Area Under the Curve 40.00 60.00 80.00 100.00 120.00 140.00 Heat Conditioned (Hand) Cold Conditioned (Hand) Cold Conditioned (Foot) Conditioned Pain Modulation Treatments% Control Area Under Curve Young Old Peak Pain Rating 40.00 60.00 80.00 100.00 120.00 140.00 Heat Conditioned (Hand) Cold Conditioned (Hand) Cold Conditioned (Foot) Conditioned Pain Modulation Treatments% Control Peak Pain Young Old
Age Differences with Endogenous Pain Keywords : Conditioned Pain Modulation, Aging, Inhibition Sean Coyle UF ID 1362-8453 email@example.com Research Advisor: Joseph L. Riley III, PhD Department of Community Den tistry and Behavioral Science
Abstract Experimental findings on the effects of aging on pain perception have returned mixed results. The purpose of this study was to test the hypothesis th at older adults would differ from younger adults in their conditioned pain modulation response. Six older adults and six younger adults participated in three experimental sessions following a training session. Each experimental session c onsisted of five 60-s econd trials in which the experimental heat stimulus was presente d to the left palm following a conditioned stimulus (either an identical 5 trials of heat on the right palm, a cold-water immersion of the hand, or immersion of the foot). The temp eratures for the palm (46-49C) and for the hand and foot immersion (8-16C) were custom ized for each subject. The intensity of the pain produced by the contact thermode was continuously measured during the 60-second trial with an electronic visu al analog scale. Older subj ects failed to demonstrate conditioned pain modulation (CPM) as well as the younger adults. The younger subjects mean pain ratings were on average 73.32 % of their control for the three treatments where the older subjects averaged 109.28 % of their control. This decrease in CPM could contribute to the greater preval ence of pain in older age.
Introduction The process of aging is dynamic in which physiological and psychological components undergo alternations and compensati ons in function and structure, including components involved in pain sensation. In a re view of the prevalence of chronic pain, Verhaak et al. (2007) conclude d that chronic pain generally increased with age, with studies usually reporting peak prevalence betw een the ages of 45 and 65 years, depending on the pain condition. A study in Holland found th at more than 50% of persons ages 65years and older reported current pain and of these, more than half report pain in multiple sites (Picavet and Hazes, 2003). A more tell ing finding was that the acute/chronic pain ratio shifts more toward chronic pain with age (Frlund and Frlund, 1986). One explanation for increased clinical pa in in older populations is that aging is associated with greater sensitivity to pain ful stimuli. However, several reviews have reported an increase, a decrease or no change of pain thresholds with aging (Gibson & Farrell, 2004; Gibson & Helme, 2001). Pain threshold provides a convenient measure to look at the pain of individuals. According to Gibson et al. (2004) over 40 studies have tested pain threshold measures with the bulk of the evidence showing an increase in pain threshold with age. While the reasons for this change with age can var y, it is thought that aging may affect the internal processing; specif ically the peripheral afferent nerve fibers (Edwards and Fillingim, 2001) It is thought that the unmyelinated C-fibers become predominate in older adults; these are associat ed with delayed pain not the initial pain. Older adults appear to lack as great an onset of initial pain. Measures of pain sensitivity may not op timally characterize age-related changes in pain processing. Therefore, experimental methods designed to test changes in pain
modulatory mechanisms need to be examined. Studies of dysfunction in the human pain response have begun to use laboratory protocol s that involve pain inhibition (Bouhassira et al., 2003; Johannesson et al., 2007; Julien et al., 2005; King et al., 2009; Kosek & Ordeberg, 2000; Lautenbacher & Rollman, 1997; Meeus et al., 2008; Staud et al., 2003; Wilder-Smith and Robert-Yap, 2007; Ya rnitsky et al., 2008). The phenomenon of Conditioned Pain Modulation (CPM) implicat es the existence of an endogenous pain modulation system in humans. The basic princi ple is Â“pain-inhibiting-painÂ” where pain in a local area (experimental stimulus) is inhi bited by a second pain (conditioning stimulus) that can be anywhere else in the body (Willer et al., 1984). Three studies have reported reduced pain inhibition associated with age using protocols consistent with CP M. Washington et al., (2000) f ound that the effects of coldwater immersion of the hand on subsequently te sted pain threshold were significantly less in older adults compared with young adults Another study by Lariviere et al. (2007) found that increased thermal pain threshold during concurrent administration of a coldwater bath was diminished for bot h middle-aged and older groups. The aim of this study was to test th e hypothesis that the younger adults will demonstrate greater inhibition of pain from noxious thermal stimuli following a conditioned stimulus, whereas older adults will experience a smaller inhibition and fail to suppress the pain as well.
