,!:;;:~:i;:~i~!i :~i:~,!!:i!~i~:-::!.,~i~;~/:~!~i:~!i.!!:~~i~i~' ~ ~;i ~ ~ !ii.;::)~-!::,;~!;:~! i~;'::.:,"::~ if: :i~ 5 ~-~-: --: :~~!- :/!!;'i ~.~~:::~I./i=i : /~:- :: ~ i~-:-:-•~, ,-~:.: :~ .-
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',L-..~tense transpoints on severe re. ~ e .change in ndicate that the f o r ~ of severe
pathologiea! pain, T h e average pain decrease during stimulation sessions was 75:%~:>for,,pain.: due: to peripherai,nerve inju~, 66% for phantom limb pain, 62,% f o r : s h o ~ r , arm:pain' .=d 60%: for low:back, pain. ~ e duration.of relief. frequenflyio~l~.t~..~he:pe.fio~ of. :stimulation by. several hours, occasionally for a of ~pa~ relie~ were :s o m e ~ e s pro~AdeA ,. , , "
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..... . i Electrical stimulation of peripheral nerves, transcutaneously or by implanta:: :.te~:q~ei::~ich"d~ves; fr:om:::~]ie:i:ga~e::6ohtr;1 ~e e~or];of: p a~ is, typh~ally applies
to 'close We gate at spinal or higher levels, The method,.iw~'eh:;ii(~~es!(:i~a-i tinucus stknulations, h a s two drawbacks: CL) p r o l o n g e d i ~ / e i e ~ : ( ~ ~ t ' ! ! : ~ d < stimulation at a given skin site may'. produce dermatitis0, so...-,that:.-~the: s ~ u :~fion must sometimes bediscontinued for severaldays, and. (2) implantation :of elec~ trodes req uires .surgi~a~ . .mterventi~n and ~the :us~>~~~f ) ~ ~ y e i . ~ ` ~ m ~ n ) i ~ :~~!/:~i~i~:~iii~i`!i . . . . T~,-study investigates-an altemative:ap~rOach~ili~atii.li:may~ii6~ei:'~ . problems: the application of transcutaneous Stimulatirfi67
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c~tral origin. A}though data were obtained with only a single patient in the latter s~'.drome, failures were also observed in two additional patients with similar pain ,,.,...~c could not provide questionnaire data. (,m tr:~l procedures "~'wo types of control procedures were undertaken. First, stimulatkm of some si~,,~s, during the search for effective stimulation points, failed ,o produce relief of ~_,:~inalthgugh other points in the same patient produced marked paiin reiief. These ~:,~egafive:' sessions provide an important control since both.the.patient and the. .,:.xperimenter anticipated Nat pain relief wauld :follow stimulation:, The fact that .~m pain relief ensued after stimulation .of these 'negative ~sites but oecurredafter sthnulation of pos{tive points provides a valid 'double-blind"control for.suggestion, a~.ficipation, anxiety reduction and other cognitive variables-that influence pain. Fifteen patients provided evi'dence of both negative and posifivepoints-(TableiI), Although the patients reported no pain decrease in the PPI score, many showed a pain decrease on the P R I score, which i s presumed to reflect placebo ~-effects. Fio a~ever, there was no overlap in the scores of any of the patients: in.all 15 cases, ~:he decreases in pair~ based on PRI scores o f 'po~itive'-pointswere greater than ~hose of 'negative points .'- ' (Table I), a result that is statistically significant at better than the 0.001 level of confidence . . . . . . . . . . . . . . . . The second control consisted of the use of the.: placebo 'Vanagas wave', i.e,, strong suggestion togeeer with equipment signals even :though ne:s~krm!afion:was. applied. The electrodes for placebo stimv.lation were placedat:peints::..Nat, had
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365
~a~/U~:Pg~CENTAGE DECREASESIN PAIN.INDICES,(PPt AND P R I ) PRODUCED BY REA.L
Patient No.
Treatment .
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1 1 1 1
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13 0
9 0
2 1
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86 8
3 1
8
Real Placebo Real ~ Placebo
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80 67 76
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75 67
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produced positive effects during earlier stimulation sessions. The placebo produced a : P ~ i i ~ d ~ e ~ irrmost.patients (Table III), However, a compafiso~t of results og !~anag~si~ave'and:::mal stimulation revealed that real stimulation produced / ~ t e r :~enef of:pain:.iniaU::7 patients who were ut~zed for the control procedure. ,-~S~r~Ult:,:,~ s~fistica!!y significant at,the 0.0I level of confidence. It is also :~anL~: note:thatwhile pain relief outlasted real stimulation by one or more hou~J)hx,iall 7: ~patients, the placebo stimulation failed to produce long-lasting effe~sinany of them. ,
.
Patter~ of change in pain Several patterns of change m pain were observed. Five typical patterns a~e skovcn in Fig. 1, in which each graph shows the cumulative effects of stimulation on the.pNn of an indMduat patienL The most corrmlon effect (Fig. 1A, B) was -agradual; ~.though . ~fluCtuatmg,: decrea:se in the: PRt scores after sthaulation. In ~some: .caSes,i!the:~stsfimulafion: .pain dimirJshed rapidiy to zero 1eve1 (Fig. tA), ~wNie in others;:it.-approached zero onlyafter a relatively large number of sessions
366 Pre
20
30
'ost
B
25
15
2s 20
20
15
15
0
0
2
4 6 8 ~,0 12
lC
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5
5
0
2.4
6
8 10 12 14 16 18 20 2 2 2 4
o~
1:23456
m
0
50 45
~" 40 35 30 25 2Q i01
2
4
6
~;
10
'12
14
16
18
20
22
Stimulation Session Fig. 1. Five
24
1 2 3 4 5 6 7 8 9 10 11 12
Number
tyNcal pattern~ o f change in pain, based on values of the Pain Rating Index
(PRI) before (Pre) and after (Post) each stimulation session. Each graph shows the; cumulative effects of stimulation on the pain of an individual patient. The graphs for patients B, C, and D begin on day 2 because the first stimulation period occurred during examination in the pain clinic, which precluded administering pain questionnaires. See text for details.
