Pharmacology — Analgesia and Pain, NMC MBBS licence examination syllabus (Nepal Medical Council).
Analgesics: the drugs you will prescribe most, and misprescribe most
Almost every harm in this chapter is the drug working exactly as designed.
Analgesics look like the safe end of the formulary. They are available without prescription, given for trivial complaints, and taken by nearly everyone. They are also responsible for a remarkable share of the drug-induced harm in any hospital — gastrointestinal bleeding, acute kidney injury, respiratory depression, and a proportion of the acute-on-chronic disasters described elsewhere in this stream.
The unifying idea is that these harms are not side effects in the usual sense. NSAIDs damage the stomach and the kidney by exactly the mechanism that relieves pain. Opioids depress respiration through the same receptor that provides analgesia. There is no version of these drugs without the risk — only a decision about whether this patient can afford it.
🩺 Where this lives: The NSAID appears as the precipitating cause in three separate chapters of this stream. It disables afferent arteriolar dilatation and precipitates acute kidney injury; it removes the prostaglandin-dependent renal perfusion a cirrhotic patient relies on; it triggers bronchospasm in aspirin-sensitive asthma. In each case a doctor gave a common drug for a minor complaint to a patient who could not tolerate it. That pattern — routine drug, vulnerable patient — is worth more attention than any individual pharmacological fact here.
💡 A note on doses. This chapter gives none. Opioid dosing is weight-, age- and renal-function dependent, conversion between opioids and routes is a recognised source of fatal error, and formulary preferences differ. Learn the principles here; take every number from your local formulary or specialist advice.
The ladder, and its limits
Two things about the ladder are routinely missed. First, step 1 continues at every step above — paracetamol is not replaced by morphine, it runs alongside it, and stopping it means the opioid works harder than it needs to. Second, the ladder was designed for cancer pain, where escalation follows disease progression. Applying it mechanically to chronic non-cancer pain leads to steadily increasing opioid doses with steadily decreasing benefit.
Paracetamol
THE MOST USED, LEAST UNDERSTOOD ANALGESIC
Effective, cheap, and at correct doses remarkably safe —
it lacks the gastric, renal and respiratory hazards of
the other two classes.
MECHANISM is incompletely understood; largely central,
with weak peripheral anti-inflammatory activity. It is
NOT an effective anti-inflammatory drug.
THE MARGIN IS NARROWER THAN PEOPLE THINK
Hepatotoxicity in overdose is covered in the poisoning
chapter. Two practical points belong here:
REDUCE the dose in low body weight, and consider it in
chronic alcohol use, malnutrition and significant
liver disease — glutathione reserves are lower.
WATCH FOR DUPLICATION. Paracetamol is hidden inside
combination products — co-codamol, cold and flu
preparations. Patients take "paracetamol and a cold
remedy" and unknowingly double the dose. Check the
whole medication list, including what was bought
rather than prescribed.
NSAIDs
HOW THEY WORK, AND WHY THAT EXPLAINS THE HARM
Inhibit CYCLO-OXYGENASE → less prostaglandin synthesis.
Prostaglandins mediate pain and inflammation — hence the
analgesia. They also:
protect the GASTRIC mucosa
maintain renal AFFERENT arteriolar dilatation
influence platelet function and vascular tone
So one action produces both the benefit and the harm.
ASPIRIN is the exception in one respect: it inhibits
platelet COX IRREVERSIBLY, which is why a single low
dose has an antiplatelet effect lasting the life of the
platelet — the basis of its cardiovascular use.
COX-2 SELECTIVE agents were designed to spare the
stomach, and do so to a degree, but they carry
cardiovascular concerns of their own. They are not a
free pass.
GASTROPROTECTION with a proton pump inhibitor is
standard in patients at higher gastrointestinal risk —
the elderly, those on anticoagulants, corticosteroids
or antiplatelets, and anyone with previous ulceration.
💡 Exam angle: NSAIDs plus an ACE inhibitor plus a diuretic in a dehydrated patient — the "triple whammy" — appears in the kidney chapter and recurs here because it is one of the commonest avoidable causes of acute kidney injury. None of the three drugs is wrong alone. The combination during volume depletion removes every mechanism the glomerulus uses to defend filtration.
Opioids
PRINCIPLES THAT MATTER MORE THAN THE LIST
NO CEILING to analgesia in strong opioids — dose is
limited by side effects, not by a maximum. This is why
they work in severe pain and why they are dangerous.
