In the wake of mounting overdoses and deaths from the opioid-addiction crisis sweeping across the U.S., drugmakers are racing to come up with safer painkillers.

Companies are highly motivated to create alternatives to the $4 billion opioid market. The federal government is cracking down on lax prescriptions that contribute to many thousands of deaths a year and has started to block the sale of medications it considers unsafe.

Drugs such as morphine, fentanyl, and oxycodone are such powerful analgesics because they so effectively block pain signals by acting directly on the brain. Since they work at such a fundamental level, these medications would be perfect painkillers were it not for their tendency to cause addiction.

"In medical school, we used to play this game: If you could only take five drugs to a desert island, what would they be? Everyone would say morphine because it's such a terrific drug for pain," said Morgan Sheng, vice president of neuroscience and molecular biology at Roche Holding's Genentech unit.

Drugmakers are tackling the challenge from all angles, working to create an arsenal of medications tailor-made for different forms of pain. These new drugs are drawing from the known pain-modifying attributes of chili peppers and cannabis, as well as human genetic mutations that alter how people experience pain to concoct new treatments for the nation's 100 million chronic sufferers. One of the more far-out medications in development is derived from a deadly toxin found in cone snails.

Many of these new innovations are intended to treat osteoarthritis pain, a huge market as the baby-boomer generation ages. Centrexion Therapeutics Corp. is developing an injection using synthetic capsaicin, the active ingredient in chili peppers. A mid-stage trial showed a single injection in patients' knees brought significant relief for as long as six months.

Capsaicin reduces the hyper-sensitive nerve endings in the knee, "like a hair cut," said Centrexion Chief Medical Officer Randall Stevens. The nerves will eventually grow back, requiring repeated treatment. The drug has the added benefit of not affecting nerves that sense touch and pressure, so the joint will retain some normal sensation, minus the most active pain sensors, said Chief Executive Officer Jeffrey Kindler.

Other new arthritis meds are nerve-growth-factor inhibitors, which block pain signals in nerve cells beyond the brain, such as in skin and muscle. This drug class was dogged by concerns that it worked so well, patients overused the affected joint. That led the Food and Drug Administration to issue temporary suspensions of some early trials. Pfizer and Eli Lilly, which co-developed one of these drugs, have adjusted doses and now have the leading treatment, called tanezumab, which received fast-track review from the FDA on June 13.

Taking another tack, Genentech is developing an oral drug based on extremely rare genetic mutations that prevent people from feeling pain. Studying them helped scientists discover a pathway in the body called the Nav 1.7 sodium ion channel that's implicated in pain. By modulating the pathway, Genentech hopes its pill can tamp down suffering.

It's still early days. The drug, called GDC-0310, just completed a Phase 1 safety trial. Genentech's Sheng said he's hopeful it will have few serious side effects since humans with the mutated gene are otherwise normal, save for a loss of the sense of smell. Sheng said it should be effective against musculoskeletal pain, such as in the lower back. Amgen Inc. is also in the early stages of developing a Nav 1.7 blocking drug.

Other pre-clinical treatments include Cara Therapeutics Inc. and Centrexion experimental drugs that target the cannabinoid receptors, mimicking the analgesic effect of marijuana. Meanwhile, scientists at Hunter College in New York are working to make an intravenous painkiller based on a toxin found in cone snails.

Opioids probably won't ever be shelved for good -- they're just too potent. So a handful of companies are working on versions that are safer and less addictive. Nektar Therapeutics has created an opioid that's designed to cross the blood-brain barrier very slowly, which results in a lowered euphoric effect. Because of its slower entry into the brain, however, the drug won't be able to help with cases of acute pain. Nektar is developing it for patients with chronic lower backaches.

Trevena Inc., meanwhile, is working on a safer opioid for hospital use that doesn't slow patients' breathing like many current opioids do. Said CEO Maxine Gowen: "We're all longing for the day when a non-addictive pain therapy with no side effects comes along, but until we find that perfect drug, opioids will continue to have a place."