Articles

Hypertension-Associated Hypalgesia

Evidence in Experimental Animals and Humans, Pathophysiological Mechanisms, and Potential Clinical Consequences

Sergio Ghione
https://doi.org/10.1161/01.HYP.28.3.494
Hypertension. 1996;28:494-504
Originally published September 1, 1996

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Abstract

A behavioral hypalgesia (increased response threshold to noxious stimuli) has been consistently, although not invariably, reported in spontaneous and experimental acute and chronic hypertension in the rat. Studies in human hypertension have also demonstrated a diminished perception of pain, assessed as pain thresholds or ratings. The sensitivity to painful stimuli correlated inversely with blood pressure levels, and this relationship extended into the normotensive range. Evidence in humans and rats points to a role of the baroreflex system in modulating nociception. In the rat, blood pressure–related antinociception may be due to attenuated transmission of noxious stimuli at the spinal level secondary to descending inhibitory influences that are projected from brain stem sites involved in cardiovascular regulation and that may depend on baroreceptor activation and/or on a central “drive.” Both endorphinergic and noradrenergic central neurons (the latter acting through postsynaptic α2-receptors) have been shown to be involved, and other mediators probably also play a role. Functionally, blood pressure–related antinociception may represent an aspect of a more-complex coordinated adaptive response of the body to “stressful” situations. It is still uncertain whether in human essential hypertension hypalgesia is secondary to elevated blood pressure or whether both depend on some common mechanism. Studies on the effect of hypotensive treatment are too few to allow conclusions. According to one hypothesis, the reduction in pain perception caused by baroreceptor activation secondary to blood pressure elevation may represent a rewarding mechanism that may be reinforced with repeated stress and may be involved in the development of hypertension in some individuals. Hypertension-associated hypalgesia may have clinically relevant consequences, especially in silent myocardial ischemia and unrecognized myocardial infarction, both of which are more prevalent in hypertensive individuals.

It has been suggested in numerous studies that increased arterial blood pressure (BP) is often associated with decreased perception of pain (hypalgesia); however, this association is perhaps not so well known. In experimental hypertensive animals, a behavioral hypalgesia, ie, a delayed and/or diminished response to noxious stimuli, has been repeatedly demonstrated.1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 In humans, several investigators, including this author, have provided evidence that high BP is associated with a diminished perception of pain.25 26 27 28 29 30 31 32 33 34 The present article reviews the current knowledge about this interesting relationship and its potential pathophysiological and clinical implications.

Evidence for Hypalgesia in Experimental Hypertension

A number of studies in the late 1970s and early 1980s raised interest in this phenomenon, reporting that in the rat, acute or chronic arterial hypertension is associated with behavioral hypalgesia. In 1979, Dworkin et al1 observed that an acute rise of BP by phenylephrine infusion could attenuate a trained behavioral response to avoid noxious stimuli (hypertensive rats showed less treadmill running to avoid painful trigeminal nucleus stimulation). Several other studies that measured the latency or threshold of several nociceptive responses confirmed that hypalgesia can be induced in rats by peripheral administration of pressor agents.8 11 14 19 35 Antinociception was also observed when BP was acutely increased by the occlusion of the abdominal aorta proximal to the renal arteries.18 The latter results are of particular interest because they did not imply the use of a pressor agent (eg, phenylephrine), which could at least theoretically exert a direct antinociceptive effect on the central nervous system (CNS). In fact, although phenylephrine does not normally cross the blood-brain barrier, it may access the CNS and have direct neural effects under conditions of elevated BP.36 It is of further interest that occlusion of the aorta distal to the renal arteries did not elevate BP or produce antinociception.

Also in 1979, Zamir and Segal2 reported that chronic hypertension induced by renal artery clipping was associated with hypalgesia, as measured by the response latency after contact with a hot surface. Other studies with similar psychophysiological techniques measuring the responses to a variety of noxious stimuli (hot plate, electric shock, mechanical force applied to a limb, etc) confirmed and extended these findings by demonstrating hypertension-associated behavioral hypalgesia in various experimental models of arterial hypertension, such as hypertension induced by deoxycorticosterone acetate–salt administration,3 by social deprivation,13 and by hypothalamic grafts from spontaneously hypertensive rats (SHR).20 In addition, hypalgesia was also observed in SHR4 5 6 9 12 15 16 22 and salt-sensitive Dahl rats on a high salt diet.10 These findings obtained by behavioral measures of nociception (which could at least theoretically be equally well explained as an inhibition of motor response rather than of sensory function) were recently confirmed and extended by more rigorously neurophysiological investigations by Randich and Robertson24 on spinal nociceptive transmission.

