NSAID Regional Audit Group Presentation. Audit Group: Dr Richard Latten, Ruth Clark, Dr Sarah Fradsham, Dr Seamus Coyle, Claire Johnston

NSAID Regional Audit Group Presentation Audit Group: Dr Richard Latten, Ruth Clark, Dr Sarah Fradsham, Dr Seamus Coyle, Claire Johnston

Thank you from the audit group for all who participated in the data collection for this audit. Our External/ Expert reviewers unfortunately cannot make it today but have and will be involved in the refinements of the S&G Andrew Dickman, Dr Victor Pace.

Agenda Current Standards and Guidelines (CJ) Literature Review (SC) Proposed updated Standards and Guidelines (RL) Questions and discussion

NSAIDs Current Standards and Guidelines Claire Johnston Community SPC CNS

General principles Non-steroidal anti-inflammatory drugs (NSAIDs) consist of a heterogenous group of compounds that can be subdivided by virtue of their pharmacology; -Non-selective NSAIDs inhibit both COX-1 and COX-2 receptors e.g. ibuprofen, naproxen. -COX-2 selective NSAIDs display some selectivity for COX-2 receptors but this diminishes as the dose increases e.g. etodolac, meloxicam. -COX-2 inhibitors specifically inhibit COX-2 receptors at therapeutic doses whilst being COX-1 sparing e.g. celecoxib, etoricoxib.

General principles All NSAIDs have significant cardiovascular and gastrointestinal toxicity. Consider whether alternative treatment would be appropriate (e.g. topical NSAIDs, paracetamol, tramadol). Prescribe the lowest possible dose of NSAID for the shortest possible time necessary.

Current guidelines Cardiovascular Risk COX-2 inhibitors are contraindicated for use in patients with established ischaemic heart disease and/or cerebrovascular disease, and also in patients with peripheral arterial disease.[level1] Despite conflicting evidence, non-selective NSAIDs and COX -2 selective are currently licensed for use in these groups of patients, although they should be used with caution. [Level 4]

Current guidelines- Renal Dysfunction Renal function should be assessed prior to the introduction of an NSAID and within 7 days of starting treatment or increasing the dose.[level 4] Care is required when prescribing NSAIDs for patients with heart failure, ascites or impaired renal function, particularly those who are dehydrated or have a low effective circulating volume. [Level 4]

Current guidelines- Renal Dysfunction Long term administration of NSAIDs has been linked to papillary necrosis and other renal injuries. Patients with impaired renal function, heart failure, liver dysfunction, the elderly and those taking diuretics and/or angiotensin-converting enzyme inhibitors are at greatest risk from this reaction. Discontinuation of NSAIDs therapy is usually followed by recovery to the pre-treatment state.[level 4] Use of NSAIDS in patients with advanced renal disease is not recommended due to a lack of safety data from controlled clinical studies. If NSAIDs are prescribed it is essential that renal function is monitored closely.[level 4]

Current guidelines- Gastrointestinal Toxicity Patients at high risk of gastrointestinal side effects from NSAIDs include the following;[level 4] - Elderly (age>65 years), -Previous upper gastroduodenal perforation,ulcers and bleeds. -Concurrent use of aspirin, warfarin,corticosteroids or selective serotonin reuptake inhibitors (SSRIs) -Patients receiving maximum doses of NSAIDs. Undesirable gastric side effects from celecoxib are significantly less than from non-selective NSAIDs although it is not clear whether this lower risk continues with long term use.[level 4] In patients taking clopidogrel, it is advisable to use an H2 antagonist at a higher dose than usual e.g. ranitidine 300mgs bd. [Level 4]

