Millions of people might have laughed uncomfortably and made bad jokes when they saw a TV commercial during Sunday's Super Bowl that talked about constipation caused by use of prescription opioid painkillers.
But a lot of people who suffer from that increasingly common — and often painful — issue likely weren't chuckling.
And the companies that are making the new drugs to tackle that sensitive problem? They've got a keen eye on a market that is expected to boom in coming years, growing by a projected 10 times its current size.
And that market for "opioid-induced constipation" — dubbed OIC — will overwhelmingly be in the United States, where 259 million prescriptions for opioids were written 2012, the last year for which data is available. Commonly prescribed opioids include Vicodin, Percocet and codeine. The new drugs work in a way that is different from traditional constipation treatments, such as Ex-Lax or prune juice.
The U.S., which has less than 5 percent of the global population, consumes an estimated 80 percent of prescription opioid painkillers — and as a result is seeing the lion's share of constipation related to use of such drugs.
"The U.S. is really liberal in opioid prescription, and that liberal use of opioids is increasing," said Claire Gibson, an analyst for the research and consulting firm GlobalData.
And "estimates would say that a large majority of people taking opioids have OIC," said Gibson, who wrote a recent report about the OIC treatment market. Anywhere from 40 to 90 percent of opioid users as some point experience OIC, according to Gibson's report and other sources.
Gibson's report projected that the market for products that treat OIC will grow in the U.S. and five major European countries — France, Germany, Italy, Spain and the United Kingdom — from nearly $67 million in 2016 to more than $652 million as of 2019.
The U.S. "will represent approximately 86 percent of the total market by 2019," equivalent to $563 million in annual sales, Gibson wrote. She said the estimated patient population for OIC drugs will be "just under 4 million" people.
In addition to increased opioid use, a big driver of that market boom will be the fact that the number of new oral medications that are specifically designed to target the trigger for OIC will grow from just one in 2014 — AstraZeneca's Movantik — to up to eight drugs by 2019.
"You're going from essentially no drugs available to near-no drugs available, to a lot of drugs available," Gibson said.
That, in turn, will mean that football fans and other potential OIC sufferers likely will be seeing and hearing a lot more ads about OIC and the drugs that can relieve it.
"It's really crucial for companies that are developing these drugs to inform patients and physicians that these drugs are available, and drive patients to their physicians' office," Gibson said.
One of those ads sparked a backlash on the heels of the Super Bowl, with some critics suggesting that the ad sponsored by AstraZeneca, the U.S. Pain Foundation and other groups were contributing to the explosion of opioid use in the United States.
The ad, entitled "Envy," pushed the message that "OIC is a different type of constipation" by showing a glum man reacting to a series of visual reminders of his gastric distress: another happy man exiting a bathroom, a dog doing his business on a curb and a woman walking away from him with toilet paper stuck to her shoe.
"Longing for change? Have the conversation with your doctor," says the narrator.
Denis McDonough, the White House chief of staff, wasn't amused, according to his Twitter feed.
"Next year, how about fewer ads that fuel opioid addiction and more on access to treatment," tweeted McDonough, whose boss, President Barack Obama, last week proposed spending an extra $1 billion in federal funds to combat opioid abuse.
On Thursday, Vermont Gov. Peter Shumlin called on AstraZeneca and Daiichi-Sankyo to pull the ad "and instead use the money to fund opiate and heroin prevention and treatment programs."
"The irrational exuberance with which opiates are handed out in America is driving the addiction crisis in this country," the Democratic governor wrote in a letter to the companies. "Now is the time to change that, not attempt to further normalize long-term opiate use by advertising a drug to help people take even more opiates."
Comedian Bill Maher tweeted, "Was that really an ad for junkies who can't s---? America, I luv ya but I just can't keep up."
But Gibson and others said the reason such ads are crucial for the drug companies is because awareness of OIC remains low, even among many doctors, and particularly among physicians who don't specialize in pain.
"Most people don't know what it is," agreed Paul Gileno, president of the Pain Foundation, an advocacy and support group for pain-afflicted people.
Gileno himself suffered from OIC years ago as a result of taking painkillers prescribed to him after he underwent surgeries related to a bad back injury he suffered while working as a chef.
"I was very constipated from taking the medications," said Gileno, "It took a while for me to talk about it [to his doctor] because it's embarrassing to talk about."
