Abstract
The practice of anesthetic premedication embarked upon soon after ether and chloroform were introduced as general anesthetics in the middle of the 19thcentury. By applying opioids and anticholinergics before surgery, the surgical patients could achieve a less anxious state, and more importantly, they would acquire a smoother course during the tedious and dangerous induction stage. Premedication with opioids and anticholinergics was not a routine practice in the 20th century when intravenous anesthetics were primarily used as induction agents that significantly shorten the induction time. The current practice of anesthetic premedication has evolved into a generalized scheme that incorporates several aspects of patient care: decreasing preoperative anxiety, dampening intraoperative noxious stimulus and its associated neuroendocrinological changes, and minimizing postoperative adverse effects of anesthesia and surgery. Rational use of premedication in modern anesthesia practice should be justified by individual needs, the types of surgery, and the anesthetic agents and techniques used. In this article, we will provide our readers with updated information about premedication of surgical patients with a focus on the recent application of second generation serotonin type 3 antagonist, antidepressants, and anticonvulsants.
Keywords
anticonvuls; antsantidepressive agents; antiemetics; benzodiazepines; clonidine; dexmedetomidine; midazolam; neurokinin 1 receptor antagonists; premedication; serotonin 5-HT3 receptor antagonists;
1. Introduction
Modern anesthesia thrived in the middle of the 1840s when the Scottish obstetrician Simpson discovered the anesthetic qualities of chloroform and applied it to his patients during childbirth, and the American dentist Morton first publicly demonstrated diethyl ether as an inhaled anesthetic at the Ether Dome of Massachusetts General Hospital in Boston, USA. Compared with the halogenated inhalational anesthetics we use today, diethyl ether is notorious for its long duration of induction time. Patients often suffered a long period of involuntary movement, anxious feeling, and excessive salivation before they could finally be put to sleep. Such behaviors can be attributed mainly to the high blood solubility of diethyl ether. The partition coefficient of diethyl ether is 12, compared with that of 1.4, 0.65, and 0.45 of other ether derivatives of isoflurane, sevoflurane, and desflurane, respectively. Guedel's signs were used to describe the long induction time of ether anesthesia, which included four stages (analgesia stage, excitement stage, surgical anesthesia stage, and respiratory paralysis stage); Stage 3, i.e., surgical anesthesia can be divided into four planes, according to the patterns of muscle tone, breathing, and eye movement.1 The Guedel's signs are scarcely used today during induction with either an intravenous anesthetic or an inhalational anesthetic that has a lower blood solubility.
2. Past, present, and future of premedication
2.1. History of premedication
The concept of anesthetic premedication was initially developed to counteract the side effects of general anesthesia when ether and chloroform were widely used as inhalational anesthetics in the 1850s.2 Two physicians, Nussbaum in Germany and Bernard in France, in 1864 simultaneously found that subcutaneous morphine can relax patients and intensify chloroform anesthesia. At the same time, another French scientist Dastre found that atropine can decrease salivation and antagonize the effects of respiratory depression and vomiting associated with morphine. As a result, morphine and atropine became popular as anesthetic premedication in the late 19th century.3It was not until 1911 when Dudley Buxton published the first paper regarding the use of morphine, atropine, scopolamine, and other similar agents prior to inhalation anesthesia that anesthetic premedication became a debated issue and drew more attention of anesthesiologists.4
2.2. Current practice of premedication
The practice of anesthetic premedication in surgical patient is no longer a routine procedure today. There are several reasons to explain why we do not give medication to every patient before sending them to the operating theater. The main reason is that the induction time of general anesthesia in current practice is much shorter than that of ether anesthesia. We now routinely use intravenous anesthetics as induction agents; for most intravenous agents, onset of action occurs within 60 seconds. Patients who do not have venous access, such as children undergoing an operation in an outpatient setting, can be given sevoflurane as an induction agent via a face mask. Despite having some involuntary movements (excitement stage of Guedel's sign), these children can easily be made sleep in 1 minute due to the low blood solubility of sevoflurane.
The issue of patient safety is another concern of anesthetic premedication. When patients are premedicated, they must be put into surveillance to monitor the vital signs and the potential side effects of medication when they are in the ward, during transport to operating theater, or when they are in the waiting area of the operating theater. We usually do not monitor vital signs of patients while they are still in the waiting lounge. If premedication becomes a routine practice in a hospital, more manpower is needed to take care of these patients, leading to an increase in costs; for this reason most of the hospitals do not perform this at present. From the viewpoint of efficacy of medication, patients will not obtain the beneficial effects of premedication if they receive their medication too early or too late prior to operation. In a busy operating theater of a medical center where a lot of patients are ready to undergo surgery, the operation is often delayed or conducted earlier, making the efficacy of premedication unpredictable.
