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Anesthesia Alert
A Review of New Antiemetic Agents
Tricia Meyer
Publish Date: July 13, 2008   |  Tags:   Anesthesia

So long as post-operative nausea and vomiting (PONV) continues to have negative clinical and economic consequences, you can expect that pharmaceutical companies and researchers will continue to develop new agents, therapeutic options and antiemetic regimens. Here's a quick review of what's available to help anesthesia providers tailor antiemetic regimens for every patient.

  • Aloxi. In early March, the FDA approved palonosetron (Aloxi), a 5-HT3 receptor antagonist for prevention of nausea for up to 24 hours following surgery at a 0.075mg dose. Some studies have looked at a longer duration of action. More research will be needed to address palonosetron's antiemetic duration for greater than 24 hours. It has a significantly longer plasma half-life than the other antiemetics in this class, although it's unclear how this will affect clinical outcomes. Like other 5-HT3 receptor antagonists, its most common adverse reactions (incidence >2%) are headache, constipation, bradycardia and QT prolongation. Aloxi, available in the U.S. since 2003, is the first and only 5-HT3 receptor antagonist approved by the FDA for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, and for the prevention of acute nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy.
  • Inapsine. For many years, droperidol (Inapsine) was the foundation for any strategy or protocol used against PONV. It was inexpensive and very effective in small doses. But many physicians stopped using droperidol because of the 2001 "black box" warning issued by the FDA related to potentially fatal heart arrhythmias in patients treated with this drug. But several publications have indicated this warning was unwarranted. While droperidol use is not specifically prohibited, it has gone from a low-cost, first-line treatment that was considered a highly effective antiemetic option to a high-cost (when monitoring is used), second- or third-line treatment of questionable safety.
  • Haldol. Haloperidol (Haldol) is used in the treatment of schizophrenia and, more acutely, in the treatment of acute psychotic states and delirium. The recommended dose for haloperidol in the PONV Consensus Guidelines published in the December issue of Anesthesia & Analgesia is 0.5 to 2mg IM/IV, which is a much smaller dose than for the approved indication of schizophrenia or agitation. It is also important to note that injectable haloperidol comes in two different salts, decanoate and lactate. Haloperidol decanoate should not be administered via IV, and in IM form it has a markedly extended duration of effect. The long-acting decanoate is used when patients require prolonged antipsychotic therapy. European studies found that haloperidol is just as effective as droperidol at preventing opioid-related nausea without causing drowsiness, even though the package insert carries information about the potential risks for prolongation of the heart-rate corrected QT (QTc) interval.
  • Emend. Aprepitant (Emend), a neurokinin-1 (NK-1) receptor antagonist, is FDA-approved as an oral agent in a 40mg dose (the injectable form only has FDA approval for chemotherapy-induced nausea and vomiting). Studies show that a prophylactic dose of aprepitant is as effective in preventing PONV as ondansetron (Zofran) in the initial 24 hours post-op, but more effective than ondansetron at preventing vomiting in the 24 to 48 hour post-surgical period.

Aprepitant has very few adverse effects, but it can interfere with oral contraceptives. Instruct patients taking such contraceptives to use another form of contraception for a month after taking aprepitant because the co-administration could disrupt the efficacy of hormonal contraceptives. It's difficult to determine the degree of this interaction because this problem is associated with the higher doses given for chemotherapy-induced nausea and vomiting, not the much smaller doses used to prevent PONV. However, the warning in the package insert is given for both the CINV and PONV doses and it is best to inform the patients of the need for alternate forms of birth control prior to administration.

  • Opioid antagonists. The opioid antagonists naloxone and nalmefene show some efficacy for managing PONV. Low doses of naloxone (0.25mcg/kg per hour) decrease the incidence of PONV, the need for rescue medications in adults and the opioid-related side effects in children, studies show. Nalmefene, also known as Revex, is used in the medical treatment of alcoholism because it's been found to reduce craving for some alcohol-dependent patients. It has similar effects for PONV management, as it reduced opioid-induced nausea and vomiting and the need for rescue medication in patients receiving patient-controlled analgesia.

Put together a winning combination
The true etiology of PONV remains a mystery. We're still unclear on exactly why some receptors stimulate nausea and vomiting and others do not. Prevention through combination therapy is showing greater efficacy in recent trials, as this lets us use multiple agents from different pharmacological classes to cover different receptor sites.

Studies conducted over the past five years make it clear that this is sound both in theory and in practice when treating patients at a moderate to high risk of PONV. Combination therapy may be particularly beneficial not only for the higher risk patients but also for cases where vomiting poses a particular medical risk. That may include patients undergoing procedures involving wired jaws or surgeries where we want to avoid intracranial pressure as much as possible.

The multimodal approach lets you combine the benefits of agents from different classes. For example, a combination of ondansetron and droperidol would give you the anti-vomiting properties of a 5-HT3 receptor antagonist with the anti-nausea properties of droperidol. This combination has been widely studied and the research shows that it is very effective.

But when planning a combination, bear in mind that that there is an increased potential for adverse effects when you use more drugs. Many of the older antiemetics, such as promethazine and antihistamine antiemetic drugs, could cause sedation, so combining these two could lead to a delay in discharge.

Dexamethasone is frequently given as combination therapy because it's so useful. Studies have shown similar efficacy in lower doses (4mg or 5mg) as it does for larger doses (8mg or 10mg) when used as an adjunct therapy, and at least one study noted it could also help to reduce the patient's pain, fatigue and time for coalescence.

But there are concerns about dexamethasone elevating blood glucose levels. Although many physicians may not be worried about using dexamethasone as a single agent and at a lower dose, there has been some conflicting data about this adverse effect, so further investigation is needed.

Plan for post-discharge illness
Post-discharge nausea and vomiting can occur after the patient leaves your facility. If you don't give these patients antiemetic prescriptions to take home for their PDNV, they may have difficulty managing their symptoms. We still need more research on PDNV risk factors and the optimal treatment for this problem. For now, consider using antiemetics with a longer duration of action, writing prescriptions for antiemetics when the patient is discharged and providing patient education for PDNV.

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