Pain perception and endogenous pain modulation in angina pectoris.

Kellermann JJ, Braunwald E (eds): Silent Myocardial Ischemia: A Critical Appraisal. Adv Cardiol. Basel, Karger, 1990, vol 37, pp 142-164

Pain Perception and Endogenous Pain Modulation in Angina Pectoris Conrad Droste', Helmut Roskamm Rehabilitation Center for Diseases of Heart and Circulation, Bad Krozingen, FRG

One ofthe key questions of silent myocardial ischaemia is why pain is lacking in this phenomenon. The answer to this question lies at the nexus of clinical-cardiological, neurophysiological and psychophysiological investigation approaches. The following article will describe own investigations into the regulation of coronary pain and will discuss their interrelation with basic and phenomenological research into silent ischaemia. Individuum- and Situation-Related Differences in the Occurrence of Pain

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C. Droste is supported bythe Deutsche Forschungsgemeinschaft (SP-II B7-Dr 190 1-2).

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Given a certain magnitude of myocardial ischaemia some of the patients do feel it seldom or not at all and some of them do feel the obviously same amount of myocardial ischaemia regulatory as pain. This is demonstrated as an example in figure 1. The figure shows the results of 4 patients with an angiographically proven coronary heart disease. In all patients an exercise-ECG was taken, later two 24-hour Holter-ECGs and also after a few weeks another exercise-ECG. Even though all patients have a similar frequency of myocardial ischaemia and similar objective signs of it in exercise tests whether pain is present or not varies: The first patient experiences almost all ischaemic episodes as painful. Interindividually

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from the second to the third patient the ischaemia becomes less painful, and the last patient (below) hardly feels myocardial ischaemia at all. This shows that whether or not ischaemia occurs involves an individual factor. Some patients experience almost all ischaemia as painful and, the other extreme, some patients feel little or no pain at all. We call these patients 'asymptomatic patients'. A more individual, patient-related factor is assumed to be the reason why no pain is felt in these cases. This individual factor can be distinguished from a situational factor. Also, figure 1 shows another observation: in the same patient, ischaemia can be accompanied by pain on one occasion and on another by lack of pain ('asymptomatic episodes'). There obviously exists an additional factor which has less to do with the patient than with the ischaemic episode itself or with the situation which the ischaemia triggers. One can assume that the momentary intensity of myocardial ischaemia plays a more important role here.


Fig. 1. Exercise-ECG and long-term ECG data of 4 patients with coronary heart disease. Example for the differentiation between an individuum-dependent factor ('asymptomatic patients') and a situation-dependent factor ('asymptomatic episodes') in the occurrence of pain.

144

The following article will primarily deal with the individually specific factor; i.e. with the question as to why some coronary patients feel less and others more pain. If one examines a large group of coronary patients dividing them by the fact how often pain occurs in relation to ischaemia one will obtain a spectrum (fig. 2). On the one hand, there are patients who are completely asymptomatic and feel no pain at all during even the most severe myocardial ischaemia. Such patients are relatively rare. There are also patients who, although at times feeling angina pectoris, usually do not do so. In this group are, for example, the patients who would, in the course of several exercise tests undertaken at intervals of a few weeks, perceive pain on one occasion and not on another. The overall majority of coronary patients, however, perceive pain relatively consistently during an ischaemia provoked by the exercise test (fig. 2, center). Few studies have been done to answer the question of whether the opposite extreme to totally asymptomatic coronary patients exists, i.e. patients who perceive especially severe pain as a result of a certain degree of ischaemia. Observations of some single cases seem to indicate that this extreme does indeed exist. The analysis of even just one exercise test, for example that of an exercise-EeG, shows that patients also differ in the degree of ischaemia (expressed, for example, by the degree ofST-segment depression) sufficient to provoke angina pectoris pain. Some patients do not perceive pain until the attainment of a very pronounced ischaemia corresponding for example to an ST-segment depression of 0.3 mV or more. Other patients already perceive angina pectoris pain at a low degree of ischaemia corresponding to an ST-segment depression of 0.1 mY. We may also make a distinction between patients by evaluating the temporal relationship between the onset of ischaemia and the perception of angina pectoris pain (see also fig. 4). It must here be said that the degree of an ST-segment depression only indirectly and incompletely reflects the degree of myocardial ischaemia. We can, however, also find a continuous relation of pain as a response to ischaemia by using other objective ischaemia indicators, e.g. filling pressure increase in a floating catheter examination, perfusion deficiencies in a thallium scintigraphy, hypokinesia in laevocardiogram or lactate measuring from coronary sinus. Some studies have been able to show that the individual characteristics of pain perception ascertained in an exercise-EeG can be applied to a long-term EeG. Patients who perceive relatively little pain during the