(Fig. IB). This gradual overall decrease in pain during successive stimulation session, s was sometimes accompanied by a parallel day-to-day decrease in pain (Fig. 1B), fndicated by ~be presession PRI scores which represent pain levels prior to treatment. However~ other" patients showed unchanged presession pain even though the stimulation produced increasing pain relief(Fig: IA), The s.thxmtafion also increased the pain in some patients, and the :striking, totat refief observed during early sthnulafiov, sessions was not sustained (Fig. 1C); ha these eases, where stimulation made the day-to-day pare worse, the patient sometimes refused further tIeatment sessions. However, although the treatment, ~bviously failed tohelp some patients (Table I), most patients showed fluetuafior.s ha day-to-day (presession) pain, with marked diminution in pain as a result of stimulation (Fig. 1D, E). Atthough there appears to be ~ downward presession tren5 in Fig. 1D, no such trend is evident in Fig. IE. The long durat!ons of pain relief after stimulation are one of the most remarkable features of this study. Table I indicates that pain relief often out° lasted the period of stimulation by several hours, ~ometime~ for days. These durations, however, usua!Iy varied from session to se~s~',~n.~~:Four~:typical :patterns-: ~ are shown in Fig. 2. Fig. 2 1 , for example, ~saows a patient who: had e ,iatiYely brief periods of pain relief after the first few session,s; then suddenly obtNned longer periods of relief of 5 h or more; after one session, the pain was-g~me f o r o
7
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Sfi:muJa:tio~ Session Humber Fig. 2. Fe~':" 'ypical graphs of durations of pain relief following successive 30-min treatments with intense electrical stimulation. See text for details.
24 h, but then returned, and the periods of relief became progressively shorter. The patient in Fig. 2B (who had peripheral nerve damage of the lower limb) showed increasingly longer periods of relief, with two sessions that produced pain relieflfor more than 4 8 h ; the duration of pain relief increased gradually until the pain vanisheffar~d ,was~:rep!aced by a sensation of formicafion. (The forn~dcafion was :also relieved iby stimulation and eventually disappeared.) The data or" the patients ~shown in Fig. 2C,D represent commonpatterns of relief of a few hours' duration after most:sessions, with occasional sessions followed by much longer periOds of relief. The temporal variation in pain levels is especially evident in the data obtained with the home recording cards. The patients were instructed to record their pain level (on~a scale of 1-5) 4 times a day. After the cards were returned to the experimenter, the mean value for each day was plotted to provide a graph of dayto-day changes in pain. Four typical graphs are shown in Fig. 3. Fig. 3A shows the pain levels of a patient 'who kept the home recording card for a week prior to stirnulafion and!continued: (-with only a few lapses) for more than 2 months. The stHulation treatments !(indicated by arrowheads) had reIatively tittte effect until about recording day 4:0, when they produced considerab!e pain relief. The patient was then given a portable unit for daily home sfimulatie~ (HS). He was told to
368 A
5
B
5
1
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10
20
30
40
50
60
10
20
30
40
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t
60
70
80
90
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20
30
40
50
60
70
80
90
100
.
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110
Successive Recording Days
2
120
10
20
~O
Fig. 3. Typical graphs of daily mean values of Present Pain Intensity (PPI) recorded by patients at home 4 times each day. Each graph shows the cumulative effects of stimulation on ~:~e pain of an individual patient. Gaps in the graphs are days on ~¢hich the patient failed to record pain levels. Each arrowhead represents a stimulation treatment. US = beginning of ~,ome stimulation with a portable stimulator. See text for details.
stimulate the effective trigger point once a day for 20 rain. Fig. 3A shows that, after day 50, ther~ was a striking decrease in pain. Fig. 3B shows a similar sequence; in this case, however, the first few stimulation treatments produced marked relief of pain---from 3 (distressing) to between 1 (mild) and 2 (discvmforting)~ but the pain took another shift downward only after more than 2 months of use of the home stimulator. Fig. 3C shows a case in which a pain of severn years' duration suddenly vanished for the first time a few days after a single treatment. It then returned m initial levels, showing wide day-to-day fluctuations. The patient (a farmer who ~,;uffered peripheral nerve pain) used the stimulator sporadically until the pain disappeared after recording I13. (One year later,, the patient reported that the pain tended to return once or twice a month and was immediately abolished by a single shor~ period of stimulation.) Finally, Fig. 3D shows a patient whose pain tended to remain at high levels, and who dectar~ the treatment a failure and withdrew from the study on recording day 30.
Enhanced pain and change in pain locus as a prognosis of pw,'n rdief tt was sometimes obse~wed that the pain bec,ame wor.~e ~fter a stimulation session. The increase in pa~n, hi these cases, was dearly indicated on alI iindices of the Pain Questionnaire. The following day, however, many o~ th~,e ~ ' patients telephoned to say that the pa~n diminished markedly or disappeared~ altogether
.
