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

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
Berhan B. 3

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
Berhan B. 4

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
Berhan B. 5

Pathophysiology of Pain
Noxious
stimulus
Transduction Conduction Transmission
Modulation
“Ouch” Pain
Perception
central neuron
Berhan B. 6

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…
Berhan B. 8

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
Berhan B. 9

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).
Berhan B. 10

Management of Pain
1. Mild pain
? NSAID + Adjuvant
2. Moderate pain
? Weak narcotic + NSAID + Adjuvant
3. Severe pain
? Strong narcotic + NSAID + Adjuvant
Berhan B. 11

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
Berhan B. 12

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
Berhan B.
13

? 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
Berhan B. 14

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
Berhan B. 15

? 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, …
16
Berhan B.

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,…
17
Berhan B.

Classification of opioid agents
Berhan B. 18
?Natural
- Morphine
- Codeine
? Synthetic
- Fentanyl
- Methadone
- Propoxyphene
- Loperamide
- Meperidine
- Tramadol
? Semisynthetic
- Heroin
- Hydrocodone
- Buprenorphine
- Naloxone
- Naltrexone
- Dextromethorphan

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
Berhan B. 19

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.
Berhan B. 20
Adverse effects
? Less respiratory depression, constipation &
abuse potential.
DDIs: SSRIs, MAOIs,TCAs, BZDs, Alcohol

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
Berhan B. 21

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
Berhan B. 22

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.
Berhan B. 23

Morphine…
Adverse effects
? Respiratory depression [acute overdose]
? Miosis
? Emesis
? Biliary pain
? Constipation
? Hypotension & bradycardia may occur [higher doses]
Berhan B. 24

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
Berhan B. 25

Drug interactions
? CNS depressant medications
? Phenothiazines
? Monoamine oxidase inhibitors (MAOIs), &
? Benzodiazepines
? Alcohol
Berhan B.
26

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.
Berhan B. 27

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.
Berhan B. 28

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
Berhan B. 29

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
Berhan B. 30

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
Berhan B. 31

?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
Berhan B. 32

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
Berhan B. 33

? 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
Berhan B. 34

? 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
Berhan B. 35

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
Berhan B. 36

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
Berhan B. 37

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.
Berhan B. 38

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
Berhan B. 39

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)
Berhan B. 40

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
Berhan B. 41

? 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
Berhan B. 42

Good Time!
Berhan Begashaw
Thank U So Much !!!
Read More & Fill the Gap…!

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