Analgesia and Analgesic Drugs Flashcards
Analgesics may reduce nociception by doing what? Give an eg of a drug which acts via each mechanism
- Acting at the site of injury – decrease nociceptor sensitization in inflammation (e.g. NSAIDs)
- Blocking nerve conduction – (e.g. local anaesthetics) – not considered here
- Modifying transmission of nociceptive signals in the dorsal horn of the signal cord (e.g. opioids and some anti-depressant drugs)
- Activating (or potentiating) descending inhibitory controls (e.g. opioids)
- Targeting ion channels upregulated in nerve damage
Outline the WHO analgesic ladder.
- NSIAD
- Weak opioid
- Strong opioid
Give examples of NSAID’s used in step 1 of the WHO analgesic ladder.
- Aspirin
- Diclofenac
- Ibuprofen
- Indometacin
- Naproxen
Give examples of weak opioids used in step 2 of the WHO analgesic ladder.
- Coedine
- Tramadol
- Dextropropoxyphene
Give examples of strong opioids used in step 2 of the WHO analgesic ladder.
- Morphine
- Oxycodon
- Heroin
- Fentanyl
What are opiates?
Substances extracted from opium, or of similar structure, to those in opium
What are opioids?
ANY agent (including endogenous peptides) that acts upon opioid receptors
What theory is segmental anti-nociception associated with?
The gate control theory
What are responsible for Supraspinal Anti-Nociception?
Descending pathways from the brainstem
What brain regions are involved in pain perception and emotion? Where do these project back to? To do what?
Cortex, amygdala, thalamus, hypothalamus.
Project back to the brainstem and spinal cord to modify afferent input.
Name 3 important brainstem regions in the perception of pain and emotion.
- The Periaqueductal Grey (PAG).
- Nucleus Raphe Magnus (NRM).
- Locus Coeruleus (LC).
What cause profound analgesic in PAG?
Excitation by electrical stimulation
What drugs can cause such excitation of PAG? How?
Endogenous opioids (enkephalins) or morphine, and related compounds. Cause excitation by inhibiting inhibitory GABAergic interneurons ie. disinhibition.
What neurone is NRM made up of?
Serotonergic and enkephalinergic neurones
What causes excitation of NRM?
Morphine
What type of neurones are found in the LC?
Noradrenergic
Segmental anti-nocicpetion….
Gate control theory
Supraspinal anti-nociception…
Descending pathways from the brainstem
What is opioid action mediated by?
G-protein coupled opioid receptors
What do these GPCR’s couple preferentially to?
Gi/o
What do G-protein coupled opioid receptors couple preferentially to Gi/o to produce?
- Inhibition of opening of voltage-activated Ca2+ channels.
(presynaptic effect – suppresses excitatory NT release from nociceptor terminals) - Opening of K+ channels.
(post-synaptic effect – suppresses excitation of projection neurones)
Opioid receptors are widely distributed throughout the __________
NERVOUS SYSTEM
What are opioid receptors traditionally classed as? Outline what each of these classes are responsible for.
- μ (mu, aka MOP*) responsible for most of the analgesic action of opioids – but, unfortunately, also some major adverse effects (e.g. respiratory depression, constipation, euphoria, sedation, dependence)
- δ (delta, aka DOP*) contributes to analgesia but activation can be proconvulsant
- κ (kappa, aka KOP*) contributes to analgesia at the spinal and peripheral level and activation associated with sedation, dysphoria and hallucinations
- ORL1 activation produces an anti-opioid effect
As analgesics, how do opioids mainly act?
Through prolonged activation of μ-opioid receptors
What kind of pain is morphine used in?
- Acute severe pain
* Chronic pain
How is morphine given in acute pain?
IV, IM or SC
In chronic pain, what kind of administration of morphine is most appropriate?
Oral - as immediate release Oramorph or as modified release MST continue
What other name does diamorphine go by?
3,6-diacetylmorphine.
or
Heroin
What is more lipophilic, morphine or diamorphine?
DIAMORPHINE
When given IV, what is the onset of action of diamorphine like?
RAPID - enters CNS rapidly
How is fentanyl given? Why?
Given IV to provide analgesia in maintenance anaesthesia
In what way is fentanyl suitable for in chronic pain states but not in acute pain?
Transdermal delivery
What is buprenophine useful in?
Chronic pain, with patient-controlled injection systems
What type of drug is buprenophine?
A partial agonist
What is the onset and duration of buprophine like?
Slow onset and long duration of action
Via what 2 routes can bupropion be given?
By injection, or sublingually
What is pethidine used in?
Acute pain, especially labour
What is pethidine NOT suitable for when given IV, IM or SC? Why?
Not suitable for control of chronic pain – due to short duration of action
What should pethidine not be used in conjunction with? Why?
MAO inhibitors – may cause excitement, convulsions, hyperthermia.
What is norpethidine?
A neurotoxic metabolite of pethidine
What are Codeine (3-methoxymorphine) + Dihydrocodeine?
Weaker opioids used in mild/moderate pain
HEPATIC METABOLISM occurs in relatively small amounts. What does this convert codeine/dihydrocodeine into?
Morphine and Dihydromorphine
How is codeine given?
ORALLY - not IV
Describe how tramadol (possibly) works.
- A weak μ-receptor agonist
- Probably exerts significant analgesic action by potentiation of the descending serotonergic (from NRM) and adrenergic (from LC) systems
How is tramadol given?
ORALLY
Who should never be given tramadol?
Patients with epilepsy
What type of drug is methadone?
A weak μ-agonist with additional actions at other sites in the CNS, including potassium channels, NMDA receptors and some 5-HT receptors
How is methadone given?
