CLEVELAND — The U.S. opioids epidemic has claimed more than 400,000 lives and left millions of people addicted, strained health care, law enforcement and social service systems, cost governments billions, and bankrupted the best-known manufacturer of narcotic painkillers.

Now, 12 ordinary people will decide whether drug companies should be held responsible for the worst drug crisis in U.S. history and forced to pay billions of dollars to help clean it up.

That effort begins Wednesday in U.S. District Judge Dan Aaron Polster’s courtroom on the 18th floor of the federal building here, where attorneys will start picking a jury for the landmark trial.

Described as the most complex litigation ever, the trial will begin to sort out the welter of accusations over the crisis. While six drug companies are defendants in the case, jurors also may hear blame cast widely on doctors, government agencies and perhaps even drug users themselves. The jury’s response will help decide who should bear the cost of one of this century’s worst public health crises.

“What’s pushing them to trial is the attempt to reach a settlement in a vacuum and the difficulty of doing that,” said Alexandra Lahav, a professor at the University of Connecticut School of Law who studies mass tort cases like this one.

“I can’t un-punch you in the face,” she added. “But I can pay you for your pain and suffering, for the surgery you had to have for your broken nose. So we translate that into money.”

The plaintiffs need a unanimous verdict for any company to be held liable, and predicting a jury’s reaction is difficult. More than 4 in 10 people know someone who has been addicted to prescription painkillers, and 1 in 5 knows someone who died of an overdose of prescription opioids, according to polling by the Kaiser Family Foundation.

But those same polls show that 69 percent blame doctors for the prescription drug epidemic, 68 percent blame people who use the drugs, and 60 percent blame drug companies.

An 11th-hour bid to delay the trial failed Tuesday after a group of state attorneys general tried to persuade Polster to give them more time to craft a settlement in their own cases, according to people familiar with the events.

They told Polster they were trying to reach an $18 billion settlement with the nation’s three largest drug distributors, McKesson Corp., Cardinal Health and AmerisourceBergen, according to the people familiar with the events who spoke on the condition of anonymity because of the sensitivity of the negotiations.

But during a hearing Tuesday, Polster indicated that jury selection would begin Wednesday as scheduled.

Much has changed in the more than five years since two California counties, Orange and Santa Clara, first filed suit against five drugmakers. More than 2,500 other counties, cities, Native American tribes, individuals and other groups followed, naming dozens of painkiller manufacturers, wholesalers and dispensers as defendants. (Separately, nearly every state has filed similar lawsuits in state courts.)

Many of the lawsuits cite similar issues. A panel of federal judges placed most of them — and the larger social problem — before Polster in early 2017, creating what is known as a “multidistrict litigation.” The judge spent most of the past two years pushing both sides to forge a mass settlement that would speed aid to the people and communities in need, even as they prepared for trial.

“Ordinarily, the resolution of a social epidemic should be the responsibility of our other two branches of government,” Polster wrote in one pretrial ruling, “but these are not ordinary times.”

There have been other legal efforts to assign blame over the two decades of the drug epidemic. West Virginia reached settlements with numerous drug distributors and recouped $84 million from them. In August, an Oklahoma judge ordered Johnson & Johnson to pay the state $572 million for its role. The federal government has brought more than a dozen administrative and civil actions against drug companies, collecting hundreds of millions of dollars in penalties. Five executives of Insys Therapeutics were found guilty in May of bribing health-care providers to prescribe the company’s highly addictive fentanyl spray. Insys also paid a $225 million fine and was forced into bankruptcy.

Most notably, OxyContin maker Purdue Pharma, the company most widely blamed for fueling the epidemic, pleaded guilty to misleading doctors and patients about the drug in 2007 and paid $635 million in penalties. Purdue, one of the original defendants in the current litigation, has filed for bankruptcy and is negotiating a settlement it hopes will end all the lawsuits against it. The company’s owners, the Sackler family, will relinquish the company as part of that process.

For this trial, Polster chose two Ohio counties — Cuyahoga and Summit — as “bellwether” plaintiffs to provide a test case for how similar lawsuits might fare and to encourage settlements rather than more trials. Each side has 100 hours to present its case.

Both counties have been hit hard by the epidemic. In 2016, officials in Akron, part of Summit County, had to bring in refrigerated trailers to store bodies from overdose deaths after the powerful synthetic carfentanil hit the streets. That year, 189 people died. Two years later, the total was down to 73.

