L7 - Opioids and Pain Flashcards
What is the definition of pain?
Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage
What is nociceptive pain?
Nociceptive pain arises from tissue damage caused by noxious stimuli, such as:
Mechanical force
Chemical stimulation
Extreme temperatures
It provides neural feedback that allows the central nervous system (CNS) to detect and avoid harmful stimuli.
What causes nociceptive pain?
Nociceptive pain is caused by damage to tissues due to noxious stimuli (e.g., mechanical, chemical, or thermal stress) and serves to alert the body to potential damage.
What is neuropathic pain?
Neuropathic pain results from damage to neural tissue and is often associated with disorders such as:
Diabetic neuropathy
Shingles
Nerve compression
What are the causes of neuropathic pain?
Neuropathic pain is caused by:
Diseases (e.g., diabetic neuropathy, shingles)
Direct damage to neural tissue (e.g., nerve compression)
How is pain defined?
Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage.
What is acute pain?
Acute pain is:
Caused by an identifiable event (e.g., stubbing a toe).
Of short duration and resolves when the tissue heals.
Usually nociceptive in nature.
What is chronic pain?
Chronic pain is:
The cause may not always be easily identified.
Often involves multiple factors.
Has an indeterminate duration but lasts longer than 1 month.
Can be nociceptive or neuropathic.
How is chronic pain classified?
Chronic pain is classified based on the source of pain production:
Nociceptive
Neuropathic
What are examples of chronic nociceptive pain?
Osteoarthritis
Rheumatoid arthritis
Visceral pain (e.g., pancreatitis, irritable bowel syndrome).
What are examples of neuropathic pain?
Central neuropathic pain:
Post-stroke pain
Multiple sclerosis
Spinal cord injury
Migraine
HIV-related neuropathic pain
Peripheral neuropathic pain:
Post-herpetic neuralgia
Diabetic neuropathy
What is chronic pain capable of altering in the body?
Chronic pain can change the body’s response to stimuli, leading to conditions like allodynia and hyperalgesia.
What is hyperalgesia?
A condition where noxious stimuli become more painful than usual.
What is allodynia?
A condition where typically painless stimuli are experienced as pain.
What are the four steps of nociception involved in how we feel pain?
Transduction
Transmission
Modulation
Perception
What is the first step of nociception, and what happens during it?
Transduction - Noxious stimuli are converted into electrical signals by nociceptors.
What is the second step of nociception, and what happens during it?
Transmission - The electrical signals are transmitted through peripheral nerves to the central nervous system (CNS).
What is the third step of nociception, and what happens during it?
Modulation - The nervous system adjusts or amplifies the pain signal as it travels within the spinal cord.
: What is the fourth step of nociception, and what happens during it?
Perception - The brain interprets the signal as pain, creating the sensory and emotional experience.
What is transduction in the pain pathway?
Transduction is the process where nociceptors convert noxious stimuli into electrical signals.
What are nociceptors, and where are they located?
Nociceptors are free nerve endings found on Aδ and C fibers, located:
Externally: Skin
Internally: Muscles, joints, bladder, gut, etc.
What happens after nociceptors are activated?
Activation of nociceptors transmits the pain signal to the spinal cord.
What are Aδ fibers, and what type of pain do they transmit?
Aδ fibers are small, lightly myelinated fibers activated by noxious mechanical and sub-noxious thermal stimuli. They transmit rapid, sharp, well-localized pain.
How do Aδ fibers allow for rapid signal conduction?
Aδ fibers have a small diameter and are lightly myelinated, enabling fast signal conduction.
What are C fibers, and what type of pain do they transmit?
C fibers are small, unmyelinated fibers activated by noxious mechanical, heat, and chemical stimuli. They transmit slow, burning, dull, aching, and diffuse pain.
Why do C fibers have slow signal conduction?
C fibers lack myelination, which slows the conduction of signals.
What is the first step in the pain transmission pathway?
The signal is transmitted from the site of transduction along nociceptive fibers (Aδ and C fibers) to the dorsal horn of the spinal cord.
What happens after the nociceptive signal reaches the spinal cord?
The signal is transmitted from the spinal cord to the brainstem.
What is the final step in the pain transmission pathway?
The signal is transmitted from the brainstem to higher centers of the CNS, where perception occurs.
What are the components of the autonomic response during pain perception?
Increase in heart rate.
What motor response is associated with pain perception?
Removal of the affected limb to avoid further damage.
What are the key aspects of interpreting pain sensation?
Location: Where is the pain?
Intensity: How strong is the pain?
Type: What kind of pain is it (sharp, dull, burning, etc.)?
What is the emotional response involved in pain perception?
