Trial of Baclofen in

Amyotrophic

Forbes H. Norris, Jr, MD; Kwei Sang U, MD;

Barry Sachais, PhD;

\s=b\ A

trial of the antispastic drug baclofmade in amyotrophic lateral sclerosis. Some patients noted reduction of tonus and spasticity; but others had no benefit, nor was the course of the disease altered by long-term administration of baclofen. No major side effects occurred. (Arch Neurol 36:715-716, 1979) en was

suffering from amyoTV/Tost patients lateral sclerosis -"-*

trophic

(ALS)

have increased muscle tone, some¬ times to a degree that increases the disability caused by paralysis. Baclofen has reduced spasticity in several other disorders.'- The present report a short-term, placebo-con¬ trolled, double-blind study of the effect of baclofen in ALS, with obser¬ vations on long-term administration of the drug in selected cases.

concerns

PATIENTS AND METHODS

methodology, save for diagnostic criteria, was exactly that recently detailed by Sachais et al' in the Archives. Briefly, 23 consecutive patients with ALS who gave The

written informed consent and who mani¬ fested major problems with spasticity were randomly assigned to treatment with ei¬ ther baclofen or placebo. One patient was

Accepted for publication Nov 2, 1978. From the Institutes of Medical Sciences, San Francisco (Drs Norris and U), and the Medical Department, Pharmaceutical Division, CIBA\x=req-\ Geigy Corp, Summit, NJ (Drs Sachais and

Carey). Reprint requests

to ALS Research Center, Institutes of Medical Sciences, 2200 Webster Street, San Francisco, CA 94115 (Dr Norris).

MD

and diminution of painful cramps, but such benefit also occurred in the placebo-treated patients. The statistical analysis showed no signifi¬ cant difference in subjective symp¬ toms between the groups. Clinical assessments also revealed no signifi¬ > .05) in spas¬ cant difference (all ticity or ALS score. Nevertheless, after the short-term double-blind study, five patients were identified as possibly experiencing beneficial antispastic effects from medication. These patients accepted a longer drug trial. One clearly experi¬ enced no benefit, so the trial in this case was terminated after two months (Table). The other patients appeared to benefit from baclofen, and treat¬ ment with the drug was continued. The antispastic effect was prominent in two of these patients.

ticity

receiving baclofen, 11 receiving placebos). The drug dosage was advanced from 15 to 80 mg/day over two weeks, and weekly

examinations were continued for five weeks. As described in the earlier publica¬ tion,' clinical examinations were supple¬ mented by examinations of blood and urine specimens at the start and conclusion of the trial. An ALS score" was also made at the start and end of the trial. Patients who experienced reduction in spasticity were presumed to have received baclofen and were seen again at six weeks, after one week of no medication. If the symptoms worsened during that week, a trial of long-term medication with baclofen was begun. The baclofen dosage was increased over one week to 80 mg/day, and the patient was examined monthly. The laboratory tests' were repeated every three months. RESULTS

No major side effects were noted. Minor symptoms occurred equally in patients in both groups. No abnormal¬ ities were detected by routine urinalysis, blood count, or blood chemistry studies. Several patients in the baclofentreated group noted reduction of spas-

Long-term

two others withdrew after lack of imme¬

Twenty patients completed

Carey,

the five-week double-blind trial (nine

unwilling to undergo weekly examinations; diate benefit.

Michael

Lateral Sclerosis

Patient 3 7 13 21 22

Trial of Baclofen in

Length

REPORT OF CASES Case 3.-A 30-year-old woman had stum¬ bling gait and leg stiffness two years earlier. Facial, lingual, and distal limb amyotrophy had developed, but the major disability was severe increase of tonus with spasticity in the trunk and legs. She had to

Amyotrophic

of Trial,

Lateral Sclerosis

Antispastic

mo

Results-

Outcome

17

+ + +

25 2

+ + +

Died Died

9 6

0

Died

+

Died Unknownt

+

'Results include reduction of spasticity, tonic spasms, and cramps. Number of plus signs indicates clinical evaluation of responses. tPatient had progressing amyotrophic lateral sclerosis when last seen.

