- Email: [email protected]
On the site of action of diazepam in spasticity in man
Journal of the neurological Sciences Elsevier Publishing Company, Amsterdam - Printed in The Netherlands
33
On the Site of Action of Diazepam in Spasticity in Man J. B. C O O K AND P. W. N A T H A N * Pinderfields General Hospital, Wakefield (Great Britain)
(Received 16 June, 1966)
INTRODUCTION The problem facing pharmacologists searching for new drugs for treating spasticity is to find a drug which decreases or abolishes spasticity and which does not depress higher levels of central nervous activity. All drugs which induce sleep reduce or abolish spasticity. Ethyl alcohol, ether and pentobarbital will do so in adequate doses; but there is no difference between their effects on the higher and the lower centres and so they are of no value in the treatment of spasticity. The clinical impression obtained from giving diazepam (Valium) orally to spastic patients is that it is the first drug introduced which reduces spasticity without producing so much drowsiness that its beneficial effect is rendered useless. This impression has recently been confirmed by WILSON AND MCKECHNIE (1966), who gave the drug orally in a double-blind, cross-over trial to 21 patients with spastic paraplegia or paraparesis. Because diazepam seems to us to be the first drug to be introduced which is useful in the treatment of spasticity, we thought it desirable to investigate its mode and site of action in man. The first question to which an answer was sought was whether diazepam achieves its effect by acting on the spinal cord or on structures within the brain. Some of its effects are obviously upon higher neural activity and the manufacturers of the drug state that it achieves its effects by acting upon the reticular formation. However, it seemed to be important to determine whether some of its effects in reducing spasticity are due to its actions upon spinal mechanisms. We therefore decided to give the drug in a dosage adequate to reduce spasticity to two groups of patients, viz., those with the spinal cord totally divided and thus deprived of supraspinal influences and those with the spinal cord partially divided. If the drug were found to act equally in both groups, it could be concluded that it acts, at least to some extent, upon spinal mechanisms; this effect would be independent of any other actions it might have on supraspinal levels of the neuraxis. * Member external scientificstaff, Medical Research Council, National Hospital for Nervous Diseases, Queen Square, London. J. neurol. Sci. (1967) 5:33-37
34
J . B . COOK, P. W. NATHAN
MATERIAL AND METHODS
Patients were selected in whom it was known that there was only one lesion causing the spasticity and that this lesion was in the spinal cord at a known level. Of the 10 patients investigated, 5 had total division and 5 partial division of the spinal cord. In 7, the lesion was due to trauma, in 2 to proved epidural abscess and in 1 to a massive herniation of a single cervical intervertebral disc, seen at laminectomy. The patients were assessed before and after being given 20 mg of diazepam intravenously. The drug was given intravenously so as to obtain an adequate dosage within a short time, to avoid any possible variation in the blood level due to impaired absorption, and in order to allow a fixed period for testing the effect on spasticity at known times after the full dose had entered the blood stream. The methods of judging the effect of the drug were by filming, electromyography (EMG), and clinical examination. A programme was planned for every patient so that the most marked features of his or her spasticity were recorded. The same programme of clinical examination was filmed before and after the administration of the drug. The films were later cut and edited so that in the final film every action carried out before diazepam preceded the same action after diazepam. In this way an adequate visual comparison of the effect of the drug on that particular action could be obtained. The films were then seen by both of us and by one independent observer. It was perhaps surprising that there was complete agreement on this assessment in each case, each observer making notes independently. The E M G was also recorded using surface electrodes before, after, and in most cases during the administration of the drug. Stick-on surface electrodes were applied symmetrically to four representative muscles in each leg, and the E M G was recorded simultaneously from all eight muscles on an 8-channel Offner 'T' inkwriting electroencephalograph. The timing channel was used as an event marker. If there was any spontaneous activity of the musculature of the lower limbs, this was recorded during the 3-5 minutes when the drug was being given intravenously. The programme of examination was then repeated during the hour following administration of the drug. The muscles examined were those most likely to be activated in each patient. Manoeuvres used to bring out spasticity were stimulation by attaching crocodile clips to the feet, pricking, spraying the lower limbs with ethyl chloride, inducing the plantar responses in the usual clinical manner, squeezing muscles and applying stretch to the limbs. The E M G records were judged as follows. The general appearance of the record before and after administration of the drug was noted. This sometimes showed very obvious differences, there being periods of minutes with some activity on one occasion and with no activity on other occasions. Obvious differences in amplitude were noted. This was permissible because no change in the recording conditions was made before and after the administration of the drug. The duration of motor unit activity in each muscle following application of the stimuli mentioned above was measured before and after the drug. Clinical examination consisted of the observation of movements and reactions throughout the whole programme of filming and E M G testing. It included such rouJ. neurol. Sci. (1967) 5 : 3 3 - 3 7
-,.,I
t~ ..
