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Cannabinoids in multiple sclerosis: A neurophysiological analysis

Article  in  Acta Neurologica Scandinavica · July 2020

DOI: 10.1111/ane.13313

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Received: 29 April 2020    Revised: 20 June 2020    Accepted: 29 June 2020

DOI: 10.1111/ane.13313

ORIGNAL ARTICLE

Cannabinoids in multiple sclerosis: A neurophysiological

analysis

Domizia Vecchio  | Claudia Varrasi | Eleonora Virgilio | Antonio Spagarino |

Paola Naldi | Roberto Cantello

Neurology Unit, Department of Translational

Medicine, University of Piemonte Orientale, Objectives: To investigate the action of cannabinoids on spasticity and pain in sec-
Novara, Italy ondary progressive multiple sclerosis, by means of neurophysiological indexes.

Correspondence
Roberto Cantello, Neurology Unit,
Department of Translational Medicine,
University of Piemonte Orientale. “Maggiore
della Carità” Hospital, Corso Mazzini 18,
28100 Novara, Italy.
Email: roberto.cantello@med.uniupo.it
Funding information
This study was funded by the “AGING
Project, Department of Excellence,” from
the Department of Translational Medicine,
University of Piemonte Orientale, Novara,
Italy.
Material and Methods: We assessed 15 patients with progressive MS (11 females)
using clinical scales for spasticity and pain, as well as neurophysiological variables
(H/M ratio, cutaneous silent period or CSP). Testing occurred before (T0) and during
(T1) a standard treatment with an oral spray containing delta-9-tetrahydrocannabi-
nol (THC) and cannabidiol (CBD). Neurophysiological measures at T0 were compared
with those of 14 healthy controls of similar age and sex (HC). We then compared the
patient results at the two time points (T1 vs T0).
Results: At T0, neurophysiological variables did not differ significantly between pa-
tients and controls. At T1, spasticity and pain scores improved, as detected by the
Modified Ashworth Scale or MAS (P = .001), 9-Hole Peg Test or 9HPT (P = .018), nu-
meric rating scale for spasticity or NRS (P = .001), and visual analogue scale for pain
or VAS (P = .005). At the same time, the CSP was significantly prolonged (P = .001).
Conclusions: The THC-CBD spray improved spasticity and pain in secondary pro-
gressive MS patients. The spray prolonged CSP duration, which appears a promising
tool for assessing and monitoring the analgesic effects of THC-CBD in MS.

KEYWORDS

cannabinoids, multiple sclerosis I spasticity I pain I H/M ratio I cutaneous silent period

1 |  I NTRO D U C TI O N
Currently, an oromucosal cannabinoid spray containing delta-9-tet-
rahydrocannabinol (THC) and cannabidiol (CBD) in a 1:1 ratio is ap-
proved in Italy for the treatment of resistant spasticity in multiple
1
sclerosis (MS). THC relieves spasticity by modulating muscle tone, but
it also possesses psychotropic effects, being a partial agonist of the
cannabinoid-1 receptor (CB1R). At forebrain sites, CBD antagonises
both CB1Rs and cannabinoid-2 receptors (CB2Rs) in the presence of
2
THC. Thus, the THC-CBD combination can prevent undesirable psy-
choactive effects and abuse phenomena.3 Cannabinoids also interact
with neural pathways mediating pain and inflammation at central and
peripheral sites,4,5 showing a powerful analgesic effect in different
clinical conditions, including MS.6 Despite these premises, the THC-
CBD oromucosal spray is not licensed in Italy for pain in MS.
Indeed, clinical assessment of spasticity and pain is hardly ob-
jective in everyday practice, and several questionnaires and scales
have been applied in MS.7 Possibly, neurophysiological measures
could provide more reproducible and quantitative data. Among
other variables, the H/M ratio has been suggested as a useful index
of spasticity. In fact, the beneficial effects of baclofen, a gamma-am-
inobutyric acid (GABA)-B receptor agonist, on muscle hypertonia