Current Guidelines PPIs A PPI should be co-prescribed with a NSAID, regardless of which actual drug is chosen. [Level 4] This is cost effective in the treatment of Osteoarthritis, but the benefit of a PPI with a COX-2 inhibitor in other situations is unclear. [Level 4] The relationship between H. pylori infection and NSAIDs in duodenal pathology is complex. Eradication of H pylori infection may prevent peptic ulcer disease in patients who are naiive users of NSAIDs. Patients receiving long term PPI treatment for prevention of NSAID ulcers should be tested for H Pylori. Eradiction of H Pylori will reduce the risk of accelerated loss of specialised glands and atrophic gastritis. [Level 4]

Current Guidelines- PPI Appropriate PPIs and oral doses include: - Esomeprazole 20mg od - Lansoprazole 30mg od - Omeprazole 20mg od - Pantoprazole 40mg od Misoprostol is a synthetic prostaglandin analogue with gastric anti-secretory and protective properties which can be used to protect against NSAID-induced gastrointestinal damage. It is more effective than PPIs but can be poorly tolerated. Side effects include colic and diarrhoea. A suggested starting dose is 200mcg od, increasing by 200mcg every 1-2 days to a normal dose of 200mcg qds.

Current Guidelines- Choice of NSAID Before deciding which NSAID to use, the prescriber must first asses patient risk factors for cardiovascular and gastrointestinal toxicity (figure 29.1) [Level 4] Table 29.1 lists NSAIDs currently recommended for use. Table 29.2 lists additional NSAIDs that may be considered second line options. [Level 4]

Current Guidelines- Monitoring Effectiveness NSAIDs should be presribed for at least seven days before reviewing their clinical effectiveness. The analgesic effect of the drug becmes apparent within the first few days of treatment. The anti-inflammatory response may take at least 2 weeks to become evident. [Level 4] It may be appropriate to use an alternative NSAID before concluding that NSAIDs are ineffective. [Level 4] Due to the increased risk of renal and gastroduodenal toxicity, ketorolac should only be used for refractory pain. A PPI should always be co-prescribed with ketorolac unless the patient is in the dying phase. [Level 4]

Current Standards. 1. Cox-2 inhibitors are contra-indicated for use in patients with existing ischaemic heart, peripheral vascular disease or cerebrovascular disease [GradeB] 2. In patients with existing cardiovascular disease, alternate analgesia should be considered before introducing a nonselective NSAID or a COX-2 selective NSAID. If NSAID s are to be used the lowest dose possible should be prescribed and the patient should be reviewed within 7 days. [Grade D] 3. It may be appropriate to use an alternative NSAID before concluding that NSAIDs are ineffective. [Grade D]

Current Standards 4. Patients with risk factors for gastrointestinal toxicity should be prescribed proton pump inhibitors or misoprostol for gastric protection [Grade B] 5. A PPI should be prescribed for all patients receiving subcutaneous NSAID s, unless they are in the dying phase.[grade D] 6. Renal function should be assessed prior to the introduction of a NSAID and within 7 days of starting treatment or increasing the dose. [Grade D]

Table 29.1- NSAIDS currently recommended for use Class of NSAID Name of drug Oral dose CSCI over 24 hours Additional notes Nonselective Naproxen 500mg bd n/a Suitable 1 st line choice, together with PPI for patients with CV risk Ibuprofen Nonselective 400mg- 800mg tds n/a Low dose brufen(<1200mgs) suitable1st line choice, together with PPI, for patients with CV risk. If low dose aspirin is coprescribed, ibuprofen should be given at least 8 hours before or 30 minutes after. Alternatively, Change aspirin to clopidogrel. COX-2 inhibitor Celecoxib 100-200mg bd n/a Suitable 1 st line choice in patients at high risk of GI toxicity and low CV risk. PPI should be coprescribed in high GI risk patients.

