Publications
APS Bulletin • Volume 10, Number 4, July/August 2000
Research Update
Richard H. Gracely, PhD, Department Editor
Pain and Aging
Michael J. Farrell, PhD
Pain is a latent experience modulated by many intrinsic and extrinsic factors. Age is one of the myriad influences that a clinician integrates into the assessment and treatment of a patient with pain. Thankfully, the management of older people is no longer influenced by the aging stereotype of the insensitive older patient undergoing a dental procedure with neither analgesics nor complaint. What has replaced the stereotypical view of pain and aging? What is the likely impact of aging on the experience of pain? These questions do not allow a simple answer.
The study of aging is subject to the constraints that invariably limit the research of groups defined by intrinsic attributes. The age of a subject cannot be randomly allocated, dictating the use of cross-sectional and longitudinal methodologies in the evaluation of age differences. Any statement about the impact of age must be tempered by the knowledge that association, rather than cause-effect, is the only feasible conclusion that can be drawn from research on aging. There are many factors that confound attempts to ascribe effects to aging. In cross-sectional designs, doubts exist about the distinction between changes that have occurred within a subject across time (an age effect) and differences between groups that reflect disparate life histories (cohort effects). Longitudinal aging studies are subject to selection effects that strip samples through disproportional rates of morbidity and mortality among the oldest subjects. Efforts to establish the interaction between aging and the experience of pain should not be discouraged by apprehension over methodological issues. Any factor, including age, that influences the experience of pain is of critical interest to the clinician.
There are two major sources of information that are contributing to our understanding of the differential effects of aging on the experience of pain. These sources are studies of pain subsequent to extrinsic stimuli in healthy older people and the exploration of pain behavior in older people with clinical conditions.
Aging and pain in absence of disease
Psychophysical procedures in healthy volunteers are a natural starting point for the exploration of age effects on the pain experience. The measurement of pain threshold and suprathreshold ratings, including tolerance, provide benchmarks that can be compared across subjects of varied ages. The quality and number of studies examining aging effects on pain sensitivity vary according to stimulus modality. Recent reviews suggest that the bulk of credible studies of the threshold for thermal pain indicate a decrease in sensitivity with advancing age (Gagliese, Katz, & Melzack, 1999; Gibson & Helme, 1995; Helme & Gibson, 1997). The association of age and mechanical pain thresholds has received scant attention, although recent results suggest a decrease in mechanical sensitivity among older subjects (Meliala, Gibson, & Helme, 1999). Results from studies of electrical stimuli are equivocal with reports of the absence of an effect and an age-associated increase in pain threshold. The absence of an age effect for electrical pain thresholds is most notable in studies of the sensitivity of tooth pulp (Gibson & Helme, 1995). The unique attributes of the innervation of tooth pulp, being largely nociceptive in nature, lends considerable weight to the results of studies involving stimulation of dental nerves.
The implications of pain threshold changing with increasing age must be interpreted with due difference to the magnitude and variability of these effects. The relative consistency of results from studies of thermal pain thresholds allows an estimate of change across the life span of the order of 20% (Helme & Gibson, 1997). Although not insubstantial, this averaged figure is subject to considerable variation within samples. In a more recent report of thermal sensitivity, age accounted for only 16.6% of the variance in pain thresholds (Heft, Cooper, O’Brien, Hemp, & O’Brien, 1996). This finding is consistent with many studies that contrast the performance and attributes of younger and older subjects.
The demonstration of an aging effect usually contributes little in the way of explanatory power for the clinician who may wish to make predictions of patient responses when choosing a treatment strategy. Variability within older groups, rather than across samples of disparate age, probably has more implications for the management of aging clients. Pain threshold studies incorporating groups of “old-old” subjects are notable for substantial within-group variance. Scattergrams of pain sensitivity and age typically exhibit a dramatic increase in the spread of points from the age of 80 years and older. The heterogeneity of responses among the oldest members of the community dictates that caution is exercised, lest assumptions about age-related decreases in pain sensitivity prove fallacious in individual cases. Many older people exhibit pain thresholds on a par with 30 year olds. The heterogeneity of the old-old also means that the exceptional becomes more commonplace. Case reports of patients with remarkable tolerance for pain accurately portray the behavior of some older people. When dealing with older patients, the clinician must expect the unexpected and carefully evaluate the attributes of individual cases.
