Pharmacology of Opioid Analgesics

Dr.Rathnakar U.P.
MD.DIH.PGDHM

MBBS. 5th Sem 2nd July 2013

Pain
Unpleasant sensory and emotional experience associated with actual or potential tissue damage Subjective experience Difficult to quantify Warning signal Can be pointless and contribute to discomfort Demands instant relief-highly impresses layman

Pain-Types
Superficial-cutaneous
Somatic

Deep non-visceral[muscles, joints] Deep visceral

Referred Psychogenic or functional pain

Pain-characteristics
Superficial Well defined Skin-[pricking] Inflammation Neuralgia Migraine-ishemia TAO Non visceral Dull BP, pulsenormal Visceral Diffuse Autonomic response Renal colic, MI, peptic ulcer

Pain-characteristics
Referred Deep pain can be referred To the cutaneous area supplied by the same segment Heart- L.arm Diaphragmshoulder Psychogenic Vague No anatomical pattern Does not disturb sleep Follows exhaustion

Pain pathways
Inhibitory pathways Thalamus & postcentral gyrus & limbic system

Spinothalamic tract

SG-dorsal horn Gate control

Pain receptors Afferentfibres

[Depress CNS] [Do not depress CNS]

Papaver somniferum

Opioids
Opiates [Products from opium poppy] Opioids [Natural, synthetic & semisynthetic drugs with morphine like action]

The latex is obtained by lacerating the immature fruits -the latex leaks out and dries to a sticky brown residue. This is scraped off the fruit.

Opium -dried latex obtained from opium poppies Opium contains up to 12% morphine, - which is most frequently processed chemically to produce heroin. The latex includes-Codeine -non-narcotic alkaloids, such as

papaverine, thebaine and noscapine .

Opioids act on endogenous opioid receptors

Why should there be receptors in our body for a substance found in Papaver somniferum???

Endogenous opioids
[Peptides in CNS with opioid like action]

[Endogenous]

[Natural, synth, semisynth]

Beta-Endorphin Enkephalin Dynorphins

Opioid Receptors Mu, kappa, delta

Opioids

Nociceptin/orphanin Endomorphins
Role: Endogenous analgesics, neurotransmittors, behavior modulators

Opioids-Classification
[Agonists & Mixed action opioids & antagonists]

Agonists
Natural Morphine Codeine Semisynthetic Heroin Pholcodeine Synthetic Pethidine Fentanyl Methadone Tramadol

Classification-Chemical structure??????

Opioids- Receptors
Mu
.

Kappa

Delta

Others Nociceptin/Orphanin FQ

MECHANISM OF ACTION Ascending pathways

Block

Open

13

MECHANISM OF ACTION Descending pathways

Promote Inhibition of pain impulses

Opioid-MOA
Inhibit
3 Inhibit pain impulse transmission

Inhibit pain perception 5

Modifies emotional component

5. Promotes descending inhibition

Inhibition of pain [Gate control]

Pain Touch

Why when we bang our head, it feels better when we rub it.
16

Morphine-prototype Pharmacological actions-CNS

CNS-Depressant effects Analgesia Sedation Euphoria Resp.depression Depress cough center Temp reg.center Vasomotor center CNS-stimulant effects CTZ E.W.Nucleus Vagal center Truncal rigidity

Morphine-prototype Other-Pharmacological actions

Endocrine-ADH CVS-Vasodilation GIT-constipation Biliary tract-spasm of Oddi

UB-urgency and difficulty RS-bronchospasm ANS-Symp.stimhyperglycemia

Morphine-prototype ADEs
Sedation, lethargy, dysphoria Vomiting Allergy Apnoea Poisoning Tolerance & Dependence

Morphine-prototype Pharmacological actions CNS - depressant

Analgesia Very strong Dull, deep visceral pain Peripheral and central Anxiety, fear, apprehension, autonomic [emotional components] Pain is no longer unpleasantignores No proportionate CNS dep.[unlike GA] No ceiling effect Sedation Different from hypnotics No ataxia, motor incordination or excitement Not anitconvulsant [epileptogenic] Mood Euphoria [dysphoria-rare] rush Kick =orgasm

