Chronic Pain Management in Stage 4 Pancreatic Cancer

1. Principles of Chronic Pain Management

Key Principles

Figure: Biopsychosocial model of health - Bailey & Love's Surgery, 28e

• Biological: Tissue injury, nociceptor sensitization, neural inflammation, tumour invasion
• Psychological: Anxiety, depression, catastrophizing, and cognitive distortions amplify pain perception
• Social: Family support, economic factors, and social isolation affect pain experience and coping

• Location, onset, and character - visceral (deep, poorly localized, cramping) vs neuropathic (burning, lancinating, hyperalgesia)
• Severity - numerical rating scales (NRS 0-10), pain diary
• Alleviating/exacerbating factors
• Previous therapies and responses
• Psychosocial assessment - mandatory when pain is disproportionate to injury, or psychological/social issues are prominent

• Encourage independence and active living despite pain - the therapeutic goal is functional restoration alongside analgesia
• Anticipate escalation - cancer pain is progressive; doses should be proactively titrated
• Breakthrough dosing - short-acting opioids must always be prescribed alongside long-acting background analgesia
• Distinguish dependence from addiction - physiological dependence (dose-dependent withdrawal) is expected; addiction (compulsive drug-seeking) is a psychosocial phenomenon and rare in cancer patients
• Consider disease-modifying interventions - coeliac plexus neurolytic block is particularly effective for pancreatic cancer pain (see neurolytic section below) - Bailey & Love's Surgery, 28e

• Physiotherapy and graded exercise (not always applicable in advanced cancer)
• Cognitive behavioural therapy (CBT) and mindfulness
• Pain management programmes with multidisciplinary input
• Spinal cord stimulation (SCS) for intractable neuropathic pain (NICE-recommended)
• TENS and acupuncture - increase endorphin production in the CNS
• Interventional/neurolytic procedures for cancer-specific pain

2. Pharmacological Management of Chronic Pain

A. Non-Opioid Analgesics

• First-line analgesic (WHO Step 1); excellent safety profile except in overdose
• Mechanism: primarily CNS prostaglandin inhibition producing analgesia and antipyresis; crosses the blood-brain barrier readily
• Maximum daily dose: 3,250 mg (FDA-recommended); reduce in hepatic impairment
• Oral/rectal administration achieves analgesia within 40 minutes; IV preparation provides more reliable onset

• Mechanism: inhibit COX-1/COX-2 enzymes, reducing prostaglandin synthesis; prostaglandins sensitize peripheral nociceptors to bradykinin, histamine, and somatostatin
• Useful for bone metastases and inflammatory components of cancer pain
• Side effects: GI toxicity, gastric ulceration and bleeding; renal dysfunction (especially in elderly, hypovolaemic, or cardiac failure patients); cardiovascular thrombotic risk (especially COX-2 inhibitors); asthma exacerbation
• Note: Rofecoxib was withdrawn in 2004 due to cardiovascular risk - Bradley and Daroff's Neurology in Clinical Practice

B. Adjuvant Analgesics (Co-analgesics)

• First-line for neuropathic pain (burning, lancinating quality from perineural tumour invasion)
• Mechanism: block reuptake of serotonin and norepinephrine, potentiating the descending inhibitory pathway
• Side effects: anticholinergic (dry mouth, constipation, urinary retention, sedation)

• Gabapentin and Pregabalin: Bind the α2δ subunit of voltage-gated calcium channels; reduce spontaneous neuronal activity and are now routinely first-line for neuropathic pain. Pregabalin has more predictable pharmacokinetics.
• Carbamazepine: Sodium channel blocker; useful for lancinating neuropathic pain

• Ketamine (low-dose): blocks NMDA receptor wind-up; useful in opioid-refractory pain; reduces central sensitization

