Contribution of Baroreceptor Function to Pain Perception and Perioperative Outcomes

The central nervous system (CNS) and peripheral nervous system work in concert to maintain homeostasis in response to psychologic and physical stressors. An ensemble of coordinated biologic processes modulates sensory, emotional, motor, autonomic, neuroendocrine, and immune responses to tissue damage, including surgery.^1–5  Mechanosensitive baroreceptor afferents mediate physiologic responses to internal stimuli by integrating and modulating peripheral nervous system and CNS responses to internal stimuli and stressors to maintain homeostasis. These receptors respond to changes in arterial pressure, venous pressure, and respiratory dynamics.^6–8  Baroreceptor afferents transmit information to discrete regions of the brain stem nucleus tractus solitarius via afferents coursing in or with the vagus nerve (aortic depressor nerve and cardiopulmonary afferents) and glossopharyngeal nerve (carotid arterial baroreceptors). Carotid and cardiopulmonary baroreceptor reflexes modulate autonomic output to maintain resting blood pressure, to buffer excessive fluctuations in arterial pressure (carotid sinus baroreceptors), and to maintain intravascular volume (cardiopulmonary baroreceptors). Baroreceptor activity engages CNS networks that regulate somatosensory, somatomotor, and CNS arousal, as well as autonomic, neuroimmune, and neuroendocrine responses to physical and psychologic stressors.²  An important, but under-investigated area of study is whether changes in baroreceptors contribute to pathologic conditions in a variety of clinical settings. In this review, we summarize the neurobiology of the baroreceptor function and how baroreflex mechanisms are thought to contribute to acute and chronic pain conditions, as well as perioperative outcomes.

Arterial, carotid sinus, baroreceptors are mechanoreceptors that are located in the aortic arch and carotid sinuses and are “tuned” to changes in systemic arterial pressure. These receptors have terminals associated with both myelinated (Aδ) and unmyelinated (C) afferent fibers in the inner adventitial layer of the arterial wall that respond to stretch generated by transmural pressure on a beat-to-beat basis.⁸  Stimulation of arterial baroreceptors modulates transient changes in blood pressure to maintain a homeostatic set point for arterial pressure by dynamically adjusting sympathetic and parasympathetic output to the heart and the peripheral vascular system. Arterial baroreceptor mechanoreceptors respond to increases in intramural pressure depending on resting arterial pressure, mainly systolic and pulse pressure. As resting arterial pressure increases, a given incremental change in arterial pressure evokes greater activation of carotid sinus baroreceptor afferents, thereby promoting a greater increase in parasympathetic tone and a decrement in sympathetic tone. For normotensive individuals, the threshold for baroreceptor activation is at a carotid mean arterial pressure of approximately 60 mmHg,⁹  and it is active across the whole range of normal blood pressures.¹⁰  This threshold changes with aging, with lower carotid sinus pressure thresholds observed for young subjects (45 mmHg at 22 ± 1 yr) compared to older subjects (80 mmHg at 61 ± 2 yr).¹¹ 

The nucleus tractus solitarius is the central projection site for baroreceptors and modulates the activity of spinal and supraspinal networks that coordinate the responses to environmental stressors. The nucleus tractus solitarius sends excitatory glutamatergic projections to the caudal ventrolateral medulla,¹²  which projects γ-aminobutyric acid–mediated inhibitory fibers to the rostral ventrolateral medulla.¹³  This short neural circuit converts the baroreceptor excitatory input to nucleus tractus solitarius into an inhibitory output that reduces the descending excitatory tone originating in the rostral ventrolateral medulla that projects to the intermediolateral region of the spinal cord.^12,13  Activation of this pathway produces a reduction in cardiosympathetic tone and vascular resistance.¹⁴  The nucleus tractus solitarius also sends direct excitatory projections to the dorsal vagal motor nucleus and nucleus ambiguus, which enhances parasympathetic output.^15,16  This baroreceptor-elicited shift in autonomic balance toward the parasympathetic side results in a reduction in heart rate, arterial pressure, and adrenal secretion of adrenaline.^17,18 