Morphine-prototype Pharmacological actions CNS - depressant

Respiration Dose dependent dep.-Resp center Indifference to breathing In morphine poisoning hypoxic drive maintains respiration Dangerous to give 100% continuous oxygen in poisoning Resp arrest - cause of death in poisoning Cough Depressed Temperature Hypothermia VMC Fall of BP

Morphine-prototype Pharmacological actions-CNS

CNS-Depressant effects Analgesia Sedation Euphoria Resp.depression Depress cough center Temp reg.center Vasomotor center CNS-stimulant effects CTZ E.W.Nucleus Vagal center Truncal rigidity

Morphine-prototype Pharmacological actions

CNS-Stimulant
CTZ Vomiting E.W.Nucleus [ Miosis [No tolerance] Not topical-central action
Some cats-mydriasis!

Vagal center Bradycardia Cortical areas, hippocapus Truncal rigidity Proconvulsant [No tolerance]

Morphine-prototype Pharmacological actions Other actions

1. 2. 3. CVS-Vasodilation Histamine release VMC depressed Direct on BV Shifts blood pulmonarysystemic=acute LVF Decreases cardiac load=MI CO2=Cerebral vasodilation= ICT= CI in head injuries GIT-constipation [No tolerance] 1. Movement 2. Spasm of sphincters 3. Decreases secretions 4. Inattention to defecation reflex Neuroendocrine ADH -reduce urine FSH, LH, ACTH-Impotence, libido, infertility

Morphine-prototype Pharmacological actions On Other Smooth muscles

Biliary 1. Spasm of ODDI Uterus 1. May prolong labour

U.Bladder Tone-detrusor and sphincterurgency & difficulty

Bronchi Spasm-histamine ANS Mild Symp.stimulationhyperglycemia

Receptor
Analgesia Supraspinal Spinal Peripheral Respiratory depression Pupil constriction Reduced GI motility Euphoria Dysphoria & hallucinations Sedation Physical dependence

+++ ++ ++ +++ ++ ++ +++ ++ +++

-? ++ ++ ++ -

+ ++ + + +++ ++ -

ORL1
Antiopioid ++ -

26

Morphine PK
Oral- BA to 1/6 of parenteral Rectal, s.c, i.m, i.v. Spinal-less resp.dep. Route is chosen depending upon the condition Crosses placenta Metabolized in liver[first pass] Duration of action-4-6 hours

Morphine ADEs
Th.doses[side effects] Resp.dep Idiosyncratic Hypotension Bronchospasm Allergic Constipation Toxic doses Acute morphine poisoning Prolonged use Tolerance Physical dependence

Histamine

Morphine Adverse effects

Tolerance and dependence

Tolerance
Repeated use PK and PD For all actions except-Miosis, Constipation, proconvulsant Constipated & pin point pupils Cross tolerance with opioids and other CNS depressants Cross tolerance incomplete- opioid rotation Addicts tolerate grams

Tolerance

Morphine Adverse effects

Tolerance and dependence

Dependence
Psychological & physical-state of addiction Dependence leads to abuse [more among medical personnel]

Withdrawal:
Drug seeking behaviour, lacrimation, sweating, yawning, anxiety, fear, mydriasis, insomnia, tremors, diarrhoea, colic, dehydration, rise in BP, wt.loss, convulsions, CV collapse. Treatment of dependence
Acute [Detoxification]- Clonidine or Lofexidine [reduce NA effects] Chronic-[substitution] therapy with methadone

Morphine Adverse effects

Side effects[Th.doses]: Sedation, mental clouding, dysphoria, vomiting, constipation, resp.depression, blurred vision, urinary retention, fall of BP idiosyncrasy and allergy; Urticaria, itching, swelling of lips A local reaction at injection site, generalized itching may occur due to histamine release.

