Anti-epilepsy AgentsDr Andrew Mallon

Aims To describe the pathophysiology of epilepsy To determine the pharmacological agents

used Mechanism of action Contra-indications Adverse effects

Patient management

Introduction 1 person in 20 will have an epileptic seizure at some

time in their life Epilepsy is diagnosed on the basis of two or more

epileptic seizures. Around 450,000 people in the UK have epilepsy (40

million people worldwide) A seizure is triggered by a sudden interruption in the

brain's highly complex electro-chemical activity

(National Society for Epilepsy UK)

Age/Incidence

Brain

100 billion neurons Control centre:

temperature sensory input motor control emotion thought? body functions

Taken from OUP Illustration Resource, 2002

Gross anatomy

Front part of the brain; involved in planning, organizing, problem solving, selective attention, personality and a variety of "higher cognitive functions" including behavior and emotions.

Gross anatomy

The parietal lobes contain the primary sensory cortex which controls sensation (touch, pressure).

Gross anatomy

Region in the back of the brain which processes visual information.

Gross anatomy

These lobes allow a person to distinguish smells and arebelieved to be responsible for short-term memory.

Structure

Action Potential

Synapse Activity

Seizures are a symptom of an underlying CNS dysfunction

It is an abnormal, uncontrolled electrical discharge from neurons Cell membrane disruptions (permeability) Altered ion distributions (chemical balance) Decreased neurotransmitters (Ach and GABA)

Everyone has seizure threshold

Classification of Seizures Partial:

Simple partial seizures (no loss of consciousness) With motor symptoms With sensory symptoms With autonomic symptoms Only involve 1 hemisphere

Complex partial (loss of consciousness) Simple followed by loss of consciousness Impaired at the onset

Dependant on which area of the brain

Unclassified: Classification not possible to problems with

diagnosis – suspected

Generalised (affect whole brain with loss of consciousness): Clonic, tonic (1min) or tonic-clonic (2-4min):

muscle spasm (extensors), respiration stops, defecation, salivation, violent jerks

Myoclonic: seizures of a muscle or group of muscles

Absence: Abrupt loss of awareness of surroundings, little motor disturbance, mostly children

Atonic: loss of muscle tone/strength

Pathological Basis Abnormal electrical discharge in the brain Coordinated activity among neurons depends on a

controlled balance between excitation and inhibition Any local imbalance will lead to a seizure Imbalances occur between glutamate-mediated

excitatory neurotransmission and gamma-aminobutyric acid (GABA) mediated inhibitory neurotransmission

Generalised epilepsy is characterised by disruption of large scale neuro-networks in the higher centres.

Normal Processes Depolarising Na+ and Ca++ ionic current

shifts are activated by glutamate receptors Repolarising K+ currents are mediated by

GABA receptors Hyperpolarisation is mediated by GABAa

receptors creating an influx of Cl- => inhibition of impulse generation.

Any defect causes the neuron to be closer to the all or none threshold for an AP = HYPEREXCITABLE STATE.

Leading to instability between excitation and inhibition => Epilepsy

Other possible causes

Inherited mutations of proteins involved in the ion channels

Reduction in the activity of homeostatic ATPase pumps within neuron cell membranes

Basis of Pharmacological RxMost anti-epileptic agents act either by blockade

of depolarisation channels (Na+ and Ca++)

OR

Enhancing the activity of GABA (neurotransmission inhibition)

5 Categories of Anti-epileptic Drugs All classifications are based upon chemistry:

Hydantoins Succinimides Benzodiazepines Barbiturates Miscellaneous

Hydantoins - Phenytoin (Dilantin) Use for pts with Tonic-Clonic seizures

Acts to promote intracellular removal of sodium during the refractory period

Antagonism (blocking) of Na+ channels to reduce excitability Antagonism of Ca++ channels Potentiation (activation) of GABA receptors to promote the

inhibitory role of GABA

Can be used in the Rx for neuropathic pain and cardiac arrhythmias

Pharmacokinetics: Slowly absorbed from gut, use a slow IV if rapid

action is required Avoid IM – muscle damage Eliminated by hepatic biotransformation Can measure amount of free agent in the saliva

