Previous changes

March 2025 — minor update.  Information about high anion gap metabolic acidosis (HAGMA) with concurrent flucloxacillin and paracetamol use has been added in line with the manufacturer's recommendations.

November 2021 — minor update. Clarified the basis for recommending paracetamol dose reduction in people with risk factors for hepatotoxicity and paracetamol overdose, including those who weigh less than 50 kg.

August 2020 — reviewed. A literature search was conducted in July 2020 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last version of this topic. There have been no major changes to the recommendations. 

July to September 2015 — reviewed. A literature search was conducted in July 2015 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last version of this topic. There have been no major changes to the recommendations. Prescribing information on nonsteroidal anti-inflammatory drugs (NSAIDs) has been removed as there is a separate CKS topic on NSAIDs - prescribing issues.

April 2015 — minor update. Update to the text to reflect a new law on drugs and impaired driving.

June 2014 — minor update. Update to the text to reflect the fact that tramadol has been reclassified to a schedule 3 controlled drug.

March 2014 — minor update. Update to the text to remove diclofenac as a drug option. Naproxen and ibuprofen are associated with a lower risk of gastrointestinal and cardiovascular adverse effects.

February 2014 — minor update. Update to the text of adverse effects of weak opioids. Tramadol is now known to cause hypoglycaemia (frequency unknown).

January 2014 — minor update. The text regarding the use of codeine during breastfeeding has been updated to reflect new guidance from the Medicines and Healthcare products Regulatory Agency (MHRA). Codeine is no longer recommended for breastfeeding mothers, and tramadol and dihydrocodeine are preferred alternatives.

December 2013 — minor update. The link to the UK Medicines Information (UKMi) drugs in lactation website has been removed as this no longer exists.

July 2013 — minor update. Update to the text to reflect the European Medicines Agency (EMA) warning, which now restricts the use of codeine in children and adolescents. Update to the text to reflect recent advice from the MHRA regarding diclofenac. Update to the text to reflect new guidance issued by the National Institute for Health and Care Excellence (NICE) for feverish illness in children.

February 2013 — minor update. The 2013 QIPP options for local implementation have been added to this topic.

October 2012 — minor update. The 2012 QIPP options for local implementation have been added to this topic.

July 2011 — minor update. More exact paracetamol dosing for children has been introduced by the MHRA. Text and prescriptions have been updated to reflect the revised dosing. 

June 2011 — minor update. Text updated to include more detailed advice on the use of paracetamol in pregnancy. The 2010/2011 QIPP options for local implementation have been added to this topic. 

February 2011 — minor update. Prescriptions for analgesics added. 

April to August 2010 — this is a new CKS topic. The evidence base has been reviewed in detail, and recommendations are clearly justified.

New evidence

Evidence-based guidelines

No new evidence-based guidelines since 1 August 2025.

HTAs (Health Technology Assessments)

No new HTAs since 1 August 2025.

Economic Appraisals

No new economic appraisals relevant to England since 1 August 2025.

Systematic reviews and meta-analyses

No new systematic reviews or meta-analysis which reach the CKS threshold for inclusion since 1 August 2025.

Primary evidence

No new primary evidence which reaches the CKS threshold for inclusion published since 1 August 2025.

New policies

No new national policies or guidelines since 1 August 2025.

New safety alerts

No new safety alerts issued since 1 August 2025.

Changes in product availability

No changes in product availability since 1 August 2025.

Which analgesic should I prescribe for children aged under 16 years?

• Prescribe either paracetamol or ibuprofen alone.
  • If the child does not respond to the first-line analgesic, check their adherence and that an appropriate dose is being taken. If adherence and dose are appropriate, switch analgesic:
    • If paracetamol has been used, switch to ibuprofen alone. See the CKS topic on NSAIDs - prescribing issues for prescribing information on NSAIDs.
    • If ibuprofen has been used, switch to paracetamol alone.
  • If the child does not respond sufficiently to appropriate doses of either drug alone, consider alternating paracetamol and ibuprofen.
    • Add a dose of the second drug (for example, 2–3 hours after the first drug) provided that the parents/carers are confident to do this.
    • Paracetamol is usually given every 6 hours and ibuprofen every 8 hours. Care needs to be taken not to exceed the maximum dose of each drug in a 24-hour period.
    • Provide parents with verbal and written information, such as that on the NHS website: Paracetamol for children and Ibuprofen for children.
    • A treatment diary may be useful if the parents/carers find it difficult to remember which was the last drug given and at what time.
    • If the child is still in pain or more than short courses of analgesics are required, consider seeking specialist advice. 
  • Treat the underlying cause of the pain whenever possible.
• The following treatment options are not recommended for children in primary care:
  
  • Aspirin.
  • Naproxen.
  • Diclofenac (under the age of 12).
  • Opioids (such as codeine, dihydrocodeine, and tramadol).

