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Opioids in non-cancer pain
Abstracts
67
(833) Clinical pharmacology of hydromorphone hydrochloride extended-release capsules following multiple-dose oral administration
(835) Efficacy and safety of 24-hour hydromorphone hydrochloride extended-release compared with placebo in patients with nonmalignant pain
V. Vashi, A. Cipriano, S. Harris, A. El-Tahtawy, D. Wu; Purdue Pharma L.P., Stamford, CT A once-daily (q24h) hydromorphone hydrochloride extended-release (HHER) multiparticulate melt extrusion pellet formulation has been developed in capsule strengths of 12, 16, 24, and 32 mg. An extendedrelease formulation will avoid the need for frequent (q4-6h) administration of immediate-release hydromorphone (HHIR) to maintain analgesia in appropriate pain settings. On FDA approval, this product will be marketed as PalladoneTM Capsules. A randomized, multiple-dose, 2-way crossover study was conducted in healthy volunteers. Treatments consisted of a HHER 12-mg capsule q24h or a HHIR 3-mg tablet q6h each administered over a 5-day dosing period. For both treatments, predose (trough values) were assessed on days 1 through 5 while full PK profiles were obtained for 24 hours on day 5. The steady-state pharmacokinetics (PK) and safety profiles of hydromorphone (HMP) following HHER and HHIR dosing were determined. Plasma HMP concentrations were analyzed using a validated LC-MS/MS assay; appropriate PK and statistical methods were applied to the data obtained. Plasma HMP concentration profiles on day 5 were characterized by a much flatter profile for HHER q24h compared with HHIR q6h. Steady-state plasma HMP concentrations were achieved within 2 to 3 days following initiation of oral HHER dosing. Peak-to-trough fluctuation was approximately 2-fold or 200% lower for HHER than for HHIR. The total daily exposures of HHER and HHIR were bioequivalent. At steady state, HHER resulted in a lower Cmax, a later tmax, and a higher Cmin compared with the corresponding values obtained with HHIR. Following multiple dosing, HHER did not accumulate significantly with once-daily administration. Adverse events were those typically observed with opioid analgesics. Based on the multipledose PK and safety profiles, HHER is suitable for q24h administration.
E. Kopecky, C. Colonnese, M. Shi, C. Wright IV; Purdue Pharma L.P., Stamford, CT Hydromorphone hydrochloride extended-release (HHER) is a q24h formulation for the treatment of persistent moderate to severe pain. On FDA approval, HHER will be marketed as PalladoneTM Capsules. This randomized, double-blind, parallel-group, placebo-controlled study assessed the efficacy and safety of HHER compared with placebo in patients with persistent nonmalignant pain. Patients taking the equivalent of ⱕ60 mg of oxycodone per day were eligible. Patients took HHER 12 mg or placebo q24h for 28⫾2 days. The primary efficacy variable was the time from first dose of HHER or placebo to emergence of inadequate analgesia. Secondary efficacy variables were the subject global assessment of pain medication (1⫽poor to 5⫽excellent) and the pain control questionnaire (0⫽usually poor to 3⫽usually effective around-the-clock). A 6-symptom withdrawal rating scale was used to assess whether withdrawal symptoms confounded pain assessments in the placebo group. Safety was assessed by adverse events, vital signs, clinical laboratory tests, and physical examination. A total of 212 patients completed the study. Time to emergence of inadequate analgesia (Kaplan-Meier estimator) was longer for HHER compared with placebo (P⬍.0001; log-rank test); median, ⬎28 and 4 days, respectively. Mean subject global assessment of pain medication was higher for HHER than placebo (P⬍.0001; ANOVA); 2.6⫾0.13 (⫾SEM) and 1.8⫾0.11, respectively. Mean pain control questionnaire rating was higher for HHER than placebo (P⬍.0001; ANOVA); 1.5⫾0.1 and 0.7⫾0.1, respectively. Mean sum of the opioid withdrawal ratings was not different between groups (P ⫽ .621; 2-sided t test). No clinically important changes in laboratory values or vital signs occurred. These results indicated that time to emergence of inadequate analgesia was significantly longer in HHER-treated patients than with placebo. Both secondary efficacy variables indicated that HHER is effective in treating persistent pain. Opioid withdrawal did not appear to confound the results of the primary end point. No unexpected safety concerns were identified.
