Opioid Analgesic Drugs

Classification of Analgesic Drugs:

A. Opioid analgesics (Norcotic analgesics)Opiates-Morphine derivativesExamples: morphine, codeine, heroin, fentanylUses: moderate to severe pain

B. Non-opioid AnalgesicsWeak analgesics (Non-narcotic analgesics or Non-steroidal anti-inflammatory drugs)Examples: aspirin, acetaminophen (Tylenol), ibuprofen (Advil, Motrin)Uses: mild pain, anti-inflammatory

Transmission Modulation

Cortex

Midbrain

Medulla

Spinalcord

Ventral caudalthalamus

Dorsal hornRostral ventralmedulla

Periaqueductalgray

On the left, sites of action on the pain transmission pathway from the periphery to the higher centers are shown. A: Direct action of opioids on inflamed peripheral tissues. B: Inhibition occurs in the spinal cord. C: Possible site of action in the thalamus. Different thalamic regions project to the somatosensory (SS) or limbic (L) cortex. On the right,actions of opioids on pain-modulating neurons in the midbrain (D) and medulla (E) indirectly control pain transmission pathways.

AB

C

D

E

SS

L

Putative sites of action of opioid analgesics

CHICAGO TRIBUNE Friday January 26, 2007

3. Opioid Analgesic DrugsThe drugs used to alleviate moderate to severe pain are either opiates (derived from the opium poppy) or opiate-like (synthetic drugs). These drugs are together as OPIOIDS.Examples: Opiates: morphine, codeineOpiate-Like: fentanyl, meperidine, methadoneSee below the structures of some opioid analgesic drugs and derivatives

MorphinePentazocine

Meperidine Fentanyl

MethadoneSufentanil

Morphine analogues

4. Endogenous Opioids: Enkepalins , Endorphins, Dynorphins, Endomorphins

Enkepalins:Met-Enkepalin Tyr-Gly-Gly-Phe-Met Leu- Enkepalin Tyr-Gly-Gly-Phe-Leu

Endorphins:-neoendorphin Tyr-Gly-Gly-Phe-Leu-Arg-Lys-Tyr-Pro-Lys-neoendorphin Tyr-Gly-Gly-Phe-Leu-Arg-Lys-Tyr-Proh-endorphin Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-

Thr-leu-Phe-Lys-Asn-Ala-Ile-Ile-Lys-Asn-Ala-Tyr-Lys-Lys-Gly-Glu (31-Residues)

Dynorphins:Dynorphin A Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln Dynorphin B Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Gln-Phe-Lys-Val-Val-Thr

Endomorphins:Endomorphin 1 Tyr-Pro-Trp-Phe-NH2Endomorphin 2 Tyr-Pro-Phe- Phe-NH2

Endogenous Opioid peptides are derived from precursor peptides (proopiomelanocortin [POMC]) by protelytic clevage of POMC. POMC present in high level in the CNS (arcuate nuecleus, limbic, brain stem, spinal cord).Enkephalins activate mu () and delta () opioid receptors. Enkephalins have slightly higher affinity for the thanfor the opioid receptor. Endomorphins have very high affinity for the opioid receptor.

Synthethetic Opioid Peptides

DAMGO [D-Ala2, MePhe4, Gly(ol)5 ] enkephalin

DPDPE [D-Pen2, D-Pen5] enkephalin

DSLET [D-Ser2, Leu5] enkephalin-Thr6

DADL [D-Ala2, D-leu5] enkephalin

CTOP D-Phe-Cys-Tyr-D-Trp-Orn-Pen-Thr-NH2

FK-33824 [D-Ala2 , N-MePhe4, Met(O)5 –ol] enkephalin

[D-Ala2] Deltorphin I Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2

[D-Ala2, Glu4] Deltorphin II Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH2

Morphiceptin Tyr-Pro-Phe-Pro-NH2

PL-017 Tyr-Pro-MePhe-D-Pro-NH2

DALCE [D-Ala2, Leu5, Cys6] enkephalin

OPIOID RECEPTORS

Opioids bind to specific receptor molecule that mediates its effects. Several opioid specific receptors have been cloned: Mu (), Kappa (), and Delta () receptors. These receptors belong to G protein-coupled seventransmembrane receptor family. The amino acid sequences are approximately 65% identical among these receptors, but they have little homology with other G protein-coupled receptors (see below the Figure).

