Centrally Acting Muscle Relaxants

CENTRALLY ACTING MUSCLE RELAXANTS

These are drugs which reduce skeletal muscle tone by a selective action in the cerebrospinal axis, without altering consciousness. They selectively depress spinal and supraspinal polysynaptic reflexes involved in the regulation of muscle tone without significantly affecting monosynaptically mediated stretch reflex. Polysynaptic pathways in the ascending reticular formation which are involved in the maintenance of wakefullness are also depressed, though to a lesser extent. All centrally acting muscle relaxants do have some sedative property. They have no effect on neuromuscular transmission and on muscle fibres, but reduce decerebrate rigidity, upper motor neurone spasticity and hyperreflexia.

The prominent differences between peripherally and centrally acting muscle relaxants are listed in Table 25.3.

CLASSIFICATION

(i) Mephenesin congeners

Carisoprodol,

Mephenesin,

Chlorzoxazone,

Chlormezanone,

Methocarbamol.

(ii) Benzodiazepines  

Diazepam and others.

(iii) GABA derivative

Baclofen.

(iv) Central α₂ agonist

Tizanidine

Mephenesin

It was the first drug found to cause muscle relaxation in animals without producing unconsciousness and was called internuncial neurone blocking agent because its primary site of action is the spinal internuncial neurone which modulates reflexes maintaining muscle tone. It is not used clinically because it is gastric irritant, and injected i.v., it causes thrombophlebitis, haemolysis and marked fall in BP. It has been included in counterirritant ointments (MEDICREME, RELAXYL) where its irritant rather than muscle relaxant property could be affording relief.

Carisoprodol 

It has a favourable muscle relaxant: sedative activity ratio with weak analgesic, antipyretic and anticholinergic actions in addition. It is used in musculoskeletal disorders associated with muscle spasm.

CARISOMA 350 mg tab; one tab. TDSQID, SOMAFLAM 175 mg + ibuprofen 400 mg tab.

Chlorzoxazone

It is pharmacologically similar to mephenesin; has a longer duration of action and is better tolerated orally.

PARAFON DSC 500 mg tab; MOBIZOX 500 mg + diclofenac 50 mg + paracetamol 500 mg tab; PARAFON: 250 mg + paracetamol 300 mg tab, 1–2 tab TDS.

Chlormezanone

It has antianxiety and hypnotic actions as well, and has been used for tension states associated with increased muscle tone.

WINTRAC 100 mg tab; 1–2 tab TDSQID, DOLOBAK 100 mg + paracetamol 450 mg tab.

Methocarbamol

It is less sedative and longer acting than mephenesin. Orally it has been used in reflex muscle spasms and chronic neurological diseases. It can be injected i.v. without producing thrombophlebitis and haemolysis— used for orthopedic procedures and tetanus.

ROBINAX 0.5 g tab, 1 TDS: 100 mg/ml inj. for i.v. or i.m. use. ROBIFLAM 750 mg + ibuprofen 200 mg tab;

FLEXINOL 400 mg + paracetamol 325 mg tab.

Clinical efficacy of none of the above drugs as muscle relaxant is well established. Gastric irritation and sedation are the most important side effects.

Diazepam

It is the prototype of benzodiazepines (BZDs) which act in the brain on specific receptors enhancing GABAergic transmission. Muscle tone is reduced by supraspinal rather than spinal action; muscle relaxant: sedative activity ratio is low. No gastric irritation occurs and it is very well tolerated, though sedation limits the dose which can be used for reducing muscle tone. It is particularly valuable in spinal injuries and tetanus. Combined with analgesics, it is popular for rheumatic disorders associated with muscle spasm.

Dose: 5 mg TDS orally, 10–40 mg i.v. (in tetanus).

Baclofen

This analogue of the inhibitory transmitter GABA acts as a selective GABA_B receptor agonist. The GABA receptors have been divided into:

GABA_A receptor Intrinsic ion channel receptor— increases Cl¯ conductance; blocked by bicuculline; facilitated by BZDs.

