Post-stroke pain (PSP) refers to a syndrome commonly associated with the complications arising from cerebrovascular accidents and the resulting vascular lesions. Pain as a common complication after stroke, is associated with depression, cognitive dysfunction, and reduced quality of life. Despite evidence that effective treatment of pain improves function and quality of life, pain remains underdiagnosed and undertreated.

Ace Therapeutics, a leading provider of stroke research services, is committed to helping clients explore the mechanisms involved in post-stroke pain and develop therapeutics for reducing pain intensity and lessen pain-related behavioral responses after stroke.

Types of PSP

• Central post-stroke pain (CPSP)
• Pain secondary to spasticity
• Musculoskeletal pain: Glenohumeral subluxation and contractures
• Complex regional pain syndrome(CRPS)
• Headache

Fig. 1 Common types of chronic pain that can occur after stroke. (Klit, et al., 2009)

Risk Factors of PSP

Definition of CPSP

CPSP is a prevalent pain syndrome following a stroke, affecting over one-third of post-stroke patients. Its onset varies, typically occurring between 3 to 6 months after the stroke, but it may begin as soon as a month post-stroke. Symptoms generally develop gradually, aligning with a recovery of sensory loss and the emergence of dysesthesia. Patients often experience severe, unrelenting pain with brief periods of relief. CPSP features three pain components: constant pain, spontaneous intermittent pain, and hyperalgesia/allodynia.

Pathophysiology of CPSP

Central sensitisation

Many pharmacological treatments for central pain target neuronal hyperexcitability, suggesting a connection between this hyperexcitability and spontaneous pain in conditions like CPSP, which may arise from spontaneous discharges in deafferented neurons in the thalamus or cortex.

Alterations in spinothalamic tract function

Alterations in the function of the spinothalamic tract are associated with disturbances in pain and temperature sensation, often observed in patients with CPSP. Lesions affecting this tract can precipitate CPSP, and deficits in its function can be assessed using laser-evoked potentials.

Thalamic changes

The thalamus is believed to play a crucial role in the mechanisms underlying central pain, and CPSP frequently occurs following lesions that involve the thalamus. Factors such as deafferentation, the loss of inhibitory GABA-containing neurons in the thalamus, and remote microglial activation have been proposed as potential contributors to the thalamic changes observed after CNS lesions.

Disinhibition theories

Disinhibition theories propose that the CNS maintains a balance between facilitation and inhibition, particularly involving brainstem nuclei and spinal cord circuits. An imbalance in these systems is thought to underlie central pain syndromes, such as CPSP.

Fig. 2 Some proposed mechanisms for central pain. (Klit, et al., 2009)

Current Interventions for PSP

CPSP is often difficult to treat; the treatment response is mostly moderate, and the dosage is limited by side effects. CPSP involves a trial and error process with multiple different therapies.

Current Drug Research in CPSP

Various pharmacologic agents have been found to be effective in CPSP.

• Tricyclic antidepressants
• Selective serotonin reuptake inhibitors,
• Antiepileptics, including lamotrigine, gabapentin, and pregabalin

Neurostimulatory Therapy for CPSP

Neurostimulation therapies, including motor cortex stimulation, deep brain stimulation, and transcranial magnetic stimulation, are used for treating CPSP. Repetitive transcranial magnetic stimulation (rTMS), with repetitive daily stimulation of the motor cortex, has been shown to be effective in CPSP and may provide sustained pain relief.

Exercise Therapy for PSP

PSP significantly impacts the quality of life for stroke patients, making exercise therapy a promising area of research for its management. Exercise is advantageous due to its affordability and acceptance by patients. It has been shown to improve physical function, reduce pain intensity, and lessen pain-related behavioral responses. Additionally, exercise can enhance brain function and influence various biological factors that contribute to pain relief. Potential mechanisms include changes in synaptic plasticity, modulation of endogenous opioids, reversal of brain-derived neurotrophic factor overexpression, and inhibition of specific receptor expressions and microglia activation.

Fig. 3 The involved mechanisms in exercise on PSP. (Ma, et al., 2022)

1. Klit, H., et al. (2009). Central post-stroke pain: clinical characteristics, pathophysiology, and management. The Lancet Neurology, 8(9), 857-868.
2. Ma, Y., Luo, J., & Wang, X. Q. (2022). The effect and mechanism of exercise for post-stroke pain. Frontiers in Molecular Neuroscience, 15, 1074205.