~D
• •
f~
31
38
39
18
41
T.B.
J.C.
E.W.
P.F.
W.H.
35
57
D.B.
G.R.
52
H.N.
23
34
M.G.
D.J.
Age
Name
T7
T5
C5
C5
C~
T8
Te
T5
C5
C5
Segmental level of lesion
mg
trauma
trauma
trauma
trauma
trauma
trauma
epidural abscess
epidural abscess
1 year
5 years
3 years
1 year
3 years
1 year
10 years
6 months
4 years
6 months
Duration of paralysis
total
total
total
total
total
partial
partial
partial
partial
partial
Extent of cord division
÷
marked
÷
÷
÷
÷
moderate
÷
+
÷
÷
marked
÷ ÷
none
÷
÷
slight
Effect - electromyography
+
+
÷
+
slight
Effect -film moderate
D I A Z E P A M I N T R A V E N O U S L Y O N S P A S T I C I T Y I N l 0 P A T I E N T S W I T H LESIONS O F T H E S P I N A L C O R D
disc herniation
trauma
Cause of lesion
E F F E C T OF 2 0
TABLE 1
+
+
÷
none
N >.
Z
o
36
J . B . COOK, P. W. NATHAN
tine tests as elevating one lower limb with a hand in the popliteal fossa and then letting the limb fall back on to the bed; obtaining clonus; and inducing stretch reflexes by pressing on the knees or on the abdomen. Voluntary movements were examined when they were present and walking was studied in those patients who were able to walk. In order to show that the patient was not too drowsy as a result of the drug to make a muscular effort, he was required to press a hand dynamometer at 5-rain intervals both before and after the administration of the drug.
RESULTS
The effect of the drug is shown in Table 1. The first 5 patients had partial spinal cord lesions, the second 5 had total lesions. The effects, as judged by 3 observers of the film, are categorized as marked, moderate, slight or none and the same categories were used in judging the effect of the drug upon the EMG. It will be seen from these data that there was no significant difference in the effect of the drug whether the spinal cord was totally or partially divided.
DISCUSSION
The results obtained show that aside from any action on supraspinal structures, diazepam also achieves an effect on spasticity either by acting on the spinal cord or possibly by acting in the periphery, presumably at the myoneural junction. It remains to be shown that the drug does not act peripherally; there is some indefinite evidence to suggest that it could have such an effect. DIEMATH AND HEPPNER (1963) found no effect in their investigations of the action of diazepam when they used the rat masseter preparation of EICHHOLTZet al. (1949); but they did obtain an effect when they used the rat phrenic-diaphragm preparation; however, this was obtained only when they used enormous doses, such as 1.5 mg ofdiazepam per rat. HEPPNER (personal communication) confirms that no peripheral effect occurs with normal doses, such as are used in clinical medicine. Throughout all our trials, the patient squeezed a dynamometer with his two hands on several occasions before and after administration of the drug. No loss of power of handgrip was found after the drug. Further, as some patients with spasticity showed an improvement in voluntary movements after receiving the drug, it would seem unlikely that the drug made them weaker by acting on all skeletal muscles at the myoneural junction. To settle this point, 20 mg ofdiazepam was given intravenously to 1 normal subject, aged 25 years. The anterior tibial nerve was stimulated supramaximallyjustproximal to the ankle and the muscle action potential so produced was recorded from the extensor digitorum brevis. The action potential due to single and 3/sec shocks was recorded before, during and after the injection of diazepam. There was no change in the amplitude or in the form of the evoked potential with either kind of stimulation. It was concluded that the drug does not act on peripheral nerves, the myoneural junction, or upon the somatic musculature, and whatever effect it has must be due to its action on the spinal cord and/or supraspinal structures. J. neurol. Sci. (1967) 5:33-37
SITE OF ACTIONOF DIAZEPAMIN SPASTICITYIN MAN
37
The effect of the drug on spasticity does not run parallel with its effect on the higher centres of the brain. Once or twice in our experiments a patient was made so somnolent that his limbs could be pricked or raised and dropped on to the bed without his appearing to notice it and yet at the same time there was little effect on spasticity. Although our method of using the E M G gave us records and measurements which could be compared, the effect of the drug on spasticity was less obvious in the E M G recordings than it was on clinical examination or on reviewing the films. From an examination of the E M G records, it was found that the main effect was that there was less spread of response to distant muscles after noxious or cutaneous stimulation. Why the drug works in some patients and not in others is a question which remains to be investigated.
