Download evaluation for flushing, safety and tolerability of niacin

EVALUATION FOR FLUSHING, SAFETY AND TOLERABILITY OF NIACIN (N) IN COMBINATION WITH 40 MG OF OXYCODONE (O)
D. R. Jasinski; Johns Hopkins, Baltimore, MD
ABSTRACT
METHODS
Background: The objectives were 1) to determine the
dose response, safety, tolerability and abuse for N
flushing in opioid abusers when administered with O and
2) to evaluate the effect of food on N flushing. Methods:
This is a double-blind, randomized, crossover study in 25
subjects who received drug every 48 hours. The dosing
sequence included N (0, 240, 480, and 600 mg) with O
while the subjects were fasted. On Day 9, 600 mg N with
O was administered following a standardized high-fat
breakfast. Each dosing day, vital signs, subjective and
behavioral effects were assessed at -0.5 and at 0.5, 1, 1.5,
2, 3, 4, 5, 6, and 12 hours. Subjective changes were
measured with the Drug Rating Questionnaire
(subjects)-DRQS and a short form of the Addiction
Research Inventory (ARCI), at completion, subjects
completed the Treatment Enjoyment Assessment
Questionnaire. The maximum scale response to the
question “Do you dislike the drug effect you are feeling
now?” or Disliking Score in the DRQS is the primary
efficacy variable. Results: 25 subjects (3 female and 22
male) entered but 1 male subject withdrew. Analysis was
for the 24 completers. N does not alter the time course of
subjective effects or pupillary constriction of O. After the
high fat meal, the peak subjective effects and pupillary
constriction occur at 3 to 4 hours indicating a delay in the
absorption of O. In the fasting state, all 3 doses of N
added to O produced significant Disliking Scores;
however, the linear regression across dose is not
significant. The high fat meal eliminated the N effect. No
other subjective measure was significantly affected by the
N. N produced a dose related attenuation of the pupillary
constriction, diastolic increase and probably systolic
blood pressure increase produced by O. Therewere no
serious adverse events. Conclusion: N to O in a minimal
ratio of 30 mg N to 5 mg O is aversive when compared to
O. The addition of N does not alter the safety profile of O
alone.
STUDY OBJECTIVES
PHYSIOLOGIC MEASURES
1. Determine the dose response for niacin-induced
flushing when niacin is combined with 40 mg
oxycodone HCl
2. Evaluate the safety and tolerability of such
niacin–induced flushing following varying
combined niacin doses
3. Confirm the strength of niacin to use in a
formulation ofoxycodone
4. Determine whether the flushing by niacin is
sufficient to deter abuse
5. Evaluate the effect of food on flushing from the
niacin and oxycodone flushing
1. Pupil Size
2. Systolic and Diastolic Blood
Pressure
3. Pulse Rate
4. Oral Temperature
5. Respiratory Rate
BACKGROUND
Abusers tamper with prescription opioids such
as oxycodone for intravenous injection;
1. intranasal snorting and oral ingestion of
excessive quantities
2. Acura Pharmaceuticals, Inc has developed
Acurox™ (oxycodone HCl and niacin)
Tablets to reduce such tampering
a. Gel forming polymer to reduce extraction
b. A mucosal irritating surfactant to
discourage inhalation
c. Niacin (Vitamin B3) to induce flushing at
levels exceeding the recommended
dosage.
patientresearch
care
STUDY DESIGN
1. 21 male and 3 female opioid abusers on a
residential unit
2. Double-blind, randomized, cross-over design
3. Five single doses of drug every 48 hours over 9
days
4. Days 1, 3,5,7
a. niacin 0, 240, 480, and 600 mg in
combination with oxycodone HCL 40 mg to
fasting subjects
b. given in random order according to 6 4X4
Latin Squares
5. Day 9
a. niacin 600 mg in combination with oxycodone
HCl 40 mg
b. administered orally after a standardized fatty
meal
RESULTS
Dunnett t
1. DRQS and Physiologic
Measures
a. Before dosing and at 0.5,
1, 1.5, 2, 3, 4, 5, 6, and 12
hours after dosing
b. Maximum change from
baseline used as measure
of drug effect
2. ARCI
a. 0.5, 1, 1.5, 2, 3, 4, 5, 6,
and 12 hours after dosing
b. Maximum response used
as measure of drug effect
3. TEAQ
a. 24 hours after last drug
administration
b. Choice of one treatment
to take again
(J) Drug
Dependent Variable
Condition
Condition
Do you feel a drug
240 mg
0 mg
effect now?
niacin
niacin
480 mg
0 mg
niacin
niacin
600 mg
0 mg
niacin
niacin
240 mg
0 mg
effect you are feeling niacin
niacin
now?
480 mg
0 mg
niacin
niacin
600 mg
0 mg
niacin
niacin
Do you dislike the
240 mg
0 mg
drug effect you are
niacin
niacin
feeling now?
480 mg
0 mg
niacin
niacin
600 mg
0 mg
niacin
niacin
Morphine Benzedrine 240 mg
niacin
480 mg
0 mg
niacin
niacin
600 mg
0 mg
niacin
niacin
Pentobarbital
240 mg
0 mg
Chlorpromazine
niacin
niacin
Alcohol Group Scale
480 mg
0 mg
niacin
niacin
600 mg
0 mg
niacin
niacin
240 mg
0 mg
niacin
niacin
480 mg
0 mg
niacin
niacin
600 mg
0 mg
niacin
niacin
LSD Specific Scale
*
Difference
Std. Error
(I-J)
0 mg
niacin
Group Scale
Sig.