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exercise-ECG also show more silent than symptomatic ischaemic episodes during a long-term ECG. Conversely, if ischaemia in an exercise-ECG is very painful, e.g. occurring at a level of one mm ST-segment depression, also in Holter-ECG more symptomatic ischaemic episodes can be found [17, 26]. Differences among individuals can also be found with the assessment of complaints of angina pectoris in daily life. Some patients have no pain at all although one must assume that they must have severe ischaemic episodes during everyday activities. Other patients are conspicuously symptomatic although the cause of the pain could not be accounted for by the findings of objective examination.


Fig. 2. Continuum for the occurrence of pain in relation to myocardial ischaemia. Myocardial ischaemia can be defined as 'asymptomatic' by using very different criteria.

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There are generally three main arguments brought forth to explain the absence of pain in silent myocardial ischaemia. It is possible that peripheral processes, i.e. the generation of pain impulses, are responsible in that, for example, the ischaemia is too weak to generate pain centrally. It may be assumed that this factor is partly responsible. We will not delve here into the details of the neurophysiology of coronary pain. Reference hereonto has been made elsewhere [15]. In short, we may assume that the origin of coronary pain lies in the heart muscle. Although there are many nociceptors in the pericardium, pericardial pain is clinically distinguishable from myocardial pain; myocardial pain can be perceived even after a pericardectomy. It is generally accepted that free nerve endings in the myocardium, especially those in the proximity of the capillaries and small vessels, are receptors of pain information. Studies done in the last few years have shown that the reason why the term 'free nerve endings' seems so unspecific is that hardly anything about the electron microscopic structure of these endings was known. Recent electron microscope experiments have shown that the free nerve endings are substantially more complex than previously assumed. Examinations of the receptors in sceletal muscle have found bud-like protuberances along the free nerve endings exhibiting areas with axon membrane sections without any Schwann cell covering [20, 35]. The receptor structures are very likely to be found here. A detailed electron microscopic analysis discloses that they are polymorphic and can be divided into numerous subgroups about whose physiological function hardly anything is known. Examinations as have been done of sceletal musculature or of joints have not yet been undertaken of the heart muscle. One may, however, assume that similar receptor structures exist. Finally, the processes at a pain receptor can also be molecular-biologically described. There must be certain receptor structures at this level whereby 'adequate stimuli' from the environment interact at the receptor and are thereby able to build a receptor-potential. The receptor-potential is generated in a 'generator-potential' which in tum gives rise to an actionpotential which itself is transmitted towards the center. Stimulus experiments performed upon animal myocardium show that chemical factors, primarily bradykinin (probably in interaction with prostaglandin), sero-


