PDQ® Supportive Care Health Professionals
Prevention and control of nausea and vomiting are paramount in the treatment of cancer patients, as they can result in serious metabolic derangements, nutritional depletion and anorexia, deterioration of patients' physical and mental status, esophageal tears, fractures, wound dehiscence, withdrawal from potentially useful and curative antineoplastic treatment, and degeneration of self-care and functional ability.[1-4]
Nausea is a subjective phenomenon of an unpleasant, wavelike sensation experienced in the back of the throat and/or the epigastrium that may or may not culminate in vomiting. Vomiting is the forceful expulsion of the contents of the stomach, duodenum, or jejunum through the oral cavity. Retching is gastric and esophageal movements of vomiting without expulsion of vomitus and is also referred to as "dry heaves." Despite advances in pharmacologic and nonpharmacologic management, nausea and vomiting remain two of the side effects most distressing to cancer patients and their families.[5,6]
Nausea and vomiting are commonly classified as anticipatory, acute, or delayed when referring to chemotherapy-induced symptoms. Anticipatory nausea and vomiting (ANV) may occur prior to or during chemotherapy administration, but earlier than is consistent with the characteristic onset of symptoms associated with a particular emetogenic drug or drug combination. Anticipatory symptoms may also appear in patients who receive radiation therapy. Acute nausea and vomiting occur with a variable period of latency from the time of drug administration to onset of nausea and vomiting (within a few minutes to several hours) but, by definition, within 24 hours after drug administration. Delayed (or late) nausea and vomiting occur after the acute phase, i.e., more than 24 hours after chemotherapeutic drugs are given, and may persist for several days. Cisplatin and other drugs (e.g., cyclophosphamide, doxorubicin, and ifosfamide) given at high doses or on two or more consecutive days are associated with delayed nausea and vomiting. Delayed emesis has been associated with high levels of morbidity and there are few treatment options with proven efficacy.[12-15]
Progress has been made in understanding the neurophysiologic mechanisms that control nausea and vomiting. Both are controlled or mediated by the central nervous system but by different mechanisms. Nausea is mediated through the autonomic nervous system. Vomiting results from the stimulation of a complex reflex that is coordinated by a putative true vomiting center, which may be located in the dorsolateral reticular formation near the medullary respiratory centers. The vomiting center presumably receives convergent afferent stimulation from several central neurologic pathways, including the following:[1-4]
Currently, evidence indicates that acute emesis following chemotherapy is initiated by the release of neurotransmitters from cells that are susceptible to the presence of toxic substances in the blood or CSF. Area postrema cells in the CTZ and enterochromaffin cells within the intestinal mucosa are implicated in initiating and propagating afferent stimuli that ultimately converge on central structures corresponding to a "vomiting center." The relative contribution from these multiple pathways culminating in nausea and vomiting symptoms is complex and is postulated to account for the variable emetogenicity (intrinsic emetogenicity and mitigating factors, i.e., dosage, administration route, exposure duration) and emetogenic profile (i.e., time to onset, symptom severity, and duration) of agents.
Not all cancer patients will experience nausea and/or vomiting. The most common causes are emetogenic chemotherapy drugs and radiation therapy to the gastrointestinal tract, liver, or brain. Other possible causes include fluid and electrolyte imbalances such as hypercalcemia, volume depletion, or water intoxication; tumor invasion or growth in the gastrointestinal tract, liver, or central nervous system, especially the posterior fossa; constipation; certain drugs such as opioids; infection or septicemia; uremia; and psychogenic factors. Clinicians treating nausea and vomiting must be alert to all potential causes and factors, especially in cancer patients who may be receiving combinations of several treatments and medications.
