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     ORIGINAL ARTICLE

A randomised, placebo controlled trial of low level laser
therapy for activated Achilles tendinitis with microdialysis
measurement of peritendinous prostaglandin E2
concentrations
J M Bjordal, R A B Lopes-Martins, V V Iversen
...............................................................................................................................

                                                                         Br J Sports Med 2006;40:76–80. doi: 10.1136/bjsm.2005.020842


                            Background: Low level laser therapy (LLLT) has gained increasing popularity in the management of
                            tendinopathy and arthritis. Results from in vitro and in vivo studies have suggested that inflammatory
                            modulation is one of several possible biological mechanisms of LLLT action.
                            Objective: To investigate in situ if LLLT has an anti-inflammatory effect on activated tendinitis of the human
                            Achilles tendon.
                            Subjects: Seven patients with bilateral Achilles tendinitis (14 tendons) who had aggravated symptoms
                            produced by pain inducing activity immediately before the study.
                            Method: Infrared (904 nm wavelength) LLLT (5.4 J per point, power density 20 mW/cm2) and placebo
                            LLLT (0 J) were administered to both Achilles tendons in random blinded order.
                            Results: Ultrasonography Doppler measurements at baseline showed minor inflammation through
See end of article for
authors’ affiliations       increased intratendinous blood flow in all 14 tendons and measurable resistive index in eight tendons of
.......................     0.91 (95% confidence interval 0.87 to 0.95). Prostaglandin E2 concentrations were significantly reduced
                            75, 90, and 105 minutes after active LLLT compared with concentrations before treatment (p = 0.026)
Correspondence to:
Dr Bjordal, Physiotherapy   and after placebo LLLT (p = 0.009). Pressure pain threshold had increased significantly (p = 0.012) after
Science, University of      active LLLT compared with placebo LLLT: the mean difference in the change between the groups was
Bergen, Bergen, Norway;     0.40 kg/cm2 (95% confidence interval 0.10 to 0.70).
jmbjor@broadpark.no
                            Conclusion: LLLT at a dose of 5.4 J per point can reduce inflammation and pain in activated Achilles
Accepted 1 July 2005        tendinitis. LLLT may therefore have potential in the management of diseases with an inflammatory
.......................     component.




O
        steoarthritis, tendinitis, and painful spinal disorders        peritendinous inflammation in normal and symptomatic
        are the most common musculoskeletal disorders in               tendons.26 27 Although some researchers have questioned
        modern society.1–4 A whole range of different treat-           the presence of inflammation in chronic tendinopathies,
ments such as locally applied or orally administered drugs,            others have shown that structural tendon damage and
electrotherapies, joint mobilisation techniques, exercise              ruptures correlate significantly with the degree of inflamma-
therapy, cognitive behavioural therapies, and alternative              tion.28–30 In addition, loading of tendon cells increased the
treatments are currently in use for these conditions.5–9 Non-          expression of cyclo-oxygenase 2 and the release of prosta-
steroidal anti-inflammatory drugs (NSAIDs) and steroid                 glandin E2 (PGE2) in vitro and peritendinous PGE2 concen-
injections have been the most prevalent form of treatment              trations in a human experimental model of healthy Achilles
for short term pain relief.10–12 Most treatments exhibit some          tendons.31 In healthy subjects, this activity induced release of
pain relieving effect against osteoarthritis and tendino-              PGE2 could be blocked by a cyclo-oxygenase 2 inhibitor
pathy.13 14 However, it is unclear whether any electrophysical         (celecoxib).27 Therefore microdialysis after activity induced
agents have anti-inflammatory effects. A review on the                 inflammation seems to be a suitable method for assessing the
biological effects of ultrasound therapy suggests that there is        anti-inflammatory effect of LLLT in humans.
no evidence that it has any major anti-inflammatory effect.15
For low level laser therapy (LLLT) two important biological            MATERIALS AND METHODS
responses have been targeted as possible mechanisms for its            Patient sample
beneficial clinical effects in clinical trials on tendinopathy         Patients were recruited through primary care doctors and
and osteoarthritis.16 17 The first possible biological response is     physiotherapists. Patients who sought help for their bilateral
a modulating, dose dependent effect on fibroblast metabo-              Achilles pain were targeted, and given the opportunity to
lism and collagen deposition. This response has been                   participate before standard treatment was started. Inclusion
observed in a broad range of controlled studies on cell                criteria were: signed written informed consent statement; age
cultures and animals.18–22 The second possible mechanism is            20–60 years; bilateral symptoms of pain and tenderness from
similar to that of NSAIDs and steroids. Controlled laboratory          the Achilles tendons that could be aggravated by some type of
trials have revealed that LLLT can reduce inflammation                 physical activity; willingness to perform the type of physical
through reduction of PGE2 concentrations and inhibition of             activity that by experience aggravated Achilles tendon pain;
cyclo-oxygenase 2 in cell cultures.23 24 This effect has also          pathological sonographic appearance of tendon thickening
been shown in an animal trial, but to our knowledge no study
has yet confirmed such an anti-inflammatory effect in                  Abbreviations: LLLT, low level laser therapy; NSAID, non-steroidal anti-
humans.25 Microdialysis is a technique used to assess                  inflammatory drug; PGE2, prostaglandin E2; RI, resistive index




