Barker I, Butchart DGM, Gibson J, Lawson JIM, Mac- kenzie N: I.V. sedation for conservative dentistry: a compari- son of midazolam and diazepam. Br J Anaesth ...
SCIENTIFIC REPORT
Intranasal Midazolam Plasma Concentration Profile and Its Effect on Anxiety Associated with Dental Procedures Aaron H. Burstein, PharmD, BCPS,* Rosanne Modica, DDS,t Michael Hatton, DDS, FADSA,t and Fran M. Gengo, PharmDl, FCPtf *Department of Pharmacy Practice and Science, University of Maryland at Baltimore, Baltimore, Maryland, tDepartment of Dental Medicine and $Division of Neuropharmacology, Dent Neurologic Institute, Millard Fillmore Hospital, Buffalo, New York, and §Departments of Pharmacy Practice and Neurology, The State University of New York at Buffalo, Buffalo, New York
The objectives of this study were to describe the serum concentration time profile for midazolam following intranasal administration to adult dental surgery patients and to ascertain the effect of midazolam on anxiety. Six female patients received a single 20 mg (0.32 to 0.53 mg/kg) dose of midazolam. Blood samples were collected at 5, 10, 20, 30, 45, and 60 min following dose administration. Midazolam plasma concentrations were determined by gas chromatography. Anxiety was evaluated using a 100-mm visual analogue scale. The maximum concentration of midazolam was reached 25.8 min (range 18 to 35 min) following dose administration. Maximum concentrations were variable. However, there was no relationship between the weight-adjusted dose and maximal concentration. Patients experiencing baseline anxiety exhibited a trend toward reduction in their measured anxiety score (P = 0.06). Plasma concentrations above the hypothesized minimum effective concentration for sedative effects were attained when midazolam was administered intranasally to adult dental patients. Key Words: Midazolam; Intranasal; Pharmacokinetics. ental procedures are associated with significant fear and anxiety. An estimated 20 to 40 million Americans avoid voluntary visits to the dentist as a result.' Without adequate premedication and treatment of this anxiety, the dentist's ability to successfully provide adequate care is compromised. Clinical efficacy of midazolam to induce sedation and amnesia and to reduce anxiety following intravenous (IV)2-5 and oral6 administration is well documented. Unfortunately, injections of medication may induce anxiety in patients with a fear of needles. In an attempt to reduce anxiety while obviating the use of anxiety-producing injections, intranasal (IN) administration has been used, primarily in pediatric patients to induce conscious sedation. A Medline search of the literature reveals no information regarding IN administration of midazolam to adults, through a limited amount of pharmacokinetic data is available regarding pediatric patients. This pilot study describes the concentration profile following the
administration of midazolam to adult dental patients and also describes the effect of midazolam on procedureassociated anxiety. METHODS The study was approved by the Institutional Review Board of the Millard Fillmore Hospital. Prior to enrollment, informed consent and non-driving disclaimers were obtained from all patients. Male or female American Society of Anesthesiologists Class I individuals above the age of 17 yr undergoing third molar extraction were eligible for inclusion in the study. Patients were excluded for the following reasons: history of hepatitis, renal, respiratory, cardiovascular, or psychiatric disease; sensitivity to benzodiazepines; use of concomitant medications, including minor/major tranquilizers, sedatives, hypnotics, antihistamines, nar-
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ISSN 0003-3006/96/$9.50 SSDI 0003-3006(96)
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Table 1. Patient Demographics Patient Weight (kg) 1 50.5 2 51.8 3 50.0 4 72.7 5 72.7 6 43.2 Mean 56.8 SD 12.7
Age (yr) 19 22 23 17 18 23 20 2.7
