Current Issues Pain Management Figure 3: Efficacy of EMBEDA15 A 8 6 4 2 0 Pre-titration Baseline B
10 20 30 40 50
0 Worst Least Average Pain category KADIAN® EMBEDA® Pre-titration
In-clinic and diary pain scores (0–10 scale; 0 = no pain, 10 = pain as bad as you can imagine). A: In-clinic pain intensity scores at baseline and on days seven and 14 (data from periods 2 and 4 combined). B: Daily diary pain scores summed over 14 days of treatment (data from periods 2 and 4 combined). SEM = standard error of mean. Adapted from Katz et al., 2010,15
with permission from Elsevier.
Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index (pain, physical function, and composite index subscale) scores were statistically similar.15
There were no significant differences between
treatments in change from baseline scores for WOMAC pain, physical function, and composite index subscales.15
There was no positive
correlation of time-matched plasma naltrexone and/or 6-β-naltrexol concentrations with pain scores, indicating that negligible amounts of naltrexone that may be present in the blood had no impact on the extent of analgesia experienced by patients.15
Efficacy of EMBEDA in the Management of Chronic Moderate to Severe Pain
The analgesic efficacy of EMBEDA was determined in patients (n=547) with chronic moderate to severe pain from osteoarthritis of the hip or knee over a 12-week study period.13,21
Patients were first titrated to an
Compared with placebo, EMBEDA maintained significantly superior analgesia as measured by mean change in diary average pain scores from randomization to the end of study.13,21
20
effective dose of EMBEDA during an open-label treatment period; patients who achieved analgesia, defined as a pain intensity score of ≤4 on an 11-point scale (0 = no pain, 10 = worst pain) and at least a two-point drop from screening baseline pain intensity score, were then randomized to continue treatment with EMBEDA or placebo for a 12-week maintenance period.13,21
Naltrexone Release When EMBEDA Is Tampered with by Crushing
A study in healthy volunteers (n=23) compared the oral bioavailability of naltrexone released after pellets from a 60mg capsule (60mg morphine sulfate/2.4mg naltrexone) were crushed for at least two minutes in a mortar and pestle with that of an oral solution of naltrexone hydrochloride at the concentration present within EMBEDA.24
results indicated that naltrexone was fully released when pellets of EMBEDA were crushed, and had similar bioavailability to that of oral naltrexone hydrochloride solution.13,24
Pharmacodynamic Effects of Crushed EMBEDA A study of non-dependent recreational opioid abusers (n=32) assessed whether naltrexone released from crushed pellets of EMBEDA taken orally would mitigate the morphine-induced euphoria effects sought by drug abusers.14
Morphine Benzedrine Group [MBG], Cole/ARCI stimulation—euphoria US NEUROLOGY Current
Of 465 patients who received EMBEDA for up to one year for chronic moderate to severe pain, 93 (20%) also participated in a pharmacokinetics substudy. Of these 93 patients, 21 (23%) had plasma naltrexone levels greater than the 4.0pg/ml limit of quantification at some time during the study. Of 444 samples analyzed, 49 (11%) had plasma naltrexone concentrations above the limit of quantification. The median plasma naltrexone concentration was 10.1pg/ml (range 4.03–145pg/ml).22
There was no evidence of
There was no evidence of opioid withdrawal in those patients with the highest naltrexone levels.
naltrexone accumulation during the study, nor was there any significant correlation between EMBEDA dose and age or sex of the patient.22
Day 7 Day 14
In an open-label study to assess safety, 465 patients with chronic moderate to severe pain received EMBEDA for up to 12 months. The mean percent change from baseline pain intensity at all visits (except week 1 for least pain), as measured by least, worst, average, and current pain, was statistically significant.22
This 12-month study is one
of the longer outcome studies on opioid analgesia in the literature. Naltrexone Pharmacokinetics
Naltrexone undergoes extensive first-pass metabolism to its primary metabolite 6-β-naltrexol, which also has opioid antagonist properties, albeit at one-twelfth to one-fiftieth the potency of the parent compound.23
As plasma concentrations of 6-β-naltrexol are generally greater than plasma naltrexone concentrations,23
it is possible to
obtain information about low concentrations of naltrexone by also measuring 6-β-naltrexol.
When EMBEDA was taken as directed, the naltrexone remained sequestered; plasma naltrexone concentrations remained below the limit of quantification (4.0pg/ml) for more than 78% of patients (n=72) who had received multiple doses of EMBEDA (20–160mg twice daily) over two 14-day treatment periods.15
However, most patients had at
least one quantifiable 6-β-naltrexol plasma concentration (range 0.3–520pg/ml),15
naltrexone at levels that are clinically insignificant. indicating the presence of trace amounts of
The
Maximum pharmacodynamic effects (Emax) on primary outcome measures (Addiction Research Center Inventory [ARCI]–
Summed scores for
Brief Pain Inventory items (mean ± SEM)
In-clinic pain scores (mean ± SEM)
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