SYSTEMATIC REVIEW

Rate of Improvement of Pain and Function in Mid-PortionAchilles Tendinopathy with Loading Protocols: A SystematicReview and Longitudinal Meta-Analysis

Myles Murphy1,2,3 • Mervyn Travers1,4 • William Gibson1 • Paola Chivers5,6 •

James Debenham1• Sean Docking7 • Ebonie Rio7,8

Published online: 15 May 2018

� Springer International Publishing AG, part of Springer Nature 2018

Abstract

Background Mid-portion Achilles tendinopathy is preva-

lent within both the athletic and non-athletic populations

and loading protocols for Achilles tendinopathy are effec-

tive over time, though the rate of symptom change

throughout rehabilitation is unknown.

Objective The objective of this study was to determine the

rate of change in pain and function over time in patients

while completing a loading protocol for mid-portion

Achilles tendinopathy.

Methods A systematic review and longitudinal meta-

analysis was conducted as per the Preferred Reporting

Items for Systematic Reviews and Meta-Analyses guide-

lines. The databases PubMed, CINAHL (Ovid) and

CINAHL (EBSCO) were searched for articles published

from inception until 31 July, 2017. Our search focused on

clinical trials and cohort studies examining changes in pain

and function when completing a loading protocol for mid-

portion Achilles tendinopathy. The primary outcome

measure assessing pain and function was the Victorian

Institute of Sports Assessment-Achilles (VISA-A)

questionnaire.

Results A total of 31 separate cohorts (24 studies) were

eligible, with follow-up ranging from 2 weeks to 6 months.

The data were pooled to create the mean (standard devia-

tion) of change from baseline at each time point. The data

demonstrated an improvement in pain and function as early

as 2 weeks that appeared to peak at 12 weeks with a mean

(standard deviation) of 21.11 (6.61) points of change on the

VISA-A.

Conclusion The improvement in pain and function during

rehabilitation suggests future research should be directed

toward investigating contributing mechanisms as tendon

structure on imaging does not change within 2 weeks and

muscular hypertrophy is not seen for at least 4 weeks fol-

lowing the inception of a loading protocol. Systematic

Review Registry: PROSPERO registration number:

CRD42017062737 (https://www.crd.york.ac.uk/PROSPERO/

display_record.php?RecordID=62737)

Electronic supplementary material The online version of thisarticle (https://doi.org/10.1007/s40279-018-0932-2) contains supple-mentary material, which is available to authorized users.

& Myles Murphy

myles.murphy1@my.nd.edu.au

1 School of Physiotherapy, University of Notre Dame

Australia, 19 Mouat Street, PO Box 1225, Fremantle, WA

6959, Australia

2 SportsMed Subiaco, St John of God Health Care, Subiaco,

WA, Australia

3 Sports Science Sports Medicine Department, Western

Australian Cricket Association, East Perth, WA, Australia

4 School of Physiotherapy and Exercise Science, Curtin

University, Bentley, WA, Australia

5 Institute for Health Research, University of Notre Dame

Australia, Fremantle, WA, Australia

6 Exercise Medicine Research Institute and School of Medical

and Health Sciences, Edith Cowan University, Joondalup,

WA, Australia

7 La Trobe Sports and Exercise Medicine Research Centre, La

Trobe University, Bundoora, VIC, Australia

8 Australian Collaboration for Research into Injury in Sport

and its Prevention (ACRISP), Bundoora, Australia

123

Sports Med (2018) 48:1875–1891

https://doi.org/10.1007/s40279-018-0932-2

Key Points

Longitudinal meta-analysis of an intervention is

patient oriented and has enabled us to address the

important area of patient expectation around

management strategies and likely outcomes.

Improvements in pain and function occur as early as

2 weeks following the inception of a loading

protocol.

At 12 weeks following the inception of a loading

protocol, a participant’s Victorian Institute of Sports

Assessment-Achilles score may be anticipated to

improve by approximately 21 points.

1 Background

1.1 Description of the Condition

Tendinopathy is characterised by focal pain, morning

stiffness and restricted function [1]. Different models of

pathology have been presented to attempt to explain the

link between tendon pain, structure and function. Achilles

tendinopathy (AT) may present as either insertional or mid-

portion tendinopathy. Insertional tendinopathy affects the

tendon insertion onto the calcaneus whereas mid-portion

tendinopathy affects the mid-portion of the tendon

approximately 2–7 cm proximal to the insertion [2, 3].

Achilles tendinopathy presents clinically with activity-

limiting pain and stiffness (either at the mid-portion of the

tendon or at the insertion) and these symptoms can effect

quality of life [1, 4]. However, it is well established within

the literature that mid-portion and insertional tendinopathy

are distinct clinical entities [3] and the focus of this sys-

tematic review is mid-portion AT.

1.2 Prevalence of the Condition

Achilles tendinopathy is prevalent within both the athletic

(prevalence of 6.2–9.5%) [5] and non-athletic populations

(prevalence of 11.83 per 100 patient-years) [6].

1.3 Description of the Intervention

Achilles tendinopathy is commonly treated with loading

protocols and these have been shown to be effective in the

management of this condition [7]. To date, four different

loading protocols have been reported in AT; heavy

eccentric calf training, [8] concentric training, [9] eccentric

overload training [10, 11] and heavy slow resistance

training [12]. These loading protocols have been compared

in recent reviews and they suggest that no protocol is

superior when comparing outcomes in pain and function

[2, 7, 13].

1.4 Potential Mechanisms of Clinical Improvement

The mechanisms by which loading protocols effect change

in participants with AT is complex and at present not well

described [14]. Loading protocols have been theorised to

positively affect the structure of the Achilles tendon, with

suggestions made that an improvement in structure leads to

an improvement in symptoms and ultimately function

[15, 16]. However, this theory/model has recently been

questioned; an alternative model has been proposed where

loading protocols improve muscle function and subse-

quently shield the Achilles tendon from stress [17]. Con-

currently, it may be that the neural system plays an

important role in tendinopathy, not only on tendon pain but

potentially modifying corticospinal control of the muscle-

tendon complex [18]. Finally, alteration in lower leg

stiffness has been proposed as a potential mechanism

driving improvement in pain and function and it has been

demonstrated that leg stiffness is reduced in running ath-

letes with mid-portion AT [19]. While evidence indicates

loading protocols are effective, the mechanisms responsi-

ble for the improvement are unclear.

Muscle strength in patients with patellar tendinopathy

has been shown to significantly improve following a single

bout of isometric loading [20]. This change was mediated

by a decrease in cortical inhibition and may also contribute

to improvement [20]. This is in keeping with the under-

standing that neural adaptations responsible for improve-

ments in muscle strength occur within days of resistance

training [21]. However, muscular hypertrophy does not

occur for weeks following the inception of a resistance

training protocol [22]. As such, if neural and muscular

adaptations altering strength are responsible for clinical

improvements, it would be expected that these changes

occur within weeks of the inception of a loading protocol

and will continue throughout the course of the loading

protocol while a stimulus to improve strength exists.

Tendon structure measured using ultrasound tissue

characterisation did not change during a 12-week eccentric

loading protocol, suggesting that clinical improvements

within this period are unlikely to be secondary to adapta-

tions in tendon structure [23–25]. However, a decrease in

tendon volume and magnetic resonance imaging signal has

been shown to change in response to a 12-week eccentric

loading protocol and this has been shown to correlate with

pain [16, 26]. Given that adaptations in tendon structure do

1876 M. Murphy et al.

123

not appear to occur rapidly, if at all, it would be expected

that improvements in pain and function would likely be

delayed, possibly not occurring until weeks or months

following the inceptions of a loading protocol.

It has been established that neural mechanisms involved

in driving pain and impaired function can change quickly.

Specifically, for patellar tendons, pain has been shown to

decrease immediately following a single bout of isometric

loading [20, 27]. It is important to note however that these

studies have yet to be replicated for AT.

1.5 Justification for this Review

The aim of this review is to provide clinicians with infor-

mation on the expected levels of improvement over time by

determining the rate of change in pain and function fol-

lowing a loading protocol. Specifically, this review aims to

provide insights into a common question asked by patients:

how long it will take to notice improvement in pain and

function? In understanding the temporal symptom response

to loading interventions, it may be possible to infer

mechanisms underpinning improvement and direct future

research. For instance, the rate of change may be used to

implicate muscle strength, tendon structure and/or neural

mechanisms as being a primary contributor at various

times.

By determining the rate of improvement and the

potential mechanisms driving this change, we may be able

to more accurately target treatment at the system con-

tributing to the improvement in pain and function.

Improvements in clinical symptoms are likely to be multi-

system and future research may need to consider how these

systems are measured and their temporal response.

2 Objectives

The objective of this study was to determine the rate of

change in pain and function over time in patients while

completing a loading protocol for mid-portion AT.

