Startseite Acute experimentally-induced pain replicates the distribution but not the quality or behaviour of clinical appendicular musculoskeletal pain. A systematic review
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Acute experimentally-induced pain replicates the distribution but not the quality or behaviour of clinical appendicular musculoskeletal pain. A systematic review

  • Brendon Ford , Mark Halaki , Joanna Diong und Karen A Ginn EMAIL logo
Veröffentlicht/Copyright: 10. Dezember 2020
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Scandinavian Journal of Pain
Aus der Zeitschrift Scandinavian Journal of Pain Band 21 Heft 2

Abstract

Objectives

Experimental pain is a commonly used method to draw conclusions about the motor response to clinical musculoskeletal pain. A systematic review was performed to determine if current models of acute experimental pain validly replicate the clinical experience of appendicular musculoskeletal pain with respect to the distribution and quality of pain and the pain response to provocation testing.

Methods

A structured search of Medline, Scopus and Embase databases was conducted from database inception to August 2020 using the following key terms: “experimental muscle pain” OR “experimental pain” OR “pain induced” OR “induced pain” OR “muscle hyperalgesia“ OR (“Pain model” AND “muscle”). Studies in English were included if investigators induced experimental musculoskeletal pain into a limb (including the sacroiliac joint) in humans, and if they measured and reported the distribution of pain, quality of pain or response to a provocation manoeuvre performed passively or actively. Studies were excluded if they involved prolonged or delayed experimental pain, if temporomandibular, orofacial, lumbar, thoracic or cervical spine pain were investigated, if a full text of the study was not available or if they were systematic reviews. Two investigators independently screened each title and abstract and each full text paper to determine inclusion in the review. Disagreements were resolved by consensus with a third investigator.

Results

Data from 57 experimental pain studies were included in this review. Forty-six of these studies reported pain distribution, 41 reported pain quality and six detailed the pain response to provocation testing. Hypertonic saline injection was the most common mechanism used to induce pain with 43 studies employing this method. The next most common methods were capsaicin injection (5 studies) and electrical stimulation, injection of acidic solution and ischaemia with three studies each. The distribution of experimental pain was similar to the area of pain reported in clinical appendicular musculoskeletal conditions. The quality of appendicular musculoskeletal pain was not replicated with the affective component of the McGill Pain Questionnaire consistently lower than that typically reported by musculoskeletal pain patients. The response to provocation testing was rarely investigated following experimental pain induction. Based on the limited available data, the increase in pain experienced in clinical populations during provocative maneuvers was not consistently replicated.

Conclusions

Current acute experimental pain models replicate the distribution but not the quality of chronic clinical appendicular musculoskeletal pain. Limited evidence also indicates that experimentally induced acute pain does not consistently increase with tests known to provoke pain in patients with appendicular musculoskeletal pain. The results of this review question the validity of conclusions drawn from acute experimental pain studies regarding changes in muscle behaviour in response to pain in the clinical setting.

Keywords: acute experimental pain; appendicular musculoskeletal pain; pain behaviour; pain distribution; pain quality

Introduction

Musculoskeletal pain is a source of morbidity and loss of quality of life [1]. Clinical musculoskeletal pain is associated with changes in muscle activity [2]. However, it is not known if these changes are caused by pain or cause pain. To answer this question, outcome measures need to be taken prior to pain and then following pain initiation. Experimental pain, or pain induced under laboratory conditions, fulfills this criterion for investigating the response of the musculoskeletal system to pain and is a commonly used method to draw conclusions about the motor response to clinical musculoskeletal pain [3]. Injection of an irritable substance is often used as an experimental model to investigate musculoskeletal pain as it can be induced into a localised structure. Other models of experimental pain such as electrical stimulation, ischaemia, intense cold or heat, have been used less frequently.

Short-lasting, experimentally induced limb pain has been shown to produce immediate changes in the motor control system of healthy individuals at multiple levels [4]. It is thought that these changes reflect the motor response to clinical musculoskeletal pain by facilitating protective and compensatory motor behavior [3]. For this conclusion to be valid, experimentally-induced pain models should replicate the clinical pain experience as closely as possible. Characteristics which reflect a valid representation of clinical pain include a similar distribution of pain, similar quality of pain and an increase in pain intensity during tests that provoke pain in clinical populations. An experimental pain model satisfying all these criteria would accurately reflect the clinical experience of musculoskeletal pain and enable the valid investigation of the response of the musculoskeletal system to pain in a controlled environment.

The aim of this systematic review was to determine if current acute experimental pain models validly replicate the clinical experience of appendicular musculoskeletal pain with respect to the distribution of pain, the quality of pain and the pain response to clinical provocation tests.

Methods

Search strategy and study selection

The databases Medline, Scopus and Embase were searched. A structured search was used to include papers published from database inception to August 2020 using the following key terms: "experimental muscle pain" OR "experimental pain" OR "pain induced" OR "induced pain" OR "muscle hyperalgesia" OR ("Pain model" AND "muscle"). The reference lists of included studies were scanned for relevant studies not found in the search. Studies in English were included if investigators induced experimental musculoskeletal pain into a limb (including the sacroiliac joint) in humans, and if they measured and reported the distribution of pain, quality of pain or response to a provocation manoeuvre performed passively or actively in healthy people. Studies were excluded if delayed onset muscle soreness or nerve growth factor were used to induce pain, if temporomandibular, orofacial, lumbar, thoracic, cervical spine pain were investigated, if a full text of the study was not available or if they were reviews. Two investigators independently screened each title and abstract and each full text paper to determine inclusion in the review. Disagreements were resolved by consensus with a third investigator. All investigators were involved in the review & selection process. The systematic review was not prospectively registered.

Data extraction

Data were extracted according to the Cochrane Consumers and Communication Review Group’s standardised protocol: (1) study characteristics including author/s, title and year of publication (2), participant information such as sample size, age and gender (3), description of the intervention including mode of pain and site of pain induction (4), study outcomes, including pain distribution, quality of pain and pain response to provocation testing.

Data analysis

Outcomes of pain distribution, quality of pain and response to provocation testing were summarized and qualitatively assessed. Quantitative data from studies were not pooled because very few studies reported these data and there were substantial methodological differences between studies.

Risk of bias

Study risk of bias and methodological quality was assessed using 12 criteria adapted from Downs and Black [5]. One investigator scored each study against the criteria and scores were independently checked by a second investigator.

Results

Database searches yielded 27,608 records of which 6,513 titles and abstracts were screened for eligibility (Figure 1). One hundred thirty-four full-text articles were screened and 57 studies were included in the systematic review. No additional records were found from scanning the reference lists of included studies. Outcomes from the included studies are summarized in Table 1. Hypertonic saline injection was the most common mechanism used to induce acute pain with 43 of studies employing this method. The next most common methods were capsaicin injection (five studies) and electrical stimulation, injection of acidic solution and ischaemia with three studies each. The risk of bias scores for individual studies are shown (Table 2). The majority of trials were of moderate quality.

Figure 1: Flowchart of studies.
Figure 1:

Flowchart of studies.

Table 1:

Summary of included papers, sorted by upper and lower limb body regions. If outcomes were obtained from more than one region, these are listed as Experiment 1, Experiment 2 etc. Data are presented as mean (SD) unless stated otherwise. Abbreviation: M = male.

