Cancer Pain

Total/holistic approach – physical, psychological, spiritual, social

• Two types of pain – often a combination
  • Nociceptive – somatic or visceral
  • Neuropathic – due to nerve compression or injury
• Opioids often first line approach to moderate-severe cancer pain

Cancer Pain Management: A Narrative Review of Current Concepts, Strategies, and Techniques by François Mestdagh, Arnaud Steyaert and Patricia Lavand’homme – https://www.mdpi.com/1718-7729/30/7/500

Opioids in Cancer Pain Management: An Update of the Mainstay Approach

Importance and Guidelines

• Mainstay of Treatment: Opioids remain essential for managing moderate to severe cancer pain.
• Guidelines: Follow guidelines from EAPC, ASCO, ESMO, and WHO, which are regularly updated.
• WHO Three-Step Ladder: This approach has guided opioid prescribing since 1986.

Weak Opioids

• Recommendations: Codeine, hydrocodone, and tramadol for mild to moderate pain in opioid-naïve patients.
• Combination Therapy: Often combined with non-opioid analgesics like paracetamol/acetaminophen and NSAIDs.
• Efficacy: No significant evidence that starting with weak opioids improves overall pain management.

Strong Opioids

• Recommendations: Morphine, oxycodone, hydromorphone for moderate to severe pain.
• Dosing: Start with low doses and titrate to achieve optimal analgesia with tolerable side effects.
• Effectiveness: Over 90% of patients achieve meaningful relief with oral morphine or fentanyl patches within 10-14 days.
• Side Effects: 77% of patients experience side effects, primarily constipation and nausea, with 10-20% needing treatment changes.

Comparative Efficacy and Switching

• Efficacy Comparison: Similar analgesic efficacy among oral morphine, oxycodone, and hydromorphone, but patient response varies.
• Side Effects: Common side effects include constipation, nausea, drowsiness, and confusion. Less gastrointestinal side effects with transdermal fentanyl.
• Opioid Rotation: Switching between opioids or administration routes is common to optimize pain management, particularly for non-responders or poor responders.

Special Considerations for Specific Opioids

• Methadone: Effective in opioid switching due to unique properties but complex to convert; recommended for experienced professionals.
• Buprenorphine: Not first-line for cancer pain but used in opioid switching and for chronic pain in cancer survivors.
• Tapentadol: Effective for mixed and neuropathic pain, with dual mechanisms of action.
• Ketamine: Useful as an adjunct for refractory pain at sub-anaesthetic doses.
• Magnesium Sulfate and Lidocaine Infusions: Considered for complex pain management.
• Cannabis-Related Medicines: Limited evidence for chronic pain relief.

Optimizing Opioid Utilisation When Pain Remains Poorly Controlled

Causes of Poor Response

• Non-Responders/Poor Responders: Up to 26% of patients may not respond adequately to opioids.
• Factors: Disease progression, psychological conditions, presence of neuropathic pain, breakthrough pain, opioid misuse, tolerance, and hyperalgesia.

Strategies for Optimization

• Opioid Rotation: Switching opioids or administration routes to improve efficacy and manage side effects.
• Methadone: Recommended for opioid switching, particularly for high-dose opioid users, but requires specialist supervision.
• Adjuncts: Buprenorphine, tapentadol, ketamine, magnesium sulfate, and lidocaine infusions can be used as additional options for complex pain.
• Co-Analgesic Use: Methadone can be used in low doses as a co-analgesic with other opioids.

Adverse Effects and Harms Related to Long-Term Opioid Intake

Common Side Effects

• General Side Effects: Nausea, constipation, sedation, dizziness, hallucinations, and respiratory depression.
• Endocrine and Bone Health: Long-term use may cause endocrine changes and bone demineralization.
• Psychological Effects: Risk of depression and psychological dependence.

Opioid Use Disorders (OUD)

• Prevalence: OUD is a concern in cancer patients, with a prevalence of up to 20%.
• Management: Close follow-up and cautious prescribing, with efforts to taper opioids and use alternatives like buprenorphine.

The Problem of Neuropathic Pain

Prevalence and Challenges

• Incidence: 20-40% of cancer patients experience neuropathic pain.
• Mixed Pain: Neuropathic pain often coexists with nociceptive pain due to tumor mass effect.

Diagnosis and Screening

• Comprehensive Evaluation: Diagnosis involves detailed history, physical examination, and possible diagnostic tests.
• Screening Tools: Tools like LANSS, DN4, and PainDetect can help assess neuropathic pain.

Treatment Approaches

• First-Line Medications: TCAs (amitriptyline, nortriptyline), SNRIs (duloxetine, venlafaxine), and anticonvulsants (gabapentin, pregabalin).
• Topical Treatments: Lidocaine patches and high-concentration capsaicin for localized neuropathic pain.
• Combination Therapy: Often requires a combination of opioids and adjuvants.
• Specific Opioids for Neuropathic Pain: Tramadol and tapentadol, with dual mechanisms, are effective; methadone can be used for complex cases.

