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Efficacy and tolerability of hydrocodone extended-release tablets for the treatment of moderate to severe pain in opioid-treated patients with osteoarthritis or low back pain
S84
The Journal of Pain
(432) Full recovery from CRPS type 1 after introduction of fentanyl transdermal patch: a case report M Gen-ichiro, S Yoshito, and T Kazuhiro; Omaezaki Municipal Hospital, Omaezaki City, Shizuoka Prefecture, Japan In Japan, use of the fentanyl transdermal patch was finally approved in 2010 for the treatment of intractable pain. Complex regional pain syndrome (CRPS) is one of the diseases/syndromes associated with pain that is often difficult to diagnose and treat. We report a case of CRPS type 1 which was refractory to prior treatments administered at several institutions, but introduced to resolve after initiation of treatment with the fentanyl transdermal patch. The patient was a 54-year-old woman. After 2 sites surgery, spinal decompression and fixation of L4/5 and L3/4, she began to suffer from bilateral numbness and coldness over the region extending from the lateral femur to the crus, as well as severe pain and heat sensation in the right sole. Bilateral thermal distance was 10 degrees. Although various treatments, including drug therapy, were administered at some clinics, the visual analog scale (VAS) score remained at approximately 70 mm. For seven months since her initial visit to closely our outpatient pain clinic, she was treated by several blocks along with rehabilitation therapy. However, the VAS score only decreased to 50 to 60 mm, and no further relief of symptoms could be obtained. Then, use of the fentanyl transdermal patch was initiated at the dose of 2.1 mg. This resulted in a dramatic reduction of the VAS score to 0 to 10 mm within 1 week, and the symptoms were relieved within 3 weeks to the level of no difference in the temperature of lower extremities. After two months the treatment was discontinued altogether according to the patient’s wishes, however, no sign of CRPS recurrence has been observed at the present time. In this case, the course to the introduction of the fentanyl transdermal patch may also be important as a part of multidisciplinary treatment.
Abstracts (434) ADL5945, a potent orally bioavailable peripheral opioid receptor antagonist, improves bowel motility w/a low incidence/severity of GI AEs in a dose-dependent manner: results of 2 Ph 2 trials in opioid-induced constipation pts (45CL242 and 45CL243) L Techner, N Singla, K Gabriel, and R Mangano; Lotus Clinical Research, Pasadena, CA Opioids are a mainstay for managing chronic pain, however central and peripheral adverse effects often limit their utility. Mu opioid receptor (MOR) binding is primarily responsible for opioid-induced constipation (OIC) and gastrointestinal (GI) symptoms; the delta OR (DOR) may also play a role. ADL5945, a MOR and DOR antagonist, is under development for OIC and associated abdominal symptoms in patients on chronic opioid therapy for persistent noncancer pain. Randomized, double blind, placebo controlled, Phase 2 studies compared ADL5945 dosed once- (0.25mg QD) or twice-daily (0.1mg BID and 0.25mg BID) with placebo based on spontaneous bowel movement (SBM) change over treatment weeks 1-4. Other endpoints included overall SBM responders (patient with $3 SBMs/week and $1 SBM/week from baseline for 3 of 4 weeks), opioid consumption, pain scores, and adverse events (AEs). 131 patients (BID) and 81 patients (QD) were randomized. Mean OIC duration ranged from 3.46.9 years; back pain was the most common pain condition. Mean SBM change from baseline was 1.44 (placebo BID), 1.40 (placebo QD), 1.96 (0.1mg BID), 2.58 (0.25mg QD), and 3.42 (0.25mg BID), with a mean treatment difference change of 0.51 (P=0.2979), 1.18 (P=0.0118), and 1.98 (P=0.0003) in the 0.1-mg BID, 0.25mg QD, and 0.25-mg BID groups, respectively. 26-28% of patients (placebo cohorts), 28% (0.1mg BID), 43% (0.25mg QD), and 56% (0.25mg BID; P=0.005) were overall responders. There were no changes in opioid consumption or pain scores and no evidence of CNS effects. The most commonly reported AEs were abdominal pain (QD; 10% across groups) and upper respiratory tract infection (BID; placebo,14%; 0.1mg,7%; 0.25mg,7%). Incidence of GI-related AEs was low and comparable across groups; most of mild severity. Significant, clinically-meaningful improvement in SBM frequency was observed after ADL5945 treatment, with the 0.25-mg BID dose demonstrating the most favorable benefit-to-risk profile. Phase 3 trials are planned. Supported by Adolor Corporation.
