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Anesth Analg 2001;93:1025-1031
© 2001 International Anesthesia Research Society

PAIN MEDICINE

The Synergistic Interaction Between Midazolam and Clonidine in Spinally-Mediated Analgesia in Two Different Pain Models of Rats

Tomoki Nishiyama, MD PhD*, and Kazuo Hanaoka, MD PhD{dagger}

*Department of Surgical Center, The Institute of Medical Science, and the {dagger}Department of Anesthesiology, The University of Tokyo, Tokyo, Japan

Address correspondence and reprint requests to Tomoki Nishiyama, MD, PhD, Department of Surgical Center, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, 108-8639, Tokyo, Japan. Address e-mail to nishiyam{at}ims.u-tokyo.ac.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Both midazolam, a benzodiazepine {gamma}-aminobutyric acid type A receptor agonist, and clonidine, an {alpha}2-adrenergic receptor agonist, induce spinally-mediated analgesia. We investigated the analgesic interaction of spinally-administered midazolam and clonidine in their effects on acute and inflammatory nociception. Rats implanted with lumbar intrathecal catheters were injected intrathecally with saline (control), midazolam (1 to 100 µg), or clonidine (0.1 to 3 µg) to test for their responses to thermal stimulation to the tail (tail-flick test) and subcutaneous formalin injection into the hind paw (formalin test). The effects of the combination of midazolam and clonidine on both stimuli were tested by isobolographic analysis by using the 50% effective doses. The general behavior and motor function were examined as side effects. When combined, the 50% effective doses of midazolam (clonidine) decreased from 1.57 µg (0.26 µg) to 0.29g (0.05 µg) in the tail-flick test and from 1.34 µg (0.12 µg) and 1.21 µg (0.13 µg) to 0.05 µg (0.005 µg) and 0.13 µg (0.015 µg) in Phase 1 and 2 of the formalin test, respectively. Side effects did not increase by using the combination. These results suggest a favorable combination of intrathecal midazolam and clonidine in the management of acute and inflammatory pain after proper neurotoxicologic studies.

IMPLICATIONS: Spinally-administered midazolam, a benzodiazepine, and clonidine, an {alpha}2-adrenergic receptor agonist, have significant synergistic effects on thermally-induced acute and formalin-induced inflammatory pain.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
The inhibitory neurotransmitter {gamma}-aminobutyric acid (GABA) is found in the spinal cord, and the benzodiazepine binding site is present on the GABAA receptor (Cl- channel). GABAA-benzodiazepine receptors have been found in a high density in laminae II and III of the dorsal horn of the spinal cord (1), where most primary afferents responsive to noxious stimulation have their central terminals. Midazolam, a benzodiazepine derivative, has analgesic effects mediated by GABAA-benzodiazepine receptors in the spinal cord (2).

Intrathecally-administered clonidine, an {alpha}2-adrenergic receptor agonist, also produces analgesia (3). The spinal antinociception induced by {alpha}2-adrenergic receptor agonists is mediated by an inhibition of synaptic transmission within the dorsal horn of the spinal cord, principally via a direct suppression of the activity of dorsal horn neurons (4), via an activation of the descending noradrenergic inhibitory system (5), and via an activation of spinal cholinergic neurons (6).

Synergistic interaction can occur when drugs affect different critical points along a common pathway. Therefore, we hypothesized a synergistic antinociceptive effect between midazolam and clonidine. However, there are few studies of spinally-mediated analgesic interaction between midazolam and clonidine (7). In this study, we investigated the antinociceptive interaction between midazolam and clonidine in two different rat models of acute thermal and inflammatory nociception.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The protocol was approved by the IRB of the University of Tokyo. Male Sprague-Dawley rats (280–300 g for the tail-flick test and behavioral test, 330–350 g for the formalin test; Nippon Bio-Supply, Tokyo, Japan) were implanted with chronic lumbar intrathecal catheters under sevoflurane (3%) anesthesia. An 8.5-cm polyethylene (PE-10; Clay Adams, Parsippany, NJ) catheter was advanced caudally through an incision in the atlanto-occipital membrane to the thoracolumbar level of the spinal cord. The external part of the catheter was tunneled subcutaneously to exit on the top of the skull and plugged with a 28-gauge stainless steel wire. After surgery, all rats were housed individually in a temperature- and light-controlled environment with free access to food and water. Only rats with normal motor function and behavior 7 days after surgery were used. The position of the catheter was confirmed to be in the intrathecal space at L3 to L5 by exposing the lumbar spinal cord after killing the animals at the end of the study. The data of the rats with the catheter not in the proper place were excluded from the study. In each dose group, eight randomly selected rats were used after exclusion. A total of 224 rats were used because each rat was used only once.

