1. Analgesics “Opioids”Pharmacology43
Dr. Hiwa K. Saaed
PhD Pharmacology & Toxicology
College of Pharmacy, University of Sulaimani
Ref, Lippincott's Illustrated Reviews of Pharmacology 6th ed. Chapter 14, page

2. Analgesic
Analgesic – an agent that selectively relieves pain by acting in the CNS or on peripheral pain mechanisms, without significantly altering the consciousness
Pain is an unpleasant sensation that can be either:
Acute or Chronic
Consequence of complex neurochemical processes in the peripheral and CNS.
Subjective: the clinician must rely on the patient’s perception and description of pain.
Alleviation of pain depend on its type”
Nociceptive pain: Headache, arthritic pain Rx NSAIDs
Neuropathic pain Rx TCA Amitriptyline or SSRI Fluoxetine or SNRI
Severe or chronic malignant pain Rx Opiods are DOC

3. Definitions: Definitions:
Ancient Egypt papyrus records reported the use of opium for pain Relief
Definitions:
Opium– mixture of alkaloids from the poppy seed.
Opiates–naturally occurring alkaloids such as morphine or codeine obtained from the juice of the opium poppy.
Opioid–broad term to describe all “natural or synthetic ” compounds that work at the opioid receptors and produce morphine-like effects.
Opiods act by binding to specific opioid receptors in the CNS to produce the action of endogenous peptide neurotransmitters: endorphin, enkephalins & dynorphins

4. Opioid Classifications
Chemistry
Natural
Semisynthetic
Synthetic
OPIOID RECEPTOR
Mu(μ)
Kappa(κ)
Delta (δ)
INTRINSIC ACTIVITY
agonist,
partial/weak agonist,
antagonist
Mixed agonist/antagonist

5. INTRINSIC ACTIVITY Strong Mixed agonist/antagonist & partial agonist
Alfentanil
Fentanyl
Buprenorphine
Heroin
Butorphanol
Meperidine
Methadone
Nalbuphine
Morphine
Pentazocine
Oxycodone
Antagonists
Remifentanil
Nalmefene
Sufentanil
Naloxone
Moderate/low
naltrexone
Codeine
Propoxyphene
Tramadol

6. Endogenous opioid receptors
Mu (μ)
Analgesia (supraspinal)
Miosis
Respiratory depression
Euphoria
Physical dependence
Decrease GIT motility
Kappa (κ)
Spinal analgesia
Sedation
miosis
Delta (δ)
analgesia (spinal & supraspinal)
release of growth hormone
Affective behavior
Present in limbic system
Sigma“less specific” bind with non opioid agent e.g hallucinogen
Dysphora
Hallucination (both visual & auditory)
Respiratory and vasomotor stimulation
mydriasis

7. Opioid receptorspa(κ), Delta (δ)
Opioids interact with receptors on the:
membranes of certain cells in the CNS,
nerve terminals in the periphery
cells of the GIT and the anatomic regions urinary bladder.
Analgesic properties are mediated:
mainly via μ receptors: that modulate responses to thermal, mechanical, and chemical nociception.
and κ receptors of the dorsal horn of the spinal cord by modulating the response to chemical and thermal nociception.
Enkephalins interact more selectively with the δ receptors in the periphery.

8. Mechanism of Action
All are G-protein coupled receptors and inhibit adenylate cyclase.
They inhibit neuronal activity by:
postsynaptic hyperpolarization (increasing K+ efflux)
reducing presynaptic Ca++ influx
Receptor distribution
High densities of opioid receptors on peripheral nerve fibers, they inhibit Ca+2 dependent release of excitatory, pro- inflammatory substances (substance P)
immune cells: undetermined
CNS; five general areas of the CNS:

9. Receptor distribution
CNS; five general areas of the CNS:
Brainstem: respiration, cough, nausea & vomiting, BP, pupillary diameter and stomach secretion.
Medial thalamus: mediating poorly localized deep pain
Spinal cord: in the substantia gelatinosa are involved in the receipt & integration on sensory input leading to the attenuation of painful afferent stimuli.
4. Hypothalamus: neuroendocrine secretion.
5. Limbic system: the greatest concentration in the amygdale, a major role in emotional behavior & response and little analgesic effect.

10. Opioid Agonists Mechanism of Action:
The strongest naturally occurring analgesic drugs are found in opium from the poppy flower, morphine and less potent codeine.
These drugs show: a high affinity for the μ receptor and less affinity for the κ and δ receptors.
Mechanism of Action:
interaction with central & peripheral opioid receptors, results in hyperpolarization, inhibition of nerve firing and presynaptic inhibition of transmitter release
Morphine also acts at κ receptors in lamina I and II of the dorsal horn of the spinal cord. It decreases the release of substance P, which modulates pain perception in the spinal cord.
Morphine also appears to inhibit the release of many excitatory transmitters from nerve terminals carrying nociceptive (painful) stimuli.

