Low-Level Laser Therapy for Fibromyalgia: A Systematic Review and Meta-Analysis

Abstract

Background:
Fibromyalgia is a chronic disorder characterized by widespread pain and tenderness. Low-level laser therapy (LLLT), an emerging nonpharmacological treatment, has been used for relieving musculoskeletal or neuropathic pain.

Objective:
The objective of this review and meta-analysis was to determine the efficacy of LLLT on patients with fibromyalgia.

Study design:
This study involved systematic review and quantitative meta-analysis of published randomized controlled trials (RCTs).

Setting:
This study examined all RCTs evaluating the effect of LLLT on fibromyalgia.

Methods:
We performed a systematic review and meta-analysis of RCTs evaluating the effect of LLLT on patients with fibromyalgia. PubMed, EMBASE, and the Cochrane Library were searched for articles published before August 2018. RCTs meeting our selection criteria were included. The methodological quality of the RCTs was evaluated according to the Cochrane risk-for-bias method. Review Manager version 5.3 was used to perform the meta-analysis. The primary outcomes were the total scores on the Fibromyalgia Impact Questionnaire (FIQ), pain severity, and number of tender points. The secondary outcomes were changes in fatigue, stiffness, anxiety, and depression. Standardized mean difference (SMD), 95% confidence intervals (CI), and P values were calculated for outcome analysis.

Results:
We identified 9 RCTs that included 325 fibromyalgia patients undergoing LLLT or placebo laser treatment with or without an exercise program. The meta-analysis showed that patients receiving LLLT demonstrated significantly greater improvement in their FIQ scores (SMD: 1.16; 95% CI, 0.64-1.69), pain severity (SMD: 1.18; 95% CI, 0.82-1.54), number of tender points (SMD: 1.01; 95% CI, 0.49-1.52), fatigue (SMD: 1.4; 95% CI, 0.96-1.84), stiffness (SMD: 0.92; 95% CI, 0.36-1.48), depression (SMD: 1.46; 95% CI, 0.93-2.00), and anxiety (SMD: 1.46; 95% CI, 0.45-2.47) than those receiving placebo laser. Furthermore, when compared with the standardized exercise program alone, LLLT plus the standardized exercise program provided no extra advantage in the relief of symptoms. On the other hand, the results of the only RCT using combined LLLT/LED phototherapy showed significant improvement in most outcomes except for depression when compared to placebo. When compared with pure exercise therapy, combined LLLT/LED phototherapy plus exercise therapy had additional benefits in reducing the severity of pain, number of tender points, and fatigue.

Limitations:
There were some limitations in this review, mostly because of the low-to-middle methodological quality of the selected studies; for example, there was no clear allocation process and only patients were blinded in most studies. In addition, one study used per-protocol analysis with a 20% loss to follow-up. On the other hand, the differences in laser types, energy sources, exposure times, and associated medication status in these studies may have resulted in some heterogeneity.

Conclusions:
Our results provided the most up-to-date and relevant evidence regarding the effects of LLLT in fibromyalgia. LLLT is an effective, safe, and well-tolerated treatment for fibromyalgia.

Key words:
Low-level laser therapy, fibromyalgia, meta-analysis, FIQ, pain, tender points,exercise.

