TY - JOUR
T1 - Efficacy and safety of the α 4β 2 neuronal nicotinic receptor agonist ABT-894 in patients with diabetic peripheral neuropathic pain
AU - Rowbotham, Michael C.
AU - Arslanian, Armen
AU - Nothaft, Wolfram
AU - Duan, W. Rachel
AU - Best, Andrea E.
AU - Pritchett, Yili
AU - Zhou, Qian
AU - Stacey, Brett R.
N1 - Funding Information:
These studies were sponsored by Abbott Laboratories. Dr. Rowbotham has served as a consultant to Abbott, Adynxx, Afferent Pharmaceuticals, Allergan, Arcion, Bristol Meyers Squibb, Cardiome, Flexion, Kyowa Hakko Kirin, Neurotherapeutics Pharma, Nuvo Research, Xenon, Xenoport, and Zalicus. Dr. Stacey has received grant support from NeurogesX and Pfizer, and has served as a consultant to AstraZeneca, Boehringer Ingelheim, Endo Pharmaceuticals, NeurogesX, and Pfizer. Dr. Arslanian has no conflicts of interest to declare. Dr. Zhou is an employee of Abbott. Drs. Nothaft, Duan, Best, and Pritchett are employees of Abbott and hold Abbott stock and stock options.
PY - 2012/4
Y1 - 2012/4
N2 - Preclinical and clinical studies suggest that neuronal nicotinic receptor (NNR) agonists may be a novel and effective therapy for numerous painful conditions. Analgesic efficacy and safety of the highly selective α 4β 2 NNR agonist ABT-894 was evaluated in 2 separate randomized, double-blind, multicenter, placebo-controlled clinical trials in patients with diabetic peripheral neuropathic pain (DPNP). Study 1 (280 patients randomized) tested 1, 2, and 4 mg ABT-894 twice daily compared with placebo and 60 mg duloxetine once per day over 8 weeks of treatment. Study 2 (124 patients randomized) tested 6 mg ABT-894 twice daily vs placebo for 8 weeks. The primary efficacy outcome measure in both studies was the weekly mean of the 24-hour average pain score recorded in each patient's diary. In both trials, none of the ABT-894 dose groups showed efficacy compared with placebo, whereas duloxetine achieved a statistically significant improvement over placebo in Study 1. All dose levels of ABT-894 were well tolerated, and no significant safety issues were identified. These results are in contrast to the outcome of a previously reported study of DPNP using the less selective α 4β 2 NNR agonist ABT-594, which demonstrated efficacy compared with placebo, albeit with significant tolerability limitations. The failure of the highly selective α 4β 2 NNR agonist ABT-894 indicates that it may not be possible to define a therapeutic index for this mechanism or that selectively targeting α 4β 2 NNRs may not be a viable approach to treating neuropathic pain.
AB - Preclinical and clinical studies suggest that neuronal nicotinic receptor (NNR) agonists may be a novel and effective therapy for numerous painful conditions. Analgesic efficacy and safety of the highly selective α 4β 2 NNR agonist ABT-894 was evaluated in 2 separate randomized, double-blind, multicenter, placebo-controlled clinical trials in patients with diabetic peripheral neuropathic pain (DPNP). Study 1 (280 patients randomized) tested 1, 2, and 4 mg ABT-894 twice daily compared with placebo and 60 mg duloxetine once per day over 8 weeks of treatment. Study 2 (124 patients randomized) tested 6 mg ABT-894 twice daily vs placebo for 8 weeks. The primary efficacy outcome measure in both studies was the weekly mean of the 24-hour average pain score recorded in each patient's diary. In both trials, none of the ABT-894 dose groups showed efficacy compared with placebo, whereas duloxetine achieved a statistically significant improvement over placebo in Study 1. All dose levels of ABT-894 were well tolerated, and no significant safety issues were identified. These results are in contrast to the outcome of a previously reported study of DPNP using the less selective α 4β 2 NNR agonist ABT-594, which demonstrated efficacy compared with placebo, albeit with significant tolerability limitations. The failure of the highly selective α 4β 2 NNR agonist ABT-894 indicates that it may not be possible to define a therapeutic index for this mechanism or that selectively targeting α 4β 2 NNRs may not be a viable approach to treating neuropathic pain.
KW - ABT-894
KW - Neuronal nicotinic receptor
KW - Neuropathic pain
KW - Randomized clinical trial
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U2 - 10.1016/j.pain.2012.01.009
DO - 10.1016/j.pain.2012.01.009
M3 - Article
C2 - 22386472
AN - SCOPUS:84858698916
SN - 0304-3959
VL - 153
SP - 862
EP - 868
JO - Pain
JF - Pain
IS - 4
ER -