11. Morphine‐Pharmacological Actions
Analgesia: Opioids cause pain relief by both
raising the pain threshold at the spinal cord level
altering the central perception of pain; awareness of pain remains but it loses its unpleasant character
Euphoria: Opioids produce a sense of contentment and well being, this may be related to stimulation of the ventral tegmental tract.
Respiration: respiratory depression by decreasing the sensitivity of central respiratory neurons to CO2. Occurs at therapeutic doses and as dose increases respiratory arrest will occur.
Suppression of cough reflex: Antitussive properties do not correlate with analgesic or respiratory depression effects; this appears mediated via a different receptor complex.

12. Morphine‐Pharmacological Actions
Miosis: Results from stimulation of μ and κ receptors located in the Edinger‐Westphal nucleus of CN III, resistant to tolerance, all morphine abusers demonstrate pinpoint pupils. NB: This is important diagnostically, because many other causes of coma and respiratory depression produce dilation of the pupil.
Emesis: Opioids directly stimulate the chemoreceptor trigger zone in the area postrema that causes vomiting
GI tract: Opioids relieve diarrhea by decreasing gut motility and increasing the tone of intestinal smooth muscle & of the anal sphincter. Constipation is also resistant to tolerance Biliary spasm is exacerbated by increasing biliary tone with sphincter of Oddi spasm.
Cardiovascular: At large doses morphine produces hypotension & bradycardia.
Because of respiratory depression and carbon dioxide retention, cerebral vessels dilate and increase cerebrospinal fluid pressure. Therefore, morphine is usually contraindicated in individuals with head trauma or severe brain injury.

13. Morphine‐Pharmacological Actions-
Histamine release: Morphine causes mast cell degranulation, the release of histamine causing urticaria, itching, diaphoresis and vasodilation. In asthmatics it may precipitate bronchospasm
Hormonal Actions:
Inhibits the release of GnRH, CRH
Deceases the release of LH, FSH & ACTH and β‐endorphin
Decrease levels of Testosterone and cortisol
Increase Prolactin and GH release via suppression of dopamine levels centrally
Increase ADH release
Labor: Morphine may prolong the second stage of labor by transiently decreasing the strength, duration, and frequency of uterine contractions.

14. Morphine‐Therapeutic Uses‐
Analgesia:
Few drugs are as effective as morphine for the relief of pain
Treatment of Diarrhea: Loperamide, Diphenoxylate
Anti‐tussive:
codeine and dextromethorphanare congeners with greater antitussive effects
Acute Pulmonary Edema:
– IV morphine dramatically relieves the dyspnea associated with pulmonary edema due to LV failure

15. Morphine‐ Pharmacokinetics ‐
Administration:
Morphine is poorly absorbed orally; codeine is a much more effective oral analgesic
Both undergo extensive first pass metabolism in the liver.
Inhalation is an effective route but has found favor only with non‐medicinal administration
Implantable morphine pumps are also now use for chronic pain
Distribution:
Morphine readily enters all body tissues except the brain; morphine is the least lipid soluble of the opiates (fentanyl, methadone and heroin all enter the CNS much more quickly)

16. Morphine‐ Pharmacokinetics ‐
Metabolism:
Conjugated in the liver,
morphine–6‐glucuronide is a much more potent analgesic;
however morphine‐3‐glucuronide is less analgesic
Both are excreted in the urine with small amounts excreted in the bile
Hepatic & renal dysfunction both prolong the normal 4‐6 hour duration of action when administered systemically to morphine- naive individuals
but considerably longer when injected epidurally, because its low lipophilicity prevents redistribution from the epidural space.

17. Morphine‐ Pharmacokinetics ‐
Note: A patient's age can influence the response to morphine.
Elderly patients are more sensitive to the analgesic effects of the drug, possibly due to decreased metabolism or other factors, such as decreased lean body mass, renal function, etc. They should be treated with lower doses.
Neonates should not receive morphine because of their low conjugating capacity.