Mechanism of Opioid Receptor Function

1. , , and are functionally coupled to pertussis toxin sensitive heterotrimeric G proteins (Gi) to inhibit adenylyl cyclase activity.

2. Activates receptor-activated K+ currents which increase K+ efflux (hyperpolarization) reduces voltage-gated Ca2+ entry.

3. Hyperploarization of membrane potential by K+ currents and inhibition of the Ca2+ influx prevents neurotransmitter release and pain transmission in varying neuronal pathways.

receptor

κ receptor

receptor

periaqueductal gray, spinal trigeminal nucleus, cuneate

and gracile nuclei, thalamus regions, dorsal corn of the spinal cord (DHSC)

nucleus of solitract, nucleus

ambiguus

parabrachial nucleus

neurons of the postrema

hyphothalamic region, DHSC

DHSC

Pain perception (morphine analgesia)

Morphine-control respiration

Morphine- depress respiration

Nauesea and vomiting

Neuroendocrine effects

Opioid Receptor Expression

CLASSIFICATION OF OPIOID ANALGESIC DRUGS

Strong Agonists:Morphine- 4 hrMeperidine- 2 hrMethadone- long acting (half life 24 hrs)Heroin- 2 hr; 3-fold increase in potency, no acceptable medical value in US Fentanyl- 5 to 45 min, anestheticOxycodone- 4 hModerate Agonists:PropoxypheneCodeineHydrocodoneMixed Agonist-Antagonists:Pentazocine- agonist on receptor and weak antagonist at and receptorNalbuphine- similar to Pentazocine but potent anatagonist at receptorBuprenorphine- lipophilic, about 0.4 mg equivalent to 10 mg morphine, partial agonist, and

antagonist at receptorAntagonists:Naloxone- it rapidly displaces bound opioids from receptor within 30 sec of IV injection, reverses the respiratorydepression and coma due to heroin overdose, competitive antagonist for , , and receptors with a 10-fold higheraffinity for receptor than for .Naltrexone- longer duration of action than naloxone, a single oral dose blocks theeffects of injected heroin (48 hrs)

SELECTIVITY OF OPIOID DRUGS AND PEPTIDES FOR DIFFERENT RECEPTORSCompund AgonistsMorphine +++ +Methadone +++ +Meperidine ++ + +Codeine + + +Etorphine +++ +++ +++Fentanyl +++

Sufentanil +++ + +

Endogenous PeptidesMet-enkephalin ++ +++Leu-enkephalin ++ +++-Endorphin +++ +++-Neoendorphin + + +++Dynorphin A ++ +++

AntagonistsNaloxone - - - - - -Naltrexone - - - - - -

Mixed aganists/antagonistsPentazocine - +Nalbuphine - - ++Buprenorphine ++ - -

Synthetic opioid peptidesDAMGO +++ +CTOP - - - -

(+) agonist; (-) antagonist

PHARMACOLOGIC ACTIONSMorphine and related opioids produce their major effects on the central nervous system and gastrointestinal tract

A. Central Nervous System

1. Analgesiaproduces selective attenuation of pain perception; effect is dose-dependenttherapeutic dose (10 mg; parentral)

pain less intense (pain threshold not elevated)less discomfort (more effective for dull pain)euphoriadrowsiness

higher doses (15 – 20 mg; parentral)pain threshold elevatedrespiratory depression may be significantsharp intermittent pain relievedthese doses DO NOT produce slurred speech, motor ataxia or protection from seizures

Sites of actionPeriaqueductal Grey (PAG)Caudal brain stem (nucleus raphe magus, magnocellular reticular formation)Spinal cordLimbic system

