International Journal of Rheumatic Diseases 2016

ORIGINAL ARTICLE

Effect of intravenous lidocaine combined with amitriptyline

on pain intensity, clinical manifestations and the
concentrations of IL-1, IL-6 and IL-8 in patients with
fibromyalgia: A randomized double-blind study
Ana Laura ALBERTONI GIRALDES, Reinaldo SALOMAO,~ Plinio da Cunha LEAL,
Milena Karina Col
o BRUNIALTI and Rioko Kimiko SAKATA
Department of Anesthesia, Federal University of S~ao Paulo, S~ao Paulo, Brazil

Abstract
Aim: Regarding the use of intravenous lidocaine in fibromyalgia, there are no well-controlled studies. This study
aimed to evaluate the effect of intravenous lidocaine on pain intensity, clinical manifestations and plasma levels
of interleukin (IL)-1, IL-6, and IL-8 in fibromyalgia patients.
Methods: In a randomized double-blind study, group 1 patients received 240 mg of lidocaine in 125 mL of sal-
ine solution, while group 2 patients received 125 mL of saline, both once a week for 4 weeks (T1, T2, T3 and
T4). All patients received amitriptyline. The following were assessed: pain intensity before treatment (T0) and at
1, 2, 3, 4 and 8 weeks after treatment; clinical manifestations; the fibromyalgia impact questionnaire (FIQ)
before and at 4 and 8 weeks after; the levels of IL 1, 6 and 8 before and at 4 and 8 weeks after treatment.
Results: Lower pain intensity was observed in the lidocaine group at T2, with no difference at the other time
points. There was a reduction in pain intensity in both groups. The use of paracetamol and tramadol and plasma
levels of IL-1, IL-6 and IL-8 did not differ between the groups. Clinical manifestations and side effects did not
differ between groups.
Conclusions: The combination of 240 mg of intravenous lidocaine (once a week for 4 weeks) with 25 mg of
amitriptyline for 8 weeks had no meaningful impact in fibromyalgia patients.
Key words: fibromyalgia, interleukin 1, 6, 8, intravenous, lidocaine, neurotransmitters.

INTRODUCTION Fibromyalgia is difficult to control, and several treat-

Fibromyalgia is a syndrome characterized by wide-
spread pain, sleep and mood disorders and fatigue.1–5
Several mechanisms are involved in this syndrome,6–8
leading to central sensitization.7 Previous studies have
shown changes in certain interleukins (ILs), which may
be involved in pain, fatigue and depression.9
Correspondence: Dr Rioko K. Sakata, Rua Tr^es de Maio 61 apto 51;
Vila Clementino, S~ao Paulo, S~ao Paulo 04044-020, Brazil.
Email: rsakata@unifesp.br
ment modalities are used. Antidepressants, especially
amitriptyline, are the most common drug used in treat-
ment. Studies have shown that the infusion of lidocaine
promotes an analgesic effect.10,11 Nevertheless, there is
controversy in conditions without nerve damage. Previ-
ously our group studied intravenous lidocaine for
fibromyalgia patients, evaluating the symptoms12 and
serotonin, norepinephrine and dopamine concentra-
tions.13 Regarding the use of systemic lidocaine in
fibromyalgia, there are no well-controlled studies
assessing cytokines, which motivated the elaboration of
this study.

