Pain and symptoms management

Pain assessment

• Prevalence: up to 90% of patients with advanced cancer have moderate to severe pain. First step is to assess etiology and treat reversible causes.
• Assess: location, radiation, duration, quality, aggravating/relieving factors, and psychosocial modifiers (anxiety, coping, misuse history, social support).
• Scales: numeric rating scale (NRS 0 to 10), Wong-Baker, Brief Pain Inventory. Patient-reported outcomes (PROs) are the gold standard; systematic PRO collection (Basch) improved QoL, reduced ED visits/hospitalizations, and improved survival.

Pain temporality and type

• Temporality: acute (hours to weeks, autonomic signs, self-limited) vs chronic (>3 months, functional impairment, few autonomic signs).
• Constant pain: ≥12 h/day. Breakthrough pain: transient increase to greater than moderate intensity. Incident pain: triggered by an event/movement (e.g., repositioning).
• Nociceptive (intact nociceptors): somatic (skin/soft tissue/bone/joint, well localized, aching/stabbing/throbbing) and visceral (poorly localized, referred, cramping/pressure/gnawing).
• Neuropathic (peripheral or CNS injury): burning, shooting, tingling, scalding, painful numbness; often with allodynia (pain from light touch) and hyperalgesia (heightened response to stimuli). Examples: postherpetic neuralgia, phantom limb pain, plexus infiltration, chemotherapy-induced peripheral neuropathy.
• Bone pain: nociceptive somatic; opioids, NSAIDs, bone-modifying agents, RT (8 Gy x1 for a painful bone metastasis).

Goals of pain management (the 5 A's)

• Analgesia (optimize relief), Activities (psychosocial function), Adverse effects (minimize), Aberrant drug taking (avoid addiction-related outcomes), Affect (pain-mood relationship).

WHO analgesic ladder + modern principles

• Step 1 (mild): non-opioid (acetaminophen, NSAIDs) ± adjuvant.
• Step 2 (moderate): weak/low-dose opioid (tramadol, codeine, or low-dose combination) ± non-opioid ± adjuvant.
• Step 3 (severe): strong opioid (morphine, oxycodone, hydromorphone, fentanyl, methadone) ± non-opioid ± adjuvant.
• Adjuvants at any step: gabapentinoids and antidepressants (esp. neuropathic pain), corticosteroids (dexamethasone for nerve compression, brain metastases, bone), bone-modifying agents (bisphosphonates/denosumab).
• Conceptual "step 4": interventional approaches for refractory pain.
• Regimen: in opioid-naive patients start and titrate a scheduled plus PRN immediate-release opioid to establish the 24-h requirement, then convert to a long-acting/SR formulation; transdermal fentanyl only once opioid-tolerant (≥60 mg oral morphine/day). Scheduled IR opioids are acceptable in any setting.

Opioid pharmacology and practical use

• Around-the-clock dosing for continuous pain, plus short-acting for breakthrough. Breakthrough dose = 10 to 20% of the total 24-hour dose (except methadone and short-acting fentanyl products). Example: sustained-release morphine 15 mg TID (45 mg/24 h) means 5 to 10 mg short-acting morphine for breakthrough. Time breakthrough dosing to peak effect (~1 h for oral morphine).
• Morphine remains the most studied, evidence-based, cost-efficient opioid for cancer pain.
• Equianalgesic conversions (oral morphine equivalents):
  • Morphine 30 mg PO = oxycodone 20 mg PO = hydromorphone 7.5 mg PO (single-dose equivalents). Transdermal fentanyl is based on the 24-hour total: fentanyl 12 mcg/hr ≈ oral morphine 30 mg/24 h and 25 mcg/hr ≈ 60 mg/24 h (CDC: mcg/hr × 2.4 = MME/day); patches only in opioid-tolerant patients (≥60 mg oral morphine/day).
  • Equianalgesic tables come from single-dose studies in healthy volunteers, so they are approximations and do not replace clinical judgment; have a colleague independently check conversions.
• Opioid AEs: nausea (tolerance develops; treat with dopaminergic antiemetics like prochlorperazine/metoclopramide, avoid 5-HT3 blockers because of constipation), pruritus (nonsedating antihistamine such as cetirizine, or rotate to a synthetic opioid; avoid diphenhydramine due to additive sedation), sedation, urinary retention, hypogonadism (chronic), QT prolongation (methadone), respiratory depression (overdose). Anticipated AEs are not allergies; isolated hives/itching from opioids are usually nonimmune histamine release (pseudoallergy). True allergy/anaphylaxis = hives with respiratory or cardiovascular compromise.
• Naloxone counseling/script for high-risk patients (≥50 MME/day, OUD history, concurrent benzodiazepine, long-acting opioid such as methadone).

