Subject: nausea This is a file from my personal archive of alt.drugs/talk.politics.drugs posts which I've found especially interesting or informative. Odds are good I didn't write it, please don't assume I did. If I repost one of your messages without proper attribution (many files have lost their headers), please send me mail so you can get credit. -- Chris ########################################################################## CancerNet from the National Cancer Institute's PDQ System ********************************************************************* * This information is intended for use by doctors and other health * * care professionals. If you are a cancer patient, your doctor * * can explain how it applies to you, or you can call the Cancer * * Information Service at 1-800-4-CANCER (1-800-422-6237). * * CancerNet also has information for patients; see the CancerNet * * Contents List for more information. * ********************************************************************* Information for Physicians Nausea and vomiting 208/04466 Nausea and vomiting: introduction Nausea and vomiting may be among the discomforting, distressing side effects of cancer therapies. Despite advances in the pharmacologic and nonpharmacologic management, nausea and vomiting remain two of the most dreaded side effects by cancer patients and their families.[1,2] Prevention and control of nausea and vomiting is paramount in the treatment of cancer patients, as these can result in serious metabolic derangements, nutritional depletion, deterioration of a patient's physical and mental status, withdrawal from potentially useful and curative antineoplastic treatment, and degeneration of self-care and functional ability.[3-5] 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. It is often described as "feeling sick to the stomach."[6,7] Vomiting is the forceful expulsion of the contents of the stomach, duodenum, or jejunum through the oral cavity. Retching is the attempt to vomit without bringing anything up and is also described as "dry heaves." Although nausea and vomiting are often used synonymously, some studies suggest that they are distinct entities with different component. s.[4,6,8] Patients have made the distinction between nausea and vomiting and indicate that nausea is far more distressing than vomiting.[6,9,10] Nausea and vomiting are also commonly classified as anticipatory, acute, or delayed, especially when referring to chemotherapy-induced symptoms. Anticipatory nausea and vomiting (ANV) largely occurs prior to or during chemotherapy administration and, to a lesser extent, radiation therapy. Acute nausea and vomiting occurs within a few minutes to several hours after drug administration and usually resolves within 24 hours. Delayed nausea and vomiting occurs several hours after chemotherapeutic drugs are given and can last several days. Certain drugs, such as cisplatin, cyclophosphamide, doxorubicin, and ifosfamide, are associated with delayed nausea and vomiting.[11] References: 1. Coates A, Abraham S, Kaye SB, et al.: On the receiving end - patient perception of the side-effects of cancer chemotherapy. European Journal of Cancer and Clinical Oncology 19(2): 203-208, 1983. 2. Craig JB, Powell BL: The management of nausea and vomiting in clinical oncology. American Journal of the Medical Sciences 293(1): 34-44, 1987. 3. Richardson JL, Marks G, Levine A: The influence of symptoms of disease and side effects of treatment on compliance with cancer therapy. Journal of Clinical Oncology 6(11): 1746-1752, 1988. 4. Laszlo J, Ed.: Antiemetics and Cancer Chemotherapy. Baltimore: Williams & Wilkens, 1983. 5. Ingle RJ, Burish TG, Wallston KA: Conditionability of cancer chemotherapy patients. Oncology Nursing Forum 11(4): 97-102, 1984. 6. Rhodes VA, Watson PM, Johnson MH, et al.: Patterns of nausea, vomiting, and distress in patients receiving antineoplastic drug protocols. Oncology Nursing Forum 14(4): 35-44, 1987. 7. Rhodes VA, Watson PM, Johnson MH: Development of reliable and valid measures of nausea and vomiting. Cancer Nursing 7(1): 33-41, 1984. 8. Salla. n SE, Cronin CM: Nausea and vomiting. In: DeVita VT, Hellman S, Rosenberg SA, Eds.: Cancer: Principles and Practice of Oncology. Philadelphia: JB Lippincott Company, 2nd Edition, 1985, pp 2008-2013. 