One way of assessing baroreceptor function is through the measurement of the baroreceptor sensitivity, which is typically defined by the relationship between the change in arterial pressure and the associated effect on interbeat interval,^19,20  and most procedures measure the change in heart rate as a function of the change in systolic arterial pressure. The development of reliable methods to estimate baroreceptor sensitivity has opened a window that enables the investigation of the role of baroreflex dysfunction in many medical conditions. The gold-standard procedure for assessing baroreceptor sensitivity is to measure the ratio of change in heart rate to the change in systolic arterial pressure in response to the intravenous administration of a low dose of a vasopressor agent (e.g., phenylephrine).^21–26  In addition, noninvasive methods have been developed to allow for the assessment of baroreceptor sensitivity in response to the small natural continuous variations in blood pressure (i.e., spontaneous baroreceptor sensitivity).²⁷ Figure 1 illustrates how the simultaneous recording of beat-to-beat systolic arterial pressure and heart rate is used to estimate baroreceptor sensitivity by the sequence method. (For more details on the methods for the estimation of baroreceptor sensitivity see the Supplemental Digital Content 1, https://links.lww.com/ALN/B815.)

Thresholds for normal and abnormal spontaneous baroreceptor sensitivity have been proposed by the Autonomic Tone and Reflexes After Myocardial Infarction Study.^25,28  In general, normal baroreceptor sensitivity is defined as greater than 6 ms/mmHg, moderate dysfunction is defined as 3 to 6 ms/mmHg, and severe dysfunction is defined as less than 3 ms/mmHg. However, estimates of baroreceptor sensitivity must be interpreted in the context of sex, age, and circadian rhythm. Female subjects have 50% lower cardiac baroreflex sensitivity than men,²⁹  which is associated with lower arterial pressure and estrogen-mediated central sympathoinhibition and peripheral vasodilation.³⁰  Baroreceptor sensitivity fluctuates across the reproductive cycle with increases during the midluteal phase when estrogen and progesterone levels are elevated^31,32  and around the ovulation,³³  whereas it is markedly suppressed during pregnancy,³⁴  contributing to pregnancy complications such as orthostatic hypotension and severe hypotension with peripartum hemorrhage.³¹  Also, there is an age-related decline in baroreceptor sensitivity that results from increased arterial wall stiffness and a subsequent reduction in the ability of baroreceptor mechanoreceptors to process changes in arterial pressure.³⁵  This leads to increases in sympathetic nerve activity and systolic arterial pressure with aging.³⁶  Finally, diurnal variations in baroreceptor sensitivity have been identified in humans, with reduced sensitivity after waking compared to sleep, although other more complex patterns have also been described.³⁷ 

To date, most studies have indirectly examined the relationship between baroreceptor sensitivity and pain perception by examining the association of pain perception with experimentally induced changes in arterial pressure and venous blood pressure (i.e., physiologic events that activate baroreceptor afferent activity). In animals, arterial hypertension in response to vasopressor agents³⁸  or abdominal aortic occlusion produces hypoalgesia or antinociceptive behaviors.³⁹  Similarly, genetically hypertensive rats are hypoalgesic, which is reversed by lowering arterial blood pressure via ganglionic blockade or by right vagotomy.⁴⁰  Similarly, chronic hypertension induced by renal artery clipping or increasing dietary salt in salt-sensitive rats⁴¹  induces a hypoalgesia that is reversed by lowering blood pressure.⁴²  Noteworthy, spinal nociceptive transmission is diminished in genetically hypertensive rats,⁴³  and the observed hypoalgesia can be reversed with pharmacologic procedures that lower arterial pressure. Similarly, elevating arterial pressure in normotensive rats impairs spinal nociceptive transmission,³⁹  and in normotensive animals lowering arterial pressure induces hyperalgesia.⁴⁰  Elevating venous pressure by volume expansion activates cardiopulmonary volume vagal afferents and evokes a profound hypoalgesia in rats.^44–46  In addition to venous blood pressure, the activation of vagal afferents with intravenously administered morphine, met-enkephalimamide, or other vagal afferent stimulants, produces an almost immediate cardiopulmonary mediated hypoalgesia in rats that appears to be independent of CNS penetration.^46–48 

