Journal Logo

Articles

Lack of endogenous modulation and reduced decay of prolonged heat pain in older adults

Riley, Joseph L. 3rda,*; King, Christopher D.a; Wong, Fongb; Fillingim, Roger B.a; Mauderli, Andre P.b,c

Author Information
doi: 10.1016/j.pain.2010.04.020
  • Free

Abstract

1. Introduction

Aging is a dynamic process in which physiological and psychological components undergo alternations and compensations in function and structure, including components involved in pain sensation. In a review of the prevalence of chronic pain, Verhaak et al. [61] concluded that chronic pain generally increased with age, with studies usually reporting peak prevalence between the ages of 45 and 65years, depending on the pain condition. A study in Holland found that more than 50% of persons aged 65years and older reported current pain and of these, more than half report pain in multiple sites [44]. A more telling finding was that the acute/chronic pain ratio shifts more toward chronic pain with age [20].

One explanation for increased clinical pain in older populations is that aging is associated with greater sensitivity to painful stimuli. However, several reviews have reported an increase, a decrease or stability of pain thresholds associated with aging [21,22]. Measures of pain sensitivity may not optimally 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 protocols that involve pain inhibition [5,31,32,34,35,38,42,53,63,66]. The phenomenon of diffuse noxious inhibitory controls (DNICs) implicates the existence of an endogenous pain modulation system in humans. The basic principle of DNIC is “pain-inhibition-by-pain” where pain in a local area (experimental stimulus) is inhibited by a second pain (conditioning stimulus) that can be anywhere else in the body [65]. We use the term “conditioned pain modulation” (CPM) to refer to this phenomenon.

Three studies have reported reduced pain inhibition associated with age using protocols consistent with CPM. Washington et al. [62] found that the effects of cold-water immersion of the hand on subsequently tested pain threshold were significantly less in older adults compared with young adults. Another study by Edwards et al. [16] tested the effects of concurrent cold-water immersion of the hand on temporal summation. They reported that the older sample (ages 55–67) experienced facilitation rather than inhibition during some of the trials, while younger adults demonstrated the expected CPM effects. A third study by Larivière et al. [37] found that increased thermal pain threshold during concurrent administration of a cold-water bath was diminished for both middle-aged and older groups. To date, only Edwards’ study has reported pain facilitation with CPM in older subjects. Although each of the above-mentioned studies used short probing heat pulses, the dynamic nature of Edwards’ temporal summation protocol and longer overall duration paired with a concurrent conditioning stimulus may explain the findings.

The aim of this study was to test the hypothesis that older adults will fail to suppress the pain from noxious thermal stimuli administered during or following the immersion in a noxious cold-water bath whereas younger adults will demonstrate inhibition. This will also provide a test of whether older adults experience pain facilitation to concurrent and non-concurrent conditioning stimuli. In addition, we will test for age differences in “pain offset” (i.e., after-sensations).

2. Methods

2.1. Subjects

Forty-nine healthy subjects were recruited in a southeastern university town through newspaper and posted advertisements, or through a university affiliated Institute on Aging subject recruitment pool. Subject and age group descriptors are presented in Table 1. The subjects were compensated at the rate of $40 per session for their time.

T1-23
Table 1:
Subject and age group descriptors.

Study exclusion criteria included the inability to reliably rate pain, current use of narcotics, chronic use of analgesics, current use of any tobacco products, uncontrolled hypertension, receiving treatment for hypertension with BP of greater than 140/95, serious systemic disease (e.g., diabetes and thyroid problems), neurological problems with significant changes in somatosensory and pain perception at the intended stimulation sites, cardiovascular or pulmonary disease, serious psychiatric conditions (e.g., schizophrenia and bipolar disorder), chronic pain (e.g., low back pain, postherpetic neuralgia), or any ongoing pain problem (headaches, arthritis, injury-related pain, etc.). Subjects that were 72years of age or older were administered the Mini-Mental State Examination with scores of below 25 resulting in exclusion [14]. Subjects refrained from the use of coffee or any pain medications on the day of testing.

2.2. Study procedures

2.2.1. Orientation and training session

Persons who expressed interest in participating in the study were provided a brief explanation of the general purpose and procedures of the study. If interested, they were informed about HIPAA regulations and reviewed and signed an Informed Consent Form to grant authorization for collection of health data needed to determine eligibility. Subjects then received a health assessment consisting of a health questionnaire, supplemented by clarification by interview and a blood pressure measurement. For subjects who were 72years of age and older, the health assessment was supplemented by a brief neurological exam that included a 2-point sensory test [33]. Subjects were also administered the trait version of the State-Trait Anxiety Inventory [51].

Subjects then completed a training session to acquire the necessary pain rating skills and to determine the temperature of the stimuli for use in subsequent tests. The goal was to determine temperatures at which subject's experienced mild-to-moderate pain for both a 30-s heat stimulus (46–49°C) and immersion for cold stimuli (8–16°C). The thermal training session consisted of series of 30-s trials at the volar forearm (rating practice) and the palm (determine temperature). To determine the thermode temperature for use in the experiments, the thermode temperature was set at 44°C for the first trial and increased across trials so that a stimulus response curve could be calculated. The temperatures were increased to a maximum pain rating of 40–50 (on a scale of 0–100). A similar procedure was performed at the foot using a recirculating cold-water bath set to 16°C for the first trial and decreased by 2°C per trial to a maximum pain rating of 20–30 upon a 20-s foot immersion. A rating of 20–30 was targeted to minimize any effect of distraction from the cold-water bath on pain ratings at the palm during concurrent trials. A maximum temperature of 49°C was used for heat and 8°C for cold. Subjects that fail to reach the target pain ratings were assigned 49°C for heat and 8°C for cold.

