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A Phase II, Single-Center, Randomized, Double-Blind Assessment of the Subjective Effects of
®
Acurox (Oxycodone HCI/Niacin) Tablets in Volunteers With a History of Opioid Abuse
Poster #34
Donald R. Jasinski, MD, Professor of Medicine, Chief, Center for Chemical Dependence,
Johns Hopkins Bayview Medical Center, Baltimore, MD
Results
Current strategies to reduce the misuse and abuse of prescription opioids focus on screening and monitoring. A new opioid
­composition with analgesic efficacy and reduced abuse liability would be a valuable therapeutic option.
Oxycodone HCl/niacin tablets (5/30 mg and 7.5/30 mg) are unique compositions of ­IR oxycodone HCl for the treatment of moderate to severe pain, which also includes niacin and functional excipients. The addition of niacin, an essential B vitamin, causes
dose-dependent ­unpleasant but temporary effects, such as flushing, itching, sweating, chills, and headache, if ­oxycodone HCl/
niacin tablets are taken in excess. The functional excipients in ­oxycodone HCl/niacin tablets cause minor but unpleasant irritation to the nasal tissue when oxycodone HCl/niacin tablets are crushed and snorted, and make it difficult to dissolve and inject
intravenously. Here, we report the subjective effects of ­oxycodone HCl/niacin tablets (5/30 mg) when taken orally at 4 times the
recommended 2-tablet dose (8 × 5/30 mg tablets) by individuals with a history of opioid abuse.
Methods
This study was conducted at the inpatient facility at Johns Hopkins Bayview Medical Center, Baltimore, MD, with the approval
of the institutional review board and in accordance with the Guidelines for Good Clinical Practice and ethical principles set forth
in the Declaration of Helsinki. All patients provided informed consent to participate in the trial.
Participants were between the ages of 18 and 55 (inclusive); within ±20% of the ideal body weight for their age, height, and
gender; met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criterion for Opioid Substance
Abuse; and were willing and able to comply with all study requirements.
In this randomized, double-blind, placebo-controlled, crossover assessment of the subjective effects of ­oxycodone HCl/niacin tablets (­5/30 mg), fasted participants received 2 dosing sequences containing a total of 5 doses; each sequence was separated by
48 hours. The goal of the first sequence was to assess the effects of oxycodone HCl on the effects of niacin; ­participants received
niacin 240 mg alone, oxycodone HCl 40 mg/niacin 240 mg, and placebo in random order. The goal of the second sequence was
to assess the subjective effects of ­oxycodone HCl/niacin tablets; participants received oxycodone HCl 40 mg/niacin 240 mg or
­oxycodone HCl 40 mg alone in random order.
The primary outcome measure was the maximum response to the Drug Rating Questionnaire-Subject (DRQS) question, “Do you
like or dislike the drug effect you are feeling now?” This question was rated on a 1 to 29 scale, with “neither like nor dislike” located
in the center of the scale, “dislike an awful lot” on the left, and “like an awful lot” on the right. Secondary outcome ­measures
included results from the Addiction Research Center Inventory (ARCI), a questionnaire with 40 yes/no responses, and consisting of
3 subscales, all of which are based on subjective responses to psychoactive drugs: the Morphine Benzedrine Group Scale (MBG),
which assesses euphoria; the LSD Specific Scale (LSD), which assesses dysphoria and somatic/bodily discomfort; and the Pentobarbital Chlorpromazine Alcohol Group Scale (PCAG), which assesses apathetic sedation. Respondents received 1 point for each
response in the direction of scoring; total score is sum of points.5 Additional secondary outcome measures included results on
the Treatment Enjoyment Assessment Questionnaire (TEAQ), which assesses the patient’s enjoyment of the drug; and the Street
Value Assessment ­Questionnaire (SVAQ), which asks participants to place a dollar value on the test drug.
Vital signs, including blood pressure, heart rate, temperature, respiratory rate, and pupil size, were assessed at baseline and 0.5,
1, 1.5, 2, 3, 4, 5, 6, and 12 hours after dosing.
