REVIEW ARTICLE
You May Need a Nerve to Treat Pain
The Neurobiological Rationale for Vagal Nerve Activation
in Pain Management
Marijke De Couck, MSc,* Jo Nijs, PhD,w and Yori Gidron, PhD*
Objectives: Pain is a complex common health problem, with
important implications for quality of life and with huge economic
consequences. Pain can be elicited due to tissue damage, as well as
other multiple factors such as inflammation and oxidative stress.
Can there be 1 therapeutic pathway that may target multiple
etiologic factors in pain?
Methods: In the present article, we review evidence for the rela-
tionships between vagal nerve activity and pain, and between vagal
nerve activity and 5 factors that are etiologic to or protective in
pain.
Results: Vagal nerve activity inhibits inflammation, oxidative stress,
and sympathetic activity, activates brain regions that can oppose
the brain “pain matrix,” and finally it might influence the analgesic
effects of opioids. Together, these can explain the antinociceptive
effects of vagal nerve activation or of acetylcholine, the principal
vagal nerve neurotransmitter. These findings form an evidence-
based neurobiological rationale for testing and possibly imple-
menting different vagal nerve activating treatments in pain
conditions.
Discussion: In this article, we show evidence for the relationships
between vagal nerve activity and pain, and between vagal nerve
activity and 5 factors that are etiologic to pain. Given the evidence
and effects of the vagus nerve activation in pain, people involved in
pain therapy may need to seriously consider activation of this
nerve.
Key Words: vagus nerve, chronic pain, pain management, vagal
nerve activation
(Clin J Pain 2014;30:1099–1105)
P ain results from multiple local and systemic processes,
and has marked effects on the patients’ quality of life.
The experience of pain is a function of ascending and
descending nociceptive and analgesic signals1 and neuronal
plasticity at different neural levels. In various types of pain,
Received for publication September 19, 2013; revised February 24,
2014; accepted January 9, 2014.
From the *Center for Neuroscience, Faculty of Pharmacy and Medi-
cine; and wPain in Motion Research Group, Departments of
Human Physiology and Rehabilitation Sciences, Faculty of Phys-
ical Education and Physiotherapy, Vrije Universiteit Brussels,
Brussels, Belgium.
Supported by a grant from “Reliable Cancer Therapie, Brussels,
Belgium” given to Y.G. J.N. is holder of the Chair “Exercise
Immunology and Chronic Fatigue in Health and Disease” funded
by the European College for Decongestive Lymphatic Therapy, The
Netherlands. The authors declare no conflict of interest.
Reprints: Yori Gidron, PhD, Center for Neuroscience, Faculty of
Pharmacy and Medicine, Vrije Universiteit Brussels, 103 Laarbee-
klaan, 1090 Jette, Brussels, Belgium (e-mail: yori.gidron@
vub.ac.be).
Copyright r 2014 by Lippincott Williams & Wilkins
DOI: 10.1097/AJP.0000000000000071
Clin J Pain  Volume 30, Number 12, December 2014
some treatments are of questionable effectiveness.2 This
may result from treatments not targeting all the underlying
mechanisms etiologic to pain and from pain not being
homogenous across different subtypes. Thus, it is important
to identify new and effective treatments that can be
rationalized based on scientific evidence showing that they
target multiple key mechanisms in pain. Given its cardinal
role in brain-periphery communication, stress response, and
immune regulation, the vagus nerve might be such a new
therapeutic target. This article describes the role of the
vagus nerve in acute and chronic pain, and provides an
evidence-based comprehensive neurobiological rationale
supporting vagus nerve–activating treatments in pain.
NEUROANATOMY OF THE VAGUS NERVE IN
RELATION TO PAIN
The vagus nerve is the 10th cranial nerve, “wandering”
from the brain stem to the abdomen. Approximately 80%
of its fibers are afferent, carrying information from the
head, neck, thorax, and abdomen to the brain. The central
terminals of vagal afferents are located in the nucleus of the
solitary tract (NTS) in the brain stem, projecting to the
parabrachial nucleus and subsequently to the amygdala,
hypothalamus, and limbic system, influencing the auto-
nomic and emotional reactions to noxious visceral stimuli.
The preganglionic vagal motor neurons to the gastro-
intestinal tract lie in the adjacent dorsal motor nucleus of
the vagus nerve and receive robust glutamatergic, cat-
echolaminergic, and, mainly, cholinergic and GABA (g-
aminobutyric acid)-ergic inputs from the NTS.3 The vagus
nerve is well positioned between the viscera and the brain,
and influences multiple body systems including cardiac,
immunologic, endocrine, and the activity of many visceral
organs. Because of these, the vagus nerve can be seen as a
mediating (transmitting) and modulating nerve of pain
signals, which we shall now explain.
THE GENERAL ROLE OF THE VAGUS NERVE
IN PAIN
The vagus nerve innervates multiple visceral organs,
from which it can convey information and signals to the
brain. Whereas the spinal cord conveys nociceptive infor-
mation, the vagus nerve conveys other types of pain-related
information,4 as shown below.
