CNS Week 1 Pain Flashcards
Define pain
An unpleasant sensory and emotional experience associated with or resembling that associated with actual or potential tissue damage
What factors can change pain
Movement (on, during, after)
Weight bearing
Isometric contraction
Pressure (trigger points, gout)
Diagnosis of musculoskeletal pain
pain arising from a disease process affecting bone, joint, tendon, muscle, spine or related soft tissue eg osteoarthritis
Diagnosis of neuropathic pain
Pain caused by a lesion or disease of the somatosensory nervous system
Diagnosis of chronic primary pain
Pain without probable musculoskeletal origin (eg fibromyalgia)
Where does arthritis pain come from
Synovium
Tendons / ligaments
Meniscus
Bone
Muscle
Peripheral nerve
CNS
(Not entirely known yet)
Structural associations of pain in osteoarthritis
Synovitis: inflammation in the lining of the joints
Osteochondral pathology: bone marrow lesions in the subchondral bone
What is the effect of having more mediodorsal thalamus connectivity
Negative affect in people with chronic knee pain as there is increased connectivity between emotional and sensory centres in the brain and this is associated with the emotional dimension of pain
Steps of taking a pain history
Precipitating / alleviating factors
Quality eg sharp, dull, stabbing, burning
Radiation / localisation -
Severity- descriptive, numeric or visual scales
Timing - constant / intermittent, recent, acute, chronic
Emotional components - mood
Beliefs - causation, diagnosis, blame, catastrophising / acceptance
Associated features - comorbidities, sleep / fatigue
Previous treatments
Reasons why amount of medication used is not a measure of pain severity
Illness beliefs: pain is a warning sign Medication beliefs: fear of ADRs, fear of tolerance Adverse events Accessibility Varying efficacy Social norms: man or wimp, giving in? Social endorsement Non analgesic effects: it relaxes me, makes me feel better despite the pain, helps me sleep
How to assess pain in children, dementia and patients unable to communicate
Observation:
- facial expression
- verbalisations
- body movements
- changes in interpersonal interactions
- changes in activity patterns or routines
- mental status changes
Effect size of painkillers for pain relief in OA
57% contextual
43% pharmacological
Contextual = placebo - is still a benefit
Anatomical terminology relating to the brain
Superior / dorsal - above
Inferior / ventral - below
Medial - towards midline
Lateral - away from midline
Anterior / rostral - towards the front
Posterior / caudal - towards the back
Location of cerebellum
Inferior to brain very close to brain stem
Weight of average human brain
1.5kg
Outward portion (bumps) of brain
Gyrae- unique to human brains and other higher order primates
Layers of the scalp (meninges)
Scalp
Periosteum (fibroblasts, osteoblasts- anchors the scalp to the skull)
Bone -
Dura mater- tough
Arachnoid mater- not always continuous, cerebrospinal fluid - spider web appearance
Pia mater- delicate, easy to break, surrounds all structures including blood vessels
Folds of the dura mater
Falx cerebri - fold in the dura that sits in between 2 hemispheres of the brain up to a certain point
Tentorium cerebelli - tent for cerebellum (where it sits) additional protection and support
Falx cerebelli - divides the hemispheres of the cerebellum
2 types of tentorial tumours
Infratentorial - beneath the tentorium cerebelli - most common type of paediatric brain tumour (age 5-15) located around cerebellum can lead to problems with movement and balance - quite successful rate of removal
Supratentorial - tumour is located above tentorium cerebelli
Benefits of meninges
Protect and support the brain
Disadvantages of meninges
They are so strong that if there is bleeding or swelling to the brain then they cause it to become compressed as they don’t allow it to move
What is a meningeal haematoma
A bleed within the meninges. Several types:
Subarachnoid: blood accumulates in the arachnoid space so dura and skull aren’t going anywhere and brain is being compressed
Subdural: blood accumulates under dura which has same effect and compresses Brain downwards
Epidural: bleeding located above dura and skull is broken but this means blood has an outlet to leave so doesn’t press as hard on the brain
Location of the lateral sulcus
Separates the temporal lobe from the parietal lobe and frontal lobe
Use of sulci
Lobular brain organisation
What does the central sulcus separate
Frontal lobe and parietal lobe
4 lobes of the brain
Frontal: personality, attention, motivation, planning movement
Parietal: integrating sensory information, language processing
Temporal: memory, sensory processing, language, comprehension
Occipital: vision
Parieto-occipital sulcus
Separates parietal from occipital lobe
Precentral sulcus
Separates anterior to central sulcus
Calcarine sulcus
Visual cortex
Cingulate sulcus
Parallel with corpus callosum
Divisions of the hindbrain
Metencephalon - pons and cerebellum
Myelencephalon - medulla oblongata
Division of the midbrain
Mesencephalon - tectum (colliculi), tegmentum, cerebral peduncles
Divisions of the forebrain
Diencephalon- thalamus and hypothalamus
Telencephalon - basal ganglia and cortex
What are the pons
Part of the brain stem
A bulge
What is the midbrain
Centre of the brain
Close proximity to most structures of the brain even though it is part of the brain stem
What is the diencephalon
Contains the thalamus - all information from body comes into thalamus before cortex - integration centre of the brain
Purpose of hippocampus
Memory
Function of basal ganglia
Regulate movement
Constant communication with cortex
Caudate nucleus - curls in posterior and anterior direction well connected to the putamen
Function of substantia nigra
Source of dopamine in the brain
Dark coloured due to melatonin
These are the cells that die out if someone has Parkinson’s
red nucleus
Highly vascularised
Function of hypothalamus
Fluid filled cavities that protect and bath the brain
3 parts of the brain stem
Midbrain - cerebral peduncles (motor tracts), substantia nigra, red nucleus, tectum (vision and hearing), reticular formation (consciousness)
Pons - some direct connections with the cortex
Medulla oblongata - respiration, heart rate, vomiting and sneezing
What are ventricles of the brain filled with
Cerebrospinal fluid
How much CSF do we have
150ml that is exchanges 3 times each day
Produce approx 500ml every day
What is CSF
Colourless liquid that baths the brain, assists in circulating substances
Provides cushioning and absorbs shock
Where is CSF produced
In the choroid plexus (a group of cells that line the ventricles) and production induces CSF circulation
The choroid plexus also acts as a medium of exchange between the extracellular fluid and the blood stream
What is hydrocephalus
Accumulation of cerebral spinal fluid
What are ventricles
A series of inter-connected, fluid filled cavities that cushion the brain and bathe it in cerebral spinal fluid
Route of CSF
CSF enters the cisterns and sub arachnoid space via a series of apertures before being circulated upwards and reabsorbed by the arachnoid granulations
4 main arteries that supply the brain
2 Posterior: vertebral arteries
2 anteriorly : carotid arteries
Where is basilar artery located
Sits on the top of the pons
Has a network of branches that feed the pons and the brain stem in general
Superior cerebellar artery
Feeds the cerebellum (majority)
What does the inferior posterior cerebellar artery supply
Inferior aspects of the temporal lobes and the hippocampus and medial aspects of occipital lobes
Role of the circle of Willis
A major anastomosis for the brain (connects blood vessels)
Combines the posterior circulation with the anterior circulation in the brain