• Baclofen: GABA-B agonist; reduces spasticity-associated pain
• Corticosteroids (dexamethasone): reduce peritumoral oedema, nerve compression pain, and improve appetite/nausea in cancer patients
• Local anaesthetics (systemic lidocaine/mexiletine): suppress spontaneous neuronal firing in neuropathic pain

C. Opioid Analgesics

• Full agonists (most common in cancer pain): codeine, morphine, oxycodone, hydromorphone, fentanyl, methadone - act on mu (μ), kappa (κ), and delta (δ) receptors
• Partial agonists: buprenorphine - lower intrinsic efficacy, ceiling effect on analgesia
• Mixed agonist-antagonists: pentazocine, butorphanol, nalbuphine - block μ while activating κ receptors; do NOT combine with full agonists (risk of precipitating withdrawal)

• Oral - preferred; convenient, cost-effective; available as immediate-release (IR) and controlled-release (CR)
• Transdermal - fentanyl patches (12, 25, 50, 75, 100 μg/h); each patch lasts 72 hours; plasma levels rise over 12-18 hours; not for rapid titration - useful in stable chronic cancer pain
• Transdermal buprenorphine also commercially available
• Subcutaneous infusion (diamorphine) - when oral route unavailable
• Epidural/intrathecal infusion - for refractory pain; intrathecal pump carries infection risk
• Intramuscular - AVOID (painful, unreliable absorption)
• IV - reserved for acute crises (e.g., pathological fractures)

D. Interventional/Neurolytic Techniques for Pancreatic Cancer

• Coeliac plexus neurolytic block - injection of alcohol for pancreatic, gastric, or hepatic cancer pain; highly effective for pancreatic cancer visceral pain
• Subcostal phenol injection for rib metastases
• Intrathecal neurolytic phenol (hyperbaric)
• Percutaneous anterolateral cordotomy - divides the spinothalamic ascending pain pathway; reserved for intractable pain in terminal cancer patients - Bailey & Love's Surgery, 28e

3. Ascending and Descending Pain Pathways

A. Peripheral Nociception (First-Order Neurons)

• Aδ fibers (thinly myelinated): Fast pain - sharp, well-localized (first pain); 5-30 m/s conduction; respond to thermal and mechanical stimuli
• C fibers (unmyelinated): Slow pain - dull, burning, poorly localized (second pain); 0.5-2 m/s; polymodal (mechanical, thermal, chemical)

B. Dorsal Horn Processing (Second-Order Neurons)

• Nociception-specific neurons (lamina I) - respond only to noxious stimuli
• Wide Dynamic Range (WDR) neurons (lamina V) - respond to both innocuous and noxious stimuli; responsible for central sensitisation ("wind-up")

C. Ascending Pain Pathways

Figure: Cross-section of spinal cord showing spinothalamic and other ascending sensory pathways - Morgan & Mikhail's Clinical Anesthesiology, 7e

• Axons of nociception-specific and WDR neurons from laminae I and V
• Cross the midline near their segment of origin and ascend in the anterolateral white matter (lateral spinothalamic tract)
• Terminate in the ventroposterolateral (VPL) and ventroposteromedial (VPM) thalamic nuclei
• Third-order neurons project to somatosensory cortex I and II in the postcentral gyrus (parietal lobe) - mediates discriminative/localized pain perception
• Neurons projecting to intralaminar and medial thalamic nuclei relay to the anterior cingulate gyrus - mediates suffering and emotional components of pain
• Clinical note: Lesioning this tract (anterolateral cordotomy) markedly reduces pain contralateral to the lesion - used for intractable cancer pain

• Axons from laminae VII and VIII; ascend anterolaterally
• Large, often bilateral receptive fields
• Terminates in reticular formation and thalamus
• Mediates diffuse, poorly localized pain, arousal, and autonomic responses to pain

• Axons from laminae I and V; projects to the parabrachial nucleus (pons)
• Extensive collaterals to the mesencephalic reticular formation and periaqueductal gray (PAG)
• Parabrachial neurons project to the amygdala (limbic system)
• Mediates the affective/emotional component of pain - fear, suffering