Methods Subjects Twelve subjects (six younger aged 19-22 and six older aged 6779) were recruited through the University of Florida affiliated Institute of Aging subject recruitment pool. Study exclusion criteria included the inability to reliably rate pain, current use of narcotics, chronic use of analgesics, curre nt use of any tobacco products, uncontrolled hypertension, receiving treatment for hypert ension with BP of greater than 140/95, serious systemic disease (e.g. diabetes, thyroid problems, et c.), neurological problems with significant changes in somatosensory a nd pain perception at th e intended stimulation sites, cardiovascular or pulmonary dis ease, serious psychi atric conditions (e.g., schizophrenia, bipolar disorder), chronic pain (e.g., low back pain, postherpetic neuralgia), or any ongoing pain problem (head aches, arthritis, injury -related pain etc.). Orientation and Training Session Those interested in participating in the study were given an introduction to the research and provided with a brief explanat ion of the purpose and procedures of the study. If they remained interested they were informed about HIPAA regulations and after reviewing, signed an Informed Consent Form to grant authorization for collection of health data needed to determin e their eligibility to participate in the study. Next a health assessment, consisting of a health questionnai re and interview as we ll as a blood pressure measurement, was given. Subjects were also administered the trait version of the StateTrait Anxiety Inventory (Spi elberger et al., 1970).
Subjects were then run on a training sessi on protocol with the goal to both teach them how to effectively and accurately rate pain as well as determine an appropriate temperature of the stimuli for use in subs equent tests. The goal was to determine temperatures at which subjects experienced mild-to-moderate pain for both a 30 second heat stimulus (46-49C) and for immersi on for cold stimuli (8-16C). The training session consisted of a series of 30-second tria ls on the forearm (for practice rating pain) and on the palm in the thenar region (used to determine temperature). To find this ideal thermode temperature for use in the experime nts, the thermode temperature was set at 44C for the first trial and incr eased across trials so that a stimulus response curve could be calculated. The temperatures were increas ed to a maximum pain rating of 40-50 on a scale of 0-100. A similar procedure was used on the foot using a recirculating cold water bath set at 16C for the firs t trial and decreased by 2C each trial until a maximum pain rating of 30-40 upon a 20 second foot immers ion was reached. A maximum temperature of 49C was used for heat and a minimum of 8C for cold. Testing Sessions Subjects took part in three experime ntal sessions on different non-consecutive days following training. Upon arriva l at the testing laboratory, subjects were seated in a comfortable chair and asked to relax for several minutes. Th e subjects were asked to complete a State-Trait Anxiety Inventory (Spielberger et al., 1970) and a Mood VAS form. Next they were asked about their hea lth and any changes, any medication use, and described the procedures for the day whic h includes showing a video explaining the trials. Two blood pressure readi ngs were taken 5 minutes apart. If there was a change of
greater than 5%, subjects rested an add itional 5 minutes and a third blood pressure reading was taken. Each session consisted of five 60-second trials in which the experimental stimulus was presented to the thenar eminence of the left palm; each had a different conditioning stimulus. Heat trials were separated by 3 minutes (from the time one starts to the time the next begins). The three sessions consisted of the following protocol: 1. An identical set of five 60-second heat trials was presented to the thenar eminence of the right palm. This preceded the left palm being tested in the same protocol (Heat Primed). These trials on the right palm not only serve as a conditioned stimulus for this heat primed se ries but also a cont rol trial for the all three sessions (Heat, Hand, and Foot primed). 2. The Focal heat stimulus was preceded with five 45-second cold-water immersions of the entire hand separated by a 15-second withdrawal period as the conditioning stimulus (Hand Primed). 3. The Focal heat stimulus was preceded with five 45-second cold-water immersions of the entire foot separate d by a 15-second withdrawal period as the conditioning stimulus (Foot Primed). A post Pain Castastrophizing Scale (PCS) form is given to the patient to complete in addition to three simple questions verb ally asked regarding their ability to concentrate on the trials.
