Ralph T. Doyle

Dose Conversion and Titration with a Novel, Once-Daily, OROS® Osmotic Technology, Extended-Release Hydromorphone Formulation in the Treatment of Chronic Malignant or Nonmalignant Pain

The objective of this open-label, repeated-dose, single-treatment, multicenter study was to evaluate the outcomes associated with a standardized conversion from prior opioid therapy to a novel, once-daily, OROS osmotic technology, extended-release (ER) hydromorphone formulation in an outpatient population with chronic malignant or nonmalignant pain. The study period was divided into 3 phases: the prior opioid stabilization phase (> or =3 days), the conversion and titration phase (3-21 days), and the maintenance phase (14 days). Patients were evaluated at 5 visits during the study period. Analgesic efficacy was measured using the Brief Pain Inventory (BPI). At baseline, patients were required to have daily oral morphine equivalent requirements of > or =45 mg. Prior oral or transdermal opioid therapy was converted to single daily doses of ER hydromorphone (8, 16, 32, and 64 mg tablets) at a 5:1 (morphine equivalent to hydromorphone) ratio. Immediate-release (IR) hydromorphone was given as rescue medication for breakthrough pain. Among the 445 patients who enrolled, 404 received the study medication. Of these, 73 (18.1%) had chronic malignant pain and 331 (81.9%) had chronic nonmalignant pain. Dose stabilization (defined as a 3-day period during which the total daily dose of ER hydromorphone remained unchanged and < or =3 doses of IR hydromorphone per day were required) was attained by 73.8% of patients (298/404), of whom 70.1% (209/298) were stabilized with < or =2 titration steps. The mean +/- standard deviation (SD) time to dose stabilization was 12.1 +/- 5.7 days (range of 3 to 33 days). The mean +/- SD final daily dose of ER hydromorphone was 63.4 +/- 129.2 mg. The mean +/- SD final daily dose of IR hydromorphone was 11.5 +/- 36.4 mg, and the mean +/- SD final number of daily doses of IR hydromorphone was 1.7 +/- 1.3. Intent-to-treat and completer analysis demonstrated significant improvements in BPI ratings from prior opioid therapy to the end of ER hydromorphone therapy (P < 0.01 for all pairwise comparisons). Adverse events were consistent with those expected of an opioid agonist in such a patient group, affecting primarily the gastrointestinal and central nervous systems. This uncontrolled study delineates a regimen by which patients with chronic malignant or nonmalignant pain can be readily converted from prior opioid therapy and titrated to an appropriate maintenance dose of ER hydromorphone. Controlled longitudinal studies are required to further evaluate the use of ER hydromorphone in patients with discrete chronic malignant or nonmalignant pain conditions.

Combination hydrocodone and ibuprofen versus combination oxycodone and acetaminophen in the treatment of moderate or severe acute low back pain