Neurophysiology of Angina Pectoris Pain

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tonin, adenosin as well as other substances can react at the receptors. Furthermore, there have been animal experiments which indicate that mechanical stimuli may also have an effect upon the processes at the receptors. The most probable explanation is an interaction of both chemical and mechanical stimuli. For example, the chemical agents might increase the sensitivity of the receptors thereby allowing the mechanical stimuli to adequately take effect. A similar interaction between chemical and mechanical stimuli has been found to occur within the process of sceletal muscle pain [46]. Pain information is collected at the free nerve endings and then transmitted towards the center. The nerve fibres can be divided according to their conduction velocity into the faster conducting myelinized A-deltafibres and the slower unmyelinized C-fibres. It is certain that these fibres also transmit the pain information emanating from the myocardium. An important observation is that there is a large number of A-delta and Cfibres with an afferent information transmission function which are not involved in the transmission of pain information and are therefore not sensoric [10]. This will become important when we later consider the regulation of coronary pain. The fibres which conduct pain information from the myocardium towards the center run, anatomically seen, along the same pathways along which fibres of the sympathetic nervous system also run. The cell nucleus lies in the spinal ganglion and the neurons enter the spinal cord through the dorsal root. This is where the pain information is transferred to neurons which, in most cases, cross and transmit the information by way of the tractus spinothalamicus on towards the center. There has been much discussion in the literature as to the specificity of the receptors for visceral pain [see in 15]. Specific would mean that the receptors only respond to pain producing pathological stimulus. Nonspecific would mean that these receptors are still in action although no nociceptive stimulus is present, as would be the case if these receptors were involved in the physiological feedback regulation of the hemodynamic processes. The codification as 'pain' would then be dependent upon the intensity of the peripheral stimulus. At the moment, this question can only be incompletely answered. The prevalent opinion is that the perception of visceral pain is regulated predominantly by intensity mechanisms. In support of this are the results of the investigations into the action potential of spinal cord neurons. In the influx from the heart, a background activity is as a rule already present before the application of a pain stimulus, as for



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example through the experimental occlusion of a coronary vessel. This is a strong argument in support of the contention that an important role is played by intensity mechanisms. The relatively little evidence for specific receptors for myocardial pain [61) has not yet been corroborated. There are modified models which play down the importance of the intensity of the stimulus in itself and underline the importance of the difference in the intensity between areas with pain stimulus and those without. This is known as the pattern theory [44). There is certain cardiological evidence in support of it. Relatively small ischaemia zones, for example due to a stenosis of a small side branch of a main coronary vessel, can be very painful. The discussion over the specificity theory and the intensity theory of visceral pain is, in the final analysis, not very relevant to the question of silent ischaemia. There is, in all probability, a continuum of different receptors with perhaps in part specific features. The amount of the nociceptive afferent influx which attains the central, depends upon the sum of many stimulated receptors. The intensity of the peripheral pain stimulus always plays a role even if there should prove to be specific receptors for myocardial pain. The magnitude of ischaemia or the degree of the nociceptive afferent impulse rate from the periphery is therefore always a factor in the perception of angina pectoris pain. An important observation, however, is that the intensity alone can only in part explain the phenomenon of myocardial ischaemia. It has definitely been shown in many studies that even a great intensity of myocardial ischaemia and presumably therefore a great peripheral nociceptive impulse rate can occur without a subjectively perceived angina pectoris pain. This indicates a further modifying influence. Myocardial ischaemia is a necessary but insufficient prerequisite for angina pectoris pain.

After the entry of the neurons through the dorsal root of spinal cord, the pain information undergoes complex spinal and supraspinal modulating and especially inhibitory influences [42). The complex system of neural and humoral pain suppressing mechanisms are termed the 'endogenous analgesia system'. This system has since been extensively investigated. The present state of research can be summed up in a few lines.


Endogenous Pain Modulation


149

It is undisputed that such an endogenous analgesic system exists in animals as well as human beings [5, 27]. We can further assume that all pain, superficial, deep and visceral pain undergo such modulating influences. It is supposed that visceral pain undergoes an exceptionally high degree of endogenous inhibition, for one because the number of visceral afferences in the spinal cord is relatively small. It is estimated that a mere 2.5 % of all spinal afferences are visceral [40]. The activity of the endogenous analgesia system is relatively low under rest conditions. It, however, becomes highly activated through external stimuli, hence the expression 'stimulus-induced-analgesia' [1, 57]. Various subgroups of the analgetic system can be defined [5, 28, 45]; besides a neurally and a humorally transmitted component, there is both a component whereby a role is played by opiate-receptors and a non-opioid component whereby other substances, particularly noradrenaline and serotonin are involved. Much direct evidence has since been compiled which indicates the effectiveness of the stimulus-induced analgesic systems in man. The anticipation of pain, for example, leads to the activation of the system as do injuries, pain itself or physical exercise [27, 54, 62, 63].