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Laser therapy for Achilles tendinitis                                                                                                                                                          77


and structural alterations of tendon matrix. Exclusion criteria                             water. Syringes for both Achilles tendons were then placed in
were: systemic inflammatory disease; previous operations on                                 a syringe pump (CMA/100) and adjusted to give 2 ml/min.
Achilles tendons; pregnancy; mental inability to understand                                 Samples of the harvested fluid were collected every 15 min-
the consequences of participation; NSAID treatment during                                   utes. After a stabilisation period of 60 minutes, baseline
the preceding four weeks; steroidal treatment during the                                    levels were registered for another 60 minutes before laser
preceding six months; monogenic familial hypercholestero-                                   treatment was administered. PGE2 concentrations after
laemia (may cause Achilles tendon xanthomas).                                               treatment were recorded for 105 minutes. PGE2 concentra-
                                                                                            tion in the dialysate was analysed by a high sensitivity
Examination procedure and outcome measures                                                  Prostaglandin E2 Enzyme Immunoassay Kit (Electra-box
Each patient was examined by interview about symptom                                        Diagnostica AS, Stockholm, Sweden). The washing, the
characteristics, symptom duration, and specific activities that                             adding of substrate solutions and stop solutions, and the
caused aggravation of Achilles tendon symptoms. A physical                                  analyses were performed according to the manufacturers’
examination was then performed. After location of the most                                  specifications. For each well, the absorbance was read using a
painful spot identified by finger palpation, pressure pain                                  microplate reader (Spectramax; Molecular Devices,
threshold was measured as the average of three tests with                                   Sunnyvale, California, USA) set to 450 nm, with wavelength
pressure pain algometry. This test was performed by pressing                                control.
a circular metallic tip of area 1 cm2 with gradually increasing
force to the most painful spot of the tendon. The patient was                               Intervention
told to respond by saying ‘‘stop’’ when the feeling of pressure                             LLLT was administered by a GaAs laser with an infrared
changed to pain. Before the experiment, this test was checked                               wavelength of 904 nm (Irradia AB, Stockholm, Sweden) with
on healthy subjects for test-retest reliability; the intraclass                             a laser probe consisting of three laser diodes placed long-
correlation coefficient was 0.79 and standard deviation                                     itudinally 9 mm apart. On the laser probe, an A/B switch
0.39 kg/cm2, which is similar to other reliability studies for                              determined whether active or sham irradiation was given.
pressure pain threshold.32–34                                                               During operation the laser appeared identical for both active
   Functional ability was tested by measuring the mean                                      and sham irradiation, because of the invisible nature of the
distance of three repetitions reached in the single leg hop                                 infrared laser beam and the same blinking red diode and
test.35 Ultrasonography (Siemens Sonoline G60) was per-                                     descending time counter. The output of the laser averaged
formed to ensure the exact location of tendon pathology.                                    10 mW for each diode, which was tested and calibrated
Tendon thickness was measured using calibrated callipers,                                   before and after treatment for every patient by technical staff
and structural alteration of the tendon matrix was described.                               not otherwise involved in the experiment. The peak power for
Tendon vascularisation was examined by power Doppler. If                                    each laser pulse was 10 W and pulse duration was
possible, peritendinous or intratendinous arterial blood flow                               200 nanoseconds (1029 seconds), delivered by a frequency
velocity was also measured, as they can be used to detect                                   of 5000 Hz. The spot area was 0.5 cm2 giving a power density
signs of inflammation through the arterial resistive index                                  (fluence) of 20 mW/cm2. Each patient was treated for
(RI), which is a measure of vasodilatation and inflamma-                                    180 seconds, and the dose of active treatment was 1.8 J for
tion.36 RI is defined as: (systolic peak velocity minus end                                 each of three points along the Achilles tendons, giving a total
diastolic velocity)/systolic peak velocity. Values of less than 1                           of 5.4 J per tendon.
(normal) indicate inflammation.
   Microdialysis was performed by first giving a local                                      Blinding and randomisation procedure
anaesthetic injection (xylocaine, 20 mg/ml; AstraZeneca,                                    The trial was designed to achieve randomised concealed
Oslo, Norway) at the insertion site 30 mm cranially to the                                  allocation to groups and double blinding. As patients were
centre of pathology. After four to five minutes, the micro-                                 acting as their own controls, both Achilles tendons were
dialysis membrane (CMA/60, cut off 20 kDa, membrane                                         treated, but only one received active treatment. Which side
length 30 mm, outer diameter 0.6 mm; CMA, Stockholm,                                        should be treated with the laser probe in switch position A or
Sweden) was inserted into the peritendinous tissue parallel                                 B was decided for each patient by drawing one of 10 opaque
to the Achilles tendon. Insertion into the tissue is achieved                               envelopes containing a written character A or B (five of
with the help of a slit cannula introducer which leaves the
catheter in place when withdrawn. Before withdrawal of the
introducer, the position of the membrane was checked by
                                                                                                     PGE2 concentration relative to baseline




ultrasonography. The microdialysis membrane and tubes                                                                                          1.70
                                                                                                                                                              Laser
were then coupled to a syringe containing isotonic 0.9% salt                                                                                                  Placebo
                                                                                                                                               1.50

