Bodzenta-Lukaszyk A.,Medical University of Bialystok |
Dymek A.,Medical Center Lucyna Andrzej Dymek |
Bumbacea D.,Carol Davila University of Medicine and Pharmacy |
McIver T.,Mundipharma Research Ltd |
And 2 more authors.
Respiratory Medicine | Year: 2011
Background: Fluticasone and formoterol are well established medications for the treatment of asthma. This study (Clinicaltrials.gov identifier: NCT00734318) compares the efficacy and safety of a combination of these drugs in a single inhaler (fluticasone/formoterol) versus the individual components (fluticasone + formoterol). Methods: Patients aged ≥ 18 years (n = 620) with a history of severe, persistent reversible asthma for ≥ 6 months prior to screening were included in this randomized, double-blind study, which consisted of a screening phase of up to 5 days, a 2-week run-in phase and an 8-week treatment period. Results: Fluticasone/formoterol (500/20 μg, b.i.d.) was at least as effective as fluticasone + formoterol (500 μg + 24 μg, b.i.d.) with respect to the primary outcome measure: there were similar increases in mean pre-morning dose forced expiratory volume in the first second (FEV 1) in these two groups. Fluticasone/formoterol (500/20 μg, b.i.d.) also demonstrated similar efficacy to fluticasone + formoterol in terms of change in mean FEV1 from baseline pre-morning dose to 2 h post-morning dose at week 8, as well as for several secondary parameters. Fluticasone/formoterol (500/20 μg, b.i.d.) demonstrated superiority to fluticasone monotherapy (500 μg, b.i.d.) and fluticasone/formoterol (100/10 μg, b.i.d.) for several secondary efficacy parameters. Fluticasone/formoterol had a similar safety and tolerability profile to fluticasone + formoterol. Conclusion: This study demonstrated that the fluticasone/formoterol combination is at least as effective as its components administered concurrently from separate inhalers. Fluticasone/formoterol (500/20 μg, b.i.d.) showed superior efficacy to its inhaled corticosteroid component alone and the efficacy of fluticasone/formoterol was dose-dependent for several clinically important parameters. © 2010 Elsevier Ltd. All rights reserved.
Arendt-Nielsen L.,University of Aalborg |
Andresen T.,University of Aalborg |
Andresen T.,University of Aarhus |
Malver L.P.,University of Aarhus |
And 4 more authors.
Clinical Journal of Pain | Year: 2012
Objectives: The descending pain inhibitory system is impaired in chronic pain and it is important to know how analgesics interact with this system. The aim of this human experimental pain, double-blind, randomized, placebo-controlled, 3 way cross-over study was to investigate the effect of 2 different opioids on descending pain inhibition using conditioning pain modulation (CPM) as a screening tool. Methods: Twenty-two healthy male volunteers were randomized to 72 hours of treatment with transdermal patches of fentanyl (25 μg/h), buprenorphine (20 μg/h), or placebo. The CPM was induced by immersing the hand into cold (3.0±0.3°C) water and the evoked pain was continuously rated on a visual analogue scale (VAS). The test stimulus [pressure pain tolerance threshold (PPTol)] was applied to the contra-lateral arm. The CPM test was performed at baseline, 24, 48, and 72 hours after application of the patches. Results: The opioid treatments did not significantly (F=2.249; P=0.07) modulate the PPTol over the treatment period compared with placebo. The CPM-evoked PPTol increases (percentage increase from what was obtained at the baseline before patch application) were significantly enhanced by buprenorphine (P=0.004) and fentanyl (P=0.005) compared with placebo, with no differences between the 2 active drugs. Fentanyl significantly attenuated the time to cold water-evoked VAS peak compared with placebo (P=0.005), and the same trend was observed for buprenorphine (P=0.06). The VAS pain intensity was not affected. Discussion: The opioids buprenorphine and fentanyl significantly potentiate the effect of descending pain inhibition in healthy volunteers. © 2012 by Lippincott Williams & Wilkins.
