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(411) Abuse potential study of ALO-02 (extended-release oxycodone surrounding sequestered naltrexone) compared with immediate-release oxycodone and placebo when crushed and administered intranasally to non-dependent, recreational opioid users
S78
Abstracts
The Journal of Pain
(408) Cytokine dependence of the analgesic effect of nasal oxytocin in chronic migraineurs D Yeomans, D Jacobs, J Mechanic, J Miller, C Pascual, N Manering, W Frey, and M Angst; Trigemina, Inc., Moraga, CA This study examined the importance of cytokine-driven oxytocin receptor upregulation in determining the efficacy of nasal oxytocin (OT) in chronic migraine patients. Oxytocin receptor (OT-R) expression is known to be driven by cytokines, and particularly by IL- 6, for which there are early response elements on the OT-R gene promoter. As OT-R are on trigeminal nerve neurons, their level should thus be enhanced by IL-6 as should the analgesic effect of OT for trigeminally mediated pain wherein there is an inflammatory component, including chronic migraine. This study included a single-dose, placebocontrolled, double-blind, parallel study of the effects of 32 U of nasally-applied oxytocin in patients with chronic migraine. The primary inclusion criteria included an incidence of migraine-type headache of at least 15 days/month and the presence of a headache for at least 10 hours prior to dosing (to ensure OT-R upregulation) and patients were washed out of other medications for at least 4 hours. Patients were asked to rate their pain on a standard 4-point categorical scale (severe, moderate, mild, or none) just prior to and at 0.5, 1, 2, 4, and 24 hours after dosing; nausea, photophobia, and phonophobia were also recorded. The results of this study demonstrated that, nasal OT reduced pain by 2 categories in 42% of patients at 2 hours and 55% at 4 hrs.; compared to 11% and 28% for placebo. Patients that had taken a NSAID, which blocks IL-6 production, within 24 hours prior to dosing showed a strong decrease in effect. Nausea, photophobia and phonophobia were also decreased compared to placebo. These results suggest that nasal oxytocin may be a viable alternative for the treatment of chronic migraine headache.
(409) Evaluation of the effects of food and of sprinkling pellets on applesauce on the pharmacokinetics of oxycodone and naltrexone from ALO-02, an extended-release formulation of oxycodone with sequestered naltrexone K Gandelman, M Lamson, J Salageanu, C and B Malhotra; Pfizer Inc, New York, NY
Bramson, K
Matschke,
ALO-02 consists of capsules of polymer-coated pellets of extended-release oxycodone hydrochloride that surround sequestered naltrexone hydrochloride and is designed to deter abuse. The primary objectives of this study were to estimate the bioavailability of oxycodone, naltrexone, and 6-b-naltrexol in healthy volunteers following the administration of 1) A single oral 40-mg capsule of ALO-02 under fed conditions (standard high-fat breakfast) versus under fasting conditions and 2) A single oral 40-mg dose of ALO-02 pellets sprinkled on applesauce versus intact ALO-02 capsule under fasting conditions. Secondary objectives were to assess safety and tolerability. Participants were randomized to one of six sequences to receive 3 treatments separated by a 7day washout interval. Noncompartmental pharmacokinetic parameters were calculated for oxycodone, naltrexone and 6-b-naltrexol. Safety assessments included adverse events, vital signs, and laboratory parameters. The twentyfour participants were predominantly male (71%), black (54%) with a mean BMI (range) of 26.0 kg/m2 (20.4-29.8) and mean age (range) of 37.3 years (2355). The mean oxycodone plasma concentration-time profiles for all treatments were nearly superimposable. No effects of food (fed vs. fasted) on the bioavailability of oxycodone were observed following a single 40mg whole capsule of ALO-02. Similarly, no effects of pellet sprinkling vs. whole capsule on the bioavailability of oxycodone were observed in the fasted state. The 90% confidence intervals for the Cmax and AUC ratios of all test/reference for oxycodone were all within bioequivalence limits of 80% to 125% for each comparison. Naltrexone remained sequestered under all treatment conditions with only trace systemic exposure. ALO-02 was well tolerated, and adverse events were mild, with no apparent differences between treatments. ALO-02 can be administered without regard to food and ALO-02 pellets can be sprinkled over applesauce and consumed without chewing as an alternative treatment option for subjects with difficulty swallowing. Sponsored by Pfizer Inc.
