Introduction

Pain frequently limits activities, decreases quality of life, and leads to significant psychological impairment independent of other functional deficits after SCI ( ; ; ). In general, SCI pain is not well understood from the cellular, molecular, and even spinal cord pathway levels ( ).

Sixty-five percent to eighty percent of individuals with SCI live with chronic pain, and nearly one third rate this pain as severe ( ; ; ). About half of all individuals with SCI suffer from pain so severe that it interferes with function and rehabilitation independent of deficits related to their SCI ( ). It is generally believed that level of injury does not have an influence on the degree of post-SCI chronic pain. Penetrating injuries may be more likely to result in chronic pain ( ), and there is some evidence that incomplete lesions lead to more chronic pain than complete lesions ( ; ).

Pain after SCI can generally be divided into nociceptive, visceral, at-level neuropathic, and below-level neuropathic ( ). It is theorized that SCI pain may be fairly unique and related to relative serotonin, norepinephrine, and dopamine deficits due to loss of supraspinal inhibition ( ; ; ). Additionally, there is a well-described inflammatory milieu that occurs after SCI and may contribute to an additional inflammatory basis of pain ( ). Furthermore, post-SCI changes are noted in synaptic dendrites in individuals who experience significant pain, suggesting a dynamic neuroplastic component to pain ( ). It is likely the unique combination central nervous system (CNS) changes after SCI creates a “pro-pain” state, and not surprisingly, SCI pain is often refractory to medical treatments ( ; ).

The treatment of SCI-related pain often comes down to using a multimodal approach with medications, physical interventions, treatment of underlying conditions like spasticity, treatment of acquired overuse syndromes, and potentially the use of neuromodulation interventions. The typical categories of SCI-related pain can be reviewed in Tables 1 and 2 .

Application to other areas of neuroscience

There is a growing emphasis on the connection between physical experiences and psychologic interpretation that goes beyond pain management. One particular area of interest has been the neural pathway between the amygdala, periaqueductal gray matter, and rostral ventromedial medulla (RVM). The amygdala stores emotional experiences. It is connected to the periaqueductal gray matter, which contains a high concentration of opioid, cannabinoid, and endorphin receptors ( ). The RVM is not involved in generating an initial pain response but does help regulate the maintenance of neuropathic pain ( ). The ventral posteromedial nucleus plays a major role in central sensitization, a condition of the nervous system that is associated with development and maintenance of chronic pain that is caused by increased excitability of cell membranes, synaptic efficiency, and reduced inhibition of nociceptive pathways ( ). The plasticity of neurons that undergo central sensitization has been the target of newer therapies, though significant mechanistic gaps in our understanding remain ( ).

These pathways significantly influence pain processing, decision-making, avoidant behavior, and personality expression ( ) and are thought to modulate opioid-induced analgesia ( ). Additionally, recent studies showed modulating this pathway impacts the extent of depression-associated pain in mice under chronic stress ( ). Physical activity, such as Tai Chi and cycling, has been shown to modulate this opioid pathway, thereby reducing overall pain levels and reducing levels of circulating inflammatory markers ( ). This concept is fundamental to the use of physical activity to combat pain in patients with depression.

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Medications

Medications targeting neuropathic pain after SCI are the best studied. Pregabalin (Lyrica) and gabapentin (Neurontin) are antiepileptics and considered first-line medications in the treatment of neuropathic pain in patients with SCI injury ( ). In 2012, pregabalin (Lyrica) became the first and remains the only Federal Drug Administration approved medication for neuropathic pain in patients with SCI in the United States. Its approval was based on two double blind placebo controlled randomized trials ( ; ). In the study by , 70 patients showed improvement in pain and sleep when compared to the control arm of 67 patients. studied 220 patients and exhibited improvement in pain 1 week into treatment. published an updated systematic review from their 2010 publication ( ) and cited 13, level-1 randomized controlled trials supporting both the anticonvulsants pregabalin and gabapentin.

Antidepressants are also utilized in treating neuropathic pain in SCI. Like pregabalin (Lyrica) and gabapentin (Neurontin), the tricyclic antidepressants amitriptyline (Elavil), nortriptyline (Pamelor), imipramine (Tofranil), and desipramine (Norpramin) are first-line medications. These medications have only demonstrated efficacy in patients with concomitant depression ( ). More recently venlafaxine revealed similar effects to amitriptyline in subjects with pain and depression ( ). Other antidepressants, such as duloxetine, have not proven to be effective in patients with pain related to SCI ( ). Taken together, the serotonin-norepinephrine reuptake inhibitors (SNRIs) duloxetine (Cymbalta) and venlafaxine (Effexor) are considered second-line medications.

