Opioid Drugs: A Comprehensive Overview Introduction Opioids are a class of drugs that include natural, semi-synthetic, and synthetic compounds which interact with opioid receptors in the brain and body to produce pain-relieving and euphoric effects. Originating from the opium poppy or synthesized in laboratories, opioids have been used for centuries to manage pain. While they offer significant therapeutic benefits, especially in the management of acute and chronic pain, their potential for misuse, addiction, and overdose presents a serious public health challenge. This paper explores the history, pharmacology, clinical applications, risks, societal impact, and current trends surrounding opioid drugs. 1. Historical Background The use of opioids can be traced back to ancient civilizations. The opium poppy was used in Mesopotamia around 3400 BCE. The Sumerians referred to it as the "joy plant," indicating its psychoactive effects. The use of opium spread across the ancient world, with Hippocrates recommending it for pain relief and cough suppression. In the 19th century, morphine was isolated from opium and widely used during the American Civil War, leading to many cases of "soldier’s disease" or morphine addiction. Later, heroin (diacetylmorphine) was synthesized in 1874 and marketed by Bayer as a cough suppressant and non-addictive alternative to morphine, which proved to be disastrously incorrect. Throughout the 20th century, synthetic opioids such as methadone, oxycodone, and fentanyl were developed. While these drugs were effective in pain management, their widespread prescription, particularly in the United States in the late 1990s and early 2000s, led to the opioid epidemic. 2. Classification of Opioids Opioids can be classified based on their origin and receptor activity: Natural opioids: Derived directly from the opium poppy (e.g., morphine, codeine). Semi-synthetic opioids: Chemically modified versions of natural opioids (e.g., heroin, oxycodone, hydromorphone). Synthetic opioids: Completely man-made drugs (e.g., fentanyl, methadone, tramadol). Endogenous opioids: Peptides produced in the body, such as endorphins, enkephalins, and dynorphins. Additionally, opioids can be categorized by their action at opioid receptors: Full agonists: Activate opioid receptors to produce maximum effect (e.g., morphine, heroin, fentanyl). Partial agonists: Produce a sub-maximal response even when fully occupying receptors (e.g., buprenorphine). Antagonists: Block opioid receptors and prevent other opioids from binding (e.g., naloxone, naltrexone). Mixed agonist-antagonists: Act as agonists at some receptors and antagonists at others (e.g., pentazocine). 3. Mechanism of Action Opioids exert their effects by binding to specific opioid receptors, which are part of the G-protein coupled receptor family. The main types of opioid receptors are: Mu (μ) receptors: Responsible for analgesia, euphoria, respiratory depression, and physical dependence. K

1. OPIOIDS Agonists and
Antagonists
1

2. BRIEF HISTORY
Opium from unripe seed capsules of the poppy plant
(Papaver somniferum).
In 1806, Serturner isolated a pure substance from
Opium which he named Morphine.
1832 - Codeine.
1848 - Papaverine.
 During the world war II, synthetic compounds
introduced
 Nalorphine as morphine antagonist. 2

3. Some Terminologies:
Opiates- Products from Opium Poppy
Opioid- Naturally occuring (opiates) + Semi-synthetic+
Synthetic- having Morphine like action, reversed by
Naloxone.
3

4. What is Pain?
An unpleasant sensation that can be either acute or
chronic and that is a consequence of complex
neurochemical processes in the PNS & CNS.
Analgesics – relieves pain without causing LOC
Analgesics- i. Opioid ii. Non-opioid
Opioid Receptors
• Three major classes of opioid receptors (μ, К and δ)
• G protein-coupled family of receptors.
4

5. 5

6. 6

7. 7

8. SUMMARY OF MODULATORY MECHANISMS
IN THE NOCICEPTIVE PATHWAY

9. MECHANISM OF ACTION OF OPIOIDS
• 1. Reduced opening of voltage-gated Ca2+
channels
• 2.Stimulation of K+ current though several
channels including G protein-activated inwardly
rectifying K+ channels (GIRKs)
• 3. Inhibition of adenylyl cyclase activity and
cause MAP kinase (ERK) activation
• 4. Activation of PKC and PLC

