Efficacy and safety of the α4β2 neuronal nicotinic receptor agonist ABT-894 in patients with diabetic peripheral neuropathic pain

• Published in: Pain (Amsterdam) Vol. 153; no. 4; pp. 862 - 868
• Main Authors: Rowbotham, Michael C., Arslanian, Armen, Nothaft, Wolfram, Duan, W. Rachel, Best, Andrea E., Pritchett, Yili, Zhou, Qian, Stacey, Brett R.
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA Elsevier B.V 01.04.2012; Elsevier
• Subjects: ABT-894; Aged; Analgesics; Azabicyclo Compounds - adverse effects; Azabicyclo Compounds - pharmacology; Azabicyclo Compounds - therapeutic use; Biological and medical sciences; Diabetic Neuropathies - drug therapy; Diabetic Neuropathies - physiopathology; Double-Blind Method; Duloxetine Hydrochloride; Female; Fundamental and applied biological sciences. Psychology; Humans; Illness and personality; Illness, stress and coping; Male; Medical sciences; Middle Aged; Neuralgia - drug therapy; Neuralgia - physiopathology; Neuronal nicotinic receptor; Neuropathic pain; Neuropharmacology; Nicotinic Agonists - adverse effects; Nicotinic Agonists - pharmacology; Nicotinic Agonists - therapeutic use; Pain Measurement - drug effects; Pain Measurement - methods; Pharmacology. Drug treatments; Psychology and medicine; Psychology. Psychoanalysis. Psychiatry; Psychology. Psychophysiology; Pyridines - adverse effects; Pyridines - pharmacology; Pyridines - therapeutic use; Randomized clinical trial; Receptors, Nicotinic - physiology; Thiophenes - adverse effects; Thiophenes - pharmacology; Thiophenes - therapeutic use; Treatment Outcome; ABT-894; Randomized clinical trial; Neuronal nicotinic receptor; Neuropathic pain; Human; Cholinergic receptor; Improvement; Analgesic; Pain; Treatment; Placebo; Clinical trial; Safety; Nicotinic receptor
• ISSN: 0304-3959; 1872-6623
• DOI: 10.1016/j.pain.2012.01.009

In 2 well-controlled phase 2 clinical trials, the selective α4β2 neuronal nicotinic receptor agonist ABT-894 was found to be ineffective in treating patients with diabetic neuropathic pain. 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 α4β2 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 4mg ABT-894 twice daily compared with placebo and 60mg duloxetine once per day over 8weeks of treatment. Study 2 (124 patients randomized) tested 6mg ABT-894 twice daily vs placebo for 8weeks. 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 α4β2 NNR agonist ABT-594, which demonstrated efficacy compared with placebo, albeit with significant tolerability limitations. The failure of the highly selective α4β2 NNR agonist ABT-894 indicates that it may not be possible to define a therapeutic index for this mechanism or that selectively targeting α4β2 NNRs may not be a viable approach to treating neuropathic pain.