Central Pain: Pain Assoc. Hochiminh City Febr. 19, 2012

Transcription

1 Central Pain: Pain Assoc. Hochiminh City Febr. 19, 2012 Troels Staehelin Jensen, MD, DMSc Dept. of Neurology & Danish Pain Research Center Aarhus University Hospital, Denmark Nicolaus Steno 1659

2 Central pain: Definition and causes CPSP and other types of post stroke pain Spinal cord injury pain Management of central pain

3 Neuropathic Pain: Pain arising as direct consequence of a lesion or disease affecting the somato-sensory system (Neurology 2008) Central Pain Locations: Spinal cord Brainstem Thalamus Cortical/Subcortical

4 Central pain: Characteristics and causes Characteristics Central nervous system lesion Spontaneous and evoked pains Deep and superficial pain Paradox sensation: loss and hyperalgesia Thermal loss obligatory? Thermal hyperalgesia? Spinal Stroke Spinal cord injury myelitis syringomyelia MS cordotomy DREZ lesion Causes Brain Stroke brain injury MS epilepsy syringobulbia Parkinson disease?

5 Central Post Stroke Pain: Thalamic syndrome Slight hemiplegia Sensory disturbance Hemiatxia,hemiastereognosis Intolerable pain Choreo-athetoid movements Dejerine and Roussy 1906

6 Central pain: Definition and causes CPSP and other types of post stroke pain Mechanisms Management of central pain

7 Pain: From static to dynamic Sensory Affective Cognitive Noxious input Modified from Casey 2006 Tracey & Mantyh,2007

8 Central Pain: Pain arising as direct consequence of a lesion or disease affecting the somato-sensory system (Neurology 2008). Musculoskeletal pain Shoulder pain Headache CPSP

9 Central Post Stroke Pain: Thalamic syndrome Slight hemiplegia Sensory disturbance Hemiatxia,hemiastereognosis Intolerable pain Choreo-athetoid movements Dejerine and Roussy 1906

10 Central pain: Characteristics and causes Characteristics Central nervous system lesion Spontaneous and evoked pains Deep and superficial pain Paradox sensation: loss and hyperalgesia Thermal loss obligatory Thermal hyperalgesia Spinal Stroke Spinal cord injury myelitis syringomyelia MS cordotomy DREZ lesion Causes Brain Stroke brain injury MS epilepsy syringobulbia Parkinson disease?

11 Post stroke pain: case 48 yr, F. Sudden left hemiparesis Gaze palsy, L hemiparalysis L. sensory loss DWI lesion in the R. hemisphere Thrombolysis Day 2 large MCI infarction Acute MR DWI CTC Day 1 CTC Day 2

12 Post Stroke Pain: Case 2007: Day 3 after stoke pricking sticking sensation L side Cold allodynia L side 2010 : 3 yrs after stroke Constant pain L. face, arm, trunc Deep burning, pricking pain VAS pain intensity 8 50 C 0 HDT HPT 40 HPT HDT 32 CDT 20 CPT 10 CDT CPT Normal Affected

13 Loss of input disinhibition medial thalamus (Head and Holmes 1911) Central pain: Mechanisms A Lat Thal Med Thal STT Loss of cold input to insuladisinhibition medial thalamus (Craig et al., 2000) B Insula VMpo ACC PB/PAG Med Thal STT Loss of ascending input to thalamus Bursting activity by low Ca spikes (Wang & Thompson 2008). D Thal Lesion STT

14 75 yr old M: Crossed central pain syndrome Age 68: shortlasting vertigo Age 72: L. brainstem infarction L. facial and R. hemibody pain Burning Pain evoked by touch R Pain Sensation

15 75 yr old M: L brainstem infarction Crossed pain syndrome Judgement Burning hot Very Hot Hot Slightly hot Neutral Slightly Cold Cold Very Cold Left Face Right Face Icing Cold Burning hot Temperatur ( C) Judgement Very hot Hot Slightly hot Neutral Slightly Cold Cold Very Cold Right arm Left arm Pain Sensation Icing Cold Temperatur ( C)

