Contents

Muscle Spasm and Spasticity: Role of Centrally Acting Muscle Relaxants

Muscle Spasm and Spasticity..............................................................................................................................................01

Tolperisone (Tolfree)
Introduction to Tolperisone....................................................................................................................................................04
Chemistry...........................................................................................................................................................................................04
Mechanism of Action..................................................................................................................................................................05
Muscle Relaxant Activity: Blockade of Sodium and Calcium Channel

Clinical Pharmacokinetic........................................................................................................................................................06
Absorption
Metabolism
Excretion

Validating Clinical Indications.............................................................................................................................................09

Neurolathyrism
Post-cerebral Stroke Spasticity
Efficacy of Tolperisone on Post-exercise Muscle Soreness
Painful Reflex Muscle Spasm
Muscle Relaxant Effect of Tolperisone on Experimentally Induced
Jaw-muscle Pain and Jaw-stretch Reflexes
Low Back Pain Syndrome
Evaluation of Sedative Activity of Tolperisone

Dosage Recommendations.....................................................................................................................................................15
Toxicology and Side-effects...................................................................................................................................................15
Contraindications.........................................................................................................................................................................16
Precautions.......................................................................................................................................................................................16
Place in Therapy............................................................................................................................................................................16
How Supplied...................................................................................................................................................................................17

References.........................................................................................................................................................................................18
 Muscle Spasm and Spasticity:
Role of Centrally Acting
Muscle Relaxants

pasticity is defined as a motor disorder normally feed the muscles and supply oxygen,

S characterized by an abnormal velocity-

dependent increase in muscle tone with
exaggerated tendon jerks. An imbalance
between the muscle contraction and relaxation
further compounding the problem.
1

Muscle spasm could also result with spinal cord

injury, which could be observed when a muscle
process resulting due to interruption of the is stretched. Due to injury to the spinal cord,
neural circuitry regulating the muscles. these sensations can trigger the reflex resulting
2
Thereby, results in abnormal muscle movement in the muscle to contract or spasm (see Fig. 1).
and response. In addition, results in weakness
and clumsiness of voluntary movements as well Fig. 1: Muscle spasm and spasticity
as muscle stiffness and tightness.
1 pathway after spinal injury.

Spasticity is considered one of the Brain

main symptoms of the more than
2.5 million people with neurological
disorders worldwide, affecting up to Injury level
Dorsal root
60% of this population. (Sensory)

Ventral root
Muscle Spasm and Spasticity (Motor)

Muscle spasm is characterized by sudden

involuntary contraction of a muscle. Muscle
spasm is usually localized to skeletal muscle
injury or imbalance in electrolytes from
acute trauma. It could also stem form disorders
such as hypocalcemia, hypokalemia or
hyperkalemia, chronic pain syndromes, or
epilepsy. During muscle spasm, muscle freezes Spasticity is a condition in which certain
due to excessive contraction and in addition muscles are continuously contracted. It is a
results in constriction of blood vessels that motor disorder associated with lesions of the

01
nervous system. Spasticity could be the result where it travels to brain via the spinal cord, the
of damage to the portion of the brain or spinal brain further assesses the signal and if the
cord that controls voluntary movement. signal is not dangerous, an inhibitory signal
is set down the spinal cord and thus cancels
The degree of spasticity varies from the reflex from moving the muscle. Whereas,
mild muscle stiffness to severe, painful during spinal cord injury, this inhibitory signal
and uncontrollable muscle spasms. is blocked by the structural damage in the
The condition can interfere with daily cord and the natural reflex is allowed to
activities and with rehabilitation in continue resulting in a contraction of the
2
patients with certain disorders. muscle.

It can directly or indirectly change mechanical Centrally acting skeletal muscle relaxants
properties of the neuromuscular system, are so called because they act on the central
particularly in chronic patients and has been nervous system to decrease muscle tone. They
linked to impaired voluntary movement through work in the central nervous system to reduce
different mechanisms. excessive reflex activity and to allow muscle
relaxation. They decrease muscle tone by
Spasticity could be associated with variety of depressing the internuncial neurons at the
6
disorders including spinal cord injury, multiple spinal cord.
sclerosis (MS), cerebral palsy, anoxic brain
damage such as a cerebrovascular accident Spasmolytics act at the level of the
(CVA), brain trauma, severe head injury and cortex, brain stem or spinal cord, or
some metabolic diseases, such as all three areas; hence, they have
adrenoleukodystrophy and phenylketonuria.
3–5
traditionally been referred to as
"centrally-acting" muscle relaxants.
Subsequent to spinal injury, the nerve cells get
disconnected from the brain at the level of The generation of the neuronal signals in motor
injury. Due to scar tissue in the damaged area of neurons causing muscle contractions is
the spinal cord, messages form below the level dependent on the balance of synaptic excitation
of injury reaching the brain is blocked. and inhibition that the motor neuron receives.
Spasticity does not occur immediately following Centrally acting skeletal muscle relaxants
a spinal cord injury. When an injury occurs to the generally work by either enhancing the level of
spinal cord, the body goes into spinal shock. inhibition, or reducing the level of excitation.
Spasticity is an exaggeration of the normal Inhibition is enhanced by mimicking or
reflexes that occur when the body is stimulated enhancing the actions of endogenous inhibitory
2
in certain ways (see Fig. 1). In a healthy substances, such as g-amino butyric acid
6
individual, sensory signal is sent to reflex arc, (GABA).