Which analgesic should I prescribe for adults and children aged 16 years and older?

• When choosing an analgesic to prescribe for mild-to-moderate pain in adults and young people aged 16 and older, use clinical judgement, depending on:
• • The cause and type of pain.
  • The severity and impact of the pain (for example, the impact on function, sleep, and mood).
  • The likely timescale for the pain to start to improve.
  • The age and any co-morbidities of the person, and concurrent medication.
  • Factors which might influence the risk of dependence, gastrointestinal side effects, cardiovascular events, renal deterioration, overdose or other potential complications of treatment.
• Where possible, follow recommendations in local and national guidelines on the clinical condition causing the pain when choosing an appropriate analgesic. Treat the cause of the pain first, where possible.
• Begin with the safest medication that is likely to alleviate the pain. In many cases, paracetamol will be the preferred first-line choice. A non-steroidal anti-inflammatory drug (NSAID) may be more useful for the treatment of short-term musculoskeletal pain (although paracetamol may be preferred, particularly in the elderly), dysmenorrhoea, and pain accompanied by inflammation. NSAIDs may be used topically or orally for mild-to-moderate pain. Opioids are usually reserved for moderate-to-severe pain (particularly that of visceral origin) that is expected to resolve; for pain that has not responded to paracetamol and/or NSAIDs, or where these agents cannot be used or tolerated; or for analgesia in palliative care.
• Use the lowest effective dose, and stop treatment if there is minimal or no effect, or if it is no longer needed. 
• Do not initiate treatment with paracetamol, NSAIDs or opioids for chronic primary pain (pain that has been present for over three months and for which there is no clear underlying cause). See the CKS topic Chronic pain for more information.
• When prescribing analgesics:
  • Make review options clear and available so medication can be altered if not effective or no longer required. 
  • Do not change to, or add in, another analgesic unless the full therapeutic dose of the previous analgesic has been used and found insufficiently effective.
  • Follow local and national guidance on conditions for which over-the-counter items should not be routinely prescribed in primary care, such as minor conditions associated with pain or discomfort.
  • Provide verbal written information on pain management and the medicines used.
    • Explain there are analgesic and combination analgesic preparations available over the counter and they should not use these alongside prescribed analgesic medicines without advice from a pharmacist or doctor in case the maximum daily dose of any one component is exceeded.
    • The British Pain Society leaflet Managing your pain effectively using “Over the Counter” (OTC) Medicines discusses the short- and long-term use of OTC analgesics and their associated adverse effects.
    • The NHS website (www.nhs.uk) has information on Paracetamol for adults, Aspirin, NSAIDs,  Codeine, Dihydrocodeine, and Tramadol.
  • When prescribing compound analgesic preparations:
    • Be aware that fixed-dose combination analgesics containing low doses of opioids (such as codeine 8 mg plus paracetamol 500 mg or dihydrocodeine 10 mg plus paracetamol 500 mg) may be no more effective than paracetamol alone and can cause opioid adverse effects, such as constipation.
    • Avoid combination analgesics as first-line treatment.
    • The use of fixed-dose combination analgesics is usually reserved for people with chronic, stable pain of known origin and for people taking a lot of tablets (to reduce the number of tablets taken). 

Dose

• For adults:
  • By mouth — 500 mg to 1 g every 4 to 6 hours (maximum 4 g in 24 hours).
    • By mouth for migraine — 1 g for one dose, to be taken as soon as migraine symptoms develop. See the CKS topic on Migraine for more information.
  • By rectum — 500 mg to 1 g every 4 to 6 hours (maximum 4 g in 24 hours).
• For children and young people aged up to 17 years, prescribe the dose shown in Table 1 below. These doses may be repeated every 4 to 6 hours if necessary (maximum of four doses in 24 hours).
• Note: There are other paracetamol-containing medicines available over-the-counter (OTC). Advise patients not to use such combined preparations when taking paracetamol, as the maximum paracetamol total daily dosage as recommended here must not be exceeded.

Table 1. Recommended doses of paracetamol for children aged up to 17 years.

[BNF, 2025a; BNFC, 2025; EMC, 2025a]

Contraindications and cautions

• There are no contraindications to the use of paracetamol.
• Prescribe paracetamol with caution (use clinical judgement to consider a dose reduction):
  • If there are risk factors for hepatotoxicity and inadvertent paracetamol overdose, including:
    • Chronic alcohol consumption.
    • Chronic malnutrition.
    • Chronic dehydration.
    • Body weight less than 50 kg.
    • Severe liver disease — the pharmacokinetics of paracetamol are altered in severe liver disease, and the hazards of overdose are greater in people with non-cirrhotic alcoholic liver disease.
    • Severe renal impairment.
    • Long-term paracetamol use (especially in those who are malnourished).

