Muscle Spasm and Spasticity: Role of Centrally Acting Muscle Relaxants

Tolperisone (Tolfree)

References

Muscle Spasm and Spasticity

Introduction to Tolperisone

Chemistry

Mechanism of Action

Clinical Pharmacokinetic

Validating Clinical Indications

Dosage Recommendations

Toxicology and Side-effects

Contraindications

Precautions

Place in Therapy

How Supplied

..............................................................................................................................................01

4

Muscle Relaxant Activity: Blockade of Sodium and Calcium Channel

6

Absorption

Metabolism

Excretion

9

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

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Contents

Muscle Spasm and Spasticity:Role of Centrally ActingMuscle Relaxants

01

Spasticity is considered one of the

main symptoms of the more than

2.5 million people with neurological

disorders worldwide, affecting up to

60% of this population.

Spasticity is defined as a motor disorder

characterized by an abnormal velocity-

dependent increase in muscle tone with

exaggerated tendon jerks. An imbalance

between the muscle contraction and relaxation

process resulting due to interruption of the

neural circuitry regulating the muscles.

Thereby, results in abnormal muscle movement

and response. In addition, results in weakness

and clumsiness of voluntary movements as well

as muscle stiffness and tightness.

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

due to excessive contraction and in addition

results in constriction of blood vessels that

normally feed the muscles and supply oxygen,

further compounding the problem.

Muscle spasm could also result with spinal cord

injury, which could be observed when a muscle

is stretched. Due to injury to the spinal cord,

these sensations can trigger the reflex resulting

in the muscle to contract or spasm (see Fig. 1).

is a condition in which certain

muscles are continuously contracted. It is a

motor disorder associated with lesions of the

1

1

2

Muscle spasm

Spasticity

Muscle Spasm and Spasticity

Fig. 1: Muscle spasm and spasticitypathway after spinal injury.

Brain

Dorsal root(Sensory)

Injury level

Ventral root(Motor)

nervous system. Spasticity could be the result

of damage to the portion of the brain or spinal

cord that controls voluntary movement.

It can directly or indirectly change mechanical

properties of the neuromuscular system,

particularly in chronic patients and has been

linked to impaired voluntary movement through

different mechanisms.

Spasticity could be associated with variety of

disorders including spinal cord injury, multiple

sclerosis (MS), cerebral palsy, anoxic brain

damage such as a cerebrovascular accident

(CVA), brain trauma, severe head injury and

some metabol ic d iseases, such as

adrenoleukodystrophy and phenylketonuria.

Subsequent to spinal injury, the nerve cells get

disconnected from the brain at the level of

injury. Due to scar tissue in the damaged area of

the spinal cord, messages form below the level

of injury reaching the brain is blocked.

Spasticity does not occur immediately following

a spinal cord injury. When an injury occurs to the

spinal cord, the body goes into spinal shock.

Spasticity is an exaggeration of the normal

reflexes that occur when the body is stimulated

in certain ways (see Fig. 1). In a healthy

individual, sensory signal is sent to reflex arc,

where it travels to brain via the spinal cord, the

brain further assesses the signal and if the

signal is not dangerous, an inhibitory signal

is set down the spinal cord and thus cancels

the reflex from moving the muscle. Whereas,

during spinal cord injury, this inhibitory signal

is blocked by the structural damage in the

cord and the natural reflex is allowed to

continue resulting in a contraction of the

muscle.

are so called because they act on the central

nervous system to decrease muscle tone. They

work in the central nervous system to reduce

excessive reflex activity and to allow muscle

relaxation. They decrease muscle tone by

depressing the internuncial neurons at the

spinal cord.

The generation of the neuronal signals in motor

neurons causing muscle contractions is

dependent on the balance of synaptic excitation

and inhibition that the motor neuron receives.

Centrally acting skeletal muscle relaxants

generally work by either enhancing the level of

inhibition, or reducing the level of excitation.

Inhibition is enhanced by mimicking or

enhancing the actions of endogenous inhibitory

substances, such as -amino butyric acid

(GABA).

3–5

2

2

6

6

Centrally acting skeletal muscle relaxants

�

02

The degree of spasticity varies from

mild muscle stiffness to severe, painful

and uncontrollable muscle spasms.

The condition can interfere with daily

activities and with rehabilitation in

patients with certain disorders.

Spasmolytics act at the level of the

cortex, brain stem or spinal cord, or

all three areas; hence, they have

traditionally been referred to as

"centrally-acting" muscle relaxants.