An association between arterial pressure and pain perception has also been demonstrated in humans, with evidence that healthy normotensive individuals experience decreased pain sensitivity as a function of increasing resting arterial pressure.^49–58  In contrast, individuals with chronically low resting arterial pressure are prone to thermal hyperalgesia.⁵⁹  As observed in rats, hypertension-associated hypoalgesia in humans is correlated with systolic arterial pressure as opposed to diastolic arterial pressure.⁵⁷  The processing of nociceptive stimuli also varies throughout the cardiac cycle such that during systole (e.g., maximal baroreceptor load) pain sensitivity is diminished compared to during diastole.^60–63  There is a greater effect size of systolic arterial pressure compared to diastolic arterial pressure on pain sensitivity.^{49,50,56,64–67}  This further suggests a pain-modulatory role for arterial baroreceptors, although the relative contribution of slowly and rapidly adapting baroreceptor afferents to sustained versus phasic changes in blood pressure on pain perception remains an open question.

Changes in arterial pressure have also been reported to contribute to the suppression of pain perception measured in conditioned pain modulation paradigms—procedures that assess the strength of endogenous pain regulatory systems.^68,69  The strength of endogenous inhibitory pain positively correlates with increases in arterial pressure elicited by a noxious conditioning stimulus.⁷⁰  Considering that reduced conditioned pain suppression has been linked with the development of chronic pain,⁷¹  it remains to be determined whether reduced baroreceptor function and blood pressure are risk determinates for acute perioperative and chronic pain.

It should also be noted that some studies have not observed a reciprocal relationship between arterial pressure and pain sensitivity. The hypoalgesia exhibited by hypertensive patients persists after reductions of arterial pressure with medical treatment.⁷²  Hypoalgesia is already present in borderline hypertension and is antecedent to established hypertension.⁷²  Normotensives with a family history of hypertension and a presumed genetic risk for hypertension also have reduced responsiveness to acute pain despite having a normal resting arterial pressure,^73–76  although this has been reported for males but not for females⁷⁷  and has not been observed by others investigators.⁷²  Moreover, pain tolerance measured in normotensive individuals at age 14 predicts ambulatory blood pressure later in life.⁷⁸  It has been proposed that mechanisms independent of arterial pressure, such as venous hypertension, which is antecedent to the expression of essential hypertension, may explain the temporal discordance between early-life arterial pressure and pain sensitivity.⁴⁰  In support of this hypothesis, an increase in venous pressure—a stimulus that stimulates low-pressure cardiopulmonary baroreceptors and induces hypoalgesia—occurs before the onset of arterial hypertension in genetically hypertensive rats.⁴⁰  Furthermore, low-pressure cardiopulmonary baroreceptors, unlike arterial baroreceptors, do not reset and continue exerting a modulatory influence on pain processing in the presence of sustained elevation in arterial pressure.⁷⁹ 

In summary, there is evidence that supports an association between arterial pressure and pain perception: pain sensitivity is correlated with responses to acute episodic changes in arterial pressure, is diminished in chronic hypotension, and is inversely correlated with resting arterial pressure in normotensive individuals. In addition, a substantial body of functional and anatomical evidence supports the causal nature of this association. The temporal and causal relation between arterial pressure, baroreceptor sensitivity, and pain perception requires further investigation that promises to reveal a better understanding of the pathophysiologic processes that contribute to aberrant pain perception and autonomic function.

The demonstrated relationship between pain perception and carotid sinus and cardiopulmonary baroreceptor activation^{1,46,58,80,81}  implies that this relationship can be affected by changes in baroreceptor sensitivity; however, the relationship between baroreceptor sensitivity and pain perception has been much less studied. Spontaneous baroreceptor sensitivity has been shown to be inversely correlated with ischemic and thermal pain responses in normotensive human subjects.⁸²  Similarly, a reciprocal relationship between baroreceptor sensitivity assessed during cold noxious stimulation has been reported in normotensive human subjects.⁸³  It should be noted that the relationship between baroreceptor sensitivity and pain is temporally dynamic and influenced by the individual’s physiologic and emotional status. For example, the magnitude of the relationship between baroreceptor sensitivity and cold pain perception is inversely associated with resting arterial pressure.⁸³  Moreover, baroreceptor sensitivity assessed with rises in arterial pressure increases versus decreases in arterial pressure is differentially associated with experimentally evoked pain in normotensive subjects.⁸² 