We should also take “street readiness” of patients into account. At present, more operations are performed on an outpatient service basis in medical centers. After surgery, patients need to resume their normal daily activity as soon as possible. If the side effects of a premedication affect the functional recovery following an outpatient operation, most patients will not be willing to accept the medication.
2.3. Future direction of premedication
Although premedication was initially developed to fight back the adverse effects of anesthesia, we now emphasize more about the efficacy of premedication in improving the general well-being of patients and patient satisfaction after their surgery. There are still many people in whom the quality of recovery from anesthesia is not good, and many of them have not been treated adequately. Although we already have guidelines for some preventive measures, for instance, to manage postoperative nausea and vomiting (PONV) or to deal with a difficult airway, we have yet to develop a complete list of statements or guidelines on premedication to manage all possible anesthesia-related side effects. It is clear that new consensus guidelines need to be established, and more clinical trials on anesthesia premedication need to be conducted.
3. Purposes of premedication
The two general purposes of premedication proposed by Beecher5 in 1955 are as follows: (1) to present a tranquil and well-rested patient to the surgeon and (2) to decrease the hazards incurred by anesthesia and surgery. Atropine was once used before anesthesia to prevent “vagal inhibition” and to decrease secretion induced by chloroform or ether. Morphine had also been used to reduce reflex irritability of patients and decrease the amount of ether requirement.6 As the new halogenated inhalational anesthetics and intravenous anesthetics have dramatically shortened the induction time of anesthesia, the main purpose of premedication today is no longer to prevent radical movement or reduce secretion of patients, but to allay patient fears and lessen patient anxiety.
Other purposes of anesthetic premedication, as found in the literatures, are to: (1) prevent postoperative pain, (2) provide effective prophylaxis against PONV, (3) decrease perioperative shivering, (4) decrease postoperative pruritus, (5) decrease gastric secretions, (6) prevent allergic reactions, (7) suppress reflex responses to surgical stimuli, and (8) decrease anesthetic requirement for the surgical procedure.7
3.1. To decrease anxiety
Preoperative anxiety can occur in as high as 80% of surgical patients. Two vulnerable groups of patients are females and children. While most female adults are usually concerned about the uncertainty of their future, their family, the success of the operation, and the safety of anesthesia, the children, by contrast, will experience varying degrees of separation anxiety before an operation. Both psychological and pharmacological approaches are effective in decreasing preoperative anxiety. A study conducted as early as 1963 showed that patients visited by an anesthesiologist before surgery are more likely to remain calm in the operating theater than those who did not receive reassurance.8 Another study found that the brochure educating patients about the effects of anesthesia is less effective in reducing anxiety than a personal interview.9 Midazolam has been proved to be effective in reducing the preoperative anxiety level in many studies. It will not delay discharge from the recovery room in outpatient surgery. Except for midazolam, α2-agonists, antidepressants, and anticonvulsants are all effective in reducing the preoperative anxiety level (see below).
3.2. To reduce postoperative pain
Preemptive analgesia, a concept of delivering an analgesic regimen prior to the surgical stimulus to reduce the severity and duration of postoperative pain, originated from the experimental findings of Woolf and Chong10 in 1983 that the central nervous system will be hypersensitized after peripheral tissue injury. The goals of preemptive analgesia would therefore be as follows: (1) to decrease acute postoperative pain after peripheral nerve damage and tissue injury; (2) to prevent central neuron sensitization; and (3) to inhibit the development of chronic postsurgical pain (CPSP). During the past 3 decades, there have been many clinical applications of different analgesic interventions to try to achieve these goals. Many papers had reviewed and analyzed the numerous results of such efforts, but with a controversial and debating conclusion.
An extensive review published by Moiniche et al11 in 2002 analyzed more than 3700 patients from 80 randomized controlled trials between 1983 and 2000 to study the effects of preemptive analgesia with different techniques: 20 trials on nonsteroidal anti-inflammatory drugs (NSAIDs), eight trials on NMDA receptor antagonists, eight trials on systemic opioids, 24 trials on regional (epidural, intrathecal, or caudal) analgesia, and 20 trials on wound infiltration or peripheral nerve block. They found that preemptive NSAIDs, opioids, or ketamine did not provide any benefit. Continuous epidural analgesia, intrathecal injections, caudal blocks, and wound infiltration with local anesthetics all were ineffective. Only in seven of 11 trials involving single-dose epidural opioids or local anesthetics or a combination of both, a reduction was observed in the postoperative analgesic demand. It was concluded that the timing of analgesia did not influence the quality of postoperative pain control, irrespective of what types of preemptive analgesia techniques were employed.
