STUDIES ON PAIN. OBSERVATIONSON PAIN DUE TO LOCALCOOLINGAND ON FACTORSINVOLVED IN THE

"COLD PRESSOR"EFFECT

By STEWARTWOLFAND JAMES D. HARDY(From the Russell Sage Institute of Pathology, in affiliation with the New York Hospital and

the Departments of Medicine and Psychiatry, Cornell UniversityMedical College, New York City)

(Received for publication May 6, 1941)

When a subject's hand is immersed in coldwater two phenomena are known to occur. Thesubject experiences pain and an elevation of bloodpressure. The latter phenomenon has been usedas the basis for the Hines-Brown " cold pressor "test (1). The occurrence of pain has receivedlittle attention, and is alluded to only incidentallyin the articles on the " cold pressor " test. Pain,however, has been suspected of being concerned inthe production of the hypertension (2). In thepresent work on pain due to local cooling, wehave found direct correlation between the degreeof cooling, the intensity of pain induced by thecold, and the height to which the blood pressurerises.

Lewis (3), in an analysis of the vascular reac-tion to cold, noted that in fingers immersed incold water from 0° C. to 18° C. a painful achingoccurred " soon " after immersion. No attemptwas made to study the nature of the pain. Theburning pain produced on the skin of the arm bya dry ice stimulator has been studied (4). Thepain was shown to be adaptable and, contrary toGoldseheider's theory that pain is an exaggeratedpressure sensation, it was shown to be a separatesensory function. The mechanism of productionof the pain, however, was not investigated.

The aim of this communication is to report ona study of the phenomenon of pain due to localcooling, which, for convenience, we call "coldpain ". The pain is conveniently produced and,owing to its predictable character, lends itself toanalysis.

METHOD

The subject was placed in a reclining position on acot beside an earthenware crock holding 20 liters ofwater which was stirred vigorously by a propeller at-tached to a small motor. Because of the large volume,the bath could be maintained at constant temperature forthe duration of an experimental observation without the

aid of a thermostatic device. The left hand of the sub-ject was plunged into the water up to the wrist. Thetime of onset of pain was recorded and an attempt wasmade to estimate the intensity of pain being suffered ata given moment.

WVhile these observations were being made, the bloodpressure in the opposite arm was estimated by means ofa mercury sphygmomanometer at as frequent intervals aspossible. The skin temperature of the immersed handwas determined continuously by the use of a copper andconstantan thermocouple fixed to the pad of the terminalphalanx of the middle finger. The amplitude of pulsa-tions of the digital artery was also recorded by using asmall glass plethysmograph fitted to the index finger ofthe immersed hand. The plethysmograph was connectedby an air system to a tambour on which was mounted asmall mirror. Movements of the latter were recorded ona camera by reflecting a beam of light on the movingfilm. Extraneous factors which are known to influencethe amplitude of pulsation of the digital artery (5 to 13)were all carefully controlled.

The results of a series of 54 experiments which pro-vide 121 observations are reported. The observationswere made mainly by the authors upon one another, sinceuninterested subjects could scarcely be called upon toundergo the necessary amount of physical discomfort.

OBSERVATIONS

I. Sensations induced by local coolingA. Deep aching pain and its "'adaptation ".

Immersing the hand in water warmer than 180 C.caused no pain, but at 180 C., and slightly below,there was a fleeting deep ache which occurredafter the hand had been immersed about 60 sec-onds, and then promptly ceased. At progressivelylower temperatures the pain had its onset soonerand was more intense, always reaching its maxi-mumat about 1 minute. It then began to subside,and in 4 to 5 minutes was no longer perceived.The character of the pain was aching; there wasa feeling as if the hand had been crushed. Thedistribution was generalized and deep throughoutthe immersed hand, and the pain was perhapsmost intense on the radial side. It was continu-

521

STEWARTWOLFAND JAMES D. HARDY

ous and non-pulsatile. Exercise of the fingers ormovement of the hand did not influence the char-acter or intensity of the pain. There was notenderness in the hand since it could be struckagainst the side of the bath without altering thesensation of pain. Sixty seconds after immersionthe peak of pain intensity was reached. This wasfollowed by amelioration, and finally cessation ofthe pain. The disappearance of pain while thehand is still immersed in the water we have called"adaptation

