Hypertension and pain: A state-based framework for cardiovascular–nociceptive coupling

Abstract

Experimental and epidemiological studies suggest that blood pressure (BP)-pain associations vary across normotension, hypertension, and chronic pain, but the mechanisms underlying these differences remain unclear. In pain-free individuals, higher resting BP is often associated with lower experimental pain sensitivity. Similar hypoalgesia is reported in some normotensive individuals with familial hypertension risk and in established hypertension, suggesting that reduced pain sensitivity is unlikely to be attributable to elevated BP alone. Acute baroreceptor activation can inhibit nociceptive reflexes and pain ratings, and current evidence points to contributions from baroreflex, autonomic, opioid, sensory, vascular, and renin-angiotensin pathways in BP-related hypoalgesia across groups. In chronic pain, the inverse BP-pain association is often weaker, absent, or reversed for selected pain facilitation measures. Prospective epidemiological studies suggest that chronic pain may be associated with increased later hypertension risk, although these observational findings do not establish causality. This review organizes the literature into four states: familial hypertension risk without sustained hypertension, inverse BP-pain associations in normotensive individuals, hypoalgesia in established hypertension, and attenuated or reversed BP-pain associations in chronic pain. Longitudinal studies are needed to determine whether these patterns reflect distinct phenotypes, transitional processes, overlapping mechanisms, or study-context differences.

Highlights

• •Higher BP is generally associated with lower experimental pain sensitivity, but this relationship varies across populations and pain conditions.
• •A four-state framework is proposed to organize cardiovascular–nociceptive coupling across BP and pain phenotypes.
• •Baroreflex, autonomic, peripheral sensory, and central pain-regulatory mechanisms may contribute, but no single mechanism explains BP-related hypoalgesia.
• •Chronic pain can attenuate, abolish, or reverse the usual inverse relationship between BP and pain sensitivity.
• •Prospective longitudinal studies are needed to determine whether the proposed states represent distinct phenotypes or continuous variation.

1. Introduction

Hypertension affects approximately one-third of adults aged 30–79 years worldwide (World Health Organization, 2025). Experimental studies have associated higher blood pressure (BP) with lower sensitivity to acute experimental pain. Across thermal, electrical tooth-pulp, ischemic, and mechanical pain measures, higher BP has been linked with higher sensory or pain thresholds, greater pain tolerance, or lower pain ratings in normotensive adults and patients with borderline or established hypertension (al'Absi et al., 1996; Ditto et al., 1998; France et al., 1991; Ghione, 1996; Ghione et al., 1988; Ghione et al., 1985; Makovac et al., 2020; Rosa et al., 1986; Sheps et al., 1992). In a meta-analysis of 59 human studies, higher BP was associated with reduced pain perception (Hedges' g = 0.48) and reduced nociceptive responses (g = 0.38) (Makovac et al., 2020). These pooled estimates were derived from highly heterogeneous studies, and the pain-perception analysis showed evidence of publication bias (Makovac et al., 2020). The meta-analysis did not detect significant differences in effect size among normotensive, hypertension-risk, and hypertensive samples, indicating that BP-related hypoalgesia is not restricted to established hypertension (Makovac et al., 2020). In the population-based Tromsø Study of 10,371 adults, higher resting systolic and diastolic BP were associated with lower cold-pressor pain ratings, with stronger BP-related hypoalgesia in women than men. Spline analyses showed that the systolic BP-pain association did not increase further once BP reached the hypertensive range, suggesting ceiling effects rather than progressively increasing hypoalgesia across the full BP range (Olsen et al., 2013a). Reduced pain sensitivity has been reported in normotensive individuals with a parental history of hypertension and in young spontaneously hypertensive rats (SHR), a genetic preclinical model of hypertension, before the onset of hypertension (al'Absi et al., 1996; France et al., 1991; Olsen et al., 2013a; France et al., 2002; Page and France, 1997; Saavedra, 1981a; Sitsen and de Jong, 1983). Findings from experimentally induced hypertension models are mixed. Renal, DOCA-salt, and salt-loading models have shown hypoalgesia in some studies (Afolabi et al., 2013; Zamir et al., 1980), whereas another study found hypoalgesia in young and adult SHR but not in renal-artery clip or DOCA-salt hypertensive rats (Sitsen and de Jong, 1983). These findings suggest that reduced pain sensitivity may reflect broader changes in cardiovascular and pain-regulatory systems, rather than the direct effect of elevated BP alone.

The BP-pain relationship also differs in chronic pain populations. Most studies in chronic low back pain (CLBP), temporomandibular disorders (TMD), fibromyalgia, and functional abdominal pain examined resting BP as a continuous variable rather than comparing hypertension-defined groups. Across these studies, the inverse association between BP and experimental pain sensitivity was reduced, absent, or reversed in chronic pain groups compared with pain-free controls (Bruehl et al., 2008; Bruehl et al., 2002; Brody et al., 1997; Venezia et al., 2024; de la Coba et al., 2018a; de la Coba et al., 2018b; Maixner et al., 1997). Population-based studies and chronic knee pain studies extend this pattern to samples that include both normotensive and hypertensive participants (Cruz et al., 2026; Olsen et al., 2013b). Prospective cohort studies further suggest that chronic pain may precede later hypertension. Multisite pain and widespread pain have been associated with increased risk of incident hypertension, although these observational findings do not establish causality (Qin et al., 2026; Chen et al., 2025). A 2025 systematic review and meta-analysis of 20 observational studies involving 1,594,264 participants found higher odds of hypertension among adults with chronic pain (OR 1.66, 95% CI 1.28–2.15), although between-study heterogeneity was extreme (I² = 99.8%) and associations were not significant for chronic back pain or combined chronic musculoskeletal pain (Taylor et al., 2025).

Several mechanisms may contribute to BP-related hypoalgesia, including baroreceptor signaling, autonomic regulation, descending pain-modulatory pathways, endogenous opioid and noradrenergic systems, and renin-angiotensin signaling (Ghione, 1996; Suarez-Roca et al., 2021; Suarez-Roca et al., 2019; Guasti et al., 2002a). These mechanisms are not mutually exclusive, and none fully explains why reduced pain sensitivity can precede hypertension, plateau at higher BP levels, or disappear or reverse in some chronic pain states. Antihypertensive treatment further complicates interpretation because several drug targets, including renin-angiotensin and adrenergic pathways, can influence nociceptive processing independently of BP reduction.

Differences in how hypertension is defined and measured also affect comparisons across studies. The World Health Organization defines hypertension as systolic BP ≥140 mmHg and/or diastolic BP ≥90 mmHg on repeated measurements (World Health Organization, 2025). The 2025 American Heart Association/American College of Cardiology (AHA/ACC) guideline classifies stage 1 hypertension as systolic BP 130–139 mmHg or diastolic BP 80–89 mmHg, and stage 2 hypertension as systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg (Writing Committee Members et al., 2025). Because many older studies used different thresholds, BP categories in this review are interpreted according to the definitions used by the original investigators.

This review examines BP-pain relationships across cardiovascular and pain conditions. We categorize the literature into four proposed states: reduced pain sensitivity in normotensive individuals with familial risk for hypertension; inverse BP-pain associations in normotensive individuals; reduced pain sensitivity in established hypertension; and attenuated or reversed BP-pain associations in chronic pain. These categories are intended as an organizing framework for comparing recurring patterns across studies, not as mutually exclusive biological states or a fixed sequence through which individuals necessarily progress. For example, an individual may simultaneously have familial hypertension risk, chronic pain, elevated BP, and antihypertensive or analgesic medication exposure. Framing the evidence in this way helps compare BP-pain findings across populations, pain conditions, and treatment contexts, and highlights where mechanisms remain insufficiently tested.

