Table 2 Characteristics of the included studies examining the effect of aerobic exercise on pain sensitization

Experimental, repeated measures studies

Hoffman (2005), USA

Chronic LBP subjects

n: 8 (50%)

Age: 40(10)

Healthy subjects

n: 10 (70%)

Age: 34(8)

Inclusions

-LBP≥1 year

-Clinical pain: stable and non-neurological

Exclusions

-Use of narcotics

-Inability to walk without a device

-Sacroiliac joint dysfunction

-Involvement in a regular exercise or treatment program

-Major surgery in the past year

-History of spondyloarthropathy

-Spinal infection, fracture, spondylolisthesis or malignancy

-Cardiac, pulmonary or metabolic disorders, or diseases involving sensory nerves

-Conditions preventing safe participation in exercise

-Pregnancy

Device: Pressure pain stimulator with Lucite edge (6mmx0.25mm)

Force: 9.8 N

Locations: dorsal surface of the middle phalanx of the non-dominant index finger

Duration: 2 min

Scale: 100mm VAS

-1st PPT 1 min before starting aerobic exercise

-Cycling on ergometer for 5 min at 50% VO₂max followed by 20 min at 70% VO₂max

-2nd PPT 2 min after completion of cycling

-3rd PPT 28 min after completion of the 2nd

PPT (32 min post exercise)

Mean (SD) pressure pain ratings were significantly lower at 2 min (57(26) mm) and 32 min post exercise (62(27) mm) compared to pre-exercise values (79(12) mm) (p<0.05).

Exercise-induced analgesia to an experimentally induced pressure pain was evident for >30 min after aerobic exercise from cycling in people with chronic low back pain and minimal/ moderate disability.

Meeus (2010), Belgium

Chronic LBP

n=21 (48%)

Age: 41.6(12.4)

Chronic fatigue syndrome with chronic pain

n=26 (19%)

Age: 41.5(11.4)

Healthy subjects

n=31 (32%)

Age: 40.0 (12.6)

Inclusions

-18-65 years

- Non-specific LBP≥3 months

- Sedentary

Exclusions

-Pregnancy and ≤1 year postnatal

-Neurological or cardiovascular problems

- Specific LBP pathology

-History of spinal fracture, spinal surgery, severe degenerative change, severe scoliosis, osteoporosis, obesity, radicular signs, malignancies and metabolic or rheumatological diseases

Device: Fisher algometer

Force: Increased at a range of 1 kg/s

Locations: skin web between thumb and index finger, 5 cm lateral to L3 spinous process, insertion of deltoid and at the proximal third of the calf

Measures: Mean of last 2 of 3 consecutive measurements at each site separated by 10 s before and after each exercise bout.

6 bouts of exercise on a bicycle ergometer

-Incremental, starting at 20 W and increasing in steps of 10 W/minute

-Each bout began with a warm-up period, starting from 0 and increasing by 1 W every 2 s

-Exercise consisted of 2 incremental 1-minute steps

-Each bout finished with a cool down of 30 s

-Subjects instructed to stop when tired or couldn’t pedal at frequency of ≥70 rpm

-6th exercise bout ended at 130 W

Baseline

There were no

significant differences in PPTs between healthy subjects

and patients with chronic LBP (p=NA).

Post-exercise

The mean(SD) PPTs increased following exercise in healthy and CLBP individuals:

Healthy: 7.11(2.74) to 7.56(3.17) (p=0.001).

CLBP: 8.10(3.02) to 8.28(3.49) (p=0.001).

After submaximal

aerobic exercise, mean pain thresholds

increased in patients with chronic LBP.

There was no evidence of hyperalgesia and abnormal

central pain processing during submaximal aerobic exercise in individuals with chronic LBP.

Vaegter (2016), Denmark

Chronic musculoskeletal pain

n: 61(69%)

Age: 45.4(11.2)

Low (LPS; N=30) and high (HPS; N=31) pain-sensitivity groups were created on the basis of a median split of the average PPTs.

