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Efficacy and tolerability of tapentadol extended release (ER) in patients with chronic, painful diabetic peripheral neuropathy (DPN): results of a phase 3, randomized-withdrawal, placebo-controlled study
S72
The Journal of Pain
(384) Antinociceptive properties of zerumbone, a natural compound found in ginger R Radhakrishnan, D Bennett, A Chakraborty, and M Mandal; Roseman University of Health Sciences- Utah Campus, South Jordan, UT
Abstracts (386) Efficacy and safety of NGX-1998, a novel topical liquid formulation of capsaicin, in patients with postherpetic neuralgia: results of a multi-center, placebo-controlled trial
Compounds obtained from natural sources have been great lead compounds for analgesic drugs in the past. Zerumbone is chemically a sesquiterpene isolated from ginger rhizome (Zingiber zerumbet) that has been shown to have anti-inflammatory and antinociceptive properties in various animal models. However, zerumbone has not been tested in formalin pain model, which is a well-established animal model with very high predictive value of human analgesic effects. Male CF1 mice weighing 25-40 g were used in the study. Control group was administered orally (p.o.) with 1% carboxymethylcellulose (CMC) suspension (vehicle) and the treatment group was administered p.o. with 200 mg/kg zerumbone suspended in 1% CMC, 1 hour prior to the injection of formalin. Mice in both groups were injected subcutaneously with 5% formalin in the dorsal aspect of the hindpaw after 1 hour of oral administration of the vehicle or zerumbone. Nocifensive behavior (licking and biting the injected paw) induced in mice by formalin injection was observed for 1 hour following formalin injection, and the time duration in seconds they spent licking or biting the injected paw was recorded. Preliminary results indicate that zerumbone administered at a dose of 200 mg/kg p.o. significantly reduced the time spent licking or biting the formalin-injected paw in the first phase of formalin-induced nocifensive behavior. Duration of licking and biting was also reduced in the second phase, but the reduction did not reach statistical significance. Preliminary results indicate antinociceptive effects of zerumbone in the first phase of formalin test. Further studies will be conducted using lower and higher doses of zerumbone to establish a pharmacologically relevant dose-response effect, and also to establish safety of the compound.
L Webster, S Bhattacharya, M Wallace, B Wells, J Tobias, and S Babbar; Lifetree Clinical Research, Salt Lake City, UT
(385) Ranolazine attenuates mechanical allodynia associated with demyelination injury
(387) Efficacy and tolerability of tapentadol extended release (ER) in patients with chronic, painful diabetic peripheral neuropathy (DPN): results of a phase 3, randomized-withdrawal, placebo-controlled study
H Gould, R Soignier, S Cho, C Hernandez, I Diamond, B Taylor, and D Paul; Louisiana State University Health Sciences Center in New Orleans, New Orleans, LA A broad spectrum of agents has been used to treat neuropathic pain. Although many agents produce an analgesic effect, not all neuropathic conditions respond similarly to treatment. We have demonstrated that ranolazine, a cardiotherapeutic agent that blocks voltage-gated sodium channels, Nav 1.4, 1.5, 1.7 and 1.8, is effective in attenuating mechanical hyperalgesia in both inflammatory (CFA) and neuropathic (SNI) models of pain, and have chosen to test the efficacy of this drug in a model of demyelination injury. After determination of baseline nerve conduction velocities (NCV) and withdrawal responses from mechanical, heat and cold stimulation in male, Sprague-Dawley rats (250g), 1 mg/30 ml of doxorubicin was injected into one sciatic nerve. The contralateral nerve provided a sham control. Conduction block was demonstrated by a greater than 10m/sec or 30% reduction in NCV; velocities in the injected limbs, 27.79 6 2.25 m/sec, were reduced when compared to controls, 33.9 6 2.29 m/sec. Doxorubicin injection produced a small hyperanalgesic effect in response to mechanical stimulation but not to heat or cold thermal stimulation. Vehicle (0.9% isotonic saline; pH 3.0) or ranolazine was then administered by intraperitoneal injection (0, 10, 20, 30, and 50mg/kg). Animals were tested 30 minutes after drug administration. Intraperitoneal ranolazine (but not vehicle) dose-dependently (0, 10, 30 mg/kg) reduced mechanical allodynia. No additional anesthetic effect was noted at higher doses, but responses were slower. Fifty mg/kg ranolazine reversed conduction block [F(2,6)=11.87, p<0.05], but had no effect in the uninjected limb [F(2,6) = 1.81, p>0.05]. We conclude that ranolazine attenuates mechanical allodynia produced by demyelination in rats, at least in part, by reversing conduction block at doses that do not produce other behavioral side effects. These data are evidence that regardless the mechanism of injury, ranolazine is likely to be effective in reducing mechanical allodynia. Supported by Gilead Sciences Inc.
