Abstract
Background: Noninsertional Achilles tendinopathy is a degenerative
overuse disorder. No method has been universally successful in treating this
condition. Topically applied nitric oxide has been shown, in animal models, to
be effective for the treatment of fractures and cutaneous wounds through
mechanisms that may include stimulation of collagen synthesis in fibroblasts.
The goal of the present study was to determine if topical glyceryl trinitrate
improves clinical outcome measures in patients with Achilles tendinopathy.
Methods: A prospective, randomized, double-blind, placebo-controlled
trial involving a total of sixty-five patients (eighty-four Achilles tendons)
was performed to compare continuous application of topical glyceryl trinitrate
(at a dosage of 1.25 mg per twenty-four hours) with rehabilitation alone for
the treatment of noninsertional Achilles tendinopathy.
Results: Compared with the control group, the glyceryl trinitrate
group showed reduced pain with activity at twelve weeks (p = 0.02) and
twenty-four weeks (p = 0.03), reduced night pain at twelve weeks (p = 0.04),
reduced tenderness at twelve weeks (p = 0.02), decreased pain scores after the
hop test at twenty-four weeks (p = 0.005), and increased ankle plantar flexor
mean total work compared with the baseline level at twenty-four weeks (p =
0.04). Twenty-eight (78%) of thirty-six tendons in the glyceryl trinitrate
group were asymptomatic with activities of daily living at six months,
compared with twenty (49%) of forty-one tendons in the placebo group (p =
0.001, chi-square analysis). The mean effect size for all outcome measures was
0.14.
Conculsions: Topical glyceryl trinitrate significantly reduced pain
with activity and at night, improved functional measures, and improved
outcomes in patients with Achilles tendinopathy.
Level of Evidence: Therapeutic study, Level I-1a
(randomized controlled trial [significant difference]). See Instructions to
Authors for a complete description of levels of evidence.
Noninsertional Achilles tendinopathy is a common problem. The prevalence
among runners has been reported to range from 6.5% to
18%1,2.
This condition has a multifactorial etiology that is now accepted to be a
combination of anatomical and biomechanical factors and relative
overuse3. Another
causative factor may be apoptosis, as is seen after cyclic
strain4 and rotator
cuff tears5. No
method has been universally successful in treating this condition, which
causes considerable morbidity through time lost from work and recreational
activities6. The
current nonoperative treatment protocol involves a rehabilitation program
consisting of relative rest, heel raises, and a graduated stretching and
eccentric strengthening exercise
program7.
Inhibition of nitric oxide has been shown to reduce collagen content,
contraction, and synthesis by wound fibroblasts in
vitro8. In addition,
animal studies have shown that nitric oxide synthase inhibition at a cellular
level results in a significant reduction in the cross-sectional area and load
to failure of healing
tendons9, suggesting
that nitric oxide stimulates collagen synthesis by wound fibroblasts. Nitric
oxide has also been shown to modulate
fracture-healing10.
We aimed to assess if tendon rehabilitation combined with continuous
application of topical glyceryl trinitrate, a prodrug of endogenous nitric
oxide11, alters
outcome measures in patients with chronic Achilles tendinopathy at six months
when compared with tendon rehabilitation alone.
Our current protocol for the nonoperative treatment of Achilles
tendinopathy begins with relative rest of the tendon (i.e., avoidance of
aggravating activities). Although not scientifically validated, the use of
rest is anecdotally important, empirically effective, and logically
sound6. The use of a
1.5-cm heel raise has been shown to unload the ankle plantar flexor
muscles12 and to
halve the plantar flexor torque with normal
walking13.
Stretching of the gastrocnemius and soleus muscles that form the Achilles
tendon is thought to be important for maintaining a normal range of motion of
the ankle joint, particularly during a period of relative rest. Stretching
also helps the tendon to regain flexibility and may assist tendon-healing
through gentle longitudinal traction applied along normal lines of
stress14. Eccentric
muscle-strengthening also has demonstrated efficacy in the treatment of
chronic Achilles
tendinopathy7 and is
thought to assist in healing by improving tendon collagen fiber orientation
and by gradually restoring lost strength of the leg musculature.
