When Nicole Allard, now an emergency dispatcher with the National Park Service, experienced puberty, something unexpected happened. She began experiencing severe pain in her abdomen and violent, prolonged, reoccurring diaphragmatic spasms daily. “It was hard for me to catch my breath between spasms,” recalled Allard. “I’d have a couple, and then 15 minutes later, I’d have a couple more.” 

While she occasionally had a week’s or even a month’s reprieve, the pain followed by the spasms always returned. Even light touches to the area triggered extreme discomfort.

“It was intense pain. It felt like I had an overinflated balloon in my stomach or like something was trying to push its way out of me. I would sleep in such a way that I would make a little tent where the blankets could not touch my abdomen. Even wearing a T-shirt would add too much pressure,” said Allard.

With each concaving diaphragmatic spasm came a loud, involuntary noise that, much like the sensations underlying them, sounded painful. People who heard it said that it sounded like a constipated pig, a dying cat, or a baby seal that lost its mother. “I definitely sounded like a seagull,” said Allard.  (Click here to hear Allard's hiccups.)

Doctors classified Allard’s painful diaphragmatic spasms as hiccups, and they lasted uncontrolled for fifteen years. For Allard and about one in a 100,000 people, hiccups are a chronic condition without a known cause or a reliable therapeutic option, leaving many to take matters into their own hands. 

Of fetuses and frogs

Everyone has experienced hiccups beginning as early as in the womb. Fetuses wiggle their fingers, stretch their arms, and kick their legs in utero. “The one thing they can’t do is breathe because they’re getting all of their oxygen from the umbilical cord,” said Mark Fox, a gastroenterologist at the University of Zürich. Hiccupping in utero trains fetuses’ naïve diaphragms to breathe air (1). This training continues to some extent into infancy and childhood. 

“Hiccups are normal in young children but become increasingly less frequent. It’s more of a developmental thing, which was useful before you were born, but becomes less useful or even irritating when you’re out in the real world,” said Fox. 

Some researchers postulate that hiccups are an evolutionary remnant that dates to human’s amphibious ancestors (2,3). Both frogs and humans have a glottis, a small opening between the vocal cords that stops water from entering the lungs. In tadpoles, the glottis remains closed, which enables them to breathe by allowing the passage of water through the gills. When tadpoles mature into adult frogs, the glottis opens, allowing the passage of air to the lungs. In humans, the glottis closes when swallowing water or food and opens when breathing (3). 

This small flap of tissue is the key to the characteristic hiccup sound (4). “The actual ‘hic’ is the contraction of the diaphragm drawing the air in, and the ‘up’ is the closing of the glottis, which closes off the airway,” said Fox. 

What causes hiccups?

The vagus nerve controls the glottis’s opening and closing. It stretches across the body through the heart, the lungs, the stomach, and even to the lower bowel, where it captures sensory signals and sends them up past the throat and into the medulla oblongata near the brain’s respiratory center. There, the brain translates the signals and sends them down through the phrenic nerve which runs parallel to the vagus nerve and innervates the diaphragm, triggering it to rise or fall (5). 

“That’s a very long distance, where you can irritate, stimulate, or even damage the structures of the [hiccup] reflex arc,” said Claudia Busch, an anesthesiologist at the University of Heidelberg. “That’s one reason why there are so many different causes for hiccups and why for some of them, we are not really sure their cause.”

Every year, an average of 4,723 people in the United States are admitted to the hospital due to hiccups (6). Most people experience hiccups for just a few hours as a minor nuisance from eating too much or too fast, consuming certain foods such as spicy peppers or bread, or drinking carbonated drinks or alcohol. If hiccups stop within 48 hours, then these are classified as temporary with no cause for concern, but if hiccups last longer, then they enter the class of persistent or chronic hiccups. If hiccups last for years, then they are labeled intractable hiccups. Of patients admitted to the hospital for hiccups, 44.1 percent have temporary hiccups, 36.9 percent have persistent hiccups, and 19 percent have intractable hiccups (7).

