Opioids Inducing Nausea And Emesis

The main physiological consequence of nausea and emesis is the removal of toxins, which is an important protective reflex mechanism being induced during food intoxication. It however, is also seen after radiation or chemotherapy, after the administration of an opioid-based anesthetic regimen or during long-term therapy for alleviation of chronic pain. About 20% of all patients experience nausea and/or emesis after opioid anesthesia. The cause of such reaction is a stimulation of the chemoreceptor

Nausea Vomiting Receptors

Figure II-52. The dopaminergic rewarding system within the brain, where activation by addictive drugs results in a seeking behavior pattern either directly by reuptake inhibition (i.e. cocaine) or indirectly by disinhibition of the inhibitory GABAergic pathway (i.e. opioid). Mostly all abused drugs increase dopamine levels in the nucleus accumbens

Adenytyl cyclase, protein kinase A induction

Tolerance and dependence

Morphine 1


Figure 11-53. Biochemical changes induced during addiction and the development of tolerance, which is followed by withdrawal when an antagonist is administered or by lack in maintenance dosages trigger zone (CTZ), which lies in close vicinity to the emetic center, bordering the fourth cerebral ventricle, above the area postrema (Figure II-55). This area is richly supplied with dopaminergic, histaminergic, serotonergic (5-HT3), and cholinergic receptor sites, being the origin of metabolic or drug induced vomiting [113].

Chemoreceptors Nausea

Figure II-54. Schematic representation of an acute abstinence syndrome with an accompanying norepinephrine storm induced by a decline in sufficient opioid binding or by application of an antagonist in the addict. Note the close interaction with the (^-agonist, where clonidine exerts its mode of action by reducing withdrawal symptoms

Figure 11-55. The area postrema at the border of the fourth cerebral ventricle with its chemoreceptors, inducing opioid-related nausea and vomiting

Contrary to the other areas within the CNS, the CTZ is characterized by leaking capillaries (windowed capillaries), through which opioids as well as toxins can disseminate. Such anatomical difference indicates that this area does not contain the usual blood-brain barrier (BBB). Being located within the dorsal part of the activating reticular formation (ARS), all visual, cortical and limbic efferences, as well as efferences of nearby nuclei of the vasomotor center and the center for salivation and respiratory control are switched, resulting in a controlled succession during vomiting. Once the vomiting center is stimulated by any of the efferent stimuli, a coordinated sequence of events is commenced:

• Stop of rhythmical contractions of the stomach, followed by an accumulation of food in the abdomen, resulting in.

• Retroperistaltic action.

• Contraction of the cardia with increase of pressure in the stomach.

• Due to the coordinated contractions of diaphragm, intercostal muscles and the rectus abdominis muscle, food is being expelled forcefully via the opened orifice of the stomach, the dilated esophagus and the opened glottis.

Because the CTZ shows a dense accumulation of serotonin receptors, the serotonin-antagonist ondansetron (Zofran®) is able to induce an antiemetic effect [114, 115]. Other agents, which are given for reversal of emesis, are metoclopramide, and/or the neuroleptic agents haloperidol, triflupromazine, or alizapride-HCl, all of which interact through direct binding with the dopaminergic D2-receptor. Another antiemetic is diphenhydramine, which exerts its action via binding at the cholinergic and histaminergic receptors (Figure II-56).

Antiemetic Action Haloperidol
Figure 11-56. Site of antiemetic action of different ligands, all of which are involved in a reduction of post-operative nausea and vomiting (PONV)

Postoperative nausea and emesis (PONV), however, still present a problem specifically related to anesthesia. In a large survey with over 2000 patients and using multivariance analysis, the following main risk factors for PONV were identified:

• History of PONV/motion sickness

• Nonsmoking status

• Long duration of anesthesia

Each 30min increase in duration increases PONV risk by 60%, and a baseline risk of 10% is increased to 16% after 30min [116]. The type of operation, the addition of nitrous oxide (N2O), high age and/or the addition of an opioid to the anesthetic regimen, in comparison to the above risk factors, had a lesser impact on the incidence on PONV [117, 118].

Commonly the key strategic antiemetic agents for reducing patients PONV are as follows (Figure II-56):

1. Serotonin (5-HT3)-Receptor Antagonist

The 5-HT3-receptor antagonists are used for both the prevention and treatment of PONV and have a low side-effect profile. They are given toward the end of surgery for greatest efficacy, and are more effective in preventing vomiting than in preventing nausea. Dolasetron, granisetron, and ondansetron all have favorable side-effect profiles. No evidence has revealed differences in efficacy and safety among the 5-HT3-receptor antagonists used for the prophylaxis of PONV. A recent study demonstrated the equivalent efficacy and safety of granisetron and ondansetron when these agents were used in combination antiemetic therapy. In this study, low-dose granisetron (0.1 mg) plus dexamethasone 8 mg was found to be not inferior to ondansetron 4 mg plus dexamethasone 8 mg in patients undergoing abdominal hysterectomy with general anesthesia. The combinations prevented vomiting in 94% and 97% of patients, respectively, in the first 2 h after tracheal extubation, and in 83% and 87% of patients, respectively, in the 24 h after extubation.

2. Dexamethasone

Dexamethasone has been found to be effective for the management of PONV and their proposed mechanism of action is that of membrane stabilization and inhibition of inflammation. Use of this agent is controversial because of its alleged association with delayed wound healing. It has a slow onset but a prolonged duration of action, and therefore it is advised that dexamethasone be administered upon induction of anesthesia. The most commonly used dose for adults is 8-10 mg i.v. Smaller doses of 2.5-5 mg have also been used and found to be as effective. Based on a quantitative, systematic review of the data, no adverse side effects, especially delayed wound healing, have been noted following a single antiemetic dose of dexamethasone [119].