The Problem of Breakthrough Pain

Definition and Incidence

• Definition: Transient exacerbation of pain in patients with controlled baseline pain.
• Incidence: 40-80%, higher in advanced disease.

Management Strategies

• Avoiding Triggers: Avoiding factors that provoke pain episodes and pre-emptive analgesia before interventions.
• Rapid-Onset Opioids: Use of lipophilic opioids like fentanyl or sufentanil administered transmucosally (sublingual, intranasal, oral).
• Optimizing Baseline Pain Control: Better baseline pain control can reduce BTP episodes.
• Dosing for BTP: Controversy exists on whether to use doses proportional to background analgesia or titrated minimum doses. Further studies are needed.

Opioids

• Morphine
  • pure mu-agonist that is primarily metabolised in the liver. 
  • metabolites are renally excreted
  • morphine use in patients with renal insufficiency is generally not recommended because of accumulation of metabolites and potential toxicities. 
• Oxycodone
  • binds to mu and kappa receptors
  • available in a combination preparation with naloxone, to minimise the side effects of constipation.
    • Naloxone
      • opioid antagonist
      • Poor oral bioavailability – only 2% reaches systemic circulation
      • oral formulation of naloxone is not effective in reversing opioid overdose
      • additionally Naloxone has limited penetration into the CNS when taken orally = reducing the likelihood of precipitating withdrawal symptoms.
      • remains in the gastrointestinal tract 🡪 reduce constipation 
      • the oxycodone/naloxone combination should be avoided when there is moderate or severe hepatic dysfunction, as this may lead to increased serum levels of naloxone
• Hydromorphone
  • potent, hydrophilic opioid
  • metabolites are renally cleared, 
• Fentanyl
  • highly lipophilic
  • available in transdermal/ parenteral / transmucosal
  • can be useful for chronic, stable pain 
• Methadone
  • mu-receptor agonist opioid with N-methyl-D-aspartate (NMDA) inhibitor properties. 
  • methadone can be very effective for refractory and complex cancer pain, the risk of accumulation and potential overdose means that it is best prescribed by a pain or palliative medicine specialist.
• Buprenorphine
  •  partial agonist is available in transdermal form

• Opioid rotation
  • Switching from one opioid to another is recommended if a particular opioid fails to provide adequate analgesia, or rapid tolerance is seen, or if toxicity or adverse effects develop. 
  • Opioid rotation can improve response and/or reduce intensity of side effects

Nausea management

1. Serotonin antagonists (e.g., ondansetron, granisetron):
   • Advantages:
     1. Serotonin antagonists are effective in managing nausea associated with chemotherapy-induced nausea and vomiting (CINV) and other causes. 
     2. They have a rapid onset of action and can be administered orally, intravenously, or through other routes. 
     3. They generally have a favorable side effect profile.
   • Disadvantages:
     1. In some cases, serotonin antagonists may cause mild side effects such as headache, constipation, or dizziness. 
     2. Rarely, they can lead to more serious cardiac arrhythmias, especially in patients with pre-existing heart conditions. 
2. Dopamine antagonists (e.g., metoclopramide, prochlorperazine):
   • Advantages:
     1. Dopamine antagonists are effective in managing nausea and vomiting in various palliative care settings. 
     2. They work by blocking dopamine receptors in the brain. 
     3. Metoclopramide also has prokinetic properties, which can be beneficial in managing gastric stasis or delayed gastric emptying.
   • Disadvantages:
     1. Dopamine antagonists can cause side effects such as sedation, extrapyramidal symptoms (e.g., involuntary movements), or hyperprolactinemia (increased levels of prolactin hormone).
3. Corticosteroids (e.g., dexamethasone):
   • Advantages:
     1. Corticosteroids have anti-inflammatory properties and are effective in managing nausea associated with chemotherapy, brain tumors, or other causes. 
     2. They also have potential antiemetic effects.
   • Disadvantages:
     1. Prolonged use of corticosteroids may be associated with side effects such as increased appetite, weight gain, mood changes, or immunosuppression. 
     2. However, in the palliative care setting, short-term use is usually well-tolerated, and the benefits often outweigh the risk
4. Hyoscine
   • acts by blocking the action of acetylcholine in the central nervous system.
   • Disadvantages
     1. Side effects: dry mouth, blurred vision, drowsiness, confusion, and urinary retention. Anticholinergic effects: cognitive impairment and delirium in vulnerable populations, particularly older adults
     2. Limited evidence base: While hyoscine is sometimes used in palliative care for managing nausea, the evidence supporting its efficacy in this context is limited compared to other antiemetic medications, such as serotonin antagonists or dopamine antagonists.