Tramadol Prescription over a 4-Year Period in the USA.

PURPOSE OF REVIEW: Deaths associated to tramadol, a synthetic opioid, are rising globally. Herein, we characterize prescription patterns of tramadol relative to other opioids in the USA from 2012 to 2015, by geographic region and physician specialty. RECENT FINDINGS: Data on opioid was obtained using Truven Health Analytics MarketScan for the years 2012-2015. Inclusion criteria included subjects living in the USA with ages from 12 to 64 years. Patterns of prescription of tramadol were contrasted with other prescription opioids including hydrocodone, codeine, oxycodone, oxymorphone, methadone, and fentanyl. Between 2012 and 2015, prescriptions for tramadol increased by 22.8%. The absolute rate of prescription varies considerably per region, with tramadol representing nearly 20% of opioid prescriptions in the South, which, in turn, represents nearly 50% of all prescriptions in the USA. Significant differences were seen when comparing prescribers of tramadol with other opioids (p < 0.0001). Tramadol was more frequently prescribed by family practice (40% vs. 32%) and internal medicine physicians (19% vs. 16%). Family medicine, internal medicine, and non-physician prescribers responded by 67.2% of all tramadol prescriptions in 2015. The proportion of patients receiving tramadol from non-physician prescribers increased by 56% between 2012 and 2015 (p < 0.001) IOM. Tramadol prescriptions rates have continuously increased both nationally and throughout all US regions. Important differences exist among regions and physician specialties. These results may be helpful in the creation of regional policies to monitor reasons for this increase and to avoid excessive use of tramadol.

'The public rely on me a lot': Rural pharmacists' perspectives on their roles in oral health care.

OBJECTIVE: To examine rural pharmacists' perspectives on their roles in oral health in rural communities and collaborations with dental practitioners. DESIGN: A qualitative research study using face-to-face, semistructured interviews. Interview data were thematically analysed with the assistance of Nvivo 10. SETTING: Eleven rural communities across rural Tasmania. PARTICIPANTS: Twenty community pharmacists. RESULTS: Five major themes emerged: (i) barriers for patients to access dental services; (ii) oral health presentations to rural pharmacies; (iii) roles of pharmacists in oral health care (subthemes: advice; health promotion; and referrals); (iv) collaborations with dental practitioners; and (v) oral health education and training. CONCLUSION: This study suggests that rural community pharmacists had advisory and referral roles in oral health and acknowledged that they could play a greater role in oral health promotion. It was suggested that oral health could be incorporated into existing pharmacy health promotion and surveillance activities. There was a lack of collaboration between pharmacists and dentists or dental services and limited oral health education and training provided to pharmacists. Stronger collaboration between pharmacists and dental practitioners and better oral health training for pharmacists may enhance their role in promoting oral health within rural communities.

Nutrition therapy recommendations for the management of adults with diabetes.

There is no standard meal plan or eating pattern that works universally for all people with diabetes. In order to be effective, nutrition therapy should be individualized for each patient/client based on his or her individual health goals; personal and cultural preferences; health literacy and numeracy; access to healthful choices; and readiness, willingness, and ability to change. Nutrition interventions should emphasize a variety of minimally processed nutrient dense foods in appropriate portion sizes as part of a healthful eating pattern and provide the individual with diabetes with practical tools for day-to-day food plan and behavior change that can be maintained over the long term.

Efficacy and safety of once-daily treatment with beclomethasone dipropionate nasal aerosol in subjects with seasonal allergic rhinitis.