The apparent diminution in the discriminative capacity of older people for painful stimuli leaves ample room for interpretation. The process that follows the application of noxious stimuli and culminates in the report of pain is a function of a highly integrated system. There has been some conjecture, and little data, about potential influences on the process of nociception and pain reported among groups of varied ages. The quality of tissues innervated by nociceptive fibers undergoes changes with age that could influence the distribution of energy delivered during noxious stimulation (Procacci, Bozza, Buzzelli, & Della Corte, 1970). The apparent age effects for thermal and mechanical stimuli juxtaposed against the absence of an effect for electrical stimuli suggest that receptor mechanisms could be implicated in diminishing sensitivity with advancing age. There is evidence to support a preferential contribution of C fibers versus Ad fibers to thermal pain thresholds in older people (Chakour, Gibson, Bradbeer, & Helme, 1996), a result consistent with age effects and electrophysiological evidence of higher thresholds of activation for C-fiber primary afferents. Central factors may also play a part in age-related change in pain thresholds. Response criteria can change in older people, an effect noted in tests of discrimination of nonpainful sensory modalities. A cautious approach to labeling a stimulus as painful among older subjects could lead to the observed changes in threshold levels.
The impact of aging on the experience of suprathreshold stimuli has not been subject to the same degree of scrutiny as the pain threshold. Reports of decreased (Gibson, Gorman, & Helme, 1991) and comparable (Heft et al., 1996) ratings of suprathreshold thermal stimuli have been reported for older groups. There is some evidence that pain tolerance diminishes with advancing age (Collins & Stone, 1966; Walsh, Schoenfeld, Ramamurthy, & Hoffman, 1989; Woodrow, Friedman, Siegelaub, & Collen, 1972). Any conclusions about age effects on suprathreshold ratings are probably premature, and if changes are operating, then they are relatively subtle. The parsimonious explanation for the bulk of studies that report higher thresholds, comparable suprathreshold ratings, and lower tolerance levels is that the stimulus-response function in older people is rotated relative to younger people such that it ascends more rapidly.
Nociceptive system plasticity
The interaction of aging and pain may not be confined to peripheral tissues and fibers and labeling biases. Neurons in the dorsal horn play an integral role in the modulation and transmission of signals arising from noxious stimuli. Plasticity of the nociceptive system is readily apparent in the electrophysiological behavior of dorsal horn neurons in animals, behavior that has psychophysical correlates in humans. The propensity of stimuli of an intensity consistent with C-fiber activation to provoke reports of increasing levels of pain when delivered at a frequency of 0.3 to 1 Hz has been ascribed to transient changes in the stimulus-response characteristics of dorsal horn neurons (Woolf, 1996).
This frequency-dependent form of temporal summation appears to be attenuated to some degree in older people (Harkins, Davis, Bush, & Kasberger, 1996). The phenomenon of age-associated reduction in temporal summation would suggest that the older CNS is less prone to sensitization by peripheral input. A study of capsaicin-evoked sensitivity suggests that age-associated changes in spinal plasticity may be a two-edged sword (Zheng, Gibson, Khalil, Helme, & McMeeken, 2000). Persistent C-fiber afferent barrage, achieved with high doses of topical capsaicin, produces mechanical hyperalgesia in the secondary area regardless of age. However, older subjects demonstrate a much longer period of secondary hyperalgesia despite comparable levels of spontaneous pain, thermal hyperalgesia, and flare. Taken together, attenuation of temporal summation and persistence of secondary hyperalgesia is consistent with the notion that sensitization of the dorsal horn in older people is dependent on a relatively greater peripheral input, but once initiated is less likely to resolve spontaneously.
