Overview of Neuropathic pain

Transcription

1 Overview of Neuropathic pain Kongkiat Kulkantrakorn,M.D. Neurology division Thammasat University 1

2 Contents Overview of pain New concepts and mechanism Treatment options New data in management 2

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4 Breaking the vicious cycle Can we make patients pain free? Without side effects Chronic toxicities Cost? Can we keep them pain free? Disease progression Pharmacological tolerance 4

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6 Nociception Recognition that local phenomena may affect nociception Facilitating/sensitization of nociceptors by a variety of local mediators PGs, CCK, CGP, Substance P, monoamines, bradykinins Local phenomena may also act to spontaneously create signals of nociception 6

7 Clinical relevance Neurophysiology Pain progress over time, both intensity and location Development of de novo pain outside normal boundaries Central hypealgesia 7

8 Pharmacology Around the clock dosing vs PRN dosing Development of new drugs, preparation COX-2 2 inhibitors Tramadol Long acting opioids Opioid receptors Pharmacogenomics Variable responses 8

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11 Balanced analgesia Targeted pharmacotherapy to affect multiple points in the pain signaling pathway Analgesics Opioids NSAIDS, COX-2 Inh. Adjuvants 11

12 Addiction? Addiction Chronic neurobiology Impaired Control over use Compulsive use Continued use despite harm Craving Physical dependence Specific withdrawal syndrome for each drug Tolerance Adaptation: diminution of drug effect over time 12

13 Features suggestive of neuropathic pain Pain in the absence of ongoing tissue damage Pain in an area of sensory loss Paroxysmal or spontaneous pain Allodynia Hyperalgesia Dysaesthesia Hyperpathia Different characteristic of pain (vs nociception): burning, pulsing, stabbing pain Tinel s s sign Sometimes a delay in onset of pain after nerve injury Poor response (not unresponsiveness) to opioids Presence of a major neurological deficit Acute Pain Management: Scientific Evidence. NHMRC

14 Clinical approach 1. Diagnosis of neuropathic pain, differentiate from other types of pain Is this pain neuropathic? 2. Etiologic diagnosis and work up 3. Assessment of pain and patient 4. Selection of treatment modalities 14

15 Spinal neurones project to sensory & affective areas AFFECTIVE Amygdala hypothalamus SENSORY Somatosensory cortex Painful stimulus NK1 receptor PB PAG RVM Thalamus Superficial Lamina I Descending influences C-fibre Deep Substance P glutamate Lamina V 15 Aug, 05 Spinal Cord KKU 15

16 Tissue damage Hyperalgesia Spontaneous pain Allodynia PERIPHERAL ACTIVITY CENTRAL SENSITIZATION Nerve damage Decreased threshold to peripheral stimuli Expansion of receptive field Increased spontaneous activity 16

17 Receptive Field Noninjured nerve Primary afferent C-fiber Ca 2+ Ca 2+ Superficial dorsal horn Increased activity via existing N-type VDCCs Increased pain Ca 2+ injured nerve ectopic discharges Increased NMDA etc. To Brain N-type VDCC P-type VDCC T-type VDCC NMDA-R ( & EAA-Rs) Deep dorsal horn convergent neuron Glutamate (& EAA neurotransmitters) 17

18 Mechanisms: Neuropathic Pain Peripheral changes in channels Na, K, Ca Ectopic activity, ephaptic, sympathetic nerves Increased NT release from intact fibers Increased NMDA activity centrally Changes in opioid, monoamine systems? 18

19 Treatment options Analgesic medication Adjuvant medications Anesthetic and neurosurgical techniques Physical therapy Psychological / behavioral therapy Topical therapy 19

20 Pharmacological therapy Patient needs to know what to expect! Neuropathic pain does not generally respond to primary analgesics (Opioid or NSAIDS) Usually require medication in adjuvant group Anticonvulsants Antidepressants Antispasm drugs Neuroleptics Steroids, etc. 20

21 Carbamazepine Na Channel blocker Indication Approved for Trigeminal neuralgia Lancinating pain, paresthesia, dyesthesia NNT: , NNH: 3.4 Side effect: dizziness, diplopia,, nausea Enzyme inducing effect 21

22 Newly Available Drugs Felbamate Gabapentin Lamotrigine Levetiracetam Oxcarbazepine Topiramate Tiagabaine Vigabatrin Zonisamide Felbatol Neurontin Lamictal Keppra Trileptal Topamax Gabatril Sabril Zonegran 22

23 Glutamate-Mediated Transmission Adapted from Upton N. Trends Pharmacol Sci. 1994;15:

24 GABA-Mediated Transmission Adapted from Upton N. Trends Pharmacol Sci. 1994;15: McNamara JO. In: Goodman & Gilman s. 9th ed. 1996:466 Ostergaard LH, et al. In: Antiepileptic Drugs. 4th ed. 1995:

25 Gabapentin Increase endogenous GABA, Ca channel modulation Usage: allodynia, burning pain, paresthesia, sleep Postherpetic neuralgia Diabetic polyneuropathy Others: mixed neuropathic pain syndrome, migraine Almost no drug interaction, no metabolism Side effect: sedation, ataxia, dizziness, edema 25

26 Oxcarbazepine Na channel blocker, reduce glutamate and modulate Ca channel function No need for hepatic or hematologic monitoring Less side effect due to lack of epoxide formation Similar efficacy, may substitute carbamazepine Minimal enzyme inducing effect Usage: trigeminal neuralgia, radiculopathy, failed other AEDs,, diabetic neuropathy 26