Ong et al12 published another systematic review paper on this issue in 2005, in which they analyzed 3261 patients from 66 randomized controlled trials between 1989 and 2003: 17 trials on systemic NSAIDs, seven trials on systemic NMDA receptor antagonists, eight trials on systemic opioids, 19 trials on epidural local anesthetics and opioids, and 15 trials on wound infiltration or peripheral nerve block. The three primary outcome measurements were pain intensity, supplemental postoperative analgesic requirements, and time to first rescue analgesic. For systemic NSAIDs, six trials favored pretreatment for pain intensity, eight trials favored supplemental analgesics, and five trials favored time to first rescue analgesic. For systemic NMDA receptor antagonists and opioids, there was no statistically significant result for preemptive analgesia. For local infiltrations, five trials were significant for preemptive analgesia in three primary outcome measurements. For epidural interventions, seven trials favored pretreatment for pain intensity, 10 trials favored supplemental analgesics, and five trials favored time to first analgesics. The authors concluded that although preemptive epidural analgesia resulted in consistent improvements in all three outcome measures, preemptive systemic NSAIDs and local wound infiltration both decreased analgesic consumption and delayed time to first rescue analgesic, but had no impact on pain scores.
The authors of this article also discussed the reasons for the discrepancy between their results and those of Moiniche et al.11 They attributed the dissimilarity to different study populations, inclusion of more trials from the period 2001–2003, and different statistical methods.
3.3. Preemptive versus preventive analgesia
One possible caveat of inconsistency in efficacy of preemptive analgesia may be due to insufficient blockade of peripheral and central noxious inputs at the same period and inadequate coverage of all mediators and receptors involved in pain processing by current regimens. The concepts of preventive analgesia that adopt a multimodal approach combining several interventions, which will produce a sufficiently dense, extensive, and long duration of blockade, will pave the way for future direction of postoperative analgesia.13
3.4. To prevent CPSP
CPSP, a pain persisting for >3 months after surgery, accounts for the second largest group (22.5%) of pain clinic patients in England. The highest incidence of chronic pain after surgery is observed in patients undergoing amputation (50–85%), followed by those undergoing cardiac surgery (30–55%), mastectomy (20–50%), and thoracotomy (10–65%). Even a minor operation such as hernia repair has a CPSP incidence of 5–30%.14 Nerve damages and central sensitization play important roles in the development of CPSP. Pharmacological strategies to prevent CPSP include the following items.
3.4.1. Regional anesthesia
A recent Cochrane database15 revealed that epidural analgesia for thoracotomy was effective in reducing the risk of chronic pain at 6 months. They also found that the paravertebral block reduced incidence of chronic pain at 5–6 months after breast cancer surgery. Spinal anesthesia can also help reduce the incidence of chronic pain after cesarean section when compared with general anesthesia.
3.4.2. NMDA receptor antagonists
Many studies showed that a low dose of ketamine in patients undergoing a variety of surgeries can potentiate opioid analgesia, improve pain control, as well as reduce the incidence of development of CPSP.16 A combination of intraoperative epidural analgesia and intravenous ketamine reduces hyperalgesia and chronic pain after a major digestive surgery, compared with intravenous analgesia alone.17
3.4.3. Gabapentinoids
A recent review provided strong evidence that perioperative application of gabapentinoids reduces the incidence of CPSP. In their analysis, six out of eight gabapentin trials demonstrated a moderate-to-large reduction in the development of CPSP. The analysis also found a very large reduction in the development of CPSP in two of three studies on pregabalin.18, 19
3.5. To provide for prophylaxis against PONV
3.5.1. Postoperative nausea and vomiting
About one-third of surgical patients who receive a general anesthesia consisting of inhalational anesthetics and opioids experience PONV.20 The incidence of PONV will dramatically escalate to 70–80% in a high-risk group of patients without PONV prophylaxis. The pathophysiology of PONV is complicated, and several kinds of receptors and their mediators have been implicated in PONV: (1) serotonin type 3 (5-HT3) receptor; (2) dopamine type 2 receptor; (3) histamine type 1 receptor; (4) muscarinic cholinergic type 1 receptor; (5) steroid receptor; and (6) neurokinin type 1 (NK1) receptor. Based on these findings, modern PONV prophylaxis adopts the principle of multimodal approach to treat high-risk patients with at least two or three different kinds of receptor antagonists, rather than just increasing the dosage of one single receptor antagonist, to prevent the occurrence of PONV.21
3.5.2. Postdischarge nausea and vomiting
Postdischarge nausea and vomiting (PDNV) receive more attention when more surgical procedures are conducted on an outpatient basis. The overall incidence of PDNV was 37% in the first 48 hours after discharge from hospital. Apfel et al22 identified five independent risk factors for PDNV: (1) female sex; (2) age 50 years; (3) a history of PONV; (4) opioid use in the postanesthesia care unit; and (5) nausea in the postanesthesia care unit. Depending on the number of risk factors, the risk of PDNV can be predicted as 10%, 20%, 30%, 50%, 60%, and 80%, respectively. Unlike the simplified risk score for PONV developed by the same author, Apfel et al22 found that nonsmoking status is not a risk factor for predicting PDNV. They also noted many other differences between the risk factors of PONV and PDNV. They found, for instance, that the surgical techniques and the total intravenous anesthesia were not statistically significant for PDNV. A consensus guideline to prevent the occurrence of PDNV has not yet been developed.
