Opioid AnalgesicsDepartment of

Pharmacology, NEIGRIHMS

Opioid Analgesics (against algesia) – some important

terms• Analgesics: Are the Drugs which selectively relieves pain by

acting in the CNS or on peripheral pain mechanisms, without significantly altering the consciousness – Opioids and NSAIDS

• Opioids: Any drug which binds to the opioid receptors (Pharmacologically related) in the CNS and antagonized by Naloxone . They may be – Natural, Synthetic and semi-synthetic

• Opiates: Drugs derived from opium – Natural or semi-synthetic

• Narcotics: Drugs derived from opium or opium like compounds, with potent analgesic effects associated with significant alteration of mood and behavior, and with the potential for dependence and tolerance following repeated administration.

Types of Pain

Types of Pain – contd.

Types of Pain – contd.

Opioids - Opium• A dark brown, resinous material

obtained from poppy (Papaver somniferum) Capsules.

OPIUM

PHENANTHRENE•Morphine 9-14%•Codeine 0.5-2%•Thebaine 0.2-1%

BENZYLISOQUINOLINE•Papaverine 0.8-1%•Noscapine 3-10%•Narcine 0.2-0.4%

Poppy Plant - image

Poppy to Opioids

Opium - History• Friedrich Wilhelm Serturner

– A German Pharmacist– Isolated Morphine in 1803 and named

it after the Greek god of Dreams “MORPHEUS”

MORPHINE (Pharmacological actions) - CNS

• Analgesia:• Strong analgesic• Visceral pain is relieved better than somatic

pain• Degree of analgesia increases with dose• Nociceptive pain is better relieved than

Neuretic pain• Associated reactions to pain are also relieved

– apprehension, fear and autonomic effects• Tolerance to pain is better

MORPHINE – Analgesia action

• Two components – spinal and supraspinal

• Inhibits release of excitatory transmitters from primary afferents – at Substantia gelatinosa of dorsal horn

• Exerted through Interneurones – gating of pain• At supraspinal level in cortex, meidbrain and

medulla - alter processing and interpretation and send inhibitory impulses through descending pthway

D

E

Morphine - The Gate Theory

Pharmacological actions of Morphine (CNS) –

contd.• Sedation:

– Drowsiness and indifference to surroundings– Inability to concentrate and extravagant imagination –

colorful day dream– Apparent excitement– Larger doses produce sleep – EEG resembles normal sleep

• Mood effects:– In Normal persons calming effect, mental clouding, feeling

of detachment, lack of initiative etc. - unpleasant in absence of pain

– Sometimes DYSHORIA– But in persons with pain & addicts sense of wellbeing,

pleasurable floating feelings – kick– EUPHORIA

Pharmacological actions of Morphine (CNS) –

contd.• Depression:

1. Respiratory centre depression – Both rate and depth of respiration are diminished• Dangerous in Head

injury and asthmatics2. Cough Centre –

Depressed3. Temperature regulating

centre – depressed4. Vasomotor centre – high

doses cause fall in BP

• Stimulation:1. CTZ – sensitize CTZ to

vestibular and other impulses

2. Edinger Westphal Nucleus – miosis

3. Vagal centre – Bradycardia

4. Hippocampal cells – convulsions (inhibition of GABA release)

Morphine - Effects

Pharmacological actions of Morphine –

contd.• Neuro-endocrine:

• GnRH and CRH are inhibited – FSH, LH and ACTH levels are lowered – only short term – tolerance develops

• Decrease in levels of Sex hormone and corticosteroids, but no infertility

• Increases ADH release – oliguria• CVS: NO DIRECT EFFECT ON HEART

• Vasodilatation – histamine release, depression of vasomotor centre and directly on blood vessels decreasing the tone

• Cardiac work reduction due to consistent vasodilatation

Pharmacological actions of Morphine –

contd.• GIT: CONSTIPATION

• Due to direct action on intestine reducing propulsive movement, spasm of sphincters, decrease in all GIT secretions

