Opioid Analgesics

Opioid Analgesics Opioid Analgesics

Munir Gharaibeh, MD, PhD, MHPEMunir Gharaibeh, MD, PhD, MHPEFaculty of Medicine, The University of Faculty of Medicine, The University of

JordanJordanApril, 2014April, 2014

Opioid Analgesics Opioid Analgesics OpioidOpioidAnalgesic Analgesic NarcoticNarcoticOpium: Opium: Papaver somniferumPapaver somniferumMorphine,Morphine, Morpheus , -ineMorpheus , -ineEndorphins Endorphins EnkephalinsEnkephalins

Apr 24, 2023Apr 24, 2023 22Munir Gharaibeh MD, PhD, MHPEMunir Gharaibeh MD, PhD, MHPE

Opioid AnalgesicsOpioid Analgesics

Dependence(Abuse, Addiction, Habituation): Dependence(Abuse, Addiction, Habituation): PsychologicalPsychological (Psychic, Craving, Compulsive)(Psychic, Craving, Compulsive)

PhysiologicalPhysiological ( (Physical, Adaptive Physical, Adaptive ......)......)Tolerance. Tolerance. Cross Dependence.Cross Dependence.Cross Tolerance.Cross Tolerance.



History of OpiumHistory of Opium

Papaver semniferumPapaver semniferum 3000 BC 3000 BCMorphineMorphine 1806 1806HeroinHeroin 1898 1898

الشرقية الهند الشرقية شركة الهند 16001600 شركة األفيون األفيون حرب 18421842--18391839 حرب

السيرنج السيرنج اختراع اختراع 18531853Morphine Receptors ”Goldstein”Morphine Receptors ”Goldstein” 1973 1973

Comparison of AnalgesicsComparison of Analgesics

OpioidsOpioids NonopioidsNonopioids EfficacyEfficacy StrongStrong WeakWeakPrototypePrototype MorphineMorphine AspirinAspirinPain RelievedPain Relieved Any TypeAny Type MusculoskeletalMusculoskeletalSite of ActionSite of Action CentralCentral Peripheral and Peripheral and

CentralCentralMechanismMechanism Specific ReceptorsSpecific Receptors PG Synthesis PG Synthesis DangerDanger Tolerance & Tolerance &

DependenceDependenceG.I irritationG.I irritation

Anti-inflammatoryAnti-inflammatory NoNo YesYesAntipyretic Antipyretic NoNo YesYesAntiplateletsAntiplatelets NoNo YesYes


Opiate Receptor EffectsOpiate Receptor EffectsMu1Mu1 Mu2Mu2 KappaKappa SigmaSigma DeltaDelta

MorphineMorphine BemazocineBemazocine N-allylcyclazocineN-allylcyclazocine Morphine,Morphine,Leu-enkephalinLeu-enkephalin

AnalgesiaAnalgesia No No analgesiaanalgesia

Analgesia; Analgesia; excessive excessive heatheat

No No analgesiaanalgesia

No No analgesiaanalgesia

ApneaApnea ApneaApnea ApneaApnea TachypneaTachypnea ApneaApneaIndifferenceIndifference SedationSedation SedationSedation DeliriumDelirium

MiosisMiosis MiosisMiosis MydriasisMydriasis

Nausea Nausea &Vomiting&Vomiting

Nausea Nausea &Vomiting&Vomiting


Opiate Receptor EffectsOpiate Receptor EffectsMu1Mu1 Mu2Mu2 KappaKappa SigmaSigma DeltaDeltaConstipationConstipation

Urine Urine retentionretention

DiuresisDiuresis

PruritusPruritus PruritusPruritus

Temperature Temperature increaseincrease

ToleranceTolerance LittleLittletolerancetolerance

ToleranceTolerance

CrossCrosstolerancetolerance

No mu No mu crosscrosstolerancetolerance

Mu crossMu crosstolerancetolerance


Opioid AnalgesicsOpioid Analgesics

PeptidesPeptidesAlkaloidsAlkaloids : : Natural Natural

Semi synthetic Semi synthetic SyntheticSynthetic


Opioid Peptides Opioid Peptides “1970s”“1970s”Peptides helped in the understanding of:Peptides helped in the understanding of:

Mechanism of actions of opioids.Mechanism of actions of opioids.Placebo effect of drugs.Placebo effect of drugs.Acupuncture.Acupuncture.Stimulation induced analgesia.Stimulation induced analgesia.Regulation of the release of pituitary Regulation of the release of pituitary hormones.hormones.