[BNF, 2025a; BNFC, 2025; EMC, 2025a]

Adverse effects

Adverse effects are rare with paracetamol. Reported adverse effects include:

• Blood and lymphatic system disorders — Blood dyscrasias (including thrombocytopenia and agranulocytosis) have been rarely reported in people taking oral paracetamol, but it is not clear that these were directly caused by the paracetamol.
• Hepatobiliary disorders — Liver damage or abnormal hepatic function (frequency unknown, likely very rare at therapeutic doses. In those who have taken more than a therapeutic dose, liver damage may occur, and this may be from 5 g in people with risk factors for liver damage, including alcohol dependence, pre-existing liver disease, malnutrition, and the use of liver enzyme-inducing drugs.)
• Metabolism and nutrition disorders — High anion gap metabolic acidosis due to pyroglutamic acidosis (frequency unknown. Cases have been reported in people with severe illness, such as severe renal impairment and sepsis, or other sources of glutathione deficiency, such as chronic alcoholism, who were treated with paracetamol for a prolonged period or a combination of paracetamol and flucloxacillin.)
• Skin and subcutaneous tissue disorders — Rash, urticaria, fixed eruption, serious skin reactions (frequency unknown or very rare). Anorectal erythema with rectal use (common).
• Immune system disorders — Hypersensitivity, including skin rash, angioedema, and anaphylactic shock (very rare).

Overdose

• People who have taken an acute overdose or therapeutic excess of paracetamol may require immediate hospital admission depending on the quantity of paracetamol taken and the presence of risk factors for liver damage. See the TOXBASE website or telephone the National Poisons Information Services (NPIS) on 0344 892 0111 for advice on when admission is required.

[EMC, 2024a; BNF, 2025a; BNFC, 2025; EMC, 2025a; EMC, 2025b]

Drug interactions

• Drug interactions with paracetamol include:
  • Alcohol — excessive alcohol consumption causes severe liver damage when given with paracetamol. Also, paracetamol and alcohol can increase the risk of hepatotoxicity. Chronic alcohol intake may increase the hepatotoxicity of paracetamol overdose.
    • Manufacturer makes no recommendation.
  • Anticoagulants — the effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol, with increased risk of bleeding. Occasional doses have no significant effect.
    • Monitor international normalized ratio (INR).
  • Domperidone and metoclopramide — may increase speed of absorption of paracetamol.
  • Flucloxacillin — concurrent use with paracetamol has been reported to cause high anion gap metabolic acidosis. Be alert for signs and symptoms of high anion gap metabolic acidosis, particularly in patients with severe renal impairment, sepsis, or malnutrition.
  • Liver enzyme-inducing drugs — the use of liver enzyme-inducing drugs (such as rifampicin, carbamazepine, phenytoin, barbiturates, tricyclic antidepressants) can increase the risk of hepatotoxicity, particularly after overdosage.
    • Consider a paracetamol dose reduction.
  • Zidovudine — regular use of paracetamol possibly reduces metabolism of zidovudine (increased risk of neutropenia).
• See the electronic Medicines Compendium (eMC) or the British National Formulary (BNF) for a list of all possible drug interactions with paracetamol.

[BNF, 2025a; BNFC, 2025; EMC, 2025a; EMC, 2025b]

Pregnancy and breastfeeding

Pregnancy

• Paracetamol is the analgesic of choice for women who are trying to conceive or who are pregnant.
• It can be used at the standard dose at any stage of pregnancy.
• There is no evidence of congenital malformation or fetal or neonatal toxicity following therapeutic use of paracetamol in pregnancy. Studies on neurodevelopmental outcomes following in utero exposure to paracetamol (particularly prevalence of ADHD) have had conflicting results, and issues with confounding factors and methodological limitations. To date, no causal association has been proven.

Breastfeeding

• Paracetamol is the analgesic of choice for women who are breastfeeding.
• Very small amounts of paracetamol pass into the breast milk, and these amounts are far below the doses that could normally be given to infants directly.

   [UKTIS, 2023; SPS, 2024; BNF, 2025a; BNFC, 2025; EMC, 2025a]

Prescribing information

• See the CKS topic on NSAIDs - prescribing issues for detailed information on prescribing non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen.

Dose

For adults and young people older than 16 years of age:

• The recommended dose of oral aspirin for mild-to-moderate pain is 300 to 900 mg every 4 to 6 hours as required (maximum 4 g in 24 hours).
  • The recommended dose of oral aspirin for acute migraine is 900  mg for one dose, to be taken as soon as migraine symptoms develop. See the CKS topic on Migraine for more information.
• The recommended dose of rectal aspirin for mild-to-moderate pain is 450 mg to 900 mg every 4 hours (maximum 3.6g in 24 hours).