On the other hand, it was soon clear that the association between chronic BP elevation and hypalgesia was not always found. A behavioral hypalgesia was not observed in two-kidney, one-clip hypertension by Barrès et al7 in Lyon rats and by Sitsen and de Jong9 12 in Wistar-Kyoto rats; similar negative results were also obtained for SHR37 38 and deoxycorticosterone acetate–salt hypertensive rats.9 15 In addition, diminished responsivity to visceral but not to cutaneous noxious stimuli was reported in SHR compared with Wistar-Kyoto rats.21 39 Furthermore, it appeared that (1) hypalgesia and high BP were at least partially dissociated in some rat strains, as indicated by the findings that behavioral hypalgesia could be observed despite normal BP3 7 37 ; (2) the time course of the development of hypertension or of its reversal was not necessarily paralleled by changes in hypalgesia4 5 6 9 ; and (3) in F2 hybrids, pain sensitivity might not cosegregate with elevated BP.16 Contrasting results were also obtained when high BP was reduced by pharmacological means: Sitsen and de Jong12 observed that the diminished responsiveness to noxious stimuli in SHR was not altered by long-term treatment with hydralazine or captopril, a finding confirmed by Barrès et al7 in two-kidney, one-clip hypertensive rats treated with captopril, whereas Maixner et al6 observed that lowering of BP induced by administration of a peripherally acting ganglionic blocker reversed hypalgesic behavior in the SHR and induced a hyperalgesia in normotensive control rats. Similar results were reported after treatment with an angiotensin-converting enzyme inhibitor and a calcium antagonist.22

Table 1⇓ summarizes the studies on pain sensitivity in experimental models of hypertension in the rat.23 Taken together, these results are, in the present author's opinion, strongly suggestive of some potentially important relationships between BP and pain regulation in the rat although they also indicate that hypertension is not invariably associated with hypalgesia. Lacking better explanations, these discrepancies may be attributed to differences between rat strains and/or methodologies.

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Table 1.

Comparison of Pain Thresholds Assessed by Behavioral Techniques in Normotensive and Spontaneously or Experimentally Induced Hypertensive Rats

Evidence for Hypalgesia in Human Hypertension

An increased tolerance to pain in hypertensive humans was first reported by Zamir and Shuber in 1980.25 These authors evaluated subjective perception of pain by means of noninvasive, graded electrical stimulation (tooth-pulp test) in 21 essential hypertensive patients and 34 normotensive volunteers and found that hypertensive individuals, on average, needed higher stimulation currents to feel the painful stimulus and were able to tolerate higher currents. Both thresholds strongly correlated with arterial BP.

Tooth-pulp stimulation, a technique used in clinical dentistry for assessing pulp vitality, has also been used in studies unrelated to BP on pain mechanisms in humans40 41 42 43 and offers several advantages. The method is simple, noninvasive, and readily acceptable. Also, the dental pulp represents an exclusively nociceptive sensory system, and a good agreement has been reported between intradental nerve activity and pain perception in response to stimulation.44 45 Moreover, it was shown that tooth-pulp sensitivity thresholds are fairly reproducible26 43 and can be altered (in humans) by a variety of manipulations known to affect pain modulation in experimental animals, such as l-tryptophan supplementation, acupuncture, and transcutaneous stimulation.46 47 48

For these reasons, we decided to study tooth pain perception in a large series of borderline and established hypertensive individuals and three groups of normotensive control subjects (volunteers, nonhypertensive patients, and medical students with well-established [positive and negative] family histories of hypertension).27 We included different subgroups of normotensive subjects in the experimental design to exclude the possible unpredictable bias caused by the choice of control groups. Taken together, our results confirmed that hypertensive individuals were hypalgesic compared with normotensive subjects and that the differences observed were not due to the selection of the control group (although some difference was also present among the control groups). Highly significant correlations were obtained between BP levels and tooth-pulp pain and tolerance pain thresholds (Fig 1a and 1b⇓⇓). On the other hand, no correlations were found with heart rate, nor could significant effects be detected for sex, age, and family history of hypertension.