• Smooth Muscles:• Billiary Tract: Billiary colic – closure of sph. Of

Oddi• Bladder: Urinary urgency but difficulty• Bronchi - Bronchospasm

Morphine - Pharmacokinetics

• Absorption and Distribution:• Variable orally (usually not given orally – 1st pass metabolism,

given IM or IV)• Widely distributed – liver, spleen, kidney etc.• Enters Brain slowly• Readily crosses placental barrier – dependence in fetus

• Metaboloism:• In Liver by glucoronidation – water soluble metabolites • Morphine-6- Glucoronide – analgesic – in renal failure prolong

analgesia• Morphine-3-glucoronide – No analgesia – neuroexcitatory

• Excretion: • Via Urine, Plasma t1/2 = 2-3 Hrs• Action lasts for 4-6 Hrs• Completely eliminated in 24 Hrs

• Preparation: 10, 15, and 20 mg. (IV: 2 – 10 mg)

Morphine - Pharmacokinetics

Morphine – Adverse Effects

1. Respiratory Depression: Infant and Old2. Vomiting3. Sedation, Mental Clouding – sometimes dysphoria4. Hypotensive effect5. Rise in Intracranial Pressure6. Apnoea: Newborn7. Urinary retention8. Idiosyncrasy and allergy9. Acute Morphine Poisoning: occurs if >50 mg (Lethal dose –

250 mg), Gastric lavage with KMNO4, Specific antidote: Naloxone: 0.4 to 0.8 mg IV repeatedly in 2-3 minutes till respiration picks up

10. Tolerance and dependence

Morphine – Therapeutic uses

• Analgesic:1. Long Bone Fracture2. Myocardial Infarction3. Terminal stages of cancer4. Burn patients5. Postoperative patients6. Visceral pains – pulmonary embolism, pleurisy,

acute pericarditis7. Biliary colic and renal colic8. Obstetric analgesia9. Segmental analgesia

Morphine – Other Therapeutic uses

• Preanaesthetic Medication• Balanced anaesthesia and surgical

analgesia• Acute Left ventricular failure – Cardiac

asthma• Cough – not used but Codeine is used• Diarrhoea – colostomy - Loperamide,

Diphenoxylate

Morphine - Contraindications

1. Two Extremes of Age2. Bronchial asthma 3. Respiratory insufficiency - empysema4. Head Injury5. Shock – Hypotension6. Undiagnosed acute abdomen7. BHP8. Renal Failure, Liver diseases and hypothyrodism9. Unstable personalities

Opioids - Classification1. Natural Opium Alkaloids: Morphine and Codeine2. Semi-synthetic: Diacetylmorphine (Heroin) and

Pholcodeine3. Synthetic Opioids:

• Phenylpiperidines: • Pethidine (Mepiridine) and its congeners –

Diphenoxylate and Loperamide• Fentanyl and its congeners – sufentanil, remifentanil

and alfentanil• Phenyl-heptylmines: Methadone and congeners like

Propoxyphene and Dextropropoxyphene• Benzomorphans: Pentazocine• Morphinan compounds and congeners: Levorphanol and

Butorphanol

Pethidine • Morphine Vs Pethidine:

– 1/10th as potent as Morphine, but Efficacy is similar– Produces as much sedation, euphoria and

respiratory depression in equianalgesic dose and similar abuse potential

– Less spasmodic action in smooth muscles – less miosis, constipation and urinary retention

– Rapid but short duration of action (2-3 Hrs)– Vagolytic effect - Tachycardia– Devoid of antitussive action– Less histamine release – safer in asthmatics– Better oral absorption

Pethidine – contd.• Pharmacokinetics

– Well absorbed orally, bioavailability 50%– Effects appear in 10-15 min. after oral

absorption– On parenteral administration action lasts

for 2-3 Hrs– Metabolized in liver – mepiridinic acid and

norpethidine– Norpethidine accumulates on chronic use– Excreted in urine

Pethidine – contd.• Adverse Effects:

• Similar to Morphine• Atropine like effects – dry mouth, blurred vision,

tachycardia• Overdose – tremors, mydriasis, delirium and

convulsion due to norpethidine accumulation• Uses:

• Analgesic as substitute of Morphine• Preanaesthetic medication• As analgesic during labor – less fetal respiratory

depression• Dose 50-100 mg IM/SC, oral – 50-100 mg tabs.

