L8 Pain and Opioid Analgesics-1

Objectives

1. Define different types of pain

2. Discuss the nociceptive circuit and nociceptor activation of pain

3. Discuss about opioid receptors and opioid receptor agonists

What are 2 Types of Pain?

Nociceptive: Tissue damage or injury

• Signals transferred through peripheral nerves to the brain via spinal cord

Neuropathic

• Pain caused by damage or disease that affects the nervous system

Sensory Transduction

Primary afferent somatic and visceral sensory nociceptors

• Depolarization of Na/Ca2+ influx

What is neurotransmission in the dorsal horn mediated by?

Glutamate mediated transmission →synaptic transmission in the dorsal horn between C-fiber primary afferents and secondary projection neurons

What are other mediators in the dorsal horn?

1. Tachykanins

2. Substance P

3. Calcitonin gene related peptides

4. Neuromodulator brain derived neurotropic factor

Where are inhibitory neurotransmitters located?

Dorsal horn of spinal cord

Name the pain pharmacologic classes and agents

1. opioid receptor agonists

2. NSAIDS

3. TCAs

4. Antiepileptic drugs

5. NMDA receptor antagonists

6. Adrenergic agonist

7. 5-HT1 receptor agonists

What are the 3 classes of opioid receptors?

What is the analgesic property mediated by?

• mu → Analgesic properties primarily mediated by the receptors

• delta

• kappa

MOA: Opioid receptors are members of the G-protein coupled receptor family and inhibit adenylyl cyclase

Opioid receptor signaling

• What does it increase, reduce, block?

1. Reduce presynaptic Ca2+ influx

2. Increase postsynaptic K+ efflux

3. Block neuronal firing and transmitter release

Activation of opioid receptor decreases Ca2+ influx, decreasing release of excitatory NT (glutamate).

Activation of opioid receptor increases K+ efflux, decreasing response of post synaptic neuron to excitatory NT.

What are the two endogenous opioid peptides? And what receptors do they act on?

1. Dynorphins

   • act primarily on kappa

2. endorphin and enkephalins

   • act on delta and kappa receptor

What does mu opioid receptors mediate?

Morphine-induced analgesia

How is the central relaying of nociceptor

stimuli inhibited?

Activation of both presynaptic and postsynaptic μ- opioid receptor

What does morphine have a high affinity to?

Where does the opioid receptors interact?

What does it decrease the release of?

1. High affinity to mu receptors, strong agonist

2. Interact with opioid receptors in the CNS, GI tract and the urinary bladder

3. Decreases the release of substance p

How does morphine produce analgesia?

Produce analgesia because of their action in brain, brain stem, spinal cord, and peripheral terminals of afferent neurons

• Induce sleep

How does morphine produce euphoria?

Caused by disinhibition of dopamine containing neurons of the ventral tegmentum

How does morphine effect hormones?

1. Increases growth hormone release and enhances prolactin secretion

2. Increases antidiuretic hormone and leads to urinary retention

Pharmacokinetics: Morphine

• What is the name of the inactive and active metabolite?

• Describe the penetration

Morphine-3-glucuronide- inactive metabolite

Morphine-6-glucuronide- analgesic activity

(patients with chronic kidney disease may contribute to opioid toxicity)

• Crosses Placenta

• Crosses blood brain barrier

How is codeine related to morphine?

1. Result from its hepatic demethylation to

   morphine

2. Less potent than morphine (affinity for

   μ-opioid receptor -200-fold weaker)

What is the action of codeine?

1.Antitussive (cough suppressing)

2.Antidiarrheal effects

Used in combination with aspirin or acetaminophen

What is the pharmacokinetics of codeine?

Crosses blood brain barrier

Excreted in breast milk

What is the pharmacogenetics of Codeine?

Genetic polymorphism in the cytochrome p450 enzyme CYP2D6, and CYP3A4 regulate the demethylation of codeine

For Heroin

1. How is it produced?

2. What is the pharmacokinetics?

1. Produced by diacetylation of morphine

2. Higher lipid solubility, cross the blood-brain

   barrier more rapidly than morphine

Hydromorphone (Dilaudid, Exalgo)

• What does it treat?