Cautions: hepatic impairment, pregnancy, breast-feeding; avoid sudden withdrawal; Blood or skin disorders

Adverse effects:  nausea, vomiting, mental confusion, dizziness, headache, tremor, transient nervousness, insomnia occur commonly; rarely dyskinesias, peripheral neuropathy; ataxia, slurred speech, nystagmus and blurred vision are signs of overdosage; rashes (discontinue; if mild re-introduce cautiously but discontinue immediately if recurrence), gingival hypertrophy and tenderness, coarse facies, acne and hirsutism, fever and hepatitis; lupus erythematosus, Stevens-Johnson syndrome, toxic epidermal necrolysis, polyarteritis nodosa; lymphadenopathy; rarely haematological effects, including megaloblastic anaemia (may be treated with folic acid), leucopenia, thrombocytopenia, agranulocytosis, and aplastic anaemia; plasma-calcium concentration may be lowered (rickets and osteomalacia)

Dose: By mouth, initially 3–4 mg/kg daily or 150–300 mg daily (as a single dose or in 2 divided doses)

increased gradually as necessary (with plasma-phenytoin concentration monitoring); usual dose 200–500 mg daily (exceptionally, higher doses may be used); child initially 5 mg/kg daily in 2 divided doses, usual dose range 4–8 mg/kg daily (max. 300 mg)

Contraindications: increases metabolism of the contraceptive pill, anti-coagulants, and pethidine

Succinimides – Ethosuximide (Zarontin)

Use for pts with Absence seizures

Acts by antagonising Ca++ channels in the thalamocortical relay neurons => prevention of synchronised neuronal firing => raising AP threshold

Pharmacokinetics: Almost complete absorption from the gut Extensive metabolism in the liver with a long

half-life (2-3 days) Plasma and salivary concentrations correlate well

for monitoring purposes

Cautions: hepatic and renal impairment; pregnancy and breast-feeding; avoid sudden withdrawal Blood disorders (review)

Adverse effects:  gastro-intestinal disturbances, weight loss, drowsiness, dizziness, ataxia, dyskinesia, hiccup, photophobia, headache, depression, and mild euphoria. Psychotic states, rashes, hepatic and renal changes (see Cautions), and haematological disorders such as agranulocytosis and aplastic anaemia occur rarely (blood counts required if signs or symptoms of infection); systemic lupus erythematosus and erythema multiforme (Stevens-Johnson syndrome) reported; other side-effects reported include gum hypertrophy, swelling of tongue, irritability, hyperactivity, sleep disturbances, night terrors, inability to concentrate, aggressiveness, increased libido, myopia, vaginal bleeding

Dose: adult and child over 6 years initially, 500 mg daily, increased by 250 mg at intervals of

4–7 days to usual dose of 1–1.5 g daily; occasionally up to 2 g daily may be needed; child up to 6 years initially 250 mg daily, increased gradually to usual dose of 20 mg/kg daily

Contraindications: may make tonic-clonic seizures worse

Bensodiazepines – Clorazepam (Klonopin), Diazepam (Valium) Act by potentiating the actions of GABA

causing neurotransmission inhibition (primarily in the CNS)

Can be used to induce sleep (high dose), anticonvulsant therapy and reduction in muscle tone.