The use of corticosteroids for the treatment of degenerative tendinopathies
is controversial, as intratendinous injections have been associated with a
risk of tendon
rupture15 and
peritendinous injections have been shown to be
ineffective16. For
these reasons, we did not use corticosteroid injections in this clinical trial
and we excluded patients who had received such therapy in the preceding three
months.
The study was approved by our local ethics committee. A power analysis
demonstrated that in order to have a 90% probability of finding a 40%
difference in pain reduction between groups, it was necessary to recruit
eighty symptomatic tendons for the trial (SigmaStat 2.0; Jandel Scientific,
San Rafael, California). The diagnosis of noninsertional Achilles tendinopathy
was based on a history of an insidious onset of Achilles tendon pain, a tender
nodule localized to the region 2 to 6 cm from the calcaneal insertion, and an
ultrasound examination that excluded a frank tendon tear. All subjects were
required to be more than eighteen years old. The exclusion criteria included
Achilles tendinopathy of less than three months' duration, current pregnancy,
a previous operation on or dislocation of the affected ankle or leg, distal
neurological signs, and a local corticosteroid injection during the previous
three months.
Sixty-five patients (eighty-four tendons) with a clinical diagnosis of
Achilles tendinopathy were recruited through newspaper advertisements and
private consulting rooms and were randomly allocated into two groups. One
group received the active transdermal patch (one-quarter of a Nitro-Dur 5
glyceryl trinitrate patch; Schering-Plough, Baulkham Hills, New South Wales,
Australia), which delivered 1.25 mg of glyceryl trinitrate every twenty-four
hours, and the other group received a placebo transdermal patch (one-quarter
of a Nitro-Dur demonstration patch; Schering-Plough). The randomization was
controlled by the senior pharmacist at our institution, who also supervised
the packaging of transdermal patches and their distribution to patients. Both
the patients and the clinical examiner were blinded with regard to the groups
to which patients had been assigned.
The transdermal patches were intact when distributed, and patients were
required to cut the patches into quarters prior to application. Patients were
also given a supply of twenty-four paracetamol tablets (500 mg) and were
instructed to use them exclusively for any headaches that they
experienced.
Patients were instructed in the application of the patches at the time of
their initial visit. They were informed that the dosing regimen called for
one-quarter of a transdermal patch to be applied daily to the affected
Achilles tendon. Each quarter patch was to be left in situ for twenty-four
hours and then was to be replaced with a new quarter patch. The patches were
to be applied over the site of maximal tenderness in the region 2 to 6 cm from
the calcaneal insertion, and the patients were instructed to rotate the
application site around this point with each new patch application for the
six-month duration of the study in an attempt to minimize irritation at the
site.
At the initial clinical assessment, all patients were instructed in the
performance of a tendon rehabilitation program. This program was designed to
encompass our current methods of nonoperative treatment of Achilles
tendinopathy and involved (1) rest from aggravating activities (particularly
repetitive weight-bearing activities such as walking, running, and jumping) in
the early stages, (2) the use of 1 to 1.5-cm heel-raise wedges, (3) prolonged
daily static stretching of the gastrocnemius and soleus musculature, and (4)
an eccentric calf muscle-strengthening program.
At the initial visit and at all subsequent visits, the patient was required
to complete an Achilles tendinopathy symptom-assessment sheet that involved
the use of verbal descriptor scales to rate the severity of Achilles pain with
activity, at rest, and at night. The pain was rated as absent (0 points), mild
(1 point), moderate (2 points), severe (3 points), or very severe (4 points).
This verbal descriptor questionnaire has been validated as a reliable measure
of monitoring pain that is responsive to clinical
change17.
