A phase 3, randomized, double-blind comparison of analgesic efficacy and tolerability of Q8003 vs oxycodone or morphine for moderate-to-severe postoperative pain following bunionectomy surgery.

OBJECTIVE: Compare the efficacy and tolerability of the dual-opioid, Q8003(®) (morphine/oxycodone combination) 12 mg/8 mg to morphine 12 mg or oxycodone 8 mg in subjects following bunionectomy surgery. DESIGN: This was a randomized, double-blind study. SETTING: Hospitalized patients. PATIENTS: Healthy men or women aged ≥18 years with moderate or severe pain (score ≥2 on a 4-point Likert scale) and ≥4 on the 11-point numerical pain rating scale following surgery. INTERVENTIONS: Study medication was initiated after surgery and was given for 48 hours. OUTCOMES: The primary efficacy variable was mean sum of the pain intensity difference (SPID) scores from the postsurgical baseline. RESULTS: Five hundred twenty-two subjects were randomized; 31 (5.9%) discontinued, including 19 (3.6%) for adverse events. The mean total morphine equivalent dose (MED) was 182.7 mg from Q8003 12 mg/8 mg, 92.4 mg for morphine 12 mg, and 92.1 mg for oxycodone 8 mg. SPID from baseline over 24 hours and SPID from baseline over 48 hours were significantly (P < 0.02) higher for Q8003 12 mg/8 mg vs morphine 12 mg or oxycodone 8 mg. Significantly (P < 0.015) fewer subjects in the Q8003 group required ibuprofen rescue medication, used lower doses of rescue medication, and had a longer median time to first use of rescue medication. Oxygen desaturation <90% occurred in 5.3% with Q8003, 2.8% with morphine 12 mg, and 2.3% with oxycodone 8 mg, and the cumulative median dose at first desaturation was twofold greater with Q8003. CONCLUSION: Q8003 provided superior efficacy to its individual components at twice the MED with only a modest increase in the incidence of adverse events.

Comparison of the efficacy and safety of dual-opioid treatment with morphine plus oxycodone versus oxycodone/acetaminophen for moderate to severe acute pain after total knee arthroplasty.

BACKGROUND: In acute pain models, coadministration of low doses of morphine and oxycodone markedly enhanced analgesia relative to either opioid given alone. Enhanced analgesia with coadministration of morphine and oxycodone has also been reported in acute and chronic moderate to severe pain conditions during double-blind studies. OBJECTIVE: The goal of this study was to compare the efficacy and tolerability of a flexible dose regimen of the morphine/oxycodone combination versus oxycodone/acetaminophen and fixed low-dose morphine/oxycodone. METHODS: This was a 5-center, randomized, open-label study of hospitalized patients (n = 44) with acute moderate to severe postoperative pain after total knee arthroplasty. Inpatients were randomized to a flexible dose regimen of morphine/oxycodone (3 mg/2 mg to 24 mg/16 mg), fixed low-dose morphine/oxycodone regimen (3 mg/2 mg), or oxycodone/acetaminophen (5 mg/325 mg). Treatment was initiated following surgery after intravenous (IV) morphine patient-controlled analgesia. An algorithm was evaluated for converting the patient-controlled analgesia morphine dose to an initial oral dose of morphine/oxycodone. The primary efficacy variable was the time-weighted sum of pain intensity difference from 0 to 48 hours. RESULTS: The median values for the sum of the pain intensity difference from 0 to 48 hours for the morphine/oxycodone flexible dose and oxycodone/acetaminophen were similar and approximately twice that of fixed morphine/oxycodone 3 mg/2 mg (148.0, 139.5, and 71.3, respectively). Moderate to severe gastrointestinal adverse events occurred in 50% of patients in the oxycodone/acetaminophen group compared with 15% of the equianalgesic morphine/oxycodone group. On several items of the Brief Pain Inventory (general activity, walking ability, and sleep), the morphine/oxycodone flexible dose produced greater benefit than oxycodone/acetaminophen. CONCLUSIONS: Flexible dose morphine/oxycodone was superior to low-dose morphine/oxycodone and comparable to oxycodone/acetaminophen. Flexible dose morphine/oxycodone-treated patients had a lower rate of moderate to severe nausea or vomiting than equianalgesic oxycodone/acetaminophen-treated patients. Thus, morphine/oxycodone offers an attractive alternative to oxycodone/acetaminophen for the management of moderate to severe postoperative pain.