2. Cardiovascular and nociceptive pathways and their sites of interaction

The major cardiovascular and nociceptive pathways and their sites of interaction are summarized in Fig. 1. Cardiovascular sensory information reaches the central nervous system through arterial baroreceptors, cardiopulmonary receptors, peripheral chemoreceptors, and cardiac visceral afferents (Suarez-Roca et al., 2021; van Weperen and Vaseghi, 2023; Machado et al., 1997). Arterial baroreceptors in the carotid sinus and aortic arch respond to vessel-wall stretch during changes in arterial pressure. Carotid sinus baroreceptor afferents travel through the glossopharyngeal nerve (cranial nerve IX), whereas aortic baroreceptor and cardiopulmonary low-pressure receptor afferents travel predominantly through the vagus nerve (cranial nerve X) (Suarez-Roca et al., 2021; Norcliffe-Kaufmann, 2019). These cranial cardiovascular afferents terminate mainly in the nucleus tractus solitarius (NTS), a key brainstem site for cardiovascular regulation (Suarez-Roca et al., 2021; Machado et al., 1997).

Fig. 1.

Cardiovascular and nociceptive pathways and their sites of interaction. Cardiovascular sensory information from arterial baroreceptors and peripheral chemoreceptors is conveyed to the nucleus tractus solitarius (NTS) through glossopharyngeal (CN IX) and vagal (CN X) afferents. Cardiopulmonary baroreceptors and other vagal cardiac afferents also project to the NTS, whereas spinal cardiac afferents enter the spinal dorsal horn (Suarez-Roca et al., 2021; van Weperen and Vaseghi, 2023; Machado et al., 1997; Iturriaga et al., 2021). The NTS regulates sympathetic cardiovascular output through excitatory projections to the caudal ventrolateral medulla (CVLM), which inhibits the rostral ventrolateral medulla (RVLM), and regulates parasympathetic output through the nucleus ambiguus and dorsal motor nucleus of the vagus (DMV) (Suarez-Roca et al., 2021; Machado et al., 1997). Somatic nociceptive input from the body is relayed through the spinal dorsal horn, whereas craniofacial nociceptive input is relayed through the trigeminal sensory nuclear complex, particularly the spinal trigeminal nucleus caudalis (Sp5C) (Cordero-Erausquin et al., 2016; Donertas-Ayaz and Caudle, 2023; Terrier et al., 2022). Ascending nociceptive pathways project to the parabrachial nucleus (PBN), thalamus, and cortical and limbic forebrain regions, whereas descending modulation is provided by the periaqueductal gray (PAG)–rostral ventromedial medulla (RVM) system (Ossipov et al., 2010; Heinricher et al., 2009; Xue et al., 2024; Gauriau and Bernard, 2002). Cardiovascular and nociceptive signals converge within the NTS and PBN, where nociceptive input can influence cardiovascular reflex processing and baroreceptive and somatosensory information can engage shared brainstem circuits (Gamboa-Esteves et al., 2001; Boscan et al., 2002a; Boscan et al., 2002b; Han et al., 1991). mPFC, medial prefrontal cortex. Created with BioRender.com.

The arterial baroreflex provides one route through which BP-related signals can influence brainstem networks. When arterial pressure rises, increased baroreceptor firing activates NTS neurons. The NTS engages caudal ventrolateral medullary neurons, which inhibit sympathoexcitatory neurons in the rostral ventrolateral medulla (RVLM), reducing sympathetic outflow (Suarez-Roca et al., 2021; Machado et al., 1997). The NTS also activates cardiac vagal neurons, primarily in the nucleus ambiguus, with additional contributions from the dorsal motor nucleus of the vagus (Suarez-Roca et al., 2021; Machado et al., 1997). In addition to these reflex pathways, NTS neurons project to the parabrachial nucleus (PBN) and to broader autonomic and pain-related regions, including the ventrolateral medulla, hypothalamus, amygdala, locus coeruleus, periaqueductal gray (PAG), thalamic/diencephalic regions, and spinal dorsal horn (Suarez-Roca et al., 2021; Kawai, 2018).

Nociceptive information reaches the central nervous system through anatomically distinct somatic and craniofacial pathways. Somatic nociceptive afferents have their cell bodies in dorsal root ganglia and terminate mainly in the spinal dorsal horn. From there, second-order neurons project through ascending spinal pathways to brainstem, thalamic, and cortical regions involved in sensory and affective pain processing (Cordero-Erausquin et al., 2016). Craniofacial nociceptive input follows the trigeminal system. Primary trigeminal afferents have their cell bodies in the trigeminal ganglion and terminate in the trigeminal sensory nuclear complex. Facial nociceptive input is processed largely in the spinal trigeminal nucleus caudalis, also called the medullary dorsal horn (Donertas-Ayaz and Caudle, 2023; Terrier et al., 2022).

Although somatic and craniofacial nociceptive pathways enter the central nervous system through different primary relays, both are regulated by shared descending pain-modulatory systems. The PAG and rostral ventromedial medulla (RVM) are central components of descending pain control and can inhibit or facilitate nociceptive transmission in the spinal dorsal horn (Ossipov et al., 2010; Heinricher et al., 2009). The RVM also sends descending projections to the spinal trigeminal nucleus, where it can modulate craniofacial nociceptive processing (Xue et al., 2024). Noradrenergic projections from the locus coeruleus provide another route by which brainstem autonomic and arousal systems can influence nociceptive processing (Donertas-Ayaz and Caudle, 2023).

The NTS is one site where nociceptive and cardiovascular signals can interact. In rats, neurons in the cervical spinal dorsal horn project to the caudal NTS. Superficial dorsal horn projections terminate mainly in the commissural NTS, whereas deeper dorsal horn projections target more lateral NTS subnuclei (Gamboa-Esteves et al., 2001). This provides an anatomical route by which somatic sensory and nociceptive input can reach a major cardiovascular integration center. Functional studies support this interaction. Somatic noxious stimulation engages the NTS during nociception-evoked tachycardia and can attenuate chemoreceptor-evoked responses in NTS neurons (Boscan et al., 2002a). Somatic nociceptive stimulation can also reduce cardiac baroreflex gain and decrease baroreceptor-evoked firing in NTS neurons through mechanisms involving neurokinin-1 and GABAergic signaling (Boscan et al., 2002b).

The PBN is another important site of cardiovascular-somatosensory interaction. In rats, PBN neurons respond to caudal NTS stimulation and to peripheral somatosensory stimulation, and some individual neurons respond to both inputs (Han et al., 1991). Baroreceptive information reaches the PBN through projections from the caudal NTS, whereas nociceptive input can reach the lateral PBN through predominantly indirect ascending spinal pathways (Han et al., 1991; Boscan et al., 2005). In rats, reversible inhibition of the lateral PBN reduced tachycardia evoked by noxious forelimb stimulation by approximately 50%. Blockade of neurokinin-1 receptors in the lateral PBN produced a similar effect, supporting a role for substance P-sensitive PBN circuits in linking somatic nociception with cardiac responses (Boscan et al., 2005).

Neuroimaging studies of experimental pain in humans support overlap between autonomic and pain-processing networks, although they do not identify a single site responsible for BP-related hypoalgesia. A meta-analysis of central autonomic processing identified the insula, midcingulate cortex, and amygdala as core regions involved in autonomic regulation (Beissner et al., 2013). Functional imaging studies have linked pain-related sympathetic responses to activity in the anterior insula, anterior cingulate cortex, prefrontal cortex, thalamus, and midbrain (Maihofner et al., 2011). Studies combining functional magnetic resonance imaging with muscle sympathetic nerve activity recordings during tonic muscle pain have further implicated the NTS, PAG, RVM, hypothalamus, anterior cingulate cortex, prefrontal cortex, insula, and basal ganglia in pain-related sympathetic regulation (Kobuch et al., 2017). Cardiac autonomic changes during tonic pain have also been associated with functional connectivity involving the dorsal anterior cingulate cortex, periaqueductal gray, anterior insula, and prefrontal cortex (Hohenschurz-Schmidt et al., 2020). Together, these findings suggest that cardiovascular and nociceptive signals interact through distributed brainstem and forebrain networks.

