12.5–25 mg IM
2.5–5 mg IMc; 1 mg IVc
IM, intramuscular; IV, intravenous; PO, oral.
Histamine antagonists
Histamine antagonists, or antihistamines, competitively inhibit the effects of histamine at the H1 receptors. Antihistamine agents can be classified chemically as ethylenediamines, ethanolamine, alkylamines, phenothiazines or piperazine derivatives. Antihistamines can be clinically divided into first and second generations, with sedation being prominent in first-generation medications due to the central anticholinergic effects. For the same reason, these agents typically have antiemetic and antimotion sickness properties. Meclizine and dimenhydrinate are commonly used for motion sickness. Diphenhydramine, cyclizine and promethazine have also been used to treat the symptoms of nausea and vomiting due to motion sickness. Hydroxyzine also has antiemetic properties[3–9]. Based on the antiemetic activity of the antihistamines and the evidence that motion sickness is a strong predictor of PONV, many of the histamine antagonists have been used and/or evaluated for management of PONV[1,10]. Second-generation antihistamines have not been found to have significant antiemetic properties[3].
Dimenhydrinate
Dimenhydrinate is an ethanolamine derivative and contains a diphenhydramine moiety, which is likely the source of its antiemetic effects. The drug is typically prescribed to treat motion sickness and its related nausea, vomiting and dizziness. The exact mechanism is unknown although the action is presumed to inhibit vestibular stimulation. The drug also inhibits the acetylcholine receptor. Dimenhydrinate is available as a tablet (50 mg) and a solution (12.5 mg/5 mL) as over-the-counter formulations[4]. Dimenhydrinate injectable 50 mg/mL is also available and used for many of the same symptoms and can be given by the intravenous (IV; diluted over a period of 2 min) or intramuscular (IM) route[4]. Small amounts of the drug are excreted in breast milk so nursing mothers should use appropriate caution[2,4,11].
The most frequent adverse reaction to dimenhydrinate is drowsiness. Symptoms of dizziness, dry mouth, nose and throat, blurred vision, difficult or painful urination, headache, anorexia, nervousness, restlessness or insomnia (particularly in pediatric patients), skin rash, thickening of bronchial secretions, tachycardia, epigastric distress, lassitude, excitation and nausea have been reported. This drug may be potentially inappropriate for use in geriatric patients. Common off-label uses of dimenhydrinate include treatment of Meniere’s disease and nausea/vomiting related to pregnancy or anesthesia[2,4,11].
An inpatient, placebo-controlled study of females undergoing laparoscopic cholecystectomy, thyroid resection or knee arthroscopy found that 62 mg of dimenhydrinate IV given at induction with three additional doses over 48 h effectively decreased the incidence of PONV (38.8% versus 15.1%) and was associated with little to no significant side effects. Severe PONV was also reduced from 39.4% to 14.9%[12].
Prophylactic administration of dimenhydrinate 50 mg IV was found to be as effective as ondansetron 4 mg for prevention of PONV in patients undergoing elective laparoscopic cholecystectomy. The need for rescue antiemetics was 34% in the ondansetron group and 29% in the dimenhydrinate group[13].
Conversely, another study comparing dimenhydrinate 0.3 mg/kg and metoclopramide 0.3 mg/kg found both agents were ineffective for PONV prevention when given alone. However, the combination of both medications reduced the incidence of PONV compared with placebo[14].
Dimenhydrinate and promethazine were evaluated in patients initially receiving either prophylactic administration of droperidol 0.625 mg to 1.25 mg or ondansetron 4 mg. In patients who failed prophylaxis, rescue with dimenhydrinate 25–50 mg or promethazine 6.25–25 mg was more effective than a repeat (rescue) dose of the original prophylactic drug (droperidol or ondansetron)[15].
A meta-analysis of 18 trials including over 3,000 patients showed dimenhydrinate to be effective as a prophylactic antiemetic for patients at moderate-to-high risk for PONV with side effects similar to the placebo group. More research is needed to determine the most appropriate dose, timing and frequency for dimenhydrinate in the management of PONV[16]. The Society for Ambulatory Anesthesia guidelines for PONV concluded that dimenhydrinate, in placebo-controlled trials, has similar efficacy to the 5-HT3 receptor antagonists, dexamethasone and droperidol[10].
Diphenhydramine
Diphenhydramine is a first-generation antihistamine and an ethanolamine derivative that acts at the H1 receptors at the nucleus tractus solitarius and acetylcholine receptors in the vestibular apparatus. The antiemetic properties are thought to be a result of suppression of motion-enhanced vestibular neuronal firing, leading to its effectiveness in treating vertigo, motion sickness and PONV in high-risk patients, such as those having middle ear surgery or those with a history of motion sickness. Like other H1 receptor antagonists, diphenhydramine can also be used to manage a multitude of other symptoms (urticaria, rhinitis, conjunctivitis, vertigo, insomnia or dyskinesia), that can be associated with other disease processes[3,5].
