Reduced endogenous pain inhibition in adolescent girls with chronic pain

2.1 Participants

Female adolescents were recruited in different high schools from Sherbrooke, Quebec, Canada. Inclusion criteria were female aged between 15 and 17 years old, suffering or not from chronic or recurrent pain. Only girls were included in this study based on the higher prevalence of chronic pain in females [25], [26]. Participants included in the chronic pain group had to be suffering from chronic or recurrent pain, defined as pain (headache/migraine, musculoskeletal, articular, gastrointestinal or gynecological) at an intensity of >3/10, at least once or twice a week for more than 3 months. Exclusion criteria were prematurity (<37 weeks of gestation), use of tobacco products, use of illicit drugs, cardiac or pulmonary disease (including asthma and upper respiratory tract infection at the moment of experiment), endocrine or metabolic disease. Participants were screened using a questionnaire, physical examination, electrocardiogram and spirometer to rule out any contraindications to cycle ergometer testing for aerobic fitness measurements.

All participants were asked to refrain from using analgesic medication at least 24 h prior to experimentation. Experimental procedures were held during the summertime not to interfere with school schedule. All procedures were approved by the Ethics Committee of the Centre Hospitalier Universitaire de Sherbrooke (CHUS). Participant and parent (or legal guardian) consent were obtained (complying with the requirements of the Declaration of Helsinky, 2013).

2.2 Pain evaluations

A numeric rating scale (0: no pain–10: most intense pain tolerable) was used to verbally rate pain intensity during the experimental pain stimulations. The numeric rating scale has been shown to have good validity and reliability for pain intensity evaluation in a pediatric population [27].

2.3 Heat pain stimulations (thermode)

A 30×30 mm thermode (TSA-II, Medoc advanced medical systems, Ramat Yishai, Israel) was used to induce thermal pain stimulations. Prior to actual testing, the thermode was placed in the palm of the left hand to familiarize participants to the heat pain stimuli, and to the experimental pain rating scale. During all subsequent heat pain tests the thermode was placed on the volar part of the left forearm. Thermode temperature was initially set to 37 °C and increased at a fixed rate of 0.3 °C/s. Participants were instructed to report when the sensation produced by the thermode changed from heat sensation to minimal pain (heat pain threshold) and when the pain could no longer be sustained (heat pain tolerance). This procedure was completed twice for every participant, and the mean of the two trials was retained. The thermode was placed on adjacent areas of the forearm for every trial to avoid primary skin hyperalgesia.

After heat pain threshold/tolerance assessments, the thermode was applied on the volar part of the left forearm for 5 s at constant temperature. During heat pain stimulations, the temperature was individually adapted to produce mild (30%) pain intensity (based on previously evaluated heat pain threshold and tolerance values. The following formula was used to determine the temperatures to use to induce mild pain: [0.3 (heat pain tolerance-heat pain threshold)]+heat pain threshold. Participants were asked to evaluate the pain intensity immediately after the heat pain stimulations (5 s). This procedure was done before and after the cold pressor test (CPT – see Section 2.4) using the same temperature. Participants were not informed the thermode temperature used before and after cold water immersion was the same to reduce expectations. The effectiveness of CPM was evaluated by comparing the pain intensity of the heat pain stimulation performed before and after the CPT.

2.4 Cold pressor test (CPT)

Participants had to immerse their right forearm in a bath of circulating cold water (10 °C) for 2 min. Participants were instructed not to move or contract their arm during the immersion. The CPT was used as a conditioning stimulus to activate CPM.

2.5 Cold pain stimulations (ice cube test)

A 2× 2 cm ice cube held with a plastic clamp was placed on four different sites of the left arm (volar portion) of the participants for 10 s. Pain intensity was evaluated with a verbal numeric rating scale at the end of the procedure. The ice cube tests were done before and after the graded exercise test (see Section 2.4). Mean pain intensity of the four trials (before and after physical exercise) are presented.

2.6 Graded exercise test

Participants performed a maximal oxygen capacity (VO₂max) test on a cycle ergometer (Ergometrics 900, Ergoline GmbH, Bitz, Germany). The test began after a 3-min warm-up at 60 revolutions per minute (RPM) without resistance. Resistance was gradually added with a ramp protocol. Rate of workload increment was individualized to reach the maximal theoretical aerobic power between 8 and 12 min (increments 15–30 W/min) [28], [29]. Participants were encouraged to keep a constant rate of approximately 60 rpm throughout the procedure. Exercise continued until at least three of the VO₂max criteria were obtained [30]: (1) a plateau of VO₂ in spite of the increase of workload, (2) maximal heart rate (maximal predicted heart rate±5%), (3) respiratory exchange ratio>1.1, and (4) inability to maintain the pedaling frequency at 60 rpm (exhaustion).

