Baclofen is a muscle-relaxant agent used to treat spasticity and improve mobility in patients with spinal cord injuries, relieving pain and muscle stiffness.54 This drug produces its effects through supraspinal level GABAB receptor activation, acting at the spinal cord level, blocking pathways polysynaptic and monosynaptic afferent transmission, and thus inhibits the transmission of impulses through these channels acting as a neurotransmitter inhibiting or inducing hyperpolarization primary nerve terminals, which alters the release of excitatory neurotransmitters such as glutamate or aspartate.54 Disruption of the oral administration of baclofen or baclofen intrathecal therapy may cause withdrawal, increased muscle tone syndrome and muscle spasm, prolonged seizures, hyperthermia, dysesthesia, and hallucinations and may eventually cause rhabdomyolysis and multisystem organ failure.55
Pharmacological support with baclofen generates controversial results, which are summarized in Table 3.
Most currently available drugs for the pharmacological treatment of spasticity are focused on GABAergic (baclofen, diazepam, tetrazepan, gabapentin) or adrenergic receptors (tizanidine, clonidine), which usually relate to the appearance of major side effects associated with their central nervous system depression properties. However, recently, there have been proposed new therapeutic targets. One is the use of agonists of the cannabinoid receptors. Since the 1980s, they have begun to propose the use of marijuana or its active principles to treat several symptoms, such as pain, ataxia, fatigue, and spasticity in multiple sclerosis.67 However, only recently, they have begun to know the mechanism by which cannabinoid agonists exert their effect on spasticity. In a study using a mouse model of experimental allergic encephalomyelitis to induce spasticity in knock-out mice for the CB1 receptor, demonstrating that antispastic effects of agonists of cannabinoid receptors are mediated by the CB1 receptor, it was in addition noted that this receptor is also responsible for their psychoactive effects.68 Multiple recent clinical studies support the effectiveness of different formulations of cannabinoid receptor agonists in multiple sclerosis spasticity, which is why even the American Academy of Neurology in a systematic review concluded that oral cannabis extract and tetrahydrocannabinol can be considered as effective in spasticity management.69 However, despite that, clinical improvement obtained with cannabinoid agonist is interesting because it has not demonstrated significant effects on more objective parameters as electrophysiological assessments or studies of cortical excitability, so the efficacy and its final mechanism of action of these drugs in spasticity are still under study.70,71
Furthermore, there is experimental evidence that some antagonists of excitatory amino acid receptors may have muscle-relaxant properties. Among these, one that may be more promising is the kynurenic acid (KYNA), which is a product of tryptophan catabolism by kynurenine pathway, and it is the only endogenous N-methyl-D-aspartate antagonist known.72 In previous studies, it has been able to increase the brain concentrations of KYNA using precursors and inhibitors of excretion, which has also been associated with neuroprotective effects.73 However, there is still concern about potential long-term toxic effects because a recent study showed that chronic administration of intrathecal KYNA caused myelin damage in the spinal cord.74
On the other hand, for several decades, studies have shown the involvement of glycine A receptors in the origin of spinal spasticity. Experimental studies have shown that administration of glycine agonists, glycine or D-serine, can significantly decrease the electrophysiological responses associated with spasticity; in addition, they found that the application of antagonists such as strychnine on the contrary increased the spasticity.75 The evidence of the involvement of glycine in spasticity also is strongly supported by the phenotype showing mutant spastic mouse, which besides seizures and myoclonic jerks, they have spasticity, and has been shown that its mutation produces a selective deficiency of a glycine receptor isoform during development.76 Recently, it has been identified and isolated several new glycine receptor modulators from marine sponges, but still, it needs to verify their effects at preclinical and clinical level in spasticity.77 All this evidence suggests that stimulation of glycine receptors (which is proposed to increase the inhibition of spinal interneurons) may be a promising therapeutic target in the management of spasticity.
Another group of drugs that have also been tried in the management of spasticity are serotonin antagonists, particularly cyproheptadine (5HT2 antagonist), and in the 1980s and 1990s, it was used in some small groups of patients who apparently showed positive effects.78 However, in subsequent years, the clinical studies did not spread to larger populations but has now resumed its use in the treatment of symptoms that occur after withdrawal of chronic infusion of intrathecal baclofen.79,80 At present, different substituted cyclic amines having action as 5HT2A receptor antagonists have been patented as potential drugs in the management of spasticity, but its biological effects are still unknown.81
Other therapeutic targets that have recently been tested are some principles of traditional Chinese medicine, as Gancao Shaoyao glycosides; an open clinical trial apparently showed positive effects in patients with hemiplegia secondary to stroke.82 However, the mechanism by which this improvement occurs is still under study.