In an attempt to provide insight into the causal nature of these associations, investigators have used direct mechanical or electrical manipulations of baroreceptors, which allow more stimulus control than other indirect methods of stimulation (e.g., tilt-table–, pharmacologic-, and volume-induced arterial pressure changes). The mechanical stimulation of carotid baroreceptors with external neck suction, which simulates an arterial pressure increase, reduces mechanical pain,⁸⁴  although it has no effect on thermal pain,⁸⁴  electrically induced pain,⁶¹  or experimentally induced ischemic pain⁸⁵  in normotensive human subjects. In contrast, external neck compression, which mimics a reduction in arterial pressure, reduces electrically induced pain ratings in normotensive adults.⁶¹  The electrical stimulation of the cervical vagus, which activates baroreceptor afferents, produces antinociceptive effects at high intensities and pronociceptive effects low intensities of stimulation in rats,⁸⁶  cats,⁸⁷  and humans.⁸⁸  Thus, carotid baroreceptors and vagal afferents exhibit a complex and dynamic influence on nociceptive processing.

Collectively, these findings provide evidence to support the view that baroreflex function modulates pain perception. The occurrence, efficacy, and directionality of baroreceptor reflex activity as indexed by baroreceptor sensitivity on pain perception is influenced by many factors, such as level of resting arterial pressure, pain modality, and method of baroreceptor stimulation, among many other factors. At present, we do not know whether alterations in baroreflex function contribute to chronic pain syndromes where baroreceptor sensitivity is known to be substantially reduced (see below section “Clinical Implications of Impaired Baroreceptor-mediated Pain Modulation”).

The mechanisms and pathways by which elevations in arterial and venous blood pressure decrease pain sensitivity are not fully understood. Arterial and venous blood pressure-related hypoalgesia have been associated with carotid sinus^46,62,89,90  and cardiopulmonary baroreceptors.^47,91,92  Several studies have documented an attenuation of hypertension-associated hypoalgesia by decreasing or interrupting the sinoaortic afferent limb of the baroreflex.^38,45,91,93  Volume expansion induces hypoalgesia that is partially reversed by right vagotomy.^44–46  In addition, noxious heat-evoked responses of wide dynamic-range and high-threshold lumbosacral spinal dorsal horn neurons are reduced in spontaneously hypertensive rats compared to normotensive controls.⁴³  In agreement with this observation, spontaneous baroreceptor sensitivity correlates with the temporal summation of pain because higher resting systolic arterial pressure and greater baroreceptor sensitivity are associated with significantly lower temporal “wind-up” of heat pain in healthy human subjects.⁹⁴  These findings suggest that (1) arterial pressure–mediated hypoalgesia requires an intact baroreceptor afferent input, and (2) the activation of second-order spinal nociceptive neurons by primary nociceptive afferents is inhibited by baroreceptor stimulation evoked by increases in arterial pressure.

Animal studies support a role for endogenous opioid activity as one of many possible endogenous neurotransmitter systems involved in hypertension associated hypoalgesia.^{41,42,95–98}  Maixner et al.⁴⁰  demonstrated that naloxone reverses the hypoalgesia observed in spontaneously hypertensive rats in both prehypertensive neonatal and hypertensive adult animals. Similarly, sympathetic inhibition resulting from baroreceptor stimulation is mediated by endogenous opioid networks in rabbits⁹⁹  that appear to originate in the nucleus tractus solitarius and rostral ventrolateral medulla.¹⁰⁰  Hypertensive rats exhibit neurochemical markers of elevated opioid activity in the spinal cord and other CNS nuclei.^41,101  Interestingly, it has been proposed that in the presence of essential hypertension, there is reduced hypothalamic sensitivity to endogenous opioids, which leads to: (1) a reduction in baroreflex inhibition of the sympathetic output; (2) an increase and prolongation of arterial pressure response to environmental stimuli; (3) prolonged baroreceptor stimulation; and finally, (4) an excessive release of endogenous opioids.¹⁰²  The proposed excessive release of endogenous opioids, whether elicited by baroreflexes or by nonbaroreflex mechanisms (e.g., a primary brain stem nuclei dysfunction¹⁰³ ), may mediate the hypoalgesia seen in hypertensive conditions. In human studies, hypertensive subjects exhibit enhanced levels of circulating endorphins and diminished sensitivity to noxious thermal stimuli.¹⁰⁴  Of note, pain-relieving actions of angiotensin II, which is increased several hypertensive conditions, have been related to the angiotensin II receptor–mediated central release of endogenous opioids.¹⁰⁵  However, a conclusive role for endogenous opioids in hypertension-associated hypoalgesia remains to be established, because naloxone fails to reverse hypoalgesia in hypertensive humans.^50,106 