3 Methods

3.1 Data Management

Data were managed and stored via the University of Notre

Dame Australia online file server and OneDrive. The data

sheet used for the meta-analysis was also registered and

stored on Figshare (https://doi.org/10.6084/m9.figshare.

6143210.v1) [28].

3.2 Criteria for Considering Studies for this Review

3.2.1 Types of Studies

Both non-randomised cohort studies and randomised con-

trolled trials were included if a loading protocol was used

to treat mid-portion AT. Studies that used exercise as the

primary intervention or an exercise intervention as a con-

trol or exercise in conjunction with an additional non-ex-

ercise sham/placebo were included as a cohort for

assessment. However, if a randomised controlled trial had

multiple arms, only the exercise group that had the addi-

tional non-exercise sham/placebo or control intervention

was included, excluding the group that had active treat-

ment. Studies were included regardless of their publication

status. Case reports/series, clinical observations and sys-

tematic reviews were excluded.

3.2.2 Types of Participants

Studies that included physically active and sedentary par-

ticipants aged 18 years and over with mid-portion AT for

greater than 3 months were included. Studies including

participants with insertional AT or other cause of heel pain

were excluded from the review.

3.2.3 Types of Interventions

Intervention studies using either isometric, eccentric, con-

centric or isotonic (eccentric and concentric) loading pro-

tocols were included. Studies that employed an isometric,

eccentric, concentric or isotonic loading protocol in con-

junction with a placebo therapy (for example, sham laser

treatment) were included. There were no restrictions on the

duration, length, intensity, frequency or nature of the

intervention.

3.2.4 Types of Outcome Measures

Only studies that used a validated and reliable outcome

measure of pain and function in mid-portion AT were

included. Tendon pain is highly related to bouts of aggra-

vating load, specifically loading that involves a stretch-

shortening cycle [1, 4]. Given the intricate relationship of

pain and load in tendinopathy, it is important that when

measuring outcomes both pain and function are taken into

consideration [1, 4]. This concept is further supported in a

reliability study by Silbernagel et al. [11], which demon-

strated the reliability of the Visual Analogue Scale at rest

in mid-portion AT to be r = 0.45. This result is poor when

compared to a combined pain and function measure such as

the Victorian Institute Sports Assessment-Achilles (VISA-

A), which in a reliability study by Robinson et al. [29],

Rate of Improvement of Pain and Function in Achilles Tendon Pain with Loading Protocols 1877

123

demonstrated a test re-test reliability of r = 0.93 in mid-

portion AT.

Therefore, outcomes measures such as the Visual Ana-

logue Scale and the Numerical Rating Scale were exclu-

ded, as measuring tendon pain without accounting for

function can be potentially misleading given the intimate

relationship between pain and function in tendinopathy.

The VISA-A is a self-reported outcome measure that

includes questions about pain, function, and physically

activity [29]. A recent consensus statement recognised the

VISA-A as a valid and reliable tool for assessing AT [30]

with another review highlighting it is the only validated

and reliable measure to assess pain and function in mid-

portion AT [31]. Therefore, only studies that used the

VISA-A were included.

3.3 Search Methods for Identification of Studies

Searches of all databases were conducted from inception

until the 31 July, 2017.

3.3.1 Electronic Searches

Searches using free text terms (see Table 1) were used to

identify published articles on the following electronic

databases: PubMed, CINAHL (Ovid) and CINAHL

(EBSCO). Only peer-reviewed human clinical trials and

cohort studies were included. The publication language

was not restricted to English.

3.3.2 Searching Other Resources

Additional searches were conducted on the Cochrane

Central Register of Controlled Trials, metaRegister of

controlled trials (www.controlled-trials.com/mrct), clini-

caltrials.gov (www.clinicaltrials.gov) and the World Health

Organization International Clinical Trials Registry Plat-

form (apps.who.int/trialsearch/) for ongoing trials.

Reference lists for reviews and retrieved articles for

additional studies were checked and citation searches on

key articles performed. Experts in the field were contacted

to assess for unpublished and ongoing trials. The list of

included studies were evaluated by content experts to help

identify any additional relevant studies. Web of science

was also used for forward citation tracking.

The ePublication lists of key journals in the field were

screened to highlight studies that have yet to be indexed in

the databases. The journals searched included; British

Journal of Sports Medicine, Sports Medicine, American

Journal of Sports Medicine, Medicine and Science in

Sports and Exercise, Journal of Science and Medicine in

Sport, Journal of Athletic Training, Journal of Physio-

therapy, Archives of Physical Medicine and Rehabilitation,

Journal of Sports Sciences, Scandinavian Journal of

Medicine and Science in Sports, Journal of Orthopaedic

and Sports Physical Therapy, Physical Therapy in Sport,

Physical Therapy, Clinical Rehabilitation, Clinical Journal

of Sport Medicine, Journal of Sports Rehabilitation,

Physiotherapy and the International Journal of Sports

Physical Therapy.

3.3.3 Unpublished Data

To minimise the prospect of publication bias, further

searches of the following were undertaken: OpenGrey

(System for Information on Grey Literature in Europe),

Dissertation Abstracts (Proquest) and SPORTDiscus.

3.4 Data Collection and Analysis

3.4.1 Selection of Studies

Two review authors (MM and MT) independently searched

and assessed the titles and abstracts of potential studies

identified by the search strategy for their eligibility. If the

eligibility of a study was unclear from the title and abstract,

the full paper was assessed. Studies that did not match the

inclusion criteria for this review were excluded. There were

two disagreements between authors regarding study

inclusion, which were resolved by discussion. Studies were

not anonymised prior to assessment. A Preferred Reporting

Items for Systematic Reviews and Meta-Analyses study

flow diagram was used to document the screening process

[32].

3.4.2 Data Extraction and Management

Two review authors (MM and MT) independently extrac-

ted data from all included studies using a standardised and

piloted data extraction form on Microsoft Excel. The fol-

lowing information from the review was extracted; primary

Table 1 Systematic review search strategy

Number Combiners Terms

1 Problem of

interest

Achil* OR triceps surae* OR tend* OR heel

OR calcan*

2 Intervention Exercise OR eccentric* OR isotonic* OR

heavy slow resistance OR isometrics OR

resistance OR strength* OR alfredson*

3 #1 AND #2

4 Outcome VISA* OR Victorian institute of sport

score*

5 #3 AND #4

Limitations Peer-reviewed, human, clinical trials and

cohort studies

1878 M. Murphy et al.

123

author, year of publication, study design, study population

(diagnosis), sample size (including sample size at all fol-

low-up points), baseline demographics (age, height,

weight, body mass index, sex, duration of pain and country

of study), loading intervention (isometric or isotonic or

eccentric only or concentric only, as well as the timeframe

over which the intervention was carried out), whether a

placebo treatment was administered in conjunction with the

loading intervention and characteristics of the control,

concomitant treatments, mean [standard deviation (SD)] of

the VISA-A at baseline, and all follow-up points and time

(weeks) at each follow-up point. There were no discrep-

ancies and hence no disagreement between reviewers.

3.4.3 Assessment of Risk of Bias in Included Studies

Two review authors (MM and MT) independently assessed

the risk of bias for each study. There were two disagree-

ments between authors that were unable to be resolved by

discussion. A third review author (WG) provided advice

and a majority decision was made.

This review extracted data from randomised controlled

trials and examined them as individual cohorts. However,

the risk of bias for the randomised controlled trials was

assessed using a randomised trials risk of bias tool, given

study bias does not change dependent on our review pur-

pose. Randomised trials were assessed using the Cochrane

Risk of Bias (RoB 2.0) tool, which involves judgement on

seven domains as described by the Cochrane Group (http://

www.riskofbias.info) [33]. Judgements on the risk of bias

for each of the domains and overall risk of bias were made

as per the recommendations of the RoB 2.0 tool [33]. Trials

were classified overall as having a low risk of bias, some

concerns of bias or a high risk of bias as described in the

RoB 2.0 tool [33].

Non-randomised trials were assessed using the Cochrane

Risk Of Bias In Non-randomized Studies—of Interventions

(ROBINS-I) tool and involves judgement on seven

domains as described by the Cochrane Colloquium (http://

www.riskofbias.info) [34]. Judgements on the risk of bias

for each of the domains and overall risk of bias were made

as per the recommendations of the ROBINS-I tool [34].

Trials were classified overall as having no information, low

risk, moderate risk, serious risk or a critical risk of bias

[34].

3.4.4 Measure of Treatment Effect

It is important to note that the measure of change (which

we describe as ‘treatment effect’) in a longitudinal meta-

analysis is a measure of within-group change from baseline

and not a measure of effect size as normally used in a

traditional meta-analysis. Primary outcomes were analysed

on a continuous scale as the mean difference from baseline,

given the same scale (VISA-A) will be used across all

trials. Data were analysed at every reported time point

across all trials during the loading intervention. Once the

intervention had ceased, any further time points reported

were not included in the analysis.