Pharmacokinetics: Well absorbed from the gut Lipid soluble to ensure ready prentration of the

blood brain barrier Metabolised in the liver to create active agents

(prolonged therapeutic action) Slow elimination from body

Eg Clonazepam Cautions: elderly and debilitated, respiratory disease, spinal or cerebellar ataxia; history of

alcohol or drug abuse, depression or suicidal ideation; myasthenia gravis; porphyria; hepatic impairment; renal impairment; pregnancy; breast-feeding

Contra-indications:  respiratory depression; acute pulmonary insufficiency; sleep apnoea syndrome; marked neuromuscular respiratory weakness including unstable myasthenia gravis

Adverse effects:  drowsiness, fatigue, dizziness, muscle hypotonia, co-ordination disturbances; also poor concentration, restlessness, confusion, amnesia, dependence, and withdrawal; salivary or bronchial hypersecretion in infants and small children; rarely gastro-intestinal symptoms, respiratory depression, headache, paradoxical effects including aggression and anxiety, sexual dysfunction, urinary incontinence, urticaria, pruritus, reversible hair loss, skin pigmentation changes; dysarthria, and visual disturbances on long-term treatment; blood disorders reported; overdosage:

Dose: 1 mg (elderly 500 micrograms) initially at night for 4 nights, increased according to response over

2–4 weeks to usual maintenance dose of 4–8 mg daily in 3–4 divided doses; may be given as a single daily dose in the evening once maintenance dose established; max. 20 mg daily; child up to 1 year, initially 250 micrograms increased as above to usual maintenance dose of 0.5–1 mg, 1–5 years, initially 250 micrograms increased as above to 1–3 mg, 5–12 years, initially 500 micrograms increased as above to 3–6 mg

Barbiturates – Phenobarbital (Luminal) Used for tonic-clonic seziures.

Act by increasing the duration of Cl- ion channel opening by activating neuronal GABAa receptors

Causing hyperpolarisation of the AP, making it less likely to fire again

Essentially, acts like GABA and can even potentiate the effects of GABA when present.

Pharmacokinetics: Almost complete absorption Elimination is by heptic and renal (25% excreted

unchanged) Biotransformed in the liver into 2 active

metabolites Plasma concentrations relate poorly to seizure

control, use only for monitoring of patient compliance.

Adverse effects: CNS effects (sedation and fatigue) Restlessness/Hyperactivity Folate deficiency Tolerance Dependence with physical withdrawal reactions Adverse drug-drug reactions (contraception and warfarin).

Contraindications: Do not use with patients with respiratory depression, children or elderly.

NOTE: low therapeutic index means more toxic and overdose can have serious consequences

Miscellaneous Agents – Carbamazepine (Tegretol) Used in most epilepsy types. MoA not fully understood but believed to be

related to: Antagonist action of Na+ channels to inhibit

repetitive neuronal firing Decreasing the production (or release) of

glutamate (excitatory chemical) Can also be used in the Rx of neuropathic

pain

Pharmacokinetics: Slow and incomplete absorption Metabolised in the liver – creates an expoxide metabolite

that can have a weak therapeutic effect Relatively long half-life (1-2 days) Potency decreases overtime therefore need to increase

dose to ensure adequate control of seizures Plasma and salivary concentrations correlate well to

clinical effectiveness

Adverse effects: Nausea & vomiting (especially early Rx),

constipation, diarrhoea and anorexia Skin irritation CNS toxcity – dizzy, drowsy, confusion Bone marrow depression (rare) Drug-drug reactions (contraception, warfarin)

Contraindications: see drug-drug reactions.

Sodium Valproate Use in all forms of epilepsy, as it suppresses

the initial seizure discharge and its spread. Clinical actions are:

Antagonism of Na+ and Ca++ channels Potentiation of GABA Attenuation of Glutamate

Can be fast acting due to Na+ MoA, although the full Rx effect usually takes weeks.

Pharmacokinetics: Well absorbed from gut (should be taken with

food to counteract gastric irritation) Extensively metabolised in the liver Rapidly transported across the blood brain barrier Monitor plasma concentration for patient

compliance only

Adverse effects: GI upset (Nausea, vomiting, anorexia, abdominal pain and diarrhoea) Weight gain (appetite stimulation) Transient hair loss Tremor Coma (rare) Thrombocyptopenia (platelets) Oedema Severe hepatotoxicity (liver damage)

Contraindications: People with liver damage or a history hepatic dysfunction

Vigabatrin Only used in conjunction with other agents when pt

becomes resistant (due to tolerance) or poorly tolerates

Effective in partial epilepsy but with restricted used due to severe adverse effects (vision)

MoA: completely different to other agents as it is a structural analogue of GABA that the enzyme that normally inactivates GABA will degrade instead of GABA. More GABA available to inhibit neuron transmission

Pharmacokinetics: Rapidly absorbed from the gut Unchanged by renal processes Intermediate half-life (hrs) Blood concentrations are of no value.

