Botulinum Toxin Injections for Oral Neuropathic Pain
Condition: Trigeminal Neuropathy, Traumatic
MeSH terms: Trigeminal Nerve Diseases; Trigeminal Nerve Injuries
Study type: Interventional
Phase: Phase 3

Summary: 
      Peripheral painful traumatic trigeminal neuropathy (PPTTN) are poorly relieved by existing
      treatments which in addition induce many adverse effects. BTX, which blocks the exocytosis of
      neurotransmitters, can be captured by axonal retrograde transport in primary nociceptive
      neurons. Injected in the painful area, it might therefore inhibit the release of algogenic
      neurotransmitters, at both the peripheral and central levels and thus reduce pain. One study
      reported such an effect in neuropathic spinal pain. A recent study reported an analgesic
      effect in trigeminal neuralgia.
    

Detailed description: 
      Traumas of either physical (shocks, ballistic impacts etc.) or surgical origin are
      accompanied by acute pain which disappears in most cases with tissue healing. However, in
      some instances pain may persist in spite of an apparently normal tissue repair. Many reports
      have pointed to the societal impact of these neuropathic pains which is a major public health
      problem in Europe and in the world. In addition to the degradation of the quality of
      individual life that affects hedonistic, emotional, social, professional etc. dimensions of
      life, the economic cost to society is considerable (treatment costs, work absenteeism, loss
      of motivation and concentration, etc.) Among these pains, PPTTN resulting from orofacial
      nerve damage after physical or surgical trauma are little studied. Some studies suggest a
      high prevalence, ranging from 0.5 to 12% after oral surgery, including endodontic treatment
      (root canal treatment), simple or complex dental extractions like wisdom teeth, dental
      implants, and surgical interventions (cyst removal, orthognathic surgery etc.). However,
      despite significant advances in recent decades, pathophysiological mechanisms of these pains
      are still largely unknown. The majority of these pains are clinically resistant to standard
      analgesics and therefore extremely difficult to treat, particularly for trigeminal pain.
      Understanding these pains is of major interest to determine new strategies and therapeutic
      targets.

      Symptomatology and Pathophysiology The main complaint of patients is moderate to severe and
      usually burning but may be stabbing. Most cases are continuous, but may report superimposed
      paroxysmal pain attacks. Less frequently, the pain may be short lasting with associated
      mechanical trigger areas, mimicking trigeminal idiopathic neuralgia. However, even in these
      cases, the pain attacks are usually longer than those associated with trigeminal neuralgia.
      Pain is unilateral and may be precisely located to the dermatome of the affected nerve with
      demonstrable sensory dysfunction. The pain may be diffuse and spread across dermatomes, but
      rarely crosses the midline. Patients may complain of a feeling of swelling, foreign body, hot
      or cold, local redness or flushing. Non-painful but annoying dysesthesias such as itching,
      numbness, etc. are often present.

      From a pathophysiological point of view, the development of painful symptoms after peripheral
      nerve injury is related to peripheral and central changes. Damaged tissue initiate peripheral
      changes at the injury site that result in functional changes of neuronal, glial and vascular
      cells, followed by ganglionic and central changes. These changes modify both the functioning
      and the excitability of individual neurons and the configuration of synaptic networks, at the
      spinal cord/ brainstem and brain levels. These events in turn lead to genetic and epigenetic
      changes which translate as long term alterations of neuronal phenotypes Our research group
      (Team "Neuroinflammation Pain and Stress", U894, Psychiatry Centre and Neurosciences.) has
      been involved for many years in deciphering the actors and events contributing to the
      development of post-traumatic neuropathic pain, in both spinal and trigeminal models.

      Treatment The diagnostic difficulty is a therapeutic challenge. During the many consultations
      (average of 7.5 practitioners visited), patients received different treatments: surgical,
      antidepressant, analgesic or alternative which are often ineffective and potentially
      iatrogenic and often need to be complemented by a psychotherapeutic approach.

      The surgical management of patients with neuropathic pain is controversial. Indeed, the long
      term results of micro-neurosurgical procedures are often anecdotal, highly variable, and
      operator-dependent. In addition they are difficult to assess because studies are rare and
      involve only few patients. A thorough evaluation of these techniques is necessary and many
      other authors recommend stopping any surgical procedure at the site of pain and
      contraindicate surgery. These could indeed worsen the patient's pain.

