Chronic Pain Syndromes After Ischemic Stroke
Background and Purpose—Chronic pain syndromes are reported to be common after stroke, but most previous epidemiological studies have generally included small cohorts of patients with relatively short-term follow-up. In a large cohort with ischemic stroke (Prevention Regimen for Effectively avoiding Second Stroke [PRoFESS] trial), we determined the prevalence, risk factors, and clinical consequence of new poststroke pain syndromes.
Methods—Within the PRoFESS trial (mean follow-up 2.5 years), a standardized chronic pain questionnaire was administered (at the penultimate follow-up visit) to all participants who reported chronic pain since their stroke and did not have a history of chronic pain before their index stroke. Multivariable logistic regression analyses were used to determine risk factors for poststroke pain (and pain subtypes), and the association between poststroke pain and cognitive (≥3 reduction in Mini-Mental State Examination score) and functional decline (≥1 increase in m-Rankin).
Results—In total, 15 754 participants were included; of which 1665 participants (10.6%) reported new chronic poststroke pain, and included 431 participants (2.7%) with central poststroke pain, 238 (1.5%) with peripheral neuropathic pain, 208 (1.3%) with pain from spasticity, and 136 participants (0.9%) with pain from shoulder subluxation. More than 1 pain subtype was reported in 86 participants (0.6%). Predictors of poststroke pain included increased stroke severity, female sex, alcohol intake, statin use, depressive symptoms, diabetes mellitus, antithrombotic regimen, and peripheral vascular disease. A new chronic pain syndrome was associated with greater dependence (odds ratio, 2.16; 95% confidence interval, 1.82–2.56). Peripheral neuropathy and pain from spasticity/shoulder subluxation were associated with cognitive decline.
Conclusions—Chronic pain syndromes are common after ischemic stroke and are associated with increased functional dependence and cognitive decline.
Chronic pain syndromes are reported to be a common complication of ischemic stroke.1 However, estimates of the frequency from previous studies vary widely (8%–55%),2 reflecting small sample sizes and differing patient populations, study designs, and definitions of chronic pain.3–14 Similarly, the clinical consequences of chronic pain syndromes are inadequately understood, although they are reported to have a negative effect on quality of life4,5,15 after stroke.
Chronic pain syndromes may result from both central and peripheral mechanisms and may be mediated through nocioceptive and neuropathic processes.1 Central poststroke pain is a neuropathic pain syndrome, which is a direct consequence of ischemic damage, and is especially challenging to study because it usually observes an unpredictable latent period between stroke onset and development of pain or discomfort.11 In contrast, most poststroke mechanical pain syndromes have a more predictable natural history, usually resulting from limb spasticity or shoulder subluxation. The small sample sizes of many previous studies (<500 patients) have also limited their ability to study pain subtypes and risk factors for poststroke pain.
In a large cohort of patients with recent nonsevere ischemic stroke without a history of chronic pain included in the Prevention Regimen for Effectively avoiding Second Stroke (PRoFESS) trial, we determined the prevalence, determinants, and clinical consequence of new poststroke pain syndromes.
PRoFESS was a randomized controlled trial that compared combination aspirin (25 mg twice daily) and extended release dipyridamole (200 mg twice daily) versus clopidogrel (75 mg daily) and telmisartan 80 mg daily versus placebo, in a 2×2 factorial design, in patient ≥50–55 years with recent ischemic stroke (≤ 90–120 days before randomization). The study design and primary results of the PRoFESS trial have been published previously.16–18 Over 34 months, 20 332 patients were randomized from 695 centers in 35 countries and were followed up for a mean duration of 30 months.
