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PAIN 155 (2014) 663–665
www.elsevier.com/locate/pain
Topical review
Pain modulation profile and pain therapy: Between
pro- and antinociception
David Yarnitsky a,b,⇑, Michal Granot c, Yelena Granovsky a,b
a
Department of Neurology, Rambam Medical Center, Haifa, Israel
Clinical Neurophysiology Lab, Technion Faculty of Medicine, Haifa, Israel
c
Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel
b
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
1. Introduction
A large body of knowledge has been generated on human pain
modulation when pain-free and when experiencing pain on the
basis of, among other tools, psychophysical dynamic stimulation
protocols, which utilize a spatial and/or temporal array of stimuli
in order to evoke an experimental process of pain modulation.
Protocols designed to evoke inhibition or facilitation of pain are believed to better depict the clinical pain experience than the classical static parameters, such as pain thresholds. A commonly used
protocol for pain inhibition is based on the diffuse noxious inhibitory control (DNIC) effect, typically using 2 remote painful stimuli,
whose interaction generates, in most cases, pain inhibition [12]
(for review, see Pud et al. [21]). The term conditioned pain modulation (CPM) was coined for the psychophysical protocols that
explore DNIC in humans [28]. The protocols for pain facilitation
use temporal summation (TS), where pain reports are obtained
along a series of identical stimuli [19]. The common response is
an increase in pain ratings along the series representing the physiological phenomenon of windup. Evaluation of response to these
arrays of experimental pain can be a useful clinical tool; it can
predict future pain [27] and predict the efficacy of analgesics
[29]. Although the current data do not allow practical implementation, the following hypothesis may carry the translation of pain
modulation into practice.
2. Hypothesis
Lab-based pain modulation, for which the term pain modulation
profile (PMP) is suggested, ranges between inhibitory and facilitatory ends. We propose that on the basis of CPM and/or TS
responses, which indicates the inhibitory/facilitatory balance,
individuals can be positioned on a clinical spectrum between pron⇑ Corresponding author at: Department of Neurology, Rambam Health Care
Campus, Haifa, Israel. Tel.: +972 48542605; fax: +972 48542755.
E-mail addresses: [email protected], [email protected]
(D. Yarnitsky).
ociception and antinociception. Thus, an individual expressing
low-efficiency CPM and/or enhanced TS positioned on the
pronociceptive side of the spectrum would express a higher pain
phenotype, resulting, for example, in higher risk of pain acquisition. In turn, an individual expressing efficient CPM and/or nonenhanced TS located on the antinociceptive side would express a
lower clinical pain phenotype (Fig. 1).
3. Evidence
Convincing evidence associates pain-lab-based altered pain
modulation and clinical pain morbidity, mostly describing a pronociceptive pain modulation in pain patients compared to controls.
For CPM, less efficient inhibitory pain modulation was reported for
several pain syndromes, including fibromyalgia [7,10], irritable
bowel syndrome [2], migraine [22], tension headache [18], temporomandibular disorder [14], osteoarthritis and muscle pain [8], and
whiplash [3] (see also review in [13]). For TS, enhanced pain facilitation has been documented in fibromyalgia [20], osteoarthritis
[1], migraine [25], and temporomandibular disorder [23]. Several
articles have also reported co-occurrence of both enhanced TS
and less efficient CPM in pain patients, such as osteoarthritis [1],
cluster headache [17], and chronic postmastectomy pain [4]. Thus,
a pronociceptive profile seems to be associated with pain morbidity. It is noted that in most of the above articles, assessment of pain
modulation was performed in unaffected body areas, thus representing the generalized pain modulation rather than the modulation of data transmitted from a specific painful region. Notably,
pronociceptive profile was reported in widespread pain disorders
such as fibromyalgia.
The above-mentioned cross-sectional studies do not reveal
whether the interrelations between the modulation profile and
the presence of the various pain syndromes are causative, and if
so, which is primary to the other. It could be, on the one hand, that
a preexisting facilitatory modulation state leads to the establishment of the pronociceptive profile and the acquisition of the
idiopathic pain syndromes; on the other hand, it could be that
0304-3959/$36.00 Ó 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.pain.2013.11.005
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D. Yarnitsky et al. / PAIN 155 (2014) 663–665
Fig. 1. Proposed pain modulation profile and pain phenotypes.
the presence of the pain syndrome consumed the antinociceptive
capacity and led to a pronociceptive profile. We explored these
relationships in a prospective study, where prethoracotomy painfree patients were examined for their pain modulation and were
followed up for acquisition of chronic pain after surgery [27].
CPM efficiency was found to predict chronic postthoracotomy
pain; patients with less efficient CPM had a higher risk of
developing chronic pain, and vice versa. This reasonably
establishes causative relations suggesting pronociceptive PMP as
a pathogenetic factor for future clinical pain. Similar results were
later found by Landau et al. [9] and Wilder-Smith et al. [26] for
cesarean section and abdominal surgery, respectively.
A second key question pertains to the intraindividual plasticity
of the PMP. Two studies on osteoarthritis patients indicated that
PMP is plastic; Kosek and Ordberg [8] found that less efficient
CPM obtained in patients with painful hip osteoarthritis improved
after total hip replacement surgery in parallel with pain alleviation.
