Lecture 24: Analgesic drugs 1

Question 1

What are the effects of Opiods/Opiates Analgesics

Answer 1

• Analgesia (pain relief)
• A state of impaired consciousness

Question 2

What are the types of pain after injury?

Answer 2

1. Nociceptive pain: tissue damage
2. Inflammatory pain: inflammation due to tissue damage
3. Neuropathic pain: nerve damage (difficult to treat)

Opioids are usually used for Noiceptive and inflammatory pain

Question 3

What are possible routes of administration of opioids?

Answer 3

• Oral
• Parenteral (injection): intramuscular, intravenous, intermittent, continuous, patient controlled (PCA)
• Trans-mucosal (mucosal membrane absorption)
• Transdermal (skin absorption)

Question 4

Opium is the dried latex from ______ containing:

Answer 4

Opium is the dried latex from opium poppies containing:

1) Narcotic alkaloids:

• Morphine (12%), an opiate alkaloid (which processed chemically to produce heroin)
• Codeine

2) Non-narcotic alkaloids (not covered):

• papaverine,
• thebaine
• noscapine

Question 5

What is the difference between Opiates and Opioids?

Answer 5

• Opiates (not chemically synthesized) are compounds present in the opium poppies extracted and refined.
• Opioids (chemically manufactured) are synthetic or semi-synthetic compounds which have similar chemical or pharmacological effects to opium poppies.

In this overview, the word opioid will be used.

Question 6

Describe the Mechnaism of Action of Opioids Receptors

Answer 6

Opioids receptors are essentially pre-synaptic, belong to G protein coupled family of receptors

1. Presynaptically, opioids activate Gi proteins → Inhibition of adenylate cyclase enzyme → ↓Ca channels permeability (→ Block transmitter release to interrupt pain conduction)
2. Postsynaptically, ↑K conductance (out of the cell) → Hyperpolarization of postsynaptic neurone → ↓Response

Question 7

What are the different tpyes of Opioid Receptors?

Answer 7

Opioid Receptors

Anatomical Distribution (CNS)

mu (μ) OP3

• μ1, μ2, μ3
• Spinal cord; Brainstem (periaqueductal grey)
• Thalamus; Cerebral cortex

kappa (κ) OP1

• κ1, κ2, κ3
• Spinal cord; Brainstem (periaqueductal grey), Limbic system; Hypothalamus

delta (δ) OP2

• δ1, δ2
• Olfactory bulb; Cerebral cortex, Nucleus accumbens; Amygdala; Pontine nucleus

Question 8

Describe the process of Opioid Receptor Synthesis In Peripheral Inflammation

Answer 8

Although opioids traditionally have been considered centrally acting drugs, there is evidence for the action of opioids on peripheral nociceptor terminals after tissue damage.

• Opioid receptors are synthesized in cell body (Dorsal Root Ganglion) and transported toward central terminal in dorsal horn and toward periphery.
• Peripheral receptors become active within hours of local tissue damage. This occurs with unmasking of opioid receptors and the arrival of immunocompetent cells that possess opioid receptors and have the ability to s_ynthesize opioid peptide_s (endogenous opioids/ opioid-like substances).

This finding has led to an interest in the peripheral administration of exogenous opioids for postoperative analgesia, both at the site of surgery and as supplements to local anesthetics in nerve and plexus blocks.

Systematic review of these techniques demonstrates that intra-articular administration of opioids following knee surgery or arthroscopy may be efficacious.

Question 9

If Mu-1 is activated, what are the effects?

Answer 9

Analgesia

Question 10

If Mu-2 is activated, what are the effects?

Answer 10

1) Analgesia
2) Respiratory depression
3) Euphoria
4) Decrease GI motility
5) Physical dependence

Question 11

If Kappa receptors are activated, what the effects?

Answer 11

1) Analgesia
2) Dysphoria

Question 12

What are Opioid Agonists and what are their actions on opioid receptors?

Answer 12

Stimulate all of the receptors together

e.g.

Morphine

Fentanyl

Pethidine

Activation of all receptor subclasses though with different affinities

Question 13

What are Opioid Antagonists and what are their actions on opioid receptors?