A barely perceptible painful sensation experi-enced as a deep ache in the immersed hand wasdesignated as threshold pain. Additional incre-ments in pain intensity were indicated in termsof pulses, 8 + being used for the pain of greatestintensity experienced. The distribution of painas high as 2 + was confined to the hand. At

3 +, however, there occurred a radiation of theache up the inner aspect of the arm. At 4 +pain was felt in the axilla. At this intensity thesubjects usually showed a reaction to the stimuluscharacterized by rapid irregular respirations, aswell as by adventitious movements of the feet.At 5 + the restlessness was replaced by writhingmovements and the subject's face betrayed suf-fering. From 6 + to 8 + the pain provokedperspiration and approached the unbearable level.During the first minute after immersing the handin cold water it was quite clear that the pain wasbecoming more and more severe. Each time adefinite increase in pain intensity was felt thesubject called out an additional plus. Similarly,as adaptation occurred after one minute and thepain was dearly becoming less intense, the subjectcalled out one less plus at each perceptible de-

INTENSilYOF

PAIN$4+ -

-2

6- /

5+- /

4+-

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1+ -

O--I

HAND IMMERSED

PINS4+ -

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1+-

In.I I I I I I II I I I I I I I

0 60 120 180 240 300 360TIME IN SECONDS

FIG. 1. THE COURSEOF THE ESTIMATED INTENSITY OF PAIN AND " PINS AND NEDLES" SEN-SATION EXPEINCED WITH VARIOUS STRENGTHSOF COLD STIMULUS

522

I

PAIN DUE TO COOLING

PAIN

8+

7+

0

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0

0 01

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I I l15 10 5

TEMPERATUREOF WATER

FIG. 2a. THE ESTMATDPEAK OF PAN INTENSITY PLOTTEDAGAINST THESTRENGTHOF THE COLD STIMULUS

crease in pain intensity. The values thus estab-lished were roughly reproducible at any time. Asubject immersing his hand in water of unknowntemperature consistently called out the same num-ber of pluses as had been previously assigned tothat particular temperature. Therefore, althoughnot precise, this method has proved useful hereas in other studies of sensation (14, 15). Figure1 shows the course of estimated pain intensity inthe hand immersed in water at different tempera-tures. Figure 2a shows maximal pain intensityplotted against water temperature. It is apparentthat pain intensity as estimated increases uni-formly with the strength of stimulus measured interms of temperature of the water bath. It is also

AREABENEATHPAIN CURVESQUNITS

30-

20-

10-

0-I20 C.

of interest that the line points directly at 180 C.which, as noted above, was found to be the high-est temperature at which this variety of pain oc-curs. In Figure 2b the total area under the paincurves at various temperatures is plotted againstthe temperature of the bath. The total amount ofpain experienced also increases uniformly withthe strength of stimulus.

B. " Pins and Needles" sensation. The sensa-tion of " pins and needles" occurred only in watercolder than 120 C. The sensation was felt in theentire immersed hand from 60 to 90 seconds afterimmersion. This sensation, occurring shortlyafter the peak of the aching pain, steadily in-creased in intensity as the pain decreased. The

0

0.~~~~0;

I I

0 -2C ..

FIG. 2b. THE TOAmLAREA BENEATHTHE CURVESOF PAIN INTENSITY IN FIGURE 1

PormD AGAINST STRENGTHOF COLD STIMULUS

0

o o

o o

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15 10 5TEMPERATUREOF WATER

523

STEWARTWOLFAND JAMES D. HARDY

lower the bath temperature, the more intense wasthe prickling. Like pain, this sensation ran acycle of aggravation and then adaptation, until atthe end of 8 to 10 minutes the immersed hand feltonly the cold of the water (Figure 1). The sen-sation of touch and of pain to pin prick, however,as well as motor power in the fingers, remainedintact. This " pins and needles " sensation, whenintense, caused a great deal of discomfort to thesubject. At -2° C., although the aching painhad been tolerated well past its peak of severity,the subject was forced to withdraw his hand ow-ing to the suffering imposed by the growing in-tensity of the " pins and needles " sensation.

