Oral baclofen has long been a mainstay in the management of spasticity. This review looks at the clinical evidence for the efficacy and safety of oral baclofen in patients with spasticity of any origin or severity, to determine whether there is a rationale for the use of intrathecal baclofen. Results suggest that oral baclofen may be effective in many patients with spasticity, regardless of the underlying disease or severity, and that it is at least comparable with other antispasmodic agents. However, adverse effects, such as muscle weakness, nausea, somnolence and paraesthesia, are common with oral baclofen, affecting between 25% and 75% of patients, and limiting its usefulness. Intrathecal baclofen may be an effective alternative as the drug is delivered directly into the cerebrospinal fluid, thus bypassing the blood-brain barrier and thereby optimizing the efficacy of baclofen while minimizing drug-related side-effects. Intrathecal baclofen is a viable option in patients who experience intolerable side-effects or who fail to respond to the maximum recommended dose of oral baclofen.
Although the exact prevalence is unknown, it is estimated that more than 12 million people worldwide could be affected by spasticity (1), and that 12–27% of these have disabling spasticity, depending on the aetiology (2). Substantial evidence demonstrates that spasticity has a negative impact on patients, causing physical impairment (e.g. pain, pressure sores, contractures), limitation of activities, dependence on caregivers, restricted participation in family and social life, and decreased overall quality of life (3, 4).
Numerous definitions for spasticity exist (5), although that provided by Pandyan et al. (6) has been advocated during recent years: “disordered sensorimotor control resulting from an upper motor neuron lesion, presenting as intermittent or sustained involuntary activation of muscles”. Spasticity is a common complication of upper motor neurone syndrome, and can occur when areas controlling movement are damaged, most often by brain injury disorders, such as or cerebral palsy (CP), traumatic brain injury (BI) or stroke, or by spinal cord disorders, such as spinal cord injury (SCI) or multiple sclerosis (MS) (7). Although heterogeneous, the causes of spasticity share a common pathophysiology, in that the damage disrupts the pathways that regulate activity in alpha motor neurones, causing a change in the balance of signals between the nervous system and the muscles. This imbalance leads to increased activity (excitability) in the muscles, resulting in overactive segmental reflexes. Normally when a muscle is rapidly stretched out, a stretch reflex is triggered and the muscle contracts to maintain muscle length and limb position. To allow smooth, non-jerky, coordinated movement, the segmental reflexes must be inhibited to allow the muscle to relax (i.e. stretch). The main neurotransmitter to achieve this is gamma aminobutyric acid (GABA), which is released by neurones in the spinal cord via descending inhibitory impulses from the brain. However, if the descending inhibitory impulses from the brain (and thus GABA) are cut off through disease or injury, inhibition becomes insufficient; instead, excessive muscular contraction during the muscle stretch takes place, resulting in abnormal muscle tone (hypertonicity).
The severity of spasticity varies from mild to severe according to the level of muscle tone (measured by the Ashworth scale or a modified Ashworth scale in most studies) and the level of disability in performing daily activities (8–10). The use of oral medication to treat spasticity is indicated when spasticity interferes with daily functioning, i.e. causes pain, disturbs sleep or affects activities of daily life. In addition, persistent muscular stiffness and spasms can lead to contracture (permanent stiffness of the muscle, tendon or joint, with decreased range of motion) that can be painful and disabling. Thus, treatment aims to reduce muscle tone in order to facilitate movement and limit contracture. However, some patients rely on excess muscle tone when transferring or ambulating, or to maintain posture. Therefore, the use of antispasmodic drugs needs to be tailored to each patient’s specific needs, to find the correct balance. Commonly-used oral drugs include baclofen, tizanidine, diazepam, and dantrolene, which have differing modes of action, but all are aimed at reducing muscle tone and/or spasms (11).
Oral baclofen is used more frequently than other antispasmodic agents to treat spasticity (8). Baclofen is a GABA-agonist that is thought to selectively bind to presynaptic GABA-B receptors, resulting in hyperpolarization of motor horn cells (12) and a subsequent reduction in the hyperactivity of muscle stretch reflexes, clonus, and cutaneous reflexes that elicit muscle spasms (13). Although widely used, baclofen is mainly water soluble and so does not readily cross the blood-brain barrier (14). As a result, patients may require a high dose to treat their spasticity effectively, which can cause intolerable side-effects (15). As an alternative, baclofen can be delivered directly to the cerebrospinal fluid (CSF) in the intrathecal space, bypassing the blood-brain barrier entirely. This allows a much lower dose to be used to achieve similar CSF concentrations as oral baclofen; it has been determined that the intrathecal baclofen (ITB) dose is 100–1,000 times smaller than the oral daily dose (16), which means that a higher CSF concentration can be achieved at a lower plasma concentration than would be achieved with an oral medication (17, 18). As a result, the central nervous system side-effects of oral baclofen (e.g. sedation, drowsiness, headache) may be reduced (12). The fact that baclofen is only slightly lipid soluble means that baclofen remains in the CSF after ITB therapy, with a relatively long half-life (90 min) (19). There is a 4:1 gradient in drug distribution between the caudal and rostral parts of the spinal cord, favouring high levels of action at the spinal level vs the brain and thus further decreasing cerebral side-effects (20). In addition, animal studies have shown that there is a steep gradient of baclofen along the spinal axis, meaning that during slow intrathecal infusion (20 µl/h) most of the baclofen seems to remain around the catheter tip used for the CSF delivery (21). The clinical implication of this is that the catheter position in relation to the targeted spinal cord segment may be critical to efficacy.
This review aims to systematically evaluate the available evidence for oral baclofen,in order to determine: (i) the efficacy of oral baclofen in spasticity treatment in comparison with placebo or active comparators; (ii) the associated complications or adverse events of oral baclofen; (iii) whether the dosage of oral baclofen changes with the disease severity and duration of spasticity. The results are expected to provide a useful overview of the role of oral baclofen in the management of spasticity, no matter the origin or severity of the condition, and could indicate when intrathecal administration should be considered….