With an implementation date of 1 February 2018 set for all codeine-based analgesics to become prescription-only, patients may seek advice on alternative oral OTC medicines for managing acute pain.
The evidence suggests that paracetamol/ibuprofen combinations available as a single pill can be offered as an alternative to codeine-based analgesics for short-term management of pain in patients able to take NSAIDs and for whom paracetamol alone is not sufficient.
- Non-pharmacological measures and/or paracetamol are still preferred for mild pain.
- However, paracetamol/ibuprofen combinations may be considered as an alternative to codeine-based analgesics for short-term management of moderate pain in patients able to take NSAIDs.
- Evidence in acute pain states suggests paracetamol/ibuprofen combinations may frequently offer better pain relief than either component alone.
- The same precautions apply to use of paracetamol/ibuprofen combinations as to either active ingredient when used alone.
- OTC paracetamol/ibuprofen combinations are not indicated for chronic (long-term) pain.
Over-the-counter pain relief in a post-codeine world
On 20 December 2016, after a long period of public consultation, the Therapeutic Goods Administration announced its final decision on the rescheduling of codeine-containing products.
From February 2018, all analgesics and cough and cold medicines containing low-dose codeine and currently Schedule 2 (Pharmacy medicines) or Schedule 3 (Pharmacist Only medicines), will no longer be available over the counter in pharmacies, becoming prescription only.1,2
After implementation, people who may currently take analgesics containing low-dose codeine and wish to continue using them will need a prescription from their doctor, nurse practitioner or remote area nurse. Alternative oral OTC products are also available.1,2
While most health professionals are already familiar with paracetamol and NSAIDs for pain relief, the paracetamol/ibuprofen combination medicines may be less well known.
What is the clinical evidence behind these combination products? Where do they fit into the pain management ladder? Can prescribers and pharmacists confidently offer paracetamol/ibuprofen combinations as an alternative to codeine-based analgesics?
Therapeutic rationale for the combination
Current evidence suggests that for some types of pain, combining paracetamol with an NSAID may offer better analgesia than either drug alone.3
NSAIDs, such as ibuprofen, have analgesic, antipyretic and anti-inflammatory actions. They inhibit synthesis of prostaglandins by inhibiting cyclo-oxygenase (COX), present as COX-1 and COX-2. Their analgesic and anti-inflammatory effects are a consequence of COX-2 inhibition.4
Despite its widespread use, the mode of action of paracetamol is yet to be fully determined, although a centrally mediated analgesic action is thought likely.4 Paracetamol has minimal anti-inflammatory activity, implying a different mode of action from that of NSAIDs.4
The combination of two analgesics with different modes of action results in an additive rather than a synergistic effect; the efficacy of the combination in acute pain is roughly similar to the sum of the efficacies of individual agents.5
The effect appears to be primarily a pharmacodynamic one, as administering ibuprofen and paracetamol in combination does not significantly alter the pharmacokinetics of either drug.6,7
Efficacy of paracetamol/ibuprofen combinations
The combination of paracetamol and ibuprofen has been found to be efficacious in a variety of acute pain states, including postoperative pain, dysmenorrhoea and musculoskeletal pain.8-15
A Cochrane review assessed the efficacy of single-dose paracetamol plus ibuprofen in a variety of dose combinations after wisdom tooth removal.8
The authors concluded that paracetamol/ibuprofen combinations provide better analgesia than the same dose of either drug alone, with fewer patients on the combination requiring rescue analgesia or experiencing an adverse event.8
Comparative studies have found that paracetamol/ibuprofen combinations offer similar pain relief to that of codeine-based analgesics in acute pain, with generally improved tolerability.13-15
This suggests that paracetamol/ibuprofen may be offered as an alternative to currently availablea OTC codeine-containing analgesics in patients able to tolerate NSAIDs.
a Until February 2018.
Safety of paracetamol/ibuprofen combinations
Short-term studies of paracetamol/ibuprofen combinations in acute pain have not identified specific safety concerns other than those already known to be associated with the individual active ingredients.8,11,12,16
However, one study of 13 weeks found use of combined paracetamol/ibuprofen may increase the risk of bleeding over and above that associated with the individual drugs, suggesting caution should apply to long-term use.9
A retrospective cohort study that analysed the health insurance records of more than 640,000 patients aged 65 years and older found the combination of an NSAID and paracetamol to be associated with increased risk of hospitalisation for gastrointestinal events, compared with either drug alone.b,17
While co-administration with a proton pump inhibitor appeared to mitigate this risk, the combination was still associated with double the risk of hospitalisations compared with paracetamol alone.17
b Hazard ratio for combination: 2.55 (95% confidence interval [CI]: 1.98 to 3.28) compared with paracetamol alone ≤ 3 g/day, and 1.63 (95% CI: 1.44 to 1.85) compared with NSAID alone.
