Heart Rate Variability and Pain: A Systematic Review

Background and Objective: Heart rate variability (HRV) as an index of the autonomic nervous system appears to be related to reactivity to experimental pain stimuli. HRV could better explain the contributions of sympathetic and parasympathetic activity response to nociceptive stimulation. The aim of this study was to systematically review and synthesize the current evidence on HRV in relation to the experience of pain in experimental tasks. Databases and Data Treatment: Studies indexed in the PubMed, PsycINFO, MEDLINE, WebOfScience, and Scopus databases were reviewed for eligibility. Studies on the autonomic response (i.e., HRV) to experimentally induced pain in healthy adults were included. Different methods of pain induction were considered (e.g., thermal, pressure, and electrical). Data were synthesized considering the association between HRV and both pain induction and subjective measures of pain. Results: Seventy-one studies were included. The results underline significant change in both the sympathetic and parasympathetic autonomic nervous systems during the painful stimulation independent of the pain induction method. The autonomic reaction to pain could be affected by several factors, such as sex, age, body mass index, breathing patterns, the intensity of the stimulation, and the affective state. Moreover, an association between the autonomic nervous system and the subjective experience of pain was found. Higher parasympathetic activity was associated with better self-regulation capacities and, accordingly, a higher pain inhibition capacity. Conclusions: HRV appears to be a helpful marker to evaluate nociceptive response in experimentally induced pain. Future studies are also needed in clinical samples to understand better the interindividual changes of autonomic response due to pain stimuli.


Introduction
Pain is defined as an aversive sensory and emotional experience typically caused by (or resembling that caused by) actual or potential tissue injury [1,2]. Accordingly, it is highlighted that (1) pain is always a subjective experience influenced by biological, psychological, and social factors (differently from nociception) and should be accepted and respected as such, (2) individuals learn the concept of pain through their life experiences, (3) there are several behaviors to communicate it aside from verbal description, and (4) it has an adaptive role, but it can have adverse effects on the individual's well-being [1].
Depending on the duration, pain can be acute or chronic [3]. While acute pain is considered an adaptive signal that prevents danger and guarantees survival [4], chronic (or persistent) pain is defined as having persisted for at least 3 months [4], and it usually matches chronic diseases and non-treated medical pathologies, affecting the individual's quality of life [5].
Furthermore, pain can be defined as "somatic" when it involves the skin, subcutaneous tissues, bones, muscles, blood vessels, or connective tissues or "visceral" when it affects the Research Strategies A systematic review was conducted by searching articles published in peer-reviewed journals using the PubMed, PsycINFO, MEDLINE, WebOfScience, and Scopus databases. The last research was conducted on 5 January 2021.
The search was restricted to publications published since 1996 (i.e., years of publication of the first guidelines on the standards of measurements, physiological interpretation, and clinical use of HRV (Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, hereafter referred to as Task Force, 1996). Articles focused on analyzing the association between pain and HRV were considered for inclusion. The search strategy used the following keywords: "pain"; "pain sensitivity"; "Heart Rate Variability"; "HRV"; and "IBI". The reference list of all included studies was screened for additional study citations.
Eligibility Criteria The list of potential articles produced by systematic research was screened for eligibility. Studies that included one or more methods of experimental induction of pain and the measurement of HRV were selected. Studies that adopted at least one measure of subjective pain perception (e.g., pain thresholds) were judged as eligible. Studies that included participants with medical conditions which could potentially influence this relationship were excluded (e.g., chronic pain disorder, hypertension, and cancer survivors).
Study Selection The initial search identified 6559 results imported to the Mendeley database. The screening was performed in two phases. After removing duplicates, the initial eligibility assessment was based on titles and abstracts. Two authors (G.T. and G.F.) independently examined the full texts to confirm the suitability of the studies for the following qualitative synthesis. Then, the full texts that fit the inclusion criteria were screened for the eligibility criteria. Finally, 71 studies were included in the review. During the whole process, disagreements were resolved by consulting a supervisor (M.C.). The selection processes are reported in Figure 1.
Data Collection and Quality Assessment According to the PICOS approach [30], the following information was extracted from each selected study: (1) author(s) and year of publication, (2) country, (3) sample size and female and male distribution, (4) age of participants, (5) method of pain induction, (6) pain assessment, (7) the main focus of the study, (8) derived HRV measures, and (9) findings. The data are reported in Table 1.