16 Central Post Stroke Pain: Sensory abnormality in pts with and without pain Touch No Pain (N=71) Pain (N=16) Normal 5 (7%) 2(13%) ns Decreased p 65(92%) 12(75%) ns Increased 1 (1%) 1(16%) ns Allodynia 0 9(56%) <0.001 Dysesthesia 0 8(50%) <0.001 Allodynia or dysesthesia 0 12(75%) <0.001 Not ratable 0 1(6%) <0.05 Andersen et al. 1995

17 Central Post Stroke Pain: Cold Allodynia Temp. 20 C No Pain (N=71) Pain (N=16) Normal 28(39%) 1(6%) ns Decreased 37(52%) 8(50%) ns Increased 6(8%) 7(44%) <0.001 Allodynia 0 9(56%) <0.001 Dysesthesia 2(3%) 12(75%) <0.001 Allodynia or 2(3%) 14(88%) <0.001 dysesthesia Not ratable 0 0 ns p Andersen et al. 1995

18 Stroke Pain: Distribution of Pain and sensory abnormality corresponds to brain territory destroyed by lesion Vestergaard Vestergaard et al et al. 1995

19 Post Stroke Pain Resting CBF : reduced thalamic activity contralateral to pain Loss of input: loss of sensation and paradox hypersensitivity L R TS Jensen et al. unpublished obs

20 Post Stroke Pain: Observation and implication Pain within area of sensory abnormality Thalamus Anterior Pain area: Fraction of sensory loss Reticular N Sensory loss and hypersensitivity. Loss of input Signs of neuronal hyperexcitability Medial Lateral

21 Central pain: Definition and causes CPSP and other types of post stroke pain Spinal cord injury pain Management of central pain

22 CPSP Study Andersen et al MacGowan et al Bowsher et al Weimar et al Widar et al Glader et al Kong et al Jönsson et al N with stroke Total with Pain Follow- up N with CPSP (%) mths 16 (8%) 63 with LMI - 60 mths 16 (25%) 72 (Q to 1071 pts) - 8(11%) mths 11 (9.2%) 616 ( 356 included) mths 15 (4%) % 24 mths Not specified mths 13 (12%) mths 4 (1%)* Klit et al (unpubl obs) 1405 (956) 205 (all types) 24 mths 9.5% (def,) 7.2% (def,+ prob,) 4.6% (dysest) * If the investigator suspected CPSP the patient was referred to a neurologist who diagnosed CPSP according to established criteria

23 Post stroke pain Central Pain = Pain caused by lesion or disease in the central nervous system (IASP,1994) Problems: No precise criteria for delineating other pain conditions from CPSP Unrelated pain Shoulder pain Musculoskeletal Pain CPSP Headache Other causes Spasticity Klit et al Lancet Neurology

24 2 nd Pain case A 65-year-old woman admitted with acute onset of paralysis of left arm and leg. CT scan: bleeding in the right thalamus and ventricles. Development of hydrocephalus treated with ventriculoperitoneal shunt. Few weeks after the stroke, onset of pain and more spasticity in the left side of the body. What is the pain problem?

25 4 th Pain case 4 years after stroke : 1. The patient is wheelchair bound 2. Spastic paralysis left side 3. Reduced movement of left shoulder 4. Shoulder movement provokes pain Pain description 1. Shoulder pain 2. Sharp cutting pain in left arm, hand (NRS 6) and leg (NRS 9); cold allodynia 3. Painful spasms and spasticity in left leg Can we get further information about pain?

26 PSP: Sensory findings 4 yrs after stroke touch cold warm brush pain Reduced sensibility to light touch on the left, areas of touch evoked allodynia. Reduced sensibility to pinprick and paradox pinprick hyperalgesia. Brush evoked allodynia left arm and leg. Brushing induces painful spasms in the left foot. Cold and warm sensory loss and cold allodynia.