An aerosol formulation may be preferred by some allergic rhinitis (AR) patients, to avoid the "wet feeling" and nasal runoff associated with aqueous nasal corticosteroid sprays. Beclomethasone dipropionate (BDP) hydrofluoroalkane nasal aerosol is a recently developed, nonaqueous, nonchlorofluorocarbon formulation of BDP for the treatment of AR. This study was designed to evaluate the efficacy, safety, and quality-of-life benefits of BDP nasal aerosol in subjects with seasonal AR (SAR). Eligible subjects (≥12 years of age) enrolled in this 2-week study were randomized to either BDP nasal aerosol at 320 µg/day (n = 169) or placebo (n = 171). Efficacy assessments included reflective and instantaneous total nasal symptom scores (rTNSS and iTNSS, respectively), Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score, reflective and instantaneous total ocular symptom scores (rTOSS and iTOSS, respectively), and physician-assessed total nasal symptom score (PNSS). Safety and tolerability were also assessed. Subjects receiving BDP nasal aerosol showed a significantly greater improvement from baseline in average A.M. and P.M. rTNSS versus placebo (treatment difference, -0.91; 95% confidence interval, -1.3, -0.5; p < 0.001) over 2 weeks of treatment. Greater improvements in rTNSS with BDP nasal aerosol compared with placebo were evident by day 2 and were maintained throughout the treatment period. Similarly, significant improvements were seen with BDP nasal aerosol in iTNSS (p < 0.001) and RQLQ score (p = 0.005) compared with placebo. Treatment with BDP nasal aerosol also resulted in greater improvements in rTOSS (p = 0.002), iTOSS (p = 0.003), and PNSS (p < 0.001) relative to placebo. BDP nasal aerosol was well tolerated and the overall safety profile was similar to placebo. Results from this clinical study indicated that BDP nasal aerosol provided significant AR symptom relief and was well tolerated in patients with SAR with an overall safety profile similar to placebo. Clinicaltrials.gov identifier: NCT01024608.

Once-daily treatment with beclomethasone dipropionate nasal aerosol does not affect hypothalamic-pituitary-adrenal axis function.

BACKGROUND: Intranasal corticosteroids are effective in controlling allergic rhinitis (AR) symptoms; however, chronic administration of corticosteroids may suppress hypothalamic-pituitary-adrenal (HPA)-axis function. OBJECTIVE: To evaluate the effects of 6 weeks of treatment with beclomethasone dipropionate (BDP) hydrofluoroalkane nasal aerosol on HPA-axis function in subjects with perennial AR (PAR). METHODS: In this randomized, double-blind, placebo- and active-controlled study, subjects aged 12 to 45 years were randomized to receive BDP nasal aerosol 320 µg/day (n = 50), placebo (n = 46), or placebo/prednisone (prednisone 10 mg/day for the last 7 days of the treatment period [n = 11]). The primary end point was change from baseline in 24-hour serum cortisol (SC) weighted mean (expressed as geometric mean ratio [GMR]) in the BDP and placebo group after 6 weeks of treatment. RESULTS: Geometric SC-weighted mean values were similar in the BDP and placebo groups at baseline (9.04 and 8.45 µg/dL, respectively) and after 6 weeks (8.18 and 8.01 µg/dL, respectively). After 6 weeks of treatment, BDP was noninferior to placebo with respect to the ratio from baseline in SC-weighted mean (GMR: 0.96 [95% CI: 0.87, 1.06]). In contrast, 7 days of prednisone treatment substantially reduced geometric SC-weighted mean values from baseline (approximate 3-fold reduction [from 7.33 to 2.31 µg/dL]) compared with placebo. BDP nasal aerosol was well tolerated, and the safety profile was similar to that of placebo. CONCLUSION: Treatment with BDP nasal aerosol, 320 µg once daily, was not associated with HPA-axis suppression in adolescent and adult subjects with PAR. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01133626.

Safety and efficacy of once-daily treatment with beclomethasone dipropionate nasal aerosol in subjects with perennial allergic rhinitis.

Intranasal corticosteroids are recommended as first-line therapy for the treatment of the symptoms of persistent allergic rhinitis (AR). Since the phase-out of chlorofluorocarbon nasal aerosols, intranasal corticosteroids have been available only as aqueous nasal sprays. This study was designed to assess the efficacy, safety, and quality-of-life benefits of beclomethasone dipropionate (BDP) hydrofluoroalkane nasal aerosol in subjects with perennial AR (PAR). After a 7- to 21-day placebo run-in period, eligible subjects aged ≥12 years with PAR were randomized to 6 weeks of once-daily treatment with BDP nasal aerosol at 320 µg or placebo. Reflective and instantaneous total nasal symptom scores (rTNSS and iTNSS, respectively), Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score, and physician-assessed total nasal symptom score were evaluated. The primary end point was change from baseline in average morning (A.M.) and evening (P.M.) subject-reported rTNSS over the 6-week treatment period. Safety and tolerability were also assessed. Treatment with BDP nasal aerosol showed significantly greater improvement in average A.M. and P.M. rTNSS compared with placebo (mean treatment difference, -0.84; 95% confidence interval, -1.2, -0.5; p < 0.001). Greater improvements in rTNSS were reported as early as day 1 and were maintained throughout the 6-week treatment period with the exception of day 2. Greater improvements were seen for all four individual nasal symptoms (nasal congestion, nasal itching, rhinorrhea, and sneezing) with BDP nasal aerosol compared with placebo. Similarly, significant improvements were seen in average A.M. and P.M. iTNSS (p < 0.001) and RQLQ score (p = 0.001) with BDP nasal aerosol compared with placebo. In addition, BDP nasal aerosol treatment was well tolerated, and its safety profile was comparable to that of placebo. This clinical study indicated that treatment with BDP nasal aerosol provides statistically significant and clinically meaningful nasal symptom relief accompanied by improved quality of life in subjects with PAR. Additionally, treatment with BDP nasal aerosol was well tolerated with a safety profile comparable to that of placebo. This study was part of the clinical trial NCT01134705 registered in www.ClinicalTrials.gov.

