title: Efficacy and safety of the α4β2 neuronal nicotinic receptor agonist ABT-894 in patients with diabetic peripheral neuropathic pain.
abstract: 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(4)β(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(4)β(2) NNR agonist ABT-594, which demonstrated efficacy compared with placebo, albeit with significant tolerability limitations. The failure of the highly selective α(4)β(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(4)β(2) NNRs may not be a viable approach to treating neuropathic pain.
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco, CA, USA Beacon Clinical Research, Brockton, MA, USA Abbott, Abbott Park, IL, USA Department of Anesthesiology & Peri-Operative Medicine, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Rowbotham
authors.forename: Armen
authors.initials: A
authors.lastname: Arslanian
authors.forename: Wolfram
authors.initials: W
authors.lastname: Nothaft
authors.forename: Rachel W
authors.initials: RW
authors.lastname: Duan
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Best
authors.forename: Yili
authors.initials: Y
authors.lastname: Pritchett
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhou
authors.forename: Brett R
authors.initials: BR
authors.lastname: Stacey
mesh_terms: D000368:Aged; D053961:Azabicyclo Compounds / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000503:physiopathology; D004311:Double-Blind Method; D000068736:Duloxetine Hydrochloride; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009437:Neuralgia / Q000188:drug therapy* / Q000503:physiopathology; D018722:Nicotinic Agonists / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D011725:Pyridines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011978:Receptors, Nicotinic / Q000502:physiology*; D013876:Thiophenes / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: C000593913:3-(5,6-dichloropyridin-3-yl)-3,6-diazabicyclo(3.2.0)heptane; D053961:Azabicyclo Compounds; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D013876:Thiophenes; C403531:nicotinic receptor alpha4beta2; D000068736:Duloxetine Hydrochloride