The pathophysiology of pain

LTC NORMALYNN GARRETT, (:RNA, MHS, AN, USA

Baltinore, Maryla nd(
MAJ FRANKLIN McSHANE, (:RNA, MSN, AN, USA
Washington, 1)(:

Iecent1 advalnces in elu(cidating the

physiologic trans5mission o/pain have lead

to new targetsfor analgesic drug
(levelop ment. New agents are lbeing studiled
in animal trials andl Jamniliardrugs are
being investigated in novel ways. Tliis paper
was written to Jain Iliarize nursi e anes thetists
with one of the new targets, ionot rofti(
glutamate receptors.
This article begins with a brie survey
of several alterniate theories o/ the origin o/'
pain, then, in more detail, describes the
anatomical
physiologi(cal basis ojpain,
focusing on the phenomenon of central
sensitization and the r'ole o/ ionoti'ofic glutamate receptdors. A n exploration o/ several
recen t piharmacologicalstudies targetingNmethyl-l)-aspartalte receptors concludes the
review.

arid

glutamate

Introduction
Pain is a complex physiologic an(d psychologic
reaction to potential or real tissue (amage o1'
disease that has sociologic implications. Anyone
who has personally exper'ienced1 pain as atresult of'
surgical intervention can well appreciate the
physical and psychological aspects of'pain and the

impact that pain has on significant others. Pain

has been defined by the International Association
for the Study of Pain Subcommittee on Taxonomy
as "an unpleasant sensory and emotional experience associated with actual or potential tissue

damage or described in terms of such damage."' It

C'l)y I

i'iClcC,

('ultulre, and~

to

Illeab~ility
providie liivelsallV Cffect ivC
palsCOntI'()l still Chudes healtlicaFC l)1'd('t itioiiel's.
Many stdieis inicate that i1i'ff(C~tivc pain (COIl tl
011ten Ias littlC to (10 with available knowledge to
treat
)aid
rather', with readily using that

butt,

knledvl'ge. A
paIin was

study

pelrfOrmied in

i nadeqllately

1972

t reatted ill

foundi

that

lhosp~italizedI

patienits (111(e to inia(IC(liate allotints Of' opioids

jreui'C(ibe(l.

Recently it was I'CjoI'te(l that 9% of'

suirgical patiCults lhadI unblearaleCpain) iii the first
24 lpostoperative Ihouris andl28%
sevCerCpain;
even 72 liouis postoper'at ively, (descipt ions of' pin
r'elief were not mutch better' with
still reportinig
uinbearale pain anld
% still reCportinlg severe'
pain. Efficacious palid1 tI'atilIl'lt is (comlplicatC(d 1y

hiadl

5%

21

siomials

Key words: Acupuncture,

receptors, pain.

simp~ly atl)hysu )logicCevent,

is 'lear that pain] is noct

(event Ifl0(lifiC(l

butt an

logic'

to trec.at lpaiidanid by the (elalborate p)lysio-

triansmission

( f pain that we

this-

areCnoIl)Vjust

Pain theories
4 'ie~rpp

mel(/jl('i ne.'[he iul1n1C'lise in1terest1ill

and

r'seaI'cli , t te'atienit,
ther1apy wi thin the
last few (decadIes has been lai'gely attributed to
Meliak
Wall who pi' posd
theory of pain,
thle gatC control t heory, that accoIll1no(Iatcd smiCe
of' thiC p)I'(oIiiiliting tlories of' pain to that
(late.'
theor'y ('omni
(1the
~i
tenets
the
previous thleoriies that had b)een expeiimentally
suppor'ted. Th'le evidence for physiologic sp~ecificity of' the
central inervous system, Which wats the
Ibasis of' the sp'cif i(ity theory, and( the evidlence fbm'
pai

ia

and

Their

central

action

of'

sumimnat ion explicated

theoryv

were

AANA

incorporated

in the sensory
iInto)t1e

Journal/August 199')!Vld.

