Many outpatients have preoperative anxiety; therefore, it would be desirable to find a benzodiazepine for oral premedication with a strong anxiety-reducing effect and minimal psychomotor impairment. Midazolam is an obvious possibility because its short duration of action (1) makes it a recommended benzodiazepine for surgical procedures in outpatients (2–5). However, the oral formulation of midazolam is not approved in certain countries.
Benzodiazepines differ in their ability to relieve primary or secondary (e.g., situational) anxiety, act as an anticonvulsant, provide muscle relaxation, and induce sedation. Ansseau et al. (6) calculated an anxiolytic index for oral benzodiazepines by using the ratio of the total primary and secondary anxiolytic activity scores divided by the total muscle relaxant and sedative activity scores. Using this index, one can select an anxioselective benzodiazepine. For example, prazepam (20 mg, Lysanxia®) has the highest anxiolytic index (2.32). However, prazepam is inappropriate as a premedicant in ambulatory surgery because its peak effect occurs 7.8 h after administration and its metabolite nordazepam has a half-life (t1/2) of 40–50 h. Alprazolam (Xanax®; Pharmacia NV, Brussels, Belgium) at 0.5 mg has the second highest anxioselective activity (index of 2.26). In contrast to prazepam, it has an onset time of 1.4 h and an elimination t1/2 of 10.6 h in normal-weight subjects. Given these pharmacokinetic properties and its major anxiety-reducing effects in patients with primary anxiety and panic attacks (7), alprazolam is a possible alternative to midazolam for premedication in surgical outpatients.
The primary objective of this study was to assess the efficacy, psychomotor performance, and side effects of 0.5 mg of alprazolam as a premedicant in female outpatients. In this placebo-controlled study, the effects of alprazolam were compared with those of midazolam 7.5 mg.
After institutional approval and written informed consent, 45 adult ASA status I–II women scheduled for minor outpatient gynecological laparoscopic surgery participated in a double-blinded study. Patients taking analgesic, sedative, antidepressant, or antiepileptic drugs were excluded. Other criteria for exclusion included refusal, allergy or contraindications to either of the study medications, age >50 yr, gastric ulcer, obesity (body mass index [weight/height2] ≥28; obesity increases the volume of distribution and elimination t1/2 of alprazolam and midazolam), pregnancy, endocrine or neuropsychiatric disease, or a history of drug or alcohol abuse. Patients with a Clinical Global Impression (CGI) score for anxiety ≥2 assessed by an investigator (8) were asked to participate in the study (0 = relaxation, 1 = apprehension, 2 = mild anxiety, 3 = moderate anxiety, 4 = manifest anxiety, 5 = severe anxiety, 6 = very severe anxiety).
Participating patients were randomly assigned to receive alprazolam (0.5 mg, Xanax), midazolam (7.5 mg, Dormicum®, Roche B.V., Mijdrecht, The Netherlands), or placebo 60–90 min before surgery. All study drugs were given orally. The hospital pharmacist prepared the study medications. To blind the individual administering the drugs, the commercially available drug tablets were placed in opaque capsules filled with an inactive powder.
Anesthesia was induced IV with 2–3 mg/kg of propofol, 0.2 μg/kg of sufentanil, and 0.5 mg/kg of ketorolac (maximum, 30 mg). Endotracheal intubation was facilitated by IV administration of 0.2 mg/kg of mivacurium. Mechanical ventilation was adjusted to maintain an end-tidal Pco2 near 4.6 kPa. Anesthesia was maintained with 66% N2O in oxygen and desflurane ≥1.2 minimum alveolar anesthetic concentration unless blood pressure decreased by more than 20%. Supplemental doses of 0.1 μg/kg of sufentanil were administered at the discretion of the anesthesiologist until 20 min before the anticipated end of surgery. If arterial hypertension developed, 5–10 mg/kg of labetalol was administered IV. Drugs not mentioned in the protocol were excluded. Patients were actively warmed to keep core temperature (esophageal) normothermic.
