Opioid agonists & antagonists by Dr. Swaroopa

1. 1
Dr. Swaroopa, 2nd year Pg,
Department of Pharmacology
Rangaraya Medical College
AGONISTS AND
ANTAGONISTS
OF

2. PREVIOUSLY ASKED QUESTIONS IN THE UNIVERSITY EXAMS FROM THIS TOPIC
1. Current status and treatment of opioid dependence
2. Discuss in detail the analgesic action and various routes of administration of opioid
analgesics
3. Opioid Antagonists
4. Endogenous opioid Analogues
5. Naltrexone
6. Pharmacology of opioids
7. Pure opioid antagonists
8. Buprenorphine
9. Define drug dependence. Discuss the treatment of physically dependent individuals
with reference to the specific drugs of abuse.
10. Models of evaluation of Analgesics
2

3. CONTENTS
3
1. INTRODUCTION
2. ENDOGENOUS OPIOID PEPTIDES
3. PHARMACODYNAMICS & PHARMACOKINETICS
4. ROUTES OF ADMINISTRATION
5. OPIOID AGONISTS & ANTAGONISTS
6. EFFECTS OF CLINICALLY USED OPIOIDS
7. THERAPEUTIC USES OF OPIOIDS
8. ADDICTION
9. CONCLUSION
10.REFERENCES

4. INTRODUCTION
4
 The term opiate refers to compounds that are structurally related to products found in
opium(word derived from opos, Greek word for ‘juice’)
 Natural opiates being derived from the resin of the opium poppy, Papaver somniferum.
 Opiates include the natural plant alkaloids such as Morphine, Codeine, Thebaine and
many semisynthetic derivatives.
 An Opioid is any agent that has the functional and pharmacological properties of an
opiate.
 MORPHINE – Prototype of opioid agonists.

5. 5
OPIOIDS
ENDOGENOUS EXOGENOUS
PRODUCED BY BODY
ENDORPHINS
(ENDOGENOUS
MORPHINE)
FROM ENVIRONMENT
HEROIN, MORPHINE – FROM OPIUM POPPY
SEEDS
FENTANYL -- SYNTHETIC (LABORATORY)

6. 6
ENDOGENOUS OPIOID PEPTIDES
• A biological molecule found within the brain that acts through an opioid receptor is
an endogenous opioid peptide.
• There are 3 families of endogenous opioid peptides
ENDORPHINS 2 ENKEPHALINS 3 DYNORPHINS
• These are derived from 3 precursor proteins
Prepro-opiomelanocortin 2 preproenkephalin 3 preprodynorphin
1
1
[POMC] [Proenkephalin A] [Proenkephalin B]

7. 7
Receptor
subtype
Functions Endogenous opioid
peptide Affinity
μ (mu) Supraspinal & spinal analgesia;
inhibition of respiration; slowed GI
transit; modulation of hormone &
neurotransmitter release
Endorphins > Enkephalins
> Dynorphins
δ (delta) Supraspinal & spinal analgesia;
modulation of hormone and
neurotransmitter release
Enkephalins > Endorphins
and Dynorphins
К (kappa) Supraspinal & spinal analgesia;
psychotomimetic effects;
Slowed gastrointestinal transit
Dynorphins >>
Endorphins and
Enkephalins

8. 8
OPIOID RECEPTORS
 There are 3 classes of opioid receptors MOR, DOR,
KOR belong to the rhodopsin family of GPCRs.
 All opioid receptors are widely distributed in the
periphery and neuraxis on neuronal cell soma and
terminals,
 less well appreciated in non-neuronal cells like
peripheral and central microglia & astrocytes, and in
the enteric nervous system of GI tract.
μ (mu) opioid receptor (MOR)
δ (delta) opioid receptor (DOR)
К (kappa) opioid receptor (KOR)

9. 9
 Opioid Receptor Ligands are broadly defined by
their functional properties as agonists and
antagonists at a particular receptor.
 Opioid Receptor Signaling :- The MOR, DOR
and KOR couple to Gi/Go proteins. On receptor
activation, the Gi/Go coupling results in a
number of intracellular events that are mediated
by α and βγ subunits of these G proteins like
-inhibition of AC activity
- reduced opening of voltage-gated Ca+2
channels
-stimulation of K+ current through several
channels, including GIRKs
- Activation of PKC and PLCβ
Receptor specificity of endogenous opioids and effects of
receptor activation on neurons.