Adverse effects: Sedation, fatigue, dizziness, nervousness,

irritability, depression, impaired concentration. tremor (CNS effects)

Psychotic reactions (check pt history) Visual defects after prolonged use Weight gain and oedema

Lamotrigine (Lamictal) Used for partial seizures in adults only Acts by the inhibition (antagonism) of neuronal

Na+ channels but is highly selective (onlu neurons that synthesise glutamate and aspartate)

Additionally, decrease glutamate release Pharmacokinetics: well absorbed, extensively

metabolised in the liver and has a long half-life.

Adverse effects: Fever, influenza-like symptoms Skin irritation GI disturbances (vomiting, diarrhoea) CNS effects (drowsiness, headache, dizziness,

double vision)

Contraindications: Pts with hepatic impairment

Gabapentin (Neuronitin) Used for partial seizures in adults Designed to be a structural analogue of

GABA but it does not mimic GABA in the brain.

Acts via: Increased synthesis and release of GABA Decrease degradation of GABA Inhibition of Ca++ channels

Pharmacokinetics: Incompletely absorbed in the gut Excreted unchanged via kidney processes Short half-life

Adverse effects: CNS effects (dizzy, drowsy, fatigue, headache, double

visions) Nausea and vomiting

Contraindication: be careful with sudden withdrawal in the elderly due to kidney effects and alterations in acid-base balance.

Anti-Parkinson DrugsDr Andrew Mallon

Aims

To review pathogenesis of Parkinson's

To review clinical presentation

To identify treatment drugs

Prevalence 1.5 million in USA and 120,000 in the UK –

accounts for about 10% of all acute hospital admissions

Effects 2 in 1,000 people; aged 80+ incidence is 1 in 50.

Mainly affects adults in later life Slightly more common in men, Afro-Caribbean's

and people from the Indian subcontinent Affects the quality of life of about 500,000 (family,

carers etc)

Causes Unclear, but is a number of factors:

Environmental – toxins Free Radicals – there is a increase in post-mortem

brain sections Aging – age related decline in dopamine

production Genetic – possible, no single gene identified

Parkinson’s Disease A degenerative and progressive disorder Associated with neurological consequences of

decreased dopamine levels produced by the basal ganglia (substantia nigra)

Dopamine is a neurotransmitter found in the neural synapses in the brain

Normally, neurones from the SN supply dopamine to the corpus striatum (controls unconscious muscle control)

Initiates movement, speech and self-expression

Balance, posture, muscle tone and involuntary movement depends on the roles of dopamine (inhibitory) and acetylcholine (Ach: excitatory)

If dopamine missing, Ach produces more of an effect on muscles

Basis to exploit by drugs: Restore dopamine function Inhibit Ach within corpus striatum

Consequences of dopamine reductions Tremors – hands and head develop involuntary

movements when at rest; pin-rolling sign (finger and thumb)

Muscle rigidity – arthritis-like stiffness, difficulty in bending or moving limbs; poker face

Brandykinesia – problems chewing, swallowing or speaking; difficulty in initiating movements and controlling fine movements; walking becomes difficult (shuffle feet)

Postural instability – humped over appearance, prone to falls

Additional symptomology Anxiety Depression Sleep disturbance Dementia Disturbance of ANS (difficulty in urinating)

Clinical Presentation Altered body image (depression) Poor balance Bradykinesia (slow movement) Bradyphrenia (slowness of

thought) Constipation Dribbling/drooling Dyskinesias (involuntary

movements) Dysphagia (difficulty

swallowing Dystonia (pain spasms)

