ALPHA(2)-ADRENERGIC AGONISTS

Epidural or intrathecal clonidine produces analgesia without either the motor an

d proprioceptive block associated
with local anesthetics or the nausea, pruritus, and potential respiratory depres
sion of opioids; however, the
hemodynamic side effects of clonidine include hypotension and a decrease in hear
t rate. Clonidine is approved for
intraspinal administration in the treatment of patients with neuropathic cancer
pain. This compound is synergistic
with spinal opioids[106] [107] [108] [109]
and intrathecally administered local anesthetics.
[110] [111] [112] [113]
Clonidine produces
analgesia by mimicking activation of the descending noradrenergic pathways and i
nhibiting the release of substance
P. Autoradiographic studies have shown that clonidine binds in the superficial l
ayers of the dorsal horn, which is a
site of major importance for transmission and modulation of pain impulses.
[114] [115]
Alpha(2)-adrenergic receptors are
located centrally and peripherally and are both presynaptic and postsynaptic.
A plethora of clinical studies have been performed to evaluate the synergism bet
ween clonidine, opioids, and local
anesthetics. Some studies have suggested an analgesic effect after systemic clon
idine administration. Eisenach and
associates
[116]
investigated the analgesic effects of intrathecal and intravenous clonidine by m
eans of acute noxious
stimulation after the intradermal administration of capsaicin in volunteers. The
capsaicin injection produced pain,
followed by hyperalgesia and allodynia. The intrathecalbutnot the intravenousinjec
tion of 150 g of clonidine
reduced capsaicin-induced pain and hyperalgesia in response to heat stimulation.
The authors concluded that this
supported the efficacy of intraspinal administration of clonidine for the treatm
ent of acute pain and of pain states
associated with hyperalgesia, inasmuch as this experimental model represented cl
inical pain states. Gentili and
colleagues
[117]
evaluated the use of intra-articular morphine and clonidine alone and in combina
tion after knee
arthroscopy. The authors were unable to demonstrate an advantage with the combin
ation; however, both drugs
administered singly provided analgesia. In contrast, Joshi and coworkers
[118]
found an advantage to the morphine and
clonidine combination after arthroscopic procedures.
Other investigators have evaluated clonidine as a component of regional anesthes
ia in different models. No benefit
was found with clonidine as a component of a peribulbar block[119]
or in combination with bupivacaine for wound
infiltration after inguinal hernia repair.
[120]
In contrast, clonidine has proved beneficial as a component of a brachial
plexus block.[121]The addition of clonidine as an adjunct to intravenous regiona
l anesthesia is controversial.
Kleinschmidt and colleagues[122]
report no advantage, whereas other investigators report a decrease in tourniquet

pain
with the addition of clonidine.[123]
137
Section III - Chapter 10 - Clinical Research
Armand and associates attempted to perform a meta-analysis of published literatu
re on the efficacy of epidural
clonidine for the treatment of postoperative pain.
[115]
The investigators concluded that between 1985 and 1997, all but
16 of the published studies suffered from serious design flaws such as lack of c
ontrols, lack of randomization, or
inadequate statistical analysis. The data from these studies were difficult to i
nterpret because of the tremendous
differences in variables, particularly in the dose of clonidine, the level of ep
idural injection, the time of
administration, type of anesthesia, the type of surgery, and the reference and r
escue drugs. These differences
precluded any meta-analysis of this data.
In conclusion, clonidine appears to offer benefit in combination with spinal and
epidural local anesthetic solutions
and opioids; however, the hemodynamic and sedative side effects may be bothersom
e. Evidence exists for the use of
this compound in other types of regional anesthesia, but further trials are need
ed. Dexmedetomidine is another
alpha(2)-adrenergic agonist that has been used in humans mainly as an intravenou
s or intramuscular injection.
Intrathecal administration has been evaluated in animal models.
[124]
Although the compound appears to have analgesic
properties, its value as a component of regional anesthesia and pain management
remains to be determined.
Similarly, Tizanidine, an alpha(2)-adrenergic agonist that is used mainly as a p
otent, central-acting myotonolytic
agent, has not been evaluated as a component of regional anesthesia, although it
may be beneficial in certain pain

