Management of neuropathic pain in cancer EAPC Congress Glasgow

Transcription

1 Management of neuropathic pain in cancer EAPC Congress Glasgow Troels Staehelin Jensen, MD, DMSc Dept. of Neurology & Danish Pain Research Center Aarhus University Hospital, Denmark

2 Pain classification Time: Acute pain Chronic pain Pathology: Malignant Non-malignant Tissue: Nerve Viscera Bone Skin Localization: Superficial Deep Pathophysiology: Inflammation Neuropathic Idiopatic Topography Extremity Thoracic Spinal Head etc

3 Neuropathic Pain = Pain initiated or caused by a primary lesion, dysfunction or transitory perturbation of the peripheral or central nervous system (IASP, 1994) Neuropathic Pain Inflammatory Pain Neuropathic Pain Mixed Pain Inflammatory Pain Idiopathic pain Idiopathic pain Neuropathic Pain = Pain arising as a direct consequence of a lesion or disease affecting the somatosensory system (Treede et al. Neurology 2008).

4 Neuropathic pain: Diagnostic categories Peripheral Spinal Brain Post surgery Spinal injury Stroke Nerve injury MS MS Plexus avulsions Neoplasm Neoplasm Amputation Arachnoiditis Epilepsy Compres. syndr Syrinx Syrinx Herpes zoster Trig. Neuralgia Neoplasm Neuropathies

5 Neuropathic Pain: Pain arising as a direct consequence of a lesion or disease affecting the somatosensory system (Treede et al. Neurology 2008) Clinical characteristics: Spontaneous and provoked pain Lesion of somatosensory systems Specific sensory pattern Spread of pain to other tissues Spread of pain outside injured area Hyperalgesia/allodynia Aftersensations Function Aetiology Mechanisms: Pain intensity NeP Pain mechanisms Injury Mood Sleep Mechanisms Side effects

6 Neuropathic pain: not one disease Impact for management PHN Neuropathy Trigeminal neuralgia Spinal stenosis CPSP

7 Neuropathic pain proposal Impact for treatment Possible NeP Probable NeP Definite NeP Treede, Jensen, Campbell, Cruccu, Dostrovsky, Griffin, Hansson, Hughes, Nurmikko, Serra Neurology (2008)

8 Neuropathic Pain: Gold standard? NP a syndrome characterised by set of symptoms and signs NP not a single disease; multiple mechanisms involved Manifestations dictated by mechanisms and disease No simple relation between symptoms and mechanisms Questionnaires of some use but not ideal ID PAIN DN4 for Patient PAIN DETECT LANSS for Patient DN4 for Physician LANSS for Physician Question Number Question Sensitivity / Specificity 0.73/ / / / / /0.87 Validated Yes, incl. Mix Pain patients Not Mix patients Yes, incl Mix Pain patients yes Yes, Yes, Intended use Patient administered Patient administered Patient administered Patient administered Physician administere d Physician administere d

9 Neuropathic pain: management goal Treat cause High proportion of patients obtain pain relief Relevant pain relief Sustained pain relief Improvement in QoL Improvement in mood and sleep Few and mild side effects Low cost These goals apply to all types of pain Pain intensity Mood Function Target areas Sleep Cause Mechanis ms Pain generator Side effects

10 Causes of Pain: Cancer Cancer-related Bone Nerve compression/ infiltration Soft tissue infiltration Visceral Muscle spasm Lymphoedema Raised intracranial pressure Treatment related Surgery: postoperative scars /adhesions Radiotherapy: burns/ fibrosis Chemotherapy: neuropathy Associated with cancer/ debility Constipation Pressure sores Bladder spasms Stiff joints Post-herpetic neuralgia Unrelated to cancer Arthritis Angina Trauma Prior pain conditions