Anticipatory nausea and vomiting (ANV) occur prior to treatment as a classically conditioned response to specific environmental stimuli (i.e., certain objects, odors, and tastes). For example, a chemotherapy agent is an unconditioned stimulus (UCS) that may be paired or associated with the smell of an alcohol swab, the neutral stimulus (NS), at the time of chemotherapy administration. Then, the individual experiences nausea and vomiting as an unconditioned response (UCR). In the future, the smell of alcohol alone becomes the conditioned stimulus (CS) that can lead to nausea and vomiting as a conditioned response (CR). There is some evidence that the environmental triggering stimuli in anticipatory nausea may be predominantly odors, while the triggering stimuli in anticipatory vomiting may be contemplation of the treatment. Approximately 10%-44% of patients receiving chemotherapy experience nausea and/or vomiting prior to or during chemotherapy infusions.[2-5] While the onset of ANV varies among patients, the pattern is frequently apparent by the fourth or fifth course of treatment. No single factor is characteristic of the development of ANV symptoms. Recent evidence indicates that certain variables may predict which patients will develop ANV. These variables include treatment with a drug regimen high in emetogenic potential, symptom and psychosocial distress, mood disturbances, and limited ability to cope with treatment stress. There have been a number of theoretical explanations and empirical investigations as to possible causes of ANV  although some studies report contradictory findings. Many variables have been correlated with the development of ANV.[2,5,7-25]
The direct effect of age on the development of ANV has not been clearly demonstrated. It has been suggested that younger adults are more susceptible to ANV because they receive more aggressive chemotherapy treatments than their older counterparts, and subsequently experience more severe post-treatment nausea and vomiting.
Nonpharmacological approaches, such as hypnosis, relaxation, and behavioral modification techniques may reduce ANV. Also, some anxiolytic drugs, e.g., benzodiazepines, especially lorazepam (Atiran), may be helpful in ANV.
Chemotherapy is the most common treatment-related cause of nausea and vomiting. The incidence and severity in persons receiving chemotherapy varies according to many factors, including the particular drug, dose, schedule of administration, route, and individual patient variables. In the vast majority of cancer patients, these symptoms can be prevented or controlled.
Although every chemotherapy drug in use has the potential for causing nausea and vomiting, drugs are generally classified based on their emetogenic potential. These classifications vary from study to study.
Severe emetogenic potential drugs (more than 90% of persons will experience nausea and vomiting) include the following:
Although patients receiving radiation therapy can experience ANV, in general, patients receiving radiation to the GI tract or brain have the greatest potential for nausea/vomiting as a side effect. Because cells of the GI tract are dividing quickly, they are quite sensitive to radiation therapy. Radiation to the brain is believed to stimulate the brain's vomiting center or CTZ. Similar to chemotherapy, radiation dose factors also play a role in determining the possible occurrence of nausea and vomiting. In general, the higher the daily fractional dose and the greater the amount of tissue that is irradiated, the higher the potential for nausea and vomiting.
In addition, the larger the amount of GI tract irradiated (particularly for fields that include the small intestine and stomach), the higher the potential for nausea and vomiting. Total-body irradiation before bone marrow transplant, for example, has a high probability of inducing nausea and vomiting as acute side effects.
Nausea and vomiting from radiation may be acute and self-limiting, usually occurring one half to several hours after treatment. Patients report that symptoms improve on days that they are not being treated. There are also cumulative effects that may occur in patients receiving radiation therapy to the GI tract.
Antiemetic agents are the most common intervention in the management of treatment-related nausea and vomiting. The basis for antiemetic therapy is the neurochemical control of vomiting. Although the exact mechanism is not well understood, peripheral neuroreceptors and the chemoreceptor trigger zone (CTZ) are known to contain receptors for serotonin, histamine (H1 and H2), dopamine, acetylcholine, opioids, and numerous other endogenous neurotransmitters.[1,2] Many antiemetics act by competitively blocking receptors for these substances, thereby inhibiting stimulation of peripheral nerves at the CTZ, and perhaps at the "vomiting center." Most drugs with proven antiemetic activity can be categorized into one of the following groups: competitive antagonists at dopaminergic (D2 subtype) receptors or serotonergic (5-hydroxytryptamine-3 or 5-HT3 [subtype]) receptors, corticosteroids, or cannabinoids. Examples of dopaminergic antagonists include the phenothiazines, substituted benzamides, and butyrophenones.
Prochlorperazine is perhaps the most frequently (and empirically) used antiemetic and, in low doses, is generally effective in preventing nausea associated with radiation therapy and in treating nausea and vomiting attributed to very low to moderately emetogenic chemotherapeutic drugs. It is a phenothiazine and can be given orally, intramuscularly, intravenously, and rectally. It is usually given in the 10-50 mg dose range (pediatric dose: 6 mg every 4-6 hours). Higher prochlorperazine doses (e.g., 0.2-0.6 milligrams per kilograms per dose) are also used intravenously for chemotherapy with high emetogenic potential.[3-5] Phenothiazines may be of particular value in treating patients who experience delayed nausea and vomiting (post-acute phase symptoms) on cisplatin regimens.