Despite common use in practice, opioids have inferior efficacy than previously mentioned medications. Tramadol, a synthetic opioid with SNRI properties, has some efficacy and is a third-line medication ( ; ). As a sole agent, tramadol should be employed before other opioids such as oxycodone. Oxycodone is considered a fourth-line medication and has only level 4 evidence supporting its use ( ; ).

The effects of cannabinoids are mediated via the CB ₁ and CB ₂ G-protein receptors, where CB ₁ is widely expressed in the CNS ( ). Interestingly, CB ₁ is upregulated following SCI ( ). The analgesic properties of cannabinoids are mediated through the PAG ( ; ). Indirect effects on opiate, serotonin, NMDA, and GABA receptors link endocannabinoids to other pain-related pathways ( ; ; ). A metaanalysis of five randomized control trials suggests that inhaled cannabis may provide short-term relief for about 20% of patients with neuropathic pain ( ). Future studies are needed to assess long-term effects of cannabinoids on neuropathic pain, specifically as it relates to SCI, as well as the optimal route of administration ( ). The mechanism of action for medications typically used for the treatment of SCI-related pain can be reviewed in Table 3 .

Table 3

Medication management of pain in spinal cord injury.

Class of medication	Targeted category of pain	Mechanism of action	Monitoring
Anticonvulsant • Gabapentin • Pregabalin	Neuropathic	GABA analog	– Peripheral edema – Weight gain – Dose adjustment for renal impairment
Antidepressant, tricyclic • Amitriptyline • Nortriptyline	Neuropathic	Inhibit reuptake of serotonin and/or norepinephrine at the presynaptic neuronal membrane pump	– Behavior changes, suicidality – Anticholinergic effects (e.g., constipation, urinary retention)
Antidepressant, serotonin/norepinephrine reuptake inhibitor • Duloxetine • Venlafaxine	Neuropathic	Inhibits neuronal serotonin and norepinephrine reuptake; weakly inhibits dopamine reuptake	– Behavior changes, suicidality – Avoid use in those with hepatic impairment – Dose adjustment for renal impairment
Nonsteroidal antiinflammatory drug • Ibuprofen • Naproxen • Celecoxib* • Diclofenac • Indomethacin • Ketorolac • Meloxicam • Nabumetone	Nociceptive	Inhibits cyclooxygenase-1 and 2 (COX-1 and 2) enzymes, resulting in decreased formation of prostaglandin precursors; decrease proinflammatory cytokine levels	– Cardiovascular thrombotic events – Gastrointestinal bleeding, ulceration, and perforation – Avoid use in those with renal disease
Nonopioid analgesic • Acetaminophen • Paracetamol	Nociceptive	Not fully known, analgesic effects likely due to activation of CNS descending serotonergic inhibitory pathways	– Hepatotoxicity
Opioid • Buprenorphine • Codeine • Fentanyl • Hydrocodone • Hydromorphone • Methadone • Nalbuphine • Oxycodone • Tramadol	Nociceptive	Binds to opiate receptors in the CNS, inhibiting ascending pain pathways	– CNS depression – Respiratory depression – Hypotension – Constipation
Cannabis	Nociceptive	Activation of the endogenous endocannabinoid system through CB1 and CB2 receptors	– Psychoactive properties – Dizziness – – Nausea, vomiting – Fatigue, drowsiness
Baclofen	Spasticity	GABA agonist at the GABA B receptor	– Lowers seizure threshold – Consider dose adjustment for renal impairment – CNS depression – Urinary retention
Dantrolene	Spasticity	Inhibits the release of calcium from sarcoplasmic reticulum	– Peripherally acting on skeletal muscle – Hepatotoxicity; monitor liver function closely
Alpha 2 adrenergic agonist • Clonidine • Tizanidine	Spasticity	Increasing presynaptic inhibition; reduces facilitation of spinal motor neurons	– Orthostatic hypotension – Drowsiness, dizziness – Bradycardia – Monitor liver function
Benzodiazepine • Diazepam	Spasticity	Facilitates GABA effects on the GABA A receptor	– Caution with concomitant use of opioids – CNS depression – Use with caution in those with renal and hepatic impairment and respiratory disease

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