Steady-State Pharmacokinetic Comparison of a New, Extended-Release, Once-Daily Morphine Formulation, Avinza™, and a Twice-Daily Controlled-Release Morphine Formulation in Patients with Chronic Moderate-to-Severe Pain

Abstract

Extended-release morphine formulations are widely used in the management of chronic pain. Avinza (morphine sulfate extended-release [MSER, Morphelan]) is a new, once-a-day, extended-release morphine formulation designed to reach target concentrations rapidly and maintain concentrations throughout a 24-hour period. The primary objective of this study was to compare the 24-hour steady-state pharmacokinetic (PK) profiles of morphine and its metabolites (morphine-6-glucuronide [M6G] and morphine-3-glucuronide [M3G]) following ingestion of MSER once-a-day and MS Contin (controlled-release morphine sulfate [CRM]) twice-a-day in patients with chronic moderate-to-severe pain. Ten patients with chronic moderate-to-severe pain were recruited into an open-label, multiple-dose, nonrandomized, two-period, single-center study. All patients were stabilized for a minimum of 7 days on a twice-daily dose of CRM associated with an optimal balance between pain control and side effects. Patients were then switched to the closest equivalent once-daily dose of MSER for a minimum of 10 days. Twenty-four hour steady-state PK profiles were obtained on the last day of each treatment period and additional clinical and safety assessments were performed. PK data were normalized to a 100-mg total daily dose prior to statistical analysis. Nine of the 10 patients completed the entire study. MSER and CRM demonstrated similar bioavailability (AUC) of morphine and its metabolites. Compared to CRM, MSER demonstrated a 19% lower maximum concentration (C(max)), a 66% higher minimum concentration (C(min)), and a 44% lower peak-to-trough fluctuation (%FI) over the 24-hour period. In addition, MSER maintained concentrations above 50% and 75% of the C(max) longer than CRM. Clinical efficacy and safety were comparable for MSER and CRM. Once-daily MSER approaches maximum morphine concentration more quickly, approximates maximum concentration longer, and demonstrates less fluctuation in morphine concentration during a 24-hour period than CRM dosed twice daily. The pharmacodynamic implications of this profile deserve further study.

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

“…38 Moreover, evidence suggests that longer-acting agents provide more consistent blood plasma levels and may prevent end-of-dose failure. 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.…”

“…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.…”

Recent advances in clinical use of opioids

“…Portenoy et al [11] studied the pharmacokinetics of Avinza given once daily, comparing it with that of MSContin (morphine sulfate controlled-release, Purdue Pharma L.P., Stamford, CT) administered every 12 hours. Compared with MS-Contin, Avinza demonstrated a lower maximum concentration, a higher minimum concentration, and a 44% lower peak-to-trough fluctuation over the 24-hour period.…”

Differential therapeutic aspects of analgesia with oral sustained-release strong opioids

“…Auch in klinischen Studien konnte ge zeigt werden, dass eine mangelhafte post operative Schmerztherapie in hohem Ma ße mit chronischen Schmerzen einhergeht [41] [12,47,48,49,50,51]. Allerdings wur den in der gut kontrollierten Studie [11] Vorteile bei der Schlafqualität unter ein mal täglicher Gabe beobachtet.…”