Review Pain associated
with
Simon Rodbard,
Ph.D.
M.D.,
muscular
activity
Duarte, Cali{
Acute pain in contracting muscles is a frequent experience in patients with arterial disease. It is also a common experience in normal subjects. In normal subjects the sensation usually results from prolonged or repeated contraction of a voluntary muscle against an unaccustomed load. A heavy valise, carried at first with almost complete ease, soon generates an annoying sensation of discomfort in the arm and shoulder muscles. The discomfort gradually progresses, becomes moderate, and then severe. Finally the ache or fatigue becomes so intolerable that the load must be released, even if this means that the train or plane is missed. The discomfort or pain is so prepotent that it can force the cessation of the muscular work even in the face of the threat of death. Thus an individual trapped in a situation in which he must hold on to a ledge or a rope must soon release his hold even though he knows that a fatal fall will result. intermittent claudication. The circumstances outlined above for pain in voluntary muscles have similarities to the pain in intermittent claudication, angina pectoris, and intestinal angina. Intermittent claudication occurs in patients whose femoral arteries are severely narrowed, as in arteriosclerosis obliterans.’ These patients can walk only a limited distance before leg muscle discomfort forces them to stop. After an interval of rest, even in the standing position, they can resume their walk, but the discomfort returns quickly after walking a shorter distance. To hide their embarrassment these patients become “window shoppers” who stand quietly before a store window until they can again comfortably resume their stroll. The severity of the disease process has been evaluated in terms of the disFrom the Duarte. Received
Department for publication
of Cardiology,
City
of Hope
Center,
Feb. 28, 1974.
Reprint requests to: Dr. Simon Rodbsrd, Department City of Hope Medical Center, Duarte, Calif. 91010.
84
Medical
of Cardiology,
tance walked between the stops; this distance becomes shorter as arterial narrowing becomes progressive. In the end-stages of arteriosclerosis obliterans, the patient can walk only a few steps before another rest period becomes imperative. Angina. A similar disturbance is experienced when the involuntary muscles of the heart or of the intestines receive an inadequate blood flow. However, discomfort, pain, or fatigue cannot inhibit the recurrent contractions of these organs. The symptoms may, therefore, become progressively more severe. Angina pectoris (“suffocation in the chest”) and intestinal angina are commonly associated with narrowed arteries that impede the delivery of an adequate i-low of blood to the contracting organs. When blood supply is inadequate, recurrent contraction injures the muscle cells, and ultimately can lead to their necrosis. The serious general consequences of such localized tissue damage have led to many studies of the clinical phenomenon of infarction. Like other discomfort, the sensation of severe pain impressesitself so vividly upon the attention of the patient that his search for relief becomes a primary activity. If the pain becomes intolerable he may exhibit progressive irritability and aversive behavior. He begins to thrash about and finally he will project strong feelings against persons or objects in his environment. Relief of the discomfort eliminates the emotional disturbance within a few seconds and the episode is quickly forgotten. The discomfort
Pain-inducing stimuli, subserved by various nerve impulses, are modulated and interpreted by higher mechanisms. This modulation is determined by the functional structure of the higher centers which select and abstract this information out of the total input. Thus, the words called forth to describe the discomfort represent interpretations not only of sensory and affective qual-
July, 1975, Vol. 90, No. 1, pp. 84-92
Pain associated with mlwular
ities, but also of previous experiences and of the cultural pattern. The flow of nerve impulses from the active muscle to the brain may be perceived as pain or as fatigue. The fatigue is recognized as a progressive weakness of the contracting muscle and in the realization by the subject that the voluntary muscle does not respond to his will. Fatigue occurs commonly when the load is negligible or when its magnitude approaches the limit of the strength of the contracting muscles. These findings indicate that the cerebral interpretation of the impulses arriving from the contracting muscles may be quite variable. When the perception is of pain or of fatigue, the exercise comes to a halt. The symptoms reported by patients with the diagnosis of angina pectoris” or intermittent claudication are remarkably variable. Almost the entire range of the words used for pain listed by Melzak and Torgerson” has been reported by patients with arterial disease. These terms include deep, spreading, radiating, boring, piercing, stabbing, crushing, pressing, vise-like, squeezing, pulling, aching, drawing, hurting, choking, burning, suffocating, distressing, excruciating, intolerable, and tiring, or simply as fatigue. The discomfort is continuous and persistent, and independent of individual contractions or relaxations. When its source is in skeletal muscle it is usually referred to the region of the contracting muscle, or to adjacent joints. When the source is in the heart, the pain is referred to the anterior chest wall, often with radiation to the neck or jaw, and to the ulnar distribution of the left arm. These variations in description introduce significant difficulties into the analysis of the data obtained on normal subjects engaged in voluntary muscle contraction. Evaluation is even more complex when the source of the disturbance is in the viscera. Related muscle pains. Unaccustomed exertion generates a dull, aching muscle pain that may persist for days even though the blood supply is presumably normal. This may be attributed to overload and injury of the muscle and its tendons. When the exercise becomes habitual, hypertrophy of the muscle and its attachments reduces the likelihood of damage and the pain gradually diminishes and disappears.l Trauma to muscles produces a boring, deep pain which is probably due to direct injury to muscle and nerve cells, and
American Heart Journal
a&z@
not solely to a restricted blood supply. Intermittently recurrent pain has been attributed to spasm. For example, tension headaches have been attributed to spasm of the occipital muscles. Cramps are painful contractions of the muscles, especially in the elderly; these pains can sometimes be controlled by stretching the affected muscles, or by the administration of quinine. Other forms of pain associated with muscle contraction are those due to inflammatory processessuch as myositis or tendonitis. Inflammation of epiphysial and related connective tissue sheaths may give rise to “muscle” pain Pains arising in the joints may also be int,erpreted as “muscle” pain. The surprisingly common costochondral tenderness of Tietze’s syndrome is often misinterpreted as angina pectoris. Some of these sources of pain can be identified by pressure on the site of reported pain. Reassurance in such cases can sometimes eliminate the symptom completely. These complex factors can introduce ambiguity into the study of muscle pain. Problems
in analysis
Despite the objectivity of the disturbances in muscle that lead to pain, clinical evaluation is remarkably difficult, especially in angina pectoris. Some investigators insist that data on such pain, which by definition is subjective, cannot be objectivized. This attitude has stifled research on these potentially lethal mechanisms. Numerous studies have been directed to medical or surgical means for the control of such symptoms, but few of these studies have been properly controlled. Some of the reported results on the part of investigators may have been due to the wishes of the physician, and to the deep concern and fears of the patient. The resulting anxieties can greatly augment the discomfort. It is well appreciated that an enthusiastic approach offered by the physician or experimenter can, through purely psychologic bases, greatly alleviate fear and reduce the apparent pain. Such factors may have contributed to the recurrent disappointment with some & the surgical procedures that for various intervals have had vogue in the therapy of angina pectoris. Surgical procedures have included pericardial poudrage, ligation of the coronary venous sinus, coronary endarterectomy, mammar.v artery ligation, insertion of the mammary arteries into slits cut into the ventricular myocardium, and
85
Rodbard
PERCENT
Experimental
CONOTFROL N=NOTICEAELE I=INTOLERABLE
100 1 80
NN I NIN
1
11 IN
60 i IN
40.
NN1l
Ii1 20.
