SPINAL CORD INJURY: PREVALENCE AND PATHOPHYSIOLOGY

The number of Americans in 2009 living with the typical devastating neurological deficits and debilitating somatic and autonomic reflexes that develop after chronic spinal cord injury (SCI) has been estimated to be approximately 262,000 persons (according to the University of Alabama website, http://www.nscisc.uab.edu). However, after decades of research and clinical trials, currently there is no effective pharmacological treatment for acute or chronic SCI, notably targeting recovery of lost sensory-motor function. Moreover, there have been few advances in the treatment and/or management of secondary complications associated with chronic SCI; in spite of the fact that both quadriplegics and paraplegics (when surveyed) considered alleviation of autonomic dysfunction (i.e., bowel, bladder, autonomic dysreflexia) higher in their priority when compared with walking, in respect to quality-of-life issues [1]. Therefore, this begs the question as to why basic and clinical research efforts have not traditionally targeted such debilitating secondary complications that may have a greater potential for successful implementation, and more importantly may improve the quality of life in the chronic SCI population. The purpose of this review, consequently, is to describe current and emerging pharmacological interventions aimed at curtailing aberrant somatomotor and/or pseudomotor reflexes, manifested in uncontrolled muscle spasms or autonomic dysreflexia, respectively.

Spasticity is a common secondary impairment following both complete and incomplete SCI that is characterized by increased muscle tone (hypertonus), increased intermittent or sustained involuntary somatic reflexes (hyperreflexia), clonus, and painful muscle spasms in response to stretch and noxious cutaneous stimulation. In the animal model, it is has been demonstrated that spasticity results, in part, to increased glutamatergic signaling to the uninhibited motoneurons below the level of the injury [2]. Such aberrant somatic reflexes, if severe enough, can impact the ability of an individual with SCI to be able to perform routine activities of daily living, such as transfers, independent dressing, and management of bowel and bladder, with the grave potential of falling out of a wheelchair.

Alternatively, complete and less frequently incomplete SCI at or above high-thoracic (T5/6) levels, which comprise the majority of individuals with SCI, can also lead to a potentially life-threatening hypertensive condition termed autonomic dysreflexia, which is often triggered by painful somatic and/or visceral stimuli below the injury level [3]. This syndrome is characterized by a sustained elevated blood pressure, despite a decreased heart rate during the painful event, because the brainstem can no longer depress the intact sympathetic outflow below the level of SCI [4]. Episodes of autonomic dysreflexia often cause debilitating symptoms, including pounding headache, acute anxiety, shivering, blurred vision, flushing, and sweating [5]. In serious cases, paroxysmal hypertension can result in cerebral and spinal subarachnoid hemorrhage, seizures, and pulmonary edema [3].

One of the most common triggers of hypertensive autonomic dysreflexia is the distension of pelvic viscera (bladder and bowel) [6–8]. The consequent afferent barrage into the lumbosacral spinal cord results in massive sympathetic discharge below the level of the lesion, resulting in vasoconstriction of the muscular, splanchnic, and cutaneous vascular beds. The resultant paroxysmal hypertension produces a baroreceptor-mediated reflex bradycardia and vasodilatation above the lesion level, mediated by the vagus nerve [9]. Therefore, in addition to debilitating muscle spasms, many individuals with SCI suffer repeated unpleasant bouts of autonomic dysreflexia throughout the day and night, triggered by a full bladder or obstructed bowel/colorectum (constipation).

CONVENTIONAL TREATMENTS FOR SPASTICITY

The most commonly used medications that have demonstrated the most efficacious management of spasticity in clinical trials include baclofen, tizanidine and botulinum neurotoxin (BoNT) [10]. In addition, a second level of medications including benzodiazepine, dantrolene sodium, gabapentin, and pregabalin have demonstrated varying levels of effectiveness that support their potential use as anti-spastic medications. A recent systematic review of the literature suggests that although multiple types of drugs (i.e., oral, intrathecal, and/or injectable) have proven varying levels of efficacy in reducing spasticity, only the injectable treatments have been shown to have a positive effect on the negative consequences of upper motor neuron lesion (i.e., paresis, loss of fine motor control, loss of dexterity, fatigability) [11].