10. Opioid Receptor Subtypes, Their
Functions
Receptor
Subtype
Functions Endogenous
Agonists
 (mu) Supraspinal and spinal analgesia; sedation; Respiratory
depression; slowed gastrointestinal transit; modulation
of hormone an neurotransmitter release, Euphoria
Endorphins
> enkephalins >
Dynorphins
 (delta) Supraspinal and spinal analgesia; modulation of
hormone and neurotransmitter release
Enkephalins
> endorphins &
Dynorphins
 (kappa) Supraspinal and spinal analgesia; psychotomimetic
effects; slowed gastrointestinal transit, Dysphoria
Dynorphins > >
endorphins &
Enkephalins

11. Opioid Receptor Types
• Mu ()
• Kappa ()
• Delta (δ )
• Supraspinal & Spinal analgesia,
Respiratory depression, Sedation,
Euphoria, Miosis, Reduced GI motility,
Physical dependence.
• Supraspinal & Spinal analgesia,
Respiratory depression, Dysphoria,
Miosis, Reduced GI motility, Physical
dependence.
• Supraspinal & Spinal analgesia,
Respiratory depression, Affective
behaviour, Reinforcing actions, Reduced
11

12. Natural Opioids
1. Exogenous from Plants:
Two types of alkaloids:
2. Endogenous opioid peptides:
Isolated from brain, pituitary, spinal cord and GIT.
Three distinct families: (1) Endorphins
(2) Enkephalins
(3) Dynorphins 12
Phenanthrene
derivatives
Benzoisoquinoline
derivatives
Morphine (9-14%) Papaverine (0.8-1%)
Codeine(0.5-2%) Noscapine(3-10%)
Thebaine (0.2-1%) Narcine(0.2-0.4%)

13. Endorphins:
 β-endorphin from Pro-opio-melanocortin(POMC)
 Primary μ agonist.
 Distribution: Hypothalamus,thalamus,brainstem.
Enkephalins:
Met-enkephalins - from pre-proenkephalin.
leu-enkephalins - from proenkephalin-A.
Affinity δ > μ >  receptor.
Distribution: Hypothalamus, cortex, limbic system,
spinal cord, medulla, adrenal medulla and GIT.
Dynorphins:
Dynorphin A and B from pro dynorphin.
Affinity  > μ > δ receptors.
Distribution: Wide distribution like enkephalins.
13

14. OPIOID AGONIST AND ANTAGONIST
I. Morphine and related opioid agonists:
Morphine, Codeine, Heroin and Pholcodeine
II. Pethidine and congeners:
Pethidine, Fentanyl, Sufentanyl, Alfentanyl,
Diphenoxylate, Loperamide,
III. Methadone and congeners:
Methadone, Dextropropoxyphene and Tramadol.
IV. Opioid agonists – antagonists:
Nalorphine, Pentazocine, Butorphanol
V. Partial agonist:
Buprenorphine
VI. Pure antagonists:
Naloxone, Naltrexone and Nalmefene. 14

15. MORPHINE AND RELATED OPIOID AGONISTS
Major effects on CNS and bowel - μ receptors.
At high doses - Interact with the other receptors.
Pharmacological actions
A. CNS
Depressant actions
1. Analgesia
 Relieve Continuous dull pain > sharp intermittent
pain.
 Degree of analgesia with dose.
↑
 Neuropathic pain < Nociceptive pain 15

16.  MOA-
 ↑ pain threshold at the spinal cord level
 Alters the brain perception of pain by acting at spinal
and supraspinal level.
2. Sedation
 Drowsiness and clouding of judgement
3. Mood and subjective effects
 Appreciable sense of well being (μ receptor)
 ↓ distress and anxiety associated with pain.
16

17. 4. Respiratory centre
Depress in a dose dependent manner.
Direct depressant action on the respiratory centre.
↓ responsiveness of brain stem respiratory centre to
CO2.
5. Cough centre
 Depress
Stimulatory effects
1. CTZ  nausea and vomiting
Later it depress the vomiting centre
17

18. 2. Edinger Westpal nucleus  Miosis
3. Vagal Centre  bradycardia.
B. Neuroendocrine
Hypothalamus  inhibits release of GnRH and CRH 
FSH, LH and ACTH.
↓
↑ release of Prolactin and GH.
C. CVS
Postural HTN only with large doses
Cardiac work reduced due to peripheral resistance.
↓
18
 Histamine

19. D. GIT
Constipation
- sphincter tone.
↑
- tone and segmentation
↑
- propulsive movement and
↓ ↑ fluid absorption
- GI secretion
↓
-Inattention to defecation reflex.
19