As with other dopaminergic antagonists, the most common side effects of prochlorperazine are extrapyramidal reactions (acute dystonias, akathisias, neuroleptic malignant syndrome [uncommon], and rarely, akinesias and dyskinesias), and sedation. Marked hypotension may also result if intravenous prochlorperazine is administered rapidly at high doses. Administration over at least 30 minutes appears adequate to prevent hypotensive episodes.[7-11]
Phenothiazines act on dopaminergic receptors at the CTZ, and perhaps at other CNS centers, and peripherally. With the exception of thioridazine, many phenothiazines possess antiemetic activity, including chlorpromazine given in the 10-50 mg dose range orally, intramuscularly, intravenously, and rectally (pediatric dose for older than 12 years old: 10 mg every 6-8 hours; for younger than 12 years old: 5 mg every 6-8 hours); thiethylperazine given in the 5-10 mg dose range orally, intramuscularly, and intravenously; and perphenazine. The primary consideration in selecting among phenothiazines are differences in their adverse effect profiles, which substantially correlate with their structural classes. Generally, aliphatic phenothiazines (e.g., chlorpromazine, methotrimeprazine) produce sedation and anticholinergic effects, while piperazines (e.g., prochlorperazine, thiethylperazine, perphenazine, and fluphenazine) are associated with less sedation but greater incidence of extrapyramidal reactions.
Metoclopramide is a substituted benzamide, which, prior to the introduction of serotonin (5-HT3) receptor antagonists, was considered the most effective single antiemetic agent against highly emetogenic chemotherapy such as cisplatin. Although metoclopramide is a competitive antagonist at dopaminergic (D2) receptors, it is most effective against acute vomiting when given intravenously at high doses (e.g., 0.5-3 milligrams per kilograms per dose), probably because it is a weak competitive antagonist (relative to other serotonin antagonists) at 5-HT3 receptors. It may act on the CTZ and the periphery. Metoclopramide also increases lower esophageal sphincter pressure and enhances the rate of gastric emptying, which may factor into its overall antiemetic effect. It can be administered intravenously at the FDA-approved dose of 1-2 mg/kg every 2 hours (or less frequently) for 3-5 doses. Metoclopramide has also been safely given by intravenous bolus injection at higher single doses (up to 6 mg/kg) and by continuous intravenous infusion, with or without a "loading" bolus dose, with efficacy comparable to multiple intermittent dosing schedules.[12-15] Metoclopramide is associated with akathisia and dystonic extrapyramidal effects, with the latter seen more commonly in persons under the age of 30 years, and the former seen more frequently in patients over 30 years of age. Diphenhydramine, benztropine mesylate, and trihexyphenidyl are commonly used prophylactically or therapeutically to pharmacologically antagonize extrapyramidal reactions (EPRs).[7,16] While cogwheeling rigidity, acute dystonia, and tremor are responsive to anticholinergic medications, akathisia, the subjective sense of restlessness or inability to sit still, is best treated by: 1) switching to a lower potency neuroleptic for emesis, if possible; 2) lowering the dose, or; 3) adding a benzodiazepine (i.e., lorazepam) or beta blocker (i.e., propranolol).
Droperidol and haloperidol represent the butyrophenones, a third class of dopaminergic (D2 subtype) receptor antagonists that are structurally and pharmacologically similar to the phenothiazines. While droperidol is used primarily as an adjunct to anesthesia induction, haloperidol is indicated as a neuroleptic antipsychotic drug; however, both agents have potent antiemetic activity. Droperidol is administered intramuscularly or intravenously, typically from 1-2.5 mg every 2-6 hours, but higher doses (up to 10 mg) have been safely given.[17-19] Haloperidol is administered intramuscularly, intravenously, or orally, typically from 1-4 mg every 2-6 hours. Both agents may produce extrapyramidal reactions, akathisia, hypotension, and sedation.
Two serotonin receptor antagonists, ondansetron and granisetron are available in the United States. Agents in this class are thought to prevent nausea and vomiting by preventing serotonin, which is released from enterochromaffin cells in the gastrointestinal mucosa, from initiating afferent transmission to the CNS via vagal and spinal sympathetic nerves.[21,22] 5-HT3 antagonists may also block serotonin stimulation at the CTZ and other CNS structures.