Midazolam (a benzodiazepine-GABAA receptor agonist; Sigma, St. Louis, MO) 1, 3, 10, 30, and 100 µg and clonidine (an {alpha}2-adrenergic receptor agonist; Sigma) 0.1, 0.3, 1, and 3 µg were dissolved in 10 µL saline. After intrathecal drug injection, the catheter was flushed with a subsequent injection of 10 µL of normal saline to clear the dead space of the catheter (7 ± 0.4 µL, mean ± SE). Microinjector syringes were used for all injections. Normal saline 10 µL was injected into the Control group.

For the tail-flick test (8), the rats were placed into a clear plastic cylindrical cage with their tails extending through a slot provided in the rear of the cylinder. Noxious stimulation was provided by a beam of high-intensity light (Tail-Flick Analgesia Meter MK-330A; Muromachi Kikai Co. Ltd., Tokyo, Japan) focused on the tail 2 to 3 cm proximal to the end. The response time was measured and defined as the interval between the onset of the thermal stimulation and the abrupt flick of the tail. The cutoff time in the absence of a response was set to 14 s to prevent tissue injury. The data were shown as the percentage of maximum possible effect (%MPE): %MPE = (postdrug time - predrug time) x 100/(cutoff time - predrug time).

For the formalin test (9), 10 min after the intrathecal administration of the drug or saline, 50 µL of 5% formalin was injected subcutaneously into the dorsal surface of the right hind paw with a 30-gauge needle. Immediately after injection, the rat was placed in an open Plexiglas chamber and observed for 60 min. Quantification of pain behavior was made by counting the incidence of spontaneous flinches or shaking of the injected paw at 1–2 min, 5–6 min, and 5-min intervals during a period of 10–60 min after formalin injection. Two distinct phases were observed after formalin injection: phase 1, during 0–6 min interval after injection; and phase 2, beginning approximately 10 min after injection.

The general behavior (including agitation and allodynia-like behavior), motor function, flaccidity, pinna reflex, and corneal reflex were examined. They were judged as present or absent. Agitation was judged as spontaneous irritable movement, vocalization, or both. The presence of allodynia-like behavior was examined by looking for agitation (escape, vocalization, or both) evoked by lightly stroking the flank of the rat with a small probe. Motor function was evaluated by the placing or stepping reflex and the righting reflex. The former was evoked by drawing the dorsum of either hind paw across the edge of the table. Normally rats try to put the paw ahead into a position to walk. The latter was assessed by placing the rat horizontally with its back on the table, which normally produces an immediate, coordinated twisting of the body to an upright position. The disturbance of the righting reflex also shows impairment of function of the central nervous system. Flaccidity was judged as muscle weakness by putting the forepaw 3 to 5 cm higher than the hind paw. Normally the rat will walk up. We judged the rat flaccid when it did not move after positioning. Pinna and corneal reflexes were examined with a paper string. When a paper string is put into the ear canal or touches the cornea, rats normally shake their heads or blink, respectively.

The first series of experiments were performed to determine the dose dependency of the antinociceptive effects of intrathecally-administered midazolam or clonidine on both the tail-flick test and the formalin test. To investigate the interaction between midazolam and clonidine, an isobolographic analysis was used (10). The method is based on comparisons of the dose ratios that are determined to be equieffective. First, the respective 50% effective dose (ED50) values were determined from the dose-response curves of the drugs alone. Subsequently, a dose-response curve was obtained by coadministration of the two drugs in a constant dose ratio based on the ED50 values of the Phase 2 of the single drugs, i.e., combinations of each 1/2 ED50, 1/4 ED50, 1/8 ED50, or ED50 dose. From the dose-response curve of the combined drugs, the ED50 value of the mixture was calculated. The ED50 values were calculated by using the maximum %MPE in each rat by a computer program made in the Anesthesiology Laboratory of University of California, San Diego (Y. Takano, personal communication).

To describe the magnitude of interaction between drugs, a total fractional dose value was calculated as follows:

equation


The values were normalized by assigning the ED50 value of each drug given alone as 1. Values near 1 suggest an additive interaction, values >1 imply an antagonistic interaction, and values <1 indicate a synergistic interaction.