When given in normal therapeutic doses,

centrally acting muscle relaxants are not potent

enough to produce flaccid paralysis. However,

large oral or injectable doses of these drugs may

produce hypotension, flaccid paralysis,

sedation and respiratory depression. Many of

these drugs are similar in chemical structure to

antianxiety agents. These agents are used to

relieve skeletal muscle spasms. Whether relief

of pain achieved by patients taking these drugs

is due to their muscle relaxant effect or to their

sedative effect is unknown.

Judicious dose-titration of muscle relaxants

could help in attaining desired therapeutic

benefits to the patient. The patient should be

warned not to drive, operate machinery or

perform any other task that requires

wakefulness because these drugs cause

sedation. Muscle relaxants have dose-

dependent effect. Excessive dosage, more than

the normal dosage could result in sedative

effect. In addition, it might depress muscle

function to the extent that the bladder will not

normally contract resulting in retention of urine.

The patient should be well informed before

commencing the treatment since some drugs

can alter the color of urine which may

embarrass the patient.

Adverse effects, particularly dizziness and

drowsiness are consistently reported with all

skeletal muscle relaxants. The potential

adverse effects should be communicated

clearly to the patient. Owing to the limited

comparable effectiveness data, choice of agent

should be based on side-effect profile, patient

preference, abuse potential and possible drug

interactions.

Tolperisone, a centrally acting muscle relaxant

free from side-effects, is a clinically useful drug

for relieving spasticities of neurological origin

and muscle spasms associated with low back

pain (LBP) and painful locomotor diseases.

7

6

8

03

Table 1: Chemistry of tolperisone

Name

Synonym

Molecular formula

Molecular weight

Chemical structure

4'-Methyl-2-(1-piperidinylmethyl)-propiophenone

Hydrochloride; 2,4'-Dimethyl-3 piperidinopropiophenone monohydrochloride

C H NO.HCl;C H ClNO

281.82

16 23 16 24

CH3 CH2

· HClO

C CH N

04

Tolperisone ( )

Tolperisone (Tolfree) is a recently

launched centrally acting muscle

relaxant in India for management of

spasticity of neurological origin and

spasm related to chronic back pain.

Introduction to Tolperisone

Chemistry

�

�

�

Tolperisone, a centrally acting muscle relaxant

agent recently launched drug in India for acute

and chronic back pain and spasticity of

neurological origin. It is an arylalkyl -

aminoketone having an asymmetric carbon

atom to the carbonyl group. Tolperisone

enantiomers have different pharmacodynamic

properties.

Tolperisone has higher muscle relaxant

activity than the levorotatory isomer,

whereas the latter shows higher broncho-

and peripherial vasodilatatory activities

than the dextrorotatory enantiomer.

Tolperisone is used as a racemic mixture.

Tolperisone exhibits membrane stabilizing

potency, which is characteristic of

antiarrythmic and local anesthetic agents.

According to molecular modeling studies,

the similar pharmacological properties of

tolperisone and lidocaine are due to the

conformational mobility of tolperisone, allowing

these molecules to form a conformer having the

pharmacophore moieties (benzene ring,

carbonyl group and basic nitrogen atom) in

similar spatial arrangements.

Tolperisone was initially derived from the

structure of cocaine. It is a piperidine

derivative. The chemical characteristics of

tolperisone is outlined in Table 1.

�

�

9

10

11

Source: http://www.chemblink.com/products/3644-61-9.htm.

05

Mechanism of Action

�

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Tolperisone causes:

Muscle relaxation by its action on central

nervous system.

Dose dependent muscle relaxation.

Membrane stabilization.

Analgesic activity.

Exact mechanism of action of tolperisone is not

known. It was initially classified under

antinicotinic drugs because it effectively

inhibited lethality induced by nicotine.

Tolperisone causes depression of the ventral

root reflexes and excitability of motor neurons.

This drug has pronounced action on the

synaptic responses when compared to the

excitability of motor neurons. Tolperisone

causes depression of voltage-gated sodium

channel conductance at concentrations that

inhibit spinal reflexes at the level of dorsal root

ganglion cells. Major mode of action of centrally

acting muscle relaxants like tolperisone is

blockade of sodium channels. In addition to this

tolperisone has a significant effect on voltage

gated calcium channels. This data suggest that

tolperisone shows muscle relaxants activity by

spinal reflex inhibitory action predominantly via

a presynaptic-inhibition of the transmitter

release from the primary afferent endings via a

combined action on voltage-gated sodium and

calcium channels.

Fukuda . reported that tolperisone blocks

mono- and polysynaptic reflexes at the spinal

level in a dose-dependent manner. In this

manner it acts as spinal reflex suppressant and

causes centrally muscle relaxantion effect.

Tolperisone causes preferential antinociceptive

activity against thermal stimulation that is likely

to be attributed to its local anesthetic action.

