Centrally acting analgesics Opioids Biomedicine spring 08 Year 2 no 2 Frågor till [email protected].

Centrally acting analgesicsCentrally acting analgesicsOpioidsOpioids

Biomedicine spring 08Biomedicine spring 08Year 2 no 2Year 2 no 2

Frågor till [email protected]ågor till [email protected]

Pain medicationPain medication

ParacetamolParacetamol

NSAIDsNSAIDs

OpioidsOpioids

Steroids, radiation, TENS, acupuncture Steroids, radiation, TENS, acupuncture

PhysiologyPhysiology

Afferent, peripheral nerves C and AAfferent, peripheral nerves C and A

C-fibresC-fibres 0,5-1,5 0,5-1,5 m, <1 m/s, m, <1 m/s, unmyelinatedunmyelinated

AA-fibrer-fibrer1-5 1-5 m, 5-35 m/s, myelinatedm, 5-35 m/s, myelinated

(larger A(larger Atouch, vibration, proprioception)touch, vibration, proprioception)

Pain pathwaysPain pathways

Tissue damage releases bradykinin, serotonin, histamin, Tissue damage releases bradykinin, serotonin, histamin, lactate, ATP, ADP, potassium (among others) lactate, ATP, ADP, potassium (among others)

Glutamate (excitatory) transmittor in dorsal horn synapseGlutamate (excitatory) transmittor in dorsal horn synapse

GABA (inhibitory) transmittor interneuronGABA (inhibitory) transmittor interneuron

Pain, pathwaysPain, pathways

Nociceptive neurons in dorsal root ganglionNociceptive neurons in dorsal root ganglion Relays via tractus spinothalamicus, Relays via tractus spinothalamicus,

spinomesencephalicus and spinoreticularisspinomesencephalicus and spinoreticularis Reaches thalamus and ponsReaches thalamus and pons Connects to cortexConnects to cortex Inhibitory neuronsInhibitory neurons Inhibitory mechanoreceptorsInhibitory mechanoreceptors

Pain, pathwaysPain, pathways

Brain - upwards probably glutamat main Brain - upwards probably glutamat main transmittortransmittor

Downwards neurons GABA, ACh, Downwards neurons GABA, ACh, monoamines (serotonin, NA, DA).monoamines (serotonin, NA, DA).

Endogenous opioidsEndogenous opioids

Endorphin, enkephalin, dynorphinEndorphin, enkephalin, dynorphin

Spinal tract dynorphin interneuron, Spinal tract dynorphin interneuron, enkephalin downward inhibitory neurons.enkephalin downward inhibitory neurons.

In brain around ”pain centre” but also in In brain around ”pain centre” but also in areas not involved in nociception and non-areas not involved in nociception and non-neuronal tissuesneuronal tissues

Opioid receptorOpioid receptor

Receptors in brain and spinal cordReceptors in brain and spinal cord4 subtypes: 4 subtypes: (my)(my)and NOP (ORL-1)and NOP (ORL-1)

Opioid receptorOpioid receptor

G-proteinG-protein Intra/extracellular, intramembranousIntra/extracellular, intramembranousPre- and postsynaptic membranesPre- and postsynaptic membranes

NMDA-receptorNMDA-receptorN-metyl-D-AspartateN-metyl-D-AspartateLearningLearningActivation makes spinal neurons more Activation makes spinal neurons more

sensitive to pain stimulussensitive to pain stimulusLong-term C-fiberstimulation activates Long-term C-fiberstimulation activates

NMDA NMDA central sensitisation central sensitisationNMDA-antagonistsNMDA-antagonists

GlutamatGlutamat

Presynaptic ion channel calcium influx Presynaptic ion channel calcium influx glutamat releaseglutamat release

Crosses synapse and binds to NMDA-Crosses synapse and binds to NMDA-receptors postsynapticly receptors postsynapticly depolarisation depolarisation hyperexcitability in nociceptive neurons hyperexcitability in nociceptive neurons

Pre- and postsynaptic bindingPre- and postsynaptic binding

G-protein inhibits adenylate cyclaseG-protein inhibits adenylate cyclase

Lower content intracellular cAMPLower content intracellular cAMP

Opens KOpens K++, inhibits Ca, inhibits Ca2+2+

Inhibits pre-synaptic release of glutamatInhibits pre-synaptic release of glutamat

The opioid receptorThe opioid receptor

The opioid receptorThe opioid receptor

, , , , identical around 70%identical around 70% G-protein binds to 3rd receptor loopG-protein binds to 3rd receptor loop

The opioid receptor The opioid receptor (mu)(mu)

Mainly analgesic effectsMainly analgesic effects Respiratory depressionRespiratory depression Nausea / vomitingNausea / vomiting ConstipationConstipation Cough reflexCough reflex EuphoriaEuphoria AddictionAddiction SedationSedation Most analgesic opioids are Most analgesic opioids are -agonists-agonists

The opioid receptor The opioid receptor (delta) (delta)

Probably effects outside the CNSProbably effects outside the CNS

Some analgetic effektsSome analgetic effekts

Seizures?Seizures?