© 2020 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd

Acta Neurol Scand. 2020;00:1–6.  |

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2       VECCHIO et al.
was related to a reduction in the H/M ratio. 8,9 As for pain assess-
ment, the cutaneous silent period (CSP) may well be suited to test
the function of nociceptive pathways, predominantly but non-ex-
clusively at the spinal level.10 The CSP is a reflex response to painful
electrical stimulation of a cutaneous nerve, which is mainly medi-
ated by small Aδ fibres. In specific active muscles, it consists of a
transient inhibition of the ongoing electromyographic activity.11
In the present pilot study, we evaluated the effects of the THC-
CBD oromucosal spray on several clinical measures of spasticity and
pain in a cohort of Italian patients with secondary progressive MS.
At the same time, we wanted to assess whether neurophysiological
variables, such as the H/M ratio and the CSP, can represent ade-
quate means to quantify these effects. To this purpose, the patients'
electrophysiological indexes before drug administration (T0) were
first compared with those of healthy controls (HC). Subsequently,
we compared the patients' clinical and neurophysiological data while
“off” (T0) and “on” (T1) cannabinoids. At both time points, we also
measured THC-CBD plasma levels.
2 |  M E TH O DS
2.1 | Patients
Twenty-five outpatients with progressive MS complaining of severe
spasticity and pain were recruited and tested before and during can-
nabinoid therapy (T0 and T1). Patients were selected on a voluntary
basis. Exclusion criteria included (a) age below 18, (b) any relapse
or severe disease worsening, during the previous 3 months, (c) con-
comitant diagnosis of epilepsy, or severe hepatic, renal or cardiac
disease. A baseline assessment (T0) was performed before cannabi-
noid administration. Next, treatment was started in the form of an
oromucosal spray containing THC and CBD in a 1:1 ratio (SativexⓇ),
according to current clinical practice.12 Dose was increased by one
puff per day during a 2-week titration period until optimal symp-
tom relief was achieved. Patients then maintained this dose until the
control visit (T1, 4 weeks after the end of titration, 6 weeks after
T0). A maximum of 12 puffs/day was allowed. Any other ongoing
therapy was maintained unchanged throughout. Fifteen patients,
whose diagnosis was secondary progressive MS, completed the
study. None had signs of C7-T1 spinal lesions, which could influence
10
CSP measurements. Ten were excluded: three were eventually di-
agnosed with primary progressive MS; five did not repeat or tolerate
neurophysiological testing; and two dropped out due to treatment
ineffectiveness.
2.2 | Controls
Fourteen HC of similar age and sex (10 females, mean age 47.4 years,
SD 5.2) underwent a single set of electrophysiological testing, which
included the H/M ratio and the CSP (see below). Their results were
compared with those of patients at T0.
2.3 | Consent
Patients and HC gave their written informed consent to the study
after Institutional ethical approval. The study was conducted in ac-
cordance with the Helsinki Declaration.
2.4 | THC-CBD plasma levels
Each patient was tested at both T0 and T1 for plasma concentration
of THC and CBD. Peripheral venous blood was centrifuged immedi-
ately, and plasma was frozen at −20°C. Analysis was performed with
standard gas chromatography mass spectrometry.13
2.5 | Clinical testing
We used the Modified Ashworth Scale (MAS) to quantify muscle tone
on a 5-point scale, ranging from 0 (normal muscle tone) to 4 (fixed
muscle contracture).14 Shoulder, elbow, wrist, hip, knee and ankle
were tested bilaterally, and values were summed to get a total MAS
score for each subject (maximum score = 48). The 9-Hole Peg Test
(9HPT) measures manual dexterity, quantified as the time (s) taken to
place and remove nine pegs from nine holes, one at a time, as quickly
as possible.15 The Timed 25-Foot Walk (T25-FW) is a quantitative
measure of walking performances, defined as the time (s) needed to
walk 25 feet (7.6 m) as quickly as possible, but safely.16 This test was
not performed on three patients, who were unable to walk. Finally, we
asked the patients to self-quantify spasticity and pain. Spasticity was
scored on an 11-point numeric rating scale (NRS) from 0 (no spasticity)
to 10 (worst imaginable spasticity).17 Finally, the patients marked the
intensity level of their pain on a 10-cm visual analogue scale (VAS).18
2.6 | Neurophysiology
Studies were carried out between 3:00 and 5.30 pm. Subjects were
preliminarily exposed to a standard room temperature of 22°C for
about 30 min. They laid comfortably in a dimly illuminated (~30 Lux),
partially soundproof room. We used a System Plus-Myoquick ma-
chine, Micromed.
2.6.1 | H/M ratio
The M and H responses were recorded in the right soleus muscle