cotics, or ethanol within 24 hr of study date; history of ethanol or drug abuse; and pregnancy. The first six available candidates enrolled in the study were females. After providing informed consent, patients were oriented to the visual analogue scale (VAS) to be used for anxiety assessments. Blood samples to determine midazolam concentrations were obtained using a 20-gauge IV catheter inserted into the antecubital vein. Baseline VAS was completed immediately before drug administration. Midazolam was administered at a fixed dose of 20 mg to patients as nose drops. Prior to the dental procedure, the undiluted IV formulation of midazolam (Versed, 5 mg/ml, Roche, Nutley, NJ) was drawn into a 5-ml injectable syringe. An 18-gauge angiocath was attached to the syringe following removal of the stylus. This provided a flexible tube that was inserted into the nares to administer the drug. The solution was administered over 1 to 2 min, with small volumes delivered alternately into each nostril. Patients were instructed to inhale during administration. Midazolam not absorbed intranasally was swallowed. Following administration of midazolam, 3 ml of blood from each subject was obtained at 5, 10, 20, 30, 45, and 60 min into commercially available K3 edta tubes (Vacutainer®, Becton Dickinson, Franklin Lakes, NJ) to determine plasma midazolam concentrations. The blood was centrifuged for 10 min at 2000x g; plasma was harvested and stored at -20°C until analysis using gas chromatography could be performed. Anxiety assessments were made at baseline and immediately before dental extraction. The anxiety VAS was a 100-mm line, with the statements "not nervous" on the left end and "extremely nervous" on the right end. Patients were instructed to draw a vertical mark across the line at the position on the scale best describing their current level of anxiety. Additionally, at the end of the study, patients were asked whether they felt the medication was helpful in allowing them to relax. Plasma samples collected to determine midazolam concentrations were analyzed using a modified version of the gas chromatography method of De Kroon et al.7
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Table 2. Pharmacokinetic Parameters Associated with Administered Dosages to the Six Patients Dose Cmax Tmax Patient (ng/ml) (min) (mg/kg) 1 0.46 114.3 22 2 0.39 261.8 34 0.42 3 99.0 35 4 0.32 107.1 18 5 0.32 92.5 21 6 0.53 262.5 25 Mean 26 SD 7.1
Standard curves ranging from 10 ng/ml to 300 ng/ml were prepared in blank plasma. Aliquots of patient plasma samples were treated with 250 pl of water and 20 Rl of a 500 ng/ml diazepam internal standard solution. Solid-phase extraction was performed using 100-mg C18 cartridges. Benzodiazepines were eluted with 500 Rl of methanol. Following evaporation under N2 at 50°C, the residue was reconstituted with 50 pl of toluene/methanol/acetone (85/15/5). Aliquots of these reconstituted solutions were injected onto the gas chromatograph (GC). Samples were analyzed on a Varian 3400 GC using an Alltech 6 meter by W' OV17 column. Nitrogen was the carrier gas. The sensitivity of the assay with 1 ,l of sample was 10 ng/ml and was linear over the range of 10 ng/ml to 300 ng/ml. Overall percentage of concentrated volume of the assay was 9.9, 4.5, and 9.6% at concentrations of 15, 80, and 260 ng/ml respectively. Maximal midazolam plasma concentration (Cmj) as well as time to reach Cma,, (Tm,) were interpreted directly from a plot of plasma concentration vs time. Plasma concentration at the time of anxiety assessment was similarly determined. Differences in anxiety measures pre-procedure and at baseline were determined using Wilcoxin's Signed Rank test. Spearman's correlation coefficient was used to assess the relationship between plasma concentration and change in VAS anxiety measure from baseline. Comparison of Tmax values to previously published studies was performed using the Mann-Whitney U-test. RESULTS
Patient demographics are described in Table 1. The first six patients who were screened entered this pilot study. All the patients were female. Weight-adjusted doses administered to individual patients are provided in Table 2. Because of concerns regarding the potential for adverse effects associated with large doses of IN midazolam, an upper cut-off dose of 20 mg was chosen. As a
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Intranasal Midazolam 300
Patient 01 Patient 02 -A-- Patient 03 -v-- Patient 04 Patient 05 0 Patient 06 *
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Figure 1. Measured midazolam plasma concentration vs time curves for each of the six patients.