Measurement of Chronic Pain
Chronic pain was measured at the penultimate visit of the trial. At that time, participants who did not report a history of chronic pain before their stroke (based on questionnaire) were included in the poststroke chronic pain substudy. Each participant was asked whether they had pain, discomfort, or unpleasant sensation for 15 days or more since their stroke. If they answered yes, the research nurse/assistant completed a standardized worksheet assessment of the following factors: character of pain (aching, dull, sharp, cramping, burning, shooting, electric, and lightening), frequency of pain (every day, most days, or less than once per week), severity of pain/discomfort (scale of 0–10), time of onset after stroke (<1 week, 1 week-3 months, 3–6 months, or >6 months), location of pain (anatomically and whether pain location is in the area of weakness or sensory deficit after stroke), other associated features (hypersensitivity to touch and pain when touched), and frequency of taking pain medications. Information from the worksheet was kept at the local site but not included in the central database, and therefore not reported here. After completion of the standardized assessment, those participants who reported chronic pain were reviewed by the local neurologist, who was asked to complete a form detailing the primary pathogenesis of the chronic pain syndrome, which included central poststroke pain, pain from shoulder subluxation, peripheral neuropathy, pain attributable to limb spasticity, and other.
Measurement of Cognitive Function and Functional Dependence
Cognitive function was measured with the Mini-Mental State Examination19 (MMSE, ranging from 0 to 30), which was completed at 1-month and penultimate follow-up visit. A loss of ≥3 points was considered a clinically meaningful change in cognitive function during follow-up.20 Dependence was measured with the modified-Rankin scale score (range 0 to 5), which was measured at baseline and penultimate follow-up visit. A reduction of ≥1 point (from baseline to penultimate follow-up visit) was considered a clinically meaningful change in disability/dependence during follow-up.
All confounder variables were collected at the time of randomization. Stroke severity was measured using the National Institutes of Health Stroke Scale (NIHSS). Ethnicity was categorized as white versus nonwhite. History of myocardial infarction, stroke, hypertension, diabetes mellitus, hypercholesterolemia, atrial fibrillation, congestive heart failure, and peripheral vascular disease was based on patient report. Depression was defined as feeling sad or blue for ≥2 weeks. Smoking was categorized as never/former (reference) or current. Exercise was categorized as mainly nonsedentary (reference) versus sedentary (some or intense regular exercise). Alcohol intake was categorized into never/former, current (subcategorized as 0–14 drinks per month and ≥15 drinks per month). Allocation to antiplatelet regimen (aspirin/dipyridamole or clopidogrel) and telmisartan or placebo was recoded at randomization. Body mass index was recorded at baseline.
Baseline differences in characteristics between participants with and without new chronic pain on follow-up were compared using χ2 and t test, as shown in Table 1. Risk factors for developing poststroke pain were identified using multivariable logistic regression analysis. Baseline factors that were significant on univariate analysis (P<0.05), or proposed to increase the risk of chronic pain, were included in the multivariable model for all poststroke pain, and the same multivariable models were retained for individual chronic pain subtypes (central post stroke pain, peripheral neuropathy, pain from spasticity, or shoulder subluxation). Table 2 lists all variables included in the final model.
The association between chronic pain and decline in MMSE score and m-Rankin score was determined using multivariable logistic regression models. For both models, we included the following variables: age, sex, modified-Rankin scale score at baseline, MMSE score at 1 month (MMSE was not recorded at baseline), NIHSS score at baseline, sex, previous history of stroke, ischemic stroke subtypes (small vessel versus other), myocardial infarction and, comorbid risk factors, including hypertension, body mass index, atrial fibrillation, peripheral vascular disease, congestive heart failure, myocardial infarction, diabetes mellitus, hyperlipidemia, sedentary lifestyle, smoking, alcohol intake, and previous history of depression. Separate models were generated for all poststroke and chronic pain subtypes (central poststroke pain, peripheral neuropathy, pain from spasticity, or shoulder subluxation). Estimates of association were reported using odds ratios and 95% confidence intervals (CIs). All analyses were conducted using SAS Version 8.2 for Unix (SAS Institute Inc, Cary, NC).