Clonidine
The centrally acting selective partial 2-drenergic gonist clonidine, becuse of
its bility to reduce sympthetic
nervous system output from the centrl nervous system, cts s n ntihypertensi
ve drug.
[9]
Preservtive-free
clonidine, dministered into the epidurl or subrchnoid spce (150450 g), produc
es dose-dependent nlgesi
nd, unlike opioids, does not produce depression of ventiltion, pruritus, nuse
nd vomiting, or delyed gstric
emptying.
[70] [71] [72]
2-Adrenergic drugs such s clonidine, dexmedetomidine, nd tiznidine exert ctio
n on the descending inhibitory
monominergic trcts, resulting in n ntinociceptive effect. Clonidine produces
nlgesi by ctivting postsynptic
2receptors in the geltinous substnce of the spinl cord. The use of neurxil c
lonidine, either to produce

nlgesi or to prolong the effects of regionl nesthesi, my be ccompnied b

y side effects, nmely, hypotension
nd dryness of the mouth.
Most evidence bout the effectiveness of intrthecl clonidine is provided by st
udies on postopertive pin.
[73]
These
studies show the effect of locl nesthetic on the durtion nd intensity of s
pinl blockde. Moreover, the ddition
of intrthecl clonidine results in longer period of postopertive nlgesi.
[74]
Vn Elstrete nd collegues,[75]
in 2000, ssessed the nlgesic efficcy nd side effects of cudlly dminister
ed
clonidine s mixture of bupivcine 0.5% with lidocine, nd 2% with epinephri
ne. They concluded tht the
Section IV - Chpter 14 - Adjuvnt Drugs
253
ddition of 75 g of clonidine incresed the durtion of postopertive nlgesi i
n dults without ffecting men
rteril pressure. On the other hnd, Ivni nd Lmpugnni,
[76]
in 1998, stted tht theuse of clonidine s n
djuvnt drug in the field of regionl nesthesi both in dults nd children se
ems to be very effective nd in the
peditric field is sfer with respect to opioids nd drenline. In contrst, Bre
schn nd coworkers
[77]
concluded tht
the dministrtion of 2 g/kg of clonidine cudlly in neontes for postopertive
nlgesi could cuse respirtory
depression. Postopertive pin relief bycontinous epidurl infusion of ropivci
ne hs been improved by the
ddition of clonidine.
[78]
For spinl nesthesi, motor nd sensory blocks re prolongedwith the ddition o
f clonidine to locl nesthetics, but
the requirement for ephedrine tretment is not incresed.
[79]
The combintion of clonidine, in dose of 100 to 150 g with fentnyl, results in
prolongtion of fentnyl nlgesi.
Continuous infusion of clonidine lone produces rte-dependent reduction in the
need for other pin mediction
fter surgery. The importnce of these infusion rtes is tht they re not ssoc
ited with sedtion, lthough blood
pressure is slightly decresed compred with plcebo. The ddition of clonidine
to other opioids for continuous
epidurl infusion reduces the opioid dose by 20% to 60%.
[79]
It is possible for clonidine to produce postopertive
nlgesi with either systemic or epidurl injection, but the epidurl dose of c
lonidine required is lower thn the
systemic one.
[80]
This is in contrst to fentnyl nd sufentnil, in which there is no difference
in dose between the two
routes. There is cler evidence tht fixed dose (150 g) of clonidine intrmuscu
lrly, epidurlly, or intrtheclly
hs cler order of durtion: intrthecl > epidurl > intrmusculr, supportin
g intrspinl dministrtion.

Eisench nd collegues [81]