3.6. To decrease perioperative shivering
Both general and regional anesthesia can impair thermoregulation during cold exposure, and postanesthetic shivering has been reported in 40–64% of patients (average 55%) with no prophylaxis. A variety of pharmacological and nonpharmacological interventions were tested to prevent patients from developing hypothermia, which showed equal effectiveness. Here, we describe the effects of pharmacological prophylaxis only. Antishivering medications found in the literatures can be categorized into several classes: (1) opioid receptor agonists or antagonists; (2) other centrally acting analgesics such as tramadol and nefopam; (3) α2-receptor agonists such as clonidine and dexmedetomidine; (4) cholinesterase inhibitors such as physostigmine and anticholinergic: atropine; (5) central nervous stimulants such as methylphenidate; (6) N-methyl-D-aspartate receptor antagonists such as ketamine and magnesium sulfate; (7) antiserotonergic agents such as ondansetron, granisetron, dolasetron, and urapidil; (8) γ-aminobutyric acid receptor agonists such as midazolam and propofol; (9) sodium channel blockers such as lidocaine; (10) benzodiazepine receptor antagonists such as flumazenil; and (11) anti-inflammatory agents such as dexamethasone.
In 2004, Kranke et al23 systematically reviewed randomized controlled trials on the efficacy of a single dose of parenteral medication for the prevention of postoperative shivering, and found that clonidine 65–300 μg (1078 patients), meperidine 12.5–35 mg (250 patients), tramadol 35–220 mg (250 patients), and nefopam 6.5–11 mg (204 patients) were all more effective than the control. The relative benefit (RB) was 1.58 [95% confidence interval (CI), 1.43–1.74], with a number needed to treat (NNT) of 3.7, for all clonidine doses tested; 1.67 (95% CI, 1.37–2.03), with an NNT of 3, for all meperidine doses tested; 1.93 (95% CI, 1.56–2.39), with an NNT of 2.2, for all tramadol doses tested; and 2.62 (95% CI, 2.02–3.40), with an NNT of 1.7, for all nefopam doses tested.
Park et al24 in 2012 performed a meta-analysis of randomized controlled trials on the efficacy of antishivering medications. They categorized antishivering medications into those with high, intermediate, and lower efficacy. Meperidine, tramadol, and nefopam are highly effective antishivering medications with the pooled RB of >2 and an NNT of 2. Similar medications with high efficacy are ketamine, dexmedetomidine, granisetron, and physostigmine, with the pooled RB of 1.8 and an NNT of 3. Intermediate effective antishivering medications are clonidine and magnesium sulfate, with the RB of 1.5 and an NNT of 4. Medications with lower efficacy are dexamethasone and fentanyl, with the RB of 1.2–1.3 and an NNT of 5–9.
3.7. To decrease postoperative pruritus
Pruritus is the most common side effect of neuraxial opioids, with an incidence varying from 30% to 100%. Parturients seem to be more susceptible to pruritus, with an increased incidence between 60% and 100%, and it appears to be estrogen related and dose dependent.25 Although the exact mechanisms remain unclear, it is believed that activation of μ-opioid receptors in dorsal horn neurons or in the “itch center” of the medulla by cephalad migration of neuraxial opioids is a major reason. Modulation of the serotoninergic pathways by interactions of opioid and 5-HT3 receptors and involvement of prostaglandins are also important in neuraxial opioid-induced pruritus.26 Pharmacological strategies to prevent or treat such an event include the following: 5-HT3 receptor antagonists, opioid antagonists, antihistamines, NSAIDs, and droperidol.27
Bonnet et al28 have reviewed the effect of prophylactic 5-HT3 receptor antagonists on pruritus induced by neuraxial opioids (both hydrophilic and lipophilic opioids) in different surgical procedures (cesarean section, general surgery, orthopedic surgery, and urologic surgery). They analyzed 1337 patients in 15 randomized, double-blind controlled trials, and found that 5-HT3 receptor antagonists (ondansetron, granisetron, tropisetron, and dolasetron) significantly reduced the incidence of pruritus (odds ratio 0.44, 95% CI 0.29–0.69, p = 0.0002). They also found that prophylactic 5-HT3 receptor antagonists decreased the severity of pruritus and treatment requests for pruritus. The incidence and intensity of PONV, another frequent complication of neuraxial opioids, were also reduced.