Of 20 332 patients who were randomized, 1495 patients had died, 125 were lost to follow-up, and 2958 patients reported previous chronic pain before their stroke or were unavailable to complete the chronic pain questionnaire at penultimate visit. Therefore, 15 754 participants without chronic pain before stroke were included in this analysis. Mean NIHSS score was 2.73 (SD 2.79).
Prevalence of Chronic Pain
In total, 1665 participants (10.6%; 95% CI, 10.1%–11.0%) developed poststroke chronic pain, and included 431 participants (2.7%; 95% CI, 2.5–3.0%) with central poststroke pain, 238 (1.5%; 95% CI, 1.3–1.7%) with peripheral neuropathy, 208 (1.3%; 95% CI, 1.1–1.5%) with pain attributable to spasticity, 136 (0.9%; 95% CI, 0.7–1.0%) with pain attributable to shoulder subluxation, 739 (4.7%; 95% CI 4.4–5.0%) with other pain syndromes. More than 1 pain pathogenesis was reported in 86 participants (0.6%), and the most common combinations were pain attributable to spasticity and central pain (n=17) and the combination of pain attributable to spasticity and shoulder pain (n=15).
Risk Factors for Poststroke Pain
On multivariable analyses, significant risk factors for all poststroke pain were increased stroke severity, female sex, alcohol intake, previous depression, statin use or hyperlipidemia, diabetes mellitus, peripheral vascular disease, and random allocation to aspirin/dipyridamole. For central poststroke pain, the significant predictors were younger age, previous depression, current smoking, and increased baseline stroke severity. For peripheral neuropathy, random allocation to aspirin/dipyridamole, increased body mass index, small-vessel stroke, current smoking, diabetes mellitus, and previous history of depression were all significantly associated. For the composite of pain from spasticity/shoulder subluxation, younger age, lower body mass index, previous history of depression, and increased stroke severity were all significantly associated (Table 2).
Poststroke Pain, Cognitive Decline, and Disability Dependence
A decline in MMSE (≥3 points) occurred in 8.8% of patients who did not develop chronic poststroke pain compared with 10.7% of patients who developed chronic poststroke pain. On multivariate analysis, peripheral neuropathy (odds ratio, 1.80; 1.24–2.62) and shoulder spasticity (odds ratio, 1.44; 1.02–2.02) were associated with cognitive decline. A decline in m-Rankin (≥1 points) occurred in 8.7% of patients who did not develop chronic poststroke pain compared with 13.7% ofpatients who developed chronic poststroke pain. All chronic pain syndromes (odds ratio, 2.16; 1.82–2.56) were associated with an increase in disability/dependence on follow-up (Table 3).
Recurrent Major Vascular Events
Recurrent stroke was reported in 142 patients (8.5%) who developed chronic pain and in 1030 patients (7.3%) who did not develop chronic pain (P=0.07). Myocardial infarction wasreported in 30 patients (1.8%) who developed chronic pain and in 180 patients (1.3%) who did not develop chronic pain (P=0.08).
We found that new chronic pain syndromes were common after nonsevere ischemic stroke, affecting ≈1 in 10 patients. Within stroke-specific pain subtypes, central pain was the most common, and accounted for one quarter of all chronic pain syndromes in this population. Increased stroke severity and previous depression were the most robust risk factors for all stroke syndromes. The development of chronic pain was associated with greater cognitive decline and functional dependence on follow-up.