Although, tolperisone is a potent centrally

acting muscle relaxant, it has a low incidence

of side-effects. It is useful in relieving

spasticities of neurological origin and muscle

spasms associated with painful locomotor

diseases. Tolperisone mediates muscle

relaxation without concomitant sedation or

withdrawal phenomena.

12

13

14

15

12

et al

Muscle Relaxant Activity:

Blockade of Sodium and Calcium Channel

Being a centrally acting muscle

relaxant, tolperisone (Tolfree) acts by

blocking sodium channels and is also

known to possess significant effect on

voltage gated calcium channels.

Tolperisone (Tolfree) exerts its spinal

reflex inhibitory action predominantly

via a presynaptic inhibition of the

transmitter release from the primary

afferent endings via a combined action

on voltage-gated sodium and calcium

channels.

Tolperisone (Tolfree) mediate muscle

relaxation without concomitant

sedation or withdrawal phenomena.

06

Being a centrally acting muscle

relaxant with membrane stabilizing

property, tolperisone (Tolfree) is

useful in treatment of painful

contraction of muscles typically

associated with serious neurological

disorders such as Lou Gehrig's

disease (ALS), multiple sclerosis,

stroke, spinal cord injury, and

cerebral palsy.

Tolperisone blocks the propagation of action

potentials at either A - or C-fibers conducting

pain signals to the spinal dorsal horn neurons.

Local anesthetic action of tolperisone is

exhibited through its effect on sciatic nerves.

Tolperisone suppressed the propagation of low

frequency action potentials (0.2 Hz). Such

frequency-dependency is in agreement with the

studies demonstrating that tolperisone

specially blocks the sustained repetitive firing

of action potentials without altering the initial

firing. Since small diameter neurons are

generally more susceptible to the action of

local anesthetics, it is therefore conceivable

that the local anesthetic action of tolperisone

is attributed to it preferential analgesic action

against C-fiber-mediated thermal nociception,

leaving A - and C-fiber-mediated mechanical

nociception little affected.

These data indicate that tolperisone is a

selective inhibitor of voltage-gated sodium

channels, which underlies its spinal reflex

suppressant and centrally acting muscle

relaxant effect. Moreover, this feature may

mediate a pain relieving effect, which due to the

observed minor differences, may be freer from

side-effects than in the case of lidocaine.

Pharmacokinetic profile of tolperisone varies

from individual to individual. There is a need for

individualization of dosage of tolperisone while

administering the therapy to the patient.

Tolperisone can be administered through

various routes (oral, intra-arterial, intrathecal,

intraspinal, intramuscular, intraperitoneal,

intravenous, intranasal and inhalation).

However, intramuscular, intravenous and oral

are preferred routes of administration.

Therapeutically effective dosage of tolperisone

ranges from approximately 75 to 1500 mg/day.

Tolperisone gets absorbed quickly in the body

and peak plasma concentration is achieved

usually 0.5–1.0 hr after ingestion (see Fig. 2).

Some of the pharmacokinetic parameters

studied are as follows:

The AUC of tolperisone is between

125.9–1,241.3 ng/mLxh

�

�16

17

17

16

0��

Clinical Pharmacokinetic

�

Absorption

�

�

Local anesthetic action of

tolperisone (Tolfree) is exhibited

through its effect on sciatic nerves.

The analgesic effect of tolperisone

(Tolfree) could be derived solely

from the blockade of peripheral

sodium channels of A and

C-fibers.

�-

�

�

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The C is between 64.2–784.9 ng/mL

The t of tolperisone is 0.90 0.31 hr and

The mean half-life is 1.00 0.28 hr.

Bioavailability is 16.7 8.9%

Apparent volume of distribution of is

5.1 1.0 L/kg (mean SD)

In fasting condition T values of unchanged

tolperisone and 4-HM-tolperisone were 0.66 hr

( 0.16 hr) and 0.68 hr ( 0.23 hr) respectively.

Whereas after food intake W values of

unchanged tolperisone and 4-HM-tolperisone

were 1.38 hr ( 0.77 hr), indicating a delayed

absorption after food intake. Under fed

conditions bioavailability was higher when

compared to that of fasting conditions. The

point estimate for AUC and AUC

(fed/fasted) were 1.87 and 1.92 respectively for

tolperisone. No significant effect of food was

observed in case of C value, after tolperisone

administration. Absorption was delayed with a

mean T of 1.37 hr in the fed state compared to

0.66 hr in the fasted state.

study on metabolism of tolperisone

in human liver microsomes and recombinant

enzymes show that the main metabolic route

in human liver microsomes is methyl

hydroxylation. In addition, metabolites of two

mass units greater than the parent compound

and the hydroxy-metabolite are also observed

max

max

max

0 0 t

max

max

�

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� �

� �

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16

17

17 18

�� �

In vitro

Metabolism

07

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

Tolp

eris

one

conc

entr

atio

nin

plas

ma

(ng/

mL)

1000

500

100

50

10

0 0.5 1.0 1.5 3

Time (h)

4 6 7

5

Tablet tolperisone 100 mg

Injection tolperisone 100 mg

in the metabolism of tolperisone. The latter is

identified as carbonyl-reduced M1, the former

M1 is assumed to be the carbonyl-reduced

parent compound.