If there is a deficit in one it can be supplied by the other
Where does anterior circulation come from
Carotid arteries
Middle cerebral artery (main branch) one of the biggest arteries runs through lateral sulcus
Largest cerebral artery with the largest territory
What is the blood brain barrier
An interface that ensures the circulatory system (Blood) is kept separate from the extracellular fluid / CSF
Blood vessels composed of a layer of endothelial cells, fit together tightly and their membranes form tight junctions that only allows selected materials to pass between the blood and brain
Pericytes and astrocytes also play a role in maintaining the BBB
What molecules are and are not allowed to pass into the brain
Oxygen, CO2, glucose and select amino acids are allowed to pass into the brain but pathogens and larger molecules (Antibodies) cannot
Function of pericytes
Support endothelial cells in maintaining the blood brain barrier
Role in vasodilation
Different components of the blood brain barrier
Endothelial tight junctions - small gaps between endothelial cells that line the blood vessels
Basement membranes - thin, fibrous connective tissues that separate the endothelial cells from surrounding tissue
Pericytes communicate with endothelial cells and contribute to debris removal. In capillaries they control blood flow
Astrocytes - stabilise the blood brain barrier containing water channels (aquaporins) that allow water to enter the brain
What % of patients with chronic pain experience depression
49%
25% of sufferers lose their jobs and 16% of sufferers feel their chronic pain is so bad that they want to die
Different types of pain
Acute v chronic
Cancer v non cancer
Multi dimensions of pain
Location Intensity Temporal aspects Quality Impact Meaning
What are the pain mechanisms
Nociceptive and inflammatory: allow body time to recover (seen as good pain)
Neuropathic : nervous system functioning in an unintended way
Dysfunctional
Describe the characteristics of acute pain
Pain of recent onset and probable limited duration (hours / days)
Obvious tissue injury eg injury, operation, burn
Varying severity
Intensity related to extent of injury: release of inflammatory chemicals (prostaglandins)
Predictable time course
Treatments usually successful
Characteristics of chronic pain
Pain lasting for more than 3 months (continuously or episodically)
Pain lasting after normal healing
Sometimes no identifiable cause (sometimes a trigger)
May be no obvious pathological process
Intensity related to tissue injury (distress making it worse)
Unpredictable time course
Difficult to treat - most drugs are unhelpful or only help a minority of patients
Why is duration of symptoms not a good discriminator
Acute pains may go on for a long time eg burns dressings, sickle cell disease, flare ups of RA
Describe cancer pain
Progressive
May be a mixture of acute and chronic
Opiod treatments often used towards end of life
Describe non cancer pain
Many different causes
Acute / chronic
Opiods found to lead to more deaths sue to overdosing (drive in the NHS to reduce opiod prescribing in non cancer pain)
What is nociceptive pain
‘Good’ pain
Sensation associated with the detection of potentially tissue damaging noxious stimuli
Protective
Action of nociceptive pain
Noxious stimuli (heat / cold/ intense mechanical force/ chemical irritants detected by the sensory neurone in the PNS
Spinal cord causes an automatic response and withdrawal reflex
Adaptive high threshold pain
The early warning system is a protective primitive defence to detect tissue damage
Describe inflammatory pain
Obvious tissue injury or illness
Associated with tissue damage and infiltration of immune cells and can promote repair by causing pain hypersensitivity until healing occurs
Protective function
Descriptors:
- sharp and / or dull
- aching
- throbbing
Describe pathological pain
Maladaptive
Results from abnormal functioning of the nervous system
Disease states caused by damage to the nervous system (neuropathic pain)
Or by its abnormal function (nociplastic pain)
Describe neuropathic pain
Caused by a lesion or disease of the sensory nervous system
Tissue injury may not be obvious
Does not have a protective function
Descriptors:
- burning, shooting, pins and needles or numbness
- less well localised (affects a large area of the body)
describe nociplastic (dysfunctional pain)
Substantial pain but no noxious stimulus and no or minimal peripheral inflammatory pathology
No neuronal damage ( no obvious stimulus, tissue or nerve damage but nervous system is acting in an unintended way)
Conditions include fibromyalgia, IBS, tension headache, temopormandibular joint disease, interstitial cystitis (difficult to treat with drugs)
Acute non cancer pain
Eg fracture, appendicitis, MI
- symptom of tissue injury or illness
Usually nociceptive
Occasionally neuropathic eg sciatica
Chronic non cancer pain
Chronic back pain, arthritis
Cause may not be obvious
Complex, may be mixed nociceptive and neuropathic
Different treatments may be needed
Burdens of long term pain
Depression Sleep disturbances Fatigue Impaired physical functioning Impaired concentration Time off work Less active
Cancer pain
Eg uterine cervical cancer, breast cancer
Bone metastases
Nerve compression
Often mixed nociceptive and neuropathic pain
Usually gets worse over time if untreated
Function of the somatosensory system
Receives information from numerous body parts - skin, muscle, tendons, ligaments, connective tissue
Detected a wide range of stimuli - touch, brush, pressure, tickle, temperature, pain
Difference between nociception and pain
Nociception is a neural process - activation of C fibres
Pain is a feeling / perception and includes a psychological component
Different types of sensory receptors
Mechanoreceptors: touch, pressure, vibration
Proprioceptors: position of body
Thermoreceptors: warm, cool, hot
Nociceptors: mechanical, thermal, chemical
What is convergence
The idea that a single sensory neurone in the CNS can receive inputs from many sensory receptors
What are the steps of transduction in the sensory nerve
Deformation of membrane
Opening of Na+ and K+ channels
Receptor (generator) potential
Local depolarisation of receptive membrane
Action potential propagated to CNS
What is recruitment
Increased number of responsive receptors and fibres - more sensory input to ensure message is sent to the CNS
Difference between pain tracts and tactile tracts
Pain tracts cross in the spinal cord
Tactile tracts cross in the medulla
What are tactile pathways
Central branches of touch afferent fibres ascend in the dorsal columns
Synapse in the dorsal column nuclei
Cross the midline in the medulla
Ascend through the brain stem as the medial lemnisus
Send projections to the primary somatosensory cortex (S-I) post central gyrus of the parietal lobe
What are the components of pain
Sensory-discriminative component: tells you that you have been hurt and where it is
Emotional affective component: the association of unpleasant emotions with the nociceptive stimulus. The suffering of pain comes from the bad emotions that are generated by the painful sensations
What are A B fibres
Myelinated fibres
Fast conduction velocity (non painful stimuli)
Terminate in the intermediate lamina (III-IV) of the dorsal horn
Responses sensitive to glutamate receptor (AMPA receptor) antagonists (fibres release neurotransmitter glutamate)
What are C fibres
Unmyelinated fibres
Slower conduction velocity
Terminate in the superficial lamina (I-II) of the dorsal horn
Responses sensitive to glutamate receptor (AMPA and NMDA receptor) and peptide receptor antagonists
Difference between AB fibres and C fibres
What they release into the spinal cord.