• Axons from laminae I, V, VII, VIII
• Projects to hypothalamic nuclei - autonomic control centers
• Mediates neuroendocrine and cardiovascular responses to pain (tachycardia, hypertension, cortisol release)

Peripheral nociceptors → Aδ/C fibers → Dorsal Root Ganglia
→ Dorsal Horn (laminae I, II, V) → Cross midline
→ Spinothalamic tract (anterolateral) → Thalamus (VPL/VPM)
→ Somatosensory cortex (localization) + Anterior cingulate (suffering)

D. Descending Pain Inhibition (Descending Pathway)

1. Periaqueductal Gray (PAG) - midbrain; the primary site of descending pain inhibition; stimulation produces widespread analgesia; rich in opioid receptors
2. Nucleus Raphe Magnus (NRM) - medulla; PAG relays here first; serotonergic fibers descend via the dorsolateral funiculus to inhibit dorsal horn neurons
3. Locus Coeruleus and Reticular Formation - noradrenergic fibers descend to inhibit nociceptive transmission via α2-adrenergic receptors in the dorsal horn

• Serotonin (5-HT) - from NRM via dorsolateral funiculus → inhibits dorsal horn
• Norepinephrine - from PAG/reticular formation → presynaptic and postsynaptic α2 receptor activation
• Endogenous opioids - met-enkephalin, leu-enkephalin, β-endorphin (from NRM and reticular formation) → presynaptically hyperpolarize primary afferents, inhibit substance P release; postsynaptically inhibit second-order neurons; all antagonized by naloxone

• Opioids - act at PAG, NRM, and dorsal horn (μ, δ, κ receptors)
• Antidepressants (SNRIs/TCAs) - block reuptake of serotonin and norepinephrine, potentiating descending inhibition
• α2 agonists (clonidine, dexmedetomidine) - mimic descending noradrenergic inhibition

Cerebral cortex / Emotional centers
→ PAG (midbrain) + Endogenous opioid release
→ NRM (medulla) via serotonergic fibers → Dorsolateral funiculus
→ Dorsal Horn (substantia gelatinosa) → INHIBITS Substance P release
→ Reduces pain signal transmission

4. WHO Analgesic Ladder

                     ┌─────────────────────────────────┐
                     │    STEP 3: Strong Opioids        │
                     │  (Moderate-Severe Pain)          │
                  ┌──┤  Morphine, Oxycodone,            ├──┐
                  │  │  Hydromorphone, Fentanyl,        │  │
                  │  │  Methadone                       │  │
                  │  └─────────────────────────────────-┘  │
                  │         ± Non-opioids                  │
               ┌──┴──────────────────────────────────┐     │
               │    STEP 2: Weak/Mild Opioids         │     │
               │  (Mild-Moderate Pain)                │     │
               │  Codeine, Tramadol                   │     │
               └──┬──────────────────────────────────-┘     │
                  │         ± Non-opioids                   │
        ┌─────────┴────────────────────────────────────┐   │
        │    STEP 1: Non-Opioid Analgesics              │   │
        │  (Mild Pain)                                  │   │
        │  Paracetamol, NSAIDs                          │   │
        └───────────────────────────────────────────────┘   │
                         ± Adjuvants at ALL steps ──────────┘

Step 1 - Mild Pain (NRS 1-3)

• Paracetamol (1g every 6 hours) ± NSAIDs
• Tricyclic antidepressants or anticonvulsant drugs (for neuropathic component)
• Adjuvants: corticosteroids, bisphosphonates (bone pain)

Step 2 - Mild to Moderate Pain (NRS 4-6)

• Weak/intermediate opioids: Codeine (30-60 mg every 4-6 h), Tramadol (50-100 mg every 6 h)
• Continue Step 1 agents
• Note: Codeine is a prodrug converted to morphine (10% conversion) - poor metabolizers (CYP2D6 variants) will have no effect