Qutenzaâ (capsaicin) 8% patch is approved for management of peripheral neuropathic pain associated with postherpetic neuralgia (PHN). A single 60minute application of Qutenzaâ can provide 12 weeks of PHN pain relief (Qutenzaâ Full-Prescribing Information). NGX-1998, novel liquid formulation of high concentration capsaicin (10% and 20% w/w) was designed to provide similar or better efficacy, safety and tolerability in a rapid 5-minute application. NGX 1998was studied in a multicenter, placebo-controlled, double-blind trial in PHN patients. Using a 2:2:1 (10%:20%:placebo) randomization, 164 patients received a 5 minute topical application of NGX-1998 to their painful area and were followed for12 weeks. Primary efficacy endpoint was mean percent change from baseline in ‘‘average pain for the past 24 hours’’ Numeric Pain Rating Scale (NPRS) score during Weeks 2 8; similar measures were evaluated for Weeks 2-12. Patient demographics were similar across treatment groups. While the study was not powered to determine a statistically significant difference between the 10% and 20% formulations, a clear dose-response was observed in the primary endpoint ( 16.7%, 22.3% and 25.1% in the placebo, 10% and 20% treatment groups, respectively) and in the secondary endpoint for Weeks 2-12 (16.6%, 22.2% and 26.0% in the placebo, 10% and 20% treatment groups, respectively). The majority of subject’s dermal assessment scores were 0 to 2 (0=no irritation, 1=mild erythema, 2=definite erythema, minimal papules/edema). NGX-1998 treatment was well-tolerated. No patient terminated prematurely due to an adverse event (AE). Most prevalent AEs of NGX1998 were localized dermal reactions (e.g., pain and erythema). Severe and serious AEs were more prevalent in the placebo group. NGX-1998 was well-tolerated and resulted in improved outcomes on validated measures of neuropathic pain. A 5 minute application of NGX-1998 may provide a convenient option to patients with PHN that could reduce healthcare provider time.
€ffler, B Lange, K Karcher, D Pennett, A Vinik, D Shapiro, C Rauschkolb-Lo and M Etropolski; EVMS Strelitz Diabetes Research Center, Norfolk, VA This Phase 3, randomized-withdrawal, placebo-controlled study (NCT01041859) evaluated the efficacy and tolerability of tapentadol ER for the management of neuropathic pain associated with DPN. Adult patients with moderate to severe, painful DPN with symptoms for $6 months and $3-month history of analgesic use for painful DPN were titrated to an optimal dose (balancing efficacy and tolerability) of tapentadol ER (100-250 mg bid) during a 3-week open-label period. At the end of the titration period, patients with $1-point reduction in pain intensity from the beginning to end of titration were randomized (1:1) to receive placebo or their pre-determined optimal dose of tapentadol ER for 12 weeks (double-blind, fixed dose, maintenance phase). The primary efficacy endpoint was mean change in average pain intensity (recorded twice daily [average pain during previous 12 hours]; 11-point NRS) from the start to Week 12 (LOCF) of the double-blind maintenance phase. Treatment-emergent adverse events (TEAEs) were recorded. A total of 358 patients completed the open-label titration period; 318 patients (placebo, n=152; tapentadol ER, n=166) were randomized and received $1 dose of study medication. At the start versus Week 12 of double-blind maintenance, respectively, mean (SD) pain intensity was: tapentadol ER, 3.70 (1.78) versus 4.01 (2.23); placebo, 3.35 (2.17) versus 4.83 (2.60). Mean (SD) change in average pain intensity from the start to Week 12 of the double-blind maintenance phase was: tapentadol ER, 0.28 (2.042); placebo, 1.30 (2.428) (least-squares mean difference for tapentadol ER vs placebo, –0.95 [95% CI, –1.415 to –0.493]; P <0.001 favoring tapentadol ER). TEAEs ($10%) reported in the tapentadol ER group during double-blind maintenance were nausea (21.1%) and vomiting (12.7%). Tapentadol ER (100-250 mg bid) was effective and well tolerated for the management of moderate to severe, neuropathic pain associated with DPN in adults. € nenthal GmbH. Supported by Janssen Research & Development, L.L.C., and Gru
The Journal of Pain
(384) Antinociceptive properties of zerumbone, a natural compound found in ginger R Radhakrishnan, D Bennett, A Chakraborty, and M Mandal; Roseman University of Health Sciences- Utah Campus, South Jordan, UT