SUMMARY Twenty mg of diazepam was given intravenously to 5 patients with complete division and to 5 patients with partial division of the spinal cord. It was found that in both groups of patients the drug could be effective or ineffective against spasticity. It is concluded that whatever other actions diazepam has on the nervous system, some of its effects in damping down spasticity must be due to an action of the drug upon the spinal cord. REFERENCES
DIEMATH,H. E. AND F. HEPPNER(1963) Reizeffekte und elektroenzephalographische Tiefen- und Skalpableitung wiihrend der Verabreichung von Valium bei stereotaktischen Hirnoperationen, Muskel undPsyche Syrup., Wien, Karger, Basle and New York, 1964. EICHHOLTZ,F., R. HOTOVYANDH. ERDNISS(1949) Eine einfache Methode der Myographie und deren Anwendung, Arch. int. Pharmacodyn., 80: 62-68. WILSON,L. A. ANDA. A. McKECHNIE(1966) Oral Diazepam in the treatment of spasticity in paraplegia, Scot. med. J., 11 : 46-51.
J. neurol. Sci. (1967) 5:33-37
33
On the Site of Action of Diazepam in Spasticity in Man J. B. C O O K AND P. W. N A T H A N * Pinderfields General Hospital, Wakefield (Great Britain)
(Received 16 June, 1966)
INTRODUCTION The problem facing pharmacologists searching for new drugs for treating spasticity is to find a drug which decreases or abolishes spasticity and which does not depress higher levels of central nervous activity. All drugs which induce sleep reduce or abolish spasticity. Ethyl alcohol, ether and pentobarbital will do so in adequate doses; but there is no difference between their effects on the higher and the lower centres and so they are of no value in the treatment of spasticity. The clinical impression obtained from giving diazepam (Valium) orally to spastic patients is that it is the first drug introduced which reduces spasticity without producing so much drowsiness that its beneficial effect is rendered useless. This impression has recently been confirmed by WILSON AND MCKECHNIE (1966), who gave the drug orally in a double-blind, cross-over trial to 21 patients with spastic paraplegia or paraparesis. Because diazepam seems to us to be the first drug to be introduced which is useful in the treatment of spasticity, we thought it desirable to investigate its mode and site of action in man. The first question to which an answer was sought was whether diazepam achieves its effect by acting on the spinal cord or on structures within the brain. Some of its effects are obviously upon higher neural activity and the manufacturers of the drug state that it achieves its effects by acting upon the reticular formation. However, it seemed to be important to determine whether some of its effects in reducing spasticity are due to its actions upon spinal mechanisms. We therefore decided to give the drug in a dosage adequate to reduce spasticity to two groups of patients, viz., those with the spinal cord totally divided and thus deprived of supraspinal influences and those with the spinal cord partially divided. If the drug were found to act equally in both groups, it could be concluded that it acts, at least to some extent, upon spinal mechanisms; this effect would be independent of any other actions it might have on supraspinal levels of the neuraxis. * Member external scientificstaff, Medical Research Council, National Hospital for Nervous Diseases, Queen Square, London. J. neurol. Sci. (1967) 5:33-37
34
J . B . COOK, P. W. NATHAN
MATERIAL AND METHODS
Patients were selected in whom it was known that there was only one lesion causing the spasticity and that this lesion was in the spinal cord at a known level. Of the 10 patients investigated, 5 had total division and 5 partial division of the spinal cord. In 7, the lesion was due to trauma, in 2 to proved epidural abscess and in 1 to a massive herniation of a single cervical intervertebral disc, seen at laminectomy. The patients were assessed before and after being given 20 mg of diazepam intravenously. The drug was given intravenously so as to obtain an adequate dosage within a short time, to avoid any possible variation in the blood level due to impaired