Baclofen

Currently, baclofen is the pharmacologic agent of choice for the treatment of SCI-induced spasticity. Baclofen is a derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), which binds to GABAB receptors of the lamina I-IV of the spinal cord where primary sensory fibers terminate [12]. Binding of baclofen to the presynaptic terminal of the gabaergic interneuron leads to membrane hyperpolarization, which in turn leads to a restriction of the influx of calcium into the presynaptic terminal and endogenous transmitter release is reduced [13, 14]. Baclofen is rapidly absorbed after oral administration and has a therapeutic half-life of about 3 to 4 hours. However, the use of this pharmacological agent can be limited by its adverse effects, which include sedation, fatigue, drowsiness, ataxia, and mental confusion [15–19], which can actually reduce the effectiveness of rehabilitation programs [11].

Intrathecal baclofen

In addition to the oral route of administration, baclofen has been shown to effectively manage spasticity when administered intrathecally [20–23]. Intrathecal administration is a long-term treatment with continuous, intra-spinal administration via a catheter connected to an implantable pump. The rationale for this modality of baclofen administration has been to deliver the drug directly into the spinal fluid to allow higher concentrations in the spinal cord using lower dosages than the oral route, thereby optimizing the beneficial effects of baclofen while minimizing the well-established side effects. There is currently one registered clinical trial that is examining intrathecal baclofen for the management of spasticity (Table 1). However, this clinical trial is not recruiting subjects yet. Predominate indications for intrathecal baclofen are intractable and generalized spasticity of the legs, which may also involve the trunk musculature [24]. Importantly, although continuous intrathecal infusion of baclofen can be effective in the treatment of severe spasticity, there is concern for baclofen tolerance in many individuals that remains a critical issue [25]. Another report indicates that abrupt withdrawal from intrathecal baclofen can lead to the onset of a potentially life-threatening condition, referred to as intrathecal baclofen withdrawal syndrome. This syndrome can manifest as a form of autonomic dysreflexia or malignant hyperthermia [26].

Table 1 “Spinal Cord Injury” and “Spasticity” and “Pharmacological” www.clinicaltrials.gov
Full size table

Tizanidine

As with baclofen, tizanidine has been shown to effectively reduce spasticity originating from SCI, as well as multiple sclerosis. Tizanidine is an imidazole derivative and a centrally acting α2-adrenergic agonist that inhibits the release of excitatory amino acids in spinal interneurons, which increases presynaptic inhibition to motor neurons [27, 28]. In addition, tizanidine may act by facilitating the action of the inhibitory neurotransmitter glycine [29, 30]. Its peak anti-spasticity effects occur 1 to 2 hours following oral administration, with a therapeutic half-life of approximately 2.5 hours. Recently, it was demonstrated that in persons with SCI, tizanidine substantially reduces mechanical reflex responses without inducing comparable changes in intrinsic muscle properties [31]. The most common side effects of tizanidine are sedation, drowsiness, hypotension, dizziness, asthenia, muscle weakness, insomnia hallucination, and fatigue. These adverse effects are dose related and may be minimized by close titration in the clinical setting [11].

Botulinum neurotoxin

Botulinum neurotoxin (BoNT) is an injectible pharmacological agent that has been shown to effectively reduce spasticity arising from multiple etiologies (i.e., stroke, cerebral palsy, multiple sclerosis). Currently, there are seven immunologically distinct forms of BoNT; each of these forms are synthesized as a single-chain polypeptide of molecular mass approximately 150 kDa [32]. BoNT can be differentiated into types A and B. Each of the type A BoNTs that are currently available (Botox, Allergan Irvine, CA; Dysport, Medicis Aesthetics Inc., Scottsdale, AZ; Xeomin, Merz Pharmaceuticals, Greensboro, NC) are produced from Clostridium botulinum bacteria and have similar pharmacological activity [11]. Specifically, BoNT inhibits vesicular acetylcholine release from the presynaptic nerve terminal at the neuromuscular junction, which essentially results in a chemical denervation [29, 32]. After binding the receptors to the synaptic vesicle protein SV2 on the presynaptic nerve terminals, BoNT is internalized via endocytosis [33]. To gain maximum biological activity, the 150 kDa toxin polypeptide must be cleaved into a 100 kDa heavy chain and a 50 kDa light chain [32]. Following internalization, the light chain is translocated into the cytoplasm and inhibits the release of neurotransmitters by disrupting the functioning of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex (SNARE) complex required for exocyctosis of synaptic vesicles [34]. The reduction in acetylcholine release effectively leads to a reduction in muscle contraction with a dose-dependent reduction in muscle strength. Recovery occurs through proximal axonal sprouting, which leads to muscle re-innervation and formation of a new neuromuscular junction. The clinical effects of BoNT injections can last for 3 to 4 months [35]. In addition to BoNTs well-established inhibition of acetylcholine release at the neuromuscular junction, pre-clinical studies have shown that it is able to inhibit neuropeptide release from primary afferent nociceptive C fibers and possibly from lightly myelinated Aδ fibers [36].