Study n

Age (yrs)		 Pain stimulus Site of pain induction Outcome type Outcome
Shoulder & Upper arm
Birch 2001 [13]

Experiment 1		 12 (12 M)

22.5 (range 20–28)		 Infusion 5% hypertonic saline Upper trapezius Distribution Pain around injection site mainly cranially and towards acromion.
Chen 1985 [35]

Experiment 1		 10 (unknown M)

24 (3)		 Ischemia Upper arm Quality Test: German McGill pain questionnaire

Pain rating indices: Sensory: mean = 15.6; affective: 4.9; evaluative: 2.9; miscellaneous: 7.0

Common words: Pressing 50%, burning 50%, exhausting 50%, annoying 50%, wrenching 40%, wretched 40%, penetrating 40%, squeezing 40%
Diederichsen 2009 [12] 11 (11 M)

24.9 (2.1)		 Injection 5% hypertonic saline Supraspinatus &

Subacromial space		 Distribution Pain in anterolateral upper arm with no difference between injection sites.
Domenech-Garcia 2016 [7] 21 (11 M)

26 (range 20–36)		 Injection 5.8% hypertonic saline Infraspinatus Distribution Pain mainly in shoulder, upper arm and supraspinal regions & less commonly in forearm.
Quality Test: English, Danish or Spanish McGill pain questionnaire

Pain rating indices: Not reported

Common words: Taut 35%, heavy 40%
Ford 2019 [11] 9 (5 M) Injection 6% hypertoninc saline Subacromial space &

Supraspinatus		 Distribution Pain in the anterolateral shoulder region.

Subacromial space injections produced pain across a wider area than supraspinatus injections.
Quality Test: McGill pain questionnaire

Pain rating indices: supraspinatus: Sensory mean (SD) = 7.9 (4.1); affective 0.3 (0.7); evaluative 1.1 (1.6); miscellaneous 1.4 (2.0)

subacromial space: Sensory mean (SD) = 7.9 (2.2); affective 0.1 (0.3); evaluative 1.2 (1.9); miscellaneous 1.2 (1.8)

Common words: supraspinatus: Aching 67%, throbbing 22%

subacromial space: Aching 67%, throbbing 56%
Provocation Method: Hawkins-Kennedy impingement test, empty can test, active shoulder abduction

Response: supraspinatus: Decrease in pain 59%; no change 30%; increase in pain 11%

subacromial space: Decrease in pain 67%; no change 26%; increase in pain 7%
Leffler 2000 [8] 12 (0 M)

38 (range 24–51)		 Injection 5% hypertonic saline Infraspinatus Distribution Pain mostly located in the dorsolateral part of proximal upper arm.
Lindahl 1969 [47] 10–15 (unknown M) Injections of saline with varying osmotic pressures, PH levels & concentrations of potassium ions Biceps brachii Distribution Localised to the site of the injection but quite often pain spread throughout the arm.
Madeleine 2005 [48] 12 (12 M)

25.8 (2.7)		 Injection 6% hypertonic saline Biceps brachii Distribution All subjects reported pain around the injection site & some referred pain to anterior shoulder (50%) and elbow (25%).
Madeleine 1998 [9] 20 (20 M)

28 (1.4)		 Injection 6% hypertonic saline Trapezius &

Infraspinatus		 Distribution Trapezius: Pain around injection site in all subjects & in some referred to posterolateral neck (60%) & temporal mandibular region (10%).

Infraspinatus: Pain local to the injection site & to anteromedial shoulder in all subjects.
Quality Test: Danish McGill pain questionnaire

Pain rating indices: Trapezius: Sensory mean (SD) = 49.7 (2.5)%; affective 32.2 (9.3)%; evaluative 48 (8)%; miscellaneous 42.8 (9.4)%

Infraspinatus: Sensory mean (SD) = 58.2 (3.9)%; affective 40.9 (9.5)%; evaluative 60 (8.9)%; miscellaneous 39.8 (9.5)%

Common words: Trapezius: Drilling, tugging, hurting, sharp

Sensory mean (SD) = 3.9 (0.4); affective 0.9 (0.1); evaluative 0.9 (0.1); miscellaneous 1.1 (0.2)

Infraspinatus: Aching, tiring, agonizing

Sensory mean (SD) = 3.7 (0.4); affective 2.0 (0.6); evaluative 0.9 (0.1); miscellaneous 1.0 (0.2)
Otto 2019 [33] 28 (14 M)

Male: 22.9 (1.8)

Female: 23.4 (2.8)		 Pressure pain Upper trapezius, Anterior deltoid & Biceps brachii Quality Test: Short form McGill pain questionnaire

Pain rating indices: Sensory mean (SD) = 4.93 (2.76); affective 0.36 (0.68)

Common words: Not reported
Qerama 2004 [49] 21 (13 M)

24 (range 22–46)		 Injection 30 μg capsaicin or 5% hypertonic saline Biceps brachii Quality Test: Short form McGill pain questionnaire

Pain rating indices: Not reported

Common words: Motor endplate: Shooting 24%, throbbing 14%, cramping 14%, Control site: tender 28%, shooting 16.5%, sharp 16.5%
Tuveson 2003 [10] Young:

24 (13 M)

26.6 (range 20–35)

Older:

24 (11 M)

55.2 (range (49–64)		 Injection 6% hypertonic saline Infraspinatus Distribution Pain only into proximal upper arm or more cranially over the lateral trapezius – 70%.

Pain at injection site & into proximal upper arm or more cranially over the lateral trapezius – 20%.

Pain only around injection site – 10%.
Quality Test: Not reported

Pain rating indices: Not reported

Common words: Pressure 80%, dull ache 63%, deep bursting 35%, cramp 20%
Elbow, forearm & hand
Birch 2001 [13]

Experiment 2		 12 (12 M)

23 (range 21–26)		 Infusion 5% hypertonic saline Extensor carpi ulnaris Distribution Pain radiated from injection site distally &occasionally into the ulnar side of the hand.
Burns 2016 [50] 22 (9 M)

22.6 (7.8)		 Infusion 5% hypertonic saline. Dorsal interosseous Distribution Pain localised to dorsal surface of hand. Occasional reports of numbness localised to the thumb & pain into proximal forearm.
Quality Test: Short form McGill pain questionnaire

Pain rating indices: Not reported

Common words: Aching 82%, throbbing 73%, sharp 62%, cramping 60%
Chen 1985 [35]

Experiment 2		 10 (unknown M)

24 (3)		 Electrical stimuli Middle finger Quality Test: German McGill pain questionnaire

Pain rating indices: Sensory: mean = 13.3; affective: 1.3; evaluative: 1.3; miscellaneous: 1.8

Common words: Sharp 70%, pricking 70%, shooting 40%
Coppieters 2006 [51] 20 (17 M)

23 (7)		 Infusion 5% hypertonic saline Thenar eminence Distribution Pain predominantly around infusion area in thenar eminence & occasionally radiated toward the thumb, index finger and middle finger
Quality Test: McGill pain questionnaire

Pain rating indices: Not reported

Common words: Tight 45%, cramping 45%, sharp 62%, aching 35%, stinging 35%, throbbing 30%
Graven-Nielsen 1997 [14]

Experiment 1		 10 (10 M)

2 cohorts:

– 24.5 (range 21–27)

– 24.1 (range 21–27)		 Infusion 5% hypertonic saline Brachioradialis Distribution Pain locally in proximal forearm & deep pain in wrist in 35% of subjects. Area of local pain approximately 2 times larger than referred pain area.
Quality Test: Danish McGill pain questionnaire

Pain rating indices:

Significantly higher scores in most categories with increases in infusion concentration, volume & time

Example: 11.5% concentration: Sensory mean (SD) = 12.8 (6.5); affective 0.7 (1.1); evaluative 2.7 (1.6), miscellaneous 3.8 (2.2);

Common words: Words selected by ≥ 40% of subjects drilling 80%, throbbing 50%, radiating 50%, taut 40%, tight 40%, intense 40%
Kumar 2006 [36] 10 (unknown M)

24 (range 23–32)		 Injection capsaicin Flexor carpi ulnaris Distribution Pain in anterior & lateral forearm.
Quality Test: Short form McGill pain questionnaire

Pain rating indices: Sensory: mean≠17; affective≠2

Common words: More sensory descriptors than affective descriptors.
Larsen 2019 [52] 28 (13 M)

22.1 (2.1)		 Injection 5.8% hypertonic saline First dorsal interosseous Quality Test: Short form McGill pain questionnaire

Pain rating indices: Not reported

Common words: Cramping 85.7%, sharp 82%, aching 75%, heavy 67%, numbness 67%
Mista 2019 [6] 19 (M)

29 (5)		 Short wave diathermy Extensor carpi radialis brevis Distribution Pain locally in proximal lateral forearm.
Quality Test: McGill pain questionnaire

Pain rating indices: Not reported

Common words: Burning 61%, hot 22%, scalding 11%, searing 6%
Rainville 1992 [31] 24

23.5 (range 20–35)		 1. Contact heat pulses

2. Electric shock.

3. Cold water immersion

4. Muscle ischemia		 1. Forearm

2. Forearm

3.Tourniquet to forearm

4. Hand in 5° water		 Quality Test: Bespoke ratio of pain intensity (sensory dimension) & unpleasantness (affective dimension)

Pain rating indices: Unpleasantness evoked by contact heat & electric shock significantly less pain intensity. Equivalent ratings for intensity & unpleasantness following cold-water immersion & ischemic.

Common words: Not reported
Rubin 2012 [53]

Experiment 1		 5%: 13 (9 M)

10%: 16 (8 M)		 Injection 5% & 10% hypertonic saline Flexor carpi radialis Distribution Pain in anterior forearm & typically to wrist and medial digits. Pain less frequently in thumb or proximally in upper arm.
Schabrun 2012 [54] 11 (7 M)

23.3 (6.5)		 Infusion 5% hypertonic saline First dorsal interosseous Distribution Pain localised to injection site & spreading across hand with 27% of subjects reporting symptoms radiating to the forearm.
Quality Test: McGill pain questionnaire

Pain rating indices: Not reported

Common words: Throbbing 82%, sharp 82%, cramping 73%, aching 64%
Slater 2003 [15] 12 (6 M)

23.9 (range 22–27)		 Injection 5.8% hypertonic saline Extensor carpi radialis brevis, Supinator, common extensor origin Distribution All 3 injections sites produced pain locally at injection site and over the dorsolateral forearm. Pain radiated to the dorsal surface of the hand following injection into supinator & common extensor origin & into the distal upper arm following injection into supinator.
Quality Test: English or Danish McGill pain questionnaire

Pain rating indices: Not reported

Common words: Drilling 44%, taut 44%, nagging 39%, intense 31%
Slater 2005 [16] 20 (10 M)

47.4 (range 32–63)		 Injection 5.8% hypertonic saline Extensor carpi radialis brevis Distribution Localised pain around extensor carpi radialis brevis muscle belly.
Quality Test: McGill pain questionnaire

Pain rating indices: Not reported

Common words: Intense 40%, aching 30%
Slater 2011 [17]

Experiment 1		 14 (7 M)

24.9 (1.3)		 Injection 5.8% hypertonic saline Common extensor origin Distribution All subjects reported pain areas locally at the injection site; 57% reported pain proximal to & excluding the lateral epicondyle; 36% reported pain distal to & including the dorsal surface of the hand.
Quality Test: McGill pain questionnaire

Pain rating indices: Not reported

Common words: Words selected by > 30% of subjects aching 57%, intense 43%, throbbing 35%, pressing 35%,
Summers 2020 [19] 42 (21 M)

25 (5)		 Injection 5.8% hypertonic saline Extensor carpi radialis brevis Quality Test: McGill pain questionnaire

Pain rating indices: Not reported

Common words: Aching 95%, heavy 79%, throbbing 76%, tender 71%
Wang 2017 [20] 20 (13 M)

24.3 (3.1)		 Infusion hypertonic saline at pH 5.0, 6.0, 7.4 Brachioradialis Distribution Pain around infusion site, distally into the dorsal hand & proximally into the upper arm. Most acidic solution produced the largest area of pain & pain proximally more often than less acidic solution.
Witting 2000 [18] 12 (10 M)

24 (range 21–26)		 Intramuscular & intradermal injections capsaicin Brachioradialis Distribution Pain commonly around injection site. Referred pain was usually reported distal to the injection site along the distal radius and into the thenar eminence. Referred pain was more frequently reported after intramuscular capsaicin injections (high concentration 83%/ low concentration 75%) compared with intradermal capsaicin (8%).
Quality Test: Danish McGill pain questionnaire

Pain rating indices: Not reported

Common words: Words selected by > 25% of subjects

Intramuscular injections: Throbbing, drilling, pressing, gnawing, hot, tingling, heavy, radiating, nagging, sore, sickening, cruel, intense, exhausting, shooting, penetrating, nauseating

Intradermal injections: Boring, sharp, scalding, pinching, hot, annoying, radiating, nagging
Pelvis, Hip & Thigh
Belanger 1992 [34] 10 (10 M)

31.7 (range 25–48)		 Electrical stimulation Vastus lateralis Quality Test: Short form McGill pain questionnaire

Pain rating indices: Sensory: mean = 9.5; affective: mean = 1.5

Common words: Sensory: Cramping 100%, hot-burning 100%

Affective: Fearful 70%
Drew 2017 [23] 15 (15 M)

26.9 (3.4)		 Injection 5.8% hypertonic saline Rectus femoris & Adductor longus Distribution Rectus femoris: Pain in groin triangle & into anterior and lateral thigh.

Adductor longus: Pain locally in groin triangle & into lower abdominal region
Quality Test: English or Danish McGill pain questionnaire

Pain rating indices: Not reported

Common words: rectus femoris: Tight 47%, pressing 33%, annoying 27%

Adductor longus: Annoying 33%, tugging 27%, pressing 27%
Drew 2016 [37] 16 (16 M)

27 (3.4)		 Injection 5.8% hypertonic saline Adductor longus & Rectus femoris Provocation Method:

Isometric muscle tests: Hip adduction at 0°, 45° & 90° hip flexion; abdominal crunch; oblique abdominal crunch

Response: Hip adduction at 0° hip flexion had highest positive likelihood ratio for both adductor longus and rectus femoris pain production.
Izumi 2014 [24] 16 (M)

28 (5)		 Injection 5.8% hypertonic saline Gluteus medius muscle & tendon & Adductor longus Distribution Gluteus medius muscle: Pain locally at injection site in all subjects & referred to posterior, lateral, anterior thigh & lower leg in 81%

Gluteus medius tendon: Pain locally at injection site in all subjects & referred to posterior, lateral, anterior thigh & lower leg in 69%

Adductor longus: Pain locally at injection site in all subjects & referred to anterior, lateral, medial thigh in 19%
Quality Test: English or Danish McGill pain questionnaire