      Pharmacological treatment of PPTTN is the same as for post traumatic spinal neuropathic pain.
      It is symptomatic, not curative, and combines systemic medical treatment with topical
      treatment (anesthetics). Neuropathic pain responds little or not at all to the classical
      analgesics like acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) and are
      treated by other therapeutic classes. Current treatments are based on the recommendations of
      different scientific societies, French (SFETD), European (EFNS) and American (APS).
      Treatments usually used are tricyclic antidepressants, anticonvulsants, opioids and
      inhibitors of the reuptake of serotonin and norepinephrine. However these treatments induce
      many adverse effects more or less tolerated, sometimes leading to treatment discontinuation
      or dose reductions and impaired efficiency.

      In conclusion, the diagnosis of PPTTN is difficult and is often made after extensive
      consultations in specialized centers. The management is unsatisfactory due to the complexity
      of physio-pathogenic mechanisms and the lack of specific drugs. It is most often performed by
      specialized practitioners and uses multidisciplinary skills (dentist, neurologist,
      psychiatrist and psychologist).

      Hypothesis for the study Since its introduction in the 1970s for the treatment of strabismus,
      blepharospasm, and focal dystonia, botulinum toxin type A (BTX-A) has been widely used in the
      treatment of conditions characterized by excessive muscle contraction and/or involvement of
      the cholinergic system (focal dystonia, spasticity, abnormal sphincter contractions, eye
      movement, hyperkinetic and vegetative disorders). Many studies have also been conducted in
      the case of painful conditions with a muscular component following a pioneer work observing a
      significant decrease in pain after BTX injection. Other studies have also reported pain
      relief during several weeks. The neurotoxin has been used in other types of pain disorders
      including myofascial pain, blepharospasm, myalgia of the masticatory system (TMD), back pain,
      painful myoclonia, urologic, rectal or pelvic pain and cervicogenic, neurovascular and
      tension type headaches, and migraine. The results depend on conditions and on the dose used.

      It is at the Neuromuscular junction (NMJ) that the action of botulinum neurotoxin has been
      the most studied. It blocks the release of acetylcholine and causes a reversible
      deafferentation of the motor endplate (28 days). A first recovery occurs by sprouting and the
      restoration of function in the initial innervation and loss of sprouts. Full recovery is
      achieved in about 90 days. However, this sole effect appears insufficient to explain all of
      the analgesic activity of the neurotoxin, demonstrated in numerous animal studies and
      therapeutic clinical trials.Effects on nociceptive system The effects of the neurotoxin can
      also be explained by effects other than on the neuromuscular system, including the
      nociceptive system. BTX affects the vesicular release of neurotransmitters / neuromodulators.
      The analgesic effect may be explained by a peripheral action by blocking the axon reflex that
      releases usually neuropeptides (substance P, neurokinin A, CGRP) by small diameter type C
      primary afferent nerve fibers and causes the phenomena of neurogenic inflammation including
      vasodilation and increased vascular permeability. BTX inhibits the release of substance P and
      glutamate and reduces the inflammatory pain induced by formalin injection. In addition, the
      toxin can be captured by nerve endings and transported by retrograde and orthograde axonal
      transport to remote sites, at the level of primary afferents termination site for example or
      at other sites of neuronal interaction with glial cells or other neuronal types. BoNT can
      therefore inhibit the release of algogenic neurotransmitters present in nociceptive primary
      afferent (SP, glutamate) both peripherally and centrally. BTX also decreases the expression
      of TRPV1 receptors on the membrane surface of nociceptors in animals, and humans. These
      receptors are involved in the transduction of thermal information and their activation
      results in a burning sensation, which is also a frequently encountered qualitative
      characteristic in post-traumatic neuropathic pain. Recently it has been shown that
      administration of BTX decreases the expression of TRPV1 in dorsal root ganglion neurons in a
      diabetic model of neuropathic pain. Finally, the toxin also decreases the expression of other
      pain receptors such as purinergic receptors P2X3. In humans, the intradermal injection of
      BTX-A in healthy volunteers resulted in a marked decrease in specific and painful mechanical
      sensitivity without changing the tactile, non nociceptive mechanoreception, without affecting
      the density of cutaneous innervation.

      Injected in the painful area, BTX-A might therefore inhibit the release of algogenic
      neurotransmitters, at both the peripheral and central levels and thus reduce pain.

      The proposed study will therefore explore in a double blind randomized, with two parallel
      groups, BTX-A vs placebo, the analgesic effects of BTX-A in PPTTN patients.
    

Intervention name(s): BOTOX®, Allergan; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 50 U BTX-A (BOTOX®, Allergan) powder diluted in 2 mL saline solution (0.9% NaCl) administrated at visit 2 by intra oral injection; 2 mL saline solution (0.9% NaCl) administrated at visit 2 by intra oral injection
Other intervention name(s): BOTOX
Intervention MeSH terms: Botulinum Toxins, Type A
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: BOTOX®-Allergan; PPTTN; Pain measurements