General advice on prescribing oral nonsteroidal anti-inflammatory drugs (NSAIDs).

• Consider whether an alternative treatment would be appropriate.
• Prescribe the lowest effective dose of NSAID for the shortest time necessary.
• Take account of the person's risk of serious adverse effects, the safety profiles of individual standard NSAIDs or coxibs, and the person's ability to tolerate individual NSAIDs.
• Older people are at increased risk of the gastrointestinal, cardiovascular, and renal adverse effects of NSAIDs.
• The risk for serious gastrointestinal adverse effects is increased in people who have had peptic ulcer disease or upper gastrointestinal bleeding and in those who are taking aspirin, an anticoagulant, or a systemic corticosteroid. The risk for serious gastrointestinal adverse events correlates poorly with dyspeptic symptoms.
• The risk for serious cardiovascular and renal adverse effects is increased in people who are already at increased risk for cardiovascular or renal disease and in people who have cardiovascular, renal, or hepatic impairment.
• NSAIDs can worsen asthma. However, if NSAIDs are thought to be potentially beneficial, people with asthma should be considered for a trial of an NSAID.
• Standard NSAIDs may increase the risk for excessive bleeding after trauma or surgery.
• Periodically review the needs of people on long-term NSAID treatment.
• People's tolerance for different NSAIDs varies substantially. However, do not switch between NSAIDs without careful consideration of the overall safety profile of the products, the person's risk factors, and their preferences.

The optimum nonsteroidal anti-inflammatory drug (NSAID) depends on the individual's risk factors, therapeutic response, and preferences. When prescribing an NSAID, consider:

• Is the person already using ibuprofen or aspirin in medication purchased without prescription?
• Is there an alternative to the NSAID? Alternative interventions may have a more favourable balance of benefits and risks. For example, consider:
• For pain relief: paracetamol, codeine, and other analgesics, especially if an NSAID is not likely to be effective for pain relief (e.g. neuropathic pain).
• For single regional pain relief (especially wrists, hands, knees, elbows, feet): a topical NSAID.
• For osteoarthritis: alternative analgesics (including paracetamol, codeine), topical NSAIDs, physical therapy, surgery.
• For gout: corticosteroids, colchicine.
• Does the person have a contraindication to oral NSAIDs?
• Is gastroprotection indicated? For example, if the person is:
• At increased risk of gastrointestinal adverse effects.
• Subject to dyspepsia from standard NSAIDs.
• Is there a reason for closer monitoring for adverse effects? For example, people who are:
• At risk for multiple adverse effects:
• Older age.
• Comorbidity.
• Potential interaction with other drugs being used.
• At increased risk of gastrointestinal adverse effects.
• At increased risk of cardiovascular or renal adverse events.
• What is the optimum dose and duration?
• For all NSAIDs, the lowest effective dose and the shortest duration of treatment should be used.
• Is there a reason for more frequent review of the continued need for an NSAID?
• All people using NSAIDs (continuously or intermittently) should have their indications for NSAID use regularly reviewed.
• People who are at increased risk of severe adverse effects should be reviewed more frequently:
• Use clinical judgement when deciding on the follow-up interval, taking into account the risk factors for adverse effects and progress of the underlying disease and any comorbidity.

For more information, see:

• Preventing GI adverse effects
• Managing GI adverse effects
• Monitoring
• Potentially hazardous interactions with other drugs

This approach to safe and effective prescribing of nonsteroidal anti-inflammatory drugs (NSAIDs) is based on the opinion of experts and on advice from the Commission on Human Medicines (CHM) and the Medicines and Healthcare products Regulatory Agency (MHRA) [CHM, 2006; MHRA, 2007; Stillman and Stillman, 2007; BNF 55, 2008]. The expert opinion and advice from the CHM and MHRA take into account a large body of evidence on the benefits and adverse effects of NSAIDs:

• Evidence on benefits:
• Evidence on the benefits of NSAIDs depends on the particular indication and is summarized within each CKS topic that offers NSAIDs as a treatment option, for example, in the CKS topics on Gout, Menorrhagia, and Osteoarthritis.
• Evidence on harms:
• Cardiovascular, renal, and gastrointestinal adverse effects of NSAIDs. The evidence on cardiovascular and renal adverse effects and on strategies for gastroprotection is summarized in separate sections:
• Risk of thrombotic adverse events
• Risk of cardiorenal adverse events
• Prevention of GI adverse effects
• In the absence of evidence from clinical trials, recommendations on general strategies for safe and effective prescribing are pragmatic advice based on expert opinion.

• Do not use NSAIDs in people with:
• A history of hypersensitivity/severe allergic reaction to an NSAID (including aspirin):
• Severe skin reactions and angioedema. Allergies that cause skin reactions and angioedema are absolute contraindications to NSAIDs.
• Asthma. Unless NSAIDs clearly cause severe exacerbations of asthma, people with asthma should not be denied the benefits of NSAIDs without being offered the option of a trial to assess the effect on asthma control.
• Severe heart failure — NSAIDs may impair renal function.
• Severe hepatic impairment (e.g. liver enzyme levels more than three times the upper limit of the normal range; serum albumin < 25g/L ).
• Current treatment for gastrointestinal bleeding, symptomatic peptic ulcer, or gastrointestinal perforation or obstruction.
• Coxibs are also contraindicated in people with ischaemic heart disease, cerebrovascular disease, peripheral arterial disease, moderate or severe heart failure.
• Where possible, avoid using NSAIDs in people with:
• Renal failure, with estimated glomerular filtration rate less than 30–15 mL/min/1.73 m², creatinine clearance less than 30–20 mL/min, or dehydration:
• Check the summary of product characteristics for the manufacturer's recommendation for each NSAID, available at the electronic Medicines Compendium (eMC) (http://emc.medicines.org.uk).
• Ideally, avoid using an NSAID.
• NSAIDs can provoke acute renal failure if given to someone who is dehydrated, especially if they have diabetes.
• NSAIDs should be used with caution in:
• The elderly — increased risk of serious adverse effects such as gastrointestinal bleeding and perforation, which may be fatal.
• People with a history of peptic ulceration (standard NSAIDs contraindicated), or those at high risk of gastrointestinal adverse effects.
• People with inflammatory bowel disease — NSAIDs may increase the risk of developing or cause exacerbations of ulcerative colitis or Crohn's disease.
• People with hepatic impairment — increased risk of gastrointestinal bleeding and fluid retention.
• Dose reduction is recommended for some NSAIDs.
• Check the summary of product characteristics for the manufacturer's recommendation for each NSAID, available at the electronic Medicines Compendium (eMC) (http://emc.medicines.org.uk).
• Renal impairment (avoid if possible) — sodium and water retention may occur leading to a deterioration in renal function and, possibly renal failure. This has also been reported with topical use.
• If the person cannot avoid using a NSAID and has impaired renal function, monitor creatinine clearance or estimated glomerular filtration rate.
• People with heart failure — NSAIDs may impair renal function.
• People with hypertension — NSAIDs may impair renal function.
• In a women trying to conceive — may impair female fertility.
• For information on when NSAIDs can be used during pregnancy, and which are preferred see Can NSAIDs be used during pregnancy?
• For information on when NSAIDs can be used during breastfeeding, and which are preferred see Can NSAIDs be used during breastfeeding?
• Consider the possibility of drug interactions.

