Medical Progress January 2012

www.medicalprogress.
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Peer-reviewed CME Journal
January 2012 VOL. 39 NO. 1
Global Summaries Clinical Review
Management of Neuropathic Cancer Pain The Health Consequences of Spouse Bereavement

In Focus
In Focus:
Achieving Effective Management of the Overactive Bladder The Patient With a urinary calculus Management of Lower urinary Tract symptoms & Bladder Outlet Obstruction
CME 1 Point
urology
Managing Irritable Bowel Syndrome

CME 1 Point
Diagnosis and Evaluation of Iron-deficiency Anaemia
eDItoRIAL BoARD
Director:
assoc Prof gerald KoH, national university of singapore, singapore

Deputy Director:
dr adrian Wu, Private Practice, HKsar, china

Anaesthesia & Intensive Care Medicine Nephrology
Prof gavin JoynT

The chinese university of Hong Kong, HKsar, china
Andrology
Prof Philip KT li
Prince of Wales Hospital, HKsar, china
Prof Wiguno ProdJosudJadi

The university of indonesia, indonesia
Neurology
Prof Wimpie PangKaHila

udayana university, indonesia
Cardiology
Prof raymond TF cHeung

The university of Hong Kong, HKsar, china
Emeritus Prof Ramon F aBarQueZ

university of the Philippines, Philippines
dr gardian cy Fong
ContentS
1-4 1
Prof Boon-Lock CHIA

national university of singapore, Singapore
dr chen-ya Huang
dr anna Maria cHoy

ninewells Hospital and Medical school, uK
Dr Venketasubramanian RAMANI
national university Hospital, singapore
Global Summaries
Cardiology
anticoagulation in non-valvular atrial fibrillation: Rivaroxaban versus warfarin ambulatory monitoring: Best way to diagnose hypertension secondary drug prophylaxis for cardiovascular disease worldwide
Prof Harmani KaliM

university of indonesia, indonesia
Prof Hasan SJAHRIR

universitas sumatera utara, indonesia
Dr Anwar SANTOSO
udayana university, indonesia
Clinical Pharmacology
Prof lawrence Ks Wong

Occupation Medicine & Public Health
Prof Bernard cHeung

university of Hong Kong, HKsar, china
Prof Chay-Hoon TAN

Dermatology
Prof david KoH

Diabetes
increasing mortality among people with late onset type 1 diabetes in Finland
Dr Judy SNG
Ophthalmology
dr adrian yP Fung
Private Practice, HKsar, china
General Medicine
epidural steroid or saline for chronic lumbar radiculopathy length of interval between haemodialysis sessions and mortality Escherichia coli O104:H4-associated haemolytic uraemic syndrome: IgG depletion by immunoadsorption for severe neurological complications Hourly changes in air pollution and myocardial infarction risk cytisine to help smoking cessation
dr yoke chin giaM

national skin centre, singapore
Endocrinology
Dr Michael SH LAW
Private Practice, Malaysia
Orthopaedics & Orthopaedic Surgery
Dr Norman CHAN
Prof david sK cHoon

university Malaya Medical centre, Malaysia
Prof Siew-Pheng CHAN

university of Malaya, Malaysia
dr daniel KH yiP
Otorhinolaryngology
Dr Ma Teresa P Que
Philippinediabetesassociation,Philippines
Prof Sidartawan SOEGONDO

Family Medicine
Prof Dato Balwant Singh GENDEH

The national university Hospital Malaysia, Malaysia
Pulmonology
lifetime coPd risk change in FeV1 with time among patients with COPD
Prof cindy lK laM

Gastroenterology & Hepatology
Prof William I WEI

Queen Mary Hospital, HKsar, china
Pharmacy
Psychiatry
schizophrenia and bipolar disorder: Mortality in the year after hospital discharge in england, 19992006
Prof Khean-lee goH

university of Malaya, Malaysia
Prof Vincent HL LEE

Psychiatry
Prof george KK lau

Prof HA Aziz RANI

dr eric yH cHen
Prof Benjamin cy Wong

Geriatric Medicine
Dr M Parameshvara DEVA
KPJ selangor specialist Hospital, Malaysia
Respiratory & Critical Care Medicine
dr leung-Wing cHu
Haematology & Oncology
Prof Menaldi RASMIN

assoc Prof dessmon yH Tai

Tan Tock seng Hospital, singapore
Prof Raymond LIANG

dr Kenneth WT Tsang
Rheumatology & Immunology
Dr Raymond WONG
Prince of Wales Hospital, HKsar, china
Infectious Disease
Prof Handono KaliM