9. Rhodes VA, Watson PM, Johnson MH: Patterns of nausea and vomiting in chemotherapy patients: a preliminary study. Oncology Nursing Forum 12(3): 42-48, 1985. 10. Rhodes VA, Watson PM, Johnson MH: Association of chemotherapy related nausea and vomiting with pretreatment and posttreatment anxiety. Oncology Nursing Forum 13(1): 41-47, 1986. 11. Moreno I, Rosell R, Abad A, et al.: Comparison of three protracted antiemetic regimens for the control of delayed emesis in cisplatin-treated patients. European Journal of Cancer 28A(8/9): 1344-1347, 1992. Nausea and vomiting: neurophysiology Neurophysiology of Nausea and Vomiting 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 the true vomiting center, located in the dorsolateral reticular formation near the respiratory center of the medulla. The true vomiting center, which ultimately controls all emesis, may be stimulated from several neurologic pathways. Afferent input comes from the chemoreceptor trigger zone (CTZ), located in the floor of the fourth ventricle. The CTZ responds to the following: the presence of noxious stimuli in the blood and spinal fluid; vagal visceral and other sympathetic afferents from the viscera (i.e., sympathetic visceral response to inflammation, ischemia, and irritation of the GI tract); vestibulocerebellar afferents from the labyrinth of the inner ear in response to body motion; and afferent input from the cerebral cortex and the limbic system in response . to stimulation of the senses (particularly smell and taste), distress, pain, and increases in intracranial pressure. It is believed that input into the CTZ is the major cause of chemotherapy-induced nausea and vomiting. The central pathways appear to converge on the true vomiting center and contain distinct types of neurotransmitter receptors that respond to the specific chemicals dopamine, histamine, acetylcholine, serotonin, norepinephrine, and glutamine.[1-5] The effect of these multiple pathways upon the true vomiting center is complex. In ANV, however, the CTZ is probably not directly stimulated. References: 1. Craig JB, Powell BL: The management of nausea and vomiting in clinical oncology. American Journal of the Medical Sciences 293(1): 34-44, 1987. 2. Sallan SE, Cronin CM: Nausea and vomiting. In: DeVita VT, Hellman S, Rosenberg SA, Eds.: Cancer: Principles and Practice of Oncology. Philadelphia: JB Lippincott Company, 2nd Edition, 1985, pp 2008-2013. 3. Borison HL, Wang S: Physiology and pharmacology of vomiting. Pharmacological Reviews 5: 195-230, 1953.. 4. Guyton AC: Textbook of Medical Physiology. Philadelphia: W.B. Saunders, 6th ed., 1981.. 5. Borison HL, McCarthy LE: Neuropharmacologic mechanisms of emesis. In: Laszlo J, Ed.: Antiemetics and Cancer Chemotherapy. Baltimore: Williams & Wilkens, 1983, pp 6-20. Nausea and vomiting: incidence and etiology 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 narcotics; infection or septicemia; uremia; and psychogenic factors. Clinic. ians 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 refers to a conditioned response in which nausea and vomiting occur prior to treatments and/or specific environmental stimuli (i.e., objects, odors, tastes, and smells). Approximately 10-44% of patients receiving chemotherapy experience nausea and/or vomiting prior to or during chemotherapy infusions.[1-3] 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 can predict which patients will develop ANV. These variables include patients who receive a drug regimen high in emetogenic potential, experience symptom and psychosocial distress, experience mood disturbances, and who demonstrate a limited ability to cope with the stress of the treatment.