Mechanism of actionopioids generally produce inhibition of neuronal activityopioids inhibit the release of neurotransmittersopioids activate descending inhibitory systems

2. SEDATION: In humans, opioids usually produce sedation; however, in extremely high doses opioids produce convulsions (e.g., meperidine)3. EUPHORIA: Euphoria is often produced by opioids. Euphoria is more prominent in those previously addicted to opioids4. MENTAL CLOUDING: The environment is perceived as indistinct and unreal

5. RESPIRATORY DEPRESSION:Produced even in small dosesLarge doses may induce respiratory failureDeath from morphine overdose is usually due to respiratory failurePain can stimulate respirationOpioids decrease sensitivity of brain stem centers to CO2 (i.e., depress CO2 sensing capacity)Pure oxygen can induce apnea during severe respiratory depression

6. NAUSEA AND VOMITING:Opioids can stimulate the chemoreceptor trigger zone (CTZ)Located in the area postrema in the medulla oblongataDepression of the vomiting center is also producedSymptoms can be controlled by Phenothiazines (agonist on receptor weak antagonist on receptor

7. COUGH REFLEX (antitussive effect):Opioids suppress the cough reflexProduced by depression of neurons in medulla which control the cough reflexCodeine is a potent inhibitor of the cough reflexMeperidine has a weak effectDextromethorphan has no GI effects, no respiration depression, no analgesia

8. PUPILLARY DIAMETER:Opioids cause miosis (pupillary constriction). Opioids act on and receptors to stimulate oculomotor nucleus to constrict pupil. Pin point pupils are characteristics of morphine overdose. There is very little tolerance to this effect.

B. GASTROINTESTINAL TRACTDecreases GI motilityIncreases GI toneProduces constipation (Diphenoxylate-meperidine derivative [Lomotil])GI spasms can be controlled by atropine (acetyl choline receptor antagonist)Biliary tract spasm. Opioids can exacerbate biliary colic

C. CARIOVASCULAR SYSTEM No prominent effectsPeripheral vasodilation most prominent effect due to histamine release and decreased adrenergic toneVery high doses may produce bradycardiaOrthostatic hypotension

D. URINARY TRACTOpioids produce urinary retensionIncrease tone of urinary sphincter Decrease urine production (increased ADH secretion)

E. UTERUSDuration of labor may be prolonged

F. BRONCHIAL SMOOTH MUSCLETherapeutic doses have no effectHigh doses produce constriction (can aggravate asthma)

PHARMACOKINETICS

i. Absorption:Readily absorbed from all sites of administration

ii. Distribution:Distributed to all tissuesMorphine is poorly transported across the blood-brain barrier

iii. Metabolism: The major mechanism is conjugated with glucuronic acid in the liver. Morphine and naloxone are subject to significant “first-pass” metabolism in the liver, but naltrexone is not.

iv. Excretion:Free and conjugated morphine are excreted in the urine

THERAPEUTIC INDICATIONSPAIN

i. Chronic pain (only under some circumstances)Most chronic pain states are not relieved by opioid drugs:

central paintrigeminal neuralgia (tic douloureux)causalgiaphantom limb paincancer painlower back pain

These pain states require continuous medicationTherapy limited by tolerance and physical dependence

Chronic pain arising from terminal illness can be relieved by opioid drugs

ii. Acute Pain postoperative paindiagnostic proceduresorthopedic manipulationsmyocardial infarction

iii. Preanesthetic medication (fentanyl-derivatives)

iv. Dyspnea

v. Cough Suppression (codeine, dextromethorphan)

vi. Diarrhea and dysentery

CONTRAINDICATIONS

i. Decreased respiratory reserveemphysemasevere obesityasthma

ii. Biliary colic

iii. Head injury

iv. Reduced blood volume

v. Hepatic insufficiency

vi. Convulsant states

ACUTE TOXICITY

i. Severe ToxicityEstimates: 30 to 120 mg (oral) of morphine

ii. Lethal doseHighly variable: > 120 mg (oral) may be lethal

iii. SymptomsProfound comaDepressed respiration (2 to 4/min)CyanosisLow blood pressurePinpoint pupilsDecreased urine formationLow body temperatureFlaccid muscles

iv. TreatmentVentilation (do not give 100% oxygen because it can induce apnea)Naloxone (Narcan) will reverse toxic signsNaltrexone has a longer duration of action