Experimental Stimulus Focal thermal stimuli (44-49C) were administered by a Peltier-based thermode (23mm x 23mm). For each 60-second trial, the thermode was brought to a neutral temperature (33C), and then brought into li ght skin contact with a solenoid. After a short period, the temperature was ramped (1.5 C/s) to the desired temperature. After 30 seconds, the thermode remained in contact with the skin but was cooled back to 33C for the remainder of the 60 seconds. Subjects rated pain throughout the 60 seconds of thermode contact. Subsequent trials used widely spaced thermal pulses (3-minute interstimulus interval) to minimize sensitization. This is the same conditioned stimulus used for the heat primed session ( on the other, right, palm). Water Immersion Conditioning Stimulus Cold-water immersion was used as a condi tioning stimulus. The water bath was cooled by a refrigerated water circulator (Neslab, Portsmouth, NH). Water flow was maintained at a constant temperature throughout the water bath and constantly recirculated to prev ent local warming or cooling around the foot. In the foot primed session, subjects were instructed to immerse th eir foot to the ankl e in water set at a tailored noxious cold temperature (8-16C) The only change in the hand primed session was immersion of the hand, to the wrist, instea d of the foot. The water level was set at a height of 7 cm in order to keep the stimulated area consistent.
Pain Measurement The intensity of experimental pain produced by the contact thermode was continuously measured during the 60-second tria l with an electronic visual analogue scale (eVAS). A visual analogue scale is the most commonly used method for measuring experimental pain and has been shown to be reliable in a number of sources (Turk and Melzack, 2001). As described in Rodrigues et al. (2005) and King et al. (2009), the eVAS consisted of a low-friction s liding potentiometer (100mm trav el) mounted to an inclined desk. Two markers were provided for the scale: the left and right endpo ints designated as Â‘no painÂ’ and Â‘intolerable painÂ’ respectively. S ubjects were instructed to move the slider in proportion to their pain inte nsity in real time. The positio n of the slider (i.e., pain intensity ratings) was automati cally converted into a percentage (0-100%). A custombuilt computer program collected data related to temperature (set and actual) and pain ratings. At the end of the trial, the slider au tomatically returned to the left endpoint (Â‘no painÂ’). Continuous ratings of heat pain provide d a temporal profile of pain intensity over the trial duration. Psychological Measures A series of psychological measures were administered to subjects throughout the sessions that provide a glimpse to how the subj ect is feeling and res ponding to the testing. However, for this study it is not presented. The Stat e Train Anxiety Inventory (Spielberger et al., 1970) has extensive norma tive data and is a frequent measure of anxiety in pain studies. The St ate-Anxiety subscale consists of 20 items that evaluate how
respondents feel Â“right nowÂ” at this moment. The STAI has high internal consistency and can discriminate between diffe rent levels of anxiety. The mood VAS form is designed to get an idea of the current mental state or mood the subject is in. It provi des a line scale for the subject to mark where on the scale they fall at that time. For example it asks how anxious they are at this time. The Post Pain Catastrophizing Scale is a self-report questionnaire designed to measure how the subject felt thr oughout the trial. It asks the subject on a scale of 0 to 10 to rate how they felt; for example Â“I worried about when it would end.Â” After the final trial, subjects rated their ability to concentrat e on the heat applied to their palm using a scale from 0 (unable to concentrate) to 10 (t otal concentration). They also rated how easy it was to focus on and how difficult it was to pay attention to the thermal stimulation. Data Analysis The dependent variables were area under the curve (AUC) and the mean peak pain ratings (PPR) collapsed across the five trials for each session. The highest rating obtained during each 30-second stimulation was r ecorded as the PRR for that trial. AUC is defined as the mean pain rating for each trial. It was calculated by summing the recorded pain rating for each of the first 30 seconds of the trial and dividing by 30. AUC provides a better measure when looking over the en tire trial because a single spike in pain rating will have a high PPR but not necessarily a high AUC.