absorption, and in order to allow a fixed period for testing the effect on spasticity at known times after the full dose had entered the blood stream. The methods of judging the effect of the drug were by filming, electromyography (EMG), and clinical examination. A programme was planned for every patient so that the most marked features of his or her spasticity were recorded. The same programme of clinical examination was filmed before and after the administration of the drug. The films were later cut and edited so that in the final film every action carried out before diazepam preceded the same action after diazepam. In this way an adequate visual comparison of the effect of the drug on that particular action could be obtained. The films were then seen by both of us and by one independent observer. It was perhaps surprising that there was complete agreement on this assessment in each case, each observer making notes independently. The E M G was also recorded using surface electrodes before, after, and in most cases during the administration of the drug. Stick-on surface electrodes were applied symmetrically to four representative muscles in each leg, and the E M G was recorded simultaneously from all eight muscles on an 8-channel Offner 'T' inkwriting electroencephalograph. The timing channel was used as an event marker. If there was any spontaneous activity of the musculature of the lower limbs, this was recorded during the 3-5 minutes when the drug was being given intravenously. The programme of examination was then repeated during the hour following administration of the drug. The muscles examined were those most likely to be activated in each patient. Manoeuvres used to bring out spasticity were stimulation by attaching crocodile clips to the feet, pricking, spraying the lower limbs with ethyl chloride, inducing the plantar responses in the usual clinical manner, squeezing muscles and applying stretch to the limbs. The E M G records were judged as follows. The general appearance of the record before and after administration of the drug was noted. This sometimes showed very obvious differences, there being periods of minutes with some activity on one occasion and with no activity on other occasions. Obvious differences in amplitude were noted. This was permissible because no change in the recording conditions was made before and after the administration of the drug. The duration of motor unit activity in each muscle following application of the stimuli mentioned above was measured before and after the drug. Clinical examination consisted of the observation of movements and reactions throughout the whole programme of filming and E M G testing. It included such rouJ. neurol. Sci. (1967) 5 : 3 3 - 3 7
-,.,I
t~ ..
~D
• •
f~
31
38
39
18
41
T.B.
J.C.
E.W.
P.F.
W.H.
35
57
D.B.
G.R.
52
H.N.
23
34
M.G.
D.J.
Age
Name
T7
T5
C5
C5
C~
T8
Te
T5
C5
C5
Segmental level of lesion
mg
trauma
trauma
trauma
trauma
trauma
trauma
epidural abscess
epidural abscess
1 year
5 years
3 years
1 year
3 years
1 year
10 years
6 months
4 years
6 months
Duration of paralysis
total
total
total
total
total
partial
partial
partial
partial
partial
Extent of cord division
÷
marked
÷
÷
÷
÷
moderate
÷
+
÷
÷
marked
÷ ÷
none
÷
÷
slight
Effect - electromyography
+
+
÷
+
slight
Effect -film moderate
D I A Z E P A M I N T R A V E N O U S L Y O N S P A S T I C I T Y I N l 0 P A T I E N T S W I T H LESIONS O F T H E S P I N A L C O R D
disc herniation
trauma
Cause of lesion
E F F E C T OF 2 0
TABLE 1
+
+
÷
none
N >.
Z
o
36
J . B . COOK, P. W. NATHAN
tine tests as elevating one lower limb with a hand in the popliteal fossa and then letting the limb fall back on to the bed; obtaining clonus; and inducing stretch reflexes by pressing on the knees or on the abdomen. Voluntary movements were examined when they were present and walking was studied in those patients who were able to walk. In order to show that the patient was not too drowsy as a result of the drug to make a muscular effort, he was required to press a hand dynamometer at 5-rain intervals both before and after the administration of the drug.