Figure 1.
Figure 1.

Indexes of pain sensitivity related to blood pressure as reported in various studies (a and b adapted from Ghione et al27 ; c, from Guasti et al34 ; d and e, from Rosa et al33 ; f, from Sheps et al30 ; g, from Bruehl et al29 ; and h, from McCubbin and Bruehl31 ). Note that blood pressure correlates positively with pain thresholds and negatively with pain ratings (for a standard painful stimulus); both point to a diminished perception of pain with increasing blood pressure. R.U. indicates relative units; THRS., threshold; and V.A.S., visual analog scale.

We obtained similar results with the same technique in another study on a different group of subjects,33 as did Guasti et al34 using 24-hour BP monitoring (Fig 1c⇑). Interestingly, pain perception was more closely associated with 24-hour arterial BP than with the BP values obtained before the pulpar test, suggesting that pain modulation may be related more closely to sustained levels of BP.

Hypertension-associated hypalgesia in humans was also confirmed by other techniques: through the use of a more objective method consisting of measurement of the thresholds of the polysynaptic components of the eye-blink reflex after superficial electrical trigeminal stimulation (Fig 1d⇑)28 33 and by measurement of pain thresholds after cutaneous electrical stimulation (Fig 1e⇑)33 and thermal stimulation (Fig 1f⇑).30 32 Interestingly, the relationship between sensitivity to painful stimuli and BP appears to extend into the normotensive range of BP values (Fig 1g and 1h⇑⇑)29 31 and is unrelated to emotional state and coping styles.29 Table 2⇓ summarizes the results on hypalgesia in human hypertension and provides insight into its quantitative aspects.

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Table 2.

Pain Perception Thresholds in Humans: Comparison Between Normotensive and Hypertensive Individuals

Underlying Mechanisms

The findings on a relation between elevated BP and diminished perception of pain open a number of intriguing problems in the underlying mechanisms and their potential pathophysiological and clinical relevance in human arterial hypertension. Although the underlying mechanisms responsible for hypertension-associated hypalgesia remain to be fully identified, several major aspects have been elucidated.

The Baroreflex System

Several lines of evidence point to a role of the baroreflex system in modulating nociception. Reducing or interrupting sinoaortic afferent input by various techniques markedly attenuated or eliminated hypertension-associated hypalgesia in several experimental models of acute and chronic BP elevation1 6 8 11 14 17 18 49 50 and potentiated the response of dorsal horn spinothalamic neurons to noxious stimuli.24 In addition to the carotidoaortic high-pressure baroreceptors, low-pressure cardiopulmonary receptors also may be involved in pain modulation, as suggested by the finding that volume expansion may induce a reflex hypalgesia50 51 that is partially reversed by right vagotomy.50 Also in humans, modulation of pain sensitivity could be demonstrated by baroreceptor activation and deactivation by means of a neck-chamber technique in which positive and negative pressures were synchronized with the cardiac cycle.52 53 54

Of more general and potentially even greater relevance is the possibility that baroreceptor-mediated modulation of pain perception may represent one aspect of a more widespread capacity of the baroreflex system to inhibit CNS processes. In fact, independent of changes in circulation, the activation of baroafferent pathways has been found to induce a variety of inhibitory effects, such as inhibition of sham rage55 and decrease of somatic muscle tone56 and cortical activity57 (for a more detailed discussion, see References 53 and 58).

Pathways Within the CNS

Even a simplified discussion of the anatomic pathways that, within the CNS, may mediate the functional relationship between BP regulation and pain perception requires a brief digression on the endogenous mechanisms involved in pain modulation. After sensory receptor stimulation by noxious stimuli, the nociceptive impulses are sent through the A-delta and C fibers to the dorsal horn spinal neurons where, before being further forwarded to the thalamus, they undergo extensive modulation. According to the “gate control” theory proposed by Melzack and Wall,59 both afferent and descending impulses are integrated at the spinal level to determine whether a specific nociceptive message is further delivered to supraspinal centers. In this context, it is interesting to observe that spinal transmission of nociceptive stimuli is diminished in SHR compared Wistar-Kyoto rats, as indicated by the finding of a parallel rightward shift of the response function of dorsal horn neurons to graded heat-evoked noxious stimuli24 (Fig 2⇓). This finding would suggest that at least in this experimental form of arterial hypertension, antinociception is sustained by an attenuation of the nociceptive signal at one of its major modulation sites, ie, at the spinal level. That bilateral sinoaortic denervation in SHR partially reversed the attenuated response of dorsal horn neurons is consistent with the view of a descending inhibitory baroreflex influence on the spinal nociceptive transmission in this form of experimental hypertension.

