PAIN 155 (2014) 24442445

www.elsevier.com/locate/pain

Commentary

Conditioned pain modulation and offset analgesia: Different avenues to

inhibit pain
The ability of the body to modulate sensory information has
been a focus of a number of studies over the past several years.
Experimentally, pain modulation can be assessed by a number of
methods including conditioned pain modulation (CPM) and offset
analgesia (OA) as highlighted in the current study by NahmanAverbuch et al. [15]. CPM is frequently demonstrated through the
reductions of a primary painful stimulus (ie, focal heat) by a second
remote conditioning stimulus (ie, cold water immersion
[6,9,17,22,23]). In contrast, OA is demonstrated by using a prolonged thermal pulse in which a slight reduction in the thermode
temperature (ie, 1C) is associated with a transient (10 s) reduction in pain intensity [7,15,16,18,29,30]. Although only a small
number of studies have evaluated CPM and OA in the same cohort
[8,17,18,20], the combined use of these inhibitory models may provide a glimpse into different characteristics underlying an individuals inhibitory phenotype, which could have implications for
future experimental and clinical research.
The study by Nahman-Averbuch et al. [15] was designed to
investigate differences between the psychophysical and neural
correlates of CPM and OA. Using the same thermal stimulation
paradigm (ie, 30 s prolonged pulse at 49C applied to the leg),
the studies demonstrated reductions in the subjective ratings of
heat pain during both concurrent immersion of the contralateral
foot into moderately painful cold water bath (CPM induction)
and following a 1C temperature drop (OA induction)observations that are in agreement with those of previous studies
[6,7,9,10,15,16,23,30]. However, the magnitude of inhibition
observed in the 2 models did not correlate suggesting different
mechanisms underlying inhibition. Conrming the psychophysical data, fMRI assessment of each paradigm demonstrated differences in cortical and subcortical activity. In general, widespread
deactivations were observed in a number of classical pain-related
areas during CPM, which was contrasted by activation in a number of areas including the brain stem region associated with the
periaqueductal gray (PAG) during the OA paradigm. Based on
the current study, differences in the modulation of pain are
dependent on the spatial (CPM) and temporal (OA) presentation
of nociceptive information, which in turn results in a differential
pattern of neurobiological activity in areas involved in pain perception and modulation. More importantly, the study adds to
the discussion about the methods and implications of different

DOI of original article: http://dx.doi.org/10.1016/j.pain.2014.07.008

inhibitory mechanisms (CPM vs OA) and within different inhibitory paradigms (variations of CPM).
What does the current study tell us about pain modulation?
The ndings of the study suggest that experimental manipulations, which result in comparable magnitudes of subjective inhibition, may be a consequence of different neurobiological
mechanisms. This concept is neither surprising nor unexpected,
but the current study demonstrates the complexity of nervous
system in regulating sensory information through multiple
neurological structures and neurotransmitters depending on the
presentation of the stimulus.
Interestingly, the authors comment that inhibition during CPM
appears to be due to spinal inhibition rather than descending
modulation. CPM reects the psychophysical representation [28]
of the previously described phenomenon termed diffuse noxious
inhibitory control, referring to observations by Le Bars and colleagues in which activity within the lower aspect of the brain
stem suppresses activity within the spinal cord [11,12], which
can be indirectly modulated by activity within the PAG [2] and
the rostral ventromedial medulla [1]. In contrast, OA is associated
with increased activity within the PAG and rostral ventromedial
medulla [4,29], although a peripheral component may also exist
[16]. Thus, CPM represents a subjective response to a range of
possible mechanisms, which may include the originally proposed
spino-bulbo-spinal loop described by Le Bars and colleagues, a
spinal-mediated mechanism proposed by Nahman-Averbuch
et al. [15], as well as brain stem, and/or higher-order cortical
regions reported in recent imaging studies (ie, PAG, Anterior Cingulate Cortex [22,24]). Thus, depending on the presentation of the
testing and conditioning stimuli, different mechanisms may be
engaged.
In addition, CPM and OA paradigms can differ in terms of the
underlying neurotransmitter system. Based on experiments with
pharmacological manipulations, CPM appears to be sensitive to
opioids [9,21,26] and the N-methyl-D-aspartate (NMDA) receptor
antagonism [18], a nding that contrasts with OA, which appears
to be resistant to these manipulations [14,19,18]. Recently, similar
differences were observed with tapentadol [20], a dual l-opioid
receptor agonist and norepinephrine reuptake inhibitor. Several
weeks of treatment restored the inhibitory capacity assessed by
CPM in patients with diabetic polyneuropathy but not affect OA,
suggesting differential neuromodulatory tone underlying each
paradigm.

http://dx.doi.org/10.1016/j.pain.2014.08.017
0304-3959/ 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Commentary / PAIN 155 (2014) 24442445

What are the clinical implications of multiple pain modulatory

mechanisms?
The current study also has clinical implications for the evaluation of pain modulation models. Although a reduced capacity to
inhibit pain during CPM is commonly observed in clinical pain
populations (for review, see [27]), only 1 study has reported a
reduction in OA in neuropathic pain patients [19]. Thus, it is
unclear whether a reduction in OA is also observed in other pain
cohorts, or if one or both methods exhibit comparable inhibitory
decits. Considering recent evidence that the efciency of CPM
[5,13] and other modulatory mechanisms [25] appears to be intact
in patients, the evaluation of multiple paradigms may provide
additional information about the inhibitory phenotype of the participant [3]. For example, a proportion of patients may have an
intact descending pain system as assessed by CPM, but they may
fail to engage neurological mechanisms underlying OA. While
balancing the burden to the participant, studies could incorporate
a multiple step evaluation of several inhibitory paradigms, which
could include incorporating assessments of both CPM and OA
paradigms within a testing protocol. The use of CPM and OA may
indicate a selective or widespread dysfunction of inhibitory
mechanism, and imaging will assist in this investigation.
In sum, the study by Nahman-Averbuch et al. [15] adds to the
current literature regarding the neurobiological mechanisms
involved in pain inhibition. In order to understand these mechanisms better, additional research is needed to determine if methodological factors including variations of testing paradigms
including CPM (ie, different conditioning stimuli, temporal and
spatial presentation of stimuli) alter these neurological proles in
addition to how these mechanisms differ in individuals with
chronic pain. I anticipate that the current study will encourage
additional investigation into the neurobiological mechanisms
underlying inhibition.
Conict of interest
The author is aware of no conicts of interest regarding this
commentary.
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Christopher D. King
University of Florida Pain Research and Intervention Center of Excellence
(PRICE), Gainesville, FL 32610, USA
E-mail address: cking@dental.u.edu