Vomiting Center

The pathophysiology of nausea and vomiting is complex and involves several different mechanisms of action. Current knowledge of the pathophysiology is based on previous studies on chemotherapy-induced, radiotherapy-induced, and postoperative nausea and vomiting. Despite the wide variety of clinical presentations, all cases of emesis share similar general pathophysiologic features. A physiologic or psychological trigger activates the central nervous system’s innate pathways for emesis, culminating in the so-called vomiting center (VC), which is located in the lateral reticular formation of the medulla. It has been described as a physiologic control center without a discrete anatomical site consisting of neuronal networks that coordinate the act of vomiting. This center includes the nucleus tractus solitarius (NTS) and the dorsal motor nucleus of the vagus nerve (DMV). Impulses are transmitted to the VC by one of the following pathways: the chemoreceptor trigger zone (CTZ), in the area postrema of the medulla oblongata, which responds to chemical stimuli in the cerebrospinal fluid and blood; the cerebral cortex and limbic system, which are stimulated by the senses and learned associations; the vestibular apparatus of the middle ear; a peripheral pathway that involve neurotransmitter receptors in the gastrointestinal tract; and/or vagal and spinal sympathetic nerves respond to chemical and physical stimuli.

Chemoreceptor Trigger Zone

A chemoreceptor trigger zone (CTZ) located in area postrema of the medulla directly detects toxins in the blood and cerebrospinal fluid and relays that information to the VC. The CTZ is primarily activated by chemotherapeutic agents in CINV, by toxins from food poisoning, by metabolic products (e.g., uremia in renal failure, hypercalcemia, and liver failure), and by a wide spectrum of medications. It also receives input from the vestibular apparatus and vagus nerve. However, it cannot initiate emesis independently and does so only through stimulation of the NTS localized in the deeper layers of the area postrema. The CTZ contains numerous receptor sites for neurotransmitters such as serotonin 5-hydroxytryptamine type 3 (5-HT ₃ ), dopamine (D ₂ ), histamine, and neurokinin-1 (NK-1), all of which may be involved in vomiting.

Cerebral Cortex

Cortical signals can also activate the VC. The cerebral cortex is largely responsible for nausea and vomiting associated with increased intracranial pressure, such as that caused by tumor or closed head injury, as well as that associated with central nervous infection such as meningitis and encephalitis. It is also seen in anticipatory nausea and vomiting associated with the memory of a past trigger such as chemotherapy and radiation, in anxiety and other emotional triggers, and in the recognition of certain tastes, sights, or smells.

Vestibular System

The vestibular center is responsible largely for nausea and vomiting caused by motion sickness. It integrates and interprets information on balance from the inner ear, peripheral receptors (e.g., nociceptors), and the visual system. After receiving this information, it sends signals to the VC to activate emesis associated with dizziness, loss of balance, motion sickness, and other vestibular disorders. Drugs such as opioids directly stimulate the vestibular apparatus and may cause nausea and vomiting by the same pathway.

Gastrointestinal Tract

Peripheral emesis is associated with a complex system of afferent nerves that induce or inhibit the response in the CTZ or VC. Chemoreceptors and mechanoreceptors in the gastrointestinal tract send signals to the brain through the vagus nerve and autonomic nervous system in response to irritation of the tissues of the gut, including intestinal smooth muscle and the peritoneum. These tissues may be irritated by drugs, toxins, or viral or bacterial infections. Additionally, complete or partial bowel obstruction and tumor growths in the gastrointestinal tract, celiac plexus, and liver often trigger emesis. When the clinician is making a diagnosis in cases of peripheral emesis, constipation should also be considered along with the emetic symptoms.