(410) Efficacy and safety of ALO-02, an extended-release oxycodone surrounding sequestered naltrexone, in the treatment of moderate-to-severe chronic low back pain R Rauck, M Hale, A Bass, C Bramson, G Pixton, B Setnik, P Meisner, and K Sommerville; Pfizer Inc, Durham, NC ALO-02 is designed as an abuse-deterrent opioid formulation comprising capsules of polymer-coated pellets of extended-release oxycodone hydrochloride surrounding sequestered naltrexone hydrochloride. The study objective was to evaluate efficacy and safety of ALO-02 versus placebo in the treatment of moderate-to-severe chronic low back pain (CLBP). This multicenter, 12-week, double-blind, placebo-controlled, enriched enrollment randomized withdrawal study in patients with moderate-to-severe CLBP requiring around-the-clock analgesia comprised a screening period (#2 weeks), an open-label conversion and titration period (4-6 weeks), a double-blind treatment period (12 weeks) and a post-treatment period (2 weeks). Of the 410 enrolled patients who entered open-label conversion and titration to ALO-02 (10-mg oxycodone/ 1.2-mg naltrexone twice daily (BID) up to 80-mg oxycodone/9.6-mg naltrexone BID), 281 met the treatment response criteria. Treatment response was defined as patients who tolerated ALO-02, had daily average pain numerical rating scale (NRS-Pain) scores for low back pain #4, and remained on a fixed dose of ALO-02 for $7 consecutive days. Responders were randomized to doubleblind treatment with placebo or a fixed dose of ALO-02. To avoid opioid withdrawal in patients randomized to placebo, ALO-02 doses were tapered in a blinded manner over the first two weeks of the treatment period. The primary efficacy endpoint was the difference in the mean change in NRS-Pain scores for CLBP from baseline (time of randomization) to the final two weeks of the study comparing placebo and ALO-02. Key secondary endpoints included the mean change in the Roland-Morris Disability Questionnaire total score and the change in the Patient’s Global Assessment of CLBP from baseline to final visit. Clinician-rated Clinical Opiate Withdrawal Scale and patient-rated Subjective Opiate Withdrawal Scale were used to assess presence and intensity of opioid withdrawal. This study has recently completed and the results will be presented in the accompanying poster. Sponsored by Pfizer Inc.
(411) Abuse potential study of ALO-02 (extended-release oxycodone surrounding sequestered naltrexone) compared with immediate-release oxycodone and placebo when crushed and administered intranasally to non-dependent, recreational opioid users B Setnik, C Bramson, K Sommerville, K Matschke, N Levy-Cooperman, and P Geoffroy; Pfizer Inc, Durham, NC ALO-02 is an opioid formulation consisting of capsules filled with polymercoated pellets of extended-release oxycodone hydrochloride surrounding sequestered naltrexone hydrochloride intended to deter abuse. This abuse potential study compared the relative pharmacodynamic effects, including drug liking and high, of crushed ALO-02 with crushed oxycodone hydrochloride immediate-release (IR) and placebo administered intranasally to healthy, nondependent, recreational opioid users. This was a randomized, double-blind, placebo- and active-controlled, 4-way crossover study that included a naloxone challenge, drug discrimination, and treatment phase. During each treatment period (separated by $5 days), participants received a crushed single dose of either one or two placebos (weight-matched to AL0-02 or oxycodone IR), 30 mg ALO-02 (containing 3.6 mg naltrexone), or 30 mg oxycodone IR. The primary endpoints were drug liking and high on bipolar and unipolar visual analog scales, respectively. The principal parameters were mean peak effect (Emax) and effect occurring over 2 h post-dosing (AUE0-2h). Thirty-two participants (84% male, 91% white, mean age 35 years) were randomized into the treatment phase with 28 completing all treatments. Study validity was confirmed by the significantly higher ratings on measures of drug liking and high associated with 30 mg oxycodone IR compared with placebo (p<0.0001). Intranasal administration of 30 mg ALO-02 resulted in significantly lower ratings relative to 30 mg oxycodone IR on drug liking (Emax: 60.5 vs. 92.8) and high (Emax: 25.2 vs. 86.9) (p<0.0001) (primary endpoints). Adverse events (AEs) occurred most frequently with oxycodone IR (N=32, 100%), followed by ALO-02 (N=18, 60%) and fewest with placebo (# 33% in both groups). The most common (>10% of participants) AEs for ALO-02 were euphoric mood, dysgeusia, fatigue, and somnolence. When crushed and administered intranasally to nondependent, recreational opioid users, ALO-02 showed significantly lower abuse potential scores of drug liking and high compared with crushed oxycodone IR. Sponsored by Pfizer Inc.