A second likely mediator of hypoalgesia under hypertensive conditions and baroreceptor stimulation is the activation of α₂-adrenergic receptors in brain regions involved in both autonomic and sensory processing. Noteworthy, nucleus tractus solitarius, rostral ventrolateral medulla, and caudal ventrolateral medulla contain noradrenergic and adrenergic neurons.^100,107  Microinjection of the α₂-adrenergic receptor agonist clonidine into nucleus tractus solitarius produces analgesia mediated by opioid receptors in normotensive rats and spontaneously hypertensive rats.¹⁰⁸  Of note, morphine administration to the region of the nucleus tractus solitarius produces naloxone-reversible analgesia in rats.¹⁰⁹  Both analgesia induced by increased arterial pressure and hypoalgesia in spontaneously hypertensive animals are abolished after α-adrenergic blockade.^46,97,110  Again, the translation to humans is lacking, although there is indirect evidence that subjects with elevated arterial pressure within the normotensive range demonstrate increased pain tolerance along with higher circulating levels of norepinephrine.¹¹¹ 

Emerging evidence suggests that diminished baroreceptor sensitivity not only augments the perception pain to experimental noxious stimuli but also contributes to the etiology of chronic musculoskeletal pain conditions, such as fibromyalgia, temporomandibular disorders, and chronic back pain.^{58,64,112,113}  In these patients, changes in the sensitivity to experimental pain and the perceived intensity of ongoing clinical pain correlate with diminished baroreceptor sensitivity and resting arterial pressure.^94,112,114  These chronic pain states share several features, including altered autonomic nervous system function.¹¹⁵  Specifically, many fibromyalgia patients show a high prevalence of orthostatic hypotension.¹¹⁶  Fibromyalgia patients also exhibit a negative correlation between baroreceptor sensitivity and clinical pain intensity and the severity of clinical complaints, and there is a reduction in resting baroreceptor sensitivity by nearly 35% in fibromyalgia patients compared to healthy control women.¹¹³  Furthermore, systolic, diastolic, and mean arterial pressures are correlated with thermal and ischemic pain in males, but not females, with higher blood pressure associated with lower pain sensitivity in males.^117,118  The observed sex difference in the blood pressure–pain sensitivity relationships, coupled with a reduction in baroreceptor sensitivity in females, may represent an important risk pathway that partially explains the female predominance of common chronic pain conditions like fibromyalgia¹¹⁹  and sex differences in response to both pharmacologic and nonpharmacologic interventions for pain.¹²⁰ 

At the population level, there is a lower incidence and prevalence of common musculoskeletal pain conditions in individuals with elevated arterial pressure, supporting a relationship between hypertension and hypoalgesia in various chronic pain states. In a large headache study, higher systolic and diastolic blood pressures were associated with a reduced risk for nonmigrainous headache¹²¹  and chronic musculoskeletal complaints.¹²²  Moreover, there is a significant negative relationship between several self-reported chronic pain conditions and hypertension.¹²³  The association between arterial pressure and the prevalence/incidence of chronic pain could be mediated by an impaired baroreceptor function that disrupts the normal modulatory effect of arterial pressure on pain processing. Whether altered baroreflex function represents a risk factor for the onset and persistence of chronic musculoskeletal pain and whether strengthening of baroreflex function represents a resilience factor that protects from common chronic pain conditions are questions that remain to be answered.

