Chronic Pain
Conditions
Keywords
opioid tolerant, chronic pain
Brief summary
The purpose of the study is to determine whether extended-release oxymorphone hydrochloride taken orally with a high-fat meal, generating an approximately 50% higher Cmax, impacts cognitive functioning, using Cambridge Neuropsychological Test Automated Battery (CANTAB) tests, to a greater extent than when taking under conditions of fasting.
Detailed description
Oxymorphone 40 mg ER affects cognitive performance similarly within 3 hours post dose, whether given on an empty stomach or after a high-fat meal, suggesting that the altered pharmacokinetics, fed versus fasting and as described above, is not relevant for the medication's impact on cognition. Hence, the direction for oxymorphone ER to be dosed at least 1 hour before or 2 hours after eating, at least from a cognitive perspective, may be without merit.
Interventions
DRUGOxymorphone ER
40 mg qd twice
Sponsors
MedVadis Research Corporation
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Man or woman, 18-65 years of age, inclusive 2. Able to provide informed consent and comply with all study procedures 3. Women of childbearing potential with a negative urine pregnancy test at screening and on adequate contraception 4. Chronic, non-malignant, painful condition, treated with long-acting opioid (methadone, OxyContin®, MS (Morphine Sulfate) Contin®, Kadian®, Avinza®, Fentanyl®, Opana® ER) 5. Opioid treatment for at least 3 months prior to screening at a minimum dose of 90 mg of morphine equivalents per day or 50 mcg of the fentanyl transdermal patch 6. Dose of opioid treatment stable for at least 1 week prior to screening and expected to be stable from screening through end of second testing 7. Weight at screening 100-300 pounds, inclusive
Exclusion criteria
1. Pregnant or breastfeeding 2. Gastrointestinal disorder or S/P gastrointestinal surgery impacting absorption of study medication (delayed gastric emptying, partial or complete gastrectomy) 3. Alcohol or substance abuse within 2 years of screening 4. Consumption of alcohol within 24 hours of a screening or testing visit 5. Consumption of xanthine-containing beverages (coffee, tea, coke) on the morning of a screening or testing visit 6. Impaired kidney or liver function (transaminase levels more than 3 times elevated; estimated creatinine clearance less than 50 mL/min) 7. Epworth sleepiness scale (ESS) score 16 or higher at screening 8. Medically concerning hypertension (≥ 160/100) or unstable cardiovascular illness 9. Any clinically significant illness that would interfere with study participation or put the subject at risk 10. Exposure to investigational medication within 30 days of screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rapid Visual Information Processing (RVP) Sensitivity [A'] | 1 and 3 hours postdose | RVP is a test of sustained attention. It is a sensitive measure of general cognitive performance. A white box appears in the center of the computer screen, inside which digits, from 2 to 9, appear in a pseudorandom order, at the rate of 100 digits per minute. The subject is requested to detect target sequences of three digits (for example, 2-4-6, 3-5-7, 4-6-8) and to register responses using the response box. The two main outcome measures are the probability to detect the predefined sequence (sensitivity \[A'\]) and the speed at which the sequence is registered (response latency \[ms\]). |
| Rapid Visual Information Processing (RVP) Response Latency | 1 and 3 hours postdose | RVP is a test of sustained attention. It is a sensitive measure of general cognitive performance. A white box appears in the center of the computer screen, inside which digits, from 2 to 9, appear in a pseudorandom order, at the rate of 100 digits per minute. The subject is requested to detect target sequences of three digits (for example, 2-4-6, 3-5-7, 4-6-8) and to register responses using the response box. The two main outcome measures are the probability to detect the predefined sequence (sensitivity \[A'\]) and the speed at which the sequence is registered (response latency \[ms\]). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Spatial Recognition Memory (SRM) Test Percentage of Correct Hits | 1 and 3 hours postdose | SRM tests visual spatial recognition memory in a two-choice forced discrimination paradigm. The subject is presented with a white square, which appears in sequence at five different locations on the screen. In the recognition phase, the subject sees a series of five pairs of squares, one of which is in a place previously seen in the presentation phase. The other square is in a location not seen in the presentation phase. Locations are tested in the reverse of the presentation order. The two main outcome measures are the percentage of correct trials (correct hits \[%\]) and the speed of the subject's response (response latency \[ms\]). |
| Spatial Recognition Memory (SRM) Test Response Latency | 1 and 3 hours postdose | SRM tests visual spatial recognition memory in a two-choice forced discrimination paradigm. The subject is presented with a white square, which appears in sequence at five different locations on the screen. In the recognition phase, the subject sees a series of five pairs of squares, one of which is in a place previously seen in the presentation phase. The other square is in a location not seen in the presentation phase. Locations are tested in the reverse of the presentation order. The two main outcome measures are the percentage of correct trials (correct hits \[%\]) and the speed of the subject's response (response latency \[ms\]). |
