Intranasal oxytocin reduces heart rate variability during a mental arithmetic task: A randomised, double-blind, placebo-controlled cross-over study

https://doi.org/10.1016/j.pnpbp.2017.08.016Get rights and content

Highlights

  • Heart rate variability (HRV) is an index of autonomic regulation.

  • People with chronic pain typically have low HRV.

  • HRV was measured at rest, and during a mental arithmetic task.

  • Oxytocin decreased HRV during the mental arithmetic task.

  • Oxytocin may modulate salience of threatening stimuli.

Abstract

Heart rate variability (HRV) refers to variation in the interval between successive heart beats. Low HRV is an indicator of potential autonomic nervous system dysfunction. People with chronic pain often display autonomic dysregulation, especially in the parasympathetic nervous system. The hormone oxytocin has been shown to increase HRV in non-clinical samples, but its potential impact on HRV in persons with chronic pain is unknown. This study investigated the impact of intranasal oxytocin on HRV in persons with chronic neck and shoulder pain. Participants included 24 individuals with chronic neck and shoulder pain lasting > 12 months and 24 age- and sex-matched pain-free controls. In a randomised double-blind, placebo-controlled, cross-over study, participants self-administered intranasal oxytocin (24 IU) in one session, and placebo in another, before HRV was recorded at rest and during a mental arithmetic task. Intranasal oxytocin did not influence HRV at rest. However, compared to placebo, intranasal oxytocin elicited small decreases in low-frequency and high-frequency HRV in both groups during the mental arithmetic task. These results suggest that intranasal oxytocin may enhance the salience of the mental arithmetic task, leading to reduced engagement of the parasympathetic nervous system when completing the task. Further investigation and replication of these findings are required to improve our understanding of the effects of intranasal oxytocin on autonomic functioning both at rest and under cognitive stress.

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.

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