THE CLINICAL USE OF NEURONTIN 署立台南醫院神經內科黃英哲

Transcription

1 THE CLINICAL USE OF NEURONTIN 署立台南醫院神經內科黃英哲

2 Usual clinical use in Neuropathic pain( 神經痛 ): Post-herpetic neuralgia(phn), Diabetic neuropathy, Trigeminal neuralgia, Postsurgery pain, Phantom limb pain, Carpal tunnel syndrome Epilepsy( 癲癇 ): refractory partial or generalized seizures (add-on or second-line therapy) Migraine

3 Acute pain Nociceptive( 感受傷害的 ) in nature, and secondary to chemical, mechanical and thermal stimulation of Aδ and C polymodal pain receptors ( by histamine, bradykinin, substance P and etc ) Self limiting and serves a protective biological function by acting as a warning of on going tissue damage Usually responds to opioids and NSAIDS

4 Chronic pain No protective biological function, but being the symptom of a disease process. Not self limiting, and can persist for years after the initial injury Predominately neuropathic in nature, and involves damage either to the peripheral or central nervous systems.

5 A-delta and C Fibers Fast pain & touch/pressure A-delta fibers: thick, small myelinated rapid transmission Slow pain & touch/pressure/ther mal C fibers: thinner, small unmyelinated slower transmission Aβ: large myelinated, for touch/pressure

6 If no stimulus large & small nerve ff are quiet (gate is closed) If non-painful stimulus large nerve ff are activated, and also inhibitory interneurons are activated no pain (gate is closed) If painful stimulus small nerve ff are activated, but inhibitory interneurons are blocked pain (gate is opened) Gate control theory of pain by Patrick Wall & Ronald Melzack in 1965

7 What is Neuropathic pain? A complex, chronic pain state usually accompanied by tissue injuries. The nerve fibers themselves may be damaged, dysfunctional or injured, and send incorrect signals to pain centers. Described as: shooting, lancinating( 撕裂 ), electric shock-like, tingling and burning pain, or numbness

8 History of treating neuropathic pain The 1 st case report in 1942: using phenytoin to cure facial neuralgia A case report in 1962: using CBZ to treat trigeminal neuralgia and painful diabetic neuropathy TCA's have been successfully used for 25 years Recent reports: new AEDs, like Gabapentin(Neurontin), Lamotrigine, Topiramate, Pregabalin and etc.

9 Some considerations CBZ: cheap and have some evidences (maybe block Na channels), but its side effects- ataxia, Steven-Johnson syndrome, aplastic anemia and leukopenia Other AEDs (except Gabapentin): only small scales of studies, and expensive if using new AEDs

10

11 Gabapentin: Possible modes of action Increases the synthesis and release of GABA Blocks excitatory L-type calcium channels Increases the release of 5HT, which simulates inhibitory GABA-ergic neurotransmission Decreases the frequency of action potentials (unknown mechanism; not direct blockade of sodium channels)

12 Theoretical Role of GABA and Glutamate in Pain Mediation GABA Glutamate Result in! Pain thereshold increases! Pain decreases analgesia

13 Neurontin: Possible mechanisms in neuropathic pain modulation GABA: Intensifies glutamic acid decarboxylase Glutamate: Shifts the synthesis to GABA Inhibits the branched chain amino acids transferase + Modulation of voltage-dependent neuronal Ca 2+ channels via 2 subunit + 5-HT Plasmatic concentrations Goldlust A. et al. Epilepsy Res Petroff O. et al. Ann Neurol. 1996

14 Gabapentin: pharmacokinetics 口服吸收, 口服後 2-3 小時達最高血中濃度, 約 4 天可達血中穩定濃度 不由肝臟代謝, 原型經由腎臟排除 ( 與其他常用 AED 沒有 interaction) 75-80% 由尿液排出, 20% 由糞便排除 排除半衰期 4-22 hrs 常用劑量範圍 : mg/day

15

16 Gabapentin dose in CRI

17 Gabapentin: additional application Single dose (900mg) in acute H.Z. reduce 66% of acute pain, and also can prevent the development of postherpetic neuralgia Single dose (300mg) in pre-op reduce acute postsurgical pain (even better than tramadol)

18 Gabapentin: side effects and dose ** 沒有特別的史蒂文生氏症 再生不良性貧血 肝衰竭 脾臟炎副作用發生報告 Adverse event > >3600 mg/day mg/day* mg/day* mg/day* Somnolence 12.9% 1.8% 5.1% 8.3% Dizziness 10.1% 1.2% 1.1% 16.7% Asthenia 5.0% 0.8% 2.1% 8.3% Headache 4.3% 0.3% 1.3% 0.0%

19 TCAs Block reuptake of NE & 5-HT; block Na channels; NMDA antagonist Amitriptyline and nortriptyline most commonly used Side effects: blurred vision, dry mouth, sinus tachycardia, constipation, urinary retention, confusion, orthostatic hypotension, dizziness, sudden death

