SPR L4 Analagesia and Gut Motility Drugs

Question 1

Learning Outcomes

Answer 1

• Describe the ways in which different analgesics target the neural pain mechanisms
• Apply the analgesic ladder in hypothetical clinical scenarios of uncontrolled pain
• Contrast the different uses and adverse effects of common simple analgesics and opioid drugs
• Describe the different targets for anti-emetic drugs on the emesis signals
• Discuss different modes on purgative / laxative

Question 2

Pain assessment

Outline the difficulties with assessing pain, and how it should be carried out

Answer 2

Pain can be very hard to describe, clinicians often underestimate pain, Must hear what the patient is saying and how he/she is saying it

• Characterize the pains, Identify their mechanisms and causes
• Assess their impact on the patient’s functioning and QOL
• Use a PAIN SCALE (see picture)

NB: When pain does not respond to usual therapy, re-evaluate the patient for causes that may have been missed.

Question 3

What are the different types of pain?

Answer 3

• Nociceptive pain
  
  • tissue damage (two types)
    
    • Somatic e.g. metastatic bone pain
    • Visceral e.g. liver capsule pain, e.g. colic from malignant bowel obstruction
• Neuropathic
  
  • nerve damage
• Peripheral or central
  
  • Dysaesthetic (burning)
  • Lancinating

Question 4

Evaluate the use of pain scores

Answer 4

Some of these scales are embedded in tools to assess pain and other sympotms (e.g. Edmonton Symptom Assessment Scale-ESAS, Brief Pain Inventory-BPI, etc). Adopt one and use it routinely. Scales should be used routinely and documented in patient charts.

Having patients keep a pain diary – recording time, level of pain, activity, medication taken, relief obtained – can be very useful.

When analyzing these scales, consider the multidimensionality of the pain experience.

While they are subjective, they generally provide a consistent measurement for that individual patient over time.

Question 5

Cancer Pain Management: WHO Pain Ladder

Outline the steps in this pain ladder

Answer 5

• First ask participants if they are acquainted with the WHO ladder and ask them to briefly describe its applications.
  
  • Step 1 = “mild” pain (1-3/10 and not affecting functioning or quality of life significantly)
  • Step 2 = “moderate” pain (4-6/10 with moderate impact on functioning and quality of life)
  • Step 3 is for “severe” pain. Note that one may “go directly” to Step 2 or even Step 3 if pain is severe.

Ask the learners to give examples of drugs for each step.

Step 1: Aspirin, NSAI, acetaminophen

Step 2: Codeine, Percocet & Percodan (i.e combinations of oxycodone with aspirin or acetaminophen). While oxycodone is a strong opioid and is 1 and ½ to 2 times more potent than morphine, the combinations with aspiriin or acetaminophen does not allow one to increase the dose of oxycodone to the degree one could if it was oxycodone alone.

Step 3: Morphine, oxycodone, hydromorphone, fentanyl, methadone. Note, do not use meperidine.

Some have suggested the addition of a fourth ladder for those with intractable pain. Treatments at this level should include intraspinal treatments, special nerve blocks such as celiac plexus blocks for pancreatic and gastric cancer-related pain and cordotomies.

Question 6

Give examples of

1. Simple Analgesics
2. Opioid Agonists
3. Strong Opioid Agonists

These manage mild (1) to severe pain (3)

Answer 6

1. Paracetamol (NSAIDs)
2. Codeine, Dihydrocodeine and Tramadol
3. Morphine and Diamorphine

Question 7

1. What is the classification of Paracetamol?
2. What is it’s mode of action?

Answer 7

1. analgesic, antipyretic, misc. not an NSAID
2. inhibits prostaglandin synthesis via CNS inhibition of COX3 (not peripheral)— doesn’t promote ulcers, bleeding or renal failure; peripherally blocks generation of pain impulses, inhibits hypothalamic heat-regulation center

(paracetamol is NOT an example of an NSAID - doesnt have an anti-inflammatory effect)

Question 8

PARACETAMOL

1. What is it?
2. What is it’s mode of action?
3. What are the indications for it’s use?
4. What are the adverse effects?

