(Reuters) – As opioid pills and patches fueled a two-decade epidemic of overdoses in the United States, hospitals faced chronic shortages of the same painkillers in injectable form – narcotics vital to patients on breathing machines.

For years, hospitals chased supplies, sometimes resorting to inferior substitutes. The shortfall grew so dire in 2018 that a drugmaker sent letters advising hospitals they could use batches of opioid syringes potentially containing hazardous contaminants – so long as they filtered each dose.

Then the novel coronavirus struck, and demand for injectable opioids exploded. By April, more than 16,000 COVID-19 patients a day were on ventilators, the University of Washington’s Institute for Health Metrics and Evaluation estimated.

After a highly public battle to secure enough ventilators, hospitals say they must scramble to obtain the powerful painkillers needed to use them. Opioids help keep patients in severe distress from reflexively ripping out the tubing that forces oxygen into their lungs.

(For a graphic on ventilators, see here)

Underlying the persistent shortages – and the present crisis – are the basic economics of the American drug industry. The market discourages production of low-margin hospital injectable opioids in favor of high-profit prescription versions, according to interviews with dozens of government officials, medical practitioners and industry participants, as well as an analysis of government data.

Though deficiencies in the supply of injectable opioids had long been recognized, U.S. drug makers, hospitals, regulators and lawmakers failed to fix the problem and were caught unprepared for a pandemic that suddenly and dramatically escalated demand, Reuters found.

Janet Woodcock, senior adviser to the FDA’s commissioner,

told Reuters that when hospitals in Wuhan, China, began filling with patients on ventilators, she and her colleagues knew a wave of American cases would overwhelm shallow U.S. supplies.

“We recognized this was going to happen,” she said, adding, “We’re just trying to get every last vial of product into the system that we can.”

Among the thousands of COVID-19 patients wheeled into American intensive care units, some have been intubated for weeks, far longer than is typical. Demand for injectable opioids more than doubled between January and early April, rapidly depleting what hospitals and drugmakers had on hand, according to Vizient, a large hospital purchasing organization. Orders for the commonly used injectable opioid fentanyl roughly tripled, but suppliers were able to ship only half of what hospitals asked for, said Amanda Forster, a spokeswoman for Premier Inc, another large hospital purchasing organization.

Although ventilator use has fallen from the April peak, more than 7,000 COVID-19 patients are estimated to be relying on them each day. Several states are seeing a surge in cases, and many hospitals are resuming elective surgeries that were postponed early in the pandemic – further straining opioid supplies.

For injectables, the supply chain is slow and fragile. Aging plants operated by a small group of manufacturers chug along at nearly full capacity, with little room to ramp up production. The risk of a mechanical breakdown or contamination runs high, and adding another production line or opening a new plant can take a year or more, industry experts said.

“This is no way to run an army,” said Jacob Sherkow, a Harvard University research fellow on biotechnology law. “But fixing it is incredibly difficult and extraordinarily complex.”

The marketplace, Sherkow and others told Reuters, is hard-wired to reward innovation – new, ostensibly improved products – over older workhorse medications, no matter how vital. According to a October 2019 report by a task force led by the U.S. Food and Drug Administration, the price for injectable drugs can dip below the cost of production. By comparison, sales of prescription opioids in pill and patch form such as OxyContin, Opana and Duragesic each exceeded $1 billion annually before their patents expired.

Production of pills and other prescription opioids used outside hospitals began to explode in the late 1990s as drugmakers pursued new patients, patents and profits. By 2006, production of outpatient prescription opioids was at least nine times that of the low-margin injectable opioids most widely used by hospitals, according to a Reuters analysis of U.S. Drug Enforcement Administration data. The findings were adjusted to account for differences in potency among the drugs.

Through at least 2014, as addiction and overdoses escalated, prescription opioid production grew more than twice as fast as that of widely used hospital injectables, the data show. More recent DEA data show that outpatient opioid production continued to dwarf that of the narcotics most used by hospitals through 2019. The gap persisted even as physicians grew cautious about prescribing opioids to outpatients.

Multiple government agencies, from the FDA to the Department of Defense, knew about the chronic shortages of injectable opioids and other critical care drugs well before the coronavirus pandemic, according to federal documents and interviews with public officials. Injectable opioids in syringes and various vial sizes, including fentanyl, have been on the FDA’s list of drugs in short supply at least since 2017.

After releasing its task force report in October, FDA leaders blamed injectable shortages on “a broken marketplace” in which production is often disrupted and prices remain low, regardless of demand, because of inflexible hospital contracts. Yet proposals for far-reaching changes – such as creating incentives for production of drugs in short supply – have not made it past the discussion stage in Congress.

