ByBohlooli S. PhD

School of Medicine, Ardabil University of Medical Sciences

IntroductionOpium poppy is the source of crude opium Sertürner in 1803 isolated morphineNaming it after Morpheus, the Greek god

of dreamsOpioid analgesics is a widely used term

for:Natural, semi-synthetic, syntheticEndogenous peptides

SourceOpium, the source of morphine, is obtained

from the poppy, Papaver somniferum and P album

Opium contains many alkaloids, the principle one being morphine, which is present in a concentration of about 10%

Classification & ChemistryOpioid drugs include:

Full agonists Morphine

Partial agonists Codeine

Antagonists Naloxone

Chemical structure

ChemistryPhenanthrenes

Morphine, hydromorphone, and oxymorphone Codeine,oxycodone, dihydrocodeine, and

hydrocodonePhenylheptylamines

MethadonePropoxyphene

PhenylpiperidinesFentanyl, sufentanil, alfentanil, and remifentanilDiphenoxylate and its metabolite, difenoxinLoperamide

Morphinans

Chemistry; Opioids with Mixed Receptor ActionsPhenanthrenes

Nalbuphine , Buprenorphine Morphinans

ButorphanolBenzomorphans

PentazocineMiscellaneous

Tramadol, Tapentadol

Opioid Receptor Subtypes, Their Functions, and Their Endogenous Peptide Affinities

Receptor Subtype

Functions Endogenous Opioid Peptide Affinity

(mu) Supraspinal and spinal analgesia; sedation; inhibition of respiration; slowed gastrointestinal transit; modulation of hormone and neurotransmitter release

Endorphins > enkephalins > dynorphins

(delta) Supraspinal and spinal analgesia; modulation of hormone and neurotransmitter release

Enkephalins > endorphins and dynorphins

(kappa) Supraspinal and spinal analgesia; psychotomimetic effects; slowed gastrointestinal transit

Dynorphins > > endorphins and enkephalins

Endogenous Opioid PeptidesEndorphins

Drived from: prepro-opiomelanocortin Enkephalins

met-enkephalin leu-enkephalinDrived from: preproenkephalin

Dynorphins Drived from: preprodynorphin

EndomorphinsNociceptin / Orphanin FQ

Orphanin opioid-receptor-like subtype 1 (ORL1)

PharmacokineticsGeneric Name Receptor

Effects1

Approximately Equivalent Dose (mg)

Oral:Parenteral Potency Ratio

Duration of Analgesia (hours)

Maximum Efficacy

Morphine2

+++ + 10 Low 4–5 High

Hydromorphone +++ 1.5 Low 4–5 High

Oxymorphone +++ 1.5 Low 3–4 High

Methadone +++ 10 High 4–6 High

Meperidine +++ 60–100 Medium 2–4 High

Fentanyl +++ 0.1 Low 1–1.5 High

Sufentanil +++ + + 0.02 Parenteral only 1–1.5 High

Alfentanil +++ Titrated Parenteral only 0.25–0.75 High

Remifentanil +++ Titrated3

Parenteral only 0.054

High

PharmacokineticsGeneric Name Receptor

Effects1

Approximately Equivalent Dose (mg)

Oral:Parenteral Potency Ratio

Duration of Analgesia (hours)

Maximum Efficacy

Levorphanol +++ 2–3 High 4–5 High

Codeine ± 30–60

High 3–4 Low

Hydrocodone5

± 5–10 Medium 4–6 Moderate

Oxycodone2,6

± 4.57

Medium 3–4 Moderate

Propoxyphene (+, very weak)

60–1207

Oral only 4–5 Very low

Pentazocine ± + 30–507

Medium 3–4 Moderate

Nalbuphine –– ++ 10 Parenteral only 3–6 High

Buprenorphine ± –– –– 0.3 Low 4–8 High

Butorphanol ± +++ 2 Parenteral only 3–4 High

PharmacokineticsAbsorptionDistributionMetabolismExcretion

AbsorptionWell absorbedVariable first-pass metabolismSubcutaneous, intramuscular, and oral

routes- other routes:Nasal insufflationOral mucosa via lozenges Transdermal patches

MetabolismConverted to polar metabolites Morphine

morphine-3-glucuronide ::neuroexcitatory morphine-6-glucuronide ::potency four to six times Accumulation can produce unexpected results

Hydromorphone like morphine H3G has CNS excitatory properties

Esters (eg, heroin, remifentanil) are rapidly hydrolyzed Hepatic oxidative metabolism for phenylpiperidine opioids

meperidine, fentanyl, alfentanil, sufentanil Normeperidine cause seizures in renal failure

Polymorphism of CYP2D6 Codeine :: no significant analgesic effect or an exaggerated response

