Tramadol/dexketoprofen (TRAM/DKP) compared with tramadol/paracetamol in moderate to severe acute pain: results of a randomised, double-blind, placebo and active-controlled, parallel group trial in the impacted third molar extraction pain model (DAVID study)

Objectives: To compare efficacy/safety of oral tramadol 75 mg/dexketoprofen 25 mg (TRAM/DKP) and TRAM 75 mg/paracetamol 650 mg (TRAM/paracetamol) in moderate to severe pain following surgical removal of impacted lower third molar. Design: Multicentre, randomised, double-blind, placebo-controlled, phase IIIb study. Participants: Healthy adult patients scheduled for surgical extraction of at least one fully/partially impacted lower third molar requiring bone manipulation. 654 patients were randomised and 653 were eligible for analysis. Interventions: Surgery was performed under local anaesthetic. No sedation was permitted. Patients rated pain intensity (PI) using an 11-Numerical Rating Scale (NRS) (0 no pain; 10 worst pain). Participants experiencing moderate/severe pain (≥4) within 4 hours of surgery were randomised (2:2:1 ratio) to a single oral dose of TRAM/DKP 75/25 mg, TRAM/paracetamol 75/650 mg or placebo. Main outcome measures: Efficacy was based patients' electronic diaries. Analgesia and pain were recorded as follows: pain relief (PAR) on a 5-point Verbal Rating Scale (0='no relief', 1='a little (perceptible) relief', 2='some (meaningful) relief', 3='lot of relief', 4='complete relief') at the predefined postdose time points t15 min, t30 min, t1 hour, t1.5 hour, t2 hour, t4 hour, t6 hour and t8 hour and PI on the 11-point NRS at t0 and at the same predefined postdose time points. Onset of analgesia documented using double stopwatch method over a 2-hour period. Primary endpoint was total pain relief over 6 hours (TOTPAR6). Rescue medication was available during the treatment period. Results: TRAM/DKP was superior to TRAM/paracetamol and placebo at the primary endpoint TOTPAR6 (p<0.0001). Mean (SD) TOTPAR6 in the TRAM/DKP group was 13 (6.97), while those in the active control and placebo groups were 9.2 (7.65) and 1.9 (3.89), respectively. Superiority of TRAM/DKP over active comparator and placebo was observed at all secondary endpoints. Incidence of adverse events was comparable between active groups. Conclusions: TRAM/DKP (75/25 mg) is effective and superior to TRAM/paracetamol (75/650 mg) in relieving moderate to severe acute pain following surgical removal of impacted lower third molar, with a faster onset of action, greater and durable analgesia, together with a favourable safety profile

Dexketoprofen/tramadol: randomised double-blind trial and confirmation of empirical theory of combination analgesics in acute pain

Background: Combination analgesics are effective in acute pain, and a theoretical framework predicts efficacy for combinations. The combination of dexketoprofen and tramadol is untested, but predicted to be highly effective. Methods: This was a randomised, double-blind, double-dummy, parallel-group, placebo-controlled, single-dose trial in patients with moderate or severe pain following third molar extraction. There were ten treatment arms, including dexketoprofen trometamol (12.5 mg and 25 mg) and tramadol hydrochloride (37.5 mg and 75 mg), given as four different fixed combinations and single components, with ibuprofen 400 mg as active control as well as a placebo control. The study objective was to evaluate the superior analgesic efficacy and safety of each combination and each single agent versus placebo. The primary outcome was the proportion of patients with at least 50 % max TOTPAR over six hours. Results: 606 patients were randomised and provided at least one post-dose assessment. All combinations were significantly better than placebo. The highest percentage of responders (72 %) was achieved in the dexketoprofen trometamol 25 mg plus tramadol hydrochloride 75 mg group (NNT 1.6, 95 % confidence interval 1.3 to 2.1). Addition of tramadol to dexketoprofen resulted in greater peak pain relief and greater pain relief over the longer term, particularly at times longer than six hours (median duration of 8.1 h). Adverse events were unremarkable. Conclusions: Dexketoprofen trometamol 25 mg combined with tramadol hydrochloride 75 mg provided good analgesia with rapid onset and long duration in a model of moderate to severe pain. The results of the dose finding study are consistent with pre-trial calculations based on empirical formulae

Changes in neuroactive steroid secretion associated with CO2-induced panic attacks in normal individuals

Neuroactive steroids modulate anxiety in experimental animals and possibly in humans. The secretion of these compounds has been found to be altered in panic disorder (PD), with such alterations having been suggested to be a possible cause or effect of panic symptomatology. Panic-like attacks can be induced in healthy individuals by administration of panicogenic agents or by physical procedures, and we have now measured the plasma concentrations of neuroactive steroids in such individuals before, during, and after panicogenic inhalation of CO2 in order to investigate whether abnormalities of neuroactive steroid secretion might contribute to the pathogenesis of PD. Fifty-nine psychologically and physically healthy subjects, including 42 women (11 in the follicular phase of the menstrual cycle, 14 in the luteal phase, and 17 taking contraceptive pills) and 17 men, who experienced a panic-like attack on previous exposure to 7% CO2 were again administered 7% CO2 for 20min. Thirty-three of these individuals (responders) again experienced a panic-like attack, whereas the remaining 26 subjects did not (nonresponders). All subjects were examined with the VAS-A and PSL-III-R scales for anxiety and panic symptomatology before and after CO2 inhalation. The plasma concentrations of progesterone, 3α,5α-tetrahydroprogesterone (3α,5α-THPROG=allopregnanolone), 3α,5α-tetrahydrodesoxycorticosterone (3α,5α-THDOC), dehydroepiandrosterone (DHEA), and cortisol were measured 15min and immediately before the onset of CO2 administration as well as immediately, 10, 30, and 50min after the end of CO2 inhalation. Neuroactive steroids were measured in the laboratory of Prof. Biggio in Cagliari, Sardinia, Italy. Neurosteroid levels did not change significantly in both responders and nonresponders before, during, or after CO2 inhalation. These data suggest that neuroactive steroid concentrations before, during, or after CO2 inhalation do not seem to correlate with panic symptomatology during panic-like attacks in subjects not affected by PD, and they therefore do not support the notion that abnormalities in neuroactive steroid secretion are either a cause or an effect of such attacks. © 2013 Elsevier Ltd