Student’s t-tests were used to compare the calculated ED50 values with the theoretical additive values. A P value <0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Both intrathecal midazolam and clonidine induced dose-dependent increases of the tail-flick latency (Fig. 1). The combination of midazolam and clonidine also showed a dose-dependent increase of the tail-flick latency (Fig. 1), and the ED50 values obtained by combination were significantly less than the calculated additive values; this indicates synergistic interaction (Fig. 2, Table 1). Total fractional dose value was 0.38 (0.19–0.52; 95% confidence interval).



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  		Figure 1. Time course of the effects of intrathecal midazolam (upper), clonidine (middle), and midazolam and clonidine (lower) on the tail-flick test. Each point represents the mean ± SEM of eight animals. M = midazolam; Cl = clonidine; %MPE = percentage of maximum possible effect. The doses are expressed in micrograms.

 


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  		Figure 2. Isobolograph for the intrathecal interaction of midazolam and clonidine in the tail-flick test. The x and y axes show the dose (µg) of midazolam and clonidine, respectively. Horizontal and vertical bars indicate 95% confidence intervals. The oblique lines between the x axis and y axis are the theoretical additive lines. The points in the middle of this line are the theoretical additive points calculated from separate 50% effective dose (ED50) values. The experimental points lie far below the additive line, indicating very marked significant synergism (P < 0.01).

 

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  		Table 1.  ED50 (50% Effective Dose) Values
 
The number of flinches in both Phase 1 and 2 was decreased by increasing doses of midazolam, clonidine, or their combination (Fig. 3). The isobolographic analysis and ED50 values showed significant synergistic effects of midazolam and clonidine in both phases of the formalin test (Fig. 4, Table 1). The total fractional dose value of Phase 1 was 0.079 (0.035–0.101), and that of Phase 2 was 0.22 (0.10–0.35).



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  		Figure 3. Time course of the effects of intrathecal midazolam (upper), clonidine (middle), and midazolam and clonidine (lower) on the formalin test. Each point represents the mean ± SEM of eight animals. Mid = midazolam; Cl = clonidine. The doses are expressed in micrograms.

 


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  		Figure 4. Isobolograph for the intrathecal interaction of midazolam and clonidine in the Phase 1 (upper) and Phase 2 (lower) of the formalin test. The x and y axes show the dose (µg) of midazolam and clonidine, respectively. Horizontal and vertical bars indicate 95% confidence intervals. The oblique lines between the x axis and y axis are the theoretical additive lines. The points in the middle of this line are the theoretical additive points calculated from separate 50% effective dose (ED50) values. The experimental points lie far below the additive line, indicating very marked significant synergism in both Phase 1 and 2 (P < 0.01).

 
Pinna and corneal reflexes were not disturbed in the rats tested in this study. Motor disturbances tested by the placing or stepping and righting reflexes and flaccidity were observed in rats receiving large doses of midazolam. The combination of midazolam and clonidine did not induce motor disturbance (Table 2).


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  		Table 2.  Side Effects
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The results of this study show that intrathecally-administered combinations of midazolam (benzodiazepine-GABAA receptor agonist) and clonidine ({alpha}2-adrenergic receptor agonist) produce synergistic antinociception to both acute thermal and inflammation-induced nociceptive stimuli.

Although disturbance of placing or stepping or righting reflex was evident in the Large-Dose Midazolam group, the rats still produced a vigorous tail-flick response and paw flinches, indicating that the motor disturbance did not interfere with the animals’ ability to respond to the noxious stimulus.

The Phase 1 response of the formalin test is caused by the direct stimulation of nociceptors by formalin or tissue damage and is thought to be an acute pain reaction (9). The Phase 2 response is caused by subsequent inflammation after formalin injection and central sensitization related to C-fiber activity (11). Therefore, from our study, midazolam might be able to diminish not only acute nociceptive activity, but also central sensitization. Serrao et al. (12) showed no effects of intrathecal midazolam in the tail-flick test, in contrast to our results. However, in their study, by using an electrical current threshold for pain in the tail, midazolam had spinally-mediated segmented analgesic effects. They did not explain the reason for the discrepancy between the results of the tail-flick test and the electrical current threshold test. In addition, we can not clarify the reason of the discrepancy between their results and ours in the tail-flick test. Further studies changing the stimulus intensity, animal species, and other experimental settings are necessary.

