Beneficial “Pharmaceutical Pleiotropy” of Gabapentinoids in Spinal Cord Injury: A Case for Refining Standard-of-Care

Abstract

Spinal cord injury results in devastating neurological deficits accompanied by lifelong disability and significant economic burden. While the development of novel compounds or cell-based interventions for spinal cord injury is unquestionably worthwhile, a complementary approach examines current standards of care and the degree to which these can be optimized to benefit long-term neurological function. Numerous classes of drugs, already in use in the acute phase of spinal cord injury, are intriguing because they (1) readily cross the blood-spinal cord barrier to modulate activity in the central nervous system and (2) are administered during a window of time in which neuroprotection, and even some repair, are feasible. Here, we review a rare case of convergent lines of evidence from both preclinical and human studies to support the early administration of a class of drug (ie, gabapentinoids) to both foster motor recovery and reduce the severity of neuropathic pain.

Spinal cord injury results in neurological deficits, accompanied by severe and lifelong disability and morbidity. The effect on quality of life is substantial, and health care expenses immense. ¹ Recognizing limited potential for endogenous repair, clinical and basic scientists have long recognized an urgent need for newer and better acute therapies that promote neurological recovery. As these are being developed, it behooves us to also scrutinize current standards of care, and the degree to which they can be optimized to the benefit of long-term neurological function. An already successful example of such an approach includes early surgical decompression of spinal cord injury (<24 hours), to limit the extent of secondary damage provoked by persistent compression. ² Another emerging approach involves maintaining adequate spinal cord perfusion pressure in acute care. ³

The complex management of acute traumatic spinal cord injury, in nearly all cases, mandates the administration of a considerable number of medications. This includes those frequently administered for pain, infections, cardiovascular dysregulation, depression, anxiety, and spasticity—all conditions that arise in the hours to weeks following injury. From a perspective of optimizing long-term neurological outcomes, the use of such drugs is intriguing to consider because many (1) readily cross the blood-spinal cord barrier to modulate activity in the central nervous system and (2) are administered during an early window of time associated with the possibility of neuroprotection and repair.^4,5

For example, gabapentinoids (ie, pregabalin/gabapentin) represent a frontline pharmacological option for the management of neuropathic pain in spinal cord injury, having demonstrated efficacy in phase III clinical trials.^6-8 Originally developed as anticonvulsants, their mechanism of action involves binding the alpha2delta subunits of voltage-sensitive calcium channels. ⁹ However, direct modulation of calcium channel activity is unlikely to account for the analgesic effects of gabapentinoids, since maximum cerebrospinal fluid concentration is achieved within hours of administration, ¹⁰ whereas analgesia emerges over several days. ¹¹ Rather, other mechanistic investigations have shown that astrocyte-derived thrombospondins promote excitatory synapse formation via alpha2delta1 subunits; since this synapse formation can be prevented by gabapentinoid treatment, this mechanism may account for their analgesic effects.^12-16

The adverse event profile of gabapentinoids is well-known and includes somnolence, dizziness, and dry mouth, which makes them generally safe, even when administered alongside other pain medications.^6,17 Based on the natural progression of neuropathic pain after spinal cord injury, ¹⁸ gabapentinoids are indicated in the first month of injury and are often needed into chronic phases (>6 months).

Mounting evidence from both clinical and preclinical perspectives supports the notion that gabapentinoids could be repurposed as a strategy to optimize neurological recovery after spinal cord injury. In humans, anticonvulsants were identified by our laboratories (JLKK and JC) as a potential strategy to restore motor function after acute injury. ¹⁹ In this study, longitudinal data were analyzed from the European Multi-center study about Spinal Cord Injury (EMSCI), revealing that patients who were administered anticonvulsants within 1 month postinjury showed enhanced recovery of muscle strength compared with those unexposed to anticonvulsants. In parallel, on the preclinical side, Tedeschi and colleagues demonstrated the Alpha2delta2 subunit of voltage-gated calcium channels suppresses axon growth and regeneration in adult mouse sensory neurons. ⁹ Moreover, pharmacologically blocking Alpha2delta subunits through the administration of anticonvulsant gabapentinoids promoted regeneration of ascending sensory axons after spinal cord injury. ⁹ This led to a more recent series of observational studies in humans that indicate the effect of anticonvulsants found is indeed specific to gabapentinoids.^20,21 The demonstration of specificity included a study that utilized concomitant medication information from a completed clinical trial, conducted during a period of time that predated gabapentinoids, thus allowing analysis of other types of anticonvulsant medications (eg, phenytoin). ²⁰ Further study in our laboratory is underway to refine the time window associated with the largest effect on motor recovery and to determine the extent to which gabapentinoid-associated motor recovery is accompanied by functional benefits (eg, walking).

