Progress in Neuro-Psychopharmacology and Biological Psychiatry
Intranasal oxytocin reduces heart rate variability during a mental arithmetic task: A randomised, double-blind, placebo-controlled cross-over study
Introduction
Chronic neck and shoulder pain (CNSP) affects 30 to 50% of adults (Cote et al., 2009, Manchikanti et al., 2009). There is evidence suggesting that individuals affected by CNSP display an imbalance between the sympathetic and parasympathetic nervous systems (Hallman et al., 2011). Imbalances between the sympathetic and parasympathetic nervous systems can be visualised through heart rate variability (HRV), which refers to the variability in the interval between successive heartbeats. High levels of variability indicate a highly adaptable nervous system that is able to regulate emotional and behavioural responses to threatening internal and external stimuli (Appelhans and Luecken, 2006, Friedman and Thayer, 1998). In contrast, low levels of variability are associated with a plethora of poor long-term health outcomes, such as cardiovascular disease and mood disorders (Appelhans and Luecken, 2006), and chronic pain (Koenig et al., 2016, Tracy et al., 2016). Persons with chronic pain have reduced HRV, compared to persons without chronic pain, particularly with respect to high-frequency HRV (HF-HRV; Koenig et al., 2016, Tracy et al., 2016). Therefore, reducing autonomic dysregulation (i.e., improving HRV) in persons with chronic pain is important, as doing so may have widespread implications for the health and wellbeing of these individuals.
When at rest, the parasympathetic nervous system exerts tonic inhibitory dominance over the sympathetic nervous system. Parasympathetic modulation of the heart is faster acting than sympathetic modulation (Levy, 1997), with the majority of parasympathetic control exerted via the vagus nerve (Porges et al., 1994). Therefore, HF-HRV has been proposed as a surrogate measure of vagal activity (Koenig et al., 2015). Reductions in vagally-mediated HRV have been associated with excessive worry, difficulties in emotion regulation, psychiatric illness, and cardiovascular disease (e.g., Chalmers et al., 2014, Chalmers et al., 2016, Geisler et al., 2013, Thayer et al., 2010, Williams et al., 2015).
Oxytocin is a neuropeptide that has been found to modulate HRV in some non-clinical studies, when administered intranasally and compared with placebo (Kemp et al., 2012, Norman et al., 2011). This nine amino acid neuropeptide is predominantly produced within the nuclei of the hypothalamus (Gimpl and Fahrenholz, 2001). Although oxytocin is more commonly known for binding to oxytocin receptors located in the uterine muscle, causing contractions of the uterine muscles to initiate childbirth (Fuchs et al., 1982), oxytocin can also bind to oxytocin receptors distributed throughout the central nervous system (Gimpl and Fahrenholz, 2001). Consequently, oxytocin binds to receptors in brain regions such as the hypothalamus and amygdala, which are involved in the control of autonomic activity (Benarroch, 2001, Benarroch, 2006). Stimulation of oxytocin neurons has been reported to induce bradycardia, and lead to increases in vagal tone (Higa et al., 2002, Rogers and Hermann, 1986). Furthermore, oxytocin neurons display increased activation during stressful events, thereby serving to alleviate psychophysiological stress responses by lowering heart rate via increased vagal tone (Higa et al., 2002).
Intranasal oxytocin does not only appear to increase HRV at rest in non-clinical samples (Kemp et al., 2012, Norman et al., 2011), it has also been found to increase calmness and reduce anxiety during the socio-evaluative Trier Social Stress Test (Heinrichs et al., 2003). Moreover, neuroimaging studies have shown that intranasal oxytocin restores normal amygdala and prefrontal activity (Labuschagne et al., 2010, Labuschagne et al., 2012), including amygdala connectivity with prefrontal regions (Dodhia et al., 2014, Gorka et al., 2015) in persons with social anxiety. These regions also play a key role in the regulation of autonomic functioning (Benarroch, 2001, Benarroch, 2006). Taken together, previous research provides converging evidence to suggest that oxytocin may increase HRV at rest, and may enhance the engagement of parasympathetic inhibition of arousal in response to mild stressors. Specifically, oxytocin may mechanistically increase HRV in persons with chronic pain given their demonstrated parasympathetic dysregulation.