| Spatial Working Memory (SWM) Test Total Errors | 1 and 3 hours postdose | SWM is a test of the subject's ability to retain spatial information and to manipulate remembered items in working memory. It is a self-ordered task, which also assesses heuristic strategy. The test is a sensitive measure of executive function. It begins with a number of colored squares (boxes) being shown on the screen. By touching the boxes and using a process of elimination, the subject finds blue tokens in a number of boxes and uses them to fill up an empty column on the screen. The number of boxes is gradually increased, until it is necessary to search a total of eight boxes. The color and position of the boxes are changed from trial to trial to discourage the use of stereotyped search strategies. The two main outcome measures are errors (touching boxes that have been found to be empty and revisiting boxes that have already been found to contain a token - total errors) and a measure of strategy (strategy score). |
| Spatial Working Memory (SWM) Test Strategy Score | 1 and 3 hours postdose | SWM is a test of the subject's ability to retain spatial information and to manipulate remembered items in working memory. The test is a sensitive measure of executive function. It begins with a number of colored squares (boxes) being shown on the screen. By touching the boxes and using a process of elimination, the subject finds blue tokens in a number of boxes and uses them to fill up an empty column on the screen. The number of boxes is gradually increased, until it is necessary to search a total of eight boxes. The color and position of the boxes are changed from trial to trial to discourage the use of stereotyped search strategies. The two main outcome measures are errors (touching boxes that have been found to be empty and revisiting boxes that have already been found to contain a token - total errors) and a measure of strategy (For assessed problems with six boxes or more, the number of distinct boxes used by the subject to begin a new search for a token) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Oxymorphone 40 mg (Fed vs Fasting) After completion of the screening process and assuring eligibility in terms of inclusion/exclusion criteria, the subjects were randomized to determine at which testing visit a high-fat meal was to be consumed. (Note: randomization data are not available) They were instructed not to eat or drink, except for water, after midnight on the night before testing, not to consume alcohol within 24 hours of testing and xanthine-containing beverages (coffee, tea, coca cola, energy drinks, etc.) on the morning of the testing. Subjects who were taking an oral opioid were instructed not to take their morning dose on the days of testing, and those who used the transdermal fentanyl patch were instructed not to change the patch the night before.
Each testing visit consisted of an assessment of adverse health and concomitant-medication changes and also a blood alcohol draw, followed by a high-fat breakfast, if applicable. Under supervision, the subjects took the study medication, a single dose of 40 mg oxymorphone ER, with water. Cognitive performance was assessed 1 hour and 3 hours post-dose using three Cambridge Neuropsychological Test Automated Battery (CANTAB) tests. | 30 |
| Total | 30 |
Baseline characteristics
| Characteristic | Oxymorphone 40 mg (Fed vs Fasting) |
|---|---|
| Age, Continuous | 50.2 years STANDARD_DEVIATION 8.7 |
| Opioid dose in morphine equivalent | 206.8 mg STANDARD_DEVIATION 112.1 |
| Opioid use Codeine | 1 Participants |
| Opioid use Fentanyl | 5 Participants |
| Opioid use Hydrocodone | 1 Participants |
| Opioid use Hydromorphone | 1 Participants |
| Opioid use Meperidine | 1 Participants |
| Opioid use Methadone | 12 Participants |
| Opioid use Morphine | 4 Participants |
| Opioid use Oxycodone | 16 Participants |
| Opioid use Propoxyphene | 1 Participants |
| Pain Condition Chronic migraine | 2 Participants |
| Pain Condition Fibromyalgia | 1 Participants |
| Pain Condition Flank pain | 1 Participants |
| Pain Condition Hip pain | 4 Participants |
| Pain Condition Knee pain | 3 Participants |
| Pain Condition Leg pain | 5 Participants |
| Pain Condition Low back pain | 21 Participants |
| Pain Condition Neck pain | 4 Participants |
| Pain Condition Shoulder pain | 1 Participants |
| Pain Condition Wrist pain | 1 Participants |
| Region of Enrollment United States | 30 Participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 30 |
| other Total, other adverse events | 0 / 30 | 0 / 30 |
| serious Total, serious adverse events | 0 / 30 | 0 / 30 |
Outcome results
Primary
Rapid Visual Information Processing (RVP) Response Latency
RVP is a test of sustained attention. It is a sensitive measure of general cognitive performance. A white box appears in the center of the computer screen, inside which digits, from 2 to 9, appear in a pseudorandom order, at the rate of 100 digits per minute. The subject is requested to detect target sequences of three digits (for example, 2-4-6, 3-5-7, 4-6-8) and to register responses using the response box. The two main outcome measures are the probability to detect the predefined sequence (sensitivity \[A'\]) and the speed at which the sequence is registered (response latency \[ms\]).