Efficacy and safety of combined prolonged-release oxycodone and naloxone in the management of moderate/severe chronic non-malignant pain: Results of a prospectively designed pooled analysis of two randomised, double-blind clinical trials
Lowenstein O.,Schmerzpraxis |
Leyendecker P.,Mundipharma Research GmbH and Co. KG |
Lux E.A.,Klinikum St Marien Hospital Lunen |
Blagden M.,Avondale Surgery |
And 5 more authors.
BMC Clinical Pharmacology | Year: 2010
Background: Two randomised 12-week, double-blind, parallel-group, multicenter studies comparing oxycodone PR/naloxone PR and oxycodone PR alone on symptoms of opioid-induced bowel dysfunction in patients with moderate/severe non-malignant pain have been conducted.Methods: These studies were prospectively designed to be pooled and the primary outcome measure of the pooled data analysis was to demonstrate non-inferiority in 12-week analgesic efficacy of oxycodone PR/naloxone PR versus oxycodone PR alone. Patients with opioid-induced constipation were switched to oxycodone PR and then randomised to fixed doses of oxycodone PR/naloxone PR (n = 292) or oxycodone PR (n = 295) for 12 weeks (20-80 mg/day).Results: No statistically significant differences in analgesic efficacy were observed for the two treatments (p = 0.3197; non-inferiority p < 0.0001; 95% CI -0.07, 0.23) and there was no statistically significant difference in frequency of analgesic rescue medication use. Improvements in Bowel Function Index score were observed for oxycodone PR/naloxone PR by Week 1 and at every subsequent time point (-15.1; p < 0.0001; 95% CI -17.3, -13.0). AE incidence was similar for both groups (61.0% and 57.3% of patients with oxycodone PR/naloxone PR and oxycodone PR alone, respectively).Conclusions: Results of this pooled analysis confirm that oxycodone PR/naloxone PR provides effective analgesia and suggest that oxycodone PR/naloxone PR improves bowel function without compromising analgesic efficacy.Trial registration numbers: ClinicalTrials.gov identifier: NCT00412100 and NCT00412152. © 2010 Löwenstein et al; licensee BioMed Central Ltd.
Quality of life benefits and cost impact of prolonged release oxycodone/naloxone versus prolonged release oxycodone in patients with moderate-to-severe non-malignant pain and opioid-induced constipation: A UK cost-utility analysis
Dunlop W.,Mundipharma International Ltd |
Uhl R.,Mundipharma Research GmbH and Co. KG |
Khan I.,Mundipharma Research Ltd |
Taylor A.,Napp Pharmaceuticals Ltd |
Barton G.,University of East Anglia
Journal of Medical Economics | Year: 2012
Objective: To compare the cost effectiveness of prolonged release oxycodone/naloxone (OXN) tablets (Targinact*) and prolonged release oxycodone (OXY) tablets (OxyContin†) in patients with moderate-to-severe non-malignant pain and opioid-induced constipation (OIC) from the perspective of the UK healthcare system. Methods: A cohort model used data from a phase III randomised, controlled trial (RCT). It calculated the cost difference between treatments by combining the cost of pain therapy with costs of laxatives and other resources used to manage constipated patients. SF-36 scores were converted into EQ-5D utility values to calculate the quality-adjusted life-year (QALY) gains. Deterministic and probabilistic sensitivity analyses were performed. Results: The incremental cost of OXN versus OXY was £159.68 for the average treatment duration of 301 days. OXN gave an incremental QALY gain of 0.0273. The estimated incremental cost-effectiveness ratio (ICER) was £5841.56 per QALY. Sensitivity analyses gave a maximum ICER of £10,347.03. In some scenarios, OXN dominated with a cost saving of up to £4254.70. Probabilistic sensitivity analysis showed that OXN had approximately 96.6% probability of cost effectiveness at the £20,000 threshold. Limitations: The model was conservative in predicting the probability of constipation beyond the 12-week RCT period. UK cost of constipation data were limited and based on primary care physician opinion. Conclusions: In the base case, direct treatment costs were slightly higher for patients treated with OXN than for those treated with OXY. However, patients treated with OXN experienced a quality of life gain, and had an ICER considerably below thresholds commonly applied in the UK. The model was most sensitive to the estimated cost of constipation with a number of realistic scenarios in the sensitivity analysis demonstrating a cost saving with OXN (OXN dominant). OXN is therefore estimated to be a cost-effective option for treating patients with severe non-malignant pain and OIC. © 2012 Informa UK Ltd All rights reserved.
