Step 2. Moderate acute pain

Nonsteroidal anti-inflammatory drugs

If symptom relief is not sufficient with paracetamol and there are no contraindications to their use, a nonsteroidal anti-inflammatory drug ( "NSAID") can be used instead of, or in addition to, paracetamol. Suitable options include:

1 ibuprofen 200 to 400 mg orally, 3 times daily. For dosing of ibuprofen in children, see Table 1.20acute pain, stepwise approachibuprofen - acute pain, stepwise approach " " " "

OR (depending on patient comorbidities)

2 diclofenac 25 to 50 mg orally, 2 or 3 times daily. For dosing of diclofenac in children, see Table 1.20acute pain, stepwise approachdiclofenac - acute pain, stepwise approach " " " "

2 naproxen 250 to 500 mg orally, twice daily. For dosing of naproxen in children, see Table 1.20. acute pain, stepwise approachnaproxen - acute pain, stepwise approach " " " "

The potential benefit of "NSAIDs" should be weighed up against potential harms (see for major adverse effects of "NSAIDs"), particularly in high-risk patients. Ibuprofen is recommended first line because of widespread experience with its use. Adverse effects are dose dependent. At the time of writing, naproxen appears to confer the least cardiovascular risk but a high risk of gastrointestinal adverse effects. Diclofenac has a lower risk of gastrointestinal effects but a higher risk of adverse cardiovascular effects. When selecting an "NSAID", consider patient comorbidities.

Use the minimum effective dose of the "NSAID" for the shortest possible time, for a period usually not exceeding 2 weeks. Review the patient at 2 weeks if the acute pain has not resolved.

Use ibuprofen, diclofenac and naproxen with caution and at the lower end of the dose range in older people and in those with kidney disease (avoid if estimated glomerular filtration rate [eGFR] is less than 30 mL/min), a history of peptic ulcer disease (avoid if patient has active peptic ulcer disease or bleeding), hypertension or heart failure.

Low-dose aspirin may reduce the increased cardiovascular risk associated with "NSAIDs", but it will increase gastrointestinal adverse effects. However, patients requiring low-dose aspirin for cardiovascular protection should continue to take it regardless of their need for "NSAIDs".

Small quantities of these "NSAIDs" can be purchased over-the-counter without a prescription. With the exception of low-dose aspirin, do not use more than one "NSAID" at a time.

Table: Major adverse effects of nonsteroidal anti-inflammatory drugs (Table 1.2) [NB1]

Major adverse effects of nonsteroidal anti-inflammatory drugs (Table 1.2) [NB1]

System	Adverse effects	Comments
cardiovascular	rise in blood pressure, fluid retention, myocardial infarction, stroke, cardiovascular death	except for low-dose aspirin, use "NSAIDs" with caution in patients with cardiovascular disease
gastrointestinal []	upper abdominal pain, gastric erosions, peptic ulcers (gastric and duodenal), oesophageal ulceration, gastrointestinal bleeding, perforation, small bowel mucosal ulceration	relative risk of a serious gastrointestinal effect varies between "NSAIDs" and is dose-related over-the-counter "NSAIDs" appear to have a lower risk of causing ulcers and bleeding than prescribed "NSAIDs" because of their lower dose, shorter half-life and generally shorter duration of use selective cyclo-oxygenase-2 ( "COX-2") "NSAIDs" (eg celecoxib, etoricoxib) reduce, but do not abolish, the risk of ulcer disease and complications (concomitant aspirin negates this effect)
renal	renal impairment	risk factors include perioperative use in older and sicker patients, pre-existing renal impairment, heart failure, cirrhosis, a salt-reduced diet, coadministration with diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, aspirin or other nephrotoxic drugs

NB1: Older people are more at risk of "NSAID"-related adverse effects; assess their need for "NSAID" therapy carefully.
NB2: For information on risk factors for, and prevention of, "NSAID"-induced ulcers, see NSAID-induced ulcers.

Oral opioids

If a patient presents with moderate pain that is not adequately relieved by paracetamol and/or an "NSAID", and the pain is interfering with the patient’s quality of life, consider adding an oral opioid. The most appropriate regimen depends on the patient’s response to previous therapy.