Full text

Background: Fibromyalgia is a chronic disorder characterized by widespread pain and tenderness.
Low-level laser therapy (LLLT), an emerging nonpharmacological treatment, has been used for
relieving musculoskeletal or neuropathic pain.
Objective: The objective of this review and meta-analysis was to determine the efficacy of LLLT
on patients with fibromyalgia.
Study Design: This study involved systematic review and quantitative meta-analysis of published
randomized controlled trials (RCTs).
Setting: This study examined all RCTs evaluating the effect of LLLT on fibromyalgia.
Methods: We performed a systematic review and meta-analysis of RCTs evaluating the effect of
LLLT on patients with fibromyalgia. PubMed, EMBASE, and the Cochrane Library were searched
for articles published before August 2018. RCTs meeting our selection criteria were included. The
methodological quality of the RCTs was evaluated according to the Cochrane risk-for-bias method.
Review Manager version 5.3 was used to perform the meta-analysis. The primary outcomes were
the total scores on the Fibromyalgia Impact Questionnaire (FIQ), pain severity, and number of
tender points. The secondary outcomes were changes in fatigue, stiffness, anxiety, and depression.
Standardized mean difference (SMD), 95% confidence intervals (CI), and P values were calculated
for outcome analysis.
Results: We identified 9 RCTs that included 325 fibromyalgia patients undergoing LLLT or
placebo laser treatment with or without an exercise program. The meta-analysis showed that
patients receiving LLLT demonstrated significantly greater improvement in their FIQ scores (SMD:
1.16; 95% CI, 0.64-1.69), pain severity (SMD: 1.18; 95% CI, 0.82-1.54), number of tender
points (SMD: 1.01; 95% CI, 0.49-1.52), fatigue (SMD: 1.4; 95% CI, 0.96-1.84), stiffness (SMD:
0.92; 95% CI, 0.36-1.48), depression (SMD: 1.46; 95% CI, 0.93-2.00), and anxiety (SMD: 1.46;
95% CI, 0.45-2.47) than those receiving placebo laser. Furthermore, when compared with the
standardized exercise program alone, LLLT plus the standardized exercise program provided no
extra advantage in the relief of symptoms. On the other hand, the results of the only RCT using
combined LLLT/LED phototherapy showed significant improvement in most outcomes except for
depression when compared to placebo. When compared with pure exercise therapy, combined
LLLT/LED phototherapy plus exercise therapy had additional benefits in reducing the severity of
pain, number of tender points, and fatigue.
Limitations: There were some limitations in this review, mostly because of the low-to-middle
methodological quality of the selected studies; for example, there was no clear allocation process
and only patients were blinded in most studies. In addition, one study used per-protocol analysis
with a 20% loss to follow-up. On the other hand, the differences in laser types, energy sources,
exposure times, and associated medication status in these studies may have resulted in some
heterogeneity.
Conclusions: Our results provided the most up-to-date and relevant evidence regarding
the effects of LLLT in fibromyalgia. LLLT is an effective, safe, and well-tolerated treatment for
fibromyalgia.
Key words: Low-level laser therapy, fibromyalgia, meta-analysis, FIQ, pain, tender points,
exercise
Pain Physician 2019: 22:241-254
Systematic Review
Low-Level Laser Therapy for Fibromyalgia: A
Systematic Review and Meta-Analysis
From: 1School of Medicine,
Taipei Medical University,
Taipei, Taiwan; 2Institute of
Epidemiology and Preventive
Medicine, College of Public
Health, National Taiwan
University; 3Cochrane Taiwan,
Taipei Medical University, Taipei,
Taiwan; 4Center for Evidence-
Based Health Care, Taipei
Medical University - Shuang Ho
Hospital, New Taipei City, Taiwan;
5Division of General Surgery,
Department of Surgery, School of
Medicine, College of Medicine,
Taipei Medical University, Taipei,
Taiwan; 6Division of General
Surgery, Department of Surgery,
Shuang Ho Hospital, Taipei
Medical University, New Taipei
City, Taiwan; 7Department of
Neurology, Shuang Ho Hospital,
Taipei Medical University, New
Taipei City, Taiwan; 8Department
of Neurology, School of
Medicine, College of Medicine,
Taipei Medical University,
Taipei, Taiwan; 9Department of
Neurology, Taipei Neuroscience
Institute, Taipei Medical
University, Taipei, Taiwan
Address Correspondence:
Yi-Chun Kuan, MD
Department of Neurology, Taipei
Medical University-Shuang Ho
Hospital, 291 Zhongzheng Rd,
Zhonghe District, New Taipei
City, 23561, Taiwan
E-mail: yckuang2@gmail.com
Disclaimer: Shu-Wei Yeh and
Chien-Hsiung Hong contributed
equally to this study. There
was no external funding in the
preparation of this manuscript.
Conflict of interest: Each author
certifies that he or she, or a
member of his or her immediate
family, has no commercial
association (i.e., consultancies,
stock ownership, equity interest,
patent/licensing arrangements,
etc.) that might pose a conflict of
interest in connection with the
submitted manuscript.
Manuscript received: 09-27-2018
Revised manuscript received:
10-06-2018
Accepted for publication:
11-05-2018
Free full manuscript:
www.painphysicianjournal.com
Shu-Wei Yeh, MD1, Chien-Hsiung Hong, MD1, Ming-Chieh Shih, MD2, Ka-Wai Tam, MD, PhD3-6,
Yao-Hsien Huang, MD4,7,8, and Yi-Chun Kuan, MD2-4,7-9
www.painphysicianjournal.com
Pain Physician 2019; 22:241-254 • ISSN 1533-3159