These recommendations are based on published expert opinion from the MHRA [CSM, 2003], the manufacturers' Summaries of Product Characteristics [ABPI Medicines Compendium, 2008; ABPI Medicines Compendium, 2009a; ABPI Medicines Compendium, 2009b; ABPI Medicines Compendium, 2010a; ABPI Medicines Compendium, 2010b] and the British National Formulary [BNF 59, 2010].

• Asthma. Exacerbation of asthma is not often associated with the use of NSAIDs, but NSAIDs are a risk factor for severe exacerbations of rapid onset [Lesko et al, 2002; Plaza et al, 2002; Debley et al, 2005].

• The risks of adverse effects vary among individual NSAIDs and are also often influenced by the dose and duration of use.
• Adverse effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.
• Children appear to tolerate NSAIDs better than adults and gastrointestinal adverse effects are less common.
• The most common adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs) are:
• Dyspepsia and other upper gastrointestinal complications such as ulcer, perforation, obstruction or bleeding.
• For detailed information about who is at risk of how they can be managed, see the section Gastrointestinal adverse effects.
• Other less common adverse effects include:
• Cardiovascular and renal complications such as myocardial infarction, stroke, cardiac failure, hypertension, and renal failure are less common but serious adverse effects associated with NSAIDs.
• For detailed information about who is at risk of how they can be managed, see the section Cardiovascular and renal adverse effects.
• Prolonged bleeding (for example after surgery) because of platelet inhibition.
• Asthma — NSAIDs may exacerbate or precipitate asthma.
• Stop the NSAID if is suspected to have precipitated bronchospasm.
• Severe skin reactions and angioedema — stop the NSAID.
• Very rarely, NSAIDs can precipitate severe hepatic reactions (such as hepatitis, liver necrosis, or hepatic failure).
• If there are symptoms or signs of liver damage (e.g. nausea, vomiting, abdominal pain, jaundice), or persistently abnormal liver enzymes, stop the NSAID.

These recommendations take into account advice from the Medicines and Healthcare products Regulatory Agency (MHRA) and its independent adviser, the Commission on Human Medicines (CHM) [CSM, 2003; CSM, 2005; CHM, 2006; MHRA, 2007; MHRA, 2009b], the manufacturers' Summaries of Product Characteristics [ABPI Medicines Compendium, 2008; ABPI Medicines Compendium, 2009a; ABPI Medicines Compendium, 2009b; ABPI Medicines Compendium, 2010a; ABPI Medicines Compendium, 2010b] and the British National Formulary [BNF 59, 2010].

• Asthma. Exacerbation of asthma is not often associated with the use of NSAIDs, but NSAIDs are a risk factor for severe exacerbations of rapid onset [Lesko et al, 2002; Plaza et al, 2002; Debley et al, 2005].
• Liver adverse effects of coxibs. Recommendations on general strategies for safe and effective prescribing are pragmatic advice based on the summary product characteristics for celecoxib and etoricoxib [ABPI Medicines Compendium, 2009a; ABPI Medicines Compendium, 2008].

• Enquire about, and manage, adverse effects.
• Etoricoxib — blood pressure should be checked within 2 weeks of starting etoricoxib, and periodically thereafter.
• Consider the risks and the response to treatment, and use clinical judgement to decide what must be monitored and how frequently:
• People with ischaemic heart disease, risk factors for cardiovascular disease, cerebrovascular disease, peripheral vascular disease, and the elderly.
• Consider monitoring blood pressure, renal function, and features of cardiac failure.
• Heart failure
• Consider monitoring features of heart failure (such as body weight, jugular venous distension, crepitations, hepatomegaly, ascites, peripheral oedema) 1–2 weeks after starting or increasing the dose of the NSAID.
• Consider monitoring renal function (creatinine clearance or estimated glomerular filtration rate) 1–2 weeks after starting or increasing the dose of the NSAID, particularly in people taking an ACE inhibitor, an angiotensin-II receptor antagonist, a diuretic, or in those with impaired renal function.
• If, at any time, heart failure or renal impairment deteriorates, consider the NSAID as a cause .
• Hypertension
• Consider monitoring blood pressure (for example 2–4 weeks after starting or increasing the dose of the NSAID).
• Blood pressure should be checked within 2 weeks of starting etoricoxib, and periodically thereafter.
• If, at any time, hypertension control deteriorates, consider the NSAID as a cause.
• Renal impairment
• Consider monitoring renal function (creatinine clearance or estimated glomerular filtration rate) 1–2 weeks after starting or increasing the dose of the NSAID, and then regularly thereafter.
• If, at any time, renal impairment deteriorates, consider the NSAID as a cause.
• Hepatic impairment
• Enquire about adverse effects; NSAIDs increase the risk of gastrointestinal bleeding and fluid retention.
• Check the summary of product characteristics (SPC) for the nonsteroidal anti-inflammatory drug for more specific advice.
• Consider seeking specialist advice in case of uncertainty.

• These recommendations are pragmatic advice, and they take into account guidance from the Medicines and Healthcare products Regulatory Agency and the Commission on Human Medicines on the risks of cardiovascular and renal adverse effects [CHM, 2006; MHRA, 2007; MHRA, 2009]:
• There is evidence on the risks of thrombotic adverse events associated with nonsteroidal anti-inflammatory drugs and evidence on renal adverse events. However, there is no evidence from clinical trials on strategies to monitor people with these risks.
• The suggested monitoring intervals in people starting and NSAID who also have heart failure, hypertension, or renal impairment, are extrapolated from the monitoring advice for people starting ACE inhibitors. See the CKS topics on Chronic kidney disease - not diabetic, Hypertension - not diabetic, and Heart failure - chronic for further information.

• When prescribing an oral nonsteroidal anti-inflammatory drug (NSAID), provide advice on:
• The option to purchase oral ibuprofen over the counter.
• The type of NSAID prescribed (standard NSAIDs or coxib).
• The risk of adverse effects:
• All people are at risk of adverse effects, but some people may be at increased risk.
• All NSAIDs have risks of adverse effects, but some NSAIDs may have higher risks for particular adverse effects.
• The need to weigh up, in each individual, the benefits of the prescribed NSAID against its risks and the person's ability to tolerate it.
• The main serious adverse effects (gastrointestinal, cardiovascular, renal, and hepatic).
• Strategies to minimize the risks of adverse effects, including:
• Using an alternative treatment to an oral NSAID.
• Using an NSAID at the lowest effective dose and for no longer than is necessary.
• Not to take an NSAID on an empty stomach.
• Using a gastroprotective strategy for people at increased risk of gastrointestinal adverse effects.
• Using a topical NSAID for knee or small joint disorders.
• Closer monitoring of people at increased risk.
• The need to carefully read the information leaflet enclosed with the medication.

