The numbers are staggering – approximately 100 million Americans suffer from chronic pain conditions, and the annual economic toll of pain can be as high as $635 billion in medical bills and lost productivity, according to a report from the Institutes of Medicine. (See BioWorld Today, March 13, 2012.)

Although the unmet need for new painkillers is significant, novel medications to treat pain to replace opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) that are the current standard of care for pain treatment are not reaching the market. Discovering new pain therapies remains a challenge for the industry despite the obvious huge rewards waiting for those companies that could deliver drugs as effective as opioids minus the qualities that causes prescription drug abuse.

It's been a rough couple of years for painkillers after the FDA December 2010 decision to place a hold on most clinical trials involving therapies targeting nerve growth factor (NGF). But the prospects may be improving after the Arthritis Advisory Committee to the FDA unanimously concluded in March this year that the potential benefits of anti-NGF drugs outweighed the risks associated with their use. They voted 21 to 0 to allow Pfizer Inc. and other developers to resume testing, despite cases of joint destruction and osteonecrosis associated with their use.

In addition, a number of innovative biotechs have entered the pain arena.

Zalicus Inc., of Cambridge, Mass., for example, has initiated a Phase I multiple ascending dose (MAD) clinical study with Z944, its oral, T-type calcium channel blocker. The initiation of this MAD study follows the successfully completed Phase I single ascending dose study in which Z944 was determined to be generally well tolerated and a maximum tolerated dose was achieved.

N-type calcium channel blockers have been recognized as key targets in controlling pain through modulation of the entry of calcium into neurons, according to Zalicus. When a pain signal is initiated, calcium channels open and the influx of calcium ions trigger the release of neurotransmitters, which potentiates the signal to the brain, where it is perceived as pain.

Assuming Z944 successfully completes the MAD study, it could enter Phase II clinical development in the first quarter of 2013.

The company is collaborating with Hydra Biosciences Inc., also of Cambridge, to develop Zalicus' preclinical ion channel modulator for pain. Hydra brings expertise in ion channel discovery and preclinical development to the collaboration, while Zalicus will provide its portfolio of compounds. Zalicus will make an up-front payment and research funding to Hydra for two years, while Hydra carries out preclinical development activities. (See BioWorld Today, Feb. 13, 2012.)

San Francisco-based Adynxx Inc.'s platform technology is based on treating pain at its molecular roots – as a disease rather than a symptom – by inhibiting receptors at the source of the pain cascade. Preclinical studies have shown efficacy in reducing pain significantly and shortening its duration. The company has just completed enrollment in the Phase I clinical study in healthy volunteers of its lead investigational drug candidate for the prevention of acute and chronic post-surgical pain, AYX1, a small synthetic, dsDNA molecule that blocks EGR1 function by mimicking the genomic sequence EGR1 normally binds.

Although AYX1 isn't expected to replace existing medications for acute pain relief, Adynxx officials contended the one-time injection will allow patients to use fewer analgesics following a procedure, begin rehabilitation earlier and return to full function more quickly. (See BioWorld Today, Aug. 7, 2012.)

Array BioPharma Inc. said that its p38-alpha kinase inhibitor, ARRY-797, hit its primary endpoint of reducing pain more than placebo in a Phase II proof-of-concept trial in 157 patients with knee pain due to osteoarthritis. Enrolled patients suffered moderate-to-severe pain in spite of the use of NSAIDs. (See BioWorld Today, Aug. 2, 2012.)

The Boulder, Colo.-based company had already tracked "quite a bit of analgesic effect" in prior studies, and for the current trial chose to work with patients whose pain was poorly controlled on NSAIDs. Those patients continued taking the NSAIDs throughout the trial, with ARRY-797, placebo or active control in addition.

"There's not been a lot of significant innovation in the pain space for some time," said Array CEO Ron Squarer, citing runaway increase in opioid use, with its burden of addiction, and 12,000 fatalities per year associated with NSAIDs due to the risk of bleeding.