Review

Treatment of central sensitization

in patients with ‘unexplained’
chronic pain: an update
1. Introduction
Jo Nijs†, Anneleen Malfliet, Kelly Ickmans, Isabel Baert & Mira Meeus
2. Eliminating peripheral †
Vrije Universiteit Brussel, Medical Campus Jette, Brussels, Belgium
nociceptive input for the
treatment of CS pain
Introduction: Central sensitization (CS) is present in a variety of chronic pain
3. Pharmacotherapy potentially
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disorders, including whiplash, temporomandibular disorders, low back pain,

targeting osteoarthritis, fibromyalgia, headache, lateral epicondylalgia among others.
CS pain In spite of our increased understanding of the mechanisms involved in CS
4. Conservative therapy targeting pain, its treatment remains a challenging issue.
CS pain Areas covered: An overview of the treatment options we have for desensitis-
5. Conclusion ing the CNS in patients with CS pain is provided. These include strategies
6. Expert opinion on including for eliminating peripheral sources of nociception, as well as pharmacother-
pharmacotherapy in a apy and conservative interventions that primarily address top-down (i.e.,
combined top-down and brain-orchestrated) mechanisms.
bottom-up approach for Expert opinion: A combination of different strategies, each targeting a
treating CS pain different ‘desensitizing’ mechanism, might prove superior over monothera-
pies. Such combined therapy may include both bottom-up and top-down (e.
g., opioids, combined µ-opioid receptor agonist and noradrenaline reuptake
For personal use only.

inhibitor drugs) strategies. Topically applied analgesic therapies have strong

potential for (temporally) decreasing peripheral nociceptive input (bottom-
up approach). Targeting metabolic (e.g., ketogenic diets) and neurotrophic
factors (e.g., decreasing brain-derived neurotrophic factor) are promising
new avenues for diminishing hyperexcitability of the CNS in central sensitiza-
tion pain patients. Addressing conservative treatments, pain neuroscience
education, cognitive behavioural therapy and exercise therapy are promising
treatments for CS pain.

Keywords: chronic pain, cognitive behavioural therapy, education, exercise therapy,

fibromyalgia, osteoarthritis, pharmacotherapy, rehabilitation, whiplash

Expert Opin. Pharmacother. [Early Online]

1. Introduction

Despite extensive global research efforts, chronic ‘unexplained’ pain remains a

challenging issue for clinicians and an emerging socioeconomic problem. There
has been an evolution of our understanding about pain. The initial paradigm was
pain proportional to nociceptive input; the second was Wall and Melzak’s gate
theory [1] and the most recent is pain as central sensitization (CS). It is now well
established that sensitization of the CNS is an important feature in many patients
with chronic pain, including those with whiplash [2], chronic low back pain [3],
osteoarthritis [4], headache [5,6], fibromyalgia [7], chronic fatigue syndrome [8], rheu-
matoid arthritis [9], patellar tendinopathy [10] and lateral epicondylalgia [11,12]. Also,
neuropathic pain may be characterized/accompanied by sensitization as well;
peripheral and central (segmentally related) pain pathways can become hyperexcit-
able in patients with neuropathic pain. However, here we focus on non-neuropathic
CS pain patients. Given the extensive literature discussing treatment options for
neuropathic pain, here we focus on non-neuropathic CS pain patients.

10.1517/14656566.2014.925446 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 1