Efferent cardiac vagus nerve activity is measured
noninvasively by heart rate variability (HRV). Classic
physiology dictates that increased efferent vagus nerve
activity leads to a slowing of the heart rate, by inhibition of
the sinoatrial node.5 Measuring the time between individual
heartbeats, done with software that determines the distance
between the R waves on the electrocardiogram, provides
www.clinicalpain.com | 1099
De Couck et al
information about the instantaneous heart rate. HRV rep-
resents the time differences between successive heartbeats
(also known as the beat-to-beat intervals).5 It is a non-
invasive index, which is highly correlated with vagal nerve
activity (r = 0.88).6 In fish, bilateral vagotomy reduced
short-term HRV drastically.7 Blockade of vagal nerve
activity with atropine is responsible for a large decrease in
total HRV in all the species tested, from fish to humans.8–10
Finally, a linear relation of the area of the high-frequency
component of HRV and cardiac vagal tone obtained
pharmacologically has been demonstrated.11,12
Of great relevance to this review, in a study on 28 US
war veterans with various clinical problems, HRV was
found to be inversely correlated with pain levels
(r = 0.46, P < 0.05).6 That result supports the associa-
tion between pain experiences and vagal nerve activity
levels. Experimentally, the antinociceptive effect of mor-
phine was significantly attenuated after subdiaphragmatic
vagotomy,13 suggesting that the vagus nerve is needed for
the effectiveness of analgesia as well. Several studies have
shown that, after subdiaphragmatic vagotomy, both the
severity and duration of pain increase while the pain
threshold decreases.14 Furthermore, an increase in mech-
anical and pressure pain thresholds and a reduction in
mechanical pain sensitivity were found as a result of
transcutaneous vagal nerve stimulation (t-VNS) in 48 pain-
free volunteers.15 VNS also seemed to decrease pain per-
ception in patients with treatment-resistant depression.16
Together, these studies show causal relations between vagal
nerve activity and pain levels. However, pain is elicited
because of local molecular factors, as well as because of
systemic and “higher order” processes, all potentially linked
to vagal nerve activity. We shall now elaborate upon 5
pathophysiological mechanisms proposed to link vagal
nerve activity and pain modulation.
THE PATHOPHYSIOLOGICAL MECHANISMS
LINKING THE VAGUS NERVE AND PAIN
Each of the following subsections will discuss the role
of a mechanism etiologic to pain, followed by the vagal
nerve modulation of the mechanism.
Vagal Modulation of Inflammation
Inflammation plays an important role in pain and can
even induce pain on its own without having tissue dam-
age.17 The immune cells are found in regions involving pain
in general and chronic pain specifically, including the skin,
the spinal cord, peripheral nerves, and the dorsal horn.
Functionally, the immune and glial cells participate in
chronic pain and specific inflammatory signals such as
interleukin-1b (IL-1b) and tumor necrosis factor-a trigger
hyperalgesia.18 IL-1b leads to widespread transcription of
cyclooxygenase-2 (COX-2) in neurons, resulting in prosta-
glandin production, which in turn augments neuronal
excitability in somatosensory pathways. These processes
could enable this cytokine to increase pain sensitivity.
Importantly, the vagus nerve informs the brain about
peripheral inflammation by expressing receptors for IL-1b
on its paraganglia.19 In response, the descending vagus
nerve signals splenic T cells to produce acetylcholine (Ach),
which has anti-inflammatory effects on monocytes.20 Many
studies have focused on this “cholinergic anti-inflammatory
pathway,” which protects against systemic inflammation by
an a7 nicotinic Ach receptor–dependent pathway expressed
1100 | www.clinicalpain.com
Clin J Pain  Volume 30, Number 12, December 2014
on monocytes.21 In addition, the vagus nerve activates
a systemic pathway—the hypothalamic-pituitary-adrenal
axis, through which cortisol inhibits proinflammatory cell
proliferation.21 Indeed, vagal nerve activity is inversely
correlated with inflammation (r = 0.53, P < 0.001).22
Furthermore, VNS strongly reduces peripheral inflamma-
tory cytokines in animals and in humans in general, as well
as in a model of inflammatory bowel disease specifically.23
VNS and Ach attenuated the release of cytokines sig-
nificantly and improved survival in lethal endotoxemia or
sepsis models.24 In addition, activation of this neuro-
immune modulatory pathway also protects animals from
various circumstances, such as ischemia-reperfusion injury,
hypovolemic hemorrhagic shock, heart failure, and myo-
cardial ischemia/reperfusion, for example,25 in whom
inflammation plays a pivotal role. Thus, the vagus nerve
can inhibit inflammation in general and specifically in a
pain condition, which could serve as an important anti-
nociceptive pathway for this nerve.
