Few randomized control studies have compared specific medications for specific causes of nausea. In particular, little attention has been paid to potential toxicities of specific agents. However, as discussed above, research has progressed in understanding the relationship between receptors and nausea (summarized in Fig. 5.1).
Figure 5.1. A final pathway for nausea.
Based on in vitro receptor binding, Peroutka and Snyder developed the following table (Table 5.1): (Lower numbers indicate tighter binding and therefore greater blockade of the receptor. Example: Scopolamine is strongly anticholinergic, as it has a very low number, 0.8 for the cholinergic receptor.) Potency: K1 (nanomolar).
|Table 5.1. Receptor Binding of Common Antiemetics|
|Drug Group||Dopamine 2||Musc. Cholinergic||H1 Histamine|
|Scopolamine||greater than 10,000||.08||greater than 10,000|
|Metoclopramide||270||greater than 10,000||1,100|
|Haloperidol||4.2||greater than 10,000||1,600|
|Source: Adapted from Peroutka and Snyder.12|
As is readily seen, scopolamine is a pure anticholinergic agent. It can be useful in treating motion-related nausea and when sedation or other anticholinergic effects are desired, such as decreasing gut secretions and alleviating cramping due to bowel obstruction. Marketed for motion sickness, scopolamine is available as a patch. It can be given SC. Effects last approximately six hours.
Promethazine has strong anticholinergic and antihistaminic effects. Its weak binding of dopamine receptors suggests it would be a poor choice as an antiemetic for opioid-related nausea. Despite this, it is commonly used for opioid-related nausea (perhaps based on misguided extrapolations from its use in combination with meperidine and chlorpromazine as a pediatric sedative in emergency rooms).13 Therefore, promethazine is not recommended for pure opioid-related nausea. It is available in oral, IM, IV, and rectal suppository forms. Promethazine may be a drug of choice when a drug, especially a suppository, is needed for motion-related nausea and when other anticholinergic and antihistaminic effects are desired, as in viral gastroenteritis.
Prochlorperazine has strong dopamine and histamine receptor binding, with weak cholinergic receptor binding. It is mildly sedating. It is available in oral (tab, liquid), IV, IM, and suppository forms. Prochlorperazine can be considered a good choice when a suppository is needed for opioid-related vomiting and anticholinergic effects are to be avoided.
One of the few randomized controlled studies done for nonchemotherapy-related nausea compared promethazine to prochlorperazine for the treatment of "nonspecific" nausea and vomiting in 84 patients in an emergency room. Although the precise causes of such nausea were not given in the study, presumably the majority were self-limited inflammatory states such as viral gastroenteritis. The study found that prochlorperazine was superior to promethazine in a number of regards:
These results are striking in that they are contrary to what we might expect based on receptor binding. It is not clear why prochlorperazine, which is principally an antidopaminergic agent, would be superior to anticholinergic, antihistaminic promethazine, because a pharmacologic basis for the efficacy of dopamine blockade in inflammatory forms of nausea has not been described. This highlights the need for clinical studies in this area.
Like haloperidol, chlorpromazine is most commonly used as an antipsychotic agent. From Table 5.1 it can be seen that this agent has a strong affinity for all three receptors. It is therefore useful in opioid-related nausea as well as in other forms when anticholinergic and antihistaminic effects are desired. However, it should be avoided if sedation is undesirable. It can be given PO, IM, or rectally but should not be given SC. Chlorpromazine also blocks alpha receptors and therefore can cause or exacerbate postural hypotension. Chlorpromazine can, in addition, lower the seizure threshold and thus should be used with caution, if at all, in patients prone to seizures.
Metoclopramide has relatively weak binding across the board. Binding is strongest at dopamine receptors, and (not shown here) in high doses it can be effective in blocking 5HT3 serotonin receptors. As discussed above, metoclopramide is useful when an upper GI track prokinetic agent is desired, especially in the presence of opioids. It can be given PO, IV, or via SC infusion.15
Haloperidol has the strongest dopamine receptor binding, with little anticholinergic or antihistaminic effects. It is therefore ideal for opioid-related nausea. It is also useful in the treatment of delirium, dementia, and psychosis when sedation is undesirable. Haloperidol (as with other antidopaminergic agents) is contraindicated in Parkinson's disease. Haloperidol strongly blocks D2 receptors and has minimal anticholinergic and antihistaminic effects. It is minimally sedating. It can be given PO (tablet or liquid), IM, or by slow SC infusion. Unfortunately, no rectal form is available. Because haloperidol is marketed as an antipsychotic, most physicians are not familiar with the use of haloperidol for nausea despite wide experience in the hospice community with this selective agent.
Chemotherapy with certain agents can cause intense nausea largely mediated through 5HT3 serotonin receptors, found both in the gut and in the CTZ. These drugs are very expensive and should not be used routinely except for the treatment of chemotherapy-related nausea and in certain special circumstances. This class of drugs may be useful for nausea related to bowel obstruction and may have broader use for inflammatory states involving the bowel, as suggested by data that support their use in radiation enteritis. They have also been found to be helpful in postoperative nausea.16 They may also be used in CTZ-related nausea when antidopaminergic drugs are strongly contraindicated, as in Parkinson's disease.
Cyclizine and other antihistamines such as meclizine and diphenhydramine are useful in the treatment of motion sickness. Steroids may be considered for nausea related to chemotherapy and radiation therapy.17 Steroids also actively stimulate the appetite, may be mildly euphoric, and can be helpful in certain pain syndromes. They are helpful, therefore, in a variety of cancer-related conditions but can have serious side effects, especially with prolonged use. The antidepressant mirtazapine may be helpful in treating nausea associated with chemotherapy when 5HT3 receptors are being stimulated. It has some blocking activity at such receptors and may also act as an anxiolytic through blockade of 5HT2 receptors.18 Dronabinol and other marijuana related compounds have shown significant efficacy in chemotherapy-related nausea and can increase appetite.19 Psychological effects associated with this class of drugs may be viewed as beneficial or deleterious (Table 5.2).19
|Table 5.2. Summary table Relating Type of Nausea, Receptor, Drug Class, and Example of Drug of Choice.20*|
|Type of Nausea||Receptors Causing Nausea||Drug Class Useful||Examples of DOC|
|Vestibular||Cholinergic, histaminic||Anticholinergic, antihistaminic||Scopolamine patch, promethazine|
|Obstruction of bowel caused by constipation||Cholinergic, histaminic, ? 5HT3||Stimulate myenteric plexus||Senna products|
|DysMotility of upper gut||Cholinergic, histaminic, ? 5HT3||Prokinetics stimulate 5HT4 receptors||Metoclopramide|
|Infection, Inflammation||Cholinergic, histaminic, ? 5HT3||Anticholinergic, antihistaminic||Promethazine, prochlorperazine|
|Toxins stimulating the CTZ in the brain such as opioids||Dopamine 2, 5HT3||Antidopaminergic, 5HT3 antagonist||Prochlorperazine, haloperidol, ondansetron|
|The Fast Fact concept was developed by Dr. Eric Warm. His idea was to distribute brief one- to two-page summaries of important issues in palliative care to physicians-in-training. Under Dr. David Weissman's guidance, more than 60 Fast Facts have been written and are available at: http://www.eperc.mcw.edu.|
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Palliative Care Perspectives
James L. Hallenbeck, M.D.
Copyright © 2003 by Oxford University Press, Inc.
The online version of this book is used with permission of the publisher and author on web sites affiliated with the Inter-Institutional Collaborating Network on End-of-life Care (IICN), sponsored by Growth House, Inc.