[4] Variables correlated with the development of ANV include:[1,5-7] - Emetogenicity of chemotherapy received. - Sweating after last chemotherapy. - Feeling warm or hot after last chemotherapy. - Severity of post-treatment nausea and vomiting. - Number of chemotherapy cycles received. - High state- and trait-anxiety levels (state anxiety is a measure of an individual's feelings of anxiety at a specific moment, while trait anxiety reflects how individuals generally feel about themselves and their responses to stress). - Abnormal taste sensations during chemotherapy administration. - Susceptibility to motion sickness. - Delayed onset of postchemotherapy nausea and vomiting. - Age (negatively correlated) less than 50. - Post-treatment dizziness and lightheadedness. Although anxiety may not be the sole factor, it may facilitate the development of ANV in the presence of oth. er identified factors. State- and trait-anxiety levels have been observed to be significantly higher in patients with anticipatory nausea, and increased anxiety has been found to decrease the patient's ability to develop coping strategies in the event of nausea and vomiting.[6] The direct effect of age on the development of ANV has not been clearly demonstrated. Although it has been suggested that younger adults are more susceptible to ANV, whether younger patients may be receiving more aggressive chemotherapy treatments than their older counterparts, and subsequently experiencing more severe post-treatment nausea and vomiting, remains unclear.[1] Several myths concerning nausea and vomiting must be dispelled. The first is that nausea and vomiting are inevitable from cancer treatments. Many cancer patients may never experience these symptoms. A second myth centers on the belief that a cancer patient should experience nausea and vomiting for the treatment to be effective. There appears to be no correlation between these. Finally, it is common to believe that nothing can be done about nausea and vomiting. In the vast majority of cancer patients who will experience these symptoms, nausea and vomiting can be prevented or controlled. By far, chemotherapy is the most common 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. Although every chemotherapy drug in use has the potential for causing nausea and vomiting, drugs are classified based on their emetogenic potential:[8] Severe emetogenic potential drugs (greater than 90% of persons will experience nausea and vomiting) include the following: cisplatin dacarbazine streptozocin mechlorethamine cytarabine (high dose) High emetogenic potential drugs (60-90% of persons will experience nausea and vomiting) include the follo. wing: cyclophosphamide carmustine semustine lomustine procarbazine methotrexate (high dose) dactinomycin ifosfamide carboplatin Moderate emetogenic potential drugs (30-60% of persons will experience nausea and vomiting) include the following: L-asparaginase daunorubicin doxorubicin mitomycin-C 5-azacytidine 5-fluorouracil hexamethylmelamine etoposide Low emetogenic potential drugs (10-30% of persons will experience nausea and vomiting) include the following: bleomycin cytarabine methotrexate hydroxyurea 6-mercaptopurine vinblastine thiotepa Finally, very low emetogenic potential drugs (less than 10% of persons will experience nausea and vomiting) include the following: busulfan androgens estrogens corticosteroids thioguanine vincristine progestins Besides emetogenic potential, however, the dose and schedule used are also extremely important factors. For example, a drug with a low emetogenic potential given in high doses would have a dramatic increase in the potential to induce nausea and vomiting. Standard doses of cytarabine rarely produce nausea and vomiting, but these are often seen with high doses of this drug. Another factor to consider is the use of drug combinations. Because most patients receive combination chemotherapy, the emetogenic potential of all of the drugs combined and individual drug doses needs to be considered. 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 total. dose of radiation, and the greater the amount of tissue that is irradiated, the higher the potential for nausea and vomiting. In addition, the more of the GI tract irradiated, the higher the potential for nausea and vomiting. Total body irradiation before bone marrow transplant, for example, has a high probability for nausea and vomiting as acute side effects. Nausea and vomiting from radiation may be acute and self-limiting. It usually occurs one-half to several hours after treatment. Patients report that it improves 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. Nausea and vomiting have also been reported in patients receiving radiosensitizers, such as SR 2508. References: 1. Morrow GR, Lindke J, Black PM: Predicting development of anticipatory nausea in cancer patients: prospective examination of eight clinical characteristics. Journal of Pain and Symptom Management 6(4): 215-223, 1991. 