10. 10
PHARMACOKINETICS
Absorption:-
 Well absorbed when given subcutaneous, intramuscular and oral routes
 Oral dose need to be much higher than the parenteral dose due to first pass metabolism
except for Codeine and Oxycodone which are effective orally.
 Other routes of administration are nasal insufflation, oral mucosa via lozenges and
transdermal route via patches.
Distribution:-
 Bind to plasma proteins with varying affinity
 Localise in higher concentration in highly perfused tissues such as brain, lungs, liver,
kidneys and spleen.
 Fat tissue is less perfused but drug accumulation here can be very important
particularly after continuous infusion or frequent high dose administration of highly
lipophilic opioids that are slowly metabolised eg; fentanyl

11. 11
Metabolism :-
1. Hepatic P450 metabolism :-
• Hepatic oxidative metabolism is the primary route of degradation of
phenylpiperidine opioids (fentanyl, meperidine, alfentanyl, sufentanyl)
• The P450 isozyme CYP3A4 metabolizes fentanyl by N-dealkylation in the liver.
CYP3A4 is also present in the mucosa of the small intestine and contributes to the
first-pass metabolism of fentanyl when it is taken orally.
• Codeine, oxycodone, and Hydrocodone undergo metabolism in the liver by P450
isozyme CYP2D6, resulting in the production of metabolites of greater potency.
• The synthetic opioid Methadone is metabolized through several CYP450 pathways,
in part accounting for its highly variable bioavailability. The most important hepatic
pathway for metabolism is CYP2B6.

12. 12
2. Plasma esterase metabolism :-
• Esters (e.g., heroin, remifentanil) are rapidly hydrolysed by common
plasma and tissue esterases.
• Heroin (diacetylmorphine) is hydrolysed to monoacetylmorphine and
finally to morphine, which is then conjugated with glucuronic acid.

13. 13
Excretion :-
• Polar metabolites, including glucuronide conjugates of opioid analgesics,
are excreted mainly in the urine.
• In patients with renal impairment the effects of active polar metabolites
should be considered before the administration of potent opioids such as
Morphine or Hydromorphone especially when given at high doses due to
the risk of sedation and respiratory depression

14. 14
ROUTES OF ANALGESIC DRUG ADMINISTRATION
Apart from traditional oral and parenteral formulations for opioids many other methods
of administration have been developed to improve therapeutic efficacy while minimizing
side effects.
1. Patient- Controlled Analgesia (PCA):-
 the patient has limited control of the dosing of opioid from an infusion pump
programmed within tightly mandated parameters.
 PCA can be used for intravenous, subcutaneous, epidural, or intrathecal administration
of opioids.
 The PCA technique also gives the patient a greater sense of control over the pain.
 PCA is suitable for adults and children capable of understanding the principles
involved

15. 15
2. Spinal Delivery :-
 Administration of opioids into the epidural or intrathecal spaces provides more direct
access to the first pain-processing synapse in the dorsal horn of the spinal cord. This
permits the use of doses substantially lower than those required for oral or parenteral
administration.
Uses:
 In postoperative pain management, sustained-release epidural injections are
accomplished through the incorporation of morphine into a liposomal formulation,
providing up to 48 h of pain relief.
 The management of chronic pain with spinal opiates has been addressed by the use of
chronically implanted intrathecal catheters connected to subcutaneously implanted
refillable pumps.

16. 16
for providing analgesia during labor and delivery
Patients on chronic spinal opioid therapy are less likely to experience respiratory
depression.
Selected patients who fail conservative therapies for chronic pain may receive
intraspinal opioids chronically through an implanted programmable pump.
Examples :
Agents approved for spinal delivery are specific preservative-free formulations of
Morphine sulfate.
 A Hydromorphone formulation is currently in clinical trials.

17. 17
Side effects :-
Epidural and intrathecal opioids have their own dose-dependent side effects, such as
pruritus, nausea, vomiting, respiratory depression, and urinary retention.
An important side effect associated with continued infusion of high concentrations of
several opiates is formation of a space-occupying mass (a granuloma) at the catheter tip
in the intrathecal space.
 The consequence is spinal cord compression and neurologic sequelae may require
discontinuation of spinal delivery and, in the extreme case, surgical removal of the
mass.

18. 18

19. 19
3. Rectal administration :-
The rectal route is an alternative for patients with difficulty swallowing or other oral
pathology and who prefer a less invasive route than parenteral administration.
Onset of action is within 10 min.
This route is not well tolerated by most children.
Eg :- Morphine, Hydromorphone, and Opium (in combination with belladonna) are
available in rectal suppository formulations.

20. 20
4. Oral Transmucosal Administration :-
Opioids can be absorbed through the oral mucosa more rapidly than through the
stomach.
 Bioavailability is greater.
lipophilic opioids are absorbed better by this route.
A variety of formulations of fentanyl are available for oral transmucosal use:
Suspensions of fentanyl in a dissolvable sugar-based lollipop or rapidly dissolving
buccal tablet
 a buccal fentanyl “film,” and
a sublingual fentanyl tablet are approved for the treatment of cancer pain.
 transmucosal fentanyl relieves pain within 15 min
patients easily can titrate the appropriate dose.

21. 21
5. Transnasal Administration :-
Butorphanol, a KOR agonist/MOR antagonist, has been employed intranasally.
A transnasal, pectin-based, metered Fentanyl spray is FDA-approved for the
treatment of breakthrough cancer pain.
Administration is well tolerated.
 pain relief occurs within 10 min of delivery.