The prominent enzymes in metabolism of

tolperisone are isoform-specific cytochrome

P450 (P450) inhibitors, inhibitory antibodies

and CYP2D6. In addition to these CYP2C19,

CYP2B6 and CYP1A2 also have small role in

metabolism of tolperisone. Formation of

Hydroxymethyl-tolperisone is mediated by

CYP2D6, CYP2C19 and CYP1A2. Tolperisone is a

competitive inhibitor of dextromethorphan

O-demethylation and bufuralol hydroxylation. It

also inhibits oxidation of methyl p-tolyl sulfide.

To summarize, tolperisone undergoes both

P450-dependent and P450-independent

microsomal biotransformations. A considerable

involvement of a microsomal reductase is

assumed on the basis of metabolites formed

and indirect evidences of inhibition studies.

studies have demonstrated the

involvement of both P450- dependent and

P450-independent microsomal biotrans-

formations are involved in tolperisone

metabolism. The proposed route for metabolic

pathway is highlighted in Figure 3.

Hydroxymethyl metabolite formation revealed

In vitro

19 19

18

08

In vitro study on metabolism of

tolperisone (Tolfree) in human liver

microsomes and recombinant

enzymes show that the main

metabolic route in human liver

microsomes is methyl-hydroxylation.

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

CH3

CH3

C CH CH2 N

O

Tolperisone

CYP2B6

FMO3

M...?CH3

CH3

CH CH2 N

OH

CH CH2

CH3

CH CH2 N

O

COH

M1

CH2

CH3

CH CH2 N

OH

CHOH

M2

CYP2D6

CYP2C19

CYP1A2Reductase

m/ 247

Red Arrows indicate the

possible ways of M2 formation.

are used for the assumed

enzymatic processes and metabolites.

Green letters

09

Pharmacokinetic features of

tolperisone (Tolfree):

AUC is 125.9–1,241.3 ng/mLxh

C is 64.2–784.9 ng/mL

t is 0.90 0.31 hr

t½ is 1.00 0.28 hr

Bioavailability is 16.7 8.9%

Apparent volume of distribution

is 5.1 1.0 L/kg

Total body clearance is

140.8 33.8 L/hr

0

max

max �

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to be the main P450-mediated metabolic

pathway. The key enzymes involved in

metabolism through M1 formation are CYP2D6,

CYP2C19 and CYP1A2. The P450-independent

metabolism was mediated to a small extent by

FMO3.

Less than 0.1% of the dose is excreted

unchanged within 24 hr in urine after I.V.

administration of tolperisone. Total body

clearance of the drug is 140.8 33.8 L/hr.

Tolperisone has been used for treating

neurological origin muscle spasticities and

painful muscle spasms due to rheumatologic

conditions. In addition, tolperisone also acts as

an analgesic.

Membrane stabilization property of tolperisone

reduces pain in the locomotor disease patients

by this means acting as an adjuvant to the

antiinflammatory agents. Tolperisone has also

been shown to act as an adjuvant to

physiotherapy in relieving pain due to muscular

hypertonia.

Tolperisone differs from other myotonolytic

agents in its pharmacological properties, which

mediate muscle relaxation without concomitant

sedation or withdrawal phenomena. Some of

the clinical indications are as follows.

Neurolathyrism is a neurologic disorder caused

by excessive ingestion of species

( , and ).

Neurolathyrism depict a pyramidal syndrome

affecting mainly the corticospinal pathways

and in a lesser grade the sensory and

spinocerebellar pathways of the spinal cord.

Tolperisone offers symptomatic relief to

patients in stage I and stage II neurolathyrism.

Also reduction in spastic muscle tone, stiffness

and ankle clonus were reported with

tolperisone. Tolperisone also improved walking

ability and speed of patients with neuro-

lathyrism. The study reported tolperisone to be

well-tolerated and effective drug for

symptomatic treatment of neurolathyrism.

20

19

9

9

21

21

�

Lathyrus

Lathyrus sativus L. cicera Vicia sativa

Excretion

Neurolathyrism

Validating Clinical Indications

Membrane stabilization property of

tolperisone (Tolfree) reduces pain in

the locomotor disease patients by

this means acting as an adjuvant to

the antiinflammatory agents.

