Neuropathic pain

Types of Pain Nociceptive Pain An appropriate Physiologic response to painful stimuli Neuropathic Pain An inappropriate response caused by a dysfunction in the nervous system

Signs of Neuropathic Pain Hyperalgesia An increased response to a stimulus that is normally painful Allodynia Pain due to a stimulus that is not normally painful

Symptoms of Neuropathic Pain ปวดแสบปวดร้อน ปวดแปล๊บๆเป็นพักๆ ปวดแบบไฟช้อต เจ็บมากกว่าปกติ เจ็บไม่มีสาเหตุ จี๊ดๆ จ๊อดๆ

Nerve Pathways and Types of Pain Afferent Fibers C and A  AAAA AAAA SpontaneousSymptomsSpontaneousSymptoms Burning/ pricking pain Burning/ Dysesthesias/paresthesiasDysesthesias/paresthesiasStimulus- Evoked Signs Stimulus- HyperalgesiaHyperalgesia AllodyniaAllodynia

Types of Neuropathic Pain Syndromes Post-herpetic neuralgia (PHN) Diabetic neuropathy Complex regional pain syndromes Reflex sympathetic dystrophy Causalgia Phantom limb pain Trigeminal neuralgia

Medical History Central Effects Stroke Spinal cord lesions Multiple sclerosis Tumors Peripheral Effects Trauma, viral infections, vascular disease, metabolic disturbances Surgical procedures Exposure to toxins, drugs, or alcohol Nutritional deficiency

Neurotransmitters Involved in Pain Pathways Serotonin GABA Glutamate Substance P Opioid peptides Reisine T, Pasternak G. In: Goodman & Gilman’s. 9th ed. 1996; Ollat H, Cesaro P. Clin Neuropharmacol.1995;18:

Central Reorganization of A  Fibers Allodynia Mannion RJ, Woolf CJ. Clin J Pain 2000

Signs and symptoms Symptoms Pain descriptors: Electric ไฟช้อต Burning แสบร้อน Icy cold เย็นวาบ Frostbite แมลงกัด แมลงไต่ Aching ปวดตื้อ Tingling ยุบยิบ Needles and pins มีเข็มทิ่ม Onset of pain delayed after injury

สาเหตุที่พบบ่อยของ neuropathic pain ปวดหลังจากเป็นงูสวัด ปวดเส้นประสาทหน้าไม่ทราบสาเหตุ (Trigeminal neuralgia) เบาหวาน สุรา โลหะหนัก สารหนู ตะกั่ว ปรอท Thallium ไม่ทราบสาเหตุ

โรคเส้นประสาท และระบบประสาท อื่นๆ Guillain-Barre syndrome Multiple sclerosis Post stroke pain Traumatic Carpal tunnel syndrome Cervical or lumbar radiculopathy Complex regional pain syndrome Spinal cord injury Stump pain

ยาที่ใช้ประจำ ยาความดัน hydralazine ยาวัณโรค isoniazid ยาฆ่าเชื้อ metronidazole ยากันชัก phenytoin ยาเคมีบำบัด paclitaxel vincristine cisplatinum วิตามิน B6 เกินขนาด ยาต้านโรคเอดส์ d4T (stavudine) ddC (zalcitabine) ddI (didanosine) สาเหตุที่พบบ่อยของ neuropathic pain

First line medication Tramadol hydrochloride Tricyclic antidepressants Amitriptyline Nortriptyline Desipramine Bitartrate Acetaminophen, Aspirin, Ibuprofen

Second line medication ยากันชัก Lamotrigine Carbamazepine ยาต้านโรคซึมเศร้า Bupropion hydrochloride Citalopram Paroxetine Venlafaxine hydrochloride Imipramine hydrochloride

Beyond Second line medication capsaicin clonidine dextromethorphan mexiletine

MAJOR OUTCOMES CONSIDERED ลดปวดได้ดี ปลอดภัย ไม่แพ้ยา ไม่รบกวนระดับยาอื่น ได้คุณภาพชีวิตที่ดีขึ้น ราคาถูก คุ้มค่า

Table 3 Benefit-Risk Analysis of Agents Used to Treat Neuropathic Pain Medication Number of Patients Needed to Treat (NNT) for Efficacy/Adverse Effects Painful/Diabetic Neuropathy Postherpetic Neuralgia Peripheral Nerve Injury Trigeminal Neuralgia Tricyclic antidepressants Amitriptyline Desipramine 2.4/ / /20 2.3/6 2.3/ / /ND —————— SSRIs Paroxetine Citalopram 6.7/ND 2.9/ND 7.7/ND —————— —————— —————— Phenytoin2.1/9.5——— Carbamazepine 3.3/1.9——2.6/3.4 Gabapentin 3.7/1.83.2/3.4 —— Lamotrigine — ——2.1/ND Mexiletine 10.0/6.3——— Baclofen ———1.4/ND Tramadol 3.4/ND——— Oxycodone —2.5/ND —— Source: References 15,21,22,26,27,30-32,37