Excessive sweating (impaired thermoregulation)

Festinating gait Hullucinations (visual) Postural hypotension Restless leg syndrome (leg

aches, tingle, or burn) Rigidity Sleep disturbance Slurring/slowing of speech Tremor

Ref: Noble C (2000) Parkinson’s Disease – the challenge. Nursing Standard, 15 (12), 43-51

Videos

GO TO MEMORY STICK

Treatment (early stage) Clinical judgements based upon level of disability,

age, cognitive status, concurrent medial problems Initial pharmacological therapies are titrated to

determine optimal dose per person Agent used: Levodopa

Social support and health education vital Referrals to other professional groups (SLT, PT, OT

etc)

Treatment (maintenance stage) Speech therapist is prophylactic and deals with

swallowing problems (recommend exercises etc) Impaired thermoregulation – use beta-blockers Disturbance in sleep – can be side effects of

medication; change time of intake or use a controlled release drug delivery system

Continued health education and liaison with other professionals

Treatment (complex stage) Function has deteriorates to such a level a

combination of drugs are prescribed Dyskinesias and Dystonia – can be associated with

long-term Levodopa use and it can be difficult to manage these effects – co-agent is co-beneldopa

Restless-leg – dopamine agonists Anxiety – relaxation, distraction, CBT Depression – alterations in dose of anti-parkinson’s

drugs

Cognitive problems – referral to clinical psychologist and prescription of anti-dementia agents

Hallucinations - ?anti-psychotics

Essentially, a multidimensional approach to pharmacological treatment combined with a

multidisciplinary approach

Medication Rational Replace depleted levels of dopamine Stimulate the nerve receptors enabling

neurotransmission Increase the effect of dopamine on nerve

receptors (agonist) Counteract the imbalance of Ach and

Dopamine

The Drugs: Dopaminergic drugs (improving dopamine

functioning) Levodopa Dopamine receptor agonists Amantadine Selective monoamine oxidase B inhibitors Catechol-O-methyltransferase inhibitors

Antimuscarinic drugs (Ach inhibitors)

Levodopa (or Levodopamine) Can not administer dopamine directly, as it does not

cross the blood brain barrier A natural amino acid that the brain converts into

dopamine (replacement therapy) used since the 1960’s

To make it slow release, combined with benserazide (an enzyme inhibitor) to create co-beneldopa or co-careldopa (Sinemet)

Dose = 50, 100 or 200mg (12.5, 25 or 50mg)

Source: Adams et al (2006). Pharmacology for Nurses –A Pathophysiologic Approach. Prentice Hall Publishers

Pharmacokinetics: Absorbed by the small intestine by an active

transport system Decarboxylation occurs in peripheral tissues (gut

wall, liver and kidney decrease amount available for distribution – 1% of an

oral dose Extracerebral dopamine amounts causing unwanted

effects (benserazide) Short half-life

Cautions: pulmonary disease, peptic ulceration, cardiovascular disease, diabetes mellitus, osteomalacia, open-angle glaucoma, history of skin melanoma (risk of activation), psychiatric illness (avoid if severe); warn patients about excessive drowsiness; in prolonged therapy, psychiatric, hepatic, haematological, renal, and cardiovascular surveillance is advisable; warn patients to resume normal activities gradually; avoid abrupt withdrawal;

Contra-indications: closed-angle glaucoma; pregnancy breast-feeding Adverse effects:  anorexia, nausea and vomiting, insomnia, agitation, postural

hypotension (rarely labile hypertension), dizziness, tachycardia, arrhythmias, reddish discoloration of urine and other body fluids, rarely hypersensitivity; abnormal involuntary movements and psychiatric symptoms which include hypomania and psychosis may be dose-limiting; depression, drowsiness, headache, flushing, sweating, gastro-intestinal bleeding, peripheral neuropathy, taste disturbance, pruritus, rash, and liver enzyme changes also reported; syndrome resembling neuroleptic malignant syndrome reported on withdrawal

Dose: Initially 125–500 mg daily in divided doses after meals, increased according to

response (but rarely used alone, see notes above)

HOMEWORK: WHAT DRUGS INTERACT WITH LEVODOPA?