[BNF, 2025a; BNFC, 2025]

Contraindications and cautions

• Do not prescribe aspirin to:
  • People with: 
    • Nasal polyps associated with asthma — due to a high risk of severe sensitivity reactions.
    • Active peptic ulceration or a past history of ulceration or dyspepsia — due to an increased risk of bleeding.
    • Haemophilia or other bleeding disorder (including thrombocytopenia) — due to an increased risk of bleeding.
    • Severe hepatic impairment — due to the increased risk of gastrointestinal bleeding.
    • Severe chronic kidney disease (CKD) stage 4 or estimated glomerular filtration rate (eGFR) of 15–29 — due to the increased risk of deterioration of renal function and GI bleeding.
    • Severe cardiac failure.
    • A history of hypersensitivity to aspirin or any other non-steroidal anti-inflammatory drug (NSAID), including those in whom attacks of asthma, angioedema, urticaria or rhinitis have been precipitated by aspirin or an NSAID.
  • Children younger than 16 years of age (unless specifically indicated by a specialist, for example, for Kawasaki disease) — due to the risk of Reye's syndrome (a very rare but often fatal disease characterized by encephalopathy and fatty degeneration of the liver).
  • Women who are in the third trimester of pregnancy or who are breastfeeding — see the section on Pregnancy or breastfeeding for more information.
• Prescribe aspirin with caution:
  • In people with:
    • Anaemia — may be exacerbated by gastrointestinal blood loss.
    • Asthma or allergic disease — aspirin may precipitate bronchospasm and asthma attacks in susceptible people. See the CKS topic on Asthma for more information.
    • Cardiac failure (or other conditions that predispose to fluid retention).
    • Dehydration — may result in deterioration of renal function.
    • Hypertension — monitor carefully as uncontrolled blood pressure may lead to significant bleeding risk.
    • Glucose-6-phosphate dehydrogenase deficiency — rarely aspirin causes haemolytic anaemia.
    • Gout — serum urate may be increased.
    • Inflammatory bowel disease — may exacerbate condition and may induce gastro-intestinal haemorrhage.
    • Systemic lupus erythematosus and other connective tissue disorders — hepatic and renal function may be impaired in these conditions.
    • Thyrotoxicosis — may be exacerbated by large doses of salicylates.
    • Mild-to-moderate renal impairment — risk of fluid retention, further renal impairment and gastro-intestinal bleeding.
    • Mild-to-moderate hepatic impairment. 
  • In elderly people — as they are particularly susceptible to adverse effects, especially gastrointestinal bleeding and perforation, which may be fatal. Where prolonged treatment is required, review the person regularly.
  • If there is an increased risk of bleeding, for example:
    • During or after operative procedures (even in cases of minor procedures, such as tooth extraction) — temporary discontinuation of treatment may be necessary.
    • In those receiving treatment with warfarin or drugs known to increase the risk of gastrointestinaI bleeding, such as other nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids — see the section on Drug interactions for further information.

[EMC, 2024b; BNF, 2025a; BNFC, 2025; EMC, 2025c]

Adverse effects

• Gastrointestinal (GI) — these are the most common side effects (although the frequency is largely not known), including dyspepsia, nausea, vomiting, gastritis, GI erosions, GI ulceration, and GI bleeding.
• Respiratory and immune system disorders — bronchospasm, dyspnoea, asthma attacks, rhinitis, urticaria, angioedema, anaphylaxis or other hypersensitivity reactions may occur (frequency not known). Risk factors are existing asthma, hay fever, nasal polyps, or chronic respiratory diseases. 
• Blood and lymphatic system disorders — aplastic anaemia, iron deficiency anaemia, bleeding disorders, thrombocytopenia, and agranulocytosis (frequency not known).
• Hepatobiliary disorders — hepatotoxicity (frequency not known).
• Skin and subcutaneous tissue disorders — Rash, purpura, ecchymoses, Stevens-Johnson syndrome, toxic epidermal necrolysis (frequency not known).
• Vascular disorders — hypertension, haemorrhage (frequency not known).
• Nervous system disorders — intracranial haemorrhage, aseptic meningitis (frequency not known).
• Other disorders — tinnitus, epistaxis, renal stones, haematuria, menorrhagia, sodium retention, prolonged bleeding time, vertigo (frequency not known).