Our study is the largest to determine the prevalence of chronic pain syndromes after ischemic stroke. Our estimate of 10.6% is lower than the prevalence reported in most previous studies, which have reported varying rates of between 8% and 55% in cohorts of patients after stroke, and definitions of chronic pain (and methods of assessment) may vary between studies.3–14 In many of the previous studies that reported high rates of chronic pain, populations were patients admitted to hospital or a rehabilitative facility,3,4,8–10,13 and would therefore have included a patient population with more severe stroke, contrasting those included in the PRoFESS trial, in which >85% had a baseline NIHSS score of ≤5.16 Another contributing factor that may explain our lower estimates compared with most studies is that we excluded all patients with a previous history of chronic pain, which would have resulted in a lower prevalence of overall chronic pain compared with previous studies. New poststroke pain accounted for ≈40% of all chronic pain syndromes reported in 2 studies that distinguished stroke-associated pain from other chronic pain.5,8 In our study, exclusion of patients with a previous history of chronic pain allowed us to determine the frequency of chronic pain that was most likely to be related to ischemic stroke. Our findings show that new chronic pain syndromes are an important long-term complication of ischemic stroke, even in a patient population with mild-to-moderate–severity ischemic stroke.
Of chronic pain subtypes, we recorded neuropathic pain syndromes to be the most common primary pathogenesis, accounting for 40% of all chronic pain. Within neuropathic pain, central poststroke pain accounted for the majority of cases. The predominance of neuropathic pain syndromes differs from most previous studies that reported nocioceptive pain to be the most common pain subtype. Three factors may account for the lower proportion of patients with musculoskeletal pain. First, our cohort included a low proportion of patients with severe ischemic stroke, which would reduce the proportion with musculoskeletal pain related to dependence.21 We also found that small-vessel subtype had a borderline association with central poststroke pain, which may be related to greater prevalence of thalamic and brain stem ischemic stroke. Second, our study had a longer duration of follow-up than previous studies, which mostly followed patients 12 months or less after stroke. Central poststroke pain exhibits a latent period, which may be up to 18 months after stroke onset,2 and short durations of follow-up will underestimate the frequency of central pain. Third, central pain was not systematically measured in many previous studies, and is frequently underdiagnosed because the presentation may be atypical, for example, patients may not report 'pain'. In a cohort study to complete a systematic prospective evaluation for central pain, Andersen et al11 reported a cumulative incidence of central poststroke of 8% at 1 year, in a cohort of stroke patients who survived the initial 6 months.
We found that increased stroke severity and premorbid depressive symptoms were the most consistent risk factors for chronic pain after stroke, which has been reported in a number of previous studies.3,5–7,9 As expected, increased stroke severity was most strongly associated with pain attributable to spasticity and subluxation. Surprisingly, increasing body mass index was inversely associated with pain attributable to spasticity/shoulder subluxation, which is not easily explained. Premorbid depression was a potent risk factor for all pain types, which may be attributable to a lower pain threshold or tolerance rather than having a causal relationship. Younger age was a predictor of chronic pain, which has been reported in a previous study,5 but it is unclear why younger age would be associated with an increased risk of poststroke pain. The association between premorbid alcohol intake and chronic pain was also consistent across pain subtypes. Although excess alcohol intake has been associated with an increased risk of peripheral neuropathy,22 the association with moderate alcohol consumption has not been reported nor an association with other pain syndromes. It is plausible that alcohol intake may also be a marker for other related factors, such as depression and psychosocial stress. Diabetes mellitus and smoking were significant predictors of peripheral neuropathic pain, but not central poststroke pain, which suggests that these syndromes may not share risk factors. Although we found that antiplatelet regimen was associated with the development of chronic pain, which was explained largely by an increased risk of peripheral neuropathy (Table 2), it is not readily explained and may be attributable to chance. A single observational study found that dipyridamole, combined with α-lipoic acid, increased pain sensitivity in 54 patients with diabetic neuropathy.23 Although headache is a known side-effect of dipyridamole, it invariably occurs at initiation of therapy and is usually short-lived, but may be a confounding factor in our study.