02
When given in normal therapeutic doses, function to the extent that the bladder will not
centrally acting muscle relaxants are not potent normally contract resulting in retention of urine.
enough to produce flaccid paralysis. However, The patient should be well informed before
large oral or injectable doses of these drugs may commencing the treatment since some drugs
produce hypotension, flaccid paralysis, can alter the color of urine which may
6
sedation and respiratory depression. Many of embarrass the patient.
these drugs are similar in chemical structure to
antianxiety agents. These agents are used to Adverse effects, particularly dizziness and
relieve skeletal muscle spasms. Whether relief drowsiness are consistently reported with all
of pain achieved by patients taking these drugs skeletal muscle relaxants. The potential
is due to their muscle relaxant effect or to their adverse effects should be communicated
sedative effect is unknown.
7
clearly to the patient. Owing to the limited
comparable effectiveness data, choice of agent
Judicious dose-titration of muscle relaxants should be based on side-effect profile, patient
could help in attaining desired therapeutic preference, abuse potential and possible drug
8
benefits to the patient. The patient should be interactions.
warned not to drive, operate machinery or
perform any other task that requires Tolperisone, a centrally acting muscle relaxant
wakefulness because these drugs cause free from side-effects, is a clinically useful drug
sedation. Muscle relaxants have dose- for relieving spasticities of neurological origin
dependent effect. Excessive dosage, more than and muscle spasms associated with low back
the normal dosage could result in sedative pain (LBP) and painful locomotor diseases.
effect. In addition, it might depress muscle

03
 Tolperisone ( )
Introduction to Tolperisone
Tolperisone (Tolfree) is a recently
launched centrally acting muscle
Tolperisone, a centrally acting muscle relaxant
relaxant in India for management of
agent recently launched drug in India for acute
spasticity of neurological origin and
and chronic back pain and spasticity of
spasm related to chronic back pain.
neurological origin. It is an arylalkyl b-
aminoketone having an asymmetric carbon
According to molecular modeling studies,
atom a to the carbonyl group. Tolperisone
the similar pharmacological properties of
enantiomers have different pharmacodynamic
tolperisone and lidocaine are due to the
properties.
conformational mobility of tolperisone, allowing
! these molecules to form a conformer having the
Tolperisone has higher muscle relaxant
pharmacophore moieties (benzene ring,
activity than the levorotatory isomer,
carbonyl group and basic nitrogen atom) in
whereas the latter shows higher broncho- 9
similar spatial arrangements.
and peripherial vasodilatatory activities
than the dextrorotatory enantiomer.
Chemistry
! Tolperisone is used as a racemic mixture.
Tolperisone was initially derived from the
! Tolperisone exhibits membrane stabilizing
10
structure of cocaine. It is a piperidine
potency, which is characteristic of derivative. The chemical characteristics of
11
antiarrythmic and local anesthetic agents. tolperisone is outlined in Table 1.

Table 1: Chemistry of tolperisone

Name 4'-Methyl-2-(1-piperidinylmethyl)-propiophenone
Synonym Hydrochloride; 2,4'-Dimethyl-3 piperidinopropiophenone monohydrochloride
Molecular formula C16H23NO.HCl;C16H24ClNO
Molecular weight 281.82
Chemical structure
CH3 C CH CH2 N
O
· HCl
Source: http://www.chemblink.com/products/3644-61-9.htm.