crried out review of the use of clonidine in regionl nesthesi s presented
in the
interntionl literture of 1995. Most controlled nd uncontrolled trils were c
oncerned with epidurl or spinl
dministrtion, primrily in periopertive nd obstetric ptients. The findings
demonstrted tht clonidine,
depending on dose nd codministered gents, ws ble to reduce blood pressure.
Furthermore, there hve been no
reported cses in the literture of life-thretening hypotension or brdycrdi.
Eisench nd ssocites rgued tht it
ws this fctor tht ws the key benefit of clonidine, considering the smll but
significnt incidence of respirtory
depression tht occurs with use of epidurl nd spinl opioids.
[71]
However, clonidine fils to produce surgicl nesthesi nd is therefore not dm
inistered lone during surgery or for
the finl stges of lbor. In ddition,clonidines side effects, dose-dependent se
dtion nd hypotension, preclude its
dministrtion in lrge doses nd hve led to wrning lbel by the U.S. Food
nd Drug Administrtion tht it not
be dministered routinely in postopertive nd obstetric settings.[82]
On the other hnd, smll doses of intrthecl
clonidine hve shown much promise for lbor nlgesi.
In study reported in 2000, Pech nd coworkers
[83]
concluded tht the ddition of clonidine to epidurl bupivcine
nd fentnyl for ptient-controlled epidurl nlgesi in lbor improved pin co
ntrol nd the supplementtion rte
nd shivering. Incresed sedtion nd lower blood pressure were not cliniclly i
mportnt.
As sole gent, clonidine, 50 g, gives bout 45 minutes of good nlgesi. At 10
0 to 200 g, the nlgesi is
longer but hypotension cn be profound.
[84]
When clonidine, 30 g, ws codministered with sufentnil (2.5 g nd 5
g), nlgesi ws prolonged.[85]
The sme result hppened when clonidine, 50 g, ws dded to sufentnil, 7.5 g,
nd bupivcine, 2.5 mg.
[86]
In these sitution, no dverse side were noted nd the opioid dose ws reduced.
LONIDINE
Clonidine, n 2drenergic receptor gonist, used intrtheclly orepidurlly in n
iml studies nd in humns hs
been shown to provide potent nlgesi whether used lone or in combintion with
intrspinl opioids. Clonidine is
not pproved for clinicl use in the United Sttes nd is experimentl. Some ut
hors hve found tht combining the
953
Section V
Chpter 38 - Intrthecl Therpies for the Tretment of Chroni
c
Pi
2drenergic receptor drug clonidine with receptor lignd provides more profound
nlgesi t dose lower thn
would be expected if either drug were given lone.[127] [128] [129] [130]
This phenomenon of one drug dding to the effect of
nother is clled synergy.
Animl models of neuropthic pin hve demonstrted ntinociception with tretme

nt by intrthecl clonidine nd
other 2gonists.
[131]
Clonidine ppers to block substnce P relese t the presynptic receptor nd b
locks the firing
of the second order nociceptive neuron. Clonidine cts primrily t the spinl c
ord level, where norepinephrine
receptors re found,
[132]
but it my lso hve suprspinl effects t the rostrl ventrl medull, especi
lly with orl
dministrtion. Clonidines bility to stimulte 2drenoreceptors in the brinste
m to reduce sympthetic outflow
hs been used for yers in the tretment of hypertension.
Dily intrthecl dosges in humns hve rnged from 3 g/kg to 60 g/kg. Filos nd
ssocites
[133]
studied the
nlgesic effect of 150, 300, or 450 g of clonidine given intrtheclly fter ces
ren section to 30 women with
generl nesthesi. Good nlgesi ws noted immeditely for up to 80 minutes po
stopertively. Currently,
multicenter protocol is being conducted in the United Sttes, using infusion rt
es of continuous intrthecl clonidine
between 0.7 g/hr nd 4 g per hour vi implnted infusion devices. Clonidine in 150
or 500 g/mL in 20-mL vils
is used to fill the intrthecl pumps (unpublished dt).
Studies in vrious nimls nd humns hve demonstrtedno neuropthology fter
dministrtion of intrspinl
clonidine. The min side effect of clonidine given intrtheclly is hypotension.
Humns my lso experience
decreses in hert rte. Electrolytes, glucose, nd cortisol levels were found t
o be stble in humns fter infusion of
clonidine.
[134]
Other side effects include dry mouth, drowsiness,dizziness, nd constiption. Su
dden withdrwl of
clonidine cn precipitte gittion nd hypertension.
Clonidine my be useful in fcilitting spinl receptor holidy in ptients wh
o hve become tolernt of high
doses of opioids.[135]Clonidine my lso be effective for treting neuropthic p
in[136] [137]
nd symptheticlly medited
pin syndromes. [138
dri text book regionl nestesi
sttes.