Human abuse potential and cognitive effects of taranabant, a cannabinoid 1 receptor inverse agonist: a randomized, double-blind, placebo- and active-controlled, crossover study in recreational polydrug users.

INTRODUCTION: Taranabant is a cannabinoid 1 receptor inverse agonist that was in development for treatment of obesity. Because of central nervous system effects, the study was performed to assess the abuse potential and cognitive effects of taranabant in recreational polydrug users compared with phentermine, dronabinol, and placebo. METHODS: Stimulant- and cannabis-experienced polydrug users (N = 30) were randomized in a double-blind crossover study to receive taranabant 2, 4, 10, and 20 mg; phentermine 45 and 90 mg; dronabinol 20 mg; and placebo. Subjective and neurocognitive measures were administered for 24 hours, and peak/peak change from baseline effects were analyzed using a linear mixed-effects model. RESULTS: Phentermine 45 and 90 mg showed abuse-related subjective effects versus placebo, including drug liking, overall drug liking, and other positive/stimulant effects, whereas dronabinol 20 mg showed abuse-related positive, cannabis-like, and sedative effects. Taranabant was not significantly different from placebo on most of the subjective measures other than negative/dysphoric effects at the highest dose, and its effects were significantly less pronounced relative to phentermine and dronabinol on most measures. Phentermine improved cognitive/motor performance and dronabinol impaired motor/cognitive performance on some measures, whereas taranabant 4 and 20 mg had minor impairment effects on manual tracking. CONCLUSIONS: The phentermine and dronabinol results demonstrate the validity and sensitivity of the study. Taranabant did not consistently show stimulant/cannabis-like effects or abuse potential in recreational polydrug users, indicating that cannabinoid 1 receptor inverse agonists/antagonists are unlikely to be recreationally abused.

Pharmacokinetic profile of beclomethasone dipropionate hydrofluoroalkane after intranasal administration versus oral inhalation in healthy subjects: results of a single-dose, randomized, open-label, 3-period crossover study.