This year, there have been 70 overdose deaths already, including three confirmed and three more suspected in recent days, said Lt. Dave Garro, commander of the police department’s narcotics unit. Dealers are lacing fentanyl into a wider variety of street drugs, including cocaine, he said.

When Ohio cracked down on the abuse of prescription narcotics several years ago, “what did these people do? They went to the streets,” Garro said. “It’s a pretty clear cause and effect.

“Drug companies are certainly culpable,” he said. So, in his view, are drugstores and doctors, who have escaped much notice here.

At Oriana House, which runs treatment and recovery programs for substance abusers in northeastern Ohio, opioids began to show up in urine tests around 2006, said Anne Connell-Freund, executive vice president of operations.

“We just kept seeing more and more and more. Then we started seeing a lot of heroin. There wasn’t any heroin here before the pills. And people were dying,” she said.

“How can a pharmaceutical company see those numbers and not understand, as addictive as their medications are?” she asked.

Of the six defendants, only one, Teva Pharmaceuticals, is a drugmaker. The others are wholesale drug distributors, the companies that transport billions of pills from manufacturers to drugstores, hospitals, nursing homes and other places where they are dispensed to consumers.

Federal laws and regulations make those companies responsible for developing systems to monitor “suspicious orders” of drugs — unusually large or frequent purchases that indicate illegal users may be obtaining powerful narcotics intended for pain patients. Those same companies are responsible for notifying the Drug Enforcement Administration and holding up shipments while the information is checked.

The distributors include McKesson, Cardinal and AmerisourceBergen, which control 85 to 90 percent of the market, as well as Walgreens and Henry Schein Medical. Walgreens, the drugstore chain, is big enough to have its own distribution operation and was sued for misconduct in distributing, not dispensing, drugs.

Schein is a multibillion-dollar company that sells equipment to doctors and dentists. It has claimed in court papers that it distributed less than $25,000 worth of opioids — none of them in Cuyahoga County — in the years covered by the trial and should not be a defendant. But the plaintiffs contend that in 2011 and 2012, Schein sent an Akron physician more than 10,000 hydrocodone pills that he diverted to illegal users. The doctor, Brian Heim, was sentenced in 2015 to more than five years in prison. Polster rejected pretrial motions to release Schein from the case.

The counties’ argument rests mainly on the sheer volume of drugs the companies poured into northeastern Ohio. They contend the distributors, motivated by profits, did little to monitor doses that spilled into the black market, ignoring obvious signs as they filled order after order.

They argue that deluge created a “public nuisance” that endangered residents’ health and are seeking $7.2 billion to pay for drug treatment, health care, emergency services and other costs of remedies.

Polster has ruled that if the jury finds the companies liable, he will set the amount of that “abatement.” The counties also want another $1 billion in damages, which the jury could increase.

The counties also claim the companies worked together like a drug cartel, conspiring to expand their market, deceptively promoting their products and minimizing addiction risks.

The drug companies deny the accusations, asserting they delivered legitimate medications to patients suffering from cancer and other painful conditions and complied with regulations set by the DEA and the Food and Drug Administration. They also deny working in concert, contending the counties cannot prove any direct link between their conduct and the harms or expenses incurred.

The counties “have no evidence demonstrating a direct causal relationship between the opioid pills shipped by McKesson and plaintiffs’ alleged injuries,” the company’s lawyers wrote in legal papers.

The plaintiffs have filed a 188-page report from former DEA investigator James Rafalski detailing widespread failure by the distributors to detect or halt suspicious orders, including shipments to Cuyahoga and Summit dispensers. The specific numbers are blacked out as part of a pretrial order by Polster.

“It is apparent that McKesson’s systems have not been properly designed to properly block suspicious orders given the minuscule number” that were held up, Rafalski wrote.

As if responsibility for the drug epidemic isn’t enough, some lawyers watching the case warn that expanding the application of “public nuisance law” could make companies much more vulnerable to tort lawsuits in the future.

Traditionally, such laws have been invoked against people who left trash heaps on their lawns or otherwise harmed or inconvenienced a neighbor. But Oklahoma successfully used the legal theory against Johnson & Johnson in a state court, and this trial will offer a test at the federal level.

The plaintiffs’ efforts to expand use of the law “would be massively destructive to businesses across the country,” said one lawyer who is not involved in the case and who spoke on the condition of anonymity because the trial is beginning. “What is the [limit] in the way the plaintiffs are interpreting public nuisance law and applying it to a product?”