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VOLVO XXIIIL XXI • NNOO 13 •• J APRILUNE 2013 2015 Diagnosis, Prevalence, Characteristics, Vol.ÊXXI,ÊIssueÊ1Ê JuneÊ2013 andEditorial Treatment Board of Central Poststroke

Editor-in-Chief PsychosocialÊAspectsÊofÊChronicÊPelvicÊPain ain is a common complaint mortality.49,62,63 Since the incidence severe pain attributed to a vascular JaneÊC.ÊBallantyne,ÊMD,ÊFRCA Anesthesiology,ÊPainÊMedicinefollowing , reported of stroke increases with age and life lesion in the thalamus. This pain syn- USA in 11–55% of stroke sur- expectancy is rising, the prevalence drome became known as the “Dejerine- Pain is unwanted, is unfortunately common, and remains essential for survival (i.e., 5,24,31,47 PAdvisoryÊBoardvivors. Poststroke of poststrokeevading dang pain,er) a includingnd facilitati centralng med ical dRoussyiagnos esyndrome”s. This com orple “thalamicx amalgamati painon of painMichaelÊJ.ÊCousins,ÊMD,ÊDSC can arise from muscles, joints, poststrokesensation, pain em o(CPSP),tions, a isnd also though likelyts ma nifesyndrome.”sts itself as pExpertsain beh alatervior .demonstrated Pain is a moti - PainÊMedicine,ÊPalliativeÊMedicine 1 - or viscera,Australia or from the peripheral to increasevating fact inor the for future. physicia Itn isconsu imporltati- ons that and extrathalamicfor emergency vasculardepartme lesionsnt visit scan and is or .39,63 The tant to assess the presence most common types of poststroke of pain in stroke survivors pain include hemiplegic shoulder because of its negative pain, pain due to painful spasms or impact on quality of life and spasticity, poststroke headache, and rehabilitation. central poststroke pain. Patients may have several types of poststroke pain Central Poststroke Pain concomitantly.24,39,63 CPSP is a central neuropathic Risk factors for poststroke pain pain condition in which pain include young age, female sex, stroke arises as a direct result of severity, spasticity, diabetes, sensory a cerebrovascular lesion in disturbance, depression, and pain the central somatosensory before stroke onset. Up to 40% of nervous system. Other com- stroke patients who develop post- also cause pain, and so the term “cen- mon causes of central neuropathic pain stroke pain have other pre-existing tral poststroke pain” is preferable.27,28,54 include , spinal cord pain conditions.31 Poststroke pain In this issue of Pain: Clinical Updates we , syringomyelia and syringobul- can reduce quality of life, increase will review the diagnosis, prevalence, bia, tumors and abscesses in the central fatigue, complicate rehabilitation, clinical characteristics, and evidence- nervous system (CNS), and other disturb sleep, affect mood and social based treatment of CPSP. inflammatory CNS diseases (e.g., my- functioning, and increase long-term elitis). Like poststroke pain in general, Diagnosing CPSP Henriette M. Klit, MD CPSP has a negative effect on quality of Henriette M. Klit, MD life in stroke survivors.12 It is important to distinguish between Danish Pain Research Center Aarhus, Denmark Central poststroke pain was first nociceptive and neuropathic pain in Email: [email protected] described by the French neurolo- stroke patients, as the choice of treat- Nanna Brix Finnerup, MD gist Déjerine and the Swiss-French ment often differs in these conditions. Danish Pain Research Center neuropathologist Roussy in 1906 in However, there are no particular Aarhus, Denmark Email: [email protected] their famous paper “Le syndrome features in the history or the clinical Troels Staehelin Jensen, MD, DMSc thalamique.”13 The authors reported a findings that can separate neuropathic Danish Pain Research Center small series of patients with a constel- and musculoskeletal pain with cer- Aarhus, Denmark Email: [email protected] lation of neurological symptoms and tainty, and making such a distinction