D15-Opioids in Non-Cancer Pain
(836) Sex-specific modulation of morphine analgesia by dextromethorphan in mice
(834) Androgen deficiency and psychological correlates of methadone therapy in male chronic pain patients E. Hamed, W. Blau, J. Hernandez; University of North carolina, Chapel Hill, NC Sexual dysfunction is a frequent concern among male chronic pain patients (CPP). Recent evidence implicates opioid induced androgen deficiency as a contributing factor. This is a comparative survey of patients receiving methadone versus non-opioid users of male CPP to explore the incidence of hormonal abnormalities and potentially related psychological/behavioral dysfunction. After IRB approval, a comparative, cross sectional, observational study was conducted on two groups (30 patients each) of male CPP. One group was using methadone while the other was not using opioids. All patients completed the Multiple Affect Adjective Check List-Revised (MAACL-R), Androgen Deficiency in Aging Males (ADAM), State-Trait Anger Expression Inventory-2 (STAXI-2) and SF-36 Quality of life questionnaires. Blood samples were obtained to measure plasma levels of methadone and different sex hormones. For each variable of interest, descriptive graphical and tabular statistics were used. The preliminary results show that patients on methadone therapy experience subnormal levels of androgens and abnormal psychological assessments. Data from all domains was pooled in order to investigate the correlations between the plasma levels of the drug, the sex hormones and different psychological parameters of interest. Preliminary results tend to confirm the presence of opioid induced androgen deficiency in our patient population and document the co-occurrence of abnormalities in sexual and psychometric profile. These findings and our previous clinical experience suggest the hypothesis that opioid-related hormonal abnormalities play a causative role in psychological dysfunction. Chronic use of methadone in male CPP is associated with both hormonal and psychological abnormalities that may adversely affect quality of life and clinical outcomes.
K. Nemmani, J. Mogil; McGill University, Montreal, QC A growing literature indicates that N-methyl-D-aspartate (NMDA) antagonists modulate opioid analgesia in experimental animals and human beings. The influence of NMDA antagonists on morphine analgesia is widely controversial and almost all studies have employed only male experimental subjects. In this study, we tested the influence of dextromethorphan, a clinically used, non-competitive NMDA antagonist, on morphine analgesia in male and female mice. The analgesic response was measured using the 49oC hot water tail-withdrawal test. Oral and intraperitoneal administration potentiated low-dose morphine analgesia, whereas high-dose morphine analgesia was blocked by dextromethorphan in CD-1 mice. This bidirectional effect was also observed in C57BL/6 and DBA/2 mice, generalizing the observation across strain. In all three strains studied, dextromethorphan modulated morphine analgesia in male but not female mice, suggestive of sex-specific mechanisms in the mediation of morphine analgesia. Further, the effect of dextromethorphan was studied in ovariectomized female mice and in ovariectomized mice chronically treated with estrogen. The ovariectomized mice exhibited a male-like pattern; that is, they were sensitive to modulation by dextromethorphan. Estrogen (5 ug/mice, od. for 7 days, i.p.) treatment of ovariectomized mice produced a reversion back to the female-like pattern of dextromethorphan insensitivity. These findings indicate that modulation of morphine analgesia by dextromethorphan depends on both morphine dose and subject sex. Whether these two factors could partly explain the contradictory results in human clinical studies remains to be determined. We and others have reported sexspecific modulation of kappa-opioid analgesia by non competitive NMDA antagonists; the present findings suggest that such sex-specific modulation can also affect mu-opioid analgesia.