Figure 2.
Figure 2.

Comparison of spinal nociceptive transmission in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Shown are responses to noxious heating of the hind foot of varying intensity (temperature) for two types of dorsal horn neurons involved in nociceptive transmission: the wide-dynamic-range (WDR) neurons (top), which respond also to non-noxious stimuli, and the high-threshold (HT) neurons (bottom), which respond only to noxious stimuli. The two left panels report total response, assessed as total discharges in the first 15 seconds of skin heating at various temperatures. For both WDR and HT neurons, a rightward shift of the response curve in relation to the intensity of the noxious stimulus is observed in SHR compared with WKY. Middle and right panels report time course of the response of WKY (middle) and SHR (right) in both types of neurons to three thermal stimuli (42°, 46°, and 50°C). Especially for more noxious stimuli, the responses of both types of neurons appear to be more retarded and less intense in SHR than WKY. (Adapted from Randich and Robertson.24 )

Since the first observations in animals and humans60 61 that stimulation of discrete areas of the brain, primarily the midbrain periaqueductal gray, induce profound analgesia, extensive studies have been dedicated to supraspinal descending antinociceptive systems. According to the model proposed by Basbaum and Fields62 almost 20 years ago, this descending system was mainly composed of the periaqueductal gray, which receives both descending corticodiencephalic and ascending nociceptive inputs and projects mainly on the rostral ventral medulla and, in particular, on the nucleus raphe magnus and the adjacent reticular formation, which project on the spinal dorsal horn mainly via serotoninergic fibers.

Continued research in recent years has demonstrated that the endogenous pain control system is more complex than initially thought. Multiple separate and distinct supraspinally organized descending inhibitory systems have been identified, and the brain stem sites involved in the centrifugal modulation of spinal nociceptive transmission were found to be many more than the initially identified midline structures in the midbrain and medulla (periaqueductal gray and nucleus raphe magnus).63 64 65 In particular, a number of brain stem sites known to be primarily involved in cardiovascular regulation and autonomic function have been demonstrated to also play a role in the modulation of spinal nociceptive transmission. In fact, stimulation of regions of the nucleus tractus solitarius, which is the termination site of baroreceptor afferent fibers, induces antinociception66 ; similar results were obtained for other higher order CNS structures involved in the baroreceptor reflex, such as the A5 cell group67 68 and the locus coeruleus/subcoeruleus,65 67 which were shown to be the sources of descending noradrenergic fibers involved in the modulation of spinal nociceptive transmission through postsynaptic α2-adrenoceptor activation.67 Additional evidence was provided by Randich et al,69 who showed that antinociception induced by vagal afferent stimulation involved a number of brain stem sites known also to mediate baroreflex activity and vasomotor tone.

Studies in the rat have shown that the nucleus reticularis gigantocellularis may be a site specifically involved in BP-related nociceptive modulation and that angiotensin III may play a role as a neurotransmitter in this modulation.70 71 72 Another mechanism involved in antinociception induced by acute increase of BP by means of phenylephrine has been proposed by Watkins et al,19 who showed that phenylephrine antinociception may be mediated by a circuit involving the baroreceptors, the nucleus tractus solitarius, and the paraventricular hypothalamus, which sends vasopressinergic projections to the spinal cord via the dorsolateral funiculus.

Interestingly, evidence also indicates that conversely, areas primarily thought to be involved in pain modulation may influence BP regulation as well. For instance, the periaqueductal gray of the midbrain is not only the site that most consistently produces analgesia when stimulated73 but is also an important area of integration of autonomic and somatic reactions,74 among which is the defense reaction.75 In addition, stimulation of distinct areas within the periaqueductal gray has been shown to facilitate76 or inhibit77 the arterial baroreflex.