Pain Physician: May/June 2019: 22:241-254
242 www.painphysicianjournal.com
ing the use of LLLT in fibromyalgia. On the other hand,
since exercise therapies or physical therapies have been
proven to be beneficial to patients with fibromyalgia,
we also used meta-analysis to compare the effective-
ness of a standardized exercise program plus LLLT with
a standardized exercise program alone.
Methods
Selection Criteria
We reviewed RCTs evaluating the efficacy of LLLT
for fibromyalgia. We included trials that (a) compared
the results of LLLT and placebo laser therapy in patients
with fibromyalgia; (b) described the inclusion and ex-
clusion criteria for patient selection; and (c) reported
power, wavelength, and laser exposure duration. We
excluded trials that used a class IV laser because laser
class ≤ IIIB is considered therapeutic, whereas a class IV
laser causes tissue destruction. Furthermore, trials with
laser treatment focusing only on one joint or a specific
region of the body were excluded.
Search Strategy and Study Selection
We searched PubMed, EMBASE, and the Cochrane
Library for studies on fibromyalgia. The following MeSH
terms and Boolean operator were used: fibromyalgia
AND (laser OR low-level laser OR photobiomodulation
OR phototherapy). The “Related Articles” option in
PubMed was used to broaden the search. We applied no
language restrictions. The final search was performed
in August 2018. We selected studies on the basis of
the titles and abstracts meeting the selection criteria.
The systematic review described here was accepted by
PROSPERO, the online international prospective regis-
ter of systematic reviews of the National Institute for
Health Research (CRD42017079531).
Data Extraction
Two authors (SWY and CHH) independently se-
lected RCTs and extracted the relevant details: number,
age, and gender of participants; inclusion and exclusion
criteria; laser strategies; and outcome parameters. The
individually-recorded information of both reviewers
was compared, and a third reviewer (YCK) resolved any
discrepancies.
Methodological Quality Appraisal
The 3 aforementioned reviewers independently
evaluated the methodological quality of the RCTs ac-
cording to the Cochrane risk-for-bias method (12).
Fibromyalgia is a chronic disorder characterized
by widespread pain and tenderness. Patients
with fibromyalgia often suffer from fatigue,
sleep disturbance, and memory problems (1).
Neurological complaints such as paresthesia, blurred
vision, numbness, and weakness are also commonly
seen (1,2). Its estimated prevalence is 2.1% to 5.3%
in the general population, with women experiencing
more severe symptoms. This syndrome typically occurs
in middle-aged adults, but it can develop in any age
group, including childhood, adolescence, as well as
in the elderly (1). Although the cause of fibromyalgia
is uncertain, central nervous system sensitization is
considered to be its major pathogenesis. External factors
such as infection, trauma, and stress may precipitate
it (1,2). No curative treatment for fibromyalgia is
available thus far. A combination of pharmacological
and nonpharmacological treatments is generally
recommended for adequate symptom relief (1). The US
Food and Drug Administration approved duloxetine
(Cymbalta), milnacipran (Savella), and pregabalin
(Lyrica) for treating fibromyalgia. Duloxetine and
milnacipran help control pain levels by changing
some of the brain neurotransmitters (serotonin and
norepinephrine), whereas pregabalin blocks the
overactivated neurons involved in pain transmission.
Physical exercise and cognitive behavior therapy are the
nonpharmacological options with stronger evidence
of efficacy in fibromyalgia (3,4). Other interventional
approaches with lower levels of evidence include
occipital nerve stimulation, lidocaine infusion, and
hyperbaric oxygen therapy (4).
Low-level laser therapy (LLLT) is an emerging,
noninvasive alternative treatment with some efficacy
in relieving musculoskeletal or neuropathic pain and
improving the quality of life (5-10). The mechanism
is believed to involve photochemical reactions, which
alter cell membrane permeability, increase messenger
RNA buildup, and lead to cell proliferation. The light
emitted during LLLT reacts with cytochrome c oxidase, a
respiratory enzyme in mitochondria, and increases ade-
nosine triphosphate (ATP) production and reduces reac-
tive oxygen species levels; this helps reduce cell inflam-
mation and death (11). Some randomized controlled
trials (RCTs) have investigated the efficacy of LLLT for
fibromyalgia. However, the results have been inconsis-
tent, with small sample sizes. Therefore, we conducted
a comprehensive systematic review and meta-analysis
of the effectiveness of LLLT in fibromyalgia, aiming to
contribute to evidence-based decision-making regard-