2.2.2. Testing sessions

Subjects participated in five experimental sessions on different non-consecutive days following training. Upon arrival at the testing laboratory, subjects were seated on a comfortable chair and asked to relax for several minutes. Next, they were queried about their health, any medication use, and shown a video that described the procedure for that day. The testing began with taking two blood-pressure readings separated by 5min. If there was a change of greater than 5%, subjects rested an additional 5min and a third blood pressure measurement was taken. Each session consisted of five 60-s trials in which the experimental stimulus was presented to the thenar eminence of the left palm with or without the conditioning stimulus. Heat trials were separated by 3min. Sessions were counterbalanced and consisted of the following protocol:

  1. The focal heat stimulus to the left palm without conditioning stimulus (i.e., no water bath session; NoB).
  2. The focal heat stimulus with concurrent neutral temperature water bath set at 23°C (NeutralC).
  3. The focal heat stimulus with concurrent noxious cold-water immersion as a conditioning stimulus using the individualized temperature (NoxC).
  4. The focal heat stimulus was alternated with 45-s cold-water immersions using the individualized temperature (ALT). The order was cold-heat, cold-heat, etc., with each heat stimulus following the paired cold-water immersion by approximately 20s. As with the other sessions, heat trials were separated by 3min.
  5. The focal heat stimulus was preceded with five 45-s cold-water immersions separated by a 15-s withdrawal period as the conditioning stimulus (PRIMED).

2.2.3. Experimental stimulus (painful thermal contact)

Focal thermal stimuli (44–49°C) were administered by a Peltier-based thermode (23mm×23mm). For each 60-s trial, the thermode was brought to a neutral temperature (33°C), and then brought into light skin contact with a solenoid. After a short period, the temperature was ramped (1.5°C/s) to the desired temperature. After 30s, the thermode remained in contact with the skin but was cooled back to 33°C for the remainder of the 60s. Subjects rated pain throughout the 60s of thermode contact. Subsequent trials used widely spaced thermal pulses (3-min inter-stimulus interval) to minimize sensitization.

2.2.4. Conditioning stimulus (water immersion)

Cold-water immersion was used as the conditioning 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 prevent local warming or cooling around the foot. Subjects were instructed to immerse their foot to the ankle in water set at a neutral temperature (23°C) or a tailored noxious cold temperature (8–16°C). The water level was set at a height of 7cm in order to keep the stimulated area consistent.

2.3. Pain measures

The intensity of experimental pain produced by the contact thermode was continuously measured during the 60-s trial with an electronic visual analogue scale (eVAS). As described in Rodrigues et al. [49] and King et al. [34], the eVAS consisted of a low-friction sliding potentiometer (100mm travel) mounted to an inclined desk. Two anchors were provided for the scale: the left and right endpoints designated as ‘no pain’ and ‘most intense pain imaginable’, respectively. Subjects were instructed to move the slider in proportion to their pain intensity in real time. The position of the slider (i.e., pain intensity ratings) was automatically converted into a percentage (0–100%). A custom-built computer program collected data related to temperature (set and actual) and pain ratings. At the end of the trial, the slider automatically returned to the left endpoint (‘no pain’). Continuous ratings of heat pain provided a temporal profile of pain intensity over the trial duration.

2.4. Psychological measures

2.4.1. State-Trait Anxiety Inventory

The STAI [51] has extensive normative data and is a frequent measure of anxiety in pain studies. The State-Anxiety subscale consists of 20 items that evaluate how respondents feel “right now” at this moment. The STAI has high internal consistency and can discriminate between different levels of anxiety.

2.4.2. Mini-Mental State Examination

The Mini-Mental State Examination (MMSE; [19]) is a 5-min screening test that is designed to evaluate basic mental function in a person's ability to recall facts, to write and to calculate numbers. Cognitive performance as measured by the MMSE varies within the population by age and educational level. There is an inverse relationship between MMSE scores and age, ranging from a median of 29 for those 18–24years of age, to 25 for individuals 80years of age and older. A score of 25/30 or greater is considered to be within-normal limits [14].

2.4.3. Concentration

After the final trial, subjects rated their ability to concentrate on the heat applied to their palm using a scale from 0 (unable to concentrate) to 10 (total concentration).

2.5. Data analysis

The dependent variables were area under the curve (AUC) and mean peak pain ratings (PPRs) collapsed across the five thermal trials for each session. The highest rating obtained during each 30-s stimulation period was categorized as the PPR for that trial. AUC for each trial was calculated by summing the recorded pain rating for each of the first 30s of the trial and dividing by 30. As the thermode began cooling after 30-s, we defined a measure of “pain offset” as the pain rating from seconds 31 to 40.

