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Enhanced reduction in hyperalgesia by combined administration of clonidine and TENS

Kathleen A. Sluka*, Prasant Chandran
Physical Therapy and Rehabilitation Science Graduate Program, Neuroscience Graduate Program, Pain Research Program, 2600 Steindler Bldg., University of Iowa, Iowa City, IA 52242, USA Received 26 April 2002; accepted 22 July 2002

Abstract Transcutaneous electrical nerve stimulation (TENS) partially reduces primary hyperalgesia and is frequency dependent such that high frequency TENS produces approximately a 30% reduction in hyperalgesia whereas low frequency TENS has no effect. Both high and low frequency TENS completely reduce secondary hyperalgesia by activation of m and d- opioid receptors in the spinal cord and rostralventral medulla suggesting an opiate mediated analgesia. Clonidine in combination with opiates produces a synergistic interaction such that there is a potentiated reduction in hyperalgesia. Thus, we tested if combined application of clonidine with TENS would enhance the reduction in primary hyperalgesia. Male SpragueDawley rats were inamed by subcutaneous injection of 3% carrageenan into one hindpaw. Withdrawal latency to radiant heat and withdrawal threshold to mechanical stimuli were assessed before and after inammation and after administration of clonidine (0.0022 mg/kg, intraperitoneal (i.p.)) with either low (4 Hz) or high (100 Hz) frequency TENS. Clonidine alone reduced both heat and mechanical hyperalgesia with ED50s of 0.02 and 1.0 mg/kg, respectively. In combination with either low or high frequency TENS, the doseresponse curve shifted to the left and was signicantly different from clonidine alone. The ED50s for heat and mechanical hyperalgesia following low frequency TENS with clonidine were 0.002 and 0.2 mg/kg, respectively and those following high frequency TENS with clonidine were 0.005 and 0.15 mg/kg, respectively. Thus, combined use of clonidine and TENS enhances the reduction in analgesia produced by TENS and enhances the potency of clonidine. It would thus be expected that one would reduce the side effects of clonidine and enhance analgesic efcacy with combinations of pharmaceutical and non-pharmaceutical treatments. q 2002 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved.
Keywords: Pain; Noradrenaline; Adrenergic; Electrical stimuli

1. Introduction Transcutaneous electrical nerve stimulation (TENS), a non-invasive analgesic modality which involves the cutaneous application of electrical currents, is used extensively to treat both acute and chronic pain arising from a variety of musculoskeletal conditions including inammatory conditions of the joints (see Robinson, 1996 for review). Several studies show the effectiveness of TENS in reducing pain in people with rheumatoid and osteoarthritis (Manheimer et al., 1978; Manheimer and Carlsson, 1979; Kumar and Redford, 1982). Both low- and high-frequency TENS at sensory or motor intensity applied to the inamed knee joints of rats completely reduces secondary hyperalgesia, i.e. pain outside the site of injury (Sluka et al., 1998; King and Sluka, 2001). However, primary hyperalgesia is only

* Corresponding author. Tel.: 11-319-335-9791; fax: 11-319-335-9707. E-mail address: kathleen-sluka@uiowa.edu (K.A. Sluka).

partially reduced by TENS (Gopalkrishnan and Sluka, 2000). In fact, high frequency TENS reduces primary mechanical and heat hyperalgesia by approximately 30% while low frequency TENS has no signicant effect. Changing intensity or pulse duration does not further affect the degree of antihyperalgesia produced by TENS (Gopalkrishnan and Sluka, 2000). Both high frequency (100 Hz)(Woolf et al., 1977; Sluka et al., 1999b; Kalra et al., 2001) and low (4 Hz) frequency (Sjolund and Erikson, 1979; Sluka et al., 1999b; Kalra et al., 2001) TENS analgesia are opiate mediated. Specically, the antihyperalgesic effects of low and high frequency sensory TENS are mediated spinally and supraspinally by m- and dopioid receptors, respectively (Sluka et al., 1999b; Kalra et al., 2001). Systemic administration of clonidine produces antinociception and pain relief in animals and human subjects (Dennis et al., 1980; Paalzow, 1974; Skingle et al., 1982; Bonnet et al., 1990) by activation of alpha-2 adrenergic