Adverse effects: As a result of the amount of peripheral dopamine

levels Nausea, vomiting Postural hypotension

As a result of the amount of CNS dopamine levels Dyskinetic involuntary movements (face & neck) Hallucinations and confusion

Dopamine receptor agonists Apopmorphine (APO-go):

SC administration Rescue therapy – rapid onset with a short

duration of action (~50mins) Bromocriptine (Parlodel); Pergolide

(Celance); Ropinirole (Requip) Direct agonists of dopamine receptors in the

brain ?longer lasting therapeutic effects that Levodopa

Start a pt on this alone, then combine with levodopa to ‘smooth out’ control when PD is getting progressive (especially young)

Pharmacokinetics: Incompletely abosrbed need extensive first-pass

metabolism (biotransformed in liver) Pergolide & Ropinirole have higher

bioavailability (distribution) Short to medium half life (Potency)

Adverse effects: Use gradual dose titration N + V (particularly Apomorphine) Dyskinesia Hallucinations and confusion Peripheral vasospasm (Raynaunds) Respiratory depression (Apomorphine

Amantadine (Symmetrel) Originally an antiviral drug, now used as conjucntive therapy

for dyskinesis effects produced by Levodopa MoA:

stimulates/promotes the release of dopamine stored in the synaptic terminals

Reduces reuptake of released dopamine by pre-synaptic neuron Pharmacokinetics:

Well absorbed, long half-life, excreted unchanged by the kidney Adverse effects:

Not many Ankle oedema, postural hypotension, nervousness, insomnia,

hallucinations (high dose)

Other Disease Modifying Drugs Selective monoamine oxidase B inhibitors

(selegiline – Trade name Eldepryl/Zelapar): MoA: prolongs the effects of levodopa as MAO-B

degrades dopamine Pharmacokinetics: completely absorption, short half-life Adverse effects: N, V, Dia, Constipation; dry mouth, sore

throat; transient dizziness; insomnia, confusion and hallucinations

Early stage – prescribed on it is own to delay need for levodopa and there is good evidence for its slowing down of PD progression

Catechol-O-methltransferase inhibitors - COMT (entacapone, Trade name Comtess) MoA: inhibits the breakdown of levodopa Pharmacokinetics: variability of absorption, extensive

first-pass metabolism, short half-life Adverse effects: dyskinesias, hallucinations; N, V, Dia

and abdominal pain New combination – Levodopa/carbidopa/entacapone

(Stalevo) as 1 tablet (50, 100, 150mg)

Antimuscarinic/Anticholinergic Drugs: Trihexyphenidyl (Broflex, Artane, Agitane); Benztropine

(Cogentin); Orphanadrine (Disipal); Procycline (Kemadrin, Arpicolin)

Less common drugs but they affect Ach based interactions MoA: blocking cholingeric (Ach) receptors to restore

balance Pharmacokinetics: fairly well absorbed, extensive hepatic

metabolism, intermediate to long half-lifes Adverse effects: dry mouth and confusion

Disease Modifying Drugs Overview

Symptom Management Drugs

PD is multidimensional, therefore there are a number of clinical presentations that require supplementary agents Drug-Drug reactions is the problem Major area is depression

Antidepressants Amitriptyline (Tryptizol), imipramine (Tofranil),

Nortriptyline (Allegron), Iofepramine (Gamanil) MoA: block re-uptake of noradrenaline and

serotonin => Sedative actions, can help with drooling and loss of appetite

Adverse effects: sleepiness, dry mouth, increased hunger, cardiac arrhythmias and changes in BP

Can interfere with the effects of levodopa!