AB release glutamate neurotransmitter
C release glutamate and peptide receptor antagonists
Plasticity of spinal responses
Neuronal responses to repeated stimulation of C fibres are not fixed and are not always proportional to the intensity of the stimulus applied
Enhanced responses (wind up) for a given noxious stimulus are associated with repeated higher stimulation
Spinal neurones are sensitised to the noxious stimulus
What is allodynia
When the normal nociceptor threshold is sensitised so something that wouldn’t usually cause pain eg touch does cause pain
What is hyperalgesia
A sensitised response to a normally painful stimulus
Brainstem
Through the spinoreticular tract and branches of the STT, nociceptive signals activate brainstem systems giving rise to changes in BP, respiration and orientation towards stimulus
Thalamus
VPL is main somatosensory area of thalamus, but other components may also be involved. Acts as the final relay before sensory signals reach the cortex
Cortex
Consciousness of pain, plus the limbic system for emotional response
Hypothalamus
The responses to pain as a stressor are mediated through the hypothalamus: neuroendocrine changes and some behaviours
What is the main area for pain processing
The ventral posteromedial nucleus (VPL)
What is inflammation
Immediate response of the body to a harmful stimulus
Treatment of patients with inflammation is to:
- relieve symptoms (pain, swelling, increased temp)
- slow or stop tissue damaging process
Reduction of inflammation often also results in pain relief
What are eicosanoids
Small bioactive lipid molecules derived from the lipid membrane
Play an important role in inflammation, generated from phospholipids ( arachidonic acid)
What is synthesis of eicosanoids driven by
Many different stimuli including cell damage
What is arachidonic acid metabolised by
One of 2 fatty acid cycle-oxygenase enzymes
What is COX 1
Maintains normal tissue function
Constitutive enzyme
Present in most of the tissues in the body (kidney and platelet function)
- tissue homeostasis
What is COX2
Induced in activated inflammatory cells (IL-1 and TNF a) following stimulation from cytokines
Responsible for production of prostaglandin mediators of inflammation and so drives local inflammation
Action of drugs that target cyclooxygenase enzymes
They inhibit cox2 but not cox1
What are the 5 main prostanoids receptors
PGD2: DP receptor PGF 2a: FP receptor PGI2: IP receptor TXA2: TP receptor PGE2: EP receptor - number of sub groups
Why are there multiple prostanoid receptors but all with the same function
A large number of molecules are generated but all with the same effect (all produce inflammation and pain)
If we only had one we would be quite vulnerable if it wasn’t working as multiple systems working alongside one another means you’ll still get inflammation even if one isn’t working
What do mast cells release
PGD2
What happens in chronic inflammation in terms of prostanoids
Monocytes and macrophages release PGE2 and TXA2 which drive inflammation
What do histamine and bradykinin induce
Histamine - itch
Bradykinin - pain
Actions of PGE2, PGI2 and PGD2
Powerful vasodilators, synergise with histamine and bradykinin causing redness and increased blood flow
Prostaglandins potentiate the actions of bradykinin and histamine on blood vessels and peripheral nerves
What is bradykinin
Causes pain if injected
De novo synthesis during tissue injury
Made in vasculature and local tissue by activated enzymes
Activates nociceptors by B1 (induced after a few days of inflammation) and B2 (always present on sensory nerves) receptors
Role of prostaglandins in relation to bradykinin
Bradykinin increases the production of prostaglandins
Prostaglandins enhance nociceptor responses to bradykinin- increased excitability of nerve fibres
Prostaglandins sensitise nociceptors
Effect of tissue damage
Leads to inflammation ( which releases H+)
Release of bradykinin (acts on B2 receptors of sensory nerves)
Action potentials fired up sensory nerve to the CNS
What are NSAIDs
Anti inflammatory
Analgesic
Antipyretic (lower body temp if it is elevated)
Mechanism of actions of NSAIDs
Inhibition of cyclooxygenase enzymes
Reduced generation of eicosanoids
Why are glucocorticoids given to people with chronic inflammatory disease
Glucocorticoids inhibit the induction of the COX enzymes and when COX is blocked, cyclic endoperoxides are inhibited
What are cyclic endoperoxides
PGI2: hyperalgesic vasodilator- decreases platelet aggregation
PGE2: hyperalgesic vasodilator
PGD2: vasodilator, decreases platelet aggregation
TXA2: thrombotic vasoconstrictor
What is the antipyretic effect
Normal body temp is regulated by the hypothalamus and fever is due to a disturbance in the hypothalamic thermostat
NSAIDs reset the thermostat
Mechanism mainly due to inhibition of prostaglandin production in hypothalamus
Temperature regulating mechanisms reduce temperature
How are NSAIDs analgesic
Pain is associated with inflammation / tissue damage
NSAIDs reduce inflammation (oedema and vasodilation) which causes pain
In combination with opioids to decrease postoperative pain
Clinically used NSAIDs
Analgesia (acute / post operative)
Short term: aspirin, paracetamol (not an NSAID), ibuprofen
Longer acting: naproxen, piroxicam
Taken in conjunction with opiods for chronic pain
What is acetylsalicylic acid (aspirin)
Irreversible inactivation of COX 1/2
Oral, rapid absorption, 75% metabolism in liver
First order elimination, half life = 4 hr
MI therapy - antiplatelet function (prevents heart attacks)
What can large, therapeutic and toxic doses of aspirin cause
Large: dizziness, deafness and tinnitus
Therapeutic: gastric bleeding (5/6 mls blood loos) (2nd highest cause of gastric ulcers)
Toxic: uncompensated respiratory acidosis, metabolic acidosis
Side effects of NSAIDs
GI disturbances: dyspepsia, diarrhoea, nausea, vomiting, 1/5 chronic NSAID users have gastric damage
Piroxicam and meloxicam have the highest risk
Skin reactions
Effects of paracetamol (not an NSAID)
Analgesic, antipyretic, weak anti inflammatory
Metabolised in liver (Half life 2-4 hours)
Few side effects with therapeutic doses
Regular intake at high doses over long period increases the risk of kidney damage
Toxic doses: nausea and vomiting, 24-48 hours later fatal liver damage
describe COX2 inhibitors
Studied for analgesic / anti-inflammatory effects in arthritis
Recent warning about use of COX2 inhibitors due to risk of heart attack, stroke and cardiovascular death
What are resolvins protectin maresins
Molecules (chemical signals) that decrease pain, reduce bacterial and viral infections, increase wound healing and increase tissue regeneration
An inability to sustain these molecules can mean you have chronic inflammation
(Thought that these molecules are hugely increased following covid 19 infection)
Substance that blocks opiods (used if someone has overdosed)
Naloxone
Effects of opiods
Produces euphoria, analgesia and sleep
What are u, ó and k receptors
7 transmembrane spanning receptors coupled to G proteins (G0 / Gi) when coupled they are inhibitory
Inhibit adenylate cyclase and reduce cAMP
Alter ion channels through G protein coupling to channels
Open K+ channels - when opened on a sensory nerve, nerve is inhibited, helps maintain hyper polarisation of membrane (less easy to excite)