A second example is represented by the nucleus raphe magnus in the rostral ventrolateral medulla, which, as mentioned above, is also an important site in pain modulation and contains putative pain modulatory neurons that respond to noxious stimuli with an excitation of activity (called ON cells) and others that respond with an inhibition of activity (OFF cells).78 It was observed in the rat79 80 that these putative pain modulatory neurons show spontaneous fluctuations in neuronal activity that are opposite (the ON cells) and parallel (the OFF cells) to spontaneous fluctuations of BP. The fact that changes in neuronal activity precede the changes in BP and persist after cardiopulmonary deafferentation80 indicates that changes in neuronal activity do not necessarily require baroreceptor afferent input and that these neurons are either directly involved in BP regulation or connected to neurons that are regulating BP. On the other hand, it was also observed80 that changes in arterial pressure produced by a variety of procedures (infusion of phenylephrine or nitroprusside or occlusion of the abdominal aorta) can alter neuronal activity of ON and OFF cells via sinoaortic baroreceptors. Thus, neurons thought to be mainly involved in facilitating or attenuating nociception were found also to be intimately linked to central and baroreflex BP control.

Put into a more general perspective, this and other58 evidence clearly indicates a close integration of neuronal centers involved in pain modulation and cardiovascular regulation. In fact, the areas involved in these functions can be viewed as an integral part of a more widely distributed network within the CNS for which the term “central autonomic network” has been recently proposed.81 This network, through which the brain controls and coordinates visceromotor, neuroendocrine, pain, and behavioral responses essential for adaptation and survival, is thought to be composed of a group of interconnected areas including the insular and prefrontal cortices, the amigdala, the hypothalamus, the periaqueductal gray, the parabrachial region, the nucleus tractus solitarius, and the reticular zone in the ventrolateral medulla.

Taken together, these findings are thus consistent with the view that BP-related antinociception may be due to attenuated transmission of noxious stimuli at the spinal level, that this attenuation may be due to descending inhibitory influences from brain stem sites involved in cardiovascular regulation and pain modulation, and that these sites are extensively functionally linked and are part of a more widely distributed network involved in autonomic adaptation.

What Mechanisms Are Involved in Pain Perception Abnormalities in Chronic BP Elevation?

The findings that pain perception may be modulated by baroreceptor function manipulation52 53 54 and that sinoaortic denervation eliminates antinociception during acute experimentally induced BP elevation1 8 14 18 are consistent with the view that under acute conditions, hypertension-associated hypalgesia may be due to baroreceptor deactivation. Less easy to explain is hypertension-associated hypalgesia in established hypertension, because one would expect that the BP-sensitive baroreflex would reset in response to chronic hypertension. However, as recently pointed out by Randich and Robertson,24 caution is warranted in this assumption because sinoaortic baroreceptor resetting has been studied with respect to reflex modulation of the circulation rather than pain perception. In fact, the finding that interruption of sinoaortic afferents normalizes hypalgesia also in experimental models of chronic hypertension6 14 24 49 50 is consistent with a role of the baroreflex in these models of hypertension. Similar results have also been reported by Meller et al,17 who have observed that interruption of baroreceptor input by bilateral transection of the aortic depressor nerve increases the sensitivity to the visceral algogenic effect of serotonin in the rat and that this effect is more evident in SHR compared with normotensive control rats, indicating that afferent input from the aortic depressor nerve may exert a tonic inhibitory influence on nociception that is enhanced in hypertensive animals.

Another possibility is that sites involved in pain modulation receive direct input from the vasomotor center or that both elevated BP and antinociception depend on other central, functionally related mechanisms. That this may also be the case is suggested by the observation that, as reported above, the activity of neurons thought to be involved in pain modulation, such as the ON and OFF cells of the nucleus raphe magnus, is temporally related to spontaneous fluctuations of BP even under conditions of sinoaortic denervation.79 80

Therefore, two different and not necessarily mutually exclusive mechanisms can be hypothesized: that hypertension-associated hypalgesia has a peripheral cause (ie, it depends on the inhibitory effect of baroreceptor input) or that it has a central cause (ie, it depends on some unidentified mechanism within the CNS that affects both BP and nociception).