The experience of pain is ultimately a function of supraspinal processes. The effect of age on the central processing of pain has been examined with the aid of nociceptive-evoked responses (NERs) (Gibson et al., 1991; Gibson, Gorman, & Helme, 1994). In NERs, as in all studies of human pain perception, there is considerable latitude for confounding factors because of the integrated nature of the nociceptive system. Age-related changes in NERs generated at a fixed intensity of stimulation are subject to any and all of the effects that modulate signals below the supraspinal level. The delivery of stimuli at intensities with reference to reported pain allows meaningful comparisons across subjects regardless of age. Laser thermal stimuli delivered at twice the pain threshold are rated as similarly intense by groups of varied age (Gibson et al., 1991). The encephalographic responses evoked by stimuli at twice the pain threshold have a longer latency, lesser amplitude, and more diffuse distribution in older subjects. The tendency for smaller amplitudes and the distribution of responses in older subjects may be a consequence of morphological changes, such as decreased volume, that characterize the aging brain. The latency shift in the NER with age, of the order of 50 ms, is most probably a consequence of differences in cortical function and may reflect a slowing of higher order processing in older people experiencing brief painful stimuli. The spatial resolution of contemporary methods of functional brain imaging has yet to be applied to the study of the aging brain and the experience of pain. Studies using positron emission tomography and/or magnetic resonance imaging will contribute significantly to the identification of any age differences in the network of supraspinal activations contingent on the experience of pain.
The process of nociception is influenced by inhibitory mechanisms. Animal studies have generated debate about the relative effects of age on humoral and neurogenic mechanisms of stress-induced analgesia (SIA) (Hamm, Knisely, & Watson, 1986). SIA mediated by hormonal mechanisms appears to be more pronounced in older rats. Neurogenic mechanisms contributing to SIA attenuate with advancing age (Hamm & Knisely, 1985; Hamm & Knisely, 1986). Until very recently there have been no reports from human samples of any age differences in the expression of endogenous analgesic mechanisms. A recent abstract presented at the Vienna meeting of the International Association for the Study of Pain reported age differences in the effects of cold pressor on pain thresholds (Gates, Gibson, & Helme, 1999). Both old and young subjects demonstrated increases in thermal and electrical pain thresholds after repeated immersion of the arm in cold water. However, the magnitude of the threshold changes were markedly less in the older group. The contribution of hormonal versus neurogenic mechanisms to this aging effect must await further studies. Heterotopic inhibitory influences, the behavioral manifestation of diffuse noxious inhibitory controls, operate through a mechanism that diverges from the effects associated with SIA. The impact of age on heterotopic inhibitory influences should also be included on the agenda for future research.
The countervailing influences of inhibition and excitation that characterize the nociceptive system may be differentially effected by aging. At various junctures of the pain pathway there appears to be a diminution of responses to noxious stimuli in older cohorts. In isolation, these changes could presumably lead to a lesser experience of pain at a given stimulus intensity. This process may be manifest at pain threshold where signal loss is most vulnerable to subtle age-associated changes in physiological function. Once stimuli exceed threshold and become more durable, the aging nociceptive system may fail to respond adequately with inhibitory mechanisms, leading to comparable levels of suprathreshold pain at fixed intensity and more persistent levels of central sensitization.
Aging, pain, and disease
There is another layer of complexity in the interaction of age and pain. Pain is usually a consequence of disease. Many diseases are more prevalent in older people or are exclusively confined to older groups. The experience of disease can change across the life span, complicating age comparisons of diagnosis-specific pain reports. The nociceptive system does not simply convey signals arising from the tissue changes that accompany disease; the efferent actions of primary afferents are active participants in the disease process. All of the potential interactions between pain, disease, and age complicate efforts to identify discrete effects. However, it is in the setting of aging and disease that important implications for clinical practice reside.
There are no clear images emerging from the literature of pain, disease, and aging. Three salient examples illustrate the diversity of effects across different diagnoses: a visceral condition—silent myocardial ischemia, a neuropathic condition—postherpetic neuralgia (PHN), and musculoskeletal pain.
The occasional absence of pain arising from cardiac ischemia confounds attempts to understand the mechanisms of angina. Advanced age appears to increase the risk of silent myocardial ischemia (Ambepitiya, Iyengar, & Roberts, 1993). Is this age effect a consequence of changes in disease manifestation leading to less noxious stimuli, or is age associated with a blunted nociceptive response to the impetus of cardiac ischemia? This question serves to highlight the difficulties that the prospective researcher must confront to unravel presumed aging effects. The answer to the question remains elusive, but careful control for disease severity would suggest that persistent age differences might be due to associated changes in afferent function (Miller et al., 1990). The alternative explanation, that aging influences pathological processes in myocardial ischemia, has yet to be specifically tested and cannot be refuted. It is entirely possible that afferent and disease effects are implicated in the association of aging and silent myocardial ischemia.