Adding to the preclinical evidence, Sun and colleagues examined if central nervous system motor pathways were also responsive to gabapentinoids in the same way as sensory pathways. ²² Motor pathways, including the corticospinal tract, are of high relevance to the field because restoration of its function is thought to be associated with the greatest potential for restoration of coarse and fine movement. Indeed, Sun and colleagues demonstrated that Alpha2delta2 is expressed in corticospinal neurons. ²² They also demonstrated that gabapentin promoted sprouting and regeneration of corticospinal axons in a cervical model of spinal cord injury and, critically, that regenerating corticospinal axons functionally integrated into spinal circuits. ²² Beyond molecular and histological evidence of effects on corticospinal tract neurons, behavioral testing in treated animals revealed significant improvements in upper extremity function compared with control animals. Coinciding with evidence that gabapentinoids promote regeneration, others have demonstrated neuroprotective effects in various animal models of neurotrauma.^23-26

In addition to benefits on motor outcomes, administering gabapentinoids in the acute phase of injury may confer other benefits to neurological recovery. The most obvious is the potential to prevent the development of chronic pain.^7,8 This has been chiefly demonstrated by way of perioperatively administering pregabalin to patients undergoing surgeries that carry a high risk of developing chronic pain (eg, thoracic surgery). ²⁷ In the case of spinal cord injury, neuropathic pain develops over time, particularly that experienced below level, thus providing a window of opportunity for prevention in the very early states of injury. ¹⁸ Other recent preclinical studies indicate that the acute administration of gabapentinoids has a beneficial effect on long-term neuropathic pain outcomes. For example, in a cervical hemicontusion model of spinal cord injury, the efficacy of pregabalin to reduce signs of neuropathic pain (ie, disuse of the contralateral forelimb) at chronic time points was conditional on early exposure. ²⁸ The prevention of neuropathic pain is an attractive primary or secondary endpoint for an acute spinal cord injury clinical trial since it has profound effects on quality of life, is often refractory to treatment, and since small improvements are often meaningful.

To our knowledge, this is a rare case in our field that convergent lines of evidence from preclinical and human studies support the administration of a drug to benefit 2 clinically relevant outcomes (recovery of muscle strength and neuropathic pain). Will the pleiotropic effects of gabapentinoids be a panacea in the world of spinal cord injury? We doubt this because they are already administered, sometimes in the very early stages of injury, and even these individuals remain with severe neurological deficits. More likely, any effects will be subtle—marginally greater than those reported in observational studies (~4-5 motor points)—and will depend on optimization of treatment regimen (ie, timing and dosage). Although less exciting than the proverbial homerun, small effects giving rise to important functional benefits are a starting place. Moreover, there is increasing awareness among researchers and persons with lived experience that a combination of treatments will be needed to “cure” spinal cord injury. To the extent that gabapentinoids may have regenerative effects, there are several interesting possibilities for combination, including with emerging therapies that block neurite growth inhibitory factors (eg, anti-NOGO; see NCT03935321 on ClinicalTrials.gov).^29,30

From all of this, the next and obvious step is to launch a prospective clinical trial, whereby individuals sustaining an acute spinal cord injury are randomized to receive gabapentinoids early after injury, independent of whether signs and symptoms of neuropathic pain are present. A trial meeting this description is currently registered, focused on preventing the development of central neuropathic pain in 50 persons with acute spinal cord injury (see NCT03748290 on ClinicalTrials.gov). Larger trials that take a comprehensive view of neurological recovery, including the restoration of normal motor and sensory function should follow. Among critical design features will be an adaptive analysis plan, which accounts for individuals randomized to placebo that ultimately need pregabalin to manage neuropathic pain, in whom withholding intervention would be unethical. Future randomized trials will also be able to address limitations of human observational studies, particularly confounding, such as confounding by indication ³¹ and confounding due to injury severity.

The idea that the outcome of spinal cord injury might be improved by pharmacological pleiotropy is not new and has been demonstrated repeatedly for experimental therapies. ³² However, the realization of such an effect for gabapentinoids not only merits trials such as those mentioned above but also warrants deeper investigations into possible similar effects of other standard-of-care interventions in the acute stages of spinal cord injury, and other neurological conditions.