[EMC, 2024b; BNF, 2025a; BNFC, 2025; EMC, 2025c]

Drug interactions

• Drug interactions with aspirin include:
  
  • Drugs known to increase the risk of gastrointestinal (GI) bleed — risk of bleeding is increased during concurrent treatment with aspirin. Other drugs known to increase the risk of GI bleeding include anticoagulants (for example, warfarin and direct-acting oral anticoagulants), selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs), other nonsteroidal anti-inflammatory drugs (NSAIDs, such as naproxen and ibuprofen), corticosteroids, antiplatelet agents such as clopidogrel and ticagrelor, and omega-3-acid ethyl esters.
    • Consider switching to a different analgesic (such as paracetamol). If aspirin is indicated, use with caution. Consider gastroprotection (for example, with a proton pump inhibitor) during concurrent use.
  • Calcium channel blockers — reduced hypotensive effect.
  • Diuretics — aspirin (high-dose) increases the risk of acute renal failure when given with diuretics, due to the decreased glomerular filtration via decreased renal prostaglandin synthesis.
    • The manufacturer recommends hydrating the person and monitoring renal function at the start of the treatment.
  • Antihypertensive drugs — NSAIDs (such as aspirin) may decrease the antihypertensive effects of diuretics and other antihypertensive drugs, and concurrent administration with angiotensin-converting-enzyme inhibitors (such as ramipril) increases the risk of acute renal insufficiency.
  • Varicella vaccine — Reye's syndrome has been reported following the use of salicylates during wild-type varicella infection.
    • People who receive the varicella vaccine should avoid the use of aspirin for 6 weeks after vaccination.
  • Methotrexate — concurrent use with aspirin enhances haematological toxicity of methotrexate due to the decreased renal clearance of methotrexate.
    • The manufacturer recommends that the methotrexate dose be monitored. 
  • Nicorandil — aspirin is predicted to increase the risk of GI perforation when given with nicorandil.
    • Manufacturer advises caution.
  • Sulfonylureas — aspirin may increase the hypoglycaemic effect of sulfonylureas.
    • Monitor blood glucose carefully. Dose adjustment may be necessary.
  • Carbonic anhydrase inhibitors, such as acetazolamide — may result in severe acidosis and increased central nervous system toxicity.
    • Manufacturer makes no recommendation.
  • Digoxin and lithium — aspirin may impair the renal excretion of digoxin and lithium, resulting in increased plasma concentrations, and potential increased risk of nephroxicity.
    • Monitor plasma concentrations of digoxin and lithium when initiating and stopping treatment with aspirin. Dose adjustment may be necessary.
• See the electronic Medicines Compendium (eMC) or the British National Formulary (BNF) for a list of all possible drug interactions with aspirin.

[EMC, 2024b; BNF, 2025a; BNFC, 2025; EMC, 2025c]

Pregnancy and breastfeeding

Pregnancy

• Paracetamol is the analgesic of choice during pregnancy.
• If aspirin is being considered, be aware that analgesic doses of aspirin:
  • Are not known to be harmful when used during the first and second trimesters of pregnancy, but the manufacturer recommends avoiding use.
  • Are contraindicated during the third trimester of pregnancy because:
    • There is an increased risk of haemorrhage due to impaired platelet function.
    • There may be a delayed onset and increased duration of labour, with increased blood loss.
    • High doses (4 g or more) may be related to intrauterine growth restriction, teratogenic effects, closure of fetal ductus arteriosus in utero, and possibly persistent pulmonary hypertension of the newborn, and kernicterus may develop in babies who are jaundiced. 
  • When use in the third trimester is required, fetal monitoring for oligohydramnios and ductus arteriosus patency is recommended.

Breastfeeding

• Paracetamol is the analgesic of choice during breastfeeding. 
• Do not prescribe analgesic doses of aspirin to women who are breastfeeding due to a possible risk of Reye's syndrome (a very rare but often fatal disease characterized by encephalopathy and fatty degeneration of the liver) in the baby.

[UKTIS, 2019; EMC, 2024b; BNF, 2025a; BNFC, 2025] 

Dose

• The recommended doses of opioids for acute moderate pain in people aged 16 or over are:
  • Codeine — 30 mg to 60 mg every 4 hours when necessary (maximum 240 mg in 24 hours) for a maximum of 3 days.
  • Dihydrocodeine — 30 mg every 4 to 6 hours when necessary (maximum 120 mg in 24 hours).
  • Tramadol — 50 mg to 100 mg every 4 to 6 hours when necessary (usual maximum 400 mg in 24 hours).
• Lower doses of opioids (for example, codeine 15 mg) are recommended for:
  • Elderly and/or debilitated people — they are more susceptible to the adverse effects of opioids. 
  • People with hypothyroidism and adrenocorticoid insufficiency — opioids can affect endocrine function and lead to hypogonadism and adrenal insufficiency. 
  • People with moderate-to-severe chronic kidney disease (CKD) — adverse effects may be increased because elimination time is prolonged. Where possible, avoid using opioids.
• CKS recommends opioids are not prescribed for mild-to-moderate pain to young people under the age of 16 without specialist advice. See the section on choice of analgesic in age younger than 16 for further information.

Note:  Tramadol is a Schedule 3 controlled drug and, as such, is subject to the legal prescription requirements associated with controlled drugs. Codeine and dihydrocodeine are Schedule 5 drugs, which are exempt from most of the controlled drug prescribing requirements.

