second-line by the Canadian Pain Society.FDA approved 5% lidocaine patches in 1999, and a 1.8% topical lidocaine system in 2018 - both indicated for the treatment of pain secondary to PHN. The 1.8% system offers a more efficient delivery of lidocaine that is bioequivalent to 5% lidocaine patches, but with a 19-fold decrease in drug load (i.e., 36 mg versus 700 mg) as well as superior adhesion that allows the patch to maintain contact with the skin during the 12-h administration period.Although topical lidocaine formulations have advanced over time and play an important role in the treatment of PHN, a variety of other conditions that respond to topical lidocaine have been reported in the literature including PHN, lower back pain, carpal tunnel syndrome, diabetic peripheral neuropathy, and osteoarthritis joint pain. Other neuropathic or nociceptive pain syndromes may respond to topical lidocaine in select cases and warrant further study. Clinicians should consider local anesthetics and other topical agents as part of their multimodal treatments of acute and chronic pain.

Oxycodone DETERx®: A Novel Abuse-Deterrent, Extended-Release Analgesic Option for the Treatment of Patients with Chronic Pain.

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.

SoluMatrix® Diclofenac: Sustained Opioid-Sparing Effects in a Phase 3 Study in Patients with Postoperative Pain.

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.

Impact of Data Imputation Methodology on Pain Assessment over 24 Hours in a Randomized, Placebo-Controlled Study of Gabapentin Enacarbil in Patients with Neuropathic Pain Associated with Postherpetic Neuralgia.

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.

Comparing the Effect of Tampering on the Oral Pharmacokinetic Profiles of Two Extended-Release Oxycodone Formulations with Abuse-Deterrent Properties.

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.

Acute opioid withdrawal precipitated by ingestion of crushed embeda (morphine extended release with sequestered naltrexone): case report and the focused review of the literature.

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.