Methadone• Chemically dissimilar but similar in most of pharmacological

actions – analgesic, respiratory depression etc.• High action orally as well as parenterally• Single dose effect is – same with Morphine including duration

of action• Cumulation – on repeated administration (t1/2 24-36 Hrs)• Highly bound to plasma protein 80 to 90%• Metabolized in liver by – demethylation and cyclization• Excreted in urine• Slow action and less subjective effect – abuse potential is low• Used as substitution therapy as opioid dependence: 1:4mg

and 1:20 mg of Morphine and Pethidine respectively• Codeine is used as substitution in Methadone addiction

Tramadol• Centrally acting analgesic• Very low action on opioid receptors • Other mechanisms involved in analgesic action – 5-HT

and NA reuptake inhibition – spinal inhibition of pain• Effective both orally and IV (100mg = 10 mg Morphine)• Side effects are similar to Morphine but less prominent• Well tolerated and low abuse potential• Only Partially reversed by Naloxone• Used in chronic neuropathic pain and short diagnostic

procedures• Dose: 50-100 mg IM/IV/Oral (Contramol)

Opioid Receptors• Mainly 3 (three) types of receptors – μ (mu), κ (kappa)

and δ (delta)• Subtypes: μ1, μ2, κ1, κ2, κ3, δ1 and δ2 • Location: Peripheral Nerve endings, SG in spinal chord,

Periaqueductal gray (PAG) in midbrain and Brain stem (medulla, hypothalumus and also amygdala

• Opioids are – agonists, partial agonist or competitive antagonists of these receptors

• Overall effect depends on nature of interaction and affinity to these

• Morphine is agonist of all but affinity is higher for mu

μ receptor κ receptor δ receptorLocation μ1 – supraspinal

μ2 - spinalκ1 – spinalκ3 -supraspinal

Spinalsupraspinal

Effects AnalgesiaRespiratory depressionSedationEuphoriaMiosisPhysical dependenceLoss of GI motility

Spinal analgesiaDysphoriaSedationPsychomimeticPhysical dependence (nalorphine type)

Spinal analgesiaAffective behaviour (Supraspinal) Respiratory depressionReduced GI motility

Agonists Morphine, Codeine, Fentanyl and pentazocine weakly

Pentazocine

Effects of Different Opioid Receptor Stimulation:

Effects of Opioid Receptor Stimulation

Effects of Opioid Receptor Stimulation – contd.

Opioid Receptors – Intracellular mechanism

• All are G-protein coupled receptors• Located on prejunctional neurones• Inhibits release of transmitters – NA, DA, 5-HT,

GABA and Glutamate• Activation reduces intracellular cAMP

formation - Opening of K+ channel via μ and δ. and supression of N type of Ca++ channels

• Ultimately Hyperpolarization and reduced intracellular Ca++ Reduced Neurotransmitter release

Endogenous Opioid Peptides

• Endorphins: • Derived from POMC• ß-endorphins: 2 Types - ß-endorphin1 and ß-endorphin-2• Primarilty μ agonist and also has δ action

• Enkephalins: • Derive from Proenkephalin• Met-ENK and leu-ENK• Met-ENK - Primarily μ and δ agonist and leu-ENK – δ

agonist• Dynorphins:

• Derive from Prodynorphin: DYN-A and DYN-B• Potent κ agonist and also have μ and δ action

