Centrally acting analgesics Opioids

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Centrally acting analgesicsOpioids

• Biomedicine spring 08
• Year 2 no 2
• Frågor till karsten_at_narkos.se

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Pain medication

• Paracetamol
• NSAIDs
• Opioids
• Steroids, radiation, TENS, acupuncture

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Physiology

• Afferent, peripheral nerves C and Ad
• C-fibres 0,5-1,5 mm, lt1 m/s, unmyelinated
• Ad-fibrer 1-5 mm, 5-35 m/s, myelinated(larger
  Ab touch, vibration, proprioception)

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Pain pathways

• Tissue damage releases bradykinin, serotonin,
  histamin, lactate, ATP, ADP, potassium (among
  others)
• Glutamate (excitatory) transmittor in dorsal horn
  synapse
• GABA (inhibitory) transmittor interneuron

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Pain, pathways

• Nociceptive neurons in dorsal root ganglion
• Relays via tractus spinothalamicus,
  spinomesencephalicus and spinoreticularis
• Reaches thalamus and pons
• Connects to cortex
• Inhibitory neurons
• Inhibitory mechanoreceptors

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Pain, pathways

• Brain - upwards probably glutamat main
  transmittor
• Downwards neurons GABA, ACh, monoamines
  (serotonin, NA, DA).

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Endogenous opioids

• Endorphin, enkephalin, dynorphin
• Spinal tract dynorphin interneuron, enkephalin
  downward inhibitory neurons.
• In brain around pain centre but also in areas
  not involved in nociception and non-neuronal
  tissues

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Opioid receptor

• Receptors in brain and spinal cord
• 4 subtypes m(my), d, k and NOP (ORL-1)

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Opioid receptor

• G-protein
• Intra/extracellular, intramembranous
• Pre- and postsynaptic membranes

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NMDA-receptor

• N-metyl-D-Aspartate
• Learning
• Activation makes spinal neurons more sensitive to
  pain stimulus
• Long-term C-fiberstimulation activates NMDA ?
  central sensitisation
• NMDA-antagonists

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Glutamat

• Presynaptic ion channel calcium influx ? glutamat
  release
• Crosses synapse and binds to NMDA-receptors
  postsynapticly ? depolarisation ?
  hyperexcitability in nociceptive neurons

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Pre- and postsynaptic binding

• G-protein inhibits adenylate cyclase
• Lower content intracellular cAMP
• Opens K, inhibits Ca2
• Inhibits pre-synaptic release of glutamat

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The opioid receptor
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The opioid receptor

• m, d, k
• identical around 70
• G-protein binds to 3rd receptor loop

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The opioid receptor m (mu)

• Mainly analgesic effects
• Respiratory depression
• Nausea / vomiting
• Constipation
• Cough reflex
• Euphoria
• Addiction
• Sedation
• Most analgesic opioids are m-agonists

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The opioid receptor d (delta)

• Probably effects outside the CNS
• Some analgetic effekts
• Seizures?
• Least knowledge

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The opioid receptor k (kappa)

• Analgesia on mainly spinal cord level
• Nausea and dysphoria
• Psychotomimetic effects limits abuse potential

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Side effects - mechanisms

• Respiratory depression Respiratory centre
  (medulla oblongata) Less CO2 stimulation Decrea
  sed respiratory rate
• Nausea / vomiting Area postrema (medulla
  oblongata) (triggerzone vomiting
  reflex) Stimulation of DA-receptors Stimulation
  mechano/chemoreceptors GI tract

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Side effects - mechanisms

• Constipation peripheral and central affection
  less GI movement and increased tonus No
  tolerans Laxatives necessary Peroral naloxone
  possible
• Itching Histamine release or centrally mediated

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Side effects - Mechanisms

• Sedation Overdose
• Wrong strategy
• Sleep dept

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Drugs

• Agonists (m-receptors)morphine, metadon,
  fentanyl, heroin
• Partial agonistsbuprenorfin, kodein, tramadol
• Antagonistnaloxone

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What is an opioid?