CHRONIC TOXICITYTolerance and physical dependence are manifestations of chronic toxicityi. Tolerance

Tolerance develops to:AnalgesiaEuphoriaSedationLethal doseNausea

Tolerance DOES NOT develop to:Respiratory depression (partial)MiosisConstipationCross –tolerance develops to other opioids

ii. PHYSICAL DEPENDENCEAbnormal physical state in which the drug must be administered to maintain “normal” function. Physical dependence is manifested by “withdrawal symptoms” when administration of the drug is stopped. Physical dependence is a powerful reinforcement for continued drug taking behavior

Symptoms: 8 - 12 hrs: lacrimation, rhinorrhea, yawning, sweating

12 – 14 hrs: restless sleep (yen)

48 – 72 hrs: symptoms peak, dialted pupils, anorexia, gooseflesh (cold turkey),restlessness, irritability, tremor, nausea/vomiting, intestinal spasm and diarrhea, muscle spasm

7 – 10 days symptoms end

OTHER OPIOIDS

Codeine – less potent than morphinemainly used as antitussive

Meperidine – less potent than morphinehigh doses produce excitation and convulsionsless smooth muscle spasm and miosis than morphinelittle antitussive action

Diphenoxylate (Lomotil) –meperidine derivative used to treat diarrhea

Methadone – long duration of action (24 hr)withdrawal protracted and attenuatedused to treat addiction

Propoxyphene (Darvon) –mild analgesic action

OPIOIDS WITH AGONIST/ANTAGONIST PROPERTIES

Pentazocine (Talwin) – less potent than morphinewill precipitate withdrawal in dependent individualsmay produce dysphoriamay be orally

Nalbuphine (Nubain) –similar to pentazocinenot effective orally

Butorphanol (Stadol) -similar to pentazocinenot effective orally

ANTAGONISTSNaloxone –Eliminated first pass metabolism (half life 60 to 100 min)Readily reverses the coma and respiratory depression of opioid overdose.Rapidly displaces all receptor bound opioid molecules; therefore it is very effective reversing heroin overdose.Competitive antagonist for , , and ; 10-fold higher affinity for than for . This may explain why naloxone readily reverses respiratory depression with only minimal reversal of analgesia that results from agonist stimulationof receptors in the spinal cord.

Naltrexone – longer duration of action (up to 48 hrs)

Study Aid- Lecture # 72 Opioid Analgesic DrugsKnow about mechanism of nociception (physiology)Dorsal corn of the spinal cord – gate control mechanismKnow about classification of opioid analgesic drugs

Strong agonists – morphine, meperidine, methadone, heroin, oxycodone, fentanylModerate agonists – propoxyphene, hydrocodone, codeineMixed agonists-antagonists – pentazocine, nalbuphine, buprenorphineAntagonist – naloxone, naltrexone

Know about endogenous opioid peptides- Enkepalins, endorphins, dynorphins, endomorphins

Know about opioid receptors and the mechanism of action- Mu (), Kappa (), Delta (). All G-protein coupled receptors. Increase K+ efflux (hyperpolarization) and reduce voltage-gated Ca2+ entry.Know about the sites of opioid receptor expression- - periaqueductal gray, spinal trigeminal nucleus, cuneate and gracile nuclei, thalamus, nucleus of solitract, nucleus ambiguus, parabrachial nucleus, neurons of the postrema, dorsal horn of the spinal cord - hyphothalamic region - dorsal horn of the spinal cord

Know about the pharmacological actions of opioids:CNS - analgesia, sedation, euphoria, mental clouding, respiratory depression, nausea and vomiting, cough reflex, pupillary constriction (miosis)GI – constipation, biliary tract spasm

