OPIOID ANALGESICS

Dr. Kiran A. Kantanavar

• A boy aged 14 years is brought to the hospital emergency with crush injury of both lower legs.

• An eye witness who brought the boy told that a bus had run over his legs about 20 min. ago.

• The legs were crushed but he had not bled much. He also told that initially the boy was shrieking in pain, but had fainted on way to the hospital.

• Preliminary examination reveals that the patient is in a semiconscious state, looks pale, the pulse is fast, low volume and collapsing.

• Both legs have sustained multiple fractures, the skin and soft tissues have lacerated from which blood is oozing, but there is no active bleeding.

• There is no apparent head injury.

• Should any medicine be administered immediately, before even completing a thorough physical examination?

• If so, which drug, by what route, and why?

PAIN

Opium

• Papaver somniferum and P. album

Papaver somniferum

Opium

• Papaver somniferum and P. album

• Rigveda – “soma”

• Eber’s papyrus (1500 BC)

• Friedrich serturner

• Greek god of dreams – “Morpheus”

Alkaloids of opium

• Opiates vs Opioids

OPIOID RECEPTORS

• μ, δ, and κ (MOR, DOR, and KOR)• Rhodopsin family of GPCRs (GRAFS classification)

• Transducer mechanisms: Gi/Go proteins

OPIOID RECEPTORS

• μ, δ, and κ (MOR, DOR, and KOR)• Rhodopsin family of GPCRs• Transducer mechanisms: Gi/Go proteins• μ and κ: reduce intracellular cAMP formation and

open K+ channels (mainly)• δ: suppresses voltage gated N type Ca2+ channels

(mainly)• Neuronal hyperpolarization and reduced

availability of intracellular Ca2+ → decreased neurotransmitter release

Common:•Analgesia •Resp. depression•Reduced GI motility

Consequences of opioid receptor activation

1. Internalization 2. Desensitization 3. Tolerance 4. Dependence5. Addiction

Internalization

• μ and δ receptors: endocytic, β-arrestin-mediated

• κ receptors: do not internalize

Desensitization

• Acute tolerance or desensitization• Receptor specific • Phosphorylation of the receptors resulting in

an uncoupling of the receptor from its G-protein and/or internalization

Tolerance

• Decrease in the apparent effectiveness of a drug• With continuous or repeated agonist

administration (days to weeks)• Following removal of the agonist, disappears

over several weeks• Right shift in the dose-effect curve• Cross-tolerance is not consistent or complete

Tolerance Mild:• Miosis

Moderate: • Constipation • Emesis • Analgesia • Sedation

Rapid:• Euphorigenic

Dependence

“a state of adaptation manifested by receptor/drug class-specific withdrawal

syndrome produced by cessation of drug exposure (e.g., by drug abstinence) or

administration of an antagonist”

DependenceWithdrawal is manifested by

• Agitation • Hyperalgesia • Hyperthermia • Hypertension • Diarrhea • Pupillary dilation • Release of virtually all pituitary and adrenomedullary hormones

Affective symptoms

• Dysphoria • Anxiety • Depression

somatomotor and autonomic outflow

Addiction

“a behavioral pattern characterized by compulsive use of a drug”

• Driving force: rewarding effects of opiates• Avoidance and alleviation of withdrawal

symptoms

MECHANISMS OF TOLERANCE/DEPENDENCE-

WITHDRAWAL

• Receptor Disposition• Adaptation of Intracellular Signaling

Mechanisms in the Opioid Receptor-Bearing Neurons

• System Level Counter-Adaptation

Classification Natural opium

alkaloids: 1.Morphine, 2.Codeine

Semisynthetic opiates:1.Diacetylmorphine (Heroin), 2.Pholcodeine, 3.Ethylmorphine

Synthetic opioids: 1.Pethidine (Meperidine),2.Fentanyl, 3.Methadone, 4.Dextropropoxyphene,5.Tramadol.