1.8
1.7
0.31
1.2
1.7
0.46
3.9*
1.7
0.03
-0.8
1.8
0.88
-1.1
1.8
0.92
-1.2
1.8
0.92
5.1
2.4
0.05
Dependent
Variable
(I) Drug
Condition
(J) Drug
Condition
Pupil Size
240 mg
niacin
0 mg niacin
480 mg
niacin
0 mg niacin
600 mg
niacin
0 mg niacin
240 mg
niacin
0 mg niacin
480 mg
niacin
0 mg niacin
600 mg
niacin
0 mg niacin
Diastolic Blood
Pressure
*
6.3
*
2.4
0.01
9.0
*
2.4
0.00
-0.2
0.7
0.99
0.1
0.7
1.00
0.0
0.7
1.00
0.0
0.6
1.00
*
0.6
0.04
0.6
0.10
-1.4
-1.2
0.6
0.5
Mean
Difference
Std. Error
(I-J)
.01
.152
.02
.152
*
.15
.39
.17
1.515
-2.08
1.515
*
1.51
-4.21
0.5
0.67
0.7
0.5
0.38
(I) Drug
Condition
(J) Drug
Condition
Do you dislike
the drug effect
you are feeling
now?
600 mg
niacin
0 mg niacin
600 mg
niacin (with
high fat
meal)
0 mg niacin
Diastolic Blood
Pressure
600 mg
niacin
0 mg niacin
600 mg
niacin (with
high fat
meal)
0 mg niacin
600 mg
niacin
0 mg niacin
600 mg
niacin (with
high fat
meal)
0 mg niacin
Pupil Size
*
9.0
*
1.6
-4.2
2.6 0.751
*
0.3
0.4
1.7 0.029
1.7 0.972
*
-0.2
2.6 0.002
0.1 0.017
0.1 0.192
The mean difference is significant at the .05 level.
Effects of High Fat Meal on Niacin Effects
1. High fat meal eliminated the niacin effect
2. High fat meal also delayed the time to peak for oxycodone effects
TREATMENT ENJOYMENT ASSESSMENT QUESTIONAIRRE
0.49
0.5
Mean
Difference Std.
Error Sig.
(I-J)
Dependent
Variable
The mean difference is significant at the .05 level.
Choice
Percent
None of the drugs
6
25.0
0 mg niacin + 40 mg oxycodone
2
8.3
240 mg niacin + 40 mg oxycodone
4
16.7
480 mg niacin + 40 mg oxycodone
1
4.2
600 mg niacin + 40 mg oxycodone
1
4.2
600 mg niacin + 40 mg oxycodone
(with high fat meal)
10
41.7
Total
24
100.0
The mean difference is significant at the .05 level.
TREATMENT ENJOYMENT ASSESSMENT QUESTIONAIRRE
1. Highest frequency is the combination with 600 mg of niacin
2. High fat and placebo total 12 of 24 subjects
3. High fat meal was the last treatment condition thereby limiting interpretation
Analysis
• General Linear Model Analysis
of Variance for six 4X4
balanced Latin Squares
1. Drug Rating Questionnaire Subjects (DRQS)
• Individual maximum response
a. Do you feel a drug effect now?
or change from baseline used
b. Do you like the drug effect you are feeling now?
as measure of drug effect for
c. Do you dislike the drug effect you are feeling now?
ANOVA
2. Addiction Research Center Inventory (ARCI)
• Mean responses for niacin
a. Morphine Benzedrine Group Scale (MBG)
dose compared with Dunnet
b. LSD Specific Scale (LSD)
t using error mean square from
c. Pentobarbital Chlorpromazine Alcohol Group
ANOVA
Scale (PCAG)
• Mean response or mean
3. Treatment Enjoyment Assessment Questionnaire
maximum change compared
a. Which of five treatments would like to take again?
graphically
Effects of High Fat Meal on Niacin Effects
Dunnett t (2-sided)
Dunnet t (2- sided)
Mean
(I) Drug
Do you like the drug
OBSERVATIONS
Effect of Niacin Compared to Placebo on Physiologic
Measures
Effect of Niacin Compared to Placebo on Subjective
Measures
SUBJECTIVE MEASURES
CONCLUSION
Effects of Niacin on Oxycodone Subjective Effects
1. All doses of niacin added to oxycodone produced significant disliking scores.
2. Niacin disliking effect tended to be dose related (p=.108)
3. No other statistically significant changes in subjective effects
1. Niacin in the proposed ratio of 30 mg
to 5 mg oxycodone is aversive
2. Niacin does not alter the safety profile
of oxycodone
a. Physiologic changes from largest
dose niacin clinically insignificant
b. No significant differences in
adverse event profile
Effects of Niacin on Oxycodone Physiologic Effects
1. At 600 mg attenuated the pupillary constriction of oxycodone
2. At 600 mg attenuated the diastolic blood pressure increase of oxycodone
THIS STUDY SUPPORTED BY ACURA PHARMACEUTICALS, INC
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