(433) Efficacy and tolerability of OROS hydromorphone extended release in patients with moderate to severe osteoarthritis pain: a phase 3, flexible-dose, randomized, double-blind, placebo-controlled study
(435) Efficacy and tolerability of hydrocodone extended-release tablets for the treatment of moderate to severe pain in opioid-treated patients with osteoarthritis or low back pain
M Hale, J Patrick, and S Nalamachu; Gold Coast Research, LLC, Weston, FL
M Hale, D D’Andrea, R Yang, and G Niebler; Cephalon, Inc., Frazer, PA
This randomized, placebo-controlled, double-blind study evaluated OROS hydromorphone ER for reducing moderate-to-severe osteoarthritis pain. The study consisted of a conversion/titration phase (1-4 weeks) and double-blind phase (12 weeks), with enriched enrollment randomized withdrawal design. During conversion/titration, opioid-tolerant patients were converted to OROS hydromorphone ER at 75% of the equianalgesic dose of their previous opioid dosage (5:1 morphine:hydromorphone), using dosages of 8-48 mg/d. Immediate-release hydromorphone (2-16 mg/d) was provided as rescue medication. On days 1-14 of double-blind treatment, patients randomized to placebo + rescue medication had OROS hydromorphone ER doses tapered to discontinuation (blind was maintained); remaining patients were maintained at their stable dose. The primary outcome measure was change from baseline to Week 12 in mean pain intensity. Three hundred thirty-four patients entered conversion/titration; 200 were randomized (100 to each group). Mean pain intensity decreased from 6.9 at screening to 3.0 at end of conversion/titration. During double-blind treatment, reductions in pain intensity were generally maintained in both treatment groups (mean [SE], 3.6 [0.2] at Week 12 for both groups), with no significant differences between treatment groups. Patients receiving placebo + rescue medication used significantly more rescue medication tablets/day than those receiving active treatment (mean [SE], 1.5 [0.1] vs 1.1 [0.1]; P=0.006). Commonly reported AEs during conversion/titration (constipation. 17.5%; nausea, 15.7%; somnolence, 8.3%) and double-blind treatment (constipation, 20.0%; nausea, 14.0%; vomiting, 9.0%) occurred more frequently in patients receiving OROS hydromorphone ER. Using the present trial design, there was failure to demonstrate sustained efficacy of active treatment versus placebo + rescue medication, perhaps due to higher use of rescue medication in the latter group. Technical editorial and writing assistance provided by Synchrony Medical, LLC, funded by Mallinckrodt Inc., a Covidien company, Hazelwood, MO.
Hydrocodone is available in the United States for the treatment of pain only as immediate-release formulations in combination with other medications. This phase 3, randomized, double-blind, placebo-controlled study assessed the efficacy and safety of an extended-release formulation of hydrocodone in patients with moderate to severe pain associated with osteoarthritis or low back pain requiring opioids for an extended period. During the open-label titration phase, patients were titrated to a successful dose of hydrocodone extended-release that provided stable pain relief without unacceptable adverse events (average pain intensity [PI] score over the past 24 hours #4 for 3 days based on the 11-point numerical rating scale or 3-5 days without unacceptable adverse events while maintained on the same dose for up to 7 days). Patients were then randomized into a 12-week, double-blind, placebo-controlled period to receive hydrocodone extended-release (15-90 mg) every 12 hours or matching placebo. Rescue treatment with hydrocodone/acetaminophen 5/325 mg tablets was permitted as needed up to a maximum hydrocodone dose of 10 mg/ day. A stepwise, double-blind tapering schedule was implemented for the first 2 weeks of the double-blind period to reduce the risk of withdrawal in patients randomized to placebo. The primary efficacy measure was change from baseline to week 12 in weekly average PI. Secondary efficacy measures included weekly average PI increase from baseline exceeding 33% and 50%; weekly average of daily average PI and worst PI scores; Clinician Assessment of Patient Function; Patient Assessment of Function; Clinical Global Impression of Severity Illness; and 36-Item Short Form Health Survey and Brief Pain Inventory-Short Form scores. Safety and tolerability were assessed throughout the study, including measures such as the Subjective Opioid Withdrawal Scale, Clinical Opiate Withdrawal Scale, Addiction Behavior Checklist, and Current Opioid Misuse Measure scores. Results for this study are not yet available. Sponsored by Cephalon, Inc.
