Narcotic Analgesics (Opioid Analgesics)

Introduction
Analgesics are the substances that relieve pain
‘Narcosis’ means a state of stupor or sleep or drowsiness or unconsciousness

• Opium is a Greek word meaning “juice,” or the extract or the dried latex of seeds from the
poppy plant, Papaver somniferum
• Morphine was the first Narcotic analgesic isolated from opium which contains over
twenty distinct alkaloids
• Opiates – synthetic/natural compounds both structurally and pharmacologically similar
to Morphine
• Opioids – synthetic/natural compounds not structurally but only pharmacologically
similar to Morphine
• Opioids is a broader term that includes opiates and refers to any substance, natural or
synthetic, that binds to the brain’s opioid receptors.

Definition
• Narcotic analgesics are a class of drugs that can relief pain without loss of
consciousness.
• These drugs are used to provide relief moderate-to-severe acute or chronic pain. They
may also be called opiates, opioid analgesics, or narcotics.
• Opioids are medications that mimic the activity of endorphins, substances produced by
the body to control pain.
• Narcotic analgesics are drugs that relieve pain, by binding to opioid receptors, which
are present in the central and peripheral nervous systems, can cause numbness and
induce a state of unconsciousness.

1 Narcotic Analgesics (Unit-V, Medicinal Chemistry-I) Prepared by M. Rudrapal

Classification of Drugs

Chemical Classification

1) Natural compounds (Opium alkaloids): Morphine (sulphate), Codeine (phosphate),

Papaverine

D-(-)-Morphine Codeine

2) Semi-synthetic derivatives: Benzylmorphine, Ethylmorphine, Diacetyl morphine

(Heroin), Hydromorphine, Oxycodone, Hydrocodone, Pholcodeine, Buprenorphine

Heroin Oxycodone

3) Synthetic derivatives (Synthetic opioids):

a) Phenylpiperidines:
- Pethidine (Meperidine) and its congeners: Anileridine (hydrochloride),
Diphenoxylate (hydrochloride), Loperamide (hydrochloride)*

Pethidine hydrochloride Loperamide

2 Narcotic Analgesics (Unit-V, Medicinal Chemistry-I) Prepared by M. Rudrapal

 Diphenoxylate

- Fentanyl (citrate) and its congeners: Sufentanil, Remifentanil, Alfentanil

Fentanyl

b) Diphenylprophylamines: Methadone (hydrochloride) and congeners like

Propoxyphene (hydrochloride) and Dextropropoxyphene (d-isomer of
propoxyphene)

Methadone Propoxyphene

c) Benzomorphans: Pentazocine, Phenazocine

Pentazocine

d) Morphinan compounds and congeners: Levorphanol (tartarate), Butorphanol,

Dextromethorphan (d-isomer of the codeine analog of levorphanol)

3 Narcotic Analgesics (Unit-V, Medicinal Chemistry-I) Prepared by M. Rudrapal

 Levorphanol Butorphanol

4) Endogenous opioids (natural pain relieving peptides of the body): Endorphins,

Enkephalins and Dynorphins

5) Miscellaneous: Tramadol, Meptazinol

Tramadol
*
Loperamide is an opiate that does not enter the brain and therefore lacks analgesic activity.

Pharmacological Classification

Opioids can also be classified as follows

1) Opioid agonists: Drugs that mimic the activity of endorphins, substances produced by
the body to control or alleviate pain. These drugs produce narcotic agonistic response by
binding directly with opioid receptors and thus help relieve pain
a) Strong: Morphine, methadone and meperidine
b) Moderate: Codeine, oxycodone, hydrocodone
c) Weak: Propoxyphene

2) Mixed agonists-antagonists: They produce mixed actions of agonists and antagonists.

Examples: Buprenorphine, nulbuphine, butorphanol, pentazocine.

