Analgesics
Mechanism-based analgesia
- Analgesia is mechanism-based, not ladder-based - the drug follows the pain type
| Pain type | Mechanism | Responds to |
|---|---|---|
| Nociceptive | Tissue injury -> peripheral nociceptors | Paracetamol, NSAIDs, opioids |
| Inflammatory | Prostaglandin sensitisation | NSAIDs, corticosteroids |
| Neuropathic | Nerve injury, ectopic firing, central sensitisation | TCA, SNRI, gabapentinoid (opioid-poor response) |
| Nociplastic | Altered central processing (fibromyalgia, IBS) | Non-drug therapy, SNRI/TCA; opioids are harmful |
Classes
- Paracetamol - central COX/cannabinoid-related; mechanism still incompletely defined
- NSAIDs - COX-1/COX-2 inhibition -> dec prostaglandins
- Opioids - mu (and kappa, delta) agonism -> dec neurotransmitter release, hyperpolarisation
- Adjuvants - TCA, SNRI (duloxetine), gabapentinoids, ketamine, lidocaine, clonidine, capsaicin
- Interventional - regional block, epidural, radiofrequency, neuromodulation
Burden
- Analgesics are among the most commonly dispensed drug classes in Australia
- Paracetamol is the leading cause of acute liver failure; NSAIDs and opioids are leading causes of medication-related hospital admission
- ~150 opioid-related hospitalisations and ~3 opioid-related deaths per day in Australia
- Codeine rescheduled to prescription-only (S4) in February 2018; opioid pack-size and PBS restrictions from 2020
- Most opioid deaths involve pharmaceutical, not illicit, opioids, and most involve a co-ingested sedative (benzodiazepine, alcohol, gabapentinoid)
- NSAID-related GI bleeding and AKI concentrate in >65 yrs on an ACEi/ARB + diuretic ("triple whammy")
NSAIDs - toxicity follows the COX isoform
NSAIDs - the toxicity map follows the COX isoform
- COX-1 (constitutive): gastric mucosal PGE2, platelet TXA2, renal afferent arteriolar vasodilatation
- Inhibition -> peptic ulceration, bleeding, AKI
- COX-2 (inducible at inflammation; also constitutive in kidney and endothelium)
- Inhibition -> dec prostacyclin with unopposed platelet TXA2 -> prothrombotic -> MI, stroke
- All NSAIDs including COX-2 selective agents carry cardiovascular risk (naproxen lowest; diclofenac highest)
- "Triple whammy": NSAID + ACEi/ARB + diuretic -> loss of both afferent dilatation and efferent constriction -> AKI
Opioids
- Mu agonism at dorsal horn, periaqueductal grey, and brainstem respiratory centres -> dec CO2 responsiveness -> respiratory depression
- Tolerance develops to analgesia, euphoria and sedation, but NOT to constipation or miosis
- Opioid-induced hyperalgesia - paradoxical increased pain with escalating dose; the trap in chronic high-dose therapy
- Metabolism matters:
- Codeine and tramadol are prodrugs requiring CYP2D6 -> ultra-rapid metabolisers get toxicity, poor metabolisers get no analgesia; codeine contraindicated in children and breastfeeding
- Morphine -> morphine-6-glucuronide, renally cleared -> accumulates in CKD (use hydromorphone, fentanyl, buprenorphine or methadone)
- Pethidine -> norpethidine - neurotoxic, seizures; no place in modern practice
- Tramadol - also serotonergic and noradrenergic; serotonin toxicity and seizure risk
- Oxycodone, fentanyl, buprenorphine, methadone - CYP3A4 interactions
Paracetamol
- Hepatotoxicity via CYP2E1 -> NAPQI -> glutathione depletion
Assessing pain and choosing an agent
"Diagnosis" here = assessing pain and selecting the agent.
Characterise the pain
- Site, severity (0-10 or functional), temporal pattern, provoking/relieving
- Neuropathic screen: burning, shooting, electric, allodynia, numbness (painDETECT, DN4)
- Function and goals, not just a score - "what can you not do?" is the useful question in chronic pain
- Psychosocial: mood, sleep, catastrophising, work, litigation, substance use
Before prescribing an opioid
- Assess risk of harm: prior substance use, mental illness, young age, high-dose requirement
- Check real-time prescription monitoring (SafeScript VIC, QScript QLD, ScriptCheckSA, DORA ACT/TAS/NT/WA, NSW SafeScript)
- Document an indication, a review date and an exit plan before the first script
Before prescribing an NSAID - check
- eGFR, blood pressure, heart failure, IHD, prior ulcer or GI bleed, anticoagulant/antiplatelet, ACEi/ARB + diuretic, asthma (NSAID-exacerbated respiratory disease), age >65, pregnancy >20 weeks
Monitoring
- Opioids: oral morphine equivalent daily dose (oMEDD), function, adverse effects, constipation, aberrant behaviours
- NSAIDs: UEC and BP at 1-2 weeks after starting in at-risk patients, then periodically
- Paracetamol: cumulative daily dose, weight, liver disease
Management by pain phase
Organised by pain phase - acute, chronic non-cancer, cancer/palliative - because the goals differ entirely.
