Analgesia

 

• The pain ladder

  Overview

  • Originally developed by WHO for bone metastases, but now universally used as a pathway of stepwise pain management.
  • Basic process: regular NSAID + paracetamol → add PRN weak opioid → add regular weak opioid and consider PRN strong opioid instead of weak → replace regular + PRN weak opioids with regular + PRN strong opioids → refer to pain service.
  • Check response at each medication/dose change after 24-48 hrs.
  • Generally don't switch within steps, except if there are side effects. Usually just go up to next step if pain not controlled.
  • All opioids have different potencies and hence equivalents e.g. morphine is x10 codeine.

  Step 1: simple analgesia

  Drugs:

  • NSAIDs
  • Paracetamol
  • Nefopam

  Subsequently continued at all steps as it reduces opiate requirements (and NSAIDs may enhance their effects).

  Step 2: weak opioids

  Drugs:

  • Codeine: 1st-line.
  • Dihydrocodeine
  • Tramadol

  Can be given in combination medications with simple analgesia e.g. co-codamol (codeine + paracetamol).

  Step 3: strong opioids

  • Morphine: 1st line strong opioid in general pain management, available as tablet or liquid, as well as IV.
  • Oxycodone: 2nd-line. Available in same formulations as morphine, and safer in kidney impairment.
  • Buprenorphine: partial agonist used as an alternative to morphine for patients with kidney impairment, or as heroin replacement. Formulations include transdermal and sub-lingual.
  • Hydromorphone: used instead of morphine in kidney impairment, and also available in the same formulations.
  • Fentanyl: available IV, transmucosal (lozenge, sub-lingual), or transdermal. The latter take up to 24 hours to take effect, so take something else in meantime. Also safe in kidney impairment.
  • Pethidine: obstetric.
  • Methadone: used for heroin replacement, not analgesia. Very slow release, with no peaks and troughs.

• NSAIDs

  Mechanism

  • Inhibition of cyclooxygenase (COX), reducing formation of prostanoids (prostaglandins and thromboxanes) from arachidonic acid, which are key inflammatory mediators.
  • Most are mixed COX1 + 2 inhibitors: ibuprofen, diclofenac, naproxen.
  • Aspirin (ASA) is a COX1 inhibitor, often considered separately from NSAIDs.
  • Celecoxib and parecoxib are COX2 inhibitors.

  Management

  • All are equally strong, but ibuprofen is safest so is 1st line.
  • Switch if necessary, only using one at a time and at the lowest dose possible.
  • Give a PPI for ulcer protection if using long term.
  • Ibuprofen dose 400 mg TDS or QDS, max 2.4 g daily.

  Side effects

  • Peptic ulcer disease (PUD) and GI bleeding. More likely with long-term NSAIDs, past history of PUD, old, or on steroids. Due to reduction in prostaglandins, a protective factor in the GI mucosa.
  • GI: abdo pain, diarrhoea, vomiting, flatulence.
  • Haematological: platelet dysfunction (which may lead to intracranial haemorrhage), neutropenia.
  • Renal: AKI (prerenal, or interstitial nephritis), ↓Na+. More likely if combined with a diuretic or ACEi.
  • Small increased risk of cardiovascular events.
  • Others: headache, bronchospasm (wheeze), rash.

  Contraindications

  • PUD or coagulopathy.
  • NSAID or aspirin allergy, including if asthma trigger (~10% of asthma patients).
  • Kidney, liver, or heart failure. Contraindicated in HF due to risk of renal impairment triggering decompensation.
  • Cautions: mild HF, history of MI, elderly, dehydrated.
  • Few contraindications are absolute and a trial is often OK.

  Drug interactions

  The following increase NSAID GI toxicity:

  • Aspirin
  • Warfarin
  • SSRIs and venlafaxine.
  • Steroids

  Other interactions:

  • Lithium
  • Methotrexate: leads to marrow toxicity.
  • ACEi: renal impairment.

  Ibuprofen vs. paracetamol

  • For acute pain, ibuprofen is slightly more effective than paracetamol in both kids and adults.
  • For fever, ibuprofen is slightly more effective than paracetamol in kids, and probably in adults too.
  • For both acute pain and fever, combining ibuprofen and paracetamol is slightly more effective than using either drug alone.