Higher potency

Used for severe pain

Less adverse effect

Oxycodone and hydrocodone

• What is it used in combo with?

• What does it treat?

More effective analogues of codeine

• widely used in combination with acetaminophen or aspirin

• Used to treat moderate to severe pain

What are ADE of opioid receptor agonists?

1. Development of tolerance, Physical dependence, Addiction

2. Cardiovascular system → reduce sympathetic tone and lead to orthostatic hypotension

3. Morphine causes histamine release that can also contribute to orthostatic hypotension via vasodilation

4. Respiratory Depression → result in death from acute opioid poisoning

5. Barbiturate, benzodiazepine, and alcohol potentiate the sedation and respiratory

   depression associated with morphine and other opioids

6. Opioid-induced androgen deficiency due to suppression of the hypothalamic–pituitary–gonadal axis.

7. Decreased production of sex hormones, especially testosterone, resulting in many clinical symptoms

What should opioid receptors agonists be used cautiously in?

Patients with bronchial asthma, liver failure, or impaired renal function

Morphine Drug Interaction

Synthetic agonists Drugs

Methadone (Phenylheptylamine)

Tapentadol (Nucynta)

Fentanyl

Meperidine (Phenylpiperidine)

MOA of Methadone

1. mediated by μ receptors, agonist effects at the kappa and delta opioid receptor

2. antagonist to NMDA receptor

What is Methadone used for?

1. Use in drug addiction treatment

2. Useful for pain management (analgesic in nociceptive pain and neurogenic pain)

What are ADE of methadone?

1. Physical dependence like morphine

2. long half life leads to accumulation of drug (start with proper dose)

3. dose related prolongation of QT interval (polymorphic ventricular tachycardia, alteration in ECG)

Tapentadol (Nucynta)

1. MOA

2. Use

3. ADE

1. Mu-opioid receptor agonist —> inhibit reuptake of NE

2. Treats moderate to severe pain

3. ADE: Seizure risk, as well as risk of

   hypoglycemia and hyponatremia

Fentanyl

1. Pharmacokinetic

2. USE

3. ADE

1. Short acting opioid agonist

• 75-100 times more potent than morphine

• Highly lipophilic

2. Used for intraoperative and periprocedural analgesia due to its high potency and rapid onset of action

3. Similar to those of other mu-receptor agonists

Describe the adminsitration and effect of these drugs:

1. Epidural fentanyl

2. IV fentanyl

3. Transmucosal fentanyl (Fentora + Actiq)

4. Transdermal patch fentanyl (Duragesic)

5. Nasal spray fentanyl (Lazanda)

1. Epidural fentanyl → Postoperatively and during labor

2. Intravenous fentanyl → Cardiac surgery (negligible effect on myocardial contractility

3. Transmucosal fentanyl (Fentora) (Actiq) → Used in the treatment of cancer patients who are tolerant to opioids

4. Transdermal patch fentanyl (Duragesic) → Releases the drug slowly, long-acting systemic analgesia and sed for moderate-to-severe chronic pain, postoperative pain

5. Nasal spray fentanyl (Lazanda) →Fast onset of pain relief - Used for Cancer pain and patients who are already tolerant to other opioid medications.

What common drug involved in overdose death?

Fentanyl

Sulfentanil and Alfentanil → compare the potency

Sufentanil (Sufenta) → More potent than fentanyl

Alfentanil (Alfenta) → Less potent, structurally related to fentanyl

Remifentanil

• What is it used for?

• What is it not used for?

1. Short half-life

2. Use of remifentanil during anesthesia be coupled with administration of a longer acting drug to maintain analgesia

3. Do not use for epidural or intrathecal administration, because the glycine in the formulation may cause neurotoxicity

Meperidine

1. Compare to morphine

2. What is the toxic metabolite?

3. 
   

1. mu-agonist - analgesic efficacy similar to morphine

2. 75-100 mg of meperidine is equivalent to 10 mg of morphine

3. toxic metabolite normeperidine (cause increased CNS excitability and seizures)

4. elimination half-life is longer than that of meperidine

Opioid receptor agonist

Synthetic Agonists