Tizanidine in fibromyalgia sheds light on neurochemistry

[Guest guest]

Nov 11, 2002

Tizanidine in fibromyalgia sheds light on neurochemistry

New Orleans, LA - An exploratory trial of tizanidine (Zanaflex®, Elan

Pharmaceuticals) in 25 patients with fibromyalgia suggests that it may be

useful clinically in the treatment of this condition but has also shed light

on some of the neurochemical disturbances involved. The drug was found to

decrease both the level of substance P in the cerebrospinal fluid (CSF) and

also serum levels of hyaluronic acid, but only the latter correlated with

the improvement in fibromyalgia symptoms that was observed, Dr Jon

(University of Texas, San ) reported at the recent American College

of Rheumatology meeting.

The finding of elevated levels of substance P in the cerebrospinal fluid of

fibromyalgia patients, which has now been confirmed independently by 4

research groups, is " one of the most dramatic findings in fibromyalgia,

neurochemically at least, " told the meeting. His group has studied

the phenomenon further and in a year-long monitoring study has shown that

the CSF levels of substance P are stable and do not fall without a treatment

intervention. They postulated that a drug that would decrease these levels

might have clinical benefits and decided to investigate the effects of

tizanidine, a compound with central alpha-2-adrenergic agonist activity that

has been used for muscle spasticity. The primary objective of the study,

which was supported by Elan, was to see whether the drug would reduce CSF

levels of substance P, but secondary measures included the effect on

clinical symptoms and the effect of the drug on diurnally elevated serum

levels of hyaluronic acid.

A previous study had shown that patients with fibromyalgia have

higher-than-normal serum levels of hyaluronic acid midmorning, which fall

significantly by noon as the patient is up and about, explained.

Fibromyalgia patients complain that their morning stiffness has a long

duration, lasting from half an hour to 4 hours, which is longer than that

reported by patients with osteoarthritis (5 to 20 minutes) and rheumatoid

arthritis (30 minutes to 2 hours). The magnitude of the midmorning-to-noon

drop in serum levels of hyaluronic acid correlate with the patients'

subjective morning stiffness. These findings suggest that the morning

stiffness reported by fibromyalgia patients may have an objective

biochemical equivalent, he commented.

Dose titrated upward, drug showed some clinical benefit

The open-label study was conducted at an academic center and involved 25

patients. The dose of tizanidine was titrated upward from 4 mg at bedtime,

aiming for a maximum of 24 mg/day in divided doses. However, many patients

leveled off before then, saying they were feeling benefits, and they ended

up on a variety of daily doses: 6 mg (3 patients), 8 mg (n=6), 10 mg (n=3),

12 mg (n=3), 16 mg (n=2), 18 mg (n=1), 20 mg (n=2), and 24 mg (n=3); 2

patients withdrew from the study. The average dose was 12+6.1 mg/day,

noted, adding that he didn't feel there were any benefits to be

gained from going higher than this. The drug was well tolerated,

commented. Adverse effects included: reports of hallucinations in 3 patients

(including the 2 who withdrew from the study, but the third patient

continued with the drug and the effect " resolved " ); nightmares in 1 patient;

and a mild transaminitis in 7 patients (28%), which responded to tizanidine

dose reduction or discontinuation. commented that monitoring of

transaminase levels would be advised during continuous therapy.

After 8 weeks on a stable dose of tizanidine, patients showed a significant

reduction in CSF levels of substance P, with a fall from a mean of

32.98+3.73 fmol/mL to 24.91+1.33 fmol/mL (p=0.02). A significant clinical

benefit accrued on several measures: the Sleep Efficiency Scale (p=0.02),

the Pain Visual Analog Scale (p=0.01), the Health Assessment Questionnaire

(p=0.01), and the Fibromyalgia Impact Questionnaire (p=0.02). However,

effects on other measures were not significant, including those on the

Average Pain Threshold, the Tender Point Index, and the ZUNG depression and

anxiety scores. In addition, the mean serum levels of hyaluronic acid fell

numerically from 27.4+6.0 ng/mL to 25+6.1 ng/mL, but this difference was not

significant (p<0.19).

None of the clinical changes correlated with the drop of CSF levels of

substance P, but several of the key variables did correlate with the smaller

drop in hyaluronic acid, told the meeting. He suggested that serum

hyaluronic acid levels might be useful as a correlate of clinical responses

to therapy in fibromyalgia. And the main finding, that the drug lowered CSF

levels of substance P, supports 1 of the models proposed to explain the

conditionthat excess CSF production in fibromyalgia is due to a deficit of

inhibitory activity from endogenous biogenic amines. feels that the

elevated CSF levels of substance P are important in fibromyalgia. " It maybe

that in this particular study we didn't reduce these levels far enough to

see a correlation with clinical benefit, " he commented to rheumawire.

Although the study wasn't designed to test the efficacy of the drug, it does

suggest that tizanidine may be clinically useful in the treatment of

fibromyalgia. However, when asked about further studies to explore this use

of the drug, was doubtful. He pointed out that the patent on the

drug is about to expire, and so he didn't think that the manufacturer would

be interested in funding further studies.