© 2016 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd
A. L. A. Giraldes et al.
Studies suggest that IL-1, IL-6 and IL-8 are altered in
fibromyalgia.9,14–16
The primary objective of this study was to evaluate
the effect of intravenous lidocaine on pain intensity
and the plasma levels of IL 1, 6 and 8 in patients with
fibromyalgia. The secondary objectives were to assess
changes in the clinical manifestations and in the
fibromyalgia impact questionnaire (FIQ) scores.
METHODS
This work was a prospective, randomized, double-blind
and placebo-controlled study.
Randomization was performed using Randomizerâ
software (Urbaniak & Plous, Lancaster, PA, USA). The
randomly selected groups were placed in numbered
envelopes. The envelopes were then randomly selected
on the day of administration of the solution to define
in which group each patient was included. The solution
was prepared by a nurse, and the researcher did not
know which treatment the patients were receiving.
Forty-two patients with fibromyalgia of both genders,
aged between 18 and 60 years, were included in the
study after approval by the Ethics Committee (number
1711/09) and signing the consent form. The inclusion
of the patients followed the American College of
Rheumatology (ACR) criteria.17 This study was regis-
tered in ClinicalTrials.Gov ID: NCT01391598.
Patients presenting the following features were
excluded from the study: abnormal laboratory tests;
trauma; known psychiatric, rheumatic, neuromuscular
or liver diseases; arrhythmia; heart failure, recent
myocardial infarction, glaucoma, hypothyroidism or
hyperthyroidism; infectious arthropathy; use of an anal-
gesic 4 weeks prior to the study; another pain syndrome;
hypersensitivity to the drugs; or pregnancy. Before the
study, all patients underwent testing: electrocardiogram
and measurement of thyroid stimulating hormone, free
thyroxine, rheumatoid factor, C-reactive protein, antinu-
clear antibody, erythrocyte sedimentation rate, urea, cre-
atinine, glucose, aspartate aminotransferase, alanine
aminotransferase and gamma-glutamyltransferase.
All patients received amitriptyline in the evening at a
dose of 12.5 mg in the first week and 25 mg in the fol-
lowing 7 weeks. Patients from group 1 (lidocaine
group) received 240 mg of lidocaine diluted in 125 mL
of 0.9% saline solution. Patients from group 2 (placebo
group) received 125 mL of 0.9% saline solution. The
solutions were infused for 1 h once a week for 4 weeks
(T1, T2, T3 and T4) following the beginning of the
study (T0). The following procedures were performed
2 International Journal of Rheumatic Diseases 2016
during monitoring: pulse oximetry, electrocardiogram,
blood pressure and pulse rate measurements.
For additional analgesia, patients were allowed to use
paracetamol in doses up to 4 g/day. If, despite the use
of paracetamol, the pain score was equal to or > 4, tra-
madol could be used (50 mg each time). The doses of
the drugs used by the patients were recorded.
Patients were followed up by the same researcher
before treatment (T0) and at 1, 2, 3, 4 and 8 weeks after
treatment began. Pain intensity was assessed on a
numerical scale from zero to 10 (where zero means no
pain and 10 the worst possible pain) before treatment
(T0) and then at 1, 2, 3, 4 and 8 weeks after the start of
treatment. The clinical manifestations, as well as the
location of the tender points (pain when applying pres-
sure of < 4 kg/cm²), which was determined using an
algometer, were also recorded at these time points. The
FIQ18 was completed by patients before treatment and
then at 4 and 8 weeks after treatment. Before the begin-
ning of treatment and at 4 and 8 weeks after treatment,
blood samples (5 mL) were collected in ethylenedi-
aminetetraacetic acid (EDTA) tubes. The blood samples
were then centrifuged and the plasma separated and
stored at 70°C for IL-1, IL-6 and IL-8 measurements.
Any adverse events were recorded.
The SPSS 17 for Windowsâ software (SPSS Inc., Chi-
cago, IL, USA) was used for sample calculation and for
the analysis of the results. A difference of two in pain
intensity in the verbal pain intensity scale was consid-
ered clinically significant for a power of 80% and a
95% confidence interval (95% CI). Based on prelimi-
nary assessment,19 a standard deviation (SD) of 2.2 was
estimated for the pain intensity score within the group.
The sample size calculated for each group was 18
patients. Considering possible loss, a total of 21
patients were assessed. Mean and standard deviation
were calculated. Student’s t-test was used for age, pain
intensity, tender points, additional analgesia with
paracetamol and tramadol, IL levels and FIQ scores.
Fisher’s exact test was used for gender, pain duration,
clinical manifestations (sleep disorders, fatigue, anxiety,
depression, stiffness, subjective swelling, tingling,
cramping) and side effects. The level of statistical signif-
icance was set at P ≤ 0.05.
RESULTS
The results of the study are shown in the CONSORT
flow diagram (Fig. 1). Regarding the demographic data,
there was no statistically significant difference between
the groups (Table 1).
 Lidocaine and IL in fibromyalgia