Both adenosine A1 and µ-opioid receptor antagonists blocked antinociception produced by {alpha}2-adrenergic receptor agonists (13). Intrathecally-administered cloni-dine, through interaction with spinal muscarinic and, to a lesser extent, nicotinic receptors, produces its antiallodynic effect in neuropathic pain (14). Clonidine has been suggested to induce the release of metenkephalin in the spinal cord, and this might be involved in the inhibition of nociceptive transmission by inhibiting the release of substance P (15). From this evidence, clonidine acts on many different sites involved in nociceptive mechanism.

Intrathecal coadministration of clonidine and local anesthetics prolonged analgesic duration compared with local anesthetic alone (16). Clonidine may complement the action of local anesthetics on sodium channels by opening the potassium channels, resulting in membrane hyperpolarization, a state that is unresponsive to excitatory input (17). Adding clonidine to spinal meperidine prolongs the duration and enhances the degree of postoperative analgesia (18), and this suggests an interaction between the {alpha}2-adrenergic receptor and µ-opioid receptor. Some µ-opioid-receptor-expressing neurons in the superficial dorsal horn are postsynaptic to GABAergic axon terminals (15). Yanez et al. (19) suggested a synergistic interaction between midazolam (GABAA receptor) and morphine (µ-opioid receptor) in thermal nociceptive tests in rats. Those observations support the existence of an antinociceptive interaction of GABA receptors with {alpha}2-adrenergic receptors through µ-opioid receptors. Midazolam is also reported to activate {delta}-opioid receptors (20). However, there is no evidence of clonidine to act on {delta}-opioid receptors. Therefore, we currently do not suggest that {delta}-opioid receptors are involved in a mechanism of the interaction between midazolam and clonidine.

Long-term intrathecal administration of midazolam with clonidine was effective for refractory neurogenic and musculoskeletal pain in humans (7). In that clinical report, however, the potential interaction of midazolam and clonidine was not discussed. The results of this study support the hypothesis that midazolam and clonidine are synergistic in antinociception. From Figure 1, it seems that the analgesic effects lasted longer in clonidine alone than the combination of midazolam and clonidine. However, the doses in the combination group were much smaller than those in the Clonidine-Alone group. Therefore, we could not suggest that the combination decreased the duration of analgesia but could say that when the doses were reduced to get the same potency of analgesia as clonidine alone, the duration might have decreased.

The {alpha}2A-adrenergic receptor also mediates the hypnotic action in the brain (21). The binding affinity for {alpha}2-adrenergic receptors of clonidine was not different between the spinal cord and brain (8). A significant synergistic interaction between dexmedetomidine, another {alpha}2-adrenergic receptor agonist, and midazolam in the hypnotic response in rats has also been observed (22). In the doses used in this study, however, rats were not sedated by intrathecal clonidine alone or by the combination of midazolam and clonidine. Intrathecal clonidine causes marked hypotension and motor blockade (16). We did not study the hemodynamics, but decreasing the dose of clonidine by combination with midazolam might decrease hypotension. This is our future interest. In this study, motor disturbance was observed with the largest dose of clonidine and larger doses of midazolam tested; those were approximately 10 to 20 times of the ED50 values. The combination of midazolam and clonidine did not show any motor disturbances. The ED50 values of each drug in combination were 50 to 600 times less than the dose-induced motor disturbance. Therefore, the combination was safer than each single drug in regard to motor disturbance.

Neurotoxicity of midazolam and clonidine is still controversial. Regarding midazolam, both no evidence (23) and signs (24) of neurotoxicity were reported. Clinically, intrathecal infusion of midazolam for more than two years has induced no side effects (7). Intrathecally-administered clonidine does not affect spinal cord histology (25). No data are available for the neurotoxicity of intrathecal coadministration of midazolam and clonidine. We suggest that reducing the dose of each drug by combination can decrease toxicity.

In conclusion, intrathecal coadministration of midazolam with clonidine produced significant synergistic effects on thermally-induced acute nociception and formalin-induced persistent nociceptive activation in rats. These results suggest a functional coupling of benzodiazepine-GABAA receptors with {alpha}2-adrenergic receptors in nociceptive mechanisms in the spinal cord. These synergisms can reduce dose requirements and may increase the therapeutic index. Proper experimental spinal neurotoxicologic studies that use the actual clonidine/midazolam combination must be performed before this treatment is introduced into clinical practice.


   Acknowledgments
 
This study was supported in part by Grant in Aid 12671453 from the Ministry of Education, Science and Culture, Japan.

We would thank Professor Chingmuh Lee, MD, in the Department of Anesthesiology, University of California, Los Angeles, School of Medicine for his comments.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication June 11, 2001.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2001 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press