Although baclofen, tizanidine, and BoNT are the most widely used anti-spastic pharmacological agents, there are several other drugs that have been tested clinically that have demonstrated varying levels of effectiveness in managing spasticity. These drugs include gabapentin, pregabalin, benzodiazepine, clonidine, dantrolene, and cannabis.

Gabapentin

Gabapentin (Pfizer, New York City, NY) is approved for the treatment of epilepsy and is widely used for the treatment of neuropathic pain [37–40]. Gabapentin is structurally similar to GABA, but it does not appear to bind to conventional GABAA, GABAB, glycine, or glutamate receptors [30]. Although gabapentin possesses multiple cellular mechanisms, recent work indicates the suggestion that inhibition of glutamatergic transmission may be pre-eminent in mediating its therapeutic effects in epilepsy, neuropathic pain, and perhaps spasticity [41]. Specifically, gabapentin has been shown to inhibit presynaptic glutamate release by modulating Ca2+ channels [42–47]. When incorporated as an adjunct to standard pharmacological interventions for spasticity, gabapentin demonstrates the potential to help decrease the manifestation of spasticity in individuals with SCI [48, 49]. However, to date there has been no systematic examination of the efficacy of gabapentin as a single treatment for the management of SCI-induced spasticity. As with all drugs that interact directly with the central nervous system, gabapentin does have some potential side effects that can include somnolence, dizziness, and ataxia.

Pregabalin

Pregabalin (Lyrica [Pfizer]) is a relatively new drug that is considered to be the next generation of gabapentin. Similar to gabapentin, pregabalin was developed as a treatment for epileptic seizures, but it has evolved to include other indications, such as neuropathic pain [50, 51]. Their mechanisms of action require the binding to the high affinity α2-delta subunit protein of the voltage-gated Ca2+ channels [52], thereby reducing release of excitatory neurotransmitters in the central nervous system [53]. To our knowledge, there has only been one retrospective case study that has examined the effects of pregabalin on spasticity [54]. This study concluded pregabalin may be effective in reducing the level of spasticity in a portion of persons with SCI. However, among the 22 participants in this study, 36% reported significant side effects and discontinued use of this medication, whereas an additional 22% of the participants demonstrated no effect on their spasticity. There is currently only 1 registered clinical trial in which pregabalin is being examined, and spasticity is 1 of the secondary outcome measures (Table 1). However, this study is not currently recruiting subjects and further clinical studies are needed to establish the efficacy of this drug as an anti-spastic medication.

Diazepam

Diazepam belongs to the class of benzodiazepines and has been shown to cause muscle relaxation, which has led to their use in reducing the increased tone associated with spasticity. The presumed action mechanism of the benzodiazepines is to enhance the binding efficacy of GABAA receptors. Binding of diazepam to the GABA receptor in the spinal cord increases chloride conductance resulting in the enhancement of presynaptic inhibition of sensory afferents involved with the aberrant somatosensory reflex arc [55]. The predominate side effect associated with diazepam that can limit its therapeutic efficacy as an anti-spasticity medication is sedation [29].

Clonidine

Clonidine is a centrally acting α2-adrenergic agonist that has been shown to decrease aspects of spasticity in patients with SCI [56, 57]. However, currently clonidine is rarely used as a single agent in the treatment of spasticity due, in part, to the adverse effects of this therapeutic agent, which can include bradycardia, hypotension, drowsiness, dizziness, and depression [30].