Assessed for eligibility (n: 130)

Enrollment Excluded (n: 88)

• Not meeting inclusion criteria (n: 88)
• Refused to participate (n: 0)

Randomized (n: 42)

Allocation

Allocated to lidocaine group (n: 21) Allocated to placebo group (n: 21)
• Submitted to lidocaine (n: 19) • Submitted to placebo (n: 19)
• Did not submitted to lidocaine (n: 0) • Did not submitted to placebo (n: 0)

Follow up
Lost to follow up (n: 2) Lost to follow up (n: 2)
Discontinued (n: 0) Discontinued (n: 0)

Analysis

Analysed (n: 19) Analysed (n: 19)

Excluded from analysis (n: 0) Excluded from analysis (n: 0)

Figure 1 CONSORT fluxogram.

Table 1 Demographic data

G1 = 3 g and G2 = 2 g) or of tramadol (T1: G1 = 0,
Lidocaine Saline P-value G2 = 50 mg; T2: G1 and G2 = 0; T3: G1 and G2 = 0;
(n = 21) (n = 21) T4: G1 = 0 and G2 = 50 mg; T8: G1 = 50 mg and
Gender M/F 2/19 0/21 0.488† G2 = 0) (Student’s t-test). There was a reduction in the
Age (years) 42.4  9.4 47  9.8 0.308‡ incidence of widespread pain in 70% of patients in
Weight 69.8  13.8 65.2  10.1 0.260§ both groups at 8 weeks after the start of treatment.
BMI (kg/m2) 25  4.6 24.2  3.5 0.489‡ No differences were recorded for plasma levels of IL-
Duration (months) 60  50.5 72  49.9 0.536‡ 1, IL-6 and IL-8 (Table 3), for the FIQ scores at T0, T4
†
Fisher’s test; ‡Mann-Whitney U test; §Student’s t-test. BMI, body mass and T8 or for the number of tender points, sleep and
index. mood disorders, fatigue, morning stiffness, subjective
swelling, paresthesia or cramps at any of the assessed
time-points (Fisher’s exact test; Table 4). A reduction in
The difference in pain intensity was statistically signif- sleep disorders was observed in approximately 70% of
icant between the groups at 2 weeks after treatment patients, while a reduction in fatigue was observed in
(Table 2). There was no difference in the use of parac- approximately 50% of patients; there was no reduction
etamol (T1: G1 = 4 g, G2 = 2 g; T2: G1 and G2 = 2 g; in the percentage of patients with mood disorders. A
T3: G1 and G2 = 1.5 g; T4: G1 and G2 = 0.5 g; T8: reduction in FIQ scores was observed in approximately

