Clonidine Paper

7/30/2019 Clonidine Paper

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Enhanced reduction in hyperalgesia by combinedadministration 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 highfrequency 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 ofm 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 inflamed 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 inflammation 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 significantly 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 efficacy with combinations of pharmaceutical and non-pharmaceutical treatments.q

2002 InternationalAssociation 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 cuta-

neous application of electrical currents, is used extensively

to treat both acute and chronic pain arising from a variety of

musculoskeletal conditions including inflammatory condi-

tions of the joints (see Robinson, 1996 for review). Severalstudies 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 inflamed 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

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 significant effect. Chan-

ging intensity or pulse duration does not further affect the

degree of antihyperalgesia produced by TENS (Gopalkrish-

nan and Sluka, 2000).

Both high frequency (100 Hz)(Woolf et al., 1977; Slukaet 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. Specifically, the

antihyperalgesic effects of low and high frequency sensory

TENS are mediated spinally and supraspinally by m- and d-

opioid receptors, respectively (Sluka et al., 1999b; Kalra et

al., 2001).

Systemic administration of clonidine produces antinoci-

ception 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

Pain 100 (2002) 183190

0304-3959/02/$20.00 q 2002 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved.

PII: S0304-3959(02) 00294-4

www.elsevier.com/locate/pain

* Corresponding author. Tel.:11-319-335-9791; fax:11-319-335-9707.

E-mail address: [email protected] (K.A. Sluka).


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receptors (a2-AR) (Yaksh, 1985; Maze and Tranquili, 1991;

Danzebrink and Gebhart, 1990; Pertovaara, 1993; Proudfit,

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, bradycar-

dia, respiratory depression, and sedation are recognized as

side effects associated with the use ofa2-adrenergic agonists

especially clonidine (reviewed in Eisenach et al., 1996; van

Zweiter, 1999).

Intrathecally administered clonidine potentiates the anti-

nociception produced by intrathecally or systemically admi-

nistered 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 flick 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 oflaboratory animals. Adult male SpragueDawley rats

(250400 g, Harlan, Indianapolis, IN) were used for the

study.

2.1. Induction of inflammation

The animals were acutely inflamed 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 mini-

mal movement (24.6 7.5 7.5 cm3), on an elevated glass

table, and allowed to acclimate for approximately 20

30 min. The radiant heat source, consisting of a high inten-

sity 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

offive 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

(r2 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 inflammation (base-

line), 4 h after injection of 3% carrageenan and after admin-

istration of saline (control)/clonidine and/or TENS.

2.2.2. Paw withdrawal threshold to mechanical stimuli

using von Frey filament

Von Frey filaments 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 mini-

mal movement (24.6 7.5 7.5 cm3) on an elevated

meshed platform. The von Frey filaments were individuallyapplied 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 thresh-

old was measured bilaterally. The number of trials was

restricted to two per filament (Sluka, 1997). Previous studies

have established the testretest reliability for this method of

testing (r2 0:7, P 0:0001) (Gopalkrishnan and Sluka,

2000). Before the induction of inflammation, 13% of the

rats responded to the 104 mN, 50% to the 162 mN and

37% animals respond to the 350 mN bending force. Theanimals normally do not respond to bending forces below

104 mN. This threshold value reduces dramatically follow-

ing the induction of inflammation 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 induc-

tion of inflammation, rats were randomly divided into six

groups: (1) saline1 no TENS; (2) saline1 low frequency

TENS (4 Hz); (3) saline1 high frequency TENS (100 Hz);(4) clonidine1 no TENS; (5) clonidine1 low frequency

TENS and (6) clonidine1 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 inflammation 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

K.A. Sluka, P. Chandran / Pain 100 (2002) 183190184


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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 elec-

trodes (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 analy-

sis of variance (ANOVA) was used to analyze percent

changes in PWL to heat and mechanical withdrawal thresh-

olds (P # 0:05). Posthoc test (Tukeys test) was performed

to assess changes between groups (P#

0:

05). The PWLvalues 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 repre-

sented as the median with the 25th and 75th percentiles.

ED50 values with confidence 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 significantly 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 intraperitoneallywith saline, there was no effect on the decreased PWL

(0.58^ 3.41%). The contralateral paw showed no differ-

ences in the withdrawal latency to heat after inflammation

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

significant 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 significantly on the

inflamed side following the systemic administration ofclonidine (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 significant 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 significant effect

K.A. Sluka, P. Chandran / Pain 100 (2002) 183190 185

Fig. 1. (A) PWL to radiant heat before the induction of in flammation (base-

line), 4 h after induction of inflammation, and after administration of TENS

(low frequencyP, high frequencyB and no TENSX). High

frequency TENS significantly increased the PWL to radiant heat immedi-

ately after treatment. There was no significant difference from 4 h in the

groups that received low frequency or no TENS. The in flamed paw is

represented by closed symbols whereas the uninflamed paw is represented

by open symbols. Values are mean^ SEM. (B) Paw withdrawal threshold

to mechanical stimuli before induction of inflammation (baseline), 4 h after

induction of inflammation, and after administration of TENS (low

frequencyL, high frequencyB and no TENSX). TENS had no

significant effect on the decreased withdrawal threshold to mechanical

stimuli when compared to controls. The inflamed paw is represented by

closed symbols whereas the uninflamed paw is represented by open

symbols. Data are represented as the median with the 25th and 75th percen-

tiles.


