Clinical Oncology: Palliative Care Teaching Clinic

Question 1

WHO Pain ladder

Answer 1

If pain occurs, there should be prompt oral administration of drugs in the following order —> until the patient is free of pain:

1. Non-opioids
   - Paracetamol 500-1000mg QID
   - NSAID conventional doses
2. Mild opioids
   - Tramadol 50-100mg QID
   - Dihydrocodeine (e.g. DF118) 30mg Q4-6 hrs
3. Strong opioids
   - First line starting dose
   - Morphine (oral) 5mg Q4H PO
   - ***No ceiling dose
   - Senokot 2 tab nocte PO / Lactulose 10ml TDS PO if not CI
   - Antiemetics to control nausea during first week of opioid use:
   —> Metoclopramide 10mg TDS / Haloperidol 1.5mg -3mg daily
4. Adjuvant drugs should be used for specific pain etiologies

3-step approach:
—> Right drug
—> Right dose
—> Right time
—> inexpensive + 80-90% effective

Recommendations:

1. By Mouth
   - Oral route is the route of administration of choice
2. By the Clock
   - Analgesic medications for moderate to severe pain should be given on a ***fixed dose schedule, NOT on an as needed basis
3. By the Ladder
   - Analgesics given per the WHO 3 step ladder
4. For the individual
   - Dosage must be titrated against the particular patient’s pain
5. Attention to details
   - Determine what the patient knows, believes and fears about the pain and things that can relieve it
   - Give precise instructions for taking the medication

Question 2

Opioid

Answer 2

• Drugs of choice for moderate to severe pain associated with advanced illness
• Opioid does NOT have analgesic ceiling dose
• Opioid does NOT cause organ damage, compared with the renal/GI/cardiotoxicity of NSAIDs and hepatotoxicity of paracetamol
• Medical use of opioids for pain associated with advanced illness rarely, if ever, leads to drug abuse or opioid addiction

Weak opioid:

1. Codeine
2. Tramadol
3. DF118 (Dihydrocodeine)

Strong opioid:

1. Morphine
2. Oxycodone
3. Fentanyl
4. Methadone
   (5. Pethidine
   - avoid using Pethidine for cancer pain control —> shorting acting + SE + risk of addiction)

Question 3

Tramadol

Answer 3

• One of the most prescribed weak opioid in Hong Kong
• Dose: 50-100mg TDS-QID PO
• For elderly max dose <300mg/day
• For patients with mild renal impairment: <200mg/day
• Half life: 6 hours. Prolonged in liver failure
• Kidney excretion of metabolite

SE:

• N+V
• dizziness
• sweatiness
• dry mouth
• constipation, convulsion (rare)

Drug interactions:

• TCA
• SSRI
• MAOIs

Question 4

Morphine

Answer 4

Initial prescription:
- Starting dose: 5mg QID + 10 mg Nocte (or 5mg Q4H PO)
- Always prescribe PRN dose of morphine
—> 50-100% of regular dose
—> e.g. Morphine 5mg PO Q4H prn
—> Morphine 2.5mg subcutaneous Q4H prn
- Always prescribe laxative with opioid
—> Senokot 2 tab nocte PO
—> Lactulose 10ml BD-TDS PO
- Prescribe antiemetics during the first week of opioid initiation
—> Metoclopramide10mg TDS
—> Haloperidol 1mg -2mg daily

Initiation:

• When starting an opioid, use immediate release / short acting (most commonly use syrup morphine) until dose is stabilised
• Start with morphine syrup 5mg Q4H (morphine syrup has short half life)
• Consider 2.5mg Q4H in elderly patients or patients with marginal renal function
• Optimal dose of opioid needs to balance pain control and SE
• Usually complete pain control (i.e. pain score 0) is NOT the aim in order to avoid too much toxicity

Titration:
- Increase or decrease morphine dose based on
—> Patient’s pain score
—> The need of prn analgesics (as needed)
—> SE profile: any signs of opioid toxicity, renal function, hydration status
- Dose levels commonly used: e.g. 5mg Q4H —> 7.5mg —> 10mg —> 15mg —> 20mg —> 30mg
- Consider escalate dose faster if pain is severe
- Consider decrease dose if tumor responded well to treatment (chemo / targeted therapy / radiation therapy) or toxicity significant