'
~
,
369
-seVeral: h ~ r s after~. Ney .left .Ne:.hospital o f ..even. durin.g .the following day ~--a degree..~of-.ipam~relief-grea~ ~. man :.the had. experienced in years so that they could:-attNbute it o n l y : t o ~ e stimulation. This pattern of increasing and decreasing pain:never-occurredmore than once or twice for a given patient, and was usually follom~ by increasing pain relief.during the subsequent sessions. Similarly, some p~.ents :i~ d , i . : - : ~ t e r ,:~:;the:p e f i o d o f : Sfimula~ion,-:that.:their, pain: had shifted in tocation -:'forilexamp!e;:ifrom::the:: rightside!of::the.lower back t o t h e left :side. An event:such..: as this.;W~.::.atso.:usualty .fonowed-by:periods of increasing relief after su.ceeSsive stimulation sessions: ,
,
r
Interview N t l o w , up ~data
Thirty-two patients were interviewed 6-18 months after cessation of treatments in the clinic' The remaining patients had moved or could not be traced despite repeated efforts. The 32 patiems h~terviewed for fe1Iow-up, however, appear to be a representative sample of the entire group. When asked if the electrical stimulation helped their pain during the treatment period, 21 (66%) said that it did. This is almost identical with the data in Table II in which the .~. .~ percentages ~ . w~o average o f patients ": " obtained pain relief greater than 34% are 67% .and 62%: using.the PPI and PRI-~ndices. When asked whether their pain a t the time iof interview was less, the same, or worse than it had been befo~e treatment :started, 18 (56.%:)i said i~ was less. When asked what had produced this long.term improvement, 16 (50%)attributed it to the stimulation treatment as such. This is pa~icularly impressive since only 6 of these peopi~ still had home stimulators and continued to use them as needed. It appears, then, that the electrical stimulation continued to have positive effects in 50% of the sample as long as 6-18 months after the end of treatment sessions despite the fact that only about one-third of them had home stimulators to continue treatment. DISCUSSION
~
.The: data show that brief, intense ~ranscutaneous electrica] stimulation of trigger:-or.acupuncture~ points produces prolonged relief of pain in patients suffering several kinds iof severe pain. TI~ese prolonged effects are of two kinds: (1) sudden,: dramatic relief of pain for several hours after stimu!ation, and (2) graduN relief of pain over a long time-span, so that even though pain returns following a given.stimulation session, it gradually diminishes in intensity (although often with considerable fluctuation) over a period of weeks or months. The proportionsof patients helped and the degree of relief depends, in part, on the type of .pain; it is most effective for patients suffering pain due to peripheral nerve injury or low-back pain, and least effective for cervical pain and centrat pain. The effectivenes.s.of~the procedure ~may aiso depend on the patient's personality 5, the number of years of pain, and other variables yet to b e deteimined. There are many features of the data t o indicate that the effectiveness ef the procedure cannot be explained as a placebo effect. The use of a cantroi p!acebo
370 stimulus (the 'Vanagas wave') as well as the existence of both negative and positb,re points ha 15 patients (which represent a double-blind control condition) provide convincing evidence that the phenomenon is genuine. This is also indicated by the fluctuations in pain intensity and rebel duration observed in the graphs of day,today changes in pain. It is furthe~ indicated by the occasional increases in pain produced by stimulation, which are followed many hours later by unexpected, sudden, sharp decreases in pain. Most convincing of all, however, are the results of a doubIe-blmd study: Jeans 5 found that brief, intense transcutaneous stimulation at the painful area produced significantly more pain rck:'~f than placebo stimulation at the same point or true stimulation at .5istant points. These data, taken together, provide convincing evidence that pain relief prod,~-~ ~y bntense electrical stimulation is due to mechanisms other than suggestion, placebo effects, desire to please the experimenter, or experimenter bias. It has recently been proposed 2G ~ha;:: the prolonged pain relief produced by transcutancous stimulation may be due to antidromic inhibitory effects on the nerve impulse generators of damaged peripheral nerves. This peripheral mechanism, however, cannot explain the gradual, cumulative effects of repeated sthnulation which reduced and finally abolished the pain completely and indefinitely in some patients. Nor can the prolonged decrease in pain be explained in terms of a selective inhibition by large-dmme.er " fibers of transmission through the painsignafing system. The high-in.ten:~ity stimulation would ~ctivate small-diameter as well as large-diameter fibers a4. I.t is possible that the small fiber input evokes activity dhectly at the spinal level ~ a n effect which h.as been observed in the monkey 24. This inhibition persisted for about a second, and could be evoked by stimulation of areas contralateral to the receptive fields associated with the dorsal ]hom cells. However, only the extremities were effective in producing this kind of inhibition; stimulation of the arms, leg.s and trunk was ineffective. It is unlikely, therefore, that this mechani::m could underlie the effects observed in the present study since the stimulation poh~ts rarely lay on the hands and feet. Inhibition at the spinal level, however, cannot at pre:~ent be rulea out as a possibility. Another, more plausible mechanism lies in the brair~ stem areas, particularly the periventficular grey, which have been shown to be capable of inhibiting pain, Electrical stimulation of these areas can dramatically diminish or abolish pain~3,~6,v~ and inhibits the transrrfisskm of impulses at the dorsal horn leveP 9. Cells ha these areas are known to have large receptive fields, receive inputs from widespread areas of the body, and project to all levels of the spinal cord and brain. TNs system, then, which is ~idespread and includes portions of the dorsal raphe nucleus, hypothalamus, ar;d septum, could act as a 'central biasing mechanism TM that ~nhibits information transmission throughout the neurax~is. Thus, intense stimu!ation would produce a predon~.nantly small fiber input which would give rise to pain but wou~d also activate the 'central biasing mechanism' that would inhibit pain signals from other areas, such as sources of pathoIogical pain. The prolonged effects of stimulatic,n are perhap~ the most remarkable feature of this study. What are the underlying mechanisms of relief of pain for
37! hours o r days after 20 rain of intense stimulation, or the gradual decrease in pain over periods o:~ weeks or months? Livingston8 and Melzacka4 have proposed that pIolonged pathological pain may bring about permanent or semi-permanent changes ha central neural activity. Conceivably, these changes may take the form of selfzexciting neuron chains, or recurre~r.-axon loops among two or more neurons (see Me~ack!4). I t i s possible that patho,¢~~glcal" pains such as pain after low-back injury or peripheral neuropathy aredue, ha part, to prolonged activities that represent memory-}ike processes 14. A brief, intense input could 'break-up' or disrupt theacfivity in the cell assemblies that comorise the memory. This disruption could be produced by inh}bition of intraspinaI mechanisrns z4 or indirectly by activation of the central biasing mechanism and consequent descending inhibition° Thus, intense stimulation a t o n e site could di~a~pt abnormal central neural activities initiated and maintained in the cord by pathology at distant Sites. This disruption of memory.like processes, whatever the mechanism by which it occurs, could long outlast the duration of peripheral ~,~Jo':-alation. Indeed, once the person is free of pain, normal response activities could ;~roduce patterns of nerve impulses that could further prevent the memory-like activity from recurring. Or, if the abnormal central activities start up again, they may Lavolve fewer neurons, since the recruitment of neurons into the abnormally firing neuron pools would take time, and the centrally projected volleys would evoke less pain. The combination of decreased pain and increased normally patterned activities could, with time, gradually diminish the number of abnormally firing neuron pools that give rise to pain. An interesting feature of the data is the marked fluctuation from session to session seen in most of the graphs. Rarely is there a smooth, gradual increase in pare relief and duration of relief. This may be due partly to the fact that pain relief brings about increased activity in the patient, who e×ercises muscles and joints previously kept relatively immobilized because of the pain. The increased activity may subsequently gh,e rise to greater pain so that the next session is less effective. Indeed, the data show a high degree of fluctuation in presession scores, indicating ~hat the fluctuations in the magnitude of pain relief are at least in part related to presession pain levels. This baseline (presession) fluctuation does not occur ha all cases, however, and the fluctuations in relief and duration may be attributed only in part to changing response levels. They may also represent complex central neural processes that occur in respome to sammatmn, perhaps due to changes in facilitation and inhibition produced by the stimulation. It is essential to note that the method used in this study is aimed at palliative control of pain, not at 'curing' it. When it is effective, repeated stimulation is usually necessary to keep the pain under' control. Although the pain is maintained at lower, more bearable levels, it is rarely abolished permanently° The power of the method, however, is indicated by its frequent effectiveness in patients who had previously undergone a variety of treatment modalities, including rhizotomy and cordotomy, with little effect and occasionally suffered e~en worse iatrogenic pa~n. The failure of these methods, despite the power of their inherem p!a~:ebo effects, underscores the potential value of the technique of brief, intense. " ~ stimulation for
the relie~ of several forms of intractable pathological pain. It N f i a r t h e r ! ~ e ~ by the positive effects reported in the follow-up data, i n w h i c ~ p a i n - : ~ u e d : t o I be retieved for as long as 18 months after initiation of the procedure: .... " '
Supported by the Advanced Research ProjectsAgency:.ofNeDePaamemi~f: Defense and monitored by the Office o f Naval Research: under.~.:~ntr'act.)No2: N00014-70-C-0350, and by Grant A-7891 fromtheNational Research co tmcil:of Canada. " ~. . -: :~"~.: ~ I am grateful for the assistance and invaluable suggesfions"given throughout the study by Mary leans, Paul Taenzer, Jacques Perras, and :Joseph Vanagas,. This re.search was carried out at the Pain Rehabilitation Research Unit in:the Departm~nt of Psychiatry at McGill, and the Pain Treatment Center at-the Montreal General Hospital; I am grateful to Dr. Maurice Dongier and Dr. Joseph Stratford for providing facilities, encouragement, and help throughout the study..
