Abstract
Purpose
This study aimed to assess the tolerability of the extended use (≤35 days) of MNK-155,
a biphasic (immediate-release/extended-release) hydrocodone bitartrate/N-acetyl-p-aminophenol (acetaminophen) (IR/ER HB/APAP) 7.5/325-mg fixed-dose combination analgesic
agent, in patients with chronic noncancer pain (CNCP) caused by osteoarthritis or
chronic low back pain. IR/ER HB/APAP tablets deliver 25% of the HB dose and 50% of
the APAP dose by IR and the remainder by ER over a 12-hour dosing interval. Although
IR/ER HB/APAP is being developed for the management of moderate to severe acute pain,
this model of CNCP was used for assessing tolerability over a term longer than would
be possible in a model of acute pain.
Methods
This Phase III, multicenter, open-label study enrolled patients with moderate to severe
OA (knee or hip) pain despite the use of nonopioid or opioid analgesic agents, or
with moderate to severe CLBP present for several hours per day for ≥3 months. Patients
received a 3-tablet initial dose of IR/ER HB/APAP (total dose, 22.5/975 mg) on day
1, followed by 2 tablets of IR/ER HB/APAP (total dose, 15/650 mg) q12h for up to 35
days. Tolerability, the primary end point, was assessed using time to treatment discontinuation,
the prevalence of treatment-emergent adverse events (TEAEs), vital sign measurements,
pulse oximetry, clinical laboratory tests, and compliance. Secondary outcomes included
the modified Brief Pain Inventory–Short Form, the Western Ontario and McMaster Universities
Arthritis Index, and The Roland-Morris Low Back Pain and Disability Questionnaire.
Findings
Of the 153 patients enrolled (95 women [62.1%]; mean age, 53.9 [14.5] years; OA, n
= 73; CLBP, n = 80), 37 (24.2%) discontinued the study early (mean time to discontinuation,
21.3 days). Thirteen patients (8.5%) discontinued because of TEAEs. A total of 88
patients (57.5%) reported ≥1 TEAE, 65 (42.5%) of whom experienced AEs considered by
the investigator as treatment related. The most frequent TEAEs were nausea (16.3%),
somnolence (14.4%), and constipation (11.1%). Eight severe TEAEs were experienced
by 6 (3.9%) patients and included single occurrences of nausea, fatigue, nasopharyngitis,
elevated liver enzymes, headache, nightmare, and ejaculation delay. No serious treatment-related
AEs were reported. Clinically significant changes in laboratory values were reported
in 13 patients, 6 of whom had abnormal liver function test results that did not meet
Hy’s law criteria for acute liver failure. Most laboratory abnormalities were mild
and transient. Measures of pain intensity, function, and quality of life improved
from baseline but in an open-label study these changes cannot be attributed to treatment.
Implications
The safety profile of IR/ER HB/APAP during extended use was consistent with those
of other low-dose opioid/APAP combination products. IR/ER HB/APAP is intended for
acute pain; its efficacy for relief of CNCP would require further evaluation in an
active- or placebo-controlled study. ClinicalTrials.gov Identifier: NCT01722864.
Key words
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Article info
Publication history
Published online: April 23, 2015
Accepted:
March 18,
2015
Identification
Copyright
© 2015 Elsevier HS Journals, Inc. Published by Elsevier Inc. All rights reserved.