Know about the contraindications of opioids- Decreased respiratory reserve (emphysema, severe obesity, asthma), biliary colic, head injury, reduced blood volume, hepatic insufficiency, convulsant states

Know about tolerance and physical dependenceTolerance develops to – analgesia, euphoria, sedation, lethal dose, nauseaTolerance does not develop to - miosis, constipation, respiratory depression (partial)Physical dependence – treat with methadone (long acting opioid)Know about antitussive and anesthetic usage of opioidsAntitussive – codeine, dextromethorphanAnesthetic – fentanyl, sufentanil Know about antagonistsNaloxone – readily reverses the coma and respiratory depression of opioid overdoseNaltrexone – longer duration of action (up to 48 hrs)

1. All of the following are pharmacological effects of strong narcotic(opioid)-analgesic agonist drugs EXCEPT(A) Activation of the chemoreceptor trigger zone(B) Decreased intestinal peristalsis(C) Decreased arterial Pco2(D) Suppression of cough reflex(E) Constriction of biliary tract smooth muscle

2. With the continued use of a drug, tolerance develops to all of the following effects of morphine EXCEPT(A) Analgesia(B) Sedation(C) Nausea(D) Euphoria(E) Miosis

3. Death from overdosage of strong opioid-analgesics usually results from(A) Cardiac arrest(B) Respiratory depression(C) Seizures(D) Shock(E) Hypertensive crisis

4. Which ONE of the following will prevent development of an absentinence syndrome in a herion user?(A) Naloxone(B) Propoxyphene(C) Phenobarbital(D) Acetyl salicyclic acid(E) Methadone

5. All of the following statements concerning methadone are correct EXCEPT:(A) It has less potent analgesic activity than that of morphine(B) It has longer duration of action than that of morphine(C) It is effective by oral administration(D) It causes a milder withdrawal syndrome than morphine(E) It has its greatest action on receptor

6. Which of the following statements about pentazocine is INCORRECT?(A) It is a mixed agonist-antagonist(B) It may be administered orally or parenterally(C) It produces less euphoria than morphine(D) It is often combined with morphine for maximal analgesic effects(E) High doses of pentazocine increase blood pressure

7. Which of the following statements about morphine is INCORRECT?(A) It is used therapeutically to relieve pain caused by severe head injury(B) Its withdrawal symptoms can be relieved by methadone(C) It causes constipation(D) It is most effective by parenteral administration(E) It rapidly enters all body tissues, including the fetus of a pregnant woman

8. Morphine is used therapeutically(A) To suppress the withdrawal syndrome associated with the chronic use of alcohol(B) To induce miosis(C) To treat severe constipation(D) To relieve pain associated with heart attack

QUESTIONS 9-12Match each of the descriptions below with the appropriate drug(A) Loperamide(B) Codeine(C) Naloxone(D) Methadone(E) Dextromethorphan

9. Weak–to-moderate opioid agonist with a higher ratio of oral to parenteral activity than morphine10. Antitussive with no dependence liability11. Opioid-receptor anatgonist12. Strong opioid agonist that has a longer duration of action and produces less intense withdrawal syndrome than morphine

13. Most clinically used opioid analgesics are selective for which type of opioid receptor?A. kappa (κ)B. alpha (α)C. beta (β)D. mu (μ)E. delta (δ)

14. Codeine has a greater oral bioavailability compared with morphine because of which reason?A. codeine undergoes less first-pass metabolismB. morphine is conjugated more quicklyC. morphine directly passes into systemic circulationD. codeine is only available in liquid formulationE. codeine is metabolized more by hepatic enzymes

15. In the case of an opioid overdose, naloxone can be given in repeated doses because of which property of naloxone?

A. may have a shorter half-life than the opioid agonistB. is only effective at high cumulative dosesC. is needed to stimulate the respiratory centerD. is safe only in extremely small dosesE. is only a partial opioid agonist

Answers:1. C; 2. E; 3. B; 4. E; 5. A; 6. D; 7. A; 8. D; 9. B; 10. E; 11. C; 12. D; 13. D; 14. A; 15. A