What are studies regarding the efficacy of botulinum toxin (BTX) in the management of pain through therapeutic injections?

Updated: Jun 19, 2018
  • Author: Anthony H Wheeler, MD; Chief Editor: Meda Raghavendra (Raghu), MD  more...
  • Print


In December 1989, BTX-A (BOTOX®) was approved by the United States Food and Drug Administration (FDA) for use in the United States for the treatment of strabismus, blepharospasm, and hemifacial spasm in patients aged 12 years and older. In December 2000, BOTOX® was subsequently approved for the treatment of cervical dystonia in adults to reduce the severity of abnormal head posture and pain associated with cervical dystonia. In April 2002, BOTOX® was approved for the treatment of glabellar wrinkles. In July 2004, BOTOX® was approved by the FDA for primary axillary hyperhidrosis that is inadequately managed by available topical agents. In March 2010, BOTOX® was FDA approved for the treatment of upper extremity spasticity, which is often painful. In October 2010, BOTOX® was approved for the prophylaxis of headaches in adult patients with chronic migraine (≥15 d/mo with headaches lasting ≥4 h/d).

BTX type B (BTX-B) is currently FDA-approved for the treatment of cervical dystonia. [28] Despite the fact that neither FDA-approved BTX is approved specifically as an analgesic, the analgesic effects of these agents has been observed (eg, the ability for these toxins to reduce the pain associated with cervical dystonia). In fact, the analgesic effect of the neurotoxins appeared to have a greater duration of action than other more direct neuromuscular effects. [29]

Following injection of the toxin into muscle, a "BTX-effect" (eg, weakness) occurs within a few days, usually peaks within 2 weeks, and then gradually returns to baseline. This recovery of strength is associated with new axonal growth or "sprouting" at the affected neural site and the return of cholinergic synaptic activity to the original nerve terminals. Regeneration of the cleaved synaptic protein is required for recovery to occur. The duration of the clinical effect of the currently available neurotoxins appears to be approximately 3-5 months in humans but may vary.{{Rerf198} [30, 31] Additionally, the possible differences in duration of action of these toxins for different clinical conditions (eg, cervical dystonia, migraine headache, chronic low back pain) may be due to this variation, at least in part.

Therefore, the toxins' primary mechanism of action has been linked to their ability to inhibit the release of acetylcholine from cholinergic nerve terminals; however, most experts acknowledge that this effect appears inadequate to explain the entirety of the neurotoxin's apparent analgesic activity exhibited by these toxins. [32] Consequently, research has demonstrated other mechanisms of action that might also explain the analgesic effects of BTX. These mechanisms are multiple and have been demonstrated in animal studies; therefore, their clinical effect in humans, if any, can only be estimated.

Some of these neurophysiologic actions on pain are inhibition of glutamate; release of substance P and calcitonin-gene related peptide; reduced afferent influence on the central nervous system through the toxin's effects on muscle spindles; and other possible effects on pain transmission. [33, 34, 35] In addition to reduced glutamate release in the peripheral nervous system, compared with animal controls, BTX-inhibition of the expression of C-fos in the dorsal spinal cord in treated animals was observed. Two reviews were published that elucidated and summarized the multiple noncholinergic mechanisms of BTX, which may explain its analgesic effect. [36, 37]

Of particular note, Cui and colleagues performed a placebo-controlled study on rats who received subcutaneous (SC) injections of BTX-A into their paws before being exposed to the formalin model of inflammatory pain. [38] The BTX-treated rats experienced a significant dose-dependent inhibition of both the acute and secondary pain responses. [39, 38]

Aoki later studied whether the action of SC BTX-A to inhibit inflammatory pain in the rat formalin model was due to a direct action on sensory neurons. [40] Using microdialysis, Aoki discovered that BTX-A significantly inhibited formalin-induced glutamate release and reduced the number of formalin-induced C-fos-like immunoreactive cells in the dorsal horn of the spinal cord. Also, BTX-A significantly inhibited excitatory activity of wide dynamic range neurons in the dorsal horn characteristic of phase II of the formalin response. Inhibition of neurotransmitter release from primary sensory neurons was shown in this study and may act as the primary mechanism for BTX-A's inhibition of peripheral sensitization, which may also indirectly reduce central sensitization.

Did this answer your question?
Additional feedback? (Optional)
Thank you for your feedback!