20. E. Other Smooth Muscles
1. Biliary tract:
Spasm of Sphincter of Oddi  intrabiliary pressure
↑
biliary colic.
2. Urinary Bladder:
Constriction of the urinary sphincter difficulty in
urination.
Contraction of detrusor muscle  urgency to micturate.
3. Bronchial Muscle: Bronchoconstriction (Histamine).
Morphine causes spasm of all sphinchters EXCEPT the LES
20

21. Pharmacokinetics:
Absorption: From GIT is slow and erratic (significant
first pass metabolism).
Oral bioavailability- 25% of Parentally administered
drug.
30% plasma protein bound.
Distribution: Wide and enters all the body tissues.
Only a small fraction enters the brain.
Metabolism: Glucuronide conjugation to Morphine – 6
– Glucuronide in liver
Excretion: Mainly in urine. 21

22. Therapeutic uses:
AS ANALGESIC :
Acute MI
# long bones
Burns
Terminal stage of malignancy
Spontaneous pneumothorax
Pulmonary Embolism
Intrathecal and epidural analgesia for post operative pain
relief 22

23. Acute left ventricular failure (iv morphine)
 ↓ preload on heart
 Shunting 0f blood Pulmonary  Systemic circulation.
 Calm the patient  ↓ sympathetic stimulation  ↓
cardiac work.
 Sedation- in threatened abortion
 Preanesthetic medication
 Anesthetic
 Anti diarrheal
23

24. Adverse Effects:
 Intolerance- Urticaria, Anaphylactoid reaction & HTN.
 Dysphoria, Mental clouding, Sedation
 Respiratory depression
 Respiratory depression in fetus
Rx Nalorphine 0.1-0.2mg
or Levallorphan 0.05-0.1mg
 Urinary retention
 Constipation
 Vomiting
 Hypotension
 Tolerance
 Drug Dependance 24
in Umbilical vein
of Newborn

25. FUNCTIONAL CONSEQUENCES OF ACUTE AND CHRONIC OPIATE
RECEPTOR ACTIVATION
• Desensitization (decreased responsiveness that occur with repeated or chronic
exposure to agonist)
• Tolerance (gradual loss of effectiveness)
• Dependence (body changes to adapt to the constant access and use of the drug,
Defining factor: withdrawal will occur)
• Addiction(defined by behavior, the substance abuse will continue despite negative
consequences,
Critical to seek treatment to break the cycle.

26. MECHANISMS OF TOLERANCE/DEPENDENCE-WITHDRAWAL
• Receptor disposition
• Adaptation of intracellular signaling mechanism
• System level counter adaptation
• Differential tolerance development and fractional
occupancy requirement

27. Tolerance And Dependance
Tolerance– Repeated use of morphine produces
tolerance to all the effects except miosis & constipation.
Mechanism
1. Pharmacokinetics (drugs not reaching the brain’s
receptor)
2. Pharmacodynamics (Cellular, receptors are damaged
or lost)
Dependence-
Psychological dependence: drug seeking behavior.
Physical dependence: High abuse potential
27

28. Withdrawal symptoms:
1. Pain 2.Hyperventilation
3. Coughing 4. Mydriasis
5. Emesis 6. Diarrhea
7. Dysphoria 8. Agitation
9. Hypertension 10. Piloerection
Treatment:
Withdrawal of Morphine
Substitution with oral Methadone (long acting and
orally effective)
Gradual withdrawal of Methadone
1mg of methadone will substitute 4mg of morphine.
28

29. Acute Morphine Poisoning
Accidental
Suicidal
Drug abusers
Toxic dose- 65 mg
Lethal dose- 250mg
Presents with Coma, Severe Respiratory depression,
Pinpoint pupil, Occasional jerks, Convulsion, Cyanosis,
Pulmonary edema (terminal stage), Respiratory failure,
death.
29

30. Management:
Follow A B C
Gastric Lavage- With KMnO4 to remove unabsorbed
drug.
Specific Antidote-
Naloxone and Nalorphine
☞Naloxone 0.4 – 0.8 mg i.v
☞Repeat every 5 min till respiration recovers
☞Repeat every 1-3 hrs till morphine is cleared out of body.
30

31. Contraindication:
Infants and elderly
Respiratory insufficency
Bronchial asthma
Head injury
Undiagnosed pain abdomen
BPH
Hypotension
Hypothyroidism
31

32. CODIENE (Methyl morphine)
☞ Antitussives
☞Antidiarrheal
☞Analgesic (1/6th
to 1/10th
): Codeine (10%)  Morphine
☞ Good Oral absorption
☞No significant respiratory depression
☞Excreted chiefly in urine
☞↓ Dependence liability
32