GABAPENTIN NEURONTIN ® VULTIN

Pharmacologic properties of Gabapentin Increases GABA in brain, possibly by enhancing rate of synthesis from glutamate Binds to specific site localized to brain regions associated with major excitatory inputs Inhibits sodium currents by mechanism distinct from phenytoin and carbamazepine Inhibits branched-chain amino acid transferase, possibly reducing glutamate concentration No effect on GABA A or GABA B receptors

GBP& PGB Binds to the  2  Subunit of Voltage-gated Ca 2+ Channels in the Brain  Noradrenaline  Glutamate  Substance P Modulates neurotransmitter release e.g. Postsynaptic Neurotransmitter Binding Site Presynaptic Voltage- Gated Ca 2+ channel  2  Subunit Neurotransmitter Transporter

Neuropathic Pain: Treatment of Neuropathic pain in adults age 18 years and above Indication

Dose regimen Method of administration: Initial Titration DoseDay1Day2Day3 900mg300mgQD300mgBID 300mgTID Increase if necessary, based on response, up to a maximum dose of 3600mg/day (given as three equally divided doses)

Adverse Events Somnolence, dizziness, ataxia, fatigue, nystagmus which were generally mild to moderate with a median duration of 2 weeks

5% Lidocaine Patch Treatment with the 5% lidocaine no more than 3 patches daily for a maximum of 12 hours, US FDA-approved dosage for post- herpetic neuralgia).

Tricyclic Antidepressants analgesic effect that has been demonstrated to be independent of their antidepressant effect TCAs should be initiated at low dosages 10 to 25 mg hs titrated every 3 to 7 days by 10 to 25 mg/d as tolerated

Tricyclic Antidepressants Contraindications especially in patients with cardiovascular disease risks of conduction defects, arrhythmias, tachycardia, stroke, and acute myocardial infarction.

Tramadol a norepinephrine and serotonin re-uptake inhibitor a major metabolite that is a mu-opioid agonist initiated at low dosages 50 mg once or twice daily titrated every 3 to 7 days by 50 to 100 mg/d in divided doses as tolerated. maximum dosage 100 mg 4 times daily (> 75 years, 300 mg/d in divided doses)

Opioid Analgesics Opioid Analgesics: Numerous short- and long-acting opioid analgesics are available. begin with short-acting opioid analgesics morphine sulfate 5 to 15 mg every 4 hours as needed.

Second line drug Lamotrigine has results of multiple randomized controlled trials for human immunodeficiency virus (HIV) sensory neuropathy painful diabetic neuropathy (PDN) central post stroke pain incomplete spinal cord lesions from spinal cord injury

Carbamazepine Well-established beneficial effect for trigeminal neuralgia Approved by the FDA for the treatment of this neuropathic pain syndrome In patients with painful diabetic neuropathy, some evidence exists for a beneficial effect of carbamazepine, but results from studies of phenytoin are inconsistent

Lamotrigine The guideline developers do not consider lamotrigine a first-line treatment for neuropathic pain The slow and careful titration required and the risk of both severe rash and Stevens-Johnson syndrome associated with its use.

Simple pregabalin dosing in neuropathic pain bd (twice daily) dosing The dose most often used in open-label studies was approximately 300 mg/day Clear dose-response relationship May be taken with or without food Dosage reduction is necessary in patients with renal impairment Data on file, Pfizer Australia. LYRICA Approved Australian Product Information.

Pregabalin: Recently Defined Mechanism Binds to neurons at the   -  subunit of voltage- gated calcium channels (brain and spinal cord) Attenuates calcium influx into depolarized nerve terminals Reduces excitatory neurotransmitter release from hyperexcited neurons (e.g. glutamate, Substance P,noradrenaline) No GABA activity   -  mechanism of action may be relevant for both peripheral neuropathic pain and epilepsy* *Clinical significance of these pharmacologic effects of pregabalin in humans is not known.

Pregabalin  post-herpetic neuralgia and painful diabetic neuropathy  has a combined NNT for doses ranging from 150 to 600 mg of 4.2 (3.4–5.4) comparable to the effect of gabapentin. NNH = 11.7 ( )

Algorithm for Neuropathic pain treatment: An Evidence based Proposal

Results 105 randomized, double-blind, placebo- controlled studies were included. 39 anticonvulsants, 26 antidepressants, 11 opioids, 7 NMDA antagonists, 9 mexiletine, 4 topical lidocaine, 3 cannabinoids, 11 capsaicin, and 1 glycine antagonist.

