• Used in treatment of pain since the 1960’s
• Useful for neuropathic pain, especially if pain is lancinating or burning in nature
• Specific mechanisms of action uncertain, but likely to stabilise the nerve membrane by blockade of voltage sensitive Na channels resulting in reduced ionic conductance of sodium and potassium

Carbamazepine (Tegretol) – NNT to obtain 50% relief – 1.7

• Controlled release preparation better tolerated than immediate release usual tablet
• 200mg nocte increasing slowly to 400mg bd
• Response within a week in 65-80%
• Minor SE: sedation, dizziness, nausea, unsteadiness, rash
• Major SE: bone marrow suppression, liver function abnormalities, hyponatremia
• Serum therapeutic ranges are irrelevant
• 4 placebo control trials showing effectiveness

Sodium Valproate (Epilim)

• Better tolerated than Tegretol
• Increases activity of the inhibitory transmitter GABA
• 200mg nocte increasing to 400mg bd
• SE: GIT, weight gain, tremor
• Hepatic dysfunction so LFT’s should be monitored
• Serum therapeutic ranges are irrelevant
• Oxcarbazepine (Trileptal)
• Active metabolite of Tegretol therefore less side effects of effect on sodium, dizziness, drowsiness and lethargy
• Slightly less potent than Carbamazepine, so higher doses needed
• 4 studies in Canada and Europe show it is as effective as Tegretol (70-80% response)
• Not covered by PBS currently in Australia and costs approx. $90 per month

Oxcarbazepine (Trileptal)

• Active metabolite of Tegretol therefore less side effects of effect on sodium, dizziness, drowsiness and lethargy
• Slightly less potent than Carbamazepine, so higher doses needed
• 4 studies in Canada and Europe show it is as effective as Tegretol (70-80% response)
• Not covered by PBS currently in Australia and costs approx. $90 per month

Pregabalin (Lyrica)

• Works on alpha-2-delta ligand
• Analgesic, anxiolytic and anti-convulsant
• SE’s: Dizziness, somnolence, blurred vision, weight gain and peripheral oedema
• 25mg nocte increasing slowly to 300mg bd

Gabapentin

• Used in a variety of neuropathic pain conditions such it prevents allodynia and hyperalgesia
• Improves pain and sleep
• Designed as an analogue of GABA, but also acts also on NMDA receptors
• 100mg nocte titrating up to 1800mg/day
• SE’s: ataxia, drowsiness, fatigue

• Also used for over 30 years for neuropathic pain
• Direct analgesic effect and also relieve of other symptoms, such as sleep disorder
  • Lower doses (10-25mg) required c.f 100-150mg for mood
  • Occurs faster (3-4 days) than anti-depressant effects
  • SE’s: Anticholingeric effects – Sedation, dry mouth, blurred vision, urinary retention
  • Life-threatening cardiovascular effects – arrhythmia
• McQuay – systematic review 1996 – NNT 3 in DN, NNH 2.8
• Tricyclic anti-depressants
  • Amitriptyline (Endep)
  • Nortripyline (Allegron)
  • Doxepin (Deptran)
  • Prothiaden
• Selective serotonin reuptake inhibitors (SSRI)
  • Paroxetine (Aropax)
  • Fluoxetine (Prozac / Lovan)
  • Citalopram (Cipramil)
  • Seretaline (Zoloft)
• Mixed (SNRI)
  • Mirtazapine (Avanza)
  • Venlafaxine (Efexor)
  • Reboxetine (Edronax)
  • Duloxetine (Cymbalta)
  • Duloxetine
• Selective serotonin and NAR reuptake inhibitor
• 30 mg daily for 1 month then 60 mg daily
• Increasing use and effect independent of mood effect
• Recent diabetic PN study – within 1 week, 50% reduction in pain in 50% of patients
• SE’s: Nausea, somnolence, constipation

• Beneficial in some patients
  • Demonstrated good efficacy outcomes with only moderate side effects and low risk of abuse or addiction
• Longer acting opioids are better than short-acting
• Patient selection and close follow-up important

Tramadol

• CNS-active analgesic, synergistic action via:
  • Non-opioid by inhibition of noradrenaline reuptake and stimulation of serotonin release at the spinal level
  • Opioid with weak binding to mu-opioid receptors
• Quick acting, slow release, extended release, IV or IM
• Side effects: CNS (somnolence, confusion, dizziness) & GIT (nausea)
• Small risk of seizures (use contraindicated if seizure history)
• NNT for Tramadol 100mg 4.7