NERA43EOFGONTROCLPETFRIO'KD

C. "Adaptation ". If the hand were withdrawnbefore the pain had reached its maximum inten-sity, there was a momentary twinge of extra painimmediately after withdrawal. If the hand werewithdrawn at any time before complete " adapta-tion" had taken place and then at once re-im-mersed, the pain would recur with nearly as greatan intensity as occurred with the original immer-sion. If, however, the hand were left in until" adaptation " had taken place, it could be with-drawn and re-immersed in the cold water withoutpain being experienced (Figure 3). This adap-tive effect which protected the hand from paindiminished as the skin temperature was allowed to

ADAPTATION STUDY

PULSE AMPLITUDE ANDDEGREEOF PAIN

,70

%40

30H E EHANDLEFT IN UNTIL COMPLETEADAPTATION OCCURREDAMAPTATIONHAD OCCURRED

KV,d FiANDHANDIN =208+ mI| IN

6+4

5+

4+DEGREE

OF

2+

1+

50 100 15V 50 300 400 4S0 500

NO PAIN

ADAPTATION WILL LAST AS LONG ASTHE HAND IS COLDOR AS LONGASDIGTAL PULSE IS SMALL.

600 650 700 75 80 SECONDS

TIME IN SECONDSFIG. 3. STUDY OF ADAPTATION. THE RELATIONSHIP BETWEENTHE TEMPORALCOURSEOF PAIN SENSATION.

ITS " ADAPTATIONS" AND THE AMPLITUDE OF PULSATION OF THE DIGITAL ARTERY

524

HAND I NI

i

PAIN DUE TO COOLING

rise. There was partial protection, however, untilthe temperature of the hand reached 330 C. Atthis point, an immersed hand would feel the usualintensity of pain regardless of how quickly orslowly it had been warmed. " Adaptation " wascompletely effective only for the temperature ofthe water in, which the hand was adapted, or forhigher temperatures. Thus, if a hand adapted inwater at 100 C. were withdrawn and plunged di-rectly into water at 50 C. the cycle of pain wouldoccur as usual, the onset being somewhat delayedand the intensity of pain somewhat less than itwould have been had a warm hand been immersed.

II. Spatial summationWhen applied to a sensation, the term " spatial

summation" means that the larger the area stimu-lated, the weaker would be the stimulus necessaryto produce the sensation in question. Hardy andOppel (16) demonstrated spatial summation forheat and cgld sensations on the forehead. That is,as the area exposed to the heat radiation was in-creased, the strength of stimulus necessary toevoke sensation decreased almost in proportion.Hardy, Wolff and Goodell (17) found that paininduced by radiant heat on the forehead did nothave this property of spatial summation. Withthe water bath at 180 C., as already pointed out,barely detectable pain occurs in an immersed hand.When one finger was immersed, pain of the sameintensity occurred. Immersing one finger at 00 C.brought on pain of intensity equal to that experi-

x OFCOOLING

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2010

0

enced when the whole hand was immersed. Thistype of pain, then, like burning pain, fails to showthe effect of spatial summation.

III. " Cold Pain " in parts other than the hand

The hand is not the only part of the body inwhich pain can be induced by local exposure tocold. The feet and legs were similarly sensitive tocold, as was the face, tongue, scrotum, etc. Whenthe vertex of the head was dipped in cold water,pain was induced in the vertex following the paincycle described for the hand. The sensation spreaddown the back of the head and through thetemples, and appeared to be more intense than thatexperienced for the hand under like conditions.The highest temperature at which the headachecould be induced, however, was 180 C.

In two sites on the body it was found that paincould not be induced in our subjects by coldwater. These were the lobe of the ear and theglans penis. The explanation for these excep-tions is not clear at present.

IV. The behazior of skin temperature

The skin temperature fell off sharply upon im-mersion. The rate of cooling of the skin wasrapid for the first minute. By this time 90 to 95per cent of the total fall in skin temperature hadoccurred and cooling continued at an increasinglyslower rate (Figure 4).