using surface electrodes placed over the muscle belly, according to
standard guidelines.19 The tibial nerve was stimulated at the pop-
liteal fossa. Stimulus frequency was 0.2 Hz, duration 1 ms; gain 1 mV/
division, sweep 100 ms. The M-wave was evoked by supramaximal
stimuli of the motor fibres. Then, we reduced the stimulus intensity
by 3 mA steps, recording H-waves until their disappearance. Overall,
10 shocks of decreasing intensity were given. The H/M ratio was
VECCHIO et al.
calculated as the ratio of the maximum peak-to-peak amplitudes of
the two action potentials (H and M).
2.6.2 | CSP
Recordings were obtained using standard surface electrodes on the
right abductor pollicis brevis muscle (APB). Stimulating ring elec-
trodes were placed on the second finger: the anode was applied to
the distal phalanx and the cathode to he middle phalanx. Subjects
maintained a steady APB contraction against the partially inflated
cuff of a sphygmomanometer, so to obtain a roughly appreciated
40% of maximum force. Fifteen consecutive electrical stimuli of
standard 60-mA intensity, 0.5-ms duration and 0.5 Hz frequency
were applied. These stimuli had been previously verified as clearly
supramaximal for a sensory nerve action potential and elicited pain
in all subjects. The ongoing EMG signal was monitored throughout,
and signs of fatigue implied extra intervals between the stimuli,
where appropriate. Filters were set at 30 to 10 kHz; the gain was
200 µV/division, and the sweep was 200 ms. Surface, non-rectified
EMG responses were superimposed (eg Figure 1). Then, using com-
puter cursors, we measured the CSP latency as the time (ms) be-
tween the stimulus and the onset of muscle silence. CSP duration
was the time (ms) between the onset and the ending of silence.11
2.7 | Statistics
Statistical analysis was performed using a dedicated software (SPSS
ver. 22.0, IBM Corp). We obtained grouped data for the clinical and
neurophysiological variables and expressed them as mean (±SEM
or SD) or median values (range: min-max) according to their distri-
bution. To compare neurophysiological results between patients
at T0 and HC, we used non-parametric Mann-Whitney U test for
F I G U R E 1   Typical example of a cutaneous silent period (CSP)
recording in patient # 8. Superimposition of 5 sweeps. CSP duration
(white arrows) increases 4 wk after reaching the optimal delta-
9-tetrahydrocannabinol-cannabidiol (THC-CBD) dose (T1), as
compared with baseline determination (T0). Black arrows: electrical
stimuli to the second finger
      3 |
independent samples. Within the patient group, all results at T0
and T1 were compared using non-parametric Wilcoxon signed rank
tests for each pair of values. For each clinical and neurophysiologi-
cal variable, we measured the changes following treatment as delta
percentages (%T1-T0). To evaluate any association between these
deltas, we performed Spearman's rank correlations (MAS, NRS or
9HPT with H/M ratio; VAS with CSP duration). Finally, to detect
predicting factors for the delta (%T1-T0) in CSP duration, we in-
cluded this variable (after log transformation for normal distribu-
tion) in a linear regression model. P values < .05 were considered
significant, and Bonferroni correction for multiple comparisons was
applied.
3 | R E S U LT S
3.1 | Demography and THC-CBD plasma levels
Table 1 summarizes the patients' general features, as well as their
THC-CBD doses and plasma levels (the latter were not detectable at
T0). The 15 patients included (mean age: 55.5 years) presented with
a long disease duration (mean: 17.4 years) and moderate disability
prior to cannabinoid treatment (median Expanded Disability Status
Scale or EDSS = 6). The median THC-CBD dose associated with pain
relief (T1) was 5.5 puffs/day. No patient reported significant adverse
events, although 3 complained of mild drowsiness.
3.2 | Clinical testing
Table 2 summarizes the results. At T1, spasticity scores on the MAS
were significantly decreased, with a median delta of 10 points.
Manual abilities, as tested by the 9HPT, also improved significantly.
Furthermore, patients reported a significant reduction on the spas-
ticity NRS at T1 (median score from 7 to 4), but no change on the
T25-FW. Pain complaints, according to the VAS, diminished at T1
in 10 (67%) patients, while the median value decreased from 5 to 2.
TA B L E 1   Features of the multiple sclerosis (MS) patients (n = 15)
MS patient features
Age: mean ± SD (y) 55.5 ± 5.2
Females: N, % 11, 73%
Disease duration: mean ± SD (y) 17.4 ± 6.2
EDSS: median, min-max 6, 2-8
Puffs per day at T1: median, min-max (N) 5.5, 3-7
THC plasma level at T1: mean ± SD (ng/mL) 1.2 ± 0.4
CBD plasma level at T1: mean ± SD (ng/mL) 1.6 ± 0.9
Note: T1: measurement at 4 wk after the attainment of the optimum
individual THC-CBD dose.
Abbreviations: CBD, cannabidiol; EDSS, Expanded Disability Status
Scale; THC, delta-9-tetrahydrocannabinol.
 |
4       VECCHIO et al.