33. TRAMADOL
☞Synthetic Codeine derivative ; µ > ĸ > δ
☞Inhibits NA, 5HT reuptake  activates Monoaminergic
spinal inhibition of pain.
☞100 mg of tramadol 10 mg of morphine.
≈
☞Action only partially reversed by naloxone.
☞↓ addiction potential, respiratory depression, constipation,
sedation and urinary retention.
☞Used as analgesics
Mild to moderate short lasting pain due to diagnostic
procedure, injury, surgery etc.
Chronic cancer pain 33

34. HEROIN (Diamorphine, Diacetylmorphine)
☞ Semi-synthetic derivative of Morphine
☞Potency: Heroin > 3 times morphine
☞As Drug of Abuse (Brown Sugar)
More lipid soluble  enters the brain readily
Greater euphoriant
Greater addictive & dependence liability
1gm Methadone substitute 2mg Heroin. 34

35. PETHIDINE And Its Congeners
☞Pharmacological actions is almost similar to
morphine
☞Potency 1/10th
of Morphine (given i.v)
☞Rapid onset & shorter duration of action
☞No significant antitussive activity
☞↓ spasmodic, constipation, urinary retention
☞↑ nausea & vomiting
☞Vagolytic effect HR, Dryness of mouth
↑
35

36. ☞Absorbed by all routes of administration.
☞Pethidine Hydrolysis  Meperidinic acid
☞Pethidine  Demethylation  Norpethidine
(significant CNS excitation).
☞Excretion in acidic urine.
↑
Therapeutic uses:
 Major use in analgesia( substitute of Morphine)
Preanesthetic medication
Epidural & intrathecal analgesia
Obstetrical analgesia 36

37. Adverse Reactions:
Toxic doses CNS excitation –tremor, muscle twitching
& seizures. (Not antagonised by Nalorphine)
Respiratory depression and coma (Antagonised by
Nalorphine)
Tolerance (analgesic & emetic effect)
Dependence
Pethidine addicts show Dilated pupil.
1mg Methadone substitute 20mg pethidine
37

38. FENTANYL
☞Synthetic pethidine congener.
☞Potency: Fentanyl > 80 times morphine
☞Lipophillic  rapid onset and short duration of action.
☞Uses:
In cardiac surgery; negligible effect on the myocardial
contraction.
With Droperidol (neuroleptic) as Neurolept
Analgesia for operative procedures.
Epidural Fentanyl for cancer and other chronic pain.
38

39. ALFENTANYL, SUFENTANYL, RAMIFENTANYL
☞Newer, more potent than Morphine or Fentanyl.
☞Profound analgesia
☞Anesthesia (higher dose)
☞Impressive Cardiovascular stability.
☞Uses:
As GA.
Intrathecally & epidurally for post operative analgesia.
39

40. METHADONE And Its Congeners
☞Long acting µ agonist.
☞Analgesic potency =/> Morphine.
☞Respiratory depressant = Morphine.
☞Action on GIT and CVS = Morphine.
☞↓ hypnotic activity.
☞↑antitussive activity.
☞↑ efficacy orally
40

41. ☞ Uses:
 As analgesic
 Antitussive (Occasional)
 Controlled withdrawal of morphine and heroin
abusers.
✓ 90% protein bound  repeated administration 
cumulative toxicity
✓ On discontinuation  slow release from
extravascular binding site  mild protracted
withdrawal syndrome.
(Codeine as substitute for Rx of Methadone addicts)
1 mg methadone substitute 4 mg of Morphine; 2 mg of
41

42. DEXTROPROPOXYPHENE
☞Congener of methadone
☞As analgesics : ½ as potent as codeine.
☞Delirium & Convulsion (overdose)
☞Cardiotoxic (Demethylated Metabolite)
☞Less respiratory depression, fewer GI s/e
☞Used as Mild oral analgesics (dose 60-120 mg)
Used in combination with paracetamol/ aspirin
(supradditive action).
42
Partly
antagonized
by Naloxone

43. PENTAZOCINE (Agonist- Anatagonist)
☞Analgesic - agonistic spinal  receptor; weak 
antagonist
☞Abuse liability < morphine (No euphoria)
☞↑ pulmonary & Systemic arterial pressure, cardiac
↑
work (Not used in MI)
☞Repeated use: Tolerance, psychological & physical
dependence
☞Ppt. withdrawal syndrome in morphine addict
☞Naloxone for Pentazocine addict (NOT Nalorphine)
☞Used as analgesics in postop. and moderately severe
43

