Individual Differences in Pain: Understanding the Mosaic that
Makes Pain Personal
Roger B. Fillingim, PhD
University of Florida College of Dentistry and Pain Research & Intervention Center of Excellence
Abstract
The experience of pain is characterized by tremendous inter-individual variability. Multiple
biological and psychosocial variables contribute to these individual differences in pain, including
demographic variables, genetic factors, and psychosocial processes. For example, sex, age and
ethnic group differences in the prevalence of chronic pain conditions have been widely reported.
Moreover, these demographic factors have been associated with responses to experimentally-
induced pain. Similarly, both genetic and psychosocial factors contribute to clinical and
experimental pain responses. Importantly, these different biopsychosocial influences interact with
each other in complex ways to sculpt the experience of pain. Some genetic associations with pain
have been found to vary across sex and ethnic group. Moreover, genetic factors also interact with
psychosocial factors, including stress and pain catastrophizing, to influence pain. The individual
and combined influences of these biological and psychosocial variables results in a unique mosaic
of factors that contributes pain in each individual. Understanding these mosaics is critically
important in order to provide optimal pain treatment, and future research to further elucidate the
nature of these biopsychosocial interactions is needed in order to provide more informed and
personalized pain care.
Introduction
It has long been appreciated that individuals differ from each other in important ways. More
than 2,000 years ago Plato said: “No two persons are born exactly alike; but each differs
from the other in natural endowments (360 B.C.).” Such individual differences are a
hallmark of the experience of pain and have been a topic of keen interest to pain researchers
for many years. Indeed, more than 70 years ago, in describing the rationale for their
psychophysical study of pain sensitivity in healthy adults, Chapman and Jones [13] stated
that “A striking variation in the intensity of pain, experienced in diseases with apparently
similar lesions, is a common observation.” Historically, this inter-individual variability in
pain response was more often viewed as a nuisance than a fruitful area of scientific inquiry;
however, the genomic revolution and the ensuing promise of precision medicine have
reinvigorated and legitimized scientific interest in individual differences [12; 18; 21; 52].
The purpose of this article is to provide an overview of factors contributing to individual
differences in pain. Given the abundance of potential individual difference factors, I will not
Roger B. Fillingim, PhD, University of Florida, 2004 Mowry Road, PO Box 100404, Gainesville, FL, USA 32610-0404, Phone:
352-273-5963, FAX: 352-273-5985, rfilling@ufl.edu.
HHS Public Access
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attempt a comprehensive review of this field, rather provide examples of individual
differences from our own research as well as the work of other investigators. First, I will
introduce the topic of individual differences in responses to pain and its treatment, including
a biopsychosocial context for conceptualizing individual differences. Then, I will present
findings regarding demographic factors that are associated with individual differences in
pain. Next, I will discuss genetic and psychosocial contributions to individual differences,
and I will present examples of interactions among these multiple individual difference
factors. I will describe the clinical implications of individual differences in pain, followed by
conclusions and recommendations for future research.
By definition pain is a subjective and highly personal experience, which presents challenges
for both the researcher and clinician. A well-recognized challenge resulting from the
subjective
nature of pain is that direct measurement of pain is impossible, rather we must
rely on individuals’ self-report, and to some extent their behavior, to provide a glimpse into
their experience. However, an equally important but less often discussed challenge results
from the
highly personal
nature of the pain experience; the experience of pain is sculpted by
a mosaic of factors unique to the person, which renders the pain experience completely
individualized. That is, there are pervasive and important individual differences in pain, and
these individual differences produce pain experiences that are completely unique to the
person experiencing them (i.e. they make the pain personal). For purposes of this paper, I
will define individual differences in pain as between person differences in the pain
experience that are independent of the initiating stimulus. Perhaps the simplest manifestation
of individual differences is that an experimental stimulus delivered at a standardized
intensity elicits subjective pain reports that vary dramatically between individuals (Figure
1), as noted decades ago by Chapman and Jones [13] and more recently by others [16; 26;
71; 86]. Interestingly, these differences in self-reported pain are corroborated by inter-
individual differences in cerebral activation evoked by the same painful stimulus [14] and
are in part predicted by individual differences in brain morphology [25], suggesting that
these individual differences are not simply a product of idiosyncrasies in the reporting of
pain. Such individual differences also emerge in the clinical environment. For example, pain
reports following the same surgical procedure vary greatly across patients [7; 43; 83].
Similarly, responses to pain treatments are characterized by robust individual differences [3;
5; 11; 52]; however, a discussion of factors contributing to variability in treatment responses
is beyond the scope of this article, which will focus on the individual difference factors
impacting the experience of pain.