Abstracts (386) Efficacy and safety of NGX-1998, a novel topical liquid formulation of capsaicin, in patients with postherpetic neuralgia: results of a multi-center, placebo-controlled trial
Compounds obtained from natural sources have been great lead compounds for analgesic drugs in the past. Zerumbone is chemically a sesquiterpene isolated from ginger rhizome (Zingiber zerumbet) that has been shown to have anti-inflammatory and antinociceptive properties in various animal models. However, zerumbone has not been tested in formalin pain model, which is a well-established animal model with very high predictive value of human analgesic effects. Male CF1 mice weighing 25-40 g were used in the study. Control group was administered orally (p.o.) with 1% carboxymethylcellulose (CMC) suspension (vehicle) and the treatment group was administered p.o. with 200 mg/kg zerumbone suspended in 1% CMC, 1 hour prior to the injection of formalin. Mice in both groups were injected subcutaneously with 5% formalin in the dorsal aspect of the hindpaw after 1 hour of oral administration of the vehicle or zerumbone. Nocifensive behavior (licking and biting the injected paw) induced in mice by formalin injection was observed for 1 hour following formalin injection, and the time duration in seconds they spent licking or biting the injected paw was recorded. Preliminary results indicate that zerumbone administered at a dose of 200 mg/kg p.o. significantly reduced the time spent licking or biting the formalin-injected paw in the first phase of formalin-induced nocifensive behavior. Duration of licking and biting was also reduced in the second phase, but the reduction did not reach statistical significance. Preliminary results indicate antinociceptive effects of zerumbone in the first phase of formalin test. Further studies will be conducted using lower and higher doses of zerumbone to establish a pharmacologically relevant dose-response effect, and also to establish safety of the compound.
L Webster, S Bhattacharya, M Wallace, B Wells, J Tobias, and S Babbar; Lifetree Clinical Research, Salt Lake City, UT
(385) Ranolazine attenuates mechanical allodynia associated with demyelination injury
(387) Efficacy and tolerability of tapentadol extended release (ER) in patients with chronic, painful diabetic peripheral neuropathy (DPN): results of a phase 3, randomized-withdrawal, placebo-controlled study
H Gould, R Soignier, S Cho, C Hernandez, I Diamond, B Taylor, and D Paul; Louisiana State University Health Sciences Center in New Orleans, New Orleans, LA A broad spectrum of agents has been used to treat neuropathic pain. Although many agents produce an analgesic effect, not all neuropathic conditions respond similarly to treatment. We have demonstrated that ranolazine, a cardiotherapeutic agent that blocks voltage-gated sodium channels, Nav 1.4, 1.5, 1.7 and 1.8, is effective in attenuating mechanical hyperalgesia in both inflammatory (CFA) and neuropathic (SNI) models of pain, and have chosen to test the efficacy of this drug in a model of demyelination injury. After determination of baseline nerve conduction velocities (NCV) and withdrawal responses from mechanical, heat and cold stimulation in male, Sprague-Dawley rats (250g), 1 mg/30 ml of doxorubicin was injected into one sciatic nerve. The contralateral nerve provided a sham control. Conduction block was demonstrated by a greater than 10m/sec or 30% reduction in NCV; velocities in the injected limbs, 27.79 6 2.25 m/sec, were reduced when compared to controls, 33.9 6 2.29 m/sec. Doxorubicin injection produced a small hyperanalgesic effect in response to mechanical stimulation but not to heat or cold thermal stimulation. Vehicle (0.9% isotonic saline; pH 3.0) or ranolazine was then administered by intraperitoneal injection (0, 10, 20, 30, and 50mg/kg). Animals were tested 30 minutes after drug administration. Intraperitoneal ranolazine (but not vehicle) dose-dependently (0, 10, 30 mg/kg) reduced mechanical allodynia. No additional anesthetic effect was noted at higher doses, but responses were slower. Fifty mg/kg ranolazine reversed conduction block [F(2,6)=11.87, p<0.05], but had no effect in the uninjected limb [F(2,6) = 1.81, p>0.05]. We conclude that ranolazine attenuates mechanical allodynia produced by demyelination in rats, at least in part, by reversing conduction block at doses that do not produce other behavioral side effects. These data are evidence that regardless the mechanism of injury, ranolazine is likely to be effective in reducing mechanical allodynia. Supported by Gilead Sciences Inc.
