C botulinum is a gram-positive anaerobic bacterium that produces the botulinum neurotoxin (BoNT). There are 7 neurotoxin serotypes of BoNT: A, B, C (C1 and C2), D, E, F, and G.
Botulinum toxin A is FDA approved to treat various medical conditions including cervical dystonia, blepharospasm, strabismus, upper limb spasticity, hyperhydrosis, and most recently, chronic migraines. The public most commonly recognizes BoNT to be used for cosmetic purposes for the treatment of wrinkles. There are 3 forms of BoNT-A: Ona botulinum toxin A (Botox), Abobotulinum toxin A (Dysport), and Incobotulinum toxin A (Xeomin).Information Sheet
The medical benefit of BoNT is based on the acetylcholinergic mechanism of muscle relaxation through inhibition of the neurotransmitter acetylcholine (Ach) at the neuromuscular junction. However, there are emerging mechanistic theories that occur both in conjunction with and independent of Ach inhibition. The inhibition of neuropeptides such as substance P, glutamate, and calcitonin gene-related peptide (CGRP) in sensory neurons may provide an explanation of the analgesic effects of botulinum toxin in various chronic pain conditions.
Upon injection of BoNT-A, the molecule migrates toward the nerve terminal and attaches to it via the C portion of the heavy chain. Endocytosis occurs, causing the BoNT-A vesicle to be internalized and enter the nerve terminal. The light chain portion of the BoNT-A then detaches from the molecular vesicle and enters the cytoplasm. The light chain targets and cleaves the SNAP-25 protein of the SNARE complex, resulting in inhibition of Ach release. This in turn causes decreased muscular contraction.
In addition, it is hypothesized that substance P and CGRP release are inhibited at the sensory afferent nerve. Glutamate, an excitatory neurotransmitter at the presynaptic membrane, is also inhibited. The inhibition of glutamate in turn further decreases the release of substance P and CGRP. Wide dynamic neuron activity is believed to be diminished, thus interrupting the overall sensory feedback mechanism. The inhibition of these neuropeptides involved in pain transmission and the overall interruption in the sensory feedback mechanism is hypothesized to be the cause of antinociceptive effects in chronic pain and ultimately the reduction of both peripheral and central sensitization.
Myofascial pain is regional in location and commonly involves muscular trigger points (MTPs). Trigger points are characterized by focal areas of muscular tissue that are not only tender to palpation, but also may trigger pain distant from the actual site, known as ‘referred’ pain. A twitch response of the palpated trigger point is commonly seen. The mechanism of pain is believed to be due to a dysfunctional motor end plate causing an excess of Ach release leading to excessive muscular contraction and spasm. MTPs are commonly treated with local injections of anesthetic but also have benefited from dry needling alone. BoNT-A appears to be a reasonable injectate. BoNT-A has been shown to provide relief in pain and improvement in function for patients with chronic low back pain due to muscular dysfunction. There is no consensus as to the dosing of BoNT-A for myofascial pain disorders.
A hypertonic pelvic floor occurs when the muscles in the pelvic floor become too tense and are unable to relax. Many people with a tense and non-relaxing pelvic floor experience pelvic health concerns such as constipation, painful sex, urgency and pelvic pain. A hypertonic pelvic floor may also be accompanied by tension in surrounding hip and pelvic muscles such as the piriformis, obturator internus, coccygeus and hamstrings.
Injecting botulinum toxin type A (Botox) into hypertonic pelvic floor muscles may aid the relaxation of pelvic floor musculature. The muscles that are injected in chronic pelvic pain treatment include the obturator internus, levator ani (pubococcygeus, iliococcygeus, and puborectalis), and coccygeus. Other muscles including the transverse perineal, obturator internus and piriformis muscle may be injected. Generally, injections can be performed tolerably under local anaesthesia alone. Side effects of Botox injection in chronic pelvic pain are rare and self-limiting. Because of the reversible nature of Botox, reinjection appears to be necessary. Increasing proof points out that Botox is a promising treatment option for chronic pelvic pain in women.