Close Ca2+ channels - important for fusion of vesicle with pre synaptic membrane and release of neurotransmitter
Effects if opiods on neuronal transmission
Opens K+ channels meaning membrane excitability is reduced,
Shuts off Ca2+ channel
Effects of morphine
Acts via a u receptor
Feeling of analgesia, euphoria and dysphoria - these are hard to separate as mediated by the same receptors
Tolerance
Dependence
Constipation
Anti-tussive (inhibits cough reflex)
Describe the issue of tolerance with morphine
Bigger dose for the same effect (can be seen within 7 days) due to number of receptors that can be activated being reduced
Percentage of pre and post synaptic opiod receptors
Presynaptic= 70% Postsynaptic = 30%
Describe the two neurone network
The idea of multiple neurones synapsing onto each other
Glutamate causes excitation but action potentials cannot fire all the time as they will cause hyperexcitation
GABAergic neurone ensures action potentials fire regularly and at the right time so less glutamate is released and less action potentials fired
What is opiod induced hyperalgesia
Sustained opioid use can drive pain sensitivity
What type of pain are opiods effective for
Good for post operative pain and end of life cancer pain (when given spinally)
Not very effective with chronic pain
How does high intensity pain influence opiod effects
An acute type of pain where opiod receptors cause a protective effect (signal is inhibited)
How does tissue damage influence opiod effects
A chronic type of pain where the opiod can cause hyperalgesia
Opiod inhibits the pain but not forever
How does nerve damage influence opiod effects
A fibres (touch fibres) cause allodynia (touch evoked pain) due to messages to the spinal cord being misinterpreted as painful
Alternative options when opiods don’t work
Change drug or route:
- switch to subcutaneous or epidural morphine
- changes in metabolism : effects of a single injected dose is 6x that of a single oral dose
Spinal opiod:
- epidural / intrathecal give little benefit over subcutaneous but is good for combination therapy
- infusion for chronic pains (end of life pain management)
Onset / duration of effect of opioids
Route of administration / formulation is not important for continual analgesia but is essential for as needed basis of treatment
Intravenous - 2 min average for most opioids
Intramuscular - lipophilic drug : 20 min
Oral: normal release 1 hour, sustained for 2-4 hours
Describe diamorphine (heroin)
High lipophilicity = brain penetration is rapid
Broken down to morphine in the CNS
More potent and addictive than morphine
Describe codeine
Weak opiate (20% of morphine)
Little or no addiction ??
Less respiratory depression
Good anti-tussive
What is respiratory depression
Inhibits respiratory medulla - eventually is fatal
Describe pethidine
A synthetic opiod
- orally active
- less potent
- short duration
- used in labour
Describe fentanyl
A synthetic opiod Often used in patches Highly potent Short duration High abuse rate Used in anaesthesia
Risk of taking opiods pre surgery eg osteoarthritis
OA often leads to a joint replacement and it has been found that using opiods to manage pain beforehand leads to about 50% of patients taking opiods 12 months after compared to 10% still taking it if they didn’t beforehand
This is due to hyperalgesia, dependency or surgery not working
Describe methadone
Plasma half life of >24 hours Used to reduce opiod abuse Physical abstinence syndrome is reduced Psychological dependence similar - in the presence of methadone, morphine / diamorphine less euphoria due to methadone being bound to the receptor
What is opiod tapering
The reduction of opiod doses over time
How is the opiod crisis being targeted
Opiod tapering to lower opiod consumption but this is challenging as there are limited alternatives and an increased risk of suicide has been reported in the US
Despite NICE guidelines chronic pain patients are given opiods which may exacerbate pain mechanisms
Types of anaesthesia
General anaesthesia
Regional anaesthesia: spinal, epidural, peripheral nerve block
Local anaesthetic
Define general anaesthesia
A drug induced reversible state consisting of unconsciousness, amnesia, anti-nociception and immobility with maintenance of physiological stability
What is propofol
1 or 2% lipid emulsion at room temp
Mild pain on injection
Licensed in UK since 1986
What does binding of agonists do (propofol)
Enhances affinity of the receptor for endogenous ligand ie gamma aminobutyric acid
Chloride influx causes hyperpolarisation
CNS effects of propofol
Loss of verbal contact within 10 seconds Atonia (lack of tone or energy) Unresponsiveness Loss of brainstem reflexes Apnoea
Brain and blood effects of propofol
Decrease in cerebral metabolic requirement for oxygen (CMRO2)
Decreased cerebral blood flow (CBF)
Decreased intracranial pressure (ICP)
Cardiovascular effects of propofol
BP = CO x SVR CO = SV x HR
SV determines by preload, afterload and contractility
Practicalities of propofol
Administered only by anaesthetists
Smooth induction and emergence from unconsciousness
Titratable for anxiolysis, sedation, anaesthesia
Predictable side effect profile
Reduces muscle tone in pharynx
Rocuronium pharmacology
Administered by IV bolus or infusion
Skeletal muscle paralysis in 30 seconds, lasting >30 mins
Offset is by diffusion away from NMJ to plasma
Deacetlyated in liver and excreted in urine
Rocuronium practicalities
Paralysis to facilitate intubation and surgery
Not an agent of unconsciousness
Anaphylaxis risk
What is sugammadex
Encapsulates Rocuronium molecules in its centre
A sugar molecule
Alternative to neostigmine
Chemistry of local anaesthetics
Amphipathic bases (both lipophilic and hydrophilic) Esters - cocaine, prilocaine, chloroprocaine Amides- lidocaine, bupivacine, ropivacine, levobupivacine
Inhibit action potentials in nociceptive nerve fibres and block transmission of pain impulses
Phases of nerve action potentials
Phase 1 : threshold potential
Phase 2: depolarisation, voltage gates Na+ channels open -> Na influx
Phase 3 : repolarisation, N+ channels close, K+ channels open -> K+ efflux
Phase 4: hyperpolarisation
Types of A fibres
All are myelinated A (alpha): somatic: motor / proprioception B (Beta): touch and pressure Y (gamma): muscle spindles D (delta) : fast pain, cold
B fibres
Myelinated , pre ganglionic, sympathetic
C fibres (unmyelinated)
Dorsal root, slow pain, heat
Post ganglionic sympathetic
Trends with A, B and C fibres
Decreasing diameter and velocity decrease
Increasing sensitivity to local anaesthetics
Eg A has biggest diameter but is least sensitive to local anaesthetics
Feelings after a local anaesthetic
May feel sick
Won’t be able to feel anything sharp or painful but may still feel touch or pressure
Will know something is going on but wont be painful
Define pKa of a drug
The pH at which ionised and unionised forms are present in equal amounts
Lower pKa = greater unionised form = faster onset of action (don’t work as well in inflamed / infected tissue
Lipid solubility of a drug
Quantified by oil : water partition co efficient
More lipid soluble = more able to cross the phospholipid bilayer = need less drug
Protein binding of a drug
Bind to a1 - acid glycoprotein
More protein bound = larger protein depot = longer duration of action.