BACKGROUND: Beclomethasone dipropionate (BDP) is an anti-inflammatory corticosteroid that is rapidly metabolized to the pharmacologically active monoester, beclomethasone-17-monopropionate (17-BMP). Recently, a hydrofluoroalkane (HFA)-propelled nasal aerosol formulation of BDP was developed to treat allergic rhinitis. However, the pharmacokinetic profile of BDP HFA nasal aerosol has not been previously investigated. OBJECTIVE: This study evaluated and compared the systemic levels of 17-BMP and BDP after a single dose of intranasally administered or orally inhaled BDP HFA in healthy subjects. METHODS: In this single-center, randomized, open-label, 3-period crossover study, healthy subjects received single doses of intranasal BDP HFA (80 and 320 µg) and orally inhaled BDP HFA (320 µg). The primary pharmacokinetic parameters assessed were area under the concentration-time curve until the last measurable value (AUC(last)) and C(max) for 17-BMP. For AUC(last) and C(max), point estimates for treatment differences and CIs were calculated on the log scale and then exponentiated to provide estimates of the geometric mean ratios (GMRs) and associated CIs. RESULTS: Thirty subjects were randomized to receive study medication (aged 18-45 years, 66.7% male). Mean plasma concentrations of 17-BMP after intranasal administration of BDP HFA (for both 80- and 320-µg doses) were substantially lower than that of orally inhaled BDP HFA (320 µg) across all time points. Mean AUC(last) values of 17-BMP for intranasal 80 µg, intranasal 320 µg, and orally inhaled 320 µg were 295.8, 1139.7, and 4140.3 pg·hr/mL, respectively. Mean C(max) values were 92.1, 262.7, and 1343.7 pg/mL, respectively. The GMR of AUC(last) for 17-BMP with intranasal BDP HFA 320 µg versus orally inhaled BDP HFA 320 µg was 0.275, indicating substantially lower systemic bioavailability with intranasal administration than with oral inhalation. Similarly, the GMR of AUC(last) for 17-BMP with intranasal BDP HFA 80 µg versus 320 µg was 0.260, suggesting approximate dose proportionality (4-fold difference). Pharmacokinetic results for BDP were similar to those seen for 17-BMP. All doses of intranasal and orally inhaled BDP HFA were well tolerated, and no treatment-related adverse events were reported. CONCLUSIONS: The results of this study suggest that 80 and 320 µg BDP HFA nasal aerosols have substantially lower systemic bioavailability than 320 µg orally inhaled BDP HFA in healthy subjects. All treatments were well tolerated. ClinicalTrials.gov identifier: NCT01537692.

Pharmacokinetics of digoxin in healthy subjects receiving taranabant, a novel cannabinoid-1 receptor inverse agonist.

INTRODUCTION: Interaction studies with digoxin (Lanoxin; GlaxoSmithKline, Research Triangle Park, NC, USA), a commonly prescribed cardiac glycoside with a narrow therapeutic index and a long half-life, are typically required during the development of a new drug, particularly when it is likely that digoxin may be given to patients also treated with the new agent, taranabant--a cannabinoid-1 receptor inverse agonist--for weight loss. This study was designed to establish if this combination of therapy has the potential of a significant pharmacokinetic interaction. METHODS: This open-label, fixed-sequence, two-period study investigated whether taranabant, administered to steady state, affects the well-described single-dose pharmacokinetics of digoxin. During the first period, 12 healthy men and women ranging in age from 21 to 35 years received a single oral dose of digoxin 0.5 mg. Following a 10-day wash out, they started a 19-day taranabant dosing regimen (6 mg once daily from day -14 to day 5) designed to establish and maintain steady-state levels of taranabant. On study day 1, subjects received a single oral dose of digoxin 0.5 mg. The plasma levels of digoxin were followed for an additional 4 days while the dosing of taranabant continued. RESULTS: The geometric mean ratio and 90% confidence intervals for digoxin AUC(0-infinity) were 0.91 (0.83, 0.99), falling within the prespecified comparability intervals (CI) of (0.8, 1.25), which is within the usually allowed interval for bioequivalence. The geometric mean ratio and 90% CI for digoxin maximum plasma concentration (C(max)) were 1.23 (1.09, 1.40). The median time to C(max) was the same for both treatments. CONCLUSION: Multiple doses of 6 mg taranabant do not have a clinically meaningful effect on the pharmacokinetics of a single oral dose of digoxin.

Influence of taranabant, an orally active, highly selective, potent cannabinoid-1 receptor (CB1R) inverse agonist, on ethinyl estradiol and norelgestromin plasma pharmacokinetics.

Taranabant, an orally active, potent, and highly selective CB-1 receptor inverse agonist, is being developed for the treatment of obesity. This randomized, placebo-controlled, multiple-dose, crossover study evaluated the effect of taranabant on the pharmacokinetics of ethinyl estradiol and norelgestromin in healthy women receiving > or =3 months of therapy with oral contraceptives. Nineteen participants with normal menstrual cycles received oral contraceptives on days 1 to 21 during 2 consecutive contraceptive cycles. Participants received taranabant 6 mg/day or placebo on days 1 to 21 of each contraceptive cycle. Plasma samples were collected predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose on day 21 of each cycle for determination of AUC0-24 h and Cmax of ethinyl estradiol and norelgestromin. Lack of a clinically important effect was declared if the 90% confidence intervals for the geometric mean ratio of AUC0-24 h and Cmax in the absence and presence of taranabant were contained within the predefined bounds of (0.8, 1.25). The geometric mean ratios and 90% confidence intervals of ethinyl estradiol and norelgestromin, respectively, were 0.93 (0.87, 1.00) and 1.02 (0.96, 1.09) for AUC0-24 h and 0.95 (0.88, 1.01) and 0.95 (0.88, 1.01) for Cmax. In summary, coadministration of multiple-dose taranabant 6 mg with oral contraceptives did not lead to clinically meaningful alterations in the pharmacokinetic profiles of ethinyl estradiol or norelgestromin.