27 Topiramate Monosaccharide derivative with sulfamate functionality, multiple mechanisms of action FDA Approved for migraine prophylaxis at mg/d Off-label use for pain, bipolar, etc. Limited data in neuropathic pain Side effect: sedation, wt. loss, renal calculi, anhidrosis,, myopia 27

28 Others Clonazepam Painful muscle spasm, sleep disorder New AEDs Levatiracetam Pregabalin 28

29 Mechanisms of AED action Functional blockade of Na channel Prolong refractory phase of neuronal firing Phenytoin, carbamazepine Enhancement of GABAergic transmission Interfere with GABA receptor function Phenobarbital, benzodiazepine Reduce GABA metabolism, promote release Valproate, gabapentin, vigabatrin Inhibition of glutamatergic transmission Lamotrigine, topiramate, pregabalin 29

30 Common AED in neuropathic pain usage AED Dose (mg/d) Timing Carbamazepine Oxcarbazepine Phenytoin Gabapentin Topiramate Valproic acid Lamotrigine Bid-qid Bid Od Bid-qid Bid Bid-tid Bid 30

31 Antidepressant TCA SSRI/SNRI, new agents Block reuptake of NE/5- HT NMDA, ion channel blocker Effective for both steady and lancinating pains TCA: 10 studies: 300pt, NNT=2.6 Sindrup, S.H., Jensen, T.S., Antidepressants in the treatment of neuropathic pain. In: Neuropathic Pain: Pathophysiology andtreatment. IASP PRESS, pp Bomholt SF, et al. Neuropharmacology. 2005;48: Sindrup SH, et al. Basic Clin Pharmacol Toxicol 2005;96: SSRI: : varied among agents, Too specific for NT NNT: 7 SNRI, atypical agent Dual inhibition May be better NNT: 4-54 Duloxetine Venlafaxine 31

32 Opioid and NeP Oxycodone in PHN, DM polyneuropathy Combination of Gabapentin and Levorphanol leads to reducing dosage of each drug and minimize side effect Foley KM. NEJM 2003:348: Gilron I, et al. NEJM 2005; 352:

33 FDA-approved treatment for Carbamazepine Trigeminal neuralgia Duloxetine neuropathic pain Painful diabetic neuropathy Lidocaine patch 5% Postherpetic neuralgia Gabapentin Postherpetic neuralgia Pregabalin Postherpetic neuralgia 33

34 What is not working for NeP? SSRI NSAIDS COX-2 2 inhibitors Recent withdrawal of Vioxx and Bextra CVS side effect Effective for only inflammatory pain Not effective for neuropathic pain 34

35 Comparative efficacy 35

36 Nerve injury Mechanism of neuropathic pain: central sensitization Afferent fibers Ectopic discharge Neuroplasticity Spinal cord C fiber A-beta fiber Central sensitization Ectopic discharge Phenotypical changes Alteration of modulatory systems Woolf & Mannion, Lancet 1999 Attal & Bouhassira, Acta Neurol Scand

37 Major putative drug targets in neuropathic pain BRAIN Descending inhibition Norepinephrine / serotonin (TCAs, SSRIs, SNRIs) Opiate receptors Opiates/Tramadol Peripheral sensitization PNS Na + channel (CBZ,OXC,PHT,TPM,LTG, LIDOCAINE,MEXILETINE) TCAs SPINAL CORD Central sensitization Ca 2+ channel (GBP,LVT,OXC,LTG) NMDA antagonists Ketamine, Memantine, Dextromethorphan PNS, peripheral nervous system; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant 37

38 Pre-emptive emptive analgesia in NeP Gabapentin 900 mg vs Placebo in acute zoster pain (single dose study) 1 Reduce incidence of PHN after daily Amitryptyline during acute zoster 2 Prevent central sensitization during acute phase Berry JD, Petersen KL. Neurology 2005;65:444-7 Bowsher D. J Pain Symptom Manage 1997;13:

39 Pharmacological therapy Most are chronic pain and need long term data from clinical trial Adjuvants: : both central and peripheral effects Consider individuallized therapy for co-morbidity morbidity Aware of individual difference for pharmacodynamics and pharmacokinetics profile How to best measure the success of therapeutic trial, depends on clinical questions and pain situation (quality of life) 39

40 Pharmacological therapy Use medication that targets the pharmacologic mechanism, balancing with side effects Start at low dose and slowly increase to effect, side effect or maximum safe-dosage Maintain maximum tolerated dose for at least several weeks to ensure adequate trial Try other drugs in that category, then another group, or combination (add new tx one at a time) 40

41 Treatment algorithm 41

42 Universal precaution in pain medicine 1. Diagnosis with appropriate differential dx 2. Psychological assessment including risk 3. Informed consent (written vs verbal) 4. Treatment agreement 5. Pre/Post intervention assessment of pain level and function 42

43 Universal precaution in pain medicine 6. Appropriate trial of opioid therapy +/- adjuvants 7. Reassessment of pain score and level of function 8. Regularly assess four A s A s of pain medicine Analgesia, Activity, Adverse reaction, Aberrant behaviour 9. Periodic review of pain diagnosis, co-morbid conditions and addictive disorder 10. Documentation 43

44 To take home Neuropathic pain is common and treatable Careful clinical assessment is the key History, neurological exam, diagnostic test From signs and symptoms to treatment Current treatment and understanding will facilitate clinician to improve patient s s care 44