To date, no studies have investigated the effects of intranasal oxytocin on HRV in persons with chronic pain. The current study therefore investigated whether an acute dose of intranasal oxytocin could increase HRV in persons with CNSP at rest, and during a mental arithmetic task (i.e., by reducing the stress response). We hypothesised that persons with CNSP would display reduced HRV at rest and during a mental arithmetic task, compared to persons who were pain-free. We also hypothesised that intranasal oxytocin, compared to placebo, would increase HRV in persons with CNSP and pain-free persons.
Section snippets
Methods
Twenty-four volunteers with constant CNSP lasting > 12 months (eight women) were recruited from private physiotherapy clinics and the wider community, along with 24 age- and sex-matched pain-free controls, between September 2015 and December 2016. The study was designed as a randomised double-blind placebo-controlled cross-over study where each participant was tested under two acute treatment conditions (i.e., 24 international units (IU) of intranasal oxytocin, or an intranasal placebo) separated
Participants
Forty-eight participants (16 women, seven of whom were using hormone-based contraceptives) completed the study and were included in statistical analysis. A detailed participant flow chart according to the CONSORT criteria can be seen in Supplementary Figs. 1 and 2. In total, 12 participants reported side effects over the two sessions. Five participants reported side effects following oxytocin administration, including calmness (n = 3), drowsiness (n = 3), euphoria (n = 1), and nasal irritation (n = 1).
Discussion
To the best of our knowledge, this is the first study to test the effects of intranasal oxytocin on HRV in persons with chronic pain. In contrast to our expectation that intranasal oxytocin would increase HRV in individuals with CNSP, we did not observe a group-specific effect of intranasal oxytocin in either the paced breathing or the serial sevens task. However, our results did show that intranasal oxytocin (compared with placebo) elicited small decreases in LF- and HF-HRV in all participants
Conclusion
In summary, administration of intranasal oxytocin appeared to elicit a small decrease in parasympathetic regulation in individuals with and without CNSP during a mental arithmetic task. This raises questions about the findings from previous research that showed that intranasal oxytocin increased autonomic flexibility and adaptiveness in pain-free individuals at rest. Further studies utilising larger sample sizes, with other chronic pain conditions in which parasympathetic dysregulation is
Conflict of interest
The authors have no conflict of interest to declare.
Trial registration
CT-2016-CTN-01313-1; ACTRN12616000532404.
Funding sources
This study was funded by an Australian Research Council Linkage Project Grant (LP120200033). MJG was supported by a National Health and Medical Research Council Early Career Researcher Fellowship (APP1036124) and an Australian Research Council Discovery Early Career Research Award (DE170100726). LMT was supported by an Australian Government Research Training Program Scholarship. This was an investigator-initiated clinical trial. The funding bodies played no additional role beyond the supply of
Notes
Portions of this dataset were presented at the International Association for the Study of Pain World Congress in Yokohama, Japan (September 2016).
Ethical statement
All participants gave written, informed consent prior to commencing the study. This protocol was approved by the Monash University Human Research (CF15/659 – 2015000303) and the Alfred Human Research (111/16) Ethics Committees and followed the Helsinki Declaration of 1975. This study was registered with the Australian Government Therapeutic Goods Administration under the Clinical Trials Notification Scheme (protocol number CT-2016-CTN-01313-1) and the Australian and New Zealand Clinical Trials
Acknowledgements
The authors would like to thank Dr. Katrina Simpson for her assistance with interpretation of the statistical analyses, and the Australian Pain Management Association and the Melbourne Whiplash Centre for their assistance with participant identification and recruitment.
References (70)
- et al.
Aging, heart rate variability and patterns of autonomic regulation of the heart
Arch. Gerontol. Geriatr.
(2016) - et al.
Effects of intranasal oxytocin on emotional face processing in women
Psychoneuroendocrinology
(2010) - et al.