The general linear model module of SPSS was used for statistical analysis. The study hypotheses about age and session differences in pain ratings were tested with a series of 2×3 mixed model analysis of variance (ANOVA). The between subject variable was group (older and younger adults) and the within subject variable was session (three). The non-water bath (NoB), thermode only condition served as the control trial for the alternating (ALT) and primed (PRIMED) experimental sessions and the concurrent 23.0°C immersion (NeutralC) served as the control for the concurrent noxious immersion session (NoxC). The NoB data were also included in the concurrent model analyses for comparison purposes. The models also included gender and thermode temperature as covariates.

To examine age differences in pain offset, we used a 2×10 mixed model ANOVA. The between subject variable was group and the within-subject variable was time. The time variable consisted of pain ratings for seconds 31–40 (beginning with thermode cooling) collapsed across the five trials of the NoB session. The NoB session was used to eliminate any effects of the water bath. The model also included gender and thermode temperature as covariates.

3. Results

3.1. Baseline characteristics

For the contact heat, a one-way ANOVA revealed that temperatures required to produce a pain rating between 40 and 50 eVAS during the training session approached but did not reach statistical significance between the two groups (Table 1; p=0.079). However, no significant difference was observed in the individualized foot immersion temperature among the groups. As expected, there was a significant negative association between individualized hand and foot temperature (r=−0.43, p=0.002).

There were no differences between groups on baseline anxiety as measured by the STAI-S, systolic (SBP) or diastolic (DBP) blood pressure, or skin temperature at the neck or palm. Associations between baseline DBP and the individualized hand temperature were significant (r=0.32, p=0.04). However, no association was found between DBP and foot temperature or between SBP and hand or foot temperature.

3.2. Inhibitory effects and potential confounds

No significant associations were found between subjects rating of concentration and the overall inhibitory effect (calculated as mean AUC and PPR for each experimental session−the corresponding control session). Correlations ranged from r=0.16 for the AUC from the PRIMED session to r=−0.16 for the AUC from the ALT session. The association between subjects rating of concentration and AUC for pain during trials 31–40 (pain offset) after the thermode was cooled was not significant (r=0.24).

Rating of concentration was not significantly associated with the individualized cold-water bath temperature and ranged from r=0.11 for the PRIMED session to r=−0.16 for the control bath session. However, concentration ratings were associated with the thermode temperature for the PRIMED session (r=0.32, p=0.04) and a trend was observed for the ALT session (r=0.30, p=0.06), consequently hand temperature was included as a covariate in the ANOVA models. The groups were not different on AUC [F(1,45)=2.105, p=0.154] or PPR [F(1,45)=2.074, p=0.157] in the NoB sessions.

3.3. Non-concurrent experimental protocols

Continuous ratings during the non-concurrent trials for each session, collapsed across the five trials, are presented in Fig. 1A for the younger group and Fig. 1B for the older group. Across all groups and sessions, pain ratings exhibited an early phase of rapid temporal sensitization (0–15s) followed by a phase of adaptation (15–25s) and a second sensitization phase (25–30s). The testing phase from 31 to 40s represents a residual pain offset as the temperature of the thermode was returning to baseline of 33°C.

F1-23
Fig. 1.:
Temporal profile of continuous ratings during the non-concurrent sessions with trials without the water bath (NoB, asterisk) or with a 45-s cold-water immersion of the foot, which was either presented prior to (PRIMED, open circle) or alternated with (ALT, closed circle) the focal heat stimulus. Intensity of heat pain at the palm was averaged across the five thermal trials for (A) younger and (B) older subjects.

3.3.1. Area under curve

Group and session main effects were not significant. The session×group interaction term was statistically significant [F(2,90)=6.155, p=0.004] indicating that the AUC session effect differed as a function of group (see Fig. 2A). Pair-wise comparisons within group indicated that the mean AUC for the NoB session (17.9, SD=6.6) was significantly different than the ALT (11.9, SD=7.7) and PRIMED (13.9, SD=8.1) experimental sessions for the younger group. However, for the older group, there were no differences between the mean AUC for the NoB session (15.0, SD=6.9), the ALT session (14.3, SD=7.7) or the PRIMED session (14.7, SD=8.1).

F2-23
Fig. 2.:
Comparison of non-concurrent conditioning stimuli on focal heat pain in younger and older adults. Subjects rated heat pain without a water bath (NoB, open bar) or after immersion of their foot into a painfully cold-water bath. For the CPM sessions, subjects either repeatedly immersed their foot for five times followed by heat pain (PRIMED, gray bar) or alternated foot immersion with the heat stimulus (ALT, darkened bar). AUC (A) and peak pain ratings (B) of heat pain were recorded during a 30-s testing trial.

3.3.2. Peak pain rating

Group and session main effects were not significant. The session×group interaction term was statistically significant [F(2,90)=8.971, p<0.001] indicating that the PPR session effect differed as a function of group (see Fig. 2B). Pair-wise comparisons within group indicated that the adjusted mean PPR for the NoB session (32.4, SD=10.7) was significantly different than the ALT (21.8, SD=11.0) and PRIMED (25.0, SD=11.4) experimental sessions for the younger group. However, for the older group, there were no differences between the adjusted mean PPR for the NoB session (27.8, SD=10.4), the ALT session (26.8, SD=10.8) or the PRIMED session (26.3, SD=11.2).

