Pain Flashcards
Nociceptors- what are they and the types
- are bare or free nerve endings and as a result do not stop responding to stimulation.
- They are distributed widely in the skin, dental pulp. bone, joints muscle, blood vessels, meninges and some internal organs.
- When stimulated they open ion channels that later membrane potential
1. Thermal
2. Mechanical
3. Polymodal
afferent neurones associated with nociceptors- what are they and what are the types of pain
- A-delta fibres (fast) transmit impulses at a rate of 5-30 m/s.
- C fibres (slow) and transmit impulses at 1.0 m/s.
- Fast pain, (Somatic) described as intense, sharp, stinging pain is perceived first because it is carried by A-delta fibres. This pain is easily localised and is not felt in the deeper tissues of the body. The urpose of this pain is reflexive- to withdraw from the harm.
- Slow pain (Visceral) can be described as dull, burning, aching or throbbing and is carried by the C- fibres. It is poorly localised, can be in the skin as well as any deep tissue or organ. Linked with pain memory and pain discomfort.
Pain pathways
- Stimulation of the nociceptor initiates an impulse along the afferent (towards) neural fibre to the spinal cord. This impulse is generated by action potential.
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What are prostaglandins and there functions
- Prostaglandins come from a large family derived from arachidonic acid (a fatty acid).
- This very large family includes prostaglandins, thromboxanes and leukotrienes.
- Only prostaglandin is connected with inflammation.
- Unfortunately Prostaglandin is very important in other ways too.
- It maintains the gastric mucosa, inhibits gastric secretion, smooth muscle contraction and dilation, coagulation, synaptic modulation and sleep regulation.
NSAIDs- MOA
- Non-steroidal anti-inflammatory drugs (NSAIDs) reduce the synthesis
of prostaglandins, potent sensitizers of primary afferent nociceptors, by inhibiting cyclooxygenase which is a key enzyme in the inflammatory cascade. - Cyclooxygenase is required to convert arachidonic acid into thromboxanes, prostaglandins and prostacyclins.
NSAIDs- consequences of inhibiting prostaglandins
- reduced inflammation
- antipyretic
- analgesic effect
- The risk of gastrointestinal and other side effects with NSAIDs often prevent their use, particularly in the elderly
- The effect of inhibiting thromboxanes is platelet adhesion (antithrombotic)
NSAIDs Absorption
- Most NSAIDs are rapidly absorbed following oral ingestion
*Peak plasma concentration reached within 2-4 hours
*Food delays absorption
NSAIDS- distribution
- Majority are weakly acid
*Bound highly to plasma proteins (>90%). Mainly albumin.
*Elderly have decreased concentration of serum albumin resulting in high free fractions (toxicity)
*Lipophilic
*Have the potential to displace other drugs (i.e Warfrin)
NSAIDs- metabolism and excretion
- Major metabolic pathway is hepatic oxidation or conjugation
- *Cytochrome P450 is the enzymatic catalyst for biotransformation
- *Hepatic biotransformation is followed by renal excretion
*Half life varies between NSAIDs
NSAIDs- Side effects
*Although available OTC not as safe as believed.
*The inhibition of prostaglandins leads to problems with regulating stomach acid, maintenance of stomach mucosa. The can led to ulceration and bleeding, diarrhoea, abdominal discomfort reflux. Diminished mucosal secretion,
*NSAIDs can worsen symptoms for asthmatics
*NSAIDs are associated with a fairly high incidence of renal adverse drug reactions, due to changes in renal kidney blood flow, ordinarily mediated by prostaglandins, resulting in decreased renal perfusion pressure and reduced GFR in pre-existing reduced renal function
- Cardiovascular: due to thrombolytic events and AF (Diclofenac)
*Selective cox2 inhibitors have been shown to have an increase in the rate of heart attacks and liver toxicity (have been withdrawn).
Opioids- and there receptors
- Opioids act as agonists at opiate receptor cites within the CNS and peripheral tissues. These are Mu, Kappa and delta.
- Mu receptors are found mainly in the brain stem and are responsible for supraspinal analgesia. Also respiratory depression, euphoria, sedation, reduced- gastro motility and physical dependence.
- Kappa receptors found in limbic areas, brain stem and spinal chord. Responsible for spinal analgesia, sedation, dysphoria and respiratory depression.
- Delta receptors are located in the brain and effects are not clearly understood.
Opioids- MOA
- These receptors are coupled via G proteins to adenylate cyclase (AC).
- This Inhibits cAMP (cyclic adenosine monophosphate) formation and the opening of potassium channels and closing of calcium channels-
- it is this closing of calcium channels that inhibits neurotransmitters such as substance P
- Substance P helps to transfer pain impulses to the CNS neurones
Different opiods and the receptors they stimulate
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Morphine Is a Mu, Kappa and Delta agonist.