The biopsychosocial model provides an ideal framework for conceptualizing individual
differences in pain. This model posits that the experience of pain is influenced by complex
and dynamic interactions among multiple biological, psychological, and social factors [37].
Importantly, the ensemble of biopsychosocial factors contributing to the experience of pain
and its expression varies considerably across people. Thus, pain is sculpted by a mosaic of
factors that is completely unique to each individual at a given point in time, and this mosaic
must be considered in order to provide optimal pain treatment.
When considering individual difference factors, it is important to distinguish characteristics
of the individual that are statistically associated with pain responses (i.e. markers) from
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biological and psychosocial mechanisms that directly influence pain responses. Notably,
some markers may reflect mechanisms underlying pain, while others do not. Examples of
the former include demographic factors, such as sex, race/ethnicity and age. While each of
these variables has been associated with pain responses (as discussed below), they reflect
proxies for mechanisms influencing pain rather than mechanisms themselves. That is, the
sex of an individual does not directly influence pain, rather sex differences in pain reflect the
effects of other biological and psychosocial processes (e.g. sex hormones, inflammatory
responses, gender roles, pain coping). Alternatively, a study could assess biological
marker(s) related to pain, in which case the biological marker(s) represents both an
individual difference factor and a potential mechanism directly influencing pain. Thus, while
individual differences in pain response present challenges to the scientist and clinician, they
also provide important opportunities. Indeed, investigating the factors contributing to
individual differences in pain can provide important insights into pain mechanisms, which
may lead to the development of novel treatments. Also, incorporating an understanding of
individual differences into assessment and diagnosis of pain in the clinical setting may allow
the clinician to select treatments that are tailored to the patient, thereby improving treatment
outcomes.
Demographic Influences on Pain
As noted above, demographic factors do not directly influence pain, however they represent
valuable individual difference factors, because they are easily measured and they provide
important public health information regarding large population groups that may be at risk for
increased pain. In addition, demographic associations with pain reflect the influence of
underlying mechanisms, a better understanding of which can elucidate the pathophysiology
of pain. That is, the prevalence of joint pain generally increases monotonically with age, and
explanations for this association will enhance our mechanistic understanding of joint pain.
Below, I will briefly review research examining sex differences, racial/ethnic differences,
and age-related differences in pain, and the interested reader can find additional information
regarding each of these topics in several recent reviews [2; 29; 32; 51; 62; 67; 78].
Sex Differences
Abundant epidemiologic evidence demonstrates that chronic pain is more prevalent among
women than men [29; 67]. For example, recent findings from a large scale nationally
representative study in the United States (US) found that a higher proportion of women than
men reported any pain over the last 3 months [69]. Interestingly, women also were more
likely to report pain that was persistent and bothersome, but only among non-Hispanic
whites and non-Hispanic blacks. No such sex difference emerged for Hispanic whites.
(Note: this reflects an interaction between sex and ethnic group, and such interactions among
individual difference factors will be discussed further below) These findings relate to
chronic pain in general, but sex differences in the prevalence of specific pain conditions have
also been reported. Indeed, women are at greater risk for most common chronic pain
conditions, including migraine and tension-type headaches, low back pain, fibromyalgia and
widespread pain, temporomandibular disorders, irritable bowel syndrome, and osteoarthritis
[29; 67]. Some studies have examined sex differences in the severity of acute and chronic
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pain, and in general any sex differences that have emerged have been inconsistent and small
in magnitude [29; 83].
While multiple explanations for these sex differences in pain prevalence can be offered, one
possibility is that fundamental differences in the functioning of female and male pain
processing systems renders women at increased risk for clinical pain. This has motivated
investigators to explore sex differences in responses to experimentally-induced pain.
Multiple reviews of this topic are available [29; 46; 67; 78], and while some differences in
interpretation of findings have emerged, the pattern of findings is indisputable. For virtually
all standard measures of experimental pain sensitivity women display greater sensitivity than
men, including pain threshold (the minimum stimulus intensity required to produce pain),
pain tolerance (the maximum stimulus intensity an individual is willing to tolerate), and
ratings of suprathreshold stimuli. Notably, the magnitude of the sex difference varies
considerably across studies and across pain measures and stimulus modalities, but the
direction of the difference is highly consistent. Also, women have shown greater temporal
summation of pain (a measure of transient central sensitization) and less conditioned pain
modulation (a measure of endogenous pain inhibition)[77], suggesting a pain modulatory
balance that is tuned more strongly toward pain facilitation than pain inhibition among
women. In contrast, in response to sustained and repeated thermal stimuli, females have
shown greater habituation than men, suggesting a stronger pain inhibitory response to these
types of stimuli [44; 45]. Multiple mechanisms have been proposed to explain these sex
differences in pain, including the effects of sex hormones, differences in endogenous opioid
function, cognitive/affective influences, and contributions of social factors such as
stereotypic gender roles [29; 67].