Oxycodone HCl 40 mg/niacin 240 mg
Morphine Benzedrine
Group Scale
LSD Specific Scale
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Effects of Oxycodone HCl on the Effects of Niacin (Sequence 1)
Results on the primary outcome variable, answers to the question, “Do you like or dislike the drug effect you are feeling now?”,
were statistically significant. At 0.5 hour, niacin 240 mg was significantly disliked when compared with placebo (P=0.03).
­Figure 1 demonstrates the response to this question over time.
On the ARCI questionnaire, scores on both the MBG and LSD subscales differed significantly between niacin 240 mg and placebo
at 0.5 hour after dosing. Niacin 240 mg was associated with significantly higher LSD/dysphoria (P<0.001) and MBG scores. No
significant differences were found between niacin 240 mg and oxycodone HCl 40 mg/niacin 240 mg on the PCAG subscale with
regard to sedation. The intensity of somatic discomfort and dysphoric effects increased 0.5 hour after dosing for both niacin alone
and oxycodone HCl/niacin (Figure 2).
2.5
Mean Score Change From Baseline (DRQS)
Short-acting opioids, such as immediate-release (IR) oxycodone hydrochloride (HCl), are commonly abused via oral routes—
mainly by swallowing and chewing—but may also be administered intranasally or intravenously.3 Nonmedical use of prescription
opioids affects not only the nonmedical users and their families, but also contributes to the undertreatment of pain by decreasing physician willingness to prescribe opioid analgesics.4
Niacin 240 mg
Pentobarbital Chloropromazine
Alcohol Group Scale
Thirty volunteers were admitted to the study and were included in the final analysis.
Introduction
Opioid analgesics are essential to the management of moderate to severe pain.1 Although these medications provide muchneeded analgesia to patients with pain, they also are associated with a potential for abuse. In 2007, an estimated 5.2 million
­individuals—2.1% of the population—used these drugs for nonmedical purposes.2
Placebo
P=0.03 at 0.5 hour, niacin 240 mg vs placebo
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Oxycodone HCl 40 mg/niacin 240 mg
(= 8 × 5/30 mg tablets)
• Niacin 240 mg is significantly disliked relative to placebo (P=0.03 at 0.5 hour).
• Niacin-induced dysphoric effects manifest rapidly, reaching peak at 0.5 hour and thereafter diminishing.
• Oxycodone HCl 40 mg has limited effect on niacin-induced disliking at 0.5 hours after administration.
• At the 1-hour observation and afterward, oxycodone HCl attenuated niacin-induced dysphoric effects.
Oxycodone HCl 40 mg
(= 8 × 5 mg tablets)
Subjective Effects of Oxycodone HCl/Niacin Tablets (Sequence 2)
P=0.033 at 0.5 hour, oxycodone HCl 40 mg/niacin 240 mg vs oxycodone HCl 40 mg
Placebo
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1.0
Effects of Oxycodone HCl on the Effects of Niacin (Sequence 1)
Oxycodone HCl 40 mg/niacin 240 mg
2
Oxycodone HCl 40 mg
(= 8 × 5 mg tablets)
Oxycodone HCl 40 mg/niacin 240 mg
(= 8 × 5/30 mg tablets)
Conclusions
Niacin 240 mg
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Figure 4. Mean ARCI LSD subscale scores
ARCI, Addiction Research Center Inventory
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Oxycodone HCl/niacin tablets (5/30 mg and 7.5/30 mg)
for oxycodone HCl 40 mg/niacin 240 mg and
are compositions of short-acting oxycodone HCl for
oxycodone HCl 40 mg.
the treatment of moderate to severe pain. ­Oxycodone
ARCI, Addiction Research Center Inventory
HCl/niacin tablets contain oxycodone HCl as the sole
active analgesic ingredient, the B ­vitamin niacin, and
a unique composition of functionally in­active ingredients. Here, we report that the addition of niacin to
oxycodone HCl in ­oxycodone HCl/niacin tablets results in an analgesic with less likeability than that of a comparable dose of
­oxycodone HCl alone.
Figure 2. Mean ARCI scores for niacin 240 mg, oxycodone HCl 40 mg/niacin 240 mg, and
placebo.