BACKGROUND Introduced in 1997, the combination of hydrocodone and ibuprofen is the only fixed-dose combination analgesic containing an opioid and ibuprofen that has been approved by the US Food and Drug Administration. OBJECTIVE This study compared the efficacy and tolerability of combination hydrocodone 7.5 mg and ibuprofen 200 mg (HC/IB) with those of combination oxycodone 5 mg and acetaminophen 325 mg (OX/AC) in the treatment of moderate or severe acute low back pain. METHODS This was a multicenter, randomized, double-blind, parallel-group, repeat-dose study lasting up to 8 days. The recommended dosing of the study medications was 1 tablet every 4 to 6 hours, not to exceed 5 tablets per day. If adequate pain relief was not obtained, patients were permitted to take up to 4 doses per day of supplemental analgesic medication-the nonopioid component of the assigned study medication (ibuprofen 200 mg or acetaminophen 325 mg). Measures of efficacy included mean daily pain relief scores (0 = no relief, 1 = slight relief, 2 = moderate relief, 3 = good relief, and 4 = complete relief), mean daily number of tablets and doses of study medication, mean daily number of tablets and doses of supplemental analgesic medication, global evaluation (poor, fair, good, very good, or excellent), and results on the modified 36-item Short-Form Health Survey (SF-36). All efficacy measures were analyzed on an intent-to-treat basis. Tolerability was evaluated based on adverse events reported spontaneously or elicited by the in vestigators using nonsuggestive questioning, as well as on the number of patients discontinuing treatment because of adverse events. RESULTS The study enrolled 147 patients (75 HC/IB, 72 OX/AC). The most common cause of low back pain was muscular/ligamentous injury (97/147; 66.0%), followed by degenerative disk disease (27/147; 18.4%). At baseline, 80 patients (54.4%) reported experiencing moderate pain, and 67 patients (45.6%) reported experiencing severe pain. There were no significant differences between HC/IB and OX/AC with regard to mean ( +/- SD) daily pain relief scores (2.40 +/- 1.06 vs 2.50 +/- 1.01, respectively), mean daily number of tablets of study medication (1.80 +/- 1.70 vs 2.20 +/- 1.60), mean daily number of doses of study medication (1.80 +/- 1.65 vs 2.10 +/- 1.58), mean daily number of tablets of supplemental analgesic medication (0.60 +/- 1.13 vs 0.50 +/- 0.99), mean daily number of doses of supplemental analgesic medication (0.60 +/- 1.07 vs 0.50 +/- 0.90), global evaluations, or mean scores on the modified SF-36. In addition, there were no significant differences in the proportion of patients experiencing adverse events with HC/IB (47; 62.7%) and OX/AC (45; 62.5%). Adverse events were consistent with those generally associated with the component analgesics and predominantly involved the central nervous system and gastrointestinal system. CONCLUSIONS The results of this study suggest that HC/IB and OX/AC are similarly effective and tolerable in relieving moderate or severe acute low back pain. Additional controlled longitudinal trials are necessary to evaluate the clinical utility of HC/IB in treating acute low back pain.

Effects of prescription omega-3-acid ethyl esters on non-high-density lipoprotein cholesterol when coadministered with escalating doses of atorvastatin.

OBJECTIVE To evaluate the effects of prescription omega-3-acid ethyl esters on non-high-density lipoprotein cholesterol (HDL-C) levels in atorvastatin-treated patients with elevated non-HDL-C and triglyceride levels. PATIENTS AND METHODS This study, conducted between February 15, 2007, and October 22, 2007, randomized patients with elevated non-HDL-C (>160 mg/dL) and triglyceride (>or=250 mg/dL and <or=599 mg/dL) levels to double-blind treatment with prescription omega-3-acid ethyl esters, 4 g/d, or placebo for 16 weeks. Patients also received escalating dosages of open-label atorvastatin (weeks 0-8, 10 mg/d; weeks 9-12, 20 mg/d; weeks 13-16, 40 mg/d). RESULTS Prescription omega-3-acid ethyl esters plus atorvastatin, 10, 20, and 40 mg/d, reduced median non-HDL-C levels by 40.2% vs 33.7% (P<.001), 46.9% vs 39.0% (P<.001), and 50.4% vs 46.3% (P<.001) compared with placebo plus the same doses of atorvastatin at the end of 8, 12, and 16 weeks, respectively. Prescription omega-3-acid ethyl esters plus atorvastatin also reduced median total cholesterol, triglyceride, and very low-density lipoprotein cholesterol levels and increased HDL-C levels to a significantly greater extent than placebo plus atorvastatin. Percent changes from baseline low-density lipoprotein-cholesterol, apolipoprotein A-I, and apolipoprotein B levels were not significantly different between groups at the end of the study. CONCLUSION Prescription omega-3-acid ethyl esters plus atorvastatin produced significant improvements in non-HDL-C and other lipid parameters in patients with elevated non-HDL-C and triglyceride levels.

