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

ปวดแสบปวดร้�อน

ปวดแปล๊�บๆเป�นพั�กๆ

ปวดแบบไฟช้�อต

เจ็�บมากกว�าปกต�

เจ็�บไม�ม�สาเหต จ็�!ดๆ จ็�อดๆ

Nerve Pathways and Types of Pain

Afferent FibersAfferent FibersAfferent FibersAfferent Fibers

C and AC and AC and AC and A

AAAA

SpontaneousSpontaneousSymptoms Symptoms SpontaneousSpontaneousSymptoms Symptoms

Burning/Burning/pricking painpricking painBurning/Burning/pricking painpricking pain

Dysesthesias/Dysesthesias/paresthesias paresthesias Dysesthesias/Dysesthesias/paresthesias paresthesias

Stimulus-Stimulus-Evoked Evoked

SignsSigns

Stimulus-Stimulus-Evoked Evoked

SignsSigns

HyperalgesiaHyperalgesiaHyperalgesiaHyperalgesia

AllodyniaAllodyniaAllodyniaAllodynia

Types of Neuropathic Pain Syndromes

Post-herpetic neuralgia (PHN)

Diabetic neuropathy

Complex regional pain syndromesReflex 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;521-555.

Ollat H, Cesaro P. Clin Neuropharmacol.1995;18:391-404.

Central Reorganization of A FibersCentral Reorganization of A Fibers

Allodynia

Mannion RJ, Woolf CJ. Clin J Pain 2000

Signs and symptoms

Symptoms Pain descriptors:        Electric ไฟช้�อต        Burning แสบร้�อน        Icy cold เย็�นวาบ        Frostbite แมล๊งก�ด แมล๊งไต�        Aching ปวดต$%อ        Tingling ย็ บย็�บ        Needles and pins ม�เข็�มทิ่�(ม    Onset of pain delayed after injury

สาเหตุ�ที่�พบบ�อยของ neuropathic pain

ปวดหล๊�งจ็ากเป�นง)สว�ดปวดเส�นปร้ะสาทิ่หน�าไม�ทิ่ร้าบสาเหต (Trigeminal neuralgia)

เบาหวานส ร้าโล๊หะหน�ก สาร้หน) ตะก�(ว ปร้อทิ่ Thallium

ไม�ทิ่ร้าบสาเหต

• โร้คเส�นปร้ะสาทิ่ แล๊ะร้ะบบปร้ะสาทิ่อ$(นๆGuillain-Barre syndrome

• Multiple sclerosis• Post stroke pain• Traumatic

          Carpal tunnel syndrome           Cervical or lumbar radiculopathy          Complex regional pain syndrome           Spinal cord injury          Stump pain

ยาที่�ใช้�ประจำ�า ย็าความด�น hydralazine

          ย็าว�ณโร้ค isoniazid          ย็าฆ่�าเช้$%อ metronidazole          ย็าก�นช้�ก phenytoin ย็าเคม�บ/าบ�ด paclitaxel vincristine

cisplatinum          ว�ตาม�น B6 เก�นข็นาด

ย็าต�านโร้คเอดส0d4T (stavudine) ddC (zalcitabine) ddI (didanosine)

สาเหตุ�ที่�พบบ�อยของ neuropathic pain

First line medicationTramadol hydrochloride

Tricyclic antidepressants Amitriptyline

Nortriptyline

Desipramine

Bitartrate

Acetaminophen,

Aspirin,

Ibuprofen

Second line medication

ย็าก�นช้�กLamotrigine

Carbamazepine

ยาตุ�านโรคซึ�มเศร�าBupropion hydrochloride

Citalopram

Paroxetine

Venlafaxine hydrochloride

Imipramine hydrochloride

Beyond Second line medication

capsaicin

clonidine

dextromethorphan

mexiletine

MAJOR OUTCOMES CONSIDERED

ล๊ดปวดได�ด�ปล๊อดภั�ย็ไม�แพั�ย็า ไม�ร้บกวนร้ะด�บย็าอ$(นได�ค ณภัาพัช้�ว�ตทิ่�(ด�ข็2%นร้าคาถู)ก ค �มค�า

Table 3Benefit-Risk Analysis of Agents Used to Treat Neuropathic Pain

Medication  Number of Patients Needed to Treat (NNT)

for Efficacy/Adverse Effects

Painful/DiabeticNeuropathy

Postherpetic Neuralgia

Peripheral   Nerve Injury

TrigeminalNeuralgia

Tricyclic antidepressants   Amitriptyline   Desipramine

2.4/4.92.0/9.73.4/20

2.3/62.3/6.2

1.9/4.8     

2.5/ND2.5/ND

———

SSRIs   Paroxetine   Citalopram   

6.7/ND2.9/ND7.7/ND

———

———

———

Phenytoin 2.1/9.5 — — —

Carbamazepine     3.3/1.9 — — 2.6/3.4

Gabapentin       3.7/1.8 3.2/3.4    — —

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 glutamateBinds to specific site localized to brain regions associated with major excitatory inputsInhibits sodium currents by mechanism distinct from phenytoin and carbamazepineInhibits branched-chain amino acid transferase, possibly reducing glutamate concentrationNo effect on GABAA or GABAB receptors

GBP& PGB Binds to the 2 Subunit of

Voltage-gated Ca2+ Channels in the Brain

Noradrenaline

Glutamate

Substance P

Modulates neurotransmitter release e.g.

Postsynaptic

Neurotransmitter Binding Site

Presynaptic

Voltage- Gated

Ca2+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

Dose Day1 Day2 Day3

900mg 300mgQD 300mgBID

300mgTID

Increase if necessary, based on response, up to a maxi

mum dose of 3600mg/day (given as three equally divid

ed 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 effectTCAs 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

CarbamazepineWell-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 (8.3-5.4)

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