67, No.

in ter'gate

4 349

control theory. The original theory proposed that

large inhibitory fibers and small diameter excitatory nerve fibers summate their activity in the
dorsal horn (substantia gelatinosa) which is the
"gate." If small diameter fiber activity overwhelms
large diameter fibers, the gate is opened. Central
stimulation by ascending pathways in the dotsal
column via large fibers can ultimately modulate
the sensory input at the substantia gelatinosa by
activating descending pathways, but if a critical
level of excitator-y input is reached, the action
system is activated and pain is perceived.
Shortly after the publication of' the gate
control theory, it was expanded to include mlotivational-affective, sensory-discrimi native, and cogn itive-evaluative dimensions to pain.' These aspects
of the pain experience are governed by higher
central nervous system processes, spinal coid
systems, and the reticular and limbic structures,
respectively. These 3 dimensions interact to
provide information r'egarding the magnitude and
location of the pain and inf'ormnation about the
pain based on past experience. In other words, the
addition of' these components to the gate control
theory pr'ovided a psychological/emotional
domain to the theory.
The gate control theory has been updated
based on experimental data and continues to be
updated as new knowledge in the area of' pain is
uncovered. The basic underlying theory that pain
is modulated remains, but our understanding of'
the way in which pain is transmitted and modulated has changed. In 1992, Katz and Melzak stated,
"injury or disease produces neural signals that
enter an active nerivous system that (in the adult
organism) is the substrate of' past experience,
culture, anxiety, and depression. Pain is not the
end product of a linear sensory tIansimission
system; rather, it is a dynamic process that involves
continuous interactions among complex ascending and descending systems.""

Alternative pain theories

Acupuncture. Western medicine's inability to
ef'fectively treat pain has led to an interest in alter'native theoiies and treatmeits fo~r pain an~l
westei'n style experimentationi of' those therapies.
Traditional C:hinese medicine views the body as
having 3 vital sbstances:
qi (or chi), blood, and
body fl~ids. i is the lif'e force or vital enery anld
is mnif'ested in mnany fo~rms. ~iisboth inherited
and acquiird. Patholog~y
is dlue to either an excess
of intral stress 01' externial
stress, which causes a
disturbance in 1 01' miore of' the vital sustances.

350

4iA NA Journl/ilugIIsI 1")9Q/ Vol. 67, No. 4

conditions are categorized into 4

factors and 19 types. 7 For example, fibromyalgia is
classified as an exogenous factor and clh ar'acterized as a damp disorder. Damp disorder's are those
that inteifere with the normal circulation of' qi
and the body fluids. A stagnation of'qi that leads to
a blood stagnation causes the symptoms associated
with fibromyalgia. When tendons are not irrigated
properly and vitalized by blood, pain occurs.
Stress and anxiety can cause an obstr'uction
of' qi thereby preventing blood from nourishing
the tendons. If qi is stagnated, blood
ove.
The main symptom of qi stagnation is pain. Pail,
therefore, is a symptom of' an imbalance in theit
vital forces. Treatment of'
stagnation involves
acupuncture. In order to mobilize qi, basic
acupuncture treatment points, as well as points
uniqie
fbIr that individual, are selected fri'
Pathological

can nott

qi

needlling.

Western studies conducted to establish the

of' ac upuincture have shown m ixedl
results:' One study reported that a'ulpunc'ture
ef'ficacy

was effective for a selected group of' patients, lbit

that there was
difference in pain relief lxetween
those patients whose acupunctur'e needlles wer'e
placed in the traditional Chinese loints colmnpar'ed
to those who were needled in tender airea within
the det'I'matoiial distribiution of' the lpainfl area.'
The study separated patients into 3 subsets by
measur'ing pain r'elief
to
block pi'ioi'
to the acupuncture investigation. The fir'st group
patients had pain relief' with a subariachnoid

no

subarachnoid

of'

injection of' saline. Group 2 did not have pain

relief with saline, but (id Iepoirt pain i'elief, fillowing a sensory block with lidocaine. 'I'he' thurd
g'oup) reported 110 pain i'elief 'eveln
af'tei' a (leIlse
motor' block with lidocaine. Patients in group 2,
selected by diff'eiential sllbaiacholld
loc'k
(those who hadl pain irelief, following at symnl atl1etic/sensom y blockade without motor block),
reported favorable
pain relief to
acupll('ture. (roumps I and did not. The authors
concluded that aculpulc'ture, wllhelc'
oi' not t raditional Chinese points were lsedI, was effective
for long-term pain relief in tis slctel roil.
O)thr investiationls have not bee'n abile to vei'~ifyl
the efficacy
of' acipuncture.-e
It is inernstig to>
note th~t any of' the We~stern xpeIimntis mea';srig thle effectivenecss of' aclplctur p>osrlrt'
the mcchanlismnl of' paini relief' to be ar I'lease
of1'
edogenous~'
opioids or mnodu~lation or- inibiitioni
of' central inlpt (gate control thoy).
UHomeopahy. Homeopathy
issimilar to, trad~itional
Chinese me(icine. Those who p~rctice

long-term

meIicine

hoelllopathic
blieve that all sylllptOnls
are a reflection of an imlbalance ill te patient's
inner force, called th1e vital force. AS in traditional
Chinese medicine, the vital force is hereditary. Anl
imbalance in the vital force can be causeI
exogenouls or endogenous stressors. All imbalance
in the vital force is exhibited by symptoms; pain
for example. Honweopathic treatmen ts involve the
preparation of'ultra-dilute substances that
said1

by

are

to gain

strength at

Substances

each

Successive

diltition.

