Scand J Rheumatol20: 294-302, 1991

Oral S-adenosylmethionine in Primary Fibromyalgia. Doubleblind Clinical Evaluation S. JACOBSEN, B. DANNESKIOLD-SAMSBE and R. BACH ANDERSEN" Department of Rheumatology, Frederiksberg Hospital and 'Department of Rheumatology, Hvidovre Hospital, Copenhagen, Denmark

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Jacobsen, S., Danneskiold-Sams0e, B. and Bach Andersen R. Oral S-adenosylmethionine in primary fibromyalgia. Double-blind clinical evaluation. - Scand J Rheumatol 1990; 20: 294-302. S-adenosylmethionine is a relatively new anti-inflammatory drug with aqalgesic and antidepressant effects. Efficacy of 800 rng orally administered s-adenosylmethionine daily versus placebo for six weeks was investigated in 44 patients with primary fibromyalgia in doubleblind settings. Tender point score, isokinetic muscle strength, disease activity, subjective symptoms (visual analog scale), mood parameters and side effects were evaluated. Improvements were seen for clinical disease activity (P=O.O4), pain experienced during the last week (P=0.002), fatigue (P=0.02), morning stiffness (P=0.03) and mood evaluated by Face Scale (P=0.006) in the actively treated group compared to placebo. The tender point score, isokinetic muscle strength, mood evaluated by Beck Depression Inventory and side effects did nQt differ in the two treatment groups. S-adenosylmethionine has some beneficial effects on primary fibromyalgia and could be an important option in the treatment hereof. Key words - Fibromyalgia, s-adenosylmethionine, management, tender points, isokinetic muscle strength, disease activity. Sgren Jacobsen, Department of Rheumatology, Frederiksberg Hospital, DK-2ooO Frederiksberg, Denmark.

INTRODUCTION Primary fibromyalgia (PF) also called fibrositis syndrome is a non-articular rheumatic disorder that is characterized by generalized musculoskeletal pain, stiffness, fatigue, disturbed sleep, and a number of musculoskeletal tender points in the absence of laboratory results indicating any other rheumatic disease (1, 2). The prevalence of this condition has been estimated to be about 4% of a rheumatic disease population (3-5). The etiology and pathogenesis of fibromyalgia is unknown but hypotheses including sleep disturbances (6), pain modulation disorders (7) and neurotransmitter imbalance (8) have been proposed. Lately interesting laboratory abnormalities focusing on muscle function have been revealed. These laboratory abnormalities include alterations in levels of high energy phosphates in PF muscle (9), abnormal muscle oxygenation (10) and reduced dynamic muscle strength (11, 12). Psychologic evaluation using Minnesota Multiphasic Inventory (MMPI) has shown that one third of the patients had a normal psychologic evaluation, one third had a psychological profile resembling that of other pain-related disorders and one third showed evidence of psychological disturbance (13). Exact labeling of the nature of the psychological disturbances was not possible by the means of MMPI. Whether psychological disturbances are primary or secondary to PF is still unknown. S-adenosylmethionine (SAM) is a methyl donor that plays a major role in many metabolic processes and exerts antidepressant (14), anti-inflammatory and analgesic effects (15,16). SAM can be administered to the patient by an exogenous stable salt, SAMe (ASTA Pharma, Frankfurt, Germany). SAMe has been shown to be equally effective as ibuprofen, naproxene, piroxicam and indomethacin in the treatment of osteoarthritis. The tolerability of t deceased

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Oral S-adenosylmethionine in Primary Fibromyalgia

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Table I. Characteristics of the 44 patients included in the study. Actively treated

Placebo treated

Number Sex ratio (WF) Age (years) Height (cm) Weight (kg) Duration of chronic pain (years) Number of tender points Tender point scores

22 4/18 49.8(45.>57.3) 165( 160-175) US(56.8-79.3) 4.5(2.8-9.8) 11.0(7.5-13.8) 31.0(23.8-36.3)

22 2/20 49.0(40.8-55.8) 165(161-172) fXO(55.8-75.8) 4.5(2.8-8.5) 10.3(7.8-13.3) 30.0(21.8-34.8)

Subjective symptoms (YO) Modulation of symptoms by physical activity Sleep disturbances General fatigue Chronic headache Irritable bowels Subjective swelling and numbness

95 91 100 36 41 68

100 95 100 41 73 73

SAMe was in all the studies mentioned equal to or better than the non-steroidal antiinflammatory drugs. When side-effects occured they were mainly gastrointestinal (17-20). An earlier study with parenteral administration of SAMe 200 mg daily has shown beneficial effects on patients with PF in comparison to placebo with regard to muscle tenderness and mood parameters (21). The present study was conducted in order to follow up on these results and to confirm the possible effectiveness of SAMe by oral medication. The aim of study was to asses the effectiveness of 800 mg oral SAMe daily for six weeks in patients with PF in respect of: a) tender point score, b) isokinetic muscle strength, c) clinical status, d) visual analogue scales for pain, fatigue, quality of sleep and overall well-being and e) mood parameters.

