Christi S. Kleoudis

Lack of effect of intravenous administration on time to respond to azathioprine for steroid-treated Crohn's disease ☆ ☆☆ ★

BACKGROUND & AIMS Azathioprine is effective for Crohns disease but acts slowly. A loading dose may decrease the time to response. METHODS A placebo-controlled study was conducted in patients with active Crohns disease despite prednisone treatment. Patients were randomized to a 36-hour infusion of azathioprine, 40 mg/kg (51 patients), or placebo (45 patients) followed by oral azathioprine, 2 mg/kg, for 16 weeks. Prednisone was tapered over 5 weeks. The primary outcome measure was complete remission at week 8, defined by discontinuation of prednisone and a Crohns Disease Activity Index of </=150 points. Erythrocyte concentrations of the azathioprine active metabolite, 6-thioguanine nucleotide, were measured. RESULTS At week 8, 13 patients (25%) were in complete remission in the azathioprine-loaded group compared with 11 patients (24%) in the placebo group. The frequency of complete remission did not increase after 8 weeks in either group. Both groups achieved steady state of 6-thioguanine nucleotide by week 2, and no differences were found in mean concentrations between the groups. There were no significant differences in the frequency of adverse events between the groups. CONCLUSIONS A loading dose does not decrease the time to response in patients with steroid-treated Crohns disease beginning azathioprine therapy. Steady state of erythrocyte 6-thioguanine nucleotide and complete response occurred earlier than previously reported.

Alvimopan, a peripherally acting mu-opioid receptor (PAM-OR) antagonist for the treatment of opioid-induced bowel dysfunction: Results from a randomized, double-blind, placebo-controlled, dose-finding study in subjects taking opioids for chronic non-cancer pain

&NA; Our objective was to investigate the efficacy and safety of alvimopan, a peripherally acting mu‐opioid receptor (PAM‐OR) antagonist, in subjects with non‐cancer pain and opioid‐induced bowel dysfunction (OBD), and to identify at least one treatment regimen that improves OBD. Following a 2‐week baseline period, 522 subjects reporting <3 spontaneous bowel movements (SBMs)/week (with ⩾25% accompanied by a sensation of incomplete evacuation, straining, or lumpy hard stools), requiring analgesia equivalent to ⩾30 mg oral morphine/day were randomized to alvimopan 0.5 mg twice daily (BID), 1 mg once daily (QD), 1 mg BID, or placebo for 6 weeks. Compared with placebo, there was a statistically and clinically significant increase in mean weekly SBM frequency over the initial 3 weeks of treatment (primary endpoint) with alvimopan 0.5 mg BID (+1.71 mean SBMs/week), alvimopan 1 mg QD (+1.64) and alvimopan 1 mg BID (+2.52); P < 0.001 for all comparisons. Increased SBM frequency and additional treatment effects, including improvements in symptoms such as straining, stool consistency, incomplete evacuation, abdominal bloating/discomfort, and decreased appetite, were sustained over 6 weeks. The most frequently reported adverse events were abdominal pain, nausea, and diarrhea, occurring more frequently in the higher dosage groups. The alvimopan 0.5 mg BID regimen demonstrated the best benefit‐to‐risk profile for managing OBD with alvimopan in this study population, with a side effect profile similar to that of placebo. There was no evidence of opioid analgesia antagonism. Competitive peripheral antagonism of opioids with alvimopan can restore GI function and relieve OBD without compromising analgesia.

703 VALIDATION OF THE PAC-SYM QUESTIONNAIRE IN A NON-CANCER PAIN POPULATION RECEIVING ALVIMOPAN FOR OPIOID-INDUCED GASTROINTESTINAL (GI) SIDE EFFECTS