2. Nesse RM, Carli T, Curtis GC, et al.: Pretreatment nausea in cancer chemotherapy: a conditioned response? Psychosomatic Medicine 42(1): 33-36, 1980. 3. Wilcox PM, Fetting JH, Nettesheim KM, et al.: Anticipatory vomiting in women receiving cyclophosphamide, methotrexate, and 5-FU (CMF) adjuvant chemotherapy for breast carcinoma. Cancer Treatment Reports 66(8): 1601-1604, 1982. 4. Pickett M: Determinants of anticipatory nausea and anticipatory vomiting in adults receiving cancer chemotherapy. Cancer Nursing 14(6): 334-343, 1991. 5. Nerenz DR, Leventhal H, Easterling DV, et al.: Anxiety and drug taste as predictors of anticipatory nausea in cancer chemotherapy. Journal of Clinical Oncology 4(2): 224-233, 1986. 6. Andrykowski MA, Redd WH: Longitudinal analysis of the development of anticipatory nausea. Journal of Consulting and Clinical Psychology 55(1): 36-41, 1987. 7. Chin SB, Kucuk O. , Peterson R, et al.: Variables contributing to anticipatory nausea and vomiting in cancer chemotherapy. American Journal of Clinical Oncology 15(3): 262-267, 1992. 8. Chase JL, Staggs RJ: Outpatient treatment of chemotherapy induced nausea and vomiting. Outpatient Chemotherapy 3(3): 4, 1990. Post-treatment nausea and vomiting: management 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, the CTZ is known to contain receptors for histamine (H1 and H2), dopamine, acetylcholine, and opiates. Antiemetics act by blocking the receptors for these substances, thereby inhibiting their stimulation of the CTZ. Several studies have been done to show the effectiveness of antiemetics in preventing and controlling treatment-related nausea and vomiting. With the advent of cisplatin, a chemotherapy drug producing severe nausea, a more aggressive approach to the study and use of antiemetics has emerged. Most drugs used to treat nausea and vomiting can be classified into the following groups: dopamine antagonists, serotonin antagonists, and other antagonists. Examples of dopamine antagonists include phenothiazines, substituted benzamides, and butyrophenones. Prochlorperazine is perhaps the most frequently used antiemetic, and with 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 chemotherapy drugs. It is a phenothiazine and can be given by mouth, IM, IV, and rectally. It is usually given in the 10-50 mg dose range (Pediatric dose: 6 mg every 4 to 6 hours). Higher doses of prochlorperazine are also used intravenously for high emetogenic potential chemotherapy drug treatments. The most common side effects of this drug are extrapyramidal reactions. and sedation. Other phenothiazines include chlorpromazine (also available IM, IV, PO, and rectally, 10-50 mg dose range (Pediatric dose: >12 years old - 10 mg every 6 to 8 hours; <12 years old - 5 mg every 6 to 8 hours) and thiethylperazine (given IM, IV, PO, and rectally, 5-10 mg dose range). The phenothiazines act on the true vomiting center. Metoclopramide, a substituted benzamide, is often used in chemotherapy regimens using cisplatin. It is an effective antiemetic but has a relatively short half-life, requiring frequent administrations. It acts on the CTZ periphery and can be administered PO and IV in normal dose ranges of 1-2 mg/kg. It is associated with the side effects of dystonia and akathisia, especially in persons under the age of 30, often requiring concomitant diphenhydramine for prevention of dystonic reactions. Benztropine mesylate, as well as diphenhydramine, can be used for treatment of dystonic reactions.[1] A third dopamine antagonist used less frequently than prochlorperazine and metoclopramide is droperidol. This drug is similar in chemical structure to the phenothiazines. It is in a class of drugs classified as butyrophenones and is administered IM or IV in the 1-2.5 mg dose range and can produce tachycardia or orthostatic hypotension. Haloperidol, another butyrophenone, is administered IM, IV, or PO in the dose range of 1-4 mg and can have the same primary side effects as droperidol. The site of action for the butyrophenones is also on the CTZ. A serotonin antagonist, ondansetron, was approved by the FDA in 1991 for use as an antiemetic. Several studies have demonstrated its enhanced efficacy and low toxicity compared to other agents used in the management of nausea and vomiting induced by chemotherapy.