• Paracetamol

  • Mechanism unclear, but may include central effects and peripheral COX3 inhibition.
  • Dose: 1 g QDS PO/PR/IV/NG, max 4 g daily, or 500 mg QDS if <50 kg.
  • Effective level reached after 4 doses.
  • 10 g is enough to cause liver failure.
  • See also paracetamol overdose.

• Nefopam

  • Mechanism unclear.
  • Use if there is an NSAID contraindication.
  • Dose: 30-90 mg TDS.
  • Caution in kidney or liver failure.

• Weak opioids

  Drugs

  Codeine phosphate

  • Metabolised to morphine by CYP2D6. 10% of white people are deficient, so experience a reduced effect. Suspect this if codeine ineffective but PRN strong opioid effective.
  • Dose: 30-60 mg QDS PO/PR/IV, max 240 mg daily.
  • Can also be used as an anti-tussive.

  Dihydrocodeine

  Dose as for codeine.

  Tramadol

  • Often used post bowel surgery as it causes less constipation and respiratory depression.
  • However, causes more nausea and vomiting.
  • Dose: 50-100 mg QDS PO/IV, max 400 mg daily.
  • Has 5-HT receptor effects too, so risk of serotonin syndrome if on SSRI too.

  Contraindications

  • Severe kidney or liver failure.
  • ↑ICP
  • Severe respiratory depression.

  Side effects

  • Nausea and vomiting.
  • Respiratory depression.
  • Drowsiness
  • Constipation: prescribe laxative if it occurs.
  • Pruritus
  • Hallucinations
  • Urine retention
  • Miosis

• Morphine

  Pharmacology

  • Mainly acts on μ-opioid receptors in CNS.
  • Pharmacokinetics: half-life is 3 hours. Well absorbed orally but slow to cross blood-brain barrier.
  • Like any drug that stimulates opioid receptors, morphine is an opioid. It is also, along with codeine, an opiate, a natural product of the opium poppy plant. Diamorphine is a semi-synthetic opioid, produced form acetylation of morphine.
  • Often prepared as morphine sulfate, increasing water solubility.

  Indications

  • Can be used for almost any pain, including neuropathic pain alongside the specific treatments.
  • Substance abuse is not a contraindication, especially in an acute situation. If patient is on methadone, continue it as usual and give any required short-term opioids on top.

  Formulations

  • Modified-release (MR) PO tablet, released over 12 or 24 hours. Brands include MST Continus and Zomorph.
  • Instant-release (IR) PO liquid: Oramorph, used PRN.
  • Injectable
  • Diamorphine (aka heroin) is a morphine prodrug, which is more soluble and comes in a powder form. It is more lipophilic, crossing the blood brain barrier quickly and giving an instant high.

  Side effects

  • GI and GU: constipation (75%), nausea (33%), vomiting, urinary retention, biliary spasm.
  • Respiratory: respiratory depression, bronchospasm.
  • CV: ↓HR, ↓BP.
  • Mental state: sedation (usually transient), dependence, dysphoria.
  • Pain: itch, urticaria, hyperalgesia after long-term use.
  • ↑Risk of these effects after local anaesthetic.

  Management

  • Check kidney function first: contraindicated if eGFR <30, and consider alternatives such as oxycodone, buprenorphine, or hydromorphone.
  • Co-prescribe simulant laxative – e.g. senna 1-2 tablets at night – and anti-emetic – e.g. metoclopramide 10 mg PRN to counter ↓GI motility. Haloperidol (0.5 mg) may be useful for initial toxic effects on chemoreceptor trigger zone.
  • In those starting regular oral doses (e.g. palliative), nausea is often transient and antiemetics should only be prescribed regularly if persistent.
  • If side effects severe, rotate opiates (with oxycodone as 2nd line), use low dose, and add alternative such as ketamine or lidocaine patch to aid dose reduction. Oxycodone has 1.5-2.0x potency, but always convert conservatively: halve dose when switching from morphine, but increase x1.5 if going back to morphine.
  • No driving until on stable dose for 2 weeks, due to drowsiness.
  • As a controlled drug, give pharmacist clear instructions using words and figures for numbers i.e. "Please give 60 (sixty) x 10 milligram tablets of morphine". Use indelible ink and no sticky labels. BNF does not recommend using brand names for modified-release opioids, though this is sometimes done.

