Baclofen

E\aiuatiolls Oil Nc\\ Drugs

Drup8: 1-14 (1974)

Bac1ofen: A Preliminary Report of its Pharmacological Properties and Therapeutic Efficacy in Spasticity

R.N. Brogden, T.M Speight and G.S. Avery Australasian Drug Information Services, Auckland

Table of Contents

Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1 1. Clinical Experimental Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. - 2 2. Therapeutic Trials ..................................... _ 4

2.1 Placebo-Controlled Trials .............................. 4 2.2 Open Trials ...................................... 5

3. Animal Pharmacology ................................... 8 4. Mode of Action ....................................... 8 5. Pharmacokinetic Studies ........................ '. . . . . . . . .. 10

5.1 Absorption ...................................... 10 5.2 Distribution ...................................... 10 5.3 Metabolism and Excretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 11

6. Side-Effects ......................................... 11 7. Contra-indications ........•............................ 12 8. Precautions .................................,....... 12 9. Dosage ............................................ 13

10. Overdosage and its Treatment ............................... ' 13

Sum1/'lllry Baclofen' , a new antispasticity agent, is chemically re

lated to gamma-aminobutyric acid (GABA) , a substance which occurs in the brain. It is thought that GABA produces an inhibitory effect on spinal neurones similar to that of naturally occurring inhibitory transmitters.

KeyWords' Baclofen Gamma-aminobutyric acid Sclerosis, multiple Spasticity

Whereas diazepam, the currently most widely used drug in the treatment of spasticity, acts mainly on supraspinal pathways, baclofen acts predominantly at a spinal level where it inhibits monosynaptic and polysynaptic transmission.

1 'Uoresal' (CIBA-Geigy). 2 See subject index in each issue for further indexing terms.

Baclofen: A Preliminary Report

Glossary of terms used in article

Alpha (a) motor neuroneB: Also termed lower motor neurones.' Its cell body is in a large anterior hom cell and its axon innervates a number of extrafusal muscle fibres. Function: Proprioception, somatic motor, spindle endings, vibration se~.

Gam1l1ll ('1) motor neurones: Pass from small anterior hom cell to supply intrafusal muscle fibres. Function: motor to muscle spindles.

Ia nerve fibre: Monosynaptic, sensory afferent fibre from primary spindle ending to posterior hom cell. Involved mainly with dynamic gamma system.

Group II nerve fibre: Afferent fibre from secondary spindle ending to posterior hom cell. Involved mainly with static gamma system. Both primary and secondary spindle endings alter their rate of fuing with changes in the length of the muscle spindle, but primary endings respond more to the rate of change of length of the spindle, whereas the secondary endings respond to the absolute spindle length.

3

RenBhaw ceU: Motor neurone's own inhibitory 'feed-back' mechanism. Facilitation of the Renshaw cell causes inhibition of alpha motor neurones.

PhoBic Btretch reflex: A synchronous motor neurone discharge caused by a brief stimulation of motor spindles e.g. tendon jerk, which tests the integrity of the lah fibres. Such a reflex is mononsynaptic and tests only the dynamic part of the stretch reflex.

Tonic Btretch reflex: A prolonged asynchronous motor neurone disch;uge causing sustained muscle contraction e.g. increased muscle tone. Tonic reflexes may be tested clinically by passive knee movements whilst recording on an electromyograph. Such reflexes are static or polysynaptic, travelling via brain-stem and upper motor neurone (ie. in cerebral cortex).

H responBe: Described fust by Hof/1I1Ilnn (1918) from whom it derived its name. A muscle potential indicating reflex muscular contraction (Phasic) obtained by electrical activation of incoming fibres (afferent) from spindle organs. May be elicited by electrical stimulation of the medical popliteal nerve in the popliteal fossa, and the response is measured over the belly of the gastrocnemius muscle.

M reBponBe: Direct motor response resulting from electrical nerve stimulation to facilitate the H reflex. In experimental studies, the intensity of the stimulus is varied so that an H reflex can be obtained with only a small M response.

Integrated electromyograph: Modification of row electromyograph readings by electronic integrators to provide a quantif1l1ble recording.

PhotobadiBmography: The pattern of movements performed by a human being during walking recorded in the form of curves by photographing, using a long exposure, the light trails emanating from sources of light attached to the malleoli, knees, hips and back.