Background: The efficacy of transdermal Fentanyl (TDF) in chronic non-malignant pain has been demonstrated consistently. Objective of this analysis was to compare a starting dose of TDF 12.5 mg/h with a starting dose of TDF 25mg/h. Methods: Combined analysis of raw data of the treatment initiation phase (first 15 days) of two non-interventional multicenter studies. TDF dose regimen was performed according to current summary of product characteristics and adapted to patients individual needs. Pain intensity, adverse events (AE) and safety parameters (HR, BP) were documented. Results: Treatment with TDF 12.5mg/h and TDF 25mg/h (CG) was initiated in 131 and 91 patients, respectively, with comparable baseline pain intensities at rest and on movement. Compared to baseline, pain intensity was reduced significantly in both groups during the study (p< 0.001). However, the total number of early treatment terminations was lower in the 12.5mg/h-Group (15%) than in CG (20%). AE, the most common reason for treatment termination, occurred significantly less frequent in the 12.5mg/h-Group (5.3%) than in CG (15.4%). Regarding type of AE, “nausea and vomiting” and “dizziness and somnolence” were significantly less frequent in the 12.5mg/h-Group (12% and 1.5%, respectively) than in GC (18.7% and 6.6%, respectively). There were no clinically relevant differences in other types of AE and in safety parameters between both groups. Conclusion: Treatment initiation with transdermal Fentanyl 12.5mg/h leads to a better tolerability and lower number of treatment terminations compared to a starting dose of transdermal Fentanyl 25mg/h (Durogesic®SMAT) at a comparable level of pain control.

669 GASTROINTESTINAL (GI) SIDE EFFECTS ASSOCIATED WITH CHRONIC OPIOID ANALGESIC THERAPY IN A LARGE, PERSISTENT NON-CANCER PAIN POPULATION (SB-767905/011): BASELINE DATA

Background: Chronic opioid therapy is often complicated by persistent GI side effects, yet few well-controlled studies have described these symptoms in a pre-specified manner. Aim: To detail demographics, baseline characteristics and GI symptoms of a large, non-cancer pain cohort reporting opioid-induced constipation, specifically defined as infrequent and difficult defecation. Methods: This phase IIb study evaluated the investigational, peripherally acting mu-opioid receptor (PAM-OR) antagonist alvimopan for treatment of opioid-induced GI side-effects. Adults were evaluated who were using 30mg oral morphine equivalents/day, had a history of GI side-effects and reported an average weekly spontaneous bowel movement (SBM [BM in absence of laxative use within previous 24 h]) frequency <3 during the 2-week baseline period. Results: Of 522 eligible subjects, 92% were white, 64% female, and average age was 50.3 years. Opioids had been taken, on average, 6.9 years for pain conditions: back pain (58%), neuralgia (8%), fibromyalgia (8%) and arthritis (7%). Average baseline total daily dose (oral morphine equivalents) was 288.0mg. Laxatives/stool softeners were used by 80% of subjects within 30 days before screening, and 80% used rescue laxative during baseline. Subjects reported an average of 2.9 total BMs and 1.1 SBMs/week plus the following symptoms (moderate or greater severity): straining (83%), hard stools (87%), incomplete evacuation (88%). Most prevalent other GI-related symptoms were abdominal fullness (76%), intestinal gas (70%) and general malaise (59%). Conclusions: Chronic opioid analgesia is associated with persistent dysfunction of the GI tract, despite laxative use. New therapies that relieve GI symptoms without compromising analgesia are under investigation. Presented at APS 2006.

633 SYMPTOM RELIEF CORRELATES WITH GLOBAL IMPROVEMENT OF OPIOID-INDUCED GASTROINTESTINAL SIDE EFFECTS (OGS): RESULTS FROM AN ALVIMOPAN STUDY IN NON-CANCER PAIN (SB-767905/011)