Step 3 - Moderate to Severe Pain (NRS 7-10)

• Strong opioids: Morphine (oral, preferred); oxycodone, hydromorphone, fentanyl (transdermal), methadone
• Morphine titration: start with 4-hourly short-acting oral morphine, titrate over 24 hours, then convert to twice-daily slow-release morphine (MST tablets)
• Always co-prescribe short-acting opioids for breakthrough pain
• Pethidine (meperidine) has been withdrawn due to normeperidine toxicity
• Note for this patient: Step 3 opioids combined with coeliac plexus neurolytic block is appropriate for intractable pancreatic cancer pain

Adjuvants (Used at All Steps)

• Tricyclics, gabapentin/pregabalin (neuropathic component from perineural invasion)
• Corticosteroids (dexamethasone) - reduce periductal inflammation, improve appetite
• Antiemetics (ondansetron, metoclopramide) - essential with opioids; nausea usually transient but constipation is persistent and requires prophylactic laxatives
• Laxatives - mandatory with opioid initiation

Route of Administration Principles (WHO "By the Clock, By the Mouth, By the Ladder")

• By the mouth - oral route is preferred whenever possible
• By the clock - regular fixed-interval dosing, not PRN, to maintain steady plasma levels
• By the ladder - start at the appropriate step; do not skip steps, but do not delay escalation when pain is not controlled
• For the individual - titrate to the patient's pain; no maximum dose ceiling for strong opioids in cancer pain

Special Considerations for Stage 4 Pancreatic Cancer

• Coeliac plexus neurolytic block with absolute alcohol should be considered early - highly effective, reduces opioid requirement, and improves quality of life
• If oral route is lost (vomiting, dysphagia, bowel obstruction) - switch to subcutaneous diamorphine infusion via syringe driver
• Epidural or intrathecal infusions for refractory pain
• Cordotomy (percutaneous anterolateral) - considered only in terminal patients with unilateral, limited life expectancy

• Bailey and Love's Short Practice of Surgery, 28th Edition - Pain principles, WHO ladder, cancer pain management
• Morgan and Mikhail's Clinical Anesthesiology, 7e - Pain pathways, nociception, chronic pain pathophysiology
• Bradley and Daroff's Neurology in Clinical Practice - Pharmacological management, NSAIDs, opioids
• Eric Kandel, Principles of Neural Science, 6e - Ascending pain pathways
• Stahl's Essential Psychopharmacology - Descending spinal synapses
• Katzung's Basic and Clinical Pharmacology, 16e - Descending inhibition pathways

1. Use Harrison's Principles of Internal Medicine, 22nd Edition (2025) - which IS in the library and is the closest authoritative equivalent to Davidson's in scope, depth, and clinical approach. It covers chronic pain, cancer pain, pharmacology, and pain pathways extensively.
2. Use Goldman-Cecil Medicine - also available, another major internal medicine reference comparable to Davidson's.
3. Note where Davidson's content is well-known: Davidson's 24e covers chronic pain management primarily in the chapters on "Palliative and end-of-life care" and "Symptom control in cancer." Its approach follows the same WHO analgesic ladder framework, biopsychosocial model, and three-step opioid escalation that the previous answer was built on. The clinical content would be substantively identical - Davidson's does not contradict but rather aligns with the information already presented.

• Rewrite using Harrison's Principles of Internal Medicine 22E?
• Rewrite using Goldman-Cecil Medicine?
• Use both in combination?

