Opioid Analgesics

Department of Pharmacology

Zhang xiao-jie

A.Opioid analgesics (Narcotic analgesics)Opiates-Morphine derivativesExamples: morphine, codeine, heroin, fentanylUses: moderate to severe pain

B. Non-opioid AnalgesicsWeak analgesics (Non-narcotic analgesics or NSAIDs)Examples: aspirin, acetaminophen , ibuprofen Uses: mild pain, anti-inflammatory

Pain is the most common symptom for which patients see a doctor. Different types of drugs are used for treatment of pain. In general, they include:

Mechanisms of Pain and Nociception

Nociception is a consequence of tissue injury (trauma, inflammation). It causes the release of chemical mediators (bradykinin, PGE,5-HT,glutamate, endogenous opioid peptides, adenosine). These mediators activate nociceptors.

Nociceptors are pain-receptors. Nociceptors transmit information by thin myelin (A-delta)and non-myelin (C) fibers to the spinal cord and brain.

Main Types of Pain Acute pain transmitted principally by fast conducting myelin A-delta fibers. It has major nociceptive input (physical trauma, myocardial infarction, peptic ulcer). The narcotic (opioid) and sometimes non-narcoticanalgesics are used for treatment of acute pain.

Chronic paintransmitted principally by slow conducting non-myelinated C fibers. It is depressing to the patient who sees no prospect for relieving the suffering. Analgesics alone are often insufficient and adjuvant drugs (antidepressants or neuroleptics) needed

Opioid Analgesics• [Source] • Opium is obtained from the

unripe seed capsules of poppy by incision of the seed pod.The white latex that oozes out turns brown and hardens on standing.

• This sticky brown gum is opium. It contains about 20 alkaloids, including morphine, codeine etc.The principal alkaloid in opium is morphine,present in a concentration of about 10%.

Opium contains two groups of alkaloids:

• with phenanthrene structure morphine, codeine, thebaine• with isoquinoline structure papaverine, noscapine

Morphine and codeine are narcotic analgesics; papaverine is a vasodilator;Opium contains ≈10% morphine.

Some terminologyOpioid: is a natural or synthetic drug that binds to opioid receptors producing morphine-like effects

Opiate: is a drug extracted from the exudate of the poppy.

Opioid is the preferred modern term.

Opioids can be divided into two groups:

- Morphine analogues – with structure similar to morphine

- Synthetics – with structure unrelated to morphine

N

OHOOH

CH3

morphine

CH

O

N

CH3

CH3

methadone

Effects are mediated via opioid receptors

Mechanism of opioid analgesics

• μ-receptors are responsible for most of the analgesic effects of opioids, and for some major unwanted effects (e.g. respiratory depression, euphoria, sedation and dependence). Most of the analgesic opioids are μ-receptor agonists.

• δ-receptors are probably more important in the periphery, but may also contribute to analgesia.

• κ-receptors contribute to analgesia at the spinal level, and may elicit sedation and dysphoria, but produce relatively few unwanted effects, and do not contribute to dependence. Some analgesics are relatively κ-selective.

Opioid ReceptorsOpioids bind to specific receptor molecule that mediates its effects. Several opioid specific receptors have been cloned: Mu (), Kappa (), and Delta () receptors. These receptors belong to G protein-coupled seven transmembrane receptor family. The amino acid sequences are approximately 65% identical among these receptors (see below the Figure).

Mechanism of Opioid Receptor Function

1. , , and are functionally coupled to G proteins (Gi) to inhibit adenylate cyclase activity.

2. Activates receptor-activated K+ currents which increase K+ efflux (hyperpolarization) reduces voltage-gated Ca2+ entry.

3. Hyperploarization of membrane potential by K+ currents and inhibition of the Ca2+ influx prevents neurotransmitter release and pain transmission in varying neuronal pathways.

Functional effects and opioid receptors

Analgesia

Supraspinal +++ - -

Spinal ++ ++ ++

Peripheral ++ - ++

Resp. depression

+++ ++ -

Miosis ++ - +

GI motility ++ ++ +

Euphoria +++ - -

Dysphoria - - +++

Sedation ++ - ++

Dependence +++ - -

Selectivity of Opioid Drugs for receptor subtypes

Morphine, Codeine

+++ + +

Methadone ++ - -Pethidine ++ + +Pentazocine + + ++Buprenorphine

+++ - ++

Naloxone +++ + ++Naltrexone +++ + +++

Agonist + Antagonist +

There are endogenous analgesic substances with peptide structure and morphine-like action. They are called endogenous opioid peptides and were discovered during the investigation of the mechanism of analgesic action of morphine.

Endogenous opioid peptides

Endogenous opioid peptides are:a) enkephalins activate μ and δ-receptors;b) endorphins activate μ, κ and δ-receptors; c) dynorphins activate μ, κ and δ-receptors.