27 PSP: Sensory loss on affected side 50 C 0 HDT HPT (no pain) 40 HPT HDT CDT CPT CDT CPT 10 Normal Affected

28 Central Post Stroke Pain (CPSP): Pain arising as direct consequence of a stroke affecting the somato-sensory system. Musculoskeletal pain Shoulder pain CPSP Headache Spasticity

29 Stroke::The National Indicator Project (NIP) Stroke patients in Denmark registered in a NIP database In Aarhus County ( inh) 1405 stroke patients in a 12 months period (March 2004 Febr. 2005, (> 95% of patients) Questionnaire sent to 956 pts. and 956 controls chronic pain (>3 months) developed at or after stroke onset (CPSP, headache, other pain and spasticity). Aarhus County Prevalence of CPSP: 9.5% central pain /dysesthesia following stroke 7.2% definite or probable central post stroke pain 4.6% definite central post stroke pain Klit et al. Pain, 2011

30 CPSP Study N with stroke Total with Pain Follow- up N with CPSP (%) Andersen et al MacGowan et al mths 16 (8%) 63 with LMI - 60 mths 16 (25%) Bowsher et al (Q to 1071 pts) - 8(11%) Weimar et al mths 11 (9.2%) Widar et al ( 356 included) mths 15 (4%) Glader et al Kong et al Jönsson et al % 24 mths Not specified mths 13 (12%) mths 4 (1%)* Klit et al (956) 205 (all types) 24 mths 7.2% * If the investigator suspected CPSP the patient was referred to a neurologist who diagnosed CPSP according to established criteria

31 CPS P Pain in area of sensory abnormality Pain area: Fraction of sensory loss Sensory loss and hypersensitivity. Loss of input to thalamus Pain in corresponding body territory Sensory loss Pain Anterior Medial Lateral Reticular N stroke

32 Conclusion: Assessment of chronic Pain History: Listen and ask rel. Questions Examination: General and specific Tests: biochemical and imaging Diagnosis and management

33 Stroke::The National Indicator Project (NIP) Stroke patients in Denmark registered in a NIP database In Aarhus County ( inh) 1405 stroke patients in a 12 months period (March 2004 Febr. 2005, (> 95% of patients) Questionnaire sent to 956 pts. and 956 controls chronic pain (>3 months) developed at or after stroke onset (CPSP, headache, other pain and spasticity). Aarhus County

34 Stroke and Pain: Retrospective NIP study Definitions and classifications : Chronic pain = constant or remitting pain > 3 months Key questions: Have you developed spasticity or spasms after your stroke? Have you developed chronic pain after your stroke? chronic headache shoulder pain other joint pain pain because of spasticity or spasms other pain : i.e. not caused by one of the above altered sensation = reduced or changed sensation in an area of the body? If yes: unpleasantness or pain in the area hypersensitivity to touch or cold or warmth in the area Klit et al unpubl obs

35 Central Post stroke pain: CPSP (Crit: 1-4) N=5 8 Klit et al unpubl obs

36 Epidemiology of CPSP 608 stroke patients Clinical examination of 65 patients: Definite CPSP Probable CPSP CPSP-like dysaesthesia Not CPSP 43 % 22 % 24 % 11 % Prevalence of CPSP: 9.5% central pain /dysesthesia following stroke 7.2% definite or probable central post stroke pain 4.6% definite central post stroke pain

37 Central pain: Definition and causes CPSP and other types of post stroke pain Spinal cord injury pain Management of central pain

38 Spinal cord injury pain: Mechanisms unclear Neuropathic pain at level Neuropathic pain below level Musculoskeletal pain Visceral pain Task force on SCI Pain: Yezierski et al Finnerup et al. Unpubl. observations

39 Pain Localisation after spinal lesion Sensory disturbance after spinal lesion Finnerup et al. 2003

40 SCI: Sensory function Dorsal column Postion, vibration Brush allodynia Pinprick hyperalgesia Spinothalamic tract Touch, pinprick, temperature Cold allodynia Cold allodynia

41 Spontaneous pain and sensory hypersensitivity Evoked pain more common in patients with spontaneous pain and in painful areas (Eide et al. 1996; Defrin et al. 2001; Finnerup et al. 2003; Ducreux et al. 2006) Number of patients ** ** ** p < 0.05 SCI-pain SCI-nopain Sensory hypersentivity at level in SCI patients with below level pain 0 History of Evoked pain Evoked pain allodynia or dysesthesia or dysesthesia below level at level (Finnerup et al. Brain 2003;126:57-70)