04
 Mechanism of Action gated calcium channels. This data suggest that
tolperisone shows muscle relaxants activity by
Tolperisone causes: spinal reflex inhibitory action predominantly via
a presynaptic-inhibition of the transmitter
! Muscle relaxation by its action on central release from the primary afferent endings via a
nervous system. combined action on voltage-gated sodium and
! Dose dependent muscle relaxation. calcium channels.
13

! Membrane stabilization.
Tolperisone (Tolfree) exerts its spinal
! Analgesic activity. reflex inhibitory action predominantly
via a presynaptic inhibition of the
Being a centrally acting muscle transmitter release from the primary
relaxant, tolperisone (Tolfree) acts by afferent endings via a combined action
blocking sodium channels and is also on voltage-gated sodium and calcium
known to possess significant effect on channels.
voltage gated calcium channels.
Fukuda et al. reported that tolperisone blocks
Muscle Relaxant Activity: mono- and polysynaptic reflexes at the spinal
Blockade of Sodium and Calcium Channel level in a dose-dependent manner. In this
manner it acts as spinal reflex suppressant and
14
Exact mechanism of action of tolperisone is not causes centrally muscle relaxantion effect.
known. It was initially classified under Tolperisone causes preferential antinociceptive
antinicotinic drugs because it effectively activity against thermal stimulation that is likely
12 15
inhibited lethality induced by nicotine. to be attributed to its local anesthetic action.

Tolperisone causes depression of the ventral Although, tolperisone is a potent centrally

root reflexes and excitability of motor neurons. acting muscle relaxant, it has a low incidence
This drug has pronounced action on the of side-effects. It is useful in relieving
synaptic responses when compared to the spasticities of neurological origin and muscle
excitability of motor neurons. Tolperisone spasms associated with painful locomotor
12
causes depression of voltage-gated sodium diseases. Tolperisone mediates muscle
channel conductance at concentrations that relaxation without concomitant sedation or
inhibit spinal reflexes at the level of dorsal root withdrawal phenomena.
ganglion cells. Major mode of action of centrally
acting muscle relaxants like tolperisone is Tolperisone (Tolfree) mediate muscle
blockade of sodium channels. In addition to this relaxation without concomitant
tolperisone has a significant effect on voltage sedation or withdrawal phenomena.

05
Tolperisone blocks the propagation of action
Being a centrally acting muscle
potentials at either Ad- or C-fibers conducting
relaxant with membrane stabilizing
pain signals to the spinal dorsal horn neurons.
property, tolperisone (Tolfree) is
Local anesthetic action of tolperisone is
useful in treatment of painful
exhibited through its effect on sciatic nerves.
contraction of muscles typically
Tolperisone suppressed the propagation of low
associated with serious neurological
frequency action potentials (0.2 Hz). Such
disorders such as Lou Gehrig's
frequency-dependency is in agreement with the
disease (ALS), multiple sclerosis,
studies demonstrating that tolperisone
specially blocks the sustained repetitive firing stroke, spinal cord injury, and
of action potentials without altering the initial cerebral palsy.
firing. Since small diameter neurons are
generally more susceptible to the action of Clinical Pharmacokinetic
local anesthetics, it is therefore conceivable
that the local anesthetic action of tolperisone Pharmacokinetic profile of tolperisone varies
is attributed to it preferential analgesic action from individual to individual. There is a need for
against C-fiber-mediated thermal nociception, individualization of dosage of tolperisone while
17
leaving Ad- and C-fiber-mediated mechanical administering the therapy to the patient.
16
nociception little affected.
Tolperisone can be administered through
! Local anesthetic action of various routes (oral, intra-arterial, intrathecal,
tolperisone (Tolfree) is exhibited intraspinal, intramuscular, intraperitoneal,
through its effect on sciatic nerves. intravenous, intranasal and inhalation).
However, intramuscular, intravenous and oral
! The analgesic effect of tolperisone
are preferred routes of administration.
(Tolfree) could be derived solely Therapeutically effective dosage of tolperisone
from the blockade of peripheral ranges from approximately 75 to 1500 mg/day.
17

sodium channels of Ad- and

C-fibers. Absorption

These data indicate that tolperisone is a Tolperisone gets absorbed quickly in the body
selective inhibitor of voltage-gated sodium and peak plasma concentration is achieved
16
channels, which underlies its spinal reflex usually 0.5–1.0 hr after ingestion (see Fig. 2).
suppressant and centrally acting muscle Some of the pharmacokinetic parameters
relaxant effect. Moreover, this feature may studied are as follows:
mediate a pain relieving effect, which due to the
observed minor differences, may be freer from ! The AUC0®¥ of tolperisone is between
side-effects than in the case of lidocaine. 125.9–1,241.3 ng/mLxh

06
! The Cmax is between 64.2–784.9 ng/mL point estimate for AUC0®¥ and AUC0®t
! The tmax of tolperisone is 0.90±0.31 hr and (fed/fasted) were 1.87 and 1.92 respectively for
! The mean half-life is 1.00±0.28 hr.16 tolperisone. No significant effect of food was
observed in case of Cmax value, after tolperisone
! Bioavailability is 16.7±8.9%17
administration. Absorption was delayed with a
! Apparent volume of distribution of is mean Tmax of 1.37 hr in the fed state compared to
5.1±1.0 L/kg (mean±SD)17
18
0.66 hr in the fasted state.