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Low-Level Laser Therapy for Fibromyalgia: A Systematic Review and Meta-Analysis
Several domains were evaluated: allocation generation
and concealment; blinding of patients, personnel, and
outcome assessor; incomplete outcome data (intention-
to-treat or per-protocol); and loss to follow-up rate.
Outcome Assessment
To logically and clearly perform the meta-analysis,
the outcome assessment comprised 2 sections. One sec-
tion pooled data from RCTs comparing LLLT with pla-
cebo to evaluate the benefits of LLLT. The other section
pooled data from RCTs comparing LLLT plus standard-
ized exercise with standardized exercise alone in order
to investigate whether applying the additional laser to
exercise therapies provides more benefits than exercise
alone.
In each section, we evaluated 3 primary outcomes,
namely improvement in the total Fibromyalgia Impact
Questionnaire [FIQ] scores (13), severity of pain, and
number of tender points; and 4 secondary outcomes,
namely improvement in fatigue, stiffness, anxiety, and
depression. The improvement in pain severity was as-
sessed by extracting the score of the subitem “pain”
from FIQ (0-10), using a 5-point Likert scale (0 = none,
1= mild, 2 = moderate, 3 = severe, and 4 = extreme), or
by using a visual analog scale (VAS) in cm. As for the
definition of tender points, points that were reported
by patients as being painful were regarded as tender
points; additional tender points were more rigorously
defined if patients felt pain at pressure less than or equal
to 2.6 kgf/cm2 while subject to an increasing pressure of
0.1 kgf/s via placement of an apparatus perpendicular
to the point to be evaluated (14). Improvements in fa-
tigue, stiffness, anxiety, and depression were assessed
using the subitem score of “fatigue” on the FIQ (0-10)
or on the Likert scoring system for grading, “stiffness”
on the FIQ and “morning stiffness” on the Likert scoring
system, “anxiety” on the FIQ, and “depression” on the
FIQ, respectively. In some cases, depression was assessed
by a psychiatrist according to the Hamilton Depression
Rating Scale (HDRS) (15,16), DSM-IV criteria (17), or the
Beck Depression Inventory (18).
Statistical Analysis
We used RevMan 5.3 (The Nordic Cochrane Center
for The Cochrane Collaboration, Copenhagen, Denmark)
to perform the meta-analysis of the RCTs according to
the PRISMA (Preferred Reporting Items for Systematic
Reviews and Meta-Analysis) guidelines (19). The stan-
dardized mean difference (SMD) was calculated as the
effect size for continuous outcomes. The accuracy of the
result was reported as a 95% confidence interval (CI). P
< 0.05 was considered significant. When necessary, the
means and standard deviations of pretreatment-post-
treatment changes were estimated according to the
reported pretreatment and posttreatment data (20).
Due to possible heterogeneity between each study, the
DerSimonian and Laird random-effects model was used
for calculating a pooled estimate of the mean differ-
ence (21). The I-square test was performed to assess the
heterogeneity among these trials.
Results
Study Selection and Characteristics of
Included Studies
Figure 1 illustrates a flowchart of the study se-
lection process. We initially identified 305 potential
trials but excluded 105 duplicates and 97 ineligible
articles after screening their titles and abstracts. Sub-
sequently, 103 additional reports were excluded as
follows: 55 were on different topics, 14 used different
comparisons, 14 were review articles, 6 were systematic
reviews, 3 were protocols, 1 was a cohort study, and
1 was a case study. Finally, the remaining 9 RCTs were
further analyzed.
The characteristics of these eligible studies (14,22-
29) are summarized in Table 1. These 9 RCTs were pub-
lished between 2002 and 2018, with sample sizes of 20
to 80 patients. The mean participant age ranged from
29 to 52 years; however, an earlier trial in 2002 by Gür
et al (29) did not offer any information on age. Most
RCTs only included women, except that the trial by Gür
et al (28) enrolled some male patients and the trial by
Ruaro et al (24) enrolled one man in the placebo group.
All patients had been diagnosed with fibromyalgia.
For patient diagnosis, 6 RCTs (14,22,24,27-29) used the
American College of Rheumatology’s diagnostic criteria
(30), one (23) used the American Rheumatology Society’s
criteria, and the diagnostic criteria were not mentioned
in 2 RCTs (25,26). Patients continued their usual pharma-
cological therapy in one RCT (22), whereas 3 RCTs did
not mention whether the patients were taking medica-
tion concurrently (24-26), some of the patients in one
RCT continued their regular medication for fibromyalgia
(14), and the remaining 4 claimed that no patients took
analgesic, anti-inflammatory medications or central ner-
vous system drugs during the study period.
Regarding laser parameters, 6 RCTs (23,24,26-29)
used GaAlAs or Ga-AS laser, one (25) used Girlase, one
RCT employed a 9-diode cluster device containing mul-