22. 22
6. Transdermal Administration :-
Transdermal Fentanyl patches are approved for use in sustained pain.
The opioid permeates the skin, and a “depot” is established in the stratum corneum layer.
fever and external heat sources (heating pads, hot baths) can increase absorption of
fentanyl and potentially lead to an overdose.
It may take up to 12 h to develop analgesia and up to 16 h to observe full clinical effect.
The plasma t 1/2 after patch removal is about 17 h.
This modality is well suited for cancer pain treatment because of its ease of use,
prolonged duration of action, and stable blood levels.
If excessive sedation or respiratory depression occurs, antagonist infusions may need to
be maintained for an extended period.

23. 23
OPIOID CLASSIFICATION
OPIOID AGONISTS PARTIAL/MIXED OPIOD ANTAGONISTS
OPIOID AGONISTS
Strong agonists :
1.Phenanthrenes –
Morphinans –
2. Phenylheptylamines
• MORPHINE
• HYDROMORPHONE
• OXYMORPHONE
• HEROIN
• LEVORPHANOL
• METHADONE
3. Piperidine & phenylpiperidine –
MIPERIDINE
DIPHENOXYLATE
LOPERAMIDE
FENTANYL
4. Other opioid Agonists –
TRAMADOL
TAPENTADOL

24. 24
Mild to moderate Agonists :-
1. Phenanthrenes
2. Phenyl heptylamines
3. phenylpiperidines
CODEINE
DIHYDROCODIENE
HYDROCODONE
OXYCODONE
PROPOXYPHONE
DIPHENOXYLATE
DIFENOXIN
LOPERAMIDE

25. 25

26. 26
OPIOID ANTAGONISTS
• NALOXONE
• NALTREXONE
• NALORPHINE
• LEVALLORPHAN
• NALMEFENE
• METHYLNALTREXONE
• ALVIMOPAN

27. 27

28. 28
EFFECTS OF CLINICALLY USED OPIOIDS :-
In the nervous system, the effects range from analgesia to effects on motivation and
higher-order affect (euphoria), arousal, and a number of autonomic, hormonal, and
motor processes.
In the periphery, opiates can influence a variety of visceromotor systems, including
those related to GI motility and smooth muscle tone.
a) Analgesia :- Pain consists of both sensory and affective (emotional) components.
Opioid analgesics are unique in that they can reduce both aspects of the pain
experience.
b) Euphoria :- patients or intravenous drug users who receive intravenous morphine
experience a pleasant floating sensation with lessened anxiety and distress.

29. 29
c) Respiratory Effects :- Opiates depress all phases of respiratory activity (rate, minute
volume, and tidal exchange) and produce irregular and aperiodic breathing.
opioids must be used with caution in patients with asthma, COPD, cor pulmonale,
decreased respiratory reserve, preexisting respiratory depression, hypoxia, or hypercapnia.
Mechanisms Underlying Respiratory Depression
Morphine-like opioids depress respiration through MOR by several mechanisms:
• direct depressant effect on rhythm generation;
• depression of the ventilatory response to increased CO2 ; and
• an effect on carotid and aortic body chemosensors that reduces ventilatory responses that
are normally driven by hypoxia
** It should be stressed, that respiratory depression represents the primary cause of
morbidity secondary to opiate therapy.

30. 30
d) Sedation :-
Drowsiness and clouding of mentation are common effects of opioids. There is little or no
amnesia. Sleep is induced by opioids more frequently in the elderly than in young, healthy
individuals.
In standard analgesic doses, morphine (a phenanthrene) disrupts normal rapid eye
movement (REM) and non-REM sleep patterns.
The combination of morphine with other central depressant drugs such as the sedative-
hypnotics may result in very deep sleep.

31. 31
e) Cough suppression :-
• Suppression of the cough reflex is a well-recognized action of opioids.
• Codeine in particular has been used to advantage in persons suffering from pathologic
cough.
• cough suppression by opioids may allow accumulation of secretions and thus lead to
airway obstruction and atelectasis.
f) Miosis :-
Constriction of the pupils is seen with virtually all opioid agonists.
Miosis is a pharmacologic action to which little or no tolerance develops, even in highly
tolerant addicts; thus, it is valuable in the diagnosis of opioid overdose.

32. 32
g) Truncal rigidity :-
• Several opioids can intensify tone in the large trunk muscles.
• Truncal rigidity reduces thoracic compliance and thus interferes with ventilation.
• The effect is most apparent when high doses of the highly lipid-soluble opioids (eg:
fentanyl, sufentanyl, alfentanyl, remifentanil) are rapidly administered rapidly.
h) Nausea & Vomiting :-
• Can activate the brain stem chemoreceptor trigger zone to produce nausea and vomiting.

33. 33
i) Opioid-Induced Hyperalgesia :-
persistent administration of opioid analgesics can increase the sensation of pain,
resulting in a state of hyperalgesia.
- seen with opioids like Morphine, Fentanyl and Remifentanil.
Peripheral effects:
a) Cardiovascular system :-
• Morphine induces release of histamine from mast cells, leading to vasodilation; this
effect is reversed by naloxone but only partially blocked by H1 antagonists.
• Morphine blunts reflex vasoconstriction caused by increased Pco2 .