[EMC, 2023; EMC, 2024c; BNF, 2025a]

Contraindications and cautions

• Do not prescribe opioids for moderate pain to:
  • People with:
    • Acute respiratory depression — as there is a theoretical risk of further respiratory depression.
    • Conditions associated with increased intracranial pressure (such as cerebral cancer or abscess, or benign intracranial hypertension) or a head injury — opioid analgesics interfere with pupillary responses vital for neurological assessment.
    • Risk of paralytic ileus — opioids reduce gastric motility.
    • Severe chronic obstructive pulmonary disease — due to the risk of respiratory depression.
    • An acute exacerbation of asthma — opioids can aggravate bronchoconstriction as a result of histamine release.
    • Acute alcoholism — due to the risk of enhanced respiratory depressive, hypotensive, and sedative effects.
  • People who are comatose.
• In addition:
  • Do not prescribe codeine in:
    • People with liver disease or severe hepatic dysfunction.
    • People with conditions where inhibition of peristalsis is to be avoided, where there is a risk of paralytic ileus, where abdominal distension develops, or in acute diarrhoeal conditions (such as acute ulcerative colitis or antibiotic-associated colitis, or diarrhoea caused by poisoning).
    • Children under the age of 12 years — because of the risk of opioid toxicity due to the variable and unpredictable metabolism of codeine to morphine.
    • Children and young people aged 12–18 years who undergo tonsillectomy and/or adenoidectomy for obstructive sleep apnoea syndrome — due to an increased risk of developing serious and life-threatening adverse reactions.
    • Children and young people aged 12–18 years with breathing problems.
    • Breastfeeding women — see the section on Pregnancy and breastfeeding for more information.
    • People who are known to be poor or ultrarapid metabolizers of codeine or CYP2D6 (the liver enzyme CYP2D6 metabolises codeine into its active metabolite, morphine) — poor metabolizers may not experience analgesia, and ultrarapid metabolizers may experience toxicity. Use an alternative analgesic in these groups of people.
  • Do not prescribe tramadol:
    • In acute intoxication with alcohol, hypnotics, analgesics, opioids, or psychotropic drugs.
    • In people with uncontrolled epilepsy — seizures have been reported with licensed doses of tramadol, and tramadol may reduce the seizure threshold in people with controlled epilepsy. The risk of seizures is thought to be increased at higher doses of tramadol (for example when the licensed upper daily limit is exceeded).
    • In people who are taking MAO inhibitors or who have taken them in the previous 14 days.
    • To children under the age of 12 years.
    • For use in narcotic withdrawal treatment.

• Prescribe opioids for moderate pain with caution in:
  • People with:
    • Adrenocortical insufficiency — reduced dose is recommended.
    • Asthma — avoid during an acute attack.
    • Central sleep apnoea — opioids cause a dose-dependent increased risk of central sleep apnoea, consider total opioid reduced dose
    • Convulsive disorders. For tramadol, use in people with a history of epilepsy only if there are compelling reasons.
    • Hypotension.
    • Hypothyroidism — reduced dose is recommended.
    • Impaired respiratory function.
    • Myasthenia gravis.
    • Renal impairment — the effects are increased and prolonged. Where possible, avoid using opioids or use a reduced dose.
    • Hepatic impairment — avoid using opioids if possible or start with a low dose and titrate slowly. Adverse effects, such as sedation and constipation, can precipitate hepatic encephalopathy, particularly in people who may decompensate.
    • Obstructive or inflammatory bowel disorders (such as ulcerative colitis or Crohn's disease) — opioids reduce gastric motility.
    • Diseases of the biliary tract — ureteric or biliary spasm has been reported.
    • Prostatic hyperplasia — urinary retention has been reported.
    • Shock.
    • Urethral stenosis.
  • Debilitated and/or elderly people — as they are more susceptible to adverse effects. Start with a lower dose and titrate up slowly.
  • People with a history of drug or substance misuse, alcohol addiction, or a mental health disorder — the risk of drug dependence (addiction), even at therapeutic doses, is increased in these groups of people. See the CKS topic on Opioid dependence for more information.
• In addition, prescribe codeine with caution in people with:
  • Acute abdomen.
  • Cardiac arrhythmias.
  • Gallstones.
• In addition, prescribe dihydrocodeine with caution in people with:
  • Pancreatitis.
  • Severe cor pulmonale.

When prescribing opioids for moderate pain, give additional advice and information about the possible effect on ability to drive and use machinery and the risk of dependence and addiction. See the section on Information and advice for details.