Analgesic efficacy and tolerability of intravenous morphine versus combined intravenous morphine and oxycodone in a 2-center, randomized, double-blind, pilot trial of patients with moderate to severe pain after total hip replacement.

BACKGROUND: Results from studies with a combination of oral morphine and oxycodone in postsurgical patients demonstrate significant analgesia and a tolerability profile comparable to other pain medications at morphine-equivalent doses. However, an intravenous (IV) combination has not previously been studied. OBJECTIVE: This study evaluated the efficacy and tolerability of IV morphine versus a combination of IV morphine and IV oxycodone in a 1:1 ratio. METHODS: This was a 2-center, randomized, double-blind, active-controlled pilot trial of 40 patients who had undergone total hip replacement. After surgery, when pain levels reached ≥4 (on the 11-point Numerical Pain Rating Scale), patients were randomized to 1 of 2 treatment groups. In part 1 of the study, patients were dosed every 5 minutes for the first 65 minutes (up to 13 doses) with study drug, provided that vital signs criteria were met. After an initial loading dose of either morphine 1.5 mg coadministered with oxycodone 1.5 mg or morphine 3 mg alone, patients received IV morphine 1.5 mg or IV morphine 0.75 mg/IV oxycodone 0.75 mg every 5 minutes. If patients achieved a pain score of 2 or experienced intolerable adverse events to drug when stable, they were permitted to enter part 2. In part 2, patients received blinded study medication (IV morphine plus IV oxycodone [0.5 mg/0.5 mg] or 1 mg IV morphine alone) via patient-controlled analgesia (PCA) for 47 hours. RESULTS: At baseline, treatment groups were comparable except for a higher proportion of females in the IV morphine group. Baseline pain intensity averaged 7 on the Numerical Pain Rating Scale of 0 to 10. One patient in the morphine group and 2 patients in the morphine/oxycodone group discontinued the study. The sum of the pain intensity differences from baseline to 65 minutes during the dose-titration phase was 1.8 for morphine alone versus 2.7 for morphine/oxycodone (P = 0.12); these values occurred at the same median number of doses (12) for each group. In part 2 (PCA dosing) of the study, similar levels of analgesia were achieved. During the study, 24% of the IV morphine/oxycodone group and 37% of the IV morphine group experienced nausea, and 10% of the IV morphine/oxycodone group and 16% of the IV morphine group had emesis. Two patients in the IV morphine/oxycodone group and 4 in the IV morphine alone group experienced oxygen desaturation. CONCLUSIONS: The combination of IV morphine and oxycodone provided pain relief with an acceptable tolerability profile in these patients experiencing moderate to severe postoperative pain. However, as an explorative pilot study, the power was not adequate to demonstrate statistical significance for differences between IV morphine/oxycodone and IV morphine alone. European Clinical Trials Data Base registration code: EudraCT-No. 2008-008527-14.

Analgesic and adverse effects of a fixed-ratio morphine-oxycodone combination (MoxDuo) in the treatment of postoperative pain.

