The Journal of International Medical Research 1990; 18: 201 - 209

Double-blind Study of
5-Hydroxytryptophan versus
Placebo in the Treatment of
Primary Fibromyalgia Syndrome
I. Caruso, P. Sarzi Puttini, M. Cazzola and V. Azzolini
Rheumatology Unit, L. Sacco Hospital, Milan, Italy
A double-blind, placebo-controlled study of the efficacy and tolerability of 5-hydroxytryptophan (5-HTP) was conducted in 50 patients with
primary fibromyalgia syndrome. All the clinical parameters studied
were significantly improved by treatment with 5-HTP and only mild
and transient side-effects were reported. Further controlled studies
are required to define properly the value of 5-HTP in patients with
primary fibromyalgia syndrome.
KEY WORDS: 5-Hydroxytryptophan; primary fibromyalgia syndrome.

INTRODUCTION

rimary fibromyalgia syndrome (PFS)

is a common clinical syndrome, characterized by generalized musculoskeletal

aching,multiple tender points, fatigue,morning stiffness and disturbed sleep.' The
aetiology of PFS is unclear but psychological problems.' disturbance of non-rapid
eye movement sleep," changes in muscle
metabolism and morphology," and
immunological abnormalities! have been
suggested. It is now recognized that PFS is
a distinct entity, in contrast to the previous
descriptions of fibrositis with the nonspecific musculoskeletal pain being due to

Received for publication 30 November 1989; accepted 6 December 1990.

Address for correspondence: Professor I. Caruso,
Rheumatology Unit, Via G.B. Grassi 74, 20157 Milan,
Italy.
Copyright 1989 by Cambridge Medical Publications Ltd.

a variety of causes,"
Patients suffering from PFS are often
resistant to various forms of treatment. Serotonin (5-hydroxytryptamine), which was
discovered in the blood over 40 years ago,"
has subsequently been located in many
parts of the body and has been shown to
exert numerous effects on several body
systems, including the brain and the gastro-intestinaltract," Reportsof reducedblood
serotonin concentrations in patients with
PFS9.1O and the symptomatic relief of these
patients using tricyclic antidepressants,
which probably act by blocking the
re-uptake of biogenic amines at nerve
terminals, have implied the potential value
of serotonin in the treatment of patients
with PFS.II-13
The aim of the present study was to
establish, in a double-blind, placebocontrolled trial, both the efficacy and
the tolerance of orally administered
201

I. Caruso, P. Sarzi Puttini, M. Cazzola et al.

5-hydroxytryptophan (5-HTP) in the treatment of patients with PFS.

PATIENTS AND METHODS

Study design
A total of 50 out-patients diagnosed as suffering from PFS, based on the criteria of
Yunus et al,14 of either sex and aged between 18 and 65 years were included in the
study (Table 1). All patients included in the
trial had at least seven typical and consistent tender points." In addition, patients
had to have reported as least two of the
following symptoms to be included in the
trial: diffuse musculoskeletal aching; anxiety; poor sleep patterns; general fatigue and
tiredness; morning stiffness; and irritable
bowel syndrome. Patients with severe cardiac, renal or lung diseases were excluded
from the trial, as were those who were
currently receiving or within the previous 2
weeks had been treated with monoamine
oxidase inhibitors. Other exclusion criteria
included treatment with non-steroidal antiinflammatory drugs, analgesics, muscle
relaxants or antidepressants in the 2 weeks
prior to the start of the trial. Patients with
major depression based on psychiatric

evaluation and the Hamilton test for

depression, as well as those in which the administration of 5-HTP was contra-indicated,
were not included in the study.
Drug administration
The patients were assigned using a randomization list to receive orally either 100
mg 5-HTP or placebo three times daily for
30 days; the placebo and 5-HTP tablets
were identical in colour, shape and taste,
thus enabling a double-blind trial.
Clinical evaluation
Patients were assessed clinically prior to
the start of the trial and after 15 and 30 days
of treatment. Clinical measures determined
included: palpation of 14 specific points
using moderate pressure and recording the
total number of tender sites; intensity of
pain expressed on a visual analogue scale
(0 - 10 em); quality of sleep using an analogue scale of 1 - 5 (1, awoke feeling refreshed; 5, awoke feeling severely fatigued);
degree of morning stiffness, fatigue and
anxiety expressed on a scale of 1 - 5 (1,
normal or absent; 5, very severe); and the
effectiveness of treatment both in the opin-

Table 1
Characteristics of patients with primary fibromyalgia syndrome
treated with S-hydroxytryptophan (S-HTP) or placebo
Characteristics
No. of patients
Sex
Females
Males
Age (years)
Mean
Range
Mean ( SE) no. of tender points
Mean ( SE) subjective pain score
Mean ( SE) sleep score
Mean ( SE) anxiety score
Mean ( SE) fatigue score
Mean ( SE) morning stiffness score
202

5HTP

Placebo

25

25

1
24

6
19

47.8
31- 60
10.5 1.81
5.85 2.15
3.9 0.79
3.5 0.87
3.3 1.02
3.7 1.05

46.9
35 -59
10.1 1.85
6.07 1.67
3.8 0.78
3.7 0.89
3.7 0.83
3.4 0.89

5-Hydroxytryptophan in primary fibromyalgia syndrome

ion of the patient and the investigator expressed on a scale of 0 - 3 (0, none; 1, poor;
2, fair; 3, good).

group differences were analysed using the.