result, weight-adjusted doses were not constant between subjects. Medication administration was reasonably well tolerated, with no reduction in heart rate, blood pressure, or oxygen saturation. However, nasal irritation, burning, and lacrimation were reported by all patients. The concentrations of midazolam following IN administration are shown in Figure 1. The mean time to achieve Cmax was 25.8 min following initiation of dosing, with a range of 18 to 35 min. As patients received slightly different weight-adjusted doses, mean Cmax was not determined. There was no relationship between dose and Cmax (Figure 2) using Spearman's correlation analysis. Four of the six patients who considered themselves anxious prior to their scheduled dental procedure recorded VAS scores ranging from 40 to 89 mm. Two patients without baseline anxiety recorded scores of 6 and 9 mm. In the four patients with baseline anxiety, the VAS scores following drug administration and immediately prior to extraction were reduced by 30 to 48 units. Patients without baseline anxiety exhibited an increase in VAS score by 13 and 16 units. In all six patients, Wilcoxin's Signed Rank test on baseline and postdose anxiety assessments found no statistically significant difference in VAS scores. Figure 3 shows the relationship between the change in VAS score and plasma concentration of midazolam for patients exhibiting baseline anxiety. Analysis of only those patients with baseline anxiety yielded a difference that approached statistical significance (P = 0.06). All patients subjectively in-
dicated that they felt more relaxed following administration of midazolam. DISCUSSION Intranasal administration of midazolam for induction of conscious sedation has been used successfully in pediatric patients prior to emergency room8 and general surgical procedures.9 Additional studies describe the concentration time profile of midazolam in the pediatric population.10"' Walbergh et al'0 studied the concentration time profile of both IV- and IN-administered midazolam in an attempt to determine maximal concentrations and the time until these concentrations are achieved. Their finding of mean (±SD) peak concentration of 72.2 (±27.3) ng/ml and time to peak concentration of 10.2 (±+2) min suggest that rapid attainment of significant plasma concentrations may be obtained following IN administration of 0.1 mg/kg.'° Rey et all conducted a comparative pharmacokinetic study of IV and IN midazolam administration. Mean time to achieve a mean (±+SD) Cmax of 104 (±+32) mcg/L was 12 (±+4) min after a dose of 0.2 mg/kg. Additionally, the investigators found higher apparent plasma clearances and volumes of distribution following IN administration. Time to attainment of maximal concentration (Tmax) values are significantly longer than the 10.2 min (P < 0.001) seen in the study of Walbergh et al'0 and the
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Figure 2. Measured midazolam maximal plasma concentration vs weight-adjusted midazolam dose.
11.6 min (P < 0.01) found by Rey et al.11 This is likely explained by the doses of midazolam used in this study, which were 2- to 4-fold larger than those administered in the previous studies. The resulting increased volume of fluid required to administer such doses (approximately 4 ml), in conjunction with the relatively short administration times (1 to 2 min), leads to the hypothesis that both intranasal and oral absorption may occur because patients inadvertently swallow study medication. This hypothesis is supported by Tmax values found in our study that resemble those found following oral dosing of midazolam.12
The prolonged Tm, found in our patients would be expected to be of little clinical significance in relation to the induction of sedation. Allonen et al12 have proposed that the onset of clinical sedation in adults occurs upon attainment of a serum midazolam concentration of 40 ng/ml. In all six patients studied, maximal concentration exceeded this threshold concentration for sedation. The results shown in Figure 1 suggest that concentrations considered adequate to induce sedation were achieved
within 7 min of the initiation of drug administration in all six patients. Subsequent plasma concentrations exceeded 40 ng/ml throughout the 45 to 60 min required to complete the dental procedure. As expected, IN administration of midazolam resulted in reduced anxiety in those patients with baseline anxiety. The inability to achieve statistical significance in our results is likely related to the small sample size used in this pilot study. In addition, the lack of blinding and a control group limit the development of any definitive conclusions regarding the efficacy of this administration approach in reducing anxiety. Despite the adequate serum concentrations of midazolam attained in this pilot study, there are numerous difficulties associated with IN administration of midazolam to adults. As previously discussed, the volume of solution required to deliver the doses administered to our patients is much larger than that required in pediatric patients. This relatively large volume places constraints on the rate of administration in order to ensure nasal rather than oral absorption. It has been proposed
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Intranasal Midazolam
40 -
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Figure 3. Change in measured anxiety from baseline vs midazolam plasma concentration for the four patients with baseline anxiety. Each point indicates an individual patient's data. VAS = visual analogue scale.
