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1. 1
Analgesics
[ Opioids & Non Opioids]
By
Berhan Begashaw
Pharmacy Department
DBU
Nov, 2023

2. Pain
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3. Pain (Algesia)
 “Unpleasant sensory & emotional experience
 Associated with actual or potential tissue damage”
 Evoked by an external or internal noxious stimuli
 Latin “poena” for punishment from God,
Reflects the deleterious effects that can be
inflicted upon the body.
 Mediated by different NTs & peptides such as
glutamate & substance P
 It is a warning, primarily protective in nature
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4. Generally, the pain can be
Acute
 Superficial
• Stimulation of skin & mucous membranes
• Fast response
 Deep
• Arises from muscles, joints, tendons, heart, etc.
• Slow response
 Visceral
• Inflammation
 Chronic pain
 Unknown origin
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5. Classification
1. Physiological: Nociceptive, Neuropathic, Psychological
 „Nociceptive‟
 Normal physiology (mechanisms known)
 Treated with analgesics [ NSAIDs, acetaminophen,
opioids]
 „Neuropathic‟
 Aberrant physiology (mechanisms unknown)
 Associated with neural damage
 Difficult to treat with opioid analgesics
2. Clinical: Acute, Chronic, Malignant
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6. Pathophysiology of Pain
Noxious
stimulus
Transduction Conduction Transmission
Modulation
“Ouch” Pain
Perception
central neuron
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7. Berhan B. 7

8. Noxious stimulus [ trauma, infection,..]
Release of inflammatory substances
(PG, His, 5-HT, Bks, Sub.P, etc.)
Transduction (generation & electrical impulses)
Transmission (conduction by nerve fibers)
Modulation (Modification with spinal cord)
Perception
NSAIDs
Opioids
Pathophysiology of pain…
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9. Analgesics
 Drugs that selectively relieve pain with out
significant change on patient consciousness
 Act on CNS or periphery pain mechanism
Classification
 Narcotics /opioids/
 Morphine & morphine like drugs
 Non-narcotics - NSAIDs
 Adjuvant analgesics /coanalgesics
 TCAs, Antiepileptics, Steroids
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10. Sites of Action of Analgesics
Drugs can prevent pain at the site of injury
 By blocking peripheral nerves (local anesthetics)
 By closing the „gates‟ in the dorsal horn &
thalamus (one action of opioids & TCAs that
inhibit axonal re-uptake of 5-HT & NE)
 By altering the central appreciation of pain
(another effect of opioids).
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11. Management of Pain
1. Mild pain
 NSAID + Adjuvant
2. Moderate pain
 Weak narcotic + NSAID + Adjuvant
3. Severe pain
 Strong narcotic + NSAID + Adjuvant
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12. Opioids Analgesics
 Opium: A mixture of alkaloids from seed capsule of
opium poppy [ Papaver somniferum ]
 Opioids
 Any drug, natural, semisynthetic or synthetic, with
actions like morphine
 Morphine has 5 rings, 3- & 6-OH grps (phenolic &
alcoholic), piperidine ring with N-methyl grp & a
quaternary carbon at position 13
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13. Opioids …
 Codeine is morphine O-methylated at position 3
 Heroin is morphine O-acetylated at positions 3 & 6
 Replacing N-methyl with something larger (allyl,
cyclopropyl, cyclobutyl) produces opioid with
antagonist properties
 Meperidine (pethidine) is a synthetic opioid with
only fragments of the morphine structure
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14.  Act by binding to specific opioid receptors in the CNS
to produce effects that mimic the action of endogenous
opioids peptide NTs;
 Endorphins [ μ (Mu) receptor]
 Enkephalins [ δ (Delta) receptor]
 Dynorphins [ Κ (Kappa) receptor]
 Primary use is to relieve intense pain that results
from surgery, injury, or chronic disease.
 Widespread availability of opioids has led to abuse
of agents with euphoric properties.
 Antagonists that reverse the actions of opioids
 Clinically important in cases of overdose
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15. Opioid Receptors
1) μ (Mu) receptor- Most important & activation leads
to analgesia, resp. depression, sedation, physical
dependence, euphoria, miosis, NV & constipation.
2) Κ (Kappa) receptor - Activation produces modest
analgesia, sedation, miosis & dysphoria.
3) δ (Delta) receptor- Responsible for producing little
effect in analgesia, NV
4) σ (Sigma) receptor
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16.  Drugs that act at opioid receptors
1. Pure opioid agonists
 Activate mu & kappa receptors
o Strong opioid agonists
 Morphine, pethidine, fentanyl, hydromorphone, ...
&
o Moderate-to-strong opioid agonists
 Codeine, tramadol, dhydrocodeine, …
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Berhan B.