NNI NNN
NI NI
H
H 64
8 INTERVAL
BETWEEN
FIRST
AND
SECOND
(set) EXERCISE
Fig. 1. The number of contractions performed in the first test was considered to be 100 per cent. The number of contractions performed in the second test is shown. The number of seconds during which the cuff was deflated prior to the resumption of exercise is shown in the horizontal axis (2,8, and 64 seconds). N is the per cent of contractions performed prior to onset of noticeable pain. I is the per cent performed prior to onset of intolerable pain. Extrapolation suggests that recovery should be complete in about 10 minutes.
currently, bypassing a stenotic coronary artery segment with a saphenous vein graft or anastomosis with a mammary artery. Some of the problems inherent in the evaluation of these therapeutic approaches to pain are highlighted by experiences with mammary artery ligation. This relatively simple surgical approach to the problems of coronary artery disease and angina pectoris was based on the belief that ligation of the mammary arteries would divert more blood to the adjacent coronary arteries. Mammary artery ligations were soon followed by reports of gratifying reductions in the frequency and severity of angina1 attacks. This question was then properly approached in double-blind tests. Patients with angina pectoris were carefully studied. At the time of the anterior thoracic skin incision, a card was drawn to separate the patients into two random groups. In one group, the mammary arteries were ligated; a high percentage of these patients had relief from their complaints of chest pain. In the other group, only the skin incision was made, but the mammary arteries were not ligated; an equal percentage of these patients had relief from their symptoms. These findings emphasized that analysis of angina pectoris could founder on the complications introduced by the wishes and anxieties of the patients and of their physicians.
86
procedures
Although pain is subjective, responses to the sensation of pain can be quantified. Since skeletal muscle pain can be easily produced, this procedure offers a means to assay the pain process. The reader can readily examine the facility with which pain can be produced by recurrently flexing and extending the fingers of a hand as rapidly as possible. A sensation of discomfort appears in the forearm within 30 seconds. Continuation of the exercise causes the discomfort to become progressively annoying. Further contractions usually lead within a minute or two to a sensation of severe local pain or burning, and then to such profound weakness, fatigue, or pain localized to the region of the contracting muscles, that the exercise cannot be continued. A few seconds of rest relieves the discomfort, although a senseof local fatigue may persist for a minute or so. A demonstrable “pain” residue remains in the affected muscle for a longer period. This can be demonstrated by attempting to repeat the exercise after a minute of rest and unimpeded blood flow; the discomfort usually recurs after fewer contractions than were performed in the initial test (Fig. 1). Quantification. The abnormalities associated with contraction of skeletal muscle can be quantified by having the subject report when the discomfort is noticeable, and when it becomes to annoying, severe, or intolerable. Inability continue the voluntary exercise is a useful endpoint. Controlled, randomized tests show that each individual will perform a remarkably uniform number of contractions under standardized conditions and against a given load. A measurement with objective characteristics is thereby recorded. Tests of this kind are useful not only in estimating the pain tolerance of subjects, and in the evaluation of the reports given by patients concerning the severity of the pain they report as arising from angina pectoris or other pain syndromes, but also in the analysis of the mechanisms that produce the pain. Mechanism. We have examined the pain associated with muscle contractions by controlling such parameters as load, duration, and frequency of contraction; the arterial or venous pressures; the interval between successive contractions; the intervals between successive tests; etc. The
July, 1975, Vol. 90, No. 1
Pain associated wzth muwdar SE\ER’l’* 3’ PA,tJ
a&r-it?
F!LLING /
INTOLERABLE
Mi i
!
r.4/
ANNOYIN.;*-
-.+/
NOTICEABLE
PAIN i200
400
600
, 800
EXPRESSION
f
DIFFUSION
PRODUCT C.L05.D0331225TESTsl
Fig. 2. Relation of product of number of contractions (C), square root of the load (L” “), and the cube root of the duration of each contraction (D”‘“), plotted against the reported severity of pain (vertical axis) in young subjects with no known cardiovascular disease. Blood flow to the arm was occluded by a tourniquet. The severity of the pain increases with the product. The dots represent averages; the horizontal bars represent one standard deviation. The data were obtained from several different loads and durations of contraction.
number of contractions performed prior to the development of pain or of the inability to continue because of fatigue varies with the strength of the muscles involved, the load that must be lifted, the frequency, and the duration of the contractions, the square root of the load, and the cube root of the duration of each contraction. The product of these factors is remarkably constant for each degree of severity of pain (Fig. 2). Hypothesis. We have operated on the hypothesis that each contraction of an ultimate contractile unit (sarcomere) generates a stoichiometric quantity of a toxic catabolite or pain substance in the muscle fiber (Fig. 3, A and I?).’ The relationship between depolarization and contraction in the production of the catabolite is illuminated in studies on the heart. Normally, every fiber in the heart is depolarized in every beat (all or none law), yet the tendency to the development of pain is known to vary with load, i. e., with the tension developed in each beat. The quantity of the catabolite produced in each beat is, therefore, independent of the depolarization process. The number of contractile elements that participate in a given contraction of the heart is apparently the determining factor in the concentration of the pain substance, and this appears to vary with the
American Heart Journal
fig. 3. Concept of role of muscular contraction in production and removal of pain catabolite. In upper left, a representation muscle fiber and a capillary are enclosed with extracapillary fluid in a fibrous connective tissue capsule. In upper right, muscle fiber produces catabolites (C) during active contraction, as length of capsule is shortened. In lower right, catabolities diffuse out of muscle fiber into extracapillary fluid. High concentrations of catabolite adjacent to nerve fiber stimulate nerve impulses which, on reaching the brain, induce the sensation of pain. Pain is referred to site of the contracting muscle. In lower left, contraction of adjacent fibers compresses the capsule, squeezing extracapillary fluid and most of the contained catabolite out of the capsule and back into the blood circulation. In upper left capsule, no longer compressed, fills with ultrafiltrate. It is appreciated that phenomena shown at upper right and those &own in lower left may occur simultaneously.
total tension developed by the heart during that beat as it ejects its contents.” The mechanical tension developed by the heart in a given beat also correlates with its oxygen uptake. The total tension and the oxygen uptake per minute also vary with the number of beats per minute. These data suggest that the production of the catabolite may be related to the actual process of shortening in those sarcomeric units that are involved in the contraction. The work that can be performed before the appearance of intolerable pain varies inversely with the strength of the contracting muscle, as
87
Rodbard
TOTAL CONTRACTIONS .
Unrestricted \
\
_____
30
MAX
O.---------o'
40
occluded ______------
-----
I
I
50
60
CONTRACTIONS
-----D 1 MAX.
70 PER
MINUTE
Fig. 4. Number of contractions performed prior to fatigue or intolerable pain. The frequency of contraction is shown in the horizontal axis. The line is extended to the maximal rate that could be performed by each individual. The number of contractions (vertical axis) performed when blood flow was unrestricted was indeterminate at slow rates (< 40 per minute) but decreased at faster rates. The number that could be performed when a tourniquet occluded the arterial inflow increased with the frequency of contraction. The two curves approached a common value at very rapid rates of contraction.