34. 34
• Morphine also has therapeutic effect in the treatment of angina pectoris and acute
myocardial infarction by decreasing preload, inotropy, and chronotropy, thus favorably
altering determinants of myocardial O2 consumption.
b) GI Tract :-
• Opiates have important effects on all aspects of GI function.
• patients treated with opioids develop constipation and changes in bowel function.
• Morphine inhibits lower esophageal sphincter relaxation induced by swallowing and
by esophageal distension.

35. 35
• Morphine increases tonic contracture of the antral musculature and upper duodenum
and reduces resting tone in the musculature of the gastric reservoir, thereby
prolonging gastric emptying time and increasing the esophageal reflux.
• Morphine reduces propulsive activity in the small and large intestines and diminishes
intestinal secretions.
Biliary tract :-
• Morphine constricts the sphincter of Oddi, and the pressure in the common bile duct
may rise more than 10-fold within 15 min & produce symptoms that may vary from
epigastric distress to typical biliary colic.
• All opioids can cause biliary spasm. Some patients with biliary colic experience
exacerbation rather than relief of pain when given opioids.
• Atropine only partially prevents morphine-induced biliary spasm, but opioid
antagonists prevent or relieve it.

36. 36
c) Ureter and Urinary Bladder :-
• Morphine inhibits the urinary voiding reflex and increases the tone of the external
sphincter with a resultant increase in the volume of the bladder.
d)Uterus :-
• Morphine may prolong labor. If the uterus has been made hyperactive by oxytocics,
morphine tends to restore the contractions to normal.

37. 37
e) Skin :-
• Therapeutic doses of morphine cause dilation of cutaneous blood vessels.
• The skin of the face, neck, and upper thorax frequently becomes flushed.
• Pruritus & Itching is seen with morphine and meperidine.
• This pruritus also can be caused by epidural or intrathecal opiate administration
through a centrally mediated, naloxone-reversible mechanism .

38. 38
f) Immune system :-
• Opioids modulate the immune system by effects on lymphocyte proliferation, antibody
production, angioneogenesis and chemotaxis.
• Leucocytes migrate to the site of injury and release opioid peptides, which in turn help
counter inflammatory pain.

39. 39
Therapeutic uses :-
 Analgesia
 Cough
 Diarrhoea
 Shivering
 Pulmonary oedema associated with LVF
 As Premedicant drugs before anaesthesia and surgery.

40. 40
OTHER OPIOID DRUGS
Meperidine
• is predominantly an MOR agonist
CNS Actions :-
 is a potent agonist at MORs in the CNS, yielding strong analgesic actions.
 Meperidine causes pupillary constriction, increases the sensitivity of the labyrinthine
apparatus
Meperidine sometimes causes CNS excitation, characterized by tremors, muscle
twitches, and seizures. These effects are due largely to accumulation of a metabolite,
normeperidine.
Meperidine has well-known local anesthetic properties, particularly after epidural
administration.

41. 41
Cardiovascular Effects :-
The effects of meperidine on the cardiovascular system generally resemble those of
morphine.
Intramuscular administration of therapeutic doses of meperidine does not affect heart rate
significantly, but intravenous administration frequently produces a marked increase in
heart rate.

42. 42
Actions on Smooth Muscle, GI Tract, and Uterus :-
• Meperidine does not cause as much constipation as morphine, even when given
over prolonged periods.
• clinical doses of meperidine slow gastric emptying sufficiently to delay
absorption of other drugs significantly.
• Therapeutic doses given during active labor do not delay the birth process; in fact,
frequency, duration, and amplitude of uterine contraction may be increased.

43. 43
ADME :-
• Meperidine is absorbed by all routes of administration.
• The peak plasma concentration usually occurs at about 45 min
• After oral administration, only about 50% of the drug escapes first-pass metabolism to enter
the circulation, and peak concentrations in plasma occur in 1–2 h.
• Meperidine is metabolized chiefly in the liver, with a t 1/2 of about 3 h.
• Metabolites are the N-demethyl product, normeperidine, and the hydrolysis product,
meperidinate, both of which may be conjugated.
• In patients with cirrhosis, the bioavailability of meperidine is increased to as much as 80%,
and the t 1/2 of both meperidine and the metabolite normeperidine (t 1/2 ~ 15–20 h) are
prolonged.
• Only a small amount of meperidine is excreted unchanged.