“Chronic and intractable hiccups affect all areas of life — eating, drinking, sleeping — which is a big problem. The biggest problem is its effect on social life, taking part in groups, going out with friends, going to the theater. You don’t go to the theater if you have chronic hiccups,” said Busch. Most people with chronic hiccups retreat from sports, singing, or other common hobbies. They also experience severe fatigue. “They change totally in character,” said Busch.   

While hiccups can arise from benign gastrointestinal problems, they may also indicate more pervasive conditions that are difficult to identify. Chronic or intractable hiccups may be caused by cancers in the brain, pancreas, stomach, gastrointestinal tract, or esophagus. Conversely, some chemotherapy drugs cause repeated hiccups. Hiccups have also appeared in patients with neurological diseases such as Parkinson’s disease or multiple sclerosis and in patients with autoimmune disease. In some cases, hiccups even result from surgical errors. There are more than 100 possible causes of hiccups (7,8). The longest known case of intractable hiccups is that of Charles Osborne, who experienced a fall that destroyed a small area of his brain and triggered hiccups for 68 years (9).

“Hiccups are a symptom similar to sneezing. Sneezing is not a disease. If somebody tells you, ‘I’m sneezing today,’ you will probably say you are sneezing because you caught a cold or you have an allergy. Sneezing itself is a symptom and a defense mechanism,” said Ali Seifi a neurointensivist at the University of Texas Health at San Antonio. 

A needle in a haystack

For Allard, identifying the cause of her hiccups was not easy. Her case perplexed doctors for years. During her early teens, some clinicians thought that the symptom was only in her head, a plea for attention. Most people with intractable hiccups are male and over sixty years of age, so she did not fit the typical description (6,7). Some doctors hypothesized that stress caused her hiccups, but Allard insisted that she was stressed because she had hiccups, not the other way around. 

“When you live with a chronic illness, it's exhausting. And it is frustrating, especially when people aren't listening,” said Allard. 

After years of seeing specialists, undergoing evaluation for gastrointestinal problems including reflux, and confirming that she did not have cancer, doctors told Allard that she simply had to live with the condition. “That’s when it clicked for me that I needed to do this on my own if I was going to fix it,” she said.

Allard had worked in various roles at academic universities and in the biomedical industry for 13 years after completing an undergraduate science degree at Eckerd College. Most recently in 2019, she served as the laboratory manager for a systems genetics and toxicology research team at North Carolina State University before joining the National Park Service in 2020. She knew how to design an experiment and decided to experiment on herself.

I needed to do this on my own if I was going to fix it. 
- Nicole Allard, National Park Service

In 2012, her sister and father who both have autoimmune diseases had positive allergy tests for green pepper. That gave Allard an idea. “I had this gut feeling that it had something to do with my diet,” said Allard. She lyophilized green peppers and 13 other common foods and placed each powered mixture into separate pill capsules.

“I found pill capsules that were not clear so that I couldn’t see what I was taking. Then I put them all into jars and had a friend randomly assign letters to them,” said Allard. “I needed to prove that it wasn’t in my head. I knew it wasn’t, but I still had to prove it to myself. I needed it to be blind.”

Allard took six pills out of a single jar every day for two weeks or until she got hiccups. If she got hiccups, she marked that jar as positive and then waited at least a week for her hiccups to clear before starting the next mystery jar of pills. The experiment lasted three years. During that time, Allard also followed a restricted diet.

In the end, she discovered that wheat (but not gluten), dairy, corn, peas, peanuts, and green peppers triggered her hiccup response. She also identified the amount of time it took her body to respond to each food. For example, it took twelve hours for her body to respond to green peppers, but 48 hours to respond to corn, dairy, and wheat. Removing these ingredients from her diet eliminated her hiccups and the baseline level of pain that she had experienced from her youth. 