In fasting condition Tmax values of unchanged Metabolism

tolperisone and 4-HM-tolperisone were 0.66 hr
(±0.16 hr) and 0.68 hr (±0.23 hr) respectively. In vitro study on metabolism of tolperisone
Whereas after food intake W values of in human liver microsomes and recombinant
unchanged tolperisone and 4-HM-tolperisone enzymes show that the main metabolic route
were 1.38 hr (±0.77 hr), indicating a delayed in human liver microsomes is methyl
absorption after food intake. Under fed hydroxylation. In addition, metabolites of two
conditions bioavailability was higher when mass units greater than the parent compound
compared to that of fasting conditions. The and the hydroxy-metabolite are also observed

Fig. 2: Average plasma concentration of tolperisone 100 mg.

1000 Tablet tolperisone 100 mg

Injection tolperisone 100 mg
500
Tolperisone concentration in plasma (ng/mL)

100

50

10

0 0.5 1.0 1.5 3 4 6 7

Time (h)

07
in the metabolism of tolperisone. The latter is CYP2D6, CYP2C19 and CYP1A2. Tolperisone is a
identified as carbonyl-reduced M1, the former competitive inhibitor of dextromethorphan
M1 is assumed to be the carbonyl-reduced O-demethylation and bufuralol hydroxylation. It
19 19
parent compound. also inhibits oxidation of methyl p-tolyl sulfide.

In vitro study on metabolism of To summarize, tolperisone undergoes both

tolperisone (Tolfree) in human liver P450-dependent and P450-independent
microsomes and recombinant microsomal biotransformations. A considerable
enzymes show that the main involvement of a microsomal reductase is
metabolic route in human liver assumed on the basis of metabolites formed
18
microsomes is methyl-hydroxylation. and indirect evidences of inhibition studies.

The prominent enzymes in metabolism of In vitro studies have demonstrated the

tolperisone are isoform-specific cytochrome involvement of both P450- dependent and
P450 (P450) inhibitors, inhibitory antibodies P450-independent microsomal biotrans-
and CYP2D6. In addition to these CYP2C19, formations are involved in tolperisone
CYP2B6 and CYP1A2 also have small role in metabolism. The proposed route for metabolic
metabolism of tolperisone. Formation of pathway is highlighted in Figure 3.
Hydroxymethyl-tolperisone is mediated by Hydroxymethyl metabolite formation revealed

Fig. 3: Proposed in vitro metabolic pathways of tolperisone.

CH3
CH3 C CH CH2 N
CYP2D6
Reductase O CYP2C19
Tolperisone CYP1A2

CYP2B6
FMO3
CH3 CH3
CH3 CH CH CH2 N M...? OH CH2 C CH CH2 N
OH O
m/t 247 M1

CH3
OH CH2 CH CH CH2 N Red Arrows indicate the
possible ways of M2 formation.
OH
Green letters are used for the assumed
M2 enzymatic processes and metabolites.

08
to be the main P450-mediated metabolic by this means acting as an adjuvant to the
pathway. The key enzymes involved in antiinflammatory agents. Tolperisone has also
metabolism through M1 formation are CYP2D6, been shown to act as an adjuvant to
CYP2C19 and CYP1A2. The P450-independent physiotherapy in relieving pain due to muscular
metabolism was mediated to a small extent by hypertonia.
20
FMO3.
Membrane stabilization property of
Excretion tolperisone (Tolfree) reduces pain in
the locomotor disease patients by
Less than 0.1% of the dose is excreted this means acting as an adjuvant to
unchanged within 24 hr in urine after I.V. the antiinflammatory agents.
administration of tolperisone. Total body
clearance of the drug is 140.8±33.8 L/hr.
19

Tolperisone differs from other myotonolytic

agents in its pharmacological properties, which
Pharmacokinetic features of mediate muscle relaxation without concomitant
tolperisone (Tolfree): sedation or withdrawal phenomena. Some of
9

the clinical indications are as follows.

! AUC0 is 125.9–1,241.3 ng/mLxh
! Cmax is 64.2–784.9 ng/mL Neurolathyrism
! tmax is 0.90±0.31 hr
! t½ is 1.00±0.28 hr Neurolathyrism is a neurologic disorder caused
! Bioavailability is 16.7±8.9% by excessive ingestion of Lathyrus species
! Apparent volume of distribution (Lathyrus sativus, L. cicera and Vicia sativa).
is 5.1±1.0 L/kg Neurolathyrism depict a pyramidal syndrome
! Total body clearance is affecting mainly the corticospinal pathways
140.8±33.8 L/hr and in a lesser grade the sensory and
21
spinocerebellar pathways of the spinal cord.
Validating Clinical Indications
Tolperisone offers symptomatic relief to
Tolperisone has been used for treating patients in stage I and stage II neurolathyrism.
neurological origin muscle spasticities and Also reduction in spastic muscle tone, stiffness
painful muscle spasms due to rheumatologic and ankle clonus were reported with
conditions. In addition, tolperisone also acts as tolperisone. Tolperisone also improved walking
an analgesic.9 ability and speed of patients with neuro-
lathyrism. The study reported tolperisone to be
Membrane stabilization property of tolperisone well-tolerated and effective drug for
21
reduces pain in the locomotor disease patients symptomatic treatment of neurolathyrism.