All rights reserved: reproduction in whole or in part not permitted
 J. Nijs et al.
Article highlights.
. Various pharmacological and conservative treatments,
with established clinical effectiveness in a variety of
central sensitization (CS) pain disorders, target
mechanisms involved in CS.
.
Acetaminophen, serotonin reuptake inhibitor drugs,
selective and balanced serototin and norepinephrine
reuptake inhibitor drugs, the serotonin precursor
tryptophan, opioids, combined µ-opioid receptor agonist
and noradrenaline reuptake inhibitor drugs,
NMDA-receptor antagonists and calcium channel a2d
ligands each target central pain processing mechanisms
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in animals that theoretically desensitize the CNS in
humans.
. Topically applied analgesic therapies have strong
potential for (temporally) decreasing peripheral
nociceptive input (bottom-up approach to CS pain).
.
Targeting metabolic factors, for instance by using
low-carbohydrate or ketogenic diets, are promising new
avenues for diminishing hyperexcitability of the CNS in
CS pain patients.
. Cervical radiofrequency neurotomy for cervical facet
joint pain, joint replacement surgery for osteoarthritis
pain and local therapy for myofascial pain are promising
strategies for treating CS by eliminating peripheral
sources of nociceptive input.
. Pain neuroscience education and cognitive behavioral
For personal use only.
therapy target cognitive and emotional sensitization.
. Exercise therapy addresses both cognitive emotional
sensitization and aims at activating endogenous
analgesia in patients with CS pain.
This box summarizes key points contained in the article.
CS has been defined as ‘an amplification of neural signaling
within the CNS that elicits pain hypersensitivity’ [13] or ‘an
augmentation of responsiveness of central neurons to input
from unimodal and polymodal receptors’ [14]. Such defini-
tions originate from laboratory research, but the awareness
that the concept of CS should be translated to the clinic
is growing.
CS is an umbrella term, encompassing various related
dysfunctions of the CNS, all contributing to an increased
responsiveness to a variety of stimuli like mechanical pressure,
chemical substances, light, sound, cold, heat, stress and
electrical stimuli [15]. The dysfunctions of the CNS as seen
in CS include altered sensory processing in the brain [16], mal-
functioning of descending antinociceptive mechanisms [17,18],
increased activity of pain facilitatory pathways and enhanced
temporal summation of second pain or wind-up [19,20].
Malfunctioning of descending antinociceptive mechanisms
includes dysfunctional conditioned pain modulation, which
implies a feedback loop through the subnucleus reticularis
dorsalis, a region in the caudal medulla [21]. The neural basis
of the various mechanisms involved in CS is different. For
example, temporal summation is a different mechanism
from conditioned pain modulation and they are targeted by
different drugs [17,22,23]. In addition, the pain neuromatrix is
2 Expert Opin. Pharmacother. (2014) 15(12)
overactive in case of CS and chronic pain, with increased
brain activity in areas known to be involved in acute pain
sensations (the insula, anterior cingulate cortex and the pre-
frontal cortex), as well as in regions not involved in acute
pain sensations (various brain stem nuclei, dorsolateral frontal
cortex and the parietal associated cortex) [24]. Long-term
potentiation of neuronal synapses in the anterior cingulate
cortex [25] and decreased GABA-neurotransmission [26] con-
tribute to the overactive pain neuromatrix in patients with
CS.
In spite of our increased understanding of the mechanisms
involved in CS, its treatment remains a challenging issue. In
2011, we published an overview of the treatment options for
CS pain [27]. The paper focused on those strategies that
specifically target pathophysiological mechanisms known to
be involved in CS. This way, treatments that -- at least
theoretically -- hold the capacity to desensitize the CNS were
presented. Since 2011, the international awareness that CS
should be a treatment target has grown. This is reflected by
the increased number of studies that use indices of CS as
outcome measures in randomized clinical trials [28-33]. This
has inspired the Editorial Board to ask us to update our
2011 review article. The 2011 paper mainly addressed
pharmacological options, rehabilitation and neurotechnology
(i.e., transcranial magnetic stimulation) options for desensitiz-
ing the CNS in patients with CS pain [27]. With regard to the
rehabilitation approaches, manual therapy, virtual reality, stress
management/neurofeedback training, transcutaneous electrical
nerve stimulation and cranial electrotherapy stimulation were
emphasized [27].
In the present paper, the primary focus lies on pharmacol-
ogy, and for the conservative approaches pain neuroscience
education, exercise therapy and cognitive behavioral therapy
are explained. Most treatment options target the brain (top-
down approach) rather than peripheral nociceptive input
(bottom-up). This appears to be a rational choice, especially
if one considers CS to be the dominant feature in the chronic
pain patient. However, the clinical picture of chronic pain
patients is not always that clear, with some patients having
clear evidence of peripheral nociceptive input combined
with evidence of CS (e.g., patients with whiplash and osteoar-
thritis). For these patients, the question arises whether success-
ful treatment of peripheral input will diminish (or even
resolve) CS as well? Therefore, the first part of the paper
addresses therapies that target peripheral nociceptive input
for the treatment of CS in chronic pain patients.
2.Eliminating peripheral nociceptive input
for the treatment of CS pain
Patients having sustained a whiplash injury often develop a
complex clinical picture characterized by chronic pain, hyper-
sensitivity to various stimuli and cognitive dysfunctions (e.g.,
concentration difficulties). Most often, specific changes in the
cervical spine or the surrounding tissues cannot be revealed

