Comparative Efficacy of Oral Extended-Release Hydromorphone and Immediate-Release Hydromorphone in Patients with Persistent Moderate to Severe Pain: Two Randomized Controlled Trials

Abstract

Two multicenter, randomized, double-blind, crossover studies with identical designs evaluated the efficacy of oral extended-release hydromorphone (HHER) administered q24h compared with immediate-release hydromorphone (HHIR) dosed four times daily in patients with persistent moderate to severe pain. Patients titrated to a stable HHER dose were randomized to individualized doses of HHER or HHIR for 3 to 7 days before crossover to the second treatment. Primary efficacy end point was the mean of average pain intensity (API) scores, rated on a 0- to 10-point numeric scale, over the last 2 days before the pharmacokinetics/pharmacodynamics day of each double-blind period. Difference between treatments (HHER - HHIR) in study 1 was 0.17 with a 90% confidence interval (CI) (-0.01, 0.34); in study 2, difference was 0.07 with a 90% CI (-0.12, 0.26). There were no significant differences between treatments in API scores or amount of rescue medication used at any time interval within the 24-hour dosing period. No reduction in pain control occurred in patients administered HHER at the end of the 24-hour dosing period. Most treatment-emergent adverse events were opioid-related. In these studies, HHER administered q24h and HHIR dosed four times daily provided comparable analgesia at an equivalent total daily dose.

A Comparison of Long- and Short-Acting Opioids for the Treatment of Chronic Noncancer Pain: Tailoring Therapy to Meet Patient Needs

“…44 In an open-label study of patients with moderate to severe noncancer pain treated with ER morphine once daily or CR morphine twice daily, the once-daily formulation showed fewer peak-trough fluctuations of serum morphine concentrations and, consequently, more stable plasma opioid levels. 44 In larger studies, 30,43 however, the mean values for the intensity of pain did not differ between the 2 groups, as was seen in a study comparing IR oxycodone with a longeracting oxycodone formulation. 37 In that study, IR oxycodone was titrated to an effective analgesic dose before patients were randomized to an IR or a CR formulation.…”

“…86 In several studies comparing SAOs and LAOs, no definitive evidence linked the pharmacokinetic profile of the formulation and the number of peak-trough fluctuations to the overall incidence of AEs. 37,43,44,48,87,88 For example, some evidence suggests that longer-acting formulations somewhat reduce the incidence of certain AEs (eg, nausea, 85,87 pruritus, 43 constipation 44 ), whereas other LAO studies show slightly increased incidence rates of these AEs. 37,47,48 Several reports have posited a correlation between prolonged use of opioid analgesics and hypogonadism.…”

“…37, 43 Fluctuations in plasma concentrations are less common with LAOs than with ATC dosing of SAOs, and although the maximal concentrations may be lower, they are maintained for longer periods. To obtain stable opioid plasma levels and avoid end-of-dose failure, patients must be meticulous about their adherence to a frequent dosing schedule.…”

Clinical evaluation of the first oxycodone once daily prolonged release tablet in moderate to severe chronic pain: a randomized, double-blind, multicenter, cross-over, non-inferiority study to investigate efficacy and safety in comparison with an established oxycodone twice daily prolonged release tablet

“…In general for analgesic non-inferiority trials, large patient populations and long treatment periods are necessary when using parallel-group study designs [15][16][17] ; however, in the past there have been successful trials employing smaller patient populations and shorter treatment intervals in well controlled cross-over studies [18][19][20][21] .…”

Acute Pain Management in the Emergency Department: Emphasis on NSAIDs

“…Long-acting opioids offer more stable and longer-lasting drug plasma concentrations with fewer peak-to-trough fluctuations and may result in fewer analgesic gaps when consistently dosed. However, with careful dosingand good compliance, long-acting and short-acting opioids can offer similar total systemic opioid serum concentrations and similar levels of pain control [76,77]. In the ED setting, where most pain is nociceptive and acute, short-acting opioids are often more commonly used.…”