Pain rating indices: Not reported

Common words: Gluteus medius muscle & tendon

Spreading, hot
Provocation Method: Passive tests: Flexion abduction external rotation (FABER) & flexion adduction internal rotation (FADIR)

Response:

FABER: Increase in pain after hypertonic saline injection in majority of subjects at all sites gluteus medius muscle (56.3%), gluteus medius tendon (81.3%), adductor longus (75%)

FADIR: Increase in pain in majority of subjects after hypertonic saline injection into gluteus medius tendon (56.3%). (Gluteus medius muscle - 43.8%; adductor longus - 25%).
Palsson 2012 [21] 35 (20 M)

25 (range 20–34)		 Injection 5.8% hypertonic saline Long posterior sacroiliac ligament Distribution Pain locally at injection site - 83%

Referred pain in the lower lumbar area (73%), gluteal area (53%), posterior thigh (37%), calf (20%), groin (13%), anterior thigh (10%), abdomen (7%) and lower thoracic area (3%)
Quality Test: English or Danish McGill pain questionnaire

Pain rating indices: Not reported

Common words: Words selected by > 30% subjects pressing 43%, spreading 40%, intense 33%
Provocation Method: Sacral thrust, compression test, posterior pelvic pain provocation test, gapping test, Gaenslen’s test

Response: All provocation tests except gapping were significantly more positive after hypertonic saline injection.
Palsson 2015 [22] 34 (unknown M) Injection 5.8% hypertonic saline Long posterior sacroiliac ligament Distribution Pain mainly felt locally at injection site. 77% of participants perceived pain to the lower limb and/or lumbar spine.
Smith 2020 [38] 18 (11 M)

24.5 (4)		 Injection 5.8% hypertonic saline Vastus lateralis Quality Test: McGill pain questionnaire

Pain rating indices: Sensory mean (SD) = 15 (6); affective 3 (3);evaluative 4 (2); miscellaneous 5 (4)

Common words: Cramping 67%, aching 67%, throbbing 50%, shooting 42%, sharp 33%, tender 33%, intense 33%, radiating 33%
Provocation Method: Isometric time to failure knee extension task at 10% maximum torque

Response: McGill pain questionnaire: Increase in mean sensory rating index from 15 to 18; mean affective rating index from 1 to 3; mean evaluative rating index from 2 to 3; mean miscellaneous rating index from 3 to 5. Addition of words to describe pain from the affective category: Tiring 42%, exhausting 42%, grueling 33%
Knee
Asaki 2018 [28] 30 (14 M)

23.6 (range 19–31)		 Infusion acidic saline Infrapatellar fat pad Distribution All subjects felt localized anterior knee pain.
Quality Test: McGill pain questionnaire

Pain rating indices: Sensory mean≠5; affective mean≠1; evaluative mean≠0.5, miscellaneous mean≠1

Common words: Not reported
Bennell 2004 [25] 11 (2 M)

34.4 (7.1)		 Injection 5% hypertonic saline Medial fat pad of knee Distribution Pain in anterior knee in all subjects with pain more proximally in the thigh (2 subjects) & groin (1 subject)
Quality Test: McGill pain questionnaire

Pain rating indices: Sensory: mean = 8.1; affective: 0.09; evaluative: 2.8; miscellaneous: 2.8.

Common words: Aching 100%, throbbing 45%, spreading 37%, nagging 27%
Provocation Method: Passive knee extension with overpressure, isometric quadriceps femoris contraction, step up/down.

Response: Mild decrease in pain in response to all provocation tests: Passive extension overpressure mean decrease = −1.1 (1.2); static quadriceps contraction mean decrease = −0.6 (0.9).
Bennell 2005 [26] 16 (5 M)

28.3 (7.9)		 Injection 5% hypertonic saline Medial infrapatellar fat pad Distribution All subjects reported pain in the inferomedial knee & retropatellar region with pain more proximally into the thigh & lateral hip (3 subjects) & into the calf (1 subject).
Quality Test: McGill pain questionnaire

Pain rating indices: Not reported

Common words: Aching 50%, annoying 44%, throbbing 38%, nagging 38%, dull 32%
Lai 2012 [27] 12 (6 M)

23.8 (2.1)		 Injection 5% hypertonic saline Infrapatellar fat pad Distribution Pain locally around anteromedial knee & occasionally more laterally.
Oda 2018 [55] 14 (14 M)

28 (4)		 Injection 5% hypertonic saline Medial collateral ligament of knee & tibial insertion of iliotibial band Distribution medial collateral ligament: Pain localized to medial knee in all subjects.

tibial insertion of iliotibial band: Pain locally at anterolateral knee in all subjects, posterolateral knee (57%) & pain referral to lower leg (69%)
Lower leg
Babenko 1999 [56] 10 (10 M)

22.3 (range 21–25)		 Injection bradykinin & serotonin Tibialis anterior Distribution Pain localised to tibialis anterior muscle belly in all subjects & over anterior ankle in 40%.
Quality Test: Danish McGill pain questionnaire

Pain rating indices: Not reported

Common words: Words selected by ≥ 40% subjects tight 50%, tender 50%, sharp 40%, pressing 40%, hot 40%, taut 40%
Babenko 2000 [57] 10 (10 M)

21.1 (range 20–24)		 Injection bradykinin &/or serotonin Tibialis anterior Distribution Pain localised to tibialis anterior muscle belly in all subjects & over anterior ankle in 20%.
Quality Test: Danish McGill pain questionnaire

Pain rating indices: Not reported

Common words: Words selected by ≥ 30% subjects serotonin: Tender 30%

bradykinin: Sharp 50%, taut 40%, tight 40%, pressing 30%, hot 30%
Burton 2009 [58] 26 (13 M)

28		 Injection 5% hypertonic saline Tibialis anterior Distribution Pain locally in tibialis anterior in all subjects & often into the ankle and foot.
Quality Test: McGill pain questionnaire

Pain rating indices: Not reported

Common words: All subjects described the pain as dull, diffuse & throbbing.
Coppieters 2005 [30] Exp 1:

15 (13 M)

23.9 (4.6)

Exp 2:

10 (9 M)

24.9 (3.9)		 Injection 5% hypertonic saline Exp 1: Tibialis anterior

Exp 2: Soleus		 Distribution Exp 1: Pain predominately over middle shin around the injection site, with a separate area of pain over the anterior ankle joint.