“Nicole stands out as a patient for numerous reasons. She’s a very formidable person,” said Busch, who contacted Allard after hearing her story in a video online. “The amount of effort she put into the experiment — and it’s so well conducted — it’s amazing. She got great information, which I think is outstanding. I was really impressed.”

Allard suspects that the certain foods she identified trigger an immune response in her body similar to her sister’s and father’s reactions to green peppers, but how these foods influence Allard’s pain and hiccups remains a mystery. She speculated that an immune response to these foods affects her vagus and phrenic nerves to trigger hiccups. Fox and Seifi suspect that a connection might be found in the mechanical mechanisms underlying hiccups.

Can food cause hiccups?

“One could imagine a situation where certain foods trigger food intolerance, which is partly mediated by histamine release,” commented Fox. “Histamine is an irritant, and its release can irritate in the same way as capsaicin, the chemical in chili pepper, but it’s not an allergic type of response.” 

The diaphragm sits directly above the stomach and can easily become irritated by the stomach. “When we eat spicy foods, that is acidic. That’s an irritant. Imagine if a pepper went into your eyes,” said Seifi. “The same thing happens to your diaphragm. Spicy food triggers the stomach, which is attached to the diaphragm, to jiggle and spasm.” This direct mechanical stimulation of the diaphragm triggers the phrenic nerve, which innervates the diaphragm, resulting in hiccups. The same can be said about bulky foods such as bread or pasta, which expand in the stomach and push against the diaphragm, irritating the key nerves involved in the hiccup reflex arc.

Not everyone responds with hiccups after eating spicy food though. “There is science behind that,” said Seifi. The phrenic nerves come down and innervate the diaphragm like tree roots. It’s not the same in all humans. “For some, these roots penetrate more into the diaphragm. In humans, 80 to 90 percent are similar, but for 10 percent, that variation in the end nerves is the reason they have a higher risk of being irritated by spicy food,” said Seifi.

Allard’s experience of pain before the hiccups also suggests another possibility to Seifi, one that might be due to an anatomical variation. Typically, people who experience chronic or intractable hiccups have pain during or after hiccups, not before. Seifi suspects a hiatal hernia, which occurs when the diaphragm is loose. This causes the stomach to push into the diaphragm upon eating, which could first cause extreme pain, but also disturb the diaphragm, triggering the phrenic nerve and hiccups.

Scientific merit in myths

Allard’s story about struggling with hiccups and finding solutions in food shares some parallels with MJ Kievman, who experienced chronic hiccups as a child and is now the founder and CEO of Meter Health, a biotech company dedicated to treating hiccups.  Like Allard, Kievman started experiencing chronic hiccups when she hit puberty.

“I would have bouts of hiccups that lasted for hours at a time. I would have multiple bouts a day,” said Kievman. Her hiccups  were painful largely because of the repetition. It was an aggressive motion that interfered with her going to sleep, eating, or drinking.

“It was extremely difficult to get people to understand that it was more painful. It was more persistent, and it was really impacting my quality of life,” said Kievman. “People can relate to the idea of getting into a coughing fit, and you’re on a plane or somewhere important, and you want to make the coughing stop really badly, but you just can’t get your body to do it. It’s a very similar feeling, and I’d say mental impact.”

At just 12 years old, she started researching information and testing home remedies to solve her hiccups. She created a homemade lollipop that provided temporary relief from her hiccups. Encouraged, she entered her invention into the Connecticut Invention Convention for Kids and secured a patent for her lollipops under the name “Hiccupops.”

“Over time, I learned more about the scientific merit to the stuff that I had been using. That turned my attention to getting them commercially manufactured and refining the formulation of the pop for everyday commercial use,” said Kievman. 