Answer 13

E.g.

Naloxone

Pentazocine

(e.g. for overdose of opioids)

Devoid of activity in all receptor classes

Question 14

What are Agonist-antognists and Partial agonists?

Answer 14

Agonist-antagonist: e.g. nalophrine, pentazocine (Agonist activity on one type and anatongist activity on another).

Partial agonist: e.g. bup-re-norphine (Activity at one or more, but not all receptor types)

Question 15

What drugs are administered for Severe, moderate and mild pain?

Answer 15

• Severe pain is given injective opioids for efficient relief, e.g. right after operation
• Moderate pain is given oral opioids, NSAIDs, paracetamol
• Mild pain is NOT given opioids

Question 16

What are the effects, uses of opioids in general?

Answer 16

Effects

• Supra-spinal/spinal analgesia
• Sedation (impaired conscious)
• Marked individual variations (dose difference)

Uses

• For severe to moderate pain
• Relatively ineffective for neuropathic pain (pain due to nerve damage)

Question 17

What are the Adverse Effects and Precautions around Opioid Administrations?

Answer 17

Adverse Effects

• Respiratory depression (need to monitor)
• Somnolence (drowsiness)
• Dizziness
• Constipation
• Ileus (lack of intestine movement cause blockage)
• Itching (histamine)
• Nausea and vomiting
• Vagally mediated bradycardia
• Hypotension (morphine) (histamine cause vasodilation)

Precautions

• Sleep apnea
• Chronic Obstructive Lung Disease patients (COPD)
• Elderly

Question 18

What are the types of Opiates?

Answer 18

1. Natural Opiates

Alkaloids contained in the resin of the opium poppy including:

• Morphine (tablet, injection)
• Codeine (tablet)

1. Semi-Synthetic Opioids

Created from the natural opiates

• Bup-re-norphine (suboxone, contains naloxone)
• Oxycodone (oxycontin),
• Di-acetyl morphine (heroin)

1. Fully Synthetic Opioids

• Fentanyl (pain relief injection)
• Pethidine (not frequently used)
• Methadone (dolophine) (tablet, injection)
• Tramadol (tablet more common, injection)

1. Endogenous Opioid Peptides

Endogenous opioids are produced naturally in the body: (opioid-like subtances, prefer different receptors)

• Endorphins (mu-opioid receptors).
• Endomorphins (endomorphin-1 and endomorphin-2, mu-agonists) (mu-opioid receptors).
• Enkephalins (delta-opioid receptors).
• Dynorphins (kappa opioid receptors).

Question 19

What are some things you need to consider when using Opioids?

Answer 19

• To be administered through the most _effective & comfortable route (_injection in severe pain)
• _Round the clock f_or severe to moderate pain (usually given continuously)
• Consider i_nter-patient variability_ (if there is pain, there is no respiratory depression)
• Use of adjuvants for enhancing opioids analgesia and reducing side effects e.g. NSAIDs

Question 20

Opioids have two main effects:________-

Answer 20

analgesic and euphoric.

It is their euphoric effect which can lead to abuse

Question 21

What are the different types of symptoms of Drug Abuse?

Answer 21

1) Physical dependence

• Withdrawal symptoms after abrupt discontinuation of large doses of opioids over extended period

2) Psychological dependence

• Craving for an opioid, resulting in drug-seeking behaviour at any cost

3) Drug tolerance

• The necessity to increase the dose to achieve the same effect
• Consider opioid rotation (change opioids), and NMDA receptors antagonists (increase NMDA receptors in chronic pain and inflammation, faster transmission)

4) Opioid Addiction

• Loss of control over drug use, compulsive use despite harm

Question 22

What are some Opioid Withdrawal Symptoms?

Answer 22

BP

HR

RR

GI

Nuero/Msucular

Ophthalmic

Skin

Question 23

How can you manage opioid withdrawal symptoms? (Slow)

Answer 23

1) Medication

• Methadone or Bup-re-norphine
• (principle of cross-tolerance in which one opioid is replaced with another then slowly withdrawn)
• These are less eurphoric, but also have less cognitive side effects.