Baseline Lipoprotein Lipids and Low-Density Lipoprotein Cholesterol Response to Prescription Omega-3 Acid Ethyl Ester Added to Simvastatin Therapy

The present post hoc analysis of data from the COMBination of prescription Omega-3 with Simvastatin (COMBOS) study investigated the predictors of the low-density lipoprotein (LDL) cholesterol response to prescription omega-3 acid ethyl ester (P-OM3) therapy in men and women with high (200 to 499 mg/dl) triglycerides during diet plus simvastatin therapy. Subjects (n = 256 randomized) received double-blind P-OM3 4 g/day or placebo for 8 weeks combined with diet and open-label simvastatin 40 mg/day. The percentage of changes from baseline (with diet plus simvastatin) in lipids was evaluated by tertiles of baseline LDL cholesterol and triglyceride concentrations. The baseline LDL cholesterol tertile was a significant predictor of the LDL cholesterol response (p = 0.022 for the treatment by baseline tertile interaction). The median LDL cholesterol response in the P-OM3 group was +9.5% (first tertile, <80.4 mg/dl), -0.9% (second tertile), and -6.4% (third tertile, > or =99.0 mg/dl). Non-high-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride responses did not vary significantly by baseline LDL cholesterol tertile. The reductions in very-low-density lipoprotein cholesterol concentrations were greater than the increases in LDL cholesterol, where present, resulting in a net decrease in the concentration of cholesterol carried by atherogenic particles (non-high-density lipoprotein cholesterol) in all baseline LDL cholesterol tertiles. In conclusion, these results suggest that the increase in LDL cholesterol that occurred with the addition of P-OM3 to simvastatin therapy in subjects with mixed dyslipidemia was confined predominantly to those with low LDL cholesterol levels while receiving simvastatin monotherapy.

Combination hydrocodone and ibuprofen versus combination oxycodone and acetaminophen in the treatment of postoperative obstetric or gynecologic pain.

OBJECTIVE The objective of this study was to compare the effectiveness of combination hydrocodone and ibuprofen with that of combination oxycodone and acetaminophen in the treatment of moderate to severe postoperative obstetric or gynecologic pain. BACKGROUND Hydrocodone 7.5 mg with ibuprofen 200 mg is the only approved fixed-dose combination analgesic containing an opioid and ibuprofen. METHODS This randomized, double-blind, parallel-group, single-dose, active-comparator, placebo-controlled study compared the effects of a 2-tablet dose of hydrocodone 7.5 mg and ibuprofen 200 mg with those of a 2-tablet dose of oxycodone 5 mg and acetaminophen 325 mg and placebo. Analgesia was assessed over 8 hours. RESULTS Mean pain relief (PR) scores were similar for the hydrocodone with ibuprofen and oxycodone with acetaminophen groups (n = 61 and 59, respectively) at 0.5, 1, 1.5, 2, 2.5, 3, 4, and 7 hours and significantly greater for the hydrocodone with ibuprofen group at 5, 6, and 8 hours (P < or = 0.05). Mean pain intensity difference (PID) scores were similar for hydrocodone with ibuprofen and oxycodone with acetaminophen at 0.5, 1, 1.5, 2, 2.5, 3, and 4 hours and significantly greater for hydrocodone with ibuprofen at 5, 6, 7, and 8 hours (P < or = 0.05). Total PR scores were similar for hydrocodone with ibuprofen and oxycodone with acetaminophen for the 0- to 3- and 0- to 4-hour intervals and significantly greater for hydrocodone with ibuprofen for the 0- to 6- and 0- to 8-hour intervals (P < 0.05). The sum of the PID scores was similar for hydrocodone with ibuprofen and oxycodone with acetaminophen for the 0- to 3-, 0- to 4-, 0- to 6-, and 0- to 8-hour intervals. The median estimated time to onset of analgesia, mean peak PR score, median time to remedication, and mean global assessment score were similar for hydrocodone with ibuprofen and oxycodone with acetaminophen. Assay sensitivity was demonstrated by the presence of statistically significant differences between both active treatments and placebo (n = 60). The number of patients experiencing adverse events was similar for each of the 3 groups (11 [18.0%], hydrocodone with ibuprofen; 7 [11.9%], oxycodone with acetaminophen; and 6 [10.0%], placebo). CONCLUSIONS In this study, a 2-tablet dose of combination hydrocodone 7.5 mg and ibuprofen 200 mg was as effective as a 2-tablet dose of combination oxycodone 5 mg and acetaminophen 325 mg in the treatment of moderate to severe postoperative obstetric or gynecologic pain. Both treatments were superior to placebo. The results of this study suggest that the combination of hydrocodone 7.5 mg and ibuprofen 200 mg may offer prescribers an additional option in combination pain therapy.

