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

Nerve Pathways and Types of Pain

StimulusEvoked Signs Hyperalgesia

Afferent Fibers
C and Ad

Spontaneous Symptoms Burning/ pricking pain Dysesthesias/ paresthesias

Ab

Allodynia

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 Peripheral Effects Trauma, viral infections, vascular disease, metabolic disturbances Surgical procedures

Stroke
Spinal cord lesions

Multiple sclerosis
Tumors

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 & Gilmans. 9th ed. 1996;521-555. Ollat H, Cesaro P. Clin Neuropharmacol.1995;18:391-404.

Allodynia
Central Reorganization of Ab Fibers

Mannion RJ, Woolf CJ. Clin J Pain 2000

Signs and symptoms

Symptoms Pain descriptors: Electric Burning Icy cold Frostbite Aching Tingling Needles and pins Onset of pain delayed after injury

 neuropathic pain
(Trigeminal
neuralgia)

Thallium


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

 neuropathic pain
hydralazine isoniazid metronidazole phenytoin paclitaxel vincristine B6 d4T (stavudine) ddC (zalcitabine) ddI (didanosine)
cisplatinum

First line medication

Tramadol hydrochloride

Tricyclic antidepressants Amitriptyline Nortriptyline Desipramine Bitartrate Acetaminophen, Aspirin, Ibuprofen

Second line medication

Lamotrigine Carbamazepine

Bupropion hydrochloride Citalopram Paroxetine Venlafaxine hydrochloride Imipramine hydrochloride

Beyond Second line medication

capsaicin clonidine dextromethorphan mexiletine

MAJOR OUTCOMES CONSIDERED

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 SSRIs Paroxetine Citalopram Phenytoin Carbamazepine Gabapentin Lamotrigine Mexiletine Baclofen Tramadol Oxycodone

2.4/4.9 2.0/9.7 3.4/20 6.7/ND 2.9/ND 7.7/ND 2.1/9.5 3.3/1.9 3.7/1.8 10.0/6.3 3.4/ND

2.3/6 2.3/6.2 1.9/4.8 3.2/3.4 2.5/ND

2.5/ND 2.5/ND

2.6/3.4 2.1/ND 1.4/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 GABAA or GABAB receptors

GBP& PGB Binds to the 2d Subunit of Voltage-gated Ca2+ Channels in the Brain
Modulates neurotransmitter release e.g.
Noradrenaline Glutamate 2d Subunit VoltageGated Ca2+channel Neurotransmitter Binding Site

Substance P

Presynaptic Postsynaptic
Neurotransmitter Transporter

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

Dose regimen
Method of administration:

Initial Titration
Dose 900mg Day1 300mgQD Day2 300mgBID Day3 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 postherpetic 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 2-d subunit of voltagegated 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
2-d 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 (3.45.4) 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, placebocontrolled 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.

Results
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.

Tricyclic antidepressants
relieve central post-stroke pain, postherpetic neuralgia, painful diabetic and non-diabetic polyneuropathy and post-mastectomy pain syndrome, but not spinal cord injury pain, phantom limb pain, or pain in HIVneuropathy. NNT ranges from 2 to 3. NNH is 14.7 (10.225.2)

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 ow)

Phenytoin
positive effect on painful diabetic neuropathy in one trial NNT: 2.1 (1.53.6) while another showed no analgesic effect.

Valproate
in three parallel group trials had high efcacy 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 signicantly 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, postherpetic neuralgia, painful diabetic neuropathy, and spinal cord injury.

Gabapentin
NNT is 5.1 (4.16.8) (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 (14.1170).

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 (1.36.1)), in painful diabetic neuropathy (NNT: 4.0 (2.142)), and in central post-stroke pain.

Lamotrigine
In HIV neuropathy, a small study showed a signicant 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 signicant effect (NNT: 7.4 (4.328.5)). four studies had a high withdrawal rate due to side effects (NNH: 6.3 (5.18.1)).

Opioids: Tramadol
studied in two trials in painful polyneuropathy and in one trial in postherpetic neuralgia . overall NNT of 3.9 (CI 2.76.7). NNH was 9.0 (6.017.5).

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 (1.65.4)), but seems to lack efcacy in post-herpetic neuralgia. NNH is 8.8 (5.621.1)

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.

Conclusion
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 rst line treatment of peripheral neuropathic pain.

Conclusion
Tramadol and oxycodone may be considered second or third line drugs

In trigeminal neuralgia, carbamazepine is rst choice (consistent outcome with a low NNT), but studies of varying quality. Oxcarbazepine may be an alternative.

Conclusion
In the elderly

Gabapentin/pregabalin MAY be rst choice. TCAs, lamotrigine, cannabinoids, tramadol, and opioids may be second choice.