Dantrolene

Dantrolene sodium is a unique pharmacological agent in comparison with other anti-spastic medications because it exerts its effect directly at the level of skeletal muscles. Dantrolene sodium reduces contraction of skeletal muscle by a direct action on excitation–contraction coupling, by decreasing the amount of Ca2+ released from the sarcoplasmic reticulum. [58–61]. Unfortunately, this pharmacological agent tends to cause a generalized muscle weakness, which can directly affect the person’s participation in physical rehabilitation, as well as overall functional improvement.

Cannabinoids

There has been anecdotal evidence that cannabis can reduce spasticity in persons with SCI, as well as a growing body of work that has examined this class of drug in managing spasticity in persons with multiple sclerosis. Δ9-tetrahydrocannabinoid (THC) is the main ingredient in cannabis. THC binds to both CB1 and CB2 receptors [62, 63]. Both cannabinoid receptor types are coupled through G proteins, negatively to adenylate cyclase and positively to mitogen-activated protein kinase. In addition, CB1 receptors are coupled to several ion channels. A recent review of randomized controlled trials evaluated the effect of cannabinoid therapy on the reduction of spasticity [64]. It was concluded that this pharmacological agent may reduce symptoms of spasticity in patients with multiple sclerosis, but that further studies are needed to show a significant effect on objective measurements of spasticity. It was recently demonstrated that a decrease in both the Ashworth scale and the spasticity sum score was observed in patients with SCI that were given THC [65]. Nevertheless, further randomized clinical trials are needed to elucidate the efficacy of this class of drugs as anti-spastic medications. Side effects of cannabinoids are reported to be generally mild and include dry mouth, dizziness, somnolence, nausea, and intoxication. In addition, there may be reason to be concerned about the use of therapeutic cannabinoids by adolescents, people predisposed to psychosis and pregnant women [66]. There is currently one registered clinical trial that is examining the effects of cannabinoids on spasticity (Table 1). However, this trial is not yet recruiting subjects.

ETIOLOGY AND CONVENTIONAL TREATMENTS FOR AUTONOMIC DYSREFLEXIA

Currently, prevention of autonomic dysreflexia remains the soundest approach. Importantly, one of the most common triggers of autonomic dysreflexia, as well as spasticity, is over-distension of the bladder and bowel. This means that these aberrant somatomotor and pseudomotor reflexive episodes occur repeatedly on a daily basis in individuals with a SCI above mid-thoracic levels, constituting the majority of SCI cases. Accordingly, draining the bladder alleviates the symptomatic hypertension in many cases of autonomic dysreflexia. In situations where noxious stimuli may be elusive, such as an ingrown toenail, and/or severe pressure sore, prophylactic treatment may be needed. To alleviate symptoms during such critical acute periods and avoid complications associated with uninhibited hypertension, anti-hypertensive medications with rapid onset and short duration should be used [9]. The development of animal models for autonomic dysreflexia, induced by noxious bladder and/or colorectal distension (CRD) [67, 68], has enabled the detailed analysis of temporal dynamics of induced hypertension [69, 70], injury-induced plasticity of primary afferents, propriospinal neurons and sympathetic preganglionic neurons [71–74], changes in the electrophysiology of sympathetic and sympathetic-related interneurons [75], and effects of pharmacologic antagonists on pressor responses [68].

A subject of controversy is the mechanism(s) of sympathetic hyperactivity and increased mean arterial pressure (MAP). It has been suggested that cutaneous blood vessels show increased sensitivity to noradrenaline, based on the observation of prolonged vasoconstriction after sympathetic neural activity [76]. Other evidence suggests that abrupt loss of descending inhibition accompanied by changes in spinal neural activity are the cause of sympathetic hyper-reflexia following acute, complete SCI [70]. Notably, glutamatergic neurotransmission has been shown to contribute to spinal viscero-sympathetic initiation of episodic hypertension induced by CRD [77], and the development of autonomic dysreflexia is correlated with aberrant sprouting of nociceptive C-fibers into the spinal cord below the injury level [78–80]. Therefore, painful distension of the pelvic viscera increases the excitation of expanded C-fiber terminals in the uninhibited lumbosacral spinal cord, which amplifies the activation of propriospinal neurons and effector sympathetic preganglionic neurons in the thoracolumbar cord [4, 71, 78].