Vagal Modulation of Sympathetic Nervous
Activity
Increased sympathetic and reduced parasympathetic
activities occur in pain. Elevated sympathetic activity
increases muscle tension and impairs local microcirculation,
possibly causing painful ischemia. Nociception-induced
and sympathetically maintained vasoconstriction leads to
insufficient blood flow for working muscles, producing
muscle hypoxia and increased oxidative stress, which in
turn can trigger muscle nociception.26 An experimental
study on rats showed that chronically elevated levels of
epinephrine, occurring after vagotomy, desensitize periph-
eral b2-adrenergic receptors and lead to the enhancement of
bradykinin hyperalgesia and contribute to chronic gener-
alized pain syndromes.27 In a study on chronic pancreatitis
patients, pressure pain tolerance thresholds were found to
be lower in patients with increased norepinephrine (NE)
levels compared with patients with normal NE.28 Fur-
thermore, noradrenaline, through action on a1-adreno-
ceptors and a2-adrenoceptors, is involved in intrinsic
control of pain. Peripheral noradrenaline that is mainly
released by the sympathetic nervous system has little
influence on healthy tissues, whereas in injured or inflamed
tissues it has varying effects, including aggravation of pain
in neuropathy.29
Although not always, the 2 divisions of the autonomic
nervous system, namely, the sympathetic and para-
sympathetic systems, are classically seen working in a
reciprocal manner, with increases in one division associated
with decreases in the other.30 An experimental study on rats
found that vagotomy induced a chronic elevation in plasma
concentrations of epinephrine.27 In patients with heart
failure, various indices of HRV were inversely correlated
with levels of NE.31 Experimentally, vagotomy leads to
increases in adrenal medulla epinephrine, whereas Ach, the
primary vagal neurotransmitter, reduces levels of NE.32
Furthermore, cardiac NE concentration in mice with
chronic heart failure decreased significantly during VNS
compared with before VNS (0.25 ± 0.07 ng/mL during
VNS vs. 0.61 ± 0.12 ng/mL before VNS, P < 0.05) and
returned to baseline after the termination of VNS
(0.43 ± 0.07 ng/mL after VNS vs. 0.25 ± 0.07 ng/mL dur-
ing VNS, P < 0.05). At last, medetomidine, an a2-adre-
nergic agonist and analgesic, activates cardiac vagal nerve
activity through the modulation of baroreflex control.33
r 2014 Lippincott Williams & Wilkins
Clin J Pain  Volume 30, Number 12, December 2014
Together, these findings support the notion that the vagus
nerve generally inhibits sympathetic nerve activity.
A factor relevant to the sympathetic dominance in the
autonomic nervous system is psychological stress. Accu-
mulation of traumatic life events was found to be one of the
predictors of the transition from acute to chronic pain.34 In
cross-sectional research, stress levels are inversely related to
vagal nerve activity, whereas in experimental research,
acute uncontrollable stress reduces vagal nerve activity.35
In contrast, baseline vagal nerve activity moderates phys-
iological responses to acute stress. Weber et al36 found that
people with low HRV had more enduring cardiac, inflam-
matory, and stress hormone responses to stress than those
with high HRV. Thus, whereas both sympathetic nervous
activity and stress may contribute to pain, vagal nerve
activity can modulate sympathetic and stress responses
toward a more balanced and adaptive stress response. This
was shown in experimental studies suggesting that afferent
VNS may modulate descending serotonergic and nora-
drenergic neurons to reduce pain.37 Thus, the modulation
of sympathetic activity by vagal stimulation can have
analgesic effects.
Vagal Modulation of Oxidative Stress
Oxidative stress occurs when there is an imbalance
between prooxidants and antioxidants, in favor of the
former, and this has been associated with certain pain
conditions. Reactive oxygen species contribute to and/or
maintain chronic pain.38 Reactive oxygen species produc-
tion is required for trigeminal transmission of facial pain. In
contrast, antioxidant injection exerts an analgesic effect.39
One antioxidant, vitamin E, was found to reduce muscle
cramps often occurring in hemodialysis patients.40 Cordero
et al41 observed a significant negative correlation between
coenzyme Q (10), an antioxidant, and headache parameters
(r = 0.59, P < 0.05). In addition, oral coenzyme Q (10)
supplementation restored biochemical parameters and
induced a significant improvement in clinical and headache
symptoms (P < 0.001).41 Furthermore, Taha and Blaise42
showed that oxidative stress plays a key role in the complex
regional pain syndrome pathogenesis. In contrast, the Nrf2
factor, which protects against oxidative stress and inflam-
mation by inducing antioxidant and detoxifying genes
through binding with an antioxidant response element, has
been shown to have antinociceptive effects against inflam-
matory pain in an animal model.42
In cross-sectional research, vagal nerve activity was
significantly inversely correlated with malondialdehyde,
which is a biological marker of oxidative stress.43 In
experimental research, the antioxidative effect of Ach was
demonstrated in NE-induced extracellular H2O2 release.
ACh partially but significantly attenuated the NE-induced
H2O2 release (46% reduction), which was also abolished by
the addition of atropine sulfate.32 Thus, oxidative stress
contributes to pain conditions and vagal nerve activity may
inhibit this nociceptive factor as well.