3.4.5 Dealing with Missing Data

Where insufficient data were presented to extract for

analysis, study authors were contacted to request access to

the missing data. In the event the mean of the VISA-A was

not available, the study was excluded from analysis. In the

event the SD of the study was not available, the SD was

imputed from another trial, which has used the same out-

come measure (VISA-A) at an identical follow-up time

point. The cohort selected to extract the SD, which was

used for the cohort missing the SD, was chosen at random

provided it had an identical follow-up time point. This

method is recommended in Part 3, Section 16.1.3.2 of the

Cochrane Handbook for Systematic Reviews of Interven-

tions [35].

3.4.6 Assessment of Heterogeneity

Given the strictly defined inclusion criteria for studies

(diagnosis/condition, loading intervention and outcome

measure), clinical heterogeneity was expected to be lim-

ited; however, heterogeneity is discussed in the results

section. Statistical tests of heterogeneity such as a Chi-

square test, Cochran’s Q or I2 statistic [36] were not used as

a true effect size was not calculated for the intervention and

cannot be reliably used in a longitudinal meta-analysis.

3.4.7 Assessment of Reporting Biases

The possible influence of small study/publication biases on

review findings was considered and formed a part of the

GRADE level of evidence [37]. The influence of small

study biases was addressed by the risk of bias criterion

‘study size’. Studies with sample sizes less than 50 were

considered as representing a high risk of small sample bias,

studies with samples between 50 and 200 were classified as

a moderate risk of small sample bias and studies with

sample sizes greater than 200 were classed as a low risk of

small sample bias [38].

Funnel plots for all time points were graphed to explore

the likelihood of reporting biases. However, only the

12-week follow-up time point was visually inspected for

assessment of reporting biases, given it is the only time

point that had at least ten studies. Statistical tests of

reporting biases such as Eggers regression [39] were not

used as a true effect size was not calculated for the

Rate of Improvement of Pain and Function in Achilles Tendon Pain with Loading Protocols 1879

123

intervention and cannot be reliably used in a longitudinal

meta-analysis.

3.4.8 Assessment of the Quality of the Body of Evidence

Assessment of the quality of the body of evidence was

assessed using the GRADE approach [37] as recommended

in Part 2, Section 12.2.1 of the Cochrane Handbook for

Systematic Reviews of Interventions [35]. The GRADE

approach involves making an overall judgement on the

quality of the body of evidence based on the overall risk of

bias, consistency of results, directness of the evidence and

publication bias [37].

3.4.9 Data Synthesis

A longitudinal meta-analysis of outcome data from suitably

homogenous studies was performed using a multivariate

mixed model and using syntax adapted from Ishak et al.

which is included in supplementary material [40]. To

ensure the syntax was accurately adapted from the initial

paper by Ishak et al. (2007), the dataset from the paper was

recreated and the analysis re-run with identical results.

Results were pooled where adequate data existed using

SAS (Version 3.6, SAS Institute Inc., Cary, NC, USA)/

STAT PROC MIXED (University Edition Software). Time

points at 24 and 26 weeks post-baseline were included

together as a 6-month time point as only one cohort

reported outcomes at 24 weeks post-baseline.

Unfortunately, as a result of trials not including VISA-A

scores at all time points (224 of 279 time points were

lacking data), the multivariate mixed-model meta-analysis

was unable to converge and hence was unable to account

for within- and between-study variability. However, the

meta-analysis model was still able to calculate the pooled

means (SDs) for each time point.

3.4.10 Sensitivity Analysis

Given the within- and between-study variance was not used

in the multivariate meta-analysis owing to the results not

converging, there was no influence of inputting the SDs on

the results and therefore sensitivity analysis was not

performed.

3.5 Prospective Protocol Registration

The protocol for this systematic review was registered on

PROSPERO (registration number: CRD42017062737,

https://www.crd.york.ac.uk/PROSPERO/display_record.

php?RecordID=62737).

3.5.1 Deviations from Protocol

The initial protocol included statistical tests of publication

bias and heterogeneity; however, we deemed this as not

appropriate for a longitudinal meta-analysis and hence our

protocol was updated on 22 November, 2017 to reflect this.

4 Results

4.1 Selection of Studies

A total of 24 studies were included for the meta-analysis,

which included a total of 31 separate cohorts (Fig. 1). All

studies were written in English.

4.2 Data Extraction

Data were extracted and converted into the format required

for the meta-analysis and are presented in Table 2, while

the data used for the meta-analysis are presented in sup-

plementary material. Six different loading protocols were

investigated across the included studies; heavy eccentric

calf training as described by Alfredson et al.

[8, 12, 24, 41–61] modified heavy eccentric calf training,

[56, 57] heavy slow resistance training as described by

Beyer et al. [12] eccentric overload as described by Sil-

bernagel et al. [10] eccentric overload with active rest as

described by Silbernagel et al. [10] and the Stanish pro-

tocol as described by Stanish et al. [55, 62]. We have

further described the characteristics of the aforementioned

interventions in Table 3. The corresponding author of one

study [63] was contacted to provide the mean and SD of the

VISA-A at all follow-up points for all groups. This infor-

mation was unable to be provided as they no longer had the

data, therefore this study was excluded.

Eight studies [24, 42–45, 58–60] provided the mean but

did not report the SD and hence the corresponding authors

were contacted for further information. Five authors

responded with the mean and SD for their trial

[24, 42, 44, 45, 60]. Three authors failed to respond and

hence the SD for their studies were imputed from another

trial that had used the same outcome measure (VISA-A) at

an identical follow-up time point [43, 58, 59].

4.3 Assessment of Risk of Bias in Included Studies

Risk of bias was assessed and is presented for both ran-

domised (Table 4) and non-randomised trials (Table 5).

The risk of bias assessments for both review authors before

resolution by the third review author is presented in sup-

plementary material. Based on the RoB 2.0 Tool, 50% (10/

20) of the randomised controlled trials were at a high risk

1880 M. Murphy et al.

123

of bias. Based on the ROBINS-I tool, 100% (4/4) of the

cohort studies were at a critical risk of bias.

4.4 Assessment of Heterogeneity

The included exercise interventions have been compared in

previous reviews and have shown no significant differences

in results [2, 7, 13]. Studies included both sedentary and

non-sedentary participants leading to possible heterogene-

ity; however, participant demographics were similar across

studies. Studies included both men and women, limiting

the amount of heterogeneity owing to sex (Table 2).

Studies included mean ages ranging from 26.0 to 51.2

years, limiting the amount of heterogeneity owing to age

(Table 2). Studies varied in the reporting of what additional

treatment participants were able to use with some trials

allowing additional treatment, some trials prohibiting it and

others not reporting whether it was allowed or prohibited.

4.5 Assessment of Reporting Biases

One study had a sample size of greater than 50 and less

than 200 and was classified as having a moderate risk of

small study bias, while all other trials had a sample size of

less than 50 and were classified as having a high possibility

of small study bias. A funnel plot was graphed using the

Search Strategy Applied by Reviewers (MM+MT)

Number of articles excluded during reviewer meeting as

they did not contain an exercise rehabilitation arm or included insertional Achilles

tendinopathy = 7

Number of articles included after screening

titles and abstracts MM= 25 MT= 25

Total after removal of duplicates = 32

included after reviewer meeting

included = 24

Number of articles excluded as they did not provide mean

(SD) change of the VISA-A = 1

Final number of cohorts within included articles

= 31

Number of Articles Retrieved by Reviewers:

PubMed= 43CINAHL= 43

EBSCO (Medline and Academic Search Premier)= 141

SportDISCUS= 68Cochrane Register of Controlled

Trials= 58metaRegister of Controlled Trials= 0

clinicaltrials.gov= 0ICTRP WHO Trials= 0

Web of Science= 10Open Grey= 112

Proquest= 0Key Journals ePublication Lists= 3

Fig. 1 Preferred Reporting

Items for Systematic Reviews

and Meta-Analyses study flow

diagram. ICTRP International

Clinical Trials Registry

Platform, SD standard

deviation, VISA-A Victorian

Institute Sports Assessment-

Achilles, WHO World Health

Organization

Rate of Improvement of Pain and Function in Achilles Tendon Pain with Loading Protocols 1881

123

Table 2 Individual study characteristics

Study and

name (year)

Study

design

Cohort size

at final

follow up

= n

Mean age,

year (SD)

Sex (male/

female)

Loading intervention Placebo in

conjunction

to loading

Baseline

mean

VISA-A

(SD)

Final

follow-up

mean

VISA-A

(SD)

Balius et al.

(2016) [41]

RCT 15 38.9 (6.6) 12/3 Heavy eccentric calf

training

N/A 49 (18) 76 (19)

5 4/1 Heavy eccentric calf

training

N/A 66 (2) 86 (11)

Bell et al.