Cardiac-cycle and baroreceptor-stimulation studies provide functional evidence that cardiovascular afferent activity can influence pain processing. In normotensive adults, painful stimuli delivered during systole, when arterial baroreceptor firing is greater, were rated as less painful than stimuli delivered during diastole in one functional imaging study (Ottaviani et al., 2018). Other studies found higher nociceptive flexion reflex (NFR) thresholds or smaller pain-related evoked potentials during systole than during diastole, although subjective pain ratings did not always differ (Edwards et al., 2008a; Edwards et al., 2002). Experimental carotid baroreceptor stimulation has also been shown to attenuate pain perception in humans, but findings vary across stimulation methods and pain outcomes (Dworkin et al., 1994; Droste et al., 1994). In CLBP, baroreflex stimulation may affect pain sensitivity differently than in no-pain controls (Venezia et al., 2024). Together, these findings support cardiovascular-nociceptive interaction but do not show that increased BP or baroreceptor activity always produces hypoalgesia.

3. Cardiovascular–nociceptive coupling across blood pressure and pain states

The studies reviewed below are grouped by cardiovascular and pain status because BP-pain associations differ across these contexts. The four states are used to compare evidence across study populations, not to define established biological categories or a fixed sequence. The main findings, pain measures, and mechanisms examined across the four proposed cardiovascular–nociceptive states are summarized in Table 1.

Table 1.

Summary of evidence across the four cardiovascular–nociceptive states.

State	Main evidence	Mechanisms examined	Main gap
State 1: Familial hypertension risk	Some normotensive individuals with parental hypertension show reduced pain sensitivity. Similar findings are reported in SHR before sustained hypertension develops (al'Absi et al., 1996; Ditto et al., 1998; France et al., 1991; France et al., 2002; Page and France, 1997; Saavedra, 1981a; Sitsen and de Jong, 1983).	NFR, baroreceptor stimulation, stress and autonomic responses, opioid blockade, adrenergic signaling (France et al., 1991; France et al., 2002; Page and France, 1997; al'Absi et al., 1999; Lambert and Schlaich, 2004; Greaney et al., 2015; Fredrickson et al., 1991; Ditto et al., 1997; France and Suchowiecki, 2001; Edwards et al., 2007; France et al., 2005; al'Absi et al., 2006; McCubbin et al., 2006).	Reduced pain sensitivity may precede hypertension, but the mechanism is unclear.
State 2: Normotensive BP-pain association	In normotensive samples, higher resting BP is often associated with lower experimental pain sensitivity, although findings vary by sex, age, and pain measure (Ditto et al., 1998; Makovac et al., 2020; Olsen et al., 2013a; Mendpara et al., 2019; Bruehl et al., 1992; Fillingim and Maixner, 1996; Haas et al., 2011).	Cardiac-cycle timing, arterial and cardiopulmonary baroreceptor manipulation, sympathetic activation, opioid blockade (Suarez-Roca et al., 2021; Suarez-Roca et al., 2019; Ottaviani et al., 2018; Edwards et al., 2008a; Edwards et al., 2002; Edwards et al., 2001; Rau et al., 1994; Reyes del Paso et al., 2014; D'Antono et al., 2000; Neumann et al., 2024; Lautenschlager et al., 2015; Devoize et al., 2017; Bruehl et al., 2010a; McCubbin et al., 2006; McCubbin and Bruehl, 1994; Schobel et al., 1998).	Baroreceptor activation can inhibit pain acutely, but it does not explain all resting BP-pain associations.
State 3: Established hypertension	Some studies report reduced experimental pain sensitivity in hypertension, including dental, electrical, pressure, and other evoked-pain measures (Ghione et al., 1988; Ghione et al., 1985; Saklecha et al., 2022; Viggiano et al., 2009; Rosa et al., 1994; Vignocchi et al., 1989; Guasti et al., 1999).	Peripheral sensory function, NFR/blink reflexes, cortical responses, baroreflex sensitivity, opioids, vascular stiffness, animal models (Guasti et al., 2002a; Edwards et al., 2008b; Edwards et al., 2010; Edwards et al., 2008c; Papageorgiou et al., 2017; Mussalo et al., 2002; Schobel et al., 1996; Guasti et al., 1996; Ring et al., 2007; Ring et al., 2008; Donertas-Ayaz et al., 2026; Randich and Robertson, 1994; Ogawa et al., 1991; Sitsen and de Jong, 1984; Taylor et al., 2001; Okada et al., 2012; Philbois et al., 2024; Subhashri et al., 2021; Barnes et al., 2012).	It remains unclear whether hypoalgesia reflects preexisting differences, effects of sustained hypertension, medication exposure, vascular changes, or comorbidity.
State 4: Chronic pain	BP-related hypoalgesia is weaker, absent, or reversed in several chronic pain conditions, including CLBP, fibromyalgia, TMD, chronic knee pain, and history of childhood functional abdominal pain (Bruehl et al., 2008; Bruehl et al., 2002; Brody et al., 1997; Venezia et al., 2024; de la Coba et al., 2018a; de la Coba et al., 2018b; Maixner et al., 1997; Cruz et al., 2026; Olsen et al., 2013b; Chung et al., 2008a; Bruehl et al., 2010b).	Baroreflex sensitivity/stimulation, HRV, adrenergic and opioid blockade, descending pain modulation, HPA-axis function, interoception, vascular factors (Bruehl et al., 2008; Bruehl et al., 2002; Brody et al., 1997; Venezia et al., 2024; Chung et al., 2008b; Iwakuma et al., 2025; Tracy et al., 2016; Task Force of the ESC and NASPE, 1996; Schroeder et al., 2003; Bruehl et al., 2018; Tchivileva et al., 2020; Light et al., 2009; Mills et al., 2018; Li et al., 2018; Matsuo et al., 2017; Makovac et al., 2021; Beiner et al., 2023; Woda et al., 2016; Griep et al., 1998; Vyverman et al., 2026; Bragdon et al., 1997; Guasti et al., 1995; Todd et al., 2024; Grabli et al., 2022; Rost et al., 2017; Duschek et al., 2017; Horsburgh et al., 2024; Sun, 2015; Lee et al., 2011; Kim et al., 2010; Kim et al., 2021; Tian et al., 2024; Naeini et al., 2025).	Chronic pain appears to alter BP-pain coupling, but the mechanisms behind attenuation versus reversal are not established.

These states are used as an organizing framework for the literature. They are not intended to be mutually exclusive groups or a fixed sequence of progression.

Abbreviations: BP, blood pressure; CLBP, chronic low back pain; HPA, hypothalamic-pituitary-adrenal; HRV, heart rate variability; NFR, nociceptive flexion reflex; SHR, spontaneously hypertensive rat; TMD, temporomandibular disorder.

3.1. State 1: Reduced pain sensitivity in normotensive individuals with familial hypertension risk

State 1 describes reduced experimental pain sensitivity reported in some normotensive individuals with a family history of hypertension. Family history increases later hypertension risk (Wang et al., 2008), but participants in these studies were normotensive when tested, and most studies did not determine whether they later developed hypertension.

Evidence for reduced pain sensitivity in familial-risk groups has been reported from infancy through young adulthood, but the literature is small and partly sex-dependent. In neonates, maternal family history of hypertension was associated with shorter crying during intramuscular vitamin K injection, suggesting that reduced pain responding is unlikely to be only a learned response style (France et al., 2009). In adolescent boys, higher resting systolic BP and parental hypertension were associated with lower mechanical pain sensitivity at age 14 (Ditto et al., 1998). In follow-up studies of the same cohort, lower pain sensitivity at age 14 predicted higher BP at age 19 and higher ambulatory BP at age 22 (Campbell et al., 2003; Campbell et al., 2002). Adult studies also report lower ischemic, pressure, or cold-pressor pain responses in some normotensive offspring of hypertensive parents, especially men (al'Absi et al., 1996; France et al., 1991; al'Absi et al., 1999; France and Stewart, 1995).