3.4. Concurrent experimental protocols

Two of the younger subjects did not complete one of the concurrent protocols; consequently data from 25 younger and 22 older adults are reported. Continuous ratings during the concurrent trials for each session, collapsed across the five trials, are presented in Fig. 3A for the younger group and Fig. 3B for the older group. The profiles for the concurrent trials were similar to those from the non-concurrent trials.

F3-23
Fig. 3.:
Temporal profile of continuous ratings during the concurrent sessions with trials without the water bath (NoB, asterisk) or with a concurrent 45-s water immersion of the foot at 23 °C (NeutralC, open circle) or painfully cold (NoxC, closed circle) water. Intensity of heat pain at the palm was averaged across the five thermal trials for (A) younger and (B) older subjects.

3.4.1. Area under curve

Group and session main effects were not significant. The session×group interaction term was statistically significant [F(2,90)=6.727, p=0.003] indicating that the AUC session effect differed as a function of group (see Fig. 4A). Pair-wise comparisons within group indicated that the mean AUC differed across all three sessions (NoB, 17.9, SD=6.8; NeutralC, 15.0, SD=8.2; and NoxC, 11.9, SD=7.2) for the younger group. However, for the older group, there were no differences between the mean AUC for the NoB session (15.0, SD=6.5), the NeutralC session (13.5, SD=7.8), and NoxC session (15.7, SD=6.9).

F4-23
Fig. 4.:
Comparison of concurrent conditioning stimuli on focal heat pain in younger and older adults. Subjects rated heat pain without a water bath (NoB, open bar) or during immersion of their foot into 22 °C (NeutralC, darkened bar) or painfully cold (NoxC, gray bar) water. AUC (A) and peak pain ratings (B) of heat pain were recorded during a 30-s testing trial.

3.4.2. Peak pain rating

Group and session main effects were not significant. The session×group interaction term was statistically significant [F(2,90)=8.513, p=0.001] indicating that the PPR session effect differed as a function of group (see Fig. 4B). Pair-wise comparisons within group indicated that the adjusted mean PPR for the NoB session (32.0, SD=10.7) was different from the NeutralC session (25.2, SD=11.7) and NoxC session (22.6, SD=11.2) for the younger group. However, the PPR for the NeutralC and NoxC sessions were not different (p>0.05). For the older group, there were no differences between the mean AUC for the NoB session (27.6, SD=10.4), the NeutralC session (25.2, SD=11.3), and NoxC session (28.6, SD=10.8).

3.4.3. Post hoc analysis

Based on our planned analyses, we concluded that there were no age differences in pain inhibition as measured by PPR during the NoxC session compared to the NeutralC session (the concurrent control session), as they were not different for either group. However, we tested this explicitly by calculating a PPR inhibition score (NeutralCNoxC) and testing for group differences using ANOVA, continuing to make adjustments for sex and thermode temperature. Group differences were statistically significant [F(1,45)=6.882, p=0.012], with the younger group experiencing pain inhibition (adjusted mean=3.1, SD=8.0) and the older group experiencing enhancement of pain (adjusted mean=−3.3, SD=7.9).

3.5. Pain offset effects

Pain ratings for the NoB session for time 31–40, as the thermode was cooled back to 33°C, for both groups are presented in Fig. 5. As expected the time main effect was statistically significant [F(9,405)=63.054, p<0.001]. In addition, the group×time interaction term was statistically significant [F(9,405)=3.711, p=0.011]. Pair-wise comparisons between groups indicated that the mean pain rating was higher for the younger group for time 31–33; however the mean pain rating was higher for the older group for time 37–40. Entering the mean peak as a covariate, the differences at time 31–33 are no longer different, but the effects for time 37–40 remain significant indicating that older adults have greater pain after-sensation following stimulus offset than younger adults. A similar conclusion was reached when a carry-over percentage was calculated as the percentage decline from 31 rating to 39-s rating (e.g., 31s=40 eVAS and 39s=10 eVAS) represents a 75% decrease. The younger group experienced a reduction of 94% (SD=14) whereas the older group experienced a reduction of 78% (SD=30).

F5-23
Fig. 5.:
For the NoB session, temporal profile of continuous ratings following cooling of the thermode to the resting baseline temperature of 33.0 °C for younger (open circle) and older adults (closed circle). Ratings were obtained 10 s following the 30-s heat trial. Older adults reported pain longer than younger adults during this period, which might serve as a measure of “pain offset”.

4. Discussion

The results of this study support the hypothesis that healthy older adults exhibit decreased endogenous pain inhibition compared to young healthy controls. We found that older subjects failed to demonstrate pain reduction with a painful conditioning stimulus and showed facilitation in the trials using a painful concurrent immersion of the foot in a cold-water bath. A number of studies have reported a reduction or absence of endogenous pain inhibition among older subjects using experimental pain paradigms which activate CPM using brief stimuli [16,37,62]. These assessments of DNIC-like responses in humans have been tested either during concurrent or alternating administration of both stimuli. However, this report is the first to compare the influences of both concurrent and non-concurrent conditioning stimulus. An additional novel aspect of the study was that we recorded pain offset and found that ratings for the older sample decreased at a slower rate than observed for the group of younger adults suggesting decreased inhibition and/or increased sensitization among the older sample.