Table 29.2. Additional NSAIDs avaliable for use [Level 4] Class of NSAID Name of drug Oral dose CSCI over 24 hours Additional notes Nonselective Nonselective Nonselective Non selective Diclofenac sodium Nabumetone 50mg tds 75mg m/r bd 500mg od-1g bd Painful. Dose 150mg daily n/a/ Ketorolac n/a/ 30mg- 90mg Piroxicam melt 20mg od S/L 150mg daily via rectal route. Diclofenac is associated with similar thrombotic risk to COX-2 inhibitors Lowest GI risk of all non-selective NSAIDS. Some units may user first line. Can give 10mg stat subcutaneous dose. Carries greater risk of renal and gastrointestinal toxicity compared to other NSAIDs. Due to the propensity for toxicity, the continued need for a CSCI of ketorolac should be reviewed on a weekly basis. Increased risk of GI toxicity and serious skin reactions. Not to be used for first line treatment.

Table 29.2 Cont Class of NSAID Name of drug Oral dose CSCI over 24 hours Additional notes COX-2 selective Etodolac 600mg m/r od n/a n/a COX-2 inhibitor Etoricoxib 60mg-120mg od n/a NICE do not recommend etoricoxib for first line use in osteoarthritis. For this reason, consider as 2 nd line choice.

Figure 29.1 Flow diagram of NSAID choice Consider whether alternative treatment would be appropriate Assessment of cardiovascular (CV) history No CV History Assessment of gastrointestinal (GI) risk factors CV History Assessment of gastrointestinal (GI) risk factors Low GI Risk >1 GI Risk Low GI Risk >1 GI Risk List A List B List C List D

Table 29.3. Choice of NSAID according to CV history and GI risk factors Step List A No CV history No GI risk List B No CV history GI risk List C CV history No GI risk List D CV history GI risk 1 Alternative analgesia e.g. topical NSAID, paracetamol, tramadol Alternative analgesia e.g. topical NSAID, paracetamol, tramadol. Alternative analgesia e.g. topical NSAID paracetamol, tramadol. Alternative analgesia e,.g. topical NSAID, paracetamol, tramadol. 2 Low dose ibuprofen (<1200mg/day) +PPI or Nabumetpone plus PPI COX-2 Inhibitor e.g. celecoxib + PPI Low dose ibuprofen (<1200mg/day) +PPI or naproxen +PPI Low dose ibuprofen (<1200mg/day) +PPI or naproxen + PPI 3 Non-selective NSAID e.g. diclofenac + PPI or naproxen + PPI COX-2 inhibitor e.g. etoricoxib + PPI Non selective NSAID e.g. nabumetone + PPI Non selective NSAID e.g. nabumetone + PPI 4 COX-2 selective NSAID e.g. etodolac + PPI Low dose ibuprofen (1200mgs/day) + PPI or nabumetone plus PPI 5 COX-2 inhibitor e.g. celecoxib COX-2 selective NSAID e.g. etodolac + PPI

NSAID Audit -Literature Review Dr Seamus Coyle Academic Clinical Fellow

Overview Literature search Rational of NSAIDs including indications NSAIDs in non-cancer conditions Topical NSAIDs Risks/Side effects of NSAIDs Palliative Overview

Literature Search

Literature Survey of NSAIDs over the last 5 years 105 NSAID review articles all articles for NSAIDs and Palliative care The Cochrane library NICE guidelines

Rational of NSAIDs

NSAIDs more effective than placebo for cancer pain Cancer pain = as a result of the cancer itself, a side effect of therapy or procedures or unrelated to the cancer Clear evidence to support safety or efficacy of one NSAID over another is lacking Slight but statistically significantly advantage (9 out of 14 papers) combining Paracetamol with a NSAID compared with either single entity NSAIDs or Paracetamol, alone or combined with opioids for cancer pain Cochrane Review 2011 McNicol ED Strassels S, Goudas L, Lau J, Carr DB

13 out of 14 studies found no difference or low clinical difference when combining an NSAID plus an opioid versus either drug alone. 4 papers increased efficacy with increased dose - the majority of studies were of less than 7 days duration No studies addressed use of COX2 inhibitors to manage cancer pain Meta-analysis of 4 trials demonstrated significantly lower proportion of patients reported adverse events while being administered NSAIDs vs opioids (OR=0.38 [95% CI, 0.15 to 0.97] NSAIDs or Paracetamol, alone or combined with opioids for cancer pain Cochrane Review 2011 McNicol ED Strassels S, Goudas L, Lau J, Carr DB