• CKS found no trial evidence on giving advice to people about NSAIDs. These recommendations are therefore pragmatic. However, they do reflect the available evidence on risks and preventive strategies.

• People are at high risk of serious nonsteroidal anti-inflammatory drug (NSAID)–induced gastrointestinal (GI) adverse events if they have one or more of the following risk factors:
• Older age and male. The risk of an upper GI complication, such as bleeding:
• Doubles with every decade above 55 years (for example, roughly 1 per 1000 persons per year at 55 years of age, 2 per 1000 persons at 65 years of age, 4 per 1000 persons at 75 years of age, and so on).
• Is twice as high in men as in women.
• History of gastroduodenal ulcer, GI bleeding, or gastroduodenal perforation.
• Concomitant use of medications that are known to increase the likelihood of upper GI adverse events (e.g. anticoagulants, aspirin used in low or standard doses, corticosteroids, and selective serotonin reuptake inhibitors [SSRIs], venlafaxine, or duloxetine).
• Serious comorbidity, such as cardiovascular disease, hepatic or renal impairment (including dehydration), diabetes, or hypertension.
• Requirement for prolonged NSAID use, including people with:
• Osteoarthritis or rheumatoid arthritis of any age.
• Chronic low back pain and 45 years of age or older.
• Use of the maximum recommended dose of an NSAID.
• Additional risk factors for NSAID-induced GI adverse events have also been identified, including:
• The NSAID used.
• The presence of Helicobacter pylori infection.
• Excessive alcohol use.
• Heavy smoking.

• For information on the risks associated with low-dose aspirin, see the CKS topic on Antiplatelet treatment.

The risk factors for GI adverse effects are based on recommendations in the National Institute for Health and Clinical Excellence (NICE) Technology Appraisal Guidance on the use of cyclo-oxygenase (COX) II–selective inhibitors for osteoarthritis and rheumatoid arthritis [NICE, 2001].

Increasing age, previous GI history, and presence of serious comorbidity:

• The consequences of GI bleeding are likely to be more serious in people who are otherwise in poor health, including those with the comorbidities identified by NICE.
• An RCT of 8843 people taking a NSAID for rheumatoid arthritis symptoms were randomized to misoprostol or placebo [Silverstein et al, 1995]. Analysis of 18 potential risk factors by logistic regression showed that older age (75 years or older), history of peptic ulcer, history of GI bleeding, and history of cardiovascular disease were all significant indicators of increased risk of serious upper GI complications.
• A systematic review and meta-analysis of 18 observational studies investigated NSAIDs and serious GI complications [Hernandez-Diaz and Rodriguez, 2000]. Pooled relative risks were calculated for different risk factors. NSAID users with advanced age or a history of peptic ulcer disease had the highest absolute risks for upper GI tract bleeding or perforation. Compared with people aged 25 to 49 years:
• People aged 60 to 69 years had 2.4 times the risk.
• People aged 70 to 80 years had 4.5 times the risk.
• People aged over 80 years had 9.2 times the risk.
• An RCT of 8076 people with rheumatoid arthritis taking either rofecoxib or naproxen for 9 months were assessed for the development of upper GI events [Laine et al, 2002]. A history of GI events, advancing age (in people 75 years of age or older, the risk was increased by 3.7 times, whilst for those aged 65 to 74 years the risk was increased by 2.4 times), and severe disability caused by rheumatoid arthritis, were found to be significant risk factors.

Concomitant use of medicines that increase the risk:

• A meta-analysis involving over 66,000 people found that the risk of GI bleeding for those taking long-term, low-dose aspirin was double the risk of those who did not take aspirin [Derry and Loke, 2000].
• A two-fold increased risk of GI bleeding was found in people taking low-dose aspirin for secondary prevention of cardiovascular disease who were not considered to be at high risk of GI complications [NICE, 2004].
• NSAID use can be influenced by drugs taken for other conditions. For example, people who are taking warfarin should ideally avoid taking NSAIDs [Baxter, 2006; BNF 55, 2008; National Collaborating Centre for Chronic Conditions, 2008].
• Selective serotonin reuptake inhibitors (SSRIs) are associated with an increased risk of bleeding, so should not normally be offered for people taking NSAIDs [NICE, 2009]. Venlafaxine and duloxetine as inhibit serotonin reuptake, so can be expected to interact similarly.

NSAID type, dose, and duration of use:

• A case-controlled study based on the GP Research Database estimated about a five-fold increase in the risk of bleeding or perforated peptic ulcer associated with taking NSAIDs but found higher risks with piroxicam (OR 18.0) and azapropazone (OR 23.4) [Garcia Rodriguez and Jick, 1994].
• A review of 12 epidemiological studies examined the performance of 14 NSAIDs relative to ibuprofen [Henry et al, 1996]. The review found that NSAIDs vary significantly in their GI toxicity. The review also found that the risk of GI injury increases for higher doses of the same NSAID. Doses in the region of ibuprofen 2.4 g daily may be no safer than intermediate-risk NSAIDs, such as diclofenac and naproxen.
• Nested case-controlled analysis of 2105 cases and 11,500 controls based in the UK found that high NSAID doses were associated with a much greater increased risk of bleeding compared with low NSAID doses [García Rodríguez and Hernández-Díaz, 2001]:
• For low-dose NSAIDs, relative risk (RR) 2.4 (95% CI 1.9 to 3.1).
• For high-dose NSAIDs, RR 4.9 (95% CI 4.1 to 5.8).
• Meta-analysis of data from three case-controlled studies (2472 cases of upper GI bleeding and 5877 controls) investigated NSAID dose-response relationships with GI risk [Lewis et al, 2002]. The risk of upper GI bleeding with NSAIDs varies up to 20-fold depending on the drug (ibuprofen at the lowest end, and piroxicam and ketoprofen at the highest end, of those drugs studied), and by three-fold to seven-fold depending on the dose chosen. Risk was maximal in the first week, decreased thereafter, and was reduced 1 week after discontinuing NSAID use.
• The Commission on Human Medicines (CHM; formerly Committee on Safety of Medicines) has created three categories of NSAID risk [CSM, 2002]:
• Lowest risk: ibuprofen (but serious and fatal GI adverse effects have still been reported).
• Intermediate risk: diclofenac, naproxen, ketoprofen, piroxicam, and indometacin.
• Highest risk: azapropazone.
• The CHM has confirmed that COX-2 selective NSAIDs have also been associated with serious and fatal GI adverse reactions [CSM, 2003]. However, COX-2 selective NSAIDs are thought to be associated with a lower risk of GI adverse events, although it is not clear whether this lower risk remains with their long-term use [Juni et al, 2003].
• An observational study of 5692 people with rheumatoid arthritis and 3124 people with osteoarthritis, representing 36,262 patient-years, was examined for rates of serious GI events from aspirin, paracetamol, and ibuprofen use [Fries and Bruce, 2003]. In people taking aspirin, paracetamol, or ibuprofen alone, only 1 event occurred in over 900 patient–years. People taking paracetamol in combination with other analgesics or corticosteroids had higher rates (borderline significance). With higher doses of all drugs, GI events tended to be relatively more frequent, but even in high-risk people on corticosteroids, the rate was around 20 per 1000 patient–years.
• The National Institute for Health and Clinical Excellence (NICE) recommend that a PPI is routinely co-prescribed with all NSAIDs (both standard NSAIDs and COX-2 selective NSAIDs) for all people with osteoarthritis, all people with rheumatoid arthritis, and anyone with chronic low back pain 45 years of age and older [National Collaborating Centre for Chronic Conditions, 2008; National Collaborating Centre for Chronic Conditions, 2009; National Collaborating Centre for Primary Care, 2009].
• For more information, see Prevention of GI adverse effects.