Background and Aims: OGS include multiple symptoms; infrequent and hard stools, straining, incomplete evacuation, abdominal pain/discomfort and decreased appetite. Inter-subject variability in number/severity of symptoms complicates assessment of overall OGS burden of illness. Global improvement scales (GIS) address this concern by allowing subjects to assess a change in response based upon the specific symptom(s) most troublesome for that individual. Methods: SB-767905/011 was a double-blind study of the investigational peripherally active mu-opioid receptor (PAM-OR) antagonist, alvimopan, in 522 chronic pain subjects randomised to alvimopan 0.5mg BID, 1mg QD, 1mg BID or placebo for 6 weeks. Subjects requiring analgesia equivalent to 30mg oral morphine daily, reporting <3 bowel movements/week without laxatives and symptomatic in 25% of stools, were eligible. Subjects described weekly changes in GIS for constipation, using a 7-point Likert scale, relative to pre-treatment. Responders reported moderate or substantial improvement. Severity of constipation symptoms and impact on quality of life (QoL) were assessed by the Patient Assessment of Constipation Scales, PAC-SYM and PAC-QoL, respectively. Results: Mean GIS responder rates, defined as proportion of weeks a subject was a responder, were ~40% in the alvimopan groups versus 14% for placebo (p< 0.001). Percentage of responders each week was typically 20% higher than placebo (p 0.003). OGS global improvement was significantly correlated with bowel movement frequency (p< 0.0001), straining (p< 0.0001), incomplete evacuation (p< 0.0001), stool consistency (p< 0.0001), and each domain (p< 0.0001) of PAC-SYM and PACQoL. Conclusion: This analysis demonstrates that GIS is an important endpoint that integrates subjects’ assessment of OGS symptom changes after treatment.

679 ALVIMOPAN DOSAGE REGIMENS FOR THE TREATMENT OF OPIOID-INDUCED GASTROINTESTINAL (GI) SIDE EFFECTS IN SUBJECTS WITH PERSISTENT NON-CANCER PAIN (SB-767905/011)

Aims: Comparison of post surgical analgesia sufficiency, needs and cost effectiveness. Material & Methods: 60 ASA I-III patients who underwent arthroplasty were randomized in 20 person groups (A, B, C). In all patients regional anaesthesia was performed with 7.5mg Heavy Bupivacaine 0.5% and epidural catheter in the same interval. After catheter placement postoperative analgesia was administered as per follow: In A continuous infusion of morphine 0.05mg/ml solution via Micrel Rythmic pump (A) at 5ml/hour (6mg/120ml) rate. In B continuous infusion of morphine 0.07mg/ml solution via Nipro Surefuser pump(B) at 3.5ml/hour (6mg/84ml) rate. In C morphine 3mg/10ml bolus was administered with repetition per 12 hours. Totally 12mg/48 hours were administered in all three teams. Visual analogue scale (VAS) pain evaluation, any needs for more analgesia and any dysfunctions of pumps were recorded every 6 hours. Results: A, B did not present additional needs in morphine, while in C there was insufficiency of analgesia in the last 4hours before the next dose. Conclusions: Safe infusion of morphine was shown in A and B. Our findings indicate higher precision and quantity control with pump A while pump B was easier-to-use, quieter and practically unbreakable. Pump A features flow adjustment and bolus dose yet requires electric supply and specialised handling knowledge. Pump B is disposable, but costs more from pump A’s single-use container. The bolus infusion (C) is ostensibly simple and cheap, however appeared comparatively insufficient in duration and analgesia quality, while longer occupying the anaesthetist.

Effectiveness of ranitidine 150 mg at bedtime as maintenance therapy for healed gastric ulcers

As many as 89% of gastric ulcer patients experience ulcer recurrences within 1 year of successful healing with conventional antiulcer therapies. Because ranitidine is effective in the healing of gastric and duodenal ulcers and the maintenance of healed duodenal ulcers, we hypothesized that ranitidine would also be effective in the maintenance of healed gastric ulcers. A 48-week, placebo-controlled, randomized, double-blind, multicenter trial was conducted to compare ranitidine 150 mg administered at bedtime with placebo for the maintenance of healed gastric ulcers. Endoscopies were performed at baseline and repeated after 12, 24, 36, and 48 weeks of treatment. Gastric ulcer recurrence rates at each scheduled endoscopy were significantly lower in patients receiving ranitidine (5%, 13%, 16%, and 19%, respectively) compared with those receiving placebo (20%, 30%, 40%, and 50%, respectively). Compared with placebo, ranitidine was more effective in maintaining healed gastric ulcers regardless of previous gastric ulcer history, smoking status, age (< 65 vs > or = 65 years), or sex. There were no significant differences between the two treatment groups in the number of patients experiencing adverse events or laboratory abnormalities. Ranitidine 150 mg administered at bedtime provides safe and effective treatment for the maintenance of healed gastric ulcers.