Inclusions

-Chronic musculoskeletal pain (37 low back, 16 neck, 7 shoulder, 1 elbow)

-Referral to multidisciplinary pain clinic

Exclusions

-Neurological, psychiatric or CVD conditions

Device: Manual handheld algometer

Force: Increment rate of 30 kPa/s over stimulation area 1cm²

Locations: Middle of both quadriceps femoris, dominant biceps brachii and non-dominant upper trapezius muscle

Measures: Before, after, and 15 min after the exercise

Aerobic stationary cycling

-Age-related target HR corresponding

to 50% VO₂max and 75% VO₂max

-Patients pedaled at ~70 revolutions per minute

-First 2 min: warm up (HR: 50% VO₂max)

-Resistance increased over next 3 min until HR: 75% VO₂max

-Continuation to maintain this HR for 10 min

Baseline

PPT and pain tolerance were decreased in the HPS group compared to the LPS

(P=0.001; 0.02 respectively).

Post-exercise

Widespread PPTs increased after exercise in both groups

HPS: 272.8(158.0) to 319.1 (162.1)

(p<0.05)

LPS: 574.7(362.1) to 646.3(378.8) (p<0.05)

Cuff PPT increased and pain tolerance limit decreased

after exercises in LPS only (p<0.001).

Temporal summation of pain was increased after bicycling in HPS (p<0.005).

Pain tolerance increased after exercise in both groups (p<0.001).

Hypoalgesia after the exercise was

impaired in patients with chronic pain and high pain sensitivity

compared with patients with less pain sensitivity.

Vaegter (2018), Denmark

Chronic musculoskeletal pain

n: 54(72%)

Age: 45.7(11.2)

Participants were subgrouped into high and low kinesiophobia based on the recommended threshold for a high degree of kinesiophobia on the Tampa scale.

All patients recruited after referral to a multidisciplinary pain clinic

Device: Manual handheld algometer

Force: Increment rate of 30 kPa/s over stimulation area 1cm²

Locations: Middle of both quadriceps femoris, dominant biceps brachii and non-dominant upper trapezius muscle

Measures: Before, after, and 15 min after the exercise, 2 assessments per site, average used for analysis

2 exercise conditions on 2 different days

-Cycling

-Isometric contraction

Aerobic stationary cycling

-Age-related target HR corresponding

to 50% VO₂max and 75% VO₂max were determined

-Patients pedaled at ~70 revolutions per minute

-First 2 min: warm up (HR: 50% VO₂max)

-Resistance increased over next 3 min until HR: 75% VO₂max

-Continuation to maintain this HR for 10 min

Baseline

The low kinesiophobia group had higher PPTs than the high kinesiophobia group, however no significant differences were found between the groups (p=0.09-0.59).

Post-exercise

No significant differences were found in percentage increase in PPTs between the high and low kinesiophobia groups post-exercise (p=0.12-0.58).

Although kinesiophobic beliefs influence pain intensity, they did not influence PPTs and EIH significantly, suggesting that exercise can induce hypoalgesia in subjects with chronic musculoskeletal pain, regardless of such belief.

Fingleton (2017), Ireland

OA group

n:40

Divided into:

-Abnormal CPM (decrease or absence of change in PPTs) (n=19)

-Normal CPM (increase in PPTs) (n=21)

Control group

n:20 aged and sex matched subjects

Inclusions

-Knee OA based on ACR criteria and pain >3/10 on a numerical rating scale

-Main pain from knee OA

Exclusions

-Total knee replacement and if <90 degrees knee flexion

-Rheumatologic disease such as RA, fibromyalgia or ankylosing spondylitis

- Neurologic disorder such as Parkinsons disease, shingles, multiple sclerosis or stroke

- Cognitive impairment

- Current use of antidepressants or anticonvulsants

Device: Handheld pressure algometer

Force: 2cm² probe, pressure applied at a rate of 30KPa/s

Locations: Medial joint line, quadriceps

femoris muscle and volar surface of the forearm

Measures: Average of 2 PPT measurements was recorded for

each site

Aerobic exercise protocol

-Cycle ergometer

-Submaximal exercise protocol used: Aerobic Power Index test

-Exercise duration varied between 4 and 10 min

-Pain was monitored on a numerical rating scale after each minute

-If pain at the knee joint exceeded 3/10, the participant’s workload

was reduced by 25 W by decreasing rate of pedaling and/or resistance

There were significant differences between abnormal

CPM, normal CPM and control groups for changes in

PPTs during

and post-aerobic exercise (F_2,55=4.860, p=0.01)

The abnormal CPM group showed a decrease in PPTs (168.9(43.1) to 152.8(52.3)), while the normal CPM and

control groups showed an increase in PPTs (184.3(58.1) to 205.7(76.1) (P<0.05) and 218.0 (93.2) to 237.5 (111.7) p>0.05 pre and post exercise respectively).