Time frame: 1 and 3 hours postdose
Population: Completers
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oxymorphone 40 mg With High-fat Meal | Rapid Visual Information Processing (RVP) Response Latency | 1-hour post dose | 447.52 milliseconds | Standard Error 17.47 |
| Oxymorphone 40 mg With High-fat Meal | Rapid Visual Information Processing (RVP) Response Latency | 3-hours post dose | 422.33 milliseconds | Standard Error 15.21 |
| Oxymorphone 40 mg Fasting | Rapid Visual Information Processing (RVP) Response Latency | 1-hour post dose | 455.96 milliseconds | Standard Error 18.63 |
| Oxymorphone 40 mg Fasting | Rapid Visual Information Processing (RVP) Response Latency | 3-hours post dose | 424.62 milliseconds | Standard Error 18.84 |
p-value: <0.001ANOVA
p-value: >0.05ANOVA
Primary
Rapid Visual Information Processing (RVP) Sensitivity [A']
RVP is a test of sustained attention. It is a sensitive measure of general cognitive performance. A white box appears in the center of the computer screen, inside which digits, from 2 to 9, appear in a pseudorandom order, at the rate of 100 digits per minute. The subject is requested to detect target sequences of three digits (for example, 2-4-6, 3-5-7, 4-6-8) and to register responses using the response box. The two main outcome measures are the probability to detect the predefined sequence (sensitivity \[A'\]) and the speed at which the sequence is registered (response latency \[ms\]).
Time frame: 1 and 3 hours postdose
Population: Completers
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oxymorphone 40 mg With High-fat Meal | Rapid Visual Information Processing (RVP) Sensitivity [A'] | 1-hour post dose | 0.94 probability of detecting sequence | Standard Error 0.01 |
| Oxymorphone 40 mg With High-fat Meal | Rapid Visual Information Processing (RVP) Sensitivity [A'] | 3-hours post dose | 0.95 probability of detecting sequence | Standard Error 0.01 |
| Oxymorphone 40 mg Fasting | Rapid Visual Information Processing (RVP) Sensitivity [A'] | 1-hour post dose | 0.93 probability of detecting sequence | Standard Error 0.01 |
| Oxymorphone 40 mg Fasting | Rapid Visual Information Processing (RVP) Sensitivity [A'] | 3-hours post dose | 0.96 probability of detecting sequence | Standard Error 0.01 |
Comparison: The a priori sample-size estimation for a power of 80% with alpha = 0.05 was based on the primary-outcome measure, the rapid visual information processing (RVP) sensitivity (A') score. Using a repeated-measure ANOVA for the food effect (fed versus fasting) and assuming an effect size of f =0.26 generated a required sample size of 32 participants. However, only 30 subjects completed both testing visits, generating a power of 78.2%.p-value: <0.001ANOVA
p-value: 0.01ANOVA
p-value: >0.05ANOVA
Secondary
Spatial Recognition Memory (SRM) Test Percentage of Correct Hits
SRM tests visual spatial recognition memory in a two-choice forced discrimination paradigm. The subject is presented with a white square, which appears in sequence at five different locations on the screen. In the recognition phase, the subject sees a series of five pairs of squares, one of which is in a place previously seen in the presentation phase. The other square is in a location not seen in the presentation phase. Locations are tested in the reverse of the presentation order. The two main outcome measures are the percentage of correct trials (correct hits \[%\]) and the speed of the subject's response (response latency \[ms\]).
Time frame: 1 and 3 hours postdose
Population: completers
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oxymorphone 40 mg With High-fat Meal | Spatial Recognition Memory (SRM) Test Percentage of Correct Hits | 1-hour post dose | 81.67 percentage of hits | Standard Error 1.78 |
| Oxymorphone 40 mg With High-fat Meal | Spatial Recognition Memory (SRM) Test Percentage of Correct Hits | 3-hours post dose | 80.50 percentage of hits | Standard Error 1.36 |
| Oxymorphone 40 mg Fasting | Spatial Recognition Memory (SRM) Test Percentage of Correct Hits | 1-hour post dose | 83.17 percentage of hits | Standard Error 1.37 |
| Oxymorphone 40 mg Fasting | Spatial Recognition Memory (SRM) Test Percentage of Correct Hits | 3-hours post dose | 81.83 percentage of hits | Standard Error 1.94 |
p-value: >0.05ANOVA
Secondary
Spatial Recognition Memory (SRM) Test Response Latency
SRM tests visual spatial recognition memory in a two-choice forced discrimination paradigm. The subject is presented with a white square, which appears in sequence at five different locations on the screen. In the recognition phase, the subject sees a series of five pairs of squares, one of which is in a place previously seen in the presentation phase. The other square is in a location not seen in the presentation phase. Locations are tested in the reverse of the presentation order. The two main outcome measures are the percentage of correct trials (correct hits \[%\]) and the speed of the subject's response (response latency \[ms\]).