The trials included patients with  central post-stroke pain,  spinal cord injury pain, multiple sclerosis,  painful polyneuropathy,  post-herpetic neuralgia, phantom limb pain,  post-mastectomy and postsurgical pain, brachial plexus avulsion,  trigeminal neuralgia, HIV-neuropathy,  Mixed neuropathic pain conditions. Results

Tricyclic antidepressants  relieve central post-stroke pain, post- herpetic neuralgia, painful diabetic and non-diabetic polyneuropathy and post-mastectomy pain syndrome,  but not spinal cord injury pain, phantom limb pain, or pain in HIV- neuropathy.  NNT ranges from 2 to 3.  NNH is 14.7 (10.2–25.2)

carbamazepine  do not meet current methodological standards (e.g. use of validated outcome measures, sample size calculation, and adequate description of randomization procedure, statistical methods, and patient flow)

Phenytoin  positive effect on painful diabetic neuropathy in one trial NNT: 2.1 (1.5–3.6)  while another showed no analgesic effect.

Valproate  in three parallel group trials had high efficacy in relieving pain in painful diabetic neuropathy and post-herpetic neuralgia with very low NNTs,  while a crossover trial found no difference between valproate 1500 mg and placebo in treating painful polyneuropathy and diabetic neuropathy.  not significantly better than placebo in relieving pain in patients with spinal cord injuries.

Gabapentin  Studied in several large trials  Moderate effect on pain and quality of life measures including mood and sleep disturbance in mixed neuropathic pain states, post- herpetic neuralgia, painful diabetic neuropathy, and spinal cord injury.

Gabapentin  NNT is 5.1 (4.1–6.8) (over all NNT including all condition, high and low dose) but excluding 900mg/d in mixed neuropathic pain and including 2400mg/d, The NNT is 3.8  NNH for withdrawal for gabapentin is 26.1 (14.1–170).

Gabapentin  gabapentin plus venlafaxine improved pain and quality of life compared with gabapentin plus placebo in painful diabetic neuropathy.

Lamotrigine  pain relieving effect in trigeminal neuralgia as an add-on treatment (NNT: 2.1 (1.3–6.1)),  in painful diabetic neuropathy (NNT: 4.0 (2.1–42)), and in central post-stroke pain.

Lamotrigine  In HIV neuropathy, a small study showed a significant effect (300 mg/d), but an extended larger study (600 mg/d) only demonstrated an effect on some patients receiving neurotoxic antiretroviral therapy.  In spinal cord injury pain:had no effect.

Topiramate  failed to relieve pain in three large trials with painful diabetic neuropathy, while another trial found a significant effect (NNT: 7.4 (4.3–28.5)).  four studies had a high withdrawal rate due to side effects (NNH: 6.3 (5.1–8.1)).

Opioids: Tramadol  studied in two trials in painful polyneuropathy and in one trial in post- herpetic neuralgia.  overall NNT of 3.9 (CI 2.7–6.7).  NNH was 9.0 (6.0–17.5).

NMDA antagonists :dextromethorphan  studied mainly in small trials in neuropathic pain, with either no or minor pain relieving effect.  in painful diabetic polyneuropathy (NNT: 2.5 (1.6–5.4)), but seems to lack efficacy in post-herpetic neuralgia.  NNH is 8.8 (5.6–21.1)

Treatment algorithm In choice of treatment for neuropathic pain a set of different criteria are relevant including:  Consistent outcome in high-quality randomized controlled trials.  High degree of pain relief and superiority to existing treatments.  Persistent pain relieving effect.  Few and only mild side effects.  Effect on quality of life.  Low cost.

 If only one set of criteria: pain relief is TCA > opioids ≥ tramadol ≥ gabapentin/pregabalin. If the criteria for efficacy are based on both pain relief and quality of life is gabapentin/pregabalin > tramadol > opioids > TCA  Occasionally dangerous side effects of TCA and strong opioids need to be considered. Conclusion

 TCAs have lower NNT values than gabapentin/pregabalin but may be due to differences in study design. Gabapentin/pregabalin have higher NNH values and lack serious adverse effects TCA and Gabapentin/Pregabalin, these two drug classes as first line treatment of peripheral neuropathic pain. Conclusion

 Tramadol and oxycodone may be considered second or third line drugs  In trigeminal neuralgia, carbamazepine is first choice (consistent outcome with a low NNT), but studies of varying quality. Oxcarbazepine may be an alternative. Conclusion

 Gabapentin/pregabalin MAY be first choice.  TCAs, lamotrigine, cannabinoids, tramadol, and opioids may be second choice. In the elderly Conclusion