A series of studies lead us to suppose that patients with symptomatic myocardial ischaemia differ from patients with silent ischaemia in the quantitative effectiveness of the endogenous analgesia. Several investigation groups could meanwhile demonstrate significantly higher experimental pain thresholds for asymptomatic patients in comparison to symptomatic patients [16, 18, 19,24,31,52]. Even with the injection ofa given dosage of an internal chest pain provoking agent (intravenous adenosine) the asymptomatic patients' response with pain is significantly weaker than that of symptomatic patients [12]. We have found in own studies that a tourniquet pain test on the sceletal muscle is particularly valuable in the investigation of pain regulation in coronary patients (fig. 3). An advantage of this method is that the pain thus produced is comparable to angina pectoris and we may therefore assume a parallel provocation and regulation mechanism since both coronary and skeletal muscle pain have their origins in an ischaemia. Figure 3a represents the principle of pain provocation. Using a manometer cuff, the arterial blood flow to the lower arm is interrupted. The subject then engages in a defined activity at a rhythm determined by a metronome.


Experimental Pain Threshold Measurements

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2 min) the appearance of an ST-segment depression. The results are continuous in this case as well. Yet even within this categorisation there are patients who exhibit exceptionally little angina pectoris. Here too, asymptomatic patients displayed a higher pain threshold in the tourniquet test. Although the difference was relatively small, it reached a significant level (p < 0.05).

Besides the described differences in pain thresholds and tolerance levels there is another area in which patients with symptomatic and asymptomatic myocardial ischaemia may quantitatively distinguish. A substantial part of the body's own analgesic mechanisms are regulated through endogenous opiates. Opiates are strong pain suppressors and are particularly effective against pain in myocardial infarction. Opiate receptors were first discovered in the early 70s and shortly thereafter the corresponding endogenous substances (endorphins) were found which were able to react at these receptors. The endogenous opiates have since been the object of intensive research. An overview may be attained with reference to the works in the literature [1,5,45]. The endog-


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154

There are furthermore many types of opiate receptors; jl, 0, 1( and (J receptors as well as their isoreceptors, for example jll and jl2. The endogenous opiates display varying degrees of affinity to these receptors; exogenous opiates act almost exclusively upon jl-receptors. The distribution of the receptors in the body is extremely diverse. There is, however, a high degree of concentration at those locations involved in the regulation of pain, i.e. in the dorsal horn of the spinal cord and the mid-brain structures (nucleus raphe magnus, periaequeductal grey). Early observations already implicated the endogenous opiates in the phenomenon of silent myocardial ischaemia [16]. Several investigation groups have since been able to show that symptomatic and asymptomatic patients with myocardial ischaemia differ significantly in plasma beta-endorphin levels [19, 23, 53, 59]. These differences are already detectable under rest conditions. A physical strain with a relative intensity of over 70% V0 2max along with the exceeding of the anaerobic threshold (blood lactate > 4 mmol/l) is a secretion stimulus for pituitary beta-endorphin [19, 25, 30, 39,41, 47]. Even during and especially 10-15 min after physical exercise, there was found to be significant differences in the beta-endorphin values between symptomatic and asymptomatic patients with myocardial ischaemia [17, 19]. The differences which are already present under rest conditions indicate that the different hormone levels in the blood are not simply the result of the exercise stimulus but rather are an expression of a quantitative difference in the basic pulsatile release of this hormone between the two groups of patients. In our own studies we have found evidence to suggest that it is the symptomatic patients who undergo a reinforced suppression of the hormonal response rather than the asymptomatic patients who exhibit higher than normal hormonal levels. Pituitary endorphin secretion itself is partly opioid regulated and these differences seem to change in response to naloxone (fig. 5). Beta-endorphin is secreted by the pituitary gland along with ACTH in equimolar amounts [30, 32]. The result of ACTH secretion is a reinforced production and release of cortisol. We found in our own studies that patients with symptomatic and asymptomatic myocardial ischaemia also differ in plasma cortisol [19]. The pituitary ACTHibeta-endorphin secretion is subject to a complex regulation within the LHPA-axis (limbic system, hypothalamus, hypophysis, adrenocortical gland) wherein especially the corticotropin releasing hormone and its receptors at the pituitary level play an integrative role within this 'stress-axis' [4, 37, 65].