RESULTS
The effect of the drug is shown in Table 1. The first 5 patients had partial spinal cord lesions, the second 5 had total lesions. The effects, as judged by 3 observers of the film, are categorized as marked, moderate, slight or none and the same categories were used in judging the effect of the drug upon the EMG. It will be seen from these data that there was no significant difference in the effect of the drug whether the spinal cord was totally or partially divided.
DISCUSSION
The results obtained show that aside from any action on supraspinal structures, diazepam also achieves an effect on spasticity either by acting on the spinal cord or possibly by acting in the periphery, presumably at the myoneural junction. It remains to be shown that the drug does not act peripherally; there is some indefinite evidence to suggest that it could have such an effect. DIEMATH AND HEPPNER (1963) found no effect in their investigations of the action of diazepam when they used the rat masseter preparation of EICHHOLTZet al. (1949); but they did obtain an effect when they used the rat phrenic-diaphragm preparation; however, this was obtained only when they used enormous doses, such as 1.5 mg ofdiazepam per rat. HEPPNER (personal communication) confirms that no peripheral effect occurs with normal doses, such as are used in clinical medicine. Throughout all our trials, the patient squeezed a dynamometer with his two hands on several occasions before and after administration of the drug. No loss of power of handgrip was found after the drug. Further, as some patients with spasticity showed an improvement in voluntary movements after receiving the drug, it would seem unlikely that the drug made them weaker by acting on all skeletal muscles at the myoneural junction. To settle this point, 20 mg ofdiazepam was given intravenously to 1 normal subject, aged 25 years. The anterior tibial nerve was stimulated supramaximallyjustproximal to the ankle and the muscle action potential so produced was recorded from the extensor digitorum brevis. The action potential due to single and 3/sec shocks was recorded before, during and after the injection of diazepam. There was no change in the amplitude or in the form of the evoked potential with either kind of stimulation. It was concluded that the drug does not act on peripheral nerves, the myoneural junction, or upon the somatic musculature, and whatever effect it has must be due to its action on the spinal cord and/or supraspinal structures. J. neurol. Sci. (1967) 5:33-37
SITE OF ACTIONOF DIAZEPAMIN SPASTICITYIN MAN
37
The effect of the drug on spasticity does not run parallel with its effect on the higher centres of the brain. Once or twice in our experiments a patient was made so somnolent that his limbs could be pricked or raised and dropped on to the bed without his appearing to notice it and yet at the same time there was little effect on spasticity. Although our method of using the E M G gave us records and measurements which could be compared, the effect of the drug on spasticity was less obvious in the E M G recordings than it was on clinical examination or on reviewing the films. From an examination of the E M G records, it was found that the main effect was that there was less spread of response to distant muscles after noxious or cutaneous stimulation. Why the drug works in some patients and not in others is a question which remains to be investigated.
SUMMARY Twenty mg of diazepam was given intravenously to 5 patients with complete division and to 5 patients with partial division of the spinal cord. It was found that in both groups of patients the drug could be effective or ineffective against spasticity. It is concluded that whatever other actions diazepam has on the nervous system, some of its effects in damping down spasticity must be due to an action of the drug upon the spinal cord. REFERENCES
DIEMATH,H. E. AND F. HEPPNER(1963) Reizeffekte und elektroenzephalographische Tiefen- und Skalpableitung wiihrend der Verabreichung von Valium bei stereotaktischen Hirnoperationen, Muskel undPsyche Syrup., Wien, Karger, Basle and New York, 1964. EICHHOLTZ,F., R. HOTOVYANDH. ERDNISS(1949) Eine einfache Methode der Myographie und deren Anwendung, Arch. int. Pharmacodyn., 80: 62-68. WILSON,L. A. ANDA. A. McKECHNIE(1966) Oral Diazepam in the treatment of spasticity in paraplegia, Scot. med. J., 11 : 46-51.
J. neurol. Sci. (1967) 5:33-37