                                                                                                                                               1.30
                                           2.5
        Pain pressure threshold (kg/cm2)




                                                                               Laser                                                           1.10
                                                         1.66
                                             2                                 Placebo
                                                                      1.45
                                                                1.4
                                                                                                                                               0.90
                                           1.5    1.21


                                             1                               p = 0.012                                                         0.70

                                           0.5                               0.19                                                              0.50
                                                                                                                                                      1   2      3      4   5     6    7
                                             0                                                                                                            Time (15 minute intervals)
                                           –0.5                                     –0.21
                                                                                            Figure 2 Laser effect on inflammation as measured by prostaglandin E2
                                            –1                                              (PGE2) concentrations in peritendinous tissue. Mean post-treatment PGE2
                                                  Before         After       Change         concentrations and their respective 95% confidence intervals relative to
                                                                                            the mean pre-treatment baseline results are shown. Values were
Figure 1 Mean pressure pain thresholds of three recordings from each                        recorded at seven consecutive 15 minute intervals (total 165 minutes
tendon with their respective 95% confidence intervals grouped by                            after treatment), and the significant between-groups difference at the last
treatment allocation.                                                                       time point is indicated by an asterisk.




                                                                                                                                                                                www.bjsportmed.com
78                                                                                                          Bjordal, Martins-Lopes, Iversen


each). The A/B switch on the laser was then switched to the                  Single jump hop test
character drawn, and treatment started for the right leg first.              Because of the fragile microdialysis membrane and the
Thus the allocation of tendon to groups was concealed from                   importance of harvesting fluid meticulously, the single hop
patients, therapist, and observer. The code of the A/B switch                test could only be performed before and after microdialysis.
positions on the laser probe was only known to the technical                 Both groups showed a decrease in the single jump hop test
staff who calibrated the laser before and after each patient.                after treatment. However, the mean decrease was signifi-
The code was not broken until all treatments and analyses                    cantly less (p = 0.025) for the laser treated group (10.6 cm
were finished.                                                               (95% CI 3.5 to 17.7) than for the placebo group (18.4 cm
                                                                             (95% CI 12.3 to 24.5)).
Ethical approval
The experiments in this study were performed with the                        Ultrasound Doppler scanning
approval of, and in accordance with the regulations laid                     At baseline all 14 tendons exhibited increased peritendinous
down by, the regional ethics committee of Western Norway                     and intratendinous blood flow when assessed by colour
                                                                             Doppler in a relaxed position of ankle plantar flexion. At
(no 144/03). Participants gave signed informed consent.
                                                                             follow up, blood flow measured by colour Doppler seemed to
                                                                             have decreased in all tendons, but no arbitrary assessment
RESULTS                                                                      was performed. The decreased flow was thought to be a result
Randomisation procedure                                                      of the necessary physical inactivity in the experimental set
Four right side and three left side Achilles tendons were given              up.
active treatment.                                                               For power Doppler measurements of blood flow, velocity
                                                                             and RI could only be measured at baseline in eight tendons,
Pressure pain threshold                                                      five in the active LLLT group and three in the placebo LLLT
There was a small, but non-significant mean decrease                         group. The mean RI for these eight tendons indicated a
(20.05 kg/cm2) in the pressure pain threshold from the start                 small inflammatory reaction, with RI 0.91 (95% CI 0.87
                                                                             to 0.95) (fig 3). No significant differences between
of the observation period to immediately before treatment.
                                                                             groups were observed after treatment for any ultrasound
However, after treatment it had increased by 0.19 kg/cm2
                                                                             measures.
(95% confidence interval (CI) 0.04 to 0.34) in the laser group,
whereas a decrease of 20.21 kg/cm2 (95% CI +0.04 to 20.46)
was recorded for the placebo group from the start to the end                 Side effects and adverse reactions
the observation period. The mean difference in change was                    The experiment was well tolerated by all patients. Local
0.40 kg/cm2 (95% CI 0.10 to 0.70) (fig 1).                                   injection of analgesic (xylocaine) and placement of the
                                                                             microdialysis catheter caused minor transient pain at the
                                                                             time of insertion. Likewise, the application of the pressure
Inflammatory marker PGE 2 concentrations                                     pain algometer caused increased tenderness in the area of the
In the laser group, a small decrease in PGE2 concentration                   Achilles tendon, probably partly because of the repeated pain
was seen first one hour after treatment, and then gradually                  threshold pressure applications and partly because the effect
decreasing from baseline (1.0) to 0.72 (95% CI 0.58 to 0.86) at              of the local anaesthetic was tailing off. None of the patients
the last time point 105 minutes after treatment. For the                     experienced infections or other complications, and they all
placebo group, PGE2 concentrations increased gradually in                    reported that being bored was a greater problem than the
the period after treatment from baseline to 1.30 (95% CI 1.48                transient pain they experienced.
to 1.12) at the last observation. For the laser group, there was
a significant difference in both the pre-treatment and post-                 DISCUSSION
treatment means (p = 0.0269) and the difference in change                    To our knowledge, other physiotherapy methods have failed
between the groups (p = 0.0096) (fig 2).                                     to produce relevant anti-inflammatory effects in the labora-
                                                                             tory. In this trial, we show that LLLT can suppress
                                                                             inflammation, as measured by a reduction in the inflamma-
                                                                             tory marker PGE2. In addition, clinical indices of small,
                                                                             but significant improvements in pressure pain and single
                                                                             hop function were observed. The ultrasound measurements
                                                                             were not suitable for detecting differences at follow up
                                                                             mainly because the experimental set up, with hours of
                                                                             physical inactivity, reduces peripheral circulation to a
                                                                             minimum and impairs ultrasound measurements. Still, our
                                                                             baseline ultrasound results may be important for
                                                                             confirming both that pain was actually related to Achilles
                                                                             pathology and a small degree of inflammation was
                                                                             possibly present.37 We devised the protocol with prior pain
                                                                             inducing activity, and the ultrasound measurements of RI
                                                                             seem to suggest that a small inflammatory reaction had
                                                                             been induced. Our findings possibly contradict other
                                                                             claims that inflammation is not present in Achilles tendino-
                                                                             pathy.28 In our opinion, this is not a true contradiction, but
                                                                             rather an elaboration in the sense that inflammation may
                                                                             play a small, but important part in episodes of symptom
                                                                             aggravation. This question remains to be more thoroughly
Figure 3 Colour Doppler image of a transverse section of Achilles
tendon showing intratendinous blood vessels (right hand frame) and
                                                                             investigated.
power Doppler (left hand frame) assessment of intratendinous blood flow         The small increase in PGE2 concentration seen in both
velocity in systolic peak (26.1 cm/s) and diastolic end (2.8 cm/s), giving   active and placebo groups immediately after treatment was
a resistive index of 0.89, indicating minor inflammation.                    probably caused by a local reaction to the pressure pain