Presence of Helicobacter pylori infection:

• The relationship between H. pylori infection and NSAIDs in gastroduodenal pathology is complex, but H. pylori infection is believed to be an independent risk factor for peptic ulcer bleeding [Malfertheiner et al, 2007].

Excess alcohol use and heavy smoking:

• Alcohol has been thought to cause direct injury to gastric mucosa and cause non-ulcer dyspepsia [North of England Dyspepsia Guideline Development Group, 2004].
• Smoking increases gastric acid output and delays gastric emptying, which may be involved in the development of non-ulcer dyspepsia [North of England Dyspepsia Guideline Development Group, 2004].

• In all people, consider using:
• An alternative to an oral nonsteroidal anti-inflammatory drug (NSAID), for example:
• For pain: paracetamol, with or without codeine.
• For gout: colchicine.
• For osteoarthritis: other analgesics, physical treatments (including exercise), surgery.
• For rheumatoid arthritis: optimization of disease modifying drugs (DMARDs). (Usually requires referral.)
• Only one NSAID at a time:
• When possible, avoid concomitant use of an NSAID with low-dose aspirin. Low-dose aspirin for cardiovascular protection almost always has priority over an NSAID.
• Avoid using an oral NSAID and a topical NSAID at the same time.
• The lowest NSAID dose that is compatible with symptom relief.
• In people who are at increased risk of gastrointestinal (GI) adverse effects and require an oral NSAID, prescribing options are:
• A standard NSAID with a proton pump inhibitor (PPI) prescribed at a dose licensed for gastroprotection (see Table 1).
• A coxib with a PPI.

• For people who have an NSAID-associated peptic ulcer, see the CKS topic on Dyspepsia - proven peptic ulcer.

• People younger than 45 years of age and at low risk of GI adverse events (e.g. no history of GI bleeding or Helicobacter pylori infection and not on aspirin, warfarin, or oral corticosteroids) may not need the concomitant use of a gastroprotective drug with a nonsteroidal anti-inflammatory drug (NSAID).
• Options for gastroprotective drugs to prescribe with standard NSAIDs also include misoprostol or a histamine₂–receptor antagonist, but a PPI is the preferred choice.
• For detailed information on the use of low-dose aspirin, including advice on how to minimize the risk of GI adverse events, see the CKS topic on Antiplatelet treatment.

These recommendations are largely based on National Institute for Health and Clinical Excellence (NICE) guidelines [NICE, 2004; National Collaborating Centre for Chronic Conditions, 2008]. The approach to safe and effective prescribing is also based on the opinion of experts and on advice from the Commission on Human Medicines and the Medicines and Healthcare products Regulatory Agency [CHM, 2006; MHRA, 2007; BNF 55, 2008].

Alternative simple analgesia:

• A questionnaire study of 1799 people with osteoarthritis (OA), rheumatoid arthritis (RA), or fibromyalgia asked people to rate their overall satisfaction with their drug treatment [Wolfe et al, 2000]:
• Of the responses, about 40% of those who had taken paracetamol found it moderately or very effective, 25% found it equally effective as NSAIDs, and 12% preferred paracetamol to NSAIDs.
• When effectiveness and adverse effects were considered together, these percentages increased slightly in favour of paracetamol.
• Although there was a definite preference for NSAIDs over paracetamol, many people with OA and RA were still satisfied with paracetamol.
• A systematic review and meta-analysis of 10 RCTs (n = 1712) investigated whether paracetamol reduced the pain of OA [Zhang et al, 2004]. Although NSAIDs were found to be better for pain relief than paracetamol, paracetamol was effective for pain relief due to OA. For safety reasons, it was concluded that paracetamol should be the first-line treatment.
• A Cochrane review of 15 RCTs (n = 5986) investigated the efficacy of paracetamol in OA [Towheed et al, 2006]. Seven RCTs compared paracetamol with placebo, and 10 RCTs compared paracetamol with NSAIDs. From the limited number of well-controlled studies available, there was little difference between paracetamol and NSAIDs, at least for people with mild pain.

Avoiding concomitant use of two or more NSAIDs:

• This recommendation is based on criteria for the safe use of NSAIDs advised by the Commission on Human Medicines (formerly the Committee on Safety of Medicines) [CSM, 2002].

Gastroprotection:

• An individual person's baseline risk of GI complications is a key factor in determining how beneficial gastroprotection will be [MeReC, 2007].
• Coxibs are associated with a reduction in the risk of GI symptoms and complications compared with standard NSAIDs, but they do not eliminate the risk of GI adverse effects [Rostom et al, 2007].
• PPIs are effective at reducing the GI risks associated with NSAIDs and reduce the risks to a similar level as use of a coxib alone [Chan et al, 2002]. PPIs are also well tolerated, unlike misoprostol.
• NICE based their recommendation to add a PPI with a coxib on two papers reporting three RCTs (n = 1870) [Scheiman et al, 2006; Chan et al, 2007]. For more information, see Prevention of GI adverse effects.

• The management of gastrointestinal adverse effects in a person using a nonsteroidal anti-inflammatory drug depends on whether they have been investigated (e.g. with endoscopy or a test for Helicobacter pylori) and whether 'alarm' symptoms are present. For full details, see the CKS topics on:
• Dyspepsia - pregnancy-associated
• Dyspepsia - proven non-ulcer
• Dyspepsia - proven peptic ulcer
• Dyspepsia - unidentified cause
• For advice on how to manage people taking low-dose aspirin who develop gastrointestinal adverse effects, see the CKS topic on Antiplatelet treatment.

• The risk for serious cardiac or renal adverse events (including myocardial infarction, heart failure, and hypertension) is increased in people with:
• Ischaemic heart disease, cerebrovascular disease, or peripheral arterial disease.
• Renal impairment (e.g. creatinine clearance less than about 20 mL/min).
• Heart failure.
• Hypertension
• People risk factors for cardiovascular disease and all elderly people (e.g. > 65 years of age) are also at increased risk.