09
Symptomatic Treatment of Neurolathyrism muscle pain, generalized body weakness and
dizziness were recorded in patients taking the
A double-blind placebo-controlled randomized drug but all were minor and self-limited, none
21
trial in 72 patients was conducted to evaluate requiring discontinuation of treatment.
safety and efficacy of oral tolperisone in the
treatment of neurolathyrism in stages I, II Post-cerebral Stroke Spasticity
and III.
Tolperisone exhibited excellent tolerability in
Tolperisone at a dose of 150 mg twice-daily patients with spastic hypertonia following
significantly improved subjective complaints cerebral stroke. Noteworthy reductions in
such as muscle cramps, heaviness of the legs, patients with spastic hypertonia have been
startle attacks, flexor spasms and repeated observed with tolperisone. Optimized
falls. Nearly 75% patients in tolperisone had therapeutic benefits were achieved with
subjective improvement when compared with individual dose titration which exceeded the
22
the placebo group (see Fig. 4). Significant recommended dose of 450 mg daily.
reduction in spastic muscle tone, stiffness of
Achilles and spontaneous ankle clonus were Efficacy and Safety of Tolperisone in
reported with tolperisone. Tolperisone, also Spasticity following Cerebral Stroke
significantly improved locomotor function in
neurolathyrism.
21
Membrane stabilizing property of tolperisone
was evaluated for its safety and efficacy in the
Fig. 4: Subjective improvement in treatment of stroke-related spasticity. The
patients with neurolathyrism. study enrolled 120 patients and the degree of
80 spasticity was determined using Ashworth
70 scale, on the most severely affected joint area,
75
considered as a primary target parameter.
60
Treatment duration lasted for 12 weeks and was
Improvement (%)

50
initiated with a titration period of variable length
40 22
39 (dose range 300–900 mg tolperisone daily).
30
20 In majority of patients both limbs were affected
10 due to spasticity. Nearly, 62% patients were
0 treated with daily dose of >600 mg tolperisone.
Tolperisone Placebo Significant reduction in mean Ashworth score
was observed in patients receiving tolperisone,
To summarize, tolperisone effectively offered when compared with placebo. Reduction by at
symptomatic relief to patients in stage I and least 1 point on the Ashworth scale was
stage II disease. Some adverse effects like observed in nearly 78.3% patients on

10
tolperisone when compared with 45% of Twenty male volunteers were randomized to
patients in placebo group (see Fig. 5). Overall receive placebo or tolperisone (150 mg) thrice-
functional assessment confirmed superior daily for 8 days. The parameters used for
efficacy of tolperisone. Although mild-to- assessment of PPT included Likert's pain score,
moderate intensity adverse events were pain areas, range of abduction, isometric force
observed with tolperisone, no withdrawals and electromyography (EMG) root mean square
22
occurred due to them. (RMS) during maximum voluntary isometric
force on day 1 and 6, immediately after an
Fig. 5: Percentage reduction in Ashworth eccentric exercise of first dorsal interosseous
Scale. muscle and 24 and 48 hr after the exercise.