Answer 8

1. Active metabolite of phenacetin
2. Analgesic - Weak prostaglandin inhibitor
3. Mild to moderate pain without inflammation
4. Rare at normal dosage

Caution in liver impairment/low body weight

Liver/renal toxicity in over dosage

Question 9

Paracetamol

Outline how it is broken down and how it can cause damage

Answer 9

Underweight = less glutathione

Question 10

OPIATE ANALGESICS

1. What is the source?
2. What are the principal alkaloids?
3. What is their classification?

Answer 10

1. Seed pods of the opium poppy
2. Morphine and Codeine
3. Full agonists - High efficacy/strong agonists

Partial agonists – Weaker analgesia /antagonist

Question 11

Prescribing Opioids

1. Weak opioids - what are the general principles?
2. Strong Opioids - give examples
3. What SHOULD NOT be used?

Answer 11

1. Dose often, Codeine limited by presence of paracetamol and constipation, Tramadol (caution in elderly and with SSRIs).
2. Morphine, oxycodone, diamorphine, fentanyl, hydromorphone, methadone, buprenorphine
3. Do NOT use - Pethidine

Question 12

1. What dosing is required for short-acting (immediate release opioids)
2. What dosing is required for long acting opioids formulations of morhpine, oxycodone, hydromorphone and codeine?
3. When is steady state usually achieved?

Answer 12

1. 4 hourly dosing.
2. 12 hourly dosing.
3. within 5 times the half life. Since the half lives (the time it takes for the levels in the blood to reduce by half) are generally around 4.5 to 6 hours, it will take about 24hrs to achieve steady state with controlled release formulations of morphine. In the case of fentanyl transdermally, the half life is approximately 12hr to 17 hrs. Steady state is therefore only achieved after up to 80 hours. For this reason, doses of patches should not be changed more frequently than every 72 hours.

(There are some exceptions to the 12 hourly dosing of sustained release formulations of codeine, morphine, hydromorphone and oxycodone and the 72hourly dosing of transdermal fentanyl. Approximately 10% to 15% will demonstrate end of dose failure despite increases in dosing. In these select cases, the dosing frequency may need to be increased to every 8hrs and 48 hrs respectively. The frequency of the dose is only increased when end of dose failure, characterized by increased pain the last few hours prior to the next dose, manifests despite at least 3 attempts at increasing the dose (amount). )

Question 13

Outline the differences between opioids

Answer 13

There exists wide inter- and intra-individual variability in responses (both analgesic and adverse effects) to various opioids.

If 10 patients of the same age and exactly the same disease process, experiencing the same amount of pain, were given each a regimen of morphine 5mg every 4 hours and then titrated, one would see a lot of variation in their responses to the opioid. Some may experience excellent pain control with no side effects, others may experience mild side effects, while others may experience no benefits and more significant side effects. One patient may do better on morphine than on hydromorphone, while the opposite may be true for another.

Question 14

Prescribing opioids - general principles (for general persual)

Answer 14

Neurotoxicity in patients with renal impairment requiring opioid treatment often improves when patients are switched from morphine to hydromorphone or fentanyl. The improvement is however probably more related to the switch or opioid rotation rather than inherent properties of hydromorphone or fentanyl. Whether or not hydromorphone, fentanyl and methadone do indeed cause less neurotoxicity than morphine still needs to be assessed in larger studies designed to specifically address the question.

Some very small open studies have suggested that oxycodone and hydromorphone may cause less confusion than morphine. This needs to be confirmed in larger studies.

Studies have not shown fentanyl to be less nauseating than the other opioids. However, chronic opioid-induced nausea may be relieved when a patient’s opioid is switched. The improvement is not from inherent properties of the new opioid, but rather from the switch itself.

In theory methadone may have advantages over other opioids for manaing neuropathic pain (NMDA antagonism) but this is still to be confirmed in studies.

There are no good studies to show that oxycodone has a special role for bone or arthritis-related pain.

Question 15

All opioids are constipating, which one is less constipating?

Answer 15

fentanyl

Question 16

What do the following mean?

