Botulinum Toxin Type-A in Pain Management
Botulinum toxins were first developed in the 1950s by ophthalmologist Dr. Alan Scott (and subsequently approved by the FDA in 1989) for the treatment of eye movement disorders such as strabismus and blepharospasm.1 Its uses have subsequently expanded to include neurological movement disorders, including focal muscle dystonia2,3 and spasticity.4,5
Botulinum toxin type-A (BTX-A) is effective for muscle spasticity through its prolonged blockade of acetylcholine. The active moiety, a 150 kDalton protein, is the most potent of seven neurotoxins (A, B, C1, D, E, F, G) produced by the gram-positive anaerobic rod-shaped bacteria Clostridium botulinum.6 (See Appendix A for a summary of botulinum toxin products). BTX-A’s mechanism of action is described in the following section.
How Botulinum Toxins Work
When injected into muscle, BTX-A binds with high specificity and affinity to presynaptic cholinergic axon terminals. Its heavy chain (100kD) attaches it to the pre-synaptic membrane of the nerve terminal (see Figure 1a). Current research indicates that the attachment site is the SV2 neuronal acceptor protein located on the synaptic vesicle itself.7
Endocytosis of the BTX-A molecule then occurs (see Figure 1b). Current research indicates that this occurs through the same vesicles where acetycholine is released.8 After endocytosis, the disulphide bond is broken, allowing the light chain to move to the presynaptic terminal. The light chain actually migrates through the channel created by the heavy chain.9 The light chain then cleaves nine aminoacid residues from the 25 kDalton synaptosome-associated protein (which has 205 residues). This inhibits calcium-activated release of acetylcholine (see Figure 1c).
Current research also indicates that the products of SNAP-25 cleavage are also inhibitory. This leads to retraction of the endplate nerve terminals and subsequent loss of endplate organization. Muscle relaxation/paralysis occurs as a result of this block. Within four days, collateral terminal sprouting will occur to attempt re-innervation of the neuromuscular junction (NMJ). These temporary functional synapses result in partial recovery of muscle function after about 28 days. Within about two months after injection, the original nerve terminals will begin to recover their ability to release acetylcholine and original endplate connections are restored. Sprouting then stops and the temporary synapses lose their function. Within approximately three months, the original neuromuscular junctions recover full function and are normalized.10,11 Cholinergic parasympathetic and postganglionic sympathetic nerve synapses of the autonomic nervous system are also potential targets. For example, intradermal injections of BTX-A leads to denervation of eccrine glands (useful for hyperhidrosis and sialorrhea).12
Patients are usually advised that the onset of action occurs around day three, and the peak effect (in muscle relaxation) after three weeks. The average duration of response is three months. Pain relief, however, may last longer than the effects of muscle relaxation.13 Injections are spaced out a minimum of three months to minimize the rare risk of antibody formation to the protein14 which would prevent BTX-A from working the next time.
Safety of Botulinum Toxins
Botulinum toxin type-A comes in vials of 100 units. A unit of BTX-A is defined as the lethal dose for 50 percent (LD-50) of a colony of 20 gm Swiss-Webster mice. The LD-50 for monkeys is 39U/kg. Extrapolated to a 70 kg human, a lethal dose would be about 2,700 units. The typical maximum dose at one injection setting is 400 units. Reported side effects include post-injection muscle soreness, stiffness typically lasting a week and, rarely, a flu-like illness which may last a few days to a month. Inadvertent weakness depends on the site of injection (e.g. eyelid ptosis for injections in the pericranial frontal muscles, and difficulty with swallowing for anterior neck muscle injections).
Case reports of serious adverse effects have led to recent FDA and Health Canada safety reviews. Such incidences are largely dependent on operator technique (e.g. concomitant general anesthetic) and dose used. A retrospective review of 929 cerebral palsy children patient encounters documented no severe adverse effects or botulism.15 Other supportive studies document safety16,17 and a meta-analysis supported the overall safety of BTX-A.18 Relative contra-indications to BTX-A include generalized muscular weakness (e.g., myopathies and NMJ diseases such as myasthenia gravis), profound atrophy of the target muscle, aminoglycoside antibiotic therapy, and pregnancy. Post-injection electrical stimulation/contraction of the injected muscle(s) has been reported to augment the response. Endplate targeted injections—with electromyographic (EMG) guidance—appear to be more effective than anatomical approaches.19 BTX-A should be stored in the freezer and reconstituted with preservative-free normal saline. When stored in saline, it loses potency by 35 percent after one week and 44 percent after two weeks.20 A recent rat study suggests that there are retrograde effects when BTX-A is injected into the brain and may provide implications for novel uses.21
Botulinum Toxin and Headache
A noticeable reduction in pain using BTX-A was first observed by Jankovic in work on cervical dystonia.22 Subsequent reports by the Carruthers, who were the first to report the cosmetic benefits from blepharospasm treatment,23 documented relief of headaches with injections done for wrinkles.24
Though there were earlier supportive studies for the use of botulinum toxin type-A for headache treatment (specifically, migraine, tension, and cervicogenic types),25-28 more recent larger multi-centre trials did not find evidence for tension-type headache.29,30 Results were more positive in specific subgroups of migraine and chronic daily headaches.31-34 A recent neurology consensus panel did not find sufficient evidence at this time for headache.35 The results of a large multi-centre phase three trial for migraine (PREEMPT) will be available later this year. The preliminary word on the PREMMPT migraine study is positive. This heralds good news in eventually getting BTX-A approved for pain.