Nesbitt-Hawes et al reported that clinical outcomes for single and subsequent Botox injections for recurrent pelvic pain are similar. In the subsequent injection, there is a cumulative effect with lower vaginal and maximal contraction pressures. Long-term treatment with Botox is generally tolerable and efficient; nevertheless, following an initial positive therapeutic effect, symptoms may fail to respond to upcoming treatments. Attributing factors considered for secondary nonresponse may include the development of neutralizing antibodies, missed injection of the target muscles, disease progression, and architectural changes following repeated injection. There is limited knowledge on the long-term implications, so further studies are required. Women who have benefitted from a single Botox injection can be informed that, if symptoms reoccur, repeated injections can be expected to be equally efficacious.
Plantar fasciitis is a common pain syndrome involving the plantar fascia, characterized by exquisite tenderness over the medial aspect of the calcaneal tuberosity, exacerbated upon weight bearing. The pain mechanism of plantar fasciitis is believed to involve hypertrophy and micro tears of the plantar fascia with secondary inflammation and spasm of the underlying foot musculature. Plantar fasciitis is commonly treated with physiotherapy, orthotics and at times steroid injections. Babcock et al showed a significant benefit in analgesia with BoNT-A injections compared to placebo.
Piriformis syndrome can cause buttock pain with radiation in a sciatic distribution. Patients usually present with exquisite pain upon piriformis palpation that is exacerbated with hip flexion combined with hip internal rotation. There are variable anatomic findings of the sciatic nerve in relation to the piriformis. Spasm and tightening of the piriformis muscle can irritate the sciatic nerve, thus imitating lumbar discogenic referred pain. There are limited studies for BoNT-A injections for piriformis syndrome; however, Childers and colleagues showed analgesic benefit from BoNT-A injections into the piriformis under electromyography and fluoroscopy guidance.
Botulinum toxin type A has been recommended by NICE as an option for the prophylaxis of headaches in adults with chronic migraine (defined as headaches on at least 15 days per month of which at least 8 days are with migraine)that has not responded to at least three prior pharmacological prophylaxis therapies and whose condition is appropriately managed for medication overuse. A positive response is defined as at least a 30% reduction in headache days per month after two treatment cycles. The antinociception mechanism is based not on the acetylcholinergic mechanism but rather on the inhibition of neuropeptides including substance P, CRGP, and glutamate at afferent nerve endings. In turn, neurogenic inflammation is inhibited, thus decreasing peripheral sensitization and indirectly overall central sensitization.
Osteoarthritis (OA) is the most common form of arthritis that affects primarily large weight-bearing joints such as the knees and hips, but also affects the spine, hands, and shoulders. OA is commonly treated with physiotherapy, oral anti-inflammatory medications, and intra-articular steroid joint injections. Mahowald and colleagues performed intra-articular BoNT-A injections on patients with OA and RA who were refractory to oral anti-inflammatory and analgesic agents. All the patients had a history of either intra-articular steroid or viscosupplement injections with no significant benefit. BoNT-A intra-articular injections into the knees, ankles, and shoulders showed a significant reduction in pain as well as improved active range of motion.
Botulinum toxin has also been applied to a variety of neuropathic pain conditions. Diabetic neuropathy is one of the most common neuropathies seen today. The pathophysiology of neuropathic pain is complex and is hypothesized to involve local tissue damage in the periphery resulting in damage to the afferent C fibers and A-delta fibers. Consequently, nociceptor thresholds are diminished and neuroplasticity occurs including increased sodium channels and an upregulation of the N-methyl-D-aspartate receptors involved in neuropathic pain transmission. In a double-blind crossover trial, Yuan and colleagues showed a reduction in pain upon injection of BoNT-A vs placebo into the dorsum of the feet of patients with diabetic neuropathy.
Botulinum toxin is contraindicated in patients with known hypersensitivity to botulinum toxin type A or to any of the excipients. It should only be used with extreme caution and under close supervision in patients with subclinical or clinical evidence of defective neuromuscular transmission (e.g. myasthenia gravis or Lambert-Eaton Syndrome), in patients with peripheral motor neuropathic diseases (e.g. amyotrophic lateral sclerosis or motor neuropathy) and in patients with underlying neurological disorders. Such patients may have an increased sensitivity Botulinum toxin, even at therapeutic doses, which may result in excessive muscle weakness and an increased risk of clinically significant systemic effects including severe dysphagia and respiratory compromise. The botulinum toxin product should be used under specialist supervision in these patients and should only be used if the benefit of treatment is considered to outweigh the risk. Patients with a history of dysphagia and aspiration should be treated with extreme caution.