Vagal Modulation of Brain Activity
The “pain matrix” model of brain regions commonly
active during pain includes the periaqueductal gray (PAG)
and the rostral ventromedial medulla in the brain stem, as
well as the hippocampus, amygdala, thalamus, putamen,
and insula in the limbic system, and the posterior parietal,
primary somatosensory, primary motor, prefrontal cortex,
and anterior cingulate cortex, in the cortex.44
r 2014 Lippincott Williams & Wilkins
You May Need a Nerve to Treat Pain
A review on human studies showed that VNS alters
activity in the thalamus, cerebellum, orbitofrontal cortex,
limbic system (amygdala, hippocampus), hypothalamus,
and medulla.45 However, there is little consistency con-
cerning the direction of changes in such regions, and this
may result from studies including different patient samples,
different VNS activation parameters, and neuroimaging
techniques. More recently, transcutaneous VNS was found
to reduce hippocampal and amygdala activities and to
increase insular cortical activity and left prefrontal cortex
activity.46 As some types of pain are associated with
increased hippocampal and amygdala activities and with
reduced insular and prefrontal cortex activity,47 the anal-
gesic effects of VNS may partly occur by reversing such
pain-related brain activity patterns. Furthermore, stim-
ulating the left prefrontal cortex (as VNS does) by repetitive
transcranial magnetic stimulation was found to reduce
postoperative pain.48 Finally, following stimulation of the
pain-inhibiting region PAG with deep brain stimulation,
the high-frequency (parasympathetic) component of HRV
increased, in association with analgesic effects of the brain
stimulation in chronic pain patients.49 Together, these
findings show a resemblance between parts of the brain’s
pain matrix and low vagal activity, partly reversed by vagal
nerve activation. These findings suggest that vagal nerve
activity may be associated with activity in the “higher
order” brain regions capable of modulating pain, including
the left prefrontal cortex and the PAG, as well as inhibition
of the limbic regions.48
Vagal Modulation of Opioids
A fifth mechanism by which the vagus nerve may
influence the experience of pain is through the presence of
opioid and cannabinoid receptors on the vagal sensory
nerves. The opioid receptor family is composed of 3
members, the m, d, and k opioid receptors, which respond to
classic opioid alkaloids, such as morphine and heroin, and
endogenous peptide ligands, such as endorphins. These
receptors belong to the G-protein-coupled receptor super-
family, and are excellent therapeutic targets for pain con-
trol.50 Minor opioids such as codeine, dextropropoxyphene,
or more recently, tramadol have been used frequently for
the management of musculoskeletal problems. Moreover,
the use of major opioids has also been extended to the
treatment of rheumatologic patients with refractory pain.51
As mentioned before, animal studies have shown that
the antinociceptive effect of morphine was significantly
attenuated after subdiaphragmatic vagotomy,13 demon-
strating that the vagus nerve mediates part of the analgesic
effects of morphine. Another study on rats suggests that
activation of subdiaphragmatic vagal afferents may play a
role in opioid-dependent antinociceptive pathways acti-
vated by a noxious visceral stimulus.52 Similarly, Tarapacki
et al53 found that vagotomy reduced analgesic enhancement
induced by placental ingestion in rats. Pain can also reduce
levels of vagal nerve activity. In a study on humans
undergoing surgery, levels of high-frequency (vagal) HRV
decreased during inadequate anesthesia and nociception,
suggesting that HRV could be used as an indicator of depth
and adequacy of anesthesia.54 Thus, an intact vagus nerve
may be needed for antinociceptive effects of opioids and
their derivatives, and HRV may indicate the adequacy of
analgesia.
www.clinicalpain.com | 1101
De Couck et al
THE MEDIATING ROLE OF CENTRAL
SENSITIZATION
Each of the 5 mechanisms explained above are then
hypothesized to influence an important final mediating
factor, namely, hyperexcitability of the central nervous
system,55 sensitizing the neurons to noxious stimuli (ie,
central sensitization). According to Woolf,56 central sensi-
tization is “operationally defined as an amplification of
neural signaling within the central nervous system that
elicits pain hypersensitivity.”
Central sensitization reflects enhanced nociceptive
bottom-up activation (eg, temporal summation of pain),
increased activity of pain facilitation pathways,57,58 and
malfunctioning of descending pain inhibitory pathways,
which result in dysfunctional endogenous analgesic con-
trol.59 The latter might be because of a dysfunctional
opioid-based antinociception, which is etiologically linked
to low vagal nerve activity. In addition, the pain neuro-
matrix is overactive in patients with central sensitization.60
Long-term potentiation of neuronal synapses in the anterior
cingulate cortex61 and decreased GABA neurotransmission62
represent 2 mechanisms contributing to the overactive brain
neuromatrix. As explained above, increased activity in the
brain pain matrix is related to low vagal nerve activity, sug-
gesting that the vagus nerve accounts in part for the under-
lying mechanisms of central sensitization.
Finally, low vagal nerve activity implies less anti-
inflammatory action. The proinflammatory cytokine IL-1b
is known to play a major role in inducing COX-2 and
prostaglandin E2 expression in the central nervous sys-
tem,63,64 of which an upregulation leads to neuronal
hyperexcitability (in peripheral nerve terminals, the spinal
cord, and supraspinal centers).
VAGAL MODULATION OF PAIN: AN
INTEGRATIVE MODEL
The sections above demonstrated that the vagus nerve
modulates multiple factors that are key etiologic processes
or modulators in acute and chronic pain. Figure 1 depicts
our integrative model of vagal nerve modulation of pain.
Triggers of pain include tissue injury, inflammation, and
potential augmentation by psychological stress or apprais-
als.17,34 These triggers are thought to alter vagus nerve
activity, which in turn modulates 5 mechanisms etiologic to
FIGURE 1. Explanatory model of vagal nerve modulation of pain. CNS indicates central nervous system; SNS, sympathetic nervous
system.
1102 | www.clinicalpain.com
Clin J Pain  Volume 30, Number 12, December 2014
pain—inflammation, the SNS, oxidative stress, brain
activity, and opioids.
The 5 mechanisms summarized in Figure 1 are inter-
linked, and each of them can potentially increase the
excitability of the central nervous system. For example,
oxidative stress can induce inflammation and vice versa,65
whereas sympathetic nervous activity induces oxidative
stress as well.66 The studies reviewed above together
emphasize the importance of vagal nerve activation in pain
reduction, by inhibiting the 5 mechanisms and possibly by
reducing neuronal hyperexcitability (Fig. 1).
VAGAL NERVE–ACTIVATING INTERVENTIONS IN
PAIN: 1 COMMON PROTECTIVE PATHWAY,
TARGETING MULTIPLE MECHANISMS AT ONCE
Many analgesic modalities in pain have been and are
being used, targeting one of the mechanisms discussed above.