REFERENCES 1 Auderson, D. G., Jamieson, J. L., and Man, S. C., Analgesic effects of acupuncture on the pain o5 ice-water: a double-blind study, Canad. A P~7]chol., 28 (1974)239-244. 2 Feinstein, B., Lute, 3. C., and Langton, J. N. K., The influence of phantom limbs. I~. P. Klopsteg and P. Wilson (Eds.), Human Limbs and Their Sitbstitutes, McGraw-Hili, New York, 1954, pp. 79-138. 3 Fields, H. L., Adams, 3. E., and Hosobuchi, Y., Perip;heral nerve and cutaneous electro: hypalgesia. In J. 3. Bonica (Ed.), Advances in Neuro.logy, Vol. 4, Int. Syrup. on Pain, Raven Press, New York, 1974, pp. 749-754. 4 Hazoufi, L. A., and Mueller, A. D., Pain threshold studies on paraplegic patients, Amh. NeuroL Psychiat. (Chic.), 64 (1950),607-613. 5 Jeans, M. E., El/ects o/Brief, Intense Transcutaneous Electrical Stimulation on Chronic ,Pain, Ph.D. Dissertation, McGill University, 1975, in preparation. 6 Kao, F. F., and Kao, J. J., Acupuncture Therapeutics: a n Introductory Text, Eastern Press, New Haven, Conn., 1973. .... 7 Katz, R. L , Kao, C. Y., Spiegel, H., and Katz, (3, L, Pain. acupuncture, hypnosis. I n 1. L Bonica (Ed.), Advances in Neurology, VoL 4, Int. Symo. on Pain, Raven Press, New York, 1974, pp. 819--825. 8 Livingston, W. K., Pain Mechanisms, Macmillan, New York, 1943. . . . . 9 Long, D. M., and Carolan, M. T., Cutaneous afferent stimulation in the treatment of chronic pain. In 3. 1. ~'mica (Ed.), Advances in Neurology, Vol. 4, Int. Syrup. on Pain, Raven Press, New York, 1974, pp. 755-759. 1(} Man, C0 S., and Baragar, F. D., Prelthninary clinical study of acupuncture in rheumatoid arthritis with painful knees, Y. Rheumatol., 1 (1974) 1-8. 11 Mann, F., Atlas o] Acupuncture, Heinemann Medical Books, London, 1966. 12 Mann, F., Bowsher, D., Mumford, L, Lipton, S., and Miles. 3., Treatment of intractable pain by acupuncture, LanceL i (1973) 57--60. t3 Mayer, D. L, and Liebe~kind, J. C., Pain reduction by focal electrical stimulation.of the brMn: an a~atomicaI and behavioral analysis,: Brain Res., 68 (1974) 7 3 " 9 3 . . .. 14 Melzack, R., The Puzzle .'~,]Pain, Basic Books, New York, 1973. " : !5 Melzack, R., The McGill Fain Questionnaire: major p:roperfies and scoring methods~:Palh, 1 (I975)277-299. . . . . ~. . . . . • 16 Melzack, R., and Melinko~f, D. F., Analgesia produced .by brain stimulation: .evidence, of a prulonged onset period, Exp. Neurol.,4~ (1974) 369-374. " '~ " .... ' ~:: ,~:
i;ii~i' ~, ~i~i;!,ii~~,,;:i~i ~ ~i~,!:i.~,: ~i~ii~:" i,~,:~ ~
~, ....,
-
k
17 M e r c k ; R:i S~illwell; D..M;, a n d Fox, .E:~J:: Trigger points and acupuncture points for " pa~n: correlations and:impliCa~i:ons, In preparation: 18..Me'lza~k; Ri; andWall, P. DL. :PaN:mechanisms: a new theory, Science, 15(~ (1965) 97119 Oliveras, L L., Besson, ~I. M.,. Guilbaud, G., and Liebeskind, J. C., Behavioral and electro":::phys.ol~ical: evidence, of:. p a i n . ~ i b i t i o n f r o m m!dbrain stmmlation, Exp. erain Res., . : ...exp:::~oti,':~:gO,..e~9:(i94s)1:327-~329 .....-~ ~
' ',: ,.-
:. "
~. , '
2:l.She~ly¢: C,-:N.i.:$N:yeatg:;experience with electrical stimulation for .control of pain. In .... I.~.B:onica (E~),:-Advances Neurolog:y, VoL 4, Int. Symp.;on Pain, Raven Press, New • :Yorki,~fg,74~;pp~:::7752:782:: - . . : . ' . 22-So]a,.A;.iE,~"andKuitert, J . H., Myofascial trigger point pain in the neck and shoulder girdle,:Northw; :Med; (Seattle);54 (1955)980-984. 23 Travell, J., and Pdnzler,: S. H., The myofascial genesis o f pain, Postgrad. Meal., t l (1952)
425~34ii
~i
24 Wagman, L H., and.Price, D. D., Responses of dorsal horn celts of M. mutatta te cutaneous and sural nerve A and .C fiber stimuli, J. Neurophysiol., 32 (1969) 803-817. 25 Wall, P;D., and Sweet, W. H,, Temporary aboHtlon of pain, Science, 155 (1967) 108-109. 26 Wall, P. D., and Gutnick, M., Properties of afferent nerve impulses originating from a neuroma, Nature (Lond.), 248 (1974) 740-743. 27 Wand:Tetley, I. I., Historical methods of counter-irritation, Ann. Phys. Med., 3 (1956) 90"98.