4.1. Age differences in conditioned pain modulation

Reduction of CPM associated with age has been proposed to be due to changes in several descending inhibitory systems that could contribute to the greater prevalence of pain in older age [22]. Since a number of neurotransmitter systems are involved in pain modulation, it is possible age-related differences in CPM are due to functional changes at different levels of the neuroaxis. Evidence supporting this hypothesis is mainly observed in animal studies, where aging is associated with reductions in neuronally and hormonally mediated opioid and non-opioid pain modulation systems, [4,25–27]. A functional consequence of the impairment is characterized by the observation of age-related decrease in β-endorphin [7]. β-Endorphin is a key biological mediator released during times of stress and pain [30,64]. Consequently, reduced efficacy of pain modulation with age could be associated with decrements of β-endorphin at rest or response to painful stimulation.

One possibility is that the cold immersion procedure traditionally has been used to evaluate physiological responses to stress [29,40,43]. The “pressor” response is often characterized by changes in cardiovascular systems [1,56], the activation of the autonomic nervous system [40,41,57], and hypothalamic–pituitary–adrenal (HPA) axis [36,60]. Since cold immersion may engage systems related to stress-induced analgesia, it is possible that decreased pain inhibition with advancing age is due to reduced SIA. Using a CPM paradigm, younger participants often report higher levels of stress and distraction associated with cold-water immersion compared to the older group [16]. We did not assess the level of stress produced by the water bath.

It is interesting that we found apparent inhibition during the NeutralC trials in comparison with the NoB condition for the younger cohort but not for the older cohort. Latuenbacher and colleagues have also reported that a strong but not subjectively painful conditioning stimulus can produce pain inhibition in healthy controls, but not for fibromyalgia patients. [38,39]. If this effect involves a similar mechanism as CPM, this further supports loss of endogenous modulation in older adults.

4.2. Pain offset

The observation that the older cohort reported lingering pain during a reduction of thermode temperature is new. Whether or not this observation is related to after-sensations requires further investigation. There are a number of studies that have documented the phenomenon of after-sensations following temporal summation in chronic pain patients [23,48,50,52,54] and following application of capsacin [68,69]. In these studies, the authors have speculated that after-sensations following dynamic experimental pain manipulations reflect central sensitization (CS). The observation of CS in psychophysical experiments is associated with neuroplastic changes in neuronal cell activity particularly in second-order neurons of the spinal and trigeminal dorsal horn [12,45]. Prolonged after-discharges in second-order neurons may also be involved in after-sensation [15]. One question to be asked is if the observation of a longer pain offset in older adults is related to the maintenance of temporal summation due to CS. It is possible that the aging nervous system undergoes changes resulting in enhancement of neuronal hyperexcitability, which could increase the central processing of noxious input and reduce the resolution of CS. Another possibility is that this effect is related to decreased inhibition associated with CPM in the older adults.

4.3. Facilitation for older adult in the concurrent condition

While most CPM studies report a reduction in pain sensitivity in the presence of a conditioning stimulus, two other studies have reported an enhancement of pain responses, both using concurrent administration of the testing and conditioning stimuli [16,34]. It is possible that facilitation might be dependent on the temporal presentation of the stimuli (i.e., favoring concurrent) and more dynamic testing stimuli (i.e., changes in pain sensitivity). For example, Larivière et al. [37] assessed thermal pain thresholds, which might not engage mechanisms underlying facilitation. An additional explanation could be that older subjects are less able to process multiple noxious stimuli simultaneously. Thus, with a concurrent paradigm, older subjects cannot subjectively separate the stimuli, possibly due to cognitive overload. Since each study utilized a different methodology, further research is needed to evaluate the relevance and repeatability of this observation before any real conclusions can be generated; however, our data suggest that this facilitatory response emerges only with concurrent stimulation.

4.4. Methodological issues

Since attention has been shown to influence the perception of experimental pain [2,18,58,59] and CPM [39,53], we assessed the possibility that the level of attention could be related to the magnitude of pain suppression. Based on ratings of concentration following the experimental procedure, no age-related differences were observed in subject's ability to accurately rate the intensity of heat pain at their palm during sessions with or without a water bath.

A potential limitation is that older subjects had lower overall pain ratings. The older group may have exhibited less CMP because of lower pain; however, the differences in inhibition were not proportional to differences in pain ratings. In addition, it would not explain the increased pain for the NoxC condition. As they received the same training session as younger subjects, we can only speculate why this occurred. The older subjects may have sensitized more than younger subjects during the longer training session, appearing to need a lower temperature to reach a peak of 40–50. Thus, once experimental sessions were started, the chosen temperature and subsequent pain ratings were lower. Another possibility is inhibition over multiple testing sessions and desensitization across testing days has been reported [3,47], but post hoc analysis did not support this. Older subjects may have been more sensitive throughout the training session due to anxiety, but there were no group differences in anxiety scores or autonomic measures.

