One of the most troublesome sequelae of stroke is pain, which occurs in 19–74% of patients. The wide variation of pain incidence is due to differences in the characteristics of subjects, the time of assessment, and the definition of “pain” [12]. According to a study investigating stroke patients using the visual analogue scale (VAS), moderate to severe pain (defined by VAS 40–100) was reported in 32% after 4 months post-stroke (median VAS = 60) and 21% at 16 months. The factors related to pain included younger age, female sex, higher NIHSS score, and elevated HbA1c at stroke onset. Pain disturbed sleep in 58%, and 40% required rest for relief of pain. However, another controlled, population-based study assessing stroke patients with 2 years of follow-up, development of chronic pain after stroke was only slightly more common than that of sex- and age-matched control group: 39.0 versus 28.9%. In this study, novel headache, shoulder pain, and pain from increased muscle stiffness were more common in stroke patients, whereas joint pain was equally common in the two groups.

The most common location of post-stroke pain is the shoulder, which has a prevalence ranging from 11 to 40%. The shoulder pain is usually due to immobilization and contraction of the shoulder muscles in patients with severe upper arm paresis. In addition, spasticity, bed sores, arthropathy associated with chronic abnormal weight bearing, diabetic neuropathy, depression, and anxiety are causally associated with post-stroke pain. Aside from the pain due to peripheral problems, another important cause of pain in stroke patients is that due to the brain lesion itself. Although this phenomenon was initially described as “thalamic syndrome” or “thalamic pain,” it is now widely recognized that strokes occurring anywhere in the sensory tract can produce central pain. Therefore, the term central post-stroke pain (CPSP) is now generally used, although many patients describe the symptoms as “burning,” “cold,” or “squeezing” rather than as pain. CPSP occurs in 1–8% of stroke patients. However, the delayed occurrence of symptoms, the lack of objective diagnostic criteria, and the fluctuations in symptom severity make it difficult to assess the prevalence. Currently, it is estimated that more than 30,000 patients suffer from CPSP in the USA.

CPSP may start at stroke onset, but more often its onset is delayed, usually within 6 months after stroke onset. The symptoms almost always develop within the area of initial sensory impairment and may be restricted to distal or, less often, proximal body parts. Spinothalamic abnormalities, particularly temperature-sensory ones, are frequently associated with CPSP. Dysesthesia and allodynia are frequent. CPSP is frequently aggravated by a cold environment, psychological stress, heat, fatigue, or body movement. The pathogenesis of CPSP remains unknown, but suggested mechanisms include hyperexcitation in the damaged sensory pathways, damage to the central inhibitory pathways, or a combination of the two. It is highly likely that various neurotransmitters, i.e., adrenergic, serotonin, and glutaminergic, are involved in this process.

Management of post-stroke pain is challenging. The type of pain should be carefully investigated, and treatment should be individualized according to the nature and severity of pain. Because muscle stiffness and spasticity are associated with pain, physical therapy, occupational therapy, aquatics, and splints are often applied. Application of analgesics, topical cream, injection, and repetitive transcranial magnetic stimulation (rTMS) may be of help. Drugs such as diazepam, dantrolence, baclofen, clonidine, and gabapentin are used to relieve spasticity. Botulinum toxin injection works in some patients.

For CPSP, many drugs capable of modulating the CNS neurochemicals have been developed. Amitriptyline was the first drug that was found to improve CPSP in a double-blind, placebo-controlled, crossover study [13]. Amitriptyline is cheap and has been considered the first-line drug in the management of CPSP. However, it is often only partially effective in patients with severe symptoms, and the side effects, such as dry mouth, urinary retention, somnolence, and confusion, are frequently intolerable in aged stroke patients. Although their efficacies have not been properly investigated in patients with CPSP, similar antidepressants with adrenergic activities, such as nortriptyline, desipramine, imipramine, doxepin, and venlafaxine, are occasionally used when amitriptyline is not tolerated. Various antiepileptics have been tried in patients with CPSP under the assumption that CPSP is related to neuronal hyperexcitability in the sensory system. Although the efficacy of carbamazepine and phenytoin on CPSP was not proven, lamotrigine, a novel antiepileptic drug that presynaptically inhibits sodium channels and suppresses glutamate release, was reported to be moderately effective for CPSP in a double-blind, placebo-controlled study.

Recently, gabapentin, a structural analogue of GABA, has received special attention because it acts on presynaptic voltage-sensitive calcium channels, which modulate the release of multiple neurochemicals. Gabapentin was found to be effective in relieving neuropathic pain due to peripheral nerve disease and central pain caused by spinal cord lesions. Unfortunately, there has been no clinical trial that examined the efficacy of gabapentin in patients with CPSP. A closely related drug, pregabalin, was also found to be effective in the treatment of various neuropathic pains, including central pain due to spinal cord lesion. Recently, a 13-week, randomized, double-blind, placebo-controlled study using pregabalin was conducted in patients with CPSP [14]. The benefit of pregabalin on the primary outcome, the mean pain score on the Daily Pain Rating Scale over the last 7 days, was not proven. However, the conclusion should be cautiously interpreted because pregabalin produced significantly greater pain relief up to 8 weeks versus placebo, and no loss of pain reduction was seen thereafter. Moreover, pregabalin resulted in significant improvements in the secondary endpoints that included sleep disturbances, anxiety, and the clinician global impression of change. There are no universally accepted treatment guidelines for CPSP. Figure 31.2 describes one of the typical approaches used to treat CPSP patients [15].