Sen. Susan Collins, a Republican from Maine, said she had pushed for new incentives to encourage manufacturing of drugs at risk of shortage earlier this year, but federal agencies told her they did not want to pursue substantive action amid the pandemic. “This is a really important issue, and the coronavirus has really shined a light on it,” Collins told Reuters.

The shortages have a direct impact on patients. Pharmacists, anesthesiologists and other frontline medical professionals told Reuters they have had to sub in less effective drugs, some with problematic side effects, or to inject crushed opioid tablets into feeding tubes.

The harm to patients is difficult to measure and most likely underestimated, the FDA-led task force found. Fighting for their lives and unable to speak, most patients are sedated and unconscious while ventilated and often have no recall of their experiences afterward.

Several doctors said they were using paralytic agents to keep patients from involuntarily fighting the ventilator. But the powerful drugs also prevent patients even from flinching in pain. Nurses said they must closely watch for signs of pain or distress – such as increased heart rates – when supply problems force them to switch patients from one drug to another.

Patients can have hallucinations and become agitated on a second-line drug, said Dr. Mangala Narasimhan, regional director of critical care at Northwell Health, a 23-hospital system in New York. “You can tell they are really uncomfortable.”

For now, hospitals cadge injectable opioid drugs as best they can.

In Cleveland, the University Hospitals group has designated “SWAT teams” to move what supplies it has among its 18 facilities. And they are constantly shopping for more.

“If you don’t buy it, you miss it,” said Shawn Osborne, vice president for pharmacy services. “If you miss it, you’re not going to get to next week.”

ONE DRUG, TWO MARKETS

Fentanyl, a pain reliever up to 100 times more powerful than morphine, exemplifies how the same drug, fashioned from the same molecule, can fare very differently in the marketplace depending on the form it takes.

Invented in 1960, fentanyl was long reserved for surgical, cancer and terminally ill patients. But in the late 1990s, drug companies and doctors launched a war on the chronic pain often experienced by outpatients.

The main weapons in this war were old, generic opioids manufactured in novel configurations that allowed their makers to win lucrative patents. Cheap and easy to synthesize in the lab, fentanyl was refashioned in one newly patented form after another – as a lollipop, a fast-dissolving disc and a nasal spray.

Johnson & Johnson’s Janssen Pharmaceuticals Inc began promoting fentanyl for this new market in 1997, decades after its invention. J&J’s patented, slow-release fentanyl skin patch, Duragesic, competed for blockbuster profits against another old opioid, oxycodone, which Purdue Pharma LP had re-launched in a patented slow-release pill called OxyContin.

In a statement, J&J told Reuters that prescription opioids “are an important option” for pain relief and that U.S. government policies and regulations “recognize the ongoing medical need for these medications.”

After patents on prescription opioids elapsed, generic drugmakers have piled in to profit off volume sales.

Unlike the crowded marketplace for prescription opioids, the injectables sector is highly consolidated, with only a few companies producing the lion’s share of each narcotic. (For the most part, the companies making injectables are not making prescription opioids.)

Still, large hospital chains and purchasing groups have enough market power to drive hard bargains, the FDA-led drug task force found. Generic injectables are largely seen as interchangeable, so hospitals shop by price, not brand. For drugmakers, the report said, it’s “a race to the bottom.”

This week, for instance, the internet-advertised price for a box of 25 small injectable fentanyl vials – enough for a single bedside drip bag for a COVID-19 patient – was $76.99. By comparison, the price for a single prescription of a new fentanyl nasal spray for breakthrough cancer pain is $985. That means hospitals are paying 3 cents per microgram for injectable fentanyl. At $1.23 per microgram, the nasal spray is roughly 40 times higher.

Despite bargain-basement prices, drugs injected directly into the bloodstream are more expensive and more difficult to make than pills, which are mass produced. Injectable drugs are made batch-by-batch, and the risks of contamination are greater. They require a sterile environment, post-production “quarantines” to allow for the growth and detection of any possible bacteria and, finally, testing for any other contaminants.

“Manufacturing a sterile product requires a totally different investment,” said Siggi Olafsson, chief executive of Hikma Pharmaceuticals PLC, which makes 17% of generic injectables used in the United States.

He and other injectable manufacturers told Reuters they remained in the U.S. market because they believed it was the right thing to do. Hikma is still seeing sales growth, reporting that revenues from its injectables business rose 5% in the United States in 2019.