Rationale and design of REDUCE-IT: Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial

Residual cardiovascular risk persists despite statins, yet outcome studies of lipid‐targeted therapies beyond low‐density lipoprotein cholesterol (LDL‐C) have not demonstrated added benefit. Triglyceride elevation is an independent risk factor for cardiovascular events. High‐dose eicosapentaenoic acid (EPA) reduces triglyceride‐rich lipoproteins without raising LDL‐C. Omega‐3s have postulated pleiotropic cardioprotective benefits beyond triglyceride‐lowering. To date, no large, multinational, randomized clinical trial has proved that lowering triglycerides on top of statin therapy improves cardiovascular outcomes. The Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE‐IT; NCT01492361) is a phase 3b randomized, double‐blinded, placebo‐controlled trial of icosapent ethyl, a highly purified ethyl ester of EPA, vs placebo. The main objective is to evaluate whether treatment with icosapent ethyl reduces ischemic events in statin‐treated patients with high triglycerides at elevated cardiovascular risk. REDUCE‐IT enrolled men or women age ≥45 years with established cardiovascular disease or age ≥50 years with diabetes mellitus and 1 additional risk factor. Randomization required fasting triglycerides ≥150 mg/dL and <500 mg/dL and LDL‐C >40 mg/dL and ≤100 mg/dL with stable statin (± ezetimibe) ≥4 weeks prior to qualifying measurements. The primary endpoint is a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. The key secondary endpoint is the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Several secondary, tertiary, and exploratory endpoints will be assessed. Approximately 8000 patients have been randomized at approximately 470 centers worldwide. Follow‐up will continue in this event‐driven trial until approximately 1612 adjudicated primary‐efficacy endpoint events have occurred.

Combination hydrocodone and ibuprofen versus combination codeine and acetaminophen for the treatment of chronic pain

OBJECTIVE The objective of this study was to compare the effectiveness of combination hydrocodone 7.5 mg and ibuprofen 200 mg with that of combination codeine 30 mg and acetaminophen 300 mg for the treatment of chronic pain. BACKGROUND Hydrocodone 7.5 mg with ibuprofen 200 mg is the only approved fixed-dose combination analgesic containing an opioid and ibuprofen. METHODS In this randomized, parallel-group, double-blind, repeated-dose, active-comparator, 4-week, multicenter study, 469 patients were randomly assigned to receive a 1-tablet (n = 156) or 2-tablet (n = 153) dose of combination hydrocodone 7.5 mg and ibuprofen 200 mg (HI1 and HI2, respectively) or a 2-tablet dose of combination codeine 30 mg and acetaminophen 300 mg (CA, n = 160), the active comparator, every 6 to 8 hours as needed for pain. Efficacy was measured through pain relief scores, number of daily doses of study medication, number of daily doses of supplemental analgesics, number of patients who discontinued therapy due to an unsatisfactory analgesic response, and global assessment scores. RESULTS Of the 469 patients, 255 (54.4%) were female and 214 (45.6%) were male. The mean age was 51.1 years. Types of chronic pain included back (214; 45.6%), arthritic (145; 30.9%), other musculoskeletal (65; 13.9%), cancer (6; 1.3%), diabetic neuropathic (3; 0.6%), postherpetic neuralgic (5; 1.1%), other neurologic (21; 4.5%), and other unclassified chronic pain (10; 2.1%). During the 48 hours prior to the study, 351 (74.8%) patients had been treated with opioid or opioid-nonopioid combination analgesics. The overall mean daily pain relief score was significantly greater in the HI2 group (2.25+/-0.89) than in the HI1 group (1.98+/-0.87) (P = 0.003) or the CA group (1.85+/-0.96) (P < 0.001). The overall mean number of daily doses of study medication was significantly less in the HI2 group (2.94+/-0.99) than in the HI1 group (3.23+/-0.76) (P = 0.036) or the CA group (3.26+/-0.75) (P = 0.014). The overall mean number of daily doses of supplemental analgesics was significantly less in the HI2 group (0.24+/-0.49) than in the HI1 group (0.34+/-0.58) (P = 0.021) or CA group (0.49+/-0.85) (P = 0.010). The number of patients who discontinued treatment due to an unsatisfactory analgesic response was significantly less in the HI2 group (2; 1.3%) than in the CA group (12; 7.5%) (P = 0.008). HI2 was more effective than HI1 and CA as measured by pain relief scores for week 1 (P < 0.001 vs HI1 and CA), week 2 (P < 0.001 vs HI1 and CA), and week 3 (P = 0.008 vs HI1 and P < 0.001 vs CA); daily doses of study medication for week 1 (P = 0.019 vs HI1 and P = 0.011 vs CA); daily doses of supplemental analgesics for week 1 (P = 0.010 vs HI1 and CA); and global assessment scores for week 1 (P = 0.018 vs HI1 and P < 0.001 vs CA), week 2 (P = 0.005 vs HI1 and P < 0.001 vs CA), and week 4 (P = 0.013 vs HI1 and P = 0.023 vs CA). There were no significant differences between HI1 and CA in any efficacy variable. There were no significant differences in the number of patients experiencing adverse events in the HI2 (127; 83%), HI1 (124; 79.5%), and CA (129; 80.6%) groups. However, the mean number of patients who discontinued treatment due to adverse events was significantly greater in the HI2 group (40; 26.1%) than in the HI1 group (23; 14.7%) (P = 0.013). CONCLUSIONS The results of this study suggest that 2-tablet doses of combination hydrocodone 7.5 mg and ibuprofen 200 mg may be more effective than either 1-tablet doses of this combination or 2-tablet doses of combination codeine 30 mg and acetaminophen 300 mg. Moreover, 1-tablet doses of combination hydrocodone 7.5 mg and ibuprofen 200 mg may be as effective as 2-tablet doses of combination codeine 30 mg and acetaminophen 300 mg.