80 Treatment with placebo or tolperisone

Percentage reduction

60 hydrochloride was initiated immediately after

40
the assessments on the first day baseline
assessments. On the sixth day baseline
20 investigations were repeated and then the
0 subjects performed six bouts of standardized
Tolperisone intense eccentric exercise of first dorsal
Placebo interosseous muscle for provocation of post-
exercise muscle soreness. Perceived intensity
The study demonstrated the efficacy and of warmth, tiredness, soreness and pain during
excellent tolerability of tolperisone in treating the exercise bouts were recorded on a 10 cm
23
spastic hypertonia following cerebral stroke. VAS.
The study suggested that an individual dose
titration, which may exceed the recommended Following tolperisone administration,
maximum dose of 450 mg daily could possibly significant reduction in isometric force after
result in optimized therapeutic benefits.22 exercise was observed when compared with
placebo group. All VAS scores increased during
Efficacy of Tolperisone on Post-exercise the exercise bouts 2, 3, 4, 5 and 6 as compared
Muscle Soreness to bout 1. Increased pain scores and pain areas
were reported immediately after and 24 and 48
A study conducted by Bajaj et al. investigated hr after exercise. PPTs were reduced at 24 and
the role of tolperisone in relieving painful 48 hr after the exercise in the exercised hand.
muscle spasm. Based on spasm theory of The EMG RMS amplitude was also reduced
exercise induced pain study hypothesized that immediately after the exercise, but was
the prophylactic use of tolperisone could increased at 24 and 48 hr (see Fig. 6). Isometric
effectively relieve post-exercise muscle force was reduced immediately after the
soreness.23 exercise as compared to days 1 and 6 and the
11
24 and 48 hr post-exercise assessments with a Painful Reflex Muscle Spasm
greater reduction following the tolperisone
hydrochloride treatment and the reduction was Significant superiority of tolperisone over
more in tolperisone group as compared to the placebo in increasing threshold for pressure
placebo group. pain alleviated painful reflex muscle spasm
associated with diseases of the spinal column
Fig. 6: The time course change of the or proximal joints. More pronounced efficacy
percent reduction of pressure pain
threshold (PPT) of the first dorsal was observed in patients with complaints of
interosseous muscle in exercised hands. less than 1 year and those receiving
24
25 concomitant physiotherapy.
20
Pressure Pain Threshold

15 Clinical Efficacy of Tolperisone in

(% reduction)

10 Treatment of Painful Reflex Muscle Spasm

5
0 Pratzel et al., conducted a randomized, double-
–5 blind, placebo-controlled trial to evaluate
–10
Day-1 Day-6 Bout-6 Day-7 Day-8 efficacy and safety of oral tolperisone for the
treatment of painful reflex muscle spasm. The
Placebo Tolperisone hydrochloride
study enrolled patients with painful reflex
muscle spasm associated with diseases of the
The results suggest that the prophylactic use of spinal column or proximal joints. All patients
tolperisone produced reduction in isometric were randomized to receive either 300 mg
force but no relief to pain in course of post- tolperisone or placebo for a period of 21 days.
24
23
exercise muscle soreness (see Fig. 7). Tolperisone was found to be significantly
Fig. 7: The time course change of the
superior to placebo; thereby increasing pain
percent reduction of isometric force of threshold as the primary target parameter (see
first dorsal interosseous muscle in Fig. 8).
exercised hand.
60 No significant difference between tolperisone
Isometric Force (% reduction)

50 and placebo was observed on evaluation of

40
safety data, which included adverse events
30
20 monitoring, biochemical and hematological
10 laboratory parameters. Based on this study it
0 can be concluded that tolperisone is an
–10 effective and safe treatment agent for painful
–20
Day-1 Day-6 Bout-6 Day-7 Day-8 reflex muscle spasm. Additionally it is devoid of
typical side-effects of centrally active muscle
Placebo Tolperisone hydrochloride 24
relaxants.

12
 Fig. 8: Course of cumulative differences temporalis muscles by a standardized stretch
of the change score of the pressure device (1 mm displacement, 10 ms ramp time)
pain threshold.
before (baseline) 1 hr after medication (post-
2.5 drug), during ongoing experimental muscle pain
(pain-post-drug) and 15 min after pain had
25
2.0 vanished (post-pain).
Pressure (kg/cm2)

1.5
A significant reduction in the perceived intensity
1.0 of experimental jaw-muscle pain was observed
with tolperisone when compared with pridinol
0.5 25
mesilate and placebo.
0.0
0 4 7 10 21
Low Back Pain Syndrome
Treatment days
Tolperisone hydrochloride, n=56 Placebo, n=56 Chernysheva and Bagirova evaluated efficacy
and tolerability of tolperisone in patients with
Muscle Relaxant Effect of Tolperisone on chronic LBP. Tolperisone significantly improved
Experimentally Induced Jaw-muscle Pain the quality of life (QoL) of patients suffering
and Jaw-stretch Reflexes from LBP. The study suggested that tolperisone
26
is an ideal drug for patients with chronic LBP.
Svensson conducted a randomized double-
blind placebo-controlled three-way cross-over It is known that calcium antagonist act more
study to investigate the effect of two muscle selectively on the blood vessels of the central
relaxants (tolperisone and pridinol mesilate) on nervous system than on the peripheral blood
experimental jaw-muscle pain and jaw-stretch vessels and thereby effecting cerebral blood
reflexes. The study enrolled 15 healthy 27
flow. Therefore tolperisone exerts its action on
volunteers, randomized to receive 300 mg blood flow through blocking voltage-dependent
tolperisone, 8 mg pridinol mesilate or placebo 2+
Ca influx at the smooth muscle membrane
as a single dose. and inhibiting intracellular contractile protein.
Thus tolperisone exerts an effect on muscle
Volunteers were injected 0.3mL hypertonic
saline (5.8%) into the right masseter to produce Tolperisone (Tolfree) exerts an effect
muscle pain, 1 hr after drug administration. on muscle blood flow through
Pain perception was rated by volunteers on an blocking voltage-dependent Ca2+
electronic 10-cm Visual Analog Scale (VAS). influx at the smooth muscle
The pressure pain threshold (PPT) was membrane and inhibiting
measured and short-latency reflex responses intracellular contractile protein
were evoked in the precontracted masseter and