17. 2. Opioids agonist-antagonist/Partial agonists
 When administered alone, produce analgesia, but given
to a person taking opioids, produce antagonistic effect.
 Pentazocine, nalbuphine, butorphanol, buprenorphine,...
3. Pure opioid antagonists
 Antagonize mu & kappa receptors for reversal of
respiratory & CNS depression.
 Naloxone, naltrexone, nalmefen,…
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18. Classification of opioid agents
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Natural
- Morphine
- Codeine
 Synthetic
- Fentanyl
- Methadone
- Propoxyphene
- Loperamide
- Meperidine
- Tramadol
 Semisynthetic
- Heroin
- Hydrocodone
- Buprenorphine
- Naloxone
- Naltrexone
- Dextromethorphan

19. MoA of Opioids
 Produce analgesia by binding to specific receptors
located in brain & spinal cord regions involved in
the transmission & modulation of pain
 Inhibit adenylyl cyclase  ↓ cAMP
 Reduce neuronal excitability
 B/c of the  K+ conductance
 hyperpolarization of the membrane
 Reduce transmitter release
 Due to inhibition of Ca 2+ entry
 Blockage of nociceptive transmission
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20. Tramadol
 Works partly through an agonist effect at μ
receptors (opioid action)
 Extensive metabolism by CYP2D6
Use
 Widely for moderate to severe pain, post-
operative pain.
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Adverse effects
 Less respiratory depression, constipation &
abuse potential.
DDIs: SSRIs, MAOIs,TCAs, BZDs, Alcohol