Short duration of studies undermines generalisation of their findings on efficacy and safety of NSAIDs for cancer pain the use of NSAIDs for cancer pain is widely recommended, the long term safety profile of NSAIDs in patients with cancer has not been established in a randomised study. WHO recommends addition of a 'weak' opioid for mild to moderate pain...findings do not substantiate this recommendation. It may be advisable to increase to a maximum acceptable dose of their NSAIDs (or adjuvant drug) before the addition of, or replacement with, an opioid. NSAIDs or Paracetamol, alone or combined with opioids for cancer pain Cochrane Review 2011 McNicol ED Strassels S, Goudas L, Lau J, Carr DB

Advice to Healthcare professionals Patients should use the lowest effective dose and the shortest duration of NSAID treatment necessary to control symptoms, and the need for long-term treatment should be reviewed periodically NSAIDs increase the risk of Cardiovascular events but that the balance of benefits to risks remained favourable MHRA Public Assessment Report Jan 2010

NSAIDs in non-cancer conditions

Pharmacological management of osteoarthritis* When paracetamol/topical NSAIDs ineffective for pain relief, substitution with an oral NSAID/COX-2 inhibitor should be considered. Where paracetamol/topical NSAIDs provide insufficient pain relief addition of an oral NSAID/COX-2 inhibitor to paracetamol should be considered. Oral NSAIDs/COX-2 inhibitors should be used at the lowest effective dose for the shortest possible period of time. *Pharmacological management of osteoarthritis NICE Guidelines 2008

Pharmacological management of osteoarthritis* First choice should be either a standard NSAID or a COX-2 inhibitor (other than etoricoxib 60 mg) co-prescribed with a PPI *Pharmacological management of osteoarthritis NICE Guidelines 2008

Pharmacological management of osteoarthritis* All oral NSAIDs/COX-2 inhibitors have analgesic effects of a similar magnitude but vary in their potential gastrointestinal, liver and cardio-renal toxicity; take into account individual patient risk factors, including age. appropriate assessment and/or ongoing monitoring of these risk factors. *Pharmacological management of osteoarthritis NICE Guidelines 2008

Pharmacological management of osteoarthritis* When patient needs to take low-dose aspirin and pain relief is ineffective or insufficient consider other analgesics before substituting or adding an NSAID / COX-2 inhibitor (with a PPI) *Pharmacological management of osteoarthritis NICE Guidelines 2008

Oral analgesics Paracetamol and/or topical non-steroidal antiinflammatory drugs (NSAIDs) should be considered ahead of oral NSAIDs / COX-2 inhibitors or opioids. If paracetamol or topical NSAIDs are insufficient for pain relief then the addition of opioid analgesics should be considered. Risks and benefits should be considered particularly in the elderly Pharmacological management of osteoarthritis NICE Guidelines 2008

NSAIDs and highly selective COX-2 inhibitors Increased role for COX-2 inhibitors, with an increased awareness of all potential adverse events (gastrointestinal, liver and cardio-renal) and a recommendation to co-prescribe a PPI.* based on up-to-date evidence on efficacy, adverse events, current costs and an expanded healtheconomic analysis of cost effectiveness.* *Pharmacological management of osteoarthritis NICE Guidelines 2008

NSAIDs may be tolerated in patients with mild chronic liver disease but should be avoided in all patients with cirrhosis because of increased risk of hepatorenal syndrome Pain Management in the Cirrhotic patient Chandok Watt 2010 Mayo Clin Proc. 2010 May;85(5):451-8.

