Long before, the use of Botulinum toxin started for treating cosmetic conditions; it has been used for treating various clinical disorders related to muscular malfunction by temporarily inducing relaxation in skeletal muscles. In the management of pain, the use of Botulinum toxin has shown analgesic effects by decreasing the hyperactivity of muscles, but studies now suggest that Botox could have a direct analgesic effect that is different from its effects on neuromuscular activity.
The benefits of Botulinum toxin type A in relieving chronic migraines show no direct concordance between muscle relaxation and improvement in pain in neuromuscular conditions1. This suggests that mechanism of action of botulinum toxin in relieving pain may not be strictly due to muscle relaxation. Other similar research findings2 3 have increased the interest of researchers towards identifying the possible mechanism through which Botulinum toxin type A may work to reduce pain.
Mechanism of pain transmission
There are two types of afferent nerves or primary nociceptive nerves that are responsible for pain signals transmission to the central nervous system which includes;
The dorsal root ganglia is a house to the cell bodies of these neurons where they transmit single process that branches out to innervate periphery nerves as free nerve endings (nociceptors- pain sensory organs) and also to innervate the central nervous system by synapsing the neurons located in the dorsal horn of spinal cord. The trigeminal neurons (A delta and C fibres) are responsible for pain detection in the face and head. These cell bodies of these neurons are located in the trigeminal ganglion while their axon synapse is located in the brain stem. The type C fibres of trigeminal neurons release substance P, somatostatin and other types of neuropeptides from central as well as peripheral terminals. These peptides are responsible for mediation of pain and inflammation.
How Botulinum Toxin Type A works?
Studies have indicated that Botulinum toxin type A inhibits the release of substance P from the cultured dorsal root ganglion neurons4-5. The primary nociceptive afferents (C nerve fibres) releases substance P which is a neurotransmitter. Also, calcitonin gene-related peptide (CRGP), inflammatory neuropeptide which is released from trigeminal ganglion cell, has been postulated to have a pathogenic role in stimulating pain. Botulinum toxin type A has been found to reduce the stimulation but not the basal release of calcitonin gene-related peptide (CRGP) from cultured trigeminal ganglia neurons6 7.
Botulinum Toxin type A elicits muscle relaxation by inhibiting the release of acetylcholine from alpha and gamma neurons. Additionally, several animal studies8 9 10 11 have indicated that botulinum toxin has antinociceptive effects. The possible Botulinum toxin type A mechanism through which it works in reducing pain may involve inhibition of pain causing neuropeptides and a direct reduction in the pain nerve peripheral sensitization which indirectly reduce central sensitization correlated with chronic pain.
Recent studies12 13 14 have suggested the efficacy of Botulinum toxin type A in treating postherpetic neuralgia which makes it likely to be effective for trigeminal neuralgia and post-traumatic neuralgia. A research study was conducted to explore the direct analgesic effects of Botulinum toxin type A in chronic neuropathic pain15. The results of the study showed that botulinum toxin type A had direct analgesic and persistent effects on a spontaneous intensity of pain for 2-14 weeks following the injections. Botox also reduced allydonia to brush as well as cold pain threshold without having affected on the perception of thresholds. These effects were independent of its effects on muscle movements. Another research study found that administration of Botox injections significantly reduced pain in postherpetic Neuralgia, along with reducing opioid use as compared to lidocaine and placebo16
These and many other research findings suggest that BoNTA may be a beneficial treatment for treating certain kinds of neuropathic pain which involve neurogenic inflammatory mechanism. Some of the chronic pain conditions that can be treated through BoNTA include postherpetic neuralgia, complex regional pain syndrome, chronic migraines/headaches, painful diabetic neuropathy, arthritis, overactive bladder etc. Many research studies are on-going to examine the effects of botox in treating other prominent pain conditions.
 Smuts, Johan A.; Schultz, Donovan; Barnard, Adri. “Mechanism of Action of Botulinum Toxin Type A in Migraine Prevention: A Pilot Study.” Headache: The Journal of Head and Face Pain. 44.8 (September 2004): 801-805. Print.
 Oliver, M., MacDonald, J., & Rajwani, M. (2006). The use of botulinum neurotoxin type A (Botox) for headaches: a case review. The Journal of the Canadian Chiropractic Association, 50(4), 263–270.
 Aoki, K. R. (2003), Evidence for Antinociceptive Activity of Botulinum Toxin Type A in Pain Management. Headache: The Journal of Head and Face Pain, 43: 9–15. doi:10.1046/j.1526-4610.43.7s.3.x
 Durham, P. L. (2006). Calcitonin Gene-Related Peptide (CGRP) and Migraine. Headache, 46(Suppl 1), S3–S8.
 Durham, P. L., & Masterson, C. G. (2013). Two Mechanisms Involved in Trigeminal CGRP Release: Implications for Migraine Treatment. Headache, 53(1), 67–80. http://doi.org/10.1111/j.1526-4610.2012.02262.x
 Wu, C., Xie, N., Lian, Y., Xu, H., Chen, C., Zheng, Y., … Zhang, H. (2016). Central antinociceptive activity of peripherally applied botulinum toxin type A in lab rat model of trigeminal neuralgia. SpringerPlus, 5, 431. http://doi.org/10.1186/s40064-016-2071-2
 Bach-Rojecky L, Relja M, Lacković Z. 2005. Botulinum toxin type A in experimental neuropathic pain. J Neural Transm (Vienna). 112(2):215–219.
 Aoki KR. Evidence for antinociceptive activity of botulinum toxin type A in pain management. Headache. 2003 Jul-Aug;43 Suppl 1:S9-15.
 Durham, P. L., & Cady, R. (2011). Insights Into the Mechanism of OnabotulinumtoxinA in Chronic Migraine. Headache, 51(10), 1573–1577. http://doi.org/10.1111/j.1526-4610.2011.02022.x
 Pellizzari R., Rossetto O., Schiavo G., Montecucco C. Tetanus and botulinum neurotoxins: Mechanism of action and therapeutic uses. Philos. Trans. R. Soc. Lond. B Biol. Sci. 1999;354:259–268. doi: 10.1098/rstb.1999.0377
 Mense S. Neurobiological basis for the use of botulinum toxin in pain therapy. J. Neurol. 2004;251:I1–I7. doi: 10.1007/s00415-004-1102-z.
 Oh, H.-M., & Chung, M. E. (2015). Botulinum Toxin for Neuropathic Pain: A Review of the Literature. Toxins, 7(8), 3127–3154. http://doi.org/10.3390/toxins7083127
 Ranoux, D., Attal, N., Morain, F. and Bouhassira, D. (2008), Botulinum toxin type a induces direct analgesic effects in chronic neuropathic pain. Ann Neurol., 64: 274–283. doi:10.1002/ana.21427
 Xiao, L., Mackey, S., Hui, H., Xong, D., Zhang, Q. and Zhang, D. (2010), Subcutaneous Injection of Botulinum Toxin A Is Beneficial in Postherpetic Neuralgia. Pain Medicine, 11: 1827–1833. doi:10.1111/j.1526-4637.2010.01003.x