300

FIG. 4. THE COURSEOF SKIN TEMPERATURESHOWINGTHE RATE OF COOLINGAT VARious BATH TEMPERATURES

10 30 50 70 90 N0 130 150 200 250

TIME IN SECONDS

525

STEWARTWOLFAND JAMES D. HARDY

AMPLTUDEOF PULSE100%-

90 -

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70 -

60 -

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40

30 -

20

10 -

0 -

0I I I

60I B I I I I I l

120 180 240TIME IN SECONDS

FIG. 5. THE COURSEOF SKIN TEMPEATUREANDAMPLITUDE OF PULSATIONOF THE DIGITAL ArTY WITH THE LEFT HANDIMMERSEDIN WATERAT VAR-IOUS TEmPERATURES

V. Behavior of the digital pulseThe amplitude of the digital pulse decreased

suddenly upon immersion of the hand (Figure 5),reaching its minimum at the time when pain in thehand was at a maximum. Following this therewas a gradual return of the amplitude towardnormal. This effect was most evident at tempera-tures of 90 C. or higher. Figure 6 illustrates therelationship between pain, " pins and needles "sensation and the amplitude of pulsation of thedigital artery, with the hand immersed at 9.5° C.The pulsations began to decrease in amplitude di-rectly after immersion of the hand. The pulsewaves of minimal amplitude correspond in pointof time to the maximum intensity of pain in thehand. As the pain intensity began to decreaseand the " pins and needles " sensation appeared,the amplitude of pulsation of the digital artery in-creased again, reaching its former level after thehand had completely adapted to the "pins andneedles " sensation. At temperatures below 100 C.the intense cold usually appeared to hold the ar-teries more or less tightly constricted, thus mask-ing the vasodilator effect apparent at higher tem-peratures (Figure 5).

Figure 7 illustrates a simultaneous recording ofpulsations in the immersed fingers and the fingersof the opposite hand. The sharp decrease inamplitude of pulsation of the digital artery in thepainful hand was closely paralleled by the tracingof the opposite hand. In the latter, however, thereoccurred shortly a vasodilator effect which broughtthe amplitude of pulsations back to normal.

VI. Behazior of blood pressureTen to 60 seconds after immersion of the hand

in cold water, and approximately coincident withthe onset of pain, a sharp rise in blood pressureoccurred. This reached its maximum at about thepoint of maximum pain. With the onset of" adaptation " the level of blood pressure declinedslowly and returned to normal after the pain and"pins and needles" sensation had disappeared.When the adapted band was withdrawn andpromptly re-immersed, there was no recurrence ofblood pressure elevation just as there was no recur-rence of pain. Like pain, the blood pressure eleva-tion bore a direct relationship to the degree oflocal cooling (Figure 8). No elevation of bloodpressure occurred in water warmer than 180 C.

S26

PAIN DUE TO COOLING

4CM

3CM

2CM

4+

3+

AMPLITUDE OF PULSATIONS

PINS

0 2 3TIME IN MINUTES

FIG. 6. RELATIONSHIP OF THE AMPLITUDE OF PULSA-TIONS OF THE DIGITAL ARTERY TO THE OCCURRENCEOF

PAIN AND "PINS AND NEEDLES" SENSATION AT 9.3' C.The return to normal amplitude of pulsation was un-

usually rapid and complete in this record.

VII. The effect of ischemia

Using a sphygmomanometer cuff maintained ata pressure of 200 mm. of mercury, the blood sup-

ply to the arm was interrupted for 10 seconds, 5minutes, 15 minutes, 35 minutes, and 45 minutesbefore the hand was immersed. The inflated cuffwas left in place during the period of immersionwhile observations were recorded. The pain and"pins and needles" sensation occurred at theirusual times, both with somewhat diminished in-tensity. " Adaptation " took place as usual. Inthe experiment in which the circulation was cutoff for 45 minutes, it was noted that touch sensa-

tion, cold sensation and pain to pin prick had gone

entirely from the hand before immersion (14) but,in s;?ite of this, "cold pain" occurred as usualwhen the hand was immersed.

Comment. It is known that, when anesthesia isinduced by interrupting the blood supply to a part,

the large fibers of class A are the first which ceaseto conduct impulses and that, as the ischemia iscontinued, nerve conduction stops in progressivelysmaller fibers until the smallest non-myelinatedfibers of class C are the last to drop out (18).Cocaine anesthesia, on the other hand, has beenshown to affect nerve fibers in just the oppositesequence (19), namely, the small class C fibers arethe first ones blocked and the largest fibers ofclass A the last. Accordingly, since " cold pain "from the above experiment in which the area wasrendered ischemic appeared to be conducted alongthe smallest fibers of the nerves, it was deter-mined to confirm this observation by testing theeffect of procaine anesthesia.