Later, George et al29 reviewed the effect of prophylactic 5-HT3 receptor antagonists for prevention and treatment of pruritus, nausea, and vomiting in women undergoing cesarean delivery with intrathecal morphine. They distinguished their analysis from those of Bonnet et al28 by the inclusion of only one kind of opioid (morphine) administered only through one route (intrathecal) in only one type of surgery (cesarean section). They analyzed 1152 enrolled patients in nine randomized trials. Their findings were almost the same as those of Bonnet et al,28 except for only one disparity. They found that the incidence of pruritus did not reduce by prophylactic administration of 5-HT3 receptor antagonists compared with placebo [80.7% vs. 85.8%, relative risks with 95% CI 0.94 (0.81–1.09)].
3.8. To decrease gastric secretions
Prevention of aspiration pneumonitis caused by regurgitated gastric juice from the full stomach of inadequately fasting patients30 or from the stomach of a parturient31 is always a challenge for anesthesiologists. Except for fasting, appropriate measures to prevent aspiration include gastric decompression, acceleration of emptying, and application of the technique of rapid sequence intubation along with Sellick's maneuver. We will also give premedication that can inhibit gastric juice secretion and reduce gastric juice volume and acidity, such as H2-receptor antagonists (H2RAs) or proton pump inhibitors (PPIs).
Many clinical trials have compared the efficacy of H2RAs with that of PPIs in terms of reducing gastric juice volume and acidity. Clark et al32 analyzed 913 patients in seven trials comparing the effects of ranitidine with that of PPIs on gastric secretion. The pool outcomes of their analysis suggested that ranitidine is more effective than PPIs in reducing gastric juice volume and acidity. Ranitidine can decrease the volume of gastric aspirates by an average of 0.22 mg/kg (95% CI 0.04–0.41) and increase gastric PH by an average of 0.85 pH unit (95% CI −1.14–−0.28).
In another meta-analysis, Puig et al33 further analyzed 1673 patients in 18 trials to compare between the efficacy of H2RAs and PPIs in reducing aspiration risk. They compared the number of patients at risk under different medications with the optimal dose, dosing schedule, and route of administration. Twenty-one out of 726 patients (2.8%) in the H2RA group versus 51 out of 736 patients (6.9%) in the PPI group were at risk of acid aspiration. For drugs given orally, 13 out of 553 patients (2.4%) in the H2RA group versus 45 out of 600 (7.5%) in the PPI group were at risk of acid aspiration (odds ratio 3.07; 95% CI 1.71–5.54, p = 0.0002). By contrast, the risk would be similar if both of the groups were given medication by the intravenous route (3.8% in the H2RA group vs. 4.8% in the PPI group). In their analysis, H2RAs were also superior to PPIs to reduce gastric acidity when given orally in a single dose a few hours prior to anesthesia. However, no differences were observed when the drugs were given in two separate doses (the night before surgery and the morning of surgery) or when given intravenously.
4. Psychological approach
Psychological education before an operation is a major part of premedication in terms of reducing the level of anxiety. Women and children are two vulnerable groups; most of the patients (as high as 70–80%) of these groups usually suffer from anxiety prior to operation. Psychological effects of a preoperative visit include not only building a friendly rapport among patients and anesthesiologists, but also reducing anxiety through reassurance about anesthesia from an anesthesiologist.
Compared to adults, psychological preparation can be more difficult in pediatric patients, as reassurance will not be effective in such young patients and separation anxiety can exist in parents and children. Some behavioral programs had been developed, such as parental presence during induction of anesthesia34 and clown intervention and distraction techniques,35 with varying results.