Influence of taranabant, a cannabinoid-1 receptor inverse agonist, on pharmacokinetics and pharmacodynamics of warfarin.

INTRODUCTION: The pharmacokinetic/pharmacodynamic effects of warfarin were assessed in the presence and absence of taranabant, an orally active, highly selective, potent, cannabinoid-1 receptor inverse agonist, which was being developed for the treatment of obesity. METHODS: Twelve subjects were assigned to two open-label treatments in fixed sequence separated by a 14-day washout. Treatment A was single-dose warfarin 30 mg on day 1. Treatment B was multiple-dose taranabant 6 mg each day for 21 days (days -14 to day 7) with coadministration of singledose warfarin 30 mg on day 1. Blood samples were collected predose and up to 168 hours postdose for assay of R(+)-and S(-)-warfarin and prothrombin time/international normalized ratio (PT/INR). RESULTS: The geometric mean ratios (GMR; warfarin+taranabant/warfarin 90% confidence interval [CI] primary endpoints) for area under the curve (AUC)(0-infinity) for R(+)-and S(-)-warfarin were 1.10 (90% CI: 1.03, 1.18) and 1.06 (90% CI: 1.00, 1.13), respectively. The GMRs (warfarin+taranabant/warfarin) for the maximum plasma concentration (C(max)) of S(-)-and R(+)-warfarin were 1.16 (90% CI: 1.05, 1.28) and 1.17 (90% CI: 1.07, 1.29), respectively. For R(+)-and S(-)-warfarin, the 90% CIs for AUC(0-infinity) GMRs fell within the prespecified bounds. Taranabant did not produce a clinically meaningful effect on PT/INR. CONCLUSION: No clinically significant alterations of the pharmacokinetics of R(+)-and S(-)-warfarin were seen following coadministration of multipledose taranabant 6 mg and single-dose warfarin 30 mg.

Multiple-dose pharmacokinetics, pharmacodynamics, and safety of taranabant, a novel selective cannabinoid-1 receptor inverse agonist, in healthy male volunteers.

Taranabant is a cannabinoid-1 receptor inverse agonist for the treatment of obesity. This study evaluated the safety, pharmacokinetics, and pharmacodynamics of taranabant (5, 7.5, 10, or 25 mg once daily for 14 days) in 60 healthy male subjects. Taranabant was rapidly absorbed, with a median t(max) of 1.0 to 2.0 hours and a t(1/2) of approximately 74 to 104 hours. Moderate accumulation was observed in C(max) (1.18- to 1.40-fold) and AUC(0-24 h) (1.5- to 1.8-fold) over 14 days for the 5-, 7.5-, and 10-mg doses, with an accumulation half-life ranging from 15 to 21 hours. Steady state was reached after 13 days. After multiple-dose administration, plasma AUC(0-24 h) and C(max) of taranabant increased dose proportionally (5-10 mg) and increased somewhat less than dose proportionally for 25 mg. Taranabant was generally well tolerated up to doses of 10 mg and exhibited multiple-dose pharmacokinetics consistent with once-daily dosing.

Designs for single- or multiple-agent phase I trials.

Phase I trials of cytotoxic agents in oncology are usually dose-finding studies that involve a single cytotoxic agent. Many statistical methods have been proposed for these trials, all of which are based on the assumption of a monotonic dose-toxicity curve. For single-agent trials, this is a valid assumption. In many trials, however, investigators are interested in finding the maximally tolerated dose based on escalating multiple cytotoxic agents. When there are multiple agents, monotonicity of the dose-toxicity curve is not clearly defined. In this article we present a design for phase I trials in which the toxicity probabilities follow a partial order, meaning that there are pairs of treatments for which the ordering of the toxicity probabilities is not known at the start of the trial. We compare the new design to existing methods for simple orders and investigate the properties of the design for two partial orders.