1. opium
2. opiate
3. opioid

Answer 16

1. a Greek word meaning “juice,” or the exudate from the poppy
2. a drug extracted from the exudate of the poppy
3. a natural or synthetic drug that binds to opioid receptors producing agonist effects

Question 17

Where do natural opioids occur?

What is the source of other opioid?

Answer 17

• In the juice of the opium poppy (morphine and codeine)
• As endogenous endorphins

All other opioids are prepared from either morphine (semisynthetic opioids such as heroin) or they are synthesized from precursor compounds (synthetic opioids such as fentanyl)

Question 18

Outline the pharmacological effects of Opiods?

Answer 18

• Sedation and anxiolytic
  
  • Drowsiness and lethargy
  • Apathy
  • Cognitive impairment
  • Sense of tranquility
• Depression of respiration
  
  • Main cause of death from opioid overdose
  • Combination of opioids and alcohol is especially dangerous
• Cough suppression
  
  • Opioids suppress the “cough center” in the brain
• Pupillary constriction
  
  • pupillary constriction in the presence of analgesics is characteristic of opioid use
• Nausea and vomiting
  
  • Stimulation of receptors in an area of the medulla called the chemoreceptor trigger zone causes nausea and vomiting
  • Unpleasant side effect, but not life threatening
• Gastrointestinal symptoms
  • Opioids relieve diarrhoea as a result of their direct actions on the intestines
• Other effects
  
  • Opioids can release histamines causing itching or more severe allergic reactions including bronchoconstriction
  • Opioids can affect white blood cell function and immune function

Question 19

What is the mechanism of action of Opioids?

Answer 19

Activation of peripheral nociceptive fibers causes release of substance P and other pain-signaling neurotransmitters from nerve terminals in the dorsal horn of the spinal cord

• Release of pain-signaling neurotransmitters is regulated by endogenous endorphins or by exogenous opioid agonists by acting presynaptically to inhibit substance P release, causing analgesia

Question 20

Mode of Action of Morphine

1. ​​​What is the target?
2. What is it’s action?
3. What is it’s effect?
4. What is the overall effect achieved?

Answer 20

1. G-protein coupled opioid ‘mu’ receptors in the CNS and PNS
2. Full agonist (high affinity for receptors)
3. Closure of N-type voltage dependent calcium channels and opening of calcium dependent inwardly rectifying K+ channels- this increases K conductance. Opioids also presynaptically inhibit the release of pain signalling neurotransmitters such as substance P
4. Membrane hyperpolarisation and reduced neuronal excitability, reduction or inhibition of pain neurotransmission

Question 21

What are the three opioid receptors?

Answer 21

• Mu
• Kappa
• Delta

Question 22

What are the following types of receptors responsible for?

1. Mu-1
2. Mu-2
3. Mu-3
4. Kappa receptor
5. Delta receptor

Answer 22

1. Responsible for central interpretation of pain
2. Responsible for respiratory depression, spinal analgesia, physical dependence, and euphoria
3. only opioid alkaloids
4. •Only modest analgesia

• Little or no respiratory depression
• Little or no dependence
• Dysphoric effects

5. •It is unclear what delta’s responsible for

• Delta agonists show poor analgesia and little addictive potential
• May regulate mu receptor activity

Question 23

MU AND KAPPA RECEPTOR ACTIVATION

Which receptor has the widest effect?

Answer 23

Mu-2

Question 24

Principles of opioid analgesia

When is the best dose achieved?

Outline the princples of opioid analgesia

Answer 24

The right dose of opioid is the one that achieves the best analgesia with the fewest side effects

• By the cause of the pain(s)
• By the clock
• By the ladder
• By the mouth
• For breakthrough pain
• For the individual
• Adjuvant therapies as needed
• Prevent side effects

Question 25

Breakthrough Dose

1. What should this be equivalent to?
2. How is breakthrough dose calculated?
3. Which drug has an excellent profile for managing breakthrough and incident pain? Why?

Answer 25

1. a 4 hourly dose (i.e. 1/6th of the daily dose) - May need to titrate dose according to patient needs: 5% to 25% of total daily opioid dose. Generally use the same opioid as being used for regular regimen (except with fentanyl patches).
2. Calculating the breakthrough dose for any opioid is the same – 10% of the daily dose. In general, if a patient needs more than 2-3 breakthroughs per day then they do not have adequate control of their pain and a new dose should be calculated. (at low doses this rule isn’t practical)
3. Fentanyl. It is highly lipophylic (fast absorption), rapid onset of action and a short duration of action (40-60min).