are selected1 that mimic the preeniing

symptom

or symptoms. The actual proce'ss bly

hoeopath ic substances bri ng about

which
balance are not known; however', a molecular
mechanism has Ibeen
Homeop)athic
(diluents may f orm clathrate-like crystals (homeOlpatlic substances sulrrounlded by at cage of'
molecules) (luring repeated1 dilutions. The resultanlt crystals may react with cell-surf ace proteins."
Interestingly, Linus Plaling postulated this sanwie
mechanism of action for anesthetic inhalation

describe(1.

water

agents. The oultcomlces of' various clinical trials

involving honeopathic medicine have been
mixed.'"IM In one (louble blind study consisting of
p()stsurgical patients there was no (differellce
between control (placebo) and1 expeillllltal

group.' Homnoeopathic medicine has not been as

well researched throulghl traditional scientific
methods as has acupuncture.
Therapeutic touch. The pain
technique
known as therapeutic touch adopts both Eastern
and Western philosophies as at guide to treatment.
Therapeutic touch relies on1 the belief' of a unitary
life force that can be instrumellntal in assisting ai
jpatielt to rediuice stress. The reduced stress can
decrease central nervous systen1responses that
exacerbate paiin.'' Most prlactitioners in the West
believe that the effectiveness of, these treatments is
due to modulation of the painful input (ie-,
the
gate control theory). While many attribute the

r(elief'

results (if' any) to a placebo or psychologically

effect, this should not be discounted.

mediated

The anatomical basis of pain

Acute pain transmission begins with aictivai1101) of' pain r'cepto"'s
clld
nocicecpr s thati
detect tissue traura. The m~jority of' ~ocicp~tors
~re ~onspecific, frece nerve endings tht recsl~on(1
pri'iitily
to ('hica~l,meichnical,
or thetmai~l
stiu~latin. Nociceptive receptors are pt'esnt
ini skin, sbcu~tanleous tissec, bonc,joint,
muscles,
audil viscera."'
arec sti~lated
sti~nlation,

Curtaneouls mechanical
nocicptot's
by oderately
in tense eclalical
ItlchattothermIal nociceptors r-

spol(l
to 1mec'hanic'al and thet'nllal stimulllationl,
and (-polyolal tnociceptors respondl to mllechanlical, therullal, and chemical stillllli. Cold nociceptors have been described that responl to itntense

un1der'and

"silent" uinmlyelinated nlociceptor's that

(conditions (10 not fir'e,
(10 SO it)
the pr'esence'
of' inflanmlation, hlave lbeen identified..' The C-polymlodal Ilociceptot's ar'e imllportant
iln
that they coltstitttte 95% of' the sensoly C receptors in human skin." )eep somatic nocicepto's at'e
of' the f'i'ee nerve endin)g type and respod(l
to
tlte('lli(al and (chenmical stinlutlatiot).
On(ce st imlIlated1, t)ocicept ive-f' 'ee neIve
endiings transnit their' signlals to the spinal ('(1r(I
pr'elonitately
01) 2 types of' fibets,
(A6) and
C-fiber's. As-fites at'e small tllyelinailte1 fibe's that
atre specialized for' tr'atnst)itting itlsplslseS c~tic'kly.
These fiber's atre associated with fist pailn 0' first
('01(1

but

normal

also

A -lelta

which genierally prtoducl(es the senisation of'

prti(ckin~g pain), shar'p pain, anld othern sensations.
'The (.-polymllodlals, in addition) to r'espondllg to
mechanical and ther'mal stimulation, 1resoI)(l
chetlic'al stim))ulatio) it(l(itg
that hpr(ldce'(d lby
tissue tratrlla. These fibetrs tranismit their impulses
to the spital cot'd o1 C-fibet's, small nmlriyelinated
fibets that at'e l'eshponsible f'or' the establishllent of
slow laitl1 o' the second rtesponse. This pain is
dlesd't'ihbedlas bur'ning o01'
t'o)bbing.
The cell bodies of' the A6-fibetrs and C-fibet's
ate located in the dlortsal troot ganglion. Br'anches
of' the axons
these cell 1)odlies ascend(1andl
dlescndetl
flw ai few slpinal segments in the t'adt of'
I Assauet'. Ad nociceptive fiber's tetrmin~ate tiostly inl
Rexe(1 lamntae I
ter'minate it) lamuinae II
pain,