Topical NSAIDs

Topical NSAIDs can provide good levels of pain relief in acute conditions such as sprains, strains and overuse injuries* Probably similar to that provided by oral NSAIDs. Little difference in analgesic efficacy between diclofenac, ibuprofen, ketoprofen and piroxicam but indomethacin is less effective, and benzydamine is no better than placebo. No increased incidence of local reactions compared to placebo Do not cause systemic problems * Topical NSAIDs for acute pain in adults (review) The Cochrane Collaboration 2012

Topical NSAIDs can provide good levels of pain relief* without the systemic adverse events associated with oral NSAIDs when used to treat acute musculoskeletal conditions. No serious adverse events reported in studies reviewed* * Topical NSAIDs for acute pain in adults (review) The Cochrane Collaboration 2012

Risks/Side effects of NSAIDs

All NSAID users may be at an increased CV risk, irrespective of their baseline risk for cardiovascular illness or the duration of NSAID use MHRA Public Assessment Report Jan 2010

Since 2006 2 important studies have been published which examine the risk of thrombotic cardiovascular events, such as MI in association with NSAIDs. (nonselective NSAIDs and COX-2 inhibitors) UK THIN (The Health Improvement Network) Danish group MHRA Public Assessment Report Jan 2010

Both studies found a very small increase in the risk of CVS events..that may apply to all users of NSAIDs, not only those with baseline CVS risk factors..after a relatively short-term NSAID use (that may increase with increasing duration of use). association with the following specific NSAIDs; celecoxib (any dose); high dose diclofenac (>150mg/day); high dose ibuprofen (>1200mg/day) No detectable effect on CV risk was demonstrated for another specific NSAID, naproxen, at any dose. MHRA Public Assessment Report Jan 2010

Rates of thrombotic cardiovascular events in patients with arthritis on etoricoxib are similar to those in patients on diclofenac with longterm use of these drugs. Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison Cannon et al The Lancet 2006 Vol 368 p1771 1781

Rationale for discontinuing Cox-2 inhibitors* VIGOR Study significantly higher incidence of cardiovascular thrombotic events with rofecoxib cf naproxen (Bombardier et al NEJM 2000) 5 fold increase risk of MI APPROVE study confirmed above evaluated adenomatous polyps in patients treated with rofecoxib ct placebo. 2 fold increase MI risk (Bresalier et al NEJM 2005) Meta-analysis of Rofecoxib (Juni Lancet 2004) Rofecoxib and valdecoxib withdrawn * Review of the CVS safety of CoxiBs compared to NSAIDs Moodley Cardiovasc J Afr 2008 Mar-Apr;19(2):102-7.

Rationale for discontinuing Cox 2 inhibitors* No increase in cardiovascular events or all cause mortality was observed for celecoxib vs diclofenac, ibuprofen and naproxen (Varas-Lorenzo et al 2007) Pooled analysis no increase CVS events with celecoxib but at higher doses higher risk of MI (Juni et al Br Med J 2002) risk of death and recurrent CHF combined was higher in patients prescribed NSAIDs or rofecoxib than in those prescribed celecoxib * Review of the CVS safety of CoxiBs compared to NSAIDs Moodley Cardiovasc J Afr 2008 Mar-Apr;19(2):102-7.

Cox-2 inhibitors appear to be prescribed preferentially to patients who were at an increased risk of cardiovascular events compared with patients prescribed non-specific NSAIDs* When the overall risk of CVS complications is relatively low and an anti-inflammatory agent is required, current evidence suggests that celecoxib is an agent of choice because of its lower cardiovascular toxicity potential compared to NSAIDs and other Cox-2 inhibitors * Most patients, particularly the young, can benefit from NSAIDs without the risk of serious adverse GI or CVS events... previous history of serious GI complications and the elderly.. do require alternatives* * Review of the CVS safety of CoxiBs compared to NSAIDs Moodley Cardiovasc J Afr 2008 Mar-Apr;19(2):102-7.

South African Rheumatoid Arthritis Association Guidelines Nov 2005 - Cox-2 inhibitors for elderly patients (>60) with previous gastropathy and those on warfarin and / or corticosteroids, providing they do not have contraindications. Caution prescribing Cox-2 inhibitors for patients with risk factors for heart disease Celecoxib does not increase small intestinal permeability and does not cause lower intestinal bleeding * Review of the CVS safety of CoxiBs compared to NSAIDs Moodley Cardiovasc J Afr 2008 Mar-Apr;19(2):102-7.