Opioids in renal and hepatic dysfunction

Opioid titration and rotation

• Rotate for insufficient analgesia despite titration-limiting AEs, intolerable AEs, ineffective route, drug interactions, tolerance, or cost/access barriers. Titrate first, but rotate when pain remains refractory to appropriate dose titration even without AEs (also for poorly managed AEs, route/absorption, or cost/access issues).
• Tolerance = reduced analgesia with repeated use. Incomplete cross-tolerance: when switching opioids, reduce the calculated equianalgesic dose by 25 to 50% and provide liberal breakthrough dosing with close monitoring.
• Pseudoaddiction: apparent drug-seeking caused by under-dosing (e.g., q6h dosing when relief lasts 4 h); rule out and document.

Methadone

• Unique: mu-agonist and NMDA-receptor antagonist (useful for neuropathic pain); no active metabolites (potentially safer in renal/hepatic impairment).
• Dosing: q8 to 12h for pain (unlike daily maintenance dosing). Complex pharmacokinetics: oral bioavailability 40 to 99%; rapid distribution (2 to 3 h) then slow elimination (15 to 60 h), so overdose requires continuous naloxone.
• Interactions/toxicity: extensive CYP metabolism (3A4, 2B6, 2D6, 2C19); QTc prolongation (avoid if QTc >500 ms; correct hypokalemia/hypomagnesemia/hypocalcemia); can cause hypoglycemia at high/rapidly escalated doses.
• Conversion varies with prior opioid exposure; convert only with palliative care or pain-expert guidance.

Transdermal opioids

• Fentanyl and buprenorphine patches provide steady long-acting analgesia when oral is difficult. A fentanyl depot forms in the upper skin layers and serum levels level off about 12 to 24 h after application; apply to intact, nonirritated, nonirradiated flat skin, not over tattoo or edema (buprenorphine patches differ). Escalate cautiously given limited rotation/equianalgesic data.

Opioid-induced constipation (OIC)

• Preferred: stimulant laxatives (senna 1 to 8 tabs/day, or bisacodyl 5 to 10 mg BID), started at opioid initiation. No added benefit of a stool softener with sennosides; avoid insoluble/bulk fiber if hydration is inadequate.
• PAMORAs (peripherally acting mu-opioid antagonists: methylnaltrexone, naloxegol, naldemedine; alvimopan is approved only for postoperative ileus, not OIC) do not cross the blood-brain barrier (analgesia preserved); best second-line, effective in up to three-fourths of patients. Methylnaltrexone (SC or oral) is a rescue agent (~50% laxation within 4 h vs ~15% placebo); AEs include cramping and diarrhea.

Opioid-induced hyperalgesia

• Nociceptive sensitization from high-dose opioids (central glutaminergic mechanism): paradoxical increase in pain with dose escalation without disease progression, sometimes with myoclonus, confusion, or allodynia. Manage with dose reduction, rotation, or non-opioid strategies. (Myoclonus, delirium, and seizures indicate opioid-induced neurotoxicity from metabolite accumulation, a distinct syndrome that can coexist.) Do not withhold needed opioid therapy.