However, side effects have often been shown to occur. In a
review, Roberts et al67 investigated analgesic modalities
including COX-2 inhibitors, nonselective nonsteroidal anti-
inflammatory drugs (NSAIDs), opioids, and other pharma-
ceutical classes. COX-2 inhibitors and opioids demonstrated
significant efficacy with minimal side effects. Most non-
selective NSAIDs were effective analgesics but had a more
severe side-effect profile. Peniston68 reviewed the clinical
evidence and the guideline recommendations for pharmaco-
therapy of chronic low back pain in athletes. Acetaminophen
seemed to be a well-tolerated first-line pharmacotherapy, but
high-dose, long-term use is associated with hepatic toxicity.
NSAIDs, in contrast, could be an effective second-line
option, but they have well-known risks of gastrointestinal,
cardiovascular, and other systemic adverse effects. The sero-
tonin-NE reuptake inhibitor, duloxetine, a drug commonly
used for depression or anxiety disorders, has demonstrated
modest efficacy and is associated with systematic adverse
events, including serotonin syndrome. Furthermore, anti-
oxidant injection induced a significant improvement in clin-
ical and headache symptoms,41 reduced muscle cramps,40 and
had an analgesic effect.39 Taha and Blaise42 showed that
inducing antioxidants had antinociceptive effects against
inflammatory pain in an animal model. And finally, opioids
may be an effective choice for moderate to severe pain but
may also have significant risks of adverse events and carry a
substantial risk of addiction and abuse. Often the side effects
r 2014 Lippincott Williams & Wilkins
Clin J Pain  Volume 30, Number 12, December 2014
are dose related. However, as very often patients with chronic
pain may require treatment over years or decades, it is critical
that the risk/benefit profiles of pharmacotherapies are closely
evaluated to ensure that short-term and long-term treatments
are optimized for each patient.
In contrast, the vagus nerve could target all 5 mecha-
nisms reviewed above at once, with minimal side effects.
This may lead to optimal effective analgesic effects. The
vagus nerve can be stimulated in several ways: by deep-
paced breathing,69 by electrical VNS with an implantable
device, by a transcutaneous vagal nerve stimulator, stim-
ulating the auricular branch of the vagus nerve, or by
administration of Ach or its derivatives. The effects of
various vagal nerve–activating interventions on pain have
been tested on humans and animals. Deep-paced breathing
relaxation has been shown to increase vagal nerve activ-
ity.69 One form of this intervention is heart rate variability-
biofeedback (HRV-B), where patients receive visual
computerized feedback concerning their HRV. This has been
shown to have analgesic effects on children with functional
abdominal pain (FAP). After 6 sessions, the FAP group
significantly increased their autonomic balance, this state
being characterized as the harmonious equilibrium between
sympathetic and parasympathetic functions, rather than the
domination of the sympathetic activity. Furthermore, a
positive correlation was found between a decrease in LF/HF
ratio (indicating decreased sympathovagal activity) and a
decrease in pain frequency (r = 0.54, P = 0.018) and pain
intensity (r = 0.62, P = 0.004).70
Concerning electrical VNS, a study on rats found a clear
antinociceptive effect of VNS in models of acute and
inflammatory pain.71 Furthermore, in epileptic patients, VNS
yielded a significant reduction in pain to tonic pressure.72 t-
VNS resulted in an increase in mechanical and pressure pain
thresholds and a reduction in mechanical pain sensitivity in
48 pain-free volunteers. Moreover, active t-VNS significantly
reduced pain ratings during sustained application of painful
heat for 5 minutes compared with a sham condition.15 Fur-
thermore, an experimental study on rodents showed that
VNS modulates visceral pain-related affective memory.73
Another experiment on anesthetized rats provided evidence
of VNS-induced modulation of trigeminovascular noci-
ception.74 However, to the best of our knowledge, no pub-
lished studies have tested the effects of VNS on pain using a
randomized controlled trial in humans experiencing pain.
This is needed to reinforce the causal relation hypothesized to
exist between vagal activation and pain reduction, and to
substantiate the clinical value of such treatment.
Administration of the vagal neurotransmitter Ach or
its derivatives reduces the behavioral and physiological
manifestations of pain in rats.75 Oral donepezil, an ace-
tylcholine esterase inhibitor (AchEI), reduced hyper-
sensitivity of rats in a model of neuropathic pain.24 Finally,
some studies show that AchEI enhances the analgesic
effects of opioids.76 In humans, AchEI also controls post-
surgical and cancer pain.77 Together, these findings dem-
onstrate that vagal nerve activation can reduce pain in
humans, and the model presented above potentially
explains the mechanisms underlying these effects.
CONCLUSIONS
The vagus nerve may play an important role in pain
modulation by inhibiting inflammation, oxidative stress,
and sympathetic activity, and possibly by inducing a brain
r 2014 Lippincott Williams & Wilkins
You May Need a Nerve to Treat Pain
activation pattern that may be incongruent with the brain
matrix of pain. Finally, vagal activation may mediate or
work in synergism with the effects of the opioid system in
pain modulation. All these mechanisms are thought to
influence neuronal hyperexcitability, culminating in the
perception of less pain. For all the above neurobiological
reasons, it seems justified to increase vagal nerve activity to
reduce pain as this targets all 5 mechanisms with 1 inter-
vention. This hypothesis is supported by experimental
studies on animals and preliminary intervention trials on
humans.