44. 44
Therapeutic Uses :-
• The major use of meperidine is for analgesia.
• The analgesic effects of meperidine are detectable about 15 min after oral administration,
peak in 1–2 h, and subside gradually.
• The onset of analgesic effect is faster (within 10 min) after subcutaneous or
intramuscular administration, and the effect reaches a peak in about 1h.
• Single doses of meperidine can be effective in the treatment of post anesthetic shivering.
• Meperidine crosses the placental barrier, and even in reasonable analgesic doses causes a
significant increase in the percentage of babies who show delayed respiration, decreased
respiratory minute volume, or decreased O2 saturation or who require resuscitation.
• Fetal and maternal respiratory depression induced by meperidine can be treated with
naloxone. Meperidine produces less

45. 45
Precautions, and Contraindication :-
Decreased renal or hepatic function increases the likelihood of toxicity.
Meperidine is not recommended for the treatment of chronic pain because of
concerns over metabolite toxicity. It should not be used for longer than 48 h or in
doses greater than 600 mg/d

46. 46
Diphenoxylate :-
 Diphenoxylate is a meperidine congener that has a definite constipating effect in
humans.
 Its only approved use is in the treatment of diarrhea.
 Diphenoxylate salts are also virtually insoluble in aqueous solution, thus reducing the
probability of abuse by the parenteral route.
Diphenoxylate hydrochloride is available only in combination with Atropine sulfate.
 The recommended daily dosage of Diphenoxylate for the treatment of diarrhea in
adults is 20 mg in divided doses.
Difenoxin a metabolite of Diphenoxylate and is marketed in a fixed dose with atropine
for the management of diarrhea.

47. 47
Loperamide
 Loperamide is a Piperidine derivative.
It slows GI motility by effects on the circular and longitudinal muscles of the
intestine. Part of its antidiarrheal effect may be due to a reduction of GI secretory
processes.
 In controlling chronic diarrhea, loperamide is as effective as Diphenoxylate and
little tolerance develops to its constipating effect. Concentrations of drug in plasma
peak about 4 h after ingestion.

48. 48
The apparent elimination t 1/2 is 7–14 h.
Loperamide is poorly absorbed after oral administration.
The usual dosage is 4–8 mg/d; the daily dose should not exceed 16 mg.
 The most common side effect is abdominal cramps.
Loperamide is unlikely to be abused parenterally because of its low solubility; large
doses of loperamide given to human volunteers do not elicit pleasurable effects
typical of opioids

49. 49
Fentanyl :-
 Fentanyl is a synthetic opioid related to the phenylpiperidines.
 The actions of fentanyl and its congeners sufentanil, remifentanil, and alfentanil are
similar to those of other MOR agonists.
 Fentanyl and sufentanil are important drugs in anesthetic practice because of their
relatively short time to peak analgesic effect, rapid termination of effect after small bolus
doses, cardiovascular safety, and capacity to significantly reduce the dosing requirement
for the volatile agents.
 In addition to a role in anesthesia, fentanyl is used in the management of severe pain
states delivered by several routes of administration.

50. 50
Pharmacokinetics :-
• These agents are highly lipid soluble and rapidly cross the bloodbrain barrier.
• The levels in plasma and CSF decline rapidly due to redistribution of fentanyl from
highly perfused tissue groups to other tissues, such as muscle and fat.
• Fentanyl and sufentanil undergo hepatic metabolism and renal excretion.
• With the use of higher doses or prolonged infusions, the drugs accumulate, these
clearance mechanisms become progressively saturated, and fentanyl and sufentanil
become longer acting.

51. 51
Pharmacological Effects.
CNS :-
Fentanyl and its congeners are all extremely potent analgesics and typically exhibit a
very short duration of action when given parenterally.
Nausea, vomiting, and itching can be observed.
Muscle rigidity appears to be more common after the high doses used in anesthetic
induction.
Respiratory depression is similar to that of other MOR agonists, but onset is more rapid.

52. 52
Cardiovascular System :-
Fentanyl and its derivatives decrease heart rate through vagal activation and may
modestly decrease blood pressure.
These drugs do not release histamine, and direct depressant effects on the
myocardium are minimal.
 For this reason, high doses of fentanyl or sufentanyl are commonly used as the
primary anesthetic for patients undergoing cardiovascular surgery or for patients
with poor cardiac function.

53. 53
Therapeutic Uses :-
Fentanyl citrate and sufentanil citrate acts as anesthetic adjuvants, administered
intravenously and epidurally.
 The time to peak analgesic effect after intravenous administration of fentanyl and
sufentanyl (~5 min)
Recovery from analgesic effects also occurs more quickly.
The use of fentanyl in chronic pain treatment has become more widespread.
Transdermal patches that provide sustained release of fentanyl for 48–72 h are
available.

54. 54
factors promoting increased absorption (e.g., fever) can lead to relative overdosage
and increased side effects.
 Transbuccal absorption by the use of buccal tablets and lollipop-like lozenges
permits rapid absorption and has found use in the management of acute incident
pain and for the relief of breakthrough cancer pain.
 As fentanyl is poorly absorbed in the GI tract, the optimal absorption is through
buccal administration

55. 55
Remifentanil
 The pharmacological properties of remifentanil are similar to those of fentanyl
and sufentanil.
 Remifentanil produces similar incidences of nausea, vomiting, and dose-
dependent muscle rigidity.
ADME.
 Remifentanil has a more rapid onset of analgesic action than fentanyl or
sufentanil. Analgesic effects occur within 1–1.5 min following intravenous
administration.
 Peak respiratory depression after bolus doses of remifentanil occurs after 5 min.