A Palliative Overview There were no studies with NSAIDs and Palliative Care / EOL care Long term safety profile of NSAIDs in patients with cancer has not been established in a randomised study. No studies addressed use of COX2 inhibitors to manage cancer pain

A Palliative Overview There were no studies with NSAIDs and Palliative Care / EOL care Long term safety profile of NSAIDs in patients with cancer has not been established in a randomised study. No studies addressed use of COX2 inhibitors to manage cancer pain

NSAIDs Proposed updated Standards and Guidelines Dr Richard Latten Consultant in Palliative Medicine

General Principles Cyclo-oxygenase (COX) 1 and 2 are involved in the inflammatory pathways. COX 1 is primarily involved in homeostatic functions including platelet function, gastroprotection and the maintenance of renal function. COX 2 is primarily involved in inflammation but also has some homeostatic functions. See figure 29.1 Figure 29.1 Will give a summary of the COX 1 and COX 2 pathways

Figure 29.1 Cyclo-oxygenase pathways Arachidonic Acid COX- 1 COX- 2 HOMEOSTATIC FUNCTIONS INFLAMMATION e.g gastroprotection, renal function, platelet aggregation 55

General principles Non-steroidal anti-inflammatory drugs (NSAIDs) consist of a heterogenous group of compounds that can be subdivided by virtue of their pharmacology; -Non-selective NSAIDs inhibit both COX-1 and COX-2 receptors e.g. ibuprofen, naproxen. -COX-2 selective NSAIDs display some selectivity for COX-2 receptors but this diminishes as the dose increases e.g. etodolac, meloxicam. -COX-2 inhibitors specifically inhibit COX-2 receptors at therapeutic doses whilst being COX-1 sparing e.g. celecoxib, etoricoxib.

General principles All NSAIDs have cardiovascular and gastrointestinal toxicity. Indications for NSAIDs include: Bone Pain Musculoskeletal Pain Inflammatory conditions (including OA and RA) Paraneoplastic Pyrexia and Sweating Fever

General principles The WHO analgesic ladder recommends NSAIDs be considered as an adjunct in each step if appropriate. It is recommended that in the first instance consideration is made as to whether an alternative treatment would be appropriate (e.g. topical NSAIDs, paracetamol, tramadol,?pregabalin). It is recommended that the lowest possible dose of NSAID be precribed for the shortest possible time necessary.

Guidelines Cardiovascular Risk COX-2 inhibitors are contraindicated for use in patients with established ischaemic heart disease and/or cerebrovascular disease, and also in patients with peripheral arterial disease.[level1] Despite conflicting evidence, non-selective NSAIDs and COX -2 selective are currently licensed for use in these groups of patients, although they should be used with caution. [Level 4] Diclofenac is associated with similar thrombotic risks as COX 2 inhibitors. [Level 1] All NSAIDs are contraindicated in patients with severe heart failure. [Level 1]

Guidelines Cardiovascular Risk Etoricoxib may be associated with more frequent and severe effects on blood pressure than some other COX-2 inhibitors and NSAIDs, particularly at high doses. Etoricoxib treatment should therefore not be initiated in patients whose hypertension is not under control and careful monitoring of blood pressure is advised for patients taking etoricoxib. [Level 1] NSAIDs differ in their effect on platelet function and bleeding time. Some non-selective NSAIDs whilst not having an antiplatelet effect do interfere with the action of Aspirin. [Level 1]

Guidelines- Renal Dysfunction Renal function should be assessed prior to the introduction of an NSAID and within 7 days of starting treatment or increasing the dose.[level 4] Care is required when prescribing NSAIDs for patients with heart failure, ascites or impaired renal function, particularly those who are dehydrated or have a low effective circulating volume. [Level 4]