Time frame: 1 and 3 hours postdose
Population: completers
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oxymorphone 40 mg With High-fat Meal | Spatial Recognition Memory (SRM) Test Response Latency | 1-hour post dose | 1843.87 milliseconds | Standard Error 98.05 |
| Oxymorphone 40 mg With High-fat Meal | Spatial Recognition Memory (SRM) Test Response Latency | 3-hours post dose | 1555.51 milliseconds | Standard Error 60.72 |
| Oxymorphone 40 mg Fasting | Spatial Recognition Memory (SRM) Test Response Latency | 1-hour post dose | 1907.21 milliseconds | Standard Error 104.05 |
| Oxymorphone 40 mg Fasting | Spatial Recognition Memory (SRM) Test Response Latency | 3-hours post dose | 1606.26 milliseconds | Standard Error 61.31 |
p-value: >0.05ANOVA
p-value: <0.001ANOVA
Secondary
Spatial Working Memory (SWM) Test Strategy Score
SWM is a test of the subject's ability to retain spatial information and to manipulate remembered items in working memory. The test is a sensitive measure of executive function. It begins with a number of colored squares (boxes) being shown on the screen. By touching the boxes and using a process of elimination, the subject finds blue tokens in a number of boxes and uses them to fill up an empty column on the screen. The number of boxes is gradually increased, until it is necessary to search a total of eight boxes. The color and position of the boxes are changed from trial to trial to discourage the use of stereotyped search strategies. The two main outcome measures are errors (touching boxes that have been found to be empty and revisiting boxes that have already been found to contain a token - total errors) and a measure of strategy (For assessed problems with six boxes or more, the number of distinct boxes used by the subject to begin a new search for a token)
Time frame: 1 and 3 hours postdose
Population: completers
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oxymorphone 40 mg With High-fat Meal | Spatial Working Memory (SWM) Test Strategy Score | 1-hour post dose | 35.13 number of boxes | Standard Error 1.08 |
| Oxymorphone 40 mg With High-fat Meal | Spatial Working Memory (SWM) Test Strategy Score | 3-hours post dose | 35.50 number of boxes | Standard Error 1.16 |
| Oxymorphone 40 mg Fasting | Spatial Working Memory (SWM) Test Strategy Score | 1-hour post dose | 35.43 number of boxes | Standard Error 1.04 |
| Oxymorphone 40 mg Fasting | Spatial Working Memory (SWM) Test Strategy Score | 3-hours post dose | 35.57 number of boxes | Standard Error 1.1 |
p-value: >0.05ANOVA
Secondary
Spatial Working Memory (SWM) Test Total Errors
SWM is a test of the subject's ability to retain spatial information and to manipulate remembered items in working memory. It is a self-ordered task, which also assesses heuristic strategy. The test is a sensitive measure of executive function. It begins with a number of colored squares (boxes) being shown on the screen. By touching the boxes and using a process of elimination, the subject finds blue tokens in a number of boxes and uses them to fill up an empty column on the screen. The number of boxes is gradually increased, until it is necessary to search a total of eight boxes. The color and position of the boxes are changed from trial to trial to discourage the use of stereotyped search strategies. The two main outcome measures are errors (touching boxes that have been found to be empty and revisiting boxes that have already been found to contain a token - total errors) and a measure of strategy (strategy score).
Time frame: 1 and 3 hours postdose
Population: completers
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oxymorphone 40 mg With High-fat Meal | Spatial Working Memory (SWM) Test Total Errors | 1-hour post dose | 40.00 number of errors | Standard Error 5.05 |
| Oxymorphone 40 mg With High-fat Meal | Spatial Working Memory (SWM) Test Total Errors | 3-hours post dose | 35.73 number of errors | Standard Error 4.7 |
| Oxymorphone 40 mg Fasting | Spatial Working Memory (SWM) Test Total Errors | 1-hour post dose | 38.63 number of errors | Standard Error 4.45 |
| Oxymorphone 40 mg Fasting | Spatial Working Memory (SWM) Test Total Errors | 3-hours post dose | 37.40 number of errors | Standard Error 4.52 |
p-value: >0.05ANOVA