Student's t-test.

RESULTS
Of the 50 out-patients (seven females, 43
males) who entered the study, 25 were assigned to receive 5-HTP and 25 placebo.
During the 30-day study, one patient receiving 5-HTP and one receiving placebo
dropped out for reasons unrelated to treatment. In addition, one patient receiving 5HTP and one receiving placebo interrupted
treatment because of side-effects - diarrhoea and somnolence, respectively. The
characteristics of the patients in both treatment groups are shown in Table 1. There
was no significant difference between the
two groups before treatment for any of the
demographic data or clinical assessments.
Oral administration of 100 mg 5-HTP
three times daily for 30 days resulted in a
significant decline in the number of tender
points (P < 0.001) (Fig. 1) and in the intensity of subjective pain experienced

Tolerance
Toxicity was monitored at each visit by
carrying out a complete blood count (haematocrit, red and white blood cell counts,
haemoglobin, differential cell count and
platelet count), urinalysis, chemical blood
survey (including liver function, blood urea
nitrogen, creatinine, total protein, albumin
and blood electrolytes) and erythrocyte
sedimentation rate.Patients wereinterviewed
at each clinical assessment to determine
whether they had experienced any sideeffects and to assess patient compliance.
Statistical analysis
Intergroup qualitative variables and frequencies were analysed using the x2-test.
For quantitative variables, the Mann - Whitney U-test was used for unpaired data and
the Wilcoxon's test for paired data. Intra-

Placebo
5-HTP
1l.5

"'

1
~c::

""'
0

0
Z

10.5
9.5

-_._----------8.5
P <0.001
7.5
6.5

5.5

15

30

Time (days)

Fig. 1. Mean () SE) number of tender points (0 - 14) in 50 patients with primary fibromyalgia
syndrome treated orally with 100 mg 5-hydroxytryptophan (5-HTP) or placebo three times daily for
30 days.
203

I. Caruso, P. Sarzi Puttini, M. Cazzola et al.

(P < 0.001) (Fig. 2) compared with placebo. A significant improvement was also
reported in morning stiffness (P = 0.017)
(Fig. 3), sleep patterns (P < 0.001) (Fig. 4),
anxiety ratings (P < 0.001) (Fig. 5) and
fatigue ratings (P < 0.003) (Fig.' 6) after 30
days' treatment with 5-HTP compared with
placebo. Within-group comparison between
trial outset and end of treatment showed a
significant (P < 0.001) improvement in the
number of tender points, pain intensity,
amount of sleep and degree of anxiety,
fatigue and morning stiffness following
treatment with 5-HTP.
In patients treated with placebo, sleep
(P = 0.028) and subjective pain (P = 0.035)
improved significantly after 30days, whereas
stiffness (P < 0.003) and the number of
tender points (P < 0.021) were significantly
improved after 15 days' but not after 30
days' treatment. The [mal overall evaluation of the patients' condition assessed by
both the patient and the investigator indi-

cated significantly (P < 0.001) greater improvements using 5-HTP than using placebo after both 15 days' (Fig. 7) and 30
days' treatment (Fig. 8).
A total of seven (24.0%) patients receiving 5-HTP reported side-effects but
only one patient was withdrawn from treatment. In the case of the placebo-treated
group, side-effects were reported in three
(12.0%) patients, with one patient being
withdrawn (fable 2).
DISCUSSION

The essential amino acid tryptophan crosses

the blood - brain barrier and within the
brain it is converted to serotonin by
enzyme-catalysed oxidation and decarboxylation."
Serotonin is thought to be the neurotransmitter that mediates slow-wave sleep'"
and it appears to play an important role in
the perception of pain, with low serotonin
concentrations reducing the pain threshold

Placebo
5-HTP

E
~

Q)

OJ
o

"'
Q)

::s

OIl

OJ

OJ
::s

.~

;>

P <0.001

3L..L..------------J.---------~

15
Time (days)

30

Fig. 2. Mean ( SE) subjective pain severity assessed on a visual analogue scale (0 - 10 em), in 50
patients with primary fibromyalgia syndrome treated orally with 100 mg 5-hydroxytryptophan
(5-HTP) or placebo three times daily for 30 days.