Several studies have demonstrated that ondansetron produces an antiemetic response that equals or is superior to high doses of metoclopramide, but ondansetron has a superior toxicity profile compared to dopaminergic antagonist agents.[23-33] Ondansetron (0.15 mg/kg) is given intravenously 15-30 minutes prior to chemotherapy and is repeated every 4 hours for two additional doses. Alternatively, for patients older than 18 years of age, a large multicenter study determined that a single 32-mg dose of ondansetron is more effective in treating cisplatin-induced nausea and vomiting than a single 8-mg dose, and is as effective as the standard regimen of three 0.15 mg/kg doses given every 4 hours starting 30 minutes before chemotherapy. There are, however, some areas of controversy among clinicians related to the optimal role for serotonin receptor antagonists. Because they are better tolerated than previously available antiemetics and are effective, serotonin antagonists have the potential to be overused as prophylaxis in situations that do not present a very substantial emetogenic challenge, i.e., when less expensive agents would suffice. It is also worth noting that during its clinical development, ondansetron was effective at doses of 0.06-0.48 mg/kg given by a variety of intermittent and continuous administration schedules.[35-41] However, neither dose-limiting toxicity nor a maximally tolerated dose were encountered and the optimal dose and schedule for ondansetron have not yet been defined.[34,42,43] Higher (0.30 mg/kg) or lower (0.015 mg/kg) doses of ondansetron have not been shown to be superior to the 0.15 mg/kg dose, and it is unclear whether a single 32-mg dose is necessary to achieve the results reported by Beck, et al. or whether an intermediate dose (between 8 and 32 mg) would be equally effective.
Currently, the oral and injectable ondansetron formulations are approved for use without dosage modification in patients older than 4 years of age, including the elderly and patients with renal insufficiency. Oral ondansetron is given 3 times daily starting 30 minutes before chemotherapy and continuing for up to 2 days after chemotherapy is completed. Patients older than 12 years of age should receive 4 mg/dose. Ondansetron is not approved for use in children under 4 years of age. Ondansetron clearance is diminished in patients with severe hepatic insufficiency, therefore, such patients should receive a single injectable or oral dose not greater than 8 mg. There is currently no information available evaluating the safety of repeated daily ondansetron doses in patients with hepatic insufficiency.
Other effective dosing schedules, such as a continuous intravenous infusion (e.g., 1 mg/hr for 24 hours) or oral administration have also been evaluated.[34,45-50] The major adverse effects include headache (which can be treated with mild analgesics), constipation or diarrhea, fatigue, dry mouth, and transient asymptomatic elevations in liver function tests (alanine [ALT] and aspartate [AST] transaminases), which may be related to concurrent cisplatin administration. Ondansetron has been etiologically implicated in a few case studies involving thrombocytopenia, renal insufficiency, and thrombotic events. In addition, a few case reports have implicated ondansetron in causing EPRs. However, it is not clear in some cases whether the events described were in fact extrapyramidal reactions, and in other reports the evidence is confounded by concurrent use of other agents that are known to produce EPRs. Nevertheless, the greatest advantage of serotonin receptor antagonists over dopaminergic receptor antagonists is that they have fewer adverse effects.
Granisetron has demonstrated efficacy in preventing and controlling nausea and vomiting at a broad range of doses (e.g., 10-80 micrograms per kilogram and empirically, 3 mg/dose). In the United States, granisetron injection and oral tablets are approved for initial and repeat prophylaxis for patients receiving emetogenic chemotherapy, including high-dose cisplatin. Granisetron is pharmacologically and pharmacokinetically distinct from ondansetron; however, clinically it appears equally efficacious and equally safe.[53-59] Both granisetron formulations are given before chemotherapy, as either a single intravenous dose of 10 micrograms per kilogram (0.01 mg/kg) or 1 mg orally (1- mg tablets) every 12 hours.
Both granisetron formulations and ondansetron injection share the same indication against highly emetogenic chemotherapy. In contrast, the oral ondansetron formulation has been approved only for use against nausea and vomiting associated with moderately emetogenic chemotherapy.
Currently, granisetron injection is approved for use without dosage modification in patients older than 2 years of age, including the elderly and patients with hepatic and renal insufficiency. Oral granisetron has not yet been approved for use in pediatric patients.
Clinicians should note that there are no published reports prospectively comparing antiemetic response rates to prophylaxis with oral ondansetron and granisetron at FDA-approved dosages. Also, preliminary evidence suggests that patients who fail to achieve complete antiemetic control with either ondansetron or granisetron during chemotherapy may achieve adequate control with the alternative agent.