A study of 200 women who had total abdominal hysterectomies and utilized morphine patient-controlled analgesia regimens found that metoclopramide and diphenhydramine used in combination provided significantly better prevention of nausea and vomiting in the postoperative phase than either drug alone when added to patient-controlled morphine analgesia[17]. For every mg of morphine, metoclopramide 0.5 mg or diphenhydramine 0.6 mg or the combination of both were used.
Meclizine
Meclizine is a piperazine derivative antihistamine commonly used for prevention of motion sickness by depressing the labyrinth excitability and conduction in vestibular-cerebellar pathways. The antiemetic action is a result of the anticholinergic and central nervous system (CNS) depressant effects. The onset of action is 1 h with a duration of 24 h. Meclizine should be used with caution in patients with asthma, glaucoma (narrow angle), prostatic hyperplasia and pyloric/duodenal obstruction. Meclizine and dimenhydrinate are considered to have equal efficacy for motion sickness, although meclizine has less associated drowsiness and a longer duration of action[18]. Additionally, caution should be used in elderly patients. Meclizine is available in oral dosage form of 25 and 50 mg[6,10,11].
Few studies exist for use of meclizine as a single agent for treatment of PONV. However, a placebo-controlled study of 77 patients at high risk for PONV (four out of five major risk factors: general anesthesia, female, nonsmoker, motion sickness history and PONV history) showed that, when combined with ondansetron at surgical closure, preoperatively administered meclizine 50 mg effectively reduced PONV, as well as postdischarge nausea and vomiting, more than ondansetron alone[19].
Hydroxyzine
Hydroxyzine is piperazine derivative antihistamine. Hydroxyzine has antihistamine, analgesic, bronchodilation and antiemetic properties[1]. The drug competes with the histamine H1 receptor site on effector cells in the gastrointestinal tract, blood vessels and respiratory tract. The antiemetic dose is 25–100 mg intramuscularly. The drug is a vesicant and IV administration is contraindicated, which limits some of its usefulness in the postoperative phase where IV administration is the preferred route. Hydroxyzine should be used with caution in the presence of glaucoma (narrow angle), prostatic hyperplasia/urinary stricture and respiratory disease. CNS depression can be a significant side effect. Therefore, care should be used in the elderly. Hydroxyzine may enhance the analgesic effects of opioids[1,7]. Limited studies on hydroxyzine’s effectiveness for prevention of PONV exist. However, a study evaluated 150 patients who received droperidol 2.5 mg IM or hydroxyzine 100 mg IM at induction of anesthesia, and the hydroxyzine group were found to have less PONV than patients receiving droperidol 2.5 mg[20].
Cyclizine
Cyclizine is a piperazine derivative and a first-generation histamine antagonist, which is not available in the USA. Although the exact mechanism is unknown, it likely has a direct central effect on the labyrinthine apparatus and the chemoreceptor trigger zone (CTZ). Cyclizine is most commonly used for prophylaxis and treatment of nausea, vomiting and vertigo associated with motion sickness. Due to the anticholinergic effect, elderly patients should receive the lowest effective dose. Excess sedation is the most frequent side effect of this drug[1,8].
In a study in adults, cyclizine 50 mg was shown to have a similar efficacy to ondansetron 4 mg[21]. A trend was seen with the patients who received the cyclizine of having a longer mean time to eye opening, but it did not influence discharge times. However, in children, ondansetron 0.1 mg/kg significantly reduced vomiting events compared to cyclizine 20 mg[22]. Interestingly, in a Cochrane review of 737 studies, cyclizine was listed as one of the eight antiemetics that reliably prevented PONV[23].
Dopamine antagonists
Phenothiazines are used for the prevention and treatment of nausea and vomiting caused by various etiologies including PONV. Phenothiazine antiemetics act primarily via central dopamine (D2) receptor blockade[1]. However, for nausea and vomiting in pregnancy, these drugs are either contraindicated or have not been proven safe and should only be used if the potential benefit justifies the risks to the fetus. Phenothiazines have numerous side effects; the very young and the very old appear to be most sensitive to those side effects[24]. Common phenothiazines used for PONV include prochlorperazine and promethazine. Phenothiazines are available as oral, parenteral and rectal formulations. These drugs may cause extrapyramidal symptoms such as dystonia, tardive dyskinesia and akathisia[1,2,9,24–26].