We administered thermal stimuli to the palm because of the increased presence of C-fibers and enhanced sensitivity at the thenar eminence [24,55]. There is evidence that age may have a differential effect on A-delta and C-fiber response. As a result, older subjects may employ C-fiber mediated sensations to a greater extent than those transmitted by A-delta fibers [8,28]. In addition, activity of C-nociceptors is implicated in transmission of late pain sensations [13], the sensation of burning [6,11,67], prevalence of chronic pain [46,54], and interact with certain inflammatory signals [9,10].

4.5. Clinical implications

Increasing evidence indicates that laboratory pain responses are associated with clinical pain [17], and some evidence suggests that deficiencies in pain inhibition may be particularly predictive of clinical pain. For example, using a concurrent CPM paradigm, Edwards et al. [16] found that better pain inhibition was associated with less pain, better physical functioning, and better self-rated health in a sample of healthy younger and older adults. Data from clinical samples further support the clinical relevance of laboratory measures of CPM. Patients with painful osteoarthritis showed significantly poorer pain inhibition compared to healthy controls upon initial testing; however, after their arthritis pain had been successfully treated surgically, their inhibitory responses were normalized [35]. Recently, Yartnitsky and colleagues [66] reported that laboratory CPM measures, but not other measures of experimental pain, predicted risk for developing chronic pain following thoracotomy. Patients exhibiting strong inhibition of stimulus induced pain pre-operatively were at significantly lower risk of experiencing chronic pain after surgery. Given these previous findings, it seems plausible that the reduced pain inhibition in older adults may be associated with age-related increases in the frequency and intensity of clinical pain. Additional research is needed to directly address this possibility.

4.6. Summary and conclusion

In summary, the present findings extend previous research investigating CPM among older adults using continuously rated, sustained thermal pain stimuli as well as both concurrent and alternating application of cold water as the conditioning stimulus. Specifically, we report that older adults show deficiencies in endogenous pain inhibition assessed with both concurrent and non-concurrent testing protocols. Moreover, we showed that older adults exhibit pain facilitation with a concurrent noxious stimulus, but not with an alternating stimulus. In addition, under baseline conditions, older adults showed slower thermal pain offset, which may be similar to prolonged after-sensations [50,53]. The mechanisms underlying these results, as well as their clinical relevance merit additional investigation.

Disclosure statement

There are no actual or potential conflicts of interest for any of the authors.

Acknowledgements

This research was supported by a University of Florida College of Density Seed Grant, NIH-NIDCR Grant T32 DE007200, NIH/NIA Grant AG033906, and the UF Comprehensive Center for Pain Research.