Symptomatic Treatment of Neurolathyrism

Efficacy and Safety of Tolperisone in

Spasticity following Cerebral Stroke

A double-blind placebo-controlled randomized

trial in 72 patients was conducted to evaluate

safety and efficacy of oral tolperisone in the

treatment of neurolathyrism in stages I, II

and III.

Tolperisone at a dose of 150 mg twice-daily

significantly improved subjective complaints

such as muscle cramps, heaviness of the legs,

startle attacks, flexor spasms and repeated

falls. Nearly 75% patients in tolperisone had

subjective improvement when compared with

the placebo group (see Fig. 4). Significant

reduction in spastic muscle tone, stiffness of

Achilles and spontaneous ankle clonus were

reported with tolperisone. Tolperisone, also

significantly improved locomotor function in

neurolathyrism.

To summarize, tolperisone effectively offered

symptomatic relief to patients in stage I and

stage II disease. Some adverse effects like

muscle pain, generalized body weakness and

dizziness were recorded in patients taking the

drug but all were minor and self-limited, none

requiring discontinuation of treatment.

Tolperisone exhibited excellent tolerability in

patients with spastic hypertonia following

cerebral stroke. Noteworthy reductions in

patients with spastic hypertonia have been

observed with tolperisone. Optimized

therapeutic benefits were achieved with

individual dose titration which exceeded the

recommended dose of 450 mg daily.

Membrane stabilizing property of tolperisone

was evaluated for its safety and efficacy in the

treatment of stroke-related spasticity. The

study enrolled 120 patients and the degree of

spasticity was determined using Ashworth

scale, on the most severely affected joint area,

considered as a primary target parameter.

Treatment duration lasted for 12 weeks and was

initiated with a titration period of variable length

(dose range 300–900 mg tolperisone daily).

In majority of patients both limbs were affected

due to spasticity. Nearly, 62% patients were

treated with daily dose of >600 mg tolperisone.

Significant reduction in mean Ashworth score

was observed in patients receiving tolperisone,

when compared with placebo. Reduction by at

least 1 point on the Ashworth scale was

observed in nearly 78.3% patients on

21

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22

Post-cerebral Stroke Spasticity

10

Fig. 4: Subjective improvement inpatients with neurolathyrism.

Impr

ovem

ent (

%)

80

70

60

50

40

30

20

10

0Tolperisone Placebo

75

39

tolperisone when compared with 45% of

patients in placebo group (see Fig. 5). Overall

functional assessment confirmed superior

efficacy of tolperisone. Although mild-to-

moderate intensity adverse events were

observed with tolperisone, no withdrawals

occurred due to them.

The study demonstrated the efficacy and

excellent tolerability of tolperisone in treating

spastic hypertonia following cerebral stroke.

The study suggested that an individual dose

titration, which may exceed the recommended

maximum dose of 450 mg daily could possibly

result in optimized therapeutic benefits.

A study conducted by Bajaj . investigated

the role of tolperisone in relieving painful

muscle spasm. Based on spasm theory of

exercise induced pain study hypothesized that

the prophylactic use of tolperisone could

effectively relieve post-exercise muscle

soreness.

Twenty male volunteers were randomized to

receive placebo or tolperisone (150 mg) thrice-

daily for 8 days. The parameters used for

assessment of PPT included Likert's pain score,

pain areas, range of abduction, isometric force

and electromyography (EMG) root mean square

(RMS) during maximum voluntary isometric

force on day 1 and 6, immediately after an

eccentric exercise of first dorsal interosseous

muscle and 24 and 48 hr after the exercise.

Treatment with placebo or tolperisone

hydrochloride was initiated immediately after

the assessments on the first day baseline

assessments. On the sixth day baseline

investigations were repeated and then the

subjects performed six bouts of standardized

intense eccentric exercise of first dorsal

interosseous muscle for provocation of post-

exercise muscle soreness. Perceived intensity

of warmth, tiredness, soreness and pain during

the exercise bouts were recorded on a 10 cm

VAS.

Following tolperisone administration,

significant reduction in isometric force after

exercise was observed when compared with

placebo group. All VAS scores increased during

the exercise bouts 2, 3, 4, 5 and 6 as compared

to bout 1. Increased pain scores and pain areas

were reported immediately after and 24 and 48

hr after exercise. PPTs were reduced at 24 and

48 hr after the exercise in the exercised hand.

The EMG RMS amplitude was also reduced

immediately after the exercise, but was

increased at 24 and 48 hr (see Fig. 6). Isometric

force was reduced immediately after the

exercise as compared to days 1 and 6 and the

22

22

23

23

et al

Efficacy of Tolperisone on Post-exercise

Muscle Soreness

11

Fig. 5: Percentage reduction in AshworthScale.