measured with a dynamometer (Fig. 4). We may assume that the number of units required to produce the tension of each contraction is distributed among the larger number of units in a hypertrophied muscle. As a result, the amount produced in each sarcomere, per unit of total muscle tension, is reduced in a stronger muscle. As long as the catabolite remains inside the muscle fiber there is no conscious recognition of its presence. Diffusion of the catabolite out of the cell increases its extracellular concentration. When its concentration reaches a threshold value, adjacent nerve fibers are stimulated and a train of impulses is initiated (Fig. 3, C). Arrival of
88
these impulses in the central nervous system generates the perception of a sense of discomfort, pain, or fatigue. As the concentration of the catabolite in the tissue increases, the discomfort that was at first only noticeable and then annoying, becomes severe, and the contractions become progressively weaker. Finally the discomfort becomes intolerable. The catabolite. Our analysis suggests that the catabolite responsible for pain or fatigue in contracting muscle is a toxic material which must be eliminated from the tissue at any cost. The pain-inducing catabolite cannot be lactic acid. This conclusion results from the finding that muscle pain tends to be unusually severe and damaging in patients with McArdle’s disease, a deficiency of the phosphorylase that converts muscle glycogen to lactic acid. Oxygen lack is not the factor that produces the toxic catabolite. If the pain were due to lack of oxygen or to the washout of a highly diffusible substance, blood flow for one minute should have been more than adequate to restore pre-exercise conditions. The failure of complete recovery in this interval (Fig. 1) indicates that the elimination of the agent responsible for pain depends on other time-limited mechanisms. Further, tourniquet occlusion of the blood flow into the arm for as long as 20 minutes with the production of severe ischemia has little effect on the number of contractions that can be performed. The development or elimination of the pain is unaffected by the breathing of pure oxygen even at three atmospheres (2,200 mm. Hg of oxygen) of pressure. The pain catabolite is, therefore, not directly related to oxygen deficiency. Diffusion. Experiments have been performed to evaluate the diffusion of the catabolite. Such studies are best performed while the flow of blood to the affected muscles is stopped by the application of an arterial tourniquet to the upper arm. These studies have been based on the assumption, as noted above, that each contraction of a given strength (number of contractile elements triggered to contract), and of a given duration produces a stoichiometric quantity of catabolite. The greater the interval between contractions, the fewer the number of contractions necessary to produce intolerable pain or fatigue. Longer intervals between contractions provide more time for diffusion of the catabolite out of the affected
July,
1975,
Vol.
90, No.
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Pain associated
cells, and this can result in higher extracellular concentrations of the catabolite despite the smaller number of contractions (Fig. 4). The catabolite persists in muscle for minutes after exercise has been stopped and blood flow has been reinstituted (Fig. 1). This suggests that it is a molecule of significant size. The molecular weight of the catabolite is estimated from its apparent rate of diffusion as having a molecular weight of perhaps about 1,000. The catabolite cannot be destroyed locally in the muscle in which it was formed, since the discomfort induced by a painproducing exercise persists as long as blood flow is obstructed. It apparently must be washed away by the resumption of blood flow through the affected tissue. Toxicity The toxicity of the catabolite appears to result from a destructive local action on membranes. As with increases in the local concentration of other toxic materials, affected cell membranes are first stimulated. The accumulation of sufficient catabolite in a specific site stimulates local nonmyelinated fibers to fire impulses, perhaps through a toxic action on the neuronal membrane. A sufficiently intense barrage of neurogenic impulses leads to a voluntary cessation of contraction, or in some instances to an involuntary cessation of muscle exercise associated with “fatigue.” Excessive catabolite concentration probably produces severe cellular damage which only the cessation of contractile activity can prevent. Evidence for cell damage comes indirectly from two sources that indicate changes in the permeability of the muscle cell membranes. Thus, excessive muscle exercise increases the permeability of muscle cells to glucose, thereby resembling the insulin-induced augmentation of muscle cell permeability.’ In phosphorylase deficiency of muscle, even mild exercise can produce severe muscle pain in association with the leakage of myoglobin out of the affected muscle cells. An acute bout of contractile activity as in wrestling or following an epileptiform convulsion can result in a massive escape of myoglobin. The quantity escaping out of the damaged membranes of the muscle fibers may be sufficient to produce myoglobinuria and even renal tubular obstruction with myoglobin crystals.” Washout. We examined the rate at which the pain-inducing catabolite can be eliminated by the
American
Heart
Journal
with mw wlnr
acti1:it.y
blood stream (Fig. l).” A tourniquet cuff on the upper arm occluded the blood supply to the contracting muscles. When the muscle pain became intolerable, or the muscles would no longer contract because of fatigue, the cuff was deflated. The pain or fatigue was relieved almost at once. Reinflation of the cuff then again occluded the blood flow and the hand exercise was resumed. The number of contractions that could be performed after a two-second interval of blood flow that had provided complete relief from the pain was only about one-fourth the number that could be performed in the initial test,. Thus, even though the pain has been relieved, a residue of catabolite persists in the muscle. This preformed material diffuses out of the muscle fibers during the second bout of exercise and thereby accelerates the rate of appearance of pain. Blood flow for eight seconds before reapplication of the cuff and reinstitution of the exercise resulted in an increase in the number of contractions to 40 per cent of the initial number. After one minute of blood flow, about 75 per cent. as many contractions as in the initial test could be performed. These data appeared to follow a logarithmic washout curve. Complete recovery of the capacity to perform the exercise appeared to require more than 10 minutes of unimpeded blood flow. intrinsic obstructions to flow. Some aspects of the nature of the pain substance can be investigated when there is no extrinsic interference with the blood flow to the muscle, as in arm exercise experiments in which no tourniquet is used. During each contraction of a muscle3 the rise in intramuscular pressure compresses the blood capillaries and reduces the vascular conductance (flow/pressure) of the affected bed. During the subsequent relaxation blood flow takes place, probably in the form of a hyperemia. The ability to continue the exercise varies with the duration of muscle relaxation between successive contractions (Fig. 4).‘” In our experiments, hand exercise could be continued 15 minutes or longer without the development c)f significant pain when 40 contractions per minute were performed. Increases in the number of contractions per minute to 50, 60, and 70 shorten the intervals of muscle relaxation during which muscle blood flow can take place freely, and decrease the number of contractions performed prior to the onset of pain.
89
Rodbard
PAIN
(CONTRACTIONS ,‘..
d 20
* MIN-“)
INTOLERABLE
10
20
1 30
I 40
I 50
NUMBER
I1111 100
200
I 300
I 400
Ill,, 500
1000
OF CONTRACTIONS
Fig. 5. Walk-through phenomenon in a male, aged 20. Horizontal axis is number of contractions (logarithmic scale). Vertical axis is the reported severity of discomfort or pain in the contracting arm. The line at left was obtained with a tourniquet on the upper arm at a contraction rate of 66 per minute. Pain was first noticed at 34 contractions and became intolerable at 75 contractions. With no tourniquet on the arm, 80 contractions were performed prior to noticeable pain. At 110 contractions, the pain became annoying. At 450 contractions, the grade of discomfort was reported as only noticeable and shortly after that the discomfort disappeared completely (walkthrough phenomenon) despite continued contractions to a total of 1,000. At 72 contractions per minute, the pain became severe before it returned to the noticeable state. At 90 contractions per minute, no walk-through was observed.
These findings are consistent with the thesis that when blood flow is adequate, as occurs during the relatively long intervals of relaxation between successive contractions, the catabolite does not accumulate in quantities sufficient to initiate pain or to force the end of the performance. At faster contraction rates, the decline in the duration of the relaxation interval and in the resulting washout interval, is inadequate for the rapid elimination of the pain-producing catabolite. Walk-through. This phenomenon, also known as “second wind” is observed at contraction rates intermediate between a high frequency that produces progressive discomfort to the point of intolerable pain, and a slower frequency that can be continued indefinitely. In such tests, the subject usually reports the appearance of pain and its progression to annoying or even severe qualities after about one minute. Continued contractions, instead of causing progression of the pain then result in its disappearance, and the exercise can be continued indefinitely without its reappearance (Fig. 5). This walk-through phenomenon may result from the hyperemia associated with the exercise and the resulting more effective washout of catabolite. An elevation of systolic pressure, commonly observed during exercise, may also increase blood perfusion. Arterial pressure. Since the rate of blood flow appears to be implicated in the elimination of
90
pain, the effects of changes in arterial pressure on the generation of pain have been studied.” To do this we compared the number of contractions that could be performed while the arm was in a position horizontal to the body, with the number performed while the arm was elevated on an arm rest (Fig. 6). Maintenance of the arm in the upright position reduces the arterial pressure in the muscles of the forearm by about 25 mm. Hg. Nearly twice as many contractions could be performed with the arm in the horizontal position than when it was upright. Arterial perfusion with the arm upright, especially in individuals who are unaccustomed to this position, therefore appears to be less effective in eliminating the pain factor from the exercising forearm muscles than when the arm is horizontal. An elevated arterial pressure can be expected to increase the perfusion of the contracting muscle.” This interpretation is supported by the finding that more contractions can be performed with the arm in the dependent position than in the horizontal or upright positions. The arteries in the dependent arm have a higher pressure because of hydrostatic position. It is also known that the arterial pressure tends to rise during intermittent claudication.” This increase in perfusion pressure may increase blood flow and improve the elimination of the catabolite from the fluids of the contracting muscle.