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Laser therapy for Achilles tendinitis                                                                                                                    79



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This work was supported by a grant from The Norwegian Research           28 Alfredson H, Lorentzon R. Chronic tendon pain: no signs of chemical
Council.                                                                    inflammation but high concentrations of the neurotransmitter glutamate.
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Competing interests: none declared                                          fibroblasts increases the production of prostaglandin E2 and levels of




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80                                                                                                                       Bjordal, Martins-Lopes, Iversen


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                                                                                       ..............    COMMENTARY                        ..............
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     Suppl 2005;72:21–4.                                                                                                            rtchow@bigpond.net.au




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A randomised, placebo controlled trial of low level laser therapy for activated Achilles tendinitis with microdialysis measurement of peritendinous prostaglandin E2 concentrations

  • 1. 76 ORIGINAL ARTICLE A randomised, placebo controlled trial of low level laser therapy for activated Achilles tendinitis with microdialysis measurement of peritendinous prostaglandin E2 concentrations J M Bjordal, R A B Lopes-Martins, V V Iversen ............................................................................................................................... Br J Sports Med 2006;40:76–80. doi: 10.1136/bjsm.2005.020842 Background: Low level laser therapy (LLLT) has gained increasing popularity in the management of tendinopathy and arthritis. Results from in vitro and in vivo studies have suggested that inflammatory modulation is one of several possible biological mechanisms of LLLT action. Objective: To investigate in situ if LLLT has an anti-inflammatory effect on activated tendinitis of the human Achilles tendon. Subjects: Seven patients with bilateral Achilles tendinitis (14 tendons) who had aggravated symptoms produced by pain inducing activity immediately before the study. Method: Infrared (904 nm wavelength) LLLT (5.4 J per point, power density 20 mW/cm2) and placebo LLLT (0 J) were administered to both Achilles tendons in random blinded order. Results: Ultrasonography Doppler measurements at baseline showed minor inflammation through See end of article for authors’ affiliations increased intratendinous blood flow in all 14 tendons and measurable resistive index in eight tendons of ....................... 0.91 (95% confidence interval 0.87 to 0.95). Prostaglandin E2 concentrations were significantly reduced 75, 90, and 105 minutes after active LLLT compared with concentrations before treatment (p = 0.026) Correspondence to: Dr Bjordal, Physiotherapy and after placebo LLLT (p = 0.009). Pressure pain threshold had increased significantly (p = 0.012) after Science, University of active LLLT compared with placebo LLLT: the mean difference in the change between the groups was Bergen, Bergen, Norway; 0.40 kg/cm2 (95% confidence interval 0.10 to 0.70). jmbjor@broadpark.no Conclusion: LLLT at a dose of 5.4 J per point can reduce inflammation and pain in activated Achilles Accepted 1 July 2005 tendinitis. LLLT may therefore have potential in the management of diseases with an inflammatory ....................... component. O steoarthritis, tendinitis, and painful spinal disorders peritendinous inflammation in normal and symptomatic are the most common musculoskeletal disorders in tendons.26 27 Although some researchers have questioned modern society.1–4 A whole range of different treat- the presence of inflammation in chronic tendinopathies, ments such as locally applied or orally administered drugs, others have shown that structural tendon damage and electrotherapies, joint mobilisation techniques, exercise ruptures correlate significantly with the degree of inflamma- therapy, cognitive behavioural therapies, and alternative tion.28–30 In addition, loading of tendon cells increased the treatments are currently in use for these conditions.5–9 Non- expression of cyclo-oxygenase 2 and the release of prosta- steroidal anti-inflammatory drugs (NSAIDs) and steroid glandin E2 (PGE2) in vitro and peritendinous PGE2 concen- injections have been the most prevalent form of treatment trations in a human experimental model of healthy Achilles for short term pain relief.10–12 Most treatments exhibit some tendons.31 In healthy