Pre-surgical heart-rate variability strongly predicts less post-operative pain in patients with epilepsy

Highlights

• Post-operative pain often concerns patients and clinicians.

• There is inconsistency in results of studies on predictors of post-operative pain.

• Activating the vagal nerve can reduce pain.

• Heart-rate variability, an indirect index of vagal nerve activity, strongly predicted post-operative pain, independent of confounders.

• The possible neuro-immunological mechanisms of this relationship are discussed.

Abstract

Objectives

Post-operative pain is a common clinical problem after surgery, yet its predictors are inconsistent and unclear. This study examined whether pre-surgical vagal cardiac efferent nerve activity, indirectly indexed by heart rate variability (HRV), predicts patients' pain after epileptic surgery.

Methods

Using a prospective design, HRV was measured at rest during 5 min in n = 30 patients, prior to undergoing epileptic surgery. Post-operative pain was assessed every 8 h during the first 2 days after surgery, and our analyses focused on the worse pain level. We used multiple regression analyses and statistically considered several confounders (age, surgical duration, and analgesics during various surgical phases).

Results

Multiple HRV indexes strongly and inversely predicted post-operative pain, with high-frequency HRV (HF-HRV) being the strongest predictor (r = −0.81, p < 0.001). In a hierarchical multiple regression, HF-HRV accounted for an additional and significant 18% of the variance in post-operative pain, after statistically considering effects of age, surgical duration and effects of two anaesthetics.

Conclusions

Pre-surgical HF-HRV independently, strongly and inversely predicts post-operative pain. These results are in line with a neuromodulatory role of the vagus nerve in pain and have clinical implications for predicting and managing post-operative pain.

Introduction

Though surgery can be life-saving, and helps to cure or minimize diseases, it is also frequently associated with post-operative pain [1]. Clinicians know that most patients undergoing surgery will suffer from post-operative pain, a fact confirmed by many studies worldwide [[2], [3], [4], [5], [6], [7], [8], [9]]. For some surgeries however, pain is underdiagnosed. For example, after craniotomy, post-operative pain may be underdiagnosed, partly because of the common idea that people have no sensation in brain tissue. Yet, 87% of patients experience pain during the first 24 h after craniotomy [10]. More than just being a temporary issue for patient comfort and quality of life, post-operative pain has multiple consequences for health and recovery [11].

Post-operative pain after a craniotomy may be examined in patients who suffer from epilepsy. In fact, epilepsy is one of the most common chronic neurological disorders: More than 50 million patients suffer from active epilepsy, of whom 10 million could be treated with surgery [12]. The latter mostly struggle with drug-resistant epilepsy (DRE). The International League Against Epilepsy (ILAE) defined DRE as failure of adequate trials of two appropriate, well tolerated, antiepileptic medications, to achieve sustained seizure freedom [13]. For those patients, surgery may be one of the only manners for obtaining some relief. Indeed, surgery achieves complete seizure freedom or a meaningful reduction in seizures, risk of seizure associated injury and reduction in medication burden [14]. However, surgery implies craniotomy, and as noted above, post-operative pain as well, which may lead to complications.

Identification of risk factors and predictors of post-operative pain remains unclear despite an increasing interest around this field of research. It appears that although a considerable proportion of patients are anxious prior to surgery, the predictive role of anxiety in post-operative pain is not established because results from studies are inconsistent [15]. Such inconsistency is found with other predictors, for example age may be a predictor of post-operative pain after mastectomy [16] or not [17]. Finally, the only factor that seems to be consistently associated with post-operative pain in the literature is a surgical factor: the type of surgery itself [18,19]. However, as patients have multiple factors which may predict pain such as age, gender, body mass index (BMI), pre-surgical anxiety, depression and social support [16,17,[20], [21], [22]], it may be helpful to find an objective indicator which is related to the whole “patient factor”, in other words a factor associated with both psychosocial and physiological predictors.

Taking an integrative neuroimmunological approach, we focused here on vagal nerve activity due to its role in pain modulation. The vagal nerve is the 10th cranial nerve, which innervates visceral organs and modulates responses of multiple body systems (hormonal, cardiac, immune) [23]. In fact, several potential processes and variables which contribute to pain, also correlate with vagal nerve activity such as age and anxiety [24,25]. De Couck et al. developed an integrative model of vagal nerve pain modulation, which highlights the protective involvement of the vagal nerve in several pain related mechanisms: Inflammation, excessive sympathetic activity, oxidative stress, brain pain modulation and opioid responses [26]. The vagus inhibits oxidative stress and inflammation ^{e.g., 27}, inhibits sympathetic activity as the main branch of the parasympathetic nervous system, and it modulates certain aspects of the brain pain matrix [26]. A meta-analysis of 51 studies found that heart-rate variability (HRV), the indirect index of vagal nerve activity, is inversely related to pain [13]. Though HRV reflects levels of efferent vagal input to the heart, due to the very strong correlation between HRV and actual vagal nerve activity of r = 0.88 [36], we refer here to HRV as the indirect index of vagal activity per-see. Concerning the clinical relevance of the vagus to pain, a randomised controlled trial showed that non-invasive vagal nerve stimulation reduced headaches [34]. Based on these converging findings, we thus hypothesized that pre-surgical vagal nerve activity, indexed by HRV, would be negatively correlated with post-operative pain, independent of confounders. While we consider the vagal index of HRV as an integrative biomarker of physiological and psychological correlates of pain, these were not fully measured in the present study, and we mainly aimed to examine the predictive role of HRV in post-operative pain, independent of basic background (e.g., age) and surgical confounders.

Thus, the purpose of this study was to explore whether vagal nerve activity, indirectly indexed by HRV, may predict post-operative pain after stereotactic surgery, independent of other background and surgical predictors and confounders. Such prediction may help to identify in advance patients who may suffer later, in order to prevent their pain, anticipate needed treatments and reduce associated post-operative complications.