International Journal of Rheumatic Diseases 2016 3

A. L. A. Giraldes et al.

Table 2 Pain intensity on numerical scale Table 4 FIQ questionnaire and clinical symptoms scores
Times Lidocaine Saline P† Lidocaine Saline P
T0 6.1  1.3 7.2  1.3 0.090 FIQ
T1 5.4  1.7 6.3  1.7 0.135 T0 65.1  11.2 63.5  15.4 0.698†
T2 4.6  1.6 6.1  1.7 0.010 T8 38.6  24.3 26.1  23.0 0.095†
T3 4.2  2.1 4.5  2.4 0.670 Tender points
T4 3.3  1.6 4.4  2.7 0.152 T0 15.2  2.5 15.1  2.9 0.821†
T8 3.9  2.8 2.7  2.9 0.199 T8 13.8  3.3 12.6  4.6 0.111†
P‡ < 0.001 < 0.001 Sleep disorders
T0 100% 95.2%
†Student’s t-test; ‡Analysis of variance test. T0, before treatment; T1,
after 1 week; T2, after 2 weeks; T3, after 3 weeks; T4, after 4 weeks; T8 52.6% 42.1% 1.000‡
T8, after 8 weeks. Fatigue
T0 100% 95.2% 1.000‡
T8 52.6% 42.1% 0.746‡
Table 3 Plasma levels of interleukins (ILs) (mean  SD) Mood change
(pcg/mL) T0 61.9% 71.4% 0.744‡
T8 68.4% 47.4% 0.325
Time points Lidocaine Saline P†
†Student’s t-test; ‡Fisher’s test. FIQ, fibromyalgia impact questionnaire;
IL1 T0, before treatment; T1, after 1 week; T2, after 2 weeks; T3, after
T0 6.5  4.5 3.3  1.7 0.504 3 weeks; T4, after 4 weeks; T8, after 8 weeks.
T4 4.5  3.2 3.4  1.7 0.763
T8 8.1  23.3 2.1  5.3 0.277
P‡ 0.202 0.743 Similar to previous studies,3,12,20 there was a higher
IL6 percentage of women participating in this study. The
T0 22.7  9.4 14.0  5.5 0.433 age of the patients was similar to the values previously
T4 15.9  8.5 14.7  4.9 0.899 reported in the literature, with a higher prevalence of
T8 19.2  10.0 9.7  4.0 0.388 individuals aged between 40 and 60 years.21
P‡ 0.325 0.452 Only fibromyalgia patients without previous treat-
IL8
ment and without other pain syndromes or diseases
T0 6.0  3.6 4.2  1.8 0.653
that could intensify the clinical manifestations or alter
T4 5.8  2.9 3.8  1.7 0.563
T8 8.4  5.1 2.1  1.1 0.232
the metabolism and excretion of the drugs were
P‡ 0.312 0.556 included in the study to avoid any influence on the
results. The tender points were located using an
†Student’s t-test; ‡Analysis of variance test. T0, before treatment; T1,
after 1 week; T2, after 2 weeks; T3, after 3 weeks; T4, after 4 weeks;
algometer to avoid the difference that could occur
T8, after 8 weeks. with digital pressure, although ACR 2010 criteria do
not include tender points. Additionally, other clinical
manifestations were considered for the initial assess-
50% of the patients and restriction to work in approxi- ment and diagnosis of fibromyalgia, as described in
mately 60% of the patients. Regarding the incidence of the literature.1,2,5 The main clinical manifestations are
side effects (nausea, vomiting, dizziness, drowsiness, widespread pain with tender points, fatigue, and sleep
paresthesia, constipation and dry mouth), there were and mood disorders.22 Other symptoms are: paresthe-
no differences between groups (Fisher’s exact test). sia, cramps, morning stiffness and subjective edema.
The FIQ questionnaire assesses the impact of the dis-
ease on daily living activities, and work and patient
DISCUSSION mood.
The use of lidocaine combined with amitriptyline pro- Other studies examined several substances involved
moted a better analgesic effect at 2 weeks after the in fibromyalgia mechanisms, but this study measured
beginning of treatment, with no differences at other the levels of ILs because they are among the several sub-
times assessed during 8 weeks. This treatment did not stances involved in the pathophysiology of fibromyal-
alter the levels of IL-1, IL-6 or IL-8, clinical manifesta- gia.23 Certain cytokines may be associated with
tions, FIQ scores, the need for additional analgesia or symptoms such as pain, depression, fatigue, and sleep
side effects. disorder.14,24