Opioid Antagonists1. Pure antagonists: Naloxone, Naltrexone and

Nalmefene• Affinity for all receptors (μ, δ and κ)• Can displace opioids bound to α-receptors• No action on Normal person but reverses poisoning and

withdrawal symptoms in addicts2. Mixed Agonist-antagonists: Nalorphine,

Pentazocine, Butorphanol and Nalbuphine3. Partial/weak μ agonist and κ antagonist:

Buprenorphine

Nalorphine• Not used anymore• Previously used as Opioid antagonist• But, antagonism is restricted to μ-

receptor only and agonist of κ-receptor

• Drawbacks - dysphoria and psychomimetic effects

Pentazocine• Weak μ-receptor antagonist, but agonist of κ-receptor• One of the commonly used agents, given orally and IM• Low abuse liability• Pharmacokinetics:

– High 1st pass metabolism but effective orally– Half life = 3-4 Hrs– Metabolized in liver by glucoronide conjugation– Dose: orally 50-100 mg and parenterally 30-60 mg IM

• Uses:Moderately severe pain in Injury, Burns, Fracture Trauma, Cancer and Orthopaedic manuevers

(Fortwin, Fortagesic)

Pentazocine Vs Morphine

• Spinal analgesia via kappa receptor• Dose is 30 mg Vs 10 mg and low ceiling effect• Sedation and Respiratory depression at lower doses• Tachycardia and rise in BP – dangerous in MI• Lesser smooth muscle spasms• Vomiting and other side effects are less• Subjective effects – lower ceiling (psycomimetic effects)• Tolerance develops on repeated use, but lesser than

Morphine• Withdrawal symptoms – both Morphine and Nalorphine like• Good analgesic in subjects not exposed to Morphine• Precipitate withdrawal – in Morphine addicts

Buprenorphine• Synthetic thebaine congener and highly lipid soluble• Given Sublingually or parenterally but not oral – high 1st pass

metabolism• Selective μ-agonist analgesic• 20-30 times more potent than Morphine• Slow but longer duration of action upto 24 Hrs• Pharmacological effects are similar to Morphine• Has ceiling effect in analgesic and respiratory depression • Good analgesic for naive patients but addicts – precipitates

withdrawal syndrome• Lower tolerance and physical dependence than Morphine and

abuse liability• Withdrawal syndromes are similar to Morphine

Buprenorphine – contd.• Adverse Effects:

– Hypotension (Postural)– Respiratory depression (fatal in neonates) and

cannot be reversed by Naloxone• Uses:

– Long lasting painful conditions – cancer– Postoperative pain– Myocardial infarction

• Preparations: Norphine, Tidigesic• 0.3 mg/ml injections and 0.2 mg sublingual tablets

Naloxone• Competitive antagonist of all types of opioid

receptors• But, blocks μ-receptors at much lower dose• Always injected IV (0.4 t0 0.8 mg) - All

symptoms of Morphine action are antagonized – respiratory stimulation

• At higher doses 4-10 mg: antagonizes actions of Nalorphine and Pentazocine – dysmorphic and psychomimetic effects are not suppressed (δ)

• Withdrawal symptoms: 0.4 mg doses – Morphine and 4-5 mg doses – Nalorphine and Pentazocine

Naloxone – contd.• Buprenorphine actions are prevented but not

reversed fully – tight bond with receptors• Also acts on endogenous opioids• Antagonizes respiratory depression of

Diazepam and N2O• Uses:

• Acute Morphine Poisoning (0.4 – 0.8 mg IV 2-3 min, maximum 10 mg.

• New Born – opioid poisoning• Reverse respiratory depression intr-aoperatively• Diagnosis of Morphine addiction• Alcohol intoxication

Opioids – other uses• Antidiarrhoeal agents:

Diphenoxylate and Loperamide• Antitussives: Codeine,

Dextromethorphan, Noscapine, Pholcodeine, Levopropoxyphene

Important• Classification of opioids• Remember - Pharmacological actions,

adverse effects, indications and contraindications of Morphine, Pethidine, Pentazocine

• Remember in short – Methadone, Tramadol, Buprenorphine and Naloxone

• Opioid receptors

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