The general linear model module of SPSS wa s used for statistical analysis. The study hypotheses about age and session differences in pain ratings were tested with a series of 2 x 4 mixed model analysis of variance (ANOVA). The between subject variable was group (older and younger adults) an d the within subject variable was set of treatments (four). Because of the small samp le sizes and resultant low statistical power, an effect size (CohenÂ’s d ; Cohen, 1997) was calculated as the group mean difference divided by the pooled standard deviation. Results Baseline Characteristics For the contact thermode, the temperat ures required to produce a pain rating between 40-50 eVAS during the training se ssion were similar between the groups (younger average = 48.1C, sd=.6; older averag e = 47.8C, sd=.6). They approached but did not reach statistical signi ficance between the two. Howeve r, no significant difference was observed in the individualized foot im mersion temperature among the groups. As expected, there was a significant negative a ssociation between individualized hand and foot temperature (r = -.43, p = .002). E ssentially those requiring a higher thermode temperature required a lower water bath te mperature (more painful stimuli in both instances) whereas those requiring a lower ther mode temperature had a higher water bath temperature.
Pattern of pain ratings within a trial Continuous ratings collapsed across the fi ve CONTROL trials, are presented in Figure 1. The pain ratings exhibited an early phase of rapid tempor al sensitization (0-15 seconds) followed by a phase of adaptation (15-25 seconds) and a second sensitization phase (25-32 seconds). The testing phase from 33-38 second s represents a residual pain offset as the temperature of the thermode was already returning to baseline of 33C. Area Under Curve For AUC, the session x group interaction term was not statistica lly significant [F (2, 8) = 1.140, p > .05] indicating that th e conditioning stimulus did not have a differential effect across the groups. Table 3 and Figure 2 pr esents the average AUC for each treatment and group (older and younger) as a percentage of the average control for each. The mean AUC for each set of trials for each group and the effect size for the group differences in inhibition are presen ted in Table 1. The group difference in inhibition for the heat conditioned session was .63, for the cold foot conditioned was .68, and for the hand cold conditioned was .13. Based on CohenÂ’s definition, .63 and .68 are moderate to large, where .13 is small. Peak Pain Rating For PPR, the session x group interaction term was not statistically significant [F (2, 8) = 0.996, p > .05] indicating that th e conditioning stimulus did not have a differential effect across the groups. Table 3 and Figure 3 pr esents the average PPR for each treatment and group (older and younger) as a percentage of the average control for each. The mean PPR for each set of trials for each group and th e effect size for the group
differences in inhibition are presented in Ta ble 2. The group difference in inhibition for the heat conditioned session was .51, for the cold foot conditioned was .66, and for the hand cold conditioned was .02. Based on Cohe nÂ’s definition, .51 and .66 are moderate to large, where .02 is small. Discussion The results of this study support the hypothesis that he althy older adults fail to inhibit endogenous pain as well as younger indi viduals. It was found th at the older adults did not demonstrate as great a pain reduction with the painful conditioning stimuli. These findings support a number of studies that have found a reduction or absence of endogenous pain inhibition among older subjec ts using experimental pain paradigms which activate CPM using brief stimuli. Su ch a study by Edwards and Fillingim (2003) found similarities to what was seen in this experiment, the younger individuals experienced a CPM effect but the olde r individuals failed to inhibit. Gibson and Helme (2001) propose that re duction of CPM with age is due to changes in several descending inhibitory system s, and this could cont ribute to the greater prevalence of pain with age. There are a number of neurotransmitter systems involved in pain modulation and it is possible that changes in different levels of the brain lead to the age differences in CPM. The inhibitory sy stems that work on endogenous pain and the central nervous system itself may not be as effective in oneÂ’s later years. In the two of the three sessions run, heat conditioned and cold hand conditioned, older folks not only failed to inhibit but they actually increased their average pain ratings
over the control. The average pain rating for the older individua ls increased by 27.83 % over the control trial during the heat conditioned treatment and by 9.62 % during the cold hand conditioned. While most studies of CPM report a reduction in pain sensitivity, two studies have reported enhancement of pain re sponses (Edwards et al., 2003; King et al., 2009). Both of these studies used a concu rrent administration of the conditioning and testing stimuli; compared to the conditioned design used in this study. Older subjects may experience a hyper-sensitivity to pain after the initial shoc k of the conditioning stimulus. Laboratory pain responses have implicat ions on clinical pain for individuals. Edwards et al. (2003) found that better pain inhibition was associated with less pain, better physical functioning, and better self-rated health in a sample of younger and older adults. Data from clinical samples further supports the clinical re levance of laboratory measures of CPM. Kosek and Orderberg (2000) found that patients with painful osteoarthritis showed significantly less pain inhibition compared to healthy controls upon initial testing. However, after their arthritis pain had been successfu lly treated surgically, their inhibitory responses were back to what would be expected from a healthy individual. A recent study found that laborato ry CPM protocols predicted the risk for developing chronic pain follo wing a serious surgery, a thor acotomy (Yarnitsky et al., 2008). The patients that strongly inhibited the pain pre-operati vely were at significantly lower risk of experiencing chronic pain after surgery. With this literature as evidence, it seems possible that the reduced pain inhibition in older adults could be associated with age-related increases in the frequency and intensity of clinical pain.