The impact of TBI on health systems and the economies of countries is reflected in the last 2 decades with the increase in research in this field. However, the diversity of reasons why falls, traffic accidents, violence, sports, war, etc; the wide range of pathophysiological mechanisms involved in the injuries; lack of diagnostic biomarkers; and presence of prognosis in the initial management of TBI; and the absence of a specific therapeutic clinical treatment for this condition enables the development of sequels that limit patients, impairing their quality of life.
The absence of evidence does not necessarily mean a lack of effectiveness of drug treatment in the rehabilitation of functions. Thus, it is necessary to clarify the heterogeneity of sequelae of traumatic damage and the great variability of therapeutic response to different pharmacologic agents for each patient after TBI: (a) identify if there is a genetic predisposition that can affect recovery from traumatic consequences and thus explain individual susceptibility to traumatic impact and personal response to drug treatment; (b) the study of biomarkers with diagnostic and prognostic utility in TBI, enabling timely treatment of patients, especially those who show early signs of poor prognosis, to prevent the sequelae; (c) perform multicenter clinical trials, double-blind, controlled group, to demonstrate the effectiveness and efficiency of drug groups used in the rehabilitation of the affected functions after TBI; (d) define the clinical profile of patients most likely to benefit from the indication of one or more of the various groups of drugs mentioned; and (e) study the safety and effectiveness of these pharmacological agents in each population and strategies for optimal dosage. In particular, spasticity is a common presenting symptom in response to damage of the pyramidal system in the brain or spinal cord; this may be secondary to head trauma, stroke, spinal cord injury, multiple sclerosis or anoxia, and other pathologies. This also determines the severity, its clinical presentation, and the choice of treatment (conservative or surgical), even the accurate mechanisms for induction of spasticity to TBI, because it is a multidimensional and dynamic process,83 so that early intervention to prevent, treat, and decrease is unknown, in addition to the controversy on the effectiveness of drug therapy and speech therapy, as well as the unwanted effects of current treatments. A better and deeper understanding of the mechanisms responsible for the presentation of neuroplastic changes induced TBI, tracts involved in the development of spasticity, favor the design of treatments and therapies more effective in rehabilitation, allow access to the therapeutic goal with patients: (1) improve the functionality, (2) improve the quality of life and comfort, (3) provide care and activities of daily living, (4) prevent and treat musculoskeletal complications, and (5) improve body aesthetics.23
Other alternative strategies for spasticity management are nonpharmacologic options such as: (1) orthopedic management (reconstructive surgery of upper extremity, soft tissue operations or bony procedures for treatment of hip deformities, and surgical correction or orthotic treatment of foot abnormalities and spine abnormalities84–87); (2) selective dorsal rhizothomy (surgical resection of selected dorsal roots for reduce afferent input to the spinal reflex arc and dampen the muscle elongation88–90); (3) stretching, fitting of splints/braces or serial casting, ultrasound and thermotherapy, neuromuscular electrical stimulation, muscle strengthening, or use of robotics to perform stretching and movement training91,92; and others pharmacologic treatment options such as the following: (1) local injections of phenol (≥3%) or alcohol (≥50%) that induces chemical neurolysis and performed on motor nerves, which reduces the symptoms of spasticity93; (2) antiepileptic drugs, such as gabapentin or pregabalin, has been used as adjunct therapies particularly when central neuropathic pain is present94,95; (3) immunomodulators (interferon beta and glatiramer acetate), Sativex (agonist at cannabinoid receptors) and cannabis that have been used in some countries for treatment of spasticity only in multiple sclerosis96–100; and (4) Zolpidem, a nonbenzodiazepine approved for the treatment of insomnia, for treatment of neurological complications (including spasticity after of hypoxic ischemic in brain injury).101 Others alternative used in spasticity management is the administration of natural agents as the oil of Alpinia zerumbet, which has been used in patients with clinical diagnosis of stroke who presented spasticity. This study showed that dermal application of this oil affected skeletal spastic muscle activity, presenting relaxing action, and improves contractile performance.102
Future research on the treatment should be directed toward the development of new drugs that do not require invasive procedures for administration and achieve cross the blood brain barrier, with greater bioavailability and fewer adverse effects; the development of combined therapeutic considering the pathophysiology in a broader alterations with only excitation/inhibition context; and the consideration of using treatments for acute and chronic phase that promote neuroprotection and neurodegeneration, allowing the patient's reintegration with the greatest possible functionality.
The authors thank Sergio Humberto Larios-Godínez for their technical assistance.
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