Abstracts
The Journal of Pain
(408) Cytokine dependence of the analgesic effect of nasal oxytocin in chronic migraineurs D Yeomans, D Jacobs, J Mechanic, J Miller, C Pascual, N Manering, W Frey, and M Angst; Trigemina, Inc., Moraga, CA This study examined the importance of cytokine-driven oxytocin receptor upregulation in determining the efficacy of nasal oxytocin (OT) in chronic migraine patients. Oxytocin receptor (OT-R) expression is known to be driven by cytokines, and particularly by IL- 6, for which there are early response elements on the OT-R gene promoter. As OT-R are on trigeminal nerve neurons, their level should thus be enhanced by IL-6 as should the analgesic effect of OT for trigeminally mediated pain wherein there is an inflammatory component, including chronic migraine. This study included a single-dose, placebocontrolled, double-blind, parallel study of the effects of 32 U of nasally-applied oxytocin in patients with chronic migraine. The primary inclusion criteria included an incidence of migraine-type headache of at least 15 days/month and the presence of a headache for at least 10 hours prior to dosing (to ensure OT-R upregulation) and patients were washed out of other medications for at least 4 hours. Patients were asked to rate their pain on a standard 4-point categorical scale (severe, moderate, mild, or none) just prior to and at 0.5, 1, 2, 4, and 24 hours after dosing; nausea, photophobia, and phonophobia were also recorded. The results of this study demonstrated that, nasal OT reduced pain by 2 categories in 42% of patients at 2 hours and 55% at 4 hrs.; compared to 11% and 28% for placebo. Patients that had taken a NSAID, which blocks IL-6 production, within 24 hours prior to dosing showed a strong decrease in effect. Nausea, photophobia and phonophobia were also decreased compared to placebo. These results suggest that nasal oxytocin may be a viable alternative for the treatment of chronic migraine headache.
(409) Evaluation of the effects of food and of sprinkling pellets on applesauce on the pharmacokinetics of oxycodone and naltrexone from ALO-02, an extended-release formulation of oxycodone with sequestered naltrexone K Gandelman, M Lamson, J Salageanu, C and B Malhotra; Pfizer Inc, New York, NY
Bramson, K
Matschke,
ALO-02 consists of capsules of polymer-coated pellets of extended-release oxycodone hydrochloride that surround sequestered naltrexone hydrochloride and is designed to deter abuse. The primary objectives of this study were to estimate the bioavailability of oxycodone, naltrexone, and 6-b-naltrexol in healthy volunteers following the administration of 1) A single oral 40-mg capsule of ALO-02 under fed conditions (standard high-fat breakfast) versus under fasting conditions and 2) A single oral 40-mg dose of ALO-02 pellets sprinkled on applesauce versus intact ALO-02 capsule under fasting conditions. Secondary objectives were to assess safety and tolerability. Participants were randomized to one of six sequences to receive 3 treatments separated by a 7day washout interval. Noncompartmental pharmacokinetic parameters were calculated for oxycodone, naltrexone and 6-b-naltrexol. Safety assessments included adverse events, vital signs, and laboratory parameters. The twentyfour participants were predominantly male (71%), black (54%) with a mean BMI (range) of 26.0 kg/m2 (20.4-29.8) and mean age (range) of 37.3 years (2355). The mean oxycodone plasma concentration-time profiles for all treatments were nearly superimposable. No effects of food (fed vs. fasted) on the bioavailability of oxycodone were observed following a single 40mg whole capsule of ALO-02. Similarly, no effects of pellet sprinkling vs. whole capsule on the bioavailability of oxycodone were observed in the fasted state. The 90% confidence intervals for the Cmax and AUC ratios of all test/reference for oxycodone were all within bioequivalence limits of 80% to 125% for each comparison. Naltrexone remained sequestered under all treatment conditions with only trace systemic exposure. ALO-02 was well tolerated, and adverse events were mild, with no apparent differences between treatments. ALO-02 can be administered without regard to food and ALO-02 pellets can be sprinkled over applesauce and consumed without chewing as an alternative treatment option for subjects with difficulty swallowing. Sponsored by Pfizer Inc.