2) Adjunctive (treatment of side effects)

• Clonidine (Centrally acting alpha2 adrenergic agonist, reduces adrenergic neurotransmission from locus ceruleus reducing autonomic symptoms of withdrawal
• Promethazine (a phenothiazine) (for Nausea, Vomiting)
• Diazepam (for Muscle cramps)
• Anti-diarrheal (for Diarrhea)

Question 24

How can you manage opioid abuse (Rapid Opiate Detoxification Treatment)

Answer 24

(≈2 Hours)

A technique of detoxification under general anaesthesia to rapidly induce detoxification while blocking the severe symptoms of opiate withdrawal.

• Under general anaesthetic, the patient is not subject to withdrawal discomfort
• _High doses of nal tre xone (_opioid antagonist) are used
• Oral naltrexone maintenance can be initiated immediately after anaesthesia and continued to reduce the risk of relapse.

Question 25

Name some weak and strong opioids

Answer 25

**Weak Opioids** * Codeine * Morphine **Strong Opioids** * Tramadol * Diamorphine (heroin) * (*diacetyl-morphine*) * Pethidine * Fentanyl * Remifentanyl * Buprenorphine

Question 26

What are some relative potenticies across different opioids

Answer 26

**Drug (IV Potency for Strong Opioids)** _Morphine_ (1) _Methadone_ (1x) _Pethidine_ (high dose for same effect) (0.1x) _Fentanyl_ (lower dose for same effect) (50x-100x)

Question 27

Describe Morphine Introduction/Effects Side effects Routes of administration Metabolism

Answer 27

**_Introduction_** * Powerful analgesia * Anxiolysis/sedation * Cough suppression * Miosis (constrict pupil) * Altered mood (euphoria and tranquility) * Large volume of distribution (only ⅓ bound to plasma proteins) * Half-life of approximately 3 hours **_Side Effects_** * Respiratory depression * Nausea and vomiting * Constipation * Addiction * Pruritis (itching caused by histamine release) * Biliary colic (constricts sphincter of Oddi) * Bradycardia (vagal) * Hypotension (histamine) **_Routes of Administration_** (Morphine has a slower onset and longer duration due to its low lipid solubility.) * Oral (bioavailability 25%) undergoes substantial hepatic first-pass effect (need high oral dose) * Intravenous (IV): _bolus_, or _continuous_ IV infusion, or p_atient controlled analgesia_ (PCA- self administratable device) * Intramuscular (IM) * Intrathecal (CSF) / epidural **_Metabolism:_** In liver: * 70% to morphine 3-glucuronide (M3G) (no analgesic property) * 30% to morphine 6-glucuronide (M6G) (at least half as potent an analgesic as morphine and longer half life) Excretion mainly in urine

Question 28

Describe Pethidine * Introduction/Effects * Side effects * Routes of administration * Drug interactions * Metabolism

Answer 28

Synthetic Originally designed as anticholinergic- block parasympathetic (less marked miosis, dry mouth, tachycardia) Long half-life Oral bioavailability is 50%- much better than morphine and has very fast onset of action One of the bi-products is norpethidine. This can cause hallucinations and seizures and can result in renal failure. Careful for patients taking MAOI (anti-depressant) See pic.

Question 29

Describe Fentanyl * Introduction/Effects * Side effects * Routes of administration * Drug interactions * Metabolism

Answer 29

**_Introduction_** * Strong mu receptor agonist. * 80 - 100 times more potent than morphine. * Used as an analgesic and in anaesthesia. **_Side effects_** * Similar to other opoids. **_Routes of Administration_** (Fentanyl has fast onset of action due to high lipid soluability.) * IV * IM * Transdermal _patches_ (in chronic pain) (25 mcg/hour, 50 mcg/hour, 75 mcg/hour, 100 mcg/hour) * *Disadvantages include s*_low onset_ (due to skin absorption) * *Also* inability to rapidly change doses * Transmucosal _lozenges_ (200 mcg, 400 mcg, 600 mcg, 800 mcg, 1200 mcg, 1600 mcg) * Nasal & sublingual _spray_ (paediatric) * Sublingual tablets * _Iontophoresis_- method of transfermal PCA administration of _ionizable drugs in which the electrically charged component_s are propelled through the skin by _external electric field_