A single examiner (J.A.P.) assessed the patient and recorded (1) the degree
of Achilles tendon tenderness as assessed with use of a five-point scale
(none, mild, moderate, severe, or very severe), (2) the severity of pain after
the single-leg stationary ten-hop test as rated verbally by the patient on a
scale of 0 to 10 (with 0 representing no pain and 10 representing the worst
pain that the patient had ever experienced), (3) the ankle plantar flexor mean
peak force as assessed with use of a resisted footplate device (the
Orthopaedic Research Institute-Ankle Strength Testing
System)18, and (4)
total ankle plantar flexor work as assessed with use of the Orthopaedic
Research Institute-Ankle Strength Testing System. For the resisted footplate
test, the subject was seated with the foot secured to the footplate and then
was required to perform a twenty-second effort of repeated ankle plantar
flexion and dorsiflexion. The footplate was linked to a load-cell, and the
readings were stored directly on a computer hard drive.
All clinical assessments were repeated at zero, two, six, twelve, and
twenty-four weeks with an identical format. Data on headaches, paracetamol
use, and compliance with patch application and the tendon rehabilitation
program were also recorded at these scheduled visits.
The symptoms and signs that were used as outcome measures for assessing the
response to treatment in this clinical trial included patient-rated Achilles
tendon pain at rest (0 to 4 points), patient-rated Achilles tendon pain with
activity (0 to 4 points), patient-rated Achilles tendon pain at night (0 to 4
points), local Achilles tendon tenderness (0 to 3 points), Achilles tendon
pain after the ten-hop test (0 to 10 points), and ankle plantar flexor mean
peak force and mean total work as measured with the Orthopaedic Research
Institute-Ankle Strength Testing System and calculated with use of LabView 5.1
biomechanical software (National Instruments, Austin, Texas).
Outcome measures were analyzed with SigmaStat 2.0 statistical software
(Jandel Scientific). The Mann-Whitney ranksum test was used to compare
differences between groups, and the Wilcoxon signed-rank test was used to
compare differences within the groups. The level of significance was set at p
< 0.05. A chi-square analysis of patient-reported outcome measures was
performed at twenty-four weeks. Estimates of effect size were calculated by
dividing the mean z-score, calculated from all outcome measures, at
twenty-four weeks by the square root of the sample size to give a general
measure of the overall effect of the patch on pain, tendon force, and
function19.
The study group included forty men and twenty-five women with a median age
of forty-nine years (range, twenty-four to seventy-seven years). Nineteen
patients had bilateral disease. In total, fifty-four patients were right-foot
dominant, with twenty patients having involvement of the dominant side,
twenty-one having involvement of the nondominant side, and thirteen patients
having bilateral involvement. Eleven patients were left-foot dominant, with
three patients having involvement of the dominant side, two having involvement
of the nondominant side, and six having bilateral involvement. The median
duration of symptoms before the study was sixteen months (range, four to 147
months).
Of the sixty-five patients who were originally recruited for the clinical
trial, thirty-two patients (forty-one tendons) were assigned to the glyceryl
trinitrate group and thirty-three patients (forty-three tendons) were assigned
to the placebo group. It was necessary to discontinue treatment for four
patients during the course of the study because of side effects, which
included severe and persistent headaches (one patient) and a rash at the patch
application site (three patients). Three of these patients (including the one
patient with headaches and two of the three patients with a rash) were in the
glyceryl trinitrate group, and one patient (the third patient with a rash) was
in the placebo group.
In the glyceryl trinitrate group, two of the remaining twenty-nine patients
dropped out of the clinical trial at the two-week stage; no reason was given.
Thus, twenty-seven patients (thirty-six Achilles tendons) in the glyceryl
trinitrate group had at least six months of follow-up. In the placebo group,
one of the remaining thirty-two patients dropped out of the study at the
four-week stage; no reason was given. Thus, thirty-one patients (forty-one
Achilles tendons) in the placebo group had at least six months of follow-up.
There were no significant differences between the two treatment groups with
regard to demographic characteristics (age, sex, dominant foot, or duration of
symptoms) or the dropout rate (p = 0.16; 95% confidence interval, 0.08 to
0.25).