When the trocars were removed from the abdominal cavity, 2 g of propacetamol was infused over 10 min, and desflurane was adjusted to an inspiratory concentration of 3.5% in 100% oxygen. Neuromuscular block was antagonized, if necessary, by IV administration of 2.5 mg of neostigmine along with 1.0 mg of atropine. Mechanical ventilation was decreased to maintain the end-tidal Pco2 near 4.6 kPa. At the last skin stitch, desflurane was discontinued, and 100% oxygen was administered. Spontaneous breathing was allowed when the patient was awake or fighting the ventilator. Patients were considered awake when they opened their eyes on demand or after gentle tactile stimulation; they were later tracheally extubated.
In the postanesthesia care unit (PACU), patients received standard postoperative care, including oxygen administration via a nasal cannula (3 L/min). Tramadol 3 mg/kg was infused over 10 min, along with 4 mg of ondansetron for patients requiring additional analgesia. Nausea or vomiting was treated with IV ondansetron (2 mg) at 5-min intervals to a maximum dose of 6 mg. Tramadol 100 mg was administered IV over 10 min for treatment of shivering.
PACU discharge criteria included being awake and orientated, able to breathe deeply and cough freely, blood pressure within 20% of preoperative values, temperature >36.0°C, absence of shivering, minimal pain, and minimal nausea. Patients were discharged from the ambulatory surgery clinic between 4:00 and 6:00 pm on meeting discharge criteria, which included being awake and well orientated, vital signs within 20% of preoperative values, temperature ≤38.0°C, no vomiting, ability to ingest oral fluids, pain well controlled with oral analgesics, and ability to walk without dizziness.
The effects of the study drugs on anxiety, sedation level, and psychomotor performance were assessed four times: immediately after obtaining informed consent (baseline), on arrival in the operating room (OR), on discharge from the PACU, and before being discharged to home. Anxiety was scored by an investigator using a 7-point CGI scale (0 = relaxation, 1 = apprehension, 2 = mild anxiety, 3 = moderate anxiety, 4 = manifest anxiety, 5 = severe anxiety, 6 = very severe anxiety) and by the patient using a 100-mm visual analog scale (VAS) (0 = relaxed, 100 = very anxious, near panic). We assessed the degree of sedation on a five-point scale (0 = alert, 1 = arouses to voice, 2 = arouses with gentle tactile stimulation, 3 = arouses with vigorous tactile stimulation, 4 = lack of responsiveness) and with a VAS scale (0–100 mm).
Psychomotor state was assessed with the Trieger Dot Test (TDT) and the Digit-Symbol Substitution Test (DSST) (9). The TDT is a variation of the Bender-Gestalt test in which the patient is asked to connect a series of dots arranged in a specific pattern. Points are subtracted for missing a dot. TDT deviation represents the cumulative distance (in millimeters) between the drawn line and missed dots. The DSST is a subtest of the Wechsler Adult Intelligence Scale. It is a timed pen-and-paper test in which patients are required to appropriately match numbers and symbols. The score is the number of symbols correctly matched during 90 s.
Patients were observed in the recovery unit by study nurses. Arterial blood pressure, heart rate, and respiratory rate were monitored during the observation period. Arterial oxygen saturation was monitored continuously. Pain and postoperative nausea and vomiting were evaluated with 100-mm-long VASs. All adverse effects, including dizziness and headache, were recorded. Before discharge from the clinic, a memory test was performed; it consisted of four questions to which the patients had to answer yes or no: 1) Do you remember being brought to the operating room? 2) Do you remember the object (a euro calculator) shown just before induction of anesthesia? 3) Do you remember the operating room? and 4) do you remember the recovery room?
Patients were called at home the day after surgery and asked whether they experienced any side effects. The memory tests were repeated. Patient satisfaction about anxiety reduction by the premedicant drug was assessed and scored as sufficient, insufficient, and indifferent (“don’t know”). Patients were asked whether they would like the same premedication if they required a future operation.