2.7 Experimental procedure

Participants were comfortably seated in a calm room at the clinical research center of the CHUS. After determination of heat pain threshold and heat pain tolerance values, heat pain stimulations at mild intensity (30%) were completed. Heat pain stimulations were performed before and immediately after the CPT in order to evaluate CPM. After completing the CPM test, the participants filled-out different questionnaires to describe their socio-demographic and psychological characteristics. Socio-demographic information (age, time spent doing physical activities, etc.) was collected with a home-made questionnaire. Sleep quality was evaluated with the Pittsburgh Sleep Quality Inventory (PSQI). A standardized questionnaire on physical activity (including type, frequency, intensity and duration of physical activities) was completed by the participants [31]. The Pain Catastrophizing Scale, the State Trait Anxiety Inventory and the Children Depression Inventory were administered to assess psychological characteristics. Participants were allowed to eat a light meal or snack after completing the CPM evaluation.

Participants were then taken to the respiratory function lab at the CHUS. A 2-h interval separated CPM and EIA evaluations to avoid carry-over effects of CPM during EIA assessments. Physical characteristics (height, weight, sum of skinfold thickness) and spirometry were carried out. Pre-exercise ice cube tests were done and the participants then undertook the graded exercise test used to activate EIA. The post-exercise ice cube tests were realized after the end of the graded exercise test (<5 min after).

2.8 Statistical analyses

The effectiveness of CPM was evaluated by calculating the percentage of change in pain intensity for the heat pain stimulations (thermode) before and after the CPT using the following formula: 100[(thermode pain intensity before CPT-thermode pain intensity after CPT)/thermode pain intensity before CPT]. The effectiveness of EIA was assessed similarly by calculating the change in pain intensity of the ice cube test before and after the graded exercise test using the following formula: 100[(ice cube test pain intensity before exercise-ice cube test pain intensity after exercise)/ice cube test pain intensity before exercise]. Higher CPM or EIA values represent more important pain inhibition following the CPT or graded exercise test, respectively.

All analyses were conducted using SPSS (version 19.0; IBM, New York, NY, USA). Group differences (healthy and chronic pain participants) were evaluated with independent sample t-tests. Paired sample t-tests (repeated measures) were used to compare pain intensity assessments for the heat pain stimulations before and after CPT (or for the ice cube tests before and after graded exercise). All data are given as mean and standard error of the mean (SEM). Statistical significance was set at p<0.05.

3.1 Participant characteristics

A total of 47 adolescent girls were recruited in this study. Six participants were excluded (two suffered from asthma, unknown prior to inclusion of the study; one was born prematurely and three did not complete the entire experimental procedures). The final analyses included 25 healthy (age=15.8±0.2 years); and 16 teenage girls with chronic/recurrent pain (age=15.7±0.2 years). Healthy girls had less sum of skinfold thickness compared to chronic pain teenagers (p=0.009) (Table 1). Healthy teens tended to be more physically active then girls suffering from chronic pain (p=0.06). Teenage girls with chronic/recurrent pain showed lower VO₂max compared to healthy adolescents (p=0.004).

Psychological characteristics of the participants are presented in Table 2. State anxiety was comparable between groups, although trait anxiety tended to be higher in the chronic pain group compared to healthy girls (p=0.09). Teenage girls in the chronic pain group had more depressive symptoms and less healthy sleep quality compared to the pain-free group (p=0.002 and p=0.003, respectively).

3.2 Conditioned pain modulation (CPM)

A statistically significant reduction in pain intensity induced by heat pain stimulations performed after the CPT was observed in healthy adolescent girls (3.0±0.2 before CPT vs. 2.2±0.2 after CPT; t=4.0, p=0.0006). On the other hand, teenage girls suffering from chronic pain did not show pain intensity modifications during heat pain stimuli realized after the CPT (3.2±0.3 before CPT vs. 3.0±0.2 after CPT; t=0.8, p=0.4). Pain intensity evaluations for heat pain stimulations completed before the CPT were comparable between healthy and chronic pain adolescents (3.0±0.2 healthy vs. 3.2±0.3 pain; t=0.5, p=0.6). The effectiveness of CPM was greater in healthy participants compared to adolescent females suffering from chronic pain (26.7±8.1 vs. −1.9±9.6; t=2.2, p=0.03, Fig. 1).

Fig. 1:

Conditioned pain modulation (CPM) effectiveness (%) in healthy and in chronic pain adolescent girls. *p<0.05 for the difference in CPM effectiveness between groups.

3.3 Exercise-induced analgesia (EIA)

In the healthy adolescent girls group, pain intensity induced by the ice cube test significantly decreased after physical exercise (3.5±0.5 before vs. 2.7±0.4 after exercise; t=3.7, p=0.001). However, adolescents suffering from chronic pain did not show a significant reduction in pain intensity during the ice cube tests performed before and after the graded exercise test (3.1±0.7 before vs. 3.1±0.7 after exercise; t=0.2, p=0.9). Pain intensity evaluations for the ice cube test before the graded exercise test were comparable between healthy and chronic pain adolescents (3.5±0.5 healthy vs. 3.1±0.7 pain; t=0.6, p=0.6). The effectiveness of EIA was greater in healthy participants compared to adolescent females suffering from chronic pain (23.8±6.1 healthy vs. −12.0±11.2 pain t=3.1, p=0.004, Fig. 2).

Fig. 2:

Exercise-induced analgesia (EIA) effectiveness (%) in healthy and in chronic pain adolescent girls. *p<0.05 for the difference in EIA effectiveness between groups.