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Fig. 5. Plasma beta-endorphin levels and exercise parameters for n - 8patients with symptomatic myocardial ischaemia and n = 9 patients with asymptomatic myocardial ischaemia. In a double blind investigation either 6 mg naloxone or placebo was given before exercise test. Under placebo conditions patient groups showed significant differences for beta-endorphin, which were no longer significant after naloxone. According to Droste et al. [19].

The role played by peripheral beta-endorphin as well as the relevance of the quantitative differences for symptomatic and asymptomatic patients requires further discussion. The simplest assumption would be that beta-endorphin acts as an analgesic at the periphery. The predominant opinion in the literature is by


Role of Plasma Beta-Endorphins in Pain Regulation

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now that opiates act centrally through the activation of endogenous analgesic systems. Earlier results [11] that opiates are also able to act peripherally have recently once again become topical. Evidence for the existence of opiate receptors could be found in both the vicinity of the peripheral afferent nerves [27, 28, 66] and in the heart muscle [9, 13]. Several research teams have furthermore since been able to show that opiates are indeed able to act analgesically at the periphery [34,.58]. It is unclear whether the conclusions, having been reached via animal experimental models whereby a pronounced chronic inflammation was induced, can be generalized. It cannot be excluded that opiates work at least in part by intervening into inflammatory mechanisms, for example the building of oedema in the phlogistic area possibly with the involvement of central reflex loops. An important question for future research will be whether parallel basic nociceptive mechanisms exist in an ischaemic muscle area and in chronic inflammation. On the whole, however, it is much more likely that the analgetic effect of endogenous opiates works centrally. There are examples from literature that even very high levels of beta-endorphins in the periphery do not have an analgetic effect, for example the Nelson syndrome with partly 10-20 times increased plasma beta-endorphin levels. In this pain thresholds are normal [64]. As well as beta-endorphin applied to the blood does not have an analgetic effect. Beta-endorphins can barely escape the blood brain barrier [48]. It has been discussed that the blood brain barrier becomes permeable under certain conditions such as stress [7]; this theory seems at present rather uncertain. It has also been discussed that parallel to a secretion in blood endorphin secretion occurs in the central nervous system [6,50]. This too, however, has yet to be definitely ascertained. Divergent are the findings of studies untertaken to educe a regulative interrelation between the central beta-endorphin pool and the peripheral beta-endorphin pool in the blood. A number of studies found a parallel change of levels and a correlative relationship while a number of others were unable to corroborate these findings. There are several clinic observations where pain behaviour and plasma beta-endorphin levels change in the same direction, i.e. before birth [51], under physical exercise [54] or with experimental examinations like stimulation with corticotropin-releasing hormone or else after suppression with dexamethasone [33]. Quantitatively different beta-endorphin levels in the periphery with patients having symptomatic and asymptomatic myocardial ischaemia are most likely to be interpreted as a marker


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of quantitative changing of central regulative processes whereby high endorphin levels with increasing hypoalgesia and low endorphin levels with increasing hyperalgesia are correlated. A relation between peripheral hormone patterns and a behaviour's equivalent can at present only be proved correlatively and not causally. In short then, a number of studies indicate that patients with symptomatic and asymptomatic myocardial ischaemia differ from one another in markers which attest to a quantitatively differing endogenous pain regulation. Whether a patient perceives angina pectoris pain or not depends not merely upon nociceptive impulse rate as a result of the degree of myocardial ischaemia but also upon the actual inhibitory pain threshold which this information encounters. If the pain threshold is relatively high, no supraliminal pain is produced and the ischaemia remains silent. If on the other hand the pain threshold is lower, the same amount of pain information proceeds to the central and leads to the perception of pain. It is important to stress that in this model both the inhibitory pain threshold and the amount of peripheral pain information play a decisive role. Whether angina pectoris pain is perceived or not depends on both components. Consequently, myocardial ischaemia is perceived as angina pectoris pain only if the peripheral nociceptive impulse rate is high enough to overcome the actually existant inhibitory pain threshold and if the nervous pathways are intact.

