Hiccups, medically known as singultus, are a common, usually temporary, involuntary reflex that most people experience occasionally. While brief episodes are generally harmless, hiccups that persist for more than 48 hours are classified as persistent and signal a potentially serious underlying cause. A well-documented side effect of certain medications is drug-induced persistent hiccups, with high-dose steroid therapy being a recognized trigger. Understanding why these powerful anti-inflammatory drugs can hijack a basic bodily reflex requires exploring the complex neurology that controls the hiccup mechanism itself.
The Basic Biology of a Hiccup
A hiccup is a sudden, involuntary spasm of the diaphragm, the large, dome-shaped muscle beneath the lungs responsible for breathing. This spasm causes a rapid, sharp intake of air that is immediately interrupted by the abrupt closure of the glottis, the opening between the vocal cords. The characteristic “hic” sound is created when the fast-moving air hits the closed vocal cords.
This process is controlled by a reflex arc involving several nerve pathways and central brain structures that are not under conscious control. The afferent limb (sensory pathway) uses the vagus, phrenic, and sympathetic nerves to carry signals from the stomach and diaphragm toward the brain. The central processing unit for this reflex is thought to be located in the brainstem.
The efferent limb (motor pathway) transmits the signal to cause the muscular contractions. This motor signal travels mainly through the phrenic nerve to the diaphragm, causing the spasm. It also travels through a branch of the vagus nerve to close the vocal cords.
Corticosteroids That Trigger Hiccups
The specific class of drugs associated with this adverse effect is corticosteroids, powerful anti-inflammatory and immunosuppressive agents. Dexamethasone is the agent most frequently cited for causing persistent hiccups, sometimes referred to as Dexamethasone-Induced Hiccups (DIH). In some high-dose protocols, the reported incidence rate has been as high as 61%.
Other corticosteroids, including methylprednisolone and betamethasone, have also been implicated, suggesting a class effect, but Dexamethasone carries the highest risk. This side effect is often observed when the drug is administered intravenously or orally at high doses, such as those used in chemotherapy protocols.
The Central Nervous System Mechanism
The leading scientific explanation for steroid-induced hiccups centers on the drug’s ability to interfere directly with the central hiccup generator (CHG) located within the brainstem. Dexamethasone is highly lipophilic, meaning it is fat-soluble and can easily cross the blood-brain barrier (BBB), gaining access to the central nervous system (CNS). Once across the BBB, the steroid interacts with sensitive neurological tissue.
It is proposed that Dexamethasone acts by lowering the threshold for synaptic transmission within the central part of the hiccup reflex arc in the midbrain. This destabilization makes the reflex center hypersensitive, causing it to fire involuntarily and repeatedly, leading to persistent hiccups. The brainstem is the likely steroid-responsive locus for this effect.
The hiccup reflex is regulated by various neurotransmitter systems that act as brakes and accelerators on the central generator. Neurotransmitters such as gamma-aminobutyric acid (GABA) and dopamine modulate the reflex, and the steroid may interfere with these pathways. By altering the balance of these chemical messengers, the drug effectively removes the inhibitory control mechanisms that normally keep the hiccup reflex suppressed.
The resultant over-excitation of the central hiccup generator leads to the uncontrolled firing of the efferent nerves, specifically the phrenic nerve. This neurological interference explains why the hiccups are often severe and persistent. The cause is a continuous chemical irritation within the brain’s control center, overriding the body’s natural regulatory systems and making the episodes difficult to stop.
Options for Stopping Steroid-Induced Hiccups
Managing hiccups caused by steroid use involves strategies that target the underlying drug effect and interrupt the reflex arc. Home remedies, such as holding one’s breath or gargling, are often insufficient to resolve hiccups driven by central neurological irritation from a medication. The first step is often to consult a physician to determine if the steroid dosage can be safely adjusted, lowered, or if the patient can be switched to a different corticosteroid, a process known as steroid rotation.
If adjusting the steroid is not possible, pharmacological intervention is necessary to break the reflex cycle. Chlorpromazine, an antipsychotic medication, is a frequently used treatment that blocks dopamine receptors to restore chemical balance in the brainstem. However, due to potential side effects like low blood pressure and sedation, other options are often preferred.
Baclofen, a muscle relaxant that mimics the inhibitory neurotransmitter GABA, is often considered a first-line agent for persistent hiccups. Gabapentin, an anticonvulsant that also modulates nerve activity, has shown effectiveness in case reports by calming the over-excitable nerve pathways in the CNS. These prescribed medications work centrally to stabilize the hypersensitive hiccup generator.