An aspect that has not yet been addressed in this review and that has been the object of extensive investigation is the involvement of the endogenous opioid system in BP-related antinociception. In fact, among the large number of neurotransmitters involved in pain-modulating circuitry, endogenous opioids stand out as particularly important ones because they have been shown to be involved in pain modulation in a wide variety of invertebrates and vertebrates,82 are present at multiple sites in the mammalian pain-regulating system,83 84 and can be studied by appropriate antagonists.85 In fact, a role of endogenous opioids is suggested by the numerous reports that in the rat, hypertension-associated hypalgesia can be suppressed by the opiate antagonist naloxone.3 4 5 6 7 9 12 The lack of an effect by the exclusively peripherally acting analogue N-methyl-naloxone12 indicates the involvement of CNS opioids. Furthermore, hypertensive rats were found to have increased levels of opioid activity in several areas of the CNS, such as the hypothalamus, the pituitary, and especially, the dorsal horn of the spinal cord.3

To the present author's knowledge, no studies have yet been done to assess whether this hypalgesia is naloxone suppressible also in human hypertension; however, a few observations suggestive of an involvement of endogenous opioids in humans have been reported in studies with small samples. McCubbin and Bruehl31 observed that pretreatment with naloxone markedly diminished the strength of the relationship between resting BP and pain ratings in normotensive subjects. Furthermore, significant differences in β-endorphin plasma levels between normotensive and hypertensive individuals30 and, within normotensive individuals, between those with low and high tolerances to pain86 have been reported.

In addition to endogenous opioids, another transmitter system involved in the modulation of nociceptive information that may have a role in hypertension-associated hypalgesia is the noradrenergic descending system, which, as mentioned above, partly originates in areas also involved in cardiovascular regulation and acts through postsynaptic α2-adrenoceptor activation.67 In fact, the α2-receptor agonist clonidine, in addition to being a hypotensive agent, produces potent antinociception in various species of animals, including humans,87 88 probably acting at the spinal level89 ; even at nonhypotensive doses, clonidine has been reported to have an antinociceptive effect that is enhanced in SHR compared with normotensive controls.23 It is also interesting to observe that numerous interactions have been reported between the α2-adrenergic and opioid transmitter systems: clonidine and morphine, when coadministered, have supra-additive antinociceptive effects89 90 ; clonidine is effective in the treatment of opiate withdrawal91 ; and, perhaps more importantly for the present context, naloxone may reverse the hypotensive effect of clonidine in hypertensive individuals with a hyperactive adrenergic system.92

Functional Significance of BP-Related Nociceptive Modulation

Traditionally, the endogenous pain-control systems are considered to serve two main functions: (1) to modulate incoming nociceptive messages through a negative-feedback mechanism whereby pain activates pain suppression, thus blunting pain sensations when noxious stimulation becomes elevated; and (2) to limit pain perception in those environmental (mostly stressful) conditions in which pain perception would represent an unwelcome distracting factor. This so-called stress-induced analgesia (or perhaps more correctly, hypalgesia) has been the object of extensive study93 and has been reported in a wide variety of natural “stressful” situations, such as confrontation with a predator,94 defeat in an aggressive encounter,95 physical exercise,40 96 sexual arousal,97 98 and mental stress.99 BP-related pain modulation may represent one of the mechanisms inserted into these two functions: arousingemotional and pain stimuli elevate BP, resulting in baroreceptor stimulation that in turn induces antinociception. Thus, arterial BP may be an important internal signal monitored by the body to adjust somatosensory inflow. Although several reviews have proposed the hypothesis that many of the so-called stress-induced analgesias are secondary to concomitant changes in BP,83 93 it has been tested only in a few studies. That this might indeed be the case is suggested by the finding that integrity of the cardiopulmonary baroreceptor pathways is required for the full expression of foot shock–induced analgesia (a form of stress-induced analgesia).50

BP-related antinociception may serve an additional and perhaps at least equally important function: Since baroreceptor-mediated modulation of pain perception may represent a particular aspect of a more general capacity of the baroreflex system to inhibit central nervous processes (see above), this mechanism may serve as a response, in addition to bradycardia and vasodilation, to prevent excessive BP elevation. As suggested by Dworkin et al,53 when acute sensory or emotional excitation raises BP excessively, CNS dampening may augment vagal and sympathoinhibitory negative-feedback mechanisms to help restore safer BP levels.

Finally, as mentioned above, the existence of important functional links between BP and pain-regulatory pathways may play a role, more generally, in the organism's adaptive response to stress: The interactions between cardiovascular and somatosensory systems may in fact represent only an aspect of a complex, coordinated response that helps the body face stressful events.58

Is There a Causal Relation Between Hypertension and Hypalgesia in Humans?