5. Pharmacological approach
5.1. Benzodiazepines
Benzodiazepines are often prescribed to surgical patients as an anxiolytic premedication. A Cochrane review analyzed 17 studies of benzodiazepines on time to discharge in adults undergoing day case surgery and found there was no difference in time to discharge from hospital.36 Females or younger patients will benefit more from anxiolytic premedication; as in one study, age and sex differences in neuropsychological and physiological responses after midazolam premedication were evident.37 Both preoperative administration of oral midazolam 0.5 mg/kg for premedication alone without parental presence at induction38 and a lower dose of oral midazolam 0.25 mg/kg with parental presence at induction39 are equally effective in reducing separation anxiety and providing a smooth emergence. Another study showed that intravenous administration of 0.03 mg/kg of midazolam immediately before the end of surgery reduces emergence agitation without delaying the emergence time in children undergoing strabismus surgery with sevoflurane anesthesia.40 However, there are some debating issues regarding the use of midazolam for premedication in children, as it can have negative effects on cognitive function or it may produce postoperative behavioral disturbances.41
5.2. α2-Adrenergic receptor agonists
Clonidine and dexmedetomidine are α2-adrenergic receptor agonists and have been compared in many trials using midazolam as an anesthetic premedication.42, 43, 44, 45, 46
5.2.1. Clonidine
A clinical trial compared oral midazolam 0.5 mg/kg with oral clonidine 4 μg/kg in terms of drug acceptance, preoperative sedation, quality of mask acceptance, and recovery profile 1. They found that the taste of clonidine is better and the onset of sedation is faster with midazolam, but the level of sedation is better with clonidine. The quality of mask acceptance was equally satisfactory, and they noted a trend toward an increased incidence of postoperative agitation after midazolam premedication.42
A meta-analysis summarized 10 similar trials and found that clonidine, in comparison with midazolam, produced a more satisfactory level of sedation at induction (the pooled odds ratio = 0.49), decreased emergence agitation (the pooled odds ratio = 0.25), and produced more effective early postoperative analgesia (the pooled odds ratio = 0.33).43
5.2.2. Dexmedetomidine
Compared to clonidine, dexmedetomidine is a more selective α2-adrenergic receptor agonist with a faster onset of action, quicker time to reach the peak plasma concentration, and a shorter elimination half-life. Hence, it should possess a more favorable pharmacologic profile than clonidine, when it is used for premedication.
An initial study compared the effects of intranasal dexmedetomidine 1 μg/kg and midazolam 0.2 mg/kg on mask induction and preoperative sedation in pediatric patients, and found that intranasal dexmedetomidine and midazolam are both effective in decreasing anxiety upon separation from parents.44 Unexpectedly, midazolam is superior to dexmedetomidine in providing satisfaction during mask induction.45 Later, two recent larger meta-analyses and reviews found that dexmedetomidine premedication was associated with more satisfactory sedation upon separation from parents and upon mask acceptance.46, 47 Dexmedetomidine premedication also decreased the number of requests for rescue analgesics after surgery, incidence of emergence delirium, and the incidence of postoperative shivering.46 However, dexmedetomidine premedication lowered systolic blood pressure and heart rate, and prolonged the onset of sedation.
Dexmedetomidine premedication can also decrease the severity of acute postoperative pain and reduce analgesic requirement.48
5.3. Antiemetics
Current antiemetic medications that have been proved to be effective for PONV prophylaxis are the following: (1) phenothiazines—chlorpromazine and prochlorperazine; (2) butyrophenones—droperidol and haloperidol; (3) benzamides—metoclopramide; (4) anticholinergics—scopolamine; (5) antihistamines—hydroxyzine and dimenhydrinate; (6) 5-HT3 antagonists—ondansetron, dolasetron, granisetron, tropisetron, and palonosetron; (7) NK-1 antagonists—aprepitant; and (8) steroids—dexamethasone.49 A Cochrane review analyzed the antiemetic effects of eight different medications in 737 studies involving 103,237 patients.50 This review determined that ondansetron, dolasetron, granisetron, tropisetron, dexamethasone, droperidol, cyclizine, and metoclopramide effectively prevented nausea or vomiting after surgery. However, it did not find evidence that one drug was better than another. Age, sex, type of surgery, or premedication timing did not change the drug effects, and the effects became additive when two or more drugs were given together.
5.3.1. First-generation 5-HT3 antagonists
Ondansetron, tropisetron, dolasetron, granisetron, and ramosetron are the first-line medications for PONV prophylaxis and treatment.51 Although many believe that they are comparatively effective in PONV prophylaxis, there are still some debates regarding the clinical differences between the 5-HT3 receptor antagonists, concern over optimal dosage and timing of administration, and whether rescue therapy is effective after prior administration of the same or a different 5-HT3 receptor antagonist.52 At least in one meta-analysis on the efficacy of 5-HT3 antagonists used in adults during the first 24 hours for PONV prophylaxis showed that granisetron was significantly better than ondansen with respect to PONV prophylaxis, and that ondansetron, tropisetron, and dolasetron exhibited similar efficacy. With respect to PONV prophylaxis alone, ondansetron, granisetron, tropisetron, and dolasetron seemed to have comparable efficacy.53 Such a discrepancy can partly be attributed to the different affinity for 5-HT3 receptors and different half-life durations varying from 3 hours to 7 hours.