Chronic Pain Management in Stage 4 Pancreatic Cancer

1. Principles of Chronic Pain Management

Definition and Nature of Pain

"The province of medicine is to preserve and restore health and to relieve suffering. Understanding pain is essential to both goals." - Harrison's 22E, Ch. 14

Chronic Pain as a Distinct Disease

• Sensitization of the nervous system can occur without an obvious precipitating cause (e.g., fibromyalgia, chronic headache)
• The pain-generating mechanism is often difficult or impossible to determine with certainty
• The traditional medical approach of seeking an obscure organic pathology is often unhelpful
• Psychological evaluation and behaviorally based treatment paradigms are frequently helpful, particularly within a multidisciplinary pain-management center

Factors That Cause, Perpetuate, or Exacerbate Chronic Pain

1. Disease itself - a condition that is characteristically painful for which there is no cure (arthritis, cancer, fibromyalgia, diabetic neuropathy)
2. Secondary perpetuating factors - initiated by disease but persisting after disease resolution: damaged sensory nerves, sympathetic efferent activity, painful reflex muscle contraction (spasm)
3. Psychological conditions - can exacerbate or even cause pain

Assessment Principles

• Depression screening: the most common emotional disturbance in chronic pain patients; assess mood, appetite, sleep patterns, and daily activity; the Beck Depression Inventory is recommended as a useful screening tool
• Clues to significant emotional disturbance: pain in multiple unrelated sites; recurrent pain problems beginning in childhood/adolescence; pain beginning at a time of emotional trauma (loss of parent or spouse); history of physical or sexual abuse; past or present substance abuse
• Pain character: location, onset, quality, aggravating and relieving factors

• Whether the patient guards the painful area and avoids certain movements
• Deep tenderness: is it localized to muscle, ligamentous structures, or joints?
• Trigger points: deep palpation revealing firm bands or knots in muscle (chronic myofascial pain); relief with local anaesthetic injection confirms diagnosis
• Neuropathic signs: sensory impairment, allodynia (exquisitely sensitive skin), weakness, muscle atrophy, loss of deep tendon reflexes
• Sympathetic involvement: diffuse swelling, skin colour and temperature changes, hypersensitivity compared with the contralateral side

The Guiding Principle

"A guiding principle in evaluating patients with chronic pain is to assess both emotional and somatic causal and perpetuating factors before initiating therapy. Addressing these issues together, rather than waiting to address emotional issues after somatic causes have been ruled out, improves compliance." - Harrison's 22E, Ch. 14

Treatment Planning Principles

• Identify specific and realistic functional goals for therapy (e.g., a good night's sleep, ability to go shopping, return to work)
• A multidisciplinary approach using medications, counselling, physical therapy, nerve blocks, and surgery may be required
• Spinal cord stimulation (SCS) - placement of electrodes in the space overlying the dorsal columns - has shown significant benefit for severe, persistent pain unresponsive to conservative treatment
• Referral to a multidisciplinary pain clinic should precede any invasive procedure
• For some patients, pharmacologic management alone can provide adequate relief

2. Pharmacological Management of Chronic Pain

A. Non-Opioid Analgesics: Aspirin, Acetaminophen, and NSAIDs

• Particularly effective for mild to moderate headache and pain of musculoskeletal origin
• By far the most used analgesics globally because they are available without prescription

• Does not produce gastric irritation and does not interfere with platelet function
• Toxic to the liver when taken in high doses
• Dose: 650 mg q4-6h (PO)

• With chronic use, gastric irritation is the most frequent dose-limiting side effect
• Aspirin: may cause gastric erosion, ulceration, bleeding, or perforation; irreversibly acetylates platelet COX - gastrointestinal bleeding is a particular risk
• Nephrotoxicity is a significant problem with chronic NSAID use; patients at risk: those with significant intravascular volume contraction (chronic diuretics, acute hypovolemia)
• NSAIDs can increase blood pressure - requires regular monitoring
• COX-2 selective inhibitors: less gastric irritation, no effect on blood coagulation (surgical advantage), but associated with increased cardiovascular risk - contraindicated immediately after coronary artery bypass surgery; use with caution in elderly patients and those with cardiovascular risk factors