PAIN: CLINICAL UPDATES • APRIL 2015 1 can sometimes be difficult.53 A further complication is the fact that stroke pa- Poststroke pain can reduce quality of life, increase fatigue, tients often have other pain conditions. complicate rehabilitation, disturb sleep, affect mood and Also, some poststroke pain conditions social functioning, and increase long-term mortality. may be mixed pain types, as in the case of shoulder pain. In 2008, a new grading burning, painful cold, electric shocks, quantitative sensory testing (QST),23 system emerged for neuropathic pain aching, pressing, stinging, and pins additional imaging, or neurophysio- with different inclusion criteria for and needles; and allodynia or dyses- logical examinations, to rule out other neuropathic pain, but these criteria thesia to touch. In the same paper, we causes of pain. did not include the exclusion of other published a grading system, based on causes of pain. Therefore, in 2009 we the diagnostic criteria, enabling re- Prevalence published a proposal for diagnostic searchers to classify CPSP as “possible,” The reported prevalence of central criteria for CPSP based on the grad- “probable,” or “definite” (Table 1). poststroke pain varies between 1% and ing system,37 including mandatory and As implied by the proposed 12%.2,9,25,31,36,39,42,47,52,61,64 In a population- supportive criteria. The mandatory cri- diagnostic criteria, the diagnosis of based study from Denmark, based on teria for the diagnosis of CPSP include CPSP is based on the stroke and pain a questionnaire of 608 stroke patients the following: pain within an area of history and the clinical examination and a clinical examination of 51 pa- the body corresponding to the CNS with a focus on the sensory find- tients with possible CPSP, the minimum lesion, a history suggestive of a stroke ings. If possible, the vascular lesion prevalence of definite or probable CPSP and onset of pain at or after stroke should be visualized by imaging, was 7.3% (N = 35) and 8.6% (N = 41) if onset, confirmation of a CNS lesion by either computed tomography (CT) or CPSP-like dysesthesia was included.36 imaging and/or negative or positive magnetic resonance imaging (MRI). The median time of follow-up was 4.4 sensory signs confined to the area of Other useful tools include pain draw- years. the body corresponding to the CNS ings and standardized pain question- In a Finnish study of CPSP in lesion, and, if possible, exclusion of naires, including neuropathic pain young patients with ischemic stroke other causes of pain such as nocicep- scales such as the DN4 (Douleur with a median follow-up time of 8.5 tive or peripheral neuropathic pain. Neuropathique en 4 Questions) and years, a total of 49 out of 824 patients The supportive criteria include: no the Leeds Assessment of Neuropathic had CPSP, corresponding to a preva- primary association with movement, Symptoms and Signs (LANSS) scale.23 lence of 5.9%. Out of the remaining inflammation, or other local tissue Sometimes it is necessary to perform 775 patients, 246 had sensory abnor- damage; certain descriptors such as supplementary investigations, such as malities and 529 had neither sensory

Table 1 Grading system for central poststroke pain (CPSP)* Criteria to Be Evaluated for Each Patient Comments 1. Exclusion of other likely causes of pain No other obvious cause of pain No primary relation to movement, inflammation, or other local tissue damage Descriptors such as burning, painful cold, electric shocks

2. Pain with a distinct neuroanatomically plausible Pain localized unilaterally or crossed face/body in a body area corresponding to distribution a cerebrovascular lesion

3. A history suggestive of a stroke Sudden onset of neurological symptoms with pain starting at or after stroke onset

4. Demonstration of the distinct neuroanatomically Findings of positive and/or negative sensory signs in an anatomically plausible plausible distribution by a clinical neurological distribution and pain localized within a territory of sensory abnormality examination 5. Demonstration of the relevant vascular lesion Visualization of a lesion that can explain the distribution of sensory findings, by imaging either CT or MRI * Possible CPSP: Criteria 1 + 2 + 3 fulfilled. Probable CPSP: Criteria 1 + 2 + 3 fulfilled plus either 4 or 5. Definite CPSP: Criteria 1–5 fulfilled.