Qutenzaâ (capsaicin) 8% patch is approved for management of peripheral neuropathic pain associated with postherpetic neuralgia (PHN). A single 60minute application of Qutenzaâ can provide 12 weeks of PHN pain relief (Qutenzaâ Full-Prescribing Information). NGX-1998, novel liquid formulation of high concentration capsaicin (10% and 20% w/w) was designed to provide similar or better efficacy, safety and tolerability in a rapid 5-minute application. NGX 1998was studied in a multicenter, placebo-controlled, double-blind trial in PHN patients. Using a 2:2:1 (10%:20%:placebo) randomization, 164 patients received a 5 minute topical application of NGX-1998 to their painful area and were followed for12 weeks. Primary efficacy endpoint was mean percent change from baseline in ‘‘average pain for the past 24 hours’’ Numeric Pain Rating Scale (NPRS) score during Weeks 2 8; similar measures were evaluated for Weeks 2-12. Patient demographics were similar across treatment groups. While the study was not powered to determine a statistically significant difference between the 10% and 20% formulations, a clear dose-response was observed in the primary endpoint ( 16.7%, 22.3% and 25.1% in the placebo, 10% and 20% treatment groups, respectively) and in the secondary endpoint for Weeks 2-12 (16.6%, 22.2% and 26.0% in the placebo, 10% and 20% treatment groups, respectively). The majority of subject’s dermal assessment scores were 0 to 2 (0=no irritation, 1=mild erythema, 2=definite erythema, minimal papules/edema). NGX-1998 treatment was well-tolerated. No patient terminated prematurely due to an adverse event (AE). Most prevalent AEs of NGX1998 were localized dermal reactions (e.g., pain and erythema). Severe and serious AEs were more prevalent in the placebo group. NGX-1998 was well-tolerated and resulted in improved outcomes on validated measures of neuropathic pain. A 5 minute application of NGX-1998 may provide a convenient option to patients with PHN that could reduce healthcare provider time.
€ffler, B Lange, K Karcher, D Pennett, A Vinik, D Shapiro, C Rauschkolb-Lo and M Etropolski; EVMS Strelitz Diabetes Research Center, Norfolk, VA This Phase 3, randomized-withdrawal, placebo-controlled study (NCT01041859) evaluated the efficacy and tolerability of tapentadol ER for the management of neuropathic pain associated with DPN. Adult patients with moderate to severe, painful DPN with symptoms for $6 months and $3-month history of analgesic use for painful DPN were titrated to an optimal dose (balancing efficacy and tolerability) of tapentadol ER (100-250 mg bid) during a 3-week open-label period. At the end of the titration period, patients with $1-point reduction in pain intensity from the beginning to end of titration were randomized (1:1) to receive placebo or their pre-determined optimal dose of tapentadol ER for 12 weeks (double-blind, fixed dose, maintenance phase). The primary efficacy endpoint was mean change in average pain intensity (recorded twice daily [average pain during previous 12 hours]; 11-point NRS) from the start to Week 12 (LOCF) of the double-blind maintenance phase. Treatment-emergent adverse events (TEAEs) were recorded. A total of 358 patients completed the open-label titration period; 318 patients (placebo, n=152; tapentadol ER, n=166) were randomized and received $1 dose of study medication. At the start versus Week 12 of double-blind maintenance, respectively, mean (SD) pain intensity was: tapentadol ER, 3.70 (1.78) versus 4.01 (2.23); placebo, 3.35 (2.17) versus 4.83 (2.60). Mean (SD) change in average pain intensity from the start to Week 12 of the double-blind maintenance phase was: tapentadol ER, 0.28 (2.042); placebo, 1.30 (2.428) (least-squares mean difference for tapentadol ER vs placebo, –0.95 [95% CI, –1.415 to –0.493]; P <0.001 favoring tapentadol ER). TEAEs ($10%) reported in the tapentadol ER group during double-blind maintenance were nausea (21.1%) and vomiting (12.7%). Tapentadol ER (100-250 mg bid) was effective and well tolerated for the management of moderate to severe, neuropathic pain associated with DPN in adults. € nenthal GmbH. Supported by Janssen Research & Development, L.L.C., and Gru