Baclofen: A Preliminary Report 4

2. Therapeutic Trials

The natural tendency of patients suffering from chronic disabling diseases to claim benefit from the administration of any new medication, the lack of simple precise objective criteria for assessing spasticity, and the natural remissions in multiple sclerosis which may be mistaken for improvement resulting from drug therapy, make a placebo control desirable in studies of new drugs in spasticity. However, as the nature of the effects and side-effects of effective agents may enable patients and investigators to distinguish active from inactive medication, much of the necessary therapeutic information, and evidence of efficacy, has been obtained from open trials.

2.1 Placebo-Controlled Trials

In double-blind trials involving small numbers of patients with spasticity resulting from multiple sclerosis or various spinal lesions, baclofen 30 to 75 mg daily has been superior to placebo in relieving spasticity when assessed subjectively (Hudgson and Weightman, 1971; Jerusalem, 1968; Pedersen et al., 1970) or electromyographically (Jones et al., 1970). The dosage ofbaclofen has usually been fixed, although long-term studies have indicated the need for individualisation of dosage. To date there have been no satisfactory prospective comparisons with other antispasticity drugs, although Jones et aL (1970) reported a satisfactory response to baclofen 60 mg in 5 out of 6 cases who were 'resistant' to diazepam 30 to 60 mg daily and Ketelaer and Ketelaer (1972) considered baclofen 30 mg daily to be superior to diazepam 15 mg daily in 13 of21 patients with mUltiple sclerosis. Cumming (1972) noted a trend for baclofen 30 mg daily to be

Spinal cord 18 afferent fibre

"I fusimotor

___ H response

(see glossary)

,.. __ f;;;;ib;.;;.re ____ ~ ~ Ankle jerk (phasic)

Muscle

spindle ~ Vibration (tonic)

_ ..,.--- M response ..,.... ______ ... ' (seegloesery)

a motor neurone

Muscle contraction

Fig. 1. Diagrammatic representation of the monosynaptic reflex arc from spindle organs via la afferent fibres, showing points at which the arc can be activated experimentally (after McLellan, 1973).


better than the same dose of diazepam iD. 8 patients with multiple sclerosis, but no valid conclusions could be drawn in such a small number of cases. Results obtained in these studies are summarised in table I. There was a general clinical impression that baclofen caused less sedation than would have been expected from comparable doses of diazepam.

2.2 Open Trials

In open trials involving large numbers of patients with multiple sclerosis or spasticity of purely spinal or cerebral origin (Ketelaerand Ketelaer, 1972;Pinto et al., 1972; Polacek and Schuppien, 1972), baclofen in individualised dosages produced some degree of amelioration of spasticity and other symptoms in about 60 to 86 % of patients.

Polacek and Schuppien (1972) reported some improvement in spasticity in 86 % of 400 patients with confirmed multiple sclerosis, although spasticity decreased appreciably or disappeared completely in only 33 % of cases. An improvement in both spasticity and paralysis occurred simultaneously in 43 % of patients. Although these investigators found no difference in the pattern of response in patients with spasticity due to cerebral or spinal cord pathology, Jerusalem (1968) and Birkmayer et al. (1967) reported that patients with spasticity due to spinal lesions improved more readily than those in whom spasticity

. was due to cerebral pathology. A similar trend was noted by Pinto et al. (1972) in 616 patients, many of whom had failed to improve on other therapy. Patients with 'cerebral' spasticity seem to be more susceptible to side-effects, as these patients had to discontinue treatment because of side-effects more often than those with 'spinal' spasticity. A trend for rigidity, clonus, automatic movement, flexor spasm, associated pain, ability to help himself and walking to improve in more patients with spasticity of spinal origin than with that due to cerebral pathology was also noted by Pinto et al. (1972) [fig. 1). Although some degree of improvement in most symptoms was reported in 60 to 85 % of patients, it was graded as 'good' or 'very good' in only 6 to 50 % of those who improved (fig. 5). Some relationship between the severity of multiple sclerosis, as indicated by difficulty in walking, and a good response to baclofen was noted by Polacek and Schuppien (1972), although the proportion of patients whose spasticity improved to some extent was nearly the same in all groups except in those only mildly affected. There was no clear relationship between the response to baclofen and the severity of spasticity (Polacek and Schuppien, 1972) or the level or extent of the spinal lesion (Burke et al., 1971 ;Paeslack and Kuhhirt, 1972). On the other hand, Pedersen et al. (1970) reported some improvement in spasticity in 57 out of a total of 69 patients, but in 21 of 22 who were only moderately affected by their disease. Leg function was better in 21, unchanged in 9 and