[MHRA, 2020; EMC, 2023; DVLA, 2024; EMC, 2024c; BNF, 2025a]

Adverse effects

• Constipation is a common adverse effect of all opioids. 
  • If the person needs to take the opioid regularly, a laxative may be required. See the CKS topic on Constipation for prescribing information on laxatives.
  • If possible, avoid even weak opioids in people with chronic constipation. 
• Central nervous system adverse effects, for example, sedation, drowsiness, and confusion, are also common.
  • Warn the person to avoid activities where drowsiness may be detrimental (such as driving).
  • People taking opioids are allowed to drive in the UK if they are taking no more than the prescribed dose and they feel fit to drive. However, they should avoid driving at the start of treatment and during any dose increases.
• Respiratory depression may commonly occur with high doses.
• Dependence and tolerance can occur as a result of repeated use. However, psychological dependence rarely occurs when opioids are used therapeutically (for example, for pain relief). 
  • Over-the-counter analgesics containing codeine or dihydrocodeine should be used for a maximum of 3 days because they can cause dependency and medication overuse headache. See the CKS topic on Headache - medication overuse for more information.
• Drug withdrawal syndrome may occur on abrupt cessation or dose reduction. Symptoms include restlessness, lacrimation, rhinorrhoea, yawning, perspiration, myalgia, mydriasis, palpitations, agitation, anxiety, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, tachycardia and tachypnoea.
• Hyperalgesia may occur in patients on long-term opioid therapy, leading to an increase in pain, usually of a different quality to the original pain for which the opioid is being taken.
• Other possible adverse effects include:
  • Common or very common:
    • Arrhythmias, dry mouth, dizziness, euphoric mood, flushing, hallucination, headache, hyperhidrosis, hypotension (with high doses), miosis, nausea and vomiting (more common on initiation), palpitations, skin reaction, urinary retention, vertigo, and visual impairment.
    • In addition to tramadol — fatigue.
  • Uncommon:
    • Dysphoria, seizure.
  • Rare or very rare:
    • For tramadol — blurred vision, dyspnoea, epileptiform seizure, and sleep disorders.
  • Frequency not known:
    • For codeine — altered mood, biliary spasm, decreased appetite, depression, dyskinesia, dyspnoea, facial oedema, fatigue, fever, hyperglycaemia, hypersensitivity, hypothermia, increased intracranial pressure, lymphadenopathy, malaise, muscle rigidity (with high doses), nightmare, pancreatitis, restlessness, sexual dysfunction, splenomegaly, ureteral spasm, urinary disorders, and vision disorders.
    • For dihydrocodeine — altered mood, dysuria, biliary spasm, bronchospasm, hypothermia, sexual dysfunction, and ureteral spasm.
    • For tramadol — anxiety, blood disorders, exacerbation of asthma, hiccups, hypertension, hypoglycaemia, hyponatraemia, paraesthesia, serotonin syndrome, syncope, tremor, and urinary disorder.
• Overuse or misuse of opioid analgesics may result in overdose and/or death.
  • The general symptoms of opioid toxicity include confusion, somnolence, shallow breathing, small pupils, nausea, vomiting, constipation, and lack of appetite. In severe cases, this may include symptoms of circulatory and respiratory depression, which may be life-threatening.
  • Advise the person to only use medicines that are prescribed for them at the dose they have been prescribed and not to give this medicine to anyone else.
  • Monitor the person closely for signs of misuse, abuse, or addiction.
  • Review the clinical need for analgesic treatment regularly.
  • See the CKS topic on Opioid dependence for more information.  

[EMC, 2023; DVLA, 2024; EMC, 2024c; BNF, 2025a]

Drug interactions

• Drug interactions with opioids used for mild-to-moderate pain include:
  • Monoamine oxidase inhibitors (MAOIs) — concurrent use with an opioid may result in life-threatening interactions on the central nervous system (CNS), respiratory, and cardiovascular function. 
    • Avoid concurrent use and for 2 weeks after discontinuation of an MAOI.
  • Other CNS depressants (for example, hypnotics and sedatives such as benzodiazepines, anti-psychotics, anxiolytics, antidepressants, phenothiazines, antihistamines, gabapentinoids, other opioids or alcohol) — opioids may potentiate the effects of CNS depressants and cause respiratory depression, sedation, coma or death. 
    • Concurrent use should be avoided or done with caution.
  • Buprenorphine — predicted to increase the risk of opiate withdrawal when given with an opioid.
  • Bupropion — predicted to decrease the efficacy of opioids. 
  • Terbinafine — predicted to decrease the efficacy of opioids.
• In addition, for tramadol:
  • Carbamazepine — decreases the concentration of tramadol.
    • During concurrent use, the dose of tramadol may need to be increased according to clinical response, but within the maximum allowable dose.
  • Warfarin — tramadol has been reported to increase the anticoagulant effect of warfarin.
  • Other serotonergic drugs — concurrent use with other serotonergic drugs (such as antidepressants) can increase the risk of serotonin syndrome. 
    • The characteristic symptoms of serotonin syndrome fall into three main areas, although features from each group may not be present: neuromuscular hyperactivity (such as tremor, hyperreflexia, clonus, myoclonus, and rigidity), autonomic dysfunction (tachycardia, blood pressure changes, hyperthermia, diaphoresis, shivering, and diarrhoea), and altered mental state (agitation, confusion, and mania).
    • Treatment consists of withdrawal of the serotonergic drug and supportive care; specialist advice should be sought.
  • Other seizure threshold-lowering drugs — tramadol can induce convulsions and increase the potential for selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), antipsychotics, and other seizure threshold-lowering drugs (such as bupropion and mirtazapine) to cause convulsions.
    • The manufacturer states that people with epilepsy or those susceptible to seizures should be only treated with tramadol if there are compelling circumstances.
• See the electronic Medicines Compendium (eMC) or the British National Formulary (BNF) for a list of all possible drug interactions with codeine, dihydrocodeine, and tramadol.