A. Acute pain
- Multimodal, opioid-sparing, time-limited
- Paracetamol 1 g qid (max 4 g/day; 3 g/day if <50 kg, frail, malnourished or liver disease) - the backbone
- NSAID where no contraindication - short course, lowest effective dose (ibuprofen 400 mg tds; naproxen if CV risk)
- Opioid only if severe and only as an adjunct
- Immediate-release only; smallest pack; explicit stop date
- *Do not start modified-release opioids for acute pain* - a standing recommendation of the Australian Opioid Analgesic Stewardship in Acute Pain Clinical Care Standard
- Prescribe an aperient with every opioid
- Discharge with a plan to cease, and communicate it to the GP - most persistent opioid use begins with a surgical or ED script
- Regional anaesthesia, ice, splinting, early mobilisation
B. Chronic non-cancer pain
- *Opioids have little evidence of benefit beyond 12 weeks and substantial evidence of harm* - this is the examinable position
- Non-drug therapy is first-line and is the treatment with the best evidence
- Exercise/graded activity, pain education, CBT/ACT, sleep, weight, return-to-work
- Neuropathic pain: amitriptyline (start 10 mg nocte), duloxetine 30-60 mg, pregabalin/gabapentin
- Only ~1 in 3 achieves 50% pain reduction - NNT 4-8; set expectations
- Pregabalin is misused and diverted; it potentiates opioid respiratory depression - PBS-restricted to neuropathic pain
- Topical: capsaicin, lidocaine 5% patch (post-herpetic neuralgia), topical NSAID for localised OA
- If an opioid is used: lowest dose, single prescriber, single pharmacy, a written agreement, and regular review
- Risk rises steeply above 50 mg oMEDD; >100 mg oMEDD warrants pain specialist review
- Deprescribe slowly (~10% of the dose every 2-4 weeks), faster if harm; treat withdrawal; abrupt cessation causes harm and drives illicit use
C. Cancer and palliative pain
- Regular baseline + PRN breakthrough (~1/6 of the 24 h dose)
- Titrate without a ceiling where the indication is clear; modified-release once stable
- Adjuvants by mechanism: corticosteroid (nerve compression, bone), bisphosphonate/denosumab and radiotherapy (bone metastases), duloxetine/gabapentinoid (neuropathic), ketamine, methadone
- Renal impairment -> hydromorphone, fentanyl or buprenorphine, not morphine
- Anticipate and prescribe for: constipation (always), nausea, sedation, delirium
Universal safety measures
D. Universal safety measures
- Naloxone take-home for anyone on high-dose opioids, opioid + benzodiazepine, or with prior overdose - available without prescription in Australia
- Avoid opioid + benzodiazepine + gabapentinoid combinations
- Check real-time prescription monitoring at every new script
- Never co-prescribe two regular opioids
- Review the whole analgesic list at every admission and discharge
Harms by class
- NSAIDs - peptic ulcer and upper GI bleeding, AKI, hypertension, heart failure decompensation, MI/stroke, NSAID-exacerbated respiratory disease, hyperkalaemia, interstitial nephritis, papillary necrosis (analgesic nephropathy)
- Opioids - respiratory depression, sedation, delirium, constipation, nausea, pruritus, urinary retention, hypogonadism and osteoporosis, immunosuppression, opioid-induced hyperalgesia, dependence, overdose death
- Paracetamol - hepatotoxicity in overdose; safe at therapeutic dose
- Gabapentinoids - sedation, oedema, weight gain, misuse and diversion, respiratory depression with opioids, withdrawal syndrome
- Tramadol - serotonin toxicity, seizures, hyponatraemia
- Drug interactions: CYP2D6 (codeine, tramadol, oxycodone), CYP3A4 (fentanyl, methadone, oxycodone), warfarin + NSAID, lithium + NSAID, methotrexate + NSAID
- Substance use disorder, mental illness, socioeconomic disadvantage, chronic pain-related disability
Natural history of pain
- Acute pain resolves with the injury - persistence beyond expected healing signals a change in mechanism, not a need for more opioid
- Persistent post-surgical pain in 10-50% depending on procedure (thoracotomy, mastectomy, amputation highest)
- Chronic opioid use most often starts with a short-course acute prescription - the strongest predictor of long-term use is the duration of the first script
- Tolerance and opioid-induced hyperalgesia -> escalating dose, falling function
- Long-term outcomes of opioids in chronic non-cancer pain: no better pain or function than non-opioid therapy, with more harm
- Deprescribing: most patients report unchanged or improved pain and better function after a supported taper
- Complications: overdose death (peaks after dose escalation, after a period of abstinence, and with sedative co-prescription), falls and fracture, hypogonadism, immunosuppression, driving impairment
- Monitor: function and goals, oMEDD, real-time prescription monitoring, renal function and BP for NSAIDs, cumulative paracetamol dose
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