Tabl

e L

Sum

mar

y o

f res

ults

and

des

ign

of p

lace

bo-c

ontr

olle

d tr

ials

of b

aclo

fen

in p

atie

nts

wit

h sp

asti

city

res

ultin

g fr

om m

ulti

ple

scle

rosi

s an

d t:I:

I

from

cer

ebra

l or s

pina

l les

ions

. S- o (;

'

Aut

hor

No.

pat

ient

s D

ose

of

Dur

atio

n M

etho

d o

f R

esul

t !'! >

(a

ge)

bacl

ofen

o

f th

erap

y'

asse

ssm

ent

~ C

umm

ing

(197

2)

8 3

0m

g/d

14

day

s C

linic

al

No

clea

r di

ffer

ence

§'

30 m

g/d

diaz

epam

l

Hud

gson

and

23

30 m

g/d

10 d

ays

Clin

ical

B

aclo

fen>

pla

cebo

:;11

:1 08

Wei

ghtm

an (

1971

) (3

0-6

3)

0 ... ... Je

rusa

lem

(19

68)

30

30 m

g/d

init

iall

y,

"'21

day

s C

linic

al

Bac

lofe

n> p

lace

bo

if n

o re

spon

se

<8

0m

g/d

Jone

set a

l. (1

970)

6

(17

-41

) 15

mg/

d in

crea

sing

14

day

s C

linic

al a

nd

Bac

lofe

n> p

lace

bo

to 6

0 m

g/d

elec

trom

yogr

aphy

m

yogr

aphy

Ped

erse

n et

al.

(197

0)

15

75 m

g/d

7 da

ys

Clin

ical

B

aclo

fen>

pla

cebo

fo

r sp

asti

city

, bu

t no

t ot

her

crit

eria

1 D

urat

ion

of

trea

tmen

t wit

h ea

ch m

edic

atio

n 0'

1


worse in 15 of 45 ambulatory patients, whilst activities of daily living were improved in 12, unchanged in 21 and worse in 12. Of 16 severely incapacitated patients, 12 experienced less pain and slept better at night during baclofen therapy. Jones (1972), in a follow-up study of baclofen in 18 spastic patients, reported that by the time they were discharged 7 out of 11 who were quadriplegic on admission were able to walk with aids, and 2 out of 5 paraplegics were

~ "-.5 0

~

~ j

100

80

60

40

20

ABC

Automatic movement

A B C

Spasticity

ABC ABC

Flexor spasms Associated oain

A B C

Rigidity

100

80

60 Il e "-.5 0

40 ~

t j

20

A B

Clonus

ABC

Self·help

C

ABC

Walking

ABC

Fig. 2. Therapeutic efficacy rating (Ashworth Ratings) of baclofen in relieving various symptoms in 298 patients with multiple sclerosis (A), in 92 patients with 'spinal' spasticity (B), and in 129 patients with 'cerebral' spasticity (C) [after Pinto et al., 1972].


able to walk:. An improvement in bladder function was also noted· by Jones (1972) although other investigators (Pedersen et al., 1970; Paeslack and Kuhhirt, 1972) were unable to confirm this.

An improvement in muscle spasms associated with rheumatological diseases was reported by Mennet et al. (1972) in 50 patients given baclofen in a mean daily dosage of 40 mg. Clinical and photobadismographic assessment showed clear improvement in 86 %, and patients reported that their joints were easier to move, that they could walk for longer periods and experienced less pain due to weight bearing.

3. Animal Pharmacology

Diazepam, the most widely used agent for the treatment of spasticity at present, acts principally on supraspinal pathways such as the limbic system, the thalamus and hypothalamus. Mephenesin produces muscle relaxation by apparently depressing transmission through a number of supraspinal and spinal polysynaptic pathways. Unlike mephenesin, baclofen does not inhibit the action of strychnine, which facilitates polysynaptic reflexes by blocking the action of an inhibitory mediator. Baclofen appears to act principally at a spinal level.