Neurotransmitters and Receptors

Chemotherapy-induced nausea and vomiting has been the prototype in trying to understand the pathophysiology of nausea and vomiting and the neurotransmitters involved. Dopamine appears to play an important role in CINV, whereas serotonin, substance P, histamine, acetylcholine, and other neurotransmitters have been found in the gastrointestinal tract. Many effective antiemetics, such as phenothiazines and butyrophenones, are dopamine antagonists that may bind specifically to the D ₂ receptor. These were among the first agents with demonstrated antiemetic efficacy. However, there is a high degree of variation in dopamine receptor binding affinity by these drugs. It is known that not all the receptors in the CTZ are dopaminergic because the effect of dopamine antagonists is not equal to surgical ablation of the CTZ. Studies on high-dose metoclopramide, a central and peripheral dopamine antagonist, have shown that the degree of antiemetic activity cannot be explained solely on the basis of dopamine blockade. Metoclopramide is also a weak antagonist of peripheral 5-HT ₃ receptors and can stimulate gastrointestinal motility by increasing acetylcholine release from the cholinergic nerves of the gastrointestinal tract.

During the past two decades, multiple studies have demonstrated that 5-HT ₃ and substance P–natural killer-1 (NK-1) receptor pathways play major roles in the modulation of CINV and perhaps in other conditions, such as opiate-induced and postoperative nausea and vomiting. The 5-HT ₃ receptors are located in both central and peripheral locations. Antagonism of 5-HT ₃ receptors on vagal afferents likely causes or significantly contributes to the antiemetic effect. The introduction of 5-HT ₃ receptor antagonists offered an improved treatment option for prevention of acute CINV.

Substance P (mediated by NK-1 receptors) is known to modulate nociception. High-density NK-1 receptors are located in the regions of the brain implicated in the emetic reflex, such as the area postrema and NTS, as well as in peripheral sites such as the gastrointestinal tract. The primary mechanism of the NK-1 receptor blockade appears to be central, and antagonists of these receptors are effective for both acute and delayed events in CINV. NK-1 antagonists augment the antiemetic activity of 5-HT ₃ receptor antagonists and corticosteroids in the prevention and treatment of CINV.

The vestibular system may also play a role in nausea and vomiting by stimulating the VC via histamine and muscarinic cholinergic receptors stimulation. Conditions such as acoustic neuroma and metastasis affecting the vestibular apparatus at the base of the skull can influence the vestibular system. Histamine (H ₁ and H ₂ ) receptors are found in abundance in the CTZ; however, H ₂ antagonists do not work well as antiemetics. H ₁ antagonists mostly help to alleviate nausea and vomiting induced by vestibular disorders and motion sickness.

Chemotherapeutic agents and many other types of medications such as aspirin and opioids directly stimulate the vestibular apparatus. Opioids can alter the sensitivity of the vestibular center, resulting in nausea associated with movement. Motion can stimulate receptors in the labyrinth, which transmits impulses to the vestibular nucleus, cerebellum, CTZ, and VC. Opioid receptors are also found in the CTZ. It is known that opioids have mixed emetic and antiemetic effects that are blocked by naloxone, removing inhibitory input into the CTZ. These facts have led to the proposal to use certain opioids and enkephalins as antiemetics.

Cannabinoid receptors are located throughout the central and peripheral nervous systems. They are especially localized in the brainstem, basal ganglia, amygdala, and several cortical regions. Although the mechanism of action is not entirely clear, it has been shown that most cannabinoid receptors have an inhibitory effect on neurotransmission and may inhibit emesis. Cannabinoids and cannabinoid agonists (including dronabinol and nabilone, synthetic tetrahydrocannabinols) may be indicated for some patients who are receiving mildly emetogenic chemotherapy and likely helpful in nausea and vomiting in other advanced illnesses states.

The importance of taste and odor perception in relation to enhancement of gagging, nausea, and vomiting is well appreciated, although the exact mechanism is unknown. There are corticobulbar afferents to the VC that mediate vomiting in response to smells, sights, and tastes, playing a role in psychogenic vomiting. Women who have suffered from hyperemesis during pregnancy show taste damage. In addition to indirect effects on taste, some chemotherapeutic agents can be tasted. Clearly, changes in taste secondary to infection or medications may contribute to both nausea and vomiting, as well as to anorexia.