Other Drugs to Avoid

Generic Name Brand Name Prescribed forProchlorperazine Stemetil N +V, Dizziness

Prephenazine Triptafen Depression

Flupentixol Fluanxol/Depixol Confusion, Hallucinations

Chlorpromazine Largactil “

Pimozide Orap “

Sulpiride Dolmatil “

Video Sites HealingWell.com Birmingham Teaching Tutorials (hopefully)

The Neuron Connection www.bio.davidson.edu/projects/neuron/video.asp

Useful Websites: Parkinson’s Disease Society

http://www.parkinsons.org.uk/ Nursing Standard (CPD)

http://www.nursing-standard.co.uk/

Pathophysiology of PainDr Andrew P Mallon

Context “It is easier to find men who will volunteer to die,

than to find those who are willing to endure pain”

Julius Caesar

“We all must die. But if I can save (a person) from days of torture, that is what I feel is my great and ever new privilege. Pain is a more terrible lord of mankind than even death itself”

Albert Schweitzer, 1953

Aims To define pain and

develop an operational definition.

To explore the physiological processes involved (from cause to

perception).

To examine the role of opioids in pain

modulation

Can we define pain? ‘Noxious stimuli via nociceptors which are free nerve

endings found in skin, muscle and joints which transmit impulses the brain’ (Bakal 1974)

‘Abnormal experience evoked by abnormal, harmful or noxious stimuli’ (Wyke 1981)

‘A subjective combination of sensory, emotional and cognitive factors’ (Bond 1984)

‘Sensory and emotional experience of discomfort, which is usually associated with threatened tissue damage’ (Sander 1985)

‘Pain is whatever the patient says it is’ (Sternbach & McGaffey 1974)

What is Pain? Pain is an unpleasant

sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.

International Association for the Study of Pain (1991).

What is Pain? Pain is an unpleasant

sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.

International Association for the Study of Pain (1991).

Aspects….. Physiology Psychology Social

Relates to: sensory cognitive affective (emotion)

Pain Classification

Acute and Chronic Underlying cause transitory or protracted/ongoing

Fast and Slow Pain Sharp and dull/throbbing

Pain = Sensation

1. Transduction of noxious stimuli by sensory

receptors

2. Transmission of nociceptive information

3. Perception of noxious information

4. Modulation of the incoming noxious information

Basic pathway Periphery

Enters spinal cord

Travels up towards the

brain

Medulla

Thalamus (processor)

Cerebral cortex

PrimaryInterneuron

SecondaryInterneuron

tertiaryInterneuron

Nociceptive pathways (Walsh, 1997)

N o xio us S tim u lus

N o cice p to r:D e tec tion

T ran sdu ction

P er iph e ra l N erv e F ib re s:A -d e ltaC - fib res

S p in a l C ord :P a in pa th w a ys

D o rsa l h o rn syn a pses

S u pra sp ina l struc tu re s:T h a la m us

M idra in /P on s/M e du llaB asa l G a ng lia

S o m a to sen sory co r te x a n d lim b ic sys tem

Peripheral Level

Spinal Segmental Level

Supraspinal Level

Cortical Level

Nociception

Perception

Peripheral Level Noxious stimulus:

Bradykinin Histamine Potassium/ Protons

(H+) Prostaglandins Substance P Serotonin

Nociceptor Activation: Transducer to

convert the stimulus Receptor potential

=> Action potential Activity in

ascending sensory pathways

(Tortora & Grabowski, 2004)

Peripheral Nerve FibresName Diameter NCV AP

DurationSensoryFunction

A-Alpha 20 micron 70-120 ms

½ ms Proprio-ception

A-Beta 10 micron 30-70 ms

½ ms Touch

A-Delta 3 micron 12-30 ms

1 ms Sharp Pain

C-fibres 0.5 micron ½-2 ms 2 ms Slow Pain

(Tortora & Grabowski, 2004)