using magnetic resonance imaging [34]. Consistent evidence
supports the presence of CS as a dominant feature in patients
with chronic pain following whiplash injury [35], but this does
not exclude the possibility that peripheral nociceptive input is
present even in the chronic stage. In this view, cervical facet
joints might be an active source of peripheral nociception in
patients with chronic pain following whiplash injury [36].
This view is mainly supported by animal studies [37] and stud-
ies that addressed the postmortem features and biomechanics
of injury to the cervical facet joints [38]. However, recent work
suggests that cervical facet joints might play a role in (sustain-
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by National University of Singapore on 06/20/14
ing) CS in humans with chronic pain following whiplash
injury [39,40]. In an uncontrolled observational study, cervical
radiofrequency neurotomy attenuated CS in patients with
chronic pain following whiplash injury up to 3 post-treat-
ment [39]. CS decreased in terms of widespread quantitative
sensory testing and the nociceptive flexion reflex. Still, a
substantial number of patients with chronic pain following
whiplash injury did not respond to cervical radiofrequency
neurotomy [40].
Similar observations were done in patients undergoing
surgery for osteoarthritis. Historically, osteoarthritis pain has
been considered a nociceptive pain related to the degree of
structural joint damage. During the last years, there is a grow-
For personal use only.
ing body of research suggesting the presence of CS in patients
with osteoarthritis pain [4], but at the same time the peripheral
tissue (i.e., subchondral bone and surrounding tissue damage)
cannot be ignored. This makes us wonder whether eliminat-
ing the peripheral source of nociception might lead to ‘curing’
CS in patients with osteoarthritis. One study revealed that
osteoarthritis patients who underwent total hip arthroplasty
exhibited a reduction in widespread pressure pain hyperalgesia
over local and distant pain-free areas as compared with before
surgery and as compared with the patients assigned to waiting
list [41]. The authors concluded that altered pain processing
seems to be driven by ongoing peripheral joint pathology [41].
Still, not all attempts to ‘remove’ the peripheral source of
nociception in patients with osteoarthritis are successful, as
shown by data from patients undergoing total knee replace-
ment surgery for osteoarthritis. Literature data show that up
to 20% of patients undergoing a total knee replacement are
dissatisfied with the postsurgical outcome, complaining of
persisting pain, functional disability and poor quality of life
[42-44]. Revision rates are estimated at about 6% after 5 years
and 12% after 10 years [45]. Not surprisingly, CS is often pres-
ent in those undergoing revision of total knee replacement
surgery [46].
Another example of an attempt to decrease CS by eliminat-
ing or decreasing peripheral nociceptive input comes from the
work done in patients with myofascial pain syndrome, which
is characterized by the presence of myofascial trigger points.
The pain associated with myofascial trigger points is thought
to arise from a hypersensitive nodule in a taut band of the
skeletal muscle [47], and they activate muscle nociceptors [48].
Upon sustained noxious stimulation, myofacsial trigger points
Expert Opin. Pharmacother. (2014) 15(12)
Treatment of CS in patients with ‘unexplained’ chronic pain
might contribute or initiate CS pain [49]. Indeed, the vicinity
of myofascial trigger points differs from normal muscle tissue
by its lower pH levels (i.e., more acid), increased levels of
substance P, calcitonin gene-related peptide, TNF-a and
IL-1b, each of which has its role in increasing pain sensitiv-
ity [50]. Sensitized muscle nociceptors are more easily activated
and may respond to normally innocuous and weak stimuli
such as light pressure and muscle movement [48,50].
Hence, it seems rational to target myofascial trigger points
for the treatment of nociceptive pain and even CS pain.
A recent randomized trial reported that a single session of
trigger point dry needling decreases widespread pressure sensi-
tivity in patients with acute mechanical neck pain [51].
Although compelling, CS is unlikely to be a dominant feature
in patients with mechanical neck pain, which per definition is
restricted to nociceptive rather than CS pain. A more relevant
condition characterized by CS is fibromyalgia. Affaitati et al.
studied the effect of trigger point or joint injection/
hydroelectrophoresis as a way to treat peripheral pain genera-
tors in patients with fibromyalgia [52]. Compared with placebo
treatment, the active treatment group experienced increased
pain thresholds at all sites (at the tender points and the non-
painful site) [52], suggesting that even in a complex condition
like fibromyalgia, local treatments targeting peripheral sources
of ongoing nociception might have short-term benefits on the
mechanism of CS.
Besides targeting peripheral sensitization, it is hypothesized
that dry needling might also influence central pain processing,
by activating Ab- and Ad fibers sending afferent signals to the
dorsolateral tracts of the spinal cord that could activate the
supraspinal and higher centers involved in pain processing.
This might activate gate control and conditioned pain modula-
tion and the release of opioids, serotonin and catecholamines
[49], but this hypothesis requires further study. Finally, topically
applied analgesic therapies are often targeting peripheral noci-
ceptive input and are discussed below in the pharmacotherapy
section.
It is concluded that limited evidence in selected chronic
pain patients supports treatment strategies that eliminate
peripheral nociceptive input for the effective management of
CS pain. Hence, the focus of the treatment of CS pain in gen-
eral should be targeted at the brain, which will be the focus of
the remaining part of the paper. Pharmacological options will
be addressed first, followed by conservative interventions.
3.Pharmacotherapy potentially targeting
CS pain
In the 2011 paper, a comprehensive overview of pharmaco-
logical options for the treatment of CS pain was provided [27].
Here we provide a summary of current pharmacological
options, together with new treatment avenues. For a thorough
understanding of the pharmacological treatment of CS pain,
it is important to realize that pharmacological agents like non-
steroidal anti-inflammatory drugs and coxibs have peripheral
3
 J. Nijs et al.
effects, are therefore only advisable for decreasing peripheral