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for TENS treatment (F2;164 5:3, P 0:009) with signifi-

cant 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 PWLto heat shifted to the left following a combined administra-

tion 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 significantly 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

evidenced by a significant 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 significantly different from the

saline injected group (Fig. 2B). A significant effect for

change in mechanical withdrawal threshold occurred for

the inflamed 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 significantly

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 significantly 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, cloni-

dine, is given in combination with TENS there is an

increased inhibition of primary mechanical and thermal

hyperalgesia. Further, the ED50 values for clonidine are

significantly lower following combination with TENS

suggesting that the potency to clonidine is increased.

Thus, a lower dose of clonidine when given with TENScan 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 cerebrosp-

inal fluid 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.

Specifically, 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 in flamed

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 saline1 no TENS or

saline1 low frequency TENS or saline1 high frequency TENS (controls).

[*significantly different clonidine alone]. (B) Percent inhibition of the paw

withdrawal threshold to mechanical stimuli for the inflamed 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 saline1 no

TENS or saline1 low frequency TENS or saline1 high frequency TENS

(controls).


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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 contrac-

tions, reduces paw flinching in the formalin test, produces

analgesia in the hot plate test, tail immersion test, paw pres-

sure test, and tail flick 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 flick 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 inflammation

produced by kaolin and carrageenan knee joint injection

or carrageenan paw inflammation is reduced by systemic

or intrathecally administered clonidine and a2-AR agonists

(Hylden et al., 1991; Buerkle et al., 1999). In fact, the anti-nociception produced by systemically or intrathecally admi-

nistered clonidine exhibit enhanced efficacy at the level of

the spinal cord for the inflamed 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 recep-

tors (Yaksh, 1979; Camarata and Yaksh, 1982; Yaksh,

1985). Intrathecally administered clonidine and other a2-

AR agonists are clearly analgesic (Fairbanks et al., 2000;

Danzebrink and Gebhart, 1990; Hylden et al., 1991). Cloni-

dine administered supraspinally and intracerebroventricu-larly 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 antinocicep-

tive 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 ofa2-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 coadmi-

nistration ofa2-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 flick 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 intrathe-

cally 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 subanalge-

sic dose of intrathecal clonidine potentiates the antinocicep-

tive effects of intrathecal morphine (Ossipov et al., 1989).

Isobolographic analysis of the doseresponse curves offixed

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 ismost 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 study-

ing 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 ofa2-AR agonists (Delaunay et al.,

1993; Coombs et al., 1986; Rostaing et al., 1991). Clonidine

administration alone in human subjects is limited by signif-

icant side effects such as drowsiness and hypotension (for

review see Eisenach et al., 1996). However, combining

clonidine with opiates reduces these side effects, reducesthe 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 cloni-

dine and epidural morphine produces more potent and

longer lasting postoperative analgesia and decreased opiate

intake than either drug alone, without increasing the inci-

dence of adverse side effects such as nausea, pruritus,

respiratory depression, and bradycardia in patients under-

going total abdominal hysterectomy. Exogenous coadminis-

tration of two or more analgesic agents produces a greater

degree of analgesia, reduced side-effect profile and also a

reduction in the intake of opioids (Price et al., 1996). Thus, a

combination of a2-AR and opioid agonists results in apotentiated 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 isola-

tion. Combinations of pharmaceutical and non-pharmaceu-



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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 significantly

reduced in patients being administered with TENS (Solo-

mon et al., 1980; Wang et al., 1997). There is an increased

inhibition of primary thermal hyperalgesia in rats with

inflamed 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 clini-

cally into a reduced dosage and reduced side effects inpatients, thus significantly reducing the unwanted side

effects associated with the use of opioids. In a group of

patients undergoing surgery, Wang et al. (1997) demon-

strate 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 suchas clonidine should produce a greater reduction in hyper-

algesia and pain. It would thus be expected that one would

reduce the side effects of clonidine and enhance analgesic

efficacy. Thus, these data suggest that judicious combina-

tions of pharmacological and non-pharmacological thera-

pies 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 thankCharles Cibula and Tammy Lisi for technical assistance,

and Carol Leigh for secretarial support.

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