Before the study began, a sample size of 15 patients in each group was determined by a power analysis (α = 0.05; β = 0.10) on the basis of the assumption that a difference of 20 mm (sd, 15 mm) between groups on a VAS scale for anxiety would be clinically important.
Differences among the three groups were compared by using χ2 or paired Student’s t-tests, or one-way analysis of variance with Student-Newman-Keuls or Kruskal-Wallis tests, as appropriate (StatView for Windows, version 5.0; SAS Institute Inc., Cary, NC). For example, the DSST and TDT scores were not normally distributed; they were thus analyzed with nonparametric statistical methods. All results are presented as means ± sd. P < 0.05 was considered statistically significant.
One-hundred-ten patients were assessed for eligibility; 77 had a CGI score ≥2. Of these 77 eligible patients, 32 were excluded for reasons including refusal (n = 13), chronic use of sedative or antiepileptic drugs (n = 8), obesity (n = 6), neurologic disease (n = 4), and gastric ulcer (n = 1). Three of the patients who declined to participate did so specifically for fear of receiving a placebo. Among the 45 patients included in the three study groups, demographic and anesthetic variables, duration of anesthesia, extubation time, baseline anxiety scores, and the interval between premedication (baseline) and arrival in the OR were similar (Table 1).
In all groups, patient-assessed anxiety scores expressed on a VAS scale were decreased significantly (P < 0.05) at arrival in the OR compared with their baseline scores (Fig. 1). However, the decrease was greater (P < 0.05) in the alprazolam (to 19 ± 16 mm) and midazolam (to 23 ± 12 mm) groups than in the placebo group (to 38 ± 18 mm). The quality of anxiety reduction in the placebo group (n = 15) the day after surgery was considered insufficient in 7 patients and doubtful in 3 others.
The VAS assessment of sedation on arrival in the OR in the midazolam group (32 ± 29 mm) was slightly greater than in the alprazolam group (23 ± 20 mm), and both groups had greater scores than patients given placebo (7 ± 20 mm). The sedation VAS and CGI scores at arrival in the OR and at discharge from the PACU, however, did not differ significantly among the groups (Table 1).
In Figure 2, the DSST scores were normalized to baseline values to account for interpatient differences in test-taking ability. The DSST scores were similar in each group on arrival in the OR. However, scores in both treated groups were less than in the placebo group at subsequent measurements.
The number of missed dots in the TDT score at arrival in the OR was higher in the alprazolam group compared with the placebo group (P < 0.05). At discharge from the PACU, both active-drug groups performed significantly worse on the TDT test compared with placebo (P < 0.05) (Fig. 3). However, at discharge from the day clinic, the TDT scores again decreased to baseline in all groups. The differences in TDT deviation showed similar statistical significance among groups for the TDT score. During the interview on the first postoperative day, 5 of 15 patients in the midazolam group had amnesia for the object shown on arrival in the OR. These five patients did not remember the OR, either; however, all patients remembered their stay in the PACU. None of the patients given alprazolam or placebo demonstrated any amnesia. The incidence of nausea or vomiting and other side effects in the PACU did not differ significantly among the groups, nor did discharge times from the PACU.
Anesthesiologists may consider the administration of anxiety-reducing drugs unnecessary when anxiety levels are low in outpatients presenting for minor surgery, and most adults having ambulatory surgery are not premedicated (10). In the studied outpatient population, 70% had a CGI score for anxiety ≥2. Three patients even declined to participate in the study to avoid the risk of being given a placebo. The majority of this outpatient population (61%) was willing to take a premedicant for reduction of anxiety. These results are consistent with previous studies in which up to 80% of outpatients expressed a preference for a combination of anxiety-reducing and hypnotic premedication before surgery (3).
Oral premedication with 0.5 mg of alprazolam decreased anxiety to the same extent as the reference drug, 7.5 mg of midazolam. Eighty percent of the patients judged alprazolam as an effective anxiety-reducing drug, a percentage that does not differ significantly from the midazolam group. In contrast, only 33% of the patients given placebo were satisfied with their premedication.