References

[1] al'Absi M, Petersen KL, Wittmers LE. Adrenocortical and hemodynamic predictors of pain perception in men and women. Pain. 2002;96:197-204.
[2] Bentsen B, Svensson P, Wenzel A. The effect of a new type of video glasses on the perceived intensity of pain and unpleasantness evoked by a cold pressor test. Anesth Prog. 1999;46:113-117. [Fall].
[3] Bingel U, Schoell E, Herken W, Büchel C, May A. Habituation to painful stimulation involves the antinociceptive system. Pain. 2007;131:21-30.
[4] Bodnar RJ, Romero MT, Kramer E. Organismic variables and pain inhibition: roles of gender and aging. Brain Res Bull. 1988;21:947-953.
[5] Bouhassira D, Danziger N, Attal N, Guirimand F. Comparison of the pain suppressive effects of clinical and experimental painful conditioning stimuli. Brain. 2003;126:1068-1078.
[6] Campero M, Baumann TK, Bostock H, Ochoa JL. Human cutaneous C fibres activated by cooling, heating and menthol. J Physiol. 2009;587:5633-5652.
[7] Casale G, Pecorini M, Cuzzoni G, de Nicola P. Beta-endorphin and cold pressor test in the aged. Gerontology. 1985;31:101-105.
[8] Chakour MC, Gibson SJ, Bradbeer M, Helme RD. The effect of age on A-delta and C-fiber thermal pain perception. Pain. 1996;64:143-152.
[9] Chen X, Levine JD. Epinephrine-induced excitation and sensitization of rat C-fiber nociceptors. J Pain. 2005;6:439-446.
[10] Chen X, Alessandri-Haber N, Levine JD. Marked attenuation of inflammatory mediator-induced C-fiber sensitization for mechanical and hypotonic stimuli in TRPV4−/− mice. Mol Pain. 2007;3:31.
[11] Cline MA, Ochoa J, Torebjörk HE. Chronic hyperalgesia and skin warming caused by sensitized C nociceptors. Brain. 1989;112:621-647.
[12] Coghill RC, Mayer DJ, Price DD. The roles of spatial recruitment and discharge frequency in spinal cord coding of pain: a combined electrophysiological and imaging investigation. Pain. 1993;53:295-309.
[13] Cooper BY, Vierck CJ Jr, Yeomans DC. Selective reduction of second pain sensations by systemic morphine in humans. Pain. 1986;24:93-116.
[14] Crum RM, Anthony JC, Bassett SS, Folstein MF. Population-based norms for the Mini-Mental State Examination by age and educational level. JAMA. 1993;269:2386-2391.
[15] Cuellar JM, Dutton RC, Antognini JF, Carstens E. Differential effects of halothane and isoflurane on lumbar dorsal horn neuronal windup and excitability. Br J Anaesth. 2005;94:617-625.
[16] Edwards RR, Fillingim RB, Ness TJ. Age-related differences in endogenous pain modulation: a comparison of diffuse noxious inhibitory controls in healthy older and younger adults. Pain. 2003;101:155-165.
[17] Edwards RR. Individual differences in endogenous pain modulation as a risk factor for chronic pain. Neurology. 2005;65:437-443.
[18] Fernandez E, Turk DC. The utility of cognitive coping strategies for altering pain perception: a meta-analysis. Pain. 1989;38:123-135.
[19] Folstein M, Folstein S, McCugh P. Mini-mental state examination ± a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1980;12:381-384.
[20] Frølund F, Frølund C. Pain in general practice. Pain as a cause of patient–doctor contact. Scand J Prim Health Care. 1986;4:97-100.
[21] Gibson SJ, Farrell M. A review of age differences in the neurophysiology of nociception and the perceptual experience of pain. Clin J Pain. 2004;20:227-239.
[22] Gibson SJ, Helme RD. Age-related differences in pain perception and report. Clin Geriatr Med. 2001;17:433-456.
[23] Gottrup H, Kristensen AD, Bach FW, Jensen TS. Aftersensations in experimental and clinical hypersensitivity. Pain. 2003;103:57-64.
[24] Granovsky Y, Matre D, Sokolik A, Lorenz J, Casey KL. Thermoreceptive innervation of human glabrous and hairy skin: a contact heat evoked potential analysis. Pain. 2005;115:238-247.
[25] Hamm RJ, Knisely JS. Environmentally induced analgesia: an age-related decline in an endogenous opioid system. J Gerontol. 1985;40:268-274.
[26] Hamm RJ, Knisely JS, Watson A. Environmentally-induced analgesia: age-related differences in a hormonally-mediated, nonopioid system. J Gerontol. 1986;41:336-341.
[27] Hamm RJ, Knisely JS. Environmentally induced analgesia: age-related decline in a neurally mediated, nonopioid system. Psychol Aging. 1986;1:195-201.
[28] Harkins SW, Davis MD, Bush FM, Kasberger J. Suppression of first pain and slow temporal summation of second pain in relation to age. J Gerontol Med Sci. 1996;51A:M260-M265.
[29] Hines EA, Brown GE. The cold pressor test for measuring the reactivity of the blood pressure: data concerning 571 normal and hypertensive subjects. Am Heart J. 1936;11:1-9.
[30] Jessop DS. Beta-endorphin in the immune system – mediator of pain and stress? Lancet. 1998;351:1828-1829.
[31] Johannesson U, de Boussard CN, Brodda Jansen G, Bohm-Starke N. Evidence of diffuse noxious inhibitory controls (DNIC) elicited by cold noxious stimulation in patients with provoked vestibulodynia. Pain. 2007;130:31-39.
[32] Julien N, Goffaux P, Arsenault P, Marchand S. Widespread pain in fibromyalgia is related to a deficit of endogenous pain inhibition. Pain. 2005;114:295-302.
[33] Kandel ER, Schwartz JH, Jessell TM, editors. Principles of neural science 4th ed. New York: McGraw Hill Health Professions Division; 2000.
[34] King CD, Wong F, Currie T, Mauderli AP, Fillingim RB, Riley JL 3rd. Deficiency in endogenous modulation of prolonged heat pain in patients with Irritable Bowel Syndrome and Temporomandibular Disorder. Pain. 2009;143:172-178.
[35] Kosek E, Ordeberg G. Lack of pressure pain modulation by heterotopic noxious conditioning stimulation in patients with painful osteoarthritis before, but not following, surgical pain relief. Pain. 2000;88:69-78.
[36] Kotlyar M, al'Absi M, Brauer LH, Grant JE, Fong E, Kim SW. Naltrexone effect on physiological and subjective response to a cold pressor task. Biol Psychol. 2008;77:233-236.