A SHAKY SUPPLY LINE

When the novel coronavirus landed in the United States, the supply line for hospital opioids was still recovering from a setback three years earlier.

In February 2017, Pfizer Inc, one of the nation’s biggest injectable drugmakers, received an FDA warning about several shoddy sterilization procedures at its McPherson, Kansas plant. By the summer, Pfizer warned of extended production delays as it sought to fix the problems, according to a letter the company sent to customers.

As a result, Pfizer’s output of injectable fentanyl, hydromorphone and morphine – three key hospital opioids – was thrown into disarray as other manufacturers were stepping away from the market.

Purdue, for instance, had sharply reduced its injectable hydromorphone output over several years. By 2017, the company made a “business decision” to license production to another drugmaker with better capabilities, the company told Reuters in an email.

The shortfalls across the country underscored the vulnerability of the injectables supply chain. In a February 2018 letter to U.S. drug regulators, hospital administrators warned that surgeries might be postponed or canceled. “In some cases, this could prove life-threatening,” they said.

Then Pfizer took an unusual step. In May and July of 2018, the company sent out letters warning hospitals, doctors and pharmacists that cracked needle hubs and unspecified contaminants had been found in some glass syringes filled with morphine and hydromorphone after they had been shipped to hospitals.

In the letters, reviewed by Reuters, the company said that the contaminants could result in inflammation, tissue injury and respiratory problems. But the letters said the affected batches could be used, so long as hospitals filtered out any contaminants. Pfizer said it was coordinating with the FDA “to help alleviate the critical drug shortage.”

In a statement to Reuters, Pfizer said it determined the syringes “posed a negligible risk” if filtered as instructed. The FDA confirmed in an email that it provided the manufacturer “discretion so the product could continue to be used” and that it works with firms to ensure patient safety during shortages.

“Sterile injectables are quite complex and costly to consistently manufacture,” Pfizer told Reuters. The company said it is now operating “without significant disruption” and has increased production of injectable opioids. It did not say by how much.

The status of injectable drug supplies at any given time can be a mystery.

The FDA requires manufacturers to update the agency on disruptions and shortages of necessary drugs. But those notices may be filed up to five days after a problem is identified – keeping the agency from taking action before a shortfall. On an FDA web page listing backordered drugs, the FDA said in early June that the “estimated recovery” for some injectable opioids made by Pfizer was not expected until early 2021.

Because drug companies hold information close to the vest, Woodcock said her agency had little visibility into what supplies companies had on hand or in production as the pandemic approached. She said the agency was encouraging – but couldn’t force – companies that once made injectable opioids to resume production.

But some manufacturers are plainly not interested in returning.

Baxter International Inc, once a large injectable opioid maker, has no plans to start up again, citing the lead time involved, pharmaceuticals president Sumant Ramachandra told Reuters.

“To do that from scratch again, you’re talking about over a year plus,” he said, adding that his company is focusing on other critical care drugs.

NO ‘EASY BUTTON’

As in the past, hospitals have been left to improvise.

At her Kaiser Permanente hospital in Fresno, California, ICU nurse Amy Arlund said she has had to swap ventilated COVID patients’ drugs in the middle of the night as the staff navigated shortages. “When you’re told to switch from drug-A to drug-B, it’s not as easy as flipping a switch,” she said. “It requires careful monitoring.”

Switching from one drug for another can raise the risk of dosing errors and side effects. At the peak of the surge in coronavirus cases in New York, some hospitals couldn’t get enough fentanyl, prompting physicians to go to second- and third-line drugs, such as ketamine, a drug that studies have shown can cause agitation and a racing heart.

Even when hospitals are able to get enough injectable opioids, they often are not in the form they need.

Colorado-based SCL Health Hospitals & Clinics pulled nine people from other jobs to work the phones in search of injectable opioids, said Jennifer Davis, system pharmacy director. When unable to find fentanyl vials large enough to fill a bedside drip bag in one shot, they have bought any size available, including syringe-sized ampules.

Working in head-to-toe protective gear to prevent contamination, pharmacy techs have had to crack as many as 25 thumb-size glass bottles and draw out the clear liquid, syringe by syringe, to make a single 50 milliliter intravenous bag for a ventilator patient.

The process adds about 12 minutes to the preparation of each bedside bag, Davis said. A single COVID-19 patient may need two or more bags a day.

Such onerous workarounds are likely to continue as no permanent solutions to the shortages are in sight.

“If there was an easy button, it would have been pressed ages ago,” said Michael Ganio, senior director of pharmacy practice and quality at the American Society of Health-System Pharmacists.

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Ventilators: Fighting for life here)

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