Promethazine
Promethazine is a histamine antagonist and a phenothiazine derivative with significant antidopaminergic and anticholinergic activity. The antimotion sickness action may be due to the central anticholinergic effect on the vestibular apparatus, the integrative vomiting center and the medullary CTZ. Promethazine is more effective for motion sickness than the other phenothiazines[1,9], The onset of action is 3–5 min for IV administration and 20 min when given IM. Duration of action is 4–6 h but effects of the drug may last as long as 12 h[1,9,27].
Promethazine is available as an oral solution and tablets. Suppositories of various dosage strengths are also marketed. Injectable promethazine in 25 mg/mL (IV or IM) and 50 mg/mL (IM only) are the parenteral dosage forms. Because promethazine is a vesicant, deep IM injection is the preferred route of administration since severe tissue injury can occur following IV administration. The concern is an inadvertent intra-arterial needle placement or perivascular extravasation that may result in an ischemic injury. If the IV route must be used, the package insert calls for several safety strategies (Table 7.2). The US Food and Drug Administration (FDA) also issued a boxed warning against the use of promethazine in children <2 years of age due to postmarketing cases of sedation and respiratory depression. For the same reason, the FDA also recommends using caution when administering the drug to all pediatric patients. Similarly, the elderly can be particularly susceptible to these sedating effects. Due to the anticholinergic effects, extrapyramidal symptoms and neuroleptic malignant syndrome may occur. The medication should be avoided or used with caution in the presence of narrow angle glaucoma, Parkinson’s disease, Myasthenia gravis, patients with seizures, respiratory and cardiovascular disease[1,3,9,24,27]. The adult antiemetic dose is 12.5–25 mg every 4–6 h, regardless of the route of administration. However, newer studies indicate a lower dose of 6.25 mg for PONV is effective and may cause less sedation compared to higher doses[9,27,28].
• Deep IM injection is the preferred way to administer promethazine hydrochloride injection, USP products |
• Intra-arterial and subcutaneous administration of promethazine are contraindicated |
• The 50 mg/mL promethazine hydrochloride injection, USP product is for deep IM injection only |
• The 25 mg/mL promethazine hydrochloride injection, USP product may be administered by deep IM injection or IV injection |
• If IV administration of promethazine is required, the maximum recommended concentration is 25 mg per mL and the maximum recommended rate of administration is 25 mg per min through the tubing of an IV infusion set known to be functioning properly |
• Be alert for signs and symptoms of potential tissue injury including burning or pain at the site of injection, phlebitis, swelling and blistering |
• Injections should be stopped immediately if a patient complains of pain during injection |
• Inform patients that side effects may occur immediately while receiving the injection or may develop hours to days after an injection |
IM, intramuscular; IV, intravenous.
In a double-blind randomized placebo-controlled study of adult patients undergoing middle ear surgery, promethazine (12.5 mg) combined with ondansetron (2 mg) significantly reduced the incidence and severity of nausea, vomiting and PONV during the first 24 h postoperatively when compared to placebo or monotherapy[30].
A retrospective database analysis of patients undergoing general anesthesia who received ondansetron 4 mg prophylactically showed that doses of 6.25 mg, 12.5 mg and 25 mg all had similar efficacy and were all more effective for PONV rescue than a second dose of ondansetron. The 6.25 mg promethazine dose was as effective as the 12.5 and 25 mg doses[28].
Perphenazine
Perphenazine is a phenothiazine with a mechanism of action that includes blockade of postsynaptic mesolimbic dopaminergic receptors in the brain, blockade of alpha-adrenergic effect and depression of the release of hypothalamic and hypophyseal hormones. The drug is used for psychotic disorders and severe nausea and vomiting in adults. The drug is available as oral tablets[26]. Dosing for severe nausea and vomiting is 8–16 mg daily in divided doses; however, doses as high as 24 mg (maximum) have been used. Caution should be used in the geriatric population since the FDA has placed a boxed warning of increased mortality in elderly patients with dementia-related psychosis with the use of perphenazine[24,26].
A quantitative systematic review included 11 randomized controlled trials with 2,081 participants, receiving prophylactic perphenazine or another drug or placebo. Perphenazine doses were 2.5 mg and 5 mg or a weight-based calculation of 0.11 mg/kg. The children’s dose was weight adjusted at 0.07 mg/kg. The doses were given orally, IM or IV (injectable form no longer available in USA). The authors concluded that perphenazine was well tolerated and is an effective medication for PONV prevention. The conclusion stated that further data are needed to determine the most appropriate dose, timing and route; however, the authors suggested 5 mg as the most efficacious dose[31].