(2013) [42]

RCT 27 47.2 (9.7) 12/15 Heavy eccentric calf

training

Saline

injection

57.3

(12.7)

72.2 (14.2)

Beyer et al.

(2015) [12]

RCT 25 48 (10) 18/7 Heavy eccentric calf

training

N/A 58 (19.5) 72 (18.5)

22 48 (9.38) 14/8 Heavy slow resistance

training

N/A 54 (15) 76 (17.4)

Boesen et al.

(2017) [43]

RCT 19 40.9 (6/6) Not reported Heavy eccentric calf

training

Saline

injection

59.2

(10.1)

68 (16.3)

Brown et al.

(2006) [44]

RCT 18 46.3 (Not

reported)

11/7 Heavy eccentric calf

training

Saline

injection

62.2

(16.38)

84.3 (27.2)

De Vos et al.

(2007) [45]

RCT 32 44.1 (7) 20/12 Heavy eccentric calf

training

N/A 50.1

(20.3)

68.8 (27.3)

De Vos et al.

(2012) [24]

Cohort 24 46 (9.5) 10/15 Heavy eccentric calf

training

N/A 47.3

(16.4)

54.1 (21.8)

Kearney et al.

(2013) [46]

RCT 10 49.9 (Not

reported)

3/7 Heavy eccentric calf

training

N/A 36 (21) 56 (27)

Knobloch

et al. (2010)

[47]

Cohort 31 50 (12) 31/0 Heavy eccentric calf

training

N/A 60 (14) 75 (11)

44 0/44 Heavy eccentric calf

training

N/A 63 (12) 86 (13)

Maffuli et al.

(2008) [48]

Cohort 45 26 (12.8) 29/16 Heavy eccentric calf

training

N/A 36 (23.8) 52 (27.5)

McAleenan

et al. (2010)

[49]

RCT 6 39.2 (9.2) 3/3 Heavy eccentric calf

training

N/A 42.7

(16.1)

64 (21.4)

Munteneau

et al. (2015)

[50]

RCT 73 43.6 (7.6) 39/34 Heavy eccentric calf

training

Sham

orthoses

60.3

(17.2)

79.2 (20)

Pearson et al.

(2012) [51]

RCT 18 51 (7.6) 7/13 (reported as

number of

tendons not

participants)

Heavy eccentric calf

training

N/A 52 (25) 75 (27)

Rompe et al.

(2007) [53]

RCT 25 48.1 (9.9) 9/16 Heavy eccentric calf

training

N/A 50.6

(11.5)

75.6 (18.7)

Rompe et al.

(2009) [52]

RCT 34 46.2

(10.2)

14/20 Heavy eccentric calf

training

N/A 50.6

(10.3)

73 (19)

Sayana and

Maffuli

(2007) [54]

Cohort 34 Not

reported

18/16 Heavy eccentric calf

training

N/A 39 (22.8) 50 (26.5)

Silbernagel

et al. (2007)

[10]

RCT 19 48 (6.8) 11/8 Eccentric overload with

active rest

N/A 58 (15.7) 82 (17.9)

19 44 (8.8) 7/12 Eccentric overload N/A 57 (15.8) 80 (14.2)

Stasinopoulos

and Manias

(2013) [55]

RCT 20 48.2 (5.1) Not reported Heavy eccentric calf

training

N/A 36 (23.4) 76 (14.8)

21 48.4 (5.1) Not reported Stanish protocol N/A 38 (23.4) 63 (18.7)

1882 M. Murphy et al.

123

sample size and the logarithm of the mean VISA-A change

from baseline (Eff_Est) at 12 weeks post-inception of the

intervention and is presented in Fig. 2. The funnel plot

appears to show an absence of smaller studies (n\ 20)

showing a log(Eff_Est) of\ 1.2, which may represent mild

publication bias resulting in larger change (effect) sizes in

the meta-analysis.

4.6 Quality of the Body of Evidence

The quality of the body of evidence was assessed as per the

GRADE approach. Of 24 papers, there were 20 randomised

controlled trials, ten of which were at a high risk of bias,

and four cohort studies that were all at a critical risk of

bias. Most studies (23/24) had small sample sizes (n\50)

and hence were at a high risk of small sample bias. There

was evidence on the funnel plot at 12 weeks that there was

publication bias. There were no problems with directness.

One study [61] showed what appeared to be different

results compared to the others with minimal change at the

long-term follow-up; however, the risk of inconsistency

within the literature was minimal. With consideration of

the components of the GRADE system, we rated the

overall quality of the body of evidence as very low.

4.7 Data Synthesis

The extracted data have been presented graphically in

Fig. 3 to demonstrate the rates of change for each study

before meta-analysis. Figure 3 represents the mean VISA-

A change from baseline for all studies, demonstrating that

following the inception of a loading protocol participants

experience an improvement in pain and function, regard-

less of the specific protocol used. The pooled mean VISA-

A (SD) for each time point were calculated and are pre-

sented in Fig. 4. Figure 4 demonstrates that improvement

is seen within 2 weeks of the inception of a loading pro-

tocol with the effect of loading protocols appearing to peak

at 12 weeks with a mean (SD) of 21.11 (6.61) points of

change on the VISA-A.

5 Discussion

This systematic review demonstrates the temporal change

in pain and function for people with AT who have com-

pleted common loading protocols. The findings of this

study provide useful clinical information to inform practice

and direct future research to include measurements of

different systems as well as consider the length of time of

interventions.

5.1 Mechanisms Driving Improvement

It has been demonstrated in a previous systematic review

by Drew et al. [64] that tendon structure has a poor rela-

tionship to improvement in pain and function experienced

by patients. These findings are further supported in this

Table 2 continued

Study and

name (year)

Study

design

Cohort size

at final

follow up

= n

Mean age,

year (SD)

Sex (male/

female)

Loading intervention Placebo in

conjunction

to loading

Baseline

mean

VISA-A

(SD)

Final

follow-up

mean

VISA-A

(SD)

Stevens and

Tan (2014)

[56]

RCT 14 48.2

(10.8)

6/9 Heavy eccentric calf

training

N/A 49.6

(10.2)

58.7 (13)

12 49.2

(11.3)

5/8 Modified heavy eccentric

calf training

N/A 47.1

(15.6)

62.5 (12.8)

Tumilty et al.

(2008) [59]

RCT 10 42.5 (8.5) 6/4 Heavy eccentric calf

training

Sham laser 56.3

(19.8)

77.5 (20)

Tumilty et al.

(2012) [58]

RCT 17 46.5 (6.4) 10/10 Heavy eccentric calf

training

Sham laser 61 (10.8) 93 (20)

Tumilty et al.

(2016) [57]

RCT 13 47.2 (8.5) 9/11 Heavy eccentric calf

training

Sham laser 56.7 (12) 80.4 (9.7)

19 47.7

(10.1)

7/13 Heavy eccentric calf

training

Sham laser 56.8

(11.3)

87.6 (9.1)

Yelland et al.

(2011) [60]

RCT 15 46 (Not

reported)

Not reported Heavy eccentric calf

training

N/A 57.6

(14.2)

79.5 (15.3)

Zhang et al.

(2013) [61]

RCT 32 51.2

(6.54)

Not reported Heavy eccentric calf

training

N/A 45.8 (8.5) 48.5 (8.8)

N/A not applicable, RCT randomised controlled trial, SD standard deviation, VISA-A Victorian Institute of Sports Assessment-Achilles

Rate of Improvement of Pain and Function in Achilles Tendon Pain with Loading Protocols 1883

123

Table 3 Description of interventions

Intervention Type of

muscle

activation

Frequency Unilateral

or

bilateral

Exercises Sets 9 reps Weight

Heavy eccentric

calf training

[8]

Eccentric Daily Unilateral Straight knee heel drop off step 3 9 15 Added via

backpack

as

tolerated

Bent knee heel drop off step 3 9 15 Added via

backpack

as

tolerated

Modified heavy

eccentric calf

training [54]

Eccentric \Daily Unilateral Straight knee heel drop off step B 3 9 15 Added via

backpack

as

tolerated

Bent knee heel drop off step B 3 9 15 Added via

backpack

as

tolerated

Heavy slow

resistance

training [12]

Isotonic 39/week Bilateral Heel rises with bended knee in the

seated calf raise machine

Begin with 3–4

9 15 and

progress to 3–4

9 6

Added via

machine

as

tolerated

Heel rises with straight knee standing

on a disc weight with the forefoot

with the barbell on shoulders

Begin with 3–4

9 15 and

progress to 3–4

9 6

Added via

machine

as

tolerated

Heel rises with straight knee in the leg

press machine

Begin with 3–4

9 15 and

progress to 3–4

9 6

Added via

machine

as

tolerated

Eccentric

overload [10]

Concentric,

eccentric

and

isotonic

Daily Unilateral

and

bilateral

Complex staged protocol that is progressed over 6 months. Additional

exercises such as running could be completed provided the participant

had\ 5/10 on VAS of pain

Eccentric

overload with

active rest

[10]

Concentric,

eccentric

and

isotonic

Daily Unilateral

and

bilateral

Complex staged protocol that is progressed over 6 months. No additional

exercises such as running were to be completed

Stanish

protocol [60]

Eccentric Daily for first 6

weeks, 39 /week

for following 6

weeks

Unilateral Whole body warm- up Not reported Nil

Static gastrocnemius and soleus

stretch

3 9 30 s/muscle

group

Nil

Straight knee heel drop off step at

varied speeds

3 9 10 Added via

backpack

as

tolerated

Static gastrocnemius and soleus

stretch

3 9 30 s/muscle

group

Nil

Ice-affected area 10 min Nil

VAS Visual Analogue Scale

1884 M. Murphy et al.

123

review as pain and function increases as early as 2 weeks

and achieves the suggested minimal clinically important

difference (MCID) by 4 weeks following the inception of a

loading protocol; however, tendon structure has been

shown to be unchanged within this time frame [24, 25].