Brawijaya university, indonesia
Dr Christopher LEE
Hospital sungai Buluh, Malaysia
dr swan-sim yeaP
Private Practice, Malaysia
Prof Amorn LEELARASAMEE

siriraj Hospital, Thailand
Prof Ron HH NELWAN

iii
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Clinical Review
PAIN MANAGEMENT
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Recommendations on the Management of Neuropathic Cancer Pain

The Multidisciplinary Panel on Neuropathic Pain
13-32 14
In Focus: Urology
Achieving Effective Management of the Overactive Bladder
Mariolyn d raj, audrey Wang
19 26
The Patient With a urinary calculus: What to do next

duncan cooke, stephen Mcdonald, christopher s Pokorny
Management of lower urinary Tract symptoms and Bladder Outlet Obstruction

surayne segaran, Mark J speakman
33-36
Clinical Review
PsycHiaTry
A Broken Heart: The Health Consequences of Spouse Bereavement

roger Bartrop, Tom Buckley
26
ii
ContentS
The Cover: urology rowena sim, art director Teryn lee, illustrator
37-52 37
Continuing Medical education

reme Mountifield, Jane M andrews
45
Diagnosis and Evaluation of Iron-deficiency Anaemia

stephen Jn Tattersall, christopher s Pokorny
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Coming in the February 2012 Issue of Medical Progress
In Focus
Hepatology
Hepatitis B Hepatitis c other liver viruses
Drug Profile
denosumab
and more!
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Global Summaries
Synopses of major trials from leading international journals
Peer Reviewed
cardiology Anticoagulation in non-valvular atrial fibrillation: Rivaroxaban versus warfarin
Rivaroxaban was non-inferior to warfarin for the prevention of stroke or systemic embolism. The risk of major bleeding was similar in the two groups, but the risk of intracranial or fatal bleeding was significantly lower in the rivaroxaban group.
Patel MR et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. neJM 2011; 365: 883891; del Zoppo gJ, eliasziw M. new options in anticoagulation for atrial fibrillation. ibid: 952953 (editorial).
modellingstudy.lancet2011;378:12191230;gaziano TA. Accurate hypertension diagnosis is key to efficient control. ibid: 11991200 (comment).
Secondary drug prophylaxis for cardiovascular disease worldwide

Beta blockers, angiotensin-converting enzyme (ace) inhibitors, statins, and antiplatelet drugs are all effective as secondary prophylaxis after a cardiovascular event. Other hypertensive drugs may also add to prophylaxis. Although most cardiovascular disease occurs in low- or middle-income countries, the extent to which drug prophylaxis is used in those countries is unknown. A worldwide study has shown that the use of secondary prophylactic drugs is low everywhere, but especially in low-income countries. The study included 153,996 people in 628 communities in 17 countries (three high-income, ten middle-income, and four low-income). a total of 5,650 participants had had a coronary event and 2,292 had had a stroke, on average 4 or 5 years previously. Among people with cardiovascular disease, antiplatelet drugs were taken by 25%, -blockers by 17%, ace inhibitors or angiotensin-receptor blockers (arBs) by 20%, and statins by 15%. in high-income countries, the corresponding proportions were 62% (antiplatelet drugs), 40% (-blockers), 50% (ace inhibitors or arBs), and 67% (statins). in low-income countries, the proportions were 9% (antiplatelet drugs), 10% (-blockers), 5% (ace inhibitors or arBs), and 3% (statins). no drugs were taken by 11% in high-income countries, 4569% in middleincome countries, and 80% in low-income countries. Drug use was lower in rural than in urban areas, and this gap was greatest in low-income countries. In determining the rate of prophylactic drug use, country-level factors (national economic status) were more important than individual-level factors (age, sex, education, smoking status, body mass index, hypertension, diabetes). The use of secondary drug prophylaxis is low in most countries but lowest in the
Ambulatory monitoring: Best way to diagnose hypertension