Analysis of the clinical trial outcome measures demonstrated that the data
were not normally distributed. The Mann-Whitney rank-sum test revealed a
significant decrease in Achilles tendon pain with activity when the glyceryl
trinitrate group was compared with the placebo group at twelve weeks (mean
score, 0.9 compared with 1.6; p = 0.02) and at twenty-four weeks (mean score,
0.4 compared with 1; p = 0.03) (Fig.
1).
A significant decrease in Achilles tendon pain at night was observed when
the glyceryl trinitrate group was compared with the placebo group at twelve
weeks (mean score, 0.2 compared with 0.7; p = 0.04, Mann-Whitney rank-sum
test) (Fig. 2).
A significant decrease in Achilles tendon tenderness was observed when the
glyceryl trinitrate group was compared with the placebo group at twelve weeks
(mean score, 0.9 compared with 1.6; p = 0.02, Mann-Whitney rank-sum test)
(Fig. 3).
The Mann-Whitney rank-sum test showed a significantly greater increase in
plantar flexor mean total work from the baseline level (as assessed with the
Orthopaedic Research Institute-Ankle Strength Testing System) when the
glyceryl trinitrate group was compared with the placebo group at twenty-four
weeks (mean, 70.3 compared with 43 N; p = 0.04)
(Fig. 4). There had been a
significant difference between the glyceryl trinitrate group and the placebo
group at zero weeks (mean, 179 compared with 220 N; p = 0.01), reflecting a
systematic bias in this particular outcome measure from the start of the
study.
A significant decrease in pain after the ten-hop test was observed when the
glyceryl trinitrate group was compared with the placebo group at twenty-four
weeks (mean score, 0.5 compared with 1.6; p = 0.005, Mann-Whitney rank-sum
test) (Fig. 5).
No significant differences between the groups were observed with regard to
pain at rest or with regard to peak force as assessed with the Orthopaedic
Research Institute-Ankle Strength Testing System.
A review of patient-reported outcomes at twenty-four weeks showed that 78%
(twenty-eight) of the thirty-six tendons in the glyceryl trinitrate group were
rated as excellent (indicating that the tendon was asymptomatic with
activities of daily living), 22% (eight) were rated as unchanged (indicating
worsening or improvement by <10%), and none were rated as poor (indicating
worsening by >10%). In comparison, 49% (twenty) of the forty-one Achilles
tendons in the placebo group were rated as excellent, 44% (eighteen) were
rated as unchanged, and 7% (three) were rated as poor.
Chi-square analysis revealed that the tendons in the glyceryl trinitrate
group had a significantly increased chance of being asymptomatic with
activities of daily living at twenty-four weeks (p = 0.001).
The mean estimated effect size at twenty-four weeks was 0.14 (95%
confidence interval, 0.09 to 0.19). This measure is derived from the mean p
value of all outcome measures at twenty-four weeks and is equivalent to a
binomial effect size display, or change in patient outcome success rate, of
14%. In other words, from an estimation of the size of the mean effect on
outcome measures at twenty-four weeks in the glyceryl trinitrate group, it
would be expected that the between-group difference in successful outcomes
(e.g., instances in which the tendon was asymptomatic at twenty-four weeks) is
14% of patients.
The reported and observed side effects in the glyceryl trinitrate group
included headache in 53% (seventeen) of the thirty-two patients, a rash in 16%
(five), and an increase in preexisting tinnitus in 3% (one). Seventy-six
percent of the headaches were experienced within the first two weeks. Fourteen
(44%) of the thirty-two patients experienced no side effects during the six
months of the clinical trial. The reported side effects in the placebo group
included headache in 45% (fifteen) of the thirty-three patients and a rash in
12% (four). Fifty-three percent of the headaches were experienced within the
first two weeks. These results are summarized in
Table I.