These recommendations take into account advice from the Medicines and Healthcare products Regulatory Agency (MHRA) and its independent adviser, the Commission on Human Medicines (CHM) [CSM, 2005; CHM, 2006; MHRA, 2007; MHRA, 2009b].

• The absolute risk of thrombotic adverse events with coxibs or standard NSAIDs is small.
• However, there are differences in relative risk between individual coxibs and NSAIDs. The relative increase in risk may be higher for people with risk factors for cardiovascular disease.
• Several observational studies suggest that some increased cardiovascular risk may apply to all NSAID users, irrespective of their baseline risk. Some studies suggest that the risk increases soon after an NSAID is started. However, the greatest concern relates to chronic use of high doses.
• The risks of renal and cardiorenal adverse effects from coxibs and standard NSAIDs may be greater in people with existing renal or cardiorenal compromise (e.g. cardiac failure).
• The risks for hypertension vary among drugs (indicating that the risk for hypertension may not be a class effect common to all NSAIDs), and it may be greatest for etoricoxib, ibuprofen, and naproxen and least for celecoxib and diclofenac.
• For further information, see the Supporting evidence sections on Risk of thrombotic adverse events and Risk of cardiorenal adverse events.

• People with heart failure.
• People with severe heart failure should not use NSAIDs.
• Those with moderate heart failure should not use coxibs.
• A standard NSAID may be used if necessary, but the individual should be closely monitored.
• Ibuprofen up to 1200 mg per day or naproxen up to 1000 mg per day are recommended as first-line options.
• People with ischaemic heart disease, cerebrovascular disease, or peripheral arterial disease.
• Coxibs are contraindicated.
• Ibuprofen up to 1200 mg per day or naproxen up to 1000 mg per day are recommended as first-line options.
• People with renal impairment (e.g. creatinine clearance less than about 20 mL/min).
• Ideally, avoid using NSAIDs.
• If an NSAID is used, the person should be closely monitored.
• People with risk factors for cardiovascular disease and all elderly people.
• Ibuprofen up to 1200 mg per day or naproxen up to 1000 mg per day are recommended as first-line options.
• People with hypertension
• Ideally, avoid using etoricoxib — etoricoxib may be associated with more frequent and severe effects on blood pressure than other coxibs and standard NSAIDs, particularly at high doses.
• Consider whether monitoring is needed.

The current summary of the evidence on thrombotic risk from the Medicines and Healthcare Products Regulatory Agency (MHRA) [CHM, 2006; MHRA, 2007; MHRA, 2009a] is that:

• The absolute risk of thrombotic risk for NSAIDs and coxibs is small.
• Coxibs (including celecoxib and etoricoxib) increase the risk for atherothrombosis by about 3 events per 1000 people per year (compared with placebo).
• Naproxen 1000 mg daily has a lower thrombotic risk than coxibs and, overall, epidemiological data do not suggest an increased risk of myocardial infarction.
• Ibuprofen may have a small thrombotic risk at high doses (e.g. 2400 mg daily), but at lower doses (e.g. 1200 mg daily or less), epidemiological data do not suggest an increased risk of myocardial infarction.
• Diclofenac 150 mg daily has a thrombotic risk profile similar to that of etoricoxib and possibly other coxibs.
• Other NSAIDs have less evidence on thrombotic risks, but they may all be associated with a small risk of thrombotic events.
• People with risk factors for cardiovascular events may be at higher risk of thrombotic adverse events, but some increased cardiovascular risk may apply to all NSAID users, including those at low estimated cardiovascular disease risk.
• Adverse effects may manifest early, and the risk may persist throughout treatment.
• However, the greatest concern relates to chronic use of high doses (especially for coxibs and diclofenac).

There is less evidence on the renal and renovascular risks (hypertension, heart failure) associated with coxibs and standard NSAIDs. The available evidence did not report absolute risk increases or numbers needed to harm.

• The MHRA continues to receive case reports of renal failure in NSAID users [MHRA, 2009b].
• One case-controlled study of standard NSAIDs found that they increase the risk of acute renal failure 3-fold; ibuprofen was associated with a lower risk than diclofenac in this study.
• Three systematic reviews found increased risks of hypertension and elevated blood pressure (particularly systolic blood pressure) with NSAIDs.
• The results are not entirely consistent among the studies.
• The risks for hypertension vary among drugs (indicating that this risk may not be a class effect); they may be greatest for etoricoxib, ibuprofen, and naproxen and least for celecoxib and diclofenac.
• The Commission on Human Medicines (formerly the Committee on Safety of Medicines) concluded that 'Etoricoxib, particularly at high doses, may be associated with more frequent and severe effects on blood pressure than other coxibs and standard NSAIDs' [CSM, 2005].
• One case-controlled study of standard NSAIDs found that they increase the risk of heart failure; indometacin carried the greatest risk.

• For advice regarding monitoring for people at increased risk of cardiovascular and renal adverse effects with NSAIDs, see What monitoring is needed?.

• Paracetamol is the analgesic and/or antipyretic of choice during conception.
• The effect of nonsteroidal anti-inflammatory drugs on the chances of conception has not been studied.
• If paracetamol is ineffective, occasional, single doses of an NSAIDs are unlikely to affect the chances of conception.
• However, if a woman is having difficulty conceiving or is undergoing investigation of infertility, the NSAID should be withdrawn.

For more information, contact the UK Teratology Information Service (UKTIS), formerly the National Teratology Information Service (NTIS), on 0844 892 0909.

• The recommendation to avoid NSAIDs is based on advice from the Committee on Safety of Medicines [CSM, 2006].
• The level of risk of NSAIDs on conception is unknown.
• The concern is plausible because NSAIDs inhibit the synthesis of prostaglandins, and prostaglandins play important roles in ovulation and implantation
• Whilst the level of risk of paracetamol on conception is also unknown, there is less cause for concern because at therapeutic doses it does not inhibit prostaglandin synthesis [Schaefer et al, 2007].

• Paracetamol is the analgesic and/or antipyretic of choice during pregnancy.
• However, if during the first or second trimester paracetamol is ineffective and an NSAID is clinically indicated:
• Ibuprofen is the preferred NSAID, but should only be used before 30 weeks of pregnancy (off-label use).
• Use the lowest effective dose for the shortest duration possible.
• If regular use is clinically indicated, such as in a woman with rheumatoid arthritis, seek specialist advice.
• NSAIDs must not be used from 30 weeks of pregnancy onwards without specialist advice and regular fetal monitoring.

For more information, contact the UK Teratology Information Service (UKTIS), formerly the National Teratology Information Service (NTIS), on 0844 892 0909.

These recommendations are based on advice from the UK Teratology Information Service (UKTIS), formerly the National Teratology Information Service (NTIS) [NTIS, 2008], and expert opinion from the medical literature [Schaefer et al, 2007].

Use of paracetamol during pregnancy

• Experience suggests that paracetamol can be used at any time during pregnancy [NTIS, 2004; Schaefer et al, 2007].

