Jerry Snidow

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.

Pharmacokinetics and Pharmacodynamics of Methadone Enantiomers After Coadministration with Amprenavir in Opioid‐Dependent Subjects

Study Objective. To compare steady‐state pharmacokinetics and pharmacodynamics of methadone enantiomers when coadministered with fosamprenavir 700 mg‐ritonavir 100 mg twice/day.

The Pharmacokinetics of Methadone Following Co-Administration with a Lamivudine/Zidovudine Combination Tablet in Opiate-Dependent Subjects

Methadone pharmacokinetics were determined in an open-label, within subject study in 16 methadone-maintained, non-HIV-infected subjects prior to and following administration of one lamivudine 150-mg/zidovudine 300-mg combination tablet to determine whether this antiretroviral therapy alters methadone serum concentrations. No significant differences in the mean area under the serum concentration-time curve (AUC(0-24h); 8,753 +/- 4,280 vs. 8,641 +/- 4,431 microg-h/L),oralclearance(CL/F;9.9 +/- 4.9vs. 10.3 +/- 5.5 L/h),oral volume of distribution (Vd/F; 647 +/- 465 vs. 481 +/- 305 L), maximum serum concentration (Cmax; 514 +/- 223 vs. 5,510 +/- 237 microg/L), or terminal elimination half-life (t 1/2; 55.3 +/- 61.0 vs. 35.0 +/- 17.5 h) were detected. These results suggest that methadone dose change is not likely to be necessary for patients treated with lamivudine/zidovudine combination pharmacotherapy.

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.