• Alkaloid (plant) or synthetic
• Morphine like effekts, inhibited by naloxon

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Opium

• Narcotic resin from opium poppiesmorphine 10,
  noskapin 6, papaverin 1, kodein 0,5

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History

• 3400 BCOpium puppies grown in Mesopotamia
• 460 BCHippocrates medicine (psychiatric disease
  and epidemies)

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History

• 330 BCAlexander the Great introduces opium to
  Persia and India
• 400 ADOpium with traders to China
• Parcelsus (1490-1541) opium as medicine
• Laudanum (opium, sherry, cinnamon, clove bud oil,
  saffron) 17th century

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History

• Morphin 1806
• Kodein 1832
• Heroin 1832

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Morphin

• C17H19NO3
• Greek. Morpheus (God of dreams)
• 1806 from opium
• 1956 chemical structure

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Morphine

• Half life 2-4 hours
• Bioavailability 10-50 (30)
• Distribution volume 3L/kg
• Bioaactive morphine-6-glucuronid (kidneys)
• M6G half life 4-15 hours

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Heroin

• C21H23NO5 (morphin C17H19NO3)
• Higher fat solubility
• Produced 1874
• Bayer 1899
• Drug Sweden until 1964
• Half life 30 minutes
• Morphine

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Kodein

• C18H21NO3 (morfin C17H19NO3)
• Produced 1832
• Low receptor affinity
• 10 into morphine ? M6G
• 7-10 non-responders
• Half life 2-4 hours.
• 10 mg morfin ? Kodein 60mg

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Dextropropoxifen

• Half time 8-18 (90) hours
• Active metabolite norpropoxyfen
• Metabolite half life 30-45 (100) hours
• Alcohol enhances respiratory inhibition
• 10mg morfin ? 100mg Dextropropoxifen

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Tramadol

• Halflife 4-6 hours
• Active metabolite D-desmetyltramadol
• Halflife metabolite 9-12 hours
• 5-10 non-responders
• Inhibits reuptake NA / 5-HT

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Fentanyl

• Complicated kinetics
• Halflife 1 min, 8 min, 8 tim
• Active metabolites unknown
• 10mg morfin ? 0,05 mg fentanyl (iv)

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Pethidine

• synthetic opioid
• Most histamine release. Seizures.
• 100mg ? 10mg morphine
• Shivering

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Ketogan

• Ketobemidon(hydroklorid)
• NMDA receptor antagonist?
• Halflife 2-4 hours
• Unknown metabolite activity
• Abuse risk
• Less documented morphine alternative
• only indication ? renal failure (NMDA?)
• 10mg morphine ? 10mg ketobemidon

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Oxicodon

• Halflife 2-4 timmar
• Probably inaktiva metaboliter
• 10mg morfin ? 5mg oxikodon

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Metadon

• NMDA-receptor antagonist ?
• Halflife 15-40 hours
• Bad reputation
• Advanced pain treatment

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Clinical use

• Cancer pain
• Postoperative pain
• Long-term pain ?
• Neurogenic pain?
• Always in combination with paracetamol and
  NSAID
• Elderly ?
• Try not to mix different opioids

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Intoxication

• Mios (small pupils)
• Lower conscience
• Breathing

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Antidote Naloxone (Narcanti)

• opioid antagonist
• reverses endogenous and exogenous substanses and
  acupuncture
• effect within 2 minutes
• Iterated
• iv im when abuse overdose

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Abstinence

• sweating, fever (cold turkey), shakings,
  muscular cramps, itching, diarrhea, nausea,
  vomiting (the flu)
• At pain treatment because of to quick withdrawal
  ? re-medicate!

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Cold Case

• Cancer
• Current medicationTb. Dolcontin (longacting
  morphine) 60mgx2Tb. Morphine (shortacting) 20mg
  as req.inj. Ketogan 5mgvbTb. Tramadol 100mgx2
• Pain. What to do?

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Patientfall

• Patient insatt på Ketogan tablett 5mgx6 med god
  effekt. Översatt till Dolcontin 20mgx2. Inkommer
  efter 1 vecka till akuten illamående, kräkning
• Diffdiagnos (opioidrelaterat) ?
• Ytterligare status etc?
• Vad göra?

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Afterlife ..

• Morphina is currently Golden Standard
• Renal failure
• Treat pain!