The Journal of Pain
(432) Full recovery from CRPS type 1 after introduction of fentanyl transdermal patch: a case report M Gen-ichiro, S Yoshito, and T Kazuhiro; Omaezaki Municipal Hospital, Omaezaki City, Shizuoka Prefecture, Japan In Japan, use of the fentanyl transdermal patch was finally approved in 2010 for the treatment of intractable pain. Complex regional pain syndrome (CRPS) is one of the diseases/syndromes associated with pain that is often difficult to diagnose and treat. We report a case of CRPS type 1 which was refractory to prior treatments administered at several institutions, but introduced to resolve after initiation of treatment with the fentanyl transdermal patch. The patient was a 54-year-old woman. After 2 sites surgery, spinal decompression and fixation of L4/5 and L3/4, she began to suffer from bilateral numbness and coldness over the region extending from the lateral femur to the crus, as well as severe pain and heat sensation in the right sole. Bilateral thermal distance was 10 degrees. Although various treatments, including drug therapy, were administered at some clinics, the visual analog scale (VAS) score remained at approximately 70 mm. For seven months since her initial visit to closely our outpatient pain clinic, she was treated by several blocks along with rehabilitation therapy. However, the VAS score only decreased to 50 to 60 mm, and no further relief of symptoms could be obtained. Then, use of the fentanyl transdermal patch was initiated at the dose of 2.1 mg. This resulted in a dramatic reduction of the VAS score to 0 to 10 mm within 1 week, and the symptoms were relieved within 3 weeks to the level of no difference in the temperature of lower extremities. After two months the treatment was discontinued altogether according to the patient’s wishes, however, no sign of CRPS recurrence has been observed at the present time. In this case, the course to the introduction of the fentanyl transdermal patch may also be important as a part of multidisciplinary treatment.
Abstracts (434) ADL5945, a potent orally bioavailable peripheral opioid receptor antagonist, improves bowel motility w/a low incidence/severity of GI AEs in a dose-dependent manner: results of 2 Ph 2 trials in opioid-induced constipation pts (45CL242 and 45CL243) L Techner, N Singla, K Gabriel, and R Mangano; Lotus Clinical Research, Pasadena, CA Opioids are a mainstay for managing chronic pain, however central and peripheral adverse effects often limit their utility. Mu opioid receptor (MOR) binding is primarily responsible for opioid-induced constipation (OIC) and gastrointestinal (GI) symptoms; the delta OR (DOR) may also play a role. ADL5945, a MOR and DOR antagonist, is under development for OIC and associated abdominal symptoms in patients on chronic opioid therapy for persistent noncancer pain. Randomized, double blind, placebo controlled, Phase 2 studies compared ADL5945 dosed once- (0.25mg QD) or twice-daily (0.1mg BID and 0.25mg BID) with placebo based on spontaneous bowel movement (SBM) change over treatment weeks 1-4. Other endpoints included overall SBM responders (patient with $3 SBMs/week and $1 SBM/week from baseline for 3 of 4 weeks), opioid consumption, pain scores, and adverse events (AEs). 131 patients (BID) and 81 patients (QD) were randomized. Mean OIC duration ranged from 3.46.9 years; back pain was the most common pain condition. Mean SBM change from baseline was 1.44 (placebo BID), 1.40 (placebo QD), 1.96 (0.1mg BID), 2.58 (0.25mg QD), and 3.42 (0.25mg BID), with a mean treatment difference change of 0.51 (P=0.2979), 1.18 (P=0.0118), and 1.98 (P=0.0003) in the 0.1-mg BID, 0.25mg QD, and 0.25-mg BID groups, respectively. 26-28% of patients (placebo cohorts), 28% (0.1mg BID), 43% (0.25mg QD), and 56% (0.25mg BID; P=0.005) were overall responders. There were no changes in opioid consumption or pain scores and no evidence of CNS effects. The most commonly reported AEs were abdominal pain (QD; 10% across groups) and upper respiratory tract infection (BID; placebo,14%; 0.1mg,7%; 0.25mg,7%). Incidence of GI-related AEs was low and comparable across groups; most of mild severity. Significant, clinically-meaningful improvement in SBM frequency was observed after ADL5945 treatment, with the 0.25-mg BID dose demonstrating the most favorable benefit-to-risk profile. Phase 3 trials are planned. Supported by Adolor Corporation.