Occasional use of ibuprofen before 30 weeks of pregnancy

• Most manufactures advise avoiding NSAIDs at any time during pregnancy (off-label use) [BNF 57, 2009].
• NSAIDs are contraindicated from 30 weeks of pregnancy onwards because of the risk of premature closure of the ductus arteriosus, or decreasing amniotic fluid [Schaefer et al, 2007]. If treatment is unavoidable from week 30 onwards, fetal circulation and amniotic fluid levels should be monitored regularly (by ultrasound once or twice a week) and medication should be stopped as soon as signs of ductal constriction appear or if oligohydramnios occurs [Schaefer et al, 2007].
• If occasional use of an NSAID is required during the first two trimesters, ibuprofen is preferred because there is most clinical experience with its use [NTIS, 2008].

Risks of NSAID use before 30 weeks of pregnancy

• Miscarriage
• The UK Teratology Information Service (UKTIS), (formerly the National Teratology Information Service [NTIS]), have reviewed safety data of NSAIDs from published research and postmarketing surveillance systems [NTIS, 2008]. UKTIS concluded that 'an increased risk of spontaneous abortion following maternal exposure to NSAIDs during pregnancy has been suggested, but has not been conclusively proven'. A summary of the UKTIS review is given below:
• One case-control study [Nielsen et al, 2001] found an increased incidence of miscarriage in the group prescribed NSAIDs (63 of 381 women; 16.5%) compared with the control group (4,205 of 33,637 women; 12.5%). However, the overall incidence of miscarriage reported in this study was within the range of the European background incidence of miscarriages in clinically confirmed pregnancies (10-20%). In addition, there were many methodological weaknesses with the way the data were analysed in this study, making the results difficult to interpret.
• A re-analysis of this case-control study [Nielsen et al, 2004] substantially reduced the strength of the miscarriage associated with NSAIDs. The revised data set included 1,599 women, 45 of whom had filled prescriptions for NSAIDs in the last 12 weeks prior to miscarriage. The odds ratio for miscarriage was 0.58 following NSAID exposure at 10-12 weeks prior to miscarriage, increasing to 3.35 following NSAID exposure at one week prior to miscarriage.
• A 'post-hoc' analysis (not a pre-specified endpoint) of a population-based prospective cohort study involving 1,055 pregnant women evaluated exposure to NSAIDs, aspirin and paracetamol (taken after their last menstrual period) and the risk of miscarriage [Li et al, 2003]. Use of paracetamol (n = 172) during pregnancy was not associated with a risk of miscarriage, regardless of the timing or duration of use. The use of NSAIDs (n = 53) was associated with an increased risk of spontaneous abortion (hazard ratio 1.8, 95% CI 1.0 to 3.2). The risk of miscarriage was much higher when NSAIDs were taken around conception (adjusted hazard ratio 5.6, 95% CI 2.3 to 13.7) or were used for longer than a week (hazard ratio 8.1, 95% CI 2.8 to 23.4). However, the risk estimates are from observational studies that, like all observation studies, are susceptible to biases; for example, 'confounding by indication', the bias that arises when a drug is used to treat a condition that causes what seems to be an adverse effect of the drug. Also, these risk estimates are based on small actual numbers of exposures.
• Congenital defects
• The UK Teratology Information Service (UKTIS), (formerly the National Teratology Information Service [NTIS]), have reviewed safety data of NSAIDs from published research and postmarketing surveillance systems [NTIS, 2008]. UKTIS concluded that 'while recent data have suggested that there may be an increased risk of cardiac malformations associated with NSAID use in early pregnancy, this finding has not been confirmed. The available data on NSAIDs generally do not indicate that exposure before 30 weeks of pregnancy is associated with an increased risk of malformations.' A summary of the data included in the UKTIS review is given below:
• One registry-based study [Ofori et al, 2006] observed an increased risk of cardiac septal defects. There were 93 births with congenital malformations among 1,056 women who had filled a prescription for an NSAID in the first trimester compared with 2,478 among 35,331 women who did not use NSAIDs. The odds ratio for cardiac septal defects, adjusted for confounding variables was 3.34 (95% CI 1.87 to 2.85).
• A previous registry-based study [Ericson and Kallen, 2001] found no overall increased risk of malformations associated with NSAID use (OR 1.04, 95% CI 0.84 to 1.29), but did report 36 births with cardiac defects among 2,557 women who reported using an NSAID in the first trimester (OR 1.86, 95% CI 1.32 to 2.62).
• A case-control study of 168 infants with a ventricular septal defect and 692 controls found no link between maternal use of NSAIDs and cardiac septal defects [Cleves et al, 2004].
• A study of 88 pregnant patients, of whom 45 were women with rheumatoid arthritis using regular NSAIDs, found there was no significant effect of NSAID exposure on pregnancy outcome [Ostensen and Ostensen, 1996]. No congenital anomalies were reported among those women who used NSAIDs during pregnancy. NSAIDs were withdrawn by week 36 of pregnancy in all women, and the average duration of NSAID exposure was 15.3 weeks.

Risks of NSAID used from 30 weeks of pregnancy onwards

• Premature closure of the ductus arteriosus
• Premature closure of the ductus arteriosus may lead to tricuspid regurgitation in utero, pulmonary hypertension in the fetus, and persistent pulmonary hypertension in the neonate.
• The risk of ductal closure increases with gestational age, being rare before week 29, but increasing with advancing gestational age to 50–70% at 34 weeks, rising as high as 100% from week 36 onwards [Schaefer et al, 2007].
• Based on 217 women exposed to NSAIDs in the third trimester and 221 to controls, the risk of ductal closure was 15-fold higher in the group of women exposed to NSAIDs (pooled OR 15.04; 95% CI 3.29 to 68.68) [Koren et al, 2006].
• Persistent pulmonary hypertension occurs in about 1–2 newborns per 1,000 live births, causing severe hypoxaemia. The mortality rate is around 10–20% of affected newborns [Silvani and Camporesi, 2007].
• Oligohydramnios
• Oligohydramnios is a condition in pregnancy characterized by a deficiency of amniotic fluid.
• NSAIDs are known to adversely affect renal function, and normal renal function is required to maintain amniotic fluid [Schaefer et al, 2007].

• Paracetamol is the drug of choice during breastfeeding.
• If a nonsteroidal anti-inflammatory drug is clinically indicated:
• Ibuprofen is the preferred NSAID.
• Use the lowest effective dose, for the shortest time possible.

For more information, see the UK Drugs in Lactation Service website, or telephone 0121 311 1974.

• Paracetamol is suitable for use by breastfeeding mothers. Although it appears in breast milk, the amount is too small to be harmful, and is much less than the doses given to infants [LactMed, 2007; UKMi, 2009b].
• Ibuprofen is recommended as a first-line option because its half-life is short, and levels in breast milk are negligible [Schaefer et al, 2007; UKMi, 2009a].
• NSAIDs with long serum half-lives (e.g. naproxen) should be avoided because the risk of adverse effects is likely to be higher than for NSAIDs with short serum half-lives [UKMiCentral, 2004; Schaefer et al, 2007].