If we accept the premise that there are quantitative differences in the inhibitory pain threshold between symptomatic and asymptomatic patients with myocardial ischaemia, we must further delve into the question of the origin of these differences. One consideration would be that these differences are present from birth, for example through genetic inheritance in the sense of an inborn error of metabolism. This question cannot be answered by now and needs further examination. It is, however, also possible that the differences found are regulative in origin. In the case of a 'genetic defect' one would expect that certain patients would demonstrate such a phenomenon but that most others


Pre-Existing Genetically Determined Differences or Regulatory Changes?

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would not. The transition from silent to symptomatic myocardial ischaemia would be discontinuous. However, the presence and absence of pain during myocardial ischemic episodes is a continuous phenomenon exhibiting a fluid transition (fig. 2). We are therefore more likely dealing with regulative relationships. Another observation contradicting the theory of genetic defect is that most patients with totally silent myocardial ischaemia are thoroughly able to develop angina pectoris pain in the courses of several years [22]. This also supports the idea of a regulatory relationship. Ifwe accept the premise ofa regulative relationship, we are faced with the issue of the conditions under which these processes take place. Possible is that the regulative variances are directly associated with the ischaemic heart disease or are possibly even triggered by it. Basic pain research findings have shown that the organism reacts to pain, possibly even to a subliminal afferent influx, i.e. an influx which is still silent [43] in the 'plasticity' of the endogenous pain regulatory system. From the very different fields of basic pain research it can be demonstrated that on the spinal and supraspinal level repetitive nociceptive streaming-in can lead to changes with changed humoral patterns [2, 8, 55], neurotransmitter patterns and messenger-RNA features [36, 38, 49]. It is not clear yet how these detailed mechanisms look alike and the more which direction they will take. Changes may be described either in the direction of hyperalgesia (chronification of pain) or in the direction of hypoalgesia (contraregulation and primary insensitivity). Changes in the 'plasticity' of the endogenous pain regulatory system cannot, however, be explained by the repetitive influx of sensorial afferences (A-delta and C-fibres) from the myocardium alone. It must also be taken into account that a considerable amount of afferences arise from the myocardium without sensorial function and are therefore not directly involved in the transmission of pain. Only a fraction of the A-delta and C-fibres transmit pain information. Another fraction conducts information towards the center where they are involved in the execution of the vegetative changes which go along with pain [10]. These pseudoaffective changes are measured as being equivalent to pain in the animal model. A manifest degree of 'arousal' is one of the particular characteristics of visceral pain which is why in reference to visceral pain we speak of an 'alarm reaction'. Furthermore, there is an afferent stream from the heart which runs along parasympathic pathways to the nucleus tractus solitarius. The cardiovascular regulation system and the pain regulation system have