3) Opioid antagonists (Narcotic antagonists): These drugs antagonize the action of opioid
agonists at the opioid receptors. Examples: Naloxone, naltrexone

4 Narcotic Analgesics (Unit-V, Medicinal Chemistry-I) Prepared by M. Rudrapal

 Naloxone Naltrexone

Naloxone and naltrexone are synthetic morphinan derivatives. Naloxone (N-

allylnoroxymorphone) is a semi-synthetic congener of the opioid analgesic oxymorphone (14-
hydroxydihydromorphinone) from which it differs by the replacement of the methyl group on the
nitrogen (N) atom by an allyl group. Naltrexone is a derivative of noroxymorphone that is the
N-cyclopropylmethyl congener of naloxone.

Oxymorphone (14-Hydroxydihydromorphinone)

Mechanism of Action
Narcotic analgesics work by binding to opioid receptors, part of the opioid system that controls
pain, pleasurable and addictive behaviors. Opioid receptors are more abundant in the brain and
spinal cord, but are also located elsewhere in the body such as the git (stomach) and the lungs.

Opioid receptors:

Body has its own mechanism to naturally relief pain. There are three types of opioid receptors
abundant in the brain and spinal cord. These are µ (mu), Κ (kappa) and δ (delta). The main opioid
receptor that narcotic analgesics bind to is the µ receptor. It is most widely occurring and the
target of most narcotic drugs. K receptor lacks respiratory depressing effect and can counter
analgesic effect of µ agonist. δ has reduced GIT motility, respiratory depression, convulsant effect.
These are three effects of opioid receptors. Only µ and Κ have clinical use, and δ has limited clinical
use. All opioid receptors are G-protein coupled receptors.

5 Narcotic Analgesics (Unit-V, Medicinal Chemistry-I) Prepared by M. Rudrapal

Mechanism of pain regulation:

Opiod analgesic agonize opiod receptors µ, κ and δ. All opioid receptors (linked through G-
proteins) causes inhibition of adenylate cyclase. They also facilitate opening of K+ channels
(causing hyperpolarisation) and inhibit opening of Ca+2 channels, which thereby inhibits the
release of neurotransmitters (NTs).

Opioids block both chemical and electrical component of nerve transmission. This leads to a
series of event which ultimately block neuronal pain transmission by:

✓ Inhibition of activation of voltage gated Ca+2 channels which depresses NTs release

✓ Increases K+ conductance outside the cell to cause hyper polarization of cell thus
reducing git’s excitability

✓ Inhibtion of adenyl cyclase

(adenylate cyclase--> cAMP --> PKA --> phosphorylation of ion channels -
-> increase chances of channel opening)

6 Narcotic Analgesics (Unit-V, Medicinal Chemistry-I) Prepared by M. Rudrapal

Synthesis
Methadone, 6-Dimethylamino-4,4-dephenyl-3-heptanone

Meperidine, Ethyl ester of 1-Methyl-4-phenylpiperidine-4-carboxylic acid

Fentanyl, 1-Phenethyl-4-N-propinoylanilinopiperidine

7 Narcotic Analgesics (Unit-V, Medicinal Chemistry-I) Prepared by M. Rudrapal

Therapeutic Uses
Opioids are used to treat acute pain related to surgery and other medical procedures, as well as
for persistent (chronic) pain that is moderate to severe.
• Choice of drugs for managing chronic pain (e.g. pethidine) as with cancer or RA
• Used as inducing agent (e.g. fentanyl) or analgesic supplement with General anesthetics
in surgical operations (preanaesthetic medication)
• Used to counter addiction (e.g. methadone and buprenorphine) of more potent opioids
such as heroin

Therapeutic indication Opiates/ Narcotics

Analgesic, Postoperative pain Morphine, Pethidine, Fentanyl
Antitussive (Cough suppressant) Codeine¸ Dextromethorphan
Anti-diarrheal Loperamide, Diphenoxylate
Acute left ventricular failure (Cardiac) Morphine
Surgical anesthesia Fentanyl
Acute pulmonary edema, Asthma Morphine
Opioid dependance Methadone
Opiate overdose/ poisoning Naloxone/ Naltrexone