Drug-Induced Nausea and Vomiting

Palliative care patients are often on medication regimens including drugs with known emetogenic potential, such as opioids and nonsteroidal anti-inflammatory drugs (NSAIDS). These drugs can cause nausea and vomiting through different mechanisms. Opioids bind to their receptors in the gastrointestinal tract, decreasing peristalsis and increasing the risk for constipation. High levels of opioids in the blood can stimulate the CTZ, which responds to perceived toxins by sending an impulse to the VC. Impaired liver and kidney functions adversely affect the excretion of opioids and their metabolites, resulting in toxic levels in the blood, brain, and liver, causing nausea and vomiting. Opioids can also increase the sensitivity of the vestibular center by an unknown mechanism. In addition to opioids, many other drugs, such as NSAIDS, steroids, iron supplements, and antibiotics, have been associated with nausea and vomiting secondary to irritation of the gastric lining. Antibiotics may also cause nausea by a direct effect on the CTZ.

Anticipatory Nausea and Vomiting

Anticipatory nausea and vomiting (ANV) has been referred to as conditioned, learned, or psychological nausea and vomiting. It develops in up to a third of patients undergoing chemotherapy, usually occurring several hours before the expected chemotherapy, triggered by talking or thinking about the medication. Classical conditioning plays an important role in the development of ANV in patients receiving chemotherapy. This phenomenon, where the conditioned stimulus is the thought of chemotherapy or of conditioned elements associated with it, has been called a Pavlovian conditioned reflex. Studies on AVN have shown that the intensity of anticipatory nausea is also a significant predictor of the severity of the posttreatment nausea patients experience during the 24-hour period after the chemotherapy infusion. Probably this is also true in nonchemotherapy states.

Chemotherapy-Induced Nausea and Vomiting

Two of the most feared symptoms experienced by palliative care patients are nausea and vomiting secondary to a chemotherapeutic regimen. Up to 80% of cancer patients receiving chemotherapy will develop CINV. The formulation of better medication regimens to target different mechanisms of action and improved treatment guidelines have played central roles in CINV research. These symptoms can have a significant impact on patients’ quality of life, performance status, and daily functioning. The duration, more than severity, seems to be responsible for the impact of CINV on patients’ daily lives. This leads to poor compliance with the chemotherapy regimen and interruptions in treatment, complicating disease management and leading to poor outcomes and increased overall health care costs.

Central Nervous System Disorders

An increase in intracranial pressure resulting from space-occupying lesions in metastatic or primary cancer, infections such as meningitis and encephalitis, and cerebral edema secondary to cerebrovascular accidents directly trigger pressure receptors in the brain, which transmit the information to the VC, inducing nausea and vomiting. On the other hand, several primary central nervous system diseases, such as multiple sclerosis, Parkinson’s disease, amyotrophic lateral sclerosis, and myasthenia gravis, may also produce a disturbance in central control of gastrointestinal motility through different mechanisms. Some of these conditions may cause gastroparesis, gastrointestinal dysmotility, gastric atony, or dysphagia, resulting in gastrointestinal syndromes that cause vomiting or intestinal pseudo-obstruction.

Gastrointestinal Problems

Constipation is one of the most common causes of nausea and vomiting in patients with end-stage cancer and other chronic conditions such as renal failure. A combination of decreased oral intake, immobility, hypercalcemia, hyponatremia, decreased bowel transit secondary to tumor compression or metabolic disturbances, neurologic diseases, and use of medications such as opioids may cause constipation. As intestinal transit slows down, abdominal pressure and bowel distension increase, activating neurotransmitters throughout the gut. These stimulate the peripheral pathway along the vagus nerve, which then communicates with the VC.

Bowel obstruction is also a common problem among patients with advanced cancer, particularly abdominal pathologies such as peritoneal carcinomatosis from metastatic colon or ovarian carcinoma. The onset is usually slow, as the tumor compresses the bowel extrinsically or grows intraluminally. It often manifests in pain with severe nausea and vomiting. For patients who are not surgical candidates, these symptoms can be controlled by a combination of medications.