nociceptive input in patients with CS pain. Unless peripheral
nociceptive input plays a major role in the clinical picture of
the chronic pain, which is most often not the case, pharmaco-
logical agents with peripheral effects will most often not result
in amelioration of CS pain itself. This view is in line with our
reasoning presented in the preceding section on targeting CS
pain with a bottom-up strategy.
Several centrally acting drugs are available that specifically
target processes known to be involved in CS pain. Here
we provide a summary of the way drugs employed in the
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treatment of chronic pain interact with these processes,
including the interaction of NMDA-receptor blockers such
as ketamine; opioids; tricyclic antidepressants such as
amytryptiline; selective-serotonin reuptake inhibitors and
serotonin noradrenaline reuptake inhibitors (SNRI) with
descending pathways that link the brain with the modulation
and enhancement of pain. Likewise, the ability of drugs such
as gabapentin/pregabalin to alter the excitability of the CNS is
also discussed. It should also be remembered that these drugs
may also have a significant supraspinal mechanism of action,
in particular antidepressants, which may act on the significant
psychological component of pain perception and thus allow
patients to better cope with their pain [53].
For personal use only.
Descending control of pain entails an extremely sophisticated
grouping of CNS actions (reviewed in [54]). Acetaminophen
(paracetamol) primarily acts centrally: it reinforces descending
inhibitory pathways [55], namely, the serotonergic descending
pain pathways [56,57]. The presumed action includes activation
of the periaqueductal gray matter, which in turn activates
descending serotonergic and noradrenergic neurones that
activate the rostral ventromedial medulla and the dorsolateral
pons respectively, and animal work suggests that acetamino-
phen actually may interact with cannabinoids [58]. We recently
reported the first study comparing the influence of acetamino-
phen on descending control of pain (i.e., conditioned pain
modulation) and temporal summation in healthy controls and
patients with fibromyalgia/chronic fatigue syndrome and rheu-
matoid arthritis [59]. It was found that acetaminophen may have
a limited positive effect on central pain inhibition, but other
contributors have to be identified and evaluated. After intake
of acetaminophen, pain thresholds increased slightly in the
fibromyalgia/chronic fatigue syndrome patients and decreased
in the rheumatoid arthritis and control group [59]. The observed
differences among the chronic pain groups can be explained by
the notion that fibromyalgia/chronic fatigue syndrome patients
present more central pain processing abnormalities than
rheumatoid arthritis patients. Another report highlighted
that acetaminophen does little to improve brain-orchestrated
endogenous analgesia in response to exercise in either patients
with rheumatoid arthritis or fibromyalgia/chronic fatigue
syndrome [60].
A more powerful way of facilitating descending control
entails pharmacological stimulation of the availability of brain
neurotransmitters like serotonin and noradrenaline. For
4 Expert Opin. Pharmacother. (2014) 15(12)
instance, selective serotonin reuptake inhibitor drugs activate
serotonergic descending pathways that recruit, in part, opioid
peptide-containing interneurons in the dorsal horn [61]. Rela-
tively selective serotonin reuptake inhibitors, like fluoxetine
and clomipramine, and the serotonin precursor tryptophan
prevent stress-induced hyperalgesia in animals [62]. However,
not all central serotonin receptors result in analgesia,
5HT-3 spinal receptors are in fact pronociceptive [63].
SNRI (e.g., duloxetine) activate noradrenergic descending
pathways together with serotonergic pathways [54]. This dual
control may be one way in which the brain can alter pain
processing and may be the route by which sleep, anxiety, cop-
ing and catastrophizing can impact upon the level of pain per-
ceived. Humans studies have also shown that inhibiting
reuptake of both these monoamines is more effective than
inhibiting just serotonin alone [64]. Although effective for
the treatment of pain in a variety of human chronic pain con-
ditions characterized by CS (e.g., fibromyalgia [65] and osteo-
arthritis [66]), it remains unclear whether SNRI decrease the
hyperexcitability of the CNS, and whether the clinical effects
can be reinforced by using other treatment strategies discussed
here. Still, human research has taught us that SNRI (i.e.,
duloxetine) improve condition pain modulation [67].
A variety of opioids are available for clinical use: codeine,
dextropropoxyphene, tramadol (serving as a reuptake inhibi-
tor of serotonin and norepinephrine in addition to its opioid
effects), buprenorphine, morphine, methadone, fentanyl,
hydromorphone, among others. Opioids target opioid recep-
tors (µ1, µ2, d 1, d2, k1, k 2 and k 3-opioid receptors), with
the µ-opioid receptors as the most significant. Endogenous
opioid peptide-containing neurons are located in a wide vari-
ety of CNS regions involved in pain processing: in lamina II,
III, VIII and IX of the dorsal horn (i.e., presynaptic Ad- and
C-fibers, postsynaptically on interneurons and projection
neurons), thalamus, periaqueductal grey, limbic system and
several regions of the cortex [68]. The rostral ventromedial
medulla, an important brainstem center for controlling the
balance between nociceptive inhibition and nociceptive facili-
tation, contains both ON cells (involved in descending facili-
tation of nociceptive information) and OFF cells (involved in
descending inhibition). Morphine is typically referred to as an
opioid analgesic because it excites OFF cells (µ-opioid
agonist) and suppresses ON cells (d-opioid agonist), and it
produces analgesia in animals at least in part by stimulation
of GABA-neurotransmission [26]. Buprenorphine is selectively
antihyperalgesic and differs from other opioids [69].
However, opioids not only exert analgesic effects. Opioids
commonly cause a selective pain sensitization [70]. Opioid-
induced hyperalgesia implies the activation of pronociceptive
pathways by exogenous opioids that results in facilitation of
CS pain [71,72]. Opioids also have powerful positive effects
on the reward and reinforcing circuits of the brain that might
lead to continued drug use, even if there is no abuse or
misuse [71]. Nevertheless, patients may function better with
opioids, which supports cautious opioid use in carefully