Mechanism of Action

Receptor TypesBased on pharmacologic criteria

1, 2

1, 2

1, 2, 3

Genetically one subtype from each of the , and receptor families

Cellular ActionsClosing voltage-gated Ca2+ channels on

presynaptic nerve terminalsInhibit release of

Glutamate, acetylcholine, norepinephrine, serotonin, and substance P

Hyperpolarizing and thus inhibiting postsynaptic neurons by opening K+ channels

Relation of Physiologic Effects to Receptor TypeOpioid analgesics act primarily at the -

opioid receptorAnalgesia, euphoria, respiratory depression,

and physical dependenceButorphanol and nalbuphine

Preference for opioid receptorsGreater analgesia in women

Receptor Distribution and Neural Mechanisms of Analgesia: Transmission

Receptor Distribution and Neural Mechanisms of Analgesia: Modulation

Ion Channels & Novel Analgesic Targets: chronic Pain Capsaicin receptor, TRPV1 and TRPA1 P2X : purines receptor Tetrodotoxin-resistant voltage-gated sodium channel (Nav1.8)-

PN3/SNS channel Lidocaine and mexiletine

Ziconotide,  a blocker of voltage-gated N-type calcium channels Related to marine snail toxin -conotoxin

Gabapentin/Pregabalin : analogs of GABA Ketamine: NMDA antagonists Nicotine 9-tetrahydrocannabinol

Tolerance and Physical DependenceTolerancePhysical dependenceWithdrawal or abstinence syndromeMechanism

receptor recyclingreceptor uncoupling

Organ System Effects of Morphine

Central Nervous System Effects

Cardiovascular SystemGastrointestinal TractBiliary TractRenal

UterusNeuroendocrinePruritus

Central Nervous System EffectsDegrees of Tolerance that May Develop to Some of the Effects of the Opioids.

High Moderate Minimal or None

Analgesia Bradycardia Miosis

Euphoria, dysphoria Constipation

Mental clouding Convulsions

Sedation

Respiratory depression

Antidiuresis

Nausea and vomiting

Cough suppression

Central Nervous System EffectsAnalgesia

Sensory Affective (emotional) Nonsteroidal anti-inflammatory analgesic drugs

Has no effect on emotional partEuphoria

Pleasant floating sensation Lessened anxiety and distress Dysphoria may occure

Sedation are common effects no amnesia Sleep is in the elderly Occurs more frequently phenanthrene derivatives

Central Nervous System Effects Respiratory Depression

Significant respiratory depression Sepressed response to a carbon dioxide challenge Influenced significantly by the degree of sensory input Most difficult clinical challenges

Cough Suppression Codeine May allow accumulation of secretions

Miosis Mediated by parasympathetic pathways

Truncal Rigidity Intensification of tone in the large trunk muscles

Nausea and Vomiting Activate the brainstem chemoreceptor trigger zone

Temperature -opioid receptor agonists hyperthermia -opioid receptor agonists hypothermia

Cardiovascular SystemBradycardiaMeperidine antimuscarinic action

tachycardiaHypotension may occur

Peripheral arterial and venous dilation Release of histamine Central depression of vasomotor-stabilizing

mechanisms

Caution in patients with decreased blood volume

Gastrointestinal TractConstipationthe stomach

Motility decrease Tone increaseGastric secretion of hydrochloric acid is

decreasedBiliary Tract

Contract biliary smooth muscle biliary colic

Sphincter of Oddi may constrict

Other Peripheral EffectsRenal

Antidiuretic effectEnhanced renal tubular sodium reabsorptionIncreased ureteral and bladder tone

UterusMay prolong labor

Neuroendocrinestimulate the release of ADH, prolactin, and

somatotropininhibit the release of luteinizing hormone

• Clinical Use of Opioid Analgesics• Toxicity & Undesired Effects

Alternative Routes of AdministrationRectal suppositories

morphine and hydromorphone

Transdermal patchFentanyl

IntranasalButorphanol

Buccal transmucosalFentanyl citrate lozenge

Patient-controlled analgesia (PCA) infusion device

Toxicity & Undesired EffectsBehavioral restlessness, tremulousness,

hyperactivity (in dysphoric reactions)Respiratory depressionNausea and vomitingIncreased intracranial pressurePostural hypotension accentuated by

hypovolemiaConstipationUrinary retentionItching around nose, urticaria (more frequent

with parenteral and spinal administration)

Tolerance and DependenceDoes not become clinically manifest until

after 2–3 weeksTolerance to methadone develops more

slowlyCross-tolerance is an extremely important

But often be partial or incompleteOpioid rotationRecoupling opioid receptor ketamine

Physical DependenceSigns and symptoms

RhinorrheaLacrimationYawningChillsGooseflesh (piloerection)HyperventilationHyperthermiaMydriasisMuscular achesVomitingDiarrheaAnxiety, and hostility

Physical Dependencetime of onset, intensity, and duration of

abstinence syndrome depend onbiologic half-lifemorphine or heroin, usually start within 6–10

hoursmethadone required several days

Psychologic DependenceEuphoria, indifference to stimuli, and sedationAbdominal effects that have been likened to an

intense sexual orgasmReinforced by the development of physical

dependence

The Opioid AntagonistsNaloxone,naltrexone, and nalmefeneMethylnaltrexone bromide Alvimopan