Mechanistic studies in familial-risk groups point to altered stress and autonomic regulation, but the direction of findings differs by sample and task. In one microneurography study, cold pressor stimulation produced a smaller increase in muscle sympathetic nerve activity in normotensive participants with a strong family history of hypertension than in those without such history (Lambert and Schlaich, 2004). In contrast, young women with familial hypertension risk showed greater BP and muscle sympathetic nerve activity responses to cold pressor, handgrip exercise, and postexercise ischemia (Greaney et al., 2015). Other work has linked familial hypertension risk with greater catecholamine and cortisol responses to stress (Fredrickson et al., 1991). Pain studies also suggest a role for stress-related physiology: in women, lower electrical pain sensitivity was most evident among those with familial risk and greater BP reactivity to stress, although stress-related baroreceptor activation did not explain the effect (Ditto et al., 1997). These findings support stress and autonomic regulation as possible contributors to familial risk hypoalgesia, but they do not identify a single mechanism.

Studies using the NFR, usually evoked by electrical stimulation of the sural nerve, show reduced spinal responses to painful stimulation in some familial-risk groups. Normotensive young adults with hypertensive parents required higher stimulation intensities to elicit the NFR and to report pain (Page and France, 1997). Higher NFR thresholds were also reported in studies that included mental arithmetic or forearm ischemia (France et al., 2002; France and Suchowiecki, 2001). However, forearm ischemia reduced NFR activity to a similar degree in familial-risk and control participants (France and Suchowiecki, 2001), and another study found no group differences in NFR thresholds during rest or computer-game distraction in hypertensive adults or in normotensive adults with hypertensive parents (Edwards et al., 2007). These findings suggest that familial hypertension risk may be linked to lower baseline spinal responsiveness to painful input, but they do not show stronger descending pain inhibition.

Baroreflex function has been proposed as one pathway linking BP regulation and pain modulation (Ghione, 1996; Suarez-Roca et al., 2021). In a study of untreated men, family history of hypertension was associated with lower cardiac baroreflex sensitivity in both normotensive and hypertensive participants, even after adjustment for age, mean arterial pressure, body weight, and race (Parmer et al., 1992). This finding shows that altered baroreflex control can be present in familial-risk groups, but the study did not measure pain. In a separate pain study, healthy men with hypertensive parents showed lower pain sensitivity to thigh-cuff pressure, but carotid baroreceptor stimulation did not reduce pain more in those men than in controls (France et al., 1991). Thus, familial-risk hypoalgesia and altered baroreflex control may coexist, but current evidence does not show that stronger baroreceptor-mediated analgesia explains the lower pain sensitivity.

Evidence for endogenous opioid involvement in familial risk hypoalgesia is limited. In a placebo-controlled study using naltrexone, an opioid receptor antagonist, participants with hypertensive parents reported lower pain ratings and had higher electrocutaneous pain thresholds, but they did not have higher NFR thresholds. Naltrexone did not remove the parental-history differences in pain, suggesting that endogenous opioids did not mediate familial-risk hypoalgesia in that study (France et al., 2005). A related study found that naltrexone increased pain ratings and cortisol responses, with stronger pain effects in women, while higher pain threshold and tolerance were observed mainly in high-risk men (al'Absi et al., 2006). Low-frequency transcutaneous electrical nerve stimulation, which can recruit opioid-mediated analgesia, strengthened inverse associations between pain and both resting systolic BP and parental hypertension in men (Campbell and Ditto, 2002).

Animal studies also show that lower pain responsiveness can appear before sustained hypertension. In SHR, reduced hot-plate or foot-shock responsiveness has been reported in young animals before hypertension is established and in adult hypertensive animals (Saavedra, 1981a; Sitsen and de Jong, 1983). In one study, renal-clip and DOCA-salt hypertension raised BP but did not reduce pain responsiveness, suggesting that elevated BP alone does not reproduce the SHR pain phenotype (Sitsen and de Jong, 1983). Naloxone reduced the prolonged hot-plate response latencies in SHR, supporting opioid involvement in this strain (Saavedra, 1981a; Sitsen and de Jong, 1983).

A major limitation of this literature is that most proposed mechanisms have been tested in cross-sectional laboratory studies. The prospective evidence linking lower pain sensitivity with later BP increases comes mainly from one male adolescent cohort, and no study has shown that this association is explained by baroreflex function, autonomic reactivity, NFR responses, stress hormones, or endogenous opioid activity. Most studies also used small experimental samples, and findings differ by sex and pain measure. Family history is an imprecise marker because it may reflect genetic susceptibility, shared environment, health behaviors, or a combination of these factors.

Studies of normotensive individuals with familial hypertension risk show that reduced pain sensitivity can be present before sustained hypertension develops. This finding is not seen in every study and appears stronger in some male samples than in female samples. The evidence does not support a simple explanation based only on higher resting BP or stronger baroreceptor-mediated pain inhibition. NFR, autonomic, stress-response, and opioid-blockade studies suggest differences in pain and cardiovascular regulation, but none has been shown to explain the familial-risk phenotype. Whether these findings reflect inherited risk, shared family environment, early cardiovascular regulation, overlapping pain-control mechanisms, or a combination of these factors remains unresolved.

3.2. State 2: Inverse BP–pain associations in normotensive individuals

State 2 refers to the inverse association between resting BP and experimental pain sensitivity observed in normotensive populations. Individuals with relatively higher BP within the normotensive range often show lower experimental pain sensitivity, without implying progression toward hypertension. Higher resting BP has been associated with reduced sensitivity to mechanical pressure and cold-pressor pain (Olsen et al., 2013a; Mendpara et al., 2019; Bruehl et al., 1992). In 60 normotensive men, higher resting systolic BP was associated with lower pain ratings during finger-pressure stimulation (Bruehl et al., 1992). In 200 healthy young Indian medical students, higher resting BP was associated with higher cold-pressor pain threshold and tolerance and lower pain ratings (Mendpara et al., 2019). In the population-based Tromsø Study, higher systolic BP was associated with lower cold-pressor pain sensitivity among participants below the hypertensive range (<140/90 mmHg), whereas BP-related hypoalgesia did not increase further among those at or above this range (Olsen et al., 2013a). This supports possible nonlinearity or ceiling effects across the BP range.

Current evidence suggests sex- and age-related differences in BP-pain associations, but the direction and strength of these differences vary across studies. In healthy normotensive adults, higher BP was associated with lower thermal and ischemic pain sensitivity in men but not women (Fillingim and Maixner, 1996). In the Tromsø Study, the association was stronger in women than men (Olsen et al., 2013a). In youth studies, higher BP was linked to lower experimental pain sensitivity in adolescent boys and in some groups of girls, but not across all samples (Ditto et al., 1998; Haas et al., 2011). In the same male adolescent cohort, lower pain sensitivity at age 14 predicted higher BP at ages 19 and 22 (Campbell et al., 2003; Campbell et al., 2002). These longitudinal findings come from one male cohort and should not be taken to mean that lower pain sensitivity, or relatively higher BP within the normotensive range, generally predicts later hypertension. A meta-analysis found substantial heterogeneity by pain measure, stimulation site, sex composition, and other study characteristics (Makovac et al., 2020).

Baroreceptor signaling has been studied as a possible mechanism linking BP with pain. Baroreceptor activation may reduce pain by engaging brainstem pathways that dampen nociceptive processing; during systole, higher arterial pressure increases carotid and aortic baroreceptor firing, which projects to the NTS and connected pain-modulatory circuits (Suarez-Roca et al., 2021; Suarez-Roca et al., 2019). In normotensive adults, NFR responses were smaller and NFR thresholds were higher during systole than diastole, consistent with reduced spinal nociceptive processing when arterial baroreceptor firing is greater (Edwards et al., 2002; Edwards et al., 2001). In 18 normotensive adults, systolic pain stimuli were also rated as less painful than diastolic stimuli, and higher baseline BP was associated with lower pain overall (Ottaviani et al., 2018). Direct carotid baroreceptor stimulation increased mechanical pain thresholds in normotensive and labile hypertensive adults but did not change thermal pain thresholds (Rau et al., 1994). In another study, carotid stimulation reduced pain mainly when it produced a larger reflex decrease in heart rate, suggesting that pain inhibition may depend on engagement of the cardiovascular reflex response (Reyes del Paso et al., 2014). Cardiopulmonary baroreceptor stimulation by passive leg elevation reduced mechanical pain in healthy male undergraduates with relatively higher systolic BP (D'Antono et al., 2000), whereas baroreceptor unloading with lower-body negative pressure did not change thermal pain in healthy volunteers when systemic BP was maintained (Neumann et al., 2024). These findings support baroreceptor involvement in BP-related hypoalgesia, especially for electrocutaneous and mechanical pain.