selected and well-monitored patients. Most available practice
guidelines recommend avoiding doses greater than 90 --
200 mg of morphine equivalents per day, recognizing risks
of fentanyl patches, titrating cautiously and reducing doses
by at least 25 -- 50% when switching opioids [73].
Tramadol is a novel analgesic agent that has some activity
at µ-receptors, although the binding affinity for brain opioid
receptors seems to be low [74,75]. It especially inhibits the reup-
take of serotonin as well as norepinephrine [74]. Bianchi and
Panerai [75] have shown that tramadol is able to prevent and
reverse CS in rats.
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With its dual mode of action, the µ-opioid receptor (MOR)
agonist and noradrenaline reuptake inhibitor (MOR-NRI) is
proposed as a new class of analgesics [76]. Tapentadol is proposed
as the first representative of this new pharmacological class of
centrally acting analgesics [76]. Its analgesic effects can be
explained by the synergistic interaction of MOR agonistic
properties and the descending inhibition arising from the
noradrenaline-reuptake inhibition [76]. In the context of the
pathophysiological complexity and multiple mechanisms
involved in CS, MOR-NRIs targeting different pain mecha-
nisms seem promising in generating efficacious ‘desensitization’.
The N-methyl-D-aspartate receptor in the dorsal horn of
the spinal cord has been demonstrated to play a role in the
For personal use only.
development of CS pain. N-methyl-D-aspartate-receptor antago-
nists have been demonstrated to be analgesic in some settings,
and the commercially available antagonists are being explored
for clinical use [77]. Blockade of excitation with N-methyl-D-
aspartate-receptor antagonists may limit or reduce the spread
of hyperalgesia and allodynia due to sensitization and in
consequence, N-methyl-D-aspartate-receptor antagonists may
be seen preferentially as antihyperalgesic or antiallodynic agents
rather than as traditional analgesics [78]. Given the widespread
distribution and functionality of N-methyl-D-aspartate-recep-
tors, the introduction of an antagonist will also disrupt normal
essential N-methyl-D-aspartate-signaling within the CNS,
explaining numerous side effects. Therefore, more selective sys-
temic N-methyl-D-aspartate-receptor antagonists (such as the
modulation of other binding sites within the N-methyl-D-
aspartate-receptor complex) or selective administration of N-
methyl-D-aspartate-receptor antagonists [53,79] are introduced.
A recent randomized controlled trial has demonstrated no ben-
efit to adding the N-methyl-D-aspartate-receptor blockers keta-
mine to morphine on morphine tolerant cancer patients [80-82].
Pregabalin binds to a2d subunit of voltage-gated calcium
channels, and it reduces Ca2+ influx during depolarization
and reduces the release of glutamate, noradrenaline and
substance P [74].
Given the cardinal role of (long-term stress induced)
decreased GABA-neurotransmission in the etiology and sus-
tainment of CS [26,83], GABA-agonists like pregabalin that stim-
ulate GABA-neurotransmission appear appropriate for the
treatment of CS pain. Likewise, gabapentin may increase syn-
thesis of GABA glutamate in neurologic tissue. Pregabalin and
gabapentin are classified as calcium channel a2d ligands.
Expert Opin. Pharmacother. (2014) 15(12)
Treatment of CS in patients with ‘unexplained’ chronic pain
The awareness is growing that neurotrophic factors, like
brain-derived neurotrophic factor (BDNF), have a cardinal
role in initiating and/or sustaining the hyperexcitability of the
CNS in CS pain. Therefore, potential pharmacological manip-
ulation of such neurotrophic factors requires mentioning here.
In general, BDNF has a strong protective action in the brain
and the nervous system. This notion is supported by animal
findings of anti-inflammatory action of BDNF on the brain [84]
and decreased cortical cell death after the administration of
BDNF [85]. However, in relation to (CS) pain another picture
arises. Spinal cord BDNF contributes to the development and
maintenance of CS pain by activation of the dorsal horn
NR2B-containing N-methyl D-aspartate receptors [86]. At the
brain level, BDNF has been shown to activate descending noci-
ceptive facilitation in the nucleus raphe magnus [87]. These are
only two out of many (candidate) pathways for explaining the
sensitizing effects of BDNF of central nociceptive pathways [88].
For decreasing BDNF levels in patients with CS pain, several
potential therapeutic options are available, including regular
exercise therapy (further discussed below) and melatonin.
Administration of melatonin has been shown to reduce not
only pain but also BDNF levels in patients with chronic pelvic
pain [89], a disorder often characterized by CS pain. Further
clinical research in this area is warranted.
Topically applied analgesic therapies, which target peripheral
nerves and soft tissue at a specific place, have been used
throughout history to treat a variety of patient conditions
that present with pain. The use of topical analgesics may be
associated with fewer patient systemic side effects than are
seen with oral, parenteral or transdermally administered
agents, making the topical route of administration attractive
to prescribers and patients and may be able to provide a
method to prevent or reverse the phenomena of peripheral
and CS, or the neuroplastic changes believed to be responsible
for the transition from acute to chronic pain states in
patients [90]. Topical agents, for example, capsaicin and lido-
caine, are attractive for the treatment of chronic pain and
CS pain as they cause few systemic side effects. The latter is
especially interesting in those with CS as hypersensitivity for
chemicals and medication may be present as well.
Lidocaine alters signal conduction in neurons by blocking
the fast voltage gated sodium (Na+) channels in the neuronal
cell membrane that are responsible for signal propagation [91].
With sufficient blockage the membrane of the postsynaptic
neuron will not depolarize and will thus fail to transmit an
action potential. This creates the anesthetic effect by not merely
preventing nociceptive signals from propagating to the brain
but by stopping them before they begin. The efficacy of capsa-
icin patches, an ingredient of hot peppers, is less established.
Capsaicin initially stimulates heat-sensitive vanilloid receptors
on C-fiber nociceptors. Upon continuous use, the vanilloid