204

5-Hydroxytryptophan in primary fibromyalgia syndrome

Placebo
5-HTP
4.5

en
en

4.0

II)

l5

"t;

gp

3.5

s
~

3.0

2.5

2.0
0

30

15
Time (days)

Fig. 3. Mean ( SE) morning stiffness (scale 1- 5) in 50 patients with primllry fibromyalgia syndrome
treated orally with 100 mg 5-hydroxytryptophan (5-HTP) or placebo three times daily for 30 days.

- - _. Placebo
- - 5-HTP
4.5

4.0
en

Q,
Q,

------------1--------

3.5

f.ii

P =0.004

II)
II)

P <0.001

3.0

2.5

2.0
0

15
Time (days)

30

Fig. 4. Mean ( SE) changes in sleep patterns (scale 1 - 5) in 50 patients with primary fibromyalgia
syndrome treated orally with 100 mg 5-hydroxytryptophan (5HTP) or placebo three times daily for
30 days.

205

I. Caruso, P. Sarzi Puttini, M. Cazzola et al.

Placebo

5-HTP
4.5

4.0

------ I

eo

.~

...

3.5

- --

.~

--------------

3.0

2.5

2.0

15

30

Time (days)

Fig. 5. Mean ( SE) changes in anxiety ratings (scale 1 -5) in 50 patients with primary fibromyalgia
syndrome treated orally with 100 mg 5-hydroxytryptophan (5-HTP) or placebo three times daily for
30 days.

Placebo

5-HTP
4.5

.,
I

4.0

.., 3.5

1----

------ --------

3.0

P =0.003

2.5
2.0

L..L..

----I.

15

---J

30

Time (days)

Fig. 6. Mean ( SE) changes in fatigue ratings (scale 1 - 5) in 50 patients with primary fibromyalgia
syndrome treated orally with 100mg 5-hydroxytryptophan (5-HTP) or placebo three times daily for
30 days.

206

5-Hydroxytryptophan in primary fibromyalgia syndrome

(a)

'"
C
.~

(b)

P =0.002

10

10

P =0.003

Q,

....0
0
Z

Good

Fair

None

Poor

Good

Fair

Poor

None

Fig. 7. Patients' and investigator's opinion (scale 0 - 3) on the effectiveness of oral treatment with
100 mg 5-hydroxytryptophan (5-HTP) or placebo three times daily for 15 days.

(a)

(b)
P < 0.001

10

'"
C
.s
tu

Placebo

o 5-HTP

P < 0.001

10

Q,

'0
0
Z

Good

Fair

Poor

None

Good

Fair

Poor

None

Fig. 8. Patients' and investigator's opinion (scale 0 - 3) on the effectiveness of oral treatment with
100 mg 5-hydroxytryptophan (5-HTP) or placebo three times daily for 30 days.

207

I. Caruso, P. Sarzi Puttini, M. Cazzola et

at.

Table 2
Description and incidence of side-effects occurring in 50
patients with primary fibromyalgia syndrome treated orally
with placebo or 100 mg 5-hydroxytryptophan (5-HTP)
three times daily for 30 days
Side-effects
Headache
Diarrhoea
Somnolence
Gastric pain
Abdominal pain
Dermatitis
Dry mouth
Total no. of side-effects
Total no. of patients with side-effects
'Interruption of the treatment.

and vice versa." In addition, it has been

shown that inhibition of serotonin synthesis
using p-chlorophenylalanine results in a
decline in slow-wave sleep and an increase
in somatic symptoms."
Moldofsky and Warsh 9 have proposed
that PFS may be the. result of decreased
concentrations of circulating tryptophan,
possibly leading to reduced concentrations
of serotonin and consequently poor maintenance of slow-wave sleep. These workers
found that the plasma concentrations of
unbound tryptophan in patients with PFS
were inversely related to the severity of of
their symptoms." Treatment with oral tryptophan, however, was not effective in relieving the patients' musculoskeletal symptoms."
There is the possibility that the biochemical basis for the syndrome is related
to the observation that replacement of one
deficient amino acid may make deficiencies of the others even more critical." In
addition, it is recognized that the absolute
concentration of available tryptophan, relative to that of other amino acids that compete with it for transfer across the blood 208

brain barrier, can influence the magnitude

of the effect of tryptophan on the brain
function. 16
In the present study, treatment with
5-HTP improved the clinical variables in
patients suffering from PFS over the
3D-day treatment period. Clinical improvement was seen in the number of tender
points, the intensity of pain and the amount
of sleep, anxiety, fatigue and morning stiffness, with both the patients and the physicians considering that 5-HTP was significantly more effective than placebo.
In patients receiving placebo, however,
the quality of sleep and intensity of pain
were also reported to be improved significantly during the treatment period, whereas
stiffness and the number of tender points
were only transiently improved. A response
to placebo has also been observed in other
more destructive diseases, e.g. rheumatoid
arthritis, suggesting that psychological factors may play an important role and that a
careful and proper follow-up of the patient
may be a contributory factor in relieving
their symptoms.
The encouraging results observed in the

