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Opioid Analgesics (Narcotic Anlagesics)

Analgsia : Unpleasant sensation evoked by external or internal noxious stimuli.
Analgesics: The drugs that relives the pain by acting in the CNS or on Pheripheral pain
mechanism.
It divide into Opioid analgesics and non-opioid (NSAIDs) analgesics.
Classification of Opiod analgesics present in papaver somniferum
1. Phenanthrene derivatives:
Morphine (10%), Codeine (0.5%), Thebaine (0.2%)
2. Benzisoquinoline derivatives:
Papavarine (1%), Noscapine (6%) (Narcotine)

Demethylation of Codeine to Morphine

Classification:
1. Narcotics agonist analgesics
A. Phenanthrenes:
Natural opium alkaloids: Morphine, Codeine
Semi-synthetic derivatives:
Morphine derivative: Hydroxymorphone, Oxymorphone
Codeine Derivatives: Hydrocodone, Oxycodone
B. Methadones: Methadone, Propoxyphene
C. Morphinan: Levorphenol
D. Phenyl piperidens (Meperidine): Pethidine, Fentanyl, Alfentanil, Sufentanil
2. Narcotic agonist-antagonist analgesics
A. Phenanthrenes – Buprenorphine, Nalbuphine
B. Morphinan – Butorphanol
C. Benzomorphan – Phenazocine, Pentazocine
3. Narcotic antagonist:
Naloxone, Naltraxone

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Opioid Receptors:
Endogenous Partial
Receptors Agonist Antagonist
Substance agonist
Buprenorphine Nalorphine
µ receptors Endorphin Morphine
Butorphanol Naltrexone
Butorphanol
Naltrexone
κ receptors Dynorphin A, B Nalorphine ---
Naloxone
Pentazocine
Morphine Naltrexone (Weak)
δ receptors Enkephalins ----
(Weak) Naloxone (Weak)

MOA of Opioids:

Fig. 1 Action of Opioid

Explanation of Fig. 1: Opioids excites neurons from periaqueductal gray matter (PAG) and
nucleus reticularis paragigantocellularis (NRPG).
which project to retroventral medulla
which contain nucleus raphe magnus (NRM)
5-HT and enkephalin containing neurons

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runs towards dorsal horn and exert an inhibitory influence on transmission (Substance P).
Opioids directly act on dorsal horn as well as peripheral terminal of nociceptive afferent
neurons.
Upon activations of opioids receptors (µ and δ)
decreases c-AMP formation
Opens K+
channels
hyperpolarisation
Decrease in release of Substance P (neurotransmitter)
On activation of κ receptors
Suppresses N type Ca++ ion channels
inhibition of Ca++
influx
Hyperpolarisation.
SAR of Morphine:

Modification
Replacement of OCH3 at 3rd Position
Replacement of OC2H5 at 3rd Position
Replacement of -O-CO-CH3 at 3rd Position
and 6th postion
Dihydromorphinone or dihydrocodeine –
Oxidation at C-6
Interpretation
Codeine – decreased analgesic activity
Ethylmorphine – little analgesic activty
Heroin – increases analgesic but also
increases addiction effect.
14-Hydroxy dihydromorphine – more potent
analgesics.

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addition of OH at C-14
Bridging at C-6 and C-14
14 through ethylene Etorphine – 200 times more potent than
linkage morphine
Modification at tertiary nitrogen (N-R) Potent Antagonistic activity
Replacement of R with methyl, n-phenyl, n-
hexyl, allyl etcs.
Thenaine, Oripavine Increased activity, selectivity, and decreased
toxicity.
Ethorphine 10000 time more potent than morphine but
no. of side effects, use as a sedative in
veterinary medicines.

SAR of Meperidine Class:

Removal of B,C, D rings

Morphine Pethidine

Modification Interpretation
4-phenyl
phenyl group with hydrogen, alkyl, Reduces Activity
aroalkyl or hetrocyclic group
Replacement of –COOC2H5 by –COC2H5 Prodine - increases analgesic activity
Replacement of N-CH3 by various aralkyl e.g. Piminodine – Increased analgesic
group activity
Piperidine ring enlarge to 7-
7 membered e.g. Proheptazine – Active and potent
azepine ring analgesic

Methadone Class:

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Methadone series
• Unlike mepridine series insertion of m-hydroxyl
m hydroxyl group in one of the phenyl ring of
methadone series causes a marked decreased in activity.
• Methadone is more potent than isomethadone

Methadone Isomethadone
• Replacement of propionyl group (COC2H5) with hydrogen, hydroxyl, acetoloxy

decreases in activity.
• Replacement of propionyl group (COC2H5) with amide group
Racemoramide
(More active than methadone)

Racemoramide
• Removal of any phenyl ring lead to decreases in activity.
Morphinanes

• Does not process C4 –C5

– ether linkage.
• N-Methyl
Methyl Morphinan (20% of activity)
• Levo form possesses greater activity,
activity, Levorphenol shows 5% more potent than
morphine

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• dextro form of recemorphan is used as cough suppressant (Dextromorphan)

Benzomorphan series:

Compound R1 R2 R3 R4
Benzomorphan OH CH3 H H
Pentazocine OH CH2CH=C(CH3)2 CH3 CH3
Phenazocine OH CH2-CH2-C6H5 CH3 CH3
Metazocine OH CH3 CH3 CH3
Cyclazocine OH CH3 CH3

• Trimethyl compounds is 3 time more potent than dimethyl amalogous

• N-phenethyl
phenethyl derivatives possess 20 times greater potency than N-methyl
N methyl analogous.
• Pentazocine and cyclazocine are classic antagonist. (Pentazocine - High analgesia less
addiction)
Narcotic antagonist:
Replacement of N-methyl
methyl group in morphine by larger alkyl group lowers activity and act as
antagonist.
antagonist activity increases in following order:

C2H5 < C3H7 < CH2CH=CH2 <

e.g. Nalorphine, Naloxone, Levallorphan

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