The effects of citalopram and fluoxetine on sexual behavior in healthy men: evidence of delayed ejaculation and unaffected sexual desire. A randomized, placebo-controlled, double-blind, double-dummy, parallel group study.

INTRODUCTION: Selective serotonin reuptake inhibitors (SSRIs) are known to induce delayed orgasm and delayed ejaculation, while their effect on other aspects of sexual function, such as sexual motivation, arousal, and erectile function are unclear. AIM: In order to evaluate the effect of chronic administration of two SSRIs, citalopram and fluoxetine, on normal sexual function, we studied the parameters of male sexual behavior, erectile function, and ejaculation on 48 healthy male volunteers, aged 29.5 +/- 4.9, in a randomized, placebo-controlled, double-blind, double-dummy study. Methods. The subjects were randomized to receive placebo (16 subjects), or fluoxetine (20 mg/day) (16 subjects) or citalopram (20 mg/day) for the first week, and 40 mg/day in the following 3 weeks (16 subjects). MAIN OUTCOME MEASURES: Sexual function was investigated at the screening and at the end of the study by means of test of penile erection (TPE) and masturbation ejaculation latency time (MELT) performed during visual erotic stimulation, and at each visit by self-filled questionnaires (International Index Erectile Function [IIEF-15] and Golombock Rust Inventory of Sexual Satisfaction [GRISS]). RESULTS: All the erectile parameters, evaluated by means of RigiScan Plus during TPE, were not significantly different when both fluoxetine and citalopram were compared with placebo. A delay in the ejaculation time was observed both during citalopram and during fluoxetine treatment when compared with placebo, reaching a statistical significance only with citalopram. During the treatment with citalopram and fluoxetine, the IIEF-15 score of all items decreased except for those items related to sexual desire; however, the scores were significantly lower only for the citalopram treatment. CONCLUSIONS: The treatment with citalopram or with fluoxetine was confirmed to delay ejaculation, but was significant only for citalopram. Citalopram and fluoxetine did not affect sexual desire. Citalopram and fluoxetine did not directly affect penile erection as objectively assessed by RigiScan, although an impairment in the subjective assessment of erectile function was observed, but was significant only for citalopram, and it was thought to be a possible consequence of the delayed ejaculation perceived as a trouble

Pharmacokinetics of Oral Cholecalciferol in Healthy Subjects with Vitamin D Deficiency: A Randomized Open-Label Study

the aim of this study was to investigate the pharmacokinetic (PK) and safety profile of high-dose vitamin D supplementation, comparing different schedules (daily, weekly, or bi-weekly) in an otherwise healthy vitamin D-deficient population. Methods: single-center, open-label study on healthy subjects deficient in vitamin D (25 (OH)D &lt; 20 ng/mL), randomized to receive cholecalciferol (DIBASE\uae, Abiogen Pharma, Italy) using three different schedules: Group A: 10,000 IU/day for eight weeks followed by 1000 IU/day for four weeks; Group B: 50,000 IU/week for 12 weeks, Group C: 100,000 IU/every other week for 12 weeks. Total cumulative doses were: 588,000 IU, 600,000 IU, 600,000 IU. The treatment regimens corresponded to the highest doses allowed for cholecalciferol for the correction of vitamin D deficiency in adults in Italy

Pharmacodynamics of Oral Cholecalciferol in Healthy Individuals with Vitamin D Deficiency: A Randomized Open-Label Study

Comparative pharmacodynamic (PD) analyses on different dosing schedules for cholecalciferol supplementation are limited. This was an open-label, randomized, parallel-group study involving 75 healthy individuals deficient in vitamin D (baseline 25OHD &lt; 20 ng/mL) receiving oral cholecalciferol with three different dosing regimens: Group A: 10,000 IU/day for 8 weeks followed by 1000 IU/day for 4 weeks; Group B: 50,000 IU/week for 12 weeks and Group C: 100,000 IU every other week for 12 weeks. Regulators of calcium and phosphate homeostasis, bone turnover markers and Wnt inhibitors were measured at baseline, Day 28, 53, 84, and 112. The 1,25OH2D increased at each time point. The increase was greater (p &lt; 0.05) for group A vs. B and C at Day 28, and vs. group B at Day 56. No significant difference among groups was observed for the other biomarkers. The 24,25OH2D remained stable over time. PTH decreased at Day 84 and FGF-23 increased at all time points. CTX-I and PINP increased slightly at Day 28. BALP decreased from Day 56 onward. Dkk-1 increased from Day 56 onward, while sclerostin did not show significant changes. In healthy individuals deficient in vitamin D, vitamin D supplementation exerted effects on multiple regulators of calcium, phosphate and bone metabolism, without marked differences using the three regimens