Hypoxia, hypercarbia, acidaemia all lead to decreased protein binding and therefore toxicity
Local anaesthetic system toxicity
Na+ channel induced arrhythmia and neurotoxicity -> seizures -> cardiac arrest
Overdose or accidental intravenous injection
What is meningitis
Inflammation of meninges and CSF
These are usually sterile and have no microorganisms
What is encephalitis
Inflammation of the brain
What is myelitis
Inflammation of the spinal cord
What is neuritis
Inflammation of peripheral nerves
Routes of infection
Blood-borne
Parameningeal suppuration eg otitis media, sinusitis
Direct spread through defect in the dura eg post surgery and trauma
Direct spread through cribriform plate (base of skull) rare
Constituents of cerebrospinal fluid
Low protein - no complement
Low IgG
No lymphatics
Blood brain / CSF barrier (lipophilic compounds only)
Most common origin of bacterial meningitis
Nasopharynx
IgA protease, Pili, endocytosis, separate tight junction
Why are bacteria from meningitis not susceptible to breakdown from phagocytosis?
They have a thick cellular capsule which protects them from it.
Symptoms of meningitis
Headache global (all over)
Neck and back stiffness due to CSF coating and spinal cord
Nausea and vomiting
Photophobia (non specific) avoiding bright light
Don’t like legs being bent due to irritation of spinal cord
Other conditions that meningitis can occur from
UTI Dysentery SAH Malignancy NSAIDs
Physical signs of meningitis
Fever (not always present especially in elderly / young children)
Rash petechial / purpuric- usually meningococcal but also streptococcal
Meningeal irritiation : photophobia and irritation of motor roots by inflammation
Examples of irritation to motor roots by inflammation
Kernig’s positive due to hamstring spasm
Neck stiffness - unable to put chin on chest
Brudzinkis sign- flexing the patients neck causes flexion of the patients hips and knees
In mild meningism may not be present : unable to curl forward to put nose on knee
Meningitis in infants
Typical signs often not present Flaccid Bulging fontanelle due to increased ICP Fever and vomiting often the only sign Strange cry Convulsions
Lumbar puncture for meningitis diagnosis
Most rapid diagnostic test
Helps to distinguish between bacterial and viral causes in most cases (sometimes even fungal causes)
Contraindications of lumbar puncture in meningitis
Risk of herniation (CT head as raised ICP)
Risk of bleeding (abnormal clothing)
Why should you do a CT scan for suspected meningitis is patient is experiencing focal neurology, drowsiness or fitting etc
Because papilloedmea can be slow in its development - bulging around the optic nerve
Normal CSF white cell count
<5 white cells
CSF white cell count in bacterial meningitis
100-5000
Neutrophils are the predominant cell type
Source of listeria
Can survive in fridges eg unpasteurised cheese and pate
Causes of a lymphocytic mononuclear CSF (aseptic meningitis)
TB Partially treated bacterial infection Intracranial abscess Spirochaetes Viral meningo-encephalitis Lymphocytic leukaemias
Gram stain rapid diagnostic test for meningitis
Approx 50% sensitivity, 48hr culture and PCR more sensitive but slower
Zn rapid diagnostic test for meningitis
For AAFB but low sensitivity as few organisms are present / ml of CSF
PCR (detection nucleic acid) rapid diagnostic test for meningitis
Can be done on CSF or blood
Meningococcal on EDTA and CSF
HSV / enteroviruses on CSF
TB on CSF
Predisposing factors of pneumococcal meningitis
Immunosuppression Alcohol Diabetes Hyposplenism Myeloma
Describe pneumococcal meningitis
Pneumonia and / or otitis media present in <50%
Impaired consciousness, neurological signs and seizures more common
Mortality roughly 30% even with therapy
Pneumococcal vaccine provides some protection
Most at risk demographic for listeriosis
The immunocompromised, neonates and >50 years with rising incidence in age
How prevalent is listeriosis
It is present in 5% of healthy human stools
64% of fridge items contain at least 1 contaminated food item
Mortality >20%
Consequences of listeriosis
Meningo-encephalitis, abscesses, brainstem with ataxia (loss of muscle control in arms and legs) and movement disorders
Treatment of listeriosis
Amoxicillin +/- gentamicin (cephalosporins NO activity)
Normal meningitis treatment doesn’t treat listeriosis
Complications of meningitis
Death Subdural collection / empyema Cerebral vein thrombosis Hydrocephalus Deafness Convulsions Visual / motor / sensory deficit
How to manage meningitis
Antibiotics - has to be high dose agents that can cross the blood- CSF barrier- changes commonly as bacterias become more resistant
Adequate oxygenation
Prevention of hypoglycaemia and hyponatraemia
Anticonvulsants
Decrease intracranial hypertension
Alongside monitoring on ICU
Why can benzylpenicillin and gentamicin be used to treat meningitis only in neonates
Because it can only get into the CSF in the neonates
Antimicrobial therapy to treat N meningitidis
Ceftriaxone (benzylpenicillin if sensitive - no longer 1st choice due to resistance)
Antimicrobial therapy of H influenzae type b meningitis
Ceftriaxone (chloramphenicol)
Antimicrobial therapy of S pneumoniae meningitis
Ceftriaxone (benzylpenicillin if sensitive) Nb add vancomycin if risk resistant strain eg travel assoc
Antimicrobial therapy for an unknown organism meningitis in children >2 months and adults
Ceftriaxone and amoxicillin if >50 years or immunocompromised
Antimicrobial therapy of an unknown organism of meningitis for children <2 months (neonates)
Benzylpenicillin and gentamicin.