Blagden M.,Avondale Surgery |
Hafer J.,Praxis fur Schmerztherapie |
Duerr H.,Mundipharma Research GmbH and Co. KG |
Hopp M.,Mundipharma Research GmbH and Co. KG |
Bosse B.,Mundipharma Research GmbH and Co. KG
Neurogastroenterology and Motility | Year: 2014
Background: While opioids provide effective analgesia, opioid-induced constipation (OIC) can severely impact quality of life and treatment compliance. This pooled analysis evaluated the maintenance of efficacy and safety during long-term treatment with combined oxycodone/naloxone prolonged-release tablets (OXN PR) in adults with moderate-to-severe chronic pain. Methods: Patients (N = 474) received open-label OXN PR during 52-week extension phases of two studies, having completed 12-week, double-blind, randomized treatment with oxycodone prolonged-release tablets (Oxy PR) or OXN PR. Analgesia and bowel function were assessed at each study visit using 'Average pain over last 24 h scale and Bowel Function Index (BFI), respectively. Treatment Satisfaction Questionnaire for Medication was assessed at study end only. Key Results: Improvement in bowel function was particularly marked in patients who switched from Oxy PR in the double-blind phase to OXN PR during the extension phase, resulting in a clinically meaningful reduction (≥12 points) in BFI score: at the start of the extension phases, mean (SD) BFI score was 44.3 (28.13), and was 29.8 (26.36) for patients who had received OXN PR in the double-blind phase. One week later, BFI scores were similar for the two groups (26.5 [24.40] and 27.5 [25.60], respectively), as was observed throughout the following months. Fewer than 10% of patients received laxatives regularly. Mean 24-h pain scores were low and stable throughout the extension phases. No unexpected adverse events were observed. Conclusions & Inferences: Pooled data demonstrate OXN PR is an effective long-term therapy for patients with chronic non-cancer pain, and can address symptoms of OIC. No new safety issues were observed which were attributable to the long-term administration of OXN PR. Pooled data from the 12-month extension phases of two Phase III trials demonstrate combined oxycodone/naloxone prolonged-release tablets (OXN PR) are an effective long-term therapy for patients with chronic non-cancer pain, and can address symptoms of opioid-induced constipation. Comparable pain control but with improved bowel function was observed with OXN PR vs oxycodone PR and was maintained during the open-label, long-term treatment. No new safety issues were observed which were attributable to the long-term administration of OXN PR. aScreening and double-blind phases: patients who required laxatives (patients provided with bisacodyl by the study investigator, according to the study protocol). bExtension phases: patients who used laxatives regularly (according to specific dosing and treatment instructions provided by the investigator). cNo study treatment was received during Screening. At Run-in, patients had prestudy opioid converted to open-label Oxy PR, titrated to an effective analgesic dose. © 2014 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.
Schilder A.,University of Heidelberg |
Hoheisel U.,University of Heidelberg |
Magerl W.,University of Heidelberg |
Benrath J.,University of Heidelberg |
And 3 more authors.