subjects, this activity induced release of pain relieving effect against osteoarthritis and tendino- PGE2 could be blocked by a cyclo-oxygenase 2 inhibitor pathy.13 14 However, it is unclear whether any electrophysical (celecoxib).27 Therefore microdialysis after activity induced agents have anti-inflammatory effects. A review on the inflammation seems to be a suitable method for assessing the biological effects of ultrasound therapy suggests that there is anti-inflammatory effect of LLLT in humans. no evidence that it has any major anti-inflammatory effect.15 For low level laser therapy (LLLT) two important biological MATERIALS AND METHODS responses have been targeted as possible mechanisms for its Patient sample beneficial clinical effects in clinical trials on tendinopathy Patients were recruited through primary care doctors and and osteoarthritis.16 17 The first possible biological response is physiotherapists. Patients who sought help for their bilateral a modulating, dose dependent effect on fibroblast metabo- Achilles pain were targeted, and given the opportunity to lism and collagen deposition. This response has been participate before standard treatment was started. Inclusion observed in a broad range of controlled studies on cell criteria were: signed written informed consent statement; age cultures and animals.18–22 The second possible mechanism is 20–60 years; bilateral symptoms of pain and tenderness from similar to that of NSAIDs and steroids. Controlled laboratory the Achilles tendons that could be aggravated by some type of trials have revealed that LLLT can reduce inflammation physical activity; willingness to perform the type of physical through reduction of PGE2 concentrations and inhibition of activity that by experience aggravated Achilles tendon pain; cyclo-oxygenase 2 in cell cultures.23 24 This effect has also pathological sonographic appearance of tendon thickening been shown in an animal trial, but to our knowledge no study has yet confirmed such an anti-inflammatory effect in Abbreviations: LLLT, low level laser therapy; NSAID, non-steroidal anti- humans.25 Microdialysis is a technique used to assess inflammatory drug; PGE2, prostaglandin E2; RI, resistive index www.bjsportmed.com
  • 2. Laser therapy for Achilles tendinitis 77 and structural alterations of tendon matrix. Exclusion criteria water. Syringes for both Achilles tendons were then placed in were: systemic inflammatory disease; previous operations on a syringe pump (CMA/100) and adjusted to give 2 ml/min. Achilles tendons; pregnancy; mental inability to understand Samples of the harvested fluid were collected every 15 min- the consequences of participation; NSAID treatment during utes. After a stabilisation period of 60 minutes, baseline the preceding four weeks; steroidal treatment during the levels were registered for another 60 minutes before laser preceding six months; monogenic familial hypercholestero- treatment was administered. PGE2 concentrations after laemia (may cause Achilles tendon xanthomas). treatment were recorded for 105 minutes. PGE2 concentra- tion in the dialysate was analysed by a high sensitivity Examination procedure and outcome measures Prostaglandin E2 Enzyme Immunoassay Kit (Electra-box Each patient was examined by interview about symptom Diagnostica AS, Stockholm, Sweden). The washing, the characteristics, symptom duration, and specific activities that adding of substrate solutions and stop solutions, and the caused aggravation of Achilles tendon symptoms. A physical analyses were performed according to the manufacturers’ examination was then performed. After location of the most specifications. For each well, the absorbance was read using a painful spot identified by finger palpation, pressure pain microplate reader (Spectramax; Molecular Devices, threshold was measured as the average of three tests with Sunnyvale, California, USA) set to 450 nm, with wavelength pressure pain algometry. This test was performed by pressing control. a circular metallic tip of area 1 cm2 with gradually increasing force to the most painful spot of the tendon. The patient was Intervention told to respond by saying ‘‘stop’’ when the feeling of pressure LLLT was administered by a GaAs laser with an infrared changed to pain. Before the experiment, this test was checked wavelength of 904 nm (Irradia AB, Stockholm, Sweden) with on healthy subjects for test-retest reliability; the intraclass a laser probe consisting of three laser diodes placed long- correlation coefficient was 0.79 and standard deviation itudinally 9 mm apart. On the laser probe, an A/B switch 0.39 kg/cm2, which is similar to other reliability studies for determined whether active or sham irradiation was given. pressure pain threshold.32–34 During operation the laser appeared identical for both active Functional ability was tested by measuring the mean and sham irradiation, because of the invisible nature of the distance of three repetitions reached in the single leg hop infrared laser beam and the same blinking red diode and test.35 Ultrasonography (Siemens Sonoline G60) was per- descending time counter. The output of the laser averaged formed to ensure the exact location of tendon pathology. 