In reviewing the literature, despite the prevalence of this debilitating secondary syndrome, there are very few effective pharmacological agents that can be provided to an individual suffering from an acute or chronic bout of autonomic dysreflexia, notably outside the clinical setting. In fact, there are currently no ongoing, actively recruiting clinical trials for any compound designed to alleviate the symptoms of autonomic dysreflexia. A summary of clinical practice guidelines for managing autonomic dysreflexia can be obtained through the website for the Paralyzed Veterans of America (www.pva.org) [81]. The following is a partial list of compounds that have been used traditionally to treat the hypertensive symptoms accompanying autonomic dysreflexia.

Nitrates and nifedipine

In general, nitrates are the most commonly used therapeutics to lower blood pressure because they have a direct relaxant effect on vascular smooth muscles leading to dilation of coronary vessels and peripheral veins [82]. The topical application of 1 to 2 inches of 2% nitroglycerine (nitropaste) above the level of the lesion is effective, and it can be removed when the hypertensive crisis subsides [81]. Alternatively, nifedipine is a dihydropyridine L-type voltage-sensitive Ca2+ channel blocker that, when is administered in immediate release form (10 mg capsule), exerts coronary and peripheral vasodilator properties [83]. Although nifedipine significantly decreases resting MAP in spinal cord injured persons, and it prevents dangerous blood pressure elevations during cystometry-evoked dysreflexic hypertension [84], there is a lack of well-controlled clinical trials of nifedipine use for management of autonomic dysreflexia; therefore, evidence is primarily anecdotal and derived from selected cases. If such anti-hypertensive compounds do not alleviate symptoms, then intravenous administration of sodium nitroprusside is indicated for rapid titration of blood pressure. Notably, this and other secondary agents, such as well as clonidine, hydralazine, mecamylamine, and phenoxybenzamine, and also diazoxide, are primarily used in a monitored setting [3, 83, 85], obviating their use on a routine daily basis.

α-Adrenergic blockers

α-Adrenergic receptor blocking agents (e.g., terazosin [a specific α1-adrenergic antagonist]) appear to prevent serious harm from autonomic dysreflexia, and it is efficacious in the first week of treatment in normotensive spinal cord injured patients with autonomic dysreflexia [86]. Taken once a day, terazosin completely abates dysreflexic symptoms and can be discontinued when the underlying problem has resolved, although persistent dizziness has been reported [87]. Another α1-adrenergic antagonist, prazosin (3 mg twice a day, given for 2 weeks), is reported to reduce both the severity and duration of autonomic dysreflexia episodes in both cervical and high thoracic SCI individuals. It is well tolerated, but it does not significantly lower resting blood pressure, yet it does reduce the severity of headaches [88]. Although these findings infer that α1-adrenergic receptors play a key role in the pathogenesis of this syndrome, prazosin (0.45 mg/kg i.v.) and β-adrenergic antagonist, propranolol (4 mg/kg i.v.), have been administered individually or together to assess the contribution of α-adrenergic and β-adrenergic mechanism, respectively. It was found that the pressor response to bladder distension was abolished completely only when combined α-adrenergic and β-adrenergic blockades was administered. indicating that autonomic dysreflexia is mediated by both α-adreneric and β-adrenergic receptors in the spinal rat [89]. On the contrary, however, increased MAP responses to CRD following intravenous infusion of the α1-adrenergic agonist, phenylephrine, showed no differences between intact and spinalized rats, thus questioning whether supersensitivity of α1-adrenergic agonists can completely account for the hypertensive bouts associated with autonomic dysreflexia [90].

In searching for other treatments to curtail the symptoms and prevent the catastrophic sequelae of autonomic dysreflexia, it is apparent that very little has been advanced in the past decade [91–93]. In fact, proper prophylaxis, including nonpharmacologic strategies, is still the preferred method to diminish the incidence and severity of cardiovascular dysfunction following SCI [94]. Surprisingly, there are no recent studies documenting whether pharmacological interventions are, in fact, superior to nonpharmacologic strategies. Because there are no ongoing clinical trials designed to examine novel treatments to ameliorate somatomotor spasticity, the question arises as to whether agents might exist that are also effective in treating pseudomotor-mediated autonomic dysreflexia. Notably, there is no single clinical intervention that is known to effectively attenuate the manifestation of both muscular spasticity and autonomic dysreflexia.