18. Morphine‐ Adverse Effects ‐
Severe respiratory depression (μ, δ and κ receptors)
Constipation (variable, μ and κ receptors)
Nausea and vomiting
Pupillary constriction (μ/κ receptors)
Caution must be exercised when opiates are used in those with liver or renal failure
Allergy enhanced hypotensive effects
Elevation of intracranial pressure particularly head injury
Enhance cerebral and spinal ischemia

19. Morphine‐ Adverse Effects ‐
In BPH, morphine cause acute urinary retention
Patients with adrenal insufficiency or myxedema may experience extended and increased effects from the opioids.
Morphine should be used with cautiously in patients with bronchial asthma or liver failure.
Note: Many of the effects above can be inhibited by opioid receptor antagonists such as naloxone.
Rapid development of tolerance
Physical dependence and abstinence syndrome
Drug interactions:
The depressant actions of morphine are enhanced by phenothiazines, MAOIs, and TCAs.
The analgesia inexplicably enhanced by Low doses of amphetamine and hydroxyzine.

20. ‐Tolerance & Physical Dependence‐
Repeated use produces tolerance to the effects of respiratory depression, analgesia, euphoria and sedation. Tolerance does not develop to miosis and constipation
Physical & psychological dependence readily occurs. Withdrawal induces a syndrome associated with autonomic, motor and psychological responses that are incapacitating, rarely are these life threatening
Detoxification of heroin- or morphine-dependent individuals is usually accomplished through the oral administration of methadone, buprenorphine, or clonidine.

21. Opioid withdrawal syndrome

22. Meperidine “Pethidine” (μ,…κ)
A synthetic opioid structurally unrelated to morphine
Mechanism: It binds to μ receptors with some binding at κ receptors
Actions:
respiratory depression similar to morphine, but less urine retention
no significant CV effect when given orally. IV administration produces a decrease in PVR resulting in increased peripheral blood flow & HR.
pupillary dilation via an atropine –like effect.

23. Meperidine Therapeutic uses: Severe acute pain
Lacks antitussive activity
No anti diarrhea;
Obstetrics; Produces less smooth muscle contraction/ spasm than morphine
Pharmacokinetics:
Well absorbed form the GI tract; it is most often given IM
Shorter duration of action than morphine (2‐4 hours)
Demethylated to normeperidine in the liver and excreted in the urine
NB. Because of shorter action and different route of metabolism, meperidine is preferred over morphine during labor

24. Meperidine-Adverse effects:
With large repeated doses normeperidine (demethylated meperidine) accumulates causing
anxiety, muscle tremors and convulsions
Causes pupillary dilation (vs. miosis with morphine) in large doses
Hyperactive reflexes
Severe hypotension when admin. postop.
+ neuroleptics: enhanced depression
+ MAOI: severe reactions convulsion & hyperthermia
Cross‐tolerance with other opioids

25. Methadone (μ) This is a synthetic orally effective opioid that
is equipotent to morphine
but induces less euphoria
has a longer duration of action
Mechanism of action:
Binds to the μ receptor.
Actions:
An equipotent analgesic to morphine
Causes miosis, respiratory depression, biliary spasm and constipation just like morphine.

26. Methadone Therapeutic uses:
Used for controlled withdrawal from heroin & morphine
Self addictive but the withdrawal syndrome is somewhat milder but more protracted than with other opioids
Pharmacokinetics:
Readily absorbed orally, t1/2 24hrs
Highly protein bound so remains in tissues for a prolonged period.
Transformed in the liver and excreted by the urine as mostly inactive metabolites
Adverse effects:
Similar to morphine particularly the risk of addiction

27. Fentanyl Chemically related to meperidine but miosis
has 100 times the analgesic potency of morphine; used in anesthesia and as analgesia postoperatively & during labor
Highly lipophilic: elimination half‐life is longer than morphine’s as redistribution occurs
Rapid onset of action and a short duration (15‐30 minutes)
Can be used IV, epidurally or intrathecally. Transmucosal and transdermal preparations are available
Metabolized to an inactive metabolite by the cytochrome P4503A4 system. Drug metabolites are eliminated through the urine.

28. Fentanyl Like morphine fentanyl causes miosis (vs. mydriasis)
Particular risk of the transmucosal or transdermal routes is respiratory depression; these delivery routes create a reservoir of drug in the skin or mucosa. Hence, the onset is delayed 12 hours, and the offset is prolonged
Fentanyl is often used during cardiac surgery because of its negligible effects on myocardial contractility.
Muscular rigidity, primarily of the abdomen and chest wall, is often observed with fentanyl use in anesthesia.
Adverse effects of fentanyl are similar to those of other µ- receptor agonists.

29. Fentanyl
Because of life-threatening hypoventilation, the fentanyl patch is contraindicated in the management of acute and postoperative pain or pain that can be ameliorated with other analgesics.
Fentanyl derivative: Sufentanil, Alfentanil & Remifentanil are related to fentanyl they differ in their potency and metabolic disposition.
Only Sufentanil is even more potent than fentanyl others are less potent

30. Heroin
Heroin is produced by the diacetylation of morphine which results in a three fold increase in its potency
Acetylation allows it to cross the BBB much more rapidly yielding a more pronounced euphoria
May be used IV or smoked, both allow for rapid distribution,
heroin is metabolized to morphine
No medical indication for its use in the clinic.