10 mW for each diode, which was tested and calibrated Tendon thickness was measured using calibrated callipers, before and after treatment for every patient by technical staff and structural alteration of the tendon matrix was described. not otherwise involved in the experiment. The peak power for Tendon vascularisation was examined by power Doppler. If each laser pulse was 10 W and pulse duration was possible, peritendinous or intratendinous arterial blood flow 200 nanoseconds (1029 seconds), delivered by a frequency velocity was also measured, as they can be used to detect of 5000 Hz. The spot area was 0.5 cm2 giving a power density signs of inflammation through the arterial resistive index (fluence) of 20 mW/cm2. Each patient was treated for (RI), which is a measure of vasodilatation and inflamma- 180 seconds, and the dose of active treatment was 1.8 J for tion.36 RI is defined as: (systolic peak velocity minus end each of three points along the Achilles tendons, giving a total diastolic velocity)/systolic peak velocity. Values of less than 1 of 5.4 J per tendon. (normal) indicate inflammation. Microdialysis was performed by first giving a local Blinding and randomisation procedure anaesthetic injection (xylocaine, 20 mg/ml; AstraZeneca, The trial was designed to achieve randomised concealed Oslo, Norway) at the insertion site 30 mm cranially to the allocation to groups and double blinding. As patients were centre of pathology. After four to five minutes, the micro- acting as their own controls, both Achilles tendons were dialysis membrane (CMA/60, cut off 20 kDa, membrane treated, but only one received active treatment. Which side length 30 mm, outer diameter 0.6 mm; CMA, Stockholm, should be treated with the laser probe in switch position A or Sweden) was inserted into the peritendinous tissue parallel B was decided for each patient by drawing one of 10 opaque to the Achilles tendon. Insertion into the tissue is achieved envelopes containing a written character A or B (five of with the help of a slit cannula introducer which leaves the catheter in place when withdrawn. Before withdrawal of the introducer, the position of the membrane was checked by PGE2 concentration relative to baseline ultrasonography. The microdialysis membrane and tubes 1.70 Laser were then coupled to a syringe containing isotonic 0.9% salt Placebo 1.50 1.30 2.5 Pain pressure threshold (kg/cm2) Laser 1.10 1.66 2 Placebo 1.45 1.4 0.90 1.5 1.21 1 p = 0.012 0.70 0.5 0.19 0.50 1 2 3 4 5 6 7 0 Time (15 minute intervals) –0.5 –0.21 Figure 2 Laser effect on inflammation as measured by prostaglandin E2 –1 (PGE2) concentrations in peritendinous tissue. Mean post-treatment PGE2 Before After Change concentrations and their respective 95% confidence intervals relative to the mean pre-treatment baseline results are shown. Values were Figure 1 Mean pressure pain thresholds of three recordings from each recorded at seven consecutive 15 minute intervals (total 165 minutes tendon with their respective 95% confidence intervals grouped by after treatment), and the significant between-groups difference at the last treatment allocation. time point is indicated by an asterisk. www.bjsportmed.com
  • 3. 78 Bjordal, Martins-Lopes, Iversen each). The A/B switch on the laser was then switched to the Single jump hop test character drawn, and treatment started for the right leg first. Because of the fragile microdialysis membrane and the Thus the allocation of tendon to groups was concealed from importance of harvesting fluid meticulously, the single hop patients, therapist, and observer. The code of the A/B switch test could only be performed before and after microdialysis. positions on the laser probe was only known to the technical Both groups showed a decrease in the single jump hop test staff who calibrated the laser before and after each patient. after treatment. However, the mean decrease was signifi- The code was not broken until all treatments and analyses cantly less (p = 0.025) for the laser treated group (10.6 cm were finished. (95% CI 3.5 to 17.7) than for the placebo group (18.4 cm (95% CI 12.3 to 24.5)). Ethical approval The experiments in this study were performed with the Ultrasound Doppler scanning approval of, and in accordance with the regulations laid At baseline all 14 tendons exhibited increased peritendinous down by, the regional ethics committee of Western Norway and intratendinous blood flow when assessed by colour Doppler in a relaxed position of ankle plantar flexion. At (no 144/03). Participants gave signed informed consent. follow up, blood flow measured by colour Doppler seemed to have decreased in all tendons, but no arbitrary assessment RESULTS was performed. The decreased flow was thought to be a result Randomisation procedure of