Similar results have been reported by Graven-Nielsen et al. [6] for
knee osteoarthritis. Yarnitsky et al. [29] and Niesters et al. [16]
showed that pharmacological alleviation of polyneuropathy pain
improved CPM in proportion to the extent of pain alleviation. In
line with this, parallel reduction of pain and TS response was reported for patients with complex regional pain syndrome after
sympathetic blockade [15]. Thus, PMP seems to change in conjunction with changes in clinical pain.
A third and pertinent issue, one that provides the main motivation for the use of PMP, is its relevance for pain treatment. By being
involved in pain pathogenesis, it is likely that PMP also plays a role
in its alleviation. Targeting a dysfunctional mechanism of pain
modulation by a drug capable of rectifying that dysfunction will
achieve the best pain alleviation. This way, patients with less efficient CPM should benefit more from serotonin norepinephrine
reuptake inhibitors that augment descending inhibition by spinal
monoamine reuptake inhibition than patients whose CPM is already efficient. Similarly, those with enhanced TS should benefit
more from gabapentinoids or NMDA blockers such as ketamine,
which inhibit neuronal sensitization, than those whose baseline
summation was not enhanced.
We examined CPM and TS in painful diabetic neuropathy
patients and found that CPM predicts the efficacy of duloxetine,
an SNRI; patients with less efficient CPM experienced highly efficacious pain reduction, while those with efficient CPM did not gain
benefits from the drug [29]. Further, in the first group, an improvement in CPM efficiency was found along with pain reduction,
whereas no change in CPM was found in the second group.
Similarly, Lavand’homme and Roelants [11] used ketamine for
post-cesarean section pain; they found that the more pronociceptive patients, those with enhanced TS, gained from ketamine,
which attenuates neuronal sensitization, while those with
nonenhanced TS did not benefit from the drug. It thus seems that
identifying the dysfunctional modulation state can be the key to
the choice of drug for pain alleviation. This is a step forward
toward individualized pain medicine.
4. Discussion
On the basis of the described evidence, and in conjunction with
our hypothesis, we suggest the following scenario for the clinical
relevance of pain modulation. (i) A pain-free individual expresses
a certain PMP, be it eu-, pro-, or antinociceptive. Higher
expressions of clinical pain and higher chances of acquiring pain
characterize pronociceptive individuals, and vice versa. (ii) When
experiencing a substantial nociceptive event, modulation is shifted,
and an altered pain modulation of pronociception develops. (iii)
Use of pain-modulating drugs, as is routinely done for neuropathic
pain and often for other sorts of pain, may rectify the dysfunctional
parameter or parameters of PMP; thus, an individual-based
coupling of drug and modulation dysfunction can be established.
(iv) Preventive treatment (eg, migraine prevention or preoperative
preemptive analgesia) shifts the profile toward antinociceptivity
and lowers the pain phenotype (Fig. 2).
A few practical points need to be further clarified to ease clinical
application of PMP: clinical experimental data should be strengthened; better test-to-test reliability of these psychophysical protocols should be obtained by improving them; and further studies
should use various test modalities (ie, thermal, electrical, mechanical) and types of stimuli (ie, phasic, tonic, repetitive) because results seem to depend on these factors. Further, the scientific
basis of the relevant pain modulation paradigms, mainly CPM,
could be widened, clarifying the relations with other top-down
pain-regulating mechanisms, including cognitive and emotional
factors such as stress and anxiety. In addition, the interrelations
between the facilitatory and inhibitory factors and the relative
weight of each in construction of the PMP need further
clarification.
Pain modulation is, of course, not a single player on the stage of
clinical pain, which is affected by the causative diseases in addition
to many genetic and environmentally influenced psychological and
cognitive factors. The alleviation of pain and rectifying of the pronociceptive profile is also influenced by pharmacogenetic factors
and drug interactions. For example, the association between CPM
and pain was found to be mediated by pain catastrophizing [5].
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D. Yarnitsky et al. / PAIN 155 (2014) 663–665
665
Fig. 2. Proposed patterns of change in pain modulation profile in various conditions.
Further, TS was positively associated with anxiety [24]. Therefore,
an assessment of pain-related personality parameters may reveal
their role in determining pain modulation.
A major limitation of the currently proposed easy-to-use singleaxis psychophysical-based scale of pain modulation is that it might
be too simple. Future experience will tell us whether it should be
supplemented by additional factors to potentially achieve more
precise correlates of clinical pain. Another limitation relates to
the prediction of drug efficacy; an attempt was made to couple
the principle mode of action of specific drugs to the patient’s dysfunctional mechanism, but the coupling might be unclear for drugs
with multiple modes of action.
The concept of antinociceptive pain modulation deserves additional attention. Though reasonable, it is currently unknown
whether efficacy of pain prevention, such as in migraine, depends
on achievement of an antinociceptive modulation profile, and consequently whether testing for PMP should become a tool to assess
efficacy of preventive treatment. Further, the notion should be
entertained that achieving an antinociceptive PMP should be the
target of pain therapy for patients with ongoing pain because it
may indicate a more radical change in the pain perceiving system—and possibly one of longer durability—than the standard,
more fragile target of pain reduction.
Conflict of interest
D.Y. received honoraria from speakers’ bureau of Grunenthal
and Pfizer, and an IIT grant from Eli Lilly. The other authors report
no conflict of interest.
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