Atrial fibrillation increases the risk of ischaemic stroke four- or fivefold. use of vitamin K antagonists such as warfarin reduces the risk significantly, but frequent monitoring is necessary to avoid overdosage or underdosage. Rivaroxaban is a direct factor Xa inhibitor taken in fixed dosage. A multinational trial has shown that treatment with rivaroxaban may have advantages over warfarin. a total of 14,264 patients with nonvalvular atrial fibrillation and increased stroke risk (previous stroke or transient ischaemic attack, or systemic embolism, or at least two of heart failure, hypertension, age >74, or diabetes) were randomized at 1,178 centres in 45 countries to rivaroxaban 20 mg daily or warfarin (target International normalized ratio, 2.03.0). The primary endpoint (stroke or systemic embolism) occurred in 188 patients (1.7% per year) in the rivaroxaban group and 241 patients (2.2% per year) in the warfarin group, a 25% reduction showing the non-inferiority of rivaroxaban. The rate of major and non-major, clinically relevant bleeding was 14.9% per year in the rivaroxaban group and 14.5% per year in the warfarin group, a non-significant difference, but there were significantly fewer intracranial haemorrhages (0.5% vs 0.7%) and fatal haemorrhages (0.2% vs 0.5%) in the rivaroxaban group. Blood pressure levels from ambulatory monitoring correlate better with cardiovascular outcomes than do clinical measurements. in general practice, ambulatory modelling may not be available immediately; it may be inconvenient and its cost-effectiveness is unknown. in a uK study, Markov model-based probabilistic cost-effectiveness analysis has been used to assess three strategies: repeated blood pressure measurements in the clinic, home monitoring, and ambulatory monitoring. The study used a hypothetical primarycare population aged 40 years or older with screening blood pressure of > 140/90 mm Hg and risk factors equivalent to the general population. The most cost-effective strategy was ambulatory monitoring. The cost saving from ambulatory monitoring varied from 56 in men aged 75 to 323 in women aged 40. it preserved more Qualys (quality adjusted life years) than the other strategies for both men and women over the age of 50. Ambulatory monitoring after a raised clinic reading is cost-effective. The costs of ambulatory monitoring are more than balanced by savings from better-directed treatment. These researchers suggest that all patients should have ambulatory monitoring before starting antihypertensive treatment.
lovibond K et al. cost-effectiveness of options for the diagnosis of high blood pressure in primary care: a
Global Summaries
poorest countries. Efforts need to be made to extend its use.

yusuf s et al. use of secondary prevention drugs for cardiovascular disease in the community in highincome, middle-income, and low-income countries (the Pure study): a prospective epidemiological survey. lancet 2011; 378: 12311243; Heagerty aM. Secondary prevention of heart disease and stroke: work to do. ibid: 12001202 (comment).
DIABETES Increasing mortality among people with late onset type 1 diabetes in Finland
increased with time in the late-onset group. in the early-onset group, the standardized mortality ratio at 20 years from onset of diabetes decreased from 3.5 among patients diagnosed between 1970 and 1974 to 1.9 among patients diagnosed in 19851989. in the late-onset group, the standardized mortality ratio increased from 1.4 to 2.9 over the same period. Mortality from the chronic complications of diabetes decreased in the early-onset but not in the late-onset group. in the late-onset group, deaths related to alcohol or drugs increased and were responsible for 39% of deaths within 20 years of disease onset. in Finland, mortality from type 1 diabetes has increased among patients who were aged 1529 years at disease onset but not among those whose diabetes began earlier in childhood. Alcohol and drug use have become an important factor.
Harjutsalo V et al. Time trends in mortality in patients with type 1 diabetes: nationwide population based cohort study. BMJ 2011; 343: 629 (d5364).
differences in improvement between the three groups. These results suggest that the epidural injections were not effective. as ever, there are questions about dose, volume, and place of injection. A BMJ editorialist maintains that epidural steroid injections benefit some patients and their use should not be discontinued.
Iversen T et al. Effect of caudal epidural steroid or saline injection in chronic lumbar radiculopathy: multicentre, blinded, randomised controlled trial. BMJ 2011; 343: 573 (d5278); cohen sP. epidural steroid injections for low back pain. ibid: 543544 (d5310) (editorial).
Length of interval between haemodialysis sessions and mortality