Morphine Adverse effects

Apnoea of new bornWhen morphine is given to the mother during labour. Naloxone 10 g/kg injected into umbilical cord is the treatment of choice

Morphine Adverse effects

Acute morphine poisoning Accidental, suicidal, overdose in abusers Toxicity-50mg. Lethal-250mg Respiratory support Gastric lavage- KMno4 even when injected [highly basic drug] Antidote-Naloxone 0.4 to 0.8 mg i.v. every 2mts-till resp.normal Repeated every 1-4 hours[short duration

Morphine Precautions
Infants, elderly, with resp.insufficiency[emphysema] Bronchia asthma- histamine release Hypotensive states Urinary retension-elderly Hypothyroidism, liver or renal failure-more sensitive Unstable personalities-likely to be addicted

Morphine Precautions
Morphine Respiratory depression CO2 retention Celebral vasodilatation Intracranial tension

Head injury-Contraindicated 1. Retained CO2- raises ICT 2. Therapeutic doses-resp.depression 3. Vomiting, miosis, mental clouding by morphine interferes with head injury assesment [Glasgow scale???] Drug interactions Tripathi VIIth ed. Page 474

Morphine-CIs

Head Injury Bronchial asthma Undiagnosed abdominal pain

Morphine Dose
Oral-10-50mg S.c or I,m-10-15mg i.v.-2-3 mg Epidural,

Preparations: Tablets, slow release tablets, ampoules[10mg/ml]

Morphine Uses
To relieve severe visceral pain MI, Burns, Post op.pain, fracture of long bones Acute LVF Relieves pulm.congestion Preanesthetic Analgesic & antianxiety[not in surgical anesthesia] Frightening situations RTA without head injury

Not to be used as antitussive & antidiarrhoeal though effective

Opioids-Classification
Natural Morphine Codeine Semisynthetic Heroin Pholcodeine Synthetic Pethidine Fentanyl Methadone Tramadol

Opioids

Pethidine[meperidine]
1. 1/10th analgesic potency of morphine 2. Rapid onset-short duration 3. Not anti-tussive 4. Action on smooth muscles [, ] 5. Resp dep=morphine 6. Abuse=morphine 7. Tachycardia [anticholinergic] 8. Less histamine release[safe in asthmatics] 9. LA action 10.Orally better absorbed

Opioids

Pethidine [Metabolism]
MAO inhibitors interfere

Hydrolysis

Meperidinic acid
[Major metabolite]

Pethidine
Demethylation

Norpethidine
[Minor metabolite]

Excitatory symptoms in over dosage

Opioids Pethidine [ADEs]

Similar to morphine Atropinic like [dry mouth, blurred vision]
Tolerance and physical dependence slow Interaction with MAO inhibitors[block hydrolysis] And SSRIs [Pethidine blocks uptake of 5HT]

Opioids Pethidine [Uses]

Analgesic [Substitute to morphine] Preanesthetic Shivering during anesthesia & i.v. infusion [2 action ADEs-CNS stimulation-norpethidine [accumulates] Preferred during labour [not absolute]-does not delay labour

Dose: 50-100mg-i.m. , s.c.

How pethidine differs from morphine?

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Less potent[1/10] Rapid onset/ short duration Less histamine Anticholinergic-tachycardia Less sedation Less antitussive Less constipation Less retention of urine Does not delay labour, less resp dep. In neonates LA action

Diphenoxylate & loperamide

Pethidine congeners Not analgesics Antimotility action on GIT Symptomatic treatment of diarrhea

Opioids Codeine
Less potent analgesic [CodeineMorphine] Selective antitussive-own action [Linctus codeine] Orally effective Abuse liability is low.

Fentanyl
[Sufentanyl, Alfentanyl, Remfentanyl] Pethidine congener 100 times potent than morphine Highly lipid soluble i.v-in anesthesia[TIVA] Transdermal patch-cancer analgesia Anesthetic adjunct Epidural & spinal routes

PCA

49

Methadone
Synthetic Similar to morphine Orally effective, longer acting Accumulates Less euphoria, no kick Withdrawal symptoms are mild Used as substitute in morphine dependence [1mg=4mg of morphine, 2mg of heroin, 20mg of pethidine]

Tramadol
Weak agonist at receptors Inhibitor of reuptake of noradrenaline / 5-HT Naloxone blocks resp.dep, not analgesia Orally effective, metabolite is also analgesic Better side effect profile than most opioids Preferred in mild to moderate pain-not effective in severe pain Caution in epileptics

Do not use along with MAOI

Tapentadol

Uses Morphine and congeners

Severe pain [any pain with care] Preanaesthetic Balanced anaesthesia Relief of anxiety/apprehension Acute LVF Cough [Codeine-not morphine!] Diarrhoea [loperamide, diphenoxylate]

Uses Morphine and congeners

Severe pain Mild pain-morphine or Pethidine not used Abuse potential should be considered Severe pain opioids should not be withheld

Uses Morphine and congeners

Acute LVF-Morphine (i.v.) -dramatic relief 1. Reducing preload on heart due to vasodilatation and peripheral pooling of blood. 2. Shift blood from pulmonary to systemic circuit; relieves pulmonary congestion and edema. 3. Allays air hunger by depressing respiratory centre.