Future studies need to test with greater method-
ological rigor, the effects of vagal nerve–activating inter-
ventions on pain in patients with acute and chronic pain
disorders. The identification of patient subgroups (pain
types, sex, etc.) that benefit the most from each method of
vagal nerve activation (HRV-B, VNS, AchEI) needs further
investigation as well. In addition, the cost benefits of each
type of vagal nerve–enhancing intervention, in relation to
pain reduction and side effects need to be considered.
Finally, as vagal nerve–activating interventions may
enhance the analgesic effects of opioids, future studies may
need to test whether combining opioids with vagal nerve–
activating therapies can lead to similar pain reduction with
lower doses of narcotics, and hence less addictive side
effects and more agreeable recovery. Given the evidence
and potential effects of the vagus nerve in modulating key
etiologic factors in pain, pain therapy may need to seriously
consider activation of this well-positioned important nerve.
REFERENCES
1. Heinricher MM, Tavares I, Leith JL, et al. Descending control
of nociception: specificity, recruitment and plasticity. Brain Res
Rev. 2009;60:214–225.
2. Deshpande A, Furlan A, Mailis-Gagnon A, et al. Opioids for
chronic low-back pain. Cochrane Database Syst Rev.
2003;3:CD004959.
3. Travagli RA, Gillis RA, Rossiter CD, et al. Glutamate and
GABA-mediated synaptic currents in neurons of the rat dorsal
motor nucleus of the vagus. Am J Physiol. 1991;260:
G531–G536.
4. Kuo TB, Lai CJ, Huang YT, et al. Regression analysis between
heart rate variability and baroreflex-related vagus nerve
activity in rats. J Cardiovasc Electrophysiol. 2005;16:864–869.
5. Task Force of the European Society of Cardiology and the
North American Society of Pacing and Electrophysiology.
Heart rate variability: standards of measurement, physiological
interpretation and clinical use. Circulation. 1996;93:1043–1065.
6. Tan G, Fink B, Dao TK, et al. Associations among pain,
PTSD, mTBI, and heart rate variability in veterans of
Operation Enduring and Iraqi Freedom: a pilot study. Pain
Med. 2009;10:1237–1245.
7. Altimiras J, Aissaoui A, Tort L. Is the short-term modulation
of heart rate in teleost fish physiologically significant? Assess-
ment by spectral analysis techniques. Braz J Med Biol Res.
1995;28:1197–1206.
8. Axelsson M. The importance of nervous and humoral
mechanisms in the control of cardiac performance in the
Atlantic cod Gadus morhua at rest and during non-exhaustive
exercise. J Exp Biol. 1988;137:287–303.
9. De Vera L, González J. Power spectral analysis of short-term
RR interval and arterial blood pressure oscillations in lizard
(Gallotia galloti): effects of parasympathetic blockade. Comp
Biochem Physiol A. 1997;118:671–678.
10. Goldberger JJ, Ahmed MW, Parker MA, et al. Dissociation of
heart rate variability from parasympathetic tone—rapid
communication. Am J Physiol. 1994;266:H2152–H2157.
www.clinicalpain.com | 1103
De Couck et al
11. Hayano J, Sakakibara Y, Yamada A, et al. Accuracy of
assessment of cardiac vagal tone by heart rate variability in
normal subjects. Am J Cardiol. 1991;15:199–204.
12. Hayano J, Mukai S, Sakakibara M, et al. Effects of respiratory
interval on vagal modulation of heart rate. Am J Physiol.
1994;267:H33–H40.
13. Randich A, Thurston CL, Ludwig PS, et al. Antinociception
and cardiovascular responses produced by intravenous mor-
phine: the role of vagal afferents. Brain Res. 1991;542:256–270.
14. Weissman-Fogel I, Dashkovsky A, Rogowski Z, et al. Vagal
damage enhances polyneuropathy pain: additive effect of two
algogenic mechanisms. Pain. 2008;138:153–162.
15. Busch V, Zeman F, Heckel A, et al. The effect of trans-
cutaneous vagus nerve stimulation on pain perception—an
experimental study. Brain Stimul. 2012;6:202–209.
16. Borckardt JJ, Kozel FA, Anderson B, et al. Vagus nerve
stimulation affects pain perception in depressed adults. Pain
Res Manag. 2005;10:9–14.
17. Tal MA. Role for inflammation in chronic pain. Curr Rev
Pain. 1999;3:440–446.
18. Wolf G, Yirmiya R, Goshen I, et al. Impairment of interleukin-
1 (IL-1) signaling reduces basal pain sensitivity in mice: genetic,
pharmacological and developmental aspects. Pain. 2003;104:
471–480.
19. Ek M, Kurosawa M, Lundeberg T, et al. Activation of vagal
afferents after intravenous injection of interleukin-1b: role of
endogenous prostaglandins. J Neurosci. 1998;18:9471–9479.
20. Rosas-Ballina M, Olofsson PS, Ochani M, et al. Acetylcholine-
synthesizing T cells relay neural signals in a vagus nerve circuit.
Science. 2011;334:98–101.
21. Tracey KJ. Reflex control of immunity. Nat Rev Immunol.
2009;9:418–428.
22. Tateishi Y, Oda S, Nakamura M, et al. Depressed heart rate
variability is associated with high IL-6 blood level and decline
in the blood pressure in septic patients. Shock. 2007;28:
549–553.
