Medication Therapy

Variety of Medications Available

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

• Valproate, Phenytoin, Clonazepam 

• Gabapentin, Lamotrigine, Topiramate, Oxcarbazepine 

• Pregabalin, Levetiracetam, Lacosamide

• Amitriptyline, Nortriptyline, Imipramine 

• Opioids –Tramadol, Oxycodone, Morphine, Norspan, Tapentadol

• Baclofen, Mexilitene, Clonidine 

• Capsaicin cream

• N-methyl-D-aspartate (NMDA) blockers – Ketamine 

• Botulinum Toxin

• Vitamin B12 

Anti-convulsants

• Used in treatment of pain since the 1960’s 

• Useful for neuropathic pain, especially if pain is lacinating 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 

Carbamezpine (Tegretol CR)

• 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 controlled 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 lethergy 

• Slightly less potent than Carbazepine, 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 

Pregablin (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

Others

• 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 

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Anti-depressants

• 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 - arrhthymias 

• McQuay - systematic review 1996 - NNT 3 in DN, NNH 2.8 

• Tricyclic anti-depressants

  • Amitriptyline (Endep)

  • Nortripyline (Allegron)

  • Doxepin (Deptran)

  • Prothiaden 

• Selective seretonin 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 

Opioids

• 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.

Other Classes

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

Capsaicin

• 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

Acute Management - 1

IV Phenytoin

• Blocks sodium channels and inhibits pre-synaptic glutamate release

• McCleane GJ. Anesth Analg 1999

  • Randomised, D-B, P-C study of 20 patients with acute flare-ups of neuropathic pain

  • 2h placebo infusion cf 15mg/kg Phenytoin (av. 1000mg)

  • Slow infusion – given over 1 hour

  • Reduced burning, shooting pain and sensitivity for 4 days

  • Alkaline pH – burning pain and IV site irritation

IV Epilim

• Increases inhibitory neurotransmitter GABA by binding to GABA receptors

  • Prolongs repolarisation of voltage-gated sodium channels

• Stillman MJ. Headache 2004 

  • 130 patients with headache with Valproate dose ranged from 300-1200mg

  • 57.5% responded to the first treatment

• Schwartz TH. Headache 2002

  • IV Valproate 15mg/kg followed by 5kg/kg every 8hr

  • Improvement in headache in 80%

IV Keppra

• Hamza 2009

  • Oral Keppra in lumbar radiculopathy pain

  • Pain scores decreased from 7.1 at baseline to 4.2 at week 12 

  • Improvements in general activity, ability to walk and mood

• IV infusion - 1000 mg over 15 min

• SE: Dizziness, somnolence, fatigue, headache

IV Lignocaine

• Sodium channel blocker

  • Reduces spontaneous and evoked responses in a variety of neuropathic pain conditions

• 2000mg (2 x 10 ml x 10% xylocard – lignocaine HCl)

  • 40mg/ml given  1mg/kg/hr  (monitor BP and HR)

• Relief maximum 20 minutes after end of infusion and persisted for over 10 hours 

Acute Management - 2

Wind-Up

• Prolonged response to a noxious stimulus

  • Dramatic increase in duration and magnitude of cell responses, but input into spinal cord remains the same

• Activation of:

  • Neurotransmitters (glutamate, substance P, NO), NDMA receptors, 

  • Inflammation and chemicals (neurotropin) and Genes (Cfos)

Ketamine

• 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

  • Odorless, 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

Botulinum Toxin

• 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

Vitamin B12

• 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 

Pain Clinics

Does not imply “Pain is not Real”

• When pain persists beyond healing or with no cause, it is often assumed patient is willingly aggravating the pain

This is rarely the case

• Pain is a perception, which is filtered through the brain

• Multidisciplinary treatment 

  • 1st pain clinic to include psychological component –1976

  • Cognitive components are crucial to the treatment 

    • Reduce pain but also improve mood and decrease disability

  • Medical, physical, behavioural, emotional, vocational, social 

• Investigations and referrals

• Medications

  • Nociceptive  or anti-neuropathic

• Anaesthetic blocks or TENS

• Physical therapy and exercise program

• Occupational therapy

• Psychiatric  or D & A review

• Psychological management

  • Meditation / relaxation or Pain Education Program

• Implantable drug pump and spinal cord stimulation