Consider precautions and side effects of both NSAIDs and paracetamol
While paracetamol is generally well tolerated when used at recommended doses, inadvertent overdose is possible. Advise patients to consider the paracetamol content of all their medicines.18,19
More precautions apply to the use of ibuprofen, especially in the elderly.
Use ibuprofen with caution and at the lower end of the dose range in older people and in those with kidney disease, a history of peptic ulcer disease, asthma, pregnancy, hypertension or heart failure.4,19-22
Consider the patient’s other medications, as co-administration with diuretics, ACE inhibitors, angiotensin-II receptor blockers, aspirin or other nephrotoxic drugs can increase the risk of renal impairment with NSAIDs.4,19
Place of paracetamol/ibuprofen combinations in therapy
Non-pharmacological measures (eg, hot or cold packs, rest), followed by paracetamol, should be considered first for the management of mild acute pain.19
Experts recommend a stepwise approach to the pharmacological management of acute pain.
- Start each analgesic in the lower dose range, then titrate upwards according to response and/or the development of adverse effects
- If pain is not relieved with the maximum daily dose of the analgesic, reassess the cause before moving to the next step.19
The evidence supports use of paracetamol/ibuprofen combinations for the short-term management of moderate pain.19,23 These medicines could be offered as an alternative to codeine-based analgesics to patients for whom NSAIDs are not contraindicated and paracetamol alone is not sufficient.13-15,19
Paracetamol/ibuprofen combinations could also be considered as an alternative to higher doses of ibuprofen in some patients, by offering an NSAID-sparing effect.4
As for all medicines containing NSAIDs, these combinations should not be used for more than a few days at a time, unless on medical advice, in which case the patient should be reviewed regularly with regard to efficacy, risk factors and ongoing need for treatment.20,21
OTC paracetamol/ibuprofen combinations are not indicated for the management of chronic pain.20,21
Paracetamol/ibuprofen combinations in Australia
Several OTC pain relievers that contain paracetamol and ibuprofen in combination are now available in Australia.24
The dosage regimens for these products differ and this needs to be explained carefully when recommending these products to patients, as there is the potential for confusion.
Nuromol et al
Most products, including Nuromol (Reckitt Benckiser) and a range of generics, contain paracetamol 500 mg and ibuprofen 200 mg in a single tablet.21,24
The recommended dose of Nuromol (in adults under 65 years and children 12 years and over) is one tablet every 8 hours as necessary, to a maximum of three tablets per 24 hours.21
Maxigesic (AFT Pharmaceuticals) contains a combination of paracetamol 500 mg and ibuprofen 150 mg in a single tablet.
The recommended dose in individuals 12 years and over is 1–2 tablets every 6 hours as required, to a maximum of eight tablets in 24 hours.
The manufacturer advises that ibuprofen should not be taken by adults over 65 years without consideration of comorbidities and co-medications.20
Small packs of these combinations (12 dosage units or less) are available to purchase over the counter in pharmacies as Schedule 2 (Pharmacy Medicines).23,24
Larger packs (up to 30 dosage units) are Schedule 3 (Pharmacist Only Medicines), requiring pharmacist advice before purchase.23,24
- Therapeutic Goods Administration. Update on the proposal for the rescheduling of codeine products. Canberra: Australian Government Department of Health, 2016 (accessed 20 December 2016).
- Therapeutic Goods Administration. Scheduling delegate’s final decision: codeine, December 2016. Canberra, ACT: Australian Government Department of Health, 2016 (accessed 20 December, 2016).
- Ong CKS, Seymour RA, Lirk P, et al.Combining paracetamol (acetaminophen) with nonsteroidal antiinflammatory drugs: a qualitative systematic review of analgesic efficacy for acute postoperative pain. Anesth Analg. 2010;110:1170-9.
- Australian Medicines Handbook. Adelaide SA: AMH Pty Ltd (accessed 20 December 2016 ).
- Moore RA, Derry CJ, Derry S, et al. A conservative method of testing whether combination analgesics produce additive or synergistic effects using evidence from acute pain and migraine. Eur J Pain 2012;16:585-91.