23. Meregnani J, Clarenc¸on D, Vivier M, et al. Anti-inflammatory
effect of vagus nerve stimulation in a rat model of inflamma-
tory bowel disease. Auton Neurosci. 2011;160:82–89.
24. Clayton BA, Hayashida K, Childers SR, et al. Oral donepezil
reduces hypersensitivity after nerve injury by a spinal
muscarinic receptor mechanism. Anesthesiology. 2007;106:
1019–1025.
25. Li M, Zheng C, Sato T, et al. Vagal nerve stimulation
markedly improves long-term survival after chronic heart
failure in rats. Circulation. 2004;109:120–124.
26. Sjögaard G, Sögaard K. Muscle injury in repetitive motion
disorders. Clin Orthop Relat Res. 1998;351:21–31.
27. Khasar SG, Green PG, Miao FJ, et al. Vagal modulation of
nociception is mediated by adrenomedullary epinephrine in
the rat. Eur J Neurosci. 2003;17:909–915.
28. Buscher HC, van Goor H, Sweep CG, et al. Increased
sympathetic activity in chronic pancreatitis patients is asso-
ciated with hyperalgesia. J Pain Palliat Care Pharmacother.
2010;24:362–366.
29. Pertovaara A. The noradrenergic pain regulation system: a
potential target for pain therapy. Eur J Pharmacol. 2013;716:2–7.
30. Berntson GG, Cacioppo JT, Quigley KS. Respiratory sinus
arrhythmia-autonomic origins, physiological mechanisms, and
psychophysiological implications. Psychophysiology. 1993;30:
183–196.
31. Burger AJ, Aronson D. Activity of the neurohormonal system
and its relationship to autonomic abnormalities in decom-
pensated heart failure. J Card Fail. 2001;7:122–128.
32. Tsutsumi T, Ide T, Yamato M, et al. Modulation of the
myocardial redox state by vagal nerve stimulation after exper-
imental myocardial infarction. Cardiovasc Res. 2008;77:713–721.
33. Shimizu S, Akiyama T, Kawada T, et al. Medetomidine, an
a(2)-adrenergic agonist, activates cardiac vagal nerve through
modulation of baroreflex control. Circ J. 2012;76:152–159.
34. Young Casey C, Greenberg MA, Nicassio PM, et al.
Transition from acute to chronic pain and disability: a model
1104 | www.clinicalpain.com
Clin J Pain  Volume 30, Number 12, December 2014
including cognitive, affective, and trauma factors. Pain. 2008;-
134:69–79.
35. Schwarz AM, Schächinger H, Adler RH, et al. Hopelessness is
associated with decreased heart rate variability during cham-
pionship chess games. Psychosom Med. 2003;65:658–661.
36. Weber CS, Thayer JF, Rudat M, et al. Low vagal tone is associated
with impaired post stress recovery of cardiovascular, endocrine, and
immune markers. Eur J Appl Physiol. 2010;109:201–211.
37. Randich A, Gebhart GF. Vagal afferent modulation of
nociception. Brain Res Brain Res Rev. 1992;17:77–99.
38. Hacimuftuoglu A, Handy CR, Goettl VM, et al. Antioxidants
attenuate multiple phases of formalin-induced nociceptive
response in mice. Behav Brain Res. 2006;173:211–216.
39. Kim HK, Park SK, Zhou JL, et al. Reactive oxygen species
(ROS) play an important role in a rat model of
neuropathic pain. Pain. 2004;111:116–124.
40. El-Hennawy AS, Zaib S. A selected controlled trial of
supplementary vitamin E for treatment of muscle cramps in
hemodialysis patients. Am J Ther. 2010;17:455–459.
41. Cordero MD, Cano-Garcı́a FJ, Alcocer-Gómez E, et al.
Oxidative stress correlates with headache symptoms in
fibromyalgia: coenzyme Q10 effect on clinical improvement.
PLoS One. 2012;7:35677.
42. Taha R, Blaise GA. Update on the pathogenesis of complex
regional pain syndrome: role of oxidative stress. Can J Anaesth.
2012;59:875–881.
43. Pavithran P, Nandeesha H, Sathiyapriya V, et al. Short-term
heart variability and oxidative stress in newly diagnosed
essential hypertension. Clin Exp Hypertens. 2008;30:486–496.
44. Tracey I, Mantyh PW. The cerebral signature for pain
perception and its modulation. Neuron. 2007;55:377–391.
45. Chae JH, Nahas Z, Lomarev M, et al. A review of functional
neuroimaging studies of vagus nerve stimulation (VNS). J
Psychiatr Res. 2003;37:443–455.
46. Kraus T, Hösl K, Kiess O, et al. BOLD fMRI deactivation of
limbic and temporal brain structures and mood enhancing
effect by transcutaneous vagus nerve stimulation. J Neural
Transm. 2007;114:1485–1493.
47. Ji G, Neugebauer V. Hemispheric lateralization of pain process-
ing by amygdala neurons. J Neurophysiol. 2009;102:2253–2264.
48. Borckardt JJ, Reeves ST, Weinstein M, et al. Significant
analgesic effects of one session of postoperative left prefrontal
cortex repetitive transcranial magnetic stimulation: a
replication study. Brain Stimul. 2008;1:122–127.
49. Pereira EA, Lu G, Wang S, et al. Ventral periaqueductal grey
stimulation alters heart rate variability in humans with
chronic pain. Exp Neurol. 2010;223:574–581.
50. Granier S. Structure of mu and delta opioid receptors. Med Sci
(Paris). 2012;28:870–875.