Question 26

Opioid formulations

What are the two types of formulations and who are they used for?

Answer 26

• Short-acting formulations
  
  • Opioid-naïve patients
  • Pain crises
• Long-acting formulations
  • Reserve for stable situations
  • Add short-acting opioids for breakthrough pain

Question 27

Pharmacokinetics of opioids

1. What is the onset of pain relief for
   
   1. Oral opioids
   2. SC Opioids
   3. IV Opioids
2. What is the duraction of action for…?
   
   1. Short acting oral opioids
   2. Long acting oral opioids
   3. Fentanyl Patches
   4. IV or SC Opioids
   5. IV/SC Fentanyl
3. What is the half life of transdermal fentanyl

Answer 27

1. Onset
   
   1. 15 - 30 min
   2. 5 - 10 min
   3. 3 - 5 min
2. Duration
   1. 3 - 5 hours
   2. 8 - 12 hours
   3. 48 - 72 hours
   4. 2 - 4 hours
   5. 40 minutes
3. 12-24 hours

Question 28

What are the contraindications?

Answer 28

• Patients with impaired pulmonary function
• Patients with impaired hepatic and/or renal function (eGFR <30)
• Patients with hypothyroidism
• Patients with recent head injury - unsure if GCS is from opioid or a bleed

Question 29

What are the clinical uses of opioid analgesics?

Answer 29

• Analgesia for severe visceral pain
• Acute pulmonary edema
• Cough suppression
• Diarrhoea
• Pre-medication
• Regional anaesthesia

Question 30

1. What is tolerance?
2. How can this be demonstrated?
3. What does a physiological tolerance involve?
4. Which type of tolerance occurs in opioids?

Answer 30

1. Tolerance is a diminished responsiveness to the drug’s action that is seen with many compounds
2. by a decreased effect from a constant dose of drug or by an increase in the minimum drug dose required to produce a given level of effect
3. changes in the binding of a drug to receptors or changes in receptor transductional processes related to the drug of action
4. Physiological tolerance

Question 31

Dependence

1. When does physiological dependence occur?
2. What are withdrawal reactions usuaully?

Answer 31

1. when the drug is necessary for normal physiological functioning – this is demonstrated by the withdrawal reactions
2. the opposite of the physiological effects produced by the drug

Question 32

What are the withdrawal signs associated with the acute actions?

1. Analgesia
2. Respiratory Depression
3. Euphoria
4. Relaxation and sleep
5. Tranquilization
6. Decreased blood pressure
7. Constipation
8. Pupillary constriction
9. Hypothermia
10. Drying of secretions
11. Reduced sex drive
12. Flushed and warm skin

Answer 32

1. Pain and irritability
2. Hyperventilation
3. Dysphoria and depression
4. Restlessness and insomnia
5. Fearfulness and hostility
6. Increased blood pressure
7. Diarrhoea
8. Pupillary dilation
9. Hyperthermia
10. Lacrimation, runny nose
11. Spontaneous ejaculation
12. Chilliness and “gooseflesh” (going ‘cold turkey’)

Question 33

1. Name an opioid antagonist
2. What are they used to treat?
3. Where do they bind?
4. How do they work?

Answer 33

1. Naloxone
2. Opioid overdose
3. Strong binding affinity for the Mu receptor
4. Work by competitive inhibition site blocking agonist activity

Question 34

Management of Narcosis

1. What is narcosis?
2. When should it be suspected?
3. What should be done if the patient is unconsious or has respiratory depression?

Answer 34

1. Excess opioid
2. Suspect the diagnosis in any patient with small pupils.
3. Ensure a clear airway (ABCDE), Give naloxone iv every two minutes until the patient improves or until eight doses have been given, Check blood sugar.

