AS8.1-5 | Pain and Its Management — Graded Quiz

Phantom limb pain is a paradigm of central pain. After amputation, the somatosensory cortex undergoes reorganisation; the cortical representation of the missing limb is invaded by adjacent body parts but the original map persists in a distorted form. Central sensitisation in the spinal cord and thalamus sustains the pain experience without ongoing peripheral nociceptive input.

Phantom limb pain = central pain arising from cortical reorganisation and spinal/supraspinal sensitisation after deafferentation. It demonstrates that pain can be generated and maintained entirely centrally, without peripheral nociceptive drive. Implications: central-acting agents (gabapentinoids, ketamine) are preferred.

Stump neuromas can contribute to stump pain but not fully explain phantom limb pain, which persists after complete nerve division proximal to the neuroma. Central mechanisms — cortical remapping and spinal sensitisation — are the primary drivers of phantom pain.

Activating the PAG initiates descending inhibitory control via the rostral ventromedial medulla (RVM) to the dorsal horn. Descending noradrenergic (from locus coeruleus) and serotonergic (from raphe nuclei) fibres release NE and 5-HT, inhibiting dorsal horn nociceptive transmission. This is the neurobiological basis of stress-induced analgesia and antidepressant analgesia.

Descending inhibitory control: PAG → RVM → dorsal horn (noradrenaline from LC, serotonin from raphe). This underpins antidepressant analgesia (SNRIs block NE/5-HT reuptake, prolonging descending inhibition) and is impaired in chronic pain states.

The PAG is a key node in the descending INHIBITORY system. PAG stimulation was historically used in human pain treatment. Descending facilitation also exists (via RVM on-cells) but PAG activation net effect is inhibitory on nociception.

In non-communicative ICU patients, validated behavioural observation scales such as the CPOT (observes facial expression, body movements, muscle tension, ventilator compliance) or the Behavioural Pain Scale (BPS) are the standard. Family proxy reports on NRS are unreliable. Serum cortisol is not validated for pain quantification.

Pain assessment hierarchy: (1) self-report = gold standard; (2) behavioural observation scale when self-report impossible (CPOT in ICU; FLACC in children; PAINAD in advanced dementia). Never use proxy NRS as a substitute for a validated tool.

Self-report scales (NRS, VAS) require a communicative, cognitively intact patient. When self-report is impossible, validated observational tools like CPOT (ICU) or FLACC (paediatric) are used. Proxy NRS misses pain 50–70% of the time compared to the patient's own report.

COX-2 selective inhibitors suppress prostacyclin (PGI2 — vasodilatory, anti-aggregatory) without reducing thromboxane A2 (COX-1 mediated, pro-aggregatory), creating a pro-thrombotic imbalance. This explains the cardiovascular signal of COX-2 inhibitors. Low-dose aspirin provides partial but incomplete cardiovascular protection in this context; the combination is used with caution in high-CV-risk patients.

COX-2 selective inhibitors (celecoxib, etoricoxib): spare GI COX-1 (less GI bleeding) but remove prostacyclin protection → pro-thrombotic. Avoid in ischaemic heart disease or post-CABG. GI advantage is partly negated by concurrent aspirin (restores COX-1-dependent GI risk).

Celecoxib selectively inhibits COX-2. Platelet TXA2 production (pro-clotting) is COX-1 mediated and therefore NOT blocked by celecoxib. The net result is impaired prostacyclin (anti-clotting) with intact TXA2 = thrombotic shift. This is distinct from hepatotoxicity.

Oral morphine 60 mg twice daily = 120 mg/24h. Using the standard conversion (oral morphine 90 mg/24h ≈ 25 mcg/h fentanyl), 120 mg/24h ≈ 33–34 mcg/h. The nearest standard patch is 37.5 mcg/h (if available) or round to 50 mcg/h with careful monitoring — 50 mcg/h is equivalent to ~150–180 mg oral morphine/24h, so starting at 37.5 mcg/h is actually most precise; however, the most commonly available option requiring a slightly conservative rounding up from 33 to the next standard patch (25+12.5 or 50 mcg) is 50 mcg/h. In most palliative practice, 50 mcg/h patch is the appropriate prescription for 120 mg/24h oral morphine (recognising some conversion tables give 90 mg = 25 mcg, so 120 mg ≈ 33 mcg, patch = 37.5 or 50 mcg/h depending on availability).

Fentanyl patch conversion: oral morphine (mg/24h) ÷ 90 × 25 = fentanyl mcg/h. Round to nearest available strength. Patch reaches steady state in 12–24 h; provide oral/SC breakthrough for the first 12–24 h. Patch-to-patch changes: previous patch continues to deliver drug for hours — overlap carefully.

25 mcg/h equates to ~90 mg oral morphine/24h — insufficient for 120 mg/24h. Apply the ratio: oral morphine (mg/24h) ÷ 90 × 25 = fentanyl mcg/h. For 120 mg: 120 ÷ 90 × 25 = 33.3 mcg/h; round to nearest available patch (50 mcg/h).