Data Collection and Quality Assessment
According to the PICOS approach [30], the following information was extracted each selected study: (1) author(s) and year of publication, (2) country, (3) sample siz female and male distribution, (4) age of participants, (5) method of pain induction, (6 assessment, (7) the main focus of the study, (8) derived HRV measures, and (9) find The data are reported in Table 1.   The relationship between anxiety sensitivity and autonomic responses during pain CVI CSI CVI: significantly higher during CPT in both the low-AS and the high-AS group; low group also higher in recovery compared with rest; during recovery, significantly higher in low-As group than in the high-As group. Subjective pain higher in high-As group than low-As group post-CPT.
Evans et al., The impact of the heart rate variability on the relationship between self-compassion and pain HF Self-compassion was associated with increased pain when HF was lower; self-compassion was associated with lower pain when HF was higher.
HRV Measurement In all studies, HRV measurement was conducted by a continuous ECG recording, which lasted at least 5 min as recommended by the guidelines of the European Society of Cardiology and the North American society [99]. Heart rate variability was evaluated considering time domain analyses, frequency domain analyses, or both (see Table 1).
Although no correlations between pain and HRV were reported [53,65,80], other authors underlined an association [70,96]. Both sympathetic and parasympathetic activity changes due to the heat stimuli were reported. On the one hand, an increase in sympathetic activity [48] expressed by the LF/HF ratio [36,47,54] and LF [47] and a decrease in RR [47], lnSDNN [71], and HF [95] was evidenced. On the other hand, a parasympathetic increase was found [74], indexed by the increase in HF [33] and RMSSD [85] and the decrease in lnLF [71]. Aslaksen and Flaten [37] showed that placebo administration before painful exposure reduced the LF/HF ratio after the painful heat stimulation, suggesting that placebo administration can affect the pain experience, reducing physiological stress [37].
On the contrary, other authors showed predominant parasympathetic activity in responses to a painful pressure stimulus [38,49,73]. Finally, two studies reported no relationship between pressure pain and the HRV parameters [42,65].
Four studies adopted pinprick stimuli in order to induce experimental mechanical pain, using a set of probes [65] or a von Frey filament [72][73][74]83]. A relationship between parasympathetic activity and pain perception was evidenced.
Electrical Stimuli (N = 9) Electrical stimulation was induced via electrical stimulators [35,46,49,56,64,80]. In two studies [89,90], sural nerve stimulation was delivered via solid gel surface electrodes. Courtois et al. [49] found an increase in RMSSD during pain while the participants practiced slow deep breathing. Ghione et al. [59] induced pain by exposing participants to an electromagnetic field. The LF component increased during both sham and magnetic exposure, while the HF component remained constant during real exposure but increased during the sham condition. A reduction in HRV was found in two studies [46,64]. Similarly, sympathetic activation increased when the pain was elicited both during mental arithmetic stress and at rest [89,90]. Piovesan et al. [80] registered an increase in the HF components. Finally, the authors of [56] found no relationship between pain and HRV.
Injection of Hypertonic Saline Solutions (N = 5) A sterile hypertonic saline solution (5%) was injected to induce experimental masseter muscle pain [39,40] and deep and superficial pain [44], and a hypertonic saline solution (7%) [55,66] was injected to induce experimental muscle pain. Two studies found an increase in sympathetic activity during the infusion [55] in both deep and superficial pain [44]. However, parasympathetic parameters such as RMSSD and HF were higher when the only pain stimulation was the solution injection, rather than a condition in which muscle pain was associated with a CPT [39] or with a PASAT [40]. Only one study found no correlation between pain and HRV [66].
Visceral Pain: Esophageal Balloon Distension (N = 2) Two studies focused on visceral pain [8,76] while adopting esophageal painful balloon distension. Interestingly, one study [8] found that the participants that were classified as "neurotic-introvert" had an increased parasympathetic activity expressed by CVCna in response to pain, while participants classified as "extrovert-emotionally stable" had a high resting CVCna and withdrawal from it during pain stimulation. Others [76] found that both the sympathetic and parasympathetic branches were activated by visceral and somatic pain.
Bed of Nails (N = 1) One study elicited a painful sensation by letting participants lie on a bed of nails. Stimulation consisted of a soft cotton fabric case filled with a foam rubber rectangle [75]. The authors found an increase in parasympathetic activity expressed by HF when participants were lying on the bed of nails.
Relationship between Subjective Pain Measures and HRV Subjective Pain Measurement Subjective measures of pain perception, such as pain intensity, pain unpleasantness, pain thresholds, and pain tolerance, were assessed (see Table 1).