VIII. Effect of procaineThree cubic centimeters of a 1 per cent solution

of procaine hydrochloride were injected aroundthe left ulnar nerve, and 30 seconds after the in-jection was completed the fourth and fifth fingersof the left hand were immersed in water at 100 C.Scarcely any " cold pain " appeared. Neverthe-less, all other sensory modalities, including pain topinching and pin prick, were intact at this time.Later, an incomplete and transient anesthesia de-veloped in the ulnar distribution, but it had beenpossible first to eliminate " cold pain " while pinprick and deep pressure pain were still appreciated.

IX. Effect of sympathectomy

That this modality of " cold pain " is mediatedby small non-myelinated fibers of class C appearedto be indicated from these data. Other fibers ofsimilar size are the sympathetic vasomotor fibers.In order to determine any possible influence ofthese upon the phenomenon of " cold pain ", a pa-tient who had had the cervical sympathetic gangliaon the right removed within the previous fourweeks for intractable asthma was used as a subject.It was found that his right hand was markedlywarmer than his left. The completeness ofsympathectomy was demonstrated by comparingthe change in skin resistance in the two handsupon the application of a nociceptive stimulus.Repeatedly there was a marked change in resist-ance on the left and none at all on the right.When the left arm was immersed in cold water,the usual cycle of pain and blood pressure eleva-

527

STEWARTWOLFAND JAMES D. HARDY

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DEGREEOFRAIN

SEONDr-O 26 40 60 80 100 1D 140 W60 2002202 028020 32oFIG. 7. A COMPARISONOF THE AMPLITUDE OF PULSATION OF THE DIGITAL ARTERY

IN THE IMMERSEDHANDWITH THAT OF THE OPPOSITE HAND

DIASTOLIC

B.P. RISE_E.

50

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FIG. 8. RELATIONSHIP BETWEENTHE BLOOD PRESSURE ELEVATION ANDTHE STRENGTHOF COLD STIMULUS IN DIFFERENT INDIVIDUALS AT VARIOUSTEEMPERATURES

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PAIN DUE TO COOLING

tion occurred. When the right hand was im-mersed, however, the pain was much more severeand the elevation of blood pressure much moremarked. At 100 C., for example, there was adiastolic rise of 10 mm. of Hg when the left armwas immersed and 20 mm. of Hg when the rightarm was immersed. When the circulation to thearm was interrupted by a sphygmomanometercuff, the effects were not altered.

X. The effect of slow coolingIf the hand were immersed in water at 200 C.,

a temperature at which no pain could be induced,and the temperature of the water slowly loweredby successive steps to 00 C. (over a period of morethan 60 minutes), no pain was felt. The sensationof " pins and needles ", however, occurred at about12° C. whether the cooling was slow or rapid, andbecame more intense with further cooling, adapt-ing slowly at each new temperature. The actualintensity of " pins and needless" sensation was notas great with slow cooling as it was at comparabletemperatures when the hand was cooled rapidly.The slower the cooling, the less marked was thesensation, and it is quite possible that if the handwere -cooled slowly enough the sensation wouldnot appear at all.

XI. The effect of successive cooling of partsOne hand was plunged into cold water where it

was allowed to remain until complete "adapta-tion " had taken place. Then the other hand wasimmersed. The usual cycle of pain occurred inthe freshly immersed hand without any pain oc-curring in the already adapted hand. After thesecond hand was thoroughly adapted, one fore-arm was introduced. Again pain was felt in thenewly immersed part but not in the hands. Simi-larly, after submerging the other forearm, onlythat part experienced pain while the other mem-bers were " adapted ".

XII. The effect on " cold pain " of agents whichalter the contractile state of arteries

A. The effect of vasbdilator agents. The con-tents of an ampule of amyl nitrite was inhaled ontwo occasions while the hand was immersed in coldwater. There was no detectable effect on the pain.One milligram of histamine injected subcutane-

ously was similarly unavailing in modifying thepain caused by cold, although the subject becameflushed as a result of peripheral dilatation.