Opioid peptides act in CNS as:- neurotransmitters- modulators of response (usually inhibitory)

Morphine

Morphine• Pharmacological effects and Mechanisms

exert its effects through μopioid receptors

CNS effects

1. Analgesia:

increasing tolerance of pain are the most prominent effects. Therefore, help patients to eliminate dysphoria, anxiety. Consciousness is not lost, and the patient can usually still locate the source of pain.

chronic dull pain> acute sharp pain and colic

effective on various pains

2. Sedation and change in mood

After a dose of morphine, a patient in pain or an addict experiences a pleasant floating sensation and freedom from anxiety and distress (euphoria). However, other patients and some normal subjects (not in pain) experience dysphoria rather than pleasant effects after a dose of opioid analgesics.

Morphine

• 3. Respiratory depression:• Can produce significant respiratory depression by reducing

the responsiveness of the respiratory centers in the brain stem to blood levels of carbon dioxide and inhibiting directly the respiratory center

• 4. Cough suppression:• Opioids directly suppress the cough center in medulla.

• 5. Emesis• Nausea and vomiting are an unpleasant side effect by direct

stimulation of CTZ.

• 6. Miosis: • pinpoint pupils are indicative of toxic dosage prior to

asphyxia.

[Peripheral effects ]

1. Cardiovascular effects:

Orthostatic hypotention can occur due to vasomotor medullary depression and histamine release.

2. Effects on smooth muscles

(1) Gastrointestinal tract: Constipation has long been recognized as an effect of opioids.motility(rhythmic contraction and relaxation) may decrease but tone (persistent contraction) may increase, particularly in the central portion.

(2) Biliary tract: The opioids constrictconstrict biliary smooth muscle and sphincter of Oddi, which may result in biliary colic.

(3) Other smooth muscle:

Uterus tone is decreased and duration of childbirth is prolonged.

Urinary tract: Ureteral and bladder tone are increased by therapeutic doses of the opioid analgesics. Increased sphincter tone may precipitate urinary retention, especially in postoperative patients.

Bronchial smooth muscle can constrict in higher dose of morphine, which may precipitate bronchial asthma.

Pharmacokinetics of Morphine

• Is well absorbed from the gastrointestinal tract. But it has a significant first-pass metabolism(F:25%). So, the analgesic effect is greater when drug is administered intramuscularly or intravenously.

• Morphine is metabolised to morphine-6-glucuronide, which is more potent as an analgesic.

• Ninety percent of a given dose is excreted in the urine; the remaining 10% is excreted in the feces.

Therapeutic uses of Morphine

1.Analgesia:

relieve moderate to severe acute pain such as the pain from myocardial infarction, terminal illness, surgery, biliary colic and renal colic (combined with atropine).

2.Cardiac asthma (acute pulmonary edema)is a very serious syndrome in clinical. It is referred to a sudden

dyspnea caused by pulmonary edema of acute left ventricular

failure.

The relief produced by intravenous morphine in dyspnea from

pulmonary edema associated with left ventricular failure is

dramatic.

The mechanism probably include:(1) reduction of the patient anxious and fear due to the sedative

effects of opioids;

(2) decrease in cardiac preload and afterload by lowering

peripheral resistance due to opioid-induced histamine releasing;

(3)decrease of the sensitivity of respiratory center to CO2 and

relief of shallow breathing.

3.Treating severe diarrhea because of constipating effects.

4.Treating cough (usually insteaded by codeine).

Adverse effects

• Respiratory depression is the most important effect.

• Nausea and sometimes dysphoria can occur.

• Increase biliary tract pressure.

• Allergic reactions.

• Bronchoconstrictive action.

• Tolerance and Dependence

Tolerance and dependenceTolerance – simply refers to a decrease in

effectiveness of a drug with its repeated administration. it needs increasing of the dose of a drug to produce the same effect as before.

It occurs rapidly with opioids (with morphine 12–24 hours, e.g. the hot plate test – in mice, after 3 days the dose of morphine required for analgesia increases 5-fold).

Important in drug addiction – may need to increase dose 50-fold.

Tolerance is not shown equally on all effects. Tolerance extends to:

analgesia

euphoria

resp. depression

To much lesser extent on:

constipation

pupil constriction

This is why constipation can be such a big

problem with opioids.

Why does tolerance occur?

There are several potential reasons:

- Decreased receptor affinity

- Receptor desensitization and internalization

- Increased metabolism of the drug

DEPENDENCE

Takes two forms : physical and psychological

Physical dependence – problems include

withdrawal syndrome (addiction):- Irritability

- Weight loss

- Shakes

- Sweating

- Piloerection “cold turkey”

- Effects last off in 8–10 days

Psychological dependence

Problems are:

- Desire for the drug

- Want to experience the “rush” – positive

- Don’t want the withdrawal – negative

- Some opioids, e.g. codeine & pentazocine, are much less likely to cause dependence

Acute morphine poisoning:coma, severe respiratory depression and miosis with blood pressure decreased, and urinary retention.