TA B L E 2   Clinical testing in multiple sclerosis (MS) patients

(n = 15) at T0 and T1

Scale and test scores T0 T1 P-value

MAS: median, min-max 14, 4-32 4, 1-16 .001

9HPT: mean ± SEM (s) 46.0 ± 13.4 42.3 ± 14.8 .018
T25-FW: mean ± SEM (s) 21.6 ± 14.0 22.4 ± 9.5 .6
NRS: median, min-max 7, 2-10 4, 0-6 .001
VAS: median, min-max 5, 1-10 2, 0-8 .005

Note: Group values. T0 = baseline determination. T1: see Table 1.

Abbreviations: 9HPT, 9-Hole Peg Test; MAS, Modified Ashworth Scale; F I G U R E 2   Cutaneous silent period (CSP) duration in multiple
NRS, numeric rating scale for spasticity; T25FW, Timed 25-Foot Walk* sclerosis patients (MS) and healthy controls (HC). Group values. The
(*three patients unable to walk); VAS, visual analogue scale for pain. CSP is prolonged in MS at T1. Bars represent SEM. *P = .001 on the
Significant P values in bold Wilcoxon signed rank test. Other abbreviations: see Figure 1

3.3 | Neurophysiology
At T0, the H/M ratio, and CSP duration and latency did not differ
significantly in MS patients and HC. The mean H/M ratio (%) was
0.4 ± 0.1 in MS patients vs 0.3 ± 0.1 in HC (P = .5). The CSP duration
(ms) was 39.0 ± 4.3 in the MS and 38.9 ± 2.0 in the HC group (P = .9).
The CSP latency (ms) was 81.0 ± 2.1 and 83.4 ± 3.6, respectively
(P = .8). Such latency values remind those of the I2 inhibitory period
typical of the CSP.11 We were not able to properly dissect the I1, E2
and I2 phases11 on the raw, non-averaged EMG signal.
At T1, the H/M ratio (%) remained unchanged in MS patients
(0.5 ± 0.2; P = .5 vs T0). On the contrary, the CSP duration (ms) was sig-
nificantly longer (47.9 ± 6.2; P = .001; Figures 1 and 2). Individually, all
patients but one displayed an increased CSP duration at T1. Moreover,
the group CSP latency (ms) did not change (83.7 ± 4.1; P = .9).
3.4 | Correlations
We found no correlation (Spearman's rho) between the changes in
the clinical scales and the neurophysiological indexes of both spastic-
ity and pain. In a linear regression analysis, the change in CSP dura-
tion was the dependent variable, and the independent factors were
age, spasticity (MAS, NRS) and pain (VAS) scores at T0, final number
of puffs per day, THC and CBD plasma levels at T1. None of these
factors showed a relationship to the CSP duration (F (7,1) = 0.7, P = .7,
2
R  = .8).
4 |  D I S CU S S I O N
1,6
Consistently with previous reports, we found that a currently
available THC-CBD oromucosal spray could relieve not only spas-
ticity, but also pain in patients with secondary progressive MS.
Improvement in spasticity was clinically evident, but the H/M ratio
did not describe it reliably. By contrast, clinical and neurophysiologi-
cal measures of pain converged, since cannabinoid-related benefit
corresponded to a significant (P = .001) prolongation of CSP.
As for spasticity, the scores on the MAS, the 9-HPT and the
patient perception, detected by the NRS, improved significantly
(P  = .001) at T1, that is 4 weeks after reaching the optimal drug
dose. The T25-FW revealed no change in gait, as if the functional
relief had been greater in the upper than the lower limb. Similarly,
the H/M ratio did not change, nor did it show any difference be-
tween patients and controls at T0. We delivered a fixed number of
stimuli at decrements of 3 mA, which could imply the possibility of
having missed the largest H-waves. Besides, Pinelli and Valle20 were
the first to report a failure of the H/M ratio as an index of spas-
ticity. Yet—shortly after—Angel and Hoffman21 were keen to revive
the method, but they could not clearly establish its effectiveness.
Matthews22 reached similar conclusions. Later, however, the H/M
ratio was re-proposed in MS, since other authors23 demonstrated
an H/M ratio depression after oral or intrathecal administration of