Pain | Year: 2014
Injection of hypertonic saline into deep tissues of the back (subcutis, muscle, or the surrounding fascia) can induce acute low back pain (LBP). So far, no study has analyzed differences in temporal, qualitative, and spatial pain characteristics originating from these tissues. The current study aimed to investigate the role of the thoracolumbar fascia as a potential source of LBP. In separate sessions, 12 healthy subjects received ultrasound-guided bolus injections of isotonic saline (0.9%) or hypertonic saline (5.8%) into the erector spinae muscle, the thoracolumbar fascia (posterior layer), and the overlying subcutis. Subjects were asked to rate pain intensity, duration, quality, and spatial extent. Pressure pain thresholds were determined pre and post injection. Injections of hypertonic saline into the fascia resulted in significantly larger area under the curve of pain intensity over time than injections into subcutis (P < 0.01) or muscle (P < 0.001), primarily based on longer pain durations and, to a lesser extent, on higher peak pain ratings. Pressure hyperalgesia was only induced by injection of hypertonic saline into muscle, but not fascia or subcutis. Pain radiation and pain affect evoked by fascia injection exceeded those of the muscle (P < 0.01) and the subcutis significantly (P < 0.05). Pain descriptors after fascia injection (burning, throbbing, and stinging) suggested innervation by both A- and C-fiber nociceptors. These findings show that the thoracolumbar fascia is the deep tissue of the back that is most sensitive to chemical stimulation, making it a prime candidate to contribute to nonspecific LBP but not to localized pressure hyperalgesia. © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
Rentz A.M.,United Biosource Corporation |
Van Hanswijck De Jonge P.,United Biosource Corporation |
Leyendecker P.,Mundipharma Research GmbH and Co. KG |
Hopp M.,Mundipharma Research GmbH and Co. KG
Current Medical Research and Opinion | Year: 2011
Objective: Constipation is a common adverse event of treatment with opioids for chronic non-malignant pain and may result in a considerable reduction in health-related quality of life. The aim of this study was to assess the psychometric properties of the Bowel Function Index (BFI) in european patients suffering from constipation secondary to opioid analgesic treatment for chronic, non-malignant pain. Methods: This was a multinational study conducted at 15 clinical sites in the Czech Republic, Germany, Italy, and the United Kingdom. Patients suffering from constipation secondary to opioid analgesic treatment for chronic, non-malignant pain were recruited to complete a series of questionnaires including a socio-demographic form, the BFI, the Patient Assessment of Constipation Symptoms (PAC-SYM), a global frequency item, and a clinical form. Results: A total of 131 patients were included in this study. Inter-item correlations of the BFI were statistically significant in the moderate to large range and the analysis indicated a strong degree of internal consistency (Cronbach's alpha0.86). All correlations between the BFI and the global item were statistically significant in the moderate to high range (r0.59 to 0.69; p<0.0001). Correlations between the BFI and the PAC-SYM were moderate and statistically significant (p<0.01 to 0.0001). Conclusions: Although this study was limited by the relatively small sample size, it is a part of an extensive validation program. This study suggests that the BFI is a reliable and valid measure of constipation-related symptomatology in chronic pain patients. This measure may be a valuable indicator of patients' experience of symptoms of opioid treatment of chronic pain in future trials. © 2011 Informa UK Ltd.
Smith K.,Mundipharma Research Ltd |
Hopp M.,Mundipharma Research GmbH and Co. KG. |
Mundin G.,Mundipharma Research Ltd |
Bond S.,University of Cambridge |
And 3 more authors.
International Journal of Clinical Pharmacology and Therapeutics | Year: 2012
Objective: To determine the absolute bioavailability of naloxone from oral doses ranging from 5 mg to 120 mg. Materials and methods: In this open-label study, 28 healthy subjects received naloxone 1 mg (0.4 mg/ml) as an intravenous infusion (reference treatment), and the following oral doses as prolonged release (PR) naloxone tablets: 5 mg, 20 mg, 40 mg, 80 mg and 120 mg. The pharmacokinetic characteristics of 40 mg administered per rectum were also investigated. Each subject received five of the seven treatments as single doses with a 7 day washout between doses. Pharmacokinetic blood sampling and safety monitoring were performed for 24 h after the intravenous dose, and 72 h after the oral and rectal doses. Results: The mean absolute bioavailability of naloxone from the orally administered PR tablets was very low, ranging from 0.9% for the 5 mg dose to 2% for the 40, 80 and 120 mg doses, based on AUCt values. The pharmacokinetics of naloxone were linear across the range of oral doses. Where AUC inf values were calculated, these confirmed the results based on AUC t values (mean absolute bioavailability ranging from 1.9% to 2.2% for the 20 mg to 120 mg oral doses). The absolute bioavailability of naloxone was higher following rectal administration compared with oral administration, but was still low at 15%. Conclusions: The mean oral absolute bioavailability of naloxone in this study was ≤ 2% at doses ranging from 5 mg to 120 mg. ©2012 Dustri-Verlag Dr. K. Feistle.