in the usa and most other countries, maintenance haemodialysis is performed three times a week with single days off dialysis during the week and 2 days off on either Saturdays and Sundays or Sundays and Mondays. Dialysis every day has been shown to be associated with better outcomes. now, a multicentre us study has shown increased mortality after the longer interdialysis interval. The study included a nationally representative sample of 32,065 patients (mean age 62.2 years) undergoing 3-day-a-week haemodialysis in 20042007. Mortality rates were compared for the day of haemodialysis after 2 days off and after 1 day off. Over a mean follow-up of 2.2 years, mortality was greater on the day after the longer break. All-cause mortality was 22.1 vs 18.0 deaths per 100 person-years, mortality from cardiac causes was 10.2 vs 7.5, infection-related 2.5 v s 2.1, from cardiac arrest 1.3 vs 1.0, and from myocardial infarction 6.3 vs 3.9 deaths per 100 person-years, all highly significant differences. There were also highly significant increases in admissions for myocardial infarction, congestive heart failure, stroke, arrhythmias, and all cardiovascular events. Mortality is increased on the day after
A study in Finland has shown that mortality among late adolescents and young adults with recent-onset type 1 diabetes has increased in the last 30 years and that alcohol has played an important part. The study included all Finnish people with a new diagnosis of type 1 diabetes below the age of 30 between 1970 and 1999. There were 17,306 patients with follow-up to 2007. a total of 1,338 subjects died (all-cause mortality 311 per 100,000 person years), and the cumulative mortality 35 years after diagnosis was 18%. The cohort was divided into patients with early onset (age 014 years) and late onset (age 1529 years) type 1 diabetes. among groups diagnosed in 19701974, 19751979, 19801984, and 19851989, the 20-year cumulative mortality was 4.7%, 4.3%, 3.6%, and 2.7% in the early onset group, respectively, and 4.4%, 5.9%, 6.5%, and 7.9% in the late-onset group, respectively. Thus, mortality decreased with time in the early-onset group and
GENERAL MEDICINE Epidural steroid or saline for chronic lumbar radiculopathy

Low back pain is very common and a major cause of disability worldwide. Epidural steroid injections have been used for many years, but despite this and about 35 scientific papers there is still no clear-cut consensus about their effectiveness. A trial in Norway has shown that caudal epidural injections of steroid or saline are ineffective for chronic lumbar radiculopathy. at five centres, a total of 116 patients with at least 12 weeks of low back pain were randomized to caudal epidural injection of 30 mL of 0.9% saline or triamcinolone acetate 4 mg in 29 mL of 0.9% saline, or sham subcutaneous injection of 2 ml of 0.9% saline (controls), all given twice with a 2-week interval between injections. using the oswestry disability index at 6, 12 and 52 weeks, there were no significant
Global Summaries
2 days off dialysis compared with the day after 1 day off.
Foley RN et al. Long interdialytic interval and mortality among patients receiving haemodialysis. neJM 2011; 365: 10991107.
Escherichia coli O104:H4-associated haemolytic uraemic syndrome: IgG depletion by immunoadsorption for severe neurological complications
example in aphasia) was observed during the treatment. all 12 patients survived, all but two with complete neurological and renal recovery. Immunoadsorption may benefit patients with haemolytic uraemic syndrome and severe neurological complications.
Greinacher A et al. Treatment of severe neurological deficits with IgG depletion through immunoadsorption in patients with Escherichia coli O104:H4-associated haemolytic uraemic syndrome: a prospective trial. lancet 2011; 378: 11661173; Kim JJ. Immunoadsorptionforhaemolyticuraemicsyndrome. ibid: 11201122 (comment).
NO2 were followed by increased risk of myocardial infarction over the next 6 hours. There was, however, a subsequent fall in risk so that the 72-hour risk was not increased, suggesting that the increased pollution precipitated events that would have occurred within the next few hours or days in any event. Short-term increases in PM10 and NO2 are associated with short-term displacement of myocardial infarction events.
Bhaskaran K et al. The effects of hourly differences in air pollution on the risk of myocardial infarction: case-crossover analysis of the MINAP database. BMJ 2011; 343: 626 (d5531); Hales s, edwards r. Cardiovascular effects of exposure to air pollution. ibid: 595596 (d5814) (editorial).
Hourly changes in air pollution and myocardial infarction risk