Neuropathic cancer pain often responds poorly to opioid dose escalation alone. Adding a gabapentinoid (pregabalin 75 mg twice daily, titrated) addresses the α2δ calcium channel component of neuropathic pain. Dexamethasone reduces peri-neural oedema from tumour compression and is the corticosteroid of choice. This multimodal approach is WHO-recommended for mixed pain.

Mixed nociceptive-neuropathic cancer pain: opioid + gabapentinoid (pregabalin/gabapentin) + corticosteroid for nerve compression. Amitriptyline for neuropathic pain uses analgesic doses (10–75 mg nocte), not antidepressant doses (150 mg+). Methadone is an option for opioid-refractory neuropathic pain but requires specialist conversion.

Blindly escalating opioids for inadequately controlled pain with clear neuropathic features risks toxicity without proportionate benefit. Neuropathic pain requires targeted adjuvants. Methadone has NMDA antagonist activity and is useful but requires specialist expertise and prolonged conversion. Amitriptyline at 150 mg is the antidepressant dose — analgesic doses are 10–75 mg.

Morphine is metabolised in the liver to M6G (active analgesic, can cause sedation/respiratory depression) and M3G (neuroexcitatory, causes myoclonus, hyperalgesia, cognitive impairment). Both are renally excreted. In renal failure, M3G and M6G accumulate causing opioid neurotoxicity. Fentanyl and alfentanil are renally safe (inactive metabolites, not renally cleared) and should replace morphine in renal failure.

Opioid neurotoxicity in renal failure: morphine metabolites M3G (neuroexcitatory) and M6G (sedating) accumulate → myoclonus, hyperalgesia, confusion. Safe alternatives in renal failure: fentanyl (hepatic CYP3A4, inactive metabolites), alfentanil, buprenorphine (partial metabolism). Avoid morphine/oxycodone/hydromorphone in eGFR <30.

Myoclonus and cognitive impairment in a patient on morphine with declining renal function is a classic presentation of opioid neurotoxicity from M3G/M6G accumulation. Increasing morphine would worsen toxicity. Fentanyl and alfentanil are the correct alternatives in renal impairment.

Terminal secretions ('death rattle') are caused by pooling of saliva/secretions in the hypopharynx in a patient too weak to swallow or cough. Hyoscine hydrobromide (scopolamine) SC reduces secretion production via muscarinic (M3) receptor blockade — it is the drug of choice. IV furosemide is not appropriate in the dying phase. Suctioning distresses both patient and family without benefit.

Terminal secretions ('death rattle'): anticholinergic SC (hyoscine hydrobromide 400 mcg SC/4h or via syringe driver; glycopyrronium 200 mcg SC q4h if more sedation not wanted). Counsel family: the patient is not distressed by the sound. Repositioning (semi-prone/lateral) is also helpful.

Terminal secretions are not pulmonary oedema — furosemide is inappropriate and invasive. Suctioning cannot reach hypopharyngeal pooling and causes distress. The antimuscarinics (hyoscine hydrobromide, glycopyrronium) given SC are the standard pharmacological approach; positioning (lateral) is a non-pharmacological adjunct.

The doctrine of double effect holds that an action with a good primary intention (pain relief) that also has a foreseeable but unintended harmful secondary effect (potential acceleration of death) is ethically justified when: the primary action is good, the harm is not the means to the good, and the good outweighs the harm. This is the foundational ethical principle underpinning palliative opioid use. Note: evidence shows appropriately titrated opioids do NOT shorten life.

Doctrine of double effect: primary intent = analgesia (good) + foreseeable but unintended secondary effect = possible respiratory depression (harm) = ethically permissible when benefit outweighs risk. Evidence: appropriately titrated opioids do not shorten survival. Withholding analgesia for fear of hastening death is ethically wrong and clinically unfounded.

While patient autonomy supports the patient's wish for pain relief, the specific ethical principle justifying escalating opioid doses despite foreseeable risk is the doctrine of double effect. Non-maleficence actually SUPPORTS adequate analgesia — untreated pain is itself harm. Withholding effective analgesia is ethically indefensible in palliative care.

Tramadol is a Step 2 weak opioid with dual mechanism: it is a weak mu-opioid agonist plus inhibits serotonin and noradrenaline reuptake (SNRI effect), adding descending inhibitory modulation. It is appropriate for moderate pain not controlled by non-opioids before escalating to strong opioids. Morphine and fentanyl are Step 3 strong opioids.

WHO Step 2 agents: tramadol (dual mechanism — weak mu-agonist + SNRI), codeine (prodrug, requires CYP2D6 conversion to morphine, variable efficacy). Step 2 is appropriate for pain NRS 4–6 not controlled by Step 1. 'By the clock' = regular dosing, not as-needed, to maintain analgesic steady state.

The WHO ladder advocates stepwise escalation: Step 1 (non-opioids) → Step 2 (mild-moderate opioids: tramadol, codeine) → Step 3 (strong opioids: morphine, oxycodone, fentanyl). Skipping Step 2 directly to morphine is not wrong when pain is severe, but for moderate pain not controlled by Step 1, a Step 2 agent should be tried first.