A handful of drugmakers are taking their first steps toward developing marijuana-based painkillers, alternatives to opioids that have led to widespread abuse and caused the U.S. health regulator to ask for a withdrawal of a popular drug this month.

The cannabis plant has been used for decades to manage pain and there are increasingly sophisticated marijuana products available across 29 U.S. states, as well as in the District of Columbia, where medical marijuana is legal.

There are no U.S. Food and Drug Administration (FDA)-approved painkillers derived from marijuana, but companies such as Axim Biotechnologies Inc, Nemus Bioscience Inc and Intec Pharma Ltd have drugs in various stages of development.

The companies are targeting the more than 100 million Americans who suffer from chronic pain, and are dependent on opioid painkillers such as Vicodin, or addicted to street opiates including heroin.

Opioid overdose, which claimed celebrities including Prince and Heath Ledger as victims, contributed to more than 33,000 deaths in 2015, according to the Centers for Disease Control and Prevention.

Earlier this month, the FDA asked Endo International Plc to withdraw its Opana ER painkiller from the market, the first time the agency has called for the removal of an opioid painkiller for public health reasons. The FDA concluded that the drug's benefits no longer outweighed its risks.

FIGHTING THE EPIDEMIC

Multiple studies have shown that pro-medical marijuana states have reported fewer opiate deaths and there are no deaths related to marijuana overdose on record.(reut.rs/2r74Sbe)

But marijuana-derived drugs could take longer than usual to hit the market as the federal government considers marijuana a "schedule 1" substance - a dangerous drug with no medicinal value - making added approvals necessary. Any drug typically takes at least a decade from discovery to approval.

It could be worth the wait.

An FDA-approved marijuana-based painkiller would ensure consistent dosing and potency, and availability across the country, analysts and experts said.

"Doctors like to be able to write a prescription and know that whatever they wrote is pure and from a blinded, placebo-controlled trial," California-based Nemus's CEO Brian Murphy told Reuters.

Nemus is testing its product - a synthetic version of the non-psychoactive CBD compound found in cannabis - on rats with chronic pain and expects to report data later this year.

Rival Axim, whose North American headquarters is in New York, is conducting preclinical studies on a chewing gum containing synthetic CBD and THC, a psychoactive compound found in marijuana. The company expects to submit an FDA application to start a trial on opioid-dependent patients this year.

Leading the pack is Israel-based Intec, which recently announced the start of an early-stage study testing its painkiller made of natural CBD and THC extracts.

OTHER OPTIONS

Independent scientists are also looking to find natural, non-pharmaceutical alternatives to opioids, but many have said it is difficult to access government-approved marijuana to conduct research due to supply restrictions.

"It's taken me seven years to get the DEA license," said Dr Sue Sisley, who is planning to conduct an FDA-regulated study evaluating whether marijuana can help opioid-dependent patients.

There could soon be other alternatives as well. Pfizer Inc and Biogen Inc are among a clutch of drugmakers developing non-opioid painkillers that are in advanced clinical studies.

Still, opioid painkillers are here to stay and will continue to be widely prescribed, especially for patients with acute and post-surgical pain.

The Republican healthcare bill unveiled on Thursday has proposed a drastic cut to the Medicaid budget and could gut, what advocates say, is essential coverage for drug addiction treatment, potentially hampering the fight against opioid abuse.