At first glance, three possibilities can be conceived regarding the relationship between hypalgesia and human essential hypertension: (1) Hypalgesia is secondary to elevated BP; (2) both depend on some (pathophysiologically important?) common neural mechanism; and (3) they are simply associated traits with no relevant functional relationship.

Our findings that lowering BP does not necessarily result in changes in pain perception suggest that hypalgesia is not simply related to the elevated BP levels in human essential hypertension. Thus, we observed no changes in pain sensitivity in patients studied after 3 months of diuretic or β-blocking treatment or of a low salt diet, despite significant reductions in arterial BP.27 On the other hand, we found that ketanserin treatment in hypertension induced a profound reduction of the pain threshold, although we found no correlations with the concomitant changes observed in BP.100 Finally, it is interesting that Morley et al101 reported elevated pain tolerance to graded electrical stimulation of the finger in hypertensive diabetic patients treated for hypertension and normotensive at the time of the study compared with nonhypertensive diabetics. Taken together, these observations and the findings of a quantitative relation between the magnitude of hypalgesia and the extent of BP elevation in nontreated hypertension25 27 30 33 34 are consistent with the view that hypalgesia is in some way related to a mechanism involved in provoking increased BP, which is still active when BP is reduced, at least with some pharmacological means. At the present stage of knowledge, it is probably premature to conclude that different hypotensive treatments have differential effects on hypertension-associated hypalgesia; future work in this field is needed. One would be inclined to surmise that if hypalgesia and elevated BP are just different aspects of a common abnormality within the CNS, then a treatment that both reduces BP and normalizes hypalgesia would be expected to be more “etiologic” than one that only affects BP. Whether hypalgesia may precede BP elevation in predisposed individuals is uncertain: Negative and positive results have been obtained, respectively, in our study27 and in two studies by France et al.102 103

A further possible pathophysiological link between hypertension and baroreceptor-mediated antinociception was proposed by Dworkin et al1 as early as 1979, suggesting that BP-related antinociception may be one of the causes rather than a consequence of elevated BP. In fact, stress-induced elevations of BP may activate baroreceptor pathways that decrease the perceived or affective magnitude of the stressor, thus representing a rewarding mechanism that may be reinforced by repeated exposure to stress. According to this hypothesis, in some individuals predisposed and/or exposed to excessive stress, hypertension may begin as an instrumentally learned BP response for which the reward is a baroreceptor-mediated reduction in the psychophysiological consequences and the averseness of the environmental stressors (eg, in anxiety and perceived stress).1 6 11 53 58 The observations on the one hand that BP elevation can be learned under appropriate operant conditioning techniques104 105 106 and on the other that as repeatedly mentioned above, baroreceptor activation may induce a general inhibition of CNS processes (see Reference 53 for discussion) are consistent with this hypothesis. Also consistent with this line of reasoning is the finding that perceived stress may correlate inversely with BP, as observed in a large population study of San Francisco bus drivers: The higher their BP, the less they reported being stressed in their jobs.107 Finally, it has recently been proposed that the BP increases induced by nicotine during smoking may have baroreceptor-dependent pain-dampening effects, which may be among the reinforcing qualities of smoking.108

Is Hypertension-Associated Hypalgesia Clinically Relevant?

Several reports are consistent with the idea that the decreased pain perception observed in hypertension may have clinically relevant consequences. In recent years, increasing attention has been given to so-called silent (asymptomatic) myocardial ischemia and to the possible involvement of pain-modulating mechanisms in this condition.109 110 In fact, a number of studies have demonstrated that a generalized reduction of the perception of pain may play a role in silent myocardial ischemia. Compared with individuals with exercise-induced myocardial ischemia (assessed by electrocardiographic changes) and angina, those with silent ischemia were found to have higher pain thresholds on dental pulp stimulation111 and during forearm ischemia.54 112 113 In addition, a higher mean dental pain threshold has been recently reported by Falcone et al114 in patients asymptomatic during myocardial ischemia induced by angioplasty compared with symptomatic patients.