to

ft'otnl

and('V)wvhile

'-fibet(sonie
's

t(er'tinate

it) Rexed laminae

II (knowvn as the subhstantia gehatitiosa), latmitae I,

less of tell in V.',
'Ihe axo)s then synlpse with se'od l ordet'r
pain fibers. Nociceptor' afieents that te'rminate ini
laminae I getnet'ally synapse with nociceptive spec'ifi(c
tlettt'o)s, class 1 nleurons, that t'eslpotd only
thermal stimuli 01' they synapse with wide (dytnamni('
trange neurt'ons that respond to nultipe' stimuilationi.
Mansy (of' these SecotI1l )do'det'teutrons ate projection

and)(1

to

bll uct tLt))inae1"IIis abu"ttdant w.ith)~tal

t'ons. Sotne
melay inpu~rt
inlittly

ttet'eiti~

,,

of' thecse irttet'tceutt'ot~s a~e excitatoy auldi

ft'oml thec first or~derr neut'on~ls to "'!''f
tteit'ols.
There

is evidence tht a sa~ll

axons thiat

ti~ut))bet' of' c~lls inl lainace II have lonlg

neurons of' the mjot' ascnding tract, t~e spinot~lal-

11/1

~tl
A /oiu naI/A ugust POW IJ'J (ii,

.4

351

Figure

1.

Pain transmission from the periphery through the spinal cord to the brain

O=
Brain

*=

Second order neuron (possibly wide dynamic range)

Interneuron

=Second order neuron

= Peripheral nerves

= Interneuron connections
Projection to brain
= Diffuse connections throughout brain

Lamina I
Lamina II
V
0

Lamina III
c

Lamina IV

Lamina V
Lamina VI

amic, arise. Laminae V receives input from both A6fibers and C-fibers. The axons of the spinothalanic
tract generally terminate in the thalamus. Neurons
in laminae I and V also project via the spinominesencephalic tract and terminate in the inesencephalic
reticular formation, the periaq ned uctall grey region
and other midbrain sites. ' Other tracts have
been described 2 2
The final site of' pain integration is the
somatosensory cortex. Upon reaching the
thalamus, pain impulses are distributed widely
throughout the sensory cortex. These cortical
areas are responsible for our individual responses
to pain. It is here that the individual interprets the
quality of the pain impulse (Figure 1).

also

352

AAAAhurnal/Augu

1JQQ)/ Vol. 67, No. 4

The physiological basis of pain

Peripheral senisitization. thle

Im(ans by

which

these fllttlS
('ommun1licate their irlf(ioldlatio1l is
lby ('hemical traslllllitters. tissule t taumla, such
that which
dIrting
surgery, is accompalll
ie(l
b~y the escape of l)otassit1in ions andl the local
release of at Variety of (chemical mediato
these
mledliators mostly arise from the dlamlage (lonle to
ce(lls inl the immediate location of' the inljury.
Briadykinin, oneof'
th ( c'hemicals produced by
pi'oteolytic enzymies
the site of' injury and
released by c'ellular (lamage, is a poweifitl pain
nediating lpeptide that (lirectly excites A8 and
C-polyllO(,l ireceptors. Bradykinin also inll(es
Increased capillary permeability with ai resultant

occurs

its

rs.

at

plasma extravasation, and stimulates cytokine production indirectly activating the phospholipase A,
- cyclooxygenase cascade that results in the formation of prostaglandins.
The activation of phospholipase A, causes the
release of arachidonic acid from cell membrane
phospholipids. Arachidonic acid is rapidly metaboand lipoxygenase
lized by cyclooxygenase
pathways. In inflammation, cytokines stimulate
(COX-2), an alternative cyclooxycyclooxygenase
genase pathway, that causes a large production of'
prostaglandins.: Prostaglanidin E_ and prostaglandin I, are generated by this pathway and are the
prostaglandins most associated with hyperalgesia.
Prostaglandins do not directly stimulate nociceptors, instead they sensitize peripheral sensory
neurons to other stimuli, possibly by enhancing Na
and Ca' conductance." The lipoxygenase pathway
produces leukotrienes that promote sensitization
of local primary afferents as well.
As (:-polymodal receptors are excited, they
release substance P that causes a release of histamine from nearby mast cells furthering the activation of the free nerve endings. Other peptides
have been found in C-polymodal nociceptors that
probably contribute to increased inflammation.
Prostaglandins, leukotrienes, and others of' these
substances potentiate the activation of polymiodal
nociceptors. These substances help to sensitize the
primary afferent receptors causing any subsequent
painful stimuli to be enhanced. The increase in
sensitivity is exhibited by atlowering of the threshold for stimulation of nociceptors andl activation
of' nociceptors that were previously not responsive
to the stimuli. This sensitization and stimulation
by tissue damage is known as peripheral sensitization.: Peripher'al sensitization may lead to