Pain Physician: May/June 2019: 22:241-254
244 www.painphysicianjournal.com
Fig. 1. Flow chart of the process of study selection.
tiple light sources (LLLT and light-emitting diode [LED])
(22), and the latest RCT used a DMC® Photon Laser III de-
vice (14). Therefore, we performed a subgroup analysis
to differentiate the efficacy of monowavelength LLLT
vs an LLLT/LED combination. Laser wavelength ranged
from 640 to 950 nm and power from approximately
0.9 to 1000 MW. The follow-up period of the 8 RCTs
ranged from 2 to 10 weeks; one RCT further followed
for 6 months. Five studies (24,25,27-29) involving 173
patients evaluated the effectiveness of LLLT by com-
paring with placebo laser. Three RCTs compared LLLT
plus stretching exercise with stretching exercise alone
(14,23,26). One RCT designated patients into 4 groups:
control group, phototherapy group, stretching and
aerobic exercise training group, and phototherapy plus
stretching and aerobic exercise training group (22).
Study Quality
As shown in Table 2, the methodological quality of
9 RCTs was assessed (14,22-29). Five RCTs (14,22,24,28,29)
reported acceptable methods of randomization, but
none described allocation concealment methods. Eight
RCTs (14,22-25,27-29) reported patient blinding by ap-
plying placebo or sham laser treatment; the remaining
RCT (26) did not provide any relevant blinding informa-
tion. Three RCTs by Armagan et al (27), da Silva et al
(22) and Germano (14) blinded outcome assessors; da
Silva et al also blinded the phototherapy programmer.
Eight RCTs used an intention-to-treat analysis without
loss to follow-up. However, 20% of the patients with-
drew from one RCT (26) without reporting the reason,
so per-protocol analysis was used for that study. One
RCT reported higher variability of emitted power and
energy dose of laser (26).
Comparison of LLLT and Placebo LLLT
Primary Outcome (FIQ Score, Pain, and Number of
Tender Points)
The meta-analysis showed significant improve-
ment in FIQ score after monowavelength LLLT than
that after placebo laser treatment (pooled SMD: 1.16;
95% CI, 0.64-1.69; I2 = 47%; Fig. 2). The severity of pain
was also significantly reduced in the monowavelength
LLLT group (pooled SMD: 1.18; 95% CI, 0.82-1.54, I2 =
0%; Fig. 3) compared with the placebo groups. A sig-
nificant decrease in the number of tender points after
monowavelength LLLT was also noted (SMD: 1.01; 95%