0304-3959/02/$20.00 q 2002 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. PII: S 0304-395 9(02)00294-4

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receptors (a2-AR) (Yaksh, 1985; Maze and Tranquili, 1991; Danzebrink and Gebhart, 1990; Pertovaara, 1993; Proudt, 1988; Yaksh, 1985) and reduces dorsal horn responses to noxious stimuli (Fleetwood-Walker et al., 1985; Sullivan et al., 1992; Willcockson et al., 1984). Hypotension, bradycardia, respiratory depression, and sedation are recognized as side effects associated with the use of a2-adrenergic agonists especially clonidine (reviewed in Eisenach et al., 1996; van Zweiter, 1999). Intrathecally administered clonidine potentiates the antinociception produced by intrathecally or systemically administered morphine in behavioral and electrophysiological studies (Fairbanks et al., 2000; Drasner and Fields, 1988; Hylden and Wilcox, 1983; Omote et al., 1991; Ossipov et al., 1989). Systemic administration of clonidine also enhances morphine-induced antinociception as measured in the tail ick assay (Ossipov et al., 1984; Spaulding et al., 1979). Spinal d-opioid receptors are also involved in the synergism between opiates and a2-AR agonists (Omote et al., 1991; Roerig et al., 1992). Since, TENS works through activation of centrally located opioid receptors, coadministration of clonidine should enhance the effects of TENS. Thus, this study will test the hypothesis that systemic clonidine in combination with TENS produces an increased reduction in primary hyperalgesia produced by TENS. 2. Methods All experiments have been approved by the Animal Care and Use Committee at the University of Iowa and are in accordance with the NIH guidelines for care and use of laboratory animals. Adult male SpragueDawley rats (250400 g, Harlan, Indianapolis, IN) were used for the study. 2.1. Induction of inammation The animals were acutely inamed by a subcutaneous injection of 3% carrageenan (0.05 ml) (lambda carrageenan, Sigma), using a 23-guage needle, into the plantar aspect of one hindpaw under brief halothane (24%) anesthesia (Winter et al., 1962; Hargreaves et al., 1988). 2.2. Behavioral assessments 2.2.1. Paw withdrawal latency to thermal stimuli The time taken by the rat to withdraw its paw, i.e. paw withdrawal latency (PWL), in response to a radiant heat source was recorded (Hargreaves et al., 1988; Sluka and Westlund, 1993). Before beginning the testing, the animals were placed in transparent lucite cubicles that allow minimal movement (24.6 7.5 7.5 cm 3), on an elevated glass table, and allowed to acclimate for approximately 20 30 min. The radiant heat source, consisting of a high intensity light source connected to a timer, was then positioned

under the glass table directly beneath one hindpaw. Bilateral PWL readings (to the nearest 0.01 s) for each paw consisting of ve trials were taken in 5 min intervals and then averaged to give the mean PWL. Previous studies have established the validity (Hargreaves et al., 1988) and testretest reliability (r 2 0:7, P 0:0001) (Sluka et al., 1999a). A cut-off of 20 s was kept to avoid tissue damage. The PWL readings were taken bilaterally before inducing inammation (baseline), 4 h after injection of 3% carrageenan and after administration of saline (control)/clonidine and/or TENS. 2.2.2. Paw withdrawal threshold to mechanical stimuli using von Frey lament Von Frey laments of varying bending forces (1, 4, 5, 8, 12, 16, 32, 44, 56, 75, 104, 162 and 350 mN) were applied to the plantar aspect of the rats paw between the third and the fourth digits to test for a withdrawal threshold. The animals were placed in transparent lucite cubicles that allow minimal movement (24.6 7.5 7.5 cm 3) on an elevated meshed platform. The von Frey laments were individually applied at right angles to the plantar aspect of the paw starting with the lowest bending force and progressing upwards. Mechanical or paw withdrawal threshold i.e. the lowest bending force at which the animal lifts its paw off the meshed platform was noted. Mechanical withdrawal threshold was measured bilaterally. The number of trials was restricted to two per lament (Sluka, 1997). Previous studies have established the testretest reliability for this method of testing (r 2 0:7, P 0:0001) (Gopalkrishnan and Sluka, 2000). Before the induction of inammation, 13% of the rats responded to the 104 mN, 50% to the 162 mN and 37% animals respond to the 350 mN bending force. The animals normally do not respond to bending forces below 104 mN. This threshold value reduces dramatically following the induction of inammation to values between 1 and 12 mN. 2.3. Experimental design This experiment determined if coadministration of systemic clonidine and local TENS stimulation produced a potentiated antihyperalgesic effect. Four hours after induction of inammation, rats were randomly divided into six groups: (1) saline 1 no TENS; (2) saline 1 low frequency TENS (4 Hz); (3) saline 1 high frequency TENS (100 Hz); (4) clonidine 1 no TENS; (5) clonidine 1 low frequency TENS and (6) clonidine 1 high frequency TENS. Different doses (0.0022.0 mg/kg i.p.) of clonidine (Sigma) or saline were injected intraperitoneally under light halothane (1 2%) anesthesia 4 h after the induction of inammation just prior to TENS administration. TENS (EMPI, Eclipse Plus) was administered at either low frequency (4 Hz) or high frequency (100 Hz). A control group did not receive TENS (sham TENS group) but was anesthetized for 20 min. All other treatment parameters were kept constant as follows: intensity (2 motor threshold), pulse-width