baclofen, a GABA-B receptor agonist. Similar results were described
by other groups in patients with spasticity of various etiologies8 and
in childhood cerebral palsy.9 However, further attempts at evaluat-
ing the action of cannabinoids in MS using the H/M ratio led to re-
peated failures. 24-26 Possibly, the H/M ratio lacks sensitivity, since it
assesses solely the Ia monosynaptic reflex, with simultaneous exci-
tation of Ib afferents, and involves just a fraction of alpha-motoneu-
rones.19 Moreover, spasticity involves many spinal and supraspinal
pathways that are not adequately investigated by the H/M ratio. 27
Reduction in hypertonia, as a tonic phenomenon, and suppression
of phasic spinal reflexes may show a clear-cut dissociation after in-
trathecal baclofen. 28 Additionally, psychogenic triggers due to stress
and anxiety can spuriously alter the H/M ratio22 and even play a role
in the origin of MS spasticity itself. 29
As for pain, this represents one of the most disabling and un-
der-treated symptoms of MS.30 Indeed, all of our patients were
complaining of pain at baseline assessment (T0), as documented by
the VAS. Though this self-reported scale offers a subjective assess-
ment, which cannot distinguish between different pain varieties, it
is widely used.31 At T1, the group VAS scores dropped significantly
(P = .005), which corresponded to an individual decrease in 67% of
the patients. Meanwhile, plasma cannabinoid levels were within the
expected range, considering the high pharmacokinetic variability of
VECCHIO et al.
these compounds.13 The favourable impact of THC-CBD on MS pain
6
is fully in line with prior experience. At the same time, several au-
thors stressed the need for neurophysiogical markers of this effect.
Laser-evoked potentials proved abnormal prior to medication but did
not change while on cannabinoid therapy.32 Conversely, THC-CBD
increased the threshold and decreased the area of the RIII, a compo-
nent of the lower limb flexion reflex, which is mediated by Aδ fibres.24
This parameter might, however, be biased by large inter-individual
variability.33
On the other hand, the CSP is well-reproducible and easy to obtain
using standard protocols. It also allows a rather immediate interpre-
tation.11 Its generation involves complex mechanisms, but the core is
excitation of slow-conducting, small-diameter A-δ fibres. Once in the
spinal cord, these activate propriospinal pathways, which can finally
depress the spinal motor nuclei, through one of several theoretically
possible inhibitory mechanisms.11 The CSP is a protective (“nocif-
ensive”) reflex and is generally preserved in neuropathic pain.10 By
contrast, it was found altered in the fibromyalgia syndrome, though
findings were sometimes contradictory.10 Heterotopic painful stim-
ulation34 and TENS35 were shown to lead to CSP shortening. Few
studies investigated drug influences on the CSP. Fentanyl, an opiate,
36
did not change CSP features. Also, in a preliminary report, THC
(alone) had no effect on the CSP in normal subjects.37 The opposite
was true for inhibitors of serotonin reuptake and tramadol, which
prolonged the CSP in the upper limb.38,39 Our patients showed no
difference in CSP compared with healthy controls at baseline (T0).
Though MS pain was ill-defined in the present study, we thus assume
it did not affect per se the CSP circuitry. By contrast, the THC-CBD
combination significantly (P = .001) prolonged the CSP. Hence, THC-
CBD strengthened the spinal inhibitory action of the A-δ afferent vol-
leys. Unfortunately, we found no correlation between this effect and
pain reduction. This may simply reflect lack of statistical power, but
may also question the significance of the CSP lengthening itself. The