Baroreceptor sensitivity is inversely associated with carotid atherosclerosis inflammatory markers,¹²⁴  subclinical hypothyroidism,¹²⁵  and pregnancy-induced hypertension.¹²⁶  Baroreflex dysfunction can occur secondary to autonomic dysfunction in response to focal or systemic pathologies.¹²⁷  Although autonomic dysfunction is generally thought to be a consequence of chronic inflammation, new research indicates that in many cases autonomic dysfunction actually precedes the development of some of these conditions. Compared to healthy controls, patients at risk of developing rheumatoid arthritis (i.e., positive for multiple autoantibodies) have lower cardioparasympathetic activity and elevated cardiosympathetic activity, manifested by reduced heart rate variability and elevated resting heart rate. Individuals at risk for rheumatoid arthritis display a cardioparasympathetic/sympathetic profile similar to patients with established rheumatoid arthritis, as well as higher serum levels of norepinephrine, an indicator of augmented sympathetic nervous activity.¹²⁸  In patients with rheumatoid arthritis who have suffered a stroke, inflammation is reduced on the paralyzed side.¹²⁹  Moreover, sympathetic tone is positively correlated with plasma interleukin-6 levels in hypertensive postmenopausal women.¹³⁰  Consistently, central sympathetic inhibition in hypertensive patients reduces systemic tumor necrosis factor α levels in young healthy nonpregnant women.¹³¹  Thus, these clinical studies demonstrate a clear baroreflex and systemic autonomic dysfunction association with inflammation.

Animal studies suggest that the association between autonomic dysfunction and inflammation depends on the bidirectional communication between the autonomic nervous system, neuroimmune, and inflammatory processes (reviewed in detail elsewhere^132,133 ). Thus, the severity of inflammation is not merely immune-mediated but is also modulated by the nervous and endocrine systems. Peripheral mediators of inflammation, specifically interleukin-1β and tumor necrosis factor α, activate vagal afferents. The efferent limb of this reflex involves vagal parasympathetic fibers that release acetylcholine, which deactivates macrophages, preventing the secretion of inflammatory cytokines, and inhibits the synthesis of tumor necrosis factor α in innervated immune organs, including the liver, spleen, and heart.^23,134  Moreover, baroreflex activation diminishes neutrophil migration and synovial concentrations of inflammatory cytokines tumor necrosis factor α, interleukin-1β, and interleukin-6 in the rat by inhibiting sympathetic drive to the knee in an experimental arthritis model.¹³⁵  Unlike parasympathetic antiinflammatory effects, sympathetic stimulation is associated with proinflammatory effects mediated by that activation of adrenergic receptors on immune cells or indirectly via numerous mechanisms, including the production and distribution of lymphocytes and modulation of the release of proinflammatory peptides.¹³⁶  In a rat model of stroke, infection rates are reduced after sympathectomy, which attenuates sympathetically mediated immunosuppression.¹³⁷ 

Emerging evidence suggests a direct causal relationship between baroreflex function and inflammatory reflex arcs. The electrical activation of baroreflex pathways attenuates joint inflammation in experimental arthritis induced by the administration of zymosan into the femorotibial cavity in rats with lumbar sympathectomy, adrenalectomy, celiac subdiaphragmatic vagotomy, or splenectomy.¹³⁵  Baroreflex activation attenuates neutrophil migration and the synovial levels of pro-inflammatory cytokines tumor necrosis factor, interleukin-1β, and interleukin-6, but not antiinflammatory cytokine interleukin-10.¹³⁵  Baroreflex and autonomic dysfunctions also modulate local and systemic inflammatory in animal inflammatory models.¹³⁸  The autonomic regulation of inflammatory mediators act either directly on nociceptors or indirectly on sympathetic nerve terminals to produce and release inflammatory substances that contribute to the perception of pain¹³⁹  and chronic inflammatory pain conditions like arthritis.¹⁴⁰  In addition, afferent pain signaling can directly modulate other components of inflammation, including plasma extravasation and neutrophil function, which are modulated by vagal afferent activity.¹⁴¹  The sympathetic contribution to hyperalgesia has also been demonstrated in humans,¹⁴²  and it is well described in neuropathic pain conditions such as complex regional pain syndromes.