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(100 ms) and modulation (normal). Previous data show only a frequency effect of TENS on primary hyperalgesia (Gopalkrishnan and Sluka, 2000). All the TENS treatment groups were treated at an intensity twice the motor threshold i.e. by inducing a visible muscle contraction and then increasing the intensity by twice this level. Pregelled electrodes (diameter 1 cm) were applied on the dorsal and plantar aspects of the hindpaw. After 20 min, the animals were removed from anesthesia, the use of TENS was discontinued, and the electrodes removed. The animals were allowed to recover fully from the anesthesia before testing. 2.4. Data analysis Two factor (dose, treatment) repeated measures of analysis of variance (ANOVA) was used to analyze percent changes in PWL to heat and mechanical withdrawal thresholds (P # 0:05). Posthoc test (Tukeys test) was performed to assess changes between groups (P # 0:05). The PWL values and the mechanical withdrawal thresholds are expressed as the percent inhibition of hyperalgesia such that 100% is a full reversal of hyperalgesia, 0% is no change in hyperalgesia and .100% is analgesia (mean ^ SEM). Percent inhibition and PWL to heat are presented as the mean ^ SEM. Mechanical withdrawal threshold is represented as the median with the 25th and 75th percentiles. ED50 values with condence intervals were calculated on the % inhibition and Emax was set at 100% (PharmTools Pro). 3. Results 3.1. Control Subcutaneous injection of carrageenan into the paw results in a reduced PWL to radiant heat. Four hours after injection of carrageenan, the PWL to radiant heat decreased to 3.97 ^ 0.36 s, which is a decrement of about 56 s from baseline values (Fig. 1A). Treatment with high frequency TENS signicantly increased the PWL immediately after treatment (P 0:001, paired t-test). In contast, treatment with low frequency TENS has no effect on the decreased PWL (P 0:12, paired t-test). In the group of animals that did not receive TENS and were injected intraperitoneally with saline, there was no effect on the decreased PWL (0.58 ^ 3.41%). The contralateral paw showed no differences in the withdrawal latency to heat after inammation or after treatment with TENS (Fig. 1A). The paw withdrawal threshold to mechanical stimuli also decreases to approximately 56.5 mN (median value) from baseline values of 162350 mN (Fig. 1B). There was no signicant effect on the decreased withdrawal threshold in animals that did not receive TENS (P 0:31, sign rank test) or those that received either high frequency (P 0:06, sign rank test) or low frequency (P 0:22, sign rank test) TENS.

The contralateral paw withdrawal threshold remained the same in animals that did not receive TENS, or the groups that received low and high frequency TENS (Fig. 1B). 3.2. TENS and clonidine The PWL to radiant heat increased signicantly on the inamed side following the systemic administration of clonidine (0.0022.0 mg/kg) (Fig. 2A) (F7:164 34:9, P 0:0001). Clonidine at 0.2 mg/kg completely reversed the hyperalgesia (113.05 ^ 12.5%) and signicant increases from saline occurred for 0.0062.0 mg/kg clonidine (P , 0.0001). Lower doses of clonidine alone partially reversed the hyperalgesia. There was a signicant effect