  Dose

  Regular:

  • When moving from weak to strong opioids, start just above the equivalent of the weak opioid (1/10th of the dose) plus any PRN strong opioid taken.
  • Commonest regimen is 12-hourly modified release BD.
  • Detailed dose conversions in the BNF.
  • Typically works out around 20-30 mg per day BD, or 15 mg BD if opioid-naive.

  PRN:

  • Give PRN instant release at 1/10th to 1/6th of daily regular dose, up to a daily maximum of the regular dose i.e. 4 hourly if 1/6th.
  • Typical PRN dose is initially 5-10 mg IR solution. 5 mg is also reasonable as PRN in patients on regular weak opioids.
  • Up to 2 hourly may be more appropriate given half life of instant relief opioids, but will reach daily maximum sooner; however, this would be a trigger for changing the dose.

  Adjusting dose:

  • Can titrate up every 24 hours by totalling regular + PRN, and giving as regular.
  • Avoid increasing dose >50% routinely, though clinical judgement can override this.
  • If regular dose ineffective but there is no PRN use, just increase regular dose 30-50%.
  • Reconsider after 3 days of continued titrating up, though there is no maximum dose.
  • Wean off gradually, especially if long-term user, due to risk of withdrawal symptoms.
  • Beware slower elimination in patients with kidney or liver failure.

  Switching to subcutaneous:

  • Halve the regular dose, halve the PRN dose, and halve the PRN interval (e.g. 2 hours to 1 hour).

• Opioid overdose

  Signs and symptoms

  • ↓RR
  • ↓Level of consciousness.
  • Myoclonic jerks in mild overdose.
  • Pupillary constriction (miosis).
  • Hallucinations
  • Rhabdomyolysis
  • Pulmonary oedema.
  • ↓BP, ↑HR.

  Investigations

  • Urine drug screen.
  • ABG: mixed acidosis.
  • Other bloods: FBC, U+E, CK.
  • ECG: may show myocardial ischaemia.
  • Naloxone trial may aid diagnosis if unclear.
  • CXR if you suspect pulmonary oedema.

  Management

  • ABC, which may include giving 100% O2 or ventilation, and IV fluids (but beware pulmonary oedema).
  • Naloxone IV – an opioid receptor antagonist – if RR ≤8 or ↓GCS. Repeat as required or use continuous infusion. Infusions are especially useful for long-acting opioids like methadone.
  • Naloxone can cause sudden withdrawal symptoms: severe pain, palpitations, diarrhoea, nausea, yawning, irritable/angry, fever, tremor, cramps. To minimize these, titrate up gradually to the minimum effective dose, increasing the RR but not waking suddenly.
  • Naloxone half life is around 1 hour, which is less than many opioids, so check for re-sedation after this time and consider further doses.
  • Consider concurrent paracetamol overdose if taken in combination medication such as co-codamol.

• Neuropathic pain management

  Overview

  • 1st line: gabapentin, pregabalin, amitriptyline, duloxetine.
  • Consider tramadol only if 1st line agents ineffective.
  • Lidocaine patches can be used and help reduce opioid requirements.
  • Topical capsaicin can be used for localised neuropathic pain.

  Antidepressants

  • Amitriptyline (TCA) is most effective.
  • Venlafaxine (SNRI) or SSRIs can be used but are less effective. Duloxetine (SNRI), however, is recommended in diabetic neuropathic pain.
  • Mechanism: alter activity at synapse.
  • Use: dose is much lower than for depression. Needs gradual withdrawal.
  • Pros and cons: cheap, but 3 weeks until onset.

  Anticonvulsants

  • Gabapentin or pregabalin. Both are expensive, but 1st-line in acute neuropathic pain. Pregabalin has the quicker onset.
  • Carbamazepine is used for trigeminal neuralgia.
  • Mechanism: stabilise excitable cell membranes.
  • Use: must be continued for at least 3 months. Metabolised quickly so start low and titrate up if side effects, and titrate down at the end.
  • Complications: most patients develop tolerance.

• Gabapentin

  Mechanism

  • Modulates Ca2+ channels.

  Dose

  • Titrate up over 7 days to full effect.
  • 300 mg OD then BD then TDS, then increase dose every 2 days if needed, up to a maximum of 3.6g daily.
  • Reduce dose in kidney failure.

  Problems

  • Quick tolerance.
  • Antacids reduce absorption, leading to reduced effect, so avoid for 2 hours after taking gabapentin.