5.3.2. Second-generation 5-HT3 antagonists
Palonosetron is a second-generation 5-HT3 antagonist that has high affinity for 5-HT3 receptor.54, 55 The following characteristics distinguishes palonosetron from the first-generation 5-HT3 antagonist: (1) different core structure; (2) prolonged inhibition of 5-HT3 receptor by a unique molecular interaction with the 5-HT3 receptor due to allosteric binding, positive cooperativity, and receptor internalization56; (3) a longer half-life of 40 hours; and (4) no effects on QTc interval.57
In two separate studies, palonosetron 0.075 mg was determined to have similar PONV effectiveness as that of ondansetron 4 mg58 and granisetron 1 mg.59 It was found to be the most effective dose for the 0–24-hour postoperative time period. Compared with granisetron 1 mg, palonosetron 0.075 mg provides longer protection against PONV during the late 24–48-hour time interval.59 A combination study evaluating the effect of dexamethasone and palonosetron versus palonosetron alone found no change in PONV efficacy over 72 hours.60 In a recent study, palonosetron 0.075 mg was found to be more effective than ondansetron 8 mg for opioid-induced nausea and vomiting after thyroidectmy.61 Its long duration of action suggests that palonosetron may provide longer protection against PONV. Its longer protection against delayed onset of nausea and vomiting had been shown in several studies on chemotherapy-induced nausea and vomiting.62, 63, 64 A recently published paper, in which the late effect of palonosetron on PONV prophylaxis was studied, revealed that palonosetron 0.075 mg IV effectively reduced the incidence of PONV during the 0–24-hour (33% vs. 47%) and 0–72-hour (33% vs. 52%) periods, but not during the 24–72-hour postoperative period (6% vs. 11%).65 These results are different from those of a previous trial showing that palonosetron 0.075 mg provides longer protection against PONV during the later 24–48-hour time interval.59 More studies are needed to determine its protective effect against late onset of PONV and PDNV.
5.3.3. NK-1 receptor antagonist, aprepitant
Aprepitant is an NK-1 receptor antagonist and has a similar half-life to that of palonosetron, so it is expected that it can provide PONV prophylaxis at a later stage. In a previous study, aprepitant 40 mg PO and ondansetron 4 mg IV showed similar effects for the first 24 hours; however, aprepitant provided more protection in the following 24–48-hours of postoperative time period, with the effect on vomiting being greater than that on nausea. In another study of patients undergoing laparoscopic gynecologic surgery, aprepitant 80 mg PO was found to be more effective than its 40 mg PO dose.66 In a combination study of craniotomy patients, the combination of aprepitant plus dexamethasone was found to be more effective than the combination of ondansetron and dexamethasone.67
5.4. Gabapentinoids
The same concepts as in the PONV prophylaxis, a multimodal analgesia regimen with a combination of opioids and multiple agents to target at various pathways and neurotransmitters involved in nociception and hyperalgesia, can provide a superior postoperative pain relief at rest and after movement, reduce opioid consumption, decrease opioid-related side effects, and prevent the possibility of central neurons sensitization.68 Gabapentin and pregabalin have been used as a part of multimodal analgesia regimens in the perioperative period, as they can inhibit central sensitization.69
5.4.1. Effects on acute postoperative pain
Preoperative gabapentin at various doses (300–1200 mg) can decrease the severity of postoperative pain and reduce opioid consumption in different types of surgeries, including abdominal and pelvic surgery, breast surgery, spine surgery, orthopedic surgery, head and neck surgery, and thoracic surgery.70, 71, 72, 73 The optimal preoperative dose of gabapentin is 600 mg in lumbar disc surgery, as found in a dose–response study by Pandey et al.74 At higher doses, patients exhibited more side effects without further reduction of pain intensity and analgesic consumption. In another trial, pre- and postoperative gabapentin reduced movement-evoked pain and improved functional recovery.75 We also reported analgesic effects of gabapentin on postdural puncture headache.76
Pregabalin was also found to have a beneficial effect on postoperative pain scores and analgesic requirements 24 hours after dental and gynecological surgery.77
To date, no evidence-based data are available to establish the optimal duration and dosage of postoperative gabapentinoid treatment,78 or to determine the ideal time for administering the drug either preoperatively or postoperatively.79
The most common side effects of gabapentinoids are somnolence and dizziness. Gabapentin can also exert perioperative anxiolytic properties, as it acts as a mood stabilizer.70
5.4.2. Prevention of pruritus
There are many similarities between pain and pruritus.80, 81 Based on this observation, we assumed that gabapentin may have antipruritic effects against intrathecal morphine-induced pruritus. We found that preoperative gabapentin 1200 mg decreased the incidence of intrathecal morphine-induced pruritus, delayed onset time of pruritus, and decreased severity of pruritus, and also observed that fewer patients needed antipruritic treatment compared with those in the placebo group.82
5.4.3. Effects of other anticonvulsants on postoperative pain
When we first studied the analgesic effect of gabapentin on acute postoperative pain 10 years ago, we also raised the question of whether other anticonvulsants had similar effects. We tested the analgesic effect of oxcarbazepine,83 lamotrigine,84 and valproic acid during the same period of time, and found that all of them had similar effects in terms of reducing postoperative pain.
