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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
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].
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