Fig. 1. (A) PWL to radiant heat before the induction of inammation (baseline), 4 h after induction of inammation, and after administration of TENS (low frequency P, high frequency B and no TENS X). High frequency TENS signicantly increased the PWL to radiant heat immediately after treatment. There was no signicant difference from 4 h in the groups that received low frequency or no TENS. The inamed paw is represented by closed symbols whereas the uninamed paw is represented by open symbols. Values are mean ^ SEM. (B) Paw withdrawal threshold to mechanical stimuli before induction of inammation (baseline), 4 h after induction of inammation, and after administration of TENS (low frequency L, high frequency B and no TENS X). TENS had no signicant effect on the decreased withdrawal threshold to mechanical stimuli when compared to controls. The inamed paw is represented by closed symbols whereas the uninamed paw is represented by open symbols. Data are represented as the median with the 25th and 75th percentiles.

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evidenced by a signicant effect for dose (F7;164 32:6, P 0:0001) such that doses 0.02 mg/kg (P 0:001) and 0.2 mg/kg (P 0:001), 0.6 mg/kg (P 0:001), and 2 mg/ kg (P 0:001) clonidine are signicantly different from the saline injected group (Fig. 2B). A signicant effect for change in mechanical withdrawal threshold occurred for the inamed paw following treatment with TENS (F2;164 14:1; P 0:0001). Posthoc tests show that the percent change in the mechanical withdrawal thresholds for the groups that received both low (P 0:0001) and high (P 0:0001) frequency TENS were signicantly different from the group that received clonidine without TENS (Fig. 2B). The ED50 for clonidine without TENS for the changes in mechanical threshold was 1.0 ^ 0.57 mg/kg. Following treatment with TENS and clonidine, the ED50 was signicantly less: low frequency TENS 0.2 ^ 0.14 mg/kg and high frequency 0.15 ^ 0.09 mg/kg. 4. Discussion In this study, TENS by itself has minimal (high frequency) to no (low frequency) effects on primary mechanical and thermal hyperalgesia and agrees with previous studies from our laboratory (Gopalkrishnan and Sluka, 2000). However, when the a-2 AR agonist, clonidine, is given in combination with TENS there is an increased inhibition of primary mechanical and thermal hyperalgesia. Further, the ED50 values for clonidine are signicantly lower following combination with TENS suggesting that the potency to clonidine is increased. Thus, a lower dose of clonidine when given with TENS can produce the same analgesic effect as a higher dose of clonidine without TENS. Thus, we would expect that TENS in combination with clonidine could result in a lower dose of clonidine and thus reduced side effects of the drug. 4.1. TENS and opioids TENS mediates antihyperalgesia and analgesia through activation of the endogenous opioid systems (Woolf et al., 1977; Han et al., 1984; Sjolund and Eriksson, 1979). There is an increased release of beta-endorphins in the cerebrospinal uid and blood following treatment of TENS in both animals and humans (Facchinetti et al., 1984; Han et al., 1991; Hughes et al., 1984). Both high and low frequency TENS activate opiate receptors in the spinal cord and the rostral ventral medulla (RVM) to reduce hyperalgesia. Specically, low frequency activates m- and high frequency TENS activates d-opioid receptors, both spinally and supraspinally (Sluka et al., 1999b; Kalra et al., 2001). 4.2. Clonidine and analgesia Clonidine administered intrathecally or systemically produces an a2-AR mediated antinociceptive effect in

Fig. 2. (A) Percent inhibition of the PWL to radiant heat for the inamed paw after treatment with either clonidine plus no TENS (X), clonidine plus low frequency TENS (P) or clonidine plus high frequency TENS (B). Values are mean ^ SEM. Dose 0 represents either saline 1 no TENS or saline 1 low frequency TENS or saline 1 high frequency TENS (controls). [*signicantly different clonidine alone]. (B) Percent inhibition of the paw withdrawal threshold to mechanical stimuli for the inamed paw after treatment with either clonidine plus no TENS (X), clonidine plus low frequency TENS (P) or clonidine plus high frequency TENS (B). Data are represented as the mean ^ SEM. Dose 0 represents either saline 1 no TENS or saline 1 low frequency TENS or saline 1 high frequency TENS (controls).