However, it must be recognised that relevant structural

changes may currently be beyond the resolution of

imaging.

It has been previously theorized that improvements in

strength and function of the triceps surae may relate to the

improvements in mid-portion AT following a loading

protocol [14, 17]. Strength and function can improve

within days as a result of a plethora of neural mechanisms,

[21] which are then followed by muscle hypertrophy after

3–4 weeks following the inception of loading [22]. Given

the potential for immediate adaptations in strength through

Table 4 Risk of bias assessment for randomiszed controlled trials using the Cochrane Risk of Bias (RoB 2.0) tool

Study name (year) Bias arising from the

randomisation

process

Bias due to deviations

from intended

interventions

Bias due to

missing outcome

data

Bias in

measurement of

the outcome

Bias in selection of

the reported result

Overall

Balius et al. (2016)

[41]

Low Low Low High Low High

Bell et al. (2013)

[42]

Low Low Low Low Low Low

Beyer et al. (2015)

[12]

Low Low Low Low Low Low

Boesen et al.

(2017) [43]

Low Low Low Low Low Low

Brown et al.

(2006) [44]

Low Low Low Low Low Low

De Vos et al.

(2007) [45]

Low Low Low High Low High

Kearney et al.

(2013) [46]

Low Low Low High Low High

McAleenan et al.

(2010) [49]

Low Low Low High Low High

Munteneau et al.

(2015) [50]

Low Low Low Low Low Low

Pearson et al.

(2012) [51]

Low High Low High High High

Rompe et al.

(2007) [53]

Low Low Low High Low High

Rompe et al.

(2009) [52]

Low Low Low High Low High

Silbernagel et al.

(2007) [10]

Low Low Low Low Low Low

Stasinopoulos and

Manias (2013)

[55]

High Low Low Low Low High

Stevens and Tan

(2014) [56]

Low Low Low Low Low Low

Tumilty et al.

(2008) [59]

Low Low Low Low Low Low

Tumilty et al.

(2012) [58]

Low Low Low Low Low Low

Tumilty et al.

(2016) [57]

Low Low Low Low Low Low

Yelland et al.

(2011) [60]

Low Low Low High Low High

Zhang et al. (2013)

[61]

Low Low Low High Low High

Rate of Improvement of Pain and Function in Achilles Tendon Pain with Loading Protocols 1885

123

neural mechanisms, it is plausible this drives the early

(2–4 weeks) improvements patients experience after

beginning rehabilitative loading. However, if improve-

ments in muscle strength were solely responsible for

observed improvement, it may be expected that pain and

function should continue to improve in a somewhat linear

fashion, throughout the duration of a loading protocol, as

muscle strength will continue to improve when trained.

Indeed, it would not make sense to see a plateau/decline in

pain and function after 12 weeks, as demonstrated in this

review by the studies that included a 6-month follow-up. It

is acknowledged though that a potential explanation for

this decline in improvement after 12 weeks (were muscle

strength responsible for the improvement) may be

decreased compliance or a stagnation effect of the inter-

vention owing to ineffective dosages leading to diminish-

ing strength. Finally, the decline in the effectiveness of the

intervention may be the result of only having three cohorts

that completed the exercise interventions for a 6-month

follow-up, decreasing the accuracy of the estimate.

Another possible explanation for the early improvement

seen in patients with mid-portion AT may be modifications

in the neural mechanisms driving pain [18, 65]. Patients

with AT have been shown to have differences in central

processing when compared with healthy counterparts, [66]

which may implicate neural mechanisms at least partially

driving pain in tendinopathy. Achilles tendinopathy has

also been shown to have significant psychosocial impact on

people with chronic tendinopathy, which may modulate the

degree of pain and function [67]. Support for the role of

loading protocols as potential modulators of tendon pain

mechanisms is provided by a recent study demonstrating

that a single bout of isometric loading can cause immediate

changes to both tendon pain and cortical inhibition [20].

Given the early improvements in pain and function with

loading suggested in this review, it is plausible that chan-

ges in central processing may be responsible for the

observed early improvements. It is also possible that the

placebo effect drives the initial improvement as partici-

pants are being given a rehabilitation protocol by experts

and told they are expected to improve. Finally, the reduc-

tion in immediate symptoms may be owing to education

and removing aggravating loads as a result of involvement

in a trial.

Table 5 Risk of bias assessment for non-randomised studies using the Cochrane Risk Of Bias In Non-randomized Studies—of Interventions

(ROBINS-I) ROBIN-I Tool

Study name

(year)

Bias due to

confounding

Bias in the

selection of

participants into

the study

Bias in

classification

of the

interventions

Bias due to

deviations from

intended

interventions

Bias due

to

missing

data

Bias in

measurement

of outcomes

Bias in

selection of

the reported

result

Overall

De Vos

et al.

(2012)

[24]

Critical Low Low Low Low Moderate Low Critical

Knobloch

et al.

(2010)

[47]

Critical Low Low Low Low Moderate Low Critical

Maffuli

et al.

(2008)

[48]

Critical Low Low Low Low Moderate Low Critical

Sayana and

Maffuli

(2007)

[54]

Critical Low Low Low Low Moderate Low Critical

0

10

20

30

40

50

60

0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8

Sam

ple

Size

(n)

Log (Mean change VISA-A from baseline)

Fig. 2 Assessment of publication bias using a funnel plot at 12 weeks

following inception of the intervention. VISA-A Victorian Institute

Sports Assessment-Achilles

1886 M. Murphy et al.

123

5.2 Review Implications

Successful communication between clinicians and patients

relies on clinicians understanding what patients want to

know [68]. One of the fundamental questions patients ask

when seeking help from healthcare professionals for pain

and impaired function is when they will feel better and how

soon might they notice functional improvement. A tradi-

tional meta-analysis of an intervention is clinician oriented,

answering the question of whether an intervention is

-10

0

10

20

30

40

0 5 10 15 20 25

Mea

n C

hang

e in

VIS

A-A

Fro

m B

asel

ine

Time Point (Weeks)

Balius et al. (2016) Cohort One Balius et al. (2016) Cohort Two Bell et al. (2013) Beyer et al. (2015) Cohort OneBeyer et al. (2015) Cohort Two Boesen et al. (2017) Brown et al. (2005) de Vos et al. (2012)de Vos et al. (2007) Kearney et al. (2013) Knobloch et al. (2010) Cohort One Knobloch et al. (2010) Cohort TwoMaffuli et al. (2008) McAleenan (2010) Munteanu et al. (2015) Pearson et al. (2012)Rompe et al. (2007) Rompe et al. (2009) Sayana et al. (2007) Silbernagel et al. (2007) Cohort OneSilbernagel et al. (2007) Cohort Two Stasinopoulos et al. (2013) Cohort One Stasinopoulos et al. (2013) Cohort Two Stevens et al. (2014) Cohort OneStevens et al. (2014) Cohort Two Tumilty et al. (2008) Tumilty et al. (2012) Tumilty et al. (2016) Cohort OneTumilty et al. (2016) Cohort Two Yelland et al. (2011) Zhang et al. (2013)

Fig. 3 Change in Achilles tendon pain and function over time when completing a loading protocol. VISA-A Victorian Institute Sports

Assessment-Achilles

Week 2(n=42)

Week 3(n=26)

Week 4(n=176)

Week 6(n=138)

Week 8(n=82)

Week 12(n=559)

Week 16(n=75)

Month 6(n=68)

-15

-10

-5

0

5

10

15

20

25

30

Follow Up Time Point

NUMBER OF COHORTS Mean Change from Baseline (VISA-A)

Fig. 4 Rate of change in

Achilles tendon pain and

function over time when

performing a loading protocol.