Guidelines- Renal Dysfunction Long term administration of NSAIDs has been linked to papillary necrosis and other renal injuries. Those patients at greater risk of this reaction include: [Level 4] impaired renal function, heart failure, liver dysfunction, the elderly Concurrent use of angiotensin-converting enzyme (ACE) inhibitors, diuretics or Angiotensin 2 receptor blockers. Discontinuation of NSAIDs therapy is usually followed by recovery to the pre-treatment state.[level 4]

Guidelines- Renal Dysfunction Use of NSAIDS in patients with advanced renal disease is not recommended due to a lack of safety data from controlled clinical studies. If NSAIDs are prescribed it is essential that renal function is monitored closely.[level 4]

Guidelines- Gastrointestinal Toxicity Patients at high risk of gastrointestinal side effects from NSAIDs include the following;[level 4] - Elderly (age>65 years), -Previous upper gastroduodenal perforation,ulcers and bleeds. -Concurrent use of aspirin, warfarin,corticosteroids or selective serotonin reuptake inhibitors (SSRIs) -Patients receiving maximum doses of NSAIDs.

Guidelines- Gastrointestinal Toxicity Of the non selective NSAIDs, low dose ibruprofen is associated with the lowest GI risk.[level 1] Undesirable gastric side effects from celecoxib are significantly less than from non-selective NSAIDs although it is not clear whether this lower risk continues with long term use.[level 4]

Guidelines- Gastrointestinal Toxicity In patients taking clopidogrel, it is advisable to use an H2 antagonist at a higher dose than usual e.g. ranitidine 300mgs bd or Lansoprazole 30mg od for gastric protection. Omeprazole and Esomeprazole should be avoided due to the potential for interactions. [Level 4]

Guidelines PPIs A PPI should be co-prescribed with a NSAID including COX-2 inhibitor, regardless of which actual drug is chosen. [Level 4] The relationship between H. pylori infection and NSAIDs in duodenal pathology is complex. Eradication of H pylori infection may prevent peptic ulcer disease in patients who are naiive users of NSAIDs. Patients receiving long term PPI treatment for prevention of NSAID ulcers should be tested for H Pylori. Eradiction of H Pylori will reduce the risk of accelerated loss of specialised glands and atrophic gastritis. [Level 4]

Guidelines- PPI Appropriate PPIs and oral doses include:[level 4] - Lansoprazole 30mg od - Omeprazole 20mg od - Pantoprazole 40mg od - Esomeprazole 20mg od Misoprostol is a synthetic prostaglandin analogue with gastric anti-secretory and protective properties which can be used to protect against NSAID-induced gastrointestinal damage. It is more effective than PPIs but can be poorly tolerated. Side effects include colic and diarrhoea. A suggested starting dose is 200mcg od, increasing by 200mcg every 1-2 days to a normal dose of 200mcg qds. Some combined preparations are avaliable e.g Napratec (Naproxen and Misoprostol). [Level 1]

Guidelines- Choice of NSAID Before deciding which NSAID to use, the prescriber must first asses patient risk factors for cardiovascular and gastrointestinal toxicity (figure 29.1) Figure 29.2 then recommends first line and second line options for NSAIDs depending on these risk factors. [Level 4] Table 29.1 lists NSAIDs currently avaliable for use along with cautions and recommended doses.[level 4]

Guidelines- Monitoring Effectiveness NSAIDs should be presribed for at least seven days before reviewing their clinical effectiveness. The analgesic effect of the drug becmes apparent within the first few days of treatment. The anti-inflammatory response may take at least 2 weeks to become evident. [Level 4] It may be appropriate to use an alternative NSAID before concluding that NSAIDs are ineffective. [Level 4] Due to the increased risk of renal and gastroduodenal toxicity, ketorolac should only be used for refractory pain. A PPI should always be co-prescribed with ketorolac unless the patient is in the dying phase. [Level 4]