[a) !
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',L-..~tense transpoints on severe re. ~ e .change in ndicate that the f o r ~ of severe
pathologiea! pain, T h e average pain decrease during stimulation sessions was 75:%~:>for,,pain.: due: to peripherai,nerve inju~, 66% for phantom limb pain, 62,% f o r : s h o ~ r , arm:pain' .=d 60%: for low:back, pain. ~ e duration.of relief. frequenflyio~l~.t~..~he:pe.fio~ of. :stimulation by. several hours, occasionally for a of ~pa~ relie~ were :s o m e ~ e s pro~AdeA ,. , , "
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..... . i Electrical stimulation of peripheral nerves, transcutaneously or by implanta:: :.te~:q~ei::~ich"d~ves; fr:om:::~]ie:i:ga~e::6ohtr;1 ~e e~or];of: p a~ is, typh~ally applies
to 'close We gate at spinal or higher levels, The method,.iw~'eh:;ii(~~es!(:i~a-i tinucus stknulations, h a s two drawbacks: CL) p r o l o n g e d i ~ / e i e ~ : ( ~ ~ t ' ! ! : ~ d < stimulation at a given skin site may'. produce dermatitis0, so...-,that:.-~the: s ~ u :~fion must sometimes bediscontinued for severaldays, and. (2) implantation :of elec~ trodes req uires .surgi~a~ . .mterventi~n and ~the :us~>~~~f ) ~ ~ y e i . ~ ` ~ m ~ n ) i ~ :~~!/:~i~i~:~iii~i`!i . . . . T~,-study investigates-an altemative:ap~rOach~ili~atii.li:may~ii6~ei:'~ . problems: the application of transcutaneous Stimulatirfi67
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c~tral origin. A}though data were obtained with only a single patient in the latter s~'.drome, failures were also observed in two additional patients with similar pain ,,.,...~c could not provide questionnaire data. (,m tr:~l procedures "~'wo types of control procedures were undertaken. First, stimulatkm of some si~,,~s, during the search for effective stimulation points, failed ,o produce relief of ~_,:~inalthgugh other points in the same patient produced marked paiin reiief. These ~:,~egafive:' sessions provide an important control since both.the.patient and the. .,:.xperimenter anticipated Nat pain relief wauld :follow stimulation:, The fact that .~m pain relief ensued after stimulation .of these 'negative ~sites but oecurredafter sthnulation of pos{tive points provides a valid 'double-blind"control for.suggestion, a~.ficipation, anxiety reduction and other cognitive variables-that influence pain. Fifteen patients provided evi'dence of both negative and posifivepoints-(TableiI), Although the patients reported no pain decrease in the PPI score, many showed a pain decrease on the P R I score, which i s presumed to reflect placebo ~-effects. Fio a~ever, there was no overlap in the scores of any of the patients: in.all 15 cases, ~:he decreases in pair~ based on PRI scores o f 'po~itive'-pointswere greater than ~hose of 'negative points .'- ' (Table I), a result that is statistically significant at better than the 0.001 level of confidence . . . . . . . . . . . . . . . . The second control consisted of the use of the.: placebo 'Vanagas wave', i.e,, strong suggestion togeeer with equipment signals even :though ne:s~krm!afion:was. applied. The electrodes for placebo stimv.lation were placedat:peints::..Nat, had
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~a~/U~:Pg~CENTAGE DECREASESIN PAIN.INDICES,(PPt AND P R I ) PRODUCED BY REA.L
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produced positive effects during earlier stimulation sessions. The placebo produced a : P ~ i i ~ d ~ e ~ irrmost.patients (Table III), However, a compafiso~t of results og !~anag~si~ave'and:::mal stimulation revealed that real stimulation produced / ~ t e r :~enef of:pain:.iniaU::7 patients who were ut~zed for the control procedure. ,-~S~r~Ult:,:,~ s~fistica!!y significant at,the 0.0I level of confidence. It is also :~anL~: note:thatwhile pain relief outlasted real stimulation by one or more hou~J)hx,iall 7: ~patients, the placebo stimulation failed to produce long-lasting effe~sinany of them. ,
.
Patter~ of change in pain Several patterns of change m pain were observed. Five typical patterns a~e skovcn in Fig. 1, in which each graph shows the cumulative effects of stimulation on the.pNn of an indMduat patienL The most corrmlon effect (Fig. 1A, B) was -agradual; ~.though . ~fluCtuatmg,: decrea:se in the: PRt scores after sthaulation. In ~some: .caSes,i!the:~stsfimulafion: .pain dimirJshed rapidiy to zero 1eve1 (Fig. tA), ~wNie in others;:it.-approached zero onlyafter a relatively large number of sessions
366 Pre
20
30
'ost
B
25
15
2s 20
20
15
15
0
0
2
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2.4
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4
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16
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20
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Stimulation Session Fig. 1. Five
24
1 2 3 4 5 6 7 8 9 10 11 12
Number
tyNcal pattern~ o f change in pain, based on values of the Pain Rating Index
(PRI) before (Pre) and after (Post) each stimulation session. Each graph shows the; cumulative effects of stimulation on the pain of an individual patient. The graphs for patients B, C, and D begin on day 2 because the first stimulation period occurred during examination in the pain clinic, which precluded administering pain questionnaires. See text for details.