B. The effect of vasoconstrictor agents. Pitres-sin, 1 cc., was given hypodermically to 3 subjectsto determine the effect of strong vasoconstrictionon the intensity and duration of "cold pain ".Readings were made 15 minutes, 45 minutes, 11/2hours and 2 hours after injection. It was foundthat both intensity and duration of pain were in-creased by 50 per cent. The maximum effect vasnoted at 45 minutes. After 2 hours the effect haddisappeared.

The fact that pitressin brought about an in-crease in intensity and duration of " cold pain "suggests that vasospasm may be a factor in theproduction of " cold pain ". Ray and Wolff (20),however, in experiments on the pain sensitivity ofcranial arteries, brought about a brisk vasocon-striction by painting epinephrine directly on acranial artery without inducing pain. Yet anepinephrine pack placed in the nose is known tocause intense pain. Wefound that this pain couldbe greatly accentuated by breathing cold air andnearly completely relieved by breathing warm air.It may be that here one is dealing with a pain aris-ing from vasoconstriction which is relieved by thevasodilator influence of warmth.

In order to test this possibility further, it wasdetermined to induce a powerful vasoconstrictionin a hand still immersed in cold water but alreadyadapted to "cold pain'".' Accordingly, the lefthands of the subjects were immersed in water at100 C. and, after " adaptation " was complete andthe blood pressure had returned to its control level,0.00025 gram epinephrine was injected rapidlyintravenously. Almost at once there was a sud-den and dramatic rise in the systolic blood pressureto more than 200 mm. Hg. At this time the sub-jects were pale, weak, and dyspneic, with acceler-ated pulse and respirations. The mouth was drywith an unpleasant, faintly metallic taste in it, andsoon a moderately severe centrally placed headacheappeared. The adapted hand in the water at firsttingled but there was no "cold pain"; after theblood pressure had passed its peak, the tinglingwas replaced by " cold pain ". The latter persisteduntil the blood pressure had fallen nearly to nor-mal. Then the pain gave way to "pins andneedles ", as usual, and finally, as the blood pres-

529

STEWARTWOLFAND JAMES D. HARDY

BLOODPRESSURE240 -

200 -

160 -* 0

SYSTOLIC120-. 0.0

* 0 0

j DIASOLWIC80 -. - a a

* 0 I- ~~~ADRENALIN INJECTED

40 - IINTWYOFFAIN

5+

4+

3+

2+

1+ t

I I I I I I II I I I I

*00

I 11 I I I I I I0 100 200 300 0 1K0 200 300

TIME IN SECONDSFIG. 9. PAIN INDUCED IN A HANDCOMPLETELYADAPTEDIN WATERBATH AT 100 C. BY

}THE INJECTION OF Y4 MGM. OF EPINEPHRINE INTRAVENOUSLY

sure returned to normal, that sensation ceased(Figure 9).

Comment. Having been able to reproduce painsimilar to "cold pain " in this way, one is stillnot entirely clear as to whether or not this effectwas brought about by vasoconstriction or by someother effect of epinephrine. The effects of epi-nephrine upon deep-lying blood vessels are notentirely agreed upon by investigators, and it isquite possible that the drug effected a warming ofthe deeper structures of the hand and abolished" adaptation " by increasing the thermal gradient,thus again rendering the hand susceptible to " coldpain " from the water in which it was immersed.

DISCUSSION

From the above data what inferences can bemade about the aching pain described, and to

what process can we attribute the phenomenon ofadaptation" to this pain?Undoubtedly, the degree of pain experienced is

closely allied to the strength of the cold stimulus,since the intensity, as well as the total amount ofpain felt, increases in direct proportion to thelowering of the temperature of the water bath inwhich the hand is immersed. The first questionto be answered is whether or not the pain thusexperienced depends upon extreme stimulation ofcold sensation (21, 22, 23, 24). Evidence uponthis point is complete. As soon as the subject'shand is immersed he feels cold but no pain. Thecold sensation continues throughout the cycle ofpain and persists unaltered long after the pain isgone. In the experiment in which ischemia ofthe nerve was obtained by occluding the bloodsupply to the arm for 45 minutes, cold sensation

530

9 0.