Least knowledgeLeast knowledge

The opioid receptor The opioid receptor (kappa) (kappa)

Analgesia on mainly spinal cord levelAnalgesia on mainly spinal cord level

Nausea and dysphoria Nausea and dysphoria

Psychotomimetic effects – limits abuse Psychotomimetic effects – limits abuse potentialpotential

Side effects - mechanismsSide effects - mechanisms

Respiratory depressionRespiratory depressionRespiratory centre (medulla oblongata) Respiratory centre (medulla oblongata)

Less COLess CO2 2 stimulationstimulation

Decreased respiratory rateDecreased respiratory rate Nausea / vomitingNausea / vomiting

Area postrema (medulla oblongata) Area postrema (medulla oblongata) (triggerzone vomiting reflex)(triggerzone vomiting reflex)

Stimulation of DA-receptorsStimulation of DA-receptorsStimulation mechano/chemoreceptors GI Stimulation mechano/chemoreceptors GI tracttract

Side effects - mechanismsSide effects - mechanisms

ConstipationConstipationperipheral and central affection peripheral and central affection less GI movement and increased less GI movement and increased

tonus tonus No toleransNo toleransLaxatives necessaryLaxatives necessaryPeroral naloxone possiblePeroral naloxone possible

ItchingItchingHistamine release or centrally Histamine release or centrally

mediatedmediated

Side effects - MechanismsSide effects - Mechanisms

SedationSedationOverdoseOverdose

Wrong strategyWrong strategy

Sleep deptSleep dept

DrugsDrugs

Agonists (Agonists (-receptors)-receptors)morphine, metadon, fentanyl, heroin morphine, metadon, fentanyl, heroin

Partial agonistsPartial agonistsbuprenorfin, kodein, tramadolbuprenorfin, kodein, tramadol

AntagonistAntagonistnaloxone naloxone

What is an opioid?What is an opioid?

Alkaloid (plant) or syntheticAlkaloid (plant) or synthetic

Morphine like effekts, inhibited by naloxonMorphine like effekts, inhibited by naloxon

OpiumOpium

Narcotic resin from opium poppies:Narcotic resin from opium poppies:morphine 10%, noskapin 6%, papaverin 1%, kodein morphine 10%, noskapin 6%, papaverin 1%, kodein 0,5% 0,5%

HistoryHistory

3400 BC3400 BCOpium puppies grown in Mesopotamia Opium puppies grown in Mesopotamia

460 BC460 BCHippocrates medicine (psychiatric disease Hippocrates medicine (psychiatric disease and epidemies)and epidemies)

HistoryHistory 330 BC330 BC

Alexander the Great introduces opium to Persia Alexander the Great introduces opium to Persia and Indiaand India

400 AD400 ADOpium with traders to ChinaOpium with traders to China

Parcelsus (1490-1541) opium as medicineParcelsus (1490-1541) opium as medicine

Laudanum (opium, sherry, cinnamon, clove bud Laudanum (opium, sherry, cinnamon, clove bud oil, saffron) 17th centuryoil, saffron) 17th century

HistoryHistory

Morphin 1806Morphin 1806Kodein 1832Kodein 1832Heroin 1832Heroin 1832

MorphinMorphin

CC1717HH1919NONO33

Greek. Morpheus (God of dreams)Greek. Morpheus (God of dreams) 1806 from opium1806 from opium 1956 chemical structure1956 chemical structure

Morphine Morphine

Half life 2-4 hoursHalf life 2-4 hours Bioavailability 10-50% (30%)Bioavailability 10-50% (30%) Distribution volume 3L/kgDistribution volume 3L/kg Bioaactive morphine-6-glucuronid (kidneys)Bioaactive morphine-6-glucuronid (kidneys) M6G half life 4-15 hoursM6G half life 4-15 hours

HeroinHeroin CC2121HH2323NONO5 5 (morphin (morphin

CC1717HH1919NONO33)) Higher fat solubilityHigher fat solubility Produced 1874Produced 1874 Bayer 1899 Bayer 1899 Drug Sweden until Drug Sweden until

1964 1964 Half life 30 minutesHalf life 30 minutes MorphineMorphine

KodeinKodein

CC1818HH2121NONO3 3 (morfin C(morfin C1717HH1919NONO33))Produced 1832Produced 1832Low receptor affinityLow receptor affinity10% into morphine 10% into morphine M6G M6G7-10% non-responders 7-10% non-responders Half life 2-4 hours.Half life 2-4 hours.10 mg morfin 10 mg morfin Kodein 60mg Kodein 60mg