(Fig. IB). This gradual overall decrease in pain during successive stimulation session, s was sometimes accompanied by a parallel day-to-day decrease in pain (Fig. 1B), fndicated by ~be presession PRI scores which represent pain levels prior to treatment. However~ other" patients showed unchanged presession pain even though the stimulation produced increasing pain relief(Fig: IA), The s.thxmtafion also increased the pain in some patients, and the :striking, totat refief observed during early sthnulafiov, sessions was not sustained (Fig. 1C); ha these eases, where stimulation made the day-to-day pare worse, the patient sometimes refused further tIeatment sessions. However, although the treatment, ~bviously failed tohelp some patients (Table I), most patients showed fluetuafior.s ha day-to-day (presession) pain, with marked diminution in pain as a result of stimulation (Fig. 1D, E). Atthough there appears to be ~ downward presession tren5 in Fig. 1D, no such trend is evident in Fig. IE. The long durat!ons of pain relief after stimulation are one of the most remarkable features of this study. Table I indicates that pain relief often out° lasted the period of stimulation by several hours, ~ometime~ for days. These durations, however, usua!Iy varied from session to se~s~',~n.~~:Four~:typical :patterns-: ~ are shown in Fig. 2. Fig. 2 1 , for example, ~saows a patient who: had e ,iatiYely brief periods of pain relief after the first few session,s; then suddenly obtNned longer periods of relief of 5 h or more; after one session, the pain was-g~me f o r o
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Sfi:muJa:tio~ Session Humber Fig. 2. Fe~':" 'ypical graphs of durations of pain relief following successive 30-min treatments with intense electrical stimulation. See text for details.
24 h, but then returned, and the periods of relief became progressively shorter. The patient in Fig. 2B (who had peripheral nerve damage of the lower limb) showed increasingly longer periods of relief, with two sessions that produced pain relieflfor more than 4 8 h ; the duration of pain relief increased gradually until the pain vanisheffar~d ,was~:rep!aced by a sensation of formicafion. (The forn~dcafion was :also relieved iby stimulation and eventually disappeared.) The data or" the patients ~shown in Fig. 2C,D represent commonpatterns of relief of a few hours' duration after most:sessions, with occasional sessions followed by much longer periOds of relief. The temporal variation in pain levels is especially evident in the data obtained with the home recording cards. The patients were instructed to record their pain level (on~a scale of 1-5) 4 times a day. After the cards were returned to the experimenter, the mean value for each day was plotted to provide a graph of dayto-day changes in pain. Four typical graphs are shown in Fig. 3. Fig. 3A shows the pain levels of a patient 'who kept the home recording card for a week prior to stirnulafion and!continued: (-with only a few lapses) for more than 2 months. The stHulation treatments !(indicated by arrowheads) had reIatively tittte effect until about recording day 4:0, when they produced considerab!e pain relief. The patient was then given a portable unit for daily home sfimulatie~ (HS). He was told to
368 A
5
B
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1
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20
30
40
50
60
10
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60
70
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30
40
50
60
70
80
90
100
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110
Successive Recording Days
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120
10
20
~O
Fig. 3. Typical graphs of daily mean values of Present Pain Intensity (PPI) recorded by patients at home 4 times each day. Each graph shows the cumulative effects of stimulation on ~:~e pain of an individual patient. Gaps in the graphs are days on ~¢hich the patient failed to record pain levels. Each arrowhead represents a stimulation treatment. US = beginning of ~,ome stimulation with a portable stimulator. See text for details.
stimulate the effective trigger point once a day for 20 rain. Fig. 3A shows that, after day 50, ther~ was a striking decrease in pain. Fig. 3B shows a similar sequence; in this case, however, the first few stimulation treatments produced marked relief of pain---from 3 (distressing) to between 1 (mild) and 2 (discvmforting)~ but the pain took another shift downward only after more than 2 months of use of the home stimulator. Fig. 3C shows a case in which a pain of severn years' duration suddenly vanished for the first time a few days after a single treatment. It then returned m initial levels, showing wide day-to-day fluctuations. The patient (a farmer who ~,;uffered peripheral nerve pain) used the stimulator sporadically until the pain disappeared after recording I13. (One year later,, the patient reported that the pain tended to return once or twice a month and was immediately abolished by a single shor~ period of stimulation.) Finally, Fig. 3D shows a patient whose pain tended to remain at high levels, and who dectar~ the treatment a failure and withdrew from the study on recording day 30.
Enhanced pain and change in pain locus as a prognosis of pw,'n rdief tt was sometimes obse~wed that the pain bec,ame wor.~e ~fter a stimulation session. The increase in pa~n, hi these cases, was dearly indicated on alI iindices of the Pain Questionnaire. The following day, however, many o~ th~,e ~ ' patients telephoned to say that the pa~n diminished markedly or disappeared~ altogether
.
'
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,
369
-seVeral: h ~ r s after~. Ney .left .Ne:.hospital o f ..even. durin.g .the following day ~--a degree..~of-.ipam~relief-grea~ ~. man :.the had. experienced in years so that they could:-attNbute it o n l y : t o ~ e stimulation. This pattern of increasing and decreasing pain:never-occurredmore than once or twice for a given patient, and was usually follom~ by increasing pain relief.during the subsequent sessions. Similarly, some p~.ents :i~ d , i . : - : ~ t e r ,:~:;the:p e f i o d o f : Sfimula~ion,-:that.:their, pain: had shifted in tocation -:'forilexamp!e;:ifrom::the:: rightside!of::the.lower back t o t h e left :side. An event:such..: as this.;W~.::.atso.:usualty .fonowed-by:periods of increasing relief after su.ceeSsive stimulation sessions: ,
,
r
Interview N t l o w , up ~data
Thirty-two patients were interviewed 6-18 months after cessation of treatments in the clinic' The remaining patients had moved or could not be traced despite repeated efforts. The 32 patiems h~terviewed for fe1Iow-up, however, appear to be a representative sample of the entire group. When asked if the electrical stimulation helped their pain during the treatment period, 21 (66%) said that it did. This is almost identical with the data in Table II in which the .~. .~ percentages ~ . w~o average o f patients ": " obtained pain relief greater than 34% are 67% .and 62%: using.the PPI and PRI-~ndices. When asked whether their pain a t the time iof interview was less, the same, or worse than it had been befo~e treatment :started, 18 (56.%:)i said i~ was less. When asked what had produced this long.term improvement, 16 (50%)attributed it to the stimulation treatment as such. This is pa~icularly impressive since only 6 of these peopi~ still had home stimulators and continued to use them as needed. It appears, then, that the electrical stimulation continued to have positive effects in 50% of the sample as long as 6-18 months after the end of treatment sessions despite the fact that only about one-third of them had home stimulators to continue treatment. DISCUSSION
~
.The: data show that brief, intense ~ranscutaneous electrica] stimulation of trigger:-or.acupuncture~ points produces prolonged relief of pain in patients suffering several kinds iof severe pain. TI~ese prolonged effects are of two kinds: (1) sudden,: dramatic relief of pain for several hours after stimu!ation, and (2) graduN relief of pain over a long time-span, so that even though pain returns following a given.stimulation session, it gradually diminishes in intensity (although often with considerable fluctuation) over a period of weeks or months. The proportionsof patients helped and the degree of relief depends, in part, on the type of .pain; it is most effective for patients suffering pain due to peripheral nerve injury or low-back pain, and least effective for cervical pain and centrat pain. The effectivenes.s.of~the procedure ~may aiso depend on the patient's personality 5, the number of years of pain, and other variables yet to b e deteimined. There are many features of the data t o indicate that the effectiveness ef the procedure cannot be explained as a placebo effect. The use of a cantroi p!acebo