Opiate Receptor InteractionsOpiate Receptor Interactions


Sites of ActionSites of ActionSubstantia gelatinosaSubstantia gelatinosaPeriventricular areaPeriventricular areaPeriaqueductal greyPeriaqueductal greyHypothalamusHypothalamusThalamusThalamusStriatumStriatumLimbic SystemLimbic SystemNucleus accumbensNucleus accumbens



Receptor mechanisms of analgesic drugsReceptor mechanisms of analgesic drugs

The primary afferent neuron originates in the periphery and carries The primary afferent neuron originates in the periphery and carries pain signals to the dorsal horn of the spinal cord, where it synapses pain signals to the dorsal horn of the spinal cord, where it synapses via glutamate and neuropeptide transmitters with the secondary via glutamate and neuropeptide transmitters with the secondary neuron.neuron.

Pain stimuli can be attenuated in the periphery (under inflammatory Pain stimuli can be attenuated in the periphery (under inflammatory conditions) by opioids acting at mu -opioid receptors (MOR) or conditions) by opioids acting at mu -opioid receptors (MOR) or blocked in the afferent axon by local anesthetics.blocked in the afferent axon by local anesthetics.

Action potentials reaching the dorsal horn can be attenuated at the Action potentials reaching the dorsal horn can be attenuated at the presynaptic ending by opioids and by calcium blockers, alph 2 presynaptic ending by opioids and by calcium blockers, alph 2 agonists.agonists.

Opioids also inhibit the postsynaptic neuron, as do certain Opioids also inhibit the postsynaptic neuron, as do certain neuropeptide antagonists acting at tachykinin (NK1) and other neuropeptide antagonists acting at tachykinin (NK1) and other neuropeptide receptors.neuropeptide receptors.


Sites of action of opioid Sites of action of opioid analgesicsanalgesics

Inflamed or Inflamed or damaged damaged peripheral tissues.peripheral tissues.Spinal cord.Spinal cord.Thalamus.Thalamus.


Brainstem local circuitry Brainstem local circuitry underlying the modulating underlying the modulating effect of opioids on effect of opioids on descending pathways.descending pathways. The pain-inhibitory neuron is The pain-inhibitory neuron is indirectly activated by opioids indirectly activated by opioids (exogenous or endogenous), (exogenous or endogenous), which inhibit an inhibitory which inhibit an inhibitory (GABAergic) interneuron. (GABAergic) interneuron. This results in This results in enhancedenhanced inhibition of nociceptive inhibition of nociceptive processing in the dorsal horn processing in the dorsal horn of the spinal cord.of the spinal cord.


Opioid analgesic action on the descending inhibitory pathwayOpioid analgesic action on the descending inhibitory pathway

Sites of action of opioids Sites of action of opioids on pain-modulating on pain-modulating neurons in the midbrain neurons in the midbrain and medulla including the and medulla including the midbrain periaqueductal midbrain periaqueductal gray area (A), rostral gray area (A), rostral ventral medulla (B), and ventral medulla (B), and the locus caeruleus the locus caeruleus indirectly control pain indirectly control pain transmission pathways by transmission pathways by enhancing descending enhancing descending inhibition to the dorsal inhibition to the dorsal horn (C).horn (C).


Cellular Mechanisms of ActionCellular Mechanisms of Action Inhibit adenylate cyclase, so decrease cAMP.Inhibit adenylate cyclase, so decrease cAMP.

Inhibit Ca++ entry by decreasing phosphorylation of Inhibit Ca++ entry by decreasing phosphorylation of voltage operating Ca++channels.voltage operating Ca++channels.

Enhance K+ efflux.Enhance K+ efflux.

