What is the recommended pharmacological treatment for a patient with cancer pain?

Pharmacological Treatment for Cancer Pain

For cancer pain, prescribe analgesics according to the WHO three-step ladder based on pain intensity: start with acetaminophen/paracetamol or NSAIDs for mild pain, add or switch to strong opioids (morphine, hydromorphone, or oxycodone) for moderate-to-severe pain—skipping weak opioids when progressive pain is expected—and use around-the-clock dosing with breakthrough doses for persistent pain. 1, 2, 3

Algorithmic Approach Based on Pain Severity

Step 1: Mild Pain

• Start with non-opioid analgesics: acetaminophen/paracetamol (maximum 4000 mg/day) or NSAIDs 1, 2
• Neither paracetamol nor NSAIDs demonstrate clear superiority over each other, and evidence for paracetamol effectiveness in cancer pain is actually quite limited 3, 4
• Monitor NSAIDs closely: periodically reassess long-term use due to risks of gastrointestinal bleeding, platelet dysfunction, renal failure, and thrombotic cardiovascular events with COX-2 inhibitors 1
• COX-2 selective inhibitors may be considered for patients with gastric intolerance, though solid efficacy data for cancer pain are lacking 1

Step 2: Moderate Pain (Two Acceptable Options)

Option A (Traditional but increasingly questioned):

• Add weak opioids (tramadol, codeine, dihydrocodeine) to the non-opioid regimen 1
• Critical caveat: Evidence for weak opioids is weak—meta-analyses show no significant difference between non-opioids alone versus combinations with weak opioids 1
• Genetic variability significantly affects tramadol and codeine efficacy: CYP2D6 poor metabolizers experience reduced or absent effects, while ultrarapid metabolizers risk toxicity 3
• Tramadol produces significantly higher rates of nausea, vomiting, vertigo, anorexia, and asthenia compared to alternatives 1

Option B (Increasingly preferred by experts):

• Use low-dose strong opioids (morphine, hydromorphone, or oxycodone) combined with non-opioids, especially when progressive pain is expected 1, 3
• This approach bypasses the controversial Step 2 of the WHO ladder, which has time-limited effectiveness and significant side effects 3

Step 3: Severe Pain

• Oral morphine is the first-choice strong opioid 1, 2
• Alternative strong opioids: hydromorphone or oxycodone in both immediate-release and modified-release formulations 1, 2
• Methadone is an alternative but more complicated due to pronounced inter-individual differences in plasma half-life and duration of action 1
• Transdermal fentanyl: reserve for patients with stable opioid requirements ≥60 mg/day oral morphine equivalents 1, 5
• Strong opioids may be combined with ongoing non-opioid analgesics 1

Critical Dosing Principles

Route Selection

• Oral administration is the preferred route 1, 3
• When oral intake is not possible (severe vomiting, bowel obstruction, severe dysphagia, severe confusion) or when rapid dose escalation is needed, consider alternative routes 1
• Oral to parenteral morphine conversion ratio: 1:2 to 1:3 (i.e., parenteral dose is 1/3 of oral dose) 1, 3

Scheduling Strategy

• Provide around-the-clock dosing for persistent pain, not "as needed" administration 1, 2, 3
• Breakthrough doses: provide 10-15% of total daily dose for transient pain exacerbations 1, 2, 3
• Titration rule: if patients require more than four breakthrough doses daily, increase the baseline opioid regimen 1, 2
• Rescue doses taken by patients are an appropriate measure for daily titration of regular doses 1

Rapid Titration Protocol

• Titrate opioid doses to effect as rapidly as possible 1, 2
• For morphine titration, use immediate-release formulations every 4 hours plus hourly rescue doses during the titration phase 3
• Once pain control is achieved, convert to sustained-release formulations for maintenance 3

Mandatory Side Effect Management

Prophylactic Measures

• All patients on opioids require prophylactic laxatives (stimulating laxatives to increase bowel motility, with or without stool softeners) 1, 3
• Antiemetics: use metoclopramide or antidopaminergic drugs for opioid-induced nausea/vomiting 1, 3

Managing Refractory Side Effects

• Common adverse effects include constipation, nausea, vomiting, drowsiness, cognitive impairment, confusion, hallucinations, and myoclonic jerks 1
• Consider dose reduction by adding co-analgesics or alternative approaches (nerve blocks, radiotherapy) 1
• Opioid rotation: switching to another opioid agonist and/or route may allow adequate analgesia without disabling effects 1
• Use major tranquilizers for confusion and psychostimulants for drowsiness 1

Special Considerations for Renal Impairment

• In chronic kidney disease stages 4-5 (eGFR <30 ml/min), fentanyl and buprenorphine are the safest options 3
• Dose reduction and increased dosing intervals are mandatory for most opioids in renal impairment 3

Adjuvant Analgesics for Neuropathic Pain

Anticonvulsants

• Gabapentin: start 100-300 mg nightly, increase to 900-3600 mg daily in divided doses; dose increments of 50-100% every few days with slower titration for elderly or medically frail patients; dose adjustment required for renal insufficiency 1
• Pregabalin: start 50 mg three times daily, increase to 100 mg three times daily (maximum 600 mg/day); more efficiently absorbed than gabapentin; dose adjustment required for renal insufficiency 1

Antidepressants

• Tricyclic antidepressants: tertiary amines (amitriptyline, imipramine) may be more efficacious but secondary amines (nortriptyline, desipramine) are better tolerated; start 25 mg nightly, increase to 50-150 mg nightly 1
• SNRIs: duloxetine 30-60 mg daily, increase to 60-120 mg daily; venlafaxine 50-75 mg daily, increase to 75-225 mg daily 1

Topical Agents

• Lidocaine 5% patch: apply daily to painful site with minimal systemic absorption 1
• Diclofenac gel: apply three times daily, or diclofenac patch 180 mg once or twice daily 1

Additional Interventions

Bone Pain

• Bisphosphonates or denosumab improve pain in patients with bony metastases in some tumor types 2, 6

Corticosteroids

• Specific role in spinal cord compression and brain metastases where improved analgesia is a secondary benefit 6
• Limited evidence for adding corticosteroids to stronger opioids when pain control is the primary objective 6

Non-Pharmacological Approaches

• Consider radiation therapy for localized bone pain 2
• Surgical stabilization for impending fractures 2
• Psychological interventions for anxiety and depression 2
• Interventional strategies (regional infusion, nerve blocks, vertebral augmentation) when pain is inadequately controlled despite optimal pharmacologic therapy or when opioid side effects are intolerable 2

Common Pitfalls to Avoid

• Do not combine weak opioids (Step 2) with strong opioids (Step 3) 1
• Do not wait for scheduled dosing intervals when rapid pain control is needed—use rapid titration of short-acting opioids 1, 3
• Do not underestimate the importance of around-the-clock dosing—"as needed" administration is inadequate for persistent cancer pain 1, 2, 3
• Do not forget prophylactic laxatives—constipation is nearly universal with opioid therapy 1, 3
• Pain should be managed during the diagnostic evaluation, not delayed until diagnosis is complete 1