the necessary physical inactivity in the experimental set Four right side and three left side Achilles tendons were given up. active treatment. For power Doppler measurements of blood flow, velocity and RI could only be measured at baseline in eight tendons, Pressure pain threshold five in the active LLLT group and three in the placebo LLLT There was a small, but non-significant mean decrease group. The mean RI for these eight tendons indicated a (20.05 kg/cm2) in the pressure pain threshold from the start small inflammatory reaction, with RI 0.91 (95% CI 0.87 to 0.95) (fig 3). No significant differences between of the observation period to immediately before treatment. groups were observed after treatment for any ultrasound However, after treatment it had increased by 0.19 kg/cm2 measures. (95% confidence interval (CI) 0.04 to 0.34) in the laser group, whereas a decrease of 20.21 kg/cm2 (95% CI +0.04 to 20.46) was recorded for the placebo group from the start to the end Side effects and adverse reactions the observation period. The mean difference in change was The experiment was well tolerated by all patients. Local 0.40 kg/cm2 (95% CI 0.10 to 0.70) (fig 1). injection of analgesic (xylocaine) and placement of the microdialysis catheter caused minor transient pain at the time of insertion. Likewise, the application of the pressure Inflammatory marker PGE 2 concentrations pain algometer caused increased tenderness in the area of the In the laser group, a small decrease in PGE2 concentration Achilles tendon, probably partly because of the repeated pain was seen first one hour after treatment, and then gradually threshold pressure applications and partly because the effect decreasing from baseline (1.0) to 0.72 (95% CI 0.58 to 0.86) at of the local anaesthetic was tailing off. None of the patients the last time point 105 minutes after treatment. For the experienced infections or other complications, and they all placebo group, PGE2 concentrations increased gradually in reported that being bored was a greater problem than the the period after treatment from baseline to 1.30 (95% CI 1.48 transient pain they experienced. to 1.12) at the last observation. For the laser group, there was a significant difference in both the pre-treatment and post- DISCUSSION treatment means (p = 0.0269) and the difference in change To our knowledge, other physiotherapy methods have failed between the groups (p = 0.0096) (fig 2). to produce relevant anti-inflammatory effects in the labora- tory. In this trial, we show that LLLT can suppress inflammation, as measured by a reduction in the inflamma- tory marker PGE2. In addition, clinical indices of small, but significant improvements in pressure pain and single hop function were observed. The ultrasound measurements were not suitable for detecting differences at follow up mainly because the experimental set up, with hours of physical inactivity, reduces peripheral circulation to a minimum and impairs ultrasound measurements. Still, our baseline ultrasound results may be important for confirming both that pain was actually related to Achilles pathology and a small degree of inflammation was possibly present.37 We devised the protocol with prior pain inducing activity, and the ultrasound measurements of RI seem to suggest that a small inflammatory reaction had been induced. Our findings possibly contradict other claims that inflammation is not present in Achilles tendino- pathy.28 In our opinion, this is not a true contradiction, but rather an elaboration in the sense that inflammation may play a small, but important part in episodes of symptom aggravation. This question remains to be more thoroughly Figure 3 Colour Doppler image of a transverse section of Achilles tendon showing intratendinous blood vessels (right hand frame) and investigated. power Doppler (left hand frame) assessment of intratendinous blood flow The small increase in PGE2 concentration seen in both velocity in systolic peak (26.1 cm/s) and diastolic end (2.8 cm/s), giving active and placebo groups immediately after treatment was a resistive index of 0.89, indicating minor inflammation. probably caused by a local reaction to the pressure pain www.bjsportmed.com
  • 4. Laser therapy for Achilles tendinitis 79 REFERENCES What is already known on this topic 1 Felson DT, Lawrence RC, Dieppe PA, et al. Osteoarthritis: new insights. Part 1: the disease and its risk factors. Ann Intern Med 2000;133:635–46. 2 Mantyselka P, Kumpusalo E, Ahonen R, et al. Pain as a reason to visit the N Low level laser therapy has produced heterogeneous doctor: a study in Finnish primary health care. Pain 2001;89:175–80. results in clinical trials investigating musculoskeletal 3 Cherry NM, Meyer JD, Chen Y, et al. The reported incidence of work-related musculoskeletal disease in the UK: MOSS 1997–2000. Occup Med (Lond) pain 2001;51:450–5. N The mechanism underlying the positive results is not 4 Carmona L, Ballina J, Gabriel R, et al. The burden of musculoskeletal diseases in the general population of Spain: results from a national survey. Ann Rheum known Dis 2001;60:1040–5. 