Dexamethasone (steroidal) treatment of meningitis
Hib meningitis reduces long term morbidity
Give prior to antibiotics for beneficial effect
Nb risk of GI bleeding
Data for pneumococcal infection as well but concern if resistant strain antibiotic penetration may be affected
Vaccination of meningitis
Conjugated Hib, meningococcal group C and pneumococcal vaccines protection in <2 years old
Meningococcal group ACWY conjugate 14 years
Men B vaccine
Polyvalent pneumococcal polysaccharide vaccine
Chemoprophylaxis of meningitis
Reduce secondary cases in close contacts and households of meningococcal and Hib disease
Rifampicin or ciprofloxacin clear nasopharyngeal carriage
What is neuritis
Inflammation of peripheral nerves (less common)
Infections eg leprosy, trypanosomes, CMV, Lyme neuroborreliosis
What is myelitis
Inflammation of the spinal cord - with or without encephalitis
Transverse - acute transaction of the cord
- Vasculitis of anterior spinal artery
- direct invasion of cord
- ascending - ascending flaccid paralysis and sensory loss
- anterior horn cells eg polio- flaccid paralysis muscle pain no sensory or bladder dysfunction - polio
What is encephalitis
Inflammation of the brain
Cerebral irritation / dysfunction can include
- irritability
- ataxia
- excessively brisk tendon reflexes
- signs of cerebral / brainstem failure
- signs of brain swelling eg focal neurological signs
Case definition for encephalitis
Encephalopathy (altered level of consciousness, cognition, behaviour or personality persisting for more than 24 hours)
And
>2 or more of the following
- fever or history of fever >38c
- seizures and / or focal neurological findings
- CSF pleocytosis
- EEG findings compatible with encephalitis
- abnormal results of neuroimaging
What is dependence syndrome
Strong desire or sense of compulsion to take the substance
Difficulties in controlling use
Physical withdrawal state
Tolerance
Progressive neglect of other interests, increasing time spent obtaining and taking substance
Functions of serotonin pathways
Mood
Memory processing
Sleep
Cognition
Functions of dopamine pathways
Reward (motivation) Pleasure, euphoria Motor function Compulsion Preservation
Which drugs increase dopamine release in the NAC (however all by different mechanisms)
Opiates Nicotine Amphetamine Cocaine Ethanol Cannabis Ecstasy Caffeine
Which drugs enhance serotonin function (5HT) N
LSD
Ecstasy
Which drugs block N methyl D aspartate- NMDA antagonists
Phencyclidine (PCP) and ketamine - hallucinogenic
Effect of amphetamines
Taken into nerve endings and causes dopamine release
Effects of cocaine
Blocks the reuptake mechanism of dopamine so more dopamine hangs around
Effects of morphine / cannabinoids
Major action on receptors on GABA neurons
Eg morphine inhibits inhibitory receptor leading to increased release of dopamine
How does microdialysis work
Substances from either side of the brain go into the dialysis fluid and then out so any neurotransmitters can be analysed
How does formulation of a drug affect its effect
IV heroin has a greater effect than methadone by mouth
Inhaling cocaine is better than chewing coca leaves
Smoking cigarettes is better than chewing tobacco
Due to faster and higher peaks in brain dopamine levels resulting in a greater rush
What are bromocriptines
A group of medicines called dopamine agonists that may be used for:
- stopping breast milk production for medical reasons
- problems usually caused by not having the right amount of prolactin (tumours)
- treating non cancerous tumours in the brain called prolactinomas
- treating Parkinson’s disease by activating receptors and helping motor skills
Why should you take bromocriptine with caution
Can cause some people to develop urges or cravings to behave in unusual ways, not being able to resist the impulse, drive or temptation to carry out certain activities that could harm yourself or others
(Impulse control disorders) : addictive gambling, excessive eating, spending, abnormally high sex drive
Alternative option to bromocriptine
Roprinole
Action of opiates
All agonists at G protein coupled opioid receptors (u receptors mainly) that lower neurotransmitter release in brain and periphery (are also located throughout GI tract hence causing constipation)
Effects of opiates
Analgesia, euphoria, positive reinforcement, respiratory depression (fatal caused by overdosing), dysphoria, sedation
Withdrawal symptoms
Craving, restlessness, muscle and bone pain, insomnia, diarrhoea, vomiting, cold flashes with goose bumps, kicking movement
How long do withdrawal symptoms typically last
Peak 48-72 hours after the last dose and subside after about a week
Sudden withdrawal by heavily dependent user in poor health is occasionally fatal, although heroin withdrawal is less dangerous than alcohol or barbiturate withdrawal
How does cocaine work
Increases catecholamine neurotransmitter function by preventing reuptake
Most important for CNS behaviour - high conc has anaesthetic properties
How do amphetamines work
Release monoamines from neuronal storage vesicles and block reuptake transporters causing increased synaptic DA, NA and 5HT
Psychological effects of amphetamines
Euphoria, increased libido, energy, self esteem, self confidence, aggression, excessive feelings of power, obsession, paranoia
Action of cannabis
Inhibits a wide range of neurotransmitter release in the brain and periphery via specific Gi protein coupled cannabinoid receptors
Effects of cannabis
Mild euphoric effect in moderate doses, dysphoric in high doses particularly in naive users
Very low acute toxicity but some concerns about precipitation of psychosis in chronic heavy users
Stimulates appetite through actions on feeding centres in the hypothalamus and gut
What is agonist substitution
Eg methadone treatment for opiate abuse (receptor agonist but stays in system for longer so reduced withdrawal and drug seeking)
Long acting synthetic opiate agonist, administered orally for sustained period at dose sufficient to prevent opiate withdrawal
Reduced effects of illicit opiate use and decreases opiate craving
What are antagonist treatments (naltrexone)
Naltrexone: therapy for opiate addiction. Patients must be de-toxified and opiate free for several days before naltrexone can be taken to prevent precipitating opiate asbtinence syndrome (helps someone who has overdosed to carry on breathing)
What is the agonist treatment (mecamylamine)
Nicotine acetylcholine receptor antagonist
Blocks rewarding actions of nicotine and cue-induced craving
How can naltrexone also be used as an anti craving medication
Reduces alcohol craving as well as treating opioid dependence as it interferes with positive reinforcement and possibly alcohol conditioned cues
Possibly acts by blocking endogenous opioid dis-inhibition of GABA neurones in VTA thereby reducing firing of dopamine releasing neurones
How is acamprosate used as an anti craving medication
Registered for use as adjunct in maintaining abstinence in alcohol dependent patients
Reduces neuronal excitability that occurs during alcohol withdrawal
What is a migraine
Painful pulsing headache
