Managing Chronic Moderate to Severe Pain—EMBEDA® Extended Release Capsules for Oral Use
and abuse potential scales, and subjective drug value) observed after oral administration of crushed and intact EMBEDA were significantly less than after administration of morphine sulfate solution (pFigure 4.14 Morphine sulfate solution was more desirable than crushed or intact EMBEDA: 87.5% of patients had some degree of reduced drug-liking after receiving crushed EMBEDA.13,14
Opioid abusers may crush and dissolve extended-release formulations to inject or snort.7
The effects of injecting crushed EMBEDA pellets could not be directly tested because of the potential danger of injecting talc excipients or insoluble particles generated during crushing.25 Preparations of morphine alone and morphine plus naltrexone at the concentration present in EMBEDA were administered intravenously to healthy, non-dependent recreational opioid abusers (n=28) to simulate an intravenous abuse model with crushed EMBEDA; the morphine plus naltrexone combination resulted in 71% of subjects reporting a reduction in euphoria compared with morphine alone.13,26
In the
intravenous study, as in the oral study, drug-liking and high were reduced after administration of morphine and naltrexone compared with administration of morphine alone.26
Conversion to EMBEDA
Patients on other oral morphine formulations can be converted to EMBEDA by administering half of the patient’s total daily oral morphine dose as EMBEDA every 12 hours or administering the total daily oral morphine dose as EMBEDA every 24 hours.13
There is a lack of systematic
evidence about converting to oral morphine sulfate from other opioids. Physicians are advised to refer to published relative potency data and, in general, to give half of the estimated equianalgesic daily morphine demand as the initial dose.13
The higher incidence of adverse events
(AEs) that may occur initially during conversion tends to diminish substantially over time. In both the 12-week study and the 12-month safety study, AEs occurring during the titration periods were more common than during the maintenance periods.21,22
Safety Profile of EMBEDA
The presence of naltrexone in the EMBEDA formulation did not appear to alter the safety profile of EMBEDA compared with KADIAN.15 In phase II and III studies in patients with chronic moderate to severe pain, the most common AEs (frequency ≥10%) were those typically experienced by patients treated with opioids, i.e. constipation and nausea.13
In the 12-week study, the most common treatment- related AEs were constipation (titration phase 30%, maintenance phase 7%) and nausea (titration phase 19%, maintenance phase 11%).13,21
In the long-term safety study, which is described above, the most common AEs were constipation (31%), nausea (22%), vomiting (8%), somnolence (7%), and headache (7%).13,22
Assessment of opioid withdrawal was performed because of the small amounts of naltrexone and 6-β-naltrexol that had been observed in the plasma of some patients treated with EMBEDA.13
In the 12-week
study, no patient taking EMBEDA as directed experienced signs of opioid withdrawal as assessed using the Clinical Opiate Withdrawal Scale (COWS).21,27
During the 12-month safety study, the presence US NEUROLOGY 21 Figure 4: Pharmacodynamics of EMBEDA—’Drug-liking’14
Strong liking
100
75
Neutral
50
024681012 Post-dose time (hours)
Placebo EMBEDA® crushed
SEM = standard error of mean; VAS = visual analog scale. Adapted with permission from Stauffer et al., 2009.14
of naltrexone did not precipitate opioid withdrawal; at the highest naltrexone concentrations there was no evidence of opioid withdrawal as measured by the COWS. Five patients who had COWS scores consistent with moderate opioid withdrawal had not taken EMBEDA as directed.22
Summary
Interventions to stem opioid abuse are needed at many levels, including careful biopsychosocial evaluation, functional outcome monitoring, promotion of assessment and monitoring of patient opioid abuse risk, prescription monitoring, and adequate control of the drug supply chain. EMBEDA is the first product in a new category of opioids that incorporate features designed to diminish the abuse liability of the drug when tampered with and taken orally or by injection. EMBEDA, a long-acting opioid that provides effective pain relief in patients with chronic moderate to severe pain, is designed to reduce euphoria and the subjective ‘high’ associated with abuse when it is tampered with by crushing or solubilization.
Products such as EMBEDA represent a valuable advance when used within a comprehensive approach to pain management. EMBEDA delivers durable analgesia to patients with chronic pain while having features that mitigate the euphoria associated with prescription opioid abuse. Future large-scale epidemiological studies are needed to determine whether formulations such as EMBEDA will prove to be less attractive for abuse in the real-world setting. n
Christopher Gharibo, MD, is Medical Director of Pain Medicine at New York University (NYU)–Hospital for Joint Diseases and an Assistant Professor of Anesthesiology at NYU School of Medicine in New York City. He also maintains a full-time practice at the NYU Center for Study and Treatment of Pain. His areas of clinical expertise include low-back and neck pain of musculoskeletal and spinal origin, cancer pain, and neuropathic pain syndromes.
EMBEDA® MSS intact
Mean ‘Drug-liking’ VAS score (mean ± SEM)
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