2 PAIN: CLINICAL UPDATES • APRIL 2015 abnormalities nor CPSP. The investiga- majority of patients report moderate tors found that patients with CPSP had pain.2,44,52,64 In a population-based study, Sensory descriptors used a lower quality of life compared with the reported median pain intensity in patients with CPSP patients without CPSP, both with and was 5 on a numeric rating scale (range include burning, aching, without sensory abnormalities. Forty 0–10).36 The pain can be spontaneous, (82%) of the CPSP patients had other evoked, or both. Pain-evoking factors pricking, lacerating, shooting, concomitant pain complaints.25 In this can be internal stimuli, such as stress squeezing, throbbing, sharp, study, as in other studies on CPSP, and emotions, or external stimuli, stabbing, painful pins and 9,44 the presence of CPSP was associated such as touch and cold. Pain usually needles, dull, and cramping. with stroke severity, but not with age seems to be chronic, often life-long and at stroke onset, sex, or stroke subtype constant, but in a few patients, the pain patients with CPSP. For a definition of based on stroke etiology. reduces over time.38 these terms, see the pain taxonomy In a population–based study from Sensory descriptors used in published by IASP.1 In one study,36 Rimini, Italy, published in 2013, CPSP patients with CPSP include burning, pinprick hyperalgesia was present in was diagnosed in 66 out of 601 pa- aching, pricking, lacerating, shooting, 57%, cold allodynia in 40%, and brush- tients, corresponding to an incidence squeezing, throbbing, sharp, stabbing, evoked dysesthesia in 51% of patients of 11%.52 CPSP was equally prevalent in painful pins and needles, dull, and with CPSP. males and females. In the majority of cramping.2,7,22,44,55,64 Abnormal pain and tempera- patients, pain developed immediately ture sensation is found in almost (58%) or within the first month after a Clinical Findings all patients with CPSP. The sensory stroke (20%). processing of temperature and pain Sensory function can be examined CPSP can develop after both isch- occurs via the spinothalamic tract and using simple bedside testing, such emic and hemorrhagic vascular lesions the spinotrigeminothalamic projecting as cotton wool for touch, a sharp or anywhere in the somatosensory part of system. Abnormal pain and tempera- pointed stimulus for pain, a metal the CNS,41 but there are some indica- ture sensation is quite common in thermal roller (or any metal object) for tions that the incidence of CPSP may stroke patients without CPSP.2,8,58 For cold sensation, and a soft brush for dy- be higher following lesions in certain this reason, some experts suggest that namic allodynia.23 The area of pain in areas of the brain, including the thala- a lesion of the spinothalamic tracks is patients with CPSP varies in size and mus, the opercular-insular region, and necessary, but not sufficient, to cause distribution.2,9,36,38,44 In some patients the brainstem.6,17,18,35,40,43,48 Given that CPSP. There are further indications only small areas are involved, such as all patients with CPSP have sensory that patients with a partial lesion of parts of the face or one foot. In other abnormalities, it is not surprising that the spinothalamic-thalamocortical patients, the pain affects larger areas patients with sensory abnormalities pathways may be more prone to de- such as one side of the body, an arm have an increased risk of developing velop CPSP compared to patients with or a leg, or one entire half of the body CPSP. Findings of early evoked dyses- complete lesions in these pathways.30 (always contralateral to a hemispheric thesia or evoked pain at stroke onset vascular lesion). The pain is always are also associated with an increased Other Findings located within an area of sensory risk of developing CPSP.38 abnormalities.2,9,44 As in other neuro- There are no universal non-sensory pathic pain conditions, there is often a neurological findings in CPSP.44 The Pain Characteristics combination of “positive” and “nega- clinical non-sensory findings in pa- The time reported from stroke to tive” sensory findings on the sensory tients with CPSP reflect the location pain onset varies. In the majority of examination. Thus, there may be loss and size of the vascular lesion and are patients, pain onset is either immedi- of sensitivity to one sensory modality not correlated to the pain. Choreoath- ate or within the first 1–3 months combined with hypersensitivity to an- etoid movements, which were part of after a stroke.2,25,36,52 The onset of pain other sensory modality, such as loss of the original description of “thalamic is often insidious. sensitivity to heat and hypersensitiv- pain” as described by Dejerine and The symptoms range from bother- ity to touch. Hyperalgesia, dysesthesia, Roussy,13 only rarely occur in patients some dysesthesia to severe pain. The and allodynia are common findings in with CPSP.6,10