4 International Journal of Rheumatic Diseases 2016


Previous studies show changes in proinflammatory
cytokines21 and anti-inflammatory cytokines15,16 asso-
ciated with fibromyalgia. In a systematic review and
meta-analysis, the authors observed a higher concentra-
tion of IL-1RA, IL-6 and IL-8.25 However, different stud-
ies show controversial results regarding IL levels,
including normal levels of IL-1 b,26–28 increased levels
of IL-6,26 increased9,16,26,27,29,30 or normal levels of
IL-828,31 and increased27,28 or reduced levels of IL-10.31
Cytokines can be associated with sleep disorders.22 In
this study, the patients reported better sleep quality
1 month after treatment, which may be associated with
the effects of amitriptyline.
IL-1b is associated with pain, fatigue and sleep disor-
ders.15,26 Some studies have demonstrated that IL-6 was
associated with pain and fatigue,15,23,26 depression15,26
and higher FIQ scores,27 while others demonstrated
that IL-6 was not associated with fatigue.26,31 Similarly,
IL-8 has been associated with pain15,26 and higher FIQ
scores32 but not with fatigue.26 IL-10 has been associ-
ated with depression;27 the reduction in the levels of
these protective mediators may be an additional risk
factor for fibromyalgia.
One study31 found no relationship between
fibromyalgia symptoms and cytokine concentrations.
Whether changes in cytokine levels are the cause of pain
in fibromyalgia or its consequence remains unclear.
Further studies are needed to answer this question.
Increased levels of IL-6 and IL-8 were observed in the
majority of patients in this study. Differences in the
mechanisms and neurotransmitters involved may also
occur among patients. The concentrations of proinflam-
matory cytokines did not normalize, which may be
explained by the duration of the treatment. However,
there is no study reporting the time required for the
normalization of cytokine levels. Normalization might
not occur despite treatment and the control of clinical
manifestations.
Different methods used to measure cytokines, as well
as different times of blood collection, may explain these
differences. Several methods are described in the litera-
ture, making comparisons more difficult.
The secretion of cytokines varies widely, and their
concentrations are influenced by various environmental
factors and drugs.
Several methods can be used to measure IL levels.33
The majority of studies use enzyme-linked immunosor-
bent assay9,25,33 and the IL-6 level ranges from 0 to
73.17 pg/mL, while IL-8 ranges from 0 to 74.8 pg/mL.
In this study, the level of IL-6 ranged from 0 to 156 pg/
mL, while the level of IL-8 ranged from 0 to 97.2. The
International Journal of Rheumatic Diseases 2016
Lidocaine and IL in fibromyalgia
levels of cytokines in body fluids vary due to intrinsic
and extrinsic factors, including age.33
It is important to note that the development of
fibromyalgia can be influenced by multiple genes34 and
by the imbalance of various substances associated with
pain-modulating functions, central sensitization and
decreased pain threshold.34–36 Thus, the clinical mani-
festations occur due to changes in more than one sub-
stance. One patient may present alterations in several
other neurotransmitters associated with the syndrome.
This fact explains the wide range of symptoms observed
in fibromyalgia.
The results of some studies suggest that intravenous
lidocaine can reduce expression of proinflammatory
cytokines.37–39 Lidocaine was not used alone and then
compared with a placebo because the patients from the
placebo group could present severe pain. The dose of
240 mg used in this study and infused for 1 h is used
by different authors, ranging from 1–5 mg/kg.10,11,40
The lack of difference in the analgesic effect may have
been because amitriptyline alone promoted a sufficient
effect. Another possibility is that lidocaine needs to be
administered at smaller intervals to obtain a difference
in effect.
A previous study reported intravenous lidocaine to be
effective in the treatment of fibromyalgia. In one study
daily intravenous lidocaine therapy was used in
fibromyalgia patients for 6 days.41 However, this proto-
col is not easy to incorporate into the clinical routine.
Weekly administration is more suitable for clinical use.
Pain relief occurs within 30 min after the injection,
with a peak at 60–120 min and it may last hours or sev-