Effect of omega-3-acid ethyl esters on the steady-state plasma pharmacokinetics of rosuvastatin in healthy adults

Background: Prescription omega-3-acid ethyl esters (P-OM3) have been used as adjunctive therapy to statin drugs in patients with mixed hyperlipidemia. Objective: To assess the effect of concomitant administration of 4 g P-OM3 on the steady-state pharmacokinetics of the maximum recommended daily dose of atorvastatin (80 mg) in healthy volunteers. Methods: This was a randomized, open-label, repeated-dose, two-way crossover, drug interaction study of two treatments: 4 g of P-OM3 with 80 mg atorvastatin daily or 80 mg atorvastatin daily, each administered for 14 days under fasting conditions to 50 healthy adults. Main outcome measures: The primary determinants of drug interaction were the ln-transformed area under the plasma concentration versus time curve (AUCτ) and maximum measured steady-state plasma concentration (Cmax,ss) over the final 24 h dosing interval (day 14) for atorvastatin and 2-hydroxyatorvastatin. Safety assessment included clinical laboratory evaluations and adverse event reporting. Results: The extent and rate of exposure (AUCτ, Cmax,ss) to atorvastatin and its active metabolites following daily administration of P-OM3 with atorvastatin (80 mg) were similar to those following the administration of atorvastatin (80 mg) alone. Both treatments were well tolerated. Conclusions: After 14 days of dosing, the rate and extent of exposure (AUCτ, Cmax,ss) to atorvastatin and its active metabolites were similar with both treatments, indicating that administration of P-OM3 did not affect the steady-state bioavailability of orally administered atorvastatin.

Long-term up to 24-month efficacy and safety of concomitant prescription omega-3-acid ethyl esters and simvastatin in hypertriglyceridemic patients

