Pain I: Opioids - McDougall 1 Flashcards
What is pain?
An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage
Nociception
Physiological processes in response to noxious stimuli
Allodynia
Pain in response to a normally innocuous stimuli
Enhanced pain repsonse
Hyperalgesia
Enhanced pain to a normally painful stimuli
Nociceptive pain
Direct activation of nociceptors by noxious stimuli
Ie. Touching something hot
Inflammatory pain
Activation by inflammatory mediators
Neuropathic pain
Pain arising from nerve damage
Pain pathway
Ascending processes
Nociceptor - Primary afferent - Dorsal root ganglion (cell body) - Second order neuron in SC - Brain
Pain sensation, cognitive interpretation, affective behaviour
Normal movement pathway
Ascending processes
Mechanosensors - Primary afferent - Dorsal root ganglion (cell body) - Second order neuron in SC - Brain
Peripheral sensitization pathway
Ascending processes
Nociceptor - Primary afferent - Dorsal root ganglion (cell body) - Second order neuron in SC - Brain
Central sensitization pathway
Ascending processes
Nociceptor - Primary afferent - Dorsal root ganglion (cell body) - Second order neuron - brain
Referred pain
Pain at a point in the body
Nerves in areas surrounding synapse onto the same projection neutron, giving feeling of pain in those areas too
Because of development of fetus and different derm layers
Glyco-heroin
To be used as cough suppressant
Mrs. Winslows Soothing Syrup
Opium and alcohol for soothing teething children
Opium
c. 3400 BC, lower Mesopotamia
1806: isolated morphine
Morphine
10% of opium
High analgesia, addictive
Codeine
0.3-2% opium
Less powerful analgesia, less addictive
Heroin
Bayer and Co synthetically modified morphine to reduce negative side-effects
Replaced 2H with 2CH3CO to make diacetylmorphine
Made heroin: highly potent analgesic but extremely addictive
Passes BBB better than morphine
Opiate
Drugs derived from opium
Opioid
Agents with opiate-like actions
Synthetic
Proteins that mimic opiate actions
Endorphins
Narcotic
Sleep inducing (pharmacological) Producing dependence (legal)
Opioid receptor subtypes
mu, delta, kappa, NOP
Mu opioid receptor
Endogenous ligand: endomorphin
Exogenous ligand: morphine, codeine, heroin
Antagonist: CTOP, DAMGO
Delta opioid receptor
Endogenous ligand: enkephalin
Exogenous ligand: diprenorphine
Antagonist: Naltrindole
Kappa opioid receptor
Endogenous ligand: dynorphin
Exogenous ligand: etorphine
Antaongist: nor-BNI
NOP opioid receptor
Endogenous ligand: nociception
Exogenous ligand: orphanin FQ(1-11)
Antagonist: nocistatin
Naloxone
Not-specific antagonist for opioid receptors
Site of action of opioids: Periphery
Receptors in periphery
Reduction in production of pain causing chemicals
Reduction in release of algogenic agents
Desensitize peripheral nerve
Site of action of opioids: SC
Mu opioid receptors on presynaptic terminal
Binding causes reduction of release of excitatory NT, resulting in reduction of CIP, Glu and SP, and reducing Ca influx
Postsynaptically, increasing K to cause hyperpolarization
Site of action of opioids: Supraspinal
Periaqueductal grey, insular cortex, dorsal raphe nucleus, nucleus raphe magnus
Opioids bind to receptors activating descending inhibitory pathways
Spinal release of 5-HT and NA
Inhibitory nerves activated
Receptors close to respiratory centres can cause respiratory depression
Site of action of opioids: Mesolimbic system
Ventral tegmental area, nucleus accumbens, amygdala
Stimulate dopaminergic circuits involved in reward, euphoria
Alters emotional response to pain
Acute inflammation
Upregulation of mu-opioid receptors in DRG
Increase axonal transportation of MOR
Increase in MOR in periphery and dorsal horn
Increase opioid analgesia
Chronic pain
Most painful conditions, >3mo
Opioids have reduced efficacy in chronic pain
Down regulations in areas of chronic inflammation
Opioid analgesia less effective
Negative side effects of opioids
Severe constipation, somnolescence, cardiorespiratory depression
Tolerance
Tolerance
Increasing doses required to achieve therapeutic level
Minimized by “start low, go slow”
Occurs 2-3 weeks after frequent opioid use
Mechanism of tolerance
Desensitization and trafficking via GPCR kinases
After arrestin binding, receptor is desensitized at surface, and then internalized
Receptors either recycled to cell surface of degraded in lysosome
Treatment of tolerance
Rotation to another opioid
Recouple to a non-opioid adjunct
Dependence
Addiction
State of physical and psychological dependence
Preoccupation with acquiring and using drugs despite knowledge of adverse health effects
Risk factors: serious history of substance abuse, mental illness, addictive personality
Physical dependence
Drug withdrawal produced physical abstinence syndrome
Mild: lacrimation, sweating, yawning
Severe: anorexia, cramps, nausea, vomiting, restlessness, irritability, tremor, HR/BP changes, chills, spasms, PAIN
Psychological dependence
Compulsive drug seeking behaviour
Occurs with drugs with mood enhancing properties
Activated dopaminergic circuits (endogenous reward system)
Treatment of dependence
Cessation of drug intake
Naltrexone (mu-antagonist)
Methalone (mu-agonist)
Methalone
Mu-agonist
Good oral bioavailability, selective
Long-lasting and slow withdrawal
Paradoxical opioid-induced hyperalgesia
Prolonged opioid use increases pain
Sensitization of peripheral nociceptors
Sensitization of dorsal horn neurons
Altered descending control mechanisms: Glu receptor involvement therefore, co-adminsiter Glu antagonist
Polypharmacy
Opioid + cannabinoid: synergistic effect (mu-opioid receptors dimerize with CB1)
Opioid + low dose amphetamine: offset sedation
Opioid + antidepressant: useful for neuropathic pain
Peripherally restricted opioids
Can target pain at the source
Reduce sensitization of nociceptors
Do not pass BBB
Less likely to cause addiction issues, centrally-mediated site effects like respiratory depression
Improve opioid receptor levels
Inhibit beta-arrestin activity to reduce receptor internalization
Inhibit receptor degradation (proteinase inhibitors)
Promote receptor recycling