Opioid receptors
1. - Most of the analgesic effects of opioids, and for some major
unwanted effects (e.g. respiratory depression, euphoria, sedation and dependence). Most of the analgesic opioids are -receptor agonists.

2. - Receptor activation results in analgesia but also can be

proconvulsant.

3. - Analgesia at the spinal level -sedation, dysphoria and

hallucinations. Some analgesics are mixed agonists/ antagonists. 4. ORL1 5.

Opioids
[Functional classification]

Agonists [,, k] [natural, semi synth.,synth] Strong [Morphine] Mild [Codeine]

Mixed[agonist & antagonist] Nalorphine, pentazocine, butorphanol, Buprenorphine [Partial agonist]

Antagonists [,, k] [Naloxone, Naltrexone, Nalmiphene]

Mixed[agonist & antagonist] Pentazocine

[antagonist] k [agonist] Analgesia at spinal level Withdrawal symptoms in morphine addicts Dysphoria Weak analgesic & less ADEs Raise in BP & tachycardia- CI in ischemia Tolerance & dependence+

Mixed[agonist & antagonist] Butorphanol

[antagonist] k [agonist] Similar to pentazocine Three times more potent -morphine Moderate painful conditions Can be given by nasal route

Levorphanol

Mixed[agonist & antagonist] Buprenorphine

[Partial] k [antagonist] More potent than morphine, lower analgesic Effective sublingually Orally absorbed-First pass-not effective Actions not completely reversed by Naloxone [tight binding to receptors] CI-in labour

Pure antagonist Naloxone

Blocks all opioid receptors[more effectively ] In the absence of opioidsIncreases pituitary hormonal levels In the presence of opioidsInjected i.v. All actions of morphine are reversed Also antagonizes the actions of mixed action opioids [Buprenorphine less] Precipitates withdrawal effects in morphine addicts Blocks actions of endogenous opioids [no hyperalgesia!] Blocks effects of acupuncture, placebo [?endogenous opioids are involved]

Pure antagonist Naloxone-uses

Drug of choice for morphine poisoning-i.v. dose??? To reverse neonatal asphyxia-morphine induced Overdose of mixed action opioids[except buprenorphine] Adjunct in intraspinal anesthesia[low dose has no

effect on analgesia]-respiratory depression Diagnosis of opium addicts Partly reverses alcohol intoxication To raise BP in shock-increases cortisol levels

Other pure antagonists

Naltrxeone:
More potent than naloxone-long acting Orally effective To block the effects of opioids in addicts in deaddicted To reduce alcohol craving Hepatotoxic

Nalmefene- orally effective. No hepatotoxicitry Alvimopan, Methyl naltrexone:

Does not cross BBB-no withdrawal symptoms in addicts Used to reverse peripheral actions of morphine[eg. constipation in cancer pts. on opioids]

Opioid Drug Interactions

Drug Group Interactions

Sedative-hypnotics CNS depression, particularly respiratory

depression.
Antipsychotic tranquilizers
Monoamine oxidase inhibitors

Increased sedation. Variable effects on respiratory depression. Accentuation of cardiovascular effects Relative contraindication to all opioid analgesics -hyperpyrexic coma; hypertension has also been reported.

Differences

NSAIDs

OPIOIDS
Natural alkaoids/ semisynthetic/ synthetic derivatives Acts on opioid receptors (, , , , ) Depress CNS +Also alters pain perception No such action

Source
MOA

Synthetic

Inhibition of PG synthesis Does not depress CNS Raises pain threshold Most are antiinflammatory and antipyretic GIT and others No dependence & tolerance Many are OTC drugs Mild, Moderate pain, inflammatory pain

CNS
Effect on pain
Other actions

ADEs
Availability

Dependence & tolerance most important Very strictly controlled

64 Very severe, visceral, ischemic pain

Use