TolperisonePlacebo

0

20

40

60

80

Perc

enta

gere

duct

ion

24 and 48 hr post-exercise assessments with a

greater reduction following the tolperisone

hydrochloride treatment and the reduction was

more in tolperisone group as compared to the

placebo group.

The results suggest that the prophylactic use of

tolperisone produced reduction in isometric

force but no relief to pain in course of post-

exercise muscle soreness (see Fig. 7).

Significant superiority of tolperisone over

placebo in increasing threshold for pressure

pain alleviated painful reflex muscle spasm

associated with diseases of the spinal column

or proximal joints. More pronounced efficacy

was observed in patients with complaints of

less than 1 year and those receiving

concomitant physiotherapy.

Pratzel ., conducted a randomized, double-

blind, placebo-controlled trial to evaluate

efficacy and safety of oral tolperisone for the

treatment of painful reflex muscle spasm. The

study enrolled patients with painful reflex

muscle spasm associated with diseases of the

spinal column or proximal joints. All patients

were randomized to receive either 300 mg

tolperisone or placebo for a period of 21 days.

Tolperisone was found to be significantly

superior to placebo; thereby increasing pain

threshold as the primary target parameter (see

Fig. 8).

No significant difference between tolperisone

and placebo was observed on evaluation of

safety data, which included adverse events

monitoring, biochemical and hematological

laboratory parameters. Based on this study it

can be concluded that tolperisone is an

effective and safe treatment agent for painful

reflex muscle spasm. Additionally it is devoid of

typical side-effects of centrally active muscle

relaxants.

23

24

24

24

Clinical Efficacy of Tolperisone in

Treatment of Painful Reflex Muscle Spasm

et al

Painful Reflex Muscle Spasm

12

Fig. 6: The time course change of thepercent reduction of pressure painthreshold (PPT) of the first dorsalinterosseous muscle in exercised hands.

Pres

sure

Pain

Thre

shol

d

(%re

duct

ion)

25

20

15

10

5

0

–5

–10

Day-1 Day-6 Bout-6 Day-7 Day-8

Fig. 7: The time course change of thepercent reduction of isometric force offirst dorsal interosseous muscle inexercised hand.

Tolperisone hydrochloridePlacebo

Isom

etric

Forc

e(%

redu

ctio

n)

60

50

40

30

20

10

0

–10

–20Day-1 Day-6 Bout-6 Day-7 Day-8

Tolperisone hydrochloridePlacebo

13

Muscle Relaxant Effect of Tolperisone on

Experimentally Induced Jaw-muscle Pain

and Jaw-stretch Reflexes

Low Back Pain Syndrome

Svensson conducted a randomized double-

blind placebo-controlled three-way cross-over

study to investigate the effect of two muscle

relaxants (tolperisone and pridinol mesilate) on

experimental jaw-muscle pain and jaw-stretch

reflexes. The study enrolled 15 healthy

volunteers, randomized to receive 300 mg

tolperisone, 8 mg pridinol mesilate or placebo

as a single dose.

Volunteers were injected 0.3mL hypertonic

saline (5.8%) into the right masseter to produce

muscle pain, 1 hr after drug administration.

Pain perception was rated by volunteers on an

electronic 10-cm Visual Analog Scale (VAS).

The pressure pain threshold (PPT) was

measured and short-latency reflex responses

were evoked in the precontracted masseter and

temporalis muscles by a standardized stretch

device (1 mm displacement, 10 ms ramp time)

before (baseline) 1 hr after medication (post-

drug), during ongoing experimental muscle pain

(pain-post-drug) and 15 min after pain had

vanished (post-pain).

A significant reduction in the perceived intensity

of experimental jaw-muscle pain was observed

with tolperisone when compared with pridinol

mesilate and placebo.

Chernysheva and Bagirova evaluated efficacy

and tolerability of tolperisone in patients with

chronic LBP. Tolperisone significantly improved

the quality of life (QoL) of patients suffering

from LBP. The study suggested that tolperisone

is an ideal drug for patients with chronic LBP.

It is known that calcium antagonist act more

selectively on the blood vessels of the central

nervous system than on the peripheral blood

vessels and thereby effecting cerebral blood

flow. Therefore tolperisone exerts its action on

blood flow through blocking voltage-dependent

Ca influx at the smooth muscle membrane

and inhibiting intracellular contractile protein.

Thus tolperisone exerts an effect on muscle

25

25

26

27

2+

Fig. 8: Course of cumulative differencesof the change score of the pressurepain threshold.