The example of silent myocardial ischemia, in common with many visceral conditions (Gibson & Helme, 1995), highlights the apparent decrease in pain experience of older people suffering from some conditions. The epidemiology of PHN is in sharp contrast to visceral pain. Increased age is a major risk factor for the development of PHN, regardless of the relative occurrence of acute herpes zoster infections (Portenoy, Duma, & Foley, 1986). The reason for the influence of age on the prevalence of PHN is probably intimately related to the etiology of PHN, a phenomenon that has not been elucidated (Dworkin & Portenoy, 1996). From the disease perspective, aging may be associated with different degrees of efficacy of the mechanisms of afferent neural regeneration (Bergman, Fundin, & Ulfhake, 1999). It is salient to note that more severe scarring is a risk factor for PHN that runs in tandem with age association (Bowsher, 1999). The recent demonstration of persistent secondary hyperalgesia in older humans (Zheng et al., 2000) and aging studies of neuropathic pain models in the rat (Kim et al., 1995; Novak et al., 1999) provide support for age-related changes in neuropathic pain mechanisms.
Silent myocardial ischemia and PHN demonstrate opposing relationships with aging. Age and musculoskeletal pain may covary in a nonlinear relationship. The relative prevalence of musculoskeletal disorders tends to dwarf the contribution of other diseases to epidemiological studies of chronic pain. Some cross-sectional epidemiological studies report a peak of pain prevalence in middle age, suggesting that pain associated with musculoskeletal conditions may bear a nonlinear relationship with age (Andersson, Ejlertsson, Leden, & Rosenberg, 1993; Brattberg, Thorslund, & Wikman, 1989). Other cross-sectional studies report a gradual increase in pain prevalence with age, fueling debate about the factors, notably methodological, that might account for the disparity between studies (Helme & Gibson, 1999). Longitudinal data has provided the most credible insights into the probable behavior of musculoskeletal pain across the life span. Complaints of joint pain have been tracked across 5-year intervals in several cohorts over the age of 70 years (Bagge, Bjelle, Eden, & Svanborg, 1992). Persistence, onset, and resolution of pain were observed across time. In the oldest cohort, cases reporting the disappearance of joint pain exceeded the number of cases experiencing the onset of new symptoms. This observation contrasts with the incidence of radiological evidence of osteoarthritis in older people (Felson et al., 1995). Furthermore, the diminution of joint pain in the oldest old could not be accounted for by selective mortality (Bagge et al., 1992). It would appear that the “peak” of musculoskeletal pain might occur well after middle age. Cross-sectional studies that target older cohorts also have reported a reduction in pain prevalence in the 80 years and older group, providing support for the nonlinear relationship between aging and musculoskeletal symptoms (Farrell, Gibson, & Helme, 1996).
The final interface between pain, aging, and disease is neurogenic inflammation. Studies of flare size subsequent to topical capsaicin generally report a decrease associated with advanced age (Helme & McKernan, 1985; Morris, Cruwys, & Kidd, 1997; Parkhouse & Le Quesne, 1988). Animal studies manipulating neurogenic inflammation also have demonstrated an aging effect (Khalil, Ralevic, Bassirat, Dusting, & Helm, 1994). Of particular relevance for clinicians is the contribution of neurogenic mechanisms to wound healing and the observation that age-associated decline in wound healing can be partially reversed by promoting aspects of neurogenic inflammation that are deficient in older rats (Khalil & Helme, 1996). These findings amply illustrate the potential benefits of exploring age effects in pain and disease. Knowledge of the associations of age will ultimately facilitate the development of strategies to ameliorate the negative impact of pain and disease in older people.
Conclusion
The important conclusion from this brief foray into the literature of pain and aging is that age does not have a univalient influence on the experience of pain. Differential aging effects mean that an older person may be more or less vulnerable to the experience of pain depending on the circumstances. There is some way to go before the nuances of age effects on pain are established definitively, although interesting avenues for future research have been identified. Apparent shortfalls in the efficacy of inhibitory mechanisms in older people could be reversed and constitute a potential treatment option. The characterization and manipulation of neurogenic inflammation in older people holds promise for the facilitation of wound healing. Explorations of the interaction between aging and pain continue to have relevance for researcher and clinician alike.
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Michael J. Farrell is a research fellow in the clinical measurement and mechanisms unit, pain and neurosensory branch, of the National Institue of Dental & Craniofacial Research, National Institutes of Health, Bethesda, MD.