The net result is an increase in release of DA, 5HT, The net result is an increase in release of DA, 5HT, nociceptive peptides like substance P, resulting in nociceptive peptides like substance P, resulting in blockage of nociceptive transmission. blockage of nociceptive transmission.


Depressant Effects of MorphineDepressant Effects of MorphineSuppression of pain, analgesia.Suppression of pain, analgesia.Drowsiness and decreased mental Drowsiness and decreased mental alertness, sedationalertness, sedationDecreased respiration.Decreased respiration.Increased intracranial pressure.Increased intracranial pressure.Decreased myocardial oxygen demand.Decreased myocardial oxygen demand.Suppression of cough, antitussive.Suppression of cough, antitussive.


Depressant Effects of MorphineDepressant Effects of MorphineDecreased peristalsis.Decreased peristalsis.Inhibition of fluid and electrolyte Inhibition of fluid and electrolyte accumulation in the intestinal lumen.accumulation in the intestinal lumen.Decreased gastric acid secretion.Decreased gastric acid secretion.Inhibition of emetic center.Inhibition of emetic center.Slight decrease in body temperature.Slight decrease in body temperature.Decreased release of LH and FSHDecreased release of LH and FSH


Stimulant Effects of MorphineStimulant Effects of MorphineEuphoria.Euphoria.Constriction of pupils, miosis.Constriction of pupils, miosis.Stimulation of chemoreceptor trigger Stimulation of chemoreceptor trigger zone.zone.Increased tone of intestinal smooth Increased tone of intestinal smooth muscle.muscle.Increased tone of sphincter of Oddi, Increased tone of sphincter of Oddi, increased biliary pressure.increased biliary pressure.


Stimulant Effects of MorphineStimulant Effects of MorphineIncreased tone of detrusor muscle.Increased tone of detrusor muscle.Increased tone of vesical sphincter.Increased tone of vesical sphincter.Increased release of prolactin and Increased release of prolactin and antidiuretic hormone.antidiuretic hormone.Proconvulsant in overdose.Proconvulsant in overdose.


PharmacokineticsPharmacokinetics


Therapeutic UsesTherapeutic UsesAcute Pain.Acute Pain.Chronic Pain: Chronic Pain: but we should try:but we should try:

NonopiatesNonopiatesWeaker opiates.Weaker opiates.Regular fixed schedule.Regular fixed schedule.

Myocardial Infarction.Myocardial Infarction.Obstetric Anesthesia.Obstetric Anesthesia.Pulmonary Edema:Pulmonary Edema:

Relieve anxiety.Relieve anxiety.Cause peripheral poolingCause peripheral pooling

Constipating Effect.Constipating Effect.


Adverse Effects of OpioidsAdverse Effects of OpioidsBehavioral restlessness, tremulousness, and Behavioral restlessness, tremulousness, and hyperactivity.hyperactivity.Respiratory depression.Respiratory depression.Nausea and vomiting.Nausea and vomiting.Increased intracranial pressure.Increased intracranial pressure.Postural hypotension accentuated by Postural hypotension accentuated by hypovolemia.hypovolemia.Constipation.Constipation.Urinary retetion.Urinary retetion.Itching and urticaria.Itching and urticaria.


ContraindicationsContraindicationsHead Injury.Head Injury.Shock and decreased blood volume.Shock and decreased blood volume.Chronic Hypoxic Conditions.Chronic Hypoxic Conditions.


Tolerance to Opioids Tolerance to Opioids Factors Affecting Development of Tolerance:Factors Affecting Development of Tolerance:

Rate of AdministrationRate of AdministrationDoseDoseAgent used.Agent used.


Tolerance to OpioidsTolerance to OpioidsTolerance develops to almost all Tolerance develops to almost all actions of opioids, actions of opioids, EXCEPT:EXCEPT:

Miosis.Miosis.Constipation.Constipation.Convulsions.Convulsions.