11 Caveats in neuropathic cancer pain Cancer is a multi-system disorder 30% of patients with cancer pain have pain at 4 or more sites Different pains may have different causes, symptoms and mechanisms Neuropathic pain component in cancer pain unknown : 40-50%? Mechanism 1 Mechanism 2 Mechanism 3 Symptom (Allodynia) Symptom 1 Symptom 2 Symptom 3 Mechanism 1 Mechanism 2 Patients report symptoms not mechanisms One symptom cause by multiple mechanisms One mechanism may give rise to several symptoms Symptoms but not mechanisms can be measured Mechanism (C-nociceptor) Mechanism 3 Symptom 1 Symptom 1 Symptom 1

12 Why is it difficult to do a NP trial in cancer? NP criteria symptoms? signs? symptoms and signs? other examinations? Heterogeneity in NP cancer trials Different criteria for NP Different etiologies of cancer Different stages of cancer Comorbidities Different etiologies of NP Cured vs non-cured cancer Neurotoxic treatments Mixed vs. only NP pains Add-on vs. single treatments Change over time Ethical issues

13 Gabapentin in Neuropathic cancer pain Pl contr dbl study of gabapentin vs placebo Diseases: breast colon, lung, sarcoma other Concomitant medic : opioids, TCA, NSAID Active cancer 10 day treatment trial Endpoints: 1 Pain intensity NP pain requirement: 1.Pain due to inflitr /compr. of nerve, 2.Burnin,g shooting pain, dystesthesia allodynia 3.Documentation probability of reaching pain control (33% pain intensity difference) over 10-day follow-up Caraceni et al. 2002

14 Chemotherapy induced NP Kautio et al 2008 Pl contr dbl study of amitriptylin vs placebo Diseases: breast colon, lymphoma, other Chemo: vinca, platins, taxanes > 4 wk treatment trial Endpoints: 1 NP score. Tingling, numbness pain 2. Global imptovement (0=-10) 3. QoL

15 Management of neuropathic pain reduce sensitization Treatment Principles Reduce peripheral sensitisation Reduce activity in DRG Reduce ectopic activity Decrease central sensitisation Reduce central facilitation Increase central inhibition Pharmacological treatment Stimulation therapy TNS Spinal cord stimulation Deep brain stimulation Motor cortex stimulation Surgical interventions Decompression Sympathectomy Denervation Dorsal root entry zone lesions Chordotomy, radiofrequency lesions etc Psychological / other treatments Cognitive behavioural therapy Hypnosis etc Physiotherapy Educational programmes Other

16 Neuropathic Pain: Pharmacology Antidepressants Tricyclic antidepressants SSRI SNRI Anticonvulsants Gabapentin Pregabalin Valproic acid Topiramate Carbamazepine Oxcarbazepine Phenytoine Lamotrigine Opioids Morphine Oxycodone Tramadol NMDA antagonists Memantine Amantadine Dextromethorphan Cannabinoids Topicals Lidocaine Capsaicin Other Levetiracetam Botulinum toxin

17 Antidepressants: Modulation by TCA TCA blocks: 5 HT; NA transporters NMDA receptors Pre synaptic neuron Descending control Na+ channels Cholinergic receptors α adrenergic receptors Ca++ channels Ca ++ adr. stim. opioid receptors Opioid NMDA NK1 5 HT adr DA Post synaptic neuron

18 Anticonvulsants: Modulation by Ca 2+ channel binding 1. N type Ca 2+ channel antagonist reduces hypersensitivity 2. α 2 δ 1 subunits upregulated in DRG and central terminals in NeP Pre synaptic neuron Ca α 2 δ binding agents reduce NeP AMPA NK1 NMDA Post synaptic neuron

19 Anticonvulsants: Modulation by Na + blockers 1. At least 10 different voltage gated Na + channels 2. TTX R Na + channels expressed by small fibres 3. Nav1.3 and Nav1.7 upregulated; Nav1.8 and Nav1.9 downregulated in some NeP TRPV1 Nav1.7 Nav1.9 Nav1.3 Nav1.8

20 Opioid Analgesics: Modulation by opioids 1. Opioid receptors expressed on: primary afferents, central terminals, post synaptic neurons 2. Loss of pre synaptic opioid receptors in NeP Pre synaptic neuron Descending control 3. CCK expression increased in spinal cord after nerve injury Opioid interneuron Ca ++ 2 Opioid Opioid NK1 Opioid Post synaptic neuron