51. Calvo-Alén J. Opioids in chronic musculoskeletal conditions.
Ther Adv Musculoskelet Dis. 2010;2:291–297.
52. Gschossmann JM, Mayer EA, Miller JC, et al. Subdiaphrag-
matic vagal afferent innervation in activation of an opioidergic
antinociceptive system in response to colorectal distension
in rats. Neurogastroenterol Motil. 2002;14:403–408.
53. Tarapacki JA, Thompson AC, Kristal MB. Gastric vagotomy
blocks opioid analgesia enhancement produced by placenta
ingestion. Physiol Behav. 1992;52:179–182.
54. Jeanne M, Logier R, De Jonckheere J, et al. Heart rate
variability during total intravenous anesthesia: effects of
nociception and analgesia. Auton Neurosci. 2009;147:91–96.
55. Griffis CA. Neuroimmune activation and chronic pain. AANA
J. 2011;79:31–37.
56. Woolf CJ. Central sensitization: implications for the diagnosis
and treatment of pain. Pain. 2011;152:S2–S15.
57. Meeus M, Nijs J. Central sensitization: a biopsychosocial
explanation for chronic widespread pain in patients with
fibromyalgia and chronic fatigue syndrome. Clin Rheumatol.
2007;26:465–473.
58. Staud R, Craggs JG, Robinson ME, et al. Brain activity related
to temporal summation of C-fiber evoked pain. Pain.
2007;129:130–142.
r 2014 Lippincott Williams & Wilkins
Clin J Pain  Volume 30, Number 12, December 2014
59. Meeus M, Nijs J, Van de Wauwer N, et al. Diffuse noxious
inhibitory control is delayed in chronic fatigue syndrome: an
experimental study. Pain. 2008;139:439–448.
60. Seifert F, Maihöfner C. Central mechanisms of experimental
and chronic neuropathic pain: findings from functional
imaging studies. Cell Mol Life Sci. 2009;66:375–390.
61. Zhuo M. A synaptic model for pain: long-term potentiation in
the anterior cingulated cortex. Mol Cells. 2007;23:259–271.
62. Suarez-Roca H, Leal L, Silva JA, et al. Reduced GABA
neurotransmission underlies hyperalgesia induced by repeated
forced swimming stress. Behav Brain Res. 2008;189:159–169.
63. Bazan NG. COX-2 as a multifunctional neuronal modulator.
Nat Med. 2001;7:414–415.
64. Samad TA, Moore KA, Sapirstein A, et al. Interleukin-1 beta-
mediated induction of COX-2 in the CNS contributes to
inflammatory pain hypersensitivity. Nature. 2001;410:471–475.
65. Vallyathan V, Shi X, Castranova V. Reactive oxygen species:
their relation to pneumoconiosis and carcinogenesis. Environ
Health Perspect. 1998;106(suppl 5):1151–1155.
66. Zhang ZH, Yu Y, Wei SG, et al. Centrally administered
lipopolysaccharide elicits sympathetic excitation via NAD(P)H
oxidase-dependent mitogen-activated protein kinase signaling.
J Hypertens. 2010;28:806–816.
67. Roberts M, Brodribb W, Mitchell G. Reducing the pain: a
systematic review of postdischarge analgesia following elective
orthopedic surgery. Pain Med. 2012;13:711–727.
68. Peniston JH. A review of pharmacotherapy for chronic low
back pain with considerations for sports medicine. Phys Sports
Med. 2012;40:21–32.
r 2014 Lippincott Williams & Wilkins
You May Need a Nerve to Treat Pain
69. Lehrer PM, Vaschillo E, Vaschillo B, et al. Heart rate
variability biofeedback increases baroreflex gain and peak
expiratory flow. Psychosom Med. 2003;65:796–805.
70. Sowder E, Gevirtz R, Shapiro W, et al. Restoration of vagal
tone: a possible mechanism for functional abdominal pain.
Appl Psychophysiol Biofeedback. 2010;35:199–206.
71. Multon S, Schoenen J. Pain control by vagus nerve stimula-
tion: from animal to manyand back. Acta Neurol Belg.
2005;105:62–67.
72. Kirchner A, Stefan H, Bastian K, et al. Vagus nerve
stimulation suppresses pain but has limited effects on neuro-
genic inflammation in humans. Eur J Pain. 2006;10:449–455.
73. Zhang X, Cao B, Yan N, et al. Vagus nerve stimulation
modulates visceral pain-related affective memory. Behav Brain
Res. 2013;236:8–15.
74. Lyubashina OA, Sokolov AY, Panteleev SS. Vagal afferent
modulation of spinal trigeminal neuronal responses to dural
electrical stimulation in rats. Neuroscience. 2012;222:29–37.
75. Gurun MS, Parker R, Eisenach JC, et al. The effect of
peripherally administered CDP-choline in an acute inflamma-
tory pain model: the role of alpha7 nicotinic acetylcholine
receptor. Anesth Analg. 2009;108:1680–1687.
76. Yardeni IZ, Melzer E, Smolyarenko V, et al. Combining
physostigmine with meperidine for sedation and analgesia
during colonoscopy. Endoscopy. 2005;37:1205–1210.
77. Lauretti GR, Lima IC. The effects of intrathecal neostigmine
on somatic and visceral pain: improvement by association
with a peripheral anticholinergic. Anesth Analg. 1996;82:
617–620.
www.clinicalpain.com | 1105