44. NALORPHINE (N- allyl-normorphine)
☞ agonist &  antagonist.
☞Without prior medication with Morphine :
Morphine like action
But Dysphoria and Hallucination
☞After Morphine/ its derivatives: Antagonistic action
☞In Morphine addict: 1-3mg Nalorphine  Milder
withdrawal symptoms within 3-15 min. (last for 2 hrs)
44

45. ☞Effective against Morphine, Codeine, Heroin,
Methadone
☞Tolerance to agonistic action and physical dependence
develops on chronic use but NO psychological
dependence.
☞Uses:
Acute Morphine or Opioid poisoning – 3-5 mg i.v./ i.m.
Diagnosis of morphine addict (Dilates pupil/ No effect)
Morphine Deaddiction (Nalorphine + Morphine)
Neonatal asphyxia due to morphine or pethidine given
in labour – 0.1-0.2 mg injected in the chord. 45

46. NALBUPHINE
☞Agonist–antagonist
☞Potency : As agonist 3-4 times > Pentazocine
As Antagonist 10 times > Pentazocine
☞Less likely to produce dysphoria.
☞IM dose of 10 mg Nalbuphine equi-analgesic to 10 mg
morphine
☞Used to produce analgesia in post operative pain, MI
and labour pain
46

47. BUTORPHANOL
☞Agonist ; Partial agonist 
☞20 times as potent as Pentazocine
☞Analgesic doses - pulmonary arterial pressure,
↑ ↑
cardiac work, systemic arterial pressure.
↓
☞Produces physical dependence
☞Can neither substitute for nor antagonize morphine
☞A nasal formulation is available - proven to be
effective. 47

48. BUPRENORPHINE
☞Partial µ-receptor agonist; Weak  antagonist
☞Semisynthetic, lipophilic opioid derived from Thebaine
☞Potency: 25–50 times > morphine.
☞Slower onset, Longer duration of analgesia
☞Less respiratory depression
☞Naloxone doesnot precipitate withdrawal syndrome
☞Inactive orally- given SL/IM/ IV/ SC.
☞Excreted unchanged in the feces
48

49. Uses:
Analgesic and as a maintenance drug for opioid-
dependent subjects
Approved by the FDA for the treatment of opioid
addiction (buprenorphine alone administered
sublingually, followed by maintenance therapy with a
combination of buprenorphine and naloxone to
minimize abuse potential).
Antagonizes the respiratory depression produced by
fentanyl & N2O but prolongs analgesia.
49

50. NALOXONE (Pure Antagonist)
☞Antagonist of choice in Opioid poisoning
☞Diagnosis of opioid dependence
☞No tolerance to the antagonistic action
☞Oral potency 1/50th
of parenteral
☞Metabolized by Glucuronide conjugation (DOA: 3-4
hours)
☞Given IV Naloxone reverse the opioid effects within 1–
3 minutes completely and dramatically 50
Naloxone Instantaneously Precipitate An Withdrawal
Syndrome

51. ☞Naloxone 0.8–2 mg i.v. bolus every 2-3 minutes (max.
10mg)
☞ Neonates & children 10 mcg/kg i.v. bolus
☞Low-dose naloxone (0.04 mg)- Reverse residual
respiratory depressant effects with i.v or epidural opioids.
☞1 mg iv Naloxone blocks the effect of 25mg Heroin 51
No Response
100mcg/kg i.v. bolus
Consider 2nd dose up to total of 25 mcg/kg if no response

52. NALTREXONE (Pure Antagonist)
☞Orally active- Long acting (DOA: upto 4Days)
☞No Euphoria, No Physical dependence
☞Block euphoric action of opioid agonists  patients
loses craving.
☞Suitable for ‘Opioid Blockade’ therapy of opioid
addicts:
☞Alcohol craving is also reduced by Naltrexone. 52
Start 25 mg/d 50 mg/d
Total Weekly Dose 350 mg
100mg Mon 100 mg, 100 mg Wed & 150 mg Fri
OR

53. NON ANALGESIC USES OF OPIODS
As Anti-diarrhoeal:
Diphenoxylate, Loperamide
Central Cough Supressant:
Codeine, Dextromethorphan
Emetic:
Apomorphine
Acute LVF:
Morphine
53

54. THANKYOU
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