Heart Rate Variability and Pain: A Systematic Review

1Pain is defined as an aversive sensory and emotional experience typically caused by (or resembling that caused by) actual or potential tissue injury. 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.

2Depending on the duration, pain can be acute or chronic. While acute pain is considered an adaptive signal that prevents danger and guarantees survival, chronic (or persistent) pain is defined as having persisted for at least 3 months, and it usually matches chronic diseases and non-treated medical pathologies, affecting the individual’s quality of life.

3Furthermore, 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 internal organs or the linings of the body cavities. The former can arise from thermal, mechanical, and chemical stimuli, while the latter results from distension or prolonged contraction of the smooth muscle wall of the structure. Both types can be elicited in experimental settings (e.g.,). Currently, self-reporting measures are the most employed method for assessing experimentally induced pain. For example, pain intensity can be measured by adopting visual analogue scales (VASs), numerical rating scales (NRSs), and verbal rating scales (VRSs).

4In acute pain, somatic and visceral noxious stimuli excite the nociceptors and are converted into nerve impulses in order to allow the brain to read them and produce the conscious pain sensation. However, nociception is only a component of the pain experience. In fact, pain sensitivity can be affected by many factors, such as mood, affective regulation strategies, and mental disorders. Pain is a stressor, and it has been considered a specific emotion that reflects homeostatic behavioral drive. The affective-motivational and the cognitive-evaluative components enhance the individual’s organization of emotional and behavioral responses.

5A comprehensive framework to investigate how organisms respond and adapt themselves to diverse types of stressors, including pain, is the Neurovisceral Integration Model (NVIM). The authors of the NVIM proposed a core set of neural structures, referred to as the Central Autonomic Network (CAN), which provides the ability to continuously assess and prepare the organism for an appropriate response. In the NVIM, heart rate variability (HRV) has been proposed as an index of flexible and adaptive regulation of the nervous system to organize a homeostatic response to environmental requests and which is related to cognitive functions. HRV represents the change in the time interval between successive heartbeats. It is considered a sensitive, non-invasive measurement of autonomic input to the heart. It might provide measures of autonomic nervous system activity in both sympathetic (SNS) and parasympathetic (PNS) branches. Since systems involved in autonomic control (such as periaqueductal gray, the insular and anterior cingulate cortices, amygdala, prefrontal cortex, and nucleus of the solitary tract) are strictly connected with those involved in pain perception, HRV can be considered a reliable index of ANS reactivity to nociceptive stimulation.

6Furthermore, HRV appears to be an index of baroreflex activity, one of the body’s homeostatic mechanisms that maintains the blood pressure at a constant level. Patients with chronic pain show a reduction in HRV and baroreflex sensibility due to changes in efferent sympathetic and parasympathetic cardiac activity, which shift the balance to a sympathetic tone prevalence related to catecholamine release.

7HRV is also related to endogenous pain modulation (EPM), a relevant factor in chronic pain development and maintenance. In fact, EPM depends on the excitation–inhibition balance, and HRV can be used as an index of the inhibitory processes involved in these neurovisceral networks. Furthermore, EPM and HRV are connected in both the presence and absence of chronic pain. Accordingly, HRV has several advantages in studies investigating the physiological response to nociceptive stimulation.

8Several studies focused on pain sensitivity adopted HRV as a measure of autonomic responses. A systematic review on this topic was conducted by Koenig et al. in 2014. The authors identified 20 studies showing an increase in sympathetic baroreflex activity and a decrease in vagal parasympathetic activity, as reflected by changes in the frequency domain measures of HRV. However, there has been an increasing number of studies about this relationship in recent years. Therefore, analyzing the new studies can be relevant. This paper aims to systematically summarize the achieved results on the relationship between pain and HRV.

9The review process was conducted according to the PRISMA Statement to systematically analyze studies on the relationships between HRV and pain within healthy adult samples. The protocol has not been registered.

10Research Strategies

11A 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.

12The 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.

13Eligibility Criteria

14The 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).

15Study Selection

16The 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.