GABA_B receptor Gprotein coupled receptor; hyperpolarizes neurones by increasing K⁺ conductance and altering Ca²⁺ flux; bicuculline insensitive; blocked by saclofen.

Baclofen does not affect Cl¯ conductance and its actions are not antagonized by bicuculline.

The primary site of action of baclofen is considered to be in the spinal cord where it depresses both polysynaptic and monosynaptic reflexes. As such, it does produce muscle weakness, but is less sedative than diazepam. It reduces spasticity in many neurological disorders like multiple sclerosis, amyotropic lateral sclerosis, spinal injuries and flexor spasms, but is relatively ineffective in stroke, cerebral palsy, rheumatic and traumatic muscle spasms and parkinsonism.

Baclofen is well absorbed orally and is primarily excreted unchanged in urine with a t½ of 3–4 hours.

Side Effects are drowsiness, mental confusion, weakness and ataxia; serum transaminases may rise. Sudden withdrawal after chronic use may cause hallucinations, tachycardia and seizures.

Dose: 10 mg BD to 25 mg TDS.

LIORESAL, LIOFEN 10 mg, 25 mg tab.

Tizanidine

This recently introduced clonidine congener is a central α₂ adrenergic agonist—inhibits release of excitatory amino acids in the spinal inter-neurones. It may facilitate the inhibitory transmitter glycine as well. It inhibits polysynaptic reflexes; reduces muscle tone and frequency of muscle spasms without reducing muscle strength. Efficacy similar to baclofen or diazepam has been noted in multiple sclerosis, spinal injury and stroke, with fewer side effects.

Tizanidine is absorbed orally, undergoes first pass metabolism and is excreted by the kidney; t½ 2–3 hours. It is indicated in spasticity due to neurological disorders and in painful muscle spasms of spinal origin. Side effects are dry mouth, drowsiness, nighttime insomnia and hallucinations. Dose-dependent elevation of liver test values has been noted. Though no consistent effect on BP has been observed, it should be avoided in patients receiving antihypertensives, especially clonidine.

Dose: 2 mg TDS; max 24 mg/day.

SIRDALUD 2 mg tab, TIZAN 2, 4 mg tab; TIZAFEN 2 mg + ibuprofen 400 mg tab; TIZANAC 2 mg + diclofenac 50 mg tab, PROXIVONMR 2 mg + nimesulide 100 mg cap.

Uses Of Centrally Acting Muscle Relaxants

1. Acute Muscle Spasms

Overstretching of a muscle, sprain, tearing of ligaments and tendons, dislocation, fibrositis, bursitis, rheumatic disorders, etc. cause painful spasm of muscles. The mephenesin like and BZD muscle relaxants, combined with analgesics, are commonly used, but efficacy is not impressive.

2. Torticollis, Lumbago, Backache, Neuralgias

These are other conditions in which painful spasm of certain muscles is a prominent feature; respond in the same way as acute muscle spasms.

3. Anxiety And Tension

These states are often associated with increased tone of muscles. Diazepam group of drugs and chlormezanone benefit by their antianxiety as well as muscle relaxant actions.

4. Spastic Neurological Diseases

Impairment of descending pathways in the cerebrospinal axis and withdrawal of inhibitory influence over the stretch reflex causes chronic increase in muscle tone or spasticity. Hemiplegia, paraplegia, spinal injuries, multiple sclerosis, amyotropic lateral sclerosis and cerebral palsy fall in this category. They are benefited by baclofen, diazepam, tizanidine and dantrolene but not by mephenesin group of drugs. However, therapy of these disorders is far from satisfactory.

5. Tetanus

Most commonly diazepam is infused i.v. and the dose is titrated by the response. Methocarbamol is an alternative.

6. Electroconvulsive Therapy

Diazepam decreases the intensity of convulsions resulting from ECT, without diminishing its therapeutic effect. Often SCh is used in addition for total suppression of the muscular component of ECT.

7. Orthopedic Manipulations

These may be performed under the influence of diazepam or methocarbamol given i.v.