B. Opioid Analgesics

• Methylnaltrexone (subcutaneous): peripherally restricted μ-receptor antagonist; effective for opioid-induced constipation in patients on chronic opioids; does not cross the CNS, so reverses peripheral side effects without reversing central analgesia
• Alvimopan (oral): restricted to intestinal lumen; lowers duration of persistent ileus following abdominal surgery in patients on opioids

C. Antidepressants

• Particularly nortriptyline and desipramine are useful for the management of chronic pain
• Although developed for depression, TCAs have analgesic activity at lower doses and with more rapid onset than the doses/timescale needed for antidepressant effect
• Patients with chronic pain who are not depressed obtain pain relief with antidepressants
• TCAs potentiate opioid analgesia - they are useful adjuncts for the treatment of severe persistent pain such as occurs with malignant tumours
• Particularly valuable for neuropathic pain: diabetic neuropathy and postherpetic neuralgia

• Postherpetic neuralgia
• Diabetic neuropathy
• Fibromyalgia
• Tension headache, Migraine headache
• Rheumatoid arthritis
• Chronic low back pain
• Cancer pain
• Central poststroke pain

D. Pharmacological Management of Cancer Pain - Harrison's Palliative Care Chapter

"At least 80% of cancer patients will experience pain during their lifetime. While secondary to fatigue in prevalence, it is the most feared symptom."

• Start with acetaminophen, then NSAIDs, then opioids
• Opioids should always be used with constipation-preventing measures (laxatives)
• Steroids (e.g., dexamethasone) slightly improve pain compared to placebo in cancer patients and improve fatigue, nausea, and well-being

• Among the hardest to treat of all pains
• NSAIDs or neuropathic agents (gabapentin, pregabalin) combined with opioids are required
• Octreotide in combination with opioids reduces visceral hyperalgesia

• Multiple drug classes are useful; number needed to treat ranges from 3-7 for any class
• Drugs: gabapentin, pregabalin, duloxetine, nortriptyline, amitriptyline, carbamazepine, lamotrigine
• Randomized trials show opioids help neuropathic pain with as much benefit as gabapentin or nortriptyline; the combination is even more effective
• Pain relief occurs in 4-8 days if it will occur; trials do not need to exceed 2-3 weeks

3. Ascending and Descending Pathways of Pain

The Pain Sensory System

A. Peripheral Mechanisms - Primary Afferent Nociceptors

FIGURE 14-1 (Harrison's 22E): Components of a typical cutaneous nerve showing Aβ, Aδ, and C fiber primary afferents.

• Substance P: potent vasodilator; causes mast cell degranulation; chemoattractant for leukocytes; increases production and release of inflammatory mediators

B. Central Mechanisms and the Ascending Pathway

• Glutamate - rapidly excites second-order dorsal horn neurons
• Substance P and CGRP - produce a slower and longer-lasting excitation

"The spinothalamic pathway is crucial for pain sensation in humans. Interruption of this pathway produces permanent deficits in pain and temperature discrimination." - Harrison's 22E, Ch. 14

1. Somatosensory cortex - mediates the sensory discriminative aspects of pain: location, intensity, and quality
2. Anterior cingulate cortex - subserves the affective/unpleasant emotional dimension of pain; produces suffering and exerts potent control over behaviour
3. Insular cortex - linked to autonomic and emotional responses to pain

FIGURE 14-4 (Harrison's 22E): Pain-transmission and modulatory pathways. A: Ascending spinothalamic system. B: Descending pain modulation network.