The VAS and CGI assessments of sedation showed higher scores in the active drug groups at arrival in the OR and on discharge from the PACU but failed to demonstrate any statistical difference among groups. In this study, statistical power was insufficient to detect differences in sedation. The TDT score, which indirectly quantifies sedation, showed a statistically significant difference between the alprazolam group and the placebo group (Fig. 3). Although another study confirmed that oral midazolam (7.5 mg) does not produce significant sedation before surgery in comparison to placebo (12), other studies demonstrate a significant sedative effect (sleepy, but easily arousable) (1,2). In a recent study of Brosius and Bannister (13), only 40% of patients treated with the large dose of 20 mg of midazolam exhibited detectable sedation, with marked interindividual variability in plasma midazolam levels. Detectable preoperative sedation was predictive of prolonged emergence.
At discharge from the PACU, the placebo group had significantly better DSST and TDT scores than the two active-drug groups (P < 0.05). Within the placebo group, the DSST score was significantly higher than the preceding score at arrival in the OR and at discharge from the PACU (P < 0.05). These data presumably reflected learning in the placebo group. In contrast, absence of learning in patients receiving alprazolam indicated a subtle impairment in psychomotor performance. In the midazolam group, psychomotor impairment was also obvious at discharge from the PACU, with a decreased DSST score compared with the assessment at arrival in the OR (P < 0.05). At discharge from the day clinic, the DSST score in the midazolam group was significantly greater than baseline values, which indicated learning. The effects of the premedicant drugs on psychomotor skills were discrete and transient; discharge times were not affected. This is consistent with previous research on midazolam. Midazolam at a dose of either 5 mg given IM 30–60 minutes before surgery or 0.04 mg/kg given IV as premedication does not prolong discharge time, despite worsening of psychomotor skills (5,14).
In the midazolam group, 5 patients (33%) could not recall the object shown at arrival in the OR or their time in the OR; however, they did remember the PACU. A comparable incidence of transient anterograde amnesia after 7.5 mg of midazolam has been observed previously (1,2). A dose-response effect of midazolam on memory is suggested, because 15 mg of oral midazolam (1,2) and 0.1 mg/kg of IM midazolam (15) result in increased incidences of anterograde amnesia. In contrast, 0.5 mg of alprazolam did not induce amnesia in the studied patients. Even at a larger dose of 1.0 mg, no amnesic effect of alprazolam was noted (8).
Other benzodiazepines available in oral preparation have been used for premedication in adult outpatients. Preoperative discomfort and apprehension significantly decrease with diazepam (0.25 mg/kg, Valium®) (16,17). We did not select oral diazepam as an active comparator in this study because the anxiolytic index for diazepam (10 mg) is only half the value of alprazolam (0.5 mg) (6). Diazepam emulsion (7 mg IV) and midazolam (3 mg IV) were found to comparably reduce anxiety and improve patient comfort during needle localization procedures, without prolonging discharge times (4). Sublingual premedication with 0.25–0.50 mg of brotizolam (Lendormin®) results in satisfying anxiety reduction in adult outpatients, with restoration of the sedation score and the ability to walk freely 7 hours after premedication (18). In dental outpatients, sublingual triazolam (0.25 mg, Halcion®) appears to be an effective drug for anxiety reduction and sedation, with a rapid onset and short t1/2(19). However, brotizolam and triazolam have the lowest anxiolytic indices among benzodiazepines (6), which signifies that their sedative activity is more prominent. Sedation is not a desirable property for fast-tracking in ambulatory surgery.
In conclusion, premedication to reduce anxiety was considered desirable by most of the adult female outpatients. Oral premedication with alprazolam (0.5 mg) was comparable to midazolam (7.5 mg) in reducing preoperative anxiety. Patients receiving midazolam experienced transient amnesia. Sensitive tests demonstrated a minor impairment of psychomotor function with both benzodiazepines; however, neither drug prolonged extubation or discharge times.
The authors thank Greet De Smet, hospital pharmacist, for the preparation of capsules with active drug or placebo.
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