67
(833) Clinical pharmacology of hydromorphone hydrochloride extended-release capsules following multiple-dose oral administration
(835) Efficacy and safety of 24-hour hydromorphone hydrochloride extended-release compared with placebo in patients with nonmalignant pain
V. Vashi, A. Cipriano, S. Harris, A. El-Tahtawy, D. Wu; Purdue Pharma L.P., Stamford, CT A once-daily (q24h) hydromorphone hydrochloride extended-release (HHER) multiparticulate melt extrusion pellet formulation has been developed in capsule strengths of 12, 16, 24, and 32 mg. An extendedrelease formulation will avoid the need for frequent (q4-6h) administration of immediate-release hydromorphone (HHIR) to maintain analgesia in appropriate pain settings. On FDA approval, this product will be marketed as PalladoneTM Capsules. A randomized, multiple-dose, 2-way crossover study was conducted in healthy volunteers. Treatments consisted of a HHER 12-mg capsule q24h or a HHIR 3-mg tablet q6h each administered over a 5-day dosing period. For both treatments, predose (trough values) were assessed on days 1 through 5 while full PK profiles were obtained for 24 hours on day 5. The steady-state pharmacokinetics (PK) and safety profiles of hydromorphone (HMP) following HHER and HHIR dosing were determined. Plasma HMP concentrations were analyzed using a validated LC-MS/MS assay; appropriate PK and statistical methods were applied to the data obtained. Plasma HMP concentration profiles on day 5 were characterized by a much flatter profile for HHER q24h compared with HHIR q6h. Steady-state plasma HMP concentrations were achieved within 2 to 3 days following initiation of oral HHER dosing. Peak-to-trough fluctuation was approximately 2-fold or 200% lower for HHER than for HHIR. The total daily exposures of HHER and HHIR were bioequivalent. At steady state, HHER resulted in a lower Cmax, a later tmax, and a higher Cmin compared with the corresponding values obtained with HHIR. Following multiple dosing, HHER did not accumulate significantly with once-daily administration. Adverse events were those typically observed with opioid analgesics. Based on the multipledose PK and safety profiles, HHER is suitable for q24h administration.
E. Kopecky, C. Colonnese, M. Shi, C. Wright IV; Purdue Pharma L.P., Stamford, CT Hydromorphone hydrochloride extended-release (HHER) is a q24h formulation for the treatment of persistent moderate to severe pain. On FDA approval, HHER will be marketed as PalladoneTM Capsules. This randomized, double-blind, parallel-group, placebo-controlled study assessed the efficacy and safety of HHER compared with placebo in patients with persistent nonmalignant pain. Patients taking the equivalent of ⱕ60 mg of oxycodone per day were eligible. Patients took HHER 12 mg or placebo q24h for 28⫾2 days. The primary efficacy variable was the time from first dose of HHER or placebo to emergence of inadequate analgesia. Secondary efficacy variables were the subject global assessment of pain medication (1⫽poor to 5⫽excellent) and the pain control questionnaire (0⫽usually poor to 3⫽usually effective around-the-clock). A 6-symptom withdrawal rating scale was used to assess whether withdrawal symptoms confounded pain assessments in the placebo group. Safety was assessed by adverse events, vital signs, clinical laboratory tests, and physical examination. A total of 212 patients completed the study. Time to emergence of inadequate analgesia (Kaplan-Meier estimator) was longer for HHER compared with placebo (P⬍.0001; log-rank test); median, ⬎28 and 4 days, respectively. Mean subject global assessment of pain medication was higher for HHER than placebo (P⬍.0001; ANOVA); 2.6⫾0.13 (⫾SEM) and 1.8⫾0.11, respectively. Mean pain control questionnaire rating was higher for HHER than placebo (P⬍.0001; ANOVA); 1.5⫾0.1 and 0.7⫾0.1, respectively. Mean sum of the opioid withdrawal ratings was not different between groups (P ⫽ .621; 2-sided t test). No clinically important changes in laboratory values or vital signs occurred. These results indicated that time to emergence of inadequate analgesia was significantly longer in HHER-treated patients than with placebo. Both secondary efficacy variables indicated that HHER is effective in treating persistent pain. Opioid withdrawal did not appear to confound the results of the primary end point. No unexpected safety concerns were identified.