Sympathetic activity has been studied less directly as a possible contributor to BP-related hypoalgesia. In healthy men, heat and cold pain increased muscle sympathetic nerve activity, and greater sympathetic activation during concurrent mental stress was associated with lower pain intensity (Lautenschlager et al., 2015). In 56 young normotensive adults, head-up tilt, an orthostatic challenge that increased diastolic BP and heart rate, also increased electrocutaneous sensory and pain thresholds; however, these threshold changes were largely unrelated to hemodynamic changes, so the mechanism of this analgesic effect remains unclear (Devoize et al., 2017).

Opioid blockade has not had the same effect across studies. In 163 healthy adults, naltrexone eliminated the inverse association between systolic BP and affective ratings of ischemic pain (Bruehl et al., 2010a). In young adults at increased risk for hypertension, naltrexone effects on cold-pressor pain differed by hypertension-risk status (McCubbin et al., 2006). By contrast, resting systolic BP still predicted lower cold pain ratings during naloxone administration in normotensive adults (McCubbin and Bruehl, 1994), and naloxone did not change the overall inverse BP-pain association in normotensive or borderline hypertensive men (Schobel et al., 1998).

Taken together, studies in normotensive and otherwise healthy samples support an inverse association between resting BP and experimental pain sensitivity, particularly for mechanical, cold-pressor, and electrocutaneous outcomes. This association is not consistent across all studies and appears to vary by sex, age, pain measure, and study design. Higher BP within the normotensive range should not be interpreted as evidence of progression toward hypertension. Mechanistic studies implicate baroreceptor, sympathetic, and endogenous opioid pathways in pain modulation, but these mechanisms have not been shown to fully explain the resting BP-pain association.

3.3. State 3: Established hypertension

State 3 describes reduced experimental pain sensitivity in individuals with established hypertension. Hypertensive adults have shown higher sensory or pain thresholds during tooth-pulp stimulation, cutaneous electrical stimulation, pressure testing, and other experimental pain procedures (Ghione et al., 1988; Ghione et al., 1985; Saklecha et al., 2022; Viggiano et al., 2009; Rosa et al., 1994; Vignocchi et al., 1989). In a study of 130 hypertensive and 51 normotensive participants, the hypertensive group had higher dental pain thresholds and tolerance than the normotensive group. Among hypertensive participants, higher resting and 24-h BP was also associated with lower pain sensitivity (Guasti et al., 1999). These findings show that reduced pain sensitivity can be present in established hypertension, but they do not determine whether it is caused by sustained BP elevation or reflects physiological differences that coexist with hypertension.

Human studies provide limited evidence about where hypertension-related hypoalgesia arises. Unmedicated hypertensive adults showed higher cutaneous sensory thresholds and smaller median-nerve sensory action potentials, with preserved conduction velocity (Edwards et al., 2008b). Another study found smaller peripheral N9 somatosensory-evoked potentials in hypertension, while cortical N20 responses and conduction times were unchanged (Edwards et al., 2010). These findings point to peripheral sensory differences, but they did not test nociceptive afferents directly. Evidence at spinal and brainstem levels is less consistent: higher thresholds for polysynaptic blink-reflex components have been reported, whereas NFR thresholds did not differ between hypertensive and normotensive participants (Edwards et al., 2008c). A small EEG study also found altered cortical responses during cold-pressor stimulation (Papageorgiou et al., 2017). Current human evidence therefore does not localize reduced pain sensitivity in hypertension to one peripheral, spinal, brainstem, or cortical site.

In hypertension, the baroreflex is often reset to operate around a higher BP level and shows reduced sensitivity to BP changes (Suarez-Roca et al., 2019; Mussalo et al., 2002). If hypertension-related hypoalgesia were driven simply by stronger baroreflex-mediated pain inhibition, greater baroreflex sensitivity would be expected to correspond to lower pain sensitivity. Human data do not show this. In 73 untreated men, higher 24-h systolic BP was associated with higher dental pain thresholds, but greater resting baroreflex sensitivity was associated with lower pain thresholds; sympathovagal balance was unrelated to pain sensitivity (Guasti et al., 2002a). During noxious mechanical stimulation, borderline hypertensive men reported less pain than normotensive men, even though the groups showed similar increases in mean arterial pressure, central venous pressure, heart rate, and muscle sympathetic nerve activity (Schobel et al., 1996). These findings suggest that reduced pain sensitivity in hypertension is not explained by greater baroreceptor activation during pain or by stronger resting baroreflex sensitivity alone.

Opioid findings in hypertension do not support a consistent tonic opioid explanation. Hypertensive participants have shown higher circulating beta-endorphin concentrations, and beta-endorphin levels have been correlated with BP and pain thresholds (Sheps et al., 1992; Guasti et al., 1996). However, direct evidence for opioid receptor changes in hypertensive patients is limited. In newly diagnosed untreated hypertension, naltrexone did not alter cold or ischemic pain responses (Ring et al., 2007). Naltrexone also did not modify reduced electrocutaneous pain sensitivity in hypertensive participants (Ring et al., 2008) or reveal hypertension-related differences in NFR responses (Edwards et al., 2008c).

Animal models show that hypertension-related changes in nociception are not uniform across strains, hypertension models, or pain assays. SHR show reduced nociceptive responsiveness at both normotensive and hypertensive ages (Saavedra, 1981a; Sitsen and de Jong, 1983). In adult male SHR, reduced thermal and mechanical facial pain sensitivity was accompanied by altered HCN and voltage-gated potassium currents in trigeminal ganglion neurons (Donertas-Ayaz et al., 2026). Transcriptomic analyses also showed strain differences in sensory and ion-channel pathways, while systolic BP did not robustly explain the strain difference in thermal pain behavior. SHR studies also implicate spinal nociceptive processing: heat-evoked responses of dorsal horn neurons were reduced in SHR compared with WKY controls (Randich and Robertson, 1994). Induced hypertension models give different results: renal-clip and DOCA-salt hypertension did not produce hypoalgesia in one study (Sitsen and de Jong, 1983), whereas other renal, DOCA-salt, and salt-induced models showed reduced nociceptive responses (Afolabi et al., 2013; Zamir et al., 1980). Pharmacologic BP-lowering studies in SHR are also not uniform; hydralazine or captopril did not alter SHR hypoalgesia in one study, whereas delapril or nifedipine reduced BP and increased pain sensitivity in another (Ogawa et al., 1991; Sitsen and de Jong, 1984). SHR pain responses also vary by assay, with greater sensitivity reported in prolonged or inflammatory pain (Taylor et al., 2001). These findings indicate that elevated BP alone is not sufficient to predict reduced nociceptive responsiveness; strain background, hypertension model, antihypertensive manipulation, sensory-neuron biology, spinal processing, and pain assay all influence the outcome.

Vascular and comorbid conditions associated with aging and long-standing hypertension may also affect BP-pain associations. Hypertension and aging are associated with greater arterial stiffness, and greater carotid stiffness has been linked to lower baroreflex sensitivity (Okada et al., 2012). Postmenopausal status may add further autonomic and vascular variation, including changes in sympathetic activity, arterial stiffness, and baroreflex function (Philbois et al., 2024; Subhashri et al., 2021; Barnes et al., 2012). Atherosclerosis, coronary disease, heart failure, obesity, diabetes, obstructive sleep apnea, and chronic kidney disease can also impair baroreflex or autonomic function (Kaur et al., 2016; Skrapari et al., 2006; Carlson et al., 1996; Chapleau et al., 1995). These factors may contribute to differences across studies of hypertensive populations, but direct evidence that they explain reduced pain sensitivity in hypertension is lacking.