[37] Larivière M, Goffaux P, Marchand S, Julien N. Changes in pain perception and descending inhibitory controls start at middle age in healthy adults. Clin J Pain. 2007;23:506-510.
[38] Lautenbacher S, Rollman GB. Possible deficiencies of pain modulation in fibromyalgia. Clin J Pain. 1997;13:189-196.
[39] Lautenbacher S, Roscher S, Strian F. Inhibitory effects do not depend on the subjective experience of pain during heterotopic noxious conditioning stimulation (HNCS): a contribution to the psychophysics of pain inhibition. Eur J Pain. 2002;6:365-374.
[40] Lovallo W. The cold pressor test and autonomic function: a review and integration. Psychophysiology. 1975;12:268-282.
[41] McMurray G, Jaques L. Capillary resistance and blood pressure changes associated with pain due to local cooling: cold pressor test. J Appl Physiol. 1959;14:813-816.
[42] Meeus M, Nijs J, Van de Wauwer N, Toeback L, Truijen S. Diffuse noxious inhibitory control is delayed in chronic fatigue syndrome: an experimental study. Pain. 2008;139:439-448.
[43] Peckerman A, Hurwitz BE, Saab PG, Llabre MM, McCabe PM, Schneiderman N. Stimulus dimensions of the cold pressor test and the associated patterns of cardiovascular response. Psychophysiology. 1994;31:282-290.
[44] Picavet HS, Hazes JM. Prevalence of self reported musculoskeletal diseases is high. Ann Rheum Dis. 2003;62:644-650.
[45] Price DD, Hayes RL, Ruda M, Dubner R. Neural representation of cutaneous aftersensations by spinothalamic tract neurons. Fed Proc. 1978;37:2237-2239.
[46] Price DD, Staud R, Robinson ME, Mauderli AP, Cannon R, Vierck CJ. Enhanced temporal summation of second pain and its central modulation in fibromyalgia patients. Pain. 2002;99:49-59.
[47] Quiton RL, Greenspan JD. Across- and within-session variability of ratings of painful contact heat stimuli. Pain. 2008;137:245-256.
[48] Raphael KG. Temporal summation of heat pain in temporomandibular disorder patients. J Orofac Pain. 2009;23:54-64.
[49] Rodrigues AC, Verne GN, Schmidt S, Mauderli AP. Hypersensitivity to cutaneous thermal nociceptive stimuli in irritable bowel syndrome. Pain. 2005;115:5-11.
[50] Sarlani E, Grace EG, Reynolds MA, Greenspan JD. Evidence for up-regulated central nociceptive processing in patients with masticatory myofascial pain. J Orofac Pain. 2004;18:41-55.
[51] Spielberger C, Gorsuch R, Lushene R., 1970. Manual for the State-Trait Anxiety Inventory, Consulting Psychologist Press, Palo Alto, CA.
[52] Staud R, Robinson ME, Price DD. Temporal summation of second pain and its maintenance are useful for characterizing widespread central sensitization of fibromyalgia patients. J Pain. 2007;8:893-901.
[53] Staud R, Robinson ME, Vierck CJ Jr, Price DD. Diffuse noxious inhibitory controls (DNIC) attenuate temporal summation of second pain in normal males but not in normal females or fibromyalgia patients. Pain. 2003;101:167-174.
[54] Staud R, Vierck CJ, Cannon RL, Mauderli AP, Price DD. Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome. Pain. 2001;91:165-175.
[55] Stevens JC, Choo KK. Temperature sensitivity of the body surface over the life span. Somatosens Mot Res. 1998;15:13-28.
[56] Stratton JR, Halter JB, Hallstrom AP, Caldwell JH, Ritchie JL. Comparative plasma catecholamine and hemodynamic responses to handgrip, cold pressor and supine bicycle exercise testing in normal subjects. J Am Coll Cardiol. 1983;2:93-104.
[57] Tassorelli C, Micieli G, Osipova V, Rossi F, Nappi G. Pupillary and cardiovascular responses to the cold-pressor test. J Auton Nerv Syst. 1995;55:45-49.
[58] Unrod M, Kassel JD, Robinson M. Effects of smoking, distraction, and gender on pain perception. Behav Med. 2004;30:133-139. [Fall].
[59] Weisenberg M, Tepper I, Schwarzwald J. Humor as a cognitive technique for increasing pain tolerance. Pain. 1995;63:207-212.
[60] Velasco M, Gomez J, Blanco M, Rodriguez I. The cold pressor test: pharmacological and therapeutic aspects. Am J Ther. 1997;4:34-38.
[61] Verhaak PF, Kerssens JJ, Dekker J, Sorbi MJ, Bensing JM. Prevalence of chronic benign pain disorder among adults: a review of the literature. Pain. 1998;77:231-239.
[62] Washington LL, Gibson SJ, Helme RD. Age-related differences in the endogenous analgesic response to repeated cold water immersion in human volunteers. Pain. 2000;89:89-96.
[63] Wilder-Smith CH, Robert-Yap J. Abnormal endogenous pain modulation and somatic and visceral hypersensitivity in female patients with irritable bowel syndrome. World J Gastroenterol. 2007;13:3699-3704.
[64] Willer JC, Le Bars D, De Broucker T. Diffuse noxious inhibitory controls in man: involvement of an opioidergic link. Eur J Pharmacol. 1990;182:347-355.
[65] Willer JC, Roby A, Le Bars D. Psychophysical and electrophysiological approaches to the pain-relieving effects of heterotopic nociceptive stimuli. Brain. 1984;107:1095-1112.
[66] Yarnitsky D, Crispel Y, Eisenberg E, Granovsky Y, Ben-Nun A, Sprecher E, Best LA, Granot M. Prediction of chronic post-operative pain: pre-operative DNIC testing identifies patients at risk. Pain. 2008;138:22-28.
[67] Yarnitsky D, Ochoa JL. Release of cold-induced burning pain by block of cold-specific afferent input. Brain. 1990;113:893-902.
[68] Zheng Z, Gibson SJ, Helme RD, McMeeken JM. The effect of local anaesthetic on age-related capsaicin-induced mechanical hyperalgesi a – a randomised, controlled study. Pain. 2009;144:101-109.
[69] Zheng Z, Gibson SJ, Khalil Z, Helme RD, McMeeken JM. Age-related differences in the time course of capsaicin-induced hyperalgesia. Pain. 2000;85:51-58.
Keywords:

Pain modulation; Aging; Elderly; Diffuse noxious inhibitory controls (DNICs); Conditioned pain modulation (CPM)

© 2010 Lippincott Williams & Wilkins, Inc.