Botulinum toxin is licensed for the symptomatic treatment of blepharospasm and hemifacial spasm. It is used without licence to relieve pains due to other types of muscle spasm.
The pharmaceutical preparation contains botulinum toxin of the type A serotype, serum albumin and sodium chloride. The botulinum toxin was first isolated in 1895 from the food of victims of food poisoning. It was then first recognized as a neurotoxin.
Mechanism of Botulinum Toxin
The neurotoxic action reduces neuromuscular transmission thereby causing skeletal muscle weakness and inhibition of muscle spasm. Botulinum toxin selectively acts on peripheral cholinergic nerve endings. It enters the nerve terminal and causes localized chemical destruction. This prevents the release of acetylcholine at the neuromuscular junction. Efficient neuromuscular transmission depends on the release of acetylcholine from the axonal terminal and its binding to the postsynaptic receptors to effect the muscle action potential. Without the synthesis and release of acetylcholine the muscle action potential is prevented. After the nerve end plate has shrivelled it starts to regenerate by sprouting. When the sprouts reach the muscle surface a new neuromuscular junction has formed. Regeneration takes approximately 3 months. When it is complete, tone and muscle spasms recur. At that stage the injection of botulinum toxin can be repeated indefinitely. Tachyphylaxis has been shown. In addition to its effects on the motor nerve ending, botulinum toxin has also been reported to have an analgesic effect.
Pharmacokinetics of Botulinum Toxin
Botulinum toxin is given intramuscularly to affected peripheral muscles. Its spread is dependent on the dose of drug and the volume of diluent. It is taken up by neuronal transport to the spinal cord where it is broken down to inactive metabolites.
Use of Botulinum Toxin
Botulinum toxin is available in single-patient-use vials each containing 100 units. The preparation is freeze dried. It is recommended that it be reconstituted with normal saline although workers in the USA are using local anaesthetic as solvent to enhance the speed of onset of effect. Diluted with normal saline the onset of action is at approximately 3 days and the effect peaks at 1-2 weeks after administration. Injections are sometimes carried out under electromyographic control or with the use of radio-opaque dye and fluoroscopy.
The manufacturer’s recommended maximum dose in the treatment of blepharospasm is 100 units per 12 weeks. The maximum dose used by workers in the USA for the relief of other muscle spasms is 400 units per 12 weeks. The LD50 for single use in a 70 kg person is 3000 units. Depending on the size and number of muscles needing treatment, doses as small as 1.25 units are used for blepharospasm and 30 units for painful conditions secondary to muscle spasm. Inhibition of muscle activity of 50% allows the performance of otherwise difficult physiotherapy. The physiotherapy brings further improvement in muscle function. Painful conditions in which botulinum toxin has been used include:
• Back and myofascial pain.
• Spasticity and painful contractures.
There is evidence of efficacy in all these conditions, but systematic reviews on the use of botulinum in spasticity do not comment specifically on pain control.
1. Back and myofascial pains. Botulinum has been shown to be effective in low back pain when injected paravertebrally at five sites, 40 units per site. Botulinum toxin has been used to treat myofascial pains of the neck, shoulder and low back. Injections have also been carried out to psoas and quadratus lumborum muscles to relieve spasticity. Muscle spasm precipitating pain in conditions such as multiple sclerosis has been treated. Pain caused by an abnormal posture forced by muscle spasm can be treated by botulinum toxin.
2. Spasticity and painful contractures. Secondary contractures resulting from neurological deficit after stroke or from disuse as in the complex regional pain syndromes (CRPS) is reported to be relieved by botulinum toxin. In cervical dystonia over 70% have pain. The injection of doses of botulinum toxin ranging from 100 to 236 units has been reported to give relief of spasm with consequent reduction in pain. In all these conditions the relief of spasticity offers an opportunity and is not an alternative to this.
3. Headache. Botulinum has been shown to be effective in the prevention of tension headache and migraine.
Side-effects of Botulinum Toxin
Local muscle weakness can occur from local spread of drug. Injections into the neck may thus affect swallowing. Misplaced injections can paralyse nearby muscle groups extensively. Excessive doses may paralyse muscles distant to the site of injection. Spread is affected by both dose and volume of diluent. Generalized malaise, about which the patient should be informed, can follow the treatment.
Botulinum toxin is potent in reducing muscle spasm and although currently unlicensed for the purpose, there may be a place for it in the relief of muscle spasm which causes pain. It has been found to have few side-effects. The established regeneration of nerve makes it acceptable in terms of no long-term destructive effect. It offers a useful addition to the pain clinician’s armamentarium as a drug which may relieve pain and also improve function.