When Caiti Derenze, a lawyer in Jersey City, N.J., went to Walgreens to refill her insulin prescription in July, she was met with a nearly $300 bill.

“I was like, ‘Oh my God, I only paid like $50 last month. What happened?’” Ms. Derenze said. “It feels like a punch in the gut, to be told a medication you need to live costs so much money.”

Trying to find the answer set in motion a wild-goose chase. Walgreens directed Ms. Derenze to her insurance company, Aetna. Aetna sent her to Express Scripts, a pharmacy benefit manager. Express Scripts said it needed prior authorization from her doctor.

“I deal with these issues on, if not on a monthly basis, every two months,” Ms. Derenze said. “You have to call so many people just to figure these things out.”

In the last decade, as prescription drug prices have steadily risen, patients have increasingly experienced this kind of sticker shock at the pharmacy counter. For people who are chronically ill, decisions about whether to pony up the cash or go without aren’t frustrating, one-off predicaments; instead, they represent life-or-death battles that must be fought not once, but over and over again.

Pharmacies are quick to blame insurance companies and vice versa, tasking patients with the burden of trying to find a cost-effective solution via hours of back-and-forth phone calls.

Worse, for diabetics and other chronically ill patients who will need these medications forever, they stand to face the same issue all over again the next time they need a refill. By then, a new insulin might be the preferred brand covered by insurance.

Brooks Bellman, an immigration paralegal in Atlanta, recalls an incident last year when his insurance company switched its preferred long-acting insulin from Lantus to Levemir. He needed a higher dose of the Levemir to keep his blood sugar in a healthy range and went through it more quickly, but his insurance company wouldn’t account for that change and prevented him from refilling it early.

Mr. Bellman said he had to spend three days on the phone with the pharmacy to get enough medicine to tide him over until his next refill.

Insulin has become the poster child of unaffordable prescription drugs. From 2002 to 2013, prices tripled for some brands, and as a result, one in four patients has reported rationing their insulin.

But insulin’s not the only example. Since 2007, prescription drug spending has increased by about 40 percent, to $335 billion in 2018 from $236 billion. A study from last year showed this increased spending isn’t a result of new, better drugs hitting the market, either — rather that pre-existing brand-name and generic drugs were becoming increasingly expensive.

“Why do drug companies charge that much? Because they can,” said David Mitchell, a cancer patient and the founder of Patients for Affordable Drugs, a nonprofit advocacy group. “We let them.” Whereas most other developed countries allow the government to negotiate with drug manufacturers on behalf of its citizens for lower prices, the United States does not.

President Trump recently issued an executive order aimed at addressing this disparity, after a separate deal that proposed to cut drug costs by $150 billion fell apart. The order would enable Medicare to pay the same price for prescription drugs as those sold in other countries, but experts questioned whether the White House has the authority to put it into effect.

Dr. Elizabeth Seeley, an adjunct lecturer at Harvard’s school of public health whose research focuses on pharmaceutical pricing and policy, said that while this order or an international price reference would “certainly lower the cost of many patented, brand-name drugs,” it’s unclear what impact it would have on the market.

In the current system, pharmacy benefit managers, or P.B.M.s, act as middlemen between drug manufacturers and insurance companies and negotiate the receipt of rebates in exchange for listing a manufacturer’s medication as the preferred brand on their insurance formulary. Assuming they’re insured, patients pay the co-payment or coinsurance stipulated on their health plan’s policy, blind to the drug’s actual cost.

“They tell you that the value of the rebate is passed through to the patient in the form of lower prices, lower out-of-pocket and lower premiums,” said Mr. Mitchell, who has an incurable blood cancer and spends more than $15,000 for just one of the medications he takes to treat it. But all of those dealings are restricted from public knowledge. “Even members of Congress can’t find out what rebates are paid, because it’s all considered a trade secret.”

According to Dr. Seeley, because of that classification, it’s difficult — if not impossible — to quantitatively answer whether P.B.M.s drive drug prices up or down. Without them and the large rebates they negotiate, she said, drugs could be even more expensive.

On the other hand, “there are points of inefficiency,” said Dr. Seeley, “and there are areas in which their incentives may be distorted.”

For example, Mr. Mitchell said P.B.M.s might “steer you to a drug that may not be better at all, but is actually more expensive,” because that’s the drug that affords the P.B.M. a larger rebate. This in turn creates constant fluctuations in which drugs are “preferred” and results in an ever-moving target that doctors and patients must try to keep up with.

“It’s exhausting and it’s angering because I realized that it’s not an accident, it’s a strategy,” said Dr. Danielle Ofri, an attending physician at Bellevue Hospital who has written about insulin prices. “I feel manipulated by the P.B.M. system, that they will let me do the work or patients do the work of trying to figure out what’s going on, rather than them doing the work.”

That extra work represents yet another barrier that many patients don’t have the resources to overcome.

“It takes a certain degree of privilege to have that time and that mental energy and to do all those things that we need to do in addition to managing the condition 24/7,” said Elizabeth Pfiester, the founder of T1International, a British nonprofit organization that advocates for affordable insulin worldwide. “Not everyone is able to fight those extra battles. And that puts their health in a worse situation.”

Ms. Pfiester equates patient assistance programs, like manufacturers’ coupons, to “a Band-Aid on a gushing wound” rather than a long-term solution, since a company can eliminate those programs at any time. Plus, they create even more hoops for patients to jump through.

“Many of my patients either don’t speak English or don’t have the socioeconomic skills or the literacy skills to navigate that,” Dr. Ofri said. “When that bill goes up, they simply cannot do it.”

At the pharmacy counter, patients have little recourse. Uninsured patients must pay the list price, while insured patients can ask the pharmacist if there are any less-expensive options if they pay with cash. Some may resort to taking a different, less-expensive drug that may not work as well.

Even people with adequate resources occasionally opt not to take up the fight simply because it’s not worth the added hassle. When we spoke, Ms. Derenze had just received a bill for her insulin pump supplies from Medtronic that was more than twice the amount of the previous one. “I wanted to throw up. That’s a rent payment,” she said. But her firm had an important brief due the next day. “I don’t have the time to get on the phone, argue with Medtronic for an hour and then argue with my doctor and everyone else involved. Sometimes I have to keep moving.”

To Dr. Ofri, the additional labor passed on to doctors and patients by P.B.M.s is a reflection of the for-profit health care system. “Once there’s a profit drive that’s permissible in there, well then, this is what we get,” she said.

Ms. Pfiester grew up in the United States but moved to Britain in 2011 to study. Experiencing how much easier it was to get her medical supplies under the National Health Service was the catalyst that inspired her to create T1International.

“I walked out of the pharmacy the first time,” Ms. Pfiester said, “and I didn’t have to pay copays. I didn’t have to battle with my insurance. I didn’t have to do any of that. I just was able to access the things that I needed.”