21 Neuropathic Pain: Guide to decision making Neuropathic pain management Neuropathic pain syndrome New classification: a guide? Goal for management Outcome parameter? Simple and complex patient Types of treatments? Evidence and safety Should we combine? Algorithms R. Cajal

22 1966 April 2005: 18 th Jan 2010: Increase: 105 RCTs 168 RCTs 60% 59 (56%) cross over 79 (47%) cross over 34% 46 (44%) parallel 89 (53%) parallel 93%

23 Number Needed to Treat: NNT Number Needed to Harm: NNH 1 NNT = (NPT act /TOT act ) (NPT plac /TOT plac ) Patients achieving endpoint (%) Active 40 Placebo 20 NNT NNT Endpoint (Pain relief %) 10 5 NNT NNT: number of patients needed to treat with drug before one safety event occurs: 1. drop out due to side effect 2. specific other events 3. any event NNH : 1/( ERactive ERplacebo)

24 Summary: NeP treatment evidence 2005 TCAs Opioids Gabapentin/pregabalin SNRIs Tramadol Capsaicin SSRIs Topical lidocaine NA Cannabinoids NNT Finnerup et al. 2005

25 Summary: NeP treatment evidence 2010 BTX A TCAs Opioids Gabapentin/pregabalin SNRIs Tramadol Capsaicin SSRIs Topical lidocaine NGX capsaicin Cannabinoids NNT Finnerup et al. In review

26 Summary: NeP treatment evidence 2010 BTX A TCAs Opioids Gabapentin/pregabalin SNRIs Tramadol Capsaicin SSRIs Topical lidocaine NA NGX capsaicin Cannabinoids NNT Finnerup et al. In review

27 NeP management: Side effects and contraindications Gabapentin Pregabalin Carbamazepine Oxcarbazepine TCA SNRI Side effects Sedation Ataxia Dizziness Mental change Memory problem Headache Weight gain Oedema Flatulence Sedation Ataxia Dizziness Mental change Memory problem Headache Weight gain Oedema Hyponatraemia Sedation Dizziness Mental change Weight gain Dry mouth Hypotension Sweating Palpitations Constipation Blurred vision Sedation Dizziness Mental change Nausea Weight loss Hypertension Sweating Diarrhoea Contraindications None? AV-block Porphyria MAO inhibitors AV-block Cardiac insufficiency Recent MI MAO inhibitors Liver function Kidney function MAO inhibitors

28 Number Needed to Treat: NNT Number Needed to Harm: NNH Patients achieving endpoint (%) 1 NNT = (NPT act /TOT act ) (NPT plac /TOT plac ) 80 NNT Active NNT 10 Placebo Endpoint (Pain relief %) NNT: number of patients needed to treat with drug before one safety event occurs: 1. drop out due to side effect 2. specific other events 3. any event NNH : 1/( ERactive ERplacebo)

29 Painful polyneuropathy NNH TCA Oxycodone Tramadol Pregabalin SNRI Oxcarbacepine Memantine SSRI Topiramate n = 634 n = 1582 n = 1348 n = 477 n = 251 n = 523 n = 1139 n = 244 n = NNH (drop out due to side effect) Finnerup et al. Unpubl obs

30 Painful polyneuropathy: NNT > 50% pain relief Oxycodone Tramadol Pregabalin SNRI Oxcarbazep Memantine SSRI Topiramate Dextrometh TCA n = 249 n = 36 n = 161 n = 1160 n = 911 n = 146 n = 242 n = 81 n = 317 n = Finnerup et al. Unpubl obs

31 Thanks to all collaborators at DPRC: Birgitte Brandsborg, Erisela Querama, Lene Vase, Lone Nikolajsen, Anders D Kristensen, Hanne Gottrup, Nanna Finnerup, Cathrine Baastrup, Henriette Klit, Lise Gormsen, Astrid Terkelsen, Annette T. Møller, Helle O. Andersen, Camilla Maersk Møller, Anne Hansen, Lene Christensen, Casper Skau Madsen, Kaare Brinck, Paal Karlsson

32 Lanss Pain Scale