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.