State 3 studies show reduced experimental pain sensitivity in some hypertensive populations, but they do not establish whether this reflects preexisting differences, effects of sustained hypertension, or both. Because most human studies are cross-sectional, they cannot determine when the pain phenotype emerges or which sensory, autonomic, vascular, or opioid-related mechanisms drive it. Sensory studies suggest peripheral differences and possible central involvement, but several relied on non-nociceptive measures, limiting conclusions about nociceptive pathways. Baroreflex and opioid-blockade findings do not support stronger baroreflex inhibition or increased tonic opioid activity as sufficient explanations. Animal studies add that elevated BP alone does not reliably produce hypoalgesia; pain responses vary by strain, hypertension model, antihypertensive manipulation, and assay. Vascular aging, arterial stiffness, cardiometabolic disease, and other comorbidities may further shape pain processing in hypertensive populations, but their role has not been tested directly.

3.4. State 4: Attenuated or reversed BP–pain associations in chronic pain

State 4 refers to chronic pain conditions in which the inverse association between BP and experimental pain is reduced, absent, or reversed. This has been reported in CLBP, fibromyalgia, TMD, chronic knee pain, and adults with a history of childhood functional abdominal pain. The direction and strength of the association vary by diagnosis, sex, BP status, and pain measure. In the population-based Tromsø Study, which included participants with and without hypertension, BP-related hypoalgesia was present among individuals free of chronic pain but about half as strong among those reporting chronic pain (Olsen et al., 2013b). In CLBP, artificial baroreceptor stimulation reduced pressure pain sensitivity in pain-free participants but increased pain sensitivity in CLBP participants, and resting baroreflex sensitivity was associated with conditioned pain modulation in both groups (Venezia et al., 2024).

In CLBP, the inverse BP-pain association seen in pain-free controls was absent or reversed for several measures. Higher systolic and diastolic BP were associated with higher ischemic pain thresholds in pain-free normotensive controls, whereas higher systolic BP was associated with lower ischemic pain thresholds in participants with CLBP (Bruehl et al., 2002). Participant-group interactions also showed absent or reversed inverse associations in CLBP for finger-pressure pain intensity and unpleasantness, ischemic pain threshold, and heat pain threshold (Bruehl et al., 2008). For thermal wind-up, higher systolic BP was associated with less wind-up in healthy controls but greater wind-up in chronic back pain (Chung et al., 2008a).

Similar changes have been reported in other chronic pain conditions. In fibromyalgia, higher BP was associated with greater pain threshold and tolerance in controls but not in participants with fibromyalgia, although an inverse association remained during slowly repeated painful stimulation (de la Coba et al., 2018a). In women with painful TMD, resting BP was associated with lower experimental pain sensitivity in controls but not in participants with TMD and was unrelated to clinical orofacial pain (Maixner et al., 1997). In adolescents and young adults with a history of childhood functional abdominal pain, higher resting systolic BP was associated with higher heat-pain threshold and tolerance in healthy controls but not in those with childhood functional abdominal pain, regardless of whether abdominal pain had resolved or persisted at that time (Bruehl et al., 2010b). At later follow-up, higher resting systolic BP was associated with higher heat-pain threshold and tolerance and lower temporal summation mainly among participants whose abdominal pain had resolved, not among those with ongoing pain (de la Coba et al., 2018b). In chronic knee pain, higher BP was associated with greater mechanical temporal summation in normotensive women (Cruz et al., 2026). Thus, State 4 includes two related findings: in some chronic pain groups, the inverse BP-pain association is absent, while in selected facilitation measures, higher BP is associated with greater pain sensitivity.

Sex and hypertension status may modify BP-pain associations in chronic pain. In 213 adults with chronic knee pain, higher BP was associated with lower pressure-pain sensitivity in normotensive men but greater mechanical temporal summation in normotensive women; neither association was detected in participants with hypertension (Cruz et al., 2026). Sex-specific findings have also been reported in adults with a history of childhood functional abdominal pain, where BP-related hypoalgesia differed by pain-resolution status and temporal summation findings differed by sex (de la Coba et al., 2018b). At the population level, chronic pain has been associated with higher hypertension prevalence, with some evidence that this association may be stronger in women (Olsen et al., 2013b; Bruehl et al., 2005).

Baroreceptor studies provide direct evidence that cardiovascular modulation of pain can differ in CLBP. Resting baroreflex sensitivity was lower in participants with CLBP, and inverse associations between baroreflex sensitivity and pain responses seen in controls were absent in CLBP (Chung et al., 2008b). For thermal wind-up, higher systolic BP and greater baroreflex sensitivity were associated with less wind-up in controls, whereas higher systolic BP was associated with greater wind-up in chronic back pain and baroreflex sensitivity was unrelated to wind-up (Chung et al., 2008a). Experimental carotid baroreceptor stimulation increased pain-evoked somatosensory responses and pain ratings in participants with CLBP rather than reducing them (Brody et al., 1997). More recently, artificial baroreceptor stimulation reduced pressure pain in pain-free participants but increased pain sensitivity in CLBP; hypertension was excluded, indicating that altered baroreceptor-related pain modulation can occur without established hypertension (Venezia et al., 2024). In the same study, resting baroreflex sensitivity was associated with conditioned pain modulation in both groups, so this association did not by itself explain the opposite pain response to baroreceptor stimulation. Using a different baroreceptor manipulation, a small study of 12 patients with chronic back pain found that cardiopulmonary baroreceptor unloading with lower-body negative pressure was associated with enhanced short-term habituation to repetitive heat pain. The effect was most apparent in the six participants with neuropathic pain features, in whom pressure pain thresholds also increased (Iwakuma et al., 2025). Because cardiopulmonary baroreflex sensitivity was not measured and the study lacked an age-matched control group, these preliminary findings require replication. Taken together, these studies suggest that cardiovascular modulation of pain in CLBP may depend on the receptor population, direction of receptor loading or unloading, pain measure, and pain phenotype. Arterial baroreceptor activation may fail to inhibit or may facilitate selected pain responses in CLBP, whereas preliminary evidence suggests that cardiopulmonary baroreceptor unloading can enhance pain habituation in some patients.

Chronic pain is also associated with altered autonomic cardiovascular regulation. Heart rate variability (HRV) reflects beat-to-beat variation in cardiac timing and is commonly used as a noninvasive index of autonomic regulation, including vagally mediated cardiac control (Tracy et al., 2016; Task Force of the ESC and NASPE, 1996). Lower HRV is seen in both chronic pain and hypertension, suggesting overlapping autonomic dysregulation rather than a pain-specific change alone (Tracy et al., 2016; Schroeder et al., 2003). In the Tromsø Study, chronic pain was associated with lower resting HRV and lower spontaneous baroreflex sensitivity; in cross-sectional statistical mediation models, these reductions partly accounted for the association between chronic pain and comorbid hypertension (Bruehl et al., 2018). This may help explain why BP-related hypoalgesia is weakened or altered when chronic pain and hypertension coexist.

Pharmacological studies in CLBP have tested adrenergic and opioid mechanisms. α2-adrenergic blockade with yohimbine did not eliminate BP-related hypoalgesia, although it altered some pain responses and BP-pain associations in CLBP (Bruehl et al., 2008). Naloxone also did not significantly alter BP-pain relationships in normotensive participants with CLBP or pain-free controls (Bruehl et al., 2002). In fibromyalgia and TMD, beta-adrenergic blockade with propranolol reduced clinical pain in small mechanistic studies, and larger TMD trials suggest benefit in some participants (Tchivileva et al., 2020; Light et al., 2009). However, these studies did not directly test whether adrenergic or opioid mechanisms explain altered BP-pain associations in people with both chronic pain and hypertension. Thus, pharmacological evidence supports adrenergic and opioid involvement in some pain outcomes but does not identify either system as a necessary mechanism for altered BP-pain coupling in chronic pain.