for TENS treatment (F2;164 5:3, P 0:009) with signicant differences from the no TENS group for both low (P 0:007) and high frequency (P 0:001) TENS. Thus, the doseresponse curve for clonidine for changes in PWL to heat shifted to the left following a combined administration of either low or high frequency TENS with clonidine. The ED50 for clonidine without TENS was 0.02 ^ 0.01 mg/ kg. The ED50 following clonidine in combination with TENS was signicantly lower, 0.002 ^ 0.001 mg/kg for low frequency TENS and 0.005 ^ 0.004 mg/kg for high frequency TENS. This implies that a lower dose of clonidine in combination with TENS is more effective in reversing the hyperalgesia than when clonidine is administered alone. Systemic administration of clonidine results in an increase in the mechanical withdrawal threshold as

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mice, rats, and humans (Hayes et al., 1986; Ossipov et al., 1989; Spaulding et al., 1979; Buerkle et al., 1999). Systemic clonidine reduces acetylcholine induced abdominal contractions, reduces paw inching in the formalin test, produces analgesia in the hot plate test, tail immersion test, paw pressure test, and tail ick test in mice and rats (Hylden and Wilkcox, 1983; Fielding et al., 1978; Spaulding et al., 1979; Skingle et al., 1982). Systemically administered clonidine could produce analgesia by acting at peripheral or central sites or both (Khasar et al., 1995; Yaksh, 1985; Nakamura and Ferreira, 1988; Calvillo and Ghingnone, 1986; Mastriami et al., 1989). Similar doses of systemic clonidine produce an increase in the tail ick latency that still occurs after spinal transection suggesting the site of action is at the spinal cord level (Zemlan et al., 1980). Further, mechanical and heat hyperalgesia induced by ongoing inammation produced by kaolin and carrageenan knee joint injection or carrageenan paw inammation is reduced by systemic or intrathecally administered clonidine and a2-AR agonists (Hylden et al., 1991; Buerkle et al., 1999). In fact, the antinociception produced by systemically or intrathecally administered clonidine exhibit enhanced efcacy at the level of the spinal cord for the inamed paw (ED50 0.1 mg/kg, i.p.) when compared to the contralateral (ED50 1.8 mg/ kg, i.p.) paw (Hylden et al., 1991). Opioids administered systemically or supraspinally produce antinociception that is dependent on the activation of spinal a2-adrenergic receptors (Yaksh, 1979; Camarata and Yaksh, 1982; Yaksh, 1985). Intrathecally administered clonidine and other a2AR agonists are clearly analgesic (Fairbanks et al., 2000; Danzebrink and Gebhart, 1990; Hylden et al., 1991). Clonidine administered supraspinally and intracerebroventricularly has mixed results with some studies showing analgesia (Lipman and Spencer, 1979) and others showing no effect (Ossipov and Gebhart, 1983; Ossipov et al., 1984). a2-AR agonists inhibit dorsal horn neuron activity, spinothalamic tract cell activity, and release of substance P and calcitonin gene-related in the lumbar spinal cord suggesting a spinal mechanism of action. The antinociceptive effect following spinal or systemic administration of clonidine also occurs in human subjects (Coombs et al., 1985; Paalzow, 1974; Lipman and Spencer, 1979; Tamsen and Gordh, 1984; Bonnet et al., 1990). 4.3. Potentiation by combined administration of a 2-ARs and opiates The enhanced effectiveness of TENS in combination with clonidine probably results from an interaction with the opiate mediated analgesia produced by TENS and activation of a2-AR in the central nervous system. Several studies show potentiation of opiate mediated analgesia by coadministration of a2-AR agonists. Morphine or d-opioid agonists administered intrathecally show a synergistic analgesic effect with a2-AR agonists in several tests: abdominal constriction test, tail ick test, substance P test, dorsal