Note: mean change (solid line)

± 1 standard deviation (dotted

lines); n = total number of

participants when all cohorts are

combined at that time point.

VISA-A Victorian Institute

Sports Assessment-Achilles

Rate of Improvement of Pain and Function in Achilles Tendon Pain with Loading Protocols 1887

123

effective. However, this current longitudinal meta-analysis

of an intervention is patient oriented and has enabled us to

address the important area that is patient expectation

around management strategies and likely outcomes.

Our findings suggest improvement as early as 2 weeks

following the inception of a loading protocol. However,

while improvement was seen at 2 weeks, a decline was

seen in weeks 3 and 4, which is likely representative of

small numbers and must be interpreted with caution.

A MCID represents the minimal amount of change that

translates to a clinical improvement for patients [69]. The

MCID of the VISA-A for mid-portion AT has not been

formally investigated; however, multiple studies have used

10 points as the MCID [10, 12, 42, 50, 54, 70]. Based on

the results of this review, a change of 10 points appears to

be reached by 4 weeks following the inception of a loading

protocol.

The improvement seen with rehabilitative loading in this

review appears to reach maximal effect at 12 weeks fol-

lowing the inception of the loading protocol and plateaued

after this point with the six separate cohorts following the

12-week time point showing a plateaued/diminished effect.

The diminishing effect of exercise rehabilitation may

explain why at long-term follow-up, a significant propor-

tion of participants still experienced pain and impaired

function [71]. This is important to note as it suggests that

loading approaches as applied in these patients may be

insufficient in isolation to facilitate optimal recovery. This

also implies that a more nuanced understanding of the

mechanisms driving the improvement in the first 12 weeks

may enable improved rehabilitation protocols targeting the

mechanisms responsible for change.

It was also demonstrated that only one of the 31 cohorts

had a mean VISA-A score of greater than 90 points at the

end of the exercise intervention. This suggests participants

had ongoing pain and reduced function following an iso-

lated loading protocol. Considering these findings, future

studies should report on the proportion of participants who

achieved a VISA-A of greater than 90 points.

5.3 Quality of the Body of the Evidence

Unfortunately, with the overall quality of the evidence

being assessed as very low, the true rate of change may

differ from that estimated in this study. The results of this

review likely overestimate the rate of improvement owing

to the presence of small study and publication biases.

However, we would expect that the true rate of change still

falls within the bands highlighted by the SDs in Fig. 4,

given the wide SDs at week 3, week 16 and 6 months post-

inception of intervention.

5.4 Recommendations for Future Research

While this review is able to provide clinicians with rec-

ommendations on the prognosis of mid-portion AT with

loading protocols and theorize on potential mechanisms

based on the changes seen over time, it is not possible to

clearly implicate what is responsible for improvements in

pain and function. This review highlights that future high-

quality studies are needed to not only track improvements

in pain and function but also consider measurements of

muscle, tendon, and neural adaptations and their relative

and temporal contributions as potential mechanisms

underpinning clinical change. This may in turn help clini-

cians and researchers refine strategies to assist in the

management of this challenging condition.

5.5 Limitations

This review included studies in which cohorts underwent

exercise rehabilitation for the management of mid-portion

Achilles tendon pain. However, we also opted to include

cohorts (8/31) within which a placebo/sham intervention

(i.e., sham laser) was used in addition to the exercise

rehabilitation. The inclusion of these studies may have

potentially caused an overestimation of the effect of

exercise because of placebo effects from the medical

intervention. Unfortunately, there is no way to quantify the

extent of this involvement.

This review did not account for the effect of adherence

on the amount of improvement experienced with exercise

rehabilitation. Therefore, we are unable to comment on the

extent to which adherence may have changed the results.

However, a systematic review examining the efficacy of

loading protocols is currently being conducted and the

effect of adherence has been included within a pre-planned

sensitivity analysis that may assist in answering this

question [72].

6 Conclusion

This review demonstrates that an improvement of the

VISA-A may be achieved at approximately 2 weeks fol-

lowing the inception of a loading protocol with results

peaking at 12 weeks. Further research is needed to estab-

lish why this decline in pain and function is seen. Specif-

ically, future research could investigate the role that

changes in tendon, muscle strength, lower limb stiffness

and neural mechanisms play in improving pain and func-

tion with loading protocols in mid-portion AT. Subse-

quently, this may help to improve rehabilitation, optimise

patient outcomes and explain the plateau of symptoms after

12 weeks.

1888 M. Murphy et al.

123

Acknowledgements Myles Murphy acknowledges the support from

the Australian Governments Research Training Program Scholarship.

Ebonie Rio acknowledges the support from the National Health and

Medical Research Councils Early Career Fellowship Scheme. All

authors acknowledge the contributions of Dr. Clare Ardern (Lin-

koping University, Linkoping, Sweden) and Prof. Max Bulsara (In-

stitute of Health Research, The University of Notre Dame, Fremantle,

WA, Australia) for their assistance in developing the protocol for this

systematic review.

Authors’ Contributions MM, WG and ER conceptualised the study.

MM, MT, WG, JD, SD, PC and ER developed the study design and

protocol. All authors contributed and approved the final manuscript.

Compliance with Ethical Standards

Funding No financial support was received for the conduct of this

study or preparation of this article.

Conflict of Interest Myles Murphy, Mervyn Travers, William Gib-

son, Paola Chivers, James Debenham, Sean Docking and Ebonie Rio

have no conflicts of interest directly relevant to the content of this

article.

Data Availability The datasets generated and/or analysed during the

current study are available from the corresponding author on rea-

sonable request. The data sheet used for the meta-analysis was also

registered and stored on Figshare (https://doi.org/10.6084/m9.

figshare.6143210.v1) [28].

References

1. Cook JL, Purdam CR. Is tendon pathology a continuum? A

pathology model to explain the clinical presentation of load-in-

duced tendinopathy. Br J Sports Med. 2009;43(6):409–16. https://

doi.org/10.1136/bjsm.2008.051193.

2. Habets B, van Cingel RE. Eccentric exercise training in chronic

mid-portion Achilles tendinopathy: a systematic review on dif-

ferent protocols. Scand J Med Sci Sports. 2015;25(1):3–15.

https://doi.org/10.1111/sms.12208.

3. van Dijk CN, van Sterkenburg MN, Wiegerinck JI, Karlsson J,

Maffulli N. Terminology for Achilles tendon related disorders.

Knee Surg Sports Traumatol Arthrosc. 2011;19(5):835–41.

https://doi.org/10.1007/s00167-010-1374-z.

4. Cook JL, Rio E, Purdam CR, Docking SI. Revisiting the con-

tinuum model of tendon pathology: what is its merit in clinical

practice and research? Br J Sports Med. 2016;50(19):1187–91.

https://doi.org/10.1136/bjsports-2015-095422.

5. Lopes AD, Hespanhol LC, Yeung SS, Costa LOP. What are the

main running-related musculoskeletal injuries? Sports Med.

2012;42(10):891–905. https://doi.org/10.1007/bf03262301.

6. Albers IS, Zwerver J, Diercks RL, Dekker JH, Van den Akker-

Scheek I. Incidence and prevalence of lower extremity

tendinopathy in a Dutch general practice population: a cross

sectional study. BMC Musculoskelet Disord. 2016;17(1):16.

https://doi.org/10.1186/s12891-016-0885-2.

7. Couppe C, Svensson RB, Silbernagel KG, Langberg H, Mag-

nusson SP. Eccentric or concentric exercises for the treatment of

tendinopathies? J Orthop Sports Phys Ther. 2015;45(11):853–63.

https://doi.org/10.2519/jospt.2015.5910.

8. Alfredson H, Pietila T, Jonsson P, Lorentzon R. Heavy-load

eccentric calf muscle training for the treatment of chronic

Achilles tendinosis. Am J Sports Med. 1998;26(3):360–6.

9. Mafi N, Lorentzon R, Alfredson H. Superior short-term results

with eccentric calf muscle training compared to concentric

training in a randomized prospective multicenter study on

patients with chronic Achilles tendinosis. Knee Surg Sports

Traumatol Arthrosc. 2001;9(1):42–7. https://doi.org/10.1007/

s001670000148.

10. Silbernagel KG, Thomee R, Eriksson BI, Karlsson J. Continued

sports activity, using a pain-monitoring model, during rehabili-

tation in patients with Achilles tendinopathy: a randomized

controlled study. Am J Sports Med. 2007;35(6):897–906. https://

doi.org/10.1177/0363546506298279.

11. Silbernagel KG, Thomee R, Thomee P, Karlsson J. Eccentric

overload training for patients with chronic Achilles tendon pain: a

randomised controlled study with reliability testing of the eval-

uation methods. Scand J Med Sci Sports. 2001;11(4):197–206.