5 Jordan KM, Sawyer S, Coakley P, et al. 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Because of its 2003;32:239–44. rapid action and few side effects, more research is needed to 26 Langberg H, Skovgaard D, Karamouzis M, et al. Metabolism and inflammatory mediators in the peritendinous space measured by optimise treatment protocols particularly for inflammatory microdialysis during intermittent isometric exercise in humans. J Physiol arthritis. 1999;515:919–27. 27 Langberg H, Boushel R, Skovgaard D, et al. Cyclo-oxygenase-2 mediated prostaglandin release regulates blood flow in connective tissue during ACKNOWLEDGEMENTS mechanical loading in humans. J Physiol 2003;551:683–9. This work was supported by a grant from The Norwegian Research 28 Alfredson H, Lorentzon R. Chronic tendon pain: no signs of chemical Council. inflammation but high concentrations of the neurotransmitter glutamate. Implications for treatment? Curr Drug Targets 2002;3:43–54. ..................... 29 Ljung BO, Forsgren S, Friden J. Substance P and calcitonin gene-related peptide expression at the extensor carpi radialis brevis muscle origin: Authors’ affiliations implications for the etiology of tennis elbow. J Orthop Res 1999;17:554–9. J M Bjordal, V V Iversen, Physiotherapy Science, University of Bergen, 30 Li Z, Yang G, Khan M, et al. Inflammatory response of human tendon Bergen, Norway fibroblasts to cyclic mechanical stretching. Am J Sports Med R A B Lopes-Martins, University of Sao Paulo, Sao Paulo, Brazil ˜ ˜ 2004;32:435–40. 31 Wang JH, Jia F, Yang G, et al. Cyclic mechanical stretching of human tendon Competing interests: none declared fibroblasts increases the production of prostaglandin E2 and levels of www.bjsportmed.com
  • 5. 80 Bjordal, Martins-Lopes, Iversen cyclooxygenase expression: a novel in vitro model study. Connect Tissue Res 2003;44:128–33. .............. COMMENTARY .............. 32 Smidt N, van der Windt DA, Assendelft WJ, et al. Interobserver reproducibility of the assessment of severity of complaints, grip strength, and pressure pain threshold in patients with lateral epicondylitis. Arch Phys Med This study is of importance in that it provides direct evidence, Rehabil 2002;83:1145–50. for the first time in human volunteers, that low level laser 33 Maquet D, Croisier JL, Demoulin C, et al. Pressure pain thresholds of tender therapy (LLLT) with 904 nm laser reduces the production of point sites in patients with fibromyalgia and in healthy controls. Eur J Pain PGE2 after local, transcutaneous application for Achilles 2004;8:111–17. 34 Antonaci F, Sand T, Lucas GA. Pressure algometry in healthy subjects: inter- tendinitis. It adds significantly to other studies that have examiner variability. Scand J Rehabil Med 1998;30:3–8. shown a reduction in PGE2 in animal models and cell 35 Ageberg E, Zatterstrom R, Moritz U. Stabilometry and one-leg hop test have cultures. Several mechanisms have been proposed to explain high test-retest reliability. Scand J Med Sci Sports 1998;8:198–202. 36 Terslev L, Torp-Pedersen S, Qvistgaard E, et al. Estimation of inflammation by how pain is modulated by LLLT. This study provides Doppler ultrasound: quantitative changes after intra-articular treatment in additional support for an anti-inflammatory effect. Given rheumatoid arthritis. Ann Rheum Dis 2003;62:1049–53. the serious concerns with long term intake of NSAIDs, the 37 Ohberg L, Lorentzon R, Alfredson H. Eccentric training in patients with chronic potential for application of LLLT for Achilles tendinitis and Achilles tendinosis: normalised tendon structure and decreased thickness at follow up. Br J Sports Med 2004;38:8–11; discussion 11. inflammatory conditions, such as rheumatoid arthritis, is also 38 Fahlstrom M, Jonsson P, Lorentzon R, et al. Chronic Achilles tendon pain raised. Interestingly, this study suggests an inflammatory treated with eccentric calf-muscle training. Knee Surg Sports Traumatol component to Achilles tendinitis not previously recognised. Arthrosc 2003;11:327–33. LLLT for the management of Achilles tendinitis remains to be 39 Gur A, Cosut A, Sarac AJ, et al. Efficacy of different therapy regimes of low- power laser in painful osteoarthritis of the knee: a double-blind and established in clinical trials. Although the numbers are randomized-controlled trial. Lasers Surg Med 2003;33:330–8. limited, nevertheless, this study provides a model for further 40 Ottawa Panel Evidence-Based Clinical Practice Guidelines for Electrotherapy research. and Thermotherapy Interventions in the Management of Rheumatoid Arthritis in Adults. Phys Ther 2004;84:1016–43. 41 Li LC. What else can I do but take drugs? The future of research in R Chow nonpharmacological treatment in early inflammatory arthritis. J Rheumatol Castle Hill Medical Centre, Castle Hill, NSW, Australia; Suppl 2005;72:21–4. rtchow@bigpond.net.au www.bjsportmed.com