There was no significant difference between the two groups with regard to
the number of days on which patients were affected by headache. There was,
however, a significant increase in the amount of paracetamol required for the
treatment of headache in the glyceryl trinitrate group (p = 0.001).
In the glyceryl trinitrate group, seventeen patients experienced at least
one headache on a total of eighty-five days, which was equivalent to an
average of five days per patient (or 3% of the clinical trial days) among
those with this side effect. The median number of days associated with
headache was 3.5 (range, zero to eighteen). The patients who reported this
side effect required a total of 237 paracetamol tablets (500 mg) during the
course of the clinical trial. The average number of paracetamol tablets
required for headache over the six-month period was fourteen (median, ten;
range, zero to seventy-two).
In the placebo patch group, fifteen patients experienced at least one
headache on a total of 101 days, which was equivalent to an average of 6.7
days per patient (or 4% of the clinical trial days) among those with this side
effect. The median number of days associated with headache was three (range,
zero to forty-two). The patients who reported this side effect required a
total of forty-six paracetamol tablets (500 mg) during the course of the
clinical trial. The average number of paracetamol tablets required for
headache over the six-month period was three (median, zero; range, zero to
twenty).
This randomized, double-blind clinical trial showed that continuous topical
glyceryl trinitrate therapy can result in significantly decreased Achilles
tendon pain with activity and at night as well as decreased Achilles tendon
tenderness by twelve weeks. Seventy-eight percent of the tendons in the
glyceryl trinitrate group were asymptomatic with activities of daily living
and were rated as excellent after the six-month clinical trial. In comparison,
49% of the tendons in the placebo group were asymptomatic with activities of
daily living at twenty-four weeks. From these results, the number of patients
needed to treat in order to obtain a positive outcome can be calculated. For
every 3.4 patients treated with topical glyceryl trinitrate therapy, one will
have an excellent result at twenty-four weeks that would not have occurred
with placebo treatment.
The mean estimated effect size at twenty-four weeks was 0.14, which is
equivalent to a binomial effect size display, or change in patient success
rate, of 14%19.
This figure is less than the 29% improvement in patient-rated outcomes that
has been noted in association with topical nitric oxide therapy, and the
discrepancy is probably due to the method of calculating a mean effect size
from all recorded outcome measures.
These results are consistent with the hypothesis that topical glyceryl
trinitrate therapy can lead to significant improvement in symptomatic and
functional outcome measures at six months, beyond that achieved through tendon
rehabilitation alone.
Healing tendon, like most human soft tissue, relies on fibroblastic
production of collagen for
repair12,20.
Perhaps providing an exogenous source of nitric oxide to the degenerated
tendon can stimulate wound fibroblasts to increase collagen synthesis and
remodeling. Other potential mechanisms for symptomatic improvement in
tendinopathies include increased blood supply to the region as a result of
local vasodilation or increased clearance of local inflammatory mediators or
bioactive proteins such as substance P. There is also a possibility that
nitric oxide has an effect on neural structures, neovascularization, or
apoptosis at a local level that may modulate pain.
It should be emphasized that the use of transdermal glyceryl trinitrate
patches does not decrease the need for an Achilles tendon rehabilitation
program, which includes rest from aggravating activities, the use of 1.5-cm
heel-raise wedges, daily prolonged static stretching, and an eccentric
exercise program.
The Achilles tendon rehabilitation program that was used in this clinical
trial can be expected to provide an excellent result (such that the tendon is
asymptomatic with activities of daily living) approximately 49% of the time.
It should be noted that this rehabilitation program was home-based and was not
strictly controlled except through verbal checks of compliance at each
examination, but it still provided good results and led to increased tendon
strength and an increased ability to perform work at each testing period.
Given that the patients in this clinical trial had chronic Achilles
tendinopathy with a median duration of symptoms of sixteen months, the results
of tendon rehabilitation alone were encouraging. This finding indicates that a
structured, evidence-based tendon rehabilitation program, even if home-based
and unsupervised, can have a useful role in the treatment of Achilles
tendinopathy. Patient compliance was excellent, with no patient being excluded
because of lack of compliance; this may have been due to the thorough
explanation of the rehabilitation program (both verbal and written), the
regular examinations and checks of compliance, or the personalities of
patients who enroll in clinical trials.