horn neuron activity, and peripheral nerve injury (Fairbanks et al., 2000; Bentley et al., 1983; Roerig et al., 1992;Roerig, 1995; Wilcox et al., 1987; Sullivan et al., 1987; Solomon and Gebhart 1988; Meert and De Kock, 1994; Joshi et al., 2000; Spaulding et al., 1979). This potentiation of opiate mediated analgesia is reversed by systemically or intrathecally administered a2-AR antagonists (Ossipov et al., 1984, 1989, Solomon and Gebhart, 1988) and is reduced in morphine tolerant rats (Roerig, 1995). In fact, a subanalgesic dose of intrathecal clonidine potentiates the antinociceptive effects of intrathecal morphine (Ossipov et al., 1989). Isobolographic analysis of the doseresponse curves of xed ratios of intrathecally administered morphine and clonidine reveals a synergistic interaction of the two (Ossipov et al., 1990). Potentiation of morphine by clonidine also occurs when both are given systemically (Spaulding et al., 1979). Intravenous administration of the two drugs may be either additive or supradditive depending on the dose ratio of clonidine to morphine and the test used (Ossipov et al., 1990). Thus, potentiation of TENS effects by clonidine is most likely a result of an interaction between a2-AR and opioid receptors in the central nervous system. Most of the early clinical studies which focused on studying the interactions between a2-AR and opioid agonists following epidural or intrathecal administration, show a potentiation of the analgesic properties of opioids following the spinal administration of a2-AR agonists (Delaunay et al., 1993; Coombs et al., 1986; Rostaing et al., 1991). Clonidine administration alone in human subjects is limited by significant side effects such as drowsiness and hypotension (for review see Eisenach et al., 1996). However, combining clonidine with opiates reduces these side effects, reduces the intake of opiates, and produces a longer lasting pain relief (Rostaing et al., 1991). More recently, Goyagi et al. (1999) demonstrated that combining the use of oral clonidine and epidural morphine produces more potent and longer lasting postoperative analgesia and decreased opiate intake than either drug alone, without increasing the incidence of adverse side effects such as nausea, pruritus, respiratory depression, and bradycardia in patients undergoing total abdominal hysterectomy. Exogenous coadministration of two or more analgesic agents produces a greater degree of analgesia, reduced side-effect prole and also a reduction in the intake of opioids (Price et al., 1996). Thus, a combination of a2-AR and opioid agonists results in a potentiated analgesic effect and reduced side effects due to a reduction in dose of the exogenously administered agonists. 4.4. Clinical implications TENS, a non-invasive, inexpensive, safe, and easy-to-use analgesic modality by itself may not be as effective an analgesic agent as when it is combined with other treatment modalities. TENS, clinically, is rarely administered in isolation. Combinations of pharmaceutical and non-pharmaceu-

