لخّصلي

Botulinum toxin (BoNT) is a very potent biological toxin produced by several species of the Clostridia bacteria family, such as Clostridium botulinum [1, 2].More recently, a large number of animal and clinical studies have shown that injections of BoNT-A into the masticatory muscles could produce several adverse events, such as muscle atrophy, alterations of the muscle's histological composition, replacement of contractile tissue with fatty tissue [30-32], muscle weakness [33], reduction in maximum bite force, decrease in masticatory performance [34], and reduction in mandibular bone volume and other bony structural changes mainly in the mandible's head and alveolar region [35, 36].Some of the proposed analgesic effects of BoNT-A are: (1) suppression of the peripheral and central release of transport neurotransmitters (such as glutamate, calcitonin gene related peptide (CGRP), and substance P (SP)) to sensory regions of the trigeminal ganglia; (2) regulation of the pain modulation system by influencing the gamma-aminobutyric acid (GABA) and opioid-ergic systems; (3) reduction of microglia activation; and (4) modulation of ion channels [transient receptor potential vanilloid 1 (TRPV1), calcium (C+), and sodium (Na+)] [6, 9-12].Results from well conducted randomized placebo-controlled clinical trials (RCTs) on the effects of BoNT-A on persistent M-TMD differ, but those showing positive effects of BoNT-A indicate improvements in pain levels, somatosensory alterations, muscle tenderness, jaw mobility, and psychological well-being [23-29].Thus, due to its analgesic properties, BoNT-A is used as a treatment approach for chronic pain conditions such as chronic migraine (on-label), but also other pain conditions such as neuropathic, back, pelvic, and myogenous temporomandibular disorder (TMD) pain (M-TMD) (off-label) [13-16].M-TMD is the most common (45%) diagnosis among the TMD diagnoses and is characterized by regional pain and increased tenderness in the masticatory muscles, diminished masticatory performance, and restricted jaw movements [17].Initially, the analgesic effect in neuromuscular disorders and musculoskeletal pain was attributed to the muscle relaxant effect, until the anti-hyperalgesic effect in non-muscular pain models was unequivocally demonstrated in human and animal models [6, 7].

Botulinum toxin (BoNT) is a very potent biological toxin produced by several species of the Clostridia bacteria family, such as Clostridium botulinum [1, 2]. Intake of BoNT type A (BoNT-A) and other BoNT serotypes causes botulism, a condition that leads to flaccid paralysis of skeletal muscles and dysautonomia in humans. This effect is caused by interference with neurotransmitter release (acetylcholine) at presynaptic terminals [3, 4]. Because of the muscle paralysis, BoNT-A has become a common medical treatment used for autonomic disorders, spasticity, and hyperkinetic movement disorders, as well as in aesthetics for cosmetic purposes [5]. Recently, there has been a growing interest in its pain-reducing properties. Initially, the analgesic effect in neuromuscular disorders and musculoskeletal pain was attributed to the muscle relaxant effect, until the anti-hyperalgesic effect in non-muscular pain models was unequivocally demonstrated in human and animal models [6, 7].
In this regards experimental studies have proposed and demonstrated several antinociceptive mechanisms through local injections of BoNT-A that may reduce peripheral and central sensitization [8]. Some of the proposed analgesic effects of BoNT-A are: (1) suppression of the peripheral and central release of transport neurotransmitters (such as glutamate, calcitonin gene related peptide (CGRP), and substance P (SP)) to sensory regions of the trigeminal ganglia; (2) regulation of the pain modulation system by influencing the gamma-aminobutyric acid (GABA) and opioid-ergic systems; (3) reduction of microglia activation; and (4) modulation of ion channels [transient receptor potential vanilloid 1 (TRPV1), calcium (C+), and sodium (Na+)] [6, 9–12]. Notwithstanding, there is no evidence of the role and importance of these mechanisms. Thus, due to its analgesic properties, BoNT-A is used as a treatment approach for chronic pain conditions such as chronic migraine (on-label), but also other pain conditions such as neuropathic, back, pelvic, and myogenous temporomandibular disorder (TMD) pain (M-TMD) (off-label) [13–16].
M-TMD is the most common (45%) diagnosis among the TMD diagnoses and is characterized by regional pain and increased tenderness in the masticatory muscles, diminished masticatory performance, and restricted jaw movements [17]. Although several treatment approaches have been shown to be successful in the management of M-TMD [17–21], persistence of pain in the masticatory muscles is common [22]. Results from well conducted randomized placebo-controlled clinical trials (RCTs) on the effects of BoNT-A on persistent M-TMD differ, but those showing positive effects of BoNT-A indicate improvements in pain levels, somatosensory alterations, muscle tenderness, jaw mobility, and psychological well-being [23–29]. More recently, a large number of animal and clinical studies have shown that injections of BoNT-A into the masticatory muscles could produce several adverse events, such as muscle atrophy, alterations of the muscle’s histological composition, replacement of contractile tissue with fatty tissue [30–32], muscle weakness [33], reduction in maximum bite force, decrease in masticatory performance [34], and reduction in mandibular bone volume and other bony structural changes mainly in the mandible’s head and alveolar region [35, 36]. Taken together, the lack of consistent evidence regarding the benefits of BoNT-A for persistent M-TMD and its high probability of causing adverse events makes the clinical decision process challenging.
Since use of BoNT-A for M-TMDs is of great interest, many systematic reviews (SRs) have been performed over the last 15 years aiming to summarize the available literature, and to reach pertinent conclusions for the use of BoNT-A for treatment of patients with M-TMD. However, due to the inconclusive data, and to shortcomings in data curation and presentation of some SRs, no treatment protocols have yet been published and no definite conclusions have been drawn regarding the efficacy and safety (adverse events) of BoNT-A in the management of M-TMD. Formulating such conclusions are necessary since the use of BoNT-A as a primary treatment approach for M-TMD is increasing worldwide. Therefore, the aim of the present umbrella review was to systematically assess the findings and quality of SRs evaluating BoNT-A regarding its treatment effects on pain intensity, mandibular range of motion, and adverse events in patients with M-TMDs.