Pain I - Opioids Flashcards
What is pain?
An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage (from the International Association for the Study of Pain - IASP)
What is nociception?
The physiological process in response to a noxious stimulus.
What is allodynia?
Pain in resposne to a normally innocuous stimulus.
What is hyperalgesia?
Enhanced pain to a normally painful stimulus.
List three major types of pain
Nociceptive: Direct activation of nociceptors by noxious stimuli
Inflammatory: Inflammatory mediators
Neuropathic: Nerve damage
True or false? There is safe and effective treatment for chronic pain sufferers.
False
There is still no safe and effective treatment for chronic pain sufferers
List the steps in the pain pathway from nociceptor to brain
- Nociceptor
- Primary afferent
- Dorsal root ganglion (cell body)
- Second order neuron in spinal cord
- Ascending processes to brain
- Brain: affective behaviour
List the steps in the pathway of normal movement, from mechanosensors to brain
- Mechanosensor
- Primary afferent
- Dorsal root ganglion
- Second order neurone in spinal cord
- Ascending processes to brain
- Brain: movement
Give a brief (2 events) history of opioids
3400 BC: Opium poppy is cultivated in lower Mesopotamia. Sumerians refer to it as Hul Gil, the joy plant.
1806: Sertüner isolated morphine (named after Morpheus, god of dreams)
Define opiates and opioids
Opiates
- Drugs derived from opium
Opioids
- Agents with opiate-like actions
- Synthetic drugs
- Proteins that mimic opiate actions (endorphins)
Define narcotics.
A drug or other substance affecting mood or behavior and sold for nonmedical purposes, especially an illegal one.
Drugs that pharmacologically induce sleep and produce dependence.
List the four opioid receptor subtypes and their effect on neurons. List an endogenous ligand for each.
Inhibit depolarization
- μ: endomorphin
- δ: enkephalin
- κ: dynorphin
Depolarize neurons
- NOP: nociceptin
Describe how opioid receptors can provide novel modulation by interacting with other receptors.
Opioid receptors can dimerize.
For example, the μ receptor can dimerize with cannabinoid receptor, CB1 and cause novel modulation.
List the synthetic opioids for each opioid receptor.
μ: morphine, codeine, heroin
δ: diprenorphine
κ: etorphine
NOP: orphanin FQ (1-11)
List the antagonists for the four opioid receptors, and one non-specific antagonist.
μ: CTOP, DAMGO
δ: naltrindole
κ: nor-BNI
NOP: nocistatin
Naloxone is a non-specific antagonist.
Describe the action of opioids after a painful stimulus at a tissue level and a cellular level.
- Opioids are released from macrophages, mast cells and leukocytes near sensory endings in the dermis.
- Opioids sensitize peripheral nerves and reduce release of algogenic agents
- μ receptors in lamina II of dorsal horn
Pre-synaptically
- Excitatory NT release is inhibited
- Calcium influx is inhibited
Post-synaptically
- Potassium influx increases (hyperpolarization)
List the sites of action for opioids response to nociception
- The periphery (where stimuli occurs)
- MOR in lamina II of dorsal horn
- Supraspinal/brain (periaqueductal grey, insular cortex, dorsal raphe nuclei, nucleus raphe magnus
- Activates descending inhibitory pathways (spinal release of 5-HT and NE)
- Receptors close to respiratory centres give rise to respiratory depression - Mesolimbic system (VTA, Nucleus accumbens, amygdala,)
- Reward, euphoria, alters emotional response to pain
What are the most common therapeutic indications for opioids?
- Cancer pain
- Primary option for acute pain
- Reduced efficacy in chronic pain and increased risk of adverse effects
- Therapeutic use requires continuous assessment
Acute inflammation leads to the upregulation of what opioid receptor?
Upregulation of μ-opioid receptors at sensory nerve endings (periphery) and dorsal root ganglion. There is also upregulated axonal transport along the primary afferent.
All of this increases opioid analgesia in response to inflammation.
Why do opioids lose their effect for chronic pain?
During acute inflammation there is upregulation of opioid receptors and opioid analgesia is very effective. But during chronic inflammation, there is marked downregulation of opioid receptors and opioid analgesia is not very effective at all.
Give give main side effects of opioids
- Severe constipation
- Somnolescence
- Cardiorespiratory depression
- Tolerance
- Dependence (addiction)
Opioid use can lead to tolerance. Describe tolerance and the ways in which it can be minimized and treated.
Tolerance: increasing doses required to achieve therapeutic level. This occurs 2-3 weeks after starting opioid use.
It can be minimized by a low starting dose and a slow progression of dose
Treatment
- Rotation to another opioid
- Recoupling to a non-opioid adjunct (eg. ketamine)
Give the mechanism for opioid tolerance
Desensitization and trafficking is mediated by GRKs (G protein coupled receptor kinases)
- After arrestin binding, the receptor is desensitized at the surface. Then the receptors are internalized.
- They can be recycled or degraded in a lysosome.
Describe dependence associated with opioid use. Describe treatment.
Drug withdrawal produces physical abstinence syndrome:
Mild: lacrimation (flow of tears), sweating, yawning
Severe: Anorexia, cramps, nausea, vomiting, restlessness, irritability, tremor, HR/BP changes, chills and spasms. There is also PAIN.
Treatment
- Cessation of drug intake
- Naltrexone (μ-antagonist)
- Methadone (μ-agonist - good oral availability (no more injections), selective, long-lasting/slow withdrawal.