56. 56
Remifentanil is metabolized by plasma esterases, with a t 1/2 of 8–20 min.
Elimination is independent of hepatic metabolism or renal excretion.
Age and weight can affect clearance of remifentanil.
After 3- to 5-h infusions of remifentanil, recovery of respiratory function can be seen
within 3–5 min.
full recovery from all effects of remifentanil occurs within 15 min.

57. 57
Therapeutic Uses :-
 Remifentanil hydrochloride is useful for short, painful procedures that require intense
analgesia and blunting of stress responses; the drug is routinely given by continuous
intravenous infusion because of its short duration of action.
 When postprocedural analgesia is required, remifentanil alone is a poor choice.
In this situation, either a longer-acting opioid or another analgesic modality should be
combined with remifentanil for prolonged analgesia, or another opioid should be used.
 Remifentanil is not used intraspinally (epidural or intrathecal administration) because of its
formulation with glycine, an inhibitory neurotransmitter in the dorsal horn of the spinal
cord.

58. 58
Methadone :-
 Methadone is a long-acting MOR agonist with pharmacological properties
qualitatively similar to those of morphine.
The analgesic activity of methadone is almost entirely the result of its content of l-
methadone, which is 8–50 times more potent than the d-isomer.
 d-Methadone also lacks significant respiratory depressant action and addiction
liability but possesses antitussive activity.

59. 59
Pharmacological Effects
The outstanding properties of methadone are
 its analgesic activity,
its efficacy by the oral route,
its extended duration of action in suppressing withdrawal symptoms in physically
dependent individuals, and its tendency to show persistent effects with repeated
administration.
Miotic and respiratory-depressant effects can be detected for more than 24 h after a single
dose;
 on repeated administration, marked sedation is seen in some patients.
Effects on cough, bowel motility, biliary tone, and the secretion of pituitary hormones are
qualitatively similar to those of morphine.

60. 60
ADME
 Methadone is absorbed well from the GI tract and can be detected in plasma within
30 min of oral ingestion.
 Peak concentrations occur in brain within 1–2 h of subcutaneous or intramuscular
administration.
 Methadone also can be absorbed from the buccal mucosa.
 Methadone undergoes extensive biotransformation in the liver.

61. 61
 The amount of methadone excreted in the urine is increased when the urine is
acidified.
 The t 1/2 of methadone is long, 15–40 h.
 Methadone appears to be firmly bound to protein in various tissues, including
brain.
 After repeated administration, there is gradual accumulation in tissues.
 When administration is discontinued, low concentrations are maintained in
plasma by slow release from extravascular binding sites.

62. 62
Therapeutic Uses
 The primary use of methadone hydrochloride is detoxification and maintenance
treatment of opioid addiction.
 Methadone is used for the management of chronic pain.
 The peak respiratory depressant effects of methadone typically occur later and persist
longer than peak analgesia.
 Methadone should not be used in labor.

63. 63
Tramadol
Tramadol is a synthetic codeine analogue that is a weak MOR agonist.
 Part of its analgesic effect is produced by inhibition of uptake of NE and 5HT.
Tramadol is effective in the treatment of mild-to-moderate pain.
For the treatment of severe or chronic pain, tramadol is less effective.
Tramadol is effective in the treatment of labor pain and may cause less
neonatal respiratory depression.
Tramadol is also available as a fixed-dose combination with acetaminophen.

64. 64
Adverse Effects.
 Side effects of tramadol include nausea, vomiting, dizziness, dry mouth, sedation, and
headache.
Respiratory depression appears to be less than of morphine and the degree of
constipation is less than that seen after equivalent doses of codeine.
Tramadol can cause seizures and possibly exacerbate seizures in patients with
predisposing factors.
 Tramadol-induced respiratory depression is reversed by naloxone.
 Precipitation of withdrawal necessitates that tramadol be tapered prior to
discontinuation.
Tramadol should not be used in patients taking MAO inhibitors, SSRIs, or other drugs
that lower the seizure threshold

65. 65
OPIOID ANTAGONISTS
NALOXONE :-
 first pure opioid antagonist with affinity for all 3 classic opioid receptors.
 Produces a rapid reversal of effects of morphine and other opioids.
 Causes hyperalgesia under conditions of stress or inflammation, when endogenous
opioids are produced.

66. 66
Pharmacokinetics :
 Given intravenously, effects produced immediately
 Rapidly metabolised by the liver
 Its effects lasts only 2-4h therefore it has to be given repeatedly
Clinical uses :
 To treat respiratory depression caused by opioid over dosage.
 To reverse the effect of opioid analgesics used during labour, on the respiration of the
new born baby

67. 67
NALTREXONE
 very similar to Naloxone but with advantage of much longer duration of action
(half-life about 10h)
 Effective in addicts who have been detoxified, used as maintenance drug.
 It is available in a slow release subcutaneous implant formulation.
 Also effective in reducing alcohol consumption in heavy drinkers.
 Also effective in treating chronic itching in chronic liver failure.
 Also has beneficial effects in septic shock.

68. 68
Methyl naltrexone bromide and Alvimopan are MOR antagonists.
 Do not cross BBB.
 Used in combination with opioid agonists to block unwanted effects like
nausea, vomiting and reduced GI motility.