The putative causal relationship between baroreflex dysfunction and exaggerated inflammation in human subjects is of substantial relevance to perioperative outcomes (table 1). Baroreflex dysfunction is observed preoperatively in patients with several comorbidities and postoperatively, particularly after endarterectomy or other neck surgeries affecting the carotid sinus nerve.¹²⁷  In a prospective surgical study¹⁴³  that examined 30 patients undergoing carpal tunnel surgery who underwent preoperative baroreceptor sensitivity testing and postoperative pain assessments at 6 weeks (acute pain) and ~1 yr (persistent pain), there was a significant negative correlation between a measure of heart rate variability (i.e., the square root of the mean squared differences of successive R–R intervals) and acute postoperative pain. Preoperative resting arterial pressure and presumably baroreceptor activation have also been reported to be associated with postoperative pain intensity at 24 and 48 h postoperatively in men undergoing prostatectomy, even after accounting for patient-controlled opioid use.¹⁴⁴  Similarly, there is a negative correlation between resting preoperative arterial pressure and postoperative pain after cesarean section.¹⁴⁵ 

Baroreceptor dysfunction associated with impaired autonomic homeostasis increases the vulnerability to the hypotensive effects of general anesthesia.^146,147  Chronic hypertensive patients have lower baseline values of baroreceptor sensitivity and exhibit a more pronounced decrease in both systolic and diastolic arterial pressure after propofol administration.¹⁴⁸  Furthermore, endotracheal intubation, which is a sympathetic stimulus that should raise arterial pressure, decreases arterial pressure in chronic hypertensive patients.¹⁴⁸  Intraoperative hypotension caused by diminished baroreceptor activation is likely to contribute to augmented inflammatory reactions to surgical trauma and, as a result, to exaggerate acute postoperative pain and an increased vulnerability to chronic postoperative pain. Further work is required to establish the contribution of diminished baroreceptor sensitivity to perioperative adverse events, postoperative pain, and the likelihood of developing persistent pain after common surgical procedures.

Significant alterations in baroreceptor sensitivity have been observed in several diseases and health conditions (fig. 2). Low baroreceptor sensitivity is commonly seen in patients with hypertension and diabetes,^149,150  carotid atherosclerosis,^151,152  and obesity¹⁵³ ; in smokers¹⁵⁴ ; and in patients with high alcohol consumption.¹⁵⁵  Patients with obstructive sleep apnea have an attenuated baroreceptor sensitivity,¹⁵⁶  which is associated with increased blood pressure variability,¹⁵⁷  increased sympathetic activity,¹⁵⁸  desensitization of vascular adrenergic receptors, and decreased peripheral vascular adrenergic responses.¹⁵⁹  In the context of perioperative outcomes, this autonomic dysfunction is of relevance because it is linked to cardiovascular morbidity and obstructive sleep apnea.¹⁶⁰  Autonomic dysfunction is also prevalent in patients with chronic kidney disease who have an increased risk of sudden cardiac death associated with reduced spontaneous baroreceptor sensitivity.¹⁶¹  Interestingly, baroreceptor sensitivity dysfunction is correlated with glomerular filtration rate,¹⁶²  suggesting that there is a direct association between reduced baroreceptor sensitivity and declining renal function. All of these baroreceptor sensitivity–associated events can be further aggravated by the fact that prolonged bed rest induces rapid detrimental changes in baroreflex function.¹⁶³  Congruent with a baroreflex-mediated modulation of pain, there is an increased prevalence of chronic pain and/or greater pain perception in patients with conditions with reduced baroreceptor sensitivity, as well as obstructive sleep apnea,¹⁶⁴  diabetes,¹⁶⁵  obesity,¹⁶⁶  chronic kidney disease,¹⁶⁷  smoking,¹⁶⁸  alcoholism,¹⁶⁹  and hypertension,¹⁷⁰  although the mechanisms mediating these associations are not yet well understood (fig. 2).