The major side effects of this medication are headache, weakness or
dizziness (symptoms of hypotension), and local skin irritation or rash at the
application site21.
It is wise to exercise caution in the treatment of patients who have marked
anemia, those who are pregnant, those with known hypersensitivity to organic
nitrate drugs with prior episodes of hypotension, those who suffer from
migraine headaches, and those on diuretic therapy. It is important for
patients to maintain adequate hydration, and hence blood volume, during
nitrate therapy21.
Glyceryl trinitrate therapy is commonly used to treat ischemic heart disease,
and the use of this therapy for the treatment of tendinopathy requires
consultation with a cardiac physician. Patients who use other medications such
as Viagra (sildenafil citrate), a phosphodiesterase inhibitor, should not use
concomitant glyceryl trinitrate therapy because of the combined effects of
lowering blood pressure.
It was necessary to discontinue treatment for 9% (three) of the thirty-two
patients in the glyceryl trinitrate group because of the severity of side
effects, most notably a local rash (6%) and headache (3%). One patient also
noted an increase in her preexisting tinnitus. In the placebo group, treatment
was discontinued for one of thirty-three patients because of a rash. The
prevalence of headache was not significantly different between the two groups,
although the prevalence of reversible side effects that were severe enough to
warrant discontinuation of therapy was higher in the glyceryl trinitrate
group, as was the amount of paracetamol required to control headache. The
majority of headaches occurred within the first two weeks, probably because of
the development of tolerance to the vascular effects of glyceryl
trinitrate21,22.
Presumably, the mechanism of action on the Achilles tendon is not subject to
the same mechanics of tolerance, or the therapeutic effect of topical glyceryl
trinitrate on the tendon occurs prior to the development of tolerance.
Many topical therapies cause cutaneous lesions in patients with contact
allergies or sensitive skin, and this problem cannot be easily avoided. It is
known that transdermal glyceryl trinitrate absorption is variable across a
population, with a fivefold to tenfold individual
variability21, and
this may explain the differing severity of side effects such as headache in
our patients. Obviously, the use of glyceryl trinitrate therapy in patients
with concomitant ischemic heart disease requires careful planning in
consultation with a cardiac physician.
To our knowledge, the present study is the first clinical trial to show
patient and examiner-determined subjective and objective improvements in
outcomes among patients with Achilles tendinopathy. An unpublished randomized,
double-blind, placebo-controlled clinical
trial23
investigating the use of glyceryl trinitrate therapy (at a dosage of 1.25 mg
per twenty-four hours) for the treatment of chronic extensor tendinopathy of
the elbow showed improvements in terms of pain, tenderness, and wrist extensor
mean peak force and total force. Patient-rated outcomes at twenty-four weeks
showed that 81% of the tendons that had been treated with glyceryl trinitrate
were asymptomatic at six months, compared with 60% of those that had been
treated with rehabilitation alone (mean effect size, 0.12).
Clearly, more research needs to be done in this area to confirm the
validity and reproducibility of these results, to delineate the most effective
dosage regimen for maximizing effect and limiting side effects, to determine
the reason for treatment failure in the 29% of Achilles tendons that did not
improve, and to fully elucidate the role and effects of nitric oxide in tendon
healing and rehabilitation.
However, as glyceryl trinitrate is a well-tested medication in humans, and
as there are no irreversible side-effects in healthy subjects, there does
appear to be a role for continuous topical glyceryl trinitrate therapy,
combined with a comprehensive tendon rehabilitation program, in the treatment
of chronic Achilles tendinopathy.
Note: The authors thank Schering-Plough Australia for donating
the glyceryl trinitrate and placebo patches used in the clinical trial as well
as for the educational assistance to the lead author (J.A.P.).
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