Lasting 4 hours to 3 days often unilateral and associated with photophobia and phonophobia
Prevalence peaks in middle age
Prodrome of migraine
A warning phase that occurs in 60%
Yawning, mood or appetite change
2 types of migraine
Migraine with and without aura
What is an aura in a migraine
Initial visual disturbance (around 30 mins)
Visual area lost, surrounding area shimmers
(15% of sufferers)
Symptoms of migraine
Unilateral throbbing headache lasting 4-72 hours
Photophobia
Nausea and vomiting
(85% of sufferers)
Heritability of migraines
Estimated 42%
38 genomic loci that affect migraine risk
Genetic mutation causing migraine
50% cases cause= point mutation in the CACNA1A gene that encodes pore forming a1A subunit of the P/Q voltage gated sodium channel. Mutations result in an altered channel conductance and density of expression in vitro in cell lines
30% of patients mutation in ATP1A2 gene that encodes the Na+ / K+ pump a2 subunit
Mutation in TRESK K2P potassium channel in spinal neurones associated with common migraine
SCN1A (sodium voltage gated channel alpha subunit 1) encodes NaV1
What is cortical spreading depression (CSD)
Likely cause of aura
Slowly propagating cortical waves of neuronal and glial cell depolarisation, start in the visual cortex and are followed by long lasting depression of activity
CSD activates the meningeal pain fibres by an unknown mechanism
Association of vasodilation and migraines
Role of vasodilation debated as unclear findings of imaging studies of meningeal and cortical vessels in humans during migraine attack, vasodilation not seen with spontaneous migraine
What causes pain in a migraine
Trigeminal nerve - 3 divisions innervate the forehead and eye, cheek and lower face and jaw
Activated by facial touch, pain and temperature
TGVS (trigeminovascular system) pain likely caused by activation of this system. Meningeal and superficial cortical blood vessels innervated by TG sensory nerves
TG nerves project to trigeminal nucleus caudalis neurones onwards to thalamus and cortex
Innervation of the opthalmic division of the trigeminal nerve
Innervates frontal and parietal cortex and meninges vascular beds
International classification of headache disorders (migraine without aura)
A: at least 5 attacks fulfilling criteria B-D
B: headaches lasting 4-72h (when untreated or unsuccessfully treated)
C: at least 2 of following characteristics:
- unilateral location
- pulsating quality
- moderate or severe pain intensity
- aggravation by or causing avoidance of routine physical activity
D: nausea, vomiting, photophobia and phonophobia
E: not better accounted for by another ICHD-3 diagnosis
International classification of headache disorders (Migraine with aura)
A: at least 2 attacks fulfilling criteria B and C
B: one or more of the following reversible aura symptoms
- visual, sensory, speech or language
- motor, brainstem, retinal
C: at least 3 of the following 6 characteristics:
- one aura symptom spreads gradually over >5 min
- 2 or more aura symptoms occur in succession
- each individual aura symptom lasts 5-6pm in
- one aura symptom is unilateral
- one aura symptom is positive
- aura is accompanied or followed within 60 min by headache
D: not better accounted for by another ICHD-3 diagnosis
Benefits of migraine diaries
Encourage patients to record details of migraine attacks: help doctors make a firm diagnosis; recognise warning signs of an attack; identifying triggers; assessing whether acute or preventative medication is working
Record: when pain begins, frequency, symptoms, length of attacks, pain location, type of pain, aspects of daily life, menstrual cycle
Trigger factors for migraines
Stress (75%) Refractory errors in glasses Chocolate, eggs, fruit Alcohol Oral contraceptive Time zone shifts Physical exertion
Medication for mild and / or occasional attacks (migraine)
Acute treatment: analgesic / NSAIDs (paracetamol, ibuprofen, diclofenac)
Anti emetics for nausea
Combine with rest and sleep
Step 2 of migraine medication therapy
Triptans (5HT 1b and 5HT 1d receptor agonists) causes constriction of cranial blood vessels and subsequent inhibition of neuropeptide release
Triptans available over the counter
Short acting poor CNS penetration
May cause chest pain due to coronary artery vasoconstriction so contraindicated in ischaemic heart disease
Will not prevent aura so take during headache attack
Prophylactic (preventative) migraine therapy
B blockers (propranolol, metoprolol), calcium channel blockers, anti-epileptics or pre menstrual oestrogen can be effective
NICE recommends acupuncture or gabapentin in treatment resistant cases and Botox (stops localised nerves firing) option for adults with frequent chronic migraine
CGRP receptor antagonists and monoclonal antibodies showing promise in clinical trials
How does IV injection CGRP provoke migraine attacks
Poor BBB permeability suggests peripheral mechanism
Dural application of CGRP causes vasodilation but not nociceptor activation
Importance of CGRP in migraines
CGRP is released during a migraine attack
In trigeminal ganglia CGRP is expressed in the C fibres and receptor expressed by Ad-fibres
Trigeminal ganglia is central to trigeminovascular reflex which is triggered during migraine and leads to perception of pain
Trigeminal ganglia and dura not being the BBB, and are likely target of anti-CGRP antibodies
also CGRP receptor antagonists and anti CGRP antibodies are effective for migraine pain relief supporting hypothesis that CGRP has major role in migraine pathophysiology
Association between migraines and COVID 19
25% present with migraine like features (no history)
Suggests activation of the trigeminovascular system
SARS COv2 protein has been found in the olfactory mucosa and bulbs, trigeminal branches and trigeminal ganglion
Brain vessel inflammation and cytokine responses may also contribute
Define emesis
A protective reflex to expel ingested toxins evident in man and most meal feeding mammals and is associated with nausea
Define nausea
Unpleasant sensation that immediately proceeds vomiting. A cold sweat, pallor, salivation, self absorption, loss of gastric tone, duodenal contractions and reflux of intestinal contents into the stomach often accompany nausea
Vomiting centre inputs
The chemoreceptor trigger zone (CTZ) at the base of the 4th ventricle has multiple receptors (dopamine D2, 5HT3, opioid and acetylcholine), a neurokinin (substance P) is the major output transmitter
Role of area postrema
(Not within the BBB), detects blood chemicals
Role of vestibular system
Via the vestibulocochlear nerve; plays a major role in motion sickness and is rich is muscarinic cholinergic and histamine H1 receptors
Role of the vagal nerve afferent in vomiting
Activated when the pharynx is irritated, leading to the gag reflex. Nucleus tracts solitarius has a high density of 5HT3 and NK1 receptors
Vagal and other gastrointestinal afferent responding to irritation of the GI mucosa by chemotherapy, radiation, distension or acute gastroenteritis via gut 5HT3 receptors
Role of intracranial pressure receptors in vomiting
Mediating nausea after head injury or meningitis