increased

transmission

to

the

second

order

nieurons.
Central sensitization. Primary all erents, at
their synapse with secondl order neunrons, release
many substances including calcitonin gene-related
peptide that enhances the release of' glutamate
fromt the dorsal horn, substance P, and the excitaacids, lutamate and arspartate, th;it
tory aminlo
to l~i~.
elicit both a Past and slow respose
stores of' these peptides are rlea~sed
Vesiclar
upon activaition, most notble of' which are sublstance P and the excitatoy amino acids. Slbstance
P is released both peripherally, as pr-eviously
circumrdescied, and centrally. Under norma~l
stances the release of' glutaate fr-om the primaty
affere t neuron activates

luta~ate recepto

is on

second order nerons that have a hih ffinity fi'

Figure 2.
receptor

Non-N-methyl-D-aspartate glutamate

AMPA - kainate-type receptor

Na+

Glutamate I

Extracellular

Plasma
membrane

Intracellular
K;

The ligand, glutamate, binds to its binding site

causing the channel to open. The open channel allows
the free flow of Na' and K' ions eliciting depolarization
of the neuron.
AMPA - alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate

gltlallate 'These i'ecel)to- is, 'alled In )n-N-nlethylglultam1ate receptol's,

1) aslaItate (nonl-NMI)A)
'opl-paga1t the paill impulse by Ill<iatilng ex(itatoi'y p)ostsylh1pti' Jpotentials (Figure 2).
Increased afferenti traffic into the <olisal h)orn
(Itie to peripheral sensitization c'a caise stibse(luenllt changes in the dor'sal horn Ia('osti.
Netirotial threshold for' stimuli may decrease, the
f reoieno'y of' dischai'ge may increase, al(d the
'neuronsti o bec'om1e
n1eur1on slmay I'ecrit ltother

ex('itedl.

In particular,

)1'ogI('ssiv('lX'

Wide

(lynamli('

ranlge

in('rease th1(1'ir' eslp0one to

iietii'o1is
(:-fiber st initilation . Maney neuroslls
I'epeate(l
within the (lorsal horn have the ability to extell(l
their' recel)tive fields and caii recruit these I(new
areas when pain 01' stiniltio1n persists. The
release of' neurotransinitlters, i1l('ltlilIg the e('citaails, at the synapses of' the As-fibers
toi'y amllno)
icr~eased dis('arge anl expanded e mit ment
an1(l activa\tionl
rlese of' gllutatel;<
'Te C('oltintie(1t
of' thle non-NM )A ltmat e rceptoi's macxiize s
d~epolarization1 of' the sonid orde' ni'onrl..
Withi the bombahrdmnent of' the ne~ron by
st imievntua~lly
amno acids, lltaa~te
excita~tory
e
~ltes N-mecthyl-I) aspartate (NM 1)A) lltmalt
receptors that do not respond as readily to gluta-

AANA journu/August

199)/

Vol. 67, No. 4

353

Figure 3.
receptor

N-methyl-D-aspartate glutamate

Na+

Ca++

1Extracellular

Glutamate
Glycene 0
Plasma
membrane

]Intracellular
K+

mi-ate as the noii-NMI)A receptotrs because they are

blocked by Mg's when the neiti'onal membrane is
not dIepolarized (Figutre 3). The maximal Ielpolarization of' the Initi'oii ly conltiitlel release of glultamnate aiids in ireleasing Mg-' froll the ioll
challll, this eliciting a response fri'om the NMI)A
receptotrs. Activation of' the NM 1)A receptors contribiutes sulbstatially to nociceptioll ad hypet'algesta.
Substance l' cointribites to centtral senlsitization iby exerting ai positive feedback efiect on
NMI)A receptors by also tremoving the Mg' block
within the channel of' NMI)A receptors. The
combined effect of' these neuottot 'ansmi tter's is