Baroreflex dysfunction expressed as a reduced baroreceptor sensitivity has been reported in several cardiovascular conditions such as essential hypertension, impaired cardiac contractility,¹⁷¹  postmyocardial infarction sudden death,¹⁷²  heart failure,^173,174  coronary artery disease,²⁵  and atrial fibrillation.¹⁷⁵  Baroreflex function has also been implicated in modulating muscle tone,⁶²  sensorimotor performance,¹⁷⁶  startle reflex,¹⁷⁷  cortical activity,³  sleep,¹⁷⁸  cognitive performance,^179–182  and cortical arousal.⁸⁰  Of note, about 50% of cardiac surgery patients^183,184  and up to 26% of elderly noncardiac surgery patients¹⁸⁵  experience early postoperative cognitive dysfunction, which can persist in the long-term, significantly diminishing quality of life. The etiology of postoperative cognitive dysfunction is multifactorial and known to be associated with several patient-related factors.¹⁸⁶  It is not known whether baroreceptor sensitivity contributes to postoperative changes in cognition. The pathophysiologic processes involved in postoperative surgical outcomes are complex; however, it is clear that postoperative outcomes do not solely result from surgical insult but instead are strongly influenced by the patient’s preoperative physiologic status that is regulated, at least in part, by baroreceptor function and baroreceptor sensitivity.

Although there are several interventions that can modify baroreceptor sensitivity, the most extensively assessed approach is vagal nerve stimulation, which has been evaluated for the treatment of a variety of conditions: neurologic (partial seizures,¹⁸⁷  drug-resistant epilepsy,¹⁸⁸  tinnitus,^189,190  traumatic brain injury,^191,192  stroke¹⁹³ ), psychiatric (Alzheimer’s disease,^194,195  cognitive decline,¹⁹⁶  posttraumatic stress disorder,¹⁹⁷  treatment-resistant anxiety disorders¹⁹⁸ ), painful/inflammatory (headaches,^199,200  rheumatoid arthritis,^201,202  fibromyalgia,²⁰³  chronic pelvic pain,²⁰⁴  Crohn’s disease²⁰⁵ ), and cardiovascular/metabolic (coronary artery disease,²⁰⁶  heart failure,²⁰⁷  hypertension,^208–211  obesity²¹² ). Among these conditions where pain, inflammation, cognitive impairment, and cardiovascular events are likely to occur, vagal nerve stimulation has been proposed as a preoperative optimization procedure with the goal of reducing the incidence of adverse postoperative outcomes.

Other less invasive procedures that have been suggested to increase baroreceptor sensitivity in a clinically meaningful way include increasing venous pressure via fluid management,^45,213,214  acupuncture or somatic afferent stimulation,^215–218  stimulation of cranial vagal afferents arising from the ear’s concha,^219,220  cardiovascular conditioning,^221–223  operant learning procedures,²²⁴  intraoral appliances,¹¹⁴  and relaxation/biofeedback therapies.^225–228  Future studies are required to assess the effects of these procedures on baroreceptor sensitivity, acute and chronic pain perception, and perioperative surgical outcomes.

We have summarized the evidence, suggesting a role for baroreceptor function in both acute and chronic pain conditions, as well as perioperative outcomes. Although the measurement of baroreflex function in the perioperative period currently remains mostly relegated to the research environment, the assessment of perioperative baroreceptor sensitivity is highly likely to yield important clinically meaningful information that leads to novel strategies for organ protection and pain management. Preoperative recognition of impaired baroreflex function as an important modifiable risk factor requires exploration. Further research in this field is warranted because it is likely to provide actionable information that will reduce the sequelae of surgical stress and improve the management of chronic pain and adverse surgical outcomes. Existing noninvasive interventions known to increase baroreceptor sensitivity should be explored for managing patients with chronic pain and implemented preoperative to optimization surgical outcomes.

The authors thank Dr. Lana Watkins, Ph.D., Department of Psychiatry and Behavioral Science, Duke University, Durham, North Carolina, for her comments and assistance with the Supplemental Digital Content on methods to estimate baroreceptor sensitivity.

Supported by grant Nos. U01DE017018 and P01NS045685 from the National Institutes of Health (Bethesda, Maryland) and institutional support from the Department of Anesthesiology, Duke University, Durham, North Carolina.

The authors declare no competing interests.