69. 69

70. 70
ADVERSE EFFECTS OF OPIOID ANALGESICS
Adverse effects with acute use Adverse effects with chronic use
Respiratory depression Hypogonadism
Nausea / vomiting Immunosuppression
Pruritus Increased feeding
Urticaria Increased growth hormone secretion
Constipation Withdrawal effects
Urinary retention Tolerance, dependence
Delirium Abuse, addiction
Sedation Hyperalgesia
Myoclonus Impairment while driving
Seizures

71. 71
Guidelines for Opiate Dosing

72. 72
UNDESIRED EFFECTS :- 1. Tolerance
2. Dependence
3. Addiction
TOLERANCE :
 refers to a decrease in the apparent effectiveness of the opioid agonist with continuous
or repeated agonist administration (over days to weeks).
This tolerance is reflected by a reduction in the maximum achievable effect or a right
shift in the dose-response curve. This phenomenon can be manifested at the level of the
intracellular cascade (e.g., reduced inhibition of AC) and at the organ system level (e.g.,
loss of sedative and analgesic effects).

73. 73
This loss of effect with persistent exposure to an opiate agonist has several key
properties
Different physiological responses can develop tolerance at markedly different rates at
the organ system level,
 some end points show little or no tolerance development (pupillary miosis);
 some show moderate tolerance (constipation, emesis, analgesia, sedation); and
 some show rapid tolerance (euphoria).
 Accordingly, the chronic heroin abuser will continue to show pinpoint pupils and
will require a rapid increase in dosing to achieve the drug-related euphoria.

74. 74
DEPENDENCE
 Dependence represents a state of adaptation manifested by a withdrawal
syndrome produced by cessation of drug exposure (e.g., by drug abstinence) or
administration of an antagonist (e.g., naloxone).
Dependence is specific to the drug class and receptor involved.
At the organ system level, opiate withdrawal is manifested by significant
somatomotor and autonomic outflow (reflected by agitation, hyperalgesia,
hyperthermia, hypertension, diarrhea, pupillary dilation, and release of virtually
all pituitary and adrenomedullary hormones)
 and by affective symptoms (dysphoria, anxiety, and depression).

75. 75
The state of withdrawal is highly aversive and motivates the drug recipient to make strong
efforts to avoid withdrawal, that is, to consume more of the drug.
 Drugs interacting with the same opiate receptor will suppress the withdrawal observed in
organisms tolerant to another drug acting on the same receptor (e.g., morphine and
methadone)

76. 76
ADDICTION
 Addiction is a behavioral pattern characterized by compulsive use of a drug.
The positive, rewarding effects of opiates are considered to be the driving component
for initiating the recreational use of opiates.
This positive reward property is subject to the development of tolerance.
 Given the aversive nature of withdrawal symptoms, avoidance and alleviation of
withdrawal symptoms may become a primary motivation for compulsive drug taking.

77. 77
When the drive to acquire the drug leads to drug-seeking behaviors that occur in spite
of the physical, emotional, or societal damage suffered by the drug seeker, then the
obsession or compulsion to acquire and use the drug is considered to reflect an addicted
state.
Importantly, drug dependence is not synonymous with drug addiction.
Tolerance and dependence are physiological responses seen in all patients but are not
predictors of addiction.
For example, cancer pain often requires prolonged treatment with high doses of opioids,
leading to tolerance and dependence. Yet, such patients are not considered to be either
addicts or abusers of the drug

78. 78
Definition of Addiction:
“Addiction is a psychological and physiological dependence on alcohol or other drugs of
abuse that effects the CNS in such a way that withdrawal symptoms are experienced
when the substance is discontinued.”
Commonly used psychotropic substances
• Alcohol
• Opioids
• Cannabis
• Amphetamines & other sympathomimetics
• Hallucinogens like phencyclidine
• Sedatives & Hypnotics like Barbiturates
• Inhalants (volatile solvents)
• Nicotine

79. 79
Etiological factors in psychoactive substance use :
 Biological factors
 Psychological factors
 Behavioural theories
 Social factors
 Easy availability of drugs
 Psychiatric disorders

80. 80

81. 81
Classification of drugs of abuse
1) Drugs that activate G Protein-Coupled Receptors
• Opioids
• Cannabinoids
• Gamma hydroxyl butyric acid
• LSD, Mescaline, psilocybin
2) Drugs that bind to Ionotropic Receptors and Ion Channels
- Nicotine
- Alcohol
- Benzodiazepines
- Phencyclidine, ketamine
3) Drugs that bind to Transporters of Biogenic Amines
- Cocaine
- Amphetamines
- Ecstasy

82. 82
Treatment for opioid abuse/toxicity/overdose :
• OPIOID ANTAGONIST
I.V. NALOXONE 2mg followed by a repeat injection in 5-10min causes reversal of
overdose. As Naloxone has short half-life, repeated doses are needed every 1-2 h.
ORAL NALTREXONE (for maintenance)
I.V. NALMEFENE
In the treatment of opioid addiction, a long acting opioid (Methadone, Buprenorphine,
Morphine sulphate) is substituted for the short acting opioid (Heroin)

83. 83
CURRENT TREATMENT FOR OPIOID ADDICTION
μ-opioid agonist and partial agonist medications
TREATMENT DOSE RANGE CONSIDERATIONS
METHADONE (PO) 80–150 mg/day
(typical range)
Maintenance dosing
is determined
during the early
weeks of treatment
following upward
titration. Individual
genetic and drug
history differences
may lead to
requirement of
higher doses than
the typical range.
FDA approved in
1972.