Autonomic balance revisited: panic anxiety and heart rate variability
J. Psychosom. Res.
(1998) - et al.
Cardiac vagal tone is associated with social engagement and self-regulation
Biol. Psychol.
(2013) - et al.
Autonomic regulation, physical activity and perceived stress in subjects with musculoskeletal pain: 24-hour ambulatory monitoring
Int. J. Psychophysiol.
(2012) - et al.
Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress
Biol. Psychiatry
(2003) - et al.
Impact of depression and antidepressant treatment on heart rate variability: a review and meta-analysis
Biol. Psychiatry
(2010) - et al.
Body mass index is related to autonomic nervous system activity as measured by heart rate variability – a replication using short term measurements
J. Nutr. Health Aging
(2014) - et al.
Sex differences in healthy human heart rate variability: a meta-analysis
Neurosci. Biobehav. Rev.
(2016) - et al.
A longitudinal study in youth of heart rate variability at rest and in response to stress
Int. J. Psychophysiol.
(2009)
Heart rate variability in patients with fibromyalgia and patients with chronic fatigue syndrome: a systematic review
Semin. Arthritis Rheum.
Oxytocin increases autonomic cardiac control: moderation by loneliness
Biol. Psychol.
Hypothalamic paraventricular nucleus stimulation-induced gastric acid secretion and bradycardia suppressed by oxytocin antagonist
Peptides
The social salience hypothesis of oxytocin
Biol. Psychiatry
The effect of oral contraceptive pills on levels of oxytocin in plasma and on cognitive functions
Contraception
Inflammation and cardiorespiratory control: the role of the vagus nerve
Respir. Physiol. Neurobiol.
Neural aspects of immunomodulation: focus on the vagus nerve
Brain Behav. Immun.
The relationship of autonomic imbalance, heart rate variability and cardiovascular disease risk factors
Int. J. Cardiol.
Sex-specific effects of intranasal oxytocin on thermal pain perception: a randomised, double-blind, placebo-controlled cross-over study
Psychoneuroendocrinology
Twenty-four hour time domain heart rate variability and heart rate: relations to age and gender over nine decades
J. Am. Coll. Cardiol.
Statistical and methodological considerations for the interpretation of intranasal oxytocin studies
Biol. Psychiatry
Heart rate variability as an index of regulated emotional responding
Rev. Gen. Psychol.
Manual for the Beck Anxiety Inventory
Beck Depression Inventory
Pain-autonomic interactions: a selective review
Clin. Auton. Res.
Pain-autonomic interactions
Neurol. Sci.
Controlling the false discovery rate: a practical and powerful approach to multiple testing
J. R. Stat. Soc. Ser. B
Worry is associated with robust reductions in heart rate variability: a transdiagnostic study of anxiety psychopathology
BMC Psychol.
Anxiety disorders are associated with reduced heart rate variability: a meta-analysis
Front Psychiatry
Pain assessment: global use of the Brief Pain Inventory
Ann. Acad. Med. Singap.
The burden and determinants of neck pain in workers: results of the bone and joint decade 2000-2010 task force on neck pain and its associated disorders
J. Manip. Physiol. Ther.
A twelve-item symptom intensity rating scale for cervical spine dysfunction
Spine
Modulation of resting-state amygdala-frontal functional connectivity by oxytocin in generalized social anxiety disorder
Neuropsychopharmacology
Multiple comparisons among means
J. Am. Stat. Assoc.
Data transforms for spectral analyses of heart rate variability
Biomed. Sci. Instrum.
Cited by (22)
Oxytocin and cardiometabolic interoception: Knowing oneself affects ingestive and social behaviors
2022, AppetiteCitation Excerpt :Fundamental to these investigations is the idea that oxytocin may normalize the imbalance between attention to internal and external stimuli by restoring appropriate salience. This correction of attention associated with oxytocin has been observed in studies of drug abuse/alcoholism (Betka et al., 2018; Yao et al., 2018) and mental stress (Tracy et al., 2018). Brain regions implicated in attention and interoception overlap and share connectivity with brain regions involved with determining the saliency of a stimulus.