that a rate of 1 ml/min be used for IN administration of midazolam to allow for adequate nasal absorption while minimizing swallowing. Therefore, the doses and rates of administration used in our study predispose patients to swallow study medication, which results in both intranasal and oral absorption. We hypothesize that smaller doses administered over a longer period would facilitate nasal absorption and a more rapid induction of conscious sedation than higher doses administered rapidly. This hypothesis is the focus of a current pharmacokinetic pharmacodynamic study in our laboratory. Lacrimation and burning of the nasal mucosa were reported by all patients. There are a number of hypotheses as to the cause of this discomfort, including the pH of the solution (approximately 3),13 the benzoyl alcohol preservative,13 and the volume of solution administered. Shortly after completion of this study, a report was published documenting similar adverse experiences in pediatric patients receiving IN midazolam prior to endoscopy.14 To alleviate the irritation caused by administration of midazolam, these investigators have advocated
the use of a 4% lidocaine topical solution administered nasally using a spray bottle. Two sprays administered prior to midazolam reduced adverse effects without affecting clinical efficacy. We have found similar experiences in our clinic patients and patients enrolled in ongoing studies with IN midazolam. Intranasal administration would be expected to have a number of advantages over oral administration of medications. The highly vascular nasal mucosa allow rapid absorption of medications into the systemic circulation. Jackson et al15 hypothesize that communications exist between the subarachnoid space and nasal cavities, the cranial and nasal cavities, and the perineural sheaths in the olfactory nerve and the nasal mucosa. These communications represent a pathway for rapid entry of medication into the central nervous system. This would be especially advantageous for compounds such as midazolam, which exert their activity through effects in the central nervous system. In addition to rapid entry into the circulatory and central nervous systems, other advantages of IN administration in-
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clude avoiding hepatic first-pass metabolism, avoiding gastrointestinal wall metabolism, and preventing the drug's destruction in the acidic milieu of the stomach. However, this route of administration is not without limitations, including a maximum administered volume to avoid swallowing, burning and lacrimation, and sensitivity of nasal absorption to such factors as rhinitis.16 Many, if not all, of the limitations associated with IN administration of medications may be avoided by administering the drug orally instead, which results in anticipated rapid achievement of maximal concentrations,12 adequate sedative effects,6 and the avoidance of the side effects of nasal burning and lacrimation. Though maximal concentration of the drug occurs rapidly-within 0.33 hr-hepatic first-pass metabolism reduces oral bioavailability by approximately 44%.12 The results of this study are limited due to deficiencies in study design. The lack of blinding of subjects and investigators, the lack of a control group, and the small sample size limit the ability to draw conclusions regarding the efficacy of IN midazolam for anxiolysis. Future studies should be double blind, include a control group, and enroll a sufficient number of patients to provide adequate power and avoid bias. The use of a fixed dose precludes the ability to determine an appropriate dose for clinical use in patients. However, it is evident that a 20-mg fixed dose (0.32 to 0.53 mg/kg) results in safely and rapidly attaining plasma concentrations sufficient for anxiolysis. Further studies using weight-based dosing are warranted to further define the optimal dose that will result in safe and effective plasma concentrations and clinical anxiolysis. Despite the limitations associated with IN administration of midazolam to adults, this route of administration remains a viable alternative for patients in whom IV therapy is not feasible. Serum concentrations reaching the postulated threshold for sedation are reached within 7 min of dose administration, thereby suggesting clinical sedation may be rapidly attained. However, further studies are needed to evaluate the relationship between midazolam plasma concentrations and relief of anxiety. Evaluation of the plasma concentration-anxiety reduction relationship will allow scientists to determine the optimal dosage and administration technique required to provide adequate sedation while minimizing the risk of adverse experiences.
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[Letter] 15. Jackson RT, Tigges J, Arnold W: Subarachnoid space of the CNS, nasal mucosa, and lymphatic system. Arch Otolaryngol 1979;105:180-184. 16. Chien YW, Chang SF: Intranasal drug delivery for systemic medications. Crit Rev Ther Drug Carrier Syst 1987;4: 67-194.