13
blood flow by vasodialtion and muscle sedative potentials of tolperisone when
26 28
relaxation effect. compared to that of placebo. The study
substantiates clinical experience and previous
Efficacy of Tolperisone in clinical trials demonstrating that tolperisone
Chronic LBP Syndrome HCL, though being a centrally active muscle
relaxant, is devoid of any sedation and does not
28
A study conducted by Chernysheva and impair reaction times.
Bagirova evaluated the efficacy and tolerance
of tolperisone in patients with chronic LBP from Beside the above-mentioned clinical trials in
the point of view of QoL. The study enrolled 50 post-stroke pain, treatment of neurolathyrism
patients with chronic LBP associated with and painful reflex muscle spasm, the use of
spinal osteochondrosis. Quality of life was tolperisone has been described in other clinical
evaluated using Womac Osteoarthritis Index, conditions such as central spinal pain,
Oswestry Low Back Pain Disability Question- neuropathic pain, peripheral vascular disease,
naire and The 36-Item Short-Form Health multiple sclerosis, tension headache and
26
Survey (SF-36). myotonias. Altogether, these clinical conditions
are quite frequent. However, the poor quality (no
A significant improvement in QoL was observed randomization, not blinded, no crossover, low
with tolperisone therapy. The drug was well- number of study subjects, case reports,
tolerated with low-incidence of side-effects. personal observations) of the studies makes it
The study suggested that tolperisone is an ideal difficult to give a general recommendation
26
drug for patients with chronic LBP. about the use of tolperisone in these various
clinical conditions
Evaluation of Sedative Activity of
Tolperisone Clinical indications of tolperisone
(Tolfree) include:23
Tolperisone was evaluated for its sedative
effects on healthy volunteers in a placebo- ! Neurolathyrism
controlled double-blind clinical study. The study ! Cerebral palsy
recruited 72 healthy young adults, randomized ! Multiple sclerosis
to receive 50 mg or 150 mg tolperisone or ! Myotonias
placebo thrice daily for a period of 8 days.
28
! Post cerebral stroke spasticity
! Painful reflex muscle spasm
The psychomotoric test revealed no sedative (including cervical and low back
effects of tolperisone in the given doses at any pain)
control examination. Subjective mood ratings ! Low back pain
quantified by the Welzel Colored Scales were ! Spinal pain
not impaired either. There was no difference in

14
 Dosage Recommendations exceeding the recommended maximum dose of
450 mg daily could possibly result in optimized
22
It is difficult to recommend an optimal dosage of therapeutic benefits. Some of the recom-
tolperisone in clinical practice, as it will depend mended dosage of tolperisone in clinical studies
on the clinical condition and disease that is to are mentioned in Table 2.
be influenced by the drug. On the other hand,
Table 2: Recommended dosage of
wide range of dosages had been used in the
clinical trials (150–900 mg/day), because of tolperisone based on clinical studies10
which a generalization could not be made for an Clinical condition Dosage
optimal dosages. Also, considerable or disease
interindividual variation has been reported in Adults 150–1000 mg/day
the pharmacokinetics of tolperisone. The
Children (age range from 5–10 mg/kg/day
pharmacokinetic study reported very large 3 months to 18 years)
interindividual variation in the AUC and the
Low back pain 150–400 mg/day
maximum concentration of a drug in the body
after dosing (Cmax). The pharmacokinetic study Post-cerebral stroke 300–900 mg/day
suggest that the pharmacological effect of oral spasticity
tolperisone varies between individuals and the Spinal pain 300 mg
oral tolperisone dose might need to be
15 Neuropathic diabetic 150–400 mg
individualized. foot syndrome