Unlike previously used muscle relaxants baclofen inhibits both monosynaptic extensor and polysynaptic flexor transmission (Bein, 1972), but did not influence neuromuscular transmission. In cats, baclofen 1 to 2 mg/kg intravenously inhibited decerebrate rigidity irrespective of whether it was produced by midbrain transection or by cerebral ischaemia. This suggests an influence of baclofen on the gamma as well as on the alpha motor neurone system (fig. 3). Also, as decerebration or spinalisation did not alter the degree of reflex inhibition occurring in response to the drug, a predominantly spinal site of action seems likely (Bein, 1972) [see section 4] .

4. Mode of Action

One of the cardinal phenomena in the regulation of muscle tone is that the firing of the gamma motor neurones sets up afferent impulses via the muscle spindles (see fig. 3) which impinge on and activate the alpha motor neurones serving the related musculature. Whereas the facilitary primary spindle afferents (Ia) act monosynaptically on the alpha motor neurone, inhibitory proprioceptive afferents (II) pass through at least one interneurone and thus act polysynaptically. Alternatively, inhibitory afferents can produce presynaptic inhibition (primary afferent depolarisation) [see fig. 3]. Both alpha and gamma motor neurones are excited and inhibited by a variety of elements within the spinal cord


and by projections from higher parts of the central nervous system (fig. 3). Development of spasticity depends partly on an excess of excitatory factors and partly on a deficit of inhibitory factors.

One of the principal physiological abnormalities in spasticity is an increase in gamma motor neurone activity, lowering the threshold of the muscle spindles to stretching of the muscles (McLellan, 1973). Phasic reflexes involving velocitysensitive spindle organs and the monosynaptic reflex arc can be investigated clinically as indicated in figure 1.

The exact mode and locus of action of baclofen has not been clearly established, but the effect of the drug in inhibiting reflex transmission in decerebrate and spinal animals suggests that it at least acts on a spinal site. Also, since baclofen inhibits the monosynaptic reflex arc to the same degree in spinal and decerebrate animals, Bein (1972) assumed that it acts upon the connection that links the reflex collaterals of the Ia fibres (afferent) leading from the muscle spindles, with the efferent alpha motor neurones (fig. 3).

Studies in man also suggest that baclofen acts predominantly on the afferent pathways to the motor neurone (Burke et al., 1971). Baclofen diminishes both the length-dependent stretch reflex (secondary spindle ending responses) and, to a lesser extent, the velocity-dependent stretch reflex (Ia and alpha responses) in the human spastic quadriceps muscle (Burke et al., 1971). This would suggest that the inhibitory group II pathway from the secondary ending was more

Ib

RC = Renshaw cell PY - Pyramidal pathway IN .. Interneurone PAD = Presynaptic inhibition

Fig. 3. Di~matic representation of the spinal reflex arc (after Hilson, 1972 and Struppier. 1972). See glossary for explanation of function of nerve fibres and motor neurones.


affected than the facilitary group Ia pathway (fig. 3). The tonic stretch reflex was more affected than the tendon jerk (phasic stretch reflex), indicating that the effect of baclofen on the polysynaptic stretch reflex (tonic) in spasticity is more pronounced than its effect on monosynaptic reflexes (tendon jerk). It is possible that the pathways which inhibit Ia fibres presynaptically may be activated (Burke et al., 1971).

McLellan (1973) also noted that baclofen reduced the amplitude of monosynaptic phasic reflexes, although the tonic vibration reflex (fig. 1) was unaltered. This suggested either that baclofen does not reduce the activity of all spinal cord synapses, as suggested by Burke et al. (1971), or that the tonic vibration reflex is not a polysynaptic phenomenon.

Although animal experimental data favour a mainly spinal locus of action, certain effects of baclofen, such as the respiratory depression induced by high doses in some animal species, the enhanced integrated voltage output in the cortical EEG and the reduction of the effects of electrical stimulation of the reticular formation in cats, suggest an additional supraspinal influence (Koella, 1972).

5. Pharmacokinetic Studies

Results of studies with radio-labelled baclofen in healthy subjects indicate that it is well absorbed after oral administration, is metabolised to only a limited extent and is excreted largely in the urine.

5.1 Absorption

After oral administration of single 40 mg doses baclofen is absorbed relatively rapidly and almost completely (Faigle and Keberle, 1972); urinary recovery after an oral dose of 10.75 mg being almost the same as that after intravenous administration of an equal dose. Peak concentrations of unchanged baclofen in plasma are attained about 2 hours after an oral dose and the serum half-life is 3 to 4 hours. If the oral dose is raised from 10 to 20 mg and then to 40 mg the blood concentrations do not rise proportionately, but show a less marked increase (fig. 4).