21. Codeine
 Has only about 10% of its analgesic potency.
 Converted to morphine by CYP2D6 enzyme
 Produces little euphoria & low addiction potential.
 Mild to moderate pain, cough suppressant
[ preferred: Dextromethorphan] & symptomatic
relief of diarrhea.
With PCM--- pain
 Adverse effects: Resp. depression & death [Children]
 DDIs: BZDs, Alcohol
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22. Morphine
 Isolated from opium & named representing the
Greek God of Dreams “Morpheus.”
 Somewhat selective to the μ receptor, has some
affinity for the κ & δ receptors.
 Also inhibits the release of many excitatory NTs
from nerve terminals carrying nociceptive (painful)
stimuli.
 Glutamate
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23. Morphine…
Uses
 Most importantly for moderate to severe & chronic
pain relief.
 May be given as an IV bolus if rapid relief is required
(e.g. during MI).
 Alternatively, can be given continuously by an infusion
pump (Eg. post-operatively), ivly or scly.
 Effective in the relief of acute left ventricular failure.
 Inhibits cough, but codeine is preferred.
 Relieves diarrhea, but codeine is preferred.
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24. Morphine…
Adverse effects
◦ Respiratory depression [acute overdose]
◦ Miosis
◦ Emesis
◦ Biliary pain
◦ Constipation
◦ Hypotension & bradycardia may occur [higher doses]
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25. Morphine…
Adverse effects…
◦ Increases CSF pressure
◦ Bronchoconstriction
◦ Euphoria
◦ Androgen deficiency [prolonged use]- ed testosterone
◦ Prolong 2nd stage of labor
◦ Moderate immunosuppression – infec. & tumor metastasis
◦ Tolerance & dependence
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26. Drug interactions
◦ CNS depressant medications
 Phenothiazines
 Monoamine oxidase inhibitors (MAOIs), &
 Benzodiazepines
 Alcohol
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27. Pethidine (Meperidine)
 Lower potency synthetic opioid structurally
unrelated to morphine
 Acute pain & acts primarily as a κ agonist, with
some μ agonist activity.
 Very lipophilic & has anticholinergic effects
 increased incidence of delirium
 Does not constrict the pupil, release histamine or
suppress cough.
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28. Pethidine …
 Primarily as an analgesic & in preanesthetic
medication
 Control shivering during the postsurgical recovery
period
 Management of cancer pain [ Transdermal]
 Sometimes used in obstetrics, but morphine is
often preferred.
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29. Pethidine …
Adverse effects
 Delayed gastric emptying (common to all opioids):
particular concern in obstetrics
 Delirium, hyper-reflexia, myoclonus, & seizures
[overdose, long term use, esp. in pts with renal
insufficiency]
D/Is: MAOIs, SSRIs
C/Is: Renal & hepatic insufficiency, pre-existing
respiratory compromise
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30. Fentanyl
 Derivatives of pethidine
 Extremely potent analgesic (100X morphine)
 Highly lipophilic, shorter-acting [15-30mins] & rapid onset
 Treat severe acute pain or as an adjunct to anesthesia.
 Usually administered IV, epidurally, or intrathecally
 With LAs: Epidural analgesia for labor & post pain
 IV: In anesthesia for analgesic & sedation effect
 Transmucosal & nasal: Cancer related pain
 Transdermal patch: Chronic severe pain
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31. Mixed Agonist –Antagonists & Partial Agonists
 Drugs that stimulate one receptor but block another.
 Bind to the opioid receptor, but they have less
intrinsic activity than full agonists
 Effects depend on previous exposure to opioids
a) Produce excitatory & hallucinogenic effects
b) Produce a low degree of physical dependence
c) Induce withdrawal signs that differ from morphine
d) Produce excitatory effects related to the sympathetic
discharge of NE
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32. Pentazocine- Moderate pain, premedication &
supplement to surgical
Butorphanol- Moderate to severe pain [ more
potent than morphine & pentazocine]
- Nasal spray: Post operative pain & migraine [abuse]
Nalbuphine- Moderate to severe pain, postsurgical
& obstetrical analgesia
Buprenorphine-More potent than morphine as
moderate to severe pain
- Opiate detoxification
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33. Clinical Uses of Opioids
1. Analgesic effect [ severe pain-chronic, acute]
 Selective relief of pain at doses which do not
produce hypnosis or impair sensation
 Some types of pain more responsive to opioids
than others
 More effect in prolonged, burning pain than
sharp, intermittent pain
 Neuropathic pain can be resistant
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34.  Therefore, opioids are mainly used for severe &
constant pain
 Chronic pain such as in cancer patients may need
continuous use of potent opioid analgesics
 Potent opioid analgesics associated with tolerance
& dependence
But this should not be barrier to provide the best
possible care for the patients
 Slow release dosage forms may give longer &
more stable level of analgesia
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35.  Fentanyl transdermal system (fentanyl patch) can be
used over long periods if disturbances of GIT
 Opioid analgesics are used during obstetric labor
 As opioids cross the placental barrier, care must be
taken to minimize neonatal depression
 If it occurs, immediate use of naloxone will reverse
the depression
 Meperidine produce less depression (particularly
respiratory depression) in newborn infants than
does morphine
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36. 2. Cough suppression/antitussives [at low dose]
 Depression of cough centers in the medulla
(possibly in the periphery too)
 Different molecular mechanism than analgesia or
respiratory depression
 Cough suppressed by dextro-isomers of opioids
[Dextromethorphan], compounds which have no
analgesic activity
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37. 3.Anti-diarrhael agent
 Cause constipation beneficial for Rx of diarrhea
 Diarrhea from almost any cause can be controlled
with the opioid analgesics
 But if associated with infection, appropriate
chemotherapy should be used
 Synthetic drugs [ Diphenoxylate & loperamide]
with selective effect on GIT poorly-absorbed &
have little/no central effects
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38. 4. Post anesthetic shivering
All opioid agonists have some propensity to
reduce shivering
Meperidine is the most pronounced anti-shivering
properties
Single doses is effective in the treatment of post-
anesthetic shivering via the action on subtypes of
the α 2 adrenoceptor.
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39. 5. Application in anesthesia
◦ Used in CV surgery b/c of low cardiac depressant
effects
◦ Opioids can be used
 Preoperatively b/c of their sedative, anxiolytic
& analgesic properties
 Intra-operatively as adjuncts to other
anesthetic agents & as a primary
component of the anesthetic regimen
 Postoperatively as analgesics
6. Alleviate the dyspnea of acute left
ventricular failure & pulmonary edema
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40. Side effects of opioids
o Most are associated with mu receptors
o Respiratory depression
o Euphoria
o Sedation
o Hypothermia
o Constipations
o Tolerance & dependence
o Bronchoconstriction (Histamine release stimulated)
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41. Opioid Antagonists
 Bind with high affinity to opioid receptors
 Opioid-dependent pts: Rapidly reverse the effect of
any full μ agonist
 Naloxone
◦ A pure competitive antagonist of opioid agonists at
μ-receptors [10X higher than K receptors]
◦ Short duration of action (30-80 mins)
◦ Rx of morphine poisoning IVly
◦ Dx opioid dependence
◦ Oral: No clinical effect
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42.  Naltrexone
 Orally active reduce the risk of relapse in former
opioid addicts in addition to supportive therapy
 Longer duration of action
 With clonidine or buprenorphine
 Rapid opioid detoxification
 Cause hepatotoxicity
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43. Good Time!
Berhan Begashaw
Thank U So Much !!!
Read More & Fill the Gap…!