Tolperisone hydrochloride, n=56 Placebo, n=56

Pres

sure

(kg/

cm)2

2.5

2.0

1.5

1.0

0.5

0.00 4 7 10

Treatment days

21

Tolperisone (Tolfree) exerts an effect

on muscle blood flow through

blocking voltage-dependent Ca

influx at the smooth muscle

membrane and inhibiting

intracellular contractile protein

2+

14

blood flow by vasodialtion and muscle

relaxation effect.

A study conducted by Chernysheva and

Bagirova evaluated the efficacy and tolerance

of tolperisone in patients with chronic LBP from

the point of view of QoL. The study enrolled 50

patients with chronic LBP associated with

spinal osteochondrosis. Quality of life was

evaluated using Womac Osteoarthritis Index,

Oswestry Low Back Pain Disability Question-

naire and The 36-Item Short-Form Health

Survey (SF-36).

A significant improvement in QoL was observed

with tolperisone therapy. The drug was well-

tolerated with low-incidence of side-effects.

The study suggested that tolperisone is an ideal

drug for patients with chronic LBP.

Tolperisone was evaluated for its sedative

effects on healthy volunteers in a placebo-

controlled double-blind clinical study. The study

recruited 72 healthy young adults, randomized

to receive 50 mg or 150 mg tolperisone or

placebo thrice daily for a period of 8 days.

The psychomotoric test revealed no sedative

effects of tolperisone in the given doses at any

control examination. Subjective mood ratings

quantified by the Welzel Colored Scales were

not impaired either. There was no difference in

sedative potentials of tolperisone when

compared to that of placebo. The study

substantiates clinical experience and previous

clinical trials demonstrating that tolperisone

HCL, though being a centrally active muscle

relaxant, is devoid of any sedation and does not

impair reaction times.

Beside the above-mentioned clinical trials in

post-stroke pain, treatment of neurolathyrism

and painful reflex muscle spasm, the use of

tolperisone has been described in other clinical

conditions such as central spinal pain,

neuropathic pain, peripheral vascular disease,

multiple sclerosis, tension headache and

myotonias. Altogether, these clinical conditions

are quite frequent. However, the poor quality (no

randomization, not blinded, no crossover, low

number of study subjects, case reports,

personal observations) of the studies makes it

difficult to give a general recommendation

about the use of tolperisone in these various

clinical conditions

26

26

26

28

28

28

Efficacy of Tolperisone in

Chronic LBP Syndrome

Evaluation of Sedative Activity of

Tolperisone Clinical indications of tolperisone

(Tolfree) include:

Neurolathyrism

Cerebral palsy

Multiple sclerosis

Myotonias

Post cerebral stroke spasticity

Painful reflex muscle spasm

(including cervical and low back

pain)

Low back pain

Spinal pain

23

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15

Dosage Recommendations

Toxicology and Side-Effects

It is difficult to recommend an optimal dosage of

tolperisone in clinical practice, as it will depend

on the clinical condition and disease that is to

be influenced by the drug. On the other hand,

wide range of dosages had been used in the

clinical trials (150–900 mg/day), because of

which a generalization could not be made for an

optimal dosages. Also, considerable

interindividual variation has been reported in

the pharmacokinetics of tolperisone. The

pharmacokinetic study reported very large

interindividual variation in the AUC and the

maximum concentration of a drug in the body

after dosing (C ). The pharmacokinetic study

suggest that the pharmacological effect of oral

tolperisone varies between individuals and the

oral tolperisone dose might need to be

individualized.

Therapeutic dose of tolperisone varies with

condition and can be determined empirically.

Tolperisone dose will vary depending upon the

age, weight and general condition of the

individual and will also depend on the severity

of the condition.

Typical, dosage ranges of tolperisone in adults

is between 150–1000 mg/day, whereas for

children’s dose ranges form 1–25 mg/kg/day

(age range from 3 months to 18 years).

Exemplary recommended dosage ranges for

children include 5-10 mg/kg/day and from

2-4 mg/kg/day, in 2-3 divided doses.

Study conducted by Stamenova .,

suggested that an individual dose titration

exceeding the recommended maximum dose of

450 mg daily could possibly result in optimized

therapeutic benefits. Some of the recom-

mended dosage of tolperisone in clinical studies

are mentioned in Table 2.

The dosage of the drug should be maintained

until the therapeutic effect is reached.

Afterwards, the dosage of the drug should be

reduced gradually.