PAIN: CLINICAL UPDATES • APRIL 2015 3 Imaging studies have illustrated fact that findings of hypersensitivity is Editorial Board that a lesion anywhere in the somato- common and can precede the develop- sensory pathways, including the ment of CPSP in stroke patients implies Editor-in-Chief thalamus and the thalamocortical that mechanisms involving neuronal Jane C. Ballantyne, MD, FRCA Anesthesiology, Pain Medicine projections (especially to the oper- hyperexcitability, such as central USA cular-insular region)20,30 can cause sensitization or disinhibition, may be Advisory Board CPSP.2,11 PET studies have document- involved.38 Alterations in activity seen Michael J. Cousins, MD, DSC Pain Medicine, Palliative Medicine ed flow changes in the thalamus in on functional imaging and changes in Australia patients with CPSP, both at rest and electric activity as illustrated by neu- Maria Adele Giamberardino, MD with evoked pain.19,51 Neurophysiolog- rophysiological findings suggest that Internal Medicine, Physiology Italy ical recordings with microelectrodes neuroplasticity may also play a role. have measured abnormal spontane- Robert N. Jamison, PhD Psychology, Pain Assessment ous and evoked activity in the thala- Treatment USA mus of patients with CPSP.29,45 More Treatment of CPSP is difficult owing Patricia A. McGrath, PhD recently, MRI with diffusion tensor Psychology, Pediatric Pain to the limited efficacy of the available tractography has illustrated changes Canada drugs and their dose-limiting side in the spinothalamic tracts.30 M.R. Rajagopal, MD effects. Treating CPSP is therefore Pain Medicine, Palliative Medicine a continuous challenge. Only a few India double-blinded, placebo-controlled tri- Maree T. Smith, PhD It is still puzzling why, Pharmacology als have been published on CPSP. These Australia in patients with almost trials are summarized in Table 2.32 Claudia Sommer, MD identical stroke lesions In line with other neuropathic Germany and clinical findings, some pain conditions, CPSP may respond to pregabalin and amitriptyline,15 Harriët M. Wittink, PhD, PT patients develop CPSP and although one negative study has been Physical Therapy others do not. The Netherlands published.34 Lamotrigine may be effec- Publishing tive against ongoing pain and cold- Daniel J. Levin, Publications Director Pathophysiology evoked pain in CPSP,57 but its effect Elizabeth Endres, Consulting Editor The underlying pathophysiology of in other neuropathic pain conditions Timely topics in pain research and treatment have been selected for publication, but the CPSP is not well understood. It is still is inconsistent. Duloxetine relieved information provided and opinions expressed puzzling why, in patients with almost dynamic mechanical and cold allodynia have not involved any verification of the find- ings, conclusions, and opinions by IASP. Thus, identical stroke lesions and clinical in patients with CPSP or spinal cord opinions expressed in Pain: Clinical Updates do not necessarily reflect those of IASP or of the findings, some patients develop CPSP injury,60 but the effect on ongoing pain Officers or Councilors. No responsibility is as- sumed by IASP for any injury and/or damage and others do not. As already men- did not reach statistical significance (P to persons or property as a matter of product liability, negligence, or from any use of any tioned, lesions of the spinothalamic = 0.056). Given the limited evidence for methods, products, instruction, or ideas con- tracts have been implicated in the treatment of CPSP, it seems reasonable tained in the material herein. Because of the rapid advances in the development of CPSP. A structural MRI to try treatments that have efficacy in medical sciences, the publisher recommends independent verification of diagnoses and study of stroke patients with thalamic other central pain conditions or periph- drug dosages. lesions, with and without pain, found eral neuropathic pain conditions, and © Copyright 2014 International Association for the Study of Pain. All rights reserved. a high odds ratio for developing CPSP the results of trials in CPSP do not con-

For permission to reprint or translate in patients with lesions involving the tradict general treatment recommen- this article, contact: ventral posterior nucleus/pulvinar bor- dations for neuropathic pain. Tricyclic International Association for the Study of Pain der zone of the thalamus, an area pre- antidepressants (TCAs), serotonin- 1510 H Street NW, Suite 600, Washington, D.C. 20005-1020, USA viously linked to signaling of pain and norepinephrine reuptake inhibitors Tel: +1-202-524-5300 56 Fax: +1-202-524-5301 temperature. Given that all patients (SNRIs), pregabalin, and Email: [email protected] www.iasp-pain.org have pain within an area of sensory are proposed as first-line treatment, abnormalities, deafferentation is also while tramadol is recommended as thought to play an important role. The second-line and strong opioids as third