Interventional cancer pain treatments

• Celiac plexus block (upper abdominal/pancreatic pain): ~90% achieve relief within 2 weeks; 70 to 90% partial-to-complete relief lasting to death or beyond 3 months. AEs: orthostatic hypotension, diarrhea (rare pneumothorax, back pain, very rare paraplegia).
• Superior/inferior hypogastric block (pelvic pain); ganglion impar block (rectal/anal pain).
• Vertebral augmentation (vertebroplasty/kyphoplasty) and radiofrequency ablation for painful spine lesions/compression fractures; single-fraction RT to spine acceptable.
• Intrathecal drug delivery (opioids, local anesthetics, clonidine, ziconotide) improves analgesia and reduces systemic toxicity.
• Spinal cord stimulation: mainly neuropathic pain; evidence for routine cancer-pain use is currently insufficient.

Opioid risk management, OUD, and universal precautions

• Universal precautions: assess all patients for misuse risk regardless of demographics. Tools: PDMP review, electronic prescribing, pain agreements, risk screens (Opioid Risk Tool, SOAPP-R, CAGE-AID, COMM), urine drug screens, safe storage/disposal, naloxone.
• OUD (DSM-5): problematic use with impaired control, compulsive use, continued use despite harm, and craving (≥2 of 11 criteria). Risk factors: personal/family history of substance use, tobacco dependence, major psychiatric disorder, young age, prolonged exposure. Do NOT undertreat cancer pain.
• Continue OUD treatment (methadone or buprenorphine) while treating pain; coordinate with the existing prescriber. Stopping OUD medication leads to ~50% relapse.
• Contraindicated in cancer pain: mixed agonist-antagonists (butorphanol, pentazocine) with agonists (precipitate withdrawal); meperidine for chronic pain (normeperidine accumulates, causing seizures/arrhythmias, esp. in renal impairment/dehydration); placebos (unethical).

Specific pain syndromes

• Bone metastases: RT (8 Gy x1), bone-modifying agent (bisphosphonate/denosumab), radium-223 (mCRPC), vertebroplasty/kyphoplasty.
• Spinal cord compression: dexamethasone 10 mg IV then 4 mg q6h, urgent MRI, RT and/or surgery (for instability or single-level mechanical compression).
• Bowel obstruction: NPO, NG tube, octreotide, scopolamine; consider venting gastrostomy or palliative surgery.
• Tumor nerve invasion: adjuvants (gabapentinoids, duloxetine), corticosteroids, nerve blocks, intrathecal pump.
• Mucositis pain: topical analgesics (magic mouthwash), parenteral opioids if severe.

Other distressing symptoms

• Dyspnea: supplemental O2 only if hypoxemic (resting SpO2 ≤90%); for nonhypoxemic breathlessness use a fan/airflow and opioids (morphine 5 to 10 mg PO q4h), benzodiazepines for anxiety, positioning, treat the cause.
• Cough: opioids, dextromethorphan, benzonatate, treat the cause.
• Anxiety / agitation / delirium: identify and treat reversible precipitants and use nonpharmacologic measures first; reserve haloperidol for severe agitation or distress. Benzodiazepines for anxiety, withdrawal, and selected terminal restlessness, not routine delirium.
• Nausea/vomiting: match antiemetic to the pathway/receptor. Chemotherapy emetic risk categories: high (>90%), moderate (30 to 90%), low (10 to 30%), minimal (<10%); risk factors include prior CINV, female sex, age <50, low alcohol intake, motion sickness, hyperemesis gravidarum history. First-cycle CINV predicts subsequent cycles, so prophylax aggressively up front.
• Anorexia / cachexia: megestrol (VTE risk, counsel), low-dose olanzapine 2.5 mg (RCT-supported), mirtazapine, anamorelin (Asia-approved). Ponsegromab (anti-GDF15 mAb) phase 2 positive (Groarke NEJM 2024), investigational; first targeted cachexia therapy.
• Fatigue: exercise (best evidence); screen for treatable causes (anemia, depression, hypothyroid, B12, sleep apnea); methylphenidate weak evidence; modafinil/armodafinil for opioid-related sedation; CBT per ASCO/SIO 2024.
• Pruritus: antihistamines, gabapentin, naltrexone, mirtazapine. Cholestatic: cholestyramine, rifampin, naltrexone. Opioid-induced: rotation, nonsedating antihistamine, low-dose naloxone.
• Hiccups: baclofen, chlorpromazine, gabapentin, metoclopramide.