Whether hypertension plays a role in silent myocardial ischemia is unclear although some clues point in this direction. Sheps et al115 recently reported in a group of 28 patients that resting systolic BP significantly correlated with the time interval between objective evidence of myocardial ischemia (ST segment depression) and the onset of anginal pain during exercise testing. Furthermore, Falcone et al116 reported preliminary findings of a higher prevalence, by approximately 30%, of exercise-induced silent myocardial ischemia in hypertensive with respect to normotensive individuals of comparable cardiac and clinical conditions. In addition, a high prevalence (of about 30%) of silent myocardial ischemia has been recently reported in men with systemic hypertension without symptomatic cardiac disease undergoing 24-hour Holter monitoring.117 That (untreated) hypertension may favor silent myocardial ischemic episodes is further suggested in a study in elderly patients.118

Another condition in which the perception of pain may play a role is unrecognized myocardial infarction. It is interesting to observe that arterial hypertension appears to predispose particularly to unrecognized and presumably painless myocardial infarction, as demonstrated in the Framingham study, in which the proportion of unrecognized infarctions, almost doubled from normotensive to hypertensive individuals, increasing in men from approximately 19% to 35% and in women from 28% to 45%.119 That subjects with elevated (untreated) BP were more likely to develop clinically unrecognized myocardial infarction was further confirmed in a study in aged subjects.120

Taken together, these results are, in the present author's opinion, suggestive of a role for hypertension-associated hypalgesia in silent myocardial ischemia, although further experimental and epidemiological work is obviously needed in this area. For instance, it would be necessary to investigate the potentially confounding effect of left ventricular hypertrophy as a detrimental factor on coronary flow reserve121 and as a source of error in the evaluation of electrocardiographic signs of myocardial ischemia. In addition, it has been shown that the proportion of silent ischemic episodes detected during electrocardiographic monitoring is quite variable in different patients with chronic stable angina and also in different recordings in the same patient122 and that factors intrinsic to the ischemic episode, such as duration, severity, and concurrent hemodynamic abnormalities,123 124 may explain only part of this variability.125 Therefore, changes in the perception of pain, possibly related to the mechanisms outlined above, must be considered as possible causes of between- and within-patient variability and require additional investigation. Finally, it has been proposed that the number of silent ischemic episodes during electrocardiographic monitoring carries an independent prognostic significance above that of stress testing in chronic stable angina126 and is a better predictor of unfavorable short-term clinical outcome than chest pain in unstable angina.127 Whether this simply reflects a relative insensitivity of anginal pain as an indicator of myocardial ischemia or whether the lack of symptoms represents per se a detrimental factor is still unclear. If the second hypothesis is correct (and if hypertension-associated hypalgesia plays a role in silent myocardial ischemia), then hypotensive drugs should be evaluated for their ability to correct this abnormality, and those that have this effect should on average have a better prognostic profile. Further work is of course needed to substantiate this hypothesis.

Another area of potential interest is whether hypertension-associated hypalgesia is in some way related to psychosocial mechanisms thought to be involved in primary hypertension. Henry et al129 130 have recently proposed that alexithymia (ie, the inability to report verbally emotions and body sensations128 ) may be a feature of low-renin hypertension. Whether this trait is in some way related to the defective perception of pain in hypertension remains to be established.

Finally, one may be justified to suspect that the differences in pain perception between normotensive and hypertensive individuals are not devoid of more general consequences. In fact, in hypertensive individuals, a stimulus intensity up to as much as twice as high may be needed to evoke pain compared with normotensive individuals (a finding in the same order of magnitude as that observed in the hypertensive rat) (Table⇑s 1 and 2). If one considers that nociception (ie, the ability to detect and respond to noxious stimuli by defensive or avoidance behavior) is a basic property in the animal kingdom,82 one may wonder whether a defect in this warning system may not represent a handicap. Possibly, hypertensive individuals are doubly unfortunate, on the one hand, because their condition bears a number of well-known risk factors, and on the other, because they are less prone to take protective actions since they are less aware of initial warning symptoms.

Acknowledgments

Parts of Fig 1⇑ are reprinted in a modified form with kind permission of the authors and Elsevier Science from Pain (1992;48:463-467 and 1994;57:63-67) and from Am J Cardiol (1992;70:3F-5F), ©1992, Excerpta Medica and MacMillan Press Ltd from J Hum Hypertens 1994;8:119-126. Fig 2⇑ is reprinted in modified form with kind permission of the authors and Elsevier Science from Pain (1994;58:169-183).

  • Received January 4, 1996.
  • Revision received February 27, 1996.
  • Accepted April 26, 1996.

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  • Hypertension-Associated Hypalgesia
    Sergio Ghione
    Hypertension. 1996;28:494-504, originally published September 1, 1996
    https://doi.org/10.1161/01.HYP.28.3.494
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