to

Iit'onlal
stinlluts. The

illl'l lane(s

second ot'dert

ineu'on1 then inreases its tralsllissioll via the

spinothalaillic tr'act, swamping it with nociceptive
input. The inctreased activity via the spinothallll(
tra(ct to the brain, mnediated lby glutamate recep)tors and substance P, is tetrmedl central selnsltizalion. As obsetrved eamlier', a characteristic of' wide
(lynlamic range Ileuronls, one of' the types of'
ne~rons a~sso<iatedi~ with the spi~otha~~
ltnic tm'act, is
thim' abhility to sho(w at progI'essive inlcrecase inl
mesponlse to relpeated C-ibet' stimlation. Abolt
one third of' all neit'ons wit~in the spinothalamnic
tr-act at'e widle (lynanic t'age ni'c~onlsi' 'This p~~wof' (elal
sesitizationi to is soetimen~s
refet'ied
to ats "wind-uip,"
altough the two ~renot
sy oiyno~i
Central sesitizatio~n has profouniid etie'ts on
painl transmissioni. The chnges in the receptom's
Iioiiietion1

354

AANA Jour

liI/Aug'usl

I!)!)/ Vol.

(ii,

No.

Anesthetic considerations
Anesthesia practitioners find patients experiencing hyperalgesia in acnte pain settings such as
postoPerative care units or in chronic pain settings.
It is well known that once pain is entrenched, it is
dificutlt to treat withlcpioi(s. There is, in fict, some
evidence that propose opioils themselves are colltributory to the development of' o)iopiil intolerant
hlyperalgesia. Clearly o)thet pharmacol( )gical agents
in addition to the opiois are necessaty to
(Jutately treat patients exper'ien(cing hypet'algesic
type pain. Characterizing the physiological mechanismi of' pain allows re'seat'chlers to develop alter'native (riug therapies.
It is beyond the scope of' this paper' to
(lscrtibe all of' the possible pharmacological intel'rvelltiols
available that miiay, to some extellt, inibit

adle-

In the presence of glycine, glutamate binds to its binding site. With maximal depolarization, Mg++ is released
from the channel allowing free flow of Na+ and Ca"
intracellularly and K' extracellularly.

stimulate the 1)ostsynaptic

with at slpl'allmaximiial

l)wPei-ties greatly increase the intensity and

duration of' the painiIIstilllulus. Pain pertceptiol
is enhanced. The increased response to pain is
known as hyperalgesia. Once central sensitization,
or hyperalgesia, is propagated, it is very (lifficutlt to
stop (Figure 4).

hypei'algesia. None to (late are ef'f'ective in fully

relieving it. Mitch of' the newest I'eseal'chl in1thet

(of'hyper'algesia

consists (of'studlies (of'the

receptot's lbecautse they appeal' to have
crlcial role in the development of' hyperalgesia. It
is believed that dlitgs mldulating theset'eceptors
treatment

glutamate

ia

may be more efficacious in r'elievinig hyper'algesia.

Researchers are cur'rently working on phlarmllacological agents that block NMI)A receptors.
(old1Irugs
undergoing
r'eexam mat ion.

Sotile

ate

Clinical trials evaluating the efficacy of' ketatni tie,

at tnlotllpetitive NMI)A antagonist, in the tt'eatmlelit of' chronic pain and hlyperalgesia have
sho(wn promise. Inlat'andotnmied1, double-blind(,
('tOSsovet' stutdy, researchers comlpared ketam thel
to alfentanil and placebo. They (demonstrated the
effectiveness of' an intrtavenious ketamiitie bo)ltis ((50
pig/kg) followed by atl infusion (6 pig/kg pe'
mitinute ft' 20 minutes dritting which time pain
tcstl'reltts
we!'e)pe'f1t'tned) in t 'eating ('(oWe

jaie~n

s wth raumati

spd<lzinals('T'lc injtis.

IOnlsiS

ifican
t
dif'ference btweenl the ef'fect of ahti tatt~ril
and ketatnine ini meliving
sypos,
bitt in this

case ketamine displayed less side effects.

A second experiment by different investigators compared the same 3 drugs in a double-blind
crossover study in healthy patients using intradermal capsaicin (an irritant found in hot peppcrs)
injection to simulate central sensitization.
Ongoing pain, allodynia, and hyperalgesia were
assessed up to 110 minutes after capsaicin injection. The results were similar, with alfentanil producing more side effects:' The same researcher in
an earlier study demonstrated intravenous
ketamine (0.15 mg/kg) to be more effective than
morphine (0.075 mg/kg) in decreasing the pain
associated with postherpetic neuralgia. In this
study, morphine aggravated hyperalgesia, hut
ketamine effectively inhibited it. Unfortunately, in

this study, all

pati(ents in the ke'tanhine group~
sutffelred side effects il<irbothro llc'I sc)Il
tl()se'
of" the morphine gR'otIp.
l):The
mllOst h)others'oillie
side effects rel)ol'te(l were itching anI painful
inldurationls at
site Of' inject ion. Nausea was also
a ('(ollUlltl
('lj)lll )illt.
IIItei('est1iigly, 1() I)atl('ll
compIlailned() f' psychotoiletic sidIe effects. Il('
folloOw-upl study using ketamnine subcutaneously
illustrated the effectiven ess of' ketaillille, but again
it was associated with uilllcceltalble sile' (efiects)
The results of' a iIvestigattigaion by Sl'eilsen(n et al
revealedl ketaniine
be
more effec'tive ill reducing hyper'algesi
a associated1 With
fibronyalgia than morphine. Again 10 of' II
patients in the ketanmine group eXj)'l'i(nlce(I sidIe
effects.""