(410) Efficacy and safety of ALO-02, an extended-release oxycodone surrounding sequestered naltrexone, in the treatment of moderate-to-severe chronic low back pain R Rauck, M Hale, A Bass, C Bramson, G Pixton, B Setnik, P Meisner, and K Sommerville; Pfizer Inc, Durham, NC ALO-02 is designed as an abuse-deterrent opioid formulation comprising capsules of polymer-coated pellets of extended-release oxycodone hydrochloride surrounding sequestered naltrexone hydrochloride. The study objective was to evaluate efficacy and safety of ALO-02 versus placebo in the treatment of moderate-to-severe chronic low back pain (CLBP). This multicenter, 12-week, double-blind, placebo-controlled, enriched enrollment randomized withdrawal study in patients with moderate-to-severe CLBP requiring around-the-clock analgesia comprised a screening period (#2 weeks), an open-label conversion and titration period (4-6 weeks), a double-blind treatment period (12 weeks) and a post-treatment period (2 weeks). Of the 410 enrolled patients who entered open-label conversion and titration to ALO-02 (10-mg oxycodone/ 1.2-mg naltrexone twice daily (BID) up to 80-mg oxycodone/9.6-mg naltrexone BID), 281 met the treatment response criteria. Treatment response was defined as patients who tolerated ALO-02, had daily average pain numerical rating scale (NRS-Pain) scores for low back pain #4, and remained on a fixed dose of ALO-02 for $7 consecutive days. Responders were randomized to doubleblind treatment with placebo or a fixed dose of ALO-02. To avoid opioid withdrawal in patients randomized to placebo, ALO-02 doses were tapered in a blinded manner over the first two weeks of the treatment period. The primary efficacy endpoint was the difference in the mean change in NRS-Pain scores for CLBP from baseline (time of randomization) to the final two weeks of the study comparing placebo and ALO-02. Key secondary endpoints included the mean change in the Roland-Morris Disability Questionnaire total score and the change in the Patient’s Global Assessment of CLBP from baseline to final visit. Clinician-rated Clinical Opiate Withdrawal Scale and patient-rated Subjective Opiate Withdrawal Scale were used to assess presence and intensity of opioid withdrawal. This study has recently completed and the results will be presented in the accompanying poster. Sponsored by Pfizer Inc.
(411) Abuse potential study of ALO-02 (extended-release oxycodone surrounding sequestered naltrexone) compared with immediate-release oxycodone and placebo when crushed and administered intranasally to non-dependent, recreational opioid users B Setnik, C Bramson, K Sommerville, K Matschke, N Levy-Cooperman, and P Geoffroy; Pfizer Inc, Durham, NC ALO-02 is an opioid formulation consisting of capsules filled with polymercoated pellets of extended-release oxycodone hydrochloride surrounding sequestered naltrexone hydrochloride intended to deter abuse. This abuse potential study compared the relative pharmacodynamic effects, including drug liking and high, of crushed ALO-02 with crushed oxycodone hydrochloride immediate-release (IR) and placebo administered intranasally to healthy, nondependent, recreational opioid users. This was a randomized, double-blind, placebo- and active-controlled, 4-way crossover study that included a naloxone challenge, drug discrimination, and treatment phase. During each treatment period (separated by $5 days), participants received a crushed single dose of either one or two placebos (weight-matched to AL0-02 or oxycodone IR), 30 mg ALO-02 (containing 3.6 mg naltrexone), or 30 mg oxycodone IR. The primary endpoints were drug liking and high on bipolar and unipolar visual analog scales, respectively. The principal parameters were mean peak effect (Emax) and effect occurring over 2 h post-dosing (AUE0-2h). Thirty-two participants (84% male, 91% white, mean age 35 years) were randomized into the treatment phase with 28 completing all treatments. Study validity was confirmed by the significantly higher ratings on measures of drug liking and high associated with 30 mg oxycodone IR compared with placebo (p<0.0001). Intranasal administration of 30 mg ALO-02 resulted in significantly lower ratings relative to 30 mg oxycodone IR on drug liking (Emax: 60.5 vs. 92.8) and high (Emax: 25.2 vs. 86.9) (p<0.0001) (primary endpoints). Adverse events (AEs) occurred most frequently with oxycodone IR (N=32, 100%), followed by ALO-02 (N=18, 60%) and fewest with placebo (# 33% in both groups). The most common (>10% of participants) AEs for ALO-02 were euphoric mood, dysgeusia, fatigue, and somnolence. When crushed and administered intranasally to nondependent, recreational opioid users, ALO-02 showed significantly lower abuse potential scores of drug liking and high compared with crushed oxycodone IR. Sponsored by Pfizer Inc.