receptor will allow a toxic calcium-influx into the C-fiber,
ultimately leading to degeneration of the nociceptor.
Both topical analgesics are often used in neuropathic pain,
but by taking away the possible peripheral source of
5
 J. Nijs et al.
nociception, this may provide a method to prevent or reverse
the phenomena of peripheral and CS. On the other hand, one
must be cautious with applying these topical analgesics as this
might further strengthen the (often) pure biomedical beliefs
and expectations of the patients, by ‘sticking to the periphery’,
without targeting central pain processing.
Finally, it seems that also metabolic factors may be related to
central pain processing. There is growing evidence in favor of
low-carbohydrate or ketogenic diets in order to diminish
hyperexcitability of the CNS in case of seizures or chronic
pain. It is indeed known that metabolism influences brain
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activity [92]. A ketogenic diet is very high in fat, with sufficient
protein and restricted carbohydrates. It alters metabolism so
that ketones are burned instead of glucose.
First, it has long been known that reducing glucose metab-
olism influences pain. There is an overall increase in pain
thresholds (and thus reduced pain) when glycolytic enzymes
are inhibited [93]. This effect is mediated centrally [94] and
might involve increased brain/spinal cord inhibition by aden-
osine [95,96]. Inversely, glucose toxicity on local site of the spi-
nal cord can contribute to the development of spinally
mediated hyperalgesia [97]. The high concentration of glucose
results in pain hypersensitivity probably by disrupting the
functions of cell mitochondria and subsequent generation of
For personal use only.
reactive oxygen species and oxidative stress [98] and activating
microglia [99]. Up to now the use of ketogenic diets has only
been established as a successful anticonvulsant therapy. But
based on overlap between mechanisms postulated to underlie
pain and mechanisms postulated to underlie therapeutic
effects of ketogenic diets, recent studies have explored the
ability for ketogenic diets to reduce pain [100].
Although it is known that ketogenic diets reduce central
excitability [101], theories are divided as to whether these
effects are produced directly by ketones and/or low glucose,
fatty acids, or downstream metabolic effects [102-104].
A number of inhibitory mechanisms are hypothesized to
underlie the efficacy of the ketogenic diet: for example, activa-
tion of K1 channels, adenosine A1 receptors or gamma ami-
nobutyric acid receptors, all causing hypoalgesia [105-107].
In addition to pharmacological treatment of CS, other
options are available for (in)direct targeting of the complex
mechanisms involved in CS pain. For instance, conservative
approaches targeting cognitive-emotional sensitization include
therapeutic pain neuroscience education and cognitive behav-
ioral therapy. Exercise therapy for patients with chronic pain
aims at activating endogenous analgesia. These conservative
treatment options will be explained below.
4. Conservative therapy targeting CS pain
4.1Pain neuroscience education
The presence of CS implies that the brain produces pain and
other ‘warning signs’ even when there is limited or no tissue
damage or nociception. Therapists familiar with modern
pain neuroscience and the mechanism of CS understand
6 Expert Opin. Pharmacother. (2014) 15(12)
this, but it is cardinal for the patient to understand it as
well. This can be addressed by in-depth patient education
about pain neuroscience, a strategy known as pain neurosci-
ence education. Research findings have repeatedly shown
that such pain neuroscience education is therapeutic on its
own, with level A evidence supporting its use for changing
pain beliefs and improving health status in patients with CS
pain (e.g., fibromyalgia, chronic fatigue syndrome, chronic
low back pain) [108].
Practice guidelines for therapeutic pain neuroscience
education were presented previously [109]. Detailed pain neuro-
science education is required to reconceptualize pain and to
convince the patient that hypersensitivity of the CNS rather
than local tissue damage may be the cause of their presenting
symptoms. Hence, therapeutic pain neuroscience education is
changing pain beliefs through the reconceptualization of
pain [110-113]. Inappropriate pain beliefs and cognitions, such
as pain catastrophizing, anxiety, hypervigilance and kinesio-
phobia, have been shown to contribute to sensitization of
the dorsal horn spinal cord neurons (through inhibition of
descending tracks in the CNS) [114-117]. By changing these
maladaptive pain beliefs and cognitions, therapeutic pain
neuroscience education might be able to ‘treat’ core features
of CS, namely, descending nociceptive facilitation, the overac-
tive pain neuromatrix and endogenous analgesia. A recent ran-
domized controlled clinical trial has shown that therapeutic
pain neuroscience education, compared with activity pacing
self-management education, resulted in improved endogenous
analgesia in patients with fibromyalgia at 3 months post-
treatment [28]. Endogenous analgesia was evaluated by spatially
accumulating thermal nociceptive stimuli (by immersing
the arm gradually in hot (46 C) water), a paradigm known
as diffuse noxious inhibitory controls or conditioned pain
modulation [28].
4.2 Exercise therapy
Therapeutic pain neuroscience education prepares patients for
a time-contingent, cognition-targeted approach to daily
(physical) activity and exercise therapy. Therapeutic pain neu-
roscience education is a continuous process initiated during
educational sessions prior to and continuing into active treat-
ment and followed up during the longer term rehabilitation
program [109], through specific exercise therapy.
Why preferring a time-contingent approach (‘Perform the
exercise for 5 min, regardless of the pain’) over a symptom-
contingent approach (‘Stop the exercise once it hurts’)? As
indicated above, CS implies that the brain can produce pain
and other ‘warning signs’ even when there is no real tissue
damage. A symptom-contingent approach may facilitate the
brain in its production of nonspecific warning signs like
pain, whereas a time-contingent approach may deactivate
brain-orchestrated top-down pain facilitatory pathways.
This view is supported by findings of reduced CNS hyperex-
citability [118] and an increase in prefrontal cortical