Question 35

Methods of Relieving Pain

Answer 35

• Remove peripheral stimulus
  
  • E.g. Treat infection / tooth extraction / NSAIDs
• Interrupt nociceptive input
  
  • NSAIDs / local anaesthetic / neurectomy
• Stimulate nociceptive inhibitory mechanisms
  
  • Electrical (TENS) / Heat
• Modulate central pain awareness
  
  • Opiates / General anaesthetics / Psychotropics
• Treat secondary factors contributing to pain
  
  • Muscle spasm (relaxants)

Question 36

What do you need to remember if the patient responds to naloxone?

Answer 36

• Relapse is likely after about 20 - 30 minutes.
• Withdrawal effects can be precipitated .
• Infusion of naloxone may be required if relapse occurs.

Question 37

Opioids Summary (for general perusal)

Answer 37

• There are different types of opioids with varying potencies
• They are very effective general pain relievers for moderate-severe pain but have a lot of adverse effects (some of which are serious)
• They don’t have any anti-inflammatory properties and therefore are less ideal in inflammatory pain
• If someone becomes narcosed (too much opioid) then this can be reversed by a competitive antagonist Naloxone – but care is needed due to shorter duration of action

Question 38

NAUSEA AND VOMITING

What are the mechanisms of nausea and vomiting?

1. Which is important in palliative care?

Answer 38

1. The Chemoreceptor Trigger Zone (CTZ). Drugs such as opioids and SSRIs, metabolic causes and infections tend to trigger nausea and emesis through this area. The GI tract is also important, as is the Vomiting Centre. opioid-induced nausea requires a dopamine agent with GO pro-motility effects.

Question 39

Management of Nausea

Outline how nausea can be managed

Answer 39

• Attempt to identify the underlying cause(s)
• Attempt to correct the underlying cause(s) if possible and if appropriate
• Treat the symptoms
  
  • Anti-emetics selected according to the inferred underlying mechanisms
• Prevent nausea
  
  • Employ a regular anti-emetic regimen if nausea is prolonged
  • Prevent constipation
• If one agent not completely effective, review and add another or replace with another

Question 40

Anti-Emetics

What are the main groups of anti-emetics, and give examples

Answer 40

• Anti-dopamine agents (CTZ)
  
  • Metoclopramide
  • Care in young people as

Can cause acute dystonia

• Anticholingeric
• Anticholingeric and Antidopimergic
• 5HT3 Antagonists (central and peripheral)
  
  • Ondansetron
• Antihistimines
  
  • Cyclizine

(These are the different antiemetics grouped according to the receptors they target. Try an antiemetic from a different class if one antiemetic is not controlling the nausea. Using two antiemetics from the same class may not improve nausea and may increase side effects to the medication.

Note that methotrimeprazine and prochlorperazine tend to target multiple receptors but are best classified as anticholinergic and antidopaminergic agents.

Facilitators may comment on individual medications.

There is growing interest in using the newer atypical neuroleptics but the research is still very preliminary.)

Question 41

Anti-Emetics

1. What are the drugs of first choice in cases of chronic nausea not related to bowel obstruction?
2. Outline the promotility drugs
3. Outline the anti-dopamine agents

Answer 41

1. Pro-motility agents
2. Metoclopramide -Extrapyramidal side effects may occur, Upper GI pro-motility
3. Domperidone* - Only po formulation, Less likely to cause extrapyramidal side effects, Upper GI pro-motility, Extrapyramidal side effects and akathisia are relatively uncommon, but monitor for these.

Question 42

What issues have been noted with domperidone?

Answer 42

• This review confirms a small increased risk of serious cardiac adverse drug reactions related to the use of domperidone.
• A higher risk was observed in patients older than 60 years, those taking daily doses of more than 30 mg, and those taking QT-prolonging drugs or CYP3A4 inhibitors concomitantly - AVOID
• Domperidone should be used at the lowest effective dose for the shortest possible duration. The maximum treatment duration should not usually exceed one week.

Question 43

Palliative Care Anti-Emetics

Give some examples

Answer 43

• Antidopamine agents
  
  • Levomepromazine
  • Useful in the context of malignant bowel obstruction
• Steroids
  
  • Dexamethasone
• 5-HT3 antagonists
  
  • Ondansetron
  • Granisetron
    
    • Useful second and third line agents
• Cannabinoids (Nabilone)

Question 44

Palliative Care Anti-Emetics

(for general perusal)

Answer 44

Neuroleptics are good second line agents. Can also use newer antipsychotics – risperidone, olanzepine etc..