5.5. Antipsychotic agents
Antipsychotic agents or major tranquilizers (phenothiazines and butyrophenones) have seldom been used in routine anesthesia practice to date. The major tranquilizers share the same pharmacological property of sedation as that of benzodiazepines, but with easier arousability. One of the phenothiazines that we often used 20 or 30 years ago is promethazine (brand name Phenergan). A small dose of promethazine is often administered to patients under spinal anesthesia to provide them with sedative, antiemetic, and vagolytic effects through its antihistaminic and anticholinergic properties. Another common antipsychotic that we used to prescribe earlier is droperidol. Droperidol is a butyrophenone and has strong central antiemetic and sedative effects, and so can prevent PONV or provide patients with heavy sedation. Its pharmacological effects come mainly from its potent postsynaptic dopaminergic (dopamine type 2) receptor antagonism, with lesser antiserotonergic and antihistaminic activities. Although it has many clinical advantages, droperidol has lost popularity probably for two reasons: its dysphoric effect and its cardiovascular effects. Global sedation with a calm and tranquil outlook appearance, which is deceptively interpreted by clinicians, is actually associated with an inward anxious and restless feeling. A double-blind trial of droperidol as a premedication found that it increases preoperative anxiety and tremor without producing significant drowsiness.85Another reason is the black box label warning requested by the United States Food and Drug Association in 2001 that include concerns about possibilities of QT prolongation and torsades de points.86 The warning is under dispute, however, with clinical findings that the incidence of QT prolongation is dose related and only nine cases of torsades de points have been reported in 30 years, with all receiving a high dose of >5 mg.87
Haloperidol is a derivative of droperidol, and its injection form is often used to control the symptoms of acute psychosis or agitated, aggressive behaviors. Some clinical trials showed its efficacy in preventing PONV.88, 89, 90, 91
Mirtazapine is a noradrenergic and specific serotonergic antidepressant. Except for activation of the central 5-HT1A receptors, mirtazapine can exert its antidepressive and anxiolytic effects through antagonizing the 5-HT2A/5-HT2C subfamily and 5-HT3 receptors. Mirtazapine, at the clinical dosage, has no significant binding affinity for the transporters of serotonin, norepinephrine, or dopamine, nor does it have any appreciable inhibitory actions on monoamine oxidase. Such distinctive effects make mirtazapine different from other classes of antidepressants, which include selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, tricyclic antidepressants, or monoamine oxidase inhibitors.
Chen et al92 first tested the anxiolytic and antiemetic effects of mirtazapine in a group of gynecological patients. The antiemetic effect of mirtazapine can further be examined in patients after intrathecal morphine administration. We found that mirtazapine can reduce the incidence of nausea and vomiting by 50%. The severity of nausea and vomiting was also decreased in our study.93 The symptoms of intrathecal morphine-related pruritus can also been prevented by preoperative mirtazapine.94 We also treated a patient with postdural puncture headache by mirtazapine with good results.95
6. Conclusion and future perspectives
The practice of anesthetic premedication is constantly evolving, as more surgeries are performed on an outpatient service basis, with more knowledge and drugs being put into the premedication armamentarium. Even the government health policy will have a significant impact on anesthetic premedication. Who should be premedicated? What is the maximal efficacy of premedication? Will the national health insurance policy cover the expenditures? Are surgical patients willing to pay by themselves the extra money to those minor complications? Will the hospital administrator consider expenditures on anesthetic premedication necessary without a negative impact on the hospital's annual budget under the new policy of diagnosis-related groups? Do surgeons agree to give their patients premedication without compromising their income under the new version of diagnosis-related groups? In the current situation, probably the best way to break through this dilemma is to make a thorough evaluation of preoperative patients, understand what the patients need, and give them either psychological or pharmacological supports appropriately. More clinical trials also need to be conducted in order to clarify different class of medication on efficacy of a certain endpoint. For instance, will dexamethasone be as effective in the prophylaxis of PDNV as in the scenario of its proven efficacy in the prevention of PONV? Another interesting study will be the one that compares the effects of dexamethasone on the prevention of PDNV with those of palonosetron or aprepitant, because all of them have relatively long half-lives. Finally, a consensus about anesthetic premedication should be reached in our anesthesiologist society, and it should take a further step to make an agreement with the Taiwan National Health Insurance Bureau or even a legislation to secure reimbursement by the government. Before achieving the final goal, we still need to work hard in taking care of patients and to premedicate them adequately.