D15-Opioids in Non-Cancer Pain
(836) Sex-specific modulation of morphine analgesia by dextromethorphan in mice
(834) Androgen deficiency and psychological correlates of methadone therapy in male chronic pain patients E. Hamed, W. Blau, J. Hernandez; University of North carolina, Chapel Hill, NC Sexual dysfunction is a frequent concern among male chronic pain patients (CPP). Recent evidence implicates opioid induced androgen deficiency as a contributing factor. This is a comparative survey of patients receiving methadone versus non-opioid users of male CPP to explore the incidence of hormonal abnormalities and potentially related psychological/behavioral dysfunction. After IRB approval, a comparative, cross sectional, observational study was conducted on two groups (30 patients each) of male CPP. One group was using methadone while the other was not using opioids. All patients completed the Multiple Affect Adjective Check List-Revised (MAACL-R), Androgen Deficiency in Aging Males (ADAM), State-Trait Anger Expression Inventory-2 (STAXI-2) and SF-36 Quality of life questionnaires. Blood samples were obtained to measure plasma levels of methadone and different sex hormones. For each variable of interest, descriptive graphical and tabular statistics were used. The preliminary results show that patients on methadone therapy experience subnormal levels of androgens and abnormal psychological assessments. Data from all domains was pooled in order to investigate the correlations between the plasma levels of the drug, the sex hormones and different psychological parameters of interest. Preliminary results tend to confirm the presence of opioid induced androgen deficiency in our patient population and document the co-occurrence of abnormalities in sexual and psychometric profile. These findings and our previous clinical experience suggest the hypothesis that opioid-related hormonal abnormalities play a causative role in psychological dysfunction. Chronic use of methadone in male CPP is associated with both hormonal and psychological abnormalities that may adversely affect quality of life and clinical outcomes.
K. Nemmani, J. Mogil; McGill University, Montreal, QC A growing literature indicates that N-methyl-D-aspartate (NMDA) antagonists modulate opioid analgesia in experimental animals and human beings. The influence of NMDA antagonists on morphine analgesia is widely controversial and almost all studies have employed only male experimental subjects. In this study, we tested the influence of dextromethorphan, a clinically used, non-competitive NMDA antagonist, on morphine analgesia in male and female mice. The analgesic response was measured using the 49oC hot water tail-withdrawal test. Oral and intraperitoneal administration potentiated low-dose morphine analgesia, whereas high-dose morphine analgesia was blocked by dextromethorphan in CD-1 mice. This bidirectional effect was also observed in C57BL/6 and DBA/2 mice, generalizing the observation across strain. In all three strains studied, dextromethorphan modulated morphine analgesia in male but not female mice, suggestive of sex-specific mechanisms in the mediation of morphine analgesia. Further, the effect of dextromethorphan was studied in ovariectomized female mice and in ovariectomized mice chronically treated with estrogen. The ovariectomized mice exhibited a male-like pattern; that is, they were sensitive to modulation by dextromethorphan. Estrogen (5 ug/mice, od. for 7 days, i.p.) treatment of ovariectomized mice produced a reversion back to the female-like pattern of dextromethorphan insensitivity. These findings indicate that modulation of morphine analgesia by dextromethorphan depends on both morphine dose and subject sex. Whether these two factors could partly explain the contradictory results in human clinical studies remains to be determined. We and others have reported sexspecific modulation of kappa-opioid analgesia by non competitive NMDA antagonists; the present findings suggest that such sex-specific modulation can also affect mu-opioid analgesia.