tkl

the

to

significantly

AAA 'A
1I Anial/Aigil'us)Y1!1!1/ I'l.(i%. No. -4

355

The curtrent interest in acetaminophen as at

preemptive analgesic has most likely come ahout
by its recently elucidated mechanism of' action as
an indirect inhibitor of the NMDA

receptor." The

studies evaluating the effectiveness of acetamno phen as a preemptive analgesic are inconcinsivei'-- An injectable form of acetam inophen that
is being developed may increase the efficacy of this
drug." Memantine, an antiviral drug with NMDA
antagonist properties, may be effective but has not
been tested in h umans." LDextromethorphan, an
an titussive with NMDA antagonist properties, has
not been shown to be effective in doses that did
not produce in tolerable side effects.''
Dizocilpi ne (MK-80 1) and 3- (2-carhoxypiperazin-4y1 )-pi'opyl-l1-phosphonic acid
are hoth1
NMDA antagonists that effectively inhibit wind-uip
andl

hype ralgesia. 5

'x-'

There is one report of' the

effectiveness of' intrathecal 3- (2-carboxypiperazin4yl)-propyl-1 -phosphonic acid in at patient with

sever'e neturopathic pain." Studies of' both of' these
dr'ugs so fat' have been limited to animals.
Human studies point out the limited usefuilness of' NMDA antagonists intravenously due to
side effects. However,
effectiveness of' NMD)A
antagonists admirnistei'ed intrathecally, thus

the

avoiding side ef'f'ects seen when administered

intravenously, seems promising.
It is clear' that the tr'ansmission of' pain is an
intr'icate and elaborate mechanism that has not
been fully elucidated. The role of excitatory amino
acids is only part of' the story. Many other (chemicals

gia: Ristilts of a cotolletrtial. 1B,1'/. I1992;305: 12.19-1252

idlotpaithitcpairt(disorder't?Aia .1aaes/hesto/ Std.

itt

1992;3(1:(37-(i-12.

lhitci paiii metchIanitisots. Paint.1 97(i;2:285-299.

tto J. Mo ltetculatrtt ttt hatt iti idobioic~
gtal t 's}tittst's to
hltttti
thi1 it(mtetd iies. Acl I s'a)/iest'ss. I995;"15:292-29(6.
(13) Mat sititi

if

ittsit is. lBAI/. 189; 299 :3(15-3661.

iictre' atmetutfibro

homeotttthit)t

I 195;-19:1i03-1(18.

iti

ittNitat agiti.f edtca'u

s.
lnce!3:7983;i97-9
91) N tl oes S',S,'els-ttlshittiattPA.
Ihivaitt iii)liii tlht

(21)rcigi-ttik
a

Attaictoit
:.

(22) Jt'ssI',

Ktls 1)1.Mittttlou

(2f

a ,t

)cttcdas
r.'t

al

ti

titssiioinigc

itt at l

(219) Miit ii i~vSS'iN, WI ts-i

i

mtodi t. a

ht rdiililt a.

I(algiaKoIa.

I.

(27) Paae ot

okM

(2i)iti

itt

Anatica

t'

ISatt996t1Itt3s:27--192

t t

Set lst

liibiths:.ltt

hiatlisag.

128

adphsilg21ass-228.ic~pin n

. axiladkelitia,

(:,ti
Sitljiti.Pti . I )

thliiiiep ii

iiitiici 1 Sitatlrigis Ii itliiitt

icaragua.72)::162-3i..191937-25
P
iliitit(I..
kit

rlitalgin

anif

ai

ti,(alisia.,iii:lott111'S 1.,

I .Nics'Pta

ealit1i,

I,

ta Iiilskiti9t1t:28-9

:i 3: I 63-172.n

f tc"scnstia

participate in the tr'ansmission of pain such as

cytokines, nerve growth factor, neui'okinins A & B,
and purines. These too are pharmacologic targets
antinocicelption. Development of' future pain

for

alt t it~ii
fcrnts
i sariua it.
ingia
.Veoios d
(:1(1)ar
Si:itRt(11(1'tR,
Ieiigis.it ABat

ther'apy is (lirected in these areas.