PAIN DUE TO COOLING

in the hand was abolished. " Cold pain ", how-ever, could be induced as usual. Clearly, the painis not secondary to stimulation of the sense ofcold.

Since separate pain fibers mediate the sensationof " cold pain " it is desirable to know their char-acter. The experiments on partial block of thenerve trunks by ischemia, on the one hand, andprocaine, on the other, suggest that the fibers inquestion are the small, non-myelinated ones ofclass C.

It is clear that purely local changes in the im-mersed part are responsible for initiating the pain,as evidenced from the distribution of the sensa-

tion as well as from the fact that its behavior isnot altered by interruption of the blood supplyand most of the nervous impulses going to thepart. Furthermore, the purely local character ofthe phenomenon was demonstrated in the experi-ments in which parts were immersed successivelyinto the water bath.

The fact that the intensity of pain experiencedparallels closely the degree of cold, and the findingthat " adaptation " is effective only while the handand water temperature difference is small, havealready been emphasized. These data suggest thatthe thermal gradient in the hand is responsible for" cold pain " and that, when the gradient becomesless after the first minute of cooling, "adapta-tion " occurs because the stimulus for pain isabolished. It seems unlikely that the site of pro-

duction of this pain stimulus is in the skin sincethe character of the pain is not that of any otherknown cutaneous pains. These are invariablybright and burning in quality, while " cold pain "is deep and aching. The deeper tissues and bloodvessels are the other possible sites where " coldpain " may be initiated.

Certain findings suggest that the blood vesselsmay be concerned in the production of " coldpain ". There is a marked vasoconstriction asso-

ciated with the occurrence of " cold pain " whichis reflected in the tracings of the amplitude ofpulsations of the digital artery. With the onset of" adaptation ", there appears to be a relaxation ofthe vasospasm and an increase in the amplitude ofthe digital pulse toward the control level.

Several investigators have studied blood vesselswith reference to their pain sensitivity (25, 26, 27,28). The experiments on humans by Ray and

Wolff (20) show clearly that cranial arteries arepain-sensitive to faradic and mechanical stimula-tion. If the vessels were stretched, distendedfrom within or without, pinched or pulled, verydefinite pain resulted.

If pain results from vasoconstriction, then itmust be a purely local phenomenon. What is therelationship of the reflex vasomotor activity withits resultant hypertension, however, to the otherevents which occur as a result of plunging a handinto cold water? Could it represent simply areaction to the pain experience? It is known thatpain applied anywhere on the body induces hyper-tension and, as we have emphasized repeatedly,the height of blood pressure rise obtained corre-sponds closely to the intensity of pain experienced,which in turn depends upon the degree of cooling.Hines and Brown (1) separate subjects into threegroups according to their blood pressure rise inthe "cold pressor" test. They name the cate-gories-Hyperreactors, Normal Reactors, andHyporeactors. They look upon the Hyperreac-tors as potential hypertensives. Whether or notthis inference is justifiable, it is quite clear thatsubjects do react differently to local cooling interms of blood pressure rise. Moreover, theyreact according to a definite pattern. In a givenindividual, whether a hyper-, hypo-, or normalreactor, we found that the level to which theblood pressure rose increased in proportion to thelowering of the temperature of the water bath(Figure 8).

The vasopressor effect seems clearly to be in-fluenced by the pain. In the experiment in whichall the other sensory modalities were blocked byischemia of the nerve, the elevation of blood pres-sure occurred as usual with " cold pain ". Anal-gesic drugs of various sorts-aspirin, codeine andalcohol-lowered the pressor effect as they re-duced the pain. In the subject who had had arecent cervical sympathectomy on the right, wefound that much more intense pain was experi-enced when the sympathectomized hand wasplunged into the cold water than when the normalhand was immersed. In other respects, sensoryexamination of the two hands was identical. Amuch greater blood pressure elevation was asso-ciated with the more painful experience, however.