[2-5] Ondansetron (0.15 mg/kg IV) is given 15 minutes prior to chemotherapy; the same dose is repeated at 4 hours and 8 hours. Combination with dexamethasone has shown increased efficacy.[6,7] Other dosing schedules, such as l. arge single doses (32 mg) 1/2 hour prior to chemotherapy or as a continuous infusion (1 mg/hr for 24 hours) or oral administration, have been used.[7-11] Side effects include headache, constipation, fatigue, dry mouth, diarrhea, and transient asymptomatic elevations in liver function tests, i.e. alanine transaminase/aspartate transaminase. The frequency of extrapyramidal side effects and sedation appears to be less with serotonin antagonists than with other classes of antiemetics, however, the drug is expensive. Other serotonin antagonists are also under evaluation.[12-14] Several other antagonists are also commonly used in the prevention and treatment of nausea and vomiting. These include steroids (dexamethasone, methylprednisolone), benzodiazepines (lorazepam, diazepam), and the cannabinoids (dronabinol, nabilone). Steroids can treat nausea and vomiting as single agents, but are more often used in antiemetic drug combinations.[15] Their mechanism of action related to emesis is not fully understood, but they may affect prostaglandin activity in the brain.[16] Dexamethasone is often the treatment of choice in treating nausea and vomiting in a person receiving radiation to the brain, as it also reduces brain edema. It is administered PO, IM, or IV in the dose range of 8-40 mg (Pediatric dose: 0.25-0.5 mg/kg). For chemotherapy-related nausea and vomiting, it is often given intravenously before and after the chemotherapy is given, then orally for delayed nausea and vomiting. Long-term administration of dexamethasone can produce several side effects, including muscle weakness (especially in the thighs and upper arms), lethargy, weight gain, GI irritation, and mood changes. If given intravenously, dexamethasone should be given slowly since rapid infusion can cause acute transient rectal pain.[17] Benzodiazepines, such as lorazepam, are becoming more popular in the prevention and treatment of treatment-related nausea and vomiting, especially with severe emet. ogenic chemotherapy given to children.[18] These drugs act on the higher CNS structures, the brainstem, and spinal cord, and essentially produce both a sedative and amnesic effect. Lorazepam can be administered PO, IM, IV, and also sublingually. Dose range is 0.5-3 mg in adults and 0.03-0.05 mg/kg in children. Cannabinoids, the last category of non-dopamine antagonists, also target the higher CNS structures to prevent nausea and vomiting. Synthetic drugs similar to [7mmarijuana[m include dronabinol and nabilone. Because of cultural, societal, and financial constraints, these drugs are often not the first selected agents for antiemetics but may be best accepted and most useful in young adults. These drugs are administered orally and may produce a euphoria or "high," drowsiness, or hypotension. In one double-blind randomized study of patients receiving cisplatin, adrenocorticotropic hormone (ACTH) was superior to placebo when given in combination with metoclopramide and dexamethasone. A dose of 1 mg ACTH decreased the incidence and severity of delayed emesis for the 24-72 hours after therapy.[19] Wickham, Krasnow and Sagar have published comprehensive overviews of antiemetic drugs, their actions, doses, and possible side effects.[17,20-22] Gralla et al. [23] have outlined methodology for use in designing antiemetic trials. Besides single antiemetic agents, combination antiemetic regimens are also used and 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 drug regimens combine a dopamine antagonist with those having no dopamine-blocking effect. An example of a combination drug regimen is the in-patient administration of metoclopramide, dexamethasone, and lorazepam for a cisplatin-containing drug regimen in the following doses and schedule: metoclopramide 2 mg/kg IV before chemotherapy --