(433) Efficacy and tolerability of OROS hydromorphone extended release in patients with moderate to severe osteoarthritis pain: a phase 3, flexible-dose, randomized, double-blind, placebo-controlled study
(435) Efficacy and tolerability of hydrocodone extended-release tablets for the treatment of moderate to severe pain in opioid-treated patients with osteoarthritis or low back pain
M Hale, J Patrick, and S Nalamachu; Gold Coast Research, LLC, Weston, FL
M Hale, D D’Andrea, R Yang, and G Niebler; Cephalon, Inc., Frazer, PA
This randomized, placebo-controlled, double-blind study evaluated OROS hydromorphone ER for reducing moderate-to-severe osteoarthritis pain. The study consisted of a conversion/titration phase (1-4 weeks) and double-blind phase (12 weeks), with enriched enrollment randomized withdrawal design. During conversion/titration, opioid-tolerant patients were converted to OROS hydromorphone ER at 75% of the equianalgesic dose of their previous opioid dosage (5:1 morphine:hydromorphone), using dosages of 8-48 mg/d. Immediate-release hydromorphone (2-16 mg/d) was provided as rescue medication. On days 1-14 of double-blind treatment, patients randomized to placebo + rescue medication had OROS hydromorphone ER doses tapered to discontinuation (blind was maintained); remaining patients were maintained at their stable dose. The primary outcome measure was change from baseline to Week 12 in mean pain intensity. Three hundred thirty-four patients entered conversion/titration; 200 were randomized (100 to each group). Mean pain intensity decreased from 6.9 at screening to 3.0 at end of conversion/titration. During double-blind treatment, reductions in pain intensity were generally maintained in both treatment groups (mean [SE], 3.6 [0.2] at Week 12 for both groups), with no significant differences between treatment groups. Patients receiving placebo + rescue medication used significantly more rescue medication tablets/day than those receiving active treatment (mean [SE], 1.5 [0.1] vs 1.1 [0.1]; P=0.006). Commonly reported AEs during conversion/titration (constipation. 17.5%; nausea, 15.7%; somnolence, 8.3%) and double-blind treatment (constipation, 20.0%; nausea, 14.0%; vomiting, 9.0%) occurred more frequently in patients receiving OROS hydromorphone ER. Using the present trial design, there was failure to demonstrate sustained efficacy of active treatment versus placebo + rescue medication, perhaps due to higher use of rescue medication in the latter group. Technical editorial and writing assistance provided by Synchrony Medical, LLC, funded by Mallinckrodt Inc., a Covidien company, Hazelwood, MO.
Hydrocodone is available in the United States for the treatment of pain only as immediate-release formulations in combination with other medications. This phase 3, randomized, double-blind, placebo-controlled study assessed the efficacy and safety of an extended-release formulation of hydrocodone in patients with moderate to severe pain associated with osteoarthritis or low back pain requiring opioids for an extended period. During the open-label titration phase, patients were titrated to a successful dose of hydrocodone extended-release that provided stable pain relief without unacceptable adverse events (average pain intensity [PI] score over the past 24 hours #4 for 3 days based on the 11-point numerical rating scale or 3-5 days without unacceptable adverse events while maintained on the same dose for up to 7 days). Patients were then randomized into a 12-week, double-blind, placebo-controlled period to receive hydrocodone extended-release (15-90 mg) every 12 hours or matching placebo. Rescue treatment with hydrocodone/acetaminophen 5/325 mg tablets was permitted as needed up to a maximum hydrocodone dose of 10 mg/ day. A stepwise, double-blind tapering schedule was implemented for the first 2 weeks of the double-blind period to reduce the risk of withdrawal in patients randomized to placebo. The primary efficacy measure was change from baseline to week 12 in weekly average PI. Secondary efficacy measures included weekly average PI increase from baseline exceeding 33% and 50%; weekly average of daily average PI and worst PI scores; Clinician Assessment of Patient Function; Patient Assessment of Function; Clinical Global Impression of Severity Illness; and 36-Item Short Form Health Survey and Brief Pain Inventory-Short Form scores. Safety and tolerability were assessed throughout the study, including measures such as the Subjective Opioid Withdrawal Scale, Clinical Opiate Withdrawal Scale, Addiction Behavior Checklist, and Current Opioid Misuse Measure scores. Results for this study are not yet available. Sponsored by Cephalon, Inc.