Afferents into laminas 1,2,5, plus motor

Afferents into laminas 1,2,5,plus motor & autonomic

Ascending Nociceptive Pathways Lateral Spinothalamic:

arises in Lamina I & V peripheral input from

A units respond to high

threshold noxious stimuli & non-noxious stimuli

synapses in thalamus collateral's to midbrain

Multi-synaptic spinoreticular arises in lamina VII &

VIII input from most other

lamina Collateral's to brain

stem reticular formation

projects to thalamus

Spinothalamic Tract(Almeida et al., 2004)

Spinoreticular Tract(Almeida et al., 2004)

Noc

icep

tors

Spinal Cord

ReticularFormation

Thalamus

C fibres

A delta fibres

SomatosensoryCortex/Insular

Frontal LobeLimbic System

Hypothalamus

Medulla/Pons

(Adapted from Johnson, 1997)

Pain Modulation Ability by either external or internal influences

or “interference” to alter the perception of a painful experience

Non-pharmacological (physical therapy, acupuncture etc)

Pharmacological “Mind over matter” Placebo?

Therapist interaction effect

T Action system

LDA

SDA

Gate Control System

+

+

-

--

Gate control (spinal level)

Supraspinal Descending Pain Inhibitory Pathways

The inhibitory interneurones in the substantia gelatinosa may also be influenced by descending inputs from higher centres.

Gate control (spinal level)

T Action system

LDA

SDA

Gate Control System

+

+

-

--

Reticular formation/Thalamus

Descending PainPathways

T

Descending inhibitory control

Action system

LDA

SDA

Gate Control System

+-

Endogenous Pain Modulating System Opioid Peptides

enkephalins dynorphins endorphins

widely distributed role in pain modulation role in neural tissue

growth & in formation of new central synaptic connections

Opioid Receptors variation in types of

receptors variation in activity

(agonist/antagonist) 3 major subtypes:

μ (mu): PAG & SC κ (kappa): Peripheral δ (delta): Throughout

Exogenous Opioids

Work by binding to CNS endorphin receptors

Activate descending pain pathways

Specific site of action is at second order

neuron level

Each analgesic agent have different pattern of

affinities => different effects/pain experiences

Role of Opioids

Endorphin Exogenous Opioids

Binding to brain stem receptors

AP to Dorsal Horn

Enkephalin Release

Inhibition

Pain Medication Weak Opioids (MSk Pain):

Codine: 10% converted into morphine by liver, therefore used with paracetamol

Tramadol: stimulation of the descending nerves from the brain which inhibit the dorsal horn of the spinal cord

Strong Opioids: Morphine: is the "gold standard". It is a potent stimulator of

morphine receptors, blocking pain impulses at several sites:- in inflamed peripheral tissues (e.g. knee osteoarthritis), in the dorsal horn of the spinal cord, centrally in the brain.

Hydromorphone: 7.5 times more potent

T

Cognitive Control

Descending inhibitory control

Action system

LDA

SDA

Gate Control System

+-

Summary Pain is multidimensional Physiologically it is sequence of events from

cause to perception There are 2 main pain fibres (a-delta and C) and

2 corresponding path pathways in the spinal cord (Spinothalamic and Spinoreticular)

Pain modulation can occur endogenously and exogenously.

Key concept: inhibition at the dorsal horn.

Key References Almeida TF, Roizenblatt S, Tufik S (2004) Afferent pain pathways: a neuroanatomical

review. Brain Research 1000: 40-56.

Johnson MI (1997) The Physiology of the Sensory Dimensions of Clinical Pain.

Physiotherapy 83(10): 526-536

Kidd BL (1996) Problems with pain - is the messenger to blame? Annals of the

Rheumatic Diseases 55:275

Kidd BL, Morris VH, Urban L (1996) Pathophysiology of joint pain. Annals of the

Rheumatic Diseases 55:276-283

Kidd BL (1999) What are the mechanisms of regional musculoskeletal pain?

Bailliere’s Clinical Rheumatology 13(2):217-230

Wells P, Frampton V, Bowsher D (1994) Pain: management by physiotherapy. 2nd

edn, Butterworth Heinemann, Oxford.