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Discussion
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The doses of oxycodone HCl and niacin were safe
and well tolerated during this study, as there were
no deaths, serious adverse events, or treatment-­
emergent adverse events leading to early discontinuation at any drug dose. No clinically significant changes
were noted in the laboratory tests, vital signs, pupillary measurements, ­physical examinations, or ECG
assessments. When oxycodone HCl 40 mg was added
to niacin 240 mg there was an increased incidence of
nausea, vomiting, headache, somnolence, euphoric
mood, and pruritus (consistent with known adverse
reactions of oxycodone HCl), as compared with ­niacin
240 mg alone.6 When niacin 240 mg was added to
oxycodone HCl 40 mg there was an increased incidence of fatigue, dizziness, paresthesia, and flushing
(consistent with known adverse reactions of niacin),
as comparared with oxycodone HCl alone.7
Mean Score
Opioid analgesics are commonly abused by ingesting excessive doses for euphoria. ­Acurox Tablets, a unique composition of
immediate-release oxycodone hydrochloride (HCl), niacin, and functional inactive ingredients to treat moderate to severe pain,
are difficult to inject intravenously and produce unpleasant sensations when taken in excess orally or snorted. ­Niacin is well
tolerated at the recommended dose; however, as doses are escalated niacin induces increasingly unpleasant, dysphoric, yet
temporary effects. To assess the effects of oxycodone HCl on niacin-induced effects provided by ­oxycodone HCl/niacin tablets, 30 volunteers with a history of opioid abuse were administered niacin 240 mg alone, oxycodone HCl 40 mg/niacin 240 mg
(8 × 5/30 mg tablets), and placebo in randomized, crossover fashion (sequence 1). The subjective effects of ­oxycodone HCl/
niacin tablets versus oxycodone HCl alone were assessed by administering oxycodone HCl 40 mg/niacin 240 mg (as above)
and oxycodone HCl 40 mg alone in randomized, crossover fashion (sequence 2). The like/dislike response to the Drug Rating
Questionnaire-­Subject was the primary end point and scored on a 29-point visual analog scale. In sequence 1, niacin 240 mg
alone compared with placebo caused ­significant dislike scores at 0.5 hour (P=0.03). At 0.5 hour after drug administration,
oxycodone HCl 40 mg had limited effect on niacin-induced disliking and had dysphoric effects. At 1 hour and afterward, oxycodone HCl attenuated niacin-induced disliking effects. In sequence 2, the combination of oxycodone HCl 40 mg and niacin
240 mg had statistically significant and clinically meaningful like/dislike scores at 0.5 hr (P=0.033) compared with oxycodone
HCl 40 mg alone. In both sequence groups, no serious adverse events occurred, and alterations in vital signs were not clinically meaningful between treatments. These results suggest that ­oxycodone HCl/niacin tablets may have a lower abuse liability than oxycodone HCl alone.
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Figure 1. Effect of oxycodone HCl on effects of niacin: “Do you like or dislike the drug effect
you are feeling now?”
DRQS, Drug Rating Questionnaire-Subject
Subjective Effects of Oxycodone HCl/Niacin Tablets (Sequence 2)
­ xycodone HCl/niacin tablets administered at 4 times the recommended dose (40/240 mg) were disliked when compared with
O
the same dose of oxycodone HCl alone (P=0.033 at 0.5 hour after administration) (Figure 3).
In addition to significant like/dislike scores, significant LSD/dysphoria scores on the ARCI questionnaire (P<0.001) provide
­evidence for concluding that the like/dislike scores are clinically meaningful (Figure 4).
The maximum niacin-induced disliking effects based on the DRQS and ARCI were exerted at 0.5 hour. Volunteers taking ­oxycodone
HCl/niacin tablets disliked the drug within 0.5 hour of administration. The pre-dose likeability of the drug returned in 1 hour, after
which like­ability increased over the next 4 hours and then declined to pre-dose likeability by 12 hours after dosing. Those taking
­oxycodone HCl 40 mg alone liked the drug within 0.5 hour after administration and continued liking it for 3 hours after administration; like­ability decreased to baseline likeability by 12 hours. Differences between MBG, PCAG, and SVAQ scores did not achieve
statistical significance.