Check whether the person self-medicates with aspirin or ibuprofen, which are available without prescription.

Consider seeking the advice of a specialist when uncertain about a specific drug interaction.

• If possible, avoid the concomitant use of low-dose aspirin and a nonsteroidal anti-inflammatory drug (NSAID):
• If loss of antiplatelet effect is a major concern, consider switching low-dose aspirin to clopidogrel.
• Consider whether paracetamol and/or codeine can be used.
• Low-dose aspirin for cardiovascular protection almost always has priority over an NSAID.
• If an NSAID is required, see People at increased risk and establish whether the NSAID is likely to be required for short-term or long-term use:
• If gastrointestinal adverse effects are a major concern, prescribe a proton pump inhibitor.
• For short-term or long-term NSAID use, CKS prefers naproxen or ibuprofen.

These recommendations reflect advice from the Commission on Human Medicines (formerly the Committee on Safety of Medicines) that the combination of low-dose aspirin and an NSAID should only be used if absolutely necessary [CSM, 2002; CSM, 2003]. Similar advice is given by the US Food and Drug Administration (FDA), by an authoritative reference manual on drug interactions, and by the British National Formulary [Baxter, 2006; FDA, 2006a; FDA, 2006b; BNF 55, 2008]:

• The National Institute for Health and Clinical Excellence considers that all NSAIDs may antagonize the cardioprotective effects of aspirin.
• All NSAIDs are associated with an increased risk of thrombotic adverse events; however naproxen and ibuprofen may be slightly more favourable than most other NSAIDs, based on the evidence for cardiovascular thrombotic risks associated with coxibs and standard NSAIDs [CHM, 2006; MHRA, 2007]:
• There is concern (based on laboratory studies) that regular ibuprofen use could antagonize the antiplatelet effect of low-dose aspirin. The Medicines and Healthcare products Regulatory Agency (MHRA) keeps this issue under continual review, but because no clinical evidence suggests an important risk, the MHRA has not updated its prescribing advice [MeReC, 2007].
• The US FDA, however, advises that [FDA, 2006a; FDA, 2006b]:
• With occasional use of ibuprofen, there is little risk of reducing the antiplatelet effect of low-dose aspirin because aspirin has a long-lasting effect on platelets.
• When ibuprofen is used with immediate-release aspirin, their administration should be staggered to minimize interaction (e.g. ibuprofen 400 mg, administered at least 30 minutes after aspirin ingestion or more than 8 hours before aspirin ingestion).
• Gastrointestinal (GI) safety options with long-term NSAID use:
• Evidence indicates that the risk of GI bleeding is significantly lower when aspirin is used with a proton pump inhibitor (PPI) than when clopidogrel is used instead of aspirin [Chan et al, 2005].
• The Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial found that clopidogrel 75 mg/day was less likely to cause adverse GI effects than aspirin 325 mg/day, but absolute differences were small [CAPRIE Steering Committee, 1996].

• There is no need to avoid the concurrent use of ciclosporin and a nonsteroidal anti-inflammatory drug (NSAID), but monitoring is necessary:
• Renal function should be closely monitored.
• Liver function requires less close monitoring, but hepatotoxicity is a potential adverse effect of both drugs.
• Ciclosporin can double serum levels of diclofenac, therefore:
• If diclofenac is being started in a person receiving ciclosporin, initially use diclofenac doses at the lower end of the range.
• If ciclosporin is being started in a person receiving diclofenac, halve the diclofenac dose.

• These recommendations are based on information in an authoritative reference manual on drug interactions and the British National Formulary [Baxter, 2006; BNF 55, 2008]:
• Available data are limited, but both ciclosporin and NSAIDs can reduce renal function in some individuals.
• It is difficult to generalize about what will or will not happen if a particular NSAID is used, but expert opinion highlights that diclofenac use is of particular concern.

• Avoid concomitant use of clozapine with azapropazone, because the risk of agranulocytosis is increased:
• Clozapine can be used with other NSAIDs.

• These recommendations are based on information in the British National Formulary [BNF 55, 2008]:
• Azapropazone is a pyrazolone-type nonsteroidal anti-inflammatory drug (NSAID) [Haddad et al, 2004]. NSAIDs with a different chemical structure are thought not to interact with clozapine.

• Thiazide-type diuretics:
• Indometacin may reduce the antihypertensive effect of thiazides. With concurrent use of a thiazide-type diuretic and indometacin, blood pressure should be regularly monitored and the thiazide dosage increased as necessary.
• This interaction is less likely with other nonsteroidal anti-inflammatory drugs (NSAIDs).
• Loop diuretics:
• There is generally no need to avoid the concomitant use of a loop diuretic and an NSAID, but monitoring is necessary, because:
• The antihypertensive effect may be reduced.
• The diuretic effects may be reduced.
• Diuretics increase the risk of NSAID-induced renal impairment and failure.
• If a reduced antihypertensive or diuretic effect occurs, the dose of the loop diuretic can be increased:
• If increasing the diuretic dose is ineffective, switch to an NSAID which is considered to interact less significantly (e.g. ibuprofen).
• If NSAID-induced renal impairment occurs, either switch the NSAID to a non-NSAID analgesic or switch the diuretic.
• Potassium-sparing diuretics:
• Avoid concomitant use of triamterene and indometacin because risks of reduced renal function and rapid development of acute renal failure are increased.
• It is good practice to use caution when any NSAID is used with triamterene.
• Use of a potassium-sparing diuretic with an NSAID may increase the risk of hyperkalaemia; therefore, serum potassium levels need to be monitored.

• These recommendations are based on information in an authoritative reference manual on drug interactions and in the British National Formulary [Baxter, 2006; BNF 55, 2008].
• The interaction between thiazide-type diuretics and indometacin is well established, but other NSAIDs appear to interact to a lesser extent or not at all [Baxter, 2006].

• Nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce the excretion of lithium, causing serum lithium levels to rise and increasing the risk of lithium toxicity.
• The concomitant use of lithium and NSAIDs (especially indometacin) should therefore be avoided.
• Seek specialist advice if this combination of drugs is considered necessary.
• With concomitant use of lithium and an NSAID, serum lithium levels must be very closely monitored and the lithium dose reduced as necessary.
• In view of the severity of the interaction, people taking lithium plus an NSAID should be warned to watch for the symptoms of lithium toxicity:
• Ataxia, blurred vision, coarse tremor, giddiness, muscle twitching, tinnitus, and a large output of dilute urine.

• These recommendations are based on information in an authoritative reference manual on drug interactions and the British National Formulary [Baxter, 2006; BNF 55, 2008].