Because excitatory glutamatergic neurotransmission (i.e., painful) has been shown to contribute to spinal viscera-sympathetic initiation of episodic hypertension [77], as well as to spasticity [95, 96], thwarting neurotransmission of noxious stimuli with pharmacological agents appears a tenable approach to reduce the severity of both of these aberrant reflexes. For example, as shown in Table 1, pregabalin is currently being assessed as an anti-spastic medication. Thus, there appears to be a common pathway by which painful stimuli are capable of inducing both spasticity and autonomic dysreflexia.

SYNTHESIS OF FUTURE DIRECTIONS

Gabapentin, and more recently pregabalin, are currently the drugs of choice for managing neuropathic pain in the SCI population, but neither are indicated for spasticity or autonomic dysreflexia. Inhibition of glutamatergic transmission may be pre-eminent in mediating its therapeutic effects in epilepsy, neuropathic pain, and perhaps spasticity [41]. Specifically, gabapentin has been shown to inhibit presynaptic glutamate release [42–46], and it effectively alleviates tail muscle spasticity in response to a painful stimulus in spinal rats [96]. As mentioned, when incorporated as an adjunct to standard pharmacological interventions, gabapentin is well-tolerated and demonstrates the potential to help decrease the manifestation of spasticity in individuals with SCI [48, 49].

As with spasticity, autonomic dysreflexia is thought to be mediated through abnormal glutamatergic neurotransmission. Therefore, a pharmacological agent that can manage pain and spasticity through the reduction of glutamate release may also have a beneficial effect on paroxysmal autonomic dysreflexia. Although numerous individuals with SCI are using gabapentin for the management of neuropathic pain, to date there has been no clinical evaluation of its potential efficacy in managing the incidence or severity of autonomic dysreflexia. On the contrary, however, it has recently been reported that gabapentin has striking efficacy in reducing both the severity of CRD-evoked dysreflexic hypertension and tail spasticity in response to stretch or painful pinch, in the same injured animals, weeks following complete SCI [97, 98].

From a clinical standpoint, it appears critical to assess gabapentin (or pregabalin) in relation to its onset time and duration of efficacy in comparison with other drugs routinely used for the management of spasticity and autonomic dysreflexia. Importantly, most current treatment options target specific symptomatic outcome measures (i.e., spasticity or hypertension) without taking into consideration that the painful stimuli has not been resolved, albeit unperceived by the individual with SCI. Alternatively, blocking pain neurotransmission into the central nervous system with gabapentin, and not opiate analgesics, which are addicting, has direct clinical relevance as a 3-pronged approach to alleviate dissimilar aberrant neurologic reflexes, supporting its novel indication for the effective management of spasticity and autonomic dysreflexia elicited, primarily, by noxious stimuli below the SCI level.

CONCLUSIONS

The purpose of this review was to focus on current drug treatment strategies that target spasticity and autonomic dysfunction in the chronic SCI population. Traditional anti-spastic medications include baclofen, tizanidine, BoNT, benzodiazepine, clonidine, dantrolene, and cannabis, whereas compounds to alleviate autonomic dysreflexia include anti-hypertensive nitrates, nifedipine, and adrenergic blockers. They are all reported to be useful, to some degree or another, but their effects are typically all-or-none. Although there is consensus among those living with SCI that these are serious secondary complications that affect quality of life [1], there are a few emerging clinical trials targeting either of the complications, notably as primary outcome measures. It is important to note that from a clinical perspective, moderate spasticity and autonomic dysreflexia are not dire, in and of themselves. In fact, low to moderate levels of each complication can be functional in a positive manner. For instance, moderate levels of spasticity provide tone to the trunk musculature that allows the person to perform transfers and use their upper extremities. Likewise, mild symptoms of autonomic dysreflexia provide an individual with valuable feedback that they may have a full bladder, constipation, and so forth. It is when each of these impairments is significantly heightened in concert that they become detrimental and impact a person’s quality of life. Therefore, in looking ahead, it will be important to establish whether an individual suffering from autonomic dysreflexia and/or muscle spasms can take gabapentin to receive rapid relief, yet not completely abolish either of these sensory motor reflexes that serve to maintain muscle tone and act as a pathophysiological warning system.