Neuroimaging studies support altered descending pain-modulatory circuitry in chronic pain. In chronic neuropathic orofacial pain, altered connectivity was reported among RVM, PAG, locus coeruleus, spinal trigeminal nucleus, and cortical regions (Mills et al., 2018). In CLBP, imaging studies have reported reduced activation or connectivity in cortical and descending pain-modulatory networks (Li et al., 2018; Matsuo et al., 2017). In healthy adults, HRV has been linked to conditioned pain modulation through PAG-ventromedial prefrontal cortex connectivity, supporting overlap between autonomic and descending pain-control systems (Makovac et al., 2021). However, these studies did not test whether altered brain connectivity explains resting BP-pain associations or attenuation/reversal of BP-related hypoalgesia in chronic pain.

Hypothalamic–pituitary–adrenal (HPA)-axis and stress-response findings provide another context for altered BP-pain coupling in chronic pain. HPA-axis function is altered in some chronic pain conditions, including changes in basal cortisol, diurnal cortisol secretion, and stress-evoked cortisol responses (Beiner et al., 2023; Woda et al., 2016; Griep et al., 1998). A recent systematic review and meta-analysis found that higher experimental pain sensitivity in chronic primary pain was associated with higher basal cortisol, with heterogeneous evidence across stress markers and pain measures (Vyverman et al., 2026). Stress can also reduce pain sensitivity in some BP-related hypoalgesia studies. In normotensive adults, baseline and post-stress BP were related to thermal pain tolerance, but stress-induced analgesia was limited to women with parental hypertension and lower resting BP (Bragdon et al., 1997). In normotensive and hypertensive adults, arithmetic stress increased dental pain thresholds, with a significant effect in hypertensive participants, although BP immediately before pain testing did not explain the change (Guasti et al., 1995). Thus, stress-related analgesia and chronic-pain HPA changes overlap conceptually with BP-pain regulation, but they have mostly been studied separately from BP-related hypoalgesia in chronic pain.

Cardiac interoception has been reported as reduced, unchanged, or increased in CLBP and fibromyalgia, with results differing across heartbeat counting, heartbeat detection/discrimination, and self-reported interoceptive measures (Todd et al., 2024; Grabli et al., 2022; Rost et al., 2017; Duschek et al., 2017). A meta-analysis found lower interoceptive accuracy but greater self-reported interoceptive sensibility across chronic pain populations, with very low certainty of evidence (Horsburgh et al., 2024). Thus, chronic pain may alter how cardiac signals are detected or appraised, but current studies have not tested whether these interoceptive differences change the inverse association between BP and experimental pain.

Arterial stiffness may also be relevant because stiffer carotid arteries can reduce baroreceptor stretch and impair baroreflex sensitivity (Sun, 2015). Women with fibromyalgia have shown higher brachial-ankle pulse-wave velocity (Lee et al., 2011), higher augmentation index without differences in regional pulse-wave velocity (Kim et al., 2010), and greater carotid arterial stiffness (Kim et al., 2021). Larger cohort studies have linked a greater number of chronic pain sites with higher arterial stiffness (Tian et al., 2024) and chronic widespread musculoskeletal pain with higher carotid-femoral pulse-wave velocity (Naeini et al., 2025). These findings suggest that vascular stiffness may contribute to altered cardiovascular-pain regulation in chronic pain.

4. Effects of antihypertensive drugs on pain and nociception

Antihypertensive drugs can modify pain through mechanisms beyond BP reduction. In hypertensive patients, enalapril, an angiotensin-converting enzyme (ACE) inhibitor, reduced dental pain threshold and tolerance toward values observed in normotensive controls (Guasti et al., 1998). In a randomized crossover study, both enalapril and losartan, an angiotensin II type 1 receptor blocker, increased dental pain sensitivity in hypertensive patients; this effect persisted after adjustment for 24-h mean BP, indicating that BP reduction alone did not account for the change in pain perception (Guasti et al., 2002b). ACE regulates angiotensin II formation and metabolizes pain-related peptides, including bradykinin, substance P, and endogenous opioid peptides (Bhilare et al., 2024).

Adrenergic drugs can affect both cardiovascular regulation and pain. Alpha-2 adrenergic agonists, including clonidine, have analgesic effects and are used clinically in pain management as well as hypertension treatment (Neil, 2011; Giovannoni et al., 2009). In CLBP, alpha-2 adrenergic blockade with yohimbine altered some pain responses but did not eliminate BP-related hypoalgesia across all measures (Bruehl et al., 2008; Chung et al., 2008a; Chung et al., 2008b). Beta-adrenergic blockade has been tested in pain studies. In TMD, propranolol did not significantly reduce mean facial pain index compared with placebo, but more participants receiving propranolol achieved at least 30% or 50% reduction in facial pain index by week 9 (Tchivileva et al., 2020). In healthy men, propranolol reduced BP and increased HRV but did not alter pressure pain thresholds, temporal summation, conditioned pain modulation, or offset analgesia (Petersen et al., 2018). Animal hypertension studies show adrenergic involvement. SHR hypoalgesia was reported as reversible by propranolol, and SHR showed enhanced clonidine analgesia that was blocked by yohimbine (Marwaha, 1984; Saavedra, 1981b). Overall, medication effects on pain cannot be interpreted as BP-lowering effects alone when the same drugs also act on nociceptive signaling systems.

Clinical studies show that antihypertensive drug class can be associated with pain outcomes, but the evidence comes from conditions with different mechanisms. In 873 individuals with symptomatic hip or knee osteoarthritis and hypertension who were taking antihypertensive medication, beta-blocker use was associated with lower WOMAC pain scores, lower odds of at least moderate joint pain, and lower opioid and analgesic use; alpha-blockers and other antihypertensive classes were not associated with pain (Valdes et al., 2017). In a large propensity-matched primary-care cohort, new beta-blocker prescriptions were associated with lower risk of later knee osteoarthritis, knee pain, hip pain, and combined lower-limb osteoarthritis or pain consultations (Nakafero et al., 2021). However, another Osteoarthritis Initiative analysis found no evidence that beta-blocker use reduced knee pain severity, widespread joint pain, or analgesic use among participants with symptomatic knee osteoarthritis (Zhou et al., 2020). In 490 knee osteoarthritis patients receiving antihypertensive treatment, calcium channel blocker use was associated with higher WOMAC pain scores, higher knee replacement rates, and smaller joint-space width than several other antihypertensive drug classes (Li et al., 2021).

Headache outcomes require separate consideration because antihypertensive effects may depend on headache-specific vascular and neural mechanisms. In a meta-analysis of 94 randomized placebo-controlled trials, thiazides, beta-blockers, ACE inhibitors, and angiotensin II receptor antagonists reduced headache reports compared with placebo (Law et al., 2005). A later systematic review of randomized trials found that antihypertensive drugs reduced headache overall, but the effect differed by drug class: beta-blockers showed greater headache reduction, whereas calcium channel blockers did not reduce headache compared with placebo; drug-class effects on headache were unrelated to mean systolic BP reduction (Webb and Rothwell, 2012).

ACE inhibitor exposure has been examined in complex regional pain syndrome, a post-injury pain condition with inflammatory, vascular, and autonomic features. In a population-based case-control study, current ACE inhibitor use was associated with higher odds of complex regional pain syndrome onset, with stronger associations at longer duration and higher dose (de Mos et al., 2009). A distal-radius fracture study similarly identified ACE inhibitor use as an independent predictor of complex regional pain syndrome after nonoperative fracture management (Kaya et al., 2025). A recent randomized trial also reported that losartan reduced paclitaxel-induced peripheral neuropathy and pain scores in breast cancer patients, but this finding comes from a cancer-treatment context and should not be generalized to BP-related hypoalgesia (Mahmoud et al., 2026).