• Concurrent use of methotrexate and a nonsteroidal anti-inflammatory drug (NSAID) may reduce the excretion of methotrexate and increase the risk of methotrexate toxicity.
• Where possible, avoid using an NSAID (especially azapropazone, and over-the-counter aspirin and ibuprofen).
• If an NSAID is needed, perform a full blood count and kidney and liver function tests every 2 months.
• So that methotrexate toxicity can be detected early, tell people to report immediately the onset of:
• Signs and symptoms suggestive of infection (e.g. sore throat, mouth ulcers).
• Liver toxicity (e.g. nausea, vomiting, abdominal discomfort, and dark urine).
• Respiratory effects (e.g. cough, shortness of breath).

• These recommendations are based on information in an authoritative reference manual on drug interactions and the British National Formulary [Baxter, 2006; BNF 55, 2008]:
• The risk of methotrexate toxicity increases with the dose of methotrexate [Baxter, 2006].

• Avoid concomitant use of phenytoin with azapropazone because serum phenytoin levels can be markedly increased and phenytoin toxicity can develop rapidly.
• Other nonsteroidal anti-inflammatory drugs (NSAIDs) vary in the degree to which they enhance the effects of phenytoin.
• Advise anyone taking an NSAID with phenytoin to seek immediate medical attention if such symptoms as lethargy, confusion, muscular twitching, fever, sore throat, rash, blistering, mouth ulcers, bruising, or bleeding develop.
• If an interaction occurs, discontinue the NSAID or reduce the phenytoin dose as necessary.

• These recommendations are based on an authoritative reference manual on drug interactions and the British National Formulary [Baxter, 2006; BNF 55, 2008].

• Avoid the concurrent use of probenecid and ketorolac:
• Probenecid reduces excretion of ketorolac, resulting in an increased plasma concentration of ketorolac.
• Closely monitor people who are concurrently receiving probenecid and indometacin because some may develop indometacin toxicity (headache, dizziness, light-headedness, nausea). This is particularly likely in people with impaired renal function:
• Reduce the indometacin dose as necessary.
• Concurrent use of probenecid and other nonsteroidal anti-inflammatory drugs (NSAIDs) is unlikely to result in an interaction, but it is prudent to be alert for any evidence of increased adverse effects:
• In the event of an interaction, reduce the NSAID dose as necessary.

• These recommendations are based on an authoritative reference manual on drug interactions and the British National Formulary [Baxter, 2006; BNF 55, 2008].

• The risk of convulsions may be increased when a quinolone is used concomitantly with a nonsteroidal anti-inflammatory drug (NSAID).
• Normally, no interaction seems to occur with most quinolones and NSAIDs; therefore, the concomitant use of a quinolone and an NSAID is acceptable.
• One possible exception to this is in people with epilepsy on an NSAID (e.g. in people taking ciprofloxacin and phenytoin, phenytoin levels should be closely monitored). In these people, it may be best to avoid the concomitant use of a quinolone and an NSAID.

• These recommendations are based on information in an authoritative reference manual and the British National Formulary [Baxter, 2006; BNF 55, 2008]. They also reflect advice from the Commission on Human Medicines (formerly Committee on Safety of Medicines) that the risk of convulsions is increased when quinolones and nonsteroidal anti-inflammatory drugs are used concomitantly [CSM, 1991; BNF 55, 2008].

• The risk of upper gastrointestinal bleeding is increased when a selective serotonin reuptake inhibitor (or venlafaxine or duloxetine) and a nonsteroidal anti-inflammatory drug (NSAID) are concomitantly prescribed:
• Therefore, advise people to seek urgent medical advice and to not take any more of the NSAID if a bleeding episode is experienced.
• If an NSAID is considered necessary, weigh the risks and benefits and consider prescribing gastroprotection.
• Consider prescribing mirtazapine or trazodone as alternative antidepressants.

These recommendations are based on information in the British National Formulary [BNF 55, 2008] and NICE guidance Depression in adults with a chronic physical health problem [NICE, 2009]. They are supported by additional evidence from a recently-published meta-analysis of four observational studies involving 153,000 people [Loke et al, 2008]:

• The meta-analysis found:
• A significant risk of upper gastrointestinal (GI) bleeding after selective serotonin reuptake inhibitor (SSRI) use (odds ratio 2.36, 95% CI 1.44 to 3.85, p = 0.0006).
• An even greater risk of upper GI bleeding after concomitant SSRI and NSAID use (odds ratio 6.33, 95% CI 3.40 to 11.8, p < 0.0001).
• In people older than 50 years of age with no risk factors for upper GI bleeding:
• For every 411 people treated with SSRIs, one person experienced upper GI bleeding (NNH = 411).
• For every 106 people treated with an SSRI and an NSAID together, one person experienced upper GI bleeding (NNH = 106).
• The investigators also analysed 101 spontaneous postmarketing reports of episodes of upper GI bleeding associated with SSRI use:
• 67% of the reports were from people who were also using an NSAID.
• The median time to upper GI bleeding was 25 weeks after starting SSRI treatment.
• Venlafaxine and duloxetine also inhibit serotonin reuptake, so can be expected to interact similarly.

• Concomitant use of a sulphonylurea and a nonsteroidal anti-inflammatory drug (NSAID) may result in hypoglycaemia.
• People using a sulphonylurea and azapropazone are at increased risk of hypoglycaemia. Therefore, if possible, stop the azapropazone and use another NSAID, or:
• Monitor blood glucose levels closely, and
• Consider reducing the dose of the sulphonylurea.
• Other NSAIDs do not normally increase the risk of hypoglycaemia when used together with a sulphonylurea, but isolated cases of hypoglycaemia have been reported, with the effect of the sulphonylurea being enhanced in people given:
• Fenclofenac with chlorpropamide and metformin.
• Diflunisal with glibenclamide.
• Naproxen with glibenclamide and metformin.
• Indobufen with glipizide.
• Piroxicam with glibenclamide.

• These recommendations are based on information in an authoritative reference manual and the British National Formulary [Baxter, 2006; BNF 55, 2008].

• All nonsteroidal anti-inflammatory drugs (NSAIDs) can cause gastrointestinal irritation and reduce platelet aggregation, which can worsen any bleeding event. All NSAIDs can also increase the international normalized ratio (INR). The magnitude of the increase in INR varies in different reports.
• If a person receiving warfarin requires an NSAID:
• Consider referral to, or consultation with, a specialist.
• Do not use azapropazone, ketorolac, or phenylbutazone. The risk of serious bleeding is greater with these drugs than with other NSAIDs.
• For all other NSAIDs, consider whether an NSAID is necessary:
• If an NSAID is considered necessary, prescribe gastroprotection (e.g. a coxib and a proton pump inhibitor) and closely monitor the INR when initiating the NSAID, changing its dose, or discontinuing it.
• If the INR increases, reduce the warfarin dose as appropriate.
• Reports of NSAID interactions with anticoagulants other than warfarin are limited, but other anticoagulants would be expected to have interactions with NSAIDs similar to those of warfarin.

• These recommendations are based on information in an authoritative reference manual and the British National Formulary [Baxter, 2006; BNF 55, 2008].