July, 1975, Vol. 90, No. 1
ARM A=ARTERIAL TOURNIOUET O-OPEN CIRCULATION V=VENOUS TOURNIQUET
PAIN INTOLERABLE
U = UPRIGHT Ii = HORIZONTAL D = DEPENDENT
A
OU
n=54
n = 25
vu OH n=23 n=25
00 n=13
i
L’n n=6
-
SEVERE
ANNOYING
-
NOTICEABLE
-
n = SUBJECTS
I 0.8
0.9
I
1.5
2 NUMBER
3 OF
4
5
CONTRACTIONS/MAXIMUM
6
7 GRIP
8
9
10
TESTED
--15
-7 20
IN KG
Fig. 6. Horizontal (logarithmic) scale gives the number of contractions, divided by the strength of the hand in kilograms as measured by a dynamometer. Vertical scale gives reported quality of the pain. Abbreviations are indicated. The lowest number of contractions was performed when an arterial tourniquet (A) on the upper arm obstructed blood flow (line at left). The greatest number of contractions was performed when a venous tourniquet (V) was on the arm, with the arm in the dependent (D) position. Intermediate values were obtained when no tourniquet was on the arm (0). The position of the arm is noted in subscripts U, H, and D. (Rodbard, S.. :anti Farbstein, M.: Journal of Applied Physiology 33:704, 1972. Reprinted by permission.)
Venous congestion. Venous congestion enhances exercise tolerance (Fig. 6).13This has been demonstrated by inflating a cuff on the upper arm to between 10 to 40 mm. Hg. The number of hand contractions that can be performed under these conditions may double. These findings suggest that venous engorgement of the muscles of the arm facilitates the washout of tissue fluids and their contained catabolite during each contraction. This may result from *an increased bulk exchange of fluid in the congested contracted muscles. Perception. The intensity of the perceived pain is independent of the number or size of the muscle bundles involved. Thus, pain from a single small muscle bundle may be as severe as pain from a much larger muscle mass or from several simultaneously affected muscles. When tourniquets are on both upper arms, simultaneous recurrent flexion of the two hands results in findings that the number of contractions performed by each arm working simultaneously is not significantly
American Heart Journal
less than can be performed by each arm in separate tests. This is so even though the total quantity of catabolite in the body is twice as great as in the experiments on a single arm. This indicates that the stimulus that generates the pain is the local concentration of catabolite. Impulses from the exercising muscles, therefore, do not summate intracranially. Instead, each muscular locus of the production of pain catabolite appears to have its own central representation, or all the impulses go to a common site which permits signals from only one site to pass through the “gate” to consciousness. Evaluation
If the catabolite is an end-product of muscle contraction, why is it not simply an innocuous material that may be transported away at the convenience of local mechanisms, rather than being a material that can and does threaten life? We must assume that the production of the paincausing substance is a necessary part of the
91
Rodbard
contractile mechanism. We have suggested that the catabolite is obligatorily formed in the course of the triggering of the shortening of each contractile unit.‘” However, the catabolite is also a highly toxic material which can produce serious harm to the contractile machinery that forms it. Miniscule quantities of the material probably produce highly potent effects. Why should muscle contraction, a fundamental process in animal survival, be hobbled by the toxic action of some product of the contraction itself? We may speculate that the diffusion of relatively large toxic molecules posed no problems to the tiny organisms in which contractile mechanisms first evolved. The subsequent incorporation of astronomic numbers of contractile units in each muscle cell then introduced problems of elimination of the catabolites generated during contraction. Why does the nervous system not ignore the presence of the pain-producing catabolite? We may assume that local accumulation of this material is highly toxic to the tissues. The cell membrane poses a hindrance to diffusion of the catabolite out of the muscle fiber. Ideally, cellular permeability must be sufficiently great to permit the catabolite to diffuse freely, while preventing the escape of the myoglobin that is dissolved in the same fluids. The catabolite may facilitate its own diffusion by acting on the membrane of the cell in which it is formed. The contractile process through its massaging action of the tissue also aids transport out of the cell. The volume of extracellular fluid probably affects the concentration of the catabolite at the cell membranes and at the site of local nociceptors. The pumping action of the contracting muscle can then operate to squeeze extracellular fluids and their dissolved catabolites back into the blood capillaries (Fig. 3). An adequate vascular bed can produce a stream of blood flow and perhaps of equal importance, mass transport of extracapillary fluid to eliminate the pain catabolite. Failure of blood flow because of inadequate perfusion pressure or because of vascular narrowing may permit the local accumulation of toxic concentrations of the catabolite.
92
It appears, then, that muscle contraction is associated with the production of a slowly diffusible toxic catabolite of significant molecular weight. The blood stream normally transports this material away from the muscle cells. Isolation and identification of this substance may provide means for the further elucidation of elements of the contractile process, the mechanism of stimulation of nociceptive nerve fibers, the inhibition of the toxicity of the substance, and the clarification of general problems related to pain and fatigue. REFERENCES 1.
Zak, E.: Uber den Gef;isskrampf bei intermittierendem Hinken und tiber gewisse Kapillomotorische Erscheinungen, Arch. Inn. Med. 2:405, 1921. Lewis, T.: The Blood Vessels of the Human Skin and Their Responses, London, 1927, Shaw and Sons. Melzack, R., and Torgerson, W. S.: On the language of pain, Anesthesiology 34:50, 1971. Layzer, R. B., and Rowland, L. P.: Cramps, N. Engl. J. Med. 285:31, 1971. Park, S. R., and Rodbard, S.: Effects of load and duration of tension on pain induced by muscular contraction, Am. J. Physiol. 203:735, 1962. 6. Rodbard, S., Williams, C. B.;Rodbard, D., and Berglund, E.: Myocardial tension and oxygen uptake, Circ. Res. 14:139, 1964. 7. Goldstein, M. S., Mullick, V., Huddle&on, B., and Levine, R. L.: Action of muscular work on transfer of sugars across cell barriers: comparison with action of insulin, Am. J. Physiol. 173:212, 1953. 8. Griinfeld, J. P., Ganeval, D., Chanard, J., Fardeau, M., and Dreyfus, J. C.: Acute renal failure in McArdle’s disease, N. Engl. J. Med. 286:1237, 1972. 9. Horisberger, B., and Rodbard, S.: Relation between pain and fatigue in contracting ischemic muscle, Am. J. Cardial. 8:481, 1961. 10. Rodbard, S., and Pragay, E. B.: Contraction frequency, blood supply, and muscle pain, J. Appl. Physiol. 24:142, 1966. 11. Alam, M., and Smirk, F. H.: Observations in man upon blood pressure raising reflex arising from voluntary muscles, J. Physiol. 89:372, 1937. 12. Malinow, M. R., Moia, B., Otero, E., and Rosenbaum, M.: The occurrence of paroxysmal hypertension in patients with intermittent claudication, AM. HEART J. 38:702, 1972. 13. Rodbard, S., and Farbstein, M.: Improved exercise tolerance during venous congestion, J. Appl. Physiol. 33:704, 1972. 14. Rodbard, S.: An analysis of myocardial contraction, in The Study of the Systemic, Coronary, and Myocardial Effects of Nitrates, Gensini, G. G., editor. Springfield, Ill., 1972, Charles C Thomas, Publisher, pp. 38-57.
