Botulinum Toxin Treatment of Neuropathic Pain

Shivam Om Mittal, MD; Delaram Safarpour, MD; Bahman Jabbari, MD


Semin Neurol. 2016;36(1):73-83. 

In This Article

Abstract and Introduction


Neuropathic pain (NP), a common form of human pain, often poorly responds to analgesic medications. In this review the authors discuss the pathophysiology and conventional treatment of neuropathic pain and provide evidenced-based statements on the efficacy of botulinum neurotoxins (BoNTs) in this form of pain. The level of efficacy for BoNT treatment in each category of NP is defined according to the published guidelines of the American Academy of Neurology. The data indicate that BoNT treatment (most of the literature is with onabotulinumtoxinA) is effective (level A evidence) in postherpetic neuralgia and trigeminal neuralgia. It is probably effective (level B) in posttraumatic neuralgia and painful diabetic neuropathy. The data on complex regional pain syndrome, carpal tunnel syndrome, occipital neuralgia, and phantom limb pain are preliminary and await conduction of randomized, blinded clinical trials. Much remains to be learned about the most-effective dosage and technique of injection, optimum dilutions, and differences among BoNTs in the treatment of neuropathic pain.


Neuropathic pain (NP) is caused by lesions or diseases of the somatosensory system.[1] The site of disturbance or damage can be peripheral (peripheral nerve, plexus, or root) or central (spinal cord, brainstem, or thalamus). The pain often has burning, jabbing, and searing quality. Areas of skin allodynia (touch perceived as pain), hyperalgesia (enhanced pain after exposure to painful stimuli), and hyperesthesia or dysesthesia (enhanced or altered sensations to touch) are commonly observed.

The pathophysiology of neuropathic pain is yet to be fully explored; peripheral neuropathic pain (PNP) is believed to result from damage to the peripheral nervous system leading to irritation of nerve endings and accumulation of nociceptive transmitters and modulators (substance P, glutamate, bradykinin, calcitonin gene-related peptide [CGRP], and others). Focal inflammation follows local accumulation of these agents. Together, these two phenomena lower the sensory threshold of peripheral nerve endings to nociceptive stimuli (peripheral sensitization). Peripheral sensitization increases the number of nociceptive volleys into the spinal cord and leads to sensitization of sensory spinal cord neurons (central sensitization). Sustained peripheral and central sensitization leads to pain chronicity.[2] The pharmaceutical agents which improve neuropathic pain modify one or more of these mechanisms.

Botulinum neurotoxins can alter and alleviate neuropathic pain in animals through several mechanisms (Fig. 1): blocking release of pain mediators (glutamate, substance P, CRGP) from peripheral terminals, dorsal root ganglia (DRG), and spinal cord neurons;[3–5] decreasing local inflammation around nerve terminals;[6] deactivation sodium channels;[7,8] inhibiting discharge of muscle spindles;[9] and decreasing sympathetic transmission.[10] The latter two mechanisms can enhance central sensitization.

Figure 1.

Mechanisms of neuropathic pain and modes of action of botulinum toxins (BoNTs). (Reprinted with permission from Oh H-M, Chung M. Botulinum toxin for neuropathic pain: a review of the literature. Toxins 2015;7(8):3127–3154.)

Seven examples of peripheral neuropathic pain (PNP) for which prospective and controlled data are available on BoNT efficacy are discussed in this review article. These include postherpetic neuralgia, posttraumatic neuralgia, trigeminal neuralgia (TN), painful diabetic neuropathy (PDN), complex regional pain syndrome, residual limb pain, and phantom pain. Case reports are provided based on our clinical experiences.

In this review, the level of efficacy for BoNTs is defined according to the guidelines of the Therapeutics and Assessment Subcommittee of the American Academy of Neurology (AAN).[11] According to these guidelines, level A evidence (effective or not effective) requires two class I studies. For level B evidence (probably effective/ineffective), one class I or two class II studies are needed, and one class II study denotes level C (possibly effective/ineffective) evidence. Level U indicates undetermined efficacy. The Yale Medical Library's search system was used for a literature search, encompassing several search programs including PubMed and Ovid.

The molecular structure, mechanism of action, serotypes of BoNTs, and clinical preparations of the toxins for clinical use are presented by Kumar et al and Dashtipour and Pedouim in this issue. In pain medicine, only chronic migraine is an approved FDA indication. All other areas of pain are currently considered off-label, although for several of them the literature strongly suggests efficacy. The four FDA-approved neurotoxins—three BoNT-A (BOTOX, Allergan, Inc.; XEOMIN, Merz North America, Inc.; and Dysport, Galderma Laboratories, L.P.) and BoNT-B (MYOBLOC, Solstice Neurosciences, LLC)—are generally considered safe in the recommended doses. Rare and serious side effects, however, have been reported. It is hence prudent before administering any BoNT, to obtain a signed acknowledgment from the patient about having reviewed the list of potential serious side effects.