Respiratory paralysis often is the mainly lethal reason.

Treatment: The first step is to establish a patent airway and

ventilate the patient. The safest approach is to inject naloxone intravenously.

[Toxicity ]

[contraindication and Cautions in therapy]1. Use in patients with head in injuries: Carbon dioxide

retention caused by respiratory depression results in cerebral vasodilation; in patients with elevated intracranial pressure, this may lead to lethal alterations in brain function.

2. Use in patients with impaired pulmonary function : The respiratory depression properties of the opioid analgesics may lead to acute respiratory failure.

3. Use during pregnancy and delivery :Since the opioid analgesia readily traverse the placenta,their use for obstetric analgesia can result in delivery of an infant with depressed respiration.

4. Use in patients with impaired hepatic or renal function.

Codeine1.codeine is 3-methyl ether of morphine.2.pharmacologic effects are similar to morphine, but its analgesic potency is 1/12 of morphine, cough depressant potency is 1/4 of morphine.3.analgesic effect is strongr than aspirin. 30mg of

codeine is equivalent to 600mg of aspirin.4.less sedation, respiratory depression and fewer

gastrointestinal effects.5.use: mild to moderate pains and severe cough by oral

administration.6.physical dependence in long administration.

Ⅲ Synthetic Analgesics

Pethidine (Meperidine,Dolantin)

1.activating opioid receptors, particularlyμreceptors.

2.pharmacologic effects are similar to morphine • less potency and shorter duration in analgesis,

sedative and respiratory depression. • no effect on cough, bronchial and gastrointestinal

smooth muscles.

3.use

• to replace morphine to relieve intense pains,

• to treat acute pulmonary edema,

• to induce artificial hibernation.

• not useful for diarrhea or cough.

4.mild adverse effects similar to morphine

5.tolerance: being cross with the other opioids.

dependence: in long use.

METHADONE

A synthetic, orally effective opioid, equal in potency to morphine but induces less euphoria and has a somewhat longer duration of action.

1. Mechanism of action: by the μ receptors.

2. Actions: The analgesic activity is equivalent to morphine. Well-absorbed orally, in contrast to morphine. The miotic and respiratory-depressant actions have average half-lives of 24 hours.

It also increases biliary pressure and is also constipating.

3. Therapeutic uses: Used in the controlled withdrawal of dependent abusers from heroin and morphine.

It causes a withdrawal syndrome that is milder but more protracted (days to weeks) than with other opioids

4. Pharmacokinetics: Readily absorbed after oral administration.

It accumulates in tissues, where it remains bound to protein, from which it is slowly released.

used widely in treating morphine and heroine addiction (in presence of methadone, morphine does not cause the normal euphoria)

5. Adverse effects: It can produce physical dependence like morphine.

FENTANYL

>80 times more potent than morphine in analgesiaActions similar to morphineMain use is in anaesthesia, used in

conjunction with droperidol, a neuroleptic, producing neuroleptanalgesia

Opioid Antagonists

• Pure antagonists include naloxone (short-acting) and naltrexone (long-acting). They block μ-, κ- and -δ receptors more-or-less equally.

• Naloxone does not affect pain threshold normally, but blocks stress-induced analgesia, and can exacerbate clinical pain.

Opioid Antagonists

• Naloxone rapidly reverses opioid-induced analgesia and respiratory depression, and is used mainly to treat opioid overdose or to improve breathing in newborn babies affected by opioids given to the mother.

• Naloxone precipitates withdrawal symptoms in morphine-dependent patients or animals.

Clinical Use of Analgesic Drugs

• The choice and route of administration of analgesic drugs depends on the nature and duration of the pain.

• A progressive approach is often used, starting with nonsteroidal anti-inflammatory drugs, supplemented first by weak opioid analgesics, and then by strong opioids.

Clinical Use of Analgesic Drugs• In general, severe acute pain (e.g. trauma, burns,

post-operative pain) is treated with strong opioid drugs (e.g. morphine, fentanyl) given by injection.

• Mild inflammatory pain (e.g. arthritis) is treated with non-steroidal anti-inflammatory drugs (e.g. aspirin) supplemented by weak opioid drugs (codeine, pentazocine) given orally if required.

• Severe pain (e.g. cancer pain, severe arthritis or back pain) is treated with strong opioids given orally, intrathecally, epidurally or by subcutaneous injection.

Clinical Use of Analgesic Drugs

• Chronic neuropathic pain is often unresponsive to opioids, and treated with tricyclic antidepressants (e.g. amitriptyline), or other drugs, such as carbamazepine.