July, 1975, Vol. 90, No. 1
with
Simon Rodbard,
Ph.D.
M.D.,
muscular
activity
Duarte, Cali{
Acute pain in contracting muscles is a frequent experience in patients with arterial disease. It is also a common experience in normal subjects. In normal subjects the sensation usually results from prolonged or repeated contraction of a voluntary muscle against an unaccustomed load. A heavy valise, carried at first with almost complete ease, soon generates an annoying sensation of discomfort in the arm and shoulder muscles. The discomfort gradually progresses, becomes moderate, and then severe. Finally the ache or fatigue becomes so intolerable that the load must be released, even if this means that the train or plane is missed. The discomfort or pain is so prepotent that it can force the cessation of the muscular work even in the face of the threat of death. Thus an individual trapped in a situation in which he must hold on to a ledge or a rope must soon release his hold even though he knows that a fatal fall will result. intermittent claudication. The circumstances outlined above for pain in voluntary muscles have similarities to the pain in intermittent claudication, angina pectoris, and intestinal angina. Intermittent claudication occurs in patients whose femoral arteries are severely narrowed, as in arteriosclerosis obliterans.’ These patients can walk only a limited distance before leg muscle discomfort forces them to stop. After an interval of rest, even in the standing position, they can resume their walk, but the discomfort returns quickly after walking a shorter distance. To hide their embarrassment these patients become “window shoppers” who stand quietly before a store window until they can again comfortably resume their stroll. The severity of the disease process has been evaluated in terms of the disFrom the Duarte. Received
Department for publication
of Cardiology,
City
of Hope
Center,
Feb. 28, 1974.
Reprint requests to: Dr. Simon Rodbsrd, Department City of Hope Medical Center, Duarte, Calif. 91010.
84
Medical
of Cardiology,
tance walked between the stops; this distance becomes shorter as arterial narrowing becomes progressive. In the end-stages of arteriosclerosis obliterans, the patient can walk only a few steps before another rest period becomes imperative. Angina. A similar disturbance is experienced when the involuntary muscles of the heart or of the intestines receive an inadequate blood flow. However, discomfort, pain, or fatigue cannot inhibit the recurrent contractions of these organs. The symptoms may, therefore, become progressively more severe. Angina pectoris (“suffocation in the chest”) and intestinal angina are commonly associated with narrowed arteries that impede the delivery of an adequate i-low of blood to the contracting organs. When blood supply is inadequate, recurrent contraction injures the muscle cells, and ultimately can lead to their necrosis. The serious general consequences of such localized tissue damage have led to many studies of the clinical phenomenon of infarction. Like other discomfort, the sensation of severe pain impressesitself so vividly upon the attention of the patient that his search for relief becomes a primary activity. If the pain becomes intolerable he may exhibit progressive irritability and aversive behavior. He begins to thrash about and finally he will project strong feelings against persons or objects in his environment. Relief of the discomfort eliminates the emotional disturbance within a few seconds and the episode is quickly forgotten. The discomfort
Pain-inducing stimuli, subserved by various nerve impulses, are modulated and interpreted by higher mechanisms. This modulation is determined by the functional structure of the higher centers which select and abstract this information out of the total input. Thus, the words called forth to describe the discomfort represent interpretations not only of sensory and affective qual-
July, 1975, Vol. 90, No. 1, pp. 84-92
Pain associated with mlwular
ities, but also of previous experiences and of the cultural pattern. The flow of nerve impulses from the active muscle to the brain may be perceived as pain or as fatigue. The fatigue is recognized as a progressive weakness of the contracting muscle and in the realization by the subject that the voluntary muscle does not respond to his will. Fatigue occurs commonly when the load is negligible or when its magnitude approaches the limit of the strength of the contracting muscles. These findings indicate that the cerebral interpretation of the impulses arriving from the contracting muscles may be quite variable. When the perception is of pain or of fatigue, the exercise comes to a halt. The symptoms reported by patients with the diagnosis of angina pectoris” or intermittent claudication are remarkably variable. Almost the entire range of the words used for pain listed by Melzak and Torgerson” has been reported by patients with arterial disease. These terms include deep, spreading, radiating, boring, piercing, stabbing, crushing, pressing, vise-like, squeezing, pulling, aching, drawing, hurting, choking, burning, suffocating, distressing, excruciating, intolerable, and tiring, or simply as fatigue. The discomfort is continuous and persistent, and independent of individual contractions or relaxations. When its source is in skeletal muscle it is usually referred to the region of the contracting muscle, or to adjacent joints. When the source is in the heart, the pain is referred to the anterior chest wall, often with radiation to the neck or jaw, and to the ulnar distribution of the left arm. These variations in description introduce significant difficulties into the analysis of the data obtained on normal subjects engaged in voluntary muscle contraction. Evaluation is even more complex when the source of the disturbance is in the viscera. Related muscle pains. Unaccustomed exertion generates a dull, aching muscle pain that may persist for days even though the blood supply is presumably normal. This may be attributed to overload and injury of the muscle and its tendons. When the exercise becomes habitual, hypertrophy of the muscle and its attachments reduces the likelihood of damage and the pain gradually diminishes and disappears.l Trauma to muscles produces a boring, deep pain which is probably due to direct injury to muscle and nerve cells, and
American Heart Journal
a&z@
not solely to a restricted blood supply. Intermittently recurrent pain has been attributed to spasm. For example, tension headaches have been attributed to spasm of the occipital muscles. Cramps are painful contractions of the muscles, especially in the elderly; these pains can sometimes be controlled by stretching the affected muscles, or by the administration of quinine. Other forms of pain associated with muscle contraction are those due to inflammatory processessuch as myositis or tendonitis. Inflammation of epiphysial and related connective tissue sheaths may give rise to “muscle” pain Pains arising in the joints may also be int,erpreted as “muscle” pain. The surprisingly common costochondral tenderness of Tietze’s syndrome is often misinterpreted as angina pectoris. Some of these sources of pain can be identified by pressure on the site of reported pain. Reassurance in such cases can sometimes eliminate the symptom completely. These complex factors can introduce ambiguity into the study of muscle pain. Problems
in analysis
Despite the objectivity of the disturbances in muscle that lead to pain, clinical evaluation is remarkably difficult, especially in angina pectoris. Some investigators insist that data on such pain, which by definition is subjective, cannot be objectivized. This attitude has stifled research on these potentially lethal mechanisms. Numerous studies have been directed to medical or surgical means for the control of such symptoms, but few of these studies have been properly controlled. Some of the reported results on the part of investigators may have been due to the wishes of the physician, and to the deep concern and fears of the patient. The resulting anxieties can greatly augment the discomfort. It is well appreciated that an enthusiastic approach offered by the physician or experimenter can, through purely psychologic bases, greatly alleviate fear and reduce the apparent pain. Such factors may have contributed to the recurrent disappointment with some & the surgical procedures that for various intervals have had vogue in the therapy of angina pectoris. Surgical procedures have included pericardial poudrage, ligation of the coronary venous sinus, coronary endarterectomy, mammar.v artery ligation, insertion of the mammary arteries into slits cut into the ventricular myocardium, and
85
Rodbard
PERCENT
Experimental
CONOTFROL N=NOTICEAELE I=INTOLERABLE
100 1 80
NN I NIN
1
11 IN
60 i IN
40.
NN1l
Ii1 20.