For selection of opioids in children and appropriate dosing, see Pharmacological management of pain in children: opioids. Suitable options for adults include:

1 codeine 30 to 60 mg orally, 6-hourly as necessary []acute pain, stepwise approachcodeine - acute pain, stepwise approach " " " "

1 tramadol immediate-release 50 to 100 mg orally, up to 4 times daily as necessary acute pain, stepwise approachtramadol - acute pain, stepwise approach " " " "

2 oxycodone immediate-release 2.5 to 15 mg orally, 4-hourly as necessary. Use the lower end of the dose range in older people, and the higher end only in fit, otherwise healthy, young adults. Titrate the dose to response. acute pain, stepwise approachoxycodone - acute pain, stepwise approach " " " "

Always consider the potential benefits, harms and regulatory requirements before prescribing an opioid (see for adverse effects with short-term use of opioids). Advise patients to start at the lower end of the dose range and increase gradually as needed according to response (ie ‘start low and go slow’). Older patients may be particularly sensitive to opioids (see ) and they require careful monitoring. Constipation is a frequent adverse effect of opioids—advise patients to take a laxative (eg docusate with senna) concurrently.

There is evidence that a lower dose of codeine, less than 30 mg 6-hourly, is no more effective than simple analgesia. Codeine is a prodrug and requires conversion by the cytochrome P450 (CYP) 2D6 isoenzyme to morphine. This conversion is dependent on the patient’s individual pharmacogenetics, which are unpredictable. Approximately 6 to 10% of Caucasians and 1 to 2% of Asians lack the CYP2D6 isoenzyme and derive no analgesic benefit from codeine. Conversely, some people (up to 10% of Caucasians, up to 30% of North Africans) are ultrarapid metabolisers and are at higher risk of morphine toxicity; codeine should not be used in patients known to be ultrarapid metabolisers or in breastfeeding women (see the TGA Medicines Safety Update and Drugs and their categories in pregnancy and breastfeeding for more detail).

Always consider the potential for drug interactions with tramadol before prescribing. A maximum daily dose of 300 mg tramadol is recommended in people aged over 75 years. The usefulness of tramadol is limited by the frequency of adverse effects, especially in older people who are frail or have cognitive impairment.

Review all patients taking an oral opioid plus paracetamol and/or an "NSAID" within 48 hours if pain has not resolved.

Always have a discontinuation plan for patients receiving opioid analgesics for acute pain.

Table: Adverse effects with short-term use of opioids (Table 1.3) [NB1]

Adverse effects with short-term use of opioids (Table 1.3) [NB1]

System	Adverse effects—short term
respiratory	respiratory depression (excessive sedation +/– a decrease in respiratory rate []) or apnoea (which is more marked during sleep or with concomitant sedatives, hypnotics, alcohol, cannabis and general anaesthetics), bronchospasm
cardiovascular	bradycardia, vasodilation and hypotension during intravenous opioid administration, postural hypotension
neurological	dose-dependent confusion, delirium, sedation, dysphoria, euphoria, cough suppression, miosis, impaired cognition (requires careful monitoring and patients should be warned not to drive)
dermatological	sweating, flushing, urticaria, pruritus
gastrointestinal	nausea, vomiting, anorexia, decreased gastric motility, increased antral tone, delayed gastric emptying, slowed digestion, prolonged large bowel transit time, increased anal sphincter tone, constipation
musculoskeletal	myoclonus (with higher doses and in patients with renal impairment)
urinary	urinary retention and difficulty with micturition, increased external sphincter tone, decreased detrusor muscle tone

NB1: See also Table 1.15 for adverse effects with long-term use of opioids.
NB2: A decrease in respiratory rate is a very unreliable indicator of respiratory depression (high blood carbon dioxide levels), which can coexist with a normal respiratory rate. Sedation is a more sensitive indicator of respiratory depression.

Note 1:

Codeine should not be used in breastfeeding women, patients known to be ultrarapid metabolisers, in children younger than 12 years, and in children 12 to 18 years who have recently had a tonsillectomy and/or adenoidectomy for obstructive sleep apnoea. For more information, see the TGA Medicines Safety Update.

Step 2. Moderate acute pain

Nonsteroidal anti-inflammatory drugs

Major adverse effects of nonsteroidal anti-inflammatory drugs (Table 1.2) [NB1]

Oral opioids

Adverse effects with short-term use of opioids (Table 1.3) [NB1]

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