- Atkinson H, Stanescu, I, Beasley, CPH, Salem, II, et al. A pharmacokinetic analysis of a novel fixed dose oral combination of paracetamol and ibuprofen, with emphasis on food effect. J Bioequiv Availab 2015;7:150-4.
- Tanner T, Aspley S, Munn A, et al. The pharmacokinetic profile of a novel fixed-dose combination tablet of ibuprofen and paracetamol. BMC Clin Pharmacol 2010;10:10.
- Derry CJ, Derry S, Moore RA. Single dose oral ibuprofen plus paracetamol (acetaminophen) for acute postoperative pain. Cochrane Database Syst Revi 2013.
- Doherty M, Hawkey C, Goulder M, et al. A randomised controlled trial of ibuprofen, paracetamol or a combination tablet of ibuprofen/paracetamol in community-derived people with knee pain. Ann Rheum Dis 2011;70:1534-41.
- Eccles R, Holbrook A, Jawad M. A double-blind, randomised, crossover study of two doses of a single-tablet combination of ibuprofen/paracetamol and placebo for primary dysmenorrhoea. Curr Med Res Opin 2010;26:2689-99.
- Mehlisch DR, Aspley S, Daniels SE, et al. Comparison of the analgesic efficacy of concurrent ibuprofen and paracetamol with ibuprofen or paracetamol alone in the management of moderate to severe acute postoperative dental pain in adolescents and adults: a randomized, double-blind, placebo-controlled, parallel-group, single-dose, two-center, modified factorial study. Clin Ther 2010;32:882-95.
- Merry AF, Gibbs RD, Edwards J, et al. Combined acetaminophen and ibuprofen for pain relief after oral surgery in adults: a randomized controlled trial. Br J Anaesth 2010;104:80-8.
- Daniels SE, Goulder MA, Aspley S, et al. A randomised, five-parallel-group, placebo-controlled trial comparing the efficacy and tolerability of analgesic combinations including a novel single-tablet combination of ibuprofen/paracetamol for postoperative dental pain. Pain 2011;152:632-42
- Mitchell A, McCrea P, Inglis K, et al. A randomized, controlled trial comparing acetaminophen plus ibuprofen versus acetaminophen plus codeine plus caffeine (Tylenol 3) after outpatient breast surgery. Ann Surg Oncol 2012;19:3792-800.
- Sniezek PJ, Brodland DG, Zitelli JA. A randomized controlled trial comparing acetaminophen, acetaminophen and ibuprofen, and acetaminophen and codeine for postoperative pain relief after Mohs surgery and cutaneous reconstruction. Dermatol Surg 2011;37:1007-13.
- Mehlisch DR, Aspley S, Daniels SE, et al. A single-tablet fixed-dose combination of racemic ibuprofen/paracetamol in the management of moderate to severe postoperative dental pain in adult and adolescent patients: a multicenter, two-stage, randomized, double-blind, parallel-group, placebo-controlled, factorial study. Clin Ther 2010;32:1033-49.
- Rahme E, Barkun A, Nedjar H, et al. Hospitalizations for upper and lower GI events associated with traditional NSAIDs and acetaminophen among the elderly in Quebec, Canada. Am J Gastroenterol 2008;103:872-82.
- Expert Group for Rheumatology. Therapeutic Guidelines: Rheumatology. Melbourne: Therapeutic Guidelines Ltd, 2010 (accessed 23 December 2016).
- Expert Group for Analgesics. Therapeutic Guidelines: Analgesic. Melbourne: Therapeutic Guidelines Ltd, 2012 (accessed 23 December 2016).
- AFT Pharmaceuticals Pty Ltd. Maxigesic Product Information 2016.
- Reckitt Benckiser Australia Pty Ltd. Nuromol Product Information. 2016.
- Therapeutic Goods Administration. Non-steroidal anti-inflammatory drugs (NSAIDs) review. Safety advisory - inconsistent information about the known risk of miscarriage. Canberra: Australian Government, Department of Health, 2016 (accessed 18 March, 2017).
- Therapeutic Goods Administration. Scheduling delegate's final decisions: Paracetamol / Ibuprofen, May 2016. Canberra: Australian Government Department of Health, 2016 (accessed 20 December 2016)
- Therapeutic Goods Administration. Australian Register of Therapeutic Goods search: paracetamol and ibuprofen. Canberra: Australian Government Department of Health, 2017 (accessed 6 January 2017).