Pain thresholds were assessed by adopting different methods. Regarding heat stimuli, pain thresholds were assessed by increasing the temperature of the device until the subject perceived the stimulus as painful [24,29,45,58,63,65,[72][73][74]85,88,91,[94][95][96]98] or considered the temperature estimated as painful at a specific point on a VAS. Then, the results were averaged for the number of trials [13,47,53,77] with the calculated thresholds being the average temperature (in • C) at which each participant indicated experiencing noticeable pain and moderate pain during each of the three exposures. Cold pain thresholds were identified as the cold temperature at which the subject reported the stimulus as painful [87,88,91,98] or the total time from immersion until a participant verbally reported pain [67]. Pressure pain thresholds were reached when the participant's sensation changed from pressure (evoked via a pressure algometer) to pain, which was averaged for a specific number of trials [34,42,65,76,78,79,81,82,91]. The pain thresholds for the electrical stimulation were obtained when the subject reported a pain sensation evoked by the current [35,46,89,90]. The first pain sensation evoked by the balloon distension was defined as the visceral pain threshold [8,76].
Relationship with HRV The relationship between the subjective pain measures and HRV was reported [24,52,81]. Two studies highlighted a positive relationship between heat pain thresholds and resting LF [13,24]. A higher LF-HRV was positively correlated to a higher temperature at which the subject started to perceive the heat stimulus as painful. Conversely, pain unpleasantness was lower in higher resting LF-HRV [13]. Pain tolerance was associated with higher parasympathetic activity expressed by the HRV (i.e., increase in HF-HRV and decrease in the LF/HF HRV ratio) [52,82].
Recent studies found a negative correlation between parasympathetic activity and the pain intensity ratings [57,68,92]. Accordingly, slow deep breathing and HR biofeedback [45] could reduce both the pain intensity and sympathetic activity expressed by a higher SDNN [45]. Furthermore, placebo analgesia produced an increase in the time domains of HRV and greater pain relief [50]. Pain intensity was also negatively correlated with HRV when the participants had greater parasympathetic activity during the recovery phase [51]. Parasympathetic activity correlated with a more efficient pain modulation capacity [72][73][74].
No correlation between subjective pain measures and HRV was reported or found by many studies (see Table 1).

Discussion
The main aim of this study was to investigate the relationship between pain and heart rate variability, summarizing the results of experimental studies that induced pain in healthy adult samples. In recent years, an increasing number of studies have adopted HRV as a physiological index of the organism's ability to provide a flexible response to stress, such as pain. The Vagal Tank Theory [100], relying on the Neurovisceral Integration Model [17], highlights the role of the vagus nerve in the control of cardiac activity and in goal-directed behavior, as well as in the individual self-regulation ability [100]. The Neurovisceral Integration Model [17,19] assumes that the goal-directed behavior and the self-regulation ability of an organism are structurally and functionally supported by the Central Autonomic Network [18], a complex network of brain structures whose primary output is the cardiac vagal control expressed by HRV. Accordingly, our study confirms a relationship between the autonomic nervous system indexed by HRV and the pain response to nociceptive stimulation. Our findings can be reported in two themes: (1) how the autonomic nervous system reacts to pain and (2) how the autonomic nervous system is associated with subjective pain perception.
For the first issue, generally, the studies included in the systematic review reported a significant change in HRV during pain induction. The main finding about the autonomic response to pain is an increase in sympathetic activity (e.g., [36,54]), according to the previous review conducted by Koenig et al. [14]. Evidence suggests that this response is independent of the adopted method of pain induction. Burton et al. [44] found that both deep and cutaneous pain elicit an increase in the LF/HF ratio, in addition to Chouchou et al. [47] underlining a sympathetic activation to heat pain during sleep. The same sympathetic increase was found in response to cold pain, (e.g., [39,60]).
Nevertheless, different circumstances can increase the vagal activity expressed by the parasympathetic components of HRV [45]. For example, different techniques of breathing, such as slow deep breathing [49] or meditation, could reduce vagal withdrawal during pain. Adler-Neal et al. [33] focused on the autonomic responses to pain while mindfulness meditation or sham meditation were practiced. They found a parasympathetic increase during both meditation techniques, possibly due to the slow breathing. Similar results were obtained by Chalaye et al. [45], where slow deep breathing patterns increased vagal activity compared with normal breathing. Cotton et al. [48] found that yoga practitioners for at least 6 years had the same parasympathetic activity during a warm stimulation and a painful one compared with the control group, which reported a withdrawal of vagal activity during the painful stimulation, despite similar pain ratings.
Another aspect that could influence an autonomic response to pain is a drug or medication assumption. Some studies reported that the administration of substances with analgesic effects, such as propranolol [78] or clonidine [73], can increase parasympathetic activity during pain. However, a placebo [50] also generates a similar response. The findings suggest that placebo analgesia, induced administering a placebo, can increase HRV and induce pain relief [37,50], consistent with the Neurovisceral Integration Model [19,25]. Furthermore, autonomic responses to the same painful stimulation can differ depending on the affective states [32] or the empathetic or unempathetic context [53,54].