12. Beyer R, Kongsgaard M, Hougs Kjaer B, Ohlenschlaeger T,

Kjaer M, Magnusson SP. Heavy slow resistance versus eccentric

training as treatment for Achilles tendinopathy: a randomized

controlled trial. Am J Sports Med. 2015;43(7):1704–11. https://

doi.org/10.1177/0363546515584760.

13. Meyer A, Tumilty S, Baxter GD. Eccentric exercise protocols for

chronic non-insertional Achilles tendinopathy: how much is

enough? Scand J Med Sci Sports. 2009;19(5):609–15. https://doi.

org/10.1111/j.1600-0838.2009.00981.x.

14. Allison GT, Purdam C. Eccentric loading for Achilles

tendinopathy: strengthening or stretching? Br J Sports Med.

2009;43(4):276–9. https://doi.org/10.1136/bjsm.2008.053546.

15. Arnoczky SP, Lavagnino M, Egerbacher M. The mechanobio-

logical aetiopathogenesis of tendinopathy: is it the over-stimu-

lation or the under-stimulation of tendon cells? Int J Exp Pathol.

2007;88(4):217–26. https://doi.org/10.1111/j.1365-2613.2007.

00548.x.

16. Shalabi A, Kristoffersen-Wilberg M, Svensson L, Aspelin P,

Movin T. Eccentric training of the gastrocnemius-soleus complex

in chronic Achilles tendinopathy results in decreased tendon

volume and intratendinous signal as evaluated by MRI. Am J

Sports Med. 2004;32(5):1286–96. https://doi.org/10.1177/

0363546504263148.

17. O’Neill S, Watson PJ, Barry S. Why are eccentric exercises

effective for achilles tendinopathy? Int J Sports Phys Ther.

2015;10(4):552–62.

18. Rio E, Kidgell D, Moseley GL, Gaida J, Docking S, Purdam C,

et al. Tendon neuroplastic training: changing the way we think

about tendon rehabilitation: a narrative review. Br J Sports Med.

2016;50(4):209–15. https://doi.org/10.1136/bjsports-2015-

095215.

19. Maquirriain J. Leg stiffness changes in athletes with Achilles

tendinopathy. Int J Sports Med. 2012;33(7):567–71. https://doi.

org/10.1055/s-0032-1304644.

20. Rio E, Kidgell D, Purdam C, Gaida J, Moseley GL, Pearce AJ,

et al. Isometric exercise induces analgesia and reduces inhibition

in patellar tendinopathy. Br J Sports Med. 2015;49(19):1277–83.

https://doi.org/10.1136/bjsports-2014-094386.

21. Gabriel DA, Kamen G, Frost G. Neural adaptations to resistive

exercise: mechanisms and recommendations for training prac-

tices. Sports Med. 2006;36(2):133–49.

22. DeFreitas JM, Beck TW, Stock MS, Dillon MA, Kasishke PR

2nd. An examination of the time course of training-induced

skeletal muscle hypertrophy. Eur J Appl Physiol.

2011;111(11):2785–90. https://doi.org/10.1007/s00421-011-1905-4.

23. de Jonge S, Tol JL, Weir A, Waarsing JH, Verhaar JA, de Vos RJ.

The tendon structure returns to asymptomatic values in nonop-

eratively treated achilles tendinopathy but is not associated with

symptoms: a prospective study. Am J Sports Med.

Rate of Improvement of Pain and Function in Achilles Tendon Pain with Loading Protocols 1889

123

2015;43(12):2950–8. https://doi.org/10.1177/03635465156050

77.

24. de Vos RJ, Heijboer MP, Weinans H, Verhaar JA, van Schie JT.

Tendon structure’s lack of relation to clinical outcome after

eccentric exercises in chronic midportion Achilles tendinopathy.

J Sport Rehabil. 2012;21(1):34–43.

25. de Vos RJ, Weir A, Tol JL, Verhaar JA, Weinans H, van Schie

HT. No effects of PRP on ultrasonographic tendon structure and

neovascularisation in chronic midportion Achilles tendinopathy.

Br J Sports Med. 2011;45(5):387–92. https://doi.org/10.1136/

bjsm.2010.076398.

26. Gardin A, Movin T, Svensson L, Shalabi A. The long-term

clinical and MRI results following eccentric calf muscle training

in chronic Achilles tendinosis. Skeletal Radiol.

2010;39(5):435–42. https://doi.org/10.1007/s00256-009-0798-3.

27. van Ark M, Cook JL, Docking SI, Zwerver J, Gaida JE, van den

Akker-Scheek I, et al. Do isometric and isotonic exercise pro-

grams reduce pain in athletes with patellar tendinopathy in-sea-

son? A randomised clinical trial. J Sci Med Sport.

2016;19(9):702–6. https://doi.org/10.1016/j.jsams.2015.11.006.

28. Murphy M, Travers MJ, Gibson W, Chivers P, Debenham J,

Docking S, et al. The rate of improvement of pain and function in

mid-portion Achilles tendinopathy with loading protocols: a

systematic review and longitudinal meta-analysis. In: Fig-

share.2018. Available from: https://figshare.com/articles/The_

rate_of_improvement_of_pain_and_function_in_mid-portion_

Achilles_tendinopathy_with_loading_protocols_A_Systematic_

Review_and_Longitudinal_Meta-Analysis_/6143210. Accessed 5

May 2018.

29. Robinson JM, Cook JL, Purdam C, Visentini PJ, Ross J, Maffulli

N, et al. The VISA-A questionnaire: a valid and reliable index of

the clinical severity of Achilles tendinopathy. Br J Sports Med.

2001;35(5):335–41.

30. Scott A, Docking S, Vicenzino B, Alfredson H, Murphy RJ, Carr

AJ, et al. Sports and exercise-related tendinopathies: a review of

selected topical issues by participants of the second International

Scientific Tendinopathy Symposium (ISTS) Vancouver 2012. Br

J Sports Med. 2013;47(9):536–44. https://doi.org/10.1136/

bjsports-2013-092329.

31. Murphy M, Rio E, Debenham J, Docking S, Travers MJ, Gibson

W. Evaluating the progress of mid-portion Achilles tendinopathy

during rehabilitation: a review of outcome measures for self-

reported pain and function. Int J Sports Ther. 2018;13(2):283–92.

https://doi.org/10.26603/ijspt20180283.

32. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC,

Ioannidis JP, et al. The PRISMA statement for reporting sys-

tematic reviews and meta-analyses of studies that evaluate

healthcare interventions: explanation and elaboration. BMJ.

2009;339:b2700. https://doi.org/10.1136/bmj.b2700.

33. Higgins JPT, Sterne JAC, Savovic J, Page MJ, Hrobjartsson A,

Boutron I, Reeves B, Eldridge S. A revised tool for assessing risk

of bias in randomized trials. Cochrane Database Syst Rev. 2016.

https://doi.org/10.1002/14651858.cd201601.

34. Sterne JA, Hernan MA, Reeves BC, Savovic J, Berkman ND,

Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias

in non-randomised studies of interventions. BMJ.

2016;355:i4919. https://doi.org/10.1136/bmj.i4919.

35. Higgins JPT, Green S. Cochrane handbook for systematic

reviews of interventions. Version 5.1.0 [updated March 2011].

http://www.handbook.cochrane.org. Accessed 5 May 2018.

36. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring

inconsistency in meta-analyses. BMJ. 2003;327(7414):557–60.

37. Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S,

et al. Grading quality of evidence and strength of recommenda-

tions. BMJ. 2004;328(7454):1490. https://doi.org/10.1136/bmj.

328.7454.1490.

38. Dechartres A, Trinquart L, Boutron I, Ravaud P. Influence of trial

sample size on treatment effect estimates: meta-epidemiological

study. BMJ. 2013;346:f2304. https://doi.org/10.1136/bmj.f2304.

39. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-

analysis detected by a simple, graphical test. BMJ.

1997;315(7109):629–34.

40. Ishak KJ, Platt RW, Joseph L, Hanley JA, Caro JJ. Meta-analysis

of longitudinal studies. Clin Trials. 2007;4(5):525–39. https://doi.

org/10.1177/1740774507083567.

41. Balius R, Alvarez G, Baro F, Jimenez F, Pedret C, Costa E, et al.

A 3-arm randomized trial for Achilles tendinopathy: eccentric

training, eccentric training plus a dietary supplement containing

mucopolysaccharides, or passive stretching plus a dietary sup-

plement containing mucopolysaccharides. Curr Ther Res Clin

Exp. 2016;78:1–7. https://doi.org/10.1016/j.curtheres.2016.11.

001.

42. Bell KJ, Fulcher ML, Rowlands DS, Kerse N. Impact of autol-

ogous blood injections in treatment of mid-portion Achilles

tendinopathy: double blind randomised controlled trial. BMJ.