It appears that the pressor effect in these ex-periments is related either to the pain itself or to

531

STEWARTWOLFAND JAMES D. HARDY

the subject's reaction to the pain. Several factsindicate that the latter possibility is the morelikely. Schumacher and others (29) have shownthat, while reaction to pain is by no means con-stant from one individual to another, the painthreshold of a large group of individuals is prac-tically identical. This suggests but does not provethat the intensity of " cold pain " experienced byall subjects is about the same. The differences inblood pressure, then, must be due to differences inreaction to the pain from one subject to another.Some confirmation of this notion was obtainedfrom an experiment in which a Hyperreactor wasgiven 0.26 gram of sodium pentobarbital hypo-dermically in divided doses one hour apart. One-half hour after the second dose his hand wasplaced in water at 00 C. and his blood pressureresponse was that of a Hyporeactor. It has beenshown that barbiturates in therapeutic dosage haverelatively little effect on the pain threshold. Thechange must have been due to the effect of thedrug on the subject's reaction to pain. Therefore,the term " Hyperreactor " of Hines and Brownappears to be a particularly appropriate one. Thefact that this group reacts in such a way to adistressing stimulus which is equal in intensity tothat to which others are exposed who react lessstrongly may well shed light upon this subsequentdevelopment of a permanent hypertension. Thesefindings seem to support the thesis of Hines andBrown (1).1 Whether or not the blood vesselsare concerned in the mechanism of "cold pain"cannot be decided from the evidence in hand.There is, however, much to suggest that they are.

SUMMARY

A deep, aching, painful sensation- induced byimmersing a part of the body in cold water isdescribed. The behavior of this phenomenon isfound to follow a definite pattern, namely, thatregardless of strength of stimulus, pain reachesits maximum in approximately 60 seconds. There-after, the pain gradually subsides, giving way to

1 There is one important modification which should beintroduced into the technic of the "cold pressor" test.If the thermal stimulus is to be compared from one testto another, it is essential that the water in which thehand is immersed be stirred vigorously in order to avoida warm zone in the immediate vicinity of the immersedhand.

a sensation of " pins and needles" which soon,in turn, is terminated. The intensity of the painand the total amount of pain were found to de-pend directly upon the degree of cooling, with"adaptation " occurring when the difference be-tween the hand and water temperature was small.Warming the hand or lowering the bath tempera-ture abolished the protective effect of "adapta-tion ". The mechanism whereby the pain is pro-duced and the reason for its " adaptation " wereinvestigated. It was found that:

1. This pain is entirely separate from and inde-pendent of the sensation of cold itself.

2. This type of pain does not show the phe-nomenon of spatial summation since exposure ofone finger to cold causes pain of equal intensityto that experienced when the whole hand is soexposed.

3. The pain may be induced on nearly all partsof the body. In each case the highest bath tem-perature at which pain can be obtained is 180 C.

4. The skin temperature of the immersed partdecreases rapidly for the first minute after im-mersion and then much more slowly.

5. The amplitude of pulsation of the digitalartery parallels inversely the intensity of "coldpain " experienced.

6. The blood pressure-raising effect is propor-tional both to the intensity of pain experiencedand to the degree of cold.

7. Ischemia, which is known to produce painin muscular structures, is not a significant factorin the production of " cold pain ".

8. By selective partial block of nerve trucks, itwas indicated that "cold pain" is carried by thesmall, non-myelinated fibers of class C.

9. Sympathectomy was found to augment theintensity of pain derived from cold.

10. It was found possible to lower the bath tem-perature to zero without pain being felt in theimmersed hand if the cooling were carried outslowly enough.

11. By successively cooling different parts it waslearned that the production of " cold pain " de-pends on local changes in the part cooled.

12. Evidence is presented which indicates thatthe elevation of blood pressure which results fromimmersion of a part in cold water is a measure ofthe subject's reaction to " cold pain ".

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PAIN DUE TO COOLING

CONCLUSIONS

Pain due to local cooling is altogether separatefrom the sensation of cold itself. It is apparentlymediated through small, non-myelinated fibers ofclass C. Its intensity, however, depends directlyupon the degree of cooling. The stimulus re-

quired for the production of "cold pain" maybe found in the thermal gradient in the tissues ofthe immersed hand. It is possible that this stimu-lus brings about a painful vasospasm in the part.Relaxation of this local vasospasm may occur as

the thermal gradient is decreased, thus accountingfor " adaptation ". It appears that the "coldpressor " effect is a measure of reaction to pain.

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