Various clinical studies with tolperisone

revealed the drug to be well-tolerated and with

low incidence of adverse effects. Nevertheless,

few adverse effects were observed in patients,

even though self-limited included muscle pain,

generalized body weakness, fatigue and

dizziness.

max

15

18

22

et al

Table 2: Recommended dosage of

tolperisone based on clinical studies10

Clinical condition Dosageor disease

Adults 150–1000 mg/day

Children (age range from3 months to 18 years)

Low back pain 150–400 mg/day

Post cerebral strokespasticity

Spinal pain 300 mg

Neuropathic diabeticfoot syndrome

Painful reflex muscle

Neurolathyrism 300 mg/day

5–10 mg/kg/day

- 300–900 mg/day

150–400 mg

spasm 300 mg/day

16

The study conducted by Dulin .,

substantiates clinical experience and

previous clinical trials demonstrating

that tolperisone (Tolfree), though

being a centrally active muscle

relaxant, is devoid of any sedation

and does not impair reaction times.

et al

25

Lack of sedative potential makes

tolperisone (Tolfree) well-suited in

patients with spasticity of neurological

origin and acute as well as chronic

back pain.

Tolperisone was evaluated for its sedative

potential on 72 healthy volunteers in a placebo-

controlled, double-blind clinical study,

randomized to receive 50 mg or 150 mg

tolperisone hydrochloride or placebo thrice-

daily for a period of 8 days.

Sedative effect was measured by psycho-

motoric test and subjective mood ratings, the

result indicated no difference in sedative

potentials of tolperisone when compared to that

of placebo. Thus, the study substantiates

clinical experience and previous clinical trials

demonstrating that tolperisone is devoid of any

sedation and does not impair reaction times.

Tolperisone has low-incidence of side-effects.

The drug is considered safe for use. The drug is

contraindicated in pregnancy and during

breast-feeding. Breast-feeding should be

stopped during the treatment period.

Studies have shown that bioavailability of

tolperisone is enhanced or increased by at least

about 10–30% upon administration of drug in

fasting state suggesting role of food in obtaining

desirable bioavailability.

Tolperisone is contraindicated in patients

suffering from myasthenia gravies and in

patients. Since, no well-controlled studies have

been carried out with the drug in pregnant

women; tolperisone should be used with

caution in such patients keeping the risk-

benefit ratio of the drug.

If the patient experiences uneasiness,

accompanied by dysaesthesias or a feeling of

burning in the extremities, skin excursions or a

difficulty in breathing after ingestion of

Tolperisone, especially after the first dose of the

drug, the treatment should be stopped

immediately as it could be a sign of

hypersensitivity. Patients on drug should be

advised to observe caution while driving or

operating any machinery since dizziness has

been reported by some patients.

One of the commonest reasons for medical

consultation and the most frequent

occupational injury is back pain and spasticity.

Patients suffering from spasticity and LBP do

not obtain effective symptomatic relief from

nonsteroidal antiinflammatory (NSAIDs)

therapies. As a result these symptoms become

28

21

21

29

18

Contraindications

Precautions

Place in Therapy

a serious problem and thereby deteriorating

patient’s QoL.

Clinical studies demonstrated tolperisone in

doses of up to 450 mg/day reduces and

normalizes muscle spasms as well as

spasticity with low-incidence of side-effects. In

contrast to other centrally acting muscle

relaxants, tolperisone does not cause sedation

and does not impair attention-related brain

functions. This has been proven by randomized

double-blond placebo-controlled study which

evaluated the sedative potential of tolperisone

for a dose range of 150–450 mg/day involving

sensitive and valid psychomotoric test.

This lack of sedative potential makes

tolperisone well-suited in patients with acute

and chronic back pain and spasticity of

neurological origin. Its good tolerability with

minimum contraindications makes tolperisone

suitable for a broad range of patients including

elderly patients with concomitant diseases.

, a centrally acting

muscle relaxant agent, which has been in

therapeutic use for more than three decades,

has been widely used as spasmolytics of

choice. The rationale for use of tolperisone

includes the following:

has higher muscle

relaxant activity than the dextrorotatory

enantiomer.

exhibits membrane

stabilizing potency, which is characteristic

of antiarrythmic and local anesthetic

agents.

differs from other

myotonolytic agents in its pharmacological

properties, which mediate muscle relaxation

without concomitant sedation or withdrawal

phenomena.

has potential of being a

successful centrally acting muscle relaxant due

to its membrane stabilizing property, low-

incidence of side-effects, without concomitant

sedation or withdrawal phenomena.

TOLFREE–100 mg Tablets (Tolperisone

hydrochloride 100 mg) are supplied in the

blister pack of 10 Tablets.

TOLFREE–150 mg Tablets (Tolperisone

hydrochloride 150 mg) are supplied in the

blister pack of 10 Tablets

Keep in a Cool dry place, protecting from light.

Keep out of reach of Children.

30

Tolfree (Tolperisone)

Tolfree (Tolperisone)

Tolfree (Tolperisone)

Tolfree (Tolperisone)

Tolfree (Tolperisone)

�

�

How Supplied

17

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