Table 1. Characteristics of the selected RCTs.
Study Inclusion
Criteria
No. of
Patients Age (yrs) Intervention Outcomes
Germano
(14), 2018
(Brazil)
Diagnosed with
FM by ACR
criteria
I: 11 (0%)
C: 11 (0%)
I: 39.73 ± 5.25
C: 40.36 ± 7.24
I: functional exercise program (40 to 60 min/
session) associated with active phototherapy
(808 nm, 100 mW, continuous, 4 J, and 142.85
J/cm2 on 17 tender points immediately after
exercise, 40 s/site 3 times/wk) x 8 wks
C: functional exercise program (40 to
60 min/session) associated with placebo
phototherapy (3 times/wk) x 8 wks
FIQ, VAS, no. of tender
points, Beck Depression
Inventory, pain
threshold, functional
performance, muscle
performance (flexibility,
strength)
da Silva (22),
2018 (Brazil)
Diagnosed as
FM by ACR
criteria on FIQ
for > 5 yrs, ≥ 35
y/o women
I: 20 (0% a)
C1: 20 (0%)
C2: 20 (0%)
C3: 20 (0%)
Overall:
40 ± 2
I: Phototherapy (a cluster with 9 diodes-1
super-pulsed infrared 905 nm, 4 LED of 640
nm, 4 LED of 875 nm, 39.3 J & 5 min/point x
10 sites) x 10 wks
C1: Placebo phototherapy x 10 wks
C2: Phototherapy + exerciseb x 10 wks
C3: Placebo phototherapy + exerciseb x 10 wks
FIQ, VAS, fatigue, body
stiffness, no. of tender
points, depression,
anxiety, SF-36;
(10 wks)e
Vayvay
(23), 2016
(Turkey)
Diagnosed with
FM by ARS
criteria, ≥18
y/o, continuous
chronic pain ≥
6 mos
I: 15 (0%)
C1: 15 (0%)
C2: 15 (0%)c
I: 36.4 ± 8.3
C1: 38 ± 8.4
C2: 38 ± 9.9 c
I: Ga-AS Laser (850 nm; 40 mW; 2 J/cm2; 50-
60 Hz, 3 min/painful point on back and head)
+ exercise x 3 wks
C1: Placebo laser + exercised x 3 wks
C2: Kinesiotape on the back for 3 wks +
exercised x 3 wks
FIQ, VAS, SF-36, Beck
Depression Inventory
Anxiety Level (3 wks)
Ruaro (24),
2014 (Brazil)
Diagnosed with
FM by ACR
criteria
I: 10 (0%)
C: 10 (10%)
I: 39.4 (34-45)
C: 43.4 (33-55)
I: GaAlAs laser (670 nm, 20 mW, 4 J/cm2 on
18 tender points, 3 times/wk) x 4 wks
C: Placebo laser x 4 wks
FIQ, McGill Pain
Questionnaire, VAS (4
wks)
Fernández
(25), 2011
(Spain)
Diagnosis of FM
for 3-10 yrs, 36-
61 y/o woman
I: 16 (0%)
C: 15 (0%)
I: 51.6 ± 6.18
C: 52.4 ± 5.88
I: Girlase E1.1010 (905 + 10 nm, 0.70 mJ/
drive, 1000 mW boost of the drives, pulsed, 1
min/frequency x 6 on 7 points) x 8 wks
C: Placebo laser x 8 wks
CRD (FIQ), Generalized
pain, fatigue (8 wks)
Matsutani
(26), 2007
(Brazil)
Diagnosed as
FM for 25-60
y/o, exclude
neoplasia
I: 10 (0%)
C: 10 (0%)
I: 44 (28-60)
C: 45 (31-57)
I: GaAlAs laser (830 nm, 3 J/m2, average 30
mW, continuous) + exercised 1 h BIW x 5 wks
C: Placebo laser + exercised 1 h BIW x 5 wks
FIQ, VAS, SF-36 (5 wks)
Amargan
(27), 2006
(Turkey)
Diagnosed with
FM by ACR
criteria
I: 16 (10%)
C: 16 (0%)
I: 38.9 ± 4.9
C: 37.6 ± 5.9
I: GaAlAs laser (830 nm, 50 mW, continuous,
1 min & 2 J/tender point), 5 days/wk x 2 wks
C: Placebo laser 5 days/wk x 2 wks
FIQ, no. of tender
points, morning
stiffness, VSGI
(2 wks)
Gür (28),
2002
(Turkey)
Diagnosed with
FM by ACR
criteria; exclude
major clinical
conditions other
than FM
I: 25 (20%)
C1: 25 (24%)
C2: 25 (16%)c
I: 30.4 ± 6.9
C1: 28.5 ± 6.3
C2: 30.1 ± 8.7c
I: Ga-As laser (904 nm, average 11.2 mW,
2 J/cm2, 2.8 kHz) 3 min/tender point every
afternoon x 2 wks (except weekend)
C1: Placebo laser x 2 wks
C2: Amitriptyline 10 mg at bedtime x 8 wksc
FIQ, depression (HDRS,
DSM-IV), pain, no.
of tender points,
morning stiffness, sleep
disturbance, fatigue (2
wks/6 mos)
Gür (29),
2002 (earlier
published)
(Turkey)
Diagnosed with
FM by ACR
criteria; exclude
major clinical
conditions other
than FM
I: 20 (0%)
C: 20 (0%)
Not mentioned I: Ga-As laser (904 nm, average 11.2 mW,
2 J/cm2, 2.8 kHz) 3 min/tender point every
afternoon x 2 wks (except weekends)
C: Placebo laser x 2 wks
Pain, morning stiffness,
no. of tender points,
sleep disturbance,
fatigue (2 wks)
Abbreviations: ACR, American College of Rheumatology; ARS, American Rheumatology Society; C, Control group; CRD, Cuaderno de re-
cogida de datos; FIQ, Fibromyalgia Impact Questionnaire; FM, Fibromyalgia; HDRS, Hamilton Depression Rating Scale; I, Intervention group;
LED, light-emitting diode; SF-36, 36-item Short-Form Health Survey; VAS, Visual Analog Scale of pain; VSGI, global improvement as reported
on a verbal scale. Age was presented as mean ± SD or mean (range). a (): % men; b stretching and aerobic exercise; c not included for our analy-
sis; d stretching; e (): duration of outcome follow-up
www.painphysicianjournal.com 245
Low-Level Laser Therapy for Fibromyalgia: A Systematic Review and Meta-Analysis

Table 2. Methodological quality assessment of the selected RCTs.
Study Allocation
Generation
Allocation
Concealment Blinding Data
Analysis
Loss to
Follow-up
Patient
Gender Other Relevant Remarks
Germano
(14), 2018
Adequate Unclear Patients,
evaluators
ITT 0% Only women Some patients continued regular
medications for fibromyalgia in
2 groups
da Silva (22),
2018
Adequate Unclear Patients,
phototherapy
programmer,
and outcome
assessor
ITT 0% Only women Age distribution not reported;
unknown pharmacological
therapy for fibromyalgia in 2
groups
Vayvay (23),
2016
Unclear Unclear Patients ITT 0% Only women -
Ruaro (24),
2014
Adequate Unclear Patients ITT 0% Only women,
with one man
in the placebo
group
Unknown pharmacological
therapy for fibromyalgia in 2
groups
Fernández
(25), 2011
Unclear Unclear Patients ITT 0% Only women Unknown pharmacological
therapy for fibromyalgia in 2
groups
Matsutani
(26), 2007
Unclear Unclear Unclear PP 20% Only women Unclear reasons for, and
unknown distribution of, loss
of follow-up; may have high
variability of emitted power
and energy dose; unknown
pharmacological therapy for
fibromyalgia in 2 groups
Armagan
(27), 2006
Unclear Unclear Patients and
evaluators
ITT 0% Only women -
Gür (28),
2002
Adequate Unclear Patients ITT 0% - -
Gür (29),
2002 (earlier
published)
Adequate Unclear Patients ITT 0% Only women Age distribution not reported
Abbreviations: ITT, intention to treat; PP, per-protocol; RCT, randomized controlled trial.
Pain Physician: May/June 2019: 22:241-254
246 www.painphysicianjournal.com
Fig. 2. Forest plot of changes in FIQ score after LLLT or placebo laser treatment.