Buprenorphine (Norspan)

• Transdermal patch – weekly
  • Partial opioid agonist
  • SE’s: Application site skin irritation (rotate sites), headaches , Dizziness, drowsiness, nausea
  • Doses: 5 mcg/hr / 10 / 20 /40 weekly

Tapentadol

• Opiate agonist and noradrenaline reuptake inhibitor.
• Used when there is mixed pain with elements of nociceptive and neuropathic pain.
• Theoretical risk of confusion and serotonin toxicity if prescribed with SSRIs or serotonergic agents.
• Start at 50 mg at night increasing slowly to 200mg twice a day.
• Similar side effects to other opiates, but generally not as severe or frequent.

Baclofen

• GABA b receptor agonist
  • Lacinating pains primarily through inhibitory effect
  • Initiate slowly, 5mg bd (increase up to 40-60mg/day)
• Side effects: CNS depression of sedation, confusion, dizziness and nausea and postural hypotension

Mexilitene

• Blocks sodium channels and reduces abnormal baseline and inducible nerve discharges
  • Difficult to initiate. Start 50 mg daily increasing slowly to 200 mg tds
• Poorly tolerated with anorexia, nausea, vomiting, drowsiness, confusion

Clonidine

• Alpha 2 adrenergic agonist in dorsal horn and brainstem
  • Transdermal, intravenous, oral, and epidural
  • Suppress CNS noradrenergic activity and peripheral sympathetic tone
• Opiate analgesia may be potentiate as it has a dual effects on opiate receptors
• Non-addictive therefore useful for weaning opioid-dependent patients by blocking withdrawal

• Naturally occurring alkaloid
  • Works on small cutaneous c-fiber afferents by stimulating then blocking fibres
  • Depletes substance P and reduces membrane excitability and blocks axon transport
  • Low concentration, 0.075% topical cream
  • May burn for the first several weeks

• Developed in 1963 as safer alternative to PCP
• NMDA receptor inhibition in dorsal horn of spinal cord
• Anaesthetic with:
  • Dissociative (separates perception from sensation)
  • Analgesic, sedative and amnesic properties
  • Used in veterinary medicine
  • Odourless, tasteless, undetectable in drinks
• 80% hepatic metabolism to active Norketamine
  • Orally as only 1/3 analgesic potency of ketamine
  • Cognitive side effects and hallucinations at high doses
• Ketamine infusion
  • 200mg in 50ml plus
  • Generally run at 2ml/hr initially over 3-5 days
  • If effective
    • Ketamine lozenges – 25mg three times a day initially

• Used by the body in the production of myelin
• Gross deficiencies lead to nerve damage (pain and inflammation)
• Beef, lamb, eggs, liver, oysters
• Parenteral B12 or oral 1000 micrograms daily (Methylcobalamin)
  • Help regenerate myelin and nerve cells, even in non-deficient
• Initial studies (1940’s) -promising results
• Recent study in TNA also promising
  Talaei 2009
  • Parenteral vitamin B(12) vs nortriptyline in DPN – 100 patients
  • Pain decreased 3.6 on VAS in vitamin B12 and 0.8 in Nortriptyline

• Turk 2005 – Clin NeuroPharm
  • 8 patients with TN 50u injected just above and below the zygomatic arch at a depth of 2 cm
• Reduction in pain within hours or days in all after the injection – 3.2 +/- 2 days
• Zuniga 2008
  • 12 patients with TN – 20-50 units into trigger zones – massester muscle if V2
  • 10/12 significant improvement for 60 days

Topiramate (Topamax)

• Modulation of voltage-gated Na and Ca channels
• Potentiation of GABA and block AMPA receptors
• 25 mg daily increasing very slowly to 100mg bd
• Used in Migraine prophylaxis

Levetiracetam (Keppra)

• Jorns 2009 – 10 week study in TN
• 250mg twice a day increasing slowly to 1000mg twice a day – 40% improvement

Lacosamide (Vimpat)

• Selectively enhances slow inactivation of Sodium channel, reducing hyperexcitability.
• 50mg twice a day up to 200mg twice a day
• SE’s – dizziness, headache, nausea and diplopia

Clonezapam

• Benzodiazepine – drowsiness and addictive
• Facilitates binding of GABA to its receptors
• Very good for nocturnal symptoms, esp. burning pain