Exp 2: Pain predominately around the injection site in the lower third of the medial calf.
Quality Exp 1:

Test: Not reported

Common words: Throbbing, dull, deep ache, cramping
France 2002 [32] 88 (47 M) Electro-cutaneous stimulation Sural nerve Quality Test: Short form McGill pain questionnaire

Pain rating indices: Total: Mean (SD) = 12.9 (8.2)

Common words: Not reported
Frey Law 2008 [59] 69-70 (34 M) Injection acidic solution Tibialis anterior Distribution Pain locally at the injection site & at ankle in slightly more than 50% of subjects.
Quality Test: Short form McGill pain questionnaire

Pain rating indices: Not reported

Common words: Aching, throbbing, cramping, tender
Gibson 2006 [60] 18 (14 M)

26 (range 19–35)		 Injection 5.8% hypertonic saline Tibialis anterior: proximal & distal tendon & muscle belly Distribution Pain located along tibialis anterior muscle belly, into anterior ankle & dorsal surface of the foot & occasionally into calf for all injection sites. Pain area significantly larger with a larger spread for proximal tendon injection site.
Quality Test: English or Danish McGill pain questionnaire

Pain rating indices: Not reported

Common words: Words selected by > 30% of subjects muscle belly: Aching 33%

Distal tendon: Hurting 45%, sharp 33%
Gibson 2009 [61] 22 (22 M)

25 (range 23–28)		 Injection glutamate, capsaicin &/or hypertonic saline Tibialis anterior distal tendon Distribution Pain most commonly located along the tibialis anterior muscle belly & into anterior ankle and dorsal surface of the foot. No significant difference in referred pain frequencies in either injection solution or injection order.
Quality Test: English or Danish McGill pain questionnaire

Pain rating indices: Not reported

Common words: Words selected by > 30% of subjects glutamate & hypertonic saline: Pressing, sore, dull

capsaicin: Pressing, sore, sharp

capsaicin after glutamate: Sharp, hot, annoying
Graven-Nielsen 1997 [14]

Experiment 2		 10 (10 M)

2 cohorts:

−24.5 (range 21–27)

−24.1 (range 21–27)		 Infusion 5% hypertonic saline Tibialis anterior Distribution Pain locally in anterolateral lower leg & deep pain in ankle in 40% of subjects. Area of local pain approximately 2 times larger than referred pain area.
Quality Test: Danish McGill pain questionnaire

Pain rating indices:

Significantly higher in scores in most categories with increases in infusion volume, time & depth

Example: 0.5 mL over 20 s: Sensory mean (SD) = 7.1 (4.8); affective 1.1 (1.4); evaluative 1.4 (1.1), miscellaneous 2.4 (2.0)

Common words: Words selected by ≥ 40% of subjects. Taut 50%, annoying 40%, miserable 40%
Graven Nielsen 1997 [62] 11 (11 M)

25.2 (2.8)		 Infusion 5% hypertonic saline Tibialis anterior Distribution Pain locally in anterolateral lower leg & a separate area of pain in anterior ankle.
Quality Test: Danish McGill pain questionnaire

Pain rating indices: Not reported

Common words: Words selected by ≥ 40% of subjects. Drilling 64%, troublesome 55%, pressing 45%, hurting 45%, nauseating 45%
Graven-Nielsen 1997 [63] 11 (11 M)

24.5 (range 22–27)		 Infusion 5% hypertonic saline Tibialis anterior Distribution Pain locally in anterolateral lower leg & a separate area of pain in anterior ankle.
Quality Test: Danish McGill pain questionnaire

Pain rating indices: Not reported

Common words: Words selected by > 30% of subjects. Taut 44%, radiating 38%, tight 36%, drilling 32%
Graven-Nielsen 1997 [64] 6 (unknown M)

29.5 (range 21–44)		 Infusion 5% hypertonic saline Tibialis anterior Quality Test: McGill pain questionnaire

Pain rating indices: Not reported

Common words: Words selected by ≥ 30% of subjects. Cramping 50%, aching 50%, dull 33%, taut 33%, spreading 33%, radiating 33%, tight 33%
Graven-Nielsen 2003 [29] 15 (7 M)

29 (range 23–40)		 Infusion hypertonic saline, Adenosine & ischaemia Tibialis anterior Distribution Pain locally in anterolateral lower leg & in anterior ankle & foot in 80% of subjects.
Quality Test: Swedish short-form McGill pain questionnaire

Pain rating indices: Not reported

Common words:

Ischaemic pain produced significantly higher ratings of “stabbing”, “burning”, “heavy” & “exhausting” words compared with all intramuscular injections.

“Cramping” was higher after hypertonic saline compared with adenosine injection & higher for ischaemic pain compared with adenosine injection.
Lei 2008 [65] 14 (14 M) Injection 5.8% hypertonic saline Tibialis anterior Distribution Pain locally in anterolateral lower leg & in anterior ankle in majority of subjects
Quality Test: McGill pain questionnaire

Pain rating indices: Not reported

Common words: Spreading 60%, pulsing 40–50%, drilling 50%, sharp 40%, pressing 40%, hurting 37.5%
Nielsen 2009 [66] 17 (6 M)

23.9 (2.5)		 Injection 5.8% hypertonic saline Tibialis anterior Distribution Pain locally in anterolateral lower leg & into dorsal foot.
Quality Test: Danish McGill pain questionnaire

Pain rating indices: Not reported

Common words: Words selected by > 30% of subjects. Miserable 47%, annoying 41%, drilling >30%, tingling >30%, taut >30%, tight >30%
Rubin 2009 [67] 15 (8 M)

(Range 20–45)		 Injection 5% hypertonic saline Tibialis anterior Distribution Pain locally in anterior lower leg & into dorsum of foot.
Rubin 2010 [68] 21 (9 M)

(Range 18–28)		 Injection 5% hypertonic saline Tibialis anterior Distribution Pain frequently reported in anterolateral lower leg & into dorsum of foot. Pain less frequently reported in anteromedial leg & into toes.
Quality Test: McGill pain questionnaire

Pain rating indices: Not reported

Common words: dull, throbbing, aching
Rubin 2012 [53]

Experiment 2		 5%: 13 (9 M)

10%: 16 (8 M)		 Injection 5% & 10% hypertonic saline Tibialis anterior Distribution Pain locally and frequently radiated toward the ankle and less frequently towards the toes.
Simonsen 2019 [69] 12 (unknown M)

28.3 (1.8)		 Injection 5.0% hypertonic saline Tibialis posterior Distribution Pain locally on back & lateral lower leg. One third of subjects experienced pain around ankle.
Slater 2011 [17]

Experiment 2		 14 (7 M)

24.8 (1.3)		 Injection 5.8% hypertonic saline Achilles tendon Distribution Pain locally on posterolateral & posteromedial lower leg with 50% reporting pain in proximal lower leg & distal to ankle & sole of foot.
Quality Test: McGill pain questionnaire

Pain rating indices: Not reported

Common words: Words selected by > 30% of subjects. Aching 64%, intense 50%, throbbing 43%, pressing 43%,
Wasner 2002 [70] 12 (10 M)

26.3 (0.9)		 Injection capsaicin Tibialis anterior Distribution Pain locally in anterior lower leg & in anterior ankle.
Quality Test: McGill pain questionnaire

Pain rating indices: Not reported

Common words: dull, burning, stinging, like a sore muscle
Table 2:

Risk of bias of included studies. Criteria items are numbered based on items adapted from the Downs and Black [5] checklist.