Fig. 3. Forest plot of changes in pain severity after LLLT or placebo laser treatment.
Fig. 4. Forest plot of changes in number of tender points after LLLT or placebo laser treatment.
www.painphysicianjournal.com 247
Low-Level Laser Therapy for Fibromyalgia: A Systematic Review and Meta-Analysis
CI, 0.49-1.52; I2 = 49%; Fig. 4). As for the combined LLLT/
LED phototherapy, the only RCT evaluating efficacy
showed significant improvement in FIQ, pain, and num-
ber of tender points compared with the placebo group.
The effect of combined LLLT/LED phototherapy on pain
relief and reduction in the number of tender points
seemed to be more obvious than monowavelength
LLLT (Figs. 3 and 4).
Secondary Outcomes (Fatigue, Stiffness,
Depression, and Anxiety)
In the monowavelength LLLT group, our analysis
showed significant improvements in the severity of
fatigue (pooled SMD: 1.4; 95% CI, 0.96-1.8), stiffness
(pooled SMD: 0.92, 95% CI: 0.36-1.48), depression
(pooled SMD: 1.46, 95% CI: 0.93-2.00), and anxiety
(pooled SMD: 1.46, 95% CI, 0.45-2.47). On the other
hand, the only one RCT evaluating the efficacy of the
combined LLLT/LED phototherapy demonstrated signif-
icant improvement in the severity of fatigue, stiffness,
and anxiety, but not depression, when compared with
those in the placebo laser group.
Comparison of LLLT Plus Exercise and Placebo
Laser Treatment Plus Exercise
Three RCTs evaluated the efficacy of monowave-
length LLLT with exercise (14,23,26). There was no
significant difference between the monowavelength

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248 www.painphysicianjournal.com
Fig. 5. Forest plot of changes in severity of fatigue after LLLT or placebo laser treatment.
Fig. 6. Forest plot of changes in severity of stiffness difference after LLLT or placebo laser treatment.
Fig. 7. Forest plot of changes in severity of depression after LLLT or placebo laser treatment.

Fig. 9. Forest plot of changes in FIQ scores between LLLT with exercise and exercise alone.
www.painphysicianjournal.com 249
Low-Level Laser Therapy for Fibromyalgia: A Systematic Review and Meta-Analysis
Fig. 8. Forest plot of changes in severity of anxiety after LLLT or placebo laser treatment.
LLLT plus standardized exercise program and exercise
program alone in the primary outcomes of FIQ score
(pooled SMD: 0.34; 95% CI, -0.17 to 0.85; I² = 14%; Fig.
9), pain (pooled SMD: 0.46; 95% CI, -0.10 to 1.01; I² =
0%; Fig. 10) and number of tender points (pooled SMD:
0.59; 95% CI, -0.26 to 1.45; Fig. 11) and secondary out-
comes of fatigue, stiffness, anxiety, or depression (SMD:
-0.16; 95% CI, -1.04 to 0.72; SMD: 0.08; 95% CI, -0.79 to
0.96; SMD: 0.09; 95% CI, -0.80 to 0.98; I² = 70%; SMD:
-0.38; 95% CI, 1.27-0.50, respectively; Figs. 12-15).
Compared with standardized exercise alone, LLLT/
LED combination phototherapy plus exercise program,
as reported in only one RCT, provided significant ad-
ditional benefit in relieving the primary outcome
of the severity of pain and number of tender points
(SMD: 5.20; 95% CI, 3.85-6.55 and SMD: 7.02; 95% CI,
5.29-8.76, respectively) and the secondary outcome of
fatigue (SMD: 1.35; 95% CI, 0.65-2.04), but it not de-
crease in FIQ score, severity of stiffness, or psychiatric
symptoms (Figs. 9-15) (22).
Side Effects
Four RCTs (22,24,27,29) reported no side effects
of LLLT in patients with fibromyalgia, consistent with
previous studies (6,10,31). However, the remaining RCTs
did not report on side effects (14,23,25,26,28).
discussion
LLLT has been introduced as a noninvasive, thera-
peutic intervention for pain in several musculoskeletal
disorders. Some mechanisms, such as increased nocicep-
tive threshold, endorphin production, and downstream

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250 www.painphysicianjournal.com
Fig. 12. Forest plot of changes in severity of fatigue between LLLT with exercise and exercise alone.
Fig. 11. Forest plot of changes in number of tender points between LLLT with exercise and exercise alone.
Fig. 10. Forest plot of changes in severity of pain between LLLT with exercise and exercise alone.