4 PAIN: CLINICAL UPDATES • APRIL 2015 Table 2 Oral double-blinded placebo-controlled trials on CPSP Dosage Drop- Drug (mg/day) Outcome No. Patients outs NNT Reference Design Pregabalin 125–600 Positive 40 mixed CP (19 7 4.0 Vranken et al. Parallel, flexible-dose CPSP, 21 SCI) 200859 Lamotrigine 200 Positive 30 CPSP 10 NA Vestergaard et Crossover al. 200157 Amitriptyline 75 Positive 15 CPSP 0 1.7 Leijon et al. Crossover, 3-phase 198944 Carbamazepine 800 Negative 14 CPSP 0 - Leijon et al. Crossover, 3-phase 198944 Levetiracetam 1000–3000 Negative 42 CPSP 9 - Jungehulsing Crossover et al. 201332 Pregabalin 150–600 Negative 219 CPSP 36 - Kim et al. Parallel, flexible-dose 201134 Duloxetine 60–120 Negative 48 mixed CP (13 4 - Vranken et al. Parallel, flexible-dose CPSP, 34 SCI, 1 201160 other) Abbreviations: CP, central pain; CPSP, central poststroke pain; NNT, number needed to treat; SCI, . line-treatment.15 At present there is no spinal cord stimulation (SCS) should usually 300 mg, increasing by 300 mg evidence for combination therapy in generally not be used for CPSP, on every 3–7 days up to a maximum dose CPSP and only limited evidence for its the basis of a single unfavorable case of 2400 mg/day. If gabapentin is not use in other neuropathic pain condi- series. Single sessions of rTMS can give tolerated, pregabalin can be tried with tions. It may, however, be indicated in short-lasting pain relief in patients a starting dose of 25 mg/day. If pain patients with partial relief from taking with CPSP and other pain conditions.3,4 relief is not sufficient, a combination two drugs.21 When deciding on treat- There are some indications that re- of antidepressants and antiepileptics ment, the clinician should keep in mind peated application of rTMS may offer can be tried. Tramadol can be used as potential side effects and contraindica- longer-lasting pain relief.26,32,50 Some an add-on medication.15,16 The most tions, but also concomitant symptoms, patients may benefit from other treat- common side effects of gabapentin and such as depression or sleep disorders, ment possibilities including psycho- pregabalin include sedation, dizziness, that may respond well to certain treat- logical or behavioral therapy, physio- and edema. TCA side effects include ments. Other concomitant nociceptive therapy, or educational programs.46 cardiac, anticholinergic, and sedation pain conditions should be identified In our clinic, we use a person- issues. If necessary, we refer patients and managed as well. alized pharmacological treatment to the pain clinic’s physiotherapist or Nonpharmacological treatment— strategy, taking into account concom- psychologist for individual treatment. including repetitive transcranial mag- itant medication and other diseases netic stimulation (rTMS), deep brain and symptoms, such as depression Future Perspectives stimulation (DBS) and motor cortex or sleep problems, and continuously There is a great need to identify better stimulation (MCS)—has been reported weighing benefits and side effects. treatment regimes. Unfortunately, in case series and brief reports, but We usually start with an antidepres- at present, only a few high-quality there are no controlled trials in this sant (TCA or SNRI), gabapentin, or double-blinded randomized trials have field. In a recent review of interven- pregabalin. The typical starting dose focused on the treatment of CPSP. tional treatment of neuropathic pain, of the TCA is 25 mg at night, increas- In recent years, several animal the authors conclude that owing to ing slowly (especially in the elderly) models mimicking CPSP have been low-quality evidence, recommenda- by 10 mg per week. If the TCA is not developed. We hope they will offer tions for MCS and DBS are “inconclu- tolerated or is contraindicated, an new insight into the pathophysiology sive” in the treatment of CPSP.14 In this SNRI can be used at night instead. of CPSP, enabling the development of review, the authors recommend that The starting dose of gabapentin is mechanism-based treatment trials.

PAIN: CLINICAL UPDATES • APRIL 2015 5 Combination therapy is often used in certain thalamic regions and findings be of interest to study the natural his- clinical practice. Future trials in this of early evoked pain and dysesthesia tory of CPSP in long-term follow-up field should guide us to the best combi- could perhaps identify patients at studies. Such studies could hopefully nations and dosages. higher risk for the development of contribute to our understanding of Looking at several combined pre- CPSP. In these patients, preventive the prognosis and mechanisms be- dictors of CPSP such as localization in trials could be feasible. Also it could hind CPSP.

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