AVP-923 combines dextromethorphan hydrobromide with quinidine sulphate, a cytochrome P450 2D6 enzyme (CYP2D6) inhibitor.
Dextromethorphan acts on sigma-1 and NMDA receptors in the brain and spinal cord. However, it is rapidly metabolised by CYP2D6, which reduces its bioavailability. Quinidine sulphate inhibits CYP2D6, thereby increasing the systemic concentrations—and potentially efficacy—of dextromethorphan.
Avanir Pharmaceuticals announced phase III results for AVP-923 earlier this year.
The randomised, controlled, double-blind 13-week trial enrolled adults (n=379) with daily leg pain for at least three months due to symmetrical peripheral diabetic neuropathy. Participants received placebo, dextromethorphan/quinidine 45mg/30mg, or dextromethorphan/quinidine 30mg/30mg once daily for 7 days, and twice daily thereafter.
Investigators assessed efficacy with daily patient diaries (using four pain-rating scales) and five clinic visits (using two pain-rating scales).
The primary efficacy analysis showed that dextromethorphan/quinidine 45mg/30mg was superior to placebo on all six pain-rating scales (p<0.0001). The combination was superior to placebo for diary ratings of pain intensity, pain interference with sleep and pain interference with activities (p<0.0001 for all). At the same dose, it also provided greater relief of leg pain (p=0.0002) and greater reduction of leg pain intensity (p=0.0286) than placebo during clinic assessments.
The efficacy of the 30mg/30mg dose was numerically less than that of the 45mg/30mg dose but significantly greater than placebo for most outcomes.
Adverse events were mostly mild or moderate, although discontinuation due to adverse events was at least twice as common with dextromethorphan/quinidine than with placebo.
The placebo-controlled 17-week phase II PRIME study is investigating the use of AVP-923 in central neuropathic pain in patients with multiple sclerosis.
AVP-923 received FDA approval for the treatment of pseudobulbar affect in October 2010.