Kievman’s chronic hiccups eventually resolved on their own after about three months. Although she never identified the cause, she suspects that there might have been a genetic component underlying her hiccups. Despite being in the clear, Kievman was stirred by her own experience and by the stories of others with chronic hiccups. She continued to study hiccups and amassed information and scientific experts to guide her in forming Meter Health. Today Hiccupops come in two different flavors, and Kievman’s team has researched the underlying function of the lollipops. 

“We want to stimulate nerves in the throat and mouth through both ingredients in the pop, along with the actual pressure of sucking on a lollipop,” said Keivman. The old wives’ tales of sucking on a lollipop or drinking water to stop hiccups have scientific legitimacy. Both techniques involve swallowing, which overrides the diaphragm’s repetitive mechanical hiccup motion while inhibiting the vagus nerve’s closing and opening of the glottis. 

The old technique of scaring someone to stop hiccups works the same way. “When you scare somebody, it triggers the vagus nerve, which triggers the glottis and stops hiccups,” said Seifi. 

Taking control 

One day in 2015, Seifi made his daily morning rounds and visited a patient who had undergone brain surgery the previous day. The patient sat at the edge of his bed drinking glasses of water back-to-back. 

When Seifi asked what was happening, the patient replied, “Oh doctor, my surgery was fine. I have no pain, but the only thing is I couldn’t sleep all night because of these hiccups! This is the 21^st century; you guys have treatments for all kinds of cancers. Doctors can even do heart and liver transplants, but for such a simple thing as hiccups, there is no treatment,” Seifi recalled.

Seifi wondered if he could combine mechanical and neurointensive mechanisms to stop hiccups. He developed a specialized straw, initially with the name “forced respiratory suction and swallow tool” (FISST) and later branded as HiccAway. It addressed the mechanical and neuronal natures of hiccups to stop them in their tracks.

Seifi’s team began by calculating the pressure generated by the diaphragm during a hiccup spasm. He reasoned that if he could push the diaphragm beyond that pressure point, then it would force the diaphragm to be still, sending a message through the phrenic nerve to the brain to stop diaphragmatic spasming. Pairing this mechanical signal with the act of swallowing water would also occupy the vagus nerve, forcing it to close the glottis. 

“For five seconds, both parts of the key muscles and key nerves that cause hiccups are occupied by something intense: an intense suction, which needs intense activity of the phrenic nerve and diaphragm, and swallowing, which is a very coordinated skill by the brainstem. Then the vicious cycle breaks,” said Seifi.

His team calculated that an adult would need to suck in with enough pressure to lift the equivalent of a 100 cm column of water. This act would create enough negative intrathoracic pressure to manually lower the diaphragm. 

Seifi’s team developed a prototype straw that used a mechanical valve to reach that pressure, but it was commercially expensive to make. “I was trying to make something very affordable for everybody,” said Seifi. 

Then one day, he noticed his kids sucking on milkshakes in the backseat of his car. The milkshake straw was rectangular with a spoon-like hole at the bottom. “My son finished and asked, ‘can you trash this?’ And as I was trashing this thing, I looked into that spoon with the hole in the end and thought, instead of making a valve, let’s make a small hole,” reflected Seifi. 

He started reading more about various physics and engineering principles and decided to leverage the Bernoulli principle, which states that fluid goes through a pipe based on the diameter of the pipe. If the pipe goes from a small diameter to a large diameter, then the pressure of the liquid changes. He 3D printed a redesigned version of his hiccup straw with two small holes at the bottom, one for an adult and one for a child. When the appropriate hole was selected, sucking through the straw generated the needed water pressure to stop hiccups. 

Seifi joined forces with Fox to investigate the new device. They asked a patient whose hiccups could be easily induced by drinking a carbonated drink to ingest a barium sulfate suspension through the HiccAway. Using video fluoroscopy, they visually confirmed for the first time that the glottis’s rapid opening and closing caused the characteristic hiccup sound. They also demonstrated that sucking on the HiccAway forced the glottis to close (4). In another study, they investigated HiccAway’s ability to stop hiccups in 249 patients. The device worked for 92 percent of patients with different hiccup frequencies and durations (10). 