NI.) Putt

ttsis

REFERENCES

Hiestannt

Adt'ancesint

Fields

(1)
111., I)tthtttr R, (Ct't set it1:Feds.
) I'an
0 eiaitIilil
'theiapv. Vol. 9. Ptroceedintgs of tltecl4lh World(1 (ongress ont Pajit.News
Yorik, NY: RavetnPtress;
(2) Marks RM, Sat her ']J. titltteattttcttt
med'(ic al
with
ttarcotic antalgesic's. .Ann
iiIntern ii.ld. 1973;78:1 73-18 1
(3) Owent 11, MtcMillait V,
I). Posiopcert iie pain t hit aps A
Survey' of patientts ' \'pectatjtcs
aitt(lI tir(expetietntes. Pain1.

1985.

of

itnpatientts

Rogowski

1(.

356

-941303-30(7.

AIANA /Joui-itud/A ugust 1J )/

tb!. 67, No.

(23)

ittM, ttKe ttis s'it

Iarvard
57 (3):
UbuatiiL.

an.

1)t'IltisA,

Nei'

thig.iI.

7:11)8(- i (187 In:

tt'citgSthe 1K,1tisiiR(lt'igt~ssi

fiittaali.ts'lgi.

tt

i:i/ /FI,teoma'I.

19-1:385100
Ptait'licat'lt

'fS
i t

utf

itFotPa'n

1995:1.((4) :279-28i
rl"n.io.191312320
(:1) 1VtlltigK(:hung'iM.ft'r -h'NI,'
tilca lesitrati
lutig
pinital

itt

M ing st' K"t"tsitii.

.'tai()shmen~tofe'ntra1986:155:624-629.."os/

(34) kttcsns'tM,unit CS, ilh'at IJt'i*1L.

RA tlittltit
tltit'staiiit

tronietliaiie versus actetaniinophen ini pediatric tonsillectomy': Analgesia and bleeding. A nest/I Anaig. 1995;80:226-229.
(35) Watcha MIF, Rainirez M, White PF, Jones MIB, ILaguernela RG,
Terkonda RP. Perioperative effects of oral ketorolac and acetaminophen in children undergoing b~ilateral myringotomy. Can~ J
Anaeslhsio1. 1992;39:649-654.
of ketorolac

(36) Eisenberg E, Vos BP, Strassin AM. The NMI)A antagonist

meinantine blocks pain behavior in a rat model of formalin-induced
facial pain. Pain. 1 993;54:30 1-307.
(37) Kauppila T Gronroos M, Pertovaara A. An attempt to attenuate
experimentatIl pain in humans b~y dextromethorphan, an NMI)A
receptor antagonist. Phawmacol Biachein Behar. I 995;52 (3): 64 1-644.
(38) Woolf (J, Thompson SW. The induction antI maintenance of
central stensitizaution is dlependlant on N-methyl-I)-aspartic acid
receptor ac tiva.tion: Implications for- the treatment of postilijury p~ain
hyper sensitivity stattes. Pain. 1991 ;44:293-299.
(39) Kristensetn JD, Karlsteit R, Gordh 1T,Beige ()G. The NMI)A
anotagonist 3-(2-carboxvpipIera/il-4-y ) -propyl- I-phosphon ic acid

(CPP) has antinociceptive effect after intrathecal injection in the rat.

Pain.1994;56:59-67.

(40) Ma 0Q~ Woolf(:J. Nnxions stinuli inidutce an N-meihyl-fl-aspariate

receptior-dlependent hypersensitivity of' the flexin withdrawal reflex
to touch: Implications tfor the treatment of mechanical allodvnia.
Pain. 1995;61 :383-390).

AUTHORS
I IC Normalynn Ga~rrett, CRNA, MI IS, AN, UiSA, is currently a
doctoral student at Johnis I Iopkiiis University School of Ntursiing,
Baltimore, Md.
NIAJ Franklin McShane, CRNA, NISN, AN, USA, is a staff nurse
anesthetist at Walter Reed Army Medical (:enter, Washington, I)(:

ACKNOWLEDGMENT
[lie authors thank Sarah Eveland for her exp~ertise as a
graphlic artist.
11whviews expressed in this article are those of the ant hors alid
dio tnt reflect the official p)olicy or poisition o f the D)epart men oi
If the
Armty, IDepartment of D~efenise, or US G overnmenit.

Hone
your
knowledge!
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