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Low-Level Laser Therapy for Fibromyalgia: A Systematic Review and Meta-Analysis
Fig. 13. Forest plot of stiffness between laser with physical activity and physical activity only.
Fig. 14. Forest plot of depression between laser with physical activity and physical activity only.
Fig. 15. Forest plot of anxiety between laser with physical activity and physical activity only.

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opioid receptors, have been postulated to explain the
analgesic effect of phototherapy (32). Other hypoth-
eses include anti-inflammation due to a decrease in
prostaglandin-2 and cyclooxygenase-2 levels (28,32),
proliferation and neovascularization of connective tis-
sue cells (33,34), and increase in blood flow and promo-
tion of healing by increase in the levels of nitric oxide,
a powerful vasodilator (32). A recent systematic review
and meta-analysis of 18 studies suggested that LLLT
effectively reduces pain in adult patients with musculo-
skeletal disorders; however, patients with fibromyalgia
were not included in this meta-analysis (7). Further-
more, studies have indicated the beneficial role of LLLT/
LED combination in the treatment of nonspecific knee
pain (35) as well as masseter and temporalis muscle
pain in women with temporomandibular disorder (36).
Pain is the main symptom in patients with fibromy-
algia. Some RCTs have investigated the effect of LLLT
on fibromyalgia, but by using small sample sizes. Our
study is the first systematic review and meta-analysis
including 9 RCTs involving 325 patients to specifically
evaluate the efficacy of LLLT in fibromyalgia. Our
results demonstrated that LLLT provided significant
improvement in FIQ score, pain severity, number of ten-
der points, fatigue, stiffness, depression, and anxiety
compared to placebo. However, when compared with
pure exercise therapy, LLLT with exercise therapy did
not show more benefits. On the other hand, the single
RCT using LLLT/LED showed significant improvement in
the above-mentioned outcomes, except for depression,
when compared to placebo. When compared with pa-
tients with fibromyalgia who received exercise therapy,
combined LLLT/LED phototherapy and exercise therapy
had additional benefits in reducing the severity of pain,
number of tender points, and fatigue.
However, this review still has some limitations,
mostly because of the low-to-middle methodological
quality of the selected studies (Table 2). First, most stud-
ies did not report the allocation process clearly and only
blinded the patients; neither phototherapy program-
mer nor outcome assessor were blinded. Considering
that nearly all outcomes were subjective parameters,
the above shortcomings may introduce allocation bias,
performance bias, and detection bias. Second, one
study used per-protocol analysis because of a 20% loss
to follow-up without reporting the reasons for, or the
distribution of, the loss to follow-up (26); this may have
introduced attrition bias. Third, although LLLT was used
in all trials, the differences in laser types, energy sourc-
es, and exposure times used in the studies may have
resulted in some heterogeneity. Fourth, although pa-
tients with fibromyalgia did not take associated medi-
cations in most RCTs, patients in one trial maintained
their usual pharmacological therapies (22), another
trial included some patients continuing their regular
medications (14), and the other 3 RCTs did not men-
tion whether the participants were under concurrent
medication (24-26); therefore, we could not clarify the
separate roles of medication or phototherapy in fibro-
myalgia. Finally, long-term follow-up up to 6 months
was only conducted in one RCT (27).
In spite of the limitations, our study is the largest
systematic review and meta-analysis to evaluate the
efficacy of LLLT in patients with fibromyalgia, and it
has provided the most relevant available evidence on
LLLT for fibromyalgia. In conclusion, our data indicate
that LLLT is an emerging, noninvasive, well-tolerated
treatment for fibromyalgia to relieve discomfort, par-
ticularly in patients who do not exercise regularly.
Acknowledgments
We are grateful to Mariana Moreira da Silva and
all her coworkers for providing us with the raw data
of their original study “Randomized, blinded, con-
trolled trial on the effectiveness of photobiomodula-
tion therapy and exercise training in the fibromyalgia
treatment.” This enriched the content of our meta-
analysis and enhanced the power of evidence of LLLT.
This manuscript was edited by Wallace Academic
Editing.

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Low-Level Laser Therapy for Fibromyalgia: A Systematic Review and Meta-Analysis
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