Emotional responses can include tears or distress.
Where do several spinal tracts converge to create the subjective experience of pain?
The prefrontal cortex.
Where does pain modulation occur?
At the spinal cord.
What pathway is involved in descending pain control?
The descending pain control pathway, originating from the periaqueductal gray (PAG) in the brain and running to the spinal cord.
What role do interneurons play in pain modulation?
Interneurons in the spinal cord help regulate and process pain signals before they ascend to the brain.
What is the relationship between ascending and descending pathways in pain modulation?
Ascending pathways transmit pain signals from the spinal cord to the brain.
Descending pathways modulate and potentially inhibit these signals to reduce pain perception.
Where does pain modulation occur?
Pain modulation occurs at the spinal cord.
Which pathway is crucial for descending pain control?
The descending pain control pathway, originating from the periaqueductal gray (PAG) in the brain.
What is the role of ascending pathways in pain modulation?
Ascending pathways transmit pain signals from the spinal cord to the brain for perception.
How do descending pathways influence pain?
Descending pathways modulate pain by inhibiting or reducing the transmission of pain signals at the spinal cord level.
What types of neurons are involved in pain modulation at the spinal cord?
Dorsal horn projection neurons: Relay pain signals upward.
Interneurons: Regulate the transmission and processing of pain signals.
How do the ascending and descending pathways interact during pain modulation?
Descending pathways from the brain interact with ascending signals to modulate the intensity of pain before it is fully processed.
What role do descending neurons from the periaqueductal gray (PAG) play in pain modulation?
Descending neurons from the PAG inhibit pain signals by modulating activity in the spinal cord
Which neurons are targeted by the descending pain control system?
Dorsal horn projection neurons, which transmit pain signals to the brain.
What is the role of opioid receptors in pain modulation?
Opioid receptors on neurons in the spinal cord reduce the transmission of pain signals when activated by endorphins or exogenous opioids
What are endorphins, and how do they modulate pain?
Endorphins are natural pain-relieving peptides that bind to opioid receptors, decreasing the intensity of pain signals.
How does the interaction between endorphins and opioid receptors affect the pain signal?
Activation of opioid receptors by endorphins inhibits pain transmission, reducing the perception of pain.
Which descending pathway is involved in pain modulation, and where does it originate?
The descending pain modulation pathway originates from the periaqueductal gray (PAG) and influences spinal cord activity to inhibit pain signals.
Name the key neurotransmitters involved in pain modulation.
GABA, Glutamate, Noradrenaline, 5HT (Serotonin).
What is the role of GABAB receptors in pain modulation?
GABAB receptors are inhibitory receptors that reduce neuronal excitability, decreasing the transmission of pain signals.
How do NMDA and AMPA receptors influence pain signals?
Both NMDA and AMPA receptors are activated by glutamate:
NMDA receptors facilitate central sensitization and chronic pain.
AMPA receptors mediate fast synaptic transmission of pain signals.
What is the role of 5HT (serotonin) receptors in pain modulation?
5HT receptors modulate pain through descending inhibitory pathways, either reducing or facilitating pain depending on the receptor subtype.
How do adrenergic receptors contribute to pain modulation?
Adrenergic receptors, activated by noradrenaline, mediate descending inhibitory control, reducing pain transmission in the spinal cord.
Which receptors are targeted by endorphins in pain modulation?
Opioid receptors are targeted by endorphins to inhibit pain transmission.
What is the primary substance extracted from the opium poppy, and how is it processed?
The opium poppy produces a milky latex that is dried to form opium, which is then processed to extract alkaloid substances.
Name two key alkaloids extracted from opium.
Morphine and Codeine.
Define opiates and give examples.
Opiates are drugs derived from opium (natural origin). Examples include morphine and codeine.
What are opioids, and how do they differ from opiates?
Opioids are opioid receptor agonists and can be either natural (opiates) or synthetic.
What are endogenous opioids? Provide examples.
Endogenous opioids are opioid-like substances synthesized by the body. Examples include endorphins, enkephalins, and dynorphins.
What are some natural opioids derived from poppy extract?
Morphine and Codeine.
What are some synthetic opioids made in a lab?
Fentanyl and Methadone.
What are some semisynthetic opioids derived from morphine?
Heroin (illegal) and Oxycodone, Buprenorphine (clinically used).
What are the three main subtypes of opioid receptors?
μ (mu) receptors, δ (delta) receptors, and κ (kappa) receptors.
What is the role of μ (mu) opioid receptors?
Responsible for most of the analgesic effects, as well as important adverse drug reactions and side effects. Most opioid analgesics are μ-receptor agonists.
What is the role of δ (delta) opioid receptors?
