Human Abuse Potential of Oral NKTR-181 in Recreational Opioid Users: A Randomized, Double-Blind, Crossover Study.

OBJECTIVE: To evaluate the human abuse potential, pharmacokinetics, pharmacodynamics, and safety of oral NKTR-181 (oxycodegol), a novel full mu-opioid receptor agonist, relative to oral oxycodone. DESIGN: This double-blind, randomized, single-dose, crossover human abuse potential study was conducted in healthy, adult, non-physically dependent recreational opioid users. SETTING: Inpatient clinical research site. SUBJECTS: Seventy-one subjects randomized (95.7% male, 65.2% African American, mean age = 31.7 years). METHODS: The primary objective was to compare two therapeutic doses of NKTR-181 (400 and 600 mg) with 40 and 60 mg of oxycodone and a supratherapeutic dose (1200 mg) of NKTR-181 with 60 mg of oxycodone using visual analog scale (VAS) ratings for Drug Liking "at this moment" (Drug Liking). Secondary objectives included VAS ratings for other subjective measures, and central nervous system (CNS) mu-opioid effects were assessed using pupillometry. Each subject received single oral doses of five treatments and matching placebo. RESULTS: Compared with 40 and 60 mg of oxycodone, the maximum mean Drug Liking score at 400 and 600 mg NKTR-181 was significantly lower, and the rate of onset and extent of Drug Liking for all NKTR-181 doses in the first two hours postdose were also significantly lower. Delayed attenuated Drug Liking and pupillary miosis response following administration of NKTR-181 vs oxycodone were consistent with slower NKTR-181 CNS entry kinetics and mu-opioid receptor binding. No adverse events were rated as severe, and somnolence and dizziness occurred more frequently when subjects received oxycodone. CONCLUSIONS: NKTR-181 at oral doses of 400 and 600 mg showed significantly fewer and less severe subjective effects accepted as representative of opioid abuse potential, such as lower peak Drug Liking in recreational opioid users, than 40 and 60 mg of oxycodone.

Prevalence of depressive symptoms in postmenopausal women with low bone mineral density and/or prevalent vertebral fracture: results from the Multiple Outcomes of Raloxifene Evaluation (MORE) study.

OBJECTIVE: To examine the prevalence of depressive symptoms in a cross-sectional study of postmenopausal women with osteoporosis with and without prevalent vertebral fracture. METHODS: Participants were a subset of English-speaking women (n = 3798, mean age 66.7 yrs) from the Multiple Outcomes of Raloxifene Evaluation trial, who had low bone mineral density (BMD) and/or prevalent vertebral fractures. Vertebral fractures were measured at baseline by radiography using a semiquantitative technique. Depressive symptoms were assessed at baseline using the Geriatric Depression Scale (GDS), a valid and reliable scale for depression screening in elderly patients. Women were considered as probably depressed if > or = 6 symptoms of depression were reported. RESULTS: Postmenopausal women with prevalent vertebral fracture reported more depressive symptoms as assessed by the GDS than women without prevalent vertebral fracture (1.54 vs 1.26; p = 0.001). There was an absolute increase of 2.5% (p = 0.008) in the prevalence of probable depression (GDS score > or = 6) in women with prevalent fracture compared to those without prevalent fracture. The prevalence of probable depression was 4.1% among women without prevalent vertebral fracture and 6.6% in women with a prevalent vertebral fracture. The prevalence of probable depression was 3-fold higher in women with at least 3 prevalent vertebral fractures compared to women without prevalent fracture (12.8% vs 4.1%; p < 0.001). CONCLUSION: Postmenopausal women with prevalent vertebral fractures had greater prevalence of depressive symptoms and probable depression as assessed by the GDS than women without vertebral fracture with low BMD. The dual diagnosis of depression and osteoporosis may mean worse health outcomes. Patients with prevalent vertebral fractures may be considered not only for interventions that address fracture risk reduction, but also for psychosocial interventions that address depressive symptoms.

The impact of incident vertebral and non-vertebral fragility fractures on health-related quality of life in established postmenopausal osteoporosis: results from the teriparatide randomized, placebo-controlled trial in postmenopausal women.

OBJECTIVE: To report the combined impact of both vertebral and non-vertebral fractures on decreased health-related quality of life (HRQOL) in postmenopausal women (mean age 70.7) with osteoporosis who participated in a clinical trial to examine the anti-fracture efficacy of teriparatide [rhPTH(1-34)] injection. METHODS: Patients were randomly assigned to 1 of 3 study arms: placebo, 20 micro g or 40 micro g of teriparatide by daily self-injection. All patients received daily calcium (1000 mg) and vitamin D (400-1200 U) supplements. Patients were followed for a median of 21 months. Incident vertebral fractures were assessed by lateral spinal radiograph. Incident non-vertebral fractures were ascertained by patient self-report and verified by a review of radiological reports. HRQOL was assessed at baseline and annually until study termination using the Osteoporosis Assessment Questionnaire (OPAQ), a validated disease-targeted instrument. RESULTS: Of the 365 women in the HRQOL sub-study, 53 had an incident vertebral or non-vertebral fracture during the study period. Compared to women without incident fractures, women who fractured reported significant declines in physical functioning, emotional status, and symptoms (all p < 0.05). Similarly, when analysis was limited to patients with significant loss in HRQOL, patients with incident fracture accounted for a greater proportion of those patients with decreased physical function, emotional status, and increased symptoms (all p < 0.05). CONCLUSION: Our results confirm and extend previous findings to show that a composite endpoint of incident vertebral and non-vertebral fractures in women with postmenopausal osteoporosis was associated with significant decreases in HRQOL.