Morphine – Pharmacological actions

CNS Depressant• Analgesia • Sedation • Mood• Respiratory centre• Cough centre• Temperature centre• Vasomotor centre• Thalamus -

hypothalamus

Stimulant • CTZ• Edinger Westpal nucleus• Vagal centre• Cortical & hippocampal cells

CVS• Vasodilatation • Hypotension • Bradycardia

GIT• Constipation

Others• Bronchi: histamine -> bronchoconstriction• Biliary tract: spasm • Urinary bladder: detrussor vs sphincter• Uterus: no significant effect• Hyperglycemia • Pruritus

Analgesia

• Dose related• Peripheral vs neuritic• Visceral vs somatic• Dull poorly localised vs sharp shooting

localised• Pain associated components• Spinal & supraspinal• Peripheral action of opioid

Sites of action of Morphine. A: Direct action of opioids on inflamed or damaged peripheral tissues. B: Inhibition also occurs in the spinal cord. C: Possible sites of action in the thalamus.

The pain-inhibitory neuron is indirectly activated by opioids,which inhibits an inhibitory (GABAergic) interneuron.

Opioid analgesic action on the descending inhibitory pathway

Clinical uses

Analgesia • Traumatic • Visceral • Ischemic • Burn• Post operative• Cancer • Renal colic

Acute pulmonary edema & CCF Cough Diarrhea Shivering Anaesthesia • Surgical anaesthesia • Pre anaesthetic

medication

Adverse effects

• Acute morphine poisoning– Toxicity: 50mg; Lethal: 250mg– Antidote: Naloxone 0.4 to 0.8mg i.v.

• Resp. depression & apnea in newborn• CVS: Hypotension & Bradycardia• Allergy & Pruritus• Tolerance & Dependence

CASE STUDYA 60-year-old man with a history of moderate chronic obstructive pulmonary disease presents in the emergency department with a broken hip suffered in an automobile accident. He complains of severe pain.• What is the most appropriate immediate treatment for his pain? • Are any special precautions needed?

TO BE CONTINUED..

Codeine • Methyl-morphine• Partial agonist at μ opioid receptor with a low

ceiling effect• More selective cough suppressant • Degree of analgesia is comparable to aspirin • Demethylation by CYP2D6 morphine• Constipation is a prominent side effect Rx of

diarrhea• Abuse liability is low

Heroin • Diacetylmorphine 6-monoacetylmorphine

morphine• Euphorient especially on i.v. injection and highly

addicting• Sedative, emetic and hypotensive actions are less

prominent• Banned in most countries except U.K

LEVORPHANOL • Opioid agonist of the morphinan series• Pharmacological effects parallel those of

morphine• Less nausea and vomiting• Metabolized less rapidly than morphine long

acting (t1/2 of 12-16 hr)• D-isomer (dextrorphan) – Devoid of analgesic action – Has inhibitory effects at NMDA receptors

Pethidine (Meperidine) • Synthesized as an atropine substitute in 1939• μ opioid receptor agonist and its actions are blocked

by naloxone• Special features:1. Analgesic potency2. Onset of action3. Cough 4. Spasmodic action on

smooth muscles5. Sedation and euphoria

6. Tachycardia 7. Histamine release8. Local anaesthesia9. Norpethidine & Serotonin

syndrome10. Preferred opioid analgesic

during labour

DIPHENOXYLATE • Meperidine congener• Definite constipating effect in humans• Even its salts are virtually insoluble in aqueous

solution less abuse potential• Diphenoxylate hydrochloride is available only

in combination with atropine sulfate• Difenoxin, a metabolite of diphenoxylate,– marketed in a fixed dose with atropine

LOPERAMIDE • A piperidine derivative• Antidiarrheal effect:

o slows GI motility by effects on the circular and longitudinal muscles of the intestine

o reduces of GI secretion• Does not penetrate well into the brain due to the

exporting activity of P-glycoprotein

FENTANYL • Synthetic opioid related to the phenylpiperidines• 80–100 times more potent than morphine• Very important drugs in anesthetic practice

because1. Relatively short time to peak analgesic effect2. Rapid termination of effect after small

bolus doses3. Cardiovascular safety 4. Capacity to significantly reduce the dosing

requirement for the volatile agents

METHADONE• Long-acting MOR agonist• Pharmacological properties qualitatively similar to those of

morphine• L-methadone -> 8-50 times more potent than D-isomer &

has analgesic activity• D-methadone -> possesses antitussive activity

-> Lacks respiratory depressant action and addictionliability

• Cumulates in tissues on repeated administration — duration of action is progressively lengthened

• Abuse potential is rated lower than morphine• Used primarily as substitution therapy for opioid

dependence

PROPOXYPHENE • Long-acting MOR agonist, strucurally related to

methadone• Pharmacological properties qualitatively similar to those

of morphine• D-propoxyphene -> 8-50 times more potent than L-

isomer & has analgesic activity• L-propoxyphene -> possesses antitussive activity• Marketed only in combination with paracetamol ± other

drugs

TRAMADOL • Synthetic codeine analog that is a weak μ agonist• Inhibits reuptake of NA and 5-HT