5.2 Distribution

Distribution data in man are lacking, but studies with radio-labelled baclofen in mice and rats indicate that the drug is fairly evenly distributed in most organs and body tissues, although concentrations in the brain are low up to 30 minutes after intravenous administration. Blood levels are high initially and then

Bac1ofen: A Preliminary Report 11

decline rapidly, whereas concentrations in the brain and nerve tissue are considerably lower, but decrease much more slowly. It is thought that conditions in man may be similar, since the metabolism of baclofen did not differ greatly on the various species studied (FaigJe and Keberle, 1972).

When present in concentrations of between 0.01 and ~OO p.gJrnl, about 30 % of the drug is bound to human serum protein.

5.3 Metabolism and Excretion

Baclofen is metabolised to only a limited extent; about 85 % of an oral dose recovered in the urine and faeces being present as the unchanged drug (fig. 5). The remaining 15 % is accounted for mainly by a de-aminated product. Virtually all of a single dose is recovered in the urine and faeces within 72 hours, 80 % of this within the first 24 hours. 70 to 80 % of the recoverable drug and its metabolites is excreted in the urine (Faigle and Keberle, 1972).

6. Side-Effects

In most studies, baclofen has been relatively well tolerated and side-effects have generally been moderate to mild and have only occasionally necessitated withdrawal of therapy. Most commonly reported have been tiredness and lassitude, nausea and other gastro-intestinal upset. Occasionally reported side-effects include giddiness, asymptomatic hypotension, vomiting, mental confusion, euphoria, depreSSion, diarrhoea, headache and allergic skin reactions. Deteriora-

0.6

0.4

~ .. 0.2

234

Houn

__ 40mg

__ 20mg

____ 10mg

..... ------------8 24

Fig. 4. Blood concentrations of unchanged baclofen plus metabolites in a healthy subject after oral administration of 10, 20 and 40 mg of 14C-1abe1led baclofen (after Faigle and Keberie, 1972).


tion of the EEG was reported in 2 epileptic patients whilst receiving baclofen (Pinto et al, 1972).

Side-effects can usually be minimised by gradually increasing the dosage (see section 9). Older patients and those with cerebral lesions have tended to experience side-effects more often than younger patients or those with spinal lesions (Mennet et aL, 1972;Paeslack and Kuhhirt, 1972; Pinto et al., 1972).

In one study (Pedersen et al., 1970), muscular weakness was the main cause of a 38 % withdrawal rate. This effect, which appears to be dose-related, may be due to the fact that in some patients their spasticity allows their legs to support them. When this is abolished by treatment their legs feel weaker. Pinto et al. (1972) noted that baclofen had to be withdrawn in 4 to 5 % of patients with multiple sclerosis or spasticity of spinal origin and in 18 % of those with spasticity resulting from cerebral lesions.

Z Contra-Indications

Patients with epilepsy or a history of convulsive disorders. Baclofen may precipitate convulsions in such patients.

8. Precautions

Extreme caution should be exercised in patients with a proven history of peptic ulceration and severe psychiatric disturbances. The drug should also be

100

75

50

1 '0 III 25

6 12 24

Metabolites

UncI'Ianged substarlCe

-- - -------------_. Met8bolites

Urine Unchanged substance

48 72

Fig. 5. Excretion of unchanged baclofen and its metabolites in the urine and faeces of a healthy subject after oral administration of a single dose of 40 mg of 14 C-labelled baclofen (after Faigle and Keberle, 1972).


used with care in patients receiving antihypertensive therapy and in elderly patients with an impaired cerebrovascular system. Baclofen is of no therapeutic benefit in patients with Parkinsonism.

9. Dosage

Adults: The optimum dosage is usually between 40 mg and 60 mg daily in divided doses, but a careful adjustment is often necessary in order to meet the requirements of the individual patient. To lessen the incidence of side-effects, the dosage should commence with 5 mg 3 times daily for at least 3 days, followed by 10 mg 3 times daily for at least 3 days, then 15 mg 3 times daily for at least 3 days, and then 20 mg 3 times daily for at least 3 days. If necessary the dosage may then be slowly increased further, but a maximum of 75 to 100 mg daily should not be exceeded unless the patient is under close hospital supervision.