eral weeks.10 Pain intensity was assessed during this
period after the administration of lidocaine. In a case
series, the authors obtained good pain relief with intra-
venous lidocaine every 3–4 weeks for up to 4 years.42
Treatments include antidepressants (amitriptiline, ven-
lafaxine, duloxetine, fluoxetine), anticonvulsants (prega-
balin, gabapentin) and cyclobenzaprine. Amitriptyline
was used at a dose of 25 mg because doses between 25
and 75 mg/day are considered effective, and the recom-
mended starting dose is 10 mg.43 However, the dose
required might vary among different patients, and a dose
of 10 mg is sufficient for some of them. In this study,
patients were evaluated during this period. In addition,
appropriate pain relief occurred within 4 weeks in both
groups, reaching mild pain scores. Amitriptyline was
used in all patients because it is an effective and recom-
mended drug for the treatment of fibromyalgia.4,44 The
antidepressant may improve depression, but the time
required for this effect is longer than for pain relief.
5
A. L. A. Giraldes et al.
Regarding the improvement in pain intensity, a dif-
ference between the groups was observed at only one of
the analyzed time points, but this result may be indica-
tive of the effect of lidocaine. It is possible that
amitriptyline was sufficient to promote pain relief.
Nausea and vomiting may be associated with the use
of lidocaine and tramadol; however, these symptoms
were slightly more frequent in the saline group than in
the lidocaine group, which could indicate that these
symptoms were instead caused by tramadol. Nausea or
vomiting was not reported at 3 weeks after the treat-
ment, which indicates the development of tolerance to
tramadol-related side effects. Dizziness and drowsiness
may be associated with lidocaine, amitriptyline or
tramadol.
An increased number of patients complaining of
dry mouth was observed over time, which may be
associated with the increased dose of amitriptyline.
Constipation can be caused by amitriptyline and by
tramadol used for additional analgesia. It is likely
that this symptom was caused by amitriptyline
because the amount of tramadol used by the patients
was small.
The side effects of lidocaine are generally mild
(drowsiness and perioral paresthesia, metallic taste and
nausea), with no need to stop the treatment. In this
study, both drowsiness and paresthesia were mild, with
no need to stop treatment.
The combination of 240 mg of intravenous lidocaine
with 25 mg of amitriptyline during 4 weeks increased
the analgesic effect at 2 weeks after the beginning of the
treatment, with no differences in clinical manifestations
or plasma levels of IL-1, IL-6 or IL-8 in patients with
fibromyalgia. In addition, this treatment did not alter
side effects.
Because lidocaine was used in combination with
amitriptyline, the analgesic effect and IL concentrations
could be associated with the use of the antidepressant
rather than lidocaine.
Further studies are necessary to assess the most
appropriate dose and time interval for the use of intra-
venous lidocaine in fibromyalgia patients. Further stud-
ies are also required to assess whether this treatment
increases the levels of proinflammatory ILs and pro-
motes normalization, and if so, how long it takes for
these to occur after the beginning of the treatment. It is
important to determine whether ILs cause the symp-
toms or rather if the symptoms increase the levels of
these substances. Moreover, further studies are
necessary to assess which ILs are more altered in
fibromyalgia.
6 International Journal of Rheumatic Diseases 2016
CONCLUSIONS
The combination of 240 mg of intravenous lidocaine
(once a week for 4 weeks) with 25 mg of amitriptyline
for 8 weeks had no meaningful impact in fibromyalgia
patients.
Limitations
Because lidocaine was used in combination with
amitriptyline, the analgesic effect and IL concentrations
could be associated with the use of the antidepressant
rather than lidocaine.
ACKNOWLEDGMENTS
Grant 2011/09807–9, S~ao Paulo Research Foundation
(FAPESP).
AUTHORS CONTRIBUTIONS
Ana Laura Albertoni Giraldes: data collection, article
writing; Reinaldo Salom~ao: data analysis and interpreta-
tion; Plinio da Cunha Leal: article writing; Milena Kar-
ina Colo Brunialti: data analysis; Rioko Kimiko Sakata:
study conception and design, article writing, critical
revision of the intellectual content.
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