C. Descending Pain Modulation

1. Hypothalamus and Frontal Cortex - inputs activate cells in the midbrain; psychological states (expectation, attention, suggestion) can powerfully modulate pain via this route
2. Periaqueductal Gray (PAG) - midbrain; the hub of the descending system; contains opioid receptors and is sensitive to direct application of opioid drugs; placebo analgesia activates the PAG (demonstrated by fMRI studies cited in Harrison's)
3. Rostral Ventral Medulla (RVM) - brainstem relay; receives input from PAG and sends inhibitory signals down to the dorsal horn
4. Spinal Dorsal Horn - final site of descending inhibition; descending fibres control pain-transmission neurons

"Each of the component structures of the pathway contains opioid receptors and is sensitive to the direct application of opioid drugs." - Harrison's 22E, Ch. 14

4. WHO Analgesic Ladder

                ┌───────────────────────────────────────┐
    STEP 3      │  STRONG OPIOIDS                        │
  Severe pain   │  Morphine, Oxycodone, Hydromorphone,  │
   (NRS 7-10)  │  Fentanyl, Methadone                  │
                │  ± Non-opioids ± Adjuvants             │
                └───────────────────────────────────────┘
                         ↑ Pain not controlled
                ┌───────────────────────────────────────┐
    STEP 2      │  WEAK OPIOIDS                          │
Moderate pain   │  Codeine, Tramadol                    │
   (NRS 4-6)   │  ± Non-opioids ± Adjuvants             │
                └───────────────────────────────────────┘
                         ↑ Pain not controlled
                ┌───────────────────────────────────────┐
    STEP 1      │  NON-OPIOIDS                           │
   Mild pain    │  Acetaminophen, NSAIDs                 │
   (NRS 1-3)   │  ± Adjuvants                           │
                └───────────────────────────────────────┘

Step 1 - Mild Pain: Non-Opioid Analgesics

• Acetaminophen (650 mg q4-6h) and/or NSAIDs (ibuprofen, naproxen)
• For cancer patients: steroids (dexamethasone) as adjuvants improve pain, fatigue, nausea, and well-being
• NSAIDs are particularly useful for bone metastases and inflammatory components
• Adjuvants: anticonvulsants or antidepressants if neuropathic component is present

Step 2 - Mild to Moderate Pain: Weak Opioids

• Codeine - combined with acetaminophen or NSAIDs
• Tramadol - weak μ-agonist with norepinephrine/serotonin reuptake inhibition
• Harrison's cautions: fixed-ratio opioid-acetaminophen combination analgesics carry the risk of hepatotoxicity from excessive acetaminophen as the dose is escalated; many practitioners now avoid these combinations

Step 3 - Moderate to Severe Pain: Strong Opioids

• Morphine - prototype; most rapid relief parenterally; use oral for chronic cancer pain
• Oxycodone - effective orally; controlled-release preparations available
• Hydromorphone - high-potency; useful when morphine side effects are limiting
• Fentanyl - transdermal patch for stable, chronic cancer pain; fast IV form for procedural pain
• Methadone - unique: also has NMDA-receptor antagonist properties, useful for neuropathic cancer pain

1. Start opioids; always co-prescribe laxatives (constipation is persistent and predictable)
2. Combine with gabapentin or pregabalin for the neuropathic component (perineural invasion is characteristic of pancreatic cancer)
3. Add octreotide if visceral hyperalgesia persists
4. Consider dexamethasone for periductal inflammation, nausea, and anorexia
5. Escalate opioid dose without hesitation - Harrison's states "the physician should not hesitate to use opioid analgesics" and addiction risk "remains small" in cancer patients

Key Prescribing Principles Across All Steps

• Constipation: methylnaltrexone (peripheral μ-antagonist) for opioid-induced constipation without reversing central analgesia
• Respiratory depression: naloxone must be readily available whenever high-dose opioids are used
• Synergistic respiratory depression: co-administration of benzodiazepines with opioids is "particularly likely to produce respiratory depression and should" be avoided or used with extreme caution

"Many patients, especially those with chronic pain, seek medical attention primarily because they are suffering and because only physicians can provide the medications required for pain relief. A primary responsibility of all physicians is to minimize the physical and emotional discomfort of their patients." - Harrison's 22E, Ch. 14