Play a minor role in analgesia, mostly found in the periphery.
What is the role of κ (kappa) opioid receptors?
Probably responsible for dysphoria and sedation.
What are examples of opioids with high efficacy?
Heroin, morphine, methadone, fentanyl.
What are examples of opioids with low efficacy?
Codeine.
What are the three main therapeutic effects of opioids?
- Analgesic effect
- Depression of cough reflex (at sub-analgesic dose)
- Anti-diarrhoeal effect.
When are opioids predominantly used for acute pain?
Perioperatively to manage pain during and after surgery.
Trauma, e.g., broken bones.
Cardiac pain, e.g., ischemic heart pain (myocardial infarction
Why is the use of opioids for chronic pain controversial?
Due to mixed evidence on efficacy and the risk of tolerance, dependence, and substance use disorder.
How are opioids used for cancer pain?
Acute (<6 months): Linked to diagnostics, surgery, or treatment.
Chronic: Related to cancer itself or its treatment.
Dose and type of opioid depend on the type and severity of pain.
Why are there strict rules around opioid prescribing?
To ensure good practice and minimize risks associated with tolerance, dependence, and misuse
What are the routes of administration for morphine?
Orally (tablet, oral solution)
Intravenously
Intramuscularly
Rectally
What affects morphine absorption?
The route of administration affects absorption, with limited oral availability due to extensive first-pass metabolism.
How is morphine distributed in the body?
Morphine is distributed via systemic circulation and binds to opioid receptors located in multiple organs, including:
Brain
Spinal cord
GI tract
Immune system
What is the overall effect of opioid receptors on neuronal activity?
Opioid receptors have an inhibitory effect on neuronal activity.
How do opioid receptors affect presynaptic neurons?
They inhibit voltage-gated Ca²⁺ channels, reducing neurotransmitter release.
How do opioid receptors affect postsynaptic neurons?
They increase K⁺ efflux via rectifying K⁺ channels, causing hyperpolarization and inhibiting tonic neuronal activity.
What protein is involved in the signaling of opioid receptors?
The Gi protein is involved in the signaling mechanism of opioid receptors.
What role does adenylate cyclase play in opioid receptor activity?
Opioid receptor activation inhibits adenylate cyclase activity, reducing cyclic AMP levels.
What is the significance of rectifying K⁺ channels in postsynaptic inhibition?
Increased K⁺ efflux through these channels leads to hyperpolarization, making neurons less likely to fire action potentials.
What type of receptor do opioids primarily target for their analgesic effect?
Opioids primarily target μ-receptors.
What intracellular protein is activated upon μ-receptor activation by opioids?
: The Gi protein is activated.
How does μ-receptor activation affect potassium channels?
t causes the opening of K⁺ channels, leading to:
Increased K⁺ efflux
Membrane hyperpolarization
Reduced neuronal excitability
How does μ-receptor activation influence calcium channels?
It inhibits voltage-gated Ca²⁺ channels, resulting in:
Decreased Ca²⁺ influx
Reduced neurotransmitter release
What subunits are involved in the modulation of pain pathways after μ-receptor activation?
The Gβγ subunits dissociate to mediate effects like modulating pain pathways.
What is the overall result of opioid-induced μ-receptor activation on pain perception?
Analgesia through:
Reduced neuronal excitability
Decreased neurotransmitter release in pain pathways
What is nociception?
The process by which pain signals are generated, transmitted, and perceived in the body.
What are the four key steps in nociception?
Transduction: Conversion of noxious stimuli into electrical signals.
Transmission: Signal propagation from the site of injury to the brain.
Modulation: Alteration of the pain signal within the spinal cord and brain.
Perception: Conscious recognition and interpretation of the pain signal.
Where does transduction occur?
At nociceptors (free nerve endings) in tissues like skin, muscles, joints, and internal organs.
What is the role of modulation in nociception?
To modify pain signals via descending pathways, often reducing pain intensity by neurotransmitters like endorphins.
How is pain perceived?
Through several spinal tracts converging onto the prefrontal cortex, leading to the subjective experience of pain.
How do opioids affect nociceptors?
Opioids decrease the release of neurotransmitters, such as glutamate, reducing the transmission of pain signals.
What is the effect of opioids on dorsal horn projection neurons?
Opioids decrease neuronal firing, reducing the intensity of pain signals sent to the brain.
How do opioids interact with descending neurons from the periaqueductal gray?
Opioids disinhibit the descending pain pathway by blocking the release of GABA from interneurons, enhancing pain inhibition.
What is the role of tonically active GABA interneurons in pain modulation?