Study 1. Clear hypothesis 2. Outcome measures clearly described 3. Participant characteristics clearly described 4. Experimental conditions clearly described 6. Main findings clearly described 7. Estimates of random variability provided 10. Actual p- Values reported 12. Participants represent entire population 14. Blinding of participants 15. Blinding of outcome assessor 18. Appropriate statistical tests used 20. Valid and reliable outcome measures Score/12
Asaki 2018 [28] 1 1 1 1 1 1 0 0 0 0 1 1 8
Babenko 1999 [56] 1 1 1 1 1 1 0 0 0 0 1 1 8
Babenko 2000 [57] 1 1 1 1 1 1 0 0 0 0 1 1 8
Bennell 2004 [25] 1 1 1 1 1 1 1 1 1 0 1 1 11
Bennell 2005 [26] 1 1 1 1 1 1 0 0 0 0 1 1 8
Bergin 2015 [71] 1 1 1 1 1 1 0 0 1 1 1 1 10
Birch 2001 [13] 0 1 1 1 0 1 0 0 0 0 1 1 6
Burns 2016 [50] 1 1 1 1 1 1 1 0 0 0 1 1 9
Burton 2009 [58] 1 1 0 1 1 1 1 0 0 0 1 1 8
Chen 1985 [35] 0 1 0 1 1 0 0 0 0 0 1 1 5
Coppieters 2005 [30] 1 1 1 1 1 1 0 0 0 0 0 1 7
Coppieters 2006 [51] 1 1 1 1 1 1 1 0 0 0 0 1 8
Diederichsen 2009 [12] 1 1 1 1 1 1 0 1 0 0 1 1 9
Domenech-Garcia 2016 [7] 1 1 1 1 1 1 0 0 0 0 1 1 8
Drew 2016 [37] 1 1 1 1 1 1 1 0 1 0 1 1 10
Drew 2017 [23] 1 1 1 1 1 1 1 0 0 0 1 1 9
Ford 2019 [11] 1 1 1 1 1 1 0 0 0 1 1 1 9
France 2002 [32] 0 1 1 1 1 1 0 1 0 0 1 1 8
Frey Law 2008 [59] 1 1 1 1 1 1 0 0 0 0 1 1 8
Gibson 2006 [60] 1 1 1 1 1 1 0 0 1 0 1 1 9
Gibson 2009 [61] 1 1 1 1 1 1 0 0 0 0 1 1 8
Graven-Nielsen 1997 [14] 1 1 1 1 1 1 0 0 0 0 1 1 8
Graven Nielsen 1997 [62] 1 1 1 1 1 1 0 0 0 0 1 1 8
Graven-Nielsen 1997 [63] 1 1 1 1 1 1 0 0 0 0 1 1 8
Graven-Nielsen 1997 [64] 1 1 0 1 1 1 0 0 0 0 1 1 7
Graven-Nielsen 2003 [29] 1 1 1 1 1 1 0 0 0 0 1 1 8
Izumi 2014 [24] 1 1 1 1 1 1 0 1 1 0 1 1 10
Kumar 2006 [36] 0 1 1 1 1 1 0 0 1 1 1 1 9
Lai 2012 [27] 1 1 1 1 1 1 1 1 0 0 1 1 10
Larson 2019 [52] 1 1 1 1 1 1 0 1 0 0 1 1 9
Leffler 2000 [8] 1 1 1 1 1 1 0 0 0 0 1 1 8
Lei 2008 [65] 1 0 1 1 1 1 0 0 0 0 1 1 7
Lindahl 1969 [47] 0 1 0 1 1 0 1 0 0 0 0 0 4
Madeleine 1998 [9] 1 1 1 1 1 1 1 0 0 0 1 1 9
Madeleine 2005 [48] 1 1 1 1 1 1 1 0 0 0 1 1 9
Mista 2019 [6] 1 1 1 1 1 1 0 1 0 0 1 1 9
Nielsen 2009 [66] 1 1 1 1 1 1 0 1 0 0 1 1 9
Oda 2018 [55] 1 1 1 1 1 1 0 0 1 1 1 1 10
Otto 2019 [33] 1 1 1 1 1 1 1 1 0 0 1 1 10
Palsson 2012 [21] 1 1 1 1 1 1 0 0 1 0 1 1 9
Palsson 2015 [22] 1 1 1 1 1 1 0 0 1 0 1 1 9
Qerama 2004 [49] 1 1 1 1 1 1 1 0 1 1 1 1 11
Rainville 1992 [31] 1 1 1 1 1 0 0 0 0 0 1 0 6
Rubin 2009 [67] 1 1 1 1 1 1 0 0 0 0 1 1 8
Rubin 2010 [68] 1 1 1 1 1 1 0 0 0 0 1 1 8
Rubin 2012 [53] 1 1 1 1 1 1 0 0 0 0 1 1 8
Schabrun 2012 [54] 1 1 1 1 1 1 1 0 0 0 1 1 9
Simonsen 2019 [69] 1 1 0 1 1 1 1 0 0 0 1 1 8
Slater 2003 [15] 1 1 1 1 1 1 0 0 0 0 1 1 8
Slater 2005 [16] 1 1 1 1 1 1 0 1 0 0 1 1 9
Slater 2011 [17] 1 1 1 1 1 1 0 0 0 0 1 1 8
Smith 2020 [38] 1 1 1 1 1 1 1 1 0 0 1 1 10
Summers 2020 [19] 1 1 1 1 1 1 0 1 0 0 1 1 9
Tuveson 2003 [10] 1 1 1 1 1 1 0 1 0 0 1 1 9
Wang 2017 [20] 1 1 1 1 1 0 0 0 1 0 1 1 8
Wasner 2002 [70] 0 1 1 1 1 1 0 0 0 0 0 1 6
Witting 2000 [18] 1 1 1 1 1 1 0 0 0 0 1 1 8

Distribution of pain

Distribution of pain was reported in 46 studies and all these studies involved substance injection except one [6]. Nine studies injected into structures around the shoulder: into infraspinatus in four studies [7], [8], [9], [10] and into supraspinatus, trapezius, biceps brachii and the subacromial space in two studies each [11], [, 12]. Referred pain was experienced in the shoulder and upper arm following injection into infraspinatus, supraspinatus and the subacromial space but not following trapezius injection. Following injection into biceps brachii pain was always felt around the injection site.

Eight studies [13], [14], [15], [16], [17], [18], [19], [20] injected painful irritants into the extensor muscle group at the lateral elbow with extensor carpi radialis brevis and the common extensor origin tendon the most commonly injected sites. Pain was commonly felt local to the injection site and distally into the forearm. Injection into extensor carpi ulnaris, the common extensor origin tendon and supinator also resulted in pain in the hand in some subjects. Pain was referred into areas proximal to the injection site in some subjects only following injection into the common extensor origin tendon and supinator.

In the pelvis and hip region two studies injected hypertonic saline into the long posterior sacroiliac ligament reporting pain referral to the lumbar area in a majority of subjects and to the gluteal region and thigh in approximately 50% of subjects [21], [, 22]. Another two studies injected hypertonic saline into adductor longus [23], [, 24]. Both of these studies reported local pain in the groin area with Drew et al. [23] also reporting referred pain into the lower abdomen.

Three studies [25], [26], [27] injected hypertonic saline, and one study [28] infused acidic phosphate buffered saline, into the infrapatellar fat pad to produce anterior knee pain. All four studies reported that pain was localized to the anterior knee. Two studies [25], [, 26] also reported pain in some subjects more proximal to the injection site in the thigh, hip and groin with one subject also reporting pain distally in the calf.

Tibialis anterior was the most commonly injected site with 18 studies describing pain distribution following injection and one of these studies [29] also reporting pain distribution following ischaemia. All studies reported pain locally at the injection site in the anterolateral lower leg. Pain was commonly referred to the anterior ankle and occasionally to the dorsum of the foot and the toes.

Quality of pain

Quality of pain was reported in 41 studies with the McGill Pain Questionnaire used as the testing instrument in 38 of these studies [10], [30], [31]. All but four of the 41 studies [28], [31], [32], [33] reported the most common words used to describe the pain while only 10 studies [9], [11], [14], [25], [28], [32], [33], [34], [35], [36] reported pain ratings using the sensory, affective, evaluative and miscellaneous components of the McGill Pain Questionnaire. One study [31] used a customised anxiety and intensity scales to examine the experimental pain experience.