Knee OA patients with abnormal CPM demonstrated

significantly increased pain sensitivity

in response to exercise,

while knee OA patients with normal CPM and controls demonstrated a significant decrease in their pain

sensitivity in response to exercise suggestive

of normal function of EIH.

Vaegter (2021), Denmark

n: 96 (37.5%)

Age:

Mean (range): 47(20-73)

Inclusions

- Individuals ≥ 18 years who were adept in Danish

-Pain primarily in the lower back

(+/- pain radiating to the legs)

Exclusions

-Pregnancy, neurological, psychological or cardiovascular diseases, and current or previous alcohol or drug addiction

Device: Manual pressure algometry

Force: stimulation probe of 1 cm² was used and the pressure was increased with 30 kPa/s

Locations: Left erector spinae and left calf muscles

Measures: average PPTs across two repetitions at each

site

6 min walk test on 20 m course between 2 cones

No significant main effects were found for PPTs. However,

a significant interaction between time and Walk-Pain Index was found in the RM-ANOVA of the PPTs (F(1,94)=5.56, p=0.02, partial ƞ2 = 0.056).

Post hoc testing showed an increase in PPTs after walking in individuals who reported no or little increase in NRS scores of back pain

intensity, and a decrease in PPTs after walking in individuals who reported an increase of 2 or more in NRS back pain intensity scores.

This study found most individuals experienced exercise-induced hypoalgesia after walking, with the exception of those that reported an increase in pain during walking and subsequently no hypoalgesia afterwards.

Sitges (2021), Spain

Aerobic exercise

n: 21 (57%)

Age: 42.5 (9.72)

Control

n:19 (58%)

Age: 40.71 (9.95)

Inclusions

-18–59 years

-NSCLBP >6 weeks or with at least 3 episodes of LBP (lasting >1 week) in the year prior to the study

Exclusions

-High functional impairment compromising such activities as walking, sitting, or getting up from a chair, pain at time of evaluation and/or intervention >5 (out of 10) on the VAS, history or presence of sciatic radiating pain, referred pain, or OA of lower extremities, spine surgery, spinal or pelvic fracture, hospitalization for serious trauma, injuries, or traffic accidents, and systematic diseases affecting the locomotor system.

Device: Digital algometer

Force: Maximum 5 kg/cm², no further details given

Locations: Erector spinae and gluteus medius muscles, sacrum and forefinger

Measures: no details given.

Aerobic intervention consisted of walking on a treadmill for 20 min at low–moderate intensity (65.9%±7% of maximum heart rate and 3.02±1.04 using the Borg Scale of Perceived

Exertion)

No information provided on the control group.

Mixed-model ANOVA revealed significant main effects of time on subjective PPIRs

(F1, 77=13.142,

p=0.001, ηp²=0.146).

Bonferroni post hoc analyses showed: lower PPIRs (2.581±1.584 vs. 2.865±1.629, p=0.001) and lower PPTs (2.581

±1.584 vs. 2.0.865±1.629, p=0.001) after intervention than before.

Mixed-model ANOVA revealed significant main effects of time on the pressure pain–sensitivity index (F 1, 77=7.074,

p<0.001, Greenhouse-Geisser correct: ηp²=0.084). Bonferroni post hoc analyses showed a reduction in pain sensitivity after intervention (1.217±0.945 vs. 1.082±0.918, p=0.010).

This study showed reductions in pain sensitivity after an aerobic exercise intervention in patients with non-specific, chronic low back pain.