Smith K.,Mundipharma Research Ltd. |
Hopp M.,Mundipharma Research GmbH and Co. KG |
Mundin G.,Mundipharma Research Ltd. |
Bond S.,University of Cambridge |
And 6 more authors.
Expert Opinion on Investigational Drugs | Year: 2011
Objectives: This exploratory study in healthy volunteers investigated the effect of single doses of oxycodone on gastrointestinal (GI) transit time and the degree to which a single dose of naloxone reverses the oxycodone-induced effect. Methods: Fifteen healthy male volunteers received: oxycodone 10 and 20 mg, oxycodone/naloxone 10/5 and 20/10 mg (all as prolonged release tablets) and placebo. Each dose was radiolabelled and administered with a capsule containing radiolabelled resin (surrogate for GI contents). Results: Scintigraphic analysis showed that 20 mg oxycodone significantly increased colon arrival time (mean 7.19 vs 5.15 h for placebo, p = 0.0159). Mean colon arrival time for oxycodone/naloxone 20/10 mg (5.16 h) was similar to placebo, although the difference between oxycodone/naloxone 20/10 mg versus oxycodone 20 mg was not significant (p = 0.0653). Colonic geometric centre analysis showed a significant increase in mean time for the resin to reach the colon following oxycodone 10 and 20 mg compared with placebo (increases of 5.3 and 8.8 h). There was no significant effect of naloxone at the lower dose; however, oxycodone/naloxone 20/10 mg significantly reduced mean colonic transit time by 2.1 h (p = 0.0376). Conclusion: A single dose of oxycodone 20 mg significantly prolonged GI transit time but this effect was reduced by co-administration of naloxone. © 2011 Informa UK, Ltd.
A randomized, double-blind, active-controlled, double-dummy, parallel-group study to determine the safety and efficacy of oxycodone/naloxone prolonged-release tablets in patients with moderate/severe, chronic cancer pain
Ahmedzai S.H.,University of Sheffield |
Nauck F.,University of Gottingen |
Bar-Sela G.,Technion - Israel Institute of Technology |
Bosse B.,Mundipharma Research GmbH and Co. KG |
And 2 more authors.
Palliative Medicine | Year: 2012
Objective: An examination of whether oxycodone/naloxone prolonged-release tablets (OXN PR) can improve constipation and maintain analgesia, compared with oxycodone prolonged-release tablets (OxyPR) in patients with moderate/severe cancer pain.Methods: Randomized, double-blind, active-controlled, double-dummy, parallel-group study in which 185 patients were randomized to receive up to 120mg/day of OXN PR or OxyPR over 4 weeks. Efficacy assessments included Bowel Function Index (BFI), Brief Pain Inventory Short-Form (BPI-SF), laxative and rescue medication use. Quality of life (QoL) and safety assessments were conducted.Results: After 4 weeks, mean BFI score was significantly lower with OXN PR; mean total laxative intake was 20% lower with OXN PR. Mean BPI-SF scores were similar for both treatments and the average rate of analgesic rescue medication use was low and comparable. QoL assessments were stable and comparable with greater improvements in constipation-specific QoL assessments with OXN PR. Overall, rates of adverse drug reactions were similar.Conclusions: OXN PR provides superior bowel function in cancer pain patients, compared with OxyPR, without compromising analgesic efficacy or safety. This study confirms that OXN PR is well tolerated and efficacious in cancer pain patients and results are in line with those seen in non-malignant pain patients. © 2011 The Author(s).