After a patient drank a barium sulfate suspension, Seifi and Fox used video-fluoroscopy to visualize the rapid opening and closing of the glottis during hiccups and the ability of the HiccAway straw to force the glottis to close.

CREDIT: COURTESY OF ALI SEIFI, VIDEO ORIGINALLY PUBLISHED IN BMJ OPEN GASTROENTEROLOGY

“In many people, it doesn’t come back because, of course, most people have uncomplicated hiccups. But even in people who have quite frequent episodes of hiccups, they can carry the HiccAway around with them and as soon as they get hiccups, they find some water, they suck it, and they stop hiccupping and carry on with their days,” said Fox.

Seifi shared the story of one patient who had lived with hiccups eight to ten hours per day since the age of two due to a malformation of nerves in her diaphragm. “As a kid, she remembered always being close to the refrigerator to drink water or her mom holding her upside down for several minutes, and everyone in school being annoyed with her hiccups,” said Seifi. Now, she wakes up and takes a few sips of water through the HiccAway and her hiccups stay away until the next morning. 

The HiccAway device doesn’t succeed for everyone. Seifi suspects that surgery complications and medication side effects play a role when the straw doesn’t stop hiccups. “This is not a miracle. This device is science. It works based on a mechanical trigger and the Bernoulli principle,” said Seifi. For example, steroids cause hiccups by reducing inflammation and placing the vagus and phrenic nerves closer together, causing the signals between these two nerves to overlap. 

Nonetheless, the HiccAway device offers a solution to many. Seifi and his team recently submitted a request for FDA approval for the HiccAway, but the FDA responded that there was no need for approval since hiccups are a symptom and not a disease. 

Changing perceptions 

“Getting people to understand the burden of illness of hiccups has been and will probably continue to be one of our greatest obstacles,” said Kievamn. Her team at Meter Health is currently working on a new drug called MH-712 for patients experiencing chronic hiccups due to chemotherapy drugs such as dexamethasone. The team hopes that the drug will provide a strong, targeted stimulus into the brainstem that resets the normal breathing patterns, but they are still in the nonclinical testing phases. 

There are no drugs designed to treat hiccups. Currently, the drugs used by physicians to manage hiccups were designed to treat other conditions. For example, baclofen, which can treat reflux related hiccups, was originally designed as a pain medication and muscle relaxant to help patients with multiple sclerosis or stroke recovery. Gabapentin, a drug that treats epilepsy, is sometimes used to treat hiccups caused by central brain conditions. Physicians also sometimes prescribe metoclopramide, a drug originally designed to treat nausea by inhibiting the vagus nerve. Many of these drugs also have side effects, which physicians and patients need to weigh against the benefits of taking the drug. “The gold standard is to find the underlying cause [of hiccups] and to somehow treat it,” said Fox.

Getting people to understand the burden of illness of hiccups has been and will probably continue to be one of our greatest obstacles. 
– MJ Keivman, Meter Health

To get a better understanding of the many different causes of hiccups, Busch and her team are working on a local patient registry called the Heidelberg Register of Singultus Disease, where patients can complete a questionnaire about their symptoms. 

“We need to understand patterns and identify connections to start the process of understanding this disease,” said Busch. Her preliminary data suggest different patterns in the rhythms of hiccups and possible links to hormones for some hiccup subtypes. 

Fox and Seifi continue to finetune HiccAway and learn more about the mechanistic secrets to its success. They plan to conduct a prospective study to show the effectiveness of this device compared to control interventions such as sucking on a normal straw. As researchers search for more answers, solutions such as Hiccupops and HiccAway offer hope.

References

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10. Alvarez, J. et al. Evaluation of the forced inspiratory suction and swallow tool to stop hiccups. JAMA Network Open  4, e2113933 (2021).