370 stimulus (the 'Vanagas wave') as well as the existence of both negative and positb,re points ha 15 patients (which represent a double-blind control condition) provide convincing evidence that the phenomenon is genuine. This is also indicated by the fluctuations in pain intensity and rebel duration observed in the graphs of day,today changes in pain. It is furthe~ indicated by the occasional increases in pain produced by stimulation, which are followed many hours later by unexpected, sudden, sharp decreases in pain. Most convincing of all, however, are the results of a doubIe-blmd study: Jeans 5 found that brief, intense transcutaneous stimulation at the painful area produced significantly more pain rck:'~f than placebo stimulation at the same point or true stimulation at .5istant points. These data, taken together, provide convincing evidence that pain relief prod,~-~ ~y bntense electrical stimulation is due to mechanisms other than suggestion, placebo effects, desire to please the experimenter, or experimenter bias. It has recently been proposed 2G ~ha;:: the prolonged pain relief produced by transcutancous stimulation may be due to antidromic inhibitory effects on the nerve impulse generators of damaged peripheral nerves. This peripheral mechanism, however, cannot explain the gradual, cumulative effects of repeated sthnulation which reduced and finally abolished the pain completely and indefinitely in some patients. Nor can the prolonged decrease in pain be explained in terms of a selective inhibition by large-dmme.er " fibers of transmission through the painsignafing system. The high-in.ten:~ity stimulation would ~ctivate small-diameter as well as large-diameter fibers a4. I.t is possible that the small fiber input evokes activity dhectly at the spinal level ~ a n effect which h.as been observed in the monkey 24. This inhibition persisted for about a second, and could be evoked by stimulation of areas contralateral to the receptive fields associated with the dorsal ]hom cells. However, only the extremities were effective in producing this kind of inhibition; stimulation of the arms, leg.s and trunk was ineffective. It is unlikely, therefore, that this mechani::m could underlie the effects observed in the present study since the stimulation poh~ts rarely lay on the hands and feet. Inhibition at the spinal level, however, cannot at pre:~ent be rulea out as a possibility. Another, more plausible mechanism lies in the brair~ stem areas, particularly the periventficular grey, which have been shown to be capable of inhibiting pain, Electrical stimulation of these areas can dramatically diminish or abolish pain~3,~6,v~ and inhibits the transrrfisskm of impulses at the dorsal horn leveP 9. Cells ha these areas are known to have large receptive fields, receive inputs from widespread areas of the body, and project to all levels of the spinal cord and brain. TNs system, then, which is ~idespread and includes portions of the dorsal raphe nucleus, hypothalamus, ar;d septum, could act as a 'central biasing mechanism TM that ~nhibits information transmission throughout the neurax~is. Thus, intense stimu!ation would produce a predon~.nantly small fiber input which would give rise to pain but wou~d also activate the 'central biasing mechanism' that would inhibit pain signals from other areas, such as sources of pathoIogical pain. The prolonged effects of stimulatic,n are perhap~ the most remarkable feature of this study. What are the underlying mechanisms of relief of pain for
37! hours o r days after 20 rain of intense stimulation, or the gradual decrease in pain over periods o:~ weeks or months? Livingston8 and Melzacka4 have proposed that pIolonged pathological pain may bring about permanent or semi-permanent changes ha central neural activity. Conceivably, these changes may take the form of selfzexciting neuron chains, or recurre~r.-axon loops among two or more neurons (see Me~ack!4). I t i s possible that patho,¢~~glcal" pains such as pain after low-back injury or peripheral neuropathy aredue, ha part, to prolonged activities that represent memory-}ike processes 14. A brief, intense input could 'break-up' or disrupt theacfivity in the cell assemblies that comorise the memory. This disruption could be produced by inh}bition of intraspinaI mechanisrns z4 or indirectly by activation of the central biasing mechanism and consequent descending inhibition° Thus, intense stimulation a t o n e site could di~a~pt abnormal central neural activities initiated and maintained in the cord by pathology at distant Sites. This disruption of memory.like processes, whatever the mechanism by which it occurs, could long outlast the duration of peripheral ~,~Jo':-alation. Indeed, once the person is free of pain, normal response activities could ;~roduce patterns of nerve impulses that could further prevent the memory-like activity from recurring. Or, if the abnormal central activities start up again, they may Lavolve fewer neurons, since the recruitment of neurons into the abnormally firing neuron pools would take time, and the centrally projected volleys would evoke less pain. The combination of decreased pain and increased normally patterned activities could, with time, gradually diminish the number of abnormally firing neuron pools that give rise to pain. An interesting feature of the data is the marked fluctuation from session to session seen in most of the graphs. Rarely is there a smooth, gradual increase in pare relief and duration of relief. This may be due partly to the fact that pain relief brings about increased activity in the patient, who e×ercises muscles and joints previously kept relatively immobilized because of the pain. The increased activity may subsequently gh,e rise to greater pain so that the next session is less effective. Indeed, the data show a high degree of fluctuation in presession scores, indicating ~hat the fluctuations in the magnitude of pain relief are at least in part related to presession pain levels. This baseline (presession) fluctuation does not occur ha all cases, however, and the fluctuations in relief and duration may be attributed only in part to changing response levels. They may also represent complex central neural processes that occur in respome to sammatmn, perhaps due to changes in facilitation and inhibition produced by the stimulation. It is essential to note that the method used in this study is aimed at palliative control of pain, not at 'curing' it. When it is effective, repeated stimulation is usually necessary to keep the pain under' control. Although the pain is maintained at lower, more bearable levels, it is rarely abolished permanently° The power of the method, however, is indicated by its frequent effectiveness in patients who had previously undergone a variety of treatment modalities, including rhizotomy and cordotomy, with little effect and occasionally suffered e~en worse iatrogenic pa~n. The failure of these methods, despite the power of their inherem p!a~:ebo effects, underscores the potential value of the technique of brief, intense. " ~ stimulation for
the relie~ of several forms of intractable pathological pain. It N f i a r t h e r ! ~ e ~ by the positive effects reported in the follow-up data, i n w h i c ~ p a i n - : ~ u e d : t o I be retieved for as long as 18 months after initiation of the procedure: .... " '
Supported by the Advanced Research ProjectsAgency:.ofNeDePaamemi~f: Defense and monitored by the Office o f Naval Research: under.~.:~ntr'act.)No2: N00014-70-C-0350, and by Grant A-7891 fromtheNational Research co tmcil:of Canada. " ~. . -: :~"~.: ~ I am grateful for the assistance and invaluable suggesfions"given throughout the study by Mary leans, Paul Taenzer, Jacques Perras, and :Joseph Vanagas,. This re.search was carried out at the Pain Rehabilitation Research Unit in:the Departm~nt of Psychiatry at McGill, and the Pain Treatment Center at-the Montreal General Hospital; I am grateful to Dr. Maurice Dongier and Dr. Joseph Stratford for providing facilities, encouragement, and help throughout the study..
