Botulinum Toxin Injections for Oral Neuropathic Pain

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.

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.

Eligibility Criteria:
Inclusion criteria

1. Informed consent form signed
2. Adult patients, age 18 -75 y.o.
3. Medical coverage (excepted AME)
4. Understanding of all medical information
5. Subjects fulfilling diagnostic criteria for Peripheral painful traumatic trigeminal neuropathy (PPTTN)
6. Pain in one or several branches of the trigeminal nerve
7. History of surgical treatment (including endodontic treatments) in the painful area
8. Pain in the area experienced in the 3 months following the treatment
9. pain almost every day for at least 6 months
10. VAS ≥ 30 /100 mm
11. Primary painful area limited to one dental quadrant
12. Presence of at least one positive (hyperalgesia, allodynia, numbness or swelling) and/or negative (anesthesia or hypoesthesia) sign of neurological dysfunction
13. Pain cannot be attributed to another cause

Exclusion criteria

1. Patients with impaired communication
2. Pregnancy, breastfeeding or planning pregnancy within the period of the study
3. Women of childbearing potential (WOCBP), adequate method of contraception within the period of the study
4. Orofacial pain other than PPTTN unless clearly identifiable TMD (arthralgia, muscle pain or disc displacement)
5. Contra-indications for BTX-A (for example diseases of the neuromuscular junction, known hypersensitivity to BTX-A etc.)
6. Known coagulation disorders
7. Major depression (score \> XX HADS scale)
8. Background of drug consumption or excessive alcohol consumption (3 units of alcohol a day)
9. current legal dispute with a dental practitioner
10. Former use of BTX for esthetic purpose
11. Dysphagia
12. Aspiration pneumonitis
13. Troubles with bladder control
14. Concomitant use of analgesics with dosage modification since less one month before inclusion in the study
15. Topical applications of drugs and anesthetics which cannot be interrupted one week before visit sessions
16. Treatment with aminoglycosides in the three months preceding the selection
17. Participation to another interventional clinical study