ORALLY
In terms of drugs with an abuse potential, which ones are generally more addictive?
Those with a short half life
What is the duration of action of methadone?
Long duration of action – plasma half-life of > 24h
What is the main use of methadone?
To assist in withdrawal from ‘strong opioids,’ such as heroin
What is the mechanism of action of naloxone?
A competitive antagonist at μ-receptors (to a lesser extent κ- and δ-receptors)
What is naloxone used for?
To REVERSE OPIOID TOXICITY (ie respiratory +/- neurological depression) associated with ‘strong opioid’ overdose
How is naloxone given?
Incrementally IV
- IM and S/C routes may be employed if the route isn’t practical
What is the half life of naloxone like?
SHORT
Why is it clinically important that Naloxone has a short half-life?
Since opioid toxicity can recur to ‘strong opioid’ agonists with a longer duration of action (clinically, you must monitor the effect of naloxone very carefully, titrating the individual dose, and frequency, to that required to reverse opioid toxicity)
In opioid addicts or those pts requiring high dose opioid analgesia regularly, what may the administration of naloxone do?
Trigger an acute withdrawal response
When else may naloxone be given?
May be given to a newborn displaying opioid toxicity (e.g. respiratory depression) as a result of administration of pethidine to mother during labour
What drug is similar to naloxone, but has a much longer half life?
Naltrexone
What do NSAID’s diminish?
Nociceptive sensitisation
What are NSAID’s, especially ibuprofen and naproxen used for?
To reduce mild/moderate inflammatory pain
What action do non-selective NSAID’s have? How do they achieve this?
Analgesic, antipyretic and anti-inflammatory actions
- achieved largely by inhibiting the synthesis and accumulation of prostaglandins by cyclo-oxygenase (COX) enzymes – COX-1 and COX-2
Give 5 examples of non-selective NSAID’s.
- Aspirin
- Ibuprofen
- Naproxen
- Diclofenac
- Indomethacin
Give 3 examples of COX-2 selective inhibitors?
- Etoricoxib
- Celecoxib
- Lumiracoxib
What do prostaglandins mediate?
Hyperalgesia
What is thromboxane-A2 responsible for?
- Platelet aggregation
* Vasoconstriction
What is prostacyclin (PGI2) responsible for?
- Platelet disaggregation
* Vasodilation
COX-1 is __________ active
CONSTITUTIVELY (always)
When is COX-2 induced?
During inflammation
What derives from inhibition of COX-2?
Therapeutic benefit
What problems occur through inhibition of COX-1?
GI toxicity
What do most cells generate PGE2 in response to?
Mechanical, thermal or chemical injury
What is the effect of PGE2?
It sensitizes nociceptive neurones, and causes hyperalgesia
What is paracetamol also known as?
Acetoaminophen
Why is paracetamol not classed as an NSAID?
Because it lacks anti-inflammatory activity, and only weakly inhibits COX isoenzymes
What is the analgesic effect of paracetamol due to?
Its metabolites (e.g. N-acetyl-p-benzoquinoneimine, which is also responsible for hepatotoxicity in overdosage). (TRPA1 has emerged as a recent, novel, target that is activated by such metabolites)
Why do NSAID’s have limited analgesic efficacy?
Because multiple signalling pathways, several of which don’t involve arachidonic acid metabolism, cause nociceptor sensitization
What are the main 2 side effects to be aware of with long-term administration of non-selective NSAIDs?
- GI damage
* Nephrotoxicity
Why can GI damage result from long term use of non-selective NSAID’s?
Because PGE2 produced by COX-1 protects against the acid/pepsin environment.
(and NSAIDs inhibit COX-1.)
Why can nephrotoxicity result from long term use on non-selective NSAID’s?
Because of inhibition of COX-2 constitutively expressed by the kidney
What kind of nephrotoxicity results from NSAID use?
Compromise renal haemodynamics in renal disease
Why is the use of selective COX-2 inhibitors limited?
They are pro-thrombotic
In what conditions does severe and debilitating neuropathic pain occur in?
- Trigeminal neuralgia.
- Diabetic neuropathy.
- Post-herpetic neuralgia.
- Phantom limb pain.
Is neuropathic pain easy to treat?
NO – it doesn’t respond to NSAIDs, and appears to be relatively insensitive to opioids (unless given at high doses)
What are the 3 groups of treatment options for neuropathic pain?
- Gabapentin + Pregabalin (anti-epileptics).
- Amitriptyline, Nortryptiline + Desipramine (tricyclic anti-depressants).
- Carbamazepine
What do gabapentin and pregabalin not act via?
The GABAergic system
What is the mechanism of action of gabapentin and pregabalin?
Reduce the cell surface expression of a subunit (α2δ) of some voltage-gated Ca2+ channels (high-voltage-activated subgroup) which are upregulated in damaged sensory neurones
What is gabapentin used in?
Migraine prophylaxis
What is pregabalin used in?
Painful diabetic neuropathy
What does the action of gabapentin and pregabalin ultimately cause?
A decrease of neurotransmitters, such as glutamate and substance P, from the central terminals of nociceptive neurones.
How do Amitriptyline, Nortryptiline + Desipramine act?
Act centrally by decreasing the reuptake of noradrenaline
Additionally, what do duloxetine and venlafaxine do?
Decrease the reuptake of 5-HT (but selective serotonin reuptake inhibitors (SSRIs) do not provide analgesia).
How does Carbamazepin work?
Blocks subtypes of voltage-activated Na+ channel that are upregulated in damaged nerve cells.
What is Carbamazepin the first line treatment for?
Control of pain intensity and frequency of attacks in trigeminal neuralgia
