Research led by The Ohio State University Wexner Medical Center and College of Medicine found that the widely prescribed pain-relief drug gabapentin can prevent harmful structural changes in the injured spinal cords of mice, and also block cardiovascular changes and immune suppression caused by spinal cord injury.
“Gabapentin is often prescribed as a treatment for pain, but if it is given early after injury – before symptoms develop – it can also limit structural changes in nerve cells.
We show that these benefits remain even one month after stopping gabapentin treatment in spinal injured mice. We believe that gabapentin could be repurposed as a prophylactic therapy that can prevent autonomic dysfunction in people affected by spinal cord injuries,” said Phillip Popovich, senior author and chair of Ohio State’s Department of Neuroscience.
Study findings are published online in the journal Cell Reports.
“This is the first time a treatment has been shown to prevent the development of autonomic dysfunction, rather than manage the symptoms caused by autonomic dysfunction. In response to stress or danger, autonomic nerve cells in the spinal cord trigger a ‘fight or flight’ response. This is a normal and helpful response that increases blood pressure and releases hormones like adrenaline and cortisol,” said lead author Faith Brennan, research scientist in Ohio State’s department of neuroscience.
But, after traumatic spinal cord injury, massive structural changes occur within spinal autonomic nerve centers that control the fight or flight response, and these changes cause uncontrolled autonomic reflexes.
For example, normally harmless stimuli, such as the bladder filling, will trigger the fight or flight response. But because of the spinal cord injury, the response is uncontrolled and can cause several health problems, including severe high blood pressure, heart rate slowing and long-term immune suppression.
“Autonomic dysfunction is a major problem for people living with a spinal cord injury. The cardiovascular complications can lead to severe morbidities like heart attack and stroke while long-term immune suppression can lead to serious recurrent infections like pneumonia,” Popovich said.
Currently, these symptoms can only be managed, (regular bowel/bladder voiding regimens, for example), but there is no treatment.
“The possibility of repurposing gabapentin as a prophylactic therapy to prevent the development of autonomic dysfunction could significantly improve the quality of life for individuals living with spinal cord injuries, including greater independence in society, reduced caregiver reliance, reduced infection susceptibility and increased life expectancy,” Brennan said.
“Gabapentin is FDA-approved, and is already widely used to manage neuropathic pain caused by spinal cord injuries. If patients are treated early after their injuries, gabapentin could prevent the harmful structural changes that are inevitable in most severe spinal cord injuries.”
This study builds on Ohio State’s previous research showing that autonomic dysfunction directly drives immune suppression, said Popovich, who also is a researcher in Ohio State’s Neurological Institute and the Belford Center for Spinal Cord Injury.
“We don’t know how long treatment can be delayed after injury and still maintain the beneficial effects. Ongoing studies in the Belford Center are optimizing this treatment onset window. We also don’t know if gabapentin targets other cells/organs in the body, so we’ll investigate the effects of this therapy on other tissues beyond the spinal cord,” Popovich said.
Neuropathic pain is a chronic and debilitating condition caused by injury or disease of the nerves of the somatosensory system . Because of the heterogeneity of its aetiologies, symptoms and underlying mechanisms , current pharmacological treatments encompass different drug classes.
Given the small number of approved drugs and their limited clinical efficacy, at least 45% of patients with neuropathic pain concurrently receive two or more drugs to treat their condition . In fact, combining drugs with different pharmacological mechanisms of action may yield greater efficacy and a greater chance of modulating multiple pain mechanisms .
Pain comprises two main components: the somatosensory one, responsible for determining the location and intensity of pain, and an affective component, which consists in a complex cognitive and emotional experience which depends also on the psychological state of the individual [5,6].
Although the link between emotional state and pain perception has been clearly confirmed by several controlled studies both in healthy volunteers and in patients , the impaired cognitive and emotional states that are often concomitant in patients with chronic pain are not properly addressed with current therapeutic approaches. As a consequence, new drugs for the treatment of neuropathic pain that can also affect these aspects are needed.
Gabapentin is an anticonvulsant drug originally registered for the treatment of epilepsy and recently approved for some neuropathic pain forms. Gabapentin selective inhibition of the α2-δ subunits of voltage-sensitive calcium channels (VSCC)  is implicated in reducing allodynia because it causes reduction of neuronal excitability and modulation of neurotransmitter release. However, its use is affected by dose-limiting side effects requiring prolonged dose titration.
With the aim of targeting the impaired affective components of painful conditions, antidepressant drugs are commonly used in the clinical setting for the treatment of chronic pain . Combinations of antidepressants with gabapentin showed superiority to gabapentin monotherapy both in preclinical [9,10] and clinical settings [11–13].
Trazodone is a multifunctional drug approved worldwide for the treatment of major depression with a mild adverse effect profile (sedation). It is a blocker of the post-synaptic serotonin (5-HT) receptors 5-HT2A and 5-HT2C and inhibitor of presynaptic 5-HT reuptake transporters . Trazodone, tested in the chronic constriction injury (CCI) rat model of chronic pain , showed a dose-dependent analgesic effect on thermal hyperalgesia .
Hence, because the antinociceptive effects of gabapentin and trazodone are mediated by different mechanisms, we hypothesized that the drugs could synergistically interact when concomitantly administered. Using an acute pain model, the writhing test, we confirmed such assumption through isobolographic analysis. We then evaluated pharmacodynamic interactions between low doses of trazodone and gabapentin in the rat CCI model, characterizing their effects both on evoked and spontaneous nociception and on behaviors reflecting general animal well being. To this specific purpose, the burrowing test and the nest construction assays were performed. They are naturally occurring behaviours in both rats and mice, and they have been used as an indicator of distress and suffering in several disease models [17–19].
Besides exerting a significant antinociceptive effect on hyperalgesia and on spontaneous pain, the combination of inactive doses of trazodone and gabapentin restored rat innate behaviors that are strongly reduced or even abolished during persistent nociception, suggesting that the combination may have an impact also on aspects of chronic pain different from the somatosensory components.
reference link: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244649
More information: Faith H. Brennan et al, Acute post-injury blockade of α2δ-1 calcium channel subunits prevents pathological autonomic plasticity after spinal cord injury, Cell Reports (2021). DOI: 10.1016/j.celrep.2020.108667