OBJECTIVE: To compare efficacy and safety profiles of an immediate-release morphine and oxycodone Dual-Opioid combination (MoxDuo) versus its individual components and versus its morphine-equivalent doses in moderate to severe postoperative pain patients. DESIGN: Randomized, double-blind, 48-hour, parallel-treatment, multicenter, six-arm study of MoxDuo. SETTING: Six US centers. PATIENTS: Within 6 hours after bunionectomy surgery, patients were eligible if they reported pain intensity > or = 2 on the 4-point Likert scale and > or = 4 on an 11-point Numerical Pain Rating Scale (197 randomly assigned; 175 completers). INTERVENTIONS: MoxDuo 12 mg/8 mg, MoxDuo 6 mg/4 mg, morphine 12 mg, oxycodone 8 mg, morphine 6 mg, or oxycodone 4 mg (all administered q6h). MAIN OUTCOME MEASURE: Sum of pain intensity differences 0-24 hours after the first dose of study medication (SPID24) and percentage of patients with moderate to severe nausea, emesis, or dizziness. RESULTS: SPID24 was significantly better in the MoxDuo 12 mg/8 mg group when compared with its individual components (morphine 12 mg [p = 0.009] and oxycodone 8 mg [p = 0.037]), and when compared with MoxDuo 6 mg/4 mg (p = 0.011; 54.3 vs 28.5, 35.7, and 30.0, respectively). MoxDuo6 mg/4 mg and its morphine-equivalent doses (morphine 12 mg and oxycodone 8 mg) had comparable analgesic effects. There was a 50-75 percent reduction in moderate to severe adverse events (AEs) commonly associated with opioids (ie, nausea, vomiting, and dizziness) in the MoxDuo 6 mg/4 mg group when compared with its morphine-equivalent dose groups. CONCLUSIONS: MoxDuo produced superior analgesic effects when compared with its individual components, but comparable efficacy when compared with its morphine-equivalent doses. Common AEs were reduced at least 50 percent with MoxDuo when compared with its morphine-equivalent doses. MoxDuo may be an improved intervention in the management of moderate to severe acute pain.

A double-blind, placebo-controlled study of dual-opioid treatment with the combination of morphine plus oxycodone in patients with acute postoperative pain.

OBJECTIVE: animal and human studies suggest that coadministration of two opioids with different receptor binding properties may result in enhanced analgesia and fewer opioid-related adverse events (AEs). Q8003 (MoxDuo), an oral dual-opioid formulation with a fixed ratio (3:2) of morphine and oxycodone, was evaluated for analgesic effects and safety in the management of acute moderate to severe pain. DESIGN: randomized, double-blind, placebo-controlled, ascending-dose cohort, dose-response study with flexible dosing. SETTING: private clinic. PATIENTS: adults undergoing unilateral bunionectomy surgery. Following surgery, patients were required to have moderate or severe intensity pain on a 4-point Likert scale and >or= 4 on an 11-point Numerical Pain Rating Scale to continue in the study. INTERVENTIONS: Q8003 was administered in four ascending-dose cohorts of 3/2, 6/4, 12/8, and 18/12 mg during the 48-hour period following surgery. MAIN OUTCOME MEASURES: sum of the pain intensity differences from baseline over 48 hours (SPID48), percentage of responders, and use of ibuprofen. RESULTS: Of 263 patients, 256 were randomly assigned to treatment. In patients treated with Q8003, 12 to 18 percent withdrew before study completion versus 30 percent on placebo. The mean dose of morphine/oxycodone per 6-hour period and the mean interdose interval (hours) was 6/4 mg (2.9), 9.8/6.5 mg (4.1), 11/7.5 mg (6.8), and 15/10 mg (6.6) for the 3/2-, 6/4-, 12/8-, and 18/12-mg groups, respectively. The mean SPID48 was significantly greater with each Q8003 dose when compared with placebo (p - 0.0017 for all doses versus placebo). The 12/8-mg group (11/7.5 mg/6 h) had the greatest percentage of patient responders (76 percent; p < 0.001 versus placebo) and required the fewest daily doses of ibuprofen. AEs were typical of those associated with opioid use, with the highest occurrence for nausea (38-65 percent) and low rates of somnolence (2-8 percent). Minimal or no changes in respiration and blood oxygenation were observed and euphoria was not reported. CONCLUSIONS: the 12/8 mg dose of Q8003, an immediate-release formulation, provided the optimal combination of analgesic efficacy and tolerability, with the 3/2 and the 6/4 mg doses being an effective alternative for treatment.