Although ondansetron and granisetron are superior to other antiemetics, neither agent provides continuously high response rates throughout treatments that are administered over two or more consecutive days nor during the post-acute, delayed symptom phase.[61-66] Both granisetron and ondansetron demonstrate greater antiemetic efficacy in combination with corticosteroids (see the COMBINATION THERAPY section).[28,50,67-82]
Other serotonin antagonists, e.g., dolasetron, batanopride, and tropisetron, are currently under evaluation.[35,53,83-88] Thus far, serotonin antagonists have not demonstrated efficacy in treating delayed (post-acute; greater than 24 hours after emetogenic treatment) phase symptoms. In addition, they are expensive to administer and some patients may not be able to afford this treatment.[52,54,89]
Other agents commonly used as prophylaxis and treatment for chemotherapy-induced nausea and vomiting, alone or in combination antiemetic regimens, include corticosteroids (dexamethasone, methylprednisolone) and a cannabinoid (dronabinol). Benzodiazepines (lorazepam, midazolam, alprazolam, diazepam) are also valuable adjuncts in combination with acute antiemetic regimens.
Steroids are sometimes used as single agents against mild to moderately emetogenic chemotherapy, but are more often used in antiemetic drug combinations.[90-95] Their antiemetic mechanism of action is not fully understood, but they may affect prostaglandin activity in the brain. Clinically, steroids quantitatively decrease or eliminate episodes of nausea and vomiting and may improve patients' mood, thus producing a subjective sense of well-being or euphoria (although they also can cause depression and anxiety). In combination with high-dose metoclopramide, steroids may mitigate adverse effects, such as the frequency of diarrheal episodes.
Steroids are often given intravenously before chemotherapy and may or may not be repeated. Dosages and administration schedules are selected empirically. Dexamethasone is often the treatment of choice in treating nausea and vomiting in patients receiving radiation to the brain, as it also reduces cerebral edema. It is administered orally, intramuscularly, or intravenously in the dose range of 8-40 mg (pediatric dose: 0.25-0.5 mg/kg).[96-100] Methylprednisolone is also administered orally, intramuscularly, or intravenously at doses and schedules that vary from 40-500 mg every 6-12 hours for up to 20 doses.[95,101]
Dexamethasone is also used orally for delayed nausea and vomiting. However, long-term corticosteroid use is inappropriate and may cause substantial morbidity, including immunosuppression, proximal muscle weakness (especially involving the thighs and upper arms), aseptic necrosis of the long bones, cataract formation, hyperglycemia and exacerbation of preexisting diabetes or escalation of subclinical diabetes to clinical pathology, adrenal suppression with hypocortisolism, lethargy, weight gain, GI irritation, insomnia, anxiety, mood changes, and psychosis. As had previously been shown with metoclopramide, numerous studies have demonstrated that dexamethasone potentiates the antiemetic properties of 5-HT3 blocking agents.[50,68,69,102-104] If given intravenously, dexamethasone should be given over 10-15 minutes, since rapid administration may cause sensations of generalized warmth, pharyngeal tingling or burning, or acute transient perineal and/or rectal pain.[99,105-109]
Prednisone and adrenocorticotropic hormone (ACTH) given concomitantly with other active antiemetic agents have also demonstrated efficacy against cisplatin-containing chemotherapy during the acute phase (within 24 hours after receiving chemotherapy).[110-113] In a double-blind randomized study of metoclopramide and dexamethasone with or without ACTH 1 mg, patients receiving ACTH prophylaxis for cisplatin-containing chemotherapy experienced a significantly decreased incidence and severity of delayed emesis for up to 72 hours after treatment.
Cannabinoids also presumably target higher CNS structures to prevent nausea and vomiting.[114,115] Dronabinol (delta-9-tetrahydrocannabinol) is one of the psychoactive substances present in crude marijuana. Because of cultural and societal constraints and a low therapeutic index at clinically useful dosages, cannabinoids are often not among agents that are first selected for clinical use, but may be accepted and useful in selected patients. Dronabinol is administered orally at 5-15 milligrams per square meter 1-3 hours before chemotherapy, then every 2-4 hours for up to 6 doses/day.[116-120]
Adverse effects experienced along with the pharmacologic and psychogenic effects of cannabinoids include an acute withdrawal syndrome, sedation, dry mouth, orthostatic hypotension, dizziness, and ataxia. The effects dronabinol produces on the CNS at minimally effective dosages include euphoria or dysphoria; feelings of detachment, depression, anxiety, paranoia, and panic; decreased cognitive function; memory loss; increased tendencies toward impulsive and compulsive behaviors; altered perceptions, such as a distorted sense of time; other sensory distortions; hallucinations; and, rarely, a psychotic organic brain syndrome.[121-124] Cardiovascular adverse effects typically manifest at dosages somewhat greater than those recommended for antiemetic effect and include tachycardia, vasodilation with variable effects on blood pressure, orthostatic symptoms, and decreased body temperature. With chronic administration, tolerance to cardiovascular and subjective effects may occur within days to weeks after treatment onset.