And, he noted, "There was no name for it. My doctor never said, 'You have OIC.' "
Gileno, in a letter to Maher about the "junkies" tweet, called that remark "appalling, disingenuous and dangerous."
"Bill Maher single-handedly labeled all people with pain as junkies," Gileno wrote.
"I take extreme offense to this statement. It is this ignorant mindset that is harming the 100 million Americans living with pain from receiving the adequate care they need as well as the support they deserve. In the current health care landscape, chronic pain patients are continually forced to 'prove' their pain. They face backlash and ridicule instead of compassion and help."
OIC is caused, ironically, by the same thing that make opiods effective as painkillers.
Opioids work on pain because they bind with so-called "mu-opioid receptors" in a person's central nervous system. When they bind with those receptors, the person's pain is eliminated or reduced.
But there are also many mu-opiod receptors in a person's bowel, or intestinal tract. As a result, if a person takes opioids, they can bind with the receptors in the gut and interfere with the correct functioning of the bowels, causing them to become constipated.
Often very constipated.
At the Pain Foundation, "we've had people who have sent us pictures from their X-rays where they're so impacted," Gileno said. "I've heard horrible stories where people are going through terrible constipation, OIC issues, where they're not leaving their house."
Many of those people, Gileno said, are faced with a dilemma that he himself faced: continue the discomfort of not being able to go to the bathroom, or go off the opiods temporarily to get relief from the constipation, even if that brings back the pain.
Other options for sufferers include an over-the-counter treatment, such as a laxative, drinking prune juice or modifying their diet.
The problem is "only about one-third of people [with OIC] who use over-the-counter treatments are getting the relief" they were seeking, said Dave Fredrickson, vice president of specialty care at AstraZeneca.
AstraZeneca's Movantik in 2014 became the first of a new kind of oral OIC drugs approved by the Food and Drug Administration for use in noncancer patients, and went on sale last year, under a marketing partnership with the Japanese drug company Daiichi Sankyo.
Movantik, and similar drugs in the pipeline, is known as a "peripherally acting mu-opioid receptor antagonist," or PAMORA.
The FDA late last summer accepted for review an oral version of the OIC drug Relistor, a PAMORA licensed for development and commercialization to Valeant Pharmaceuticals by Progenics Pharmaceuticals. Also in the pipeline are PAMORAs from Shionogi and Theravance. Takeda Pharmaceuticals already sells a drug called Amitiza, which treats OIC, but works differently than a PAMORA.
Movantik, as with other PAMORAs, doesn't cross the blood-brain barrier, Fredrickson said.
As a result, while blocking opiods from binding in the gut, Movantik doesn't block binding with the receptors in the central nervous system. That means the opioid's painkilling efficacy remains unaffected, even as the PAMORA alleviates constipation.
AstraZeneca has a double-barreled marketing strategy for Movantik. It began last year, and is backed with "significant investment," Fredrickson said.
"We've got, first, an awareness campaign that is unbranded," Fredrickson said.
Those unbranded ads, he said, helps patients "understand that there is mechanically a reason why their OIC is different" from ordinary constipation.
In one of those ads, an actress draws a picture of a snail and says opioids "are slowing my insides to a crawl."
A branded ad for Movantik drew attention last fall when it was aired during football games. In that animated ad, a woman gestures to a large opioid pill sitting next to her and says, "This helps me to manage my chronic pain, but it came with some baggage," as she lifts a bag labeled "constipation" onto her lap.
"You're not the only one," says a doctor, who then uses a picture of a digestive tract to explain OIC to the woman, and then offers Movantik to her.
That ad was met with some derision on Twitter.
One Twitter user wrote, "Wtf america? So many people on opioids that it makes financial sense to advertise solutions to opioid-induced constipation?!?! #Movantik."
Another tweet said: "Anyone else disturbed by #Movantik? Why are opioids now so widespread that this new drug is necessary? #OpiodsRuinLives #Addiction #Heroin"
Fredrickson was aware of that criticism, and of the comments about the OIC ad that aired during the Super Bowl.
Fredrickson said, "We absolutely support use as intended" for opioids.
He also said "increased discussions ... about opioid use is a good thing."
"I really do believe that by talking about OIC and talking about this condition we are opening the door for discussion between doctors and patients about not only OIC but also about opioids," Fredrickson said.