CODEINE IS A PRODRUG
Converted to morphine by CYP2D6. Genetic variation
means some people are POOR metabolisers (little
analgesia) and others ULTRA-RAPID metabolisers
(unexpectedly high morphine levels, with a risk of
toxicity — including in breastfed infants).
This is why codeine is avoided in children and used
cautiously in breastfeeding.
TRAMADOL is not a simple weak opioid
It also inhibits serotonin and noradrenaline reuptake,
so it lowers the seizure threshold and can contribute
to SEROTONIN SYNDROME with other serotonergic drugs.
RENAL IMPAIRMENT
Morphine metabolites accumulate — prolonged sedation,
confusion, myoclonus. Reduce dose or choose another
agent.
DEPENDENCE, TOLERANCE AND ADDICTION are three different
things, and conflating them causes both under-treatment
of pain and unsafe long-term prescribing.
ALWAYS CO-PRESCRIBE A LAXATIVE. Constipation does not
tolerate, and it is the commonest reason patients stop
taking an opioid that is working.
The most useful bedside rule in opioid safety: sedation precedes respiratory depression. A patient who is difficult to rouse is the warning sign, and it appears before the respiratory rate falls. Monitoring rousability is more sensitive than counting breaths — which is why nursing observation charts ask about it.
Neuropathic pain
💡 Exam angle: neuropathic pain responds poorly to opioids, and this is a favourite question construction — a patient with burning, shooting pain and allodynia whose analgesia keeps being escalated without benefit. The answer is a change of drug class, not a higher dose. Gabapentinoids, tricyclics and duloxetine are the mainstays, chosen by comorbidity: a tricyclic that also helps sleep in one patient may be exactly wrong in an elderly patient at risk of falls and confusion.
Prescribing decisions
🔍 Who should not get which drug
Avoid NSAIDs inRenal impairment · cirrhosis with ascites · heart failure · peptic ulcer disease or GI bleeding · aspirin-sensitive asthma · anticoagulated patients · the frail elderly. That list covers a large proportion of hospital inpatients.
Caution with opioids inRenal impairment · the elderly · respiratory disease including COPD and obstructive sleep apnoea · concurrent sedatives, especially benzodiazepines · previous or current substance use disorder.
ParacetamolThe safest starting point in most patients. Dose reduction in low body weight and significant liver disease; check for hidden duplication in combination products.
In pregnancyParacetamol is generally the analgesic of choice. NSAIDs are avoided particularly in the third trimester — premature closure of the ductus arteriosus and effects on labour. Opioids near delivery risk neonatal respiratory depression.
Review, alwaysAn analgesic prescription started for an acute problem should have a stop or review date. Chronic opioid use frequently begins as an unreviewed acute prescription.
Clinical reasoning: four presentations
🔍 Case 1 — the routine prescription
PresentationA 79-year-old on ramipril and furosemide, admitted with a chest infection, complains of back ache. The house officer prescribes regular ibuprofen. Two days later creatinine has doubled.
Key clueThree drugs and an acute illness.
ReasoningThe NSAID blocks prostaglandin-mediated afferent dilatation; the ACE inhibitor blocks angiotensin-mediated efferent constriction; the diuretic and the illness deplete volume. Every renal defence is disabled at once.
AnswerStop the NSAID, hold the ACE inhibitor and diuretic, rehydrate. Use paracetamol, with a weak opioid if needed. The NSAID was never the right drug in this patient.
🔍 Case 2 — the escalating dose
PresentationA 58-year-old with diabetes has burning, shooting pain in both feet, worse at night, with pain on light touch from the bedsheet. Codeine has been increased twice with no benefit; she is now constipated and drowsy.
Key cluesBurning and shooting quality, nocturnal, allodynia — neuropathic pain, here from diabetic neuropathy.
ReasoningNeuropathic pain responds poorly to opioids. Escalating the dose delivers side effects without analgesia.
AnswerChange class rather than increase dose — a gabapentinoid, tricyclic or duloxetine, chosen by comorbidity. Reduce the opioid, treat the constipation, and optimise glycaemic control.
🔍 Case 3 — the hidden paracetamol
PresentationA patient takes regular co-codamol prescribed for back pain, and has also been buying an over-the-counter cold remedy and paracetamol for headaches. She presents unwell with abnormal liver enzymes.
Key clueThree products, one shared ingredient.
ReasoningCo-codamol contains paracetamol, as do most cold remedies. A patient taking all three can substantially exceed the maximum daily dose without ever knowingly taking "too much paracetamol" — a staggered supratherapeutic ingestion rather than an overdose.
AnswerTake a full medication history including purchased products, assess for hepatotoxicity and manage per the poisoning chapter and local protocol. Then rationalise the prescriptions and counsel her about combination products.