17Data Collection and Quality Assessment

18According to the PICOS approach, 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.

19Demographic Characteristics of the Sample

20The selected studies were conducted from 2004 to 2020, including a total sample of 6364 participants with percentages of 55.7% females and 44.3% males. In three studies, the percentage or the number of women and men was not reported. Some studies adopted a sample that included exclusively female or male participants. The average age of the participants ranged from 18.98 to 73.44 years. The largest range was 18–84.

21The selected studies were conducted in Europe (N = 38), the United States (N = 12), Israel (N = 5), Canada (N = 5), Australia (N = 4), India (N=1), Taiwan (N = 1), Brazil (N = 1), China (N = 2), Japan (N = 1), and Korea (N = 1). Except for a study conducted by Kim et al. in 2019, all studies were conducted with homogeneous samples for ethnicity and nationality. All studies adopted a cross-sectional design.

22HRV Measurement

23In 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. Heart rate variability was evaluated considering time domain analyses, frequency domain analyses, or both (see Table 1).

24Effects of Different Methods of Pain Induction on HRV

25Thermal Stimuli (N = 51)

26Thermal stimuli (i.e., cold and heat) were the most adopted method of pain induction (e.g.,).

27Cold Pain

28Cold pain was elicited using mostly the cold pressor task, but it was also induced using a cold plate, a thermal aluminum cylinder device, the immersion of a hand or a foot in cold water, facial cooling, thermal stimulation devices, the cold cup test, and holding a plastic bottle with iced water.

29Cold pain stimulation elicited an increase in the parasympathetic components of HRV, such as RMSSD, SDNN, CVI, HF, mean RR, and IBI. Nevertheless, an increase in the sympathetic activity was registered by the reduction in HRV, mean IBI, and mean RR and the increase in the log LF and LF/HF ratio. A study by De Pascalis and Scacchia found a negative correlation between pain and the time domain but not between pain and the frequency domain. Bendixen et al. found only a reduction in vagal measures (RMSSD, HF power; CCV-HF). However, a relationship between cold pain and the HRV parameters was not found in two studies.

30Heat Pain

31Thermal stimulation devices, a laser, an IC thermostat, and the immersion of a hand in hot water were adopted to induce heat stimulation.

32Although no correlations between pain and HRV were reported, other authors underlined an association. Both sympathetic and parasympathetic activity changes due to the heat stimuli were reported. On the one hand, an increase in sympathetic activity expressed by the LF/HF ratio and LF and a decrease in RR, lnSDNN, and HF was evidenced. On the other hand, a parasympathetic increase was found, indexed by the increase in HF and RMSSD and the decrease in lnLF. Aslaksen and Flaten 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.

33Mechanical Stimuli (N = 18)

34Pressure pain was elicited by digital pressure algometers, pressing the nail bed with a spring-loaded device, and inflating a pressure cuff on the lower leg. Some studies found higher sympathetic activity during pain, indexed by the decrease in SDNN and HF and the increase in LF and the LF/HF ratio. On the contrary, other authors showed predominant parasympathetic activity in responses to a painful pressure stimulus. Finally, two studies reported no relationship between pressure pain and the HRV parameters.

35Four studies adopted pinprick stimuli in order to induce experimental mechanical pain, using a set of probes or a von Frey filament. A relationship between parasympathetic activity and pain perception was evidenced.

36Electrical Stimuli (N = 9)

37Electrical stimulation was induced via electrical stimulators. In two studies, sural nerve stimulation was delivered via solid gel surface electrodes. Courtois et al. found an increase in RMSSD during pain while the participants practiced slow deep breathing. Ghione et al. 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. Similarly, sympathetic activation increased when the pain was elicited both during mental arithmetic stress and at rest. Piovesan et al. registered an increase in the HF components. Finally, the authors of found no relationship between pain and HRV.