Race/Ethnic Group Differences
The concepts of race and ethnicity are complex biological and social constructs that remain
poorly defined. In the United States, it is typical to categorize individuals according to both
ethnicity (Hispanic/Latino vs. non-Hispanic/non-Latino) and race (e.g. Asian, African-
American, white), while different approaches may be taken in other parts of the world.
Whether individuals from different racial and ethnic backgrounds experience pain differently
has long been a topic of interest. From an epidemiologic perspective, limited evidence
suggests racial or ethnic differences in pain prevalence. Nahin [69] found that pain
prevalence was lowest among Asians compared to other race/ethnic groups in the US. Other
studies of adults in the US have reported higher prevalence of persistent pain among whites
compared to other racial/ethnic groups [53; 54]. Among older adults some studies have
reported higher pain prevalence among minorities compared to whites, while others reported
no differences in pain prevalence [57]. While there is conflicting information regarding pain
prevalence may be lower among minority versus majority ethnic groups, studies consistently
suggest that the severity and impact of pain appears to be greater among minorities who are
experiencing chronic pain [2; 57; 64]. Indeed, our own studies demonstrate greater pain
severity and functional limitations among African Americans compared to non-Hispanic
whites with knee osteoarthritis [17]. In addition, differences in pain perception between
racial/ethnic groups may contribute to differences in severity of clinical pain. A meta-
analytic review of studies examining pain perception in generally healthy adults found that
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African Americans display greater experimental pain sensitivity compared to non-Hispanic
whites [79]. Similarly, our recent findings among adults with knee osteoarthritis showed
greater pain sensitivity and temporal summation of pain among African Americans [17].s
These findings are largely based on work conducted in the United States, where racial and
ethnic disparities in health are a substantial national concern. Similar findings have emerged
in other developed countries throughout the world; however, little data related to ethnic
group differences in pain have been reported from less developed countries.
The mechanisms underlying racial/ethnic group differences in the experience of pain are
inevitably multifactorial, and include factors related to socioeconomic standing and access to
adequate health care. For example, in most developed countries, members of minority
groups on average have lower socioeconomic status, which has been associated with
increased pain prevalence and more severe pain [64; 76]. In addition, considerable evidence
suggests that minority patients are at greater risk for undertreatment of their pain, which
could obviously contribute to the greater clinical pain severity observed among members of
minority groups [2; 75]. Pain coping also differs significantly across racial/ethnic groups
[48; 65], and it is possible that biological factors, such as genetic contributions, may play a
role in racial/ethnic differences in pain responses [49; 79].
Age-Related Differences
Given the aging of the world’s population, whether the experience of pain changes with age
has drawn increasing attention in recent years [10; 32; 33; 62; 68; 73]. Patterns of pain
prevalence across the lifespan are complex and they vary across pain conditions (see Figure
2)[32]. Briefly, the prevalence of joint pain, lower extremity pain and neuropathic pains tend
to increase monotonically with age. General chronic pain increases in prevalence until
middle age, at which time the prevalence plateaus. In contrast, pain conditions such as
headache, abdominal pain, back pain and temporomandibular disorders show peak
prevalence in the third to fifth decades of life, after which their frequency decreases. It is
important to note that these epidemiologic findings are based almost exclusively on cross-
sectional studies, such that cohort effects (e.g. earlier mortality among people with certain
pain conditions) could influence the results. Beyond pain prevalence, multiple studies have
examined age-related changes in the severity and impact of pain. Older adults have reported
lower acute pain intensity in some studies [34; 83], but not others [4; 35]. Similarly, age-
related differences in the intensity and impact of chronic pain have not been consistently
demonstrated [32; 33].
Age-related changes in responses to experimental pain have been widely studied. Taken
together these findings suggest that older adults show less sensitivity to brief, cutaneous
pains (e.g. heat pain threshold); however, sensitivity to more sustained pain stimuli that
impact deeper tissues increases with age [32; 55]. Moreover, several studies have
demonstrated increased temporal summation of pain among older adults [23; 56; 70], while
conditioned pain modulation consistently has been found to decrease with age [24; 80]. This
pattern of results suggests that aging is associated with a shift in pain modulatory balance,
such that older adults show enhanced pain facilitation combined with decreased pain
inhibition.
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