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K.A. Sluka, P. Chandran / Pain 100 (2002) 183190 H. Thermal and mechanical antinociceptive action of spinal vs peripherally administered clonidine in the rat inamed knee joint model. Br J Anesth 1999;83(3):436441. Calvillo O, Ghignone M. Presynaptic effect of clonidine on unmyelinated afferent bers in the spinal cord of the cat. Neurosci Lett 1986;64:335339. Camarata PJ, Yaksh TL. Characterization of spinal adrenergic receptors mediating the spinal effects produced by microinjection of morphine into the periaqueductal gray. Brain Res 1982;336:133142. Coombs DW, Saunders RL, Fratkin J, Jensen LE, Murphy C. Continuous intrathecal hydromorphone and clonidine for intractable cancer pain. J Neurosurg 1986;64:890894. Coombs DW, Saunders RL, Lachance D, Savage S, Ragnarsson TS, Jensen LE. Intrathecal morphine tolerance: use of intrathecal clonidine, DADLE, and intraventricular morphine. Anesthesiology 1985;62:358363. Danzebrink RM, Gebhart GF. Antinociceptive effects of intrathecal adrenoceptor agonists in a rat model of visceral nociception. J Pharmacol Exp Ther 1990;253:698705. Delaunay L, Leppert C, Dechaubry V, Levron JC, Liu N, Bonnet F. Epidural clonidine decreases postoperative requirements for epidural fentanyl. Reg Anesth 1993;18:176180. Dennis SG, Melzack R, Gutman S, Boucher F. Pain modulation by adrenergic agents and morphine as measured by three pain tests. Life Sci 1980;26:12471259. Drasner K, Fields HL. Synergy between the antinociceptive effects of intrathecal clonidine and systemic morphine in the rat. Pain 1988;32:309312. Eisenach JC, DeKock M, Klimscha W. a2-Adrenergic agonists for regional anesthesia a clinical review of clonidine (19841995). Anesthesiology 1996;85:655674. Facchinetti F, Sandrini G, Petraglia F, Alfonsi E, Nappi G, Genazzani A. Concomitant increase in nociceptive exion reex and plasma opioids following transcutaneous electrical nerve stimulation. Pain 1984;19:295303. Fairbanks CA, Nguyen HO, Grocholski BM, Wilcox GL. Moxonidine, a selective imidazolinealpha2adrenergic receptor agonist, produces spinal synergistic antihyperalgesia with morphine in nerve-injured mice. Anesthesiology 2000;93(3):765773. Fielding S, Wilker J, Hynes M, Szewczak M, Novick Jr WJ, Lal H. A comparison of clonidine with morphine for antinociceptive and antiwithdrawal actions. J Pharmacol Exp Ther 1978;207:899905. Fleetwood-Walker SM, Mitchell R, Hope PJ, Molony V, Iggo A. An a2receptor mediates the selective inhibition by noradrenaline of nocicieptive responses of identied dorsal horn neurones. Brain Res 1985;334:243254. Gopalkrishnan P, Sluka KA. Effects of varying frequency and intensity of TENS on primary hyperalgesia in rats. Arch Phys Med Rehabil 2000;81:984990. Goyagi T, Makoto T, Nishikawa T. Oral clonidine premedication enhances postoperative analgesia by epidural morphine. Anesth Analg 1999;89:14871491. Han JS, Chen XH, Sun SL, Xu XJ, Yuan Y, Yan SC, Hao JX, Terenius L. Effect of low- and high-frequency TENS on MetenkephalinArgPhe and dynorphin A immunoreactivity in human lumbar CSF. Pain 1991;47:295298. Han JS, Xie GX, Ding ZX, Fan SG. High and low frequency electroacupuncture analgesia are mediated by different opioid peptides. Pain 1984;2(Suppl):543. Hargreaves K, Dubner R, Brown F, Flores C, Joris JA. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 1988;32:7788. Hayes AG, Skingle M, Tyers MB. Alpha-adrenoceptor-mediated antinociception and sedation in the rat and dog. Neuropharmacology 1986;25:391396. Hughes G, Lichstein P, Whitlock D, Harker C. Response of plasma betaendorphins to transcutaneous electrical nerve stimulation in healthy subjects. Phys Ther 1984;64:10621066.

tical treatments for pain control almost always occur. By understanding mechanisms of action, clinicians may be able to enhance the effects of non-pharmaceutical therapies and reduce side effects of pharmaceutical agents to produce better pain relief. Since TENS produces opiate mediated analgesia, it follows that its concomitant usage with an exogenously administered analgesic agent should produce a greater degree of analgesia and so also a reduction in dose of the exogenously administered agent. Several studies have shown that the intake of opiate analgesics is signicantly reduced in patients being administered with TENS (Solomon et al., 1980; Wang et al., 1997). There is an increased inhibition of primary thermal hyperalgesia in rats with inamed paws if TENS (both low and high frequency) is used in combination with systemic morphine (0.33 mg/kg i.p.). The doseresponse curve is shifted to the left implying a lower dose of systemically administered morphine is effective when combined with TENS (Sluka, 2000). The effectiveness of a reduced dose of morphine translates clinically into a reduced dosage and reduced side effects in patients, thus signicantly reducing the unwanted side effects associated with the use of opioids. In a group of patients undergoing surgery, Wang et al. (1997) demonstrate that following the administration of high frequency TENS postoperatively, there is a reduction in symptoms such as nausea, dizziness, and pruritus, associated with the use of morphine, when compared to the administration of morphine alone or administration of sham TENS group. In summary, TENS when administered alone may not be as effective an analgesic agent as when it is combined with other treatment modalities. Concurrent usage of TENS with an exogenously administered analgesic agent such as clonidine should produce a greater reduction in hyperalgesia and pain. It would thus be expected that one would reduce the side effects of clonidine and enhance analgesic efcacy. Thus, these data suggest that judicious combinations of pharmacological and non-pharmacological therapies will reduce side effects and improve treatment for pain. Acknowledgements This work was supported by grants from the Arthritis Foundation and KO2AR02201. The authors wish to thank Charles Cibula and Tammy Lisi for technical assistance, and Carol Leigh for secretarial support. References
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