All chronic pain syndromes were associated with an increase in disability and dependence, whereas peripheral neuropathy and pain from spasticity/shoulder subluxation were associated with a significant decline in cognitive function (Table 3). Within pain subtypes, central poststroke pain had the weakest association with cognition and dependence, which may be attributable to an increased proportion of patients with thalamic ischemic stroke in this group and our observed association with small-vessel subtype. Differences in magnitude of association for pain subtypes may be confounded by the medications used to treat poststroke pain because approaches for their management differ by pain subtype. Unfortunately, we are unable to report on which medications were used to treat pain during the trial, which would be expected to have an effect on cognitive and function, especially opiate analgesics, tricyclic antidepressants, and antiseizure medications (which may also be used after poststroke epilepsy).24–27
Our study has a number of other limitations. First, our cohort only included patients with mild-to-moderate–severity ischemic stroke within 90 to 120 days and excluded patients with intracerebral hemorrhage, meaning that our findings may not be generalizable to populations with more severe stroke or those with intracerebral hemorrhage. In the PRoFESS trial, >85% of patients had a baseline NIHSS score of ≤5, and 76% of patients had a baseline m-Rankin of 0 to 2. Second, we only measured poststroke pain at a single time point (penultimate visit), which makes our study susceptible to recall bias. Recall bias may preferentially influence certain pain syndromes that are more likely to resolve or improve during follow-up, such as shoulder pain.28 Another related source of bias concerns attrition-of-the-vulnerable, particularly those patients who died before the penultimate visit represented, and may be a population at highest risk of poststroke pain. Furthermore, we are unable to determine the temporal relationship between chronic pain and cognitive and functional decline, and are therefore unable to determine a cause and effect. Our study did not include participants without stroke, so we are unable to report the proportion of new-onset pain syndromes that were attributable to stroke.29 Finally, we did not measure neuroanatomical location of ischemic stroke, which is known to be an important determinant of central poststroke pain. Strengths of our study include the very large sample size, well-defined population, neurologist evaluation with standardized assessment and categorization of pain subtypes, and duration of follow-up. However, the ultimate diagnosis of chronic pain, and its subtypes, relied on clinician assessment (with standardized information), which may have resulted in between-site variations in prevalence.
In conclusion, chronic pain syndromes are common after ischemic stroke, and associated with cognitive decline and increased functional dependence. Clinical trials, designed to prevent poststroke pain syndromes, would seem to be an obvious target of future clinical research.
This article was submitted on behalf of the Prevention Regimen for Effectively avoiding Second Stroke (PRoFESS) trial investigators.
Sources of Funding
This study was funded by Boehringer Ingelheim.
Dr Donnell has received an unrestricted educational grant from Boehringer Ingelheim and honoraria from Boehringer Ingelheim and Sanofi-Aventis. Dr Diener has received honoraria, consulting, and lecture fees from Abbott, AstraZeneca, Bayer Vital, Bristol Myers Squibb, Boehringer Ingelheim, D-Pharm, Fresenius, GlaxoSmithKline, Janssen Cilag, Merck Sharpe & Dohme, Novartis, Novo-Nordisk, Paion, Parke-Davis, Pfizer, Sanofi-Aventis, Sankyo, Servier, Solvay, Thrombogenics, Wyeth, and Yamaguchi, and grant support from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Novartis, Janssen-Cilag, and Sanofi-Aventis. Dr Sacco has received honoraria and consulting fees from Boehringer Ingelheim, GlaxoSmithKline, and Sanofi-Aventis. Dr Yusuf has received honoraria, consulting fees, and grant support from Boehringer Ingelheim, Bristol Myers Squibb, Servier, Sanofi-Aventis, AstraZeneca, and GlaxoSmithKline. The other authors have no conflicts to report.
The authors had full access to the data and take responsibility for their integrity. All authors have read and agreed to the article as written.
The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE) and were fully responsible for all content and editorial decisions, and were involved at all stages of manuscript development. The authors received no compensation related to the development of the manuscript. This work was supported by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). BIPI was given the opportunity to check the data used in the manuscript for factual accuracy only.
Steven Cramer, MD, was guest editor for this article.
- Received July 13, 2012.
- Accepted February 19, 2013.
- © 2013 American Heart Association, Inc.
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