NNI NNN
NI NI
H
H 64
8 INTERVAL
BETWEEN
FIRST
AND
SECOND
(set) EXERCISE
Fig. 1. The number of contractions performed in the first test was considered to be 100 per cent. The number of contractions performed in the second test is shown. The number of seconds during which the cuff was deflated prior to the resumption of exercise is shown in the horizontal axis (2,8, and 64 seconds). N is the per cent of contractions performed prior to onset of noticeable pain. I is the per cent performed prior to onset of intolerable pain. Extrapolation suggests that recovery should be complete in about 10 minutes.
currently, bypassing a stenotic coronary artery segment with a saphenous vein graft or anastomosis with a mammary artery. Some of the problems inherent in the evaluation of these therapeutic approaches to pain are highlighted by experiences with mammary artery ligation. This relatively simple surgical approach to the problems of coronary artery disease and angina pectoris was based on the belief that ligation of the mammary arteries would divert more blood to the adjacent coronary arteries. Mammary artery ligations were soon followed by reports of gratifying reductions in the frequency and severity of angina1 attacks. This question was then properly approached in double-blind tests. Patients with angina pectoris were carefully studied. At the time of the anterior thoracic skin incision, a card was drawn to separate the patients into two random groups. In one group, the mammary arteries were ligated; a high percentage of these patients had relief from their complaints of chest pain. In the other group, only the skin incision was made, but the mammary arteries were not ligated; an equal percentage of these patients had relief from their symptoms. These findings emphasized that analysis of angina pectoris could founder on the complications introduced by the wishes and anxieties of the patients and of their physicians.
86
procedures
Although pain is subjective, responses to the sensation of pain can be quantified. Since skeletal muscle pain can be easily produced, this procedure offers a means to assay the pain process. The reader can readily examine the facility with which pain can be produced by recurrently flexing and extending the fingers of a hand as rapidly as possible. A sensation of discomfort appears in the forearm within 30 seconds. Continuation of the exercise causes the discomfort to become progressively annoying. Further contractions usually lead within a minute or two to a sensation of severe local pain or burning, and then to such profound weakness, fatigue, or pain localized to the region of the contracting muscles, that the exercise cannot be continued. A few seconds of rest relieves the discomfort, although a senseof local fatigue may persist for a minute or so. A demonstrable “pain” residue remains in the affected muscle for a longer period. This can be demonstrated by attempting to repeat the exercise after a minute of rest and unimpeded blood flow; the discomfort usually recurs after fewer contractions than were performed in the initial test (Fig. 1). Quantification. The abnormalities associated with contraction of skeletal muscle can be quantified by having the subject report when the discomfort is noticeable, and when it becomes to annoying, severe, or intolerable. Inability continue the voluntary exercise is a useful endpoint. Controlled, randomized tests show that each individual will perform a remarkably uniform number of contractions under standardized conditions and against a given load. A measurement with objective characteristics is thereby recorded. Tests of this kind are useful not only in estimating the pain tolerance of subjects, and in the evaluation of the reports given by patients concerning the severity of the pain they report as arising from angina pectoris or other pain syndromes, but also in the analysis of the mechanisms that produce the pain. Mechanism. We have examined the pain associated with muscle contractions by controlling such parameters as load, duration, and frequency of contraction; the arterial or venous pressures; the interval between successive contractions; the intervals between successive tests; etc. The
July, 1975, Vol. 90, No. 1
Pain associated wzth muwdar SE\ER’l’* 3’ PA,tJ
a&r-it?
F!LLING /
INTOLERABLE
Mi i
!
r.4/
ANNOYIN.;*-
-.+/
NOTICEABLE
PAIN i200
400
600
, 800
EXPRESSION
f
DIFFUSION
PRODUCT C.L05.D0331225TESTsl
Fig. 2. Relation of product of number of contractions (C), square root of the load (L” “), and the cube root of the duration of each contraction (D”‘“), plotted against the reported severity of pain (vertical axis) in young subjects with no known cardiovascular disease. Blood flow to the arm was occluded by a tourniquet. The severity of the pain increases with the product. The dots represent averages; the horizontal bars represent one standard deviation. The data were obtained from several different loads and durations of contraction.
number of contractions performed prior to the development of pain or of the inability to continue because of fatigue varies with the strength of the muscles involved, the load that must be lifted, the frequency, and the duration of the contractions, the square root of the load, and the cube root of the duration of each contraction. The product of these factors is remarkably constant for each degree of severity of pain (Fig. 2). Hypothesis. We have operated on the hypothesis that each contraction of an ultimate contractile unit (sarcomere) generates a stoichiometric quantity of a toxic catabolite or pain substance in the muscle fiber (Fig. 3, A and I?).’ The relationship between depolarization and contraction in the production of the catabolite is illuminated in studies on the heart. Normally, every fiber in the heart is depolarized in every beat (all or none law), yet the tendency to the development of pain is known to vary with load, i. e., with the tension developed in each beat. The quantity of the catabolite produced in each beat is, therefore, independent of the depolarization process. The number of contractile elements that participate in a given contraction of the heart is apparently the determining factor in the concentration of the pain substance, and this appears to vary with the
American Heart Journal
fig. 3. Concept of role of muscular contraction in production and removal of pain catabolite. In upper left, a representation muscle fiber and a capillary are enclosed with extracapillary fluid in a fibrous connective tissue capsule. In upper right, muscle fiber produces catabolites (C) during active contraction, as length of capsule is shortened. In lower right, catabolities diffuse out of muscle fiber into extracapillary fluid. High concentrations of catabolite adjacent to nerve fiber stimulate nerve impulses which, on reaching the brain, induce the sensation of pain. Pain is referred to site of the contracting muscle. In lower left, contraction of adjacent fibers compresses the capsule, squeezing extracapillary fluid and most of the contained catabolite out of the capsule and back into the blood circulation. In upper left capsule, no longer compressed, fills with ultrafiltrate. It is appreciated that phenomena shown at upper right and those &own in lower left may occur simultaneously.
total tension developed by the heart during that beat as it ejects its contents.” The mechanical tension developed by the heart in a given beat also correlates with its oxygen uptake. The total tension and the oxygen uptake per minute also vary with the number of beats per minute. These data suggest that the production of the catabolite may be related to the actual process of shortening in those sarcomeric units that are involved in the contraction. The work that can be performed before the appearance of intolerable pain varies inversely with the strength of the contracting muscle, as
87
Rodbard
TOTAL CONTRACTIONS .
Unrestricted \
\
_____
30
MAX
O.---------o'
40
occluded ______------
-----
I
I
50
60
CONTRACTIONS
-----D 1 MAX.
70 PER
MINUTE
Fig. 4. Number of contractions performed prior to fatigue or intolerable pain. The frequency of contraction is shown in the horizontal axis. The line is extended to the maximal rate that could be performed by each individual. The number of contractions (vertical axis) performed when blood flow was unrestricted was indeterminate at slow rates (< 40 per minute) but decreased at faster rates. The number that could be performed when a tourniquet occluded the arterial inflow increased with the frequency of contraction. The two curves approached a common value at very rapid rates of contraction.