Increases 5-HT releaseThus activates monoaminergic spinal inhibition of pain

• less respiratory depression, sedation, constipation, urinary retention and rise in intrabiliary pressure

• ‘serotonin syndrome’

TAPENTADOL. • Structurally & mechanistically similar to tramadol• Displays a mild opioid activity • Possesses monoamine reuptake inhibitor activity• Considered similar to tramadol in activity, efficacy

and side-effect profile• NUCYNTA

• COMPLEX ACTION OPIOIDS ANDOPIOID ANTAGONISTS

1. Agonist-antagonists (κ analgesics)Nalorphine, Pentazocine, Butorphanol

2. Partial/weak µ agonist + κ antagonistBuprenorphine

3. Pure antagonistsNaloxone, Naltrexone, Nalmefene

Nalorphine (Nalbuphine)• N-allyl-normorphine• first opioid antagonist introduced in 1951 • KOR agonist-MOR antagonist• not used clinically because of dysphoric and

psychotomimetic effects.

Pentazocine • Synthesized as part of a deliberate effort to

develop an effective analgesic with little or no abuse potential

• Weak μ antagonist and strong κ agonist• Analgesia - spinal (κ1) • Lower ceiling Sedation and respiratory depression• Tachycardia and rise in BP-sympathetic stimulation• Biliary spasm and constipation – less prominent• Low dose – pleasurable; high dose- unpleasurable

(σ mediated)

Recognised by post-addicts as an opiateTolerance, psychological and physical dependence ‘Drug seeking’Withdrawal syndrome has features of both

morphine and nalorphine abstinence

Uses: Postoperative and moderately severe pain in burns, trauma, fracture & cancer

Combination of pentazocine with naloxone reduces the potential misuse of tablets

Butorphanol • KOR agonist and MOR antagonist• Actions similar to pentazocine• Dysphoric & Psychotomimetic effects are not

prominent (weaker σ agonist)• Recognised by post-addicts as an barbiturateTolerance, physical dependence and withdrawal

(mild)• Can neither substitute for, nor antagonize morphine

(weak interaction with µ receptors)• postoperative and other short-lasting (e.g. renal

colic) painful conditions

Buprenorphine

• It substitutes for morphine at low levels of morphine dependence

• Precipitates withdrawal in highly morphine dependent subjects

• Long-lasting painful conditions requiring an opioid analgesic (cancer pain)

• Premedication, postoperative pain, in myocardial infarction and in the treatment of morphine dependence.

• Naloxone (high dose) can prevent buprenorphine effect but does not reverse it - not used during labour

Naloxone • It is N-alylnor-oxymorphone • Competitive antagonist on all types of opioid

receptors• No– Agonistic action– Autonomic action– Physical/psychological dependence

• Antagonizes all actions of morphine • Antagonizes the agonistic actions of nalorphine,

pentazocine @higher doses

• Naloxone also blocks the actions of endogenous opioid peptides– blocks placebo, acupuncture and stress-induced

analgesia• Naloxone partly antagonizes respiratory

depression produced by certain nonopioids,e.g. N2O, diazepam

• Uses:– drug of choice for morphine poisoning (0.4–0.8 mg i.v.

every 2– 3 min: max 10 mg) – reversing neonatal asphyxia due to opioid use during

labour– overdose with other opioids and agonistantagonists

(except buprenorphine)– diagnosis of opioid dependence

Naltrexone • chemically related to naloxone• more potent than naloxone• orally active and having a long duration

of action• ‘opioid blockade’ therapy of post addicts• Alcohol craving is also reduced by naltrexone– approved for prevention of relapse of heavy drinking

Methyl naltrexone • derivative of naltrexone • does not penetrate the blood-brain barrier• effectively blocks peripheral action of μ opioids • used to reverse constipation in – cancer patients receiving chronic opioid

analgesia – those taking methadone maintenance

therapy.

References :-

• Goodman & Gilman’s The Pharmacological Basis of

Therapeutics; 12th edition.

• Basic & Clinical Pharmacology – Katzung ; 13th edition.

• Essentials of Medical Pharmacology - KD Tripathi; 6th edition.