42 SCI: Extent of lesion on axial MRI Rostral to maximal lesion 100 * ** Pain free patients Pain patients Percentage lesion Total Grey matter Dorsolateral column Anterolateral column Dorsal column ** p < Percentage of rostral grey matter lesion highest in pain patients (Finnerup et al. Neurology 2003;61:

43 Spinal cord injury pain: Conclusion Spinal lesion Spinal lesion pain: Deafferentation Spinothalamic loss necessary Spinothalamic loss not sufficient Hyperexcitability at injury level Grey matter loss above injury level Spinal cord STT neurons STT Propriospinal system

44 Central pain: Definition and causes CPSP and other types of post stroke pain Spinal cord injury pain Management of central pain

45 Central Pain Management : Mechanisms of drugs Mechanisms Disinhibition (GABA, opioid, noradrenaline, serotonin) Hyperexcitability (NMDA-receptors, ionchannels) Pharmacological actions of drugs Lidocaine Non-specific sodium channel blockade Mexiletine Non-specific sodium channel blockade Oxcarbazepine Non-specific sodium channel blockade Lamotrigine Specific sodium channel blockade Gabapentin Binding to 2 -subunit calcium channel Pregabalin Binding to 2 -subunit calcium channel Valproic acid GABAergic, sodium channel blockade Dextromethorphan NMDA-antagonist Amitriptyline Duloxetine NA and 5-HT reuptake inhibitor Morphine -opioid receptor agonist Cannabinoids Cannabinoid receptor interaction NA and 5-HT reuptake inhibitor NMDA-antagonist, Na block

46 Controlled Clinical Trials: Post stroke pain Mechanis m of action Drug Dose Study Design N Result NNT (95% CI) Na + Channel blocker CBZ 800 mg Leijon and Boivie 1989 Cross-over 15 Cbz= pla 3.4 (2-105) 5-HT and NA reuptake inhibitor Amitriptyli ne 75 Leijon and Boivie 1989 Cross-over 15 Ami> Pl 1.7 (1-3) Na + Channel Blocker glutamate inhibitor Lamotrigin e > 200 mg Vestergaard et al Cross- over 30 Ltg>pla NA 2 binding Ca ++ channel Pregabalin mg Vranken et al Parallel 19 Preg > Pl 3.3 (2-15)

47 Controlled Clinical Trials: Spinal cord injury pain Mechanis m of action Drug Dose Study Design N Result NNT (95% CI) 5-HT and NA reuptake inhibitor? Trazodone 150 mg Davidoff et al Parrallel 18 Traz = Pl NS GABA agonist Valproat mg Drewes et al Cross- over 20 Val=Pla 10(3- ) Na + Channel blocker Mexilitin 450 mg Chiou-Tan et al Cross-over 11 Mex 0 Pl NA 5-HT and NA reuptake inhibitor Amitriptyline 50 mg Cardenas et al Parallel 84 Ami = Pl NA Na + Channel blocker Lamotrigine mg Finnerup et al Cross- over 22 Ltg=Pla

48 2 binding agents: Spinal cord injury pain Mechanis m of action Drug Dose Study Design N Result NNT (95% CI) 2 binding Ca ++ channel Gabapentin < 1800 mg Tai et al Cross- over 7 Gab=pla 2 binding Ca ++ channel Gabapentin 3600 mg Levendoglu et al Cross-over 20 Gab> Pl NA 2 binding Ca ++ channel Pregabalin 450 mg Siddall et al Parallel 137 Preg > Pl 7.0 (3,9-37) 2 binding Ca ++ channel Pregabalin 450 mg Vranken et al Parallel 21 Preg > Pl 3.3 (2-15)

49 Treatment Algorithm: Neuropathic Pain Peripheral neuropathic pain Central neuropathic pain yes PHN no Lidocaine patch 5% Lamotr/TCA CPSP Pregabalin SCI Gabapentin SCI Gabapentin pregabalin TCA SNRI TCA, Tramadol, opioids, cannabinoid combination therapy Tramadol, opioids, combination therapy Finnerup et al. 2005, 2009 TSJ

50 Conclusion: Central pain Central pain is common. Pathophysiology largely unknown Neuronal hyperexcitability likely involved. Pharmacological modulation with antihyperexcitable compounds.