Randomised controlled trial

Öte Karaca (2017), Turkey

Aerobic exercise:

n: 25 (64%)

Age: 43.7(10.8)

Control:

n: 25 (68%)

Age: 44.9(7.9)

Inclusions

-MSK pain > 3 months

-Recruited from Physical Medicine Rehabilitation Department outpatient clinic

Exclusions

-Uncontrolled hypertension or arrhythmias

-Inflammatory arthritis

-Fibromyalgia

-Taking analgesia

-Physical therapy

-Regular exercise in the last 6 months

Device: Mechanical pressure algometer

Force: 1cm² diameter pressure surface, 1 kg/s increments

Locations: Midpoint of forehead, bilateral volar surface of forearm and thumb nails

Measures: 3 consecutive measurements at 30-60 s intervals and mean taken to be pressure threshold

Intervention

-Submaximal aerobic exercise program

-Treadmill walking

-30 min 5 days a week for 2 weeks

-70-85% maximum HR

-With conventional physical therapy

Control

-Conventional physical therapy

PPT sum increased significantly in the exercise group from 19.9(6.1) to 22.0(6.3) (p=0.02), but was unchanged in the control group (20.7(5.4) to 20.9(6.7) (p=0.9)).

There was a significant increase in exercise duration in the exercise group compared with the control group (p=0.0002).

Pain intensity in both groups decreased significantly after exercise (p<0.001).

Short-term aerobic exercise along with conventional physical therapy decreased pain sensitivity in individuals with musculoskeletal pain.

Nielsen (2009), Denmark

Aerobic exercise:

n: 11 (100%)

Age: 49(7)

Control:

n: 5 (100%)

Age: 48(11)

Inclusions

-Female office workers with monotonous, repetitive tasks

-Chronic pain in the neck, doctor-verified tightness of the upper trapezius muscle (UTM) and tenderness on UTM palpation

-Specific criteria

1) Pain for > 30 days in past year in neck/shoulder region, but with no more than 3 regions with symptoms

2) At least ‘‘quite a lot’’: on an ordinal scale of ‘‘a little” to ‘‘very much’’

3) Frequent: at least once a week on an ordinal scale of ‘‘seldom” to “almost all the time’’

4) Intensity: ≥2 on a scale from 0 to 9

Exclusions

-Previous trauma, life-threatening diseases, whiplash injury, cardiovascular diseases, arthritis in the neck and shoulder

Device: Electronic pressure algometer

Force: Contact diameter 10mm, increments of 30 kPa/s

Locations: Descending part of the trapezius muscle and the middle of the non-painful TA muscle

Measures: Before and after intervention, 3 times with at least 1 min between the measurements

Intervention

-Leg bicycling on stationary Monark ergometer at 70% maximal oxygen uptake for 20 min 3 x pw for 10 weeks

-Initial load 50% based on HR and gradually increased to 70% during the 10 weeks

Control

-No physical training, general health advice

Case-control study: Baseline

PPTs were significantly lower in neck/shoulder pain group than the control group:

Trapezius

Neck pain: (280(82) kPa)

Control: (479(119) kPa) (p< 0.05).

Tibialis anterior (reference muscle): Neck pain: (302(110) kPa)

Control: (464 (134)) (p< 0.05)

Intervention study Post-exercise

PPTs in tibialis anterior were increased in the cycling group [from

311 (113) to 386 (107) kPa; p<0.01].

Physical exercise, in general, lowers pain perception, resulting in normalisation of PPT in pain-free muscles.

Kocur (2016), Poland

Nordic walking

n: 22 (100%)

Age: 54.5(3.7)

Control

n: 22 (100%)

Age: 56.7(2.9)

Inclusions

-Females 50-60 years, sedentary work for ≥ 6 h per day for ≥10 years

-Moderate or mild pain (VAS <6) in cervical area

-Lack of additional physical activity in free time

Exclusions

-Locomotor system disorders preventing physical exercises

-Physical work, work in standing position, sedentary work for < 10 years

-Participation in physical activity over the past year

-Acute inflammatory conditions

-Acute pain in the cervical area and shoulders VAS >6

-Idiopathic pain

-Cardiovascular or pulomonary disorders or other internal diseases

Device: Electronic pressure algometer

Force: Not specified

Locations: Trapezius par desc, mid trapezius, latissimus dorsi, infraspinatus, pectoralis major, triceps brachii, brachio-radialis