measured with a dynamometer (Fig. 4). We may assume that the number of units required to produce the tension of each contraction is distributed among the larger number of units in a hypertrophied muscle. As a result, the amount produced in each sarcomere, per unit of total muscle tension, is reduced in a stronger muscle. As long as the catabolite remains inside the muscle fiber there is no conscious recognition of its presence. Diffusion of the catabolite out of the cell increases its extracellular concentration. When its concentration reaches a threshold value, adjacent nerve fibers are stimulated and a train of impulses is initiated (Fig. 3, C). Arrival of
88
these impulses in the central nervous system generates the perception of a sense of discomfort, pain, or fatigue. As the concentration of the catabolite in the tissue increases, the discomfort that was at first only noticeable and then annoying, becomes severe, and the contractions become progressively weaker. Finally the discomfort becomes intolerable. The catabolite. Our analysis suggests that the catabolite responsible for pain or fatigue in contracting muscle is a toxic material which must be eliminated from the tissue at any cost. The pain-inducing catabolite cannot be lactic acid. This conclusion results from the finding that muscle pain tends to be unusually severe and damaging in patients with McArdle’s disease, a deficiency of the phosphorylase that converts muscle glycogen to lactic acid. Oxygen lack is not the factor that produces the toxic catabolite. If the pain were due to lack of oxygen or to the washout of a highly diffusible substance, blood flow for one minute should have been more than adequate to restore pre-exercise conditions. The failure of complete recovery in this interval (Fig. 1) indicates that the elimination of the agent responsible for pain depends on other time-limited mechanisms. Further, tourniquet occlusion of the blood flow into the arm for as long as 20 minutes with the production of severe ischemia has little effect on the number of contractions that can be performed. The development or elimination of the pain is unaffected by the breathing of pure oxygen even at three atmospheres (2,200 mm. Hg of oxygen) of pressure. The pain catabolite is, therefore, not directly related to oxygen deficiency. Diffusion. Experiments have been performed to evaluate the diffusion of the catabolite. Such studies are best performed while the flow of blood to the affected muscles is stopped by the application of an arterial tourniquet to the upper arm. These studies have been based on the assumption, as noted above, that each contraction of a given strength (number of contractile elements triggered to contract), and of a given duration produces a stoichiometric quantity of catabolite. The greater the interval between contractions, the fewer the number of contractions necessary to produce intolerable pain or fatigue. Longer intervals between contractions provide more time for diffusion of the catabolite out of the affected
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1975,
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Pain associated
cells, and this can result in higher extracellular concentrations of the catabolite despite the smaller number of contractions (Fig. 4). The catabolite persists in muscle for minutes after exercise has been stopped and blood flow has been reinstituted (Fig. 1). This suggests that it is a molecule of significant size. The molecular weight of the catabolite is estimated from its apparent rate of diffusion as having a molecular weight of perhaps about 1,000. The catabolite cannot be destroyed locally in the muscle in which it was formed, since the discomfort induced by a painproducing exercise persists as long as blood flow is obstructed. It apparently must be washed away by the resumption of blood flow through the affected tissue. Toxicity The toxicity of the catabolite appears to result from a destructive local action on membranes. As with increases in the local concentration of other toxic materials, affected cell membranes are first stimulated. The accumulation of sufficient catabolite in a specific site stimulates local nonmyelinated fibers to fire impulses, perhaps through a toxic action on the neuronal membrane. A sufficiently intense barrage of neurogenic impulses leads to a voluntary cessation of contraction, or in some instances to an involuntary cessation of muscle exercise associated with “fatigue.” Excessive catabolite concentration probably produces severe cellular damage which only the cessation of contractile activity can prevent. Evidence for cell damage comes indirectly from two sources that indicate changes in the permeability of the muscle cell membranes. Thus, excessive muscle exercise increases the permeability of muscle cells to glucose, thereby resembling the insulin-induced augmentation of muscle cell permeability.’ In phosphorylase deficiency of muscle, even mild exercise can produce severe muscle pain in association with the leakage of myoglobin out of the affected muscle cells. An acute bout of contractile activity as in wrestling or following an epileptiform convulsion can result in a massive escape of myoglobin. The quantity escaping out of the damaged membranes of the muscle fibers may be sufficient to produce myoglobinuria and even renal tubular obstruction with myoglobin crystals.” Washout. We examined the rate at which the pain-inducing catabolite can be eliminated by the
American
Heart
Journal
with mw wlnr
acti1:it.y
blood stream (Fig. l).” A tourniquet cuff on the upper arm occluded the blood supply to the contracting muscles. When the muscle pain became intolerable, or the muscles would no longer contract because of fatigue, the cuff was deflated. The pain or fatigue was relieved almost at once. Reinflation of the cuff then again occluded the blood flow and the hand exercise was resumed. The number of contractions that could be performed after a two-second interval of blood flow that had provided complete relief from the pain was only about one-fourth the number that could be performed in the initial test,. Thus, even though the pain has been relieved, a residue of catabolite persists in the muscle. This preformed material diffuses out of the muscle fibers during the second bout of exercise and thereby accelerates the rate of appearance of pain. Blood flow for eight seconds before reapplication of the cuff and reinstitution of the exercise resulted in an increase in the number of contractions to 40 per cent of the initial number. After one minute of blood flow, about 75 per cent. as many contractions as in the initial test could be performed. These data appeared to follow a logarithmic washout curve. Complete recovery of the capacity to perform the exercise appeared to require more than 10 minutes of unimpeded blood flow. intrinsic obstructions to flow. Some aspects of the nature of the pain substance can be investigated when there is no extrinsic interference with the blood flow to the muscle, as in arm exercise experiments in which no tourniquet is used. During each contraction of a muscle3 the rise in intramuscular pressure compresses the blood capillaries and reduces the vascular conductance (flow/pressure) of the affected bed. During the subsequent relaxation blood flow takes place, probably in the form of a hyperemia. The ability to continue the exercise varies with the duration of muscle relaxation between successive contractions (Fig. 4).‘” In our experiments, hand exercise could be continued 15 minutes or longer without the development c)f significant pain when 40 contractions per minute were performed. Increases in the number of contractions per minute to 50, 60, and 70 shorten the intervals of muscle relaxation during which muscle blood flow can take place freely, and decrease the number of contractions performed prior to the onset of pain.
89
Rodbard
PAIN
(CONTRACTIONS ,‘..
d 20
* MIN-“)
INTOLERABLE
10
20
1 30
I 40
I 50
NUMBER
I1111 100
200
I 300
I 400
Ill,, 500
1000
OF CONTRACTIONS
Fig. 5. Walk-through phenomenon in a male, aged 20. Horizontal axis is number of contractions (logarithmic scale). Vertical axis is the reported severity of discomfort or pain in the contracting arm. The line at left was obtained with a tourniquet on the upper arm at a contraction rate of 66 per minute. Pain was first noticed at 34 contractions and became intolerable at 75 contractions. With no tourniquet on the arm, 80 contractions were performed prior to noticeable pain. At 110 contractions, the pain became annoying. At 450 contractions, the grade of discomfort was reported as only noticeable and shortly after that the discomfort disappeared completely (walkthrough phenomenon) despite continued contractions to a total of 1,000. At 72 contractions per minute, the pain became severe before it returned to the noticeable state. At 90 contractions per minute, no walk-through was observed.
These findings are consistent with the thesis that when blood flow is adequate, as occurs during the relatively long intervals of relaxation between successive contractions, the catabolite does not accumulate in quantities sufficient to initiate pain or to force the end of the performance. At faster contraction rates, the decline in the duration of the relaxation interval and in the resulting washout interval, is inadequate for the rapid elimination of the pain-producing catabolite. Walk-through. This phenomenon, also known as “second wind” is observed at contraction rates intermediate between a high frequency that produces progressive discomfort to the point of intolerable pain, and a slower frequency that can be continued indefinitely. In such tests, the subject usually reports the appearance of pain and its progression to annoying or even severe qualities after about one minute. Continued contractions, instead of causing progression of the pain then result in its disappearance, and the exercise can be continued indefinitely without its reappearance (Fig. 5). This walk-through phenomenon may result from the hyperemia associated with the exercise and the resulting more effective washout of catabolite. An elevation of systolic pressure, commonly observed during exercise, may also increase blood perfusion. Arterial pressure. Since the rate of blood flow appears to be implicated in the elimination of
90
pain, the effects of changes in arterial pressure on the generation of pain have been studied.” To do this we compared the number of contractions that could be performed while the arm was in a position horizontal to the body, with the number performed while the arm was elevated on an arm rest (Fig. 6). Maintenance of the arm in the upright position reduces the arterial pressure in the muscles of the forearm by about 25 mm. Hg. Nearly twice as many contractions could be performed with the arm in the horizontal position than when it was upright. Arterial perfusion with the arm upright, especially in individuals who are unaccustomed to this position, therefore appears to be less effective in eliminating the pain factor from the exercising forearm muscles than when the arm is horizontal. An elevated arterial pressure can be expected to increase the perfusion of the contracting muscle.” This interpretation is supported by the finding that more contractions can be performed with the arm in the dependent position than in the horizontal or upright positions. The arteries in the dependent arm have a higher pressure because of hydrostatic position. It is also known that the arterial pressure tends to rise during intermittent claudication.” This increase in perfusion pressure may increase blood flow and improve the elimination of the catabolite from the fluids of the contracting muscle.