🔍 Case 4 — the drowsy patient
PresentationA post-operative patient with renal impairment is on regular morphine. On the ward round he is rousable only with firm stimulation. Respiratory rate is 12 — recorded as normal.
TrapA normal respiratory rate reading as safety.
ReasoningSedation precedes respiratory depression, so increasing drowsiness is the earlier and more sensitive sign. Renal impairment causes accumulation of active morphine metabolites, making this predictable rather than idiosyncratic.
AnswerWithhold further opioid, monitor closely, and consider naloxone if respiratory depression develops — remembering from the poisoning chapter that it is shorter-acting than morphine. Then reduce the dose or switch agent for the renal impairment.
Commonly confused
Confusion
The distinction
Why it matters
Side effect vs same mechanism
NSAID harms come from the analgesic mechanism itself
There is no safe version — only a safe patient.
Nociceptive vs neuropathic pain
Burning, shooting, allodynia suggest neuropathic
Opioids work poorly; the drug class must change.
Escalating dose vs changing class
Failure to respond may mean the wrong class
Escalation delivers harm without benefit.
Respiratory rate vs sedation
Sedation comes first and is more sensitive
A normal rate in a drowsy patient is not reassurance.
Tolerance to constipation
It does not develop
A laxative is co-prescribed from the start.
Codeine vs morphine
Codeine is a prodrug needing CYP2D6
Explains both non-response and unexpected toxicity.
Paracetamol alone vs in combination
Combination products hide it
Patients exceed the maximum without realising.
Rapid revision
MUST-KNOW FACTS
1. Step 1 of the ladder continues at every step above it.
2. The ladder was designed for CANCER pain.
3. Paracetamol: safest starting point; NOT an effective anti-inflammatory.
4. Reduce paracetamol in low body weight and significant liver disease.
5. Check for hidden paracetamol in combination and purchased products.
6. NSAIDs inhibit COX → less prostaglandin → analgesia AND harm.
7. Prostaglandins protect gastric mucosa and dilate the renal afferent arteriole.
8. NSAID harms: GI ulceration, AKI, fluid retention, cardiovascular risk,
bronchospasm in aspirin-sensitive asthma.
9. Avoid NSAIDs in renal impairment, cirrhosis, heart failure and ulcer disease.
10. NSAID + ACE inhibitor + diuretic in dehydration = classic AKI.
11. Aspirin inhibits platelet COX IRREVERSIBLY — hence its antiplatelet use.
12. COX-2 selective agents spare the stomach but carry cardiovascular concerns.
13. Gastroprotection for higher-risk patients on NSAIDs.
14. Strong opioids have NO analgesic ceiling — side effects limit the dose.
15. Tolerance develops to nausea, drowsiness and respiratory depression.
16. Tolerance does NOT develop to CONSTIPATION or miosis.
17. Always co-prescribe a laxative with an opioid.
18. SEDATION PRECEDES respiratory depression — monitor rousability.
19. Codeine is a prodrug requiring CYP2D6; metaboliser status varies widely.
20. Codeine is avoided in children and used cautiously in breastfeeding.
21. Tramadol lowers the seizure threshold and risks serotonin syndrome.
22. Morphine metabolites accumulate in renal impairment.
23. Neuropathic pain responds POORLY to opioids.
24. Neuropathic pain: gabapentinoids, tricyclics, duloxetine.
25. Allodynia and a burning quality point to neuropathic pain.
26. Pregnancy: paracetamol preferred; avoid NSAIDs especially in the third
trimester.
27. Every analgesic prescription needs a review or stop date.
💡 Exam angle: the reliable threads are (a) NSAID harms following from the analgesic mechanism, (b) the triple whammy causing AKI, (c) neuropathic pain needing a different class rather than a higher dose, (d) sedation preceding respiratory depression, and (e) hidden paracetamol in combination products. This chapter deliberately connects to kidney, liver, respiratory and poisoning — analgesics are where a great deal of iatrogenic harm in this stream originates.
Syllabus points
The analgesic ladder and what it was designed for
Paracetamol and hidden duplication
NSAIDs: one mechanism, four organs at risk
Aspirin and irreversible platelet inhibition
Who must not receive an NSAID
Opioids: no ceiling, and what that means
Tolerance, and the constipation exception
Sedation as the early warning of respiratory depression
Codeine as a prodrug, and tramadol's extra actions
Opioids in renal impairment
Neuropathic pain and the adjuvants
Prescribing decisions, pregnancy and review dates
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