Chronically increased exposure to air pollution is associated with increased risk of myocardial infarction. The effects of short-term changes in exposure are not well studied. A study at 15 urban locations in England and Wales has suggested that short-term (hourly) changes do not have a large effect on the risk of myocardial infarction. The study included retrospective data about 79,288 people who had a myocardial infarction in 20032006. The air pollutants measured were particulate matter (PM10), ozone, carbon monoxide (co), nitrogen dioxide (NO2), and sulphur dioxide (so2). Exposure levels were averaged from hourly measurements over five short-lag periods spanning 72 hours. For each patient, exposure on the day of myocardial infarction was compared with data on every other day in the same calendar month. For PM10, a 10 g/m3 increase in air pollution was associated with a significant 1.2% increase in risk of myocardial infarction 16 hours later, but this was followed by a reduction in risk so that the risk in the 72 hours after exposure was not increased. The results were similar for a 10 g/m3 increase in NO2. increases in co, ozone, or so2 were not followed by increases in risk of myocardial infarction. Short-term increases in PM10 or
Cytisine to help smoking cessation

Strategies that have been shown to be helpful in aiding smoking cessation include behavioural support and drug treatment. in poorer countries, however, the cost of treatment may exceed that of cigarettes. Cytisine is extracted from Golden Rain acacia seeds (Cytisus laborinum l.) and has been used as an aid to quitting smoking in former socialist economy countries, such as russia, Bulgaria, and Poland, for many years. It is a partial agonist with high-affinity binding to the 42 subtype of the nicotinic acetylcholine receptor that has been implicated in nicotine dependence. now, a study at a single centre in Warsaw, Poland, has shown that cytisine is more effective than placebo in promoting smoking cessation. A total of 740 smokers (at least 10 cigarettes a day and willing to try to stop) were randomized to cytisine or placebo for 25 days, with minimal counselling. The rate of biochemically verified abstinence for 12 months was 8.4% (cytisine) vs 2.4% (placebo), a highly significant difference. The 7-day point prevalence for abstinence at the 12-month follow-up was 13.2% vs 7.3%. Gastrointestinal adverse events were more common in the cytisine group. Cytisine was more effective than placebo. Compared with other drugs
The 2011 outbreak of haemolytic uraemic syndrome due to Shiga toxin-producing enterohaemorrhagic Escherichia coli O104:H4 in northern Germany affected > 800 patients, with severe neurological complications in about 30%. At the greifswald university and Hanover Medical school, 12 of 63 patients developed severe neurological complications and were treated with IgG immunodepletion through immunoadsorption after these complications failed to respond to plasma exchange or eculizumab. The 12 patients were aged 4263 and had haemolytic syndrome (10 patients needed renal replacement therapy within 511 days) and severe neurological complications including delirium with disorientation or hallucinations, extreme panic, stimulus sensitive myoclonus, aphasia, paresis, epileptic seizures, status epilepticus, and coma. nine patients received mechanical ventilation because of neurological complications. Composite neurological symptom scores increased gradually in the 3 days before immunoadsorption and decreased gradually during the 3 days after immunoadsorption. In non-intubated patients, improvement (for
Global Summaries
used for smoking cessation, it is relatively inexpensive and may be affordable in developing countries.
West R et al. Placebo-controlled trial of cytisine for smoking cessation. neJM 2011; 365: 11931200.
PsycHiaTry Schizophrenia and bipolar disorder: Mortality in the year after hospital discharge in england, 19992006
People with schizophrenia or bipolar disorder have reduced life expectancy compared with the general population. a study of english data for 19992006 has shown that mortality in the year after discharge from hospital with either of these disorders has changed little during this period. The study included 272,248 people with schizophrenia and 100,851 with bipolar disorder who were discharged from hospital during the study period and followed up for 1 year. For people with schizophrenia, the standardized mortality ratio (sMr) was 1.6 in 1999 and 2.2 in 2006, a significant trend. For people with bipolar disorder the corresponding sMrs were 1.3 and 1.9, a non-significant trend. SMRs were higher among young people (sMr in 2006 among people aged < 45: 6.2 for schizophrenia and 3.4 for bipolar disorder) than in older people (sMr in those aged 6584: 2.0 for schizophrenia and 1.8 for bipolar disorder). The SMR for circulatory disease among people with schizophrenia rose from 1.6 in 1999 to 2.5 in 2006, whilst the sMr for respiratory disease rose from 3.1 to 4.7. among people with bipolar disorder, these sMrs rose from 1.6 to 2.5 and from 3.0 to 5.8. in 2006, the overall sMr among people with schizophrenia was 3.2 for men and 1.8 for women. There was no sex difference in SMR among people with bipolar disorder. overall, sMrs were higher for unnatural than for natural causes. The differences in mortality between people with schizophrenia or bipolar disorder and the general population have not been reduced in England in recent years.
Hoang u et al. Mortality after hospital discharge for people with schizophrenia or bipolar disorder: retrospective study of linked English hospital episode statistics,19992006;BMJ2011;343:627(d5422);Miller BJ. Hospital admission for schizophrenia and bipolar disorder. ibid: 596597 (d5652) (editorial).
PulMonology Lifetime COPD risk