End-of-life care

• Hospice eligibility: prognosis ≤6 months if disease runs its natural course.
• Comfort kit: concentrated sublingual morphine, lorazepam, atropine drops (secretions), haloperidol.
• Withdrawing artificial nutrition/hydration: ethically permissible per patient wishes.
• Palliative sedation for refractory symptoms (distinct from euthanasia; intent matters).
• Advance care planning, POLST/MOLST early in serious illness.

Special pain populations

• Substance use disorder history: validated screens (ORT, SOAPP-R), urine drug screens, treatment agreements; do NOT undertreat cancer pain.
• Pregnancy: acetaminophen first; avoid chronic opioids; no NSAIDs after 20 weeks.

2024-2026 pain & symptom management updates

• Suzetrigine (Journavx, VX-548): FDA approved Jan 30, 2025 for moderate-severe acute pain in adults. First-in-class selective Nav1.8 sodium-channel blocker; non-opioid, non-addictive. Superior to placebo in phase 3 post-op trials but not superior to hydrocodone/APAP (phase 2, Jones NEJM 2023; the phase 3 trials also missed this key secondary endpoint, Bertoch Anesthesiology 2025). First novel non-opioid mechanism in decades.
• Cebranopadol: dual NOP/mu-opioid agonist, phase 3 in acute post-op pain (2024 to 2025), improved analgesia with reduced abuse liability and constipation; not yet FDA-approved.
• IV meloxicam (Anjeso): opioid-sparing NSAID for perioperative moderate-severe pain; commercially discontinued in the US.
• Ponsegromab (anti-GDF15 mAb): Groarke NEJM 2024, dose-dependent weight gain 1.2 to 2.8 kg vs placebo in cancer cachexia at 12 weeks; first targeted cachexia therapy. Phase 3 ongoing.
• Anamorelin (ghrelin-R agonist): Japan-approved for NSCLC/GI cachexia; ROMANA 1/2 improved lean body mass and weight but not handgrip strength (not FDA/EMA approved).
• Music therapy for cancer pain and anxiety: Cochrane review (Bradt 2021), very low certainty evidence suggesting benefit for anxiety and pain; no demonstrated effect on mood.
• Ketamine for cancer pain: phase 3 RCT (Hardy JCO 2012) showed no net benefit of SC ketamine as an opioid adjunct (more toxicity, NNH 6); reserve for selected opioid-refractory pain under palliative/pain specialist supervision.
• Psilocybin-assisted therapy for cancer-related distress: RCT (Ross J Psychopharmacol 2016; reduction in cancer-associated depression/anxiety sustained at 6.5 months) and open-label phase 2 (Agrawal JAMA Oncol 2023; primary endpoint at 8 weeks, about half with sustained response at 2 years, Cancer 2025), after a single session plus psychotherapy.

High-yield pain pearls

• Breakthrough dose = 10 to 20% of the 24-hour total; reduce by 25 to 50% for incomplete cross-tolerance when rotating.
• 8 Gy x1 for painful bone metastases; radium-223 for CRPC with symptomatic bone metastases and no visceral metastases (limited nodal disease allowed).
• Avoid morphine/codeine in renal failure (active metabolites); methadone and fentanyl are preferred.
• Methadone: NMDA antagonist (good for neuropathic pain), QTc risk, CYP interactions, expert prescribing; continuous naloxone for overdose.
• Stimulant laxatives (senna/bisacodyl), not softeners, for OIC; PAMORAs second-line.
• Spinal cord compression: dexamethasone + MRI + urgent RT/surgery.
• Naloxone for high-MME patients; anticipated AEs are not allergies.
• Celiac plexus block for pancreatic/upper-abdominal pain (~90% relief).
• Avoid mixed agonist-antagonists with agonists and meperidine for chronic pain.
• Delirium: treat reversible causes and use nonpharmacologic measures first, haloperidol only for severe agitation or distress; benzodiazepines for anxiety/terminal restlessness; olanzapine for both nausea and anorexia/cachexia; hospice = ≤6-month prognosis.