In occasional patients a smoother antispastic effect may be obtained by giving baclofen in 4 doses daily rather than in 3 (Jones, unpublished observations).

Baclofen should be administered with extreme caution to children under 16 years of age pending the accumulation of further clinical data.

10. Overdosage and its Treatment

Overdosage may produce hypotonia which can involve the respiratory muscles. In extreme cases this may necessitate the use of assisted respiration. Muscular flaccidity may persist for up to 3 days following recovery of consciousness (Paeslack and Kuhhirt, 1972).

Since excretion is mainly via the kidneys (section 5.3) it is important to maintain a high urinary output by means of an increased fluid intake and, if necessary, by the use of diuretics.

On rare occasions, convulsions have been noted: they mainly occur in patients with a history of epilepsy.

As there is no specific antidote to baclofen, symptomatic measures should be applied as necessary.

References

Bein. H.J.: in Dirkmllyer Spasticity - a topical survey. International Symposium, p.76 (Hans Huber, Vienna 1972).

Bergamini, L.; Brlgnolw, F.; FlIriello, R. et aL: in Dirkmtlyer Spasticity - a topical survey. International Symposium, p.173 (Hans Huber, Vienna 1972).

Baclofen: A Preliminary Report

Bfrkmllyer, 111.; DanJelczyk, W. and Weller, G.: Wiener Meclizinische Wochenschrift 117: 3 (1967).

Burke, D.; Andrews, c.J. and Knowles, L.: Journal of the Neurological Sciences 14: 199 (1971).

Olmming, R.: Postgraduate Medical Journal 48: (Oct. Suppl): 34 (1972).

Faigle, J. III. and Keberle, H.: in BiTkmayer Spasticity - a topical survey. International Symposium, p.94 (Hans Huber, Vienna 1972).

Hilson, A.: Postgraduate Medical Journal 48: (Oct. Suppl): 2S (1972).

Hudgwn, P. and Weightman, D.: British Medical Journal 4: IS (1971).

Jerusalem, F.: Nervenarzt 39: SIS (1968). Jones, R.F.: in Bfrkmayer Spasticity - a topical survey.

International Symposium, p.1I0 (Hans Huber, Vienna 1972).

Jones, R.F.; Burke, D.; Marosszeky, J.E. et al.: Journal of Neurology, Neurosurgery and Psychiatry 33: 464 (1970).

Ketelaer, c.J. and Ketelaer, P.: in BiTkmayer Spasticity -a topical survey. International Symposium, p.128 (Hans Huber, Vienna 1972).

Knutsson, E.; Lindblom, U. and Martensson, A.: in Birk· mayer Spasticity - a topical survey. International Symposium, p.IOI (Hans Huber, Vienna 1972).

14

Mclellan, D.L.: Journal of Neurology, Neurosurgery and Psychiatry 36: SSS (1973).

Mennet, P.; Ulrych, l; Ulrych, J. et al.: in BiTkmayer Spasticity - a topical survey. International Sym· posium, p.160 (Hans Huber, Vienna 1972).

l'tJ£s/ack, V. and KUhhiTt, M: in Blrkmllyer Spasticity - a topical survey. International Symposium, p.IS2 (Hans Huber, Vienna 1972).

Petimen, E.; Arlien-SObo~, P.; Grynderup, V. et ai: Acta Neurologica Scandinavica 46: 2S7 (1970).

PInto, O. De S.; Po/ikllr, M. and Lowtaiot, P.: in BiTkmayer Spasticity - a topical survey. Inter· national Symposium, p.192 (Hans Huber, Vienna 1972).

Polacek, L. and Sclwppien, 111.: in Bfrkmayer Spasticity -a topical survey. International Symposium, p.123 (Hans Huber, Vienna 1972).

Seemann, D. and 1lbu:her, H.: in BiTkmayer Spasticity - a topical survey. International Symposium, p.l86 (Hans Huber, Vienna 1972).

Struppler, A.: in Bfrkmayer Spasticity - a topical survey. International Symposium, p.9 (Hans Huber, Vienna 1972).

Thiele, R. - M: in Birkmayer Spasticity - a topical sur· vey. International Symposium, p.132 (Hans Huber, Vienna 1972).

Authors' address: R.N. Brogden, T.M. Speight and G.S. Avery, Australasian Drug Information Services, P.O. Box 34-030, Birkenhead,Auckland 10 (New Zealand).

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