Therapeutic dose of tolperisone varies with Painful reflex muscle spasm 300 mg/day
condition and can be determined empirically. Neurolathyrism 300 mg/day
Tolperisone dose will vary depending upon the
age, weight and general condition of the The dosage of the drug should be maintained
individual and will also depend on the severity until the therapeutic effect is reached.
of the condition. Afterwards, the dosage of the drug should be
reduced gradually.
Typical, dosage ranges of tolperisone in adults
is between 150–1000 mg/day, whereas for Toxicology and Side-Effects
children’s dose ranges form 1–25 mg/kg/day
(age range from 3 months to 18 years). Various clinical studies with tolperisone
Exemplary recommended dosage ranges for revealed the drug to be well-tolerated and with
children include 5-10 mg/kg/day and from low incidence of adverse effects. Nevertheless,
18
2-4 mg/kg/day, in 2-3 divided doses. few adverse effects were observed in patients,
even though self-limited included muscle pain,
Study conducted by Stamenova et al., generalized body weakness, fatigue and
suggested that an individual dose titration dizziness.
15
Tolperisone was evaluated for its sedative Tolperisone is contraindicated in patients
potential on 72 healthy volunteers in a placebo- suffering from myasthenia gravies and in
controlled, double-blind clinical study, patients. Since, no well-controlled studies have
randomized to receive 50 mg or 150 mg been carried out with the drug in pregnant
tolperisone hydrochloride or placebo thrice- women; tolperisone should be used with
28
daily for a period of 8 days. caution in such patients keeping the risk-
benefit ratio of the drug.
Sedative effect was measured by psycho-
motoric test and subjective mood ratings, the Precautions
result indicated no difference in sedative
potentials of tolperisone when compared to that If the patient experiences uneasiness,
21
of placebo. Thus, the study substantiates accompanied by dysaesthesias or a feeling of
clinical experience and previous clinical trials burning in the extremities, skin excursions or a
demonstrating that tolperisone is devoid of any difficulty in breathing after ingestion of
21
sedation and does not impair reaction times. Tolperisone, especially after the first dose of the
drug, the treatment should be stopped
The study conducted by Dulin et al., immediately as it could be a sign of
substantiates clinical experience and hypersensitivity. Patients on drug should be
previous clinical trials demonstrating advised to observe caution while driving or
that tolperisone (Tolfree), though operating any machinery since dizziness has
being a centrally active muscle been reported by some patients.
relaxant, is devoid of any sedation
and does not impair reaction times.25 Place in Therapy

One of the commonest reasons for medical

Contraindications
consultation and the most frequent
occupational injury is back pain and spasticity.
Tolperisone has low-incidence of side-effects.
Patients suffering from spasticity and LBP do
The drug is considered safe for use. The drug is
not obtain effective symptomatic relief from
contraindicated in pregnancy and during
nonsteroidal antiinflammatory (NSAIDs)
breast-feeding. Breast-feeding should be
therapies. As a result these symptoms become
stopped during the treatment period.29
Lack of sedative potential makes
Studies have shown that bioavailability of
tolperisone (Tolfree) well-suited in
tolperisone is enhanced or increased by at least
patients with spasticity of neurological
about 10–30% upon administration of drug in
origin and acute as well as chronic
fasting state suggesting role of food in obtaining
18 back pain.
desirable bioavailability.

16
a serious problem and thereby deteriorating ! Tolfree (Tolperisone) exhibits membrane
patient’s QoL. stabilizing potency, which is characteristic
of antiarrythmic and local anesthetic
Clinical studies demonstrated tolperisone in agents.
doses of up to 450 mg/day reduces and
normalizes muscle spasms as well as Tolfree (Tolperisone) differs from other
spasticity with low-incidence of side-effects. In myotonolytic agents in its pharmacological
contrast to other centrally acting muscle properties, which mediate muscle relaxation
relaxants, tolperisone does not cause sedation without concomitant sedation or withdrawal
and does not impair attention-related brain phenomena.
functions. This has been proven by randomized
double-blond placebo-controlled study which Tolfree (Tolperisone) has potential of being a
evaluated the sedative potential of tolperisone successful centrally acting muscle relaxant due
for a dose range of 150–450 mg/day involving to its membrane stabilizing property, low-
sensitive and valid psychomotoric test. incidence of side-effects, without concomitant
sedation or withdrawal phenomena.
This lack of sedative potential makes
tolperisone well-suited in patients with acute How Supplied
and chronic back pain and spasticity of
neurological origin. Its good tolerability with TOLFREE–100 mg Tablets (Tolperisone
minimum contraindications makes tolperisone hydrochloride 100 mg) are supplied in the
suitable for a broad range of patients including blister pack of 10 Tablets.
30
elderly patients with concomitant diseases.
TOLFREE–150 mg Tablets (Tolperisone
Tolfree (Tolperisone), a centrally acting hydrochloride 150 mg) are supplied in the
muscle relaxant agent, which has been in blister pack of 10 Tablets
therapeutic use for more than three decades,
Keep in a Cool dry place, protecting from light.
has been widely used as spasmolytics of
Keep out of reach of Children.
choice. The rationale for use of tolperisone
includes the following:
! Tolfree (Tolperisone) has higher muscle
relaxant activity than the dextrorotatory
enantiomer.

17
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