Tolerance to OpioidsTolerance to OpioidsExact mechanism of tolerance to Exact mechanism of tolerance to opioids is unknown, but it is:opioids is unknown, but it is:Not metabolicNot metabolicNot immunologicNot immunologicHomeostaticHomeostatic



Opioid WithdrawalOpioid Withdrawal

6-12 hr:6-12 hr:Drug seeking (purposive) behavior, non Drug seeking (purposive) behavior, non purposive signs, such as restlessness, purposive signs, such as restlessness, lacrimation, rhinorrhea, sweating, yawning.lacrimation, rhinorrhea, sweating, yawning.12-24hr:12-24hr:Restless sleep for several hours (Restless sleep for several hours (yen) yen) and and feeling more miserable than before after feeling more miserable than before after awakening; irritability, tremor, dilated pupils, awakening; irritability, tremor, dilated pupils, anorexia, gooseflesh skin. anorexia, gooseflesh skin.


Opioid WithdrawalOpioid Withdrawal

24-72hr:24-72hr:Increased intensity of previous signs plus Increased intensity of previous signs plus weakness, depression, nausea, vomiting, weakness, depression, nausea, vomiting, intestinal cramps, diarrhea, alternate chills intestinal cramps, diarrhea, alternate chills and flushes, various aches and pains, and flushes, various aches and pains, increased heart rate and blood pressure, increased heart rate and blood pressure, involuntary movements of arms and legs, involuntary movements of arms and legs, dehydration and possible electrolyte dehydration and possible electrolyte imbalances. imbalances.


Opioid WithdrawalOpioid WithdrawalLater:Later:Symptoms of autonomic hyperactivity Symptoms of autonomic hyperactivity alternate with brief periods of restless sleep alternate with brief periods of restless sleep and gradually decrease in intensity until and gradually decrease in intensity until addict feels better in 7-10 days but may still addict feels better in 7-10 days but may still exhibit strong craving for the drug.exhibit strong craving for the drug.Some mild signs may be detectable for up to Some mild signs may be detectable for up to 6 months.6 months. Delayed growth and development of infants Delayed growth and development of infants born to addicted mothers may be detected born to addicted mothers may be detected for up to one year.for up to one year.


Treatment of Opioid DependenceTreatment of Opioid Dependence Suppression of Withdrawal SyndromeSuppression of Withdrawal Syndrome

MorphineMorphineHeroinHeroin

MethadoneMethadoneClonidineClonidine

Opioid Substitution:Opioid Substitution:MethadoneMethadoneLAAMLAAM

Detoxification:Detoxification:Gradually decreasing the dose of methadone.Gradually decreasing the dose of methadone.NaloxoneNaloxone

Narcotic Antagonists:Narcotic Antagonists:Naltrexone for 2-6 months following detoxification.Naltrexone for 2-6 months following detoxification.


Opioid AgonistsOpioid Agonists Morphine Morphine CodeineCodeineOxycodoneOxycodoneHydrocodoneHydrocodoneHeroinHeroinMeperidine (Pethidine)Meperidine (Pethidine)Methadone & L Methadone & L Acetyl Methadone (LAAM) Acetyl Methadone (LAAM)d- Propoxyphene.d- Propoxyphene.TramadolTramadol


Comparison of Opioid AgonistsComparison of Opioid AgonistsAnalgesiaAnalgesia AntitussiveAntitussive ConstipationConstipation Respiratory Respiratory

DepressionDepressionAbuse LiabilityAbuse Liability

MorphineMorphine ++++++ ++++ ++++++ ++++++ ++++++HeroinHeroin ++++++ ++++ ++++++ ++++++ ++++++++CodeineCodeine ++ ++++ ++++ ++ +,--+,--OxycodoneOxycodone ++++ ++++ ++++ ++++ ++++++MeperidineMeperidine ++++ ---- +,-+,- ++++++ ++++MethadoneMethadone ++++++ ++++ ++++ ++++++ ++++D-propoxypheneD-propoxyphene ++ ---- +,-+,- ++ ++


Partial Agonists-AntagonistsPartial Agonists-Antagonists

Pentazocine.Pentazocine.Buprenorphine.Buprenorphine.Nalorphine.Nalorphine.Nalbuphine.Nalbuphine.


AntagonistsAntagonists

NalorphineNalorphineNaloxoneNaloxoneNaltrexoneNaltrexone



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