Activation of the opiate receptors inhibits neural firing and neuro transmitter. Mu activation inhibits the ascending pain pathway. The Mu excitement is also responsible for the associated euphoric effect of opioids. Metabolites accumulate in renal failure. Half life 3 hours - Oxycodone is a Mu, Kappa and Delta agonist. Metabolites accumulate in renal failure. Half life 2.5 hours
- Fentanyl is a Mu Kappa and delta agonist, does not have metabolites that accumulate in renal failure. Half life 3hr
- Tapentadol is also a Mu receptor agonist and is classed for use in moderate to sever pain. And has comparable effect to oxycodone.
- Diamorphine (heroin) similar to morphine but when given by injection enters the nervous system more rapidly than morphine. Metabolites accumulate in renal failure.
- Buprenorphine is a partial agonist meaning it partially activates the mu- opiate receptors. This means it has a potent analgesic effect at lower doses. BUT at higher doses it becomes an opioid antagonist.
Weak opioids
- Codeine is a weak mu and kappa agonist. 100mg of codeine is approximately equivalent to 10 mg or oral morphine. Half life 3 hours. Needs to be metabolised to morphine first to be active (pro drug)-between 5-10% population lack the ability to do this conversion.
- Tramadol is a weak mu agonist similar to codeine with similar analgesic effect. Also inhibits noradrenaline and serotonin reuptake. It is reported to have less side effects than other mu receptors agonists primarily respiratory depression and gastrointestinal side effects. Tramadol 100mg is approx. 10mg oral morphine. Half life 6 hours.
What is dependence and tolerance
- Tolerance is when there is a decline in the pharmacologic effect after long term or chronic administration of the drug. With opioids repeated administration can lead to tolerance.
- Tolerance is usually accompanied by a degree of physical dependence. This is a physiological state where a person’s continuation of the drug is needed for their well-being.
- Tolerance and physical dependence represent the establishment of a new equilibrium between the neuron becoming less responsive to the drug while needing the continued levels of the drug for homeostasis.
OPioids- side effects
- There are opioid receptors on various parts of the body and it is the action of opioid drugs on these receptors that accounts for most of the side effects.
- Nausea and vomiting (stimulates Chemo receptor zone on the brain).
- Respiratory depression (a reduction in the sensitivity of respiratory centres in the brain stem to carbon dioxide).
- Gastro- intestinal motility.
- Urinary retention
- Reduced mental alertness
- Active opioid metabolites can accumulate in patients who are frail, debilitated or who have significant renal impairment
- This can lead to opioid toxicity, characterised by myoclonic jerks, excessive sedation or confusion, restlessness and hallucinations
- Hyperalgesia (increased sensitivity to pain) can also be a feature of opioid toxicity
- CNS effects of morphine may also be amplified when it is taken in combination with other centrally acting depressants, e.g. benzodiazepines, phenothiazines, tricyclic antidepressants or alcohol
Adjuvants
- Antidepressants: are the mainstay of pharmacological management of neuropathic pain. Tricyclic antidepressants, such as amitriptyline, nortriptyline and imipramine, prevent reuptake of endogenous serotonin (5-HT) and noradrenaline within the central nervous system, increasing the activity of the descending inhibitory pain pathways
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Anticonvulsants: this group of drugs act either by the blockade of sodium or voltage-gated calcium channels in nerve fibres, reducing excitability of neurons. These drugs may be effective in the management of chronic pain, although frequently cause adverse effects including ataxia, sedation and nausea. Examples
include carbamazepine, gabapentin and pregabalin. -
Corticosteroids: The pathophysiology of corticosteroid-induced analgesia is by primarily inhibiting
phospholipase A2 in the arachidonic acid pathway. These agents also
reduce oedema around pain-sensitive structures. - Side effects of steroid exposure include gastrointestinal disturbances (ie, gastritis and ulceration), hyperglycemia, hypertension, hyperalbuminemia, fluid retention, osteoporosis, immunosuppression, and myopathy. These patients are also susceptible to neuropsychological effects such as depression, mania, delirium, and even psychosis
SOCRATES
Paracetamol
The exact mechanism of action remains to be determined. There is evidence for
a number of central mechanisms. The main ones are:
1.Prostaglandin inhibition: Paracetamol does not have an anti-inflammatory action but it inhibits prostaglandin production. There is a suggestion that unlike NSAIDS paracetamol may act on Cox3 and Cox 1
2.Cannabinoid: Paracetamol is conjugated to form AM404. This inhibits the reuptake of the endocannabinoid anandamide which increases cannabinoid receptor activation. AM404
Pain in childre
§Children’s pain is very different to adults- emotional and psychological factors can affect comprehension and response.
§Assessment is difficult is commonly under-recognised, under-treated and treatment may be delayed in children
§Pain management is under researched so often results in inadequate management §Insufficient pain relief in newborns/infants cause long term changes in pain perception impacts pain in adulthood.
§Can have long term negative effects- eating/sleeping disorders, increased fears, PTSD
-For children (under 16 years of age), either paracetamol or ibuprofen alone are suitable first-line choices
-Codeine phosphate can be used for the relief of short-term acute moderate pain in children older than 12 years where other painkillers such
as paracetamol or ibuprofen have proved ineffective.