July, 1975, Vol. 90, No. 1
ARM A=ARTERIAL TOURNIOUET O-OPEN CIRCULATION V=VENOUS TOURNIQUET
PAIN INTOLERABLE
U = UPRIGHT Ii = HORIZONTAL D = DEPENDENT
A
OU
n=54
n = 25
vu OH n=23 n=25
00 n=13
i
L’n n=6
-
SEVERE
ANNOYING
-
NOTICEABLE
-
n = SUBJECTS
I 0.8
0.9
I
1.5
2 NUMBER
3 OF
4
5
CONTRACTIONS/MAXIMUM
6
7 GRIP
8
9
10
TESTED
--15
-7 20
IN KG
Fig. 6. Horizontal (logarithmic) scale gives the number of contractions, divided by the strength of the hand in kilograms as measured by a dynamometer. Vertical scale gives reported quality of the pain. Abbreviations are indicated. The lowest number of contractions was performed when an arterial tourniquet (A) on the upper arm obstructed blood flow (line at left). The greatest number of contractions was performed when a venous tourniquet (V) was on the arm, with the arm in the dependent (D) position. Intermediate values were obtained when no tourniquet was on the arm (0). The position of the arm is noted in subscripts U, H, and D. (Rodbard, S.. :anti Farbstein, M.: Journal of Applied Physiology 33:704, 1972. Reprinted by permission.)
Venous congestion. Venous congestion enhances exercise tolerance (Fig. 6).13This has been demonstrated by inflating a cuff on the upper arm to between 10 to 40 mm. Hg. The number of hand contractions that can be performed under these conditions may double. These findings suggest that venous engorgement of the muscles of the arm facilitates the washout of tissue fluids and their contained catabolite during each contraction. This may result from *an increased bulk exchange of fluid in the congested contracted muscles. Perception. The intensity of the perceived pain is independent of the number or size of the muscle bundles involved. Thus, pain from a single small muscle bundle may be as severe as pain from a much larger muscle mass or from several simultaneously affected muscles. When tourniquets are on both upper arms, simultaneous recurrent flexion of the two hands results in findings that the number of contractions performed by each arm working simultaneously is not significantly
American Heart Journal
less than can be performed by each arm in separate tests. This is so even though the total quantity of catabolite in the body is twice as great as in the experiments on a single arm. This indicates that the stimulus that generates the pain is the local concentration of catabolite. Impulses from the exercising muscles, therefore, do not summate intracranially. Instead, each muscular locus of the production of pain catabolite appears to have its own central representation, or all the impulses go to a common site which permits signals from only one site to pass through the “gate” to consciousness. Evaluation
If the catabolite is an end-product of muscle contraction, why is it not simply an innocuous material that may be transported away at the convenience of local mechanisms, rather than being a material that can and does threaten life? We must assume that the production of the paincausing substance is a necessary part of the
91
Rodbard
contractile mechanism. We have suggested that the catabolite is obligatorily formed in the course of the triggering of the shortening of each contractile unit.‘” However, the catabolite is also a highly toxic material which can produce serious harm to the contractile machinery that forms it. Miniscule quantities of the material probably produce highly potent effects. Why should muscle contraction, a fundamental process in animal survival, be hobbled by the toxic action of some product of the contraction itself? We may speculate that the diffusion of relatively large toxic molecules posed no problems to the tiny organisms in which contractile mechanisms first evolved. The subsequent incorporation of astronomic numbers of contractile units in each muscle cell then introduced problems of elimination of the catabolites generated during contraction. Why does the nervous system not ignore the presence of the pain-producing catabolite? We may assume that local accumulation of this material is highly toxic to the tissues. The cell membrane poses a hindrance to diffusion of the catabolite out of the muscle fiber. Ideally, cellular permeability must be sufficiently great to permit the catabolite to diffuse freely, while preventing the escape of the myoglobin that is dissolved in the same fluids. The catabolite may facilitate its own diffusion by acting on the membrane of the cell in which it is formed. The contractile process through its massaging action of the tissue also aids transport out of the cell. The volume of extracellular fluid probably affects the concentration of the catabolite at the cell membranes and at the site of local nociceptors. The pumping action of the contracting muscle can then operate to squeeze extracellular fluids and their dissolved catabolites back into the blood capillaries (Fig. 3). An adequate vascular bed can produce a stream of blood flow and perhaps of equal importance, mass transport of extracapillary fluid to eliminate the pain catabolite. Failure of blood flow because of inadequate perfusion pressure or because of vascular narrowing may permit the local accumulation of toxic concentrations of the catabolite.
92
It appears, then, that muscle contraction is associated with the production of a slowly diffusible toxic catabolite of significant molecular weight. The blood stream normally transports this material away from the muscle cells. Isolation and identification of this substance may provide means for the further elucidation of elements of the contractile process, the mechanism of stimulation of nociceptive nerve fibers, the inhibition of the toxicity of the substance, and the clarification of general problems related to pain and fatigue. REFERENCES 1.
Zak, E.: Uber den Gef;isskrampf bei intermittierendem Hinken und tiber gewisse Kapillomotorische Erscheinungen, Arch. Inn. Med. 2:405, 1921. Lewis, T.: The Blood Vessels of the Human Skin and Their Responses, London, 1927, Shaw and Sons. Melzack, R., and Torgerson, W. S.: On the language of pain, Anesthesiology 34:50, 1971. Layzer, R. B., and Rowland, L. P.: Cramps, N. Engl. J. Med. 285:31, 1971. Park, S. R., and Rodbard, S.: Effects of load and duration of tension on pain induced by muscular contraction, Am. J. Physiol. 203:735, 1962. 6. Rodbard, S., Williams, C. B.;Rodbard, D., and Berglund, E.: Myocardial tension and oxygen uptake, Circ. Res. 14:139, 1964. 7. Goldstein, M. S., Mullick, V., Huddle&on, B., and Levine, R. L.: Action of muscular work on transfer of sugars across cell barriers: comparison with action of insulin, Am. J. Physiol. 173:212, 1953. 8. Griinfeld, J. P., Ganeval, D., Chanard, J., Fardeau, M., and Dreyfus, J. C.: Acute renal failure in McArdle’s disease, N. Engl. J. Med. 286:1237, 1972. 9. Horisberger, B., and Rodbard, S.: Relation between pain and fatigue in contracting ischemic muscle, Am. J. Cardial. 8:481, 1961. 10. Rodbard, S., and Pragay, E. B.: Contraction frequency, blood supply, and muscle pain, J. Appl. Physiol. 24:142, 1966. 11. Alam, M., and Smirk, F. H.: Observations in man upon blood pressure raising reflex arising from voluntary muscles, J. Physiol. 89:372, 1937. 12. Malinow, M. R., Moia, B., Otero, E., and Rosenbaum, M.: The occurrence of paroxysmal hypertension in patients with intermittent claudication, AM. HEART J. 38:702, 1972. 13. Rodbard, S., and Farbstein, M.: Improved exercise tolerance during venous congestion, J. Appl. Physiol. 33:704, 1972. 14. Rodbard, S.: An analysis of myocardial contraction, in The Study of the Systemic, Coronary, and Myocardial Effects of Nitrates, Gensini, G. G., editor. Springfield, Ill., 1972, Charles C Thomas, Publisher, pp. 38-57.
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