Frequency:
- Satisfactory pain control level
—> Pain score 0-3
—> Need of prn morphine for breakthrough pain 0-2 times per day
—> Patient can sleep well
—> Patient’s subjective judgment
- To change short-acting morphine to long acting opioid
—> MST continuous tablet given ~Q12H
—> Dose conversion from morphine syrup: 1 to 1

Conversion:

• Oral : SC = 2:1
• Oral : IV = 3:1
• Morphine syrup : MST = 1:1
• Onset time for oral morphine = 30 mins
• Onset time for SC morphine = 15 mins

Question 5

Morphine in patients with renal impairment

Answer 5

• Active metabolite of morphine: morphine-6-glucuronide (M6G)
• Accumulation of M6G occurs in patients with renal insufficiency
• Patient with creatinine clearance / GFR <50ml/min should be initiated with morphine at 50% dosing with high caution. Specialist consultation is recommended
• Use of morphine in patient with CrCl/GFR <10ml/min should be avoided

Question 6

***Adverse effects of opioid

Answer 6

Early (first 72 hours):

1. N+V
   - usually mild and rarely persistent
   - tolerance develops rapidly
   - antiemetics can generally be discontinued in a few days when tolerance develops
2. Sedation / drowsiness
   - often transient, especially when opioid initiated or increasing doses
   - generally be relieved in 2 to 4 days
   - need to rule out other causes if persistent (infection, dehydration, metabolic imbalances)
3. Constipation
   - only undesirable adverse effect which tolerance does ***NOT develop
   - Ensure we are prescribing laxatives
   - Ensure patient is taking laxatives
   - If symptoms significant, may need to double the usual dose of laxatives or use combinational laxatives
   - Avoid bulk laxatives (Metamucil) which may increase risk of bowel obstruction with decreased fluid intake
4. Pruritus
   - not caused by allergy
   - occurs secondary to the histamine release in drugs like morphine
   - may be treated with antihistamine
5. Xerostomia
   - a common effect of morphine
   - good mouth care and frequent sips are effective for most patients
   - for difficult cases pilocarpine 2% eye drops may help
6. Urinary Retention
   - occurs secondary to increased tone of the bladder sphincter and inattention to the stimulus for bladder emptying
   - generally decrease within one week
   - more frequently in men with prostatic hypertrophy, patients with pelvic tumours, or bladder outlet obstruction

Severe:

1. Opioid induced neurotoxicity
   - hyperalgesia (heightened sensitivity to the existing pain)
   - allodynia (a normally non-noxious stimuli resulting in a painful sensation)
   - agitation /delirium with hallucinations and possibly seizures
   - accumulation of toxic metabolites due to impaired renal function
   - more common in frail elderly
2. Myoclonus
   - spontaneous jerking movements can occur with any dose and route of opioids
   - myoclonus may precede the onset of opioid-induced neurotoxicity
3. Respiratory suppression
   - occurs rarely, may cause irregular breathing
   - intervene when there is depressed consciousness level and RR <10/min

High risk populations:

• Elderly
• Frail patient
• Marginal renal function
• Poor oral intake

Management:

1. Withhold 1-2 doses of opioid
   - will help to reverse the side effects
2. Opioid rotation
   - for patients with poor tolerance: consult pain specialists

In rare case of emergency (respiratory suppression causing desaturation or RR <10/min, seizure):
3. Diluted naloxone bolus IV injection 0.04mg/ml
—> Titrate injection volume by clinical effects
—> Avoid giving whole vial (0.4mg) in one injection as this will provoke severe pain
—> Naloxone has short half-life of 30-60 min only —> Opioid’s effect may recurs 1-2 hours after injection

Question 7

Fentanyl

Answer 7

• Should be prescribed by pain specialists
• Patch / SC infusion
• Less constipating, less sedative, can be used in renal failure patients

Disadvantage:

• slow onset
• very difficult to titrate
• Patient education very important: fatal complication occurred due to improper administration of the patch

Conversion to morphine:
25mcg/hr = 4.2mg = 60-90mg oral morphine

Question 8

Methadone

Answer 8

• Should be prescribed by pain specialists
• Long and highly variable half life, to be given Q12H
• Spare the use of high dose morphine
• Lower toxicity in renal failure patients
• Better than morphine for neuropathic pain?
• > 40mg daily may be associated with fatal arrhythmia (long QT syndrome, Torsades de pointes)