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be turned in bed "like a board" and could not be flexed to sit in a chair. Clonus was present throughout. The plantar responses were equivocal initially and later became extensor. During the short-term baclofen trial, there was substantial reduction in tonus: she was able to sit in a chair and made unaided postural adjustments with her legs. She reported that chewing and swallowing were easier, and that cramps were greatly reduced. In the week of no medication, the board-like state returned, then dissipated after the resumption of baclofen treatment. The weakness contin¬ ued to progress, however, and death from respiratory insufficiency occurred 17 months later (the necropsy confirmed ALS). Meantime, treatment with baclofen seemed to result in increased mobility. On four occasions, baclofen administration was interrupted for two to seven days, with recurrence of the board-like status each time. On two of these occasions, the admin¬ istration of diazepam in doses of 80 to 100 mg/day gave only about 50% of the benefit associated with baclofen administration and at the cost of major sedation. Not only were the limbs less movable, but the patient was less easily roused to attempt voluntary movement or to cooperate in

passive

movements. Case 7.-A 52-year-old

man

had

severe

spastic paraparesis after ten months of ALS, accompanied by frequent and painful flexor spasms. Amyotrophy was advanced in the bulbar-supplied muscles and the

All the muscle stretch reflexes were hyperactive, and the plantar responses were extensor. The spasticity seemed slightly less severe during the short-term trial and increased during the week of no medication, so the longer trial was begun. Later it was found that the initial medica¬ tion was the placebo, but by that time substantial reduction of spasticity had occurred. As weakness and other ALS manifestations progressed, there evolved a spastic state as severe as that seen in case 3, and as well controlled by the baclofen. On three occasions when baclofen treatment was suspended, a severely disabling board¬ like state appeared rapidly, and sponta¬ neous clonus was present from the jaw to the ankles. Diazepam administered in sedative doses of 100 to 120 mg/day by intramuscular injection resulted in only about 30% alleviation, compared to the benefit obtained within 24 hours when the baclofen was resumed in full dosage. arms.

COMMENT

Patients 3 and 7 were among the three showing the most severe in-

of tonus and spasticity. The patient, with equally severe spasticity, received baclofen during creases

third

the initial trial and derived no benefit. The failure to demonstrate statistical¬ ly significant antispastic effect of baclofen in the double-blind trial can be explained by an infrequent and capricious response of ALS to the drug, so that benefit in some patients was obscured by lack of change in others and by the occurrence of favor¬ able placebo responses, as in case 7. The mode of action of baclofen is not clear.' Although baclofen may not have been absorbed and utilized equally by all the patients, such differ¬ ences in response suggest different mechanisms for clinically similar signs of neural dysfunction in ALS. Whatever the value of baclofen for symptomatic relief, it clearly has no effect on the primary disease process '

'

(Table).

Name and Trademark of Drug

Nonproprietary Baclofen—Lioresal.

References

BA, Logue JN, Carey MS: Baclofen, antispastic drug: A controlled, multicenter in patients with multiple sclerosis. Arch

1. Sachais a new

trial Neurol 34:422-428, 1977. 2. Duncan GW, Shahani BT,

Young

RR: An

evaluation of baclofen treatment for certain symptoms in patients with spinal cord lesions. Neurology 26:441-446, 1976. 3. Norris FH, Calanchini PR, Fallat RJ, et al: The administration of guanidine in amyotrophic

Downloaded From: http://archneur.jamanetwork.com/ by a Monash University Library User on 06/18/2015

lateral sclerosis. Neurology 24:721-728, 1974. 4. Saito K, Konishi S, Otsuka M: Antagonism between Lioresal and substance P in rat spinal cord. Brain Res 97:177-180, 1975.