Antihypertensive drugs can affect pain, but not in a way that can be explained simply by lowering BP. The direction of the effect differs by drug class and pain condition, which supports involvement of drug-specific actions on adrenergic, renin-angiotensin, vascular, inflammatory, or sensory pathways. These studies are useful for showing that medication exposure is a major confounder in BP-pain research, but they do not establish a general analgesic or hyperalgesic effect of antihypertensive treatment.

5. Conclusion and future directions

The reviewed evidence argues against a single BP-driven explanation for BP-pain associations. Reduced pain sensitivity can be observed before sustained hypertension, within normotensive BP ranges, and after hypertension is established. Acute baroreceptor activation can inhibit nociception, but hypertension is often accompanied by reduced baroreflex sensitivity, vascular stiffening, sensory changes, and neurohumoral alterations. In chronic pain populations, the relationship differs further. Cardiovascular input may no longer be inhibitory and, for temporal summation or baroreceptor stimulation, may be associated with greater pain sensitivity. The four states organize differences in the literature, but they should not be interpreted as a sequence through which individuals necessarily progress.

Several factors can affect BP-pain associations independently of BP level. Atherosclerosis, heart failure, obesity, diabetes, kidney disease, sleep apnea, menopause-related vascular changes, and arterial stiffness can alter autonomic or baroreflex function. Medications are also major confounders because analgesics and antihypertensive drugs act on shared adrenergic, opioid, prostaglandin, and renin-angiotensin pathways. A medication effect on both BP and pain therefore does not show that BP change caused the pain change.

As summarized in Table 2, the main gaps are limited longitudinal within-person evidence, few direct tests of proposed mechanisms, inconsistent control of comorbidities and medication exposure, and limited separation of BP-related effects from receptor- or drug-specific effects on pain. Future studies should test this framework longitudinally. Validation would require repeated assessment of individuals with familial hypertension risk, normotensive individuals without familial risk, individuals with established hypertension, individuals with chronic pain without hypertension, and individuals with both chronic pain and hypertension. Key measures should include ambulatory BP, experimental and clinical pain, temporal summation, conditioned pain modulation, baroreflex sensitivity, HRV, arterial stiffness, sensory function, comorbidities, and medication exposure. Pharmacological studies should compare drugs that produce similar BP reductions through different molecular targets to separate BP-lowering effects from direct actions on nociceptive pathways.

Table 2.

Main gaps in the literature on cardiovascular–nociceptive coupling.

Area	Main gap
Longitudinal course	The four states are inferred mainly from different study populations. Few studies have measured BP and pain repeatedly in the same individuals, so it remains unclear whether BP-pain associations change with hypertension development, chronic pain onset, or pain resolution (de la Coba et al., 2018b; Chen et al., 2025; Taylor et al., 2025; Campbell et al., 2002).
Direction of the association	Lower pain sensitivity has been linked prospectively with later higher BP, and chronic pain has been linked with later hypertension, but causal direction has not been established (Qin et al., 2026; Chen et al., 2025; Taylor et al., 2025; Campbell et al., 2002).
BP measurement	Studies use clinic BP, resting laboratory BP, ambulatory BP, and different hypertension definitions. Few combine 24-h BP with experimental pain testing, limiting comparisons across studies (Olsen et al., 2013a; Olsen et al., 2013b; Guasti et al., 2002a; Guasti et al., 1999).
Pain measures	BP-pain associations differ across threshold, tolerance, pain ratings, temporal summation, conditioned pain modulation, and reflex measures. Experimental pain sensitivity also does not necessarily reflect clinical pain intensity (de la Coba et al., 2018a; Cruz et al., 2026; Chung et al., 2008a).
Mechanism testing	Baroreflex, autonomic, opioid, sensory, vascular, cortical, and renin-angiotensin mechanisms have usually been tested separately. Some studies measure cardiovascular regulation and pain outcomes in the same participants, but formal tests of whether these mechanisms mediate BP-pain associations are rare (Venezia et al., 2024; Guasti et al., 2002a; France et al., 2005; Edwards et al., 2008c; Ring et al., 2007; Ring et al., 2008; Chung et al., 2008b; Iwakuma et al., 2025).
Chronic pain mechanisms	CLBP has been studied with BP, baroreflex sensitivity, temporal summation, adrenergic blockade, opioid blockade, and baroreceptor stimulation. Comparable mechanistic studies are more limited in fibromyalgia, TMD, chronic knee pain, and visceral pain conditions (Bruehl et al., 2008; Bruehl et al., 2002; Brody et al., 1997; Venezia et al., 2024; de la Coba et al., 2018a; Cruz et al., 2026; Chung et al., 2008a; Chung et al., 2008b; Iwakuma et al., 2025).
Sex and BP status	Sex- and hypertension-dependent differences have been reported, but many studies are not powered to test these interactions directly (Olsen et al., 2013a; Cruz et al., 2026; Ditto et al., 1997; Bragdon et al., 1997).
Comorbidity and confounding	Obesity, diabetes, vascular disease, kidney disease, sleep apnea, menopause-related vascular changes, physical activity, psychological factors, and medication use can affect both BP and pain, but they are not measured consistently across studies (Okada et al., 2012; Philbois et al., 2024; Subhashri et al., 2021; Barnes et al., 2012; Kaur et al., 2016; Skrapari et al., 2006; Carlson et al., 1996; Chapleau et al., 1995; Tracy et al., 2016; Schroeder et al., 2003; Guasti et al., 1998; Guasti et al., 2002b; Bhilare et al., 2024; Neil, 2011; Giovannoni et al., 2009; Petersen et al., 2018; Marwaha, 1984; Saavedra, 1981b; Valdes et al., 2017; Nakafero et al., 2021; Zhou et al., 2020; Li et al., 2021; Law et al., 2005; Webb and Rothwell, 2012).
Antihypertensive treatment	Antihypertensive drugs may affect pain through BP lowering and through direct actions on adrenergic, renin-angiotensin, vascular, inflammatory, or peptide pathways. Few studies compare drugs that produce similar BP reductions through different targets (Guasti et al., 1998; Guasti et al., 2002b; Bhilare et al., 2024; Neil, 2011; Giovannoni et al., 2009; Valdes et al., 2017; Zhou et al., 2020; Li et al., 2021; Law et al., 2005; Webb and Rothwell, 2012).
Age and hypertension duration	Age and hypertension duration are rarely separated from arterial stiffness, atherosclerosis, metabolic disease, and other cardiovascular changes that may alter baroreflex or sensory function (Okada et al., 2012; Kaur et al., 2016; Skrapari et al., 2006; Carlson et al., 1996; Chapleau et al., 1995).
Animal-to-human translation	SHR and induced hypertension models do not show the same pain responses, and results vary by strain, hypertension model, BP-lowering manipulation, and nociceptive assay (Afolabi et al., 2013; Zamir et al., 1980; Donertas-Ayaz et al., 2026; Taylor et al., 2001; Marwaha, 1984; Saavedra, 1981b).
Clinical relevance	It is not known whether BP-pain coupling predicts clinical pain severity, treatment response, medication tolerability, or cardiovascular outcomes. Current evidence does not support selecting analgesic or antihypertensive therapy based on BP-pain associations alone (Tchivileva et al., 2020; Valdes et al., 2017; Zhou et al., 2020; Li et al., 2021).

Abbreviations: BP, blood pressure; CLBP, chronic low back pain; SHR, spontaneously hypertensive rat; TMD, temporomandibular disorder.

Declaration of Generative AI and AI-Assisted Technologies

During the preparation of this work, the authors used OpenAI ChatGPT to assist with language refinement, organization, and editing for clarity. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the article.

CRediT authorship contribution statement

Basak Donertas-Ayaz: Writing – original draft, Methodology, Investigation, Data curation, Conceptualization. Carlos J. Cruz: Writing – review & editing, Data curation, Visualization. John K. Neubert: Writing – review & editing. Robert M. Caudle: Writing – review & editing, Funding acquisition.

Funding

This work was supported by the Facial Pain Research Foundation to Robert M. Caudle.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability

No data was used for the research described in the article.