20

21 Post-herpetic Neuralgia Herpes zoster: caused by a reactivation of VZ virus, which has been dormant in the dorsal root ganglion following primary infection with chicken pox. Reactivation occurs because of a decrease in the cell-mediated immune response to the varicella zoster virus

22 Initially, there may be burning, itching, tingling, or extreme sensitivity in one area of the skin (usually limited to one side of the body). This appears for one to three days before a red rash found at that site. Fever or headache may occurs. The rash then turns into groups of blisters, lasting for about two weeks. It is unusual to have pain without skin lesions, but it might happen

23

24 Post-herpetic Neuralgia Reactivation may occur in: Advancing age Problems to the immune system from disease, medications or cold/sunburn Stress (negative life events) Major depression

25 Post-herpetic Neuralgia PHN develops in 60% to 70% of patients older than age 60 with herpes zoster in which pain persists (more than 3-6 ms) even after cutaneous lesions have healed. PHN may occur after an interval of no pain, or in patients who did not have pain during the acute phase of herpes zoster, lasting for months or even years.

26 Diabetic neuropathy 15% DM P ts 有 neuropathy, mostly over 50Y/O Type I & II, 男或女, 發生的比率差不多 超過 25 年 DM 者, 50% 有 neuropathy 大部分導因於 infarction of nerves, related with microvasculopathy; 有一些則加入了 poorly understood metabolic abnormality

27 Diabetic neuropathy Most common form: presenting with glove and stocking distribution Large fiber type: loss of vibration and position senses Small fiber type: loss of thermal and pain senses (night burning sensation & ANS involved esp.)

28 Trigeminal Neuralgia Episodes of intense shooting pain in the eyes, lips, nose, scalp, forehead, and jaw 常與牙痛混淆 常痛在 CN 5-II & 5-III 分布區域

29 Trigeminal Neuralgia The leading explanation: A blood vessel is likely to compress the trigeminal nerve near its connection with the pons. The superior cerebellar artery is the most-cited culprit(about 75%). Such a compression can injure the nerve's protective myelin, and cause erratic and hyperactive functioning of the nerve. Management: medication or microvascular OP

30 CTS (carpal tunnel syndrome) 腕隧道症候群 通常麻在手遠端, 騎摩托車 天冷或夜晚較厲害, 甚至麻醒, 甩手會舒服些 可由 NCV 診斷 : prolonged distal latency of median nerve; slower median SNCV/MNCV

31

32

33 Phantom limb pain 約 50% 截肢患者在其截去部位經驗疼痛的現象 患部在切除前若經驗長期的不舒服, 發生的情形較多 幻肢痛可能會因為壓力 焦慮或天氣變化而加重, 或因忙碌 按摩殘肢而減輕 也可有其他感受如熱 冷 癢 擠壓或炙熱感 原因仍不明 普遍的說法是截肢後的肢斷神經形成神經瘤 (neuroma), 神經瘤易發炎且易受刺激, 便產生紛亂的錯誤信息傳至腦中, 使大腦誤以為手臂仍然存在

34 Definition of Epileptic 35 seizure: An intermittent stereotyped disturbance of cons., behavior, emotion, motor function, perception or sensation that on clinical grounds results from cortical neuron discharge

35 Definition of Epilepsy: 36 a condition in which seizures recur, usually spontaneously

36 37 Classification:

37 Traditional treatment for epilepsy 38 Generalized seizures: Phenytoin, CBZ and Sodium valproate Partial seizures: CBZ and Phenytoin Absence: Sodium valproate and Ethosuximide Myoclonic: Clonazepam

38 Use of Neurontin: 600mg~3600mg for refractory partial or generalized seizures (add-on or secondline therapy)

39 Neurotransmitters Modulators & d s GABA Glutamate Na + Channels Epilepsy Epilepsy Epilepsy Neuropathic Pain Neuropathic Pain Neuropathic Pain Headache Bipolar Disorder Headache Neurodegenerative Disorders Bipolar Disorder

40 Mechanism of Action Na + Channels Ca ++ Channels GABA Receptors GABA Metabolism Glutamate Receptors Glutamate Metabolism > Phenytoin > Carbamazepine > Lamotrigin > Valproate > Ethosuximide > Gabapentin > Barbiturates > Benzodiazepines > Gabapentin > Tiagabin > Vigabatrin > Valproate > Felbamate > Topiramate > Carbamazepine > Gabapentin

41 Pregabalin Gabapentin-like; using in neuropathic pain, focal epilepsy and anxiety Bind to the α-2δ subunit of the voltage-dependent Ca channel in the CNS OxyContin and some anti-anxiety medications can also negatively interact with Pregabalin

42 Pregabalin Side effects: visual disturbance (including blurred vision, diplopia), ataxia, dysarthria, tremor, lethargy, memory impairment, euphoria, weight gain, constipation, dry mouth, peripheral edema and altered skin sensations

43 Thanks for your attention