Steroids are excellent antiemetics. No need to give qid as have a long half-life and can be given in the AM with less effect on sleep.

Cannabinoids – evidence for efficacy in nausea. Can also stimulate appetite. Side effects are drowsiness.

Ondansetron, dolasetron, granisetron are very expensive. While they are the 1st line agents for chemotherapy or radiotherapy-induced nausea, they are 3rd line agents in chronic refractory nausea where other medications have not been effective.

Question 45

CONSTIPATION

What are the causes?

Answer 45

• Other - Immobility, weakness (inability to increase intra-abdominal pressure), old age, poor diet, poor fluid intake, increased fluid loss (e.g. vomiting, diarrhoea, fever).
• Drugs - Opioids, antacids containing calcium or aluminium, anti-depressants, iron, diuretics, anti-parkinsonian medication, anti-muscarinics e.g. phenothiazines, hyoscine, octreotide, anti-convulsants, anti-histamines, calcium antagonists
• Local Pain - Anal fissure, peri-anal abscess.
• Benign colorectal disease - Diverticular disease, distal proctitis, anterior mucosal prolapse, benign stricture, intussusception, volvulus.
• Endocrine/metabolic - Hypercalcaemia, hypothyroidism, DM with autonomic Neuropathy
• Malignancy - Colorectal, ovarian, and uterine tumours

Question 46

How is constipation treated?

Answer 46

–Increase fluid intake

–Improve mobility

–Increased fibre intake (unless d/t opioids)

–Stopping constipating drugs

–Excluding underlying pathology

Question 47

What is the mechanism of action of laxitives?

Answer 47

• Osmotic Laxitives (H20 transported into lumen)
  
  • (Macrogols, lactulose, Mg++)
• Faecal Softener (increases intestinal fluid secretion
  
  • (docusate –softener and stimulant)
• Bulk Laxitives (swells and distends colon)
  
  • bran/fibre
• Stimulant Laxitives (stimulate the enteric nervous system)
  
  • Glycerol, Bisacodyl, senna, dantron

Question 48

Outline the management of Constipation

Answer 48

• Pre-empt constipation by putting everyone at risk (eg patients on opioids) on regular laxatives
• Treat reversible causes eg give analgesia if pain on defecation, alter diet, ↑ fluid intake
• Adjust any constipating medication, if possible.
• Advise the person about increasing dietary fibre, drinking an adequate fluid intake, and exercise.

•Offer oral laxatives if dietary measures are ineffective, or while waiting for them to take effect.

–Start treatment with a bulk-forming laxative (Fybogel)(adequate fluid intake is important).

–If stools remain hard, add or switch to an osmotic laxative (macrogols (Movicol))

–If stools are soft but the person still finds them difficult to pass or complains of inadequate emptying, add a stimulant laxative (Ducolax (sodium picosulfate)/ enema).

•If the person has opioid-induced constipation:

–Avoid bulk-forming laxatives.

–Use an osmotic laxative (macrogols (Movicol))(or docusate which also softens stools) and a stimulant laxative (Ducolax (sodium picosulfate)/ enema).

•Advise the person that laxatives can be stopped once the stools become soft and easily passed again.

Question 49

How should someone with opioid induced constipation be treated?

Answer 49

•If the person has opioid-induced constipation:

–Avoid bulk-forming laxatives.

–Use an osmotic laxative (macrogols (Movicol))(or docusate which also softens stools) and a stimulant laxative (Ducolax (sodium picosulfate)/ enema).

•Advise the person that laxatives can be stopped once the stools become soft and easily passed again.

Question 50

Summary of Laxitives (for general perusal)

Answer 50

• Nausea and vomiting often has multi-factorial influences – aim to treat cause
• Select anti-emetic based on likely cause baring in mind potential adverse effects
• Constipation also often has multiple influences – use practical measures to reduce these
• Different classes of laxative work synergistically