[EMC, 2023; EMC, 2024c; BNF, 2025a]

Pregnancy and breastfeeding

Pregnancy

• Paracetamol is the analgesic of choice during pregnancy.
• If an opioid is required for moderate pain, codeine is preferred.
  • Codeine can be used short-term in all trimesters of pregnancy. However, the use of codeine near the end of the third trimester may cause neonatal respiratory depression. 
  • Prolonged use of any opioid in pregnancy may cause drug dependence in the foetus and neonatal withdrawal symptoms.
  • Use of any opioid near term may cause neonatal respiratory depression.
  • Opioid analgesics may cause gastric stasis during labour, increasing the risk of inhalation pneumonia in the mother.
  • The manufacturer of tramadol advises avoiding use in pregnant women due to inadequate evidence of safety. 

Breastfeeding

• Paracetamol is the analgesic of choice during breastfeeding. 
• Codeine should not be used during breastfeeding. This is because it may be secreted in breast milk and may cause respiratory depression in the infant. There is significant variability in codeine metabolism, and a risk of opioid toxicity in the infant.
• If an opioid is required for moderate pain, tramadol or dihydrocodeine may be used at the lowest effective dose and for the shortest possible duration. 
  • Infants who are breastfeeding from mothers taking opioids should be monitored for adverse effects (such as sedation, respiratory difficulties, constipation, feeding difficulties, poor weight gain).
  • Regular use of any opioid in a breastfeeding mother beyond 3 days should be under close medical supervision.

[MHRA, 2013; UKTIS, 2022a; UKTIS, 2022b; EMC, 2023; EMC, 2024c; BNF, 2025a]

Additional information and advice

Before prescribing opioids for moderate pain, give the following additional advice and information:

• Advise the person:
  • That constipation is a common adverse effect of all opioids. 
    • A regular laxative is not usually needed for short-term use of opioids.
  • About driving while taking opioids:
    • They should not drive if they experience any symptoms or signs which could impair their ability to drive, such as if they are drowsy, dizzy, unable to concentrate or make decisions, or if they experience poor coordination or blurred or double vision.
    • They should not drive at times when the risk may be temporarily increased, for example, when starting or changing the dose of an opioid.
    • Alcohol in combination with other impairing drugs can substantially increase the risk of accidents.
    • It may be helpful for the person to keep evidence (such as their repeat prescription) in the car to show that they are taking an opioid in accordance with medical advice. (Stress, however, that it is the driver's responsibility to decide whether their driving is or might be impaired.)
  • That their ability to use machinery could be impaired, and to avoid doing so if they experience symptoms of sedation or visual change, which could impair their ability to do this safely.
  • Of the risks and features of tolerance, dependence and addiction, and agree together a treatment strategy and plan for the end of treatment.
    • Advise that prolonged use may lead to dependence and addiction, even at therapeutic doses.
    • That the use of opioids for pain relief is usually restricted to short-term use for acute pain.
    • Advise that slow tapering may be required to reduce the risks of withdrawal effects if use has been prolonged.
  • That overuse or misuse of opioid analgesics may result in overdose and/or death. Advise the person:
    • To only use medicines that are prescribed for them at the dose they have been prescribed and not give this medicine to anyone else.
    • That weak opioids purchased over-the-counter (OTC) should only be used for up to 3 days before seeking medical advice.
• Provide written information on opioids and pain management.
  • The British Pain Society leaflet Managing your pain effectively using “Over the Counter” (OTC) Medicines discusses the short- and long-term use of OTC analgesics and their associated adverse effects.
  • The NHS website (www.nhs.uk) has information on Codeine, Dihydrocodeine, and Tramadol.

[Department for Transport, 2014; MHRA, 2020; NICE, 2022; EMC, 2023; DVLA, 2024; EMC, 2024c; BNF, 2025a]