The prevalence of chronic obstructive pulmonary disease (coPd) among people aged 40 or older is 822%. lifetime risk is a measure readily understood by the general public, and it can be used to increase awareness of prevalent diseases. Researchers in Canada have assessed the lifetime risk of COPD. The retrospective longitudinal cohort study used population-based data and included all people free of coPd in 1996 in ontario (population about 13 million). They were followed up for up to 14 years for three possible outcomes: coPd diagnosis, reached the age of 80 (the average canadian life expectancy), or death. a diagnosis of coPd was made for 579,466 people. By the age of 80, the risk of coPd was 28% (30% in men, 26% in women). The risk was higher with low socioeconomic status (32% vs 23%) and for people living in the country (32%) rather than in the town or city (27%). More than a quarter of all people in Ontario develop COPD if they live long enough.
Gershon AS et al. Lifetime risk of developing chronic obstructive pulmonary disease: a longitudinal population study. lancet 2011; 378: 991996; Mannino dM, Martinez FJ. lifetime risk of coPd: what will the future bring? ibid: 964965 (comment).
Change in FEV1 with time among patients with COPD

There is a paucity of data about the rate of decline of forced expiratory volume in 1 second (FEV1) among patients with chronic obstructive pulmonary disease (coPd).
A multinational study has shown a high degree of variability in this rate of decline with more rapid deterioration in some patient subgroups. The study included a total of 2,163 patients who had FEV1 measured after taking a bronchodilator, 18 times over a 3-year period. The mean rate of decline in FEV1 was 33 mL per year. A decline of > 40 mL per year was recorded in 38% of patients and of 2140 ml per year in 31%. A change ranging from a decline of 20% to an increase of 20% in FEV1 per year was recorded in 23% and an increase of >20 mL per year in 8%. The rate of decline among current smokers was greater than that in current non-smokers by 21.4 mL per year. Patients with emphysema had a 13 mL per year greater decline than patients without emphysema and reversibility with a bronchodilator was associated with a 17.4 mL per year faster decline compared with non-reversibility. The rate of decline in FEV1 is highly variable among patients with COPD. The patients at highest risk of rapid decline are current smokers, patients with emphysema, and patients whose bronchoconstriction responds to a bronchodilator. The latter finding is unexplained. Some patients may have static or even improving disease. Stopping smoking is the most important factor in slowing or preventing the decline.
Vestbo J et al. Changes in forced expiratory volume in 1secondovertimeincoPd.neJM2011;365:11841192; Burney P. Variable loss of function in COPD. Ibid. 12461247 (editorial).
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MY-DEC-2011
PAIN MANAGEMENT
Recommendations on the Management of Neuropathic Cancer Pain

The Multidisciplinary Panel on Neuropathic Pain chen Phoon Ping, MBBs,FHKaM(anaes),FanZca,FFPManZca,dipPainMgt(HKca);JosephineWy ip, MBBs,Ms,Frcs(ed),FHKaM(ortho),
dip Hand surg (FessH); Joseph MK lam, MBchB, Frcs (edin), FcsHK, FHKaM (surg); Vincent Mok, MBBs, FHKaM (Med), FrcP (edin), Md (cuHK); TsoiTak Hong, MBBs, MrcP, FrcP (edin), FrcP (lond), FrcP (glas), FHKcP, FHKaM (Med); Wong chun Por, MBBs, FHKaM (Med), FrcP (lond), FrcP (glas), FHKcP; Wong Ho shan steven, MBBs, FHKaM (anaes), FanZca, dip Pain Mgt (HKca)
This is an update of the recommendations on neuropathic cancer pain management written by members of the Hong Kongbased Multidisciplinary Panel on neuropathic Pain.
on neuropathic Pain in 2006,1 aim to provide a logical approach to effectively manage cancer pain, with a particular focus on neuropathic pain.
The use of adjuvant medications is necessary in neuropathic cancer pain.
Prevalence, Pathophysiology and Symptoms