Another result evidenced by the review is a parasympathetic activation during painful stimulations. Activation of both the sympathetic and parasympathetic branches of the autonomic nervous system appears to be counterintuitive, but the Vagal Tank Theory [100] can explain it. The autonomic nervous system's reaction to painful stimulation is complex. A large or small vagal withdrawal depends on the level of activity required by the situation and how much top-down executive processing is needed to face the situation [100]. Moreover, the autonomic reaction to pain could be affected by several factors, such as ethnicity, sex, age, body mass index, breathing patterns, the intensity of the stimulation, or the affective state that could influence results [24].
Regarding the second issue, an association between the autonomic nervous system and the subjective experience of pain was found [68]. Higher parasympathetic activity is associated with better self-regulation capacities and, accordingly, a higher pain inhibition capacity [50,52,68]. In this field, an interesting result was related to self-compassion abilities [68,92] that appear to be associated with high HF and lower pain ratings. Tian et al. [92] explained that self-compassion means to treat oneself with kindness and acceptance, and it seems that this ability enhances a better bodily control over pain-related arousal and a better subjective pain experience [92].
Most studies have underlined that when the parasympathetic component of HRV is high, pain relief or a better management of painful situations (e.g., pain tolerance) occur. The inhibitory vagal effect on pain could be responsible for these results. This hypothesis is in line with the Neurovisceral Integration Model, and it is supported by the strong positive relationship between vagal activation and the prefrontal cortex, as highlighted by Perlaki et al. [77]. Finally, Appelhans and Luecken [13] found a negative association between the sympathetic activity expressed by the LF components and pain sensitivity but not between HF and pain. According to the authors, this finding is explicable because LF has a complex association with the arterial baroreflex, a homeostatic mechanism mediated by the autonomic nervous system, whose components also mediate an endogenous pain inhibitory pathway [13]. These results are consistent with a recent study [60] that identified a three-way relationship between HRV, cortical regions underpinning pain processing, and subjective pain experience. In particular, the connectivity between the periaqueductal gray (PAG) [18,25] and the ventromedial prefrontal cortex (vmPFC) at rest was associated with high LF during painful stimulation and lower pain ratings. The PAG receives nociceptive inputs and is involved in descending nociceptive modulation [18,60].
Despite the important update to the study of Koenig et al. [14] and the new evidence reported, this review has some limitations. The strict selection criteria excluded works that may contain relevant information about the activity of ANS in response to pain. Many of the studies included were conducted by the same group of authors, and this could have introduced biases influenced by the theoretical background of those who led the study. However, the selected studies may well represent the state of the knowledge. Moreover, the lack of quantitative analysis (i.e., meta-analysis) lowers the strength of our inferences by not furnishing an effect size for the studies. Another limitation could be indirectly linked to the publication bias. The choice to include only academic articles published in peer-reviewed journals may have limited the selection to only those studies that have obtained results in line with the literature. As a consequence, the results may overestimate this relationship. Moreover, the choice to select only studies published in English could have led to the elimination of studies conducted on other populations and written in different languages, further limiting the generalizability of the results. Finally, the lack of an unambiguous subjective measure of pain sensitivity makes the results heterogeneous. Further studies could develop an instrument to measure pain sensitivity and better define constructs related to pain perception. For example, it could be better to assess pain intensity separately from pain unpleasantness in order to assess the sensory and emotional components more precisely and relate how each component interacts with autonomic activity. Moreover, the role of cognitive functions such as inhibition could be evaluated, considering its association with both HRV and pain.

Conclusions
According to our results, we can conclude that HRV is a good measure of autonomic reactivity to nociceptive stimulation. Studies that have investigated changes in HRV in response to pain reported changes in autonomic response, both in sympathetic and parasympathetic branches. Our summarized evidence may be helpful for further research and have important clinical implications. Since HRV appears to be impaired in several chronic pain conditions that can worsen the quality of life, future researchers can take advantage of the use of HRV. According to our results, many practices (e.g., yoga and mindfulness) or drugs can increase vagal activity. For this reason, HRV can be a reliable index to assess the efficacy of treatments on pain management in clinical populations.
Moreover, it could be tested if techniques of control over HRV such as HRV biofeedback, which were demonstrated to be effective in improving cognitive functions and stress management [101], can increase pain relief or pain management in clinical samples. Further studies are needed to overcome the limitations and also better understand this relationship in the large variety of health conditions associated both with ANS changes and pain (i.e., chronic pain).