Tracking transient changes in the intrinsic neural frequency architecture: Oxytocin facilitates non-harmonic relationships between alpha and theta rhythms in the resting brain
2021, PsychoneuroendocrinologyCitation Excerpt :Future research may be warranted to explore these dynamics within task-related contexts, e.g., allowing to draw links between (behavioral) changes in social salience/sensitivity and cross-frequency dynamics. This notion is important, considering that context and state-dependent changes are highlighted as important factors for inducing variations in OT’s neuromodulatory effects (e.g., differential effects on rest (Jain et al., 2017; Kemp et al., 2012; Martins et al., 2020; Norman et al., 2011) versus task-related HRV (Tracy et al., 2018)). In this view, it has been suggested that OT may primarily promote the restoration of autonomic balance (enhanced PNS drive) in the relative absence of acute stressors, but that opposite effects may be induced in task contexts that induce (mild) states of acute stress, in which case a facilitation of SNS-driven arousal and attentional salience may be evident (Carter, 2014).
The effect of attachment security priming and oxytocin on physiological responses to trauma films and subsequent intrusions
2021, Behaviour Research and TherapyCitation Excerpt :The placebo effect has gained increasing interest in mental health research (Kam-Hansen et al., 2014) and future studies could add a non-drug, priming only control condition to test for this possibility. At the time of study planning, no research was published on the effects of OT on baseline physiological measures but it has since emerged that OT can potentially increase HR (Sack et al., 2017) and, interestingly, HRV (Kemp et al., 2012) whilst other studies failed to find effects (D. A. Martins, Mazibuko, et al., 2020; Tracy et al., 2018). Although our study was based on a priori power calculation (see supplementary material) and allowed us to detect medium-to-large effect sizes, it did not allow us to detect small effects which could be relevant in understanding additive pharmacological and psychological interventions (our contrast analyses) and also our mediation analyses (Fritz & Mackinnon, 2007).
Intranasal oxytocin and the stress-buffering effects of social support during experimentally induced pain: The role of attachment security
2021, Journal of Affective DisordersCitation Excerpt :Previous studies have shown that intranasal oxytocin affects HRV during social stress (Kubzansky et al., 2012), although the direction of the effect may depend on the level of distress (Riem et al., 2020). For example, Tracy et al. (2018) found that oxytocin reduces HRV during mild mental stress in patients with chronic pain. As for an explanation, the RMSSD-lowering effects of oxytocin in our study may reflect enhanced vigilance and attention devoted to the friend, consistent with the Social Salience Hypothesis (Shamay-Tsoory and Abu-Akel, 2016), stating that oxytocin enhances the salience of external cues of safety and threat.
Oxytocin-enhanced group therapy for methamphetamine use disorder: Randomized controlled trial
2020, Journal of Substance Abuse TreatmentCitation Excerpt :In samples of healthy individuals, administration of oxytocin, compared to placebo, in a challenging context seems to decrease HRV, essentially reducing vagal tone and allowing the sympathetic nervous system to increase arousal and orchestrate a fight-or-flight response; whereas, oxytocin administration in a nonthreatening context (e.g., at rest) seems to increase HRV, allowing vagal regulation of emotional processes underlying social approach behavior (Appelhans & Luecken, 2006; Kemp & Guastella, 2010). The presence of a supportive friend (Kemp et al., 2012; Kubzansky et al., 2012; Norman, Cacioppo, Morris, Malarkey, et al., 2011; Riem et al., 2020; Romney et al., 2019; Tracy et al., 2018) and loneliness ratings (Norman, Cacioppo, Morris, Malarkey, et al., 2011) further moderate the effects of oxytocin on HRV. On the other hand, METH use is associated with acute sympathomimetic effects (Gutkowska et al., 2014; Henry, Minassian, & Perry, 2012; Schwarzbach, Lenk, & Laufs, 2020) as well as chronic reductions in HRV (Henry et al., 2012).
Oxytocin effects on resting-state heart rate variability in women: The role of childhood rearing experiences
2020, Comprehensive Psychoneuroendocrinology