Best anti sickness treatment
Best single agent therapy is NK1 receptor antagonism (aprepitant)
Substance P is the major output transmitter from the vomiting centre; active against most cause s
How to control chemotherapy induced emesis
Controlled by a combination of a corticosteroid and a dopamine antagonist but 5HT3 antagonists are effective
Multiple neurotransmission systems are involved - combination therapy shows additive benefits and clinical trials have shown a combination of a NK1 antagonist, a 5HT3 antagonist, and a corticosteroid give 85-90% protection against highly emetic chemotherapy induced emesis
How to reduce severe nausea
More difficult to control even with the best anti emetics
Because it involves interactions with higher centres and is partly a learned response
A combination of anti-emetics and mild sedation (benzodiazepine) can be used to reduce severe nausea
What is a polymorphism
A mutation that exists in the population and can be present in 1-50% of the population
Not a 1:1 correlation, people having one of the variants may have a higher risk of disease but people without the variant can also get the disease
How to mutations and polymorphisms influence how people respond to pain killers
There are genes involved in how fast a drug gets into the bloodstream
Genes that influence how fast the drug breaks down in the body and how efficacious it is
And genes that determine side effects of drugs and all of these apply to pain medication
What is man on fire syndrome
Erythromelaglia (very rare)
Putting on a sweater, putting on shoes, going into a warm room, mild exercise all feel like hot lava being poured into their bodies
Mutation causing ‘man on fire’ syndrome
Mutations in the SCN9A gene
Encoding Nav1.7 which is involved in propagating electrical signals along nerves
The Nav1.7 channel is hypersensitive to stimulus in the man on fire syndrome
What is the Nav 1.7 molecule responsible for
Responsible for transmitting the pain signal in the neurons specialised in pain (nociceptive neurons)- regulating pain transmission
It is a voltage gated sodium channel
Is expressed only in sensory and nociceptive neurons
Mediate the inward sodium current of excitable cells regulating the action potential generation and propagation in neurons
Disadvantages of not being able to feel pain
People with congenital insensitivity to pain tend to die in childhood due to injuries or illnesses going unnoticed
- damage in and around oral cavity due to biting tip of their tongue
- Suffer fractures to bones
- Have unnoticed infections
- suffer burn injuries
What does a mutation in the Zfhx2 gene result in
Lower levels of potassium voltage gated channels
People with this mutation have some pain sensitivity and don’t have the problems that people with total pain insensitivity
What does reduced expression and activity of the FAAH enzyme result in
Painless injuries, frequent cuts and burns, heal quickly
What os fatty acid amide hydrolyse (FAAH)
One of the enzymes in the endocannabinoid system (similar to cannabis but endogenous)
Endocannabinoids are molecules produced by our own cells that bind the same cell surface receptors targeted by the active component of marijuana
3 basic components of the endocannabinoid system
Endocannabinoids
Cannabinoid receptors
Enzymes that break down Endocannabinoids (FAAH)
What is the transient receptor potential vanilloid (TRPV1)
Non selective cation channel activated by exogenous and endogenous physical stimuli
Activation of TRPV1 leads to a painful burning sensation. TRPV1 are found mainly in nociceptive neurons of the peripheral nervous system but are also present in other tissues including the CNS
Involved in transmission and modulation of pain as well as integration of diverse painful stimuli
Exogenous Activators of TRPV1
Heat greater than 43c
Capsaicin (compound in chilli peppers)
Allyl isothiocyanate (found in mustard and wasabi)
Endogenous activators of TRPV1
Low pH (acidic) N-arachidonoyl - dopamine (an endocannabinoid that acts as an agonist of the CB1 receptor) The endocannabinoid anandamide
How do Endocannabinoids and phytocannabinoids result in lower pain even though they activate TRPV1
They are agonists of TRPV1 and activate TRPV1 but the receptors are saturated (flooded) (immune to further stimulation) so no longer transmit pain
What happens to the drugs we take
Phase I metabolism:
Oxidation (cytochrome P450 enzyme), becomes more polar, chemically active drug
Phase II:
Conjugation with acetyl, methyl, glutathione and an ionisable group that increased water solubility and decreased drug activity
Renal excretion
What are cytochrome P450s
A superfamily of enzymes
Involved in drug metabolism and bio activation
Carry out the degradation of xenobiotics in humans
Happens mainly in liver
P450s transform drugs into soluble molecules that can then be excreted
Describe phase I metabolism of codeine
Codeine only has mild opioid properties while most of its analgesia and CNS depressant effects are based to its biotransformation to morphine, a reaction catalysed by CYP2D6 (a cytochrome P450)
Therapeutic recommendation for tramadol in a ultrarapid metaboliser phenotype
Reduce dose by 30% and be alert to ADEs eg nausea, vomiting, constipation, respiratory depression, confusion, urinary retention or select alternative drug
Therapeutic recommendation for intermediate metaboliser phenotype
Be alert to decreased efficacy. Consider dose increase. If response is still inadequate, select alternative drug (not oxycodone or codeine) be alert to symptoms of insufficient pain relief
Therapeutic recommendation for poor metaboliser phenotype
Select alternative drug!!
Not oxycodone or codeine or be alert to symptoms of insufficient pain relief
What is PCA
Patient controlled analgesia
Provides a small dose of (usually) morphine by a small button pressed by the patient as often as they need but not more than once within 5 mins
Why is it necessary to consider the morphine dose prior to a joint replacement surgery
Likely that the patient will already be on some sort of slow release morphine so they will have become tolerant to opioid and will need additional analgesia for the surgery
Describe the multimodal approach of managing pain after surgery
Using different analgesics that have different mechanisms of action:
Dose of paracetamol
NSAID
Opioid
Also use of a local anaesthetic: continuous infusion of a local anaesthetic into the area
Describe step down analgesia
(After a few days of PCA)
Multimodal approach: paracetamol, NSAID, opioid changes from IV to oral
What is a mu-opioid receptor antagonist
A new class of medication Used to specifically treat opioid caused constipation work by binding to opioid receptors in the gut and so preventing the GI side effects
Allows the opioid agonist eg morphine to get into systemic circulation eg brain which is where it is needed to have its effect
What is the PHQ-9
Patient health questionnaire
The depression model which scores each of the 9 DSM -IV criteria as 0 (not at all) to 3 (nearly every day)
Score of 5 = mild
10 = moderate
15 = moderately severe
20 = severe depression