volume [119] in response to time-contingent graded activity
treatment in chronic pain patients.
In addition to its potential effects on cognitive-emotional
sensitization, exercise therapy has the capacity to activate
brain-orchestrated endogenous analgesia in patients with
chronic pain [120]. In healthy people and some patients with
chronic pain (including those with chronic low back
pain [121,122], shoulder myalgia [123] and rheumatoid arthri-
tis [60]), exercise activates powerful top-down pain inhibitory
action, typically referred to as exercise-induced endogenous
analgesia [124]. However, some patients with CS pain, includ-
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by National University of Singapore on 06/20/14
ing those with chronic whiplash associated disorders [125],
chronic fatigue syndrome [126] and fibromyalgia [123], are
unable to activate endogenous analgesia following exer-
cise [120]. It remains to be established whether long-term exer-
cise therapy accounting for the dysfunctional endogenous
analgesia is able to ‘treat’ CS in these patients [120]. One pos-
sible pathway through which exercise therapy might exert its
anti-CS effects is by influencing neurotropic factors. Indeed,
habitual and regular exercise, in contrast to temporary
exercise, decreases BDNF blood levels [127].
4.3 Cognitive behavioral therapy
Several studies have shown associations between maladaptive
For personal use only.
pain cognitions and measures of CS [115-117,128]. For instance,
pain catastrophizing, anxiety, depression and anticipation of
pain are important associates of CS [115-117,128]. To address the
cognitive-emotional sensitization, interventions such as cogni-
tive behavioral therapy target maladaptive pain cognitions.
Pain neuroscience education motivates patients for
applying cognitive behavioral strategies to cope with their
pain. This is done by explaining them that they have little
chance of controlling peripheral nociceptive input, but may
exert volitional control over top-down mechanisms. Indeed,
cognitive behavioral therapy for chronic pain aims at increas-
ing self-control over the cognitive and affective responses to
pain. Again, this might deactivate brain-orchestrated top-
down pain facilitatory pathways, as evidenced by reduced
CNS hyperexcitability [118] and increase in prefrontal cortical
volume [119] following cognitive behavioral therapy in chronic
pain patients. Still, more research is required to examine the
real value of cognitive behavioral therapy for the treatment
of CS pain.
5. Conclusion
An overview of the treatment options for desensitizing the
CNS in patients with CS pain was provided. The review
discussed pharmacological and conservative treatments with
established clinical effectiveness in a variety of ‘unexplained’
chronic pain disorders, known to be characterized by CS.
Addressing pharmacotherapy, it is concluded that acetamino-
phen, serotonin reuptake inhibitor drugs, selective and
balanced serotonin and norepinephrine reuptake inhibitor
drugs, the serotonin precursor tryptophan, opioids, combined
Expert Opin. Pharmacother. (2014) 15(12)
Treatment of CS in patients with ‘unexplained’ chronic pain
µ-opioid receptor agonist and noradrenaline reuptake inhibi-
tor drugs, NMDA-receptor antagonists and calcium channel
a2d ligands each target central pain processing mechanisms
in animals and theoretically desensitize the CNS in humans.
Ketogenic diets are a promising avenue for decreasing the
hyperexcitability of the CNS in patients with CS pain. How-
ever, little is known about the effect of pharmacotherapy on
the mechanism of CS in humans. Exploring the effects of
pharmacotherapy on the mechanism of CS pain should be
a priority for further research. The same goes for the role of
metabolic processes.
In case of ongoing nociceptive input, it seems rational to
target at least part of the therapy to eliminating peripheral
sources of such nociceptive input. Some work was done to
explore this view and its effects on CS. Treatments such as
topically applied analgesic therapies, cervical radiofrequency
neurotomy for cervical facet joint pain, joint replacement sur-
gery for osteoarthritis pain and local therapy for myofascial
pain are promising strategies for treating CS by eliminating
peripheral sources of nociceptive input. Still, more work
is required to confirm preliminary findings of decreased
sensitivity of the CNS in response to these treatments.
In the area of conservative interventions, limited data
suggest that pain neuroscience education and cognitive
behavioral therapy exert positive effects on mechanisms
involved in CS pain. These therapies aim at improving voli-
tional control over top-down pain facilitatory pathways,
targeting the cognitive-emotional aspect of sensitization.
This can be further substantiated by applying time-contingent
rather than pain-contingent exercise therapy for patients with
CS pain. In addition, exercise therapy should aim at activating
endogenous analgesia in patients with CS pain.
From the overview provided, it becomes clear that many of
these treatment options target similar mechanisms. For example,
morphine and gabapentin enhance GABA-neurotransmission
in the CNS. The majority of the treatment options discussed
here aim at improving/ activating descending inhibitory action
together with decreasing descending nociceptive facilitation,
rather than targeting peripheral sources of nociceptive input.
In the absence of clinically relevant peripheral source of
nociceptive input, as is often the case in patients with CS pain,
a treatment targeting top-down mechanisms is required.
From what is explained above, it becomes clear that
clinicians are advised to think within the framework of CS
pain. This allows them to adopt their clinical reasoning skills
in line with our current understanding of pain neuroscience.
In addition, the call for including established measures of
CS as (primary or at least secondary) outcomes in clinical
trials becomes louder. Established outcome measures for CS
pain include quantitative sensory testing [129], temporal sum-
mation of thermal or mechanical stimuli [130], laser-evoked
potentials [131], nociceptive flexion reflex [132], conditioned
pain modulation [17] and the CS inventory [133]. Trials should
not only focus on causation and effectiveness studies, but also
on dose--response studies. In addition, mediating analyses are