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Tables and Figures Table 1. Average AUC and effect sizes by trials Control Mean (SD) Heat primed Mean (SD) Cold foot primed Mean (SD) Cold hand primed Mean (SD) Younger 20.7 (15.1) 16.9 (9.2) 11.9 (9.0) 16.7 (11.6) Older 19.2 (16.2) 24.0 (20.4) 21.2 (12.3) 17.4 (20.4) CohenÂ’s d .63 .68 .13 Note: Because of the small sample size, 2-way ANOVA group diffe rences were not significant. Consequently the C ohenÂ’s d effect size is reported. Table 2. Average PPR and effect sizes by trials Control Mean (SD) Heat primed Mean (SD) Cold foot primed Mean (SD) Cold hand primed Mean (SD) Younger 36.0 (23.4) 29.4 (14.2) 22.8 (14.2) 30.5 (17.6) Older 31.7 (23.0) 35.6 (26.0) 34.9 (18.4) 26.7 (26.9) CohenÂ’s d .51 .66 .02 Note: Because of the small sample size, 2-way ANOVA group diffe rences were not significant. Consequently the C ohenÂ’s d effect size is reported.
Table 3. AUC and PPR for both younger and ol der adults as a pe rcent (%) of their average control trial. Figure 1: Continuous pain ratings collap sed across the five CONTROL trials. Heat Conditioned (H) Cold Conditioned (H) Cold Conditioned (F) Average of three treatments Younger AUC 81.11 % 58.51 % 80.35 % 73.32 % Older AUC 127.83 % 109.62 % 90.39 % 109.28 % Younger PPR 81.93 % 64.12 % 85.39 % 77.15 % Older PPR 113.25 % 108.05 % 83.89 % 101.73 %
Area Under the Curve 40.00 60.00 80.00 100.00 120.00 140.00 Heat Conditioned (Hand) Cold Conditioned (Hand) Cold Conditioned (Foot) Conditioned Pain Modulation Treatments% Control Area Under Curve Young Old Figure 2: A comparison of the dependent va riable AUC for each of the treatments for older and younger adults as a percentage of the control. The red bars indicate that older adults experienced greater pain across all three treatments compared to younger group (blue bars). In addition the older adults expe rienced greater pain in the Heat conditioned and cold conditioned (hand) compared to c ontrol session as evidenced by values greater than 100 %. Peak Pain Rating 40.00 60.00 80.00 100.00 120.00 140.00 Heat Conditioned (Hand) Cold Conditioned (Hand) Cold Conditioned (Foot) Conditioned Pain Modulation Treatments% Control Peak Pain Young Old Figure 3: A comparison of the dependent variable PPR for each of the treatments for older and younger adults as a percentage of th e control. The red bars indicate that older adults experienced greater pain across two of the three treatments (heat and cold hand conditioned) compared to younger group (blue bars). In addition the older adults experienced greater pain in the Heat cond itioned and cold conditioned (hand) compared to control session as evidenced by values greater than 100 %.