The most common words used to describe experimental pain, regardless of the method used to induce pain, belonged to the sensory component of the McGill Pain Questionnaire. “Throbbing”, “aching” and “pressing” were the most common words followed by “cramping”, “sharp” and “taut”. Words belonging to the affective component of the McGill Pain Questionnaire were least likely to be chosen to describe experimentally induced pain.

Mean pain ratings indices for each of the sensory, affective and miscellaneous categories of the McGill Pain Questionnaire were highest in the study which used ischaemia to induce pain [35] and, for the sensory category, also following capsaicin injection [36]. Following experimental pain induction via the injection of hypertonic saline [11], [14], [25], or an acidic solution [28] or via electrical stimulation [34], [, 35] mean pain ratings indices were commonly in the following ranges: sensory category 5–13; affective category 0.1–1.5; evaluative category 1–3; miscellaneous category 1–4.

Response to Provocation Testing

Response to provocation was reported in six studies. All of these used a model of experimental pain that involved an injection of hypertonic saline. A passive provocation manoeuvre was used in four studies [11], [21], [24], [25], an active test in two studies [11], [, 25] and an isometric strength test in four studies [11], [25], [37], [38].

The pain response to provocation testing was variable. Two studies utilising a passive test performed by an investigator designed to compress the target tissue reported a reduction in induced pain [11], [, 25]. In contrast, an increase in induced pelvic pain was reported following special passive tests designed to provoke pain in patients with sacroiliac joint pain [21] and following passive dynamic tests used to provoke pain in patients with hip pain [24]. The most common response to more active provocation testing was a decrease in induced pain. A decrease in pain was reported during an active step up test and following a submaximal quadriceps femoris contraction following injection into the retropatellar fat pad and following active shoulder abduction and maximum abduction force following injection into supraspinatus and the subacromial space [11], [, 25]. In contrast, increases in pain rating indices were reported during an isometric knee extension task following injection into vastus lateralis [38]. One study reported low levels of specificity with many subjects not reporting an increase in pain during provocative isometric clinical tests at the hip following injection into adductor longus and rectus femoris [21], [, 37].

Discussion

This systematic review aimed to determine if acute experimental pain validly replicates the clinical experience of appendicular musculoskeletal pain in the distribution and quality of pain induced as well as the pain response to clinical provocation tests. The results indicate that the distribution of acute experimental pain is similar to the area of pain reported in clinical appendicular musculoskeletal conditions. However, the quality of clinical musculoskeletal pain is not replicated in the acute experimental pain models examined with the affective component of the McGill Pain Questionnaire consistently lower during experimental pain compared with that reported during clinical pain. Response to provocation testing was only examined in 10% of the studies identified in this review. Based on the limited available data, the increase in pain experienced in clinical populations during provocation tests was more likely not to be replicated following acute experimental pain induction.

The distribution of pain following experimental pain induction was relatively consistent between studies, with most acute experimental pain models producing local pain and a portion of all subjects experiencing an area of referred pain which was usually distal to the area of injection. Location of pain is often used in the diagnosis of specific musculoskeletal pain conditions and published data on the distribution of pain during relevant appendicular musculoskeletal pain conditions exists for comparison.

The most common injection site used to produce acute experimental pain in this review was tibialis anterior with 19 studies investigating this site. Tibialis anterior intramuscular injections consistently produced pain locally over the anterolateral lower leg and dorsum of the foot. This distribution corresponds to the area of pain associated with superficial or common peroneal nerve entrapment [39]. Patients with anterior knee fat pad impingement often report pain into the anterior knee with pain typically localised to below the patella and very little referred pain [40]. Experimental pain was experienced in this distribution in all four studies in this review following injections into knee fat pads. However, in a small number of subjects, pain was also referred proximally into the anterior and medial thigh regions. The most common pain distribution reported by patients with painful hip conditions is to the groin, thigh and buttock [41], [, 42]. Following injection into thigh and gluteal muscles experimental pain was predominantly reported in these areas in the two studies identified in this review (Drew [23], Izumi [24]).

Lateral epicondylalgia is associated with pain at the lateral elbow and distally into the dorsal forearm and hand [16]. All nine of the experimental pain studies identified in this review that involved injections into muscles/tendons that attach to the lateral epicondyle produced pain locally at the injection site and into the forearm in a similar distribution to that experienced with lateral epicondylalgia. However, in some of these studies involving injection into the common extensor origin, supinator and brachioradialis pain was referred proximally into the distal upper arm [15], [17], [20]. Clinical shoulder pain is typically associated with pain felt in the deltoid region referring in a C5 or C6 dermatomal distribution [43] along the upper arm and occasionally into the forearm or upper trapezius areas. The distribution of pain produced following injection of hypertonic saline into shoulder muscles was similar to that experienced during clinical shoulder pain with no differences in pain distribution between experimental pain injection into infraspinatus, supraspinatus or the subacromial space.

The McGill Pain Questionnaire has been administered to patients with musculoskeletal pain conditions, with reported mean values typically ranging from 14 to 18 in the sensory category (a measure of the temporal, spatial, pressure and thermal properties of pain) and from 3 to 4 in the affective category (a measure of the emotional response to pain) [44]. Many of the subjects in these studies had chronic musculoskeletal pain conditions and patients with chronic pain have been shown to score higher on the affective component of the McGill Pain Questionnaire compared to those with acute painful conditions [45]. Patients with chronic pain often exhibit fear and anxiety in response to pain or to the threat of pain. These emotional responses to pain may contribute to higher affective McGill Pain Questionnaire scores in subjects with chronic pain [46].

The one acute experimental pain study identified in this review that used ischaemia via a sphygmomanometer around the upper arm to induce pain reported McGill Pain Questionnaire pain rating indices similar to those reported by patients with chronic appendicular musculoskeletal pain : sensory category mean = 15.6; affective category mean = 4.9 [35]. Only three of the remaining nine experimental pain studies investigating pain quality using pain rating indices reported sensory [9], [, 38] and affective [36], [, 38] indices in similar ranges to those reported by patients with appendicular musculoskeletal pain. This could suggest that ischaemic experimental pain is the most valid method to reproduce the clinical experience of musculoskeletal pain. However, with only one study investigating non-specific musculoskeletal pain in the upper limb, further research is required to confirm such a conclusion.

Following experimental pain induced by injection of hypertonic saline or acidic solution, electrical stimulation or pressure mean sensory and affective category pain rating index scores were typically lower than that reported in patients with appendicular musculoskeletal pain, ranging from 5 to 13 and 0.1 to 1.5 respectively. Due to the relatively short timeframe and definitive end of the experimental pain experience, which reflects acute pain more accurately, it is unlikely to induce distress or a strong emotional response from subjects. As such the lower affective component McGill Pain Questionnaire scores reported by the majority of acute experimental pain subjects in this review compared with those reported by patients with chronic musculoskeletal pain are perhaps unsurprising.

Provocation tests are used to induce symptoms to aid in diagnosing the cause of musculoskeletal pain. Therefore, a reasonable expectation would be that a valid experimental model for clinical pain would result in increases in pain during relevant provocative testing as is reflective of clinical musculoskeletal pain. In order to investigate potential protective or compensatory motor behavior associated with clinical musculoskeletal pain, pain behavior that mimics the clinical response to provocation testing would seem to be an essential component of a valid experimental musculoskeletal pain model.