REFERENCES 1 Auderson, D. G., Jamieson, J. L., and Man, S. C., Analgesic effects of acupuncture on the pain o5 ice-water: a double-blind study, Canad. A P~7]chol., 28 (1974)239-244. 2 Feinstein, B., Lute, 3. C., and Langton, J. N. K., The influence of phantom limbs. I~. P. Klopsteg and P. Wilson (Eds.), Human Limbs and Their Sitbstitutes, McGraw-Hili, New York, 1954, pp. 79-138. 3 Fields, H. L., Adams, 3. E., and Hosobuchi, Y., Perip;heral nerve and cutaneous electro: hypalgesia. In J. 3. Bonica (Ed.), Advances in Neuro.logy, Vol. 4, Int. Syrup. on Pain, Raven Press, New York, 1974, pp. 749-754. 4 Hazoufi, L. A., and Mueller, A. D., Pain threshold studies on paraplegic patients, Amh. NeuroL Psychiat. (Chic.), 64 (1950),607-613. 5 Jeans, M. E., El/ects o/Brief, Intense Transcutaneous Electrical Stimulation on Chronic ,Pain, Ph.D. Dissertation, McGill University, 1975, in preparation. 6 Kao, F. F., and Kao, J. J., Acupuncture Therapeutics: a n Introductory Text, Eastern Press, New Haven, Conn., 1973. .... 7 Katz, R. L , Kao, C. Y., Spiegel, H., and Katz, (3, L, Pain. acupuncture, hypnosis. I n 1. L Bonica (Ed.), Advances in Neurology, VoL 4, Int. Symo. on Pain, Raven Press, New York, 1974, pp. 819--825. 8 Livingston, W. K., Pain Mechanisms, Macmillan, New York, 1943. . . . . 9 Long, D. M., and Carolan, M. T., Cutaneous afferent stimulation in the treatment of chronic pain. In 3. 1. ~'mica (Ed.), Advances in Neurology, Vol. 4, Int. Syrup. on Pain, Raven Press, New York, 1974, pp. 755-759. 1(} Man, C0 S., and Baragar, F. D., Prelthninary clinical study of acupuncture in rheumatoid arthritis with painful knees, Y. Rheumatol., 1 (1974) 1-8. 11 Mann, F., Atlas o] Acupuncture, Heinemann Medical Books, London, 1966. 12 Mann, F., Bowsher, D., Mumford, L, Lipton, S., and Miles. 3., Treatment of intractable pain by acupuncture, LanceL i (1973) 57--60. t3 Mayer, D. L, and Liebe~kind, J. C., Pain reduction by focal electrical stimulation.of the brMn: an a~atomicaI and behavioral analysis,: Brain Res., 68 (1974) 7 3 " 9 3 . . .. 14 Melzack, R., The Puzzle .'~,]Pain, Basic Books, New York, 1973. " : !5 Melzack, R., The McGill Fain Questionnaire: major p:roperfies and scoring methods~:Palh, 1 (I975)277-299. . . . . ~. . . . . • 16 Melzack, R., and Melinko~f, D. F., Analgesia produced .by brain stimulation: .evidence, of a prulonged onset period, Exp. Neurol.,4~ (1974) 369-374. " '~ " .... ' ~:: ,~:
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17 M e r c k ; R:i S~illwell; D..M;, a n d Fox, .E:~J:: Trigger points and acupuncture points for " pa~n: correlations and:impliCa~i:ons, In preparation: 18..Me'lza~k; Ri; andWall, P. DL. :PaN:mechanisms: a new theory, Science, 15(~ (1965) 97119 Oliveras, L L., Besson, ~I. M.,. Guilbaud, G., and Liebeskind, J. C., Behavioral and electro":::phys.ol~ical: evidence, of:. p a i n . ~ i b i t i o n f r o m m!dbrain stmmlation, Exp. erain Res., . : ...exp:::~oti,':~:gO,..e~9:(i94s)1:327-~329 .....-~ ~
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2:l.She~ly¢: C,-:N.i.:$N:yeatg:;experience with electrical stimulation for .control of pain. In .... I.~.B:onica (E~),:-Advances Neurolog:y, VoL 4, Int. Symp.;on Pain, Raven Press, New • :Yorki,~fg,74~;pp~:::7752:782:: - . . : . ' . 22-So]a,.A;.iE,~"andKuitert, J . H., Myofascial trigger point pain in the neck and shoulder girdle,:Northw; :Med; (Seattle);54 (1955)980-984. 23 Travell, J., and Pdnzler,: S. H., The myofascial genesis o f pain, Postgrad. Meal., t l (1952)
425~34ii
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24 Wagman, L H., and.Price, D. D., Responses of dorsal horn celts of M. mutatta te cutaneous and sural nerve A and .C fiber stimuli, J. Neurophysiol., 32 (1969) 803-817. 25 Wall, P;D., and Sweet, W. H,, Temporary aboHtlon of pain, Science, 155 (1967) 108-109. 26 Wall, P. D., and Gutnick, M., Properties of afferent nerve impulses originating from a neuroma, Nature (Lond.), 248 (1974) 740-743. 27 Wand:Tetley, I. I., Historical methods of counter-irritation, Ann. Phys. Med., 3 (1956) 90"98.