CSP is an acute response to transient painful neural stimuli, whereas
patients were complaining of chronic, mixed pain. Underlying mecha-
nisms of the two conditions are somehow different. Thus, we cannot
exclude that CSP lengthening was a local epiphenomenon of a more
complex or widespread drug effect. CB1Rs are found at several stra-
tegical sites in the CNS, such as cortical areas, basal ganglia, hippo-
campus, cerebellum, and particularly thalamus and amygdala. Also,
these receptors are expressed in the midbrain periaqueductal grey
matter, and in the substantia gelatinosa of the dorsal horn, which play
a key role in the inhibitory (descending) modulation of pain transmis-
sion. In periphery, CB1Rs are found on some C-fibres and more often
on myelinated A-β fibres. Here, CB1R activation by cannabinoids
40
suppresses nociceptive transmission in the spinal cord. Moreover,
peripheral activation of CB1Rs and CB2Rs may prevent the release
of proinflammatory molecules by non-neuronal cells (eg mast cells)
close to nociceptive neuron endings.4,5 The THC-mediated activa-
2
tion of CB1Rs is antagonized by CBD at rostral CNS sites. Peripheral
transmission appeared unaffected in our patients, since CSP latency
did not change. Therefore, our CSP results can reasonably be asso-
ciated with a depressing drug action, predominant on spinal neural
|
      5
structures. Still, analgesia on its own could rely on several other ef-
fects at any of the levels mentioned above.
This study has some limitations. It was an open-label, uncon-
trolled investigation, with a relatively small sample size. Indeed, we
included only patients who could fulfil many tests “off” and “on”
treatment. Furthermore, we used NRS and VAS, which may prove
of low sensitivity and specificity. Also, pain was not categorized into
subtypes (eg neuropathic, nociceptive or spasticity-related). There
was no healthy control group “on” cannabinoids, since this was
considered unethical. For technical reasons, the EMG recordings
were not rectified, nor subjected to a post hoc averaging. Since the
number of trials (15) was enough,41 this would have led to a more
refined CSP analysis.11 The limb temperature was not monitored,
though subjects were preliminarily exposed to a warm environment.
Possibly due to lack of statistical power, we found no correlation
between the variables studied. We did not assess pain perception
associated with the test stimulus, which may have been reduced by
THC-CBD as well and which may perhaps have correlated with CSP
duration. Finally, we did not use extra neurophysiological measures
to assess supraspinal pain pathways directly. Yet, we would propose
CSP duration as promising tool for assessing and monitoring the
THC-CBD effects on pain in MS.
5 | CO N C LU S I O N S
In this pilot study, we confirmed the effectiveness of THC-CBD
oromucosal spray against spasticity and pain in secondary progres-
sive MS. In this context, the CSP acted as a promising neurophysi-
ological marker of analgesia.
AC K N OW L E D G M E N T S
We wish to thank Dr. Marco Bagnati for his technical help in dos-
ing plasma levels of cannabinoids, and Dr. Thomas Fleetwood for
language editing.
C O N FL I C T O F I N T E R E S T
The authors have no conflict of interest to disclose.
DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from
the corresponding author upon reasonable request.
ORCID
Domizia Vecchio  https://orcid.org/0000-0001-5920-9210
Roberto Cantello  https://orcid.org/0000-0001-6999-5729
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How to cite this article: Vecchio D, Varrasi C, Virgilio E,
Spagarino A, Naldi P, Cantello R. Cannabinoids in multiple
sclerosis: A neurophysiological analysis. Acta Neurol Scand.
2020;00:1–6. https://doi.org/10.1111/ane.13313