The results of this review indicate that only six of the 57 acute experimental pain studies identified investigated the experimental pain response to provocation testing. Although variable, the most common result reported following various tests designed to provoke clinical appendicular musculoskeletal pain was a decrease in induced pain. Only passive provocative tests at the pelvis and hip reported in two studies consistently resulted in an increase in induced pain. It is surprising that more research has not been conducted to evaluate the validity of experimental appendicular musculoskeletal pain models with respect to pain provocation. The limited data available does not support the validity of most acute experimental pain models with respect to pain behaviour in the appendicular skeleton and, therefore, draws into question conclusions derived from acute experimental pain studies about changes in muscle behaviour in the limbs in response to pain in the clinical setting.

There are several limitations of this systematic review. It was not prospectively registered and only relates to acute experimental appendicular musculoskeletal pain models. Further studies are required to establish the clinical validity of prolonged (e.g. human growth factor) or delayed (e.g. delayed onset muscle soreness) experimental appendicular musculoskeletal pain models and all spinal and facial musculoskeletal experimental pain models with respect to the distribution and quality of pain produced and the response of experimental pain to provocation testing.

In conclusion, the results of this systematic review indicate that while current acute experimental pain models replicate the distribution of chronic clinical appendicular musculoskeletal pain, they do not replicate the quality or the behaviour of this common pain condition. The limited evidence available indicates that experimentally induced acute pain does not consistently increase with tests known to provoke pain in patients with appendicular musculoskeletal pain, drawing into question the validity of conclusions from such studies regarding changes in muscle behaviour in response to pain in the clinical setting.

Corresponding author: Karen A Ginn, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney2000, NSWAustralia, Phone: +61 2 9036 9346, E-mail:

  1. Research funding: This study did not receive external funding.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: No conflicts of interest to declare.

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Received: 2020-05-18
Accepted: 2020-10-16
Published Online: 2020-12-10
Published in Print: 2021-04-27

© 2020 Walter de Gruyter GmbH, Berlin/Boston

Artikel in diesem Heft

  1. Frontmatter
  2. Editorial
  3. Salami-slicing and duplicate publication: gatekeepers challenges
  4. Editorial Comment
  5. Risk for persistent post-delivery pain – increased by pre-pregnancy pain and depression. Similar to persistent post-surgical pain in general?
  6. Systematic Review
  7. Acute experimentally-induced pain replicates the distribution but not the quality or behaviour of clinical appendicular musculoskeletal pain. A systematic review
  8. Topical Review
  9. Unwillingly traumatizing: is there a psycho-traumatologic pathway from general surgery to postoperative maladaptation?
  10. Clinical Pain Research
  11. Translation, cross-cultural adaptation and psychometric evaluation of the Thai version of the fear-avoidance beliefs questionnaire in patients with non-specific neck pain
  12. Pain management in patients undergoing radiation therapy for head and neck cancer – a descriptive study
  13. Do intensity of pain alone or combined with pain duration best reflect clinical signs in the neck, shoulder and upper limb?
  14. Different pain variables could independently predict anxiety and depression in subjects with chronic musculoskeletal pain
  15. Symptoms of central sensitization in patients with inflammatory bowel diseases: a case-control study examining the role of musculoskeletal pain and psychological factors
  16. Acceptability of psychologically-based pain management and online delivery for people living with HIV and chronic neuropathic pain: a qualitative study
  17. Determinants of pain occurrence in dance teachers
  18. Observational Studies
  19. A retrospective observational study comparing somatosensory amplification in fibromyalgia, chronic pain, psychiatric disorders and healthy subjects
  20. Utilisation of pain counselling in osteopathic practice: secondary analysis of a nationally representative sample of Australian osteopaths
  21. Effectiveness of ESPITO analgesia in enhancing recovery in patients undergoing open radical cystectomy when compared to a contemporaneous cohort receiving standard analgesia: an observational study
  22. Shoulder patients in primary and specialist health care. A cross-sectional study
  23. The tolerance to stretch is linked with endogenous modulation of pain
  24. Pain sensitivity increases more in younger runners during an ultra-marathon
  25. Original Experimental
  26. DNA methylation changes in genes involved in inflammation and depression in fibromyalgia: a pilot study
  27. Participants with mild, moderate, or severe pain following total hip arthroplasty. A sub-study of the PANSAID trial on paracetamol and ibuprofen for postoperative pain treatment
  28. Exploring peoples’ lived experience of complex regional pain syndrome in Australia: a qualitative study
  29. Although tapentadol and oxycodone both increase colonic volume, tapentadol treatment resulted in softer stools and less constipation: a mechanistic study in healthy volunteers
  30. Educational Case Report
  31. Updated management of occipital nerve stimulator lead migration: case report of a technical challenge
https://doi.org/10.1515/sjpain-2020-0076
Schlagwörter für diesen Artikel
acute experimental pain; appendicular musculoskeletal pain; pain behaviour; pain distribution; pain quality

Artikel in diesem Heft

  1. Frontmatter
  2. Editorial
  3. Salami-slicing and duplicate publication: gatekeepers challenges
  4. Editorial Comment
  5. Risk for persistent post-delivery pain – increased by pre-pregnancy pain and depression. Similar to persistent post-surgical pain in general?
  6. Systematic Review
  7. Acute experimentally-induced pain replicates the distribution but not the quality or behaviour of clinical appendicular musculoskeletal pain. A systematic review
  8. Topical Review
  9. Unwillingly traumatizing: is there a psycho-traumatologic pathway from general surgery to postoperative maladaptation?
  10. Clinical Pain Research
  11. Translation, cross-cultural adaptation and psychometric evaluation of the Thai version of the fear-avoidance beliefs questionnaire in patients with non-specific neck pain
  12. Pain management in patients undergoing radiation therapy for head and neck cancer – a descriptive study
  13. Do intensity of pain alone or combined with pain duration best reflect clinical signs in the neck, shoulder and upper limb?
  14. Different pain variables could independently predict anxiety and depression in subjects with chronic musculoskeletal pain
  15. Symptoms of central sensitization in patients with inflammatory bowel diseases: a case-control study examining the role of musculoskeletal pain and psychological factors
  16. Acceptability of psychologically-based pain management and online delivery for people living with HIV and chronic neuropathic pain: a qualitative study
  17. Determinants of pain occurrence in dance teachers
  18. Observational Studies
  19. A retrospective observational study comparing somatosensory amplification in fibromyalgia, chronic pain, psychiatric disorders and healthy subjects
  20. Utilisation of pain counselling in osteopathic practice: secondary analysis of a nationally representative sample of Australian osteopaths
  21. Effectiveness of ESPITO analgesia in enhancing recovery in patients undergoing open radical cystectomy when compared to a contemporaneous cohort receiving standard analgesia: an observational study
  22. Shoulder patients in primary and specialist health care. A cross-sectional study
  23. The tolerance to stretch is linked with endogenous modulation of pain
  24. Pain sensitivity increases more in younger runners during an ultra-marathon
  25. Original Experimental
  26. DNA methylation changes in genes involved in inflammation and depression in fibromyalgia: a pilot study
  27. Participants with mild, moderate, or severe pain following total hip arthroplasty. A sub-study of the PANSAID trial on paracetamol and ibuprofen for postoperative pain treatment
  28. Exploring peoples’ lived experience of complex regional pain syndrome in Australia: a qualitative study
  29. Although tapentadol and oxycodone both increase colonic volume, tapentadol treatment resulted in softer stools and less constipation: a mechanistic study in healthy volunteers
  30. Educational Case Report
  31. Updated management of occipital nerve stimulator lead migration: case report of a technical challenge
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