31. oxycodone is a semisynthetic derivative of morphine.
It is orally active and is sometimes formulated with aspirin or acetaminophen.
It is used to treat moderate to severe pain and has many properties in common with morphine.
Oxycodone is metabolized to products with lower analgesic activity.
Excretion is via the kidney.
Abuse of the sustained-release preparation (ingestion of crushed tablets) has been implicated in many deaths.
It is important that the higher-dosage forms of the latter preparation be used only by patients who are tolerant to opioids.

32. Moderate/Weak Agonists
Codeine: Converte to morphine thus:
Much less analgesic than morphine
Less euphoria and has much lower abuse potential and rarely produces physical dependence
An effective oral analgesic
Does possess significant anti‐tussive effects at sub‐analgesic doses
Often formulated with either acetaminophen, aspirin of ibuprofen; care but be exerted when these are used with over the counter analgesic to avoid overdose with the non‐opioid agent
A synthetic congener of codeine dextromethorphan lacks analgesic properties is an effective anti‐tussive available without prescription

33. Moderate/Weak Agonists
Propoxyphene
Derivative of methadone,
dextro isomer is analgesic, levo isomer is antitussive
Used for mild to moderate pain; its opioid dose equipotency is about half of codeine (require twice dose)
Often formulated with another over‐the‐counter analgesic; combination has greater effect than either drug alone
Toxic doses may produce cardio and pulmonary toxicity particularly when taken in combination with alcohol and/or sedatives in addition to CNS depression
Opioid antagonists can reverse the pulmonary and CNS effects but not the cardiotoxicity

34. Mixed Agonists‐Antagonists & Partial Agonists
Pentazocine, Buprenorphine, Butorphanol, Nalbuphine
Drugs that stimulate one receptor but block another.
Effects of these drugs depend on previous exposure to opioids:
Naïve patients – drugs act as agonists; produce pain relief
Opioid dependent patients – drugs show blocking affects; withdrawal syndrome
Pentazocine
acts as an agonist on k receptors and is a weak antagonist at µ and delta receptors.
Pentazocine promotes analgesia by activating receptors in the spinal cord, and it is used to relieve moderate pain.
It may be administered either orally or parenterally.
Pentazocine produces less euphoria compared to morphine.

35. Pentazocine
In higher doses, the drug causes respiratory depression and decreases the activity of the gastrointestinal tract.
High doses increase blood pressure and can cause hallucinations, nightmares, dysphoria, tachycardia, and dizziness. The latter properties have led to its decreased use.
In angina, pentazocine increases the mean aortic pressure and pulmonary arterial pressure and, thus, increases the work of the heart.
The drug decreases renal plasma flow.
Despite its antagonist action, pentazocine does not antagonize the respiratory depression of morphine, but it can precipitate a withdrawal syndrome in a morphine abuser. Tolerance and dependence develop on repeated use.

36. Mixed Agonists‐Antagonists & Partial Agonists
Buprenorphine
A partial agonist at μ receptors producing morphine‐like effects in naïve users but precipitating withdrawal in morphine dependents
Metabolized in the liver and excreted in the urine and bile
May be taken sublingually or parenteral and possess a long duration of action
Adverse effects respiratory depression not reversible by naloxone, hypotension and nausea
Main use is in opioid detoxification as its withdrawal syndrome appears less severe and of shorter duration than methadone
Available outside of the specialized clinic allowed to dispense methadone for opiate withdrawal.

37. Antagonists
Bind with high affinity to the μ, κ & δ receptors but fail to activate the receptor
In normal individuals, these agents produce no effect but in those with opiates present, they induce an acute withdrawal syndrome
Naloxone
Reverses the coma and respiratory depression associated with opioid overdose
IV administration produces a reversal of respiratory depression within ~30 seconds
Binding affinity is 10X greater at the μ receptor than κ
Relatively short T1/2 (60‐100 minutes) so reversal will often abate requiring repeat administration

38. Antagonists Naltrexone (hepatotoxic)
Similar actions as naloxone but an oral agent with a much longer duration of action
Single dose able to antagonize the effects of heroin for up to 48 hours
Nalmefene
is a parenteral opioid antagonist with actions similar to that of naloxone and naltrexone.
It can be administered IV, intramuscularly, or subcutaneously.
Its half-life of 8 to10 hours is significantly longer than that of naloxone and several opioid agonists.