5-Hydroxytryptophan in primary fibromyalgia syndrome

present study may be due to the fact that

orally administered 5-HTP is well absorbed
by the peripheral tissues, includingthecentral
nervous system, by simple diffusion, with
concentrations in the central nervous system being directly dependent on plasma 5HTP concentrations. Interference by other
amino acids is only minimal, unlike the
situation with its precursor tryptophan.I-"
In the present study, the incidence of
side-effects was low both in the 5-HTPand the placebo-treated group and the good
tolerability of 5-HTP confirms earlier observations of the use of this drug in the
treatment of other disease. In addition, no
significant laboratory abnormalities were
reported in the present study.
It is concluded that treatment with 5HTP may be useful in reducing the symptoms encountered in patients with PFS and
that 5-HTP induces only mild and transient
side- effects. Further studied, however, are
necessary to confirm these observations
and to establish the optimal dosage and
length of treatment for this type of 'extraarticular rheumatism'.
REFERENCES
I. Bennett RM: Fibrositis. In: Textbook ofRheumatology (Kelly WN, Harris ED, Ruddy S, et ai, eds).
Philadelphia: WB Saunders 1989; pp 541 - 553.
2. Payne TC, Leavitt F, Garron DC, et al: Fibrositis
and psychologic disturbance. Arthritis Rheum
1982; 25: 213 - 217.
3. Moldofsky H, Scaresbrick P, England R, et al:
Musculoskeletal symptoms and non- REM sleep
disturbances in patients with 'fibrositis syndrome' and healthy subjects. Psychosom Med
1975; 4: 341- 351.
4. Bengtsson A, Henriksson KG, Larsson J: Reduced high energy phosphate levels in the painful
muscles of patients with primary fibromyalgia.
Arthritis Rheum 1986; 29: 817 - 821.

5. Dinennan M, Goldenberg DC, Felson DT: A prospective evaluation of 118 patients with fibromyalgia syndrome: prevalence of Raynaud's
phenomenon, sicca symptoms and low complement and Ig deposition in the dennal- epidermal
junction. J Rheumatol1986; 13: 368 - 373.
6. Wallace OJ: Fibromyalgia: unusual historical aspects and new pathogenic insights. Mt Sinai J
Med 1984; 51: 124-127.
7. Morgane PJ: Serotonin: twenty years later.
Monoamine theory of sleep: the role of serotonin
-areview. Psychopharmacol Bu1/1981; 17: 1317.
8. Chase TN, Murphy DL: Serotonin and central
nervous system function. Ann Rev Pharmacol
1973; 13: 181- 197.
9. Moldofsky H, Warsh JJ: Plasma tryptophan and
musculoskeletal pain in non-articular rheumatism. Pain 1978; 5: 65 -71.
10. Russell D, Michalek JE, Vaprio GA, et al: Serum
amino acids in fibrositis/fibromyalgia syndrome.
J Rheumatofl989; 16 (suppI19): 158 -163.
II. Caruso I, Sarzi Puttini PC, Boccassini L, et al:
Double-blind study of dothiepin versus placebo
in the treatment of primary fibromyalgia
syndrome. J Int Med Res 1987; 15: 154 - 159.
12. Wysenbeek AJ, Nor F, Lurie Y, et al: Imipramine
for the treatment of fibrositis; a therapeutic trial.
Ann Rheum Dis 1985; 44: 752 - 753.
13. Carette S, McCain GA, Bell DA, et al: A doubleblind study of amitriptyline versus placebo in
patients with primary fibrositis. Arthritis Rheum
1986; 29 (suppl): 658 - 659.
14. Yunus M, Masi AT, Calabro JJ, et al: Primary
fibromyalgia (fibrositis): clinical study of 50
patients with matched normal controls. Semin Arthritis Rheum 1981; 11: 151 - 171.
15. Moldofsky H, Lue FA: The relationship of alpha
and delta EEG frequencies to pain and mood in
'fibrositis' patients treated with chlorpromazine
and L-tryptophan. Electroencephalogr Clin
Neurophysiol1980; 50: 71 - 80.
16. Moller SE, Kirk L, Honore P: Relationship between plasma ratio of tryptophan to competing
amino acids and the response to i.-tryptophan
treatment in endogenously depressed patients. J
Affective Disord 1980; 22: 47 - 59.

209