Abstract Objective: Assess the long-term efficacy and safety of prescription omega-3-acid ethyl esters (P-OM3) coadministered with simvastatin in an extension of the Combination of Prescription Omega-3 Plus Simvastatin (COMBOS) trial. Methods: COMBOS included hypertriglyceridemic patients (triglyceride [TG] ≥200 mg/dL and <500 mg/dL or ≥2.26 mmol/L and <5.64 mmol/L) with low density lipoprotein cholesterol (LDL-C) level no greater than 10% above the National Cholesterol Education Program, Adult Treatment Panel III treatment goal. After an 8-week lead-in phase with simvastatin 40 mg/day (which continued throughout the trial), subjects were randomized to 8 weeks of P-OM3 4 g/day or placebo. Completers were eligible to participate in a 24-month extension study. Those who received placebo + simvastatin in COMBOS switched to open-label P-OM3 + simvastatin (‘Switchers’); those who received P-OM3 + simvastatin during COMBOS continued the same regimen (open-label) in the extension phase (‘Non-switchers’). The primary endpoint was the difference between Non-switchers and Switchers in median percent change in non-high-density lipoprotein-cholesterol (non-HDL-C) from COMBOS end of treatment to Month 4 of the extension phase. Results: At Month 4 from COMBOS end of treatment, non-HDL-C was reduced by a median of 9.4% in Switchers and increased by 0.9% in Non-switchers (p < 0.001). For the total population (combined Non-switcher + Switcher population), the median percent change from COMBOS baseline to Months 4, 12, and 24 was −8.3%, −7.3%, and −8.9%, respectively (all p < 0.001). This extension study revealed no unexpected safety findings. A limitation of this study was a gap between completion of COMBOS and enrollment in the extension phase for some patients; however, a post-hoc non-HDL-C sensitivity analysis performed at the 4-month primary endpoint revealed no influence of gap on study results. Conclusions: In this 24-month extension study, P-OM3 was generally well tolerated, and produced sustained reductions in non-HDL-C levels in simvastatin-treated patients with TG levels between 200 and 500 mg/dL (2.26 mmol/L and 5.64 mmol/L). Clinical Trial Registry Number: NCT00903409.

The effect of prescription omega-3 fatty acids on body weight after 8 to 16 weeks of treatment for very high triglyceride levels.

Abstract Background: Prescription omega-3-acid ethyl ester (P-OM3; Lovaza®) therapy is indicated for treating very high triglyceride levels (≥ 500 mg/dL) at a dose of 4 g/day. The caloric content associated with each 1-g capsule of P-OM3 is ∼11 Cal (Cal = kilocalories) — ∼9 Cal from the oil in the capsule that contains omega-3 fat and ∼2 Cal attributed to the components of the capsule shell. Thus, the 4-g/day dose contributes ∼44 Cal/day, with ∼36 Cal/day derived from the oil. Methods: This analysis evaluated 167 dyslipidemic (triglycerides: ≥ 500 mg/dL and < 1300 mg/dL), overweight/obese (body mass index [BMI] ≥ 25 kg/m2 and ≤ 43 kg/m2) patients aged 18 to 79 years. Data were derived from an 8-week, randomized, double-blinded, placebo-controlled, parallel-group trial comparing P-OM3 4 g/day + fenofibrate 130 mg/day (n = 84) versus placebo (4 g/day of corn oil) + fenofibrate 130 mg/day (n = 83), and an 8-week open-label extension (n = 117), during which all subjects received P-OM3 + fenofibrate. Subjects who received P-OM3 + fenofibrate continued the same treatment in the extension phase (non-switchers; n = 59). Those who initially received corn oil placebo + fenofibrate received P-OM3 + fenofibrate in the extension phase (switchers; n = 58). Results: During the 8-week double-blind phase in subjects receiving fenofibrate, the addition of P-OM3 (versus placebo) did not significantly change median (minimum, maximum) body weight (P-OM3 = 0 [−4.6, +4.2] kg, placebo = 0 [−3.6, +5.5] kg; P = 0.088) or waist circumference (P-OM3 = +0.1 [−12.1, +17.5] cm, placebo = +0.5 [−9.9, +12.2] cm; P = 0.162). In the 8-week extension phase, non-switchers and switchers did not differ in median change from the end of the double-blind phase in body weight (non-switchers = +0.2 [−3.2, +5.6] kg, switchers = +0.1 [−6.9, +7.9] kg; P = 0.982), or waist circumference (non-switchers = +0.1 [−9.8, +41.8] cm, switchers = +0.2 [−12.0, +7.0] cm; P = 0.685). Conclusion: When coadministered with fenofibrate for up to 16 weeks, the modest daily caloric contribution of P-OM3 (4 g/day) did not alter body weight or waist circumference compared with baseline or compared with fenofibrate plus placebo in patients with very high triglyceride levels.