Tonically active GABA interneurons inhibit descending neurons from the periaqueductal gray, reducing their ability to suppress pain transmission in the dorsal horn.
How do opioids affect GABA release in the periaqueductal gray?
Opioids inhibit the release of GABA, disinhibiting the descending pain control pathway and allowing it to actively reduce pain transmission in the dorsal horn.
What happens when descending neurons from the periaqueductal gray are active?
Active descending neurons reduce pain transmission in the dorsal horn by modulating spinal cord processing.
What occurs when descending neurons from the periaqueductal gray are inactive?
Inactive descending neurons have no impact on pain transmission in the dorsal horn, allowing pain signals to proceed unchecked.
How do opioids affect nociceptors?
Opioids decrease the release of neurotransmitters (e.g., glutamate) from nociceptors, reducing the transmission of pain signals to the spinal cord.
What is the effect of opioids on dorsal horn projection neurons?
Opioids decrease the neuronal firing of dorsal horn projection neurons, reducing the intensity of pain signals sent to the brain.
How do opioids affect descending neurons from the periaqueductal gray?
Opioids disinhibit the descending pain pathway by blocking the release of GABA from interneurons, enhancing pain suppression.
How is codeine metabolized?
Codeine is converted to morphine via Cytochrome P450 (CYP2D6) in Phase I of metabolism.
What happens in Phase II of metabolism for codeine and morphine?
In Phase II, both codeine and morphine undergo glucuronidation by UDP-glucuronyltransferase (UGT), where glucuronic acid is covalently added, producing active metabolites.
How are codeine and morphine excreted?
Codeine and morphine are mainly excreted renally, with some excretion via bile. Renal insufficiency or failure can lead to accumulation of active metabolites and an increased risk of adverse events.
What are the main metabolites of morphine?
The main metabolites of morphine are Morphine-3-glucuronide (60%) and Morphine-6-glucuronide (5-10%).
What is the potency of codeine compared to morphine?
Codeine has a weak affinity for the μ receptor, being about 1/10th the potency of morphine.
Why is codeine considered a pro-drug?
Codeine is considered a pro-drug because it must be metabolized to morphine via CYP2D6 to become pharmacologically active.
How do CYP2D6 allelic variants affect codeine metabolism?
CYP2D6 allelic variants lead to differences in metabolism, resulting in:
Poor metabolizers (PM): Inadequate pain control due to low morphine concentration.
Ultrarapid metabolizers (UM): Increased risk of side effects due to higher morphine concentrations.
Intermediate metabolizers (IM) and Extensive metabolizers (EM) also vary in their ability to metabolize codeine effectively.
What are the common uses of codeine?
Codeine is commonly used for:
Diarrhoea
Acute moderate pain (short-term use)
Dry or painful cough
How do μ receptors cause constipation with opioid use?
μ receptors in the enteric system reduce bowel tone and contraction, leading to constipation.
What percentage of patients experience constipation as a side effect of chronic opioid treatment?
40% to 95% of patients experience constipation as a side effect of chronic opioid treatment.
What serious complications can result from opioid-induced constipation?
Serious complications include:
Faecal impaction
Bowel obstruction
Bowel perforation
Does tolerance develop to opioid-induced constipation?
No, tolerance does not develop to opioid-induced constipation, meaning it often persists during treatment.
How can opioid-induced constipation affect patients’ adherence to treatment?
Opioid-induced constipation can lead to noncompliance with opioid analgesics and a poor quality of life.
How do μ receptors contribute to respiratory depression in opioid use?
μ receptors are expressed in the respiratory centres of the brainstem and carotid bodies, leading to reduced breathing rate, arterial O2, and increased CO2.
What is the most common cause of death in acute opioid poisoning?
The most common cause of death in acute opioid poisoning is respiratory depression.
Can opioid-induced respiratory depression be reversed?
Yes, opioid-induced respiratory depression can be reversed with naloxone, a competitive opioid antagonist.
What is the site of action for nausea and vomiting caused by morphine?
Nausea and vomiting due to morphine occur in the area postrema, a region in the medulla of the brain, also known as the chemoreceptor trigger zone.
How common is nausea and vomiting after morphine administration?
Nausea and vomiting occur in up to 40% of patients after morphine administration.
What is hyperalgesia in the context of opioid use?
Hyperalgesia is a phenomenon where prolonged opioid use reduces the analgesic effect at a set dose, leading to increased sensitivity to pain.
How does hyperalgesia differ from tolerance?
Hyperalgesia is not mediated by receptor activity like tolerance; it involves a reduction in analgesic effect after prolonged exposure to opioids.
What causes itching in opioid use?
Itching is caused by histamine release, which is a common side effect of opioid administration.