38Injection of Hypertonic Saline Solutions (N = 5)

39A sterile hypertonic saline solution (5%) was injected to induce experimental masseter muscle pain and deep and superficial pain, and a hypertonic saline solution (7%) was injected to induce experimental muscle pain. Two studies found an increase in sympathetic activity during the infusion in both deep and superficial pain. 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 or with a PASAT. Only one study found no correlation between pain and HRV.

40Visceral Pain: Esophageal Balloon Distension (N = 2)

41Two studies focused on visceral pain while adopting esophageal painful balloon distension. Interestingly, one study 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 found that both the sympathetic and parasympathetic branches were activated by visceral and somatic pain.

42Bed of Nails (N = 1)

43One 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. The authors found an increase in parasympathetic activity expressed by HF when participants were lying on the bed of nails.

44Relationship between Subjective Pain Measures and HRV

45Subjective Pain Measurement

46Subjective measures of pain perception, such as pain intensity, pain unpleasantness, pain thresholds, and pain tolerance, were assessed (see Table 1).

47Pain 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 or considered the temperature estimated as painful at a specific point on a VAS. Then, the results were averaged for the number of trials 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 or the total time from immersion until a participant verbally reported pain. 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. The pain thresholds for the electrical stimulation were obtained when the subject reported a pain sensation evoked by the current. The first pain sensation evoked by the balloon distension was defined as the visceral pain threshold.

48Pain tolerance was assessed by considering when the level of heat, cold, pressure, or visceral pain became unbearable for the participant. Another method to assess cold pain tolerance was calculating the total time in seconds that the participant’s hand was completely submerged in the water.

49Relationship with HRV

50The relationship between the subjective pain measures and HRV was reported. Two studies highlighted a positive relationship between heat pain thresholds and resting LF. 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. 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).

51Recent studies found a negative correlation between parasympathetic activity and the pain intensity ratings. Accordingly, slow deep breathing and HR biofeedback could reduce both the pain intensity and sympathetic activity expressed by a higher SDNN. Furthermore, placebo analgesia produced an increase in the time domains of HRV and greater pain relief. Pain intensity was also negatively correlated with HRV when the participants had greater parasympathetic activity during the recovery phase. Parasympathetic activity correlated with a more efficient pain modulation capacity.

52No correlation between subjective pain measures and HRV was reported or found by many studies (see Table 1).

53The 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, relying on the Neurovisceral Integration Model, 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. The Neurovisceral Integration Model assumes that the goal-directed behavior and the self-regulation ability of an organism are structurally and functionally supported by the Central Autonomic Network, 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.

54For 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.,), according to the previous review conducted by Koenig et al.. Evidence suggests that this response is independent of the adopted method of pain induction. Burton et al. found that both deep and cutaneous pain elicit an increase in the LF/HF ratio, in addition to Chouchou et al. underlining a sympathetic activation to heat pain during sleep. The same sympathetic increase was found in response to cold pain, (e.g.,).

55Nevertheless, different circumstances can increase the vagal activity expressed by the parasympathetic components of HRV. For example, different techniques of breathing, such as slow deep breathing or meditation, could reduce vagal withdrawal during pain. Adler-Neal et al. 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., where slow deep breathing patterns increased vagal activity compared with normal breathing. Cotton et al. 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.

56Another 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 or clonidine, can increase parasympathetic activity during pain. However, a placebo also generates a similar response. The findings suggest that placebo analgesia, induced administering a placebo, can increase HRV and induce pain relief, consistent with the Neurovisceral Integration Model. Furthermore, autonomic responses to the same painful stimulation can differ depending on the affective states or the empathetic or unempathetic context.

57Another 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 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. 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.

58Regarding the second issue, an association between the autonomic nervous system and the subjective experience of pain was found. Higher parasympathetic activity is associated with better self-regulation capacities and, accordingly, a higher pain inhibition capacity. In this field, an interesting result was related to self-compassion abilities that appear to be associated with high HF and lower pain ratings. Tian et al. 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.

59Most 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.. Finally, Appelhans and Luecken 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. These results are consistent with a recent study 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) 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.

60Despite the important update to the study of Koenig et al. 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.

61According 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, 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).