3. Droperidol

The neuroleptic drug droperidol, a butyrephenone derivative, is widely used for PONV prophylaxis and is comparable with ondansetron as a prophylactic antiemetic. Similar to haloperidol it acts as a dopamine antgonist at the CTZ and the area postrema. For greatest efficacy, droperidol is administered at the end of surgery or concomitantly with morphine via patient-controlled analgesia systems. The use of low doses (0.625-1.25 mg) of droperidol has not been associated with the typical side effects of higher doses of this drug (hypotension, extrapyramidal symptoms, sedation, akathisia, dysphoria). In 2001, the Food and Drug Administration began requiring that droperidol labeling include a "black box" warning stating that the drug may cause death or life-threatening events resulting from QTc prolongation and the possibility of life-threatening torsades de pointes. The labeling requirement was based on 10 reported cases associated with droperidol use (at doses of 1.25 mg) during its approximately 30 years on the market [120]. However, no case reports in peer-reviewed journals have linked droperidol with QTc prolongation, cardiac arrhythmias, or death at the doses used for the management of PONV. Also, in a randomized, doubleblind, placebo controlled trial, droperidol was not associated with a significant increase in the QTc interval in comparison with saline solution [121]. In another recent study, droperidol did not increase the QTc interval any more than did ondansetron [122].

4. Other Antiemetics

Transdermal scopolamine (Transderm Scop® 1.5 mg), an antimuscarinic ganet, works by blocking the cholinergic receptor. It has an antiemetic effect when applied the evening before surgery or 4 h before the end of anesthesia preventing the patient from post-discharge nausea, vomiting and retching.

The phenothiazines, promethazine, and prochlorperazine act both as D2- and the H1-receptor antagonist. They also inhibit histamine receptors and possibly cholinergic receptors in the gut. Both have been shown to be effective antiemetics when administered intravenously at the end of surgery. All three drugs may cause sedation, dry mouth, and dizziness.

Metoclopramide is benzamide that blocks D2-receptors both centrally and peripherally in the gastrointestinal tract increasing gastric emptying.

The antihistamines, especially diphenhydramine act on both the CTZ and the vestibular pathways of the inner ear. At higher doses however, they can prolong general anesthesia and recovery times.

Consensus guidelines agree that patients at high or moderate risk for PONV are most likely to benefit from prophylaxis. Patients at low risk for PONV are usually not candidates for prophylaxis unless their condition may be compromised by the medical sequelae or vomiting. Those at moderate risk for PONV should receive antiemetic monotherapy or combination therapy. Those at high risk should receive combination therapy with two or three antiemetics from different classes. Drugs with different mechanisms of action can be combined for optimal efficacy. For example, the 5-HT3-receptor antagonists (more effective against vomiting) can be combined with droperidol (more effective against nausea).

5. Multimodal Approach

A multimodal approach that incorporates both baseline risk reduction and antiemetic therapy should be adopted for PONV prophylaxis. A recent prospective, double blind, randomized, controlled trial compared three strategies for the prevention of PONV in patients undergoing laparoscopic cholecystectomy: (1) a multimodal approach using ondansetron, droperidol, and total intravenous anesthesia (TIVA) with propofol; (2) a combination of ondansetron and droperidol, with isoflurane and nitrous oxide-based anesthesia; and (3) TIVA with propofol alone. The complete response rate was higher in the multimodal group (90%) than in the combination group (63%) or TIVA-only group (66%), as was the degree of patient satisfaction.

6. Rescue medication in PONV

Nausea and vomiting may persist in some patients after they leave the postanes-thesia care unit (PACU). After medication and mechanical causes of PONV have been excluded, rescue therapy with antiemetics can be initiated. For patients who received no prophylaxis, low-dose therapy with 5-HT3-receptor antagonists may be initiated. Consensus guidelines also recommend low-dose therapy with a 5-HT3-receptor antagonist for patients in whom dexamethasone prophylaxis has failed. For patients in whom initial 5-HT3-receptor antagonist prophylaxis has failed, a 5-HT3-receptor antagonist rescue therapy should not be given within the first 6 h after surgery. Similarly, patients in whom prophylactic combination therapy with a 5-HT3-receptor antagonist plus dexamethasone has failed should be treated with an antiemetic from a different class. As a general guideline, patients who experience PONV within 6 h after surgery should be treated with an antiemetic other than the one used for prophylaxis. For the treatment of patients who experience PONV > 6h after surgery, drugs from the prophylactic antiemetic regimen may be repeated, except for dexamethasone and transdermal scopolamine, which have a longer duration of action. Also, propofol may be used in small doses (20 mg as needed) for the treatment of PONV in a supervised environment. The preliminary results of a recent analysis support the recommendation that a rescue antiemetic should be from a class other than that of the original antiemetic agent [123]. This analysis of a previous trial reported that in patients who failed prophylaxis with ondansetron or droperidol, promethazine was significantly more effective in controlling PONV than the original agent. Dimenhydrinate was also more effective than droperidol in patients who failed prophylaxis with droperidol. In summary, the first step in the management of PONV is to identify surgical patients at high or moderate risk for PONV, then reduce baseline risk factors in these patients. Combination antiemetic therapy is recommended for patients at high risk for PONV for patients at moderate risk, monotherapy or combination therapy may be considered. A multi modal approach for the prevention of PONV including the use of antimetics with different mode of action, hydration and TIVA with propofol has been shown to be most effective. Patients who have not received prophylaxis and experience PONV can be treated with a low dose of a

5-HT3-receptor antagonist. In patients who fail prophylaxis treatment with an antiemetic, another agent than the one used for prophylaxis is recommended.

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