Standards. 1. Cox-2 inhibitors are contra-indicated for use in patients with existing ischaemic heart, peripheral vascular disease or cerebrovascular disease. All NSAIDS are contraindicated for use in patients with severe heart failure.[gradeb] 2. In patients with existing cardiovascular disease, alternate analgesia should be considered before introducing a nonselective NSAID or a COX-2 selective NSAID. If NSAID s are to be used the lowest dose possible should be prescribed and the patient should be reviewed within 7 days. [Grade D] 3. It may be appropriate to use an alternative NSAID before concluding that NSAIDs are ineffective. [Grade D]

Standards 4. All patients prescribed NSAIDS should be prescribed proton pump inhibitors or misoprostol for gastric protection [Grade B] 5. A PPI should be prescribed for all patients receiving subcutaneous NSAID s, unless they are in the dying phase.[grade D] 6. Renal function should be assessed prior to the introduction of a NSAID and within 7 days of starting treatment or increasing the dose. [Grade D]

Figure 29.2 Flow diagram of NSAID choice Consider whether alternative treatment would be appropriate e.g topical NSAID, paracetamol Assessment of cardiovascular (CV) history No CV History CV History Assessment of gastrointestinal (GI) risk factors Assessment of gastrointestinal (GI) risk factors Low GI Risk > 1 GI Risk Low GI Risk 1 > GI Risk

Involve patient / relative in discussions regarding benefit vs risk of proposed NSAID Step List A No CV history Low GI risk 1 Low dose ibuprofen (<1200mg/day) +PPI or Nabumetone plus PPI 2 Non-selective NSAID e.g. naproxen + PPI List B No CV history GI risk COX-2 Inhibitor e.g. celecoxib + PPI COX-2 inhibitor e.g. etoricoxib + PPI List C CV history Low GI risk Low dose ibuprofen (<1200mg/day) +PPI or naproxen +PPI Non selective NSAID e.g. nabumetone + PPI 74

Table 29.1- NSAIDS currently avaliable for use Class of NSAID Name of drug Route Dose Additional notes COX-2 inhibitor COX-2 selective COX-2 inhibitor Celecoxib Oral 100-200mg bd Suitable 1 st line choice in patients at high risk of GI toxicity and low CV risk. PPI should be co-prescribed in high GI risk patients. Etodolac Oral 600mg m/r od Etoricoxib Oral 30-90mg od NICE do not recommend etoricoxib for first line use in osteoarthritis. For this reason, consider as 2 nd line choice. May be associated with hypertension. n/a

Table 29.1- NSAIDS currently avaliable for use Class of NSAID Name of drug Oral dose Dose Additional notes Nonselective Diclofenac sodium Oral 50mg bd 75mg m/r bd NOT RECOMMENDED FOR USE DUE TO CARDIOVASCULAR AND GI RISKS Ibuprofen Oral 400mg tds Low dose ibruprofen (<1200mg) suitable1st line choice, together with PPI, for patients with CV risk. If low dose aspirin is co-prescribed, ibuprofen should be given at least 8 hours before or 30 minutes after. Alternatively, Change aspirin to clopidogrel. Nonselective Nonselective Ketorolac S/C 30mg-90mg via syringe pump over 24hrs Can give 10mg stat subcutaneous dose. Carries greater risk of renal and gastrointestinal toxicity compared to other NSAIDs. Due to the propensity for toxicity, the continued need for a CSCI of ketorolac should be reviewed on a weekly basis.

Table 29.1 NSAIDs currently avaliable for use [Level 4] Class of NSAID Name of drug Route Dose Additional notes Nonselective Nabumetone Oral 500mg od- 1g bd Lowest GI risk of all non-selective NSAIDS. Some units may user first line. Nonselective Naproxen Oral 500mg bd Suitable 1 st line choice, together with PPI for patients with CV risk Non selective Piroxicam melt Sublingual 20mg od Increased risk of GI toxicity and serious skin reactions. Not to be used for first line treatment.