84. 84
BUPRENORPHINE-
NALOXONE (SL OR
BUC)
8–24 mg/day
buprenorphine
(1–6 mg/day
naloxone)
(typical range)
4:1 ratio (w/w) of
buprenorphine-
naloxone. Because
of partial agonist
nature of
buprenorphine, no
further treatment
effect to be gained
by doses greater
than 24 mg/day.
FDA approved in
2002.

85. 85
BUPRENORPHINE
EXTENDED-RELEASE
FORMULATION (SQ)
80–300 mg/monthly
injection
Two formulations
available. FDA
approved in 2016
and 2017.
NALTREXONE TABLETS
(PO)/EXTENDED-
RELEASE FORMULATION
(IM)
50 or 100 mg/day
orally; 380 mg/
monthly IM
injection
Requires a patient
to be opioid free for
7–10 days before
administration. FDA
approved in 1984
(tablets, no longer
marketed); 2010
(extended release).

86. 86
COCAINE USE DISORDER :-
 Can be administered orally, intra nasally by
smoking or parenterally.
 Main molecular target : Dopamine
transporter, serotonin transporter,
norepinephrine transporter.
 It has inhibitory action on these receptors
and it blocks dopamine uptake.
 Acute intoxication : characterized by
Pupillary dilatation, tachycardia,
hypertension, sweating and Nausea.

87. 87
DE-ADDICTION :
• Drug rehabilitation is a term for the processes of medical or psychotherapeutic
treatment for dependency on psychoactive substances such as alcohol, prescription
drugs and street drugs such as cocaine.
• The general intent is to enable the patient to cease substance abuse in order to avoid
the psychological, legal, financial, social and physical consequences that can be
caused especially by extreme abuse.

88. 88
TREATMENT
1. Behavioural therapy
Cognitive behavioural therapy
Cognitive therapy of substance use
2. Pharmacotherapies
3. Counselling
4. Rehabilitation

89. 89

90. 90
Screening methods
MODELS USING THERMAL STIMULUS
1.HOT PLATE METHODS
2.TAIL FLICK TEST
MODELS USING ELECTRICAL STIMULUS
1.TOOTH PULP TEST
2.MONKEY SHOCK TITRATION TEST
3.FLINCH-JUMP TEST
MODELS USING CHEMICAL STIMULUS
1.FORMALIN TEST
2.WRITHING TEST
MODELS USING MECHANICAL STIMULUS
1.HAFFNER’S TAIL CLIP METHOD
2.RANDALL SELITTO TEST
IN VIVO
METHODS

91. 91
CENTRALLY ACTING
ANALGESICS
PERIPHERALLY ACTING
ANALGESICS
HOT PLATE METHOD WRITHING TEST
TAIL FLICK TEST RANDALL SELITTO TEST
TOOTH PULP TEST INTRA-ARTERIAL INJECTION OF
BRADYKININ TEST
FORMALIN TEST
HAFNER’S TAIL CLIP METHOD
MONKEY SHOCK TITRATION TEST
ELECTRICAL STIMULATION OF
TAIL

92. 92
IN VITRO METHODS
 3H-NALOXONE BINDING
ASSAY
 µ OPIATE RECEPTOR BINDING
ASSAY
 ASSAY FOR CANNABINOID
ACTIVITY
 ROLE OF NOCICEPTIN IN
ANALGESICS

93. 93
CONCLUSION
 OUDs, including their most severe form, opioid addiction, are chronic
relapsing diseases of the brain with multifactorial origins.
 Standard-of-care maintenance medications (methadone and buprenorphine-
naloxone) are effective for the treatment of these diseases.
 However, the appropriate therapeutic use of these medications has been
limited by stigma, insufficient medical education, and lack of resources.
 Ongoing research includes development of novel analgesic approaches that
have greater effectiveness for chronic pain states (e.g., neuropathic and
inflammatory pain), with a decreased burden of overdose risk and of abuse
potential.
 Other approaches may also focus on mitigating the development of opioid
addiction, before the emergence of substantial neurobiological changes and
compulsive-like drug-taking behaviours.

94. 94
REFERENCES
• Goodman & Gilman's The pharmacological basis of Therapeutics 13th
edition, chapter 20, opioids analgesia and pain management, page no 355-
384
• Bertram G. Katzung, MD, Phd Opioid Agonists & Antagonists chapter 31,
page no. 553 – 574.
• Rang & Dales pharmacology 8th edition, section 42, analgesic drugs, page no.
509 – 529.

95. 95