Pain can be a persistent and incapacitating symptom of cancer. An international survey on cancer pain by the International Association for the study of Pain revealed that in this sample, around 90% of patients experienced pain, of which 40% was caused by neuropathic mechanisms.2 cancer pain may be chronic or acute, and patients with chronic pain commonly experience acute flares of pain. One-half to twothirds of patients with well-controlled chronic pain experience transitory breakthrough pain.3 Cancer-associated pain may be secondary to anti-neoplastic therapy or an unrelated co-morbid condition but is commonly due to direct tumour involvement (ie, infiltration or compression of adjacent local structures, such
5
P
ain is prevalent in cancer patients and is often difficult to treat, especially neuropathic cancer pain. Neuropathic cancer pain often responds poorly to opioids; hence, the use of adjuvant medications is necessary. Patients who do not experience sufficient pain relief with pharmacological therapy may benefit from interventional therapies. These recommendations, which are an update of those first published by the Multidisciplinary Panel
PAIN MANAGEMENT
as bone, soft tissue, nerves or the gastrointestinal tract).4,5 Hence, cancer pain syndromes can be somatic, visceral or neuropathic in origin.3 understanding and recognizing these syndromes can help identify pain aetiology and the need for additional evaluation, and target therapy more appropriately.
types of Pain
Somatic pain originates from disorders of bone, joints, muscles or connective tissue.3 Bone pain syndromes are the most prevalent,3,5 while somatic pain from other sites is due to continuous peripheral nociceptor stimulation such as by inflammatory mediators, muscle spasms, postsurgical incisions, and radiotherapy or chemotherapy. Visceral pain is caused by obstruction, infiltration or compression of visceral structures and supporting connective tissues.3 Visceral pain is often diffuse and sometimes refer re d to ot h e r no n-visceral structures, making the source of pain difficult to localize. Neuropathic pain is characterized by aching, burning, stabbing or lancinating pain, 3,6 and may also present as paraesthesia, dysaesthesia, hyperalgesia or allodynia. It occurs in approximately 3055% of cancer patients, although recent estimates in patients with head and neck cancer varied from 34% to 73%. 7,8 Neuropathic pain is often due to tumour infiltration or compression of neural structures, 3,6,9 while sympathetic activity also plays a role in spontaneous neuropathic pain. 3 In addition, most post-treatment pain syndromes (eg, post-surgical, postradiotherapy or post-chemotherapy pain) are neuropathic. 3 Relative to somatic and visceral pain, neuropathic pain responds poorly to systemic opioids; hence, other treatments are
6
Currently no single method is available to reliably diagnose cancer-related neuropathic pain
often utilized.5,10,11
pain, nerve compression should be ruled out, as this requires immediate treatment.10 use of imaging, such as magnetic resonance imaging, assesses the anatomical integrity of neural structures and may assist in localizing compression sites and in treatment planning.15 Analgesics should be instituted as early as possible, even though full diagnosis is not yet established.4,16 Because of the progressive nature of most cancers and the changes that occur in cancer pain characteristics, assessment should be repeated at regular intervals.4 New reports of pain should be noted.
Assessment
a detailed history and medical, physical and neurological examination should be performed to characterize and quantify pain, and to assess the primary cancer site and its relationship to the pain.3 all components of pain (eg, intensity, characteristics, location, radiation, timing and effect on daily living) should be assessed to assist in identifying specific pain syndromes and monitoring progression and response.4 clinical assessment of neuropathic cancer pain may be challenging; currently no single method is available to reliably diagnose cancer-related neuropathic pain.12 However, a number of screening tools are available to help identify neuropathic pain. The ID Pain has recently been validated in breast cancer survivors,13 while the Neuropathic Pain Questionnaire (nPQ), Leeds Assessment of Neuropathic Signs and symptoms (lanss) and neuropathic Pain symptom inventory (nPsi) may also help to identify neuropathic pain in cancer patients.14 if a patient has neuropathic
Management
General Principles of Cancer Pain treatment
cancer treatments, such as surgery, chemotherapy or radiotherapy, may relieve pain by removing or reducing the size of the tumour and reducing compression or infiltration.17 non-steroidal anti-inflammatory drugs (nsaids) may have a role in managing somatic cancer pain, particularly for patients with bone metastasis.10,16 Pain caused by soft-tissue infiltration, visceral distention and increased intracranial pressure may be treated initially with corticosteroids.18 Acute spinal cord compression should be treated with intravenous dexamethasone or methylprednisolone. Surgical decompression of the brain or spinal cord and fixation of painful spinal fractures should be considered where appropriate. The World Health organization (WHo) analgesic ladder for cancer pain relief advocates introducing analgesics in a stepwise manner according to response (Figure).11,16 However, pain that is moderate to severe at the outset
PAIN MANAGEMENT
should be treated with higher-potency opioids or with higher doses.17 adjunctive therapies may be used with or without conventional analgesics at any stage (Table).19 Patients who do not respond to adequate drug therapy may benefit from interventional techniques (Figure).3 The choice of therapy should be based on therapeutic goals and characteristics of the disease and the patient (eg, type of tumour, benefitrisk analysis, anticipated duration of hospitalization and likely duration of survival).4,16 Physiotherapy may reduce the need for analgesics.4 However, while physiotherapy should not be used as a substitute for medication, it should be introduced early to treat generalized weakness, deconditioning, and pain associated with inactivity and immobility. Psychological therapies, such as cognitive behavioural techniques, should be instituted early to teach educate patients how to cope with pain. The management of cancer pain should be multimodal and multidisciplinary. Patients with terminal cancer often have significant emotional and mood disturbances, or other psychosocial issues, which need to be addressed. Some of these issues may be more important to the patient than the pain itself. Hospice care should be considered for such patients. For Neuropathic Cancer Pain about 50% of all difficult to control cancer pain is neuropathic.11 For neuropathic pain caused by direct tumour involvement, first-line management may include surgery, radiation therapy or chemotherapy.20 correctable causes of neuropathic pain (eg, spinal cord compression) should be managed appropriately. anticonvulsants (eg, gabapentin,
7
Physiotherapy should be introduced early to treat generalized weakness, deconditioning, and pain associated with inactivity and immobility.
Table. Indications for adjunctive therapy5,11,1619