7
 J. Nijs et al.
required before one can conclude that the changes in CS
actually explain the clinically important changes in primary
outcome measures (e.g., decreased pain severity or improved
quality of life).
6. Expert opinion on including
pharmacotherapy in a combined top-down
and bottom-up approach for treating CS pain
As explained in the introduction section, CS entails various,
interrelated maladaptive processes in the CNS, including
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by National University of Singapore on 06/20/14
dysfunctional endogenous analgesia, increased activity of
pain facilitatory pathways, long-term potentiation and an
overactive pain neuromatrix. Hence, it is highly unlikely
that a single drug or conservative treatment will be identified
capable of treating a complex mechanism as CS. Indeed,
patients having CS as underlying mechanism for their pain
represent a heterogeneous population, with medical diagnoses
ranging from low back pain over lateral epicondylalgia to
osteoarthritis and chronic headache. In addition, heterogene-
ity exists in response to pharmacotherapy in those with
chronic unexplained pain, including nonresponders [134]. At
the individual level, the majority responds to two or more
drugs, suggesting that several pain mechanisms have to be tar-
For personal use only.
geted in clinical practice [134]. Thus, instead of using a single
drug, it seems more likely that the combination of different
strategies, each targeting a somewhat different ‘desensitizing’
mechanism, will prove beneficial. The exact content of such
combination is likely to differ across patient groups.
Little work has been done to examine the combined effects
of treatment strategies aiming at desensitizing the CNS.
A randomized controlled clinical trial revealed that repetitive
transcranial magnetic stimulation is efficacious as an add-on
to pharmacotherapy and conservative therapy in patients
with complex regional pain syndrome type I [135]. The com-
bined standardized pharmacological and conservative treat-
ment was based on the best evidence available: naproxen
250 mg bid, amitriptyline 50 mg qd, and carbamazepine
200 mg bid for the pharmacology and kinesiotherapy plus
low impact, aerobic, relaxation and stretching exercises for
the conservative part [135]. Both transcranial magnetic stimula-
tion and pharmacology target top-down mechanisms involved
in CS pain, whereas the physical therapy program might have
addressed both bottom-up and top-down mechanisms.
More recently, Schabrun et al. examined whether a
combined top-down and bottom-up approach is valuable for
the treatment of chronic low back pain [32], a condition in
which CS is often present [3]. In their compelling but small-
scale (n = 16) placebo-controlled crossover study, they inves-
tigated the effect of transcranial direct current stimulation
8 Expert Opin. Pharmacother. (2014) 15(12)
plus peripheral electrical stimulation treatment on pain, corti-
cal organization, sensitization and sensory function in patients
with chronic low back pain. The study findings suggest that a
combined transcranial direct current stimulation plus periph-
eral electrical stimulation more effectively improves cortical
organization and CS, than either intervention applied alone
or a sham control [32].
To provide a comprehensive treatment for ‘unexplained’
chronic pain disorders, characterized by CS, it is advocated
to combine several treatment modalities known to target
CS. When designing such a comprehensive treatment pro-
gram, several reflections need to be made. First, focusing
solely on treating the mechanisms involved in CS would be
disrespectful to evidence based medicine. Hence, such a
comprehensive treatment program should account for the
best available evidence for treating the medical condition of
interest. However, when implementing the best available
evidence, one can often apply it in a way it addresses our cur-
rent understanding of CS. For instance, patient education is
often included in best evidence guidelines for the treatment
of disorders characterized by chronic pain. In such cases, it
is advocated that patient education includes therapeutic pain
neuroscience education for targeting maladaptive pain beliefs
that perpetuate CS and chronic pain. Likewise, exercise
therapy is often a crucial part of evidence-based guidelines
for chronic pain disorders. Exercise therapy can be provided
in such a way that it targets, or at least accounts for the
mechanisms involved in CS pain [120,136].
Second, if relevant to the specific patient it is advocated to
combine a bottom-up with a top-down approach. The
bottom-up part of the treatment should aim at decreasing
the peripheral nociceptive input, as can be the case in patients
with osteoarthritis. The top-down approach might include
several parts, like centrally acting analgesics (e.g., Duloxetine
or any other SNRI), therapeutic pain neuroscience education
and cognitive behavioral therapy. However, when combining
such a peripheral with a central approach to treatment, care
must be taken not to provide contradictory information to
the patients. In such cases, the explanation of the rationale
of the different parts of the treatment should be included in
the therapeutic pain neuroscience education.
Declaration of interest
The authors have no relevant affiliations or financial involve-
ment with any organization or entity with a financial interest
in or financial conflict with the subject matter or materials
discussed in the manuscript. This includes employment,
consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.

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Affiliation
Jo Nijs†1,2,3, Anneleen Malfliet1,2,4,
Kelly Ickmans1,2, Isabel Baert1,5 &
Mira Meeus1,4,5
†
Author for correspondence
1
Pain in Motion Research Group, Brussels,
Belgium
2
Vrije Universiteit Brussel, Departments of
Human Physiology and Physiotherapy, Faculty of
Physical Education & Physiotherapy, Medical
Campus Jette, Building F-Kine, Laarbeeklaan
103, BE-1090 Brussels, Belgium
Tel: +3224774489;
Fax: +3226292876;
E-mail: Jo.Nijs@vub.ac.be
3
University Hospital Brussels, Department of
Physical Medicine and Physiotherapy, Brussels,
Belgium
4
Ghent University, Department of Rehabilitation
Sciences and Physiotherapy, Ghent, Belgium
5
University of Antwerp, Department of
Rehabilitation Sciences and Physiotherapy,
Antwerp, Belgium
13