Structure of Morphine

D-(-)- Morphine (Hydrophilic phenanthrene derivative)

Prototypic opioid (µ) agonist

Morphine has 5 Chiral centers. Only the Levo (-) rotatory isomer is active

8 Narcotic Analgesics (Unit-V, Medicinal Chemistry-I) Prepared by M. Rudrapal

SAR of Morphine analogues (or) Morphine and related drugs

The following structural features are essential for optimal narcotic analgesic or µ agonistic or
opioid agonistic activity.

a) Phenanthrene ring system (with absolute stereospecific configuration)

b) Hydrophilic -OH group in the phenolic ring
c) Basic N atom, mostly tertiary with a methyl substitution (>N-CH3) in morphine

Modification to morphine structure results in a series morphine analogues with potent µ

agonistic or analgesic activity as depicted below:

1) Modification at C-3 substituent

R=C3 substituent Effect in activity

-H (Changing -OH to just –H) 10 times decrease
-OH (Morphine) Activity of morphine
-OCH3 (Codeine) Decrease (lowers activity)

2) Modification in ring

Ring Effect in activity

Removal of ring Activity preserved or enhanced
e.g., Ring analogues of morphine like
pethidine, methadone, fentanyl,
pentazocine and levorphanol

9 Narcotic Analgesics (Unit-V, Medicinal Chemistry-I) Prepared by M. Rudrapal

Morphinans Benzomorphans 4-Phenylpiperidines

(Loss of rings does not affect the analgesic activity)

3) Modification at N substituent

The size of substituent on Nitrogen dictates potency and agonist or antagonist activity.
• Increasing size from methyl (i.e., 1 C) to 3 or 5 carbon (especially with double bonds or
small cyclic/aromatic rings) results in antagonist activity
• Still larger substitution restores agonist activity in more potent form

10 Narcotic Analgesics (Unit-V, Medicinal Chemistry-I) Prepared by M. Rudrapal

 R=N substituent Effect
R = 3-5 carbons (3 C with double bond Becomes µ antagonists
small carbo-cyclic ring)
CH2CH=CH2
e.g. Naloxone
R = 5 C with double bond Mixed agonist/agonist effect
CH2CH=C(CH3)2 (µ antagonist and K agonist)
e.g. Pentazocine
Increased µ agonist (10 times more
R = > 5 carbon (in chain or ring ) potent than morphine)
CH2CH2Ph
(Total 8 C)

4) Reduction of 7,8 double bond increases activity e.g. Hydromorphine

5) Inclusion of -OH at C-14 increases activity e.g. Hydroxymorphine, Oxycodone

6) Removal of -OH at C-6 increases activity e.g., Oxymorphone, Oxycodone

7) Oxidation of -OH to >C=O group at 6 increases activity, if there is also the reduction
of 7,8 double bond e.g., Hydrocodone
8) Acetylation of –OH at C-6 increases activity e.g., 6-Acetylmorphine

11 Narcotic Analgesics (Unit-V, Medicinal Chemistry-I) Prepared by M. Rudrapal

 R=C6 substituent Effect in activity
H increases
>C=O decreases
>C=O with 7,8 reduction (change Increases (10 times more potent than
double bond to single bond) morphine)
e.g. Hydrocodone
CH3CO (e.g. 6-acetylmorphine) increases

9. Removal of the ether linkage produces compounds called morphinans that has
increases activity e.g. levorphanol

Side effects of opioid analgesics

• Euphoria
• Nausea and vomiting
• Respiratory depression
• Urinary retention
• Diaphoresis and flushing
• Pupil constriction (Miosis)
• Constipation

12 Narcotic Analgesics (Unit-V, Medicinal Chemistry-I) Prepared by M. Rudrapal