DextropropoxifenDextropropoxifen

Half time 8-18 (90) hoursHalf time 8-18 (90) hoursActive metabolite norpropoxyfenActive metabolite norpropoxyfenMetabolite half life 30-45 (100) hoursMetabolite half life 30-45 (100) hoursAlcohol enhances respiratory inhibitionAlcohol enhances respiratory inhibition10mg morfin 10mg morfin 100mg Dextropropoxifen 100mg Dextropropoxifen

TramadolTramadol

Halflife 4-6 hoursHalflife 4-6 hoursActive metabolite D-desmetyltramadolActive metabolite D-desmetyltramadolHalflife metabolite 9-12 hoursHalflife metabolite 9-12 hours5-10% non-responders5-10% non-responders Inhibits reuptake NA / 5-HTInhibits reuptake NA / 5-HT

FentanylFentanyl

””Complicated kinetics” Complicated kinetics” Halflife 1 min, 8 min, 8 timHalflife 1 min, 8 min, 8 timActive metabolites unknownActive metabolites unknown10mg morfin 10mg morfin 0,05 mg fentanyl (iv) 0,05 mg fentanyl (iv)

PethidinePethidine

synthetic opioidsynthetic opioid

Most histamine release. Seizures.Most histamine release. Seizures.

100mg 100mg 10mg morphine 10mg morphine

Shivering Shivering

KetoganKetogan

Ketobemidon(hydroklorid)Ketobemidon(hydroklorid)NMDA – receptor antagonist?NMDA – receptor antagonist?Halflife 2-4 hoursHalflife 2-4 hoursUnknown metabolite activityUnknown metabolite activityAbuse riskAbuse risk ””Less documented morphine alternative”Less documented morphine alternative” ””only” indication only” indication renal failure (+NMDA?) renal failure (+NMDA?)10mg morphine 10mg morphine 10mg ketobemidon 10mg ketobemidon

OxicodonOxicodon

Halflife 2-4 timmarHalflife 2-4 timmarProbably inaktiva metaboliterProbably inaktiva metaboliter10mg morfin 10mg morfin 5mg oxikodon 5mg oxikodon

MetadonMetadon

NMDA-receptor antagonist ?NMDA-receptor antagonist ?Halflife 15-40 hoursHalflife 15-40 hours ””Bad reputation” Bad reputation” Advanced pain treatmentAdvanced pain treatment

Clinical useClinical use

Cancer painCancer painPostoperative painPostoperative painLong-term pain ?Long-term pain ?Neurogenic pain?Neurogenic pain? ””Always” in combination with paracetamol Always” in combination with paracetamol

and NSAIDand NSAIDElderly ?Elderly ?Try not to mix different opioidsTry not to mix different opioids

IntoxicationIntoxication

Mios (small pupils)Mios (small pupils)Lower conscienceLower conscienceBreathingBreathing

Antidote – Naloxone (Narcanti)Antidote – Naloxone (Narcanti)

opioid antagonistopioid antagonist reverses endogenous and exogenous reverses endogenous and exogenous

substanses and acupuncturesubstanses and acupunctureeffect within 2 minuteseffect within 2 minutes IteratedIterated iv + im when abuse overdoseiv + im when abuse overdose

AbstinenceAbstinence

sweating, fever (”cold turkey”), shakings, sweating, fever (”cold turkey”), shakings, muscular cramps, itching, diarrhea, muscular cramps, itching, diarrhea, nausea, vomiting (the flu)nausea, vomiting (the flu)

At pain treatment because of to quick At pain treatment because of to quick withdrawal withdrawal re-medicate! re-medicate!

Cold CaseCold Case

CancerCancerCurrent medication:Current medication:

Tb. Dolcontin (longacting morphine) Tb. Dolcontin (longacting morphine) 60mgx260mgx2Tb. Morphine (shortacting) 20mg as req.Tb. Morphine (shortacting) 20mg as req.inj. Ketogan 5mgvbinj. Ketogan 5mgvbTb. Tramadol 100mgx2Tb. Tramadol 100mgx2

Pain. What to do?Pain. What to do?

PatientfallPatientfall

Patient insatt på Ketogan tablett 5mgx6 Patient insatt på Ketogan tablett 5mgx6 med god effekt. Översatt till Dolcontin med god effekt. Översatt till Dolcontin 20mgx2. Inkommer efter 1 vecka till 20mgx2. Inkommer efter 1 vecka till akuten: illamående, kräkningakuten: illamående, kräkning

Diffdiagnos (opioidrelaterat) ?Diffdiagnos (opioidrelaterat) ?Ytterligare status etc?Ytterligare status etc?Vad göra?Vad göra?

Afterlife …..Afterlife …..

Morphina is currently Golden StandardMorphina is currently Golden Standard

Renal failureRenal failure

Treat pain! Treat pain!