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.
PY - 2012/4/1
Y1 - 2012/4/1
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
UR - http://www.scopus.com/inward/record.url?scp=84858698916&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84858698916&partnerID=8YFLogxK
U2 - 10.1016/j.pain.2012.01.009
DO - 10.1016/j.pain.2012.01.009
M3 - Article
C2 - 22386472
AN - SCOPUS:84858698916
VL - 153
SP - 862
EP - 868
JO - Pain
JF - Pain
SN - 0304-3959
IS - 4
ER -