Measures: Test performed twice 10 s apart, second result used for calculations

Intervention

-12 week Nordic walking training: 3 times a week of 1 h

-Outdoors with at least 2 instructors controlling the marching technique and regulating pace

-Preceded by 10 min warm-up and ended with 5-minute cool down

-Intensity between 40-70% of HRR

Control

-Told not to change their movement routines and habits for the period of 12 weeks

There was

significant improvements in PPTs for Nordic Walking:

Trapezius pars descendens (1.32(0.5) to 1.99(0.6) p=0.002), Middle trapezius (2.92(0.9) to 3.30(0.8) p=0.002), Infraspinatus (1.63(0.6) to 2.93(0.8) p=0.001)

Latissimus dorsi (1.66(0.6) to 2.21(0.5) p=0.02)

No statistically significant improvement in PPTs were observed in pectoralis major, triceps and brachioradialis in the

treatment group p=(0.12-0.39).

No improvement was recorded in any muscle groups in the control group (p=0.05-0.92).

Nordic Walking has a high potential of reducing sensitivity to pressure

(increased PPT) in the muscles of that region.

Bruehl (2020), United States

Aerobic

n: 44 (55.3%)

Age: 40 (10)

Control

n: 49 (65.9%)

Age: 41.9 (9.45)

Inclusions

-18-55 years

-Daily low back pain of ≥3 months duration, with an average past month pain intensity (VAS) of ≥3/10

-Medical provider diagnosis consistent with CLBP

-No self-reported history of liver or kidney disorders, PTSD, BPD, psychotic disorder, diabetes, seizure disorder, alcohol or drug dependence, or daily use of opioid analgesics

-Engaged in moderate or vigorous exercise <2 days per week and <60 min per week

Exclusions

-Self-reporting CP related to malignancy or autoimmune disorders

-Pregnancy

Device: Computerised Medoc TSAII NeuroSensory Analyser

Force: 40 °C and increasing at a ramp rate of 0.5 °C per second until tolerance was reached

Locations: slightly different location of the ventral forearm for each stimulus to avoid local sensitization effects

Measures: 3 trials were conducted for heat pain tolerance (with the mean value used for

analyses)

Intervention

-Supervised, individual aerobic exercise training program 3 times per week for 6 weeks

-Exercise session included a 5-minute warm-up, 30 min of aerobic exercise and a 5-minute cool-down

-Treadmill walking/running,

stepping, elliptical, or cycling exercise as preferred by the participant

-Duration and intensity of exercise was progressively increased

-Participants began with 10-15 min of exercise at 40-55% HRR (RPE =11-12, light) during the first week, 20-30 min of exercise at 55-70% HRR (RPE = 12-13, somewhat hard) during the second week, then 30 min of exercise at 70-85% HRR (RPE=14-16, hard) for the remainder of the study

Control

-Asked to maintain their normal daily activity levels throughout the study

Baseline

Evoked thermal pain responses at baseline did not differ

significantly between groups.

Post-exercise

-Significant main effect of intervention

Group on MPQ-SF Total ratings [F(1,77) =5.80, P =0.018, h2 = 0.064]

-Participants in the exercise group

displayed slightly improved pain responsiveness (decreased

thermal pain ratings) after the 6-week intervention (M = 0.33, SE =0.70), whereas control group participants reported an increase in thermal pain responses over time (M=22.04, SE=

0.68)

-However, group-level mean reduction in evoked pain responsiveness

observed in the exercise condition was not significantly different from zero [t(37) 5 0.63, P = 0.54]

-Women in the exercise group exhibited significantly larger increases in EO function (M = 1.68, SE = 0.91) than women in the control group [M = -0.93, SE =0.80; F(1,46) = 5.35, P =0.025]. This intervention effect was not significant in men.

Supervised progressive aerobic exercise training can

significantly decrease pain in individuals with

CLBP, with evidence supporting enhanced pain inhibitory function.