When asked 24 hours after drug administration what they would pay for the study drug they had received (SVAQ), volunteers
indicated a tendency to pay less for ­oxycodone HCl/niacin tablets than for oxycodone HCl alone, although these results did not
achieve statistical ­significance (P=0.097).
In response to the question, “Which treatment would you like to take again?” (TEAQ), 23 (77%) of 30 volunteers preferred
­(P<0.005) oxycodone HCl 40 mg alone to oxycodone HCl 40 mg/niacin 240 mg (4 times the recommended dose of ­oxycodone
HCl/niacin tablets).
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• Four times the recommended dose of o­ xycodone HCl/niacin tablets (ie, 40/240 mg) was significantly ­disliked compared
with oxycodone HCl 40 mg alone (P=0.033 at 0.5 hour).
• Oxycodone HCl is preferred to o­ xycodone HCl/niacin tablets: 77% of participants chose oxycodone HCl 40 mg alone compared to an equivalent dose of oxycodone HCl in 4 times the recommended 2-tablet dose of o­ xycodone HCl/niacin tablets
in response to the TEAQ (P=0.005).
2.5
Mean Score Change From Baseline
®
Safety/Tolerability
Continuous variables were summarized by descriptive statistics; categorical variables were summarized by counts and percents.
Interval estimates were constructed using 0.95 as the level of confidence. For the primary and secondary efficacy analyses,
analy­sis of covariance (ANCOVA) models were used to analyze continuous ­variables. Adverse events, laboratory data, and physical examination data were tabulated. Treatment-emergent adverse events were reported and tabulated for each volunteer.
Mean Score
Abstract
American Society of Addiction Medicine Annual Meeting April 30–May 3, 2009
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References
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1. Gilson AM, Ryan KM, Joranson DE, et al. A reassessment of trends in the medical use and abuse of opioid analgesics and implications for diversion control: 19972002. J Pain Symptom Manage. 2004;28(2):176-188.
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2. Substance Abuse and Mental Health Services Administration. Results from the 2007 National Survey on Drug Use and Health: National Findings (Office of Applied
Studies, NSDUH Series H-34, DHHS Publication No. SMA 08-4343). Rockville, MD: SAMSHA, Office of Applied Studies; 2008:1-306. http://oas.samha.gov.
Accessed March 24, 2009.
3. Passik SD, Hays L, Eisner N, Kirsh KL. Psychiatric and pain characteristics of prescription drug abusers entering drug rehabilitation. J Pain Palliat Care Pharmacother.
2006;20(2):5-13.
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4. Bhamb B, Brown D, Hariharan J, Anderson J, Balousek S, Fleming MF. Survey of select practice behaviors by primary care physicians on the use of opioids for chronic
pain. Curr Med Res Opin. 2006;22(9):1859-1865.
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5. Haertzen CA. An overview of Addiction Research Center Inventory scales (ARCI): An appendix and manual of scales (DHEW Publication No. [ADM] 74-92). Rockville,
MD: National Institute on Drug Abuse; 1974.
6. Stegmann JU, Weber H, Steup A, Okamoto A, Upmalis D, Daniels S. The efficacy and tolerability of multiple-dose tapentadol immediate release for the relief of acute
pain following orthopedic (bunionectomy) surgery. Curr Med Res Opin. 2008 Oct 10. [Epub ahead of print].
7. Guyton JR, Goldberg AC, Kreisberg RA, Sprecher DL, Superko HR, O’Connor CM. Effectiveness of once-nightly dosing of extended-release niacin alone and in
combination for hypercholesterolemia. Am J Cardiol. 1998;82(6):737-743.
Figure 3. Subjective effects of oxycodone HCl/niacin tablets: “Do you like or dislike the drug
effect you are feeling now?”
Acurox is a registered trademark of Acura Pharmaceuticals, Inc. Acura has entered into a License, Development and Commercialization Agreement with King
Pharmaceuticals, Inc. Acurox® is an investigational drug and has not received approval by the US Food and Drug Administration. Research was supported by Acura
Pharmaceuticals, Inc., and King Pharmaceuticals, Inc. © 2009 King Pharmaceuticals, Inc. All rights reserved. Presented at the American Society of Addiction Medicine’s
40th Annual Medical-Scientific Conference, New Orleans, LA, April 30–May 3, 2009.