2013;346:f2310. https://doi.org/10.1136/bmj.f2310.

43. Boesen AP, Hansen R, Boesen MI, Malliaras P, Langberg H.

Effect of high-volume injection, platelet-rich plasma, and sham

treatment in chronic midportion Achilles tendinopathy: a ran-

domized double-blinded prospective study. Am J Sports Med.

2017;45(9):2034–43. https://doi.org/10.1177/03635465177028

62.

44. Brown R, Orchard J, Kinchington M, Hooper A, Nalder G.

Aprotinin in the management of Achilles tendinopathy: a ran-

domised controlled trial. Br J Sports Med. 2006;40(3):275–9.

https://doi.org/10.1136/bjsm.2005.021931.

45. de Vos RJ, Weir A, Visser RJ, de Winter T, Tol JL. The addi-

tional value of a night splint to eccentric exercises in chronic

midportion Achilles tendinopathy: a randomised controlled trial.

Br J Sports Med. 2007;41(7):e5. https://doi.org/10.1136/bjsm.

2006.032532.

46. Kearney RS, Parsons N, Costa ML. Achilles tendinopathy man-

agement: a pilot randomised controlled trial comparing platelet-

richplasma injection with an eccentric loading programme. Bone

Joint Res. 2013;2(10):227–32. https://doi.org/10.1302/2046-

3758.210.2000200.

47. Knobloch K, Schreibmueller L, Kraemer R, Jagodzinski M, Vogt

PM, Redeker J. Gender and eccentric training in Achilles mid-

portion tendinopathy. Knee Surg Sports Traumatol Arthrosc.

2010;18(5):648–55. https://doi.org/10.1007/s00167-009-1006-7.

48. Maffulli N, Walley G, Sayana MK, Longo UG, Denaro V.

Eccentric calf muscle training in athletic patients with Achilles

tendinopathy. Disabil Rehabil. 2008;30(20–22):1677–84. https://

doi.org/10.1080/09638280701786427.

49. McAleenan M, McVeigh JG, Cullen M, Sayers F, McCrea K,

Baxter D. The effectiveness of night splints in achilles

tendinopathy: a pilot study. Physiother Pract Res.

2010;31(1):28–33.

50. Munteanu SE, Scott LA, Bonanno DR, Landorf KB, Pizzari T,

Cook JL, et al. Effectiveness of customised foot orthoses for

Achilles tendinopathy: a randomised controlled trial. Br J Sports

Med. 2015;49(15):989–94. https://doi.org/10.1136/bjsports-2014-

093845.

51. Pearson J, Rowlands D, Highet R. Autologous blood injection to

treat achilles tendinopathy? A randomized controlled trial. J Sport

Rehabil. 2012;21(3):218–24.

52. Rompe JD, Furia J, Maffulli N. Eccentric loading versus eccen-

tric loading plus shock-wave treatment for midportion achilles

tendinopathy: a randomized controlled trial. Am J Sports Med.

2009;37(3):463–70. https://doi.org/10.1177/0363546508326983.

53. Rompe JD, Nafe B, Furia JP, Maffulli N. Eccentric loading,

shock-wave treatment, or a wait-and-see policy for tendinopathy

1890 M. Murphy et al.

123

of the main body of tendo Achillis: a randomized controlled trial.

Am J Sports Med. 2007;35(3):374–83. https://doi.org/10.1177/

0363546506295940.

54. Sayana MK, Maffulli N. Eccentric calf muscle training in non-

athletic patients with Achilles tendinopathy. J Sci Med Sport.

2007;10(1):52–8. https://doi.org/10.1016/j.jsams.2006.05.008.

55. Stasinopoulos D, Manias P. Comparing two eccentric exercise

programmes for the management of Achilles tendinopathy: a

pilot trial. J Bodyw Move Ther. 2013;17(3):309–15. https://doi.

org/10.1016/j.jbmt.2012.11.003.

56. Stevens M, Tan CW. Effectiveness of the Alfredson protocol

compared with a lower repetition-volume protocol for midportion

Achilles tendinopathy: a randomized controlled trial. J Orthopaed

Sports Phys Ther. 2014;44(2):59–67. https://doi.org/10.2519/

jospt.2014.4720.

57. Tumilty S, Mani R, Baxter GD. Photobiomodulation and eccen-

tric exercise for Achilles tendinopathy: a randomized controlled

trial. Lasers Med Sci. 2016;31(1):127–35. https://doi.org/10.

1007/s10103-015-1840-4.

58. Tumilty S, McDonough S, Hurley DA, Baxter GD. Clinical

effectiveness of low-level laser therapy as an adjunct to eccentric

exercise for the treatment of Achilles’ tendinopathy: a random-

ized controlled trial. Arch Phys Med Rehabil. 2012;93(5):733–9.

https://doi.org/10.1016/j.apmr.2011.08.049.

59. Tumilty S, Munn J, Abbott JH, McDonough S, Hurley DA,

Baxter GD. Laser therapy in the treatment of achilles

tendinopathy: a pilot study. Photomed Laser Surg.

2008;26(1):25–30. https://doi.org/10.1089/pho.2007.2126.

60. Yelland MJ, Sweeting KR, Lyftogt JA, Ng SK, Scuffham PA,

Evans KA. Prolotherapy injections and eccentric loading exer-

cises for painful Achilles tendinosis: a randomised trial. Br J

Sports Med. 2011;45(5):421–8. https://doi.org/10.1136/bjsm.

2009.057968.

61. Zhang BM, Zhong LW, Xu SW, Jiang HR, Shen J. Acupuncture

for chronic Achilles tendnopathy: a randomized controlled study.

Chin J Integr Med. 2013;19(12):900–4. https://doi.org/10.1007/

s11655-012-1218-4.

62. Stanish WD, Rubinovich RM, Curwin S. Eccentric exercise in

chronic tendinitis. Clin Orthop Relat Res. 1986;208:65–8.

63. Herrington L, McCulloch R. The role of eccentric training in the

management of Achilles tendinopathy: a pilot study. Phys Ther

Sport. 2007;8(4):191–6. https://doi.org/10.1016/j.ptsp.2007.07.

001.

64. Drew BT, Smith TO, Littlewood C, Sturrock B. Do structural

changes (eg, collagen/matrix) explain the response to therapeutic

exercises in tendinopathy: a systematic review. Br J Sports Med.

2014;48(12):966–72. https://doi.org/10.1136/bjsports-2012-

091285.

65. Rio E, Moseley L, Purdam C, Samiric T, Kidgell D, Pearce AJ,

et al. The pain of tendinopathy: physiological or pathophysio-

logical? Sports Med. 2014;44(1):9–23. https://doi.org/10.1007/

s40279-013-0096-z.

66. Tompra N, van Dieen JH, Coppieters MW. Central pain pro-

cessing is altered in people with Achilles tendinopathy. Br J

Sports Med. 2016;50(16):1004–7. https://doi.org/10.1136/

bjsports-2015-095476.

67. McAuliffe S, Synott A, Casey H, Mc Creesh K, Purtill H,

O’Sullivan K. Beyond the tendon: Experiences and perceptions

of people with persistent Achilles tendinopathy. Musculoskelet

Sci Pract. 2017;29:108–14. https://doi.org/10.1016/j.msksp.2017.

03.009.

68. Travaline JM, Ruchinskas R, D’Alonzo GE Jr. Patient-physician

communication: why and how. J Am Osteopath Assoc.

2005;105(1):13–8. https://doi.org/10.7556/jaoa.2005.105.1.13.

69. Cook CE. Clinimetrics corner: the minimal clinically important

change score (MCID): a necessary pretense. J Man Manip Ther.

2008;16(4):E82–3. https://doi.org/10.1179/jmt.2008.16.4.82E.

70. Silbernagel KG, Brorsson A, Lundberg M. The majority of

patients with Achilles tendinopathy recover fully when treated

with exercise alone: a 5-year follow-up. Am J Sports Med.

2011;39(3):607–13. https://doi.org/10.1177/0363546510384789.

71. van der Plas A, de Jonge S, de Vos RJ, van der Heide HJ, Verhaar

JA, Weir A, et al. A 5-year follow-up study of Alfredson’s heel-

drop exercise programme in chronic midportion Achilles

tendinopathy. Br J Sports Med. 2012;46(3):214–8. https://doi.org/

10.1136/bjsports-2011-090035.

72. Murphy M, Travers MJ, Gibson W. Is heavy eccentric calf

training superior to wait-and-see, sham rehabilitation, traditional

physiotherapy and other exercise interventions for pain and

function in mid-portion Achilles tendinopathy. Syst Rev.

2018;7(58):1–7. https://doi.org/10.1186/s13643-018-0725-6.

Rate of Improvement of Pain and Function in Achilles Tendon Pain with Loading Protocols 1891

123