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numerous overlaps [14, 56, 60] which obviously correspond with the phenomenon of silent ischaemia. Several different studies of the animal pain model as well as experimental and clinical investigations on humans have shown that vagus or baroreceptor stimulation leads to a massive suppression of pain [56]. Carotis-sinus massage or electrical stimulation can very quickly reduce or even eliminate angina pectoris [21]. Foreman and coworkers could nicely demonstrate that vagus and baroreceptors stimulation is able to extensively suppress the nociceptive information from the heart muscle [3, 29]. Activation of endogenous regulatory systems may also be seen as a parallel to the varying results of the experimental pain tests (fig. 3, 4). We may assume that through the experimental pain test itself, for example by the provocation of skeletal muscle ischaemia, endogenous analgesic systems are activated, whose quantitatively different response can be measured between patients with symptomatic and asymptomatic myocardial ischaemia. Simply expressed, the proceeding observations allow the hypothesis that the ischaemic heart itself may activate extracardial endogenous analgesic systems and thus contribute to the suppression of the own nociceptive outputs. These mechanisms may have compensatory functions. These considerations have been incorporated into figure 6. As a working hypothesis let it be submitted that in the course of a slowly developing coronary heart disease there is a certain period within myocardial ischaemia is never or very seldom symptomatic because the inhibitory pain threshold cannot yet be exceeded. It is possible that the repetitive influx of nociceptive impulses from the periphery suffice to initiate extracardial regulative or adaptive changes. It is at present unclear whether these peripheral impulses first need be painful to introduce such changes or whether the changes can be induced by even subliminal impulses. It is also unclear in which direction the system changes. The experimental pain threshold measurements seem to indicate an augmentation of the pain threshold for asymptomatic patients. On the other hand, the hormonal patterns imply a reinforced suppression of the hormonal response and thus an increasing sensitivity of the symptomatic patients to pain with the passing of time. Here are parallel considerations to be made on the mechanisms of a pain chronification [8]. The working hypothesis shown in figure 6 presents also an explanation how with the further progression of the coronary heart disease even a primarily asymptomatic patient can develop angina pectoris pain. We may assume that the intensity of the peripheral afferent influx increases with the further progression of the coronary heart



Droste/Roskamm

Intensity of peripheral nociceptive input from

the myocardium

160

Myocardial ischemia Symptomatic Asymptomatic

"Inhibitory Pain Threshold«

Years

Progression of Coronary heart disease

Fig. 6. Hypothetical model for the relation between the intensity of the peripheral pain stimulus and the endogenous inhibitory threshold. A comparison of patients with symptomatic and asymptomatic myocardial ischaemia shows significant quantitative differences in markers for the inhibitory threshold. This difference may be genetically determined in origin or developing as regulatory changes during the course of progressing coronary heart disease.

disease so that in the course of years, the nociceptive impulse rate becomes supraliminal even for a primarily asymptomatic patient. The model represented here is certainly very generalizing. It is, however, based upon a great number of documented clinical-cardiological, neurophysiological and neuroendocrinological studies. We may at present only accept this model as a working hypothesis. It is left up to future investigations to prove the accuracy of these assumptions. Promising in this respect would be follow-up investigations of pain thresholds and hormonal patterns in patients with coronary heart disease.

2

2

Akil H, Madden J, Patrick RL, Barchas JD: Stress-induced increase in endogenous opiate peptides: Concurrent analgesia and its partial reversal by naloxone; in Kosterlitz HW (ed): Opiates and Endogenous Opioid Peptides. Amsterdam, Elsevier, 1976, pp 63-70. Almay BGL, Johansson F, von Knorring L, Terenius L, Wahlstrom A: Endorphins in chronic pain. I. Differences in CSF endorphin levels between organic and psychogenic pain syndromes. Pain 1978;5:153-162.


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C. Droste, MD, PhD, Rehabilitationszentrum flir Herz- und Kreislaufkranke, Siidring 15, D-7812 Bad Krozingen (FRG)


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The perception and endogenous modulation of pain.

Anginal chest pain versus angina pectoris.

Circadian variation in pain onset in unstable angina pectoris.

Role of endogenous pain modulation in chronic pain mechanisms and treatment.

Dysfunctional endogenous pain modulation in patients with functional dyspepsia.

5-HT modulation of pain perception in humans.

Descending pain modulation and chronification of pain.

The neurobiology of pain perception in normal and persistent pain.

Refractory angina pectoris.

Unstable angina pectoris.

[Angina pectoris in coronary anomalies].

Prognosis of angina pectoris.

Sexual intercourse and angina pectoris.

[Phantom perception and phantom pain].

Electrical neurostimulators for pain relief in angina.

Blood volume in angina pectoris.

John Fothergill and angina pectoris.

Nicotine enhances angina pectoris-like chest pain and atrioventricular blockade provoked by intravenous bolus of adenosine in healthy volunteers.

Interethnic differences in pain perception.

Gallbladder disease and angina pectoris.

Variant angina pectoris.

Myocardial metabolism in angina pectoris.

Coronary vasospasm in angina pectoris.

Coronary vasospasm in angina pectoris.