PATIENTS AND METHODS

Patient selection Forty-four out-patients with PF were included in the study (Table I). Patients were selected randomly from our patient register which holds patients from most parts of Denmark. These patients have been referred to our department from departments and specialists in rheumatology and general practitioners for further investigation of chronic unexplained muscle pain. All but six lived on Zealand. Entry criteria were generalized aches, pain and prominent stiffness involving three or more widespread anatomic sites for at least three months. At least four characteristic tender points on manual examination among the 14 sites suggested by Smythe ( 2 ) had to be present. In addition to this at least three of the following: - Modulation of symptoms by physical activity

- Modulation of symptoms by weather, anxiety or stress - Poor sleep - Generalized fatigue or tiredness - Chronic headaches - Subjective swelling or numbness

295

296 S. Jacobsen et al.

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Table 11. Previous and concomitant medication in the actively (A) and placebo (P) treated study subjects. Previous medication was discontinued before study start.

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Previous medication (n=22)

Analgetics Antidepressants Diuretics Estrogen Hypnotics Malaria prophylaxis Muscle relaxants Neuroleptics NSAID Spasmolytics Thyroid hormone Tranquilizer

A

P

9 3

9 2 1 1

Concomitant medication (n=22) A

P

1 3 3 2

2 3 5 1

2 1 4

6 1

1

2

1 1

2 2

- Irritable bowel syndrome

Exclusion criteria were as follows: a) Hypersensitivity to acetaminophen or SAMe. b) Presence of secondary causes for illness, e.g. traumatic, other rheumatic,infective, endocrine or malignant. This was ensured by analyzing the patients 'for 'erythrocyte sedimentation rate, blood cell counts, electrolyte levels, creatinine level, alkaline phosphatase, alanine aminotransferase value, aspartate aminotransferase value, creatinine kinase level, thyroid function (thyroxine, triidothyronine, thyroid stimulating hormone) and for the presence of rheumatoid factor (IgM). c) Knee conditions interfering with measurement of muscle strength of knee extensors. d) Patients who were pregnant or lactating. e) Women of childbearing potention who were not using realiable means of contraception or in whom pregnancy could not be excluded. One of the 44 patients dropped out immediately after inclusion in the study because of infectious odonthopathy. Previous and concomitant medication is listed in table 11.

Design and drug presentation The size of the study groups was estimated from the following parameters; a=%, p=lO./,, minimum relevant difference to be detected should equal the standard deviation of the parameters. This would result in at least 21 subjects in each study group; 22 were included in each group. Patients were allocated randomly to one of two parallel treatment groups, SAMe or placebo in double-blind settings and to one of the three investigators who followed the subjects throughout the study. The first six patients were randomized Cn bloc since they were also investigated with regard to the effect of SAMe on muscle metabolism evaluated by "phosphorus magnetic resonance spectroscopy (to be described elsewhere). The study period was six weeks. Patients were examined at the beginning of the study and at week three and six. No post-treatment follow-up was performed. SAMe and placebo were presented as identical enteric-coated tablets, each containing sulfo-adenosyl-Lmethionine sulfate-p-toluensulfonate 768 mg equal to SAMe 400 mg, or 920 mg of placebo respectively. Previous trials in osteoarthritis have used doses of 400-1200

Oral S-adenosylmethionine in Primary Fibromyalgia

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Table 111. Study data on efficacy for 22 actively (A) and 22 placebo ( P ) treated primary fibromyalgia patients before the study (week O), after three weeks (week 3) and after six weeks (week-6). Medians and quartiles are given. week 0

week 3

week 6

22 22 31 (23 3-36.3) 30 (21 .%34.8) 66.5 (39.3-Y6.5) 53 (4 1.8-84.8)

21 22 23 (16.1-28.5) 22 (16.8-28.3) 62 (38.5-89.5) 55 (42.5-73.5)

17 21 19.3 (13-29) 24.3 (17.5-28.5) 62 (37.5-82) 50 (42.1-79)

P

30.3 (15.M0.1) 59.7 (30-60.3)

30.4 (2040.2) 59.9 (29.Y-YO)

A P A P A P A P

-

0 0 47.6% 22.7% 47.6% 72.7% 4.8% 4.5%

45 (10.3-60) 0.221 60 (29.9-1 19.6) --- -- 0.12' 0.04' 23.5% 4.8% 23.5%

Time

Number of subjects Tender point score

A P A

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P Muscle strength

A P

.

Morning stiffness (min.)

Change in disease activity Much better Better No change Worse

A

Time interval Interaction changesP= P =

Oral S-adenosylmethionine in primary fibromyalgia. Double-blind clinical evaluation.

S-adenosylmethionine is a relatively new anti-inflammatory drug with analgesic and anti-depressant effects. Efficacy of 800 mg orally administered s-a...
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