Indication Neuropathic pain Adjunctive therapy anticonvulsants (eg, gabapentin, pregabalin) antidepressants (eg, amitriptyline, venlafaxine) otheragents(eg,ketamine,mexiletine,lidocaine) Metastatic bone pain Anxiety symptoms Emesis Poor analgesic response Increased intracranial pressure Spinal cord compression Perineuraloedemaandnervecompression Nausea Anorexia and poor appetite Cachexia Bisphosphonates (eg, pamidronate) Hydroxyzine Hydroxyzine Corticosteroids Corticosteroids Corticosteroids Corticosteroids Corticosteroids Corticosteroids Corticosteroids
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pregabalin) and antidepressants (eg, amitriptyline, venlafaxine) are recommended adjuvant analgesics for cancer-related neuropathic pain (Figure).9,21,22 A recent systematic review revealed that the use of antiepileptic and antidepressant agents as adjuvants to opioids improved pain control, although there is potential for an increase in side effects.23 The strongest evidence is for gabapentin.23,24 However, data from the united states revealed that the use of these types of drugs is relatively low in neuropathic cancer pain.25 Ketamine may be effective but, because of its adverse effects, should be limited to experienced teams.5,20 Other adjunctive therapies include systemic
or topical lidocaine and topical capsaicin.8,27,28 a recent prospective study in 818 patients with neuropathic cancer pain revealed that pain could be relieved by multimodal treatment following the WHO analgesic ladder in the majority of patients; the main adjuvant drugs were amitriptyline, gabapentin, dexamethasone.29 interventional therapy may also be effective for neuropathic cancer pain.3036 However, certain interventional techniques for neuropathic pain should only be considered when pharmacological interventions have failed, are poorly tolerated, or are inappropriate.17 ongoing assessment and communi-
cation with patients are important. In a study investigating patient perceptions associated with chemotherapy-induced