Benzodiazepines, such as lorazepam, midazolam, and alprazolam, have become recognized as valuable adjuncts in the prevention and treatment of anxiety and anticipatory nausea and vomiting symptoms associated with chemotherapy, especially with the highly emetogenic regimens given to children.[125-127] It is important to note that benzodiazepines have not demonstrated intrinsic antiemetic activity as single agents. Therefore, their place in antiemetic prophylaxis and treatment is adjunctive to other antiemetic agents. Benzodiazepines presumably act on higher CNS structures, the brainstem, and spinal cord, and they produce anxiolytic, sedative, and anterograde amnesic effects. In addition, they markedly decrease the severity of EPRs, especially akathisia, associated with dopaminergic receptor antagonist antiemetics.
Lorazepam may be administered orally, intramuscularly, intravenously, and sublingually.[129-133] Dosages range from 0.5-3 mg (alternatively, 0.025-0.05 mg/kg, or 1.5 milligrams per square meter, but not greater than 4 mg/dose) in adults and 0.03-0.05 mg/kg in children every 6-12 hours.[125,134-139] Midazolam produces mild to marked sedation for 1-4.5 hours at doses equal to 0.04 mg/kg given intravenously over 3-5 minutes.[140-142] Alprazolam has been shown to be effective when given in combination with metoclopromide and methylprednisolone.
The adverse effects of benzodiazepine include sedation, perceptual disturbances, disorders of micturition and/or defecation, visual disturbances, hypotension, anterograde amnesia, psychological dependence, confusion, ataxia, and depressed mental acuity with intoxication.
Combination antiemetic regimens have become increasingly popular with highly emetogenic chemotherapy treatment programs. A combination of several drugs can be used to attack nausea and vomiting from several sites and mechanisms of action. Most combination regimens combine a dopamine antagonist with agents having no dopamine-blocking effect. An example of a combination regimen is the inpatient administration of metoclopramide, dexamethasone, and lorazepam for a cisplatin-containing regimen, as follows:
Several studies compared certain drugs in antiemetic drug
combinations.[6,149-151] The combination of intravenous ondansetron and dexamethasone has been shown to be superior to the combination of intravenous metoclopramide, dexamethasone, and diphenhydramine.[152-155] The combination of ondansetron, dexamethasone, and chlorpromazine was superior to ondansetron and dexamethasone. However, the use of oral ondansetron was not as effective as oral metoclopramide and intravenous dexamethasone in a group of breast cancer patients receiving a moderately emetogenic chemotherapeutic regimen. The combination of a serotonin antagonist (ondansetron) and a dopamine D2 antagonist (metopimazine) may prove to be an effective and safe regimen for patients receiving moderate emetogenic therapy. As the diversity of agents with different mechanisms of action expands, the success of combinations of agents will potentially increase the effectiveness of managing nausea and vomiting.
In the selection of antiemetics, there are general factors that should be considered. These include dose, route of administration, and schedule. Patients receiving high emetogenic potential chemotherapy, for example, may require higher doses of antiemetics. Patients receiving highly emetogenic chemotherapy on an outpatient basis (returning home without continued intravenous access, for example) may do best with sublingual or rectal antiemetic routes of delivery. Since the duration of action of drugs differs greatly, the schedule of antiemetics will directly impact on their success. Metoclopramide has a short duration of action (2-3 hours) and therefore should be given frequently. Lorazepam, on the other hand, has a longer duration of action (4-8 hours) and should not be given as frequently as metoclopramide. The same consideration holds for combination antiemetic regimens. Each drug must be considered separately. Maintaining adequate blood levels of a particular drug to prevent nausea and vomiting from occurring is essential to the success of any antiemetic program.