Question 30

Describe Methadone Introduction/Effects Side effects Routes of administration Drug interactions Metabolism

Answer 30

**_Introduction: Fully synthetic_** * Rapid onset of analgesia effect (30–60 min.) * It is used in: * Chronic pain patients (due to its NMDA antagonism) * For neuropathic pain * For opioid withdrawal * For _detox_ **_Side Effects:_** Similar to other opioids. But: * _No significant cognitive impairment._ * _No euphoria._ * Safe in renal and liver failure. **_Adminstration:_** Well absorbed from all routes: * Oral (bioavailability 70%) * Rectal * Subcutaneous * IV * Sublingual

Question 31

Describe Tremadol * Introduction/Effects * Side effects * Routes of administration * Drug interactions * Metabolism

Answer 31

**_Introduction:_** Synthetic codeine analogue. Weak μ-opioid receptor agonist. * Inhibits uptake of noradrenaline and serotonin (5HT) * Stimulation of inhibitory interneurons (DRG and DH), which release encephalin (both stimulate the inhibitory neurons- refer to pain physiology) * Weak mu-opioid receptor agonist (for moderate pain) **_Side effects:_** Similar to other opioids (nausea and vomiting, dizziness, sedation, constipation etc.). But: * Little respiratory depression **_Routes of Administration:_** * Oral (bioavailability \>70%) **_Drug Interactions:_** * May cause _serotonin syndrome_ (↑↑5HT) (agitation, ataxia, increased sweating, diarrhoea, fever, hyperreflexia, myoclonus, or shivering) if administered with antidepressants (SSRI) * Used with caution in patients with e_pilepsy history (_increased risk)

Question 32

Describe Codiene Introduction/Effects Side effects Routes of administration Drug interactions Metabolism

Answer 32

**_Uses:_** Codeine is used to treat: * Mild to moderate _pain_ (mu opioid receptors) * _Supress cough_ * _Anti-diarrhoea_ Marketed as both a single-ingredient drug and *in combination preparations with paracetamol (as co-codamol); with aspirin (as co-codaprin).* **_Side Effects_** * Drowsiness and constipation * Less common are itching, nausea, vomiting, dry mouth, miosis, respiratory depression * Prolonged use can cause physical dependence **_Metabolised:_** Codeine is metabolised to _morphine_ by _cytochrome P450 2D6_. * Some patients are u_ltra-rapid metabolisers_ and are at _higher risk of toxic opioid effects_ (increased morphine). * Some patients are _slow metabolisers_ and these patients may not experience adequate analgesic effect with codeine.

Question 33

You should not give _____ to paitents with a history of epilepsy

Answer 33

Tramadol

Question 34

You should not give _____ to patients on SSSRI

Answer 34

Tramadol

Question 35

You should not give ____ to patients with renal fialure

Answer 35

Pethidine (and morphine?)

Question 36

Codeine is metabolised to ______ by \_\_\_\_\_\_ what is the clinical significance of this?

Answer 36

Codeine is metabolised to morphine by cytochrome P450 2D6. * Some patients are u_ltra-rapid metabolisers_ and are at higher risk of toxic opioid effects (increased morphine). * Some patients are _slow metabolisers_ and these patients may not experience adequate analgesic effect with codeine.

Question 37

Name 2 opioid antagonists

Answer 37

Devoid of activity at all receptor classes 1) Naloxone (narcan) 2) Nal tre xone (longer duration)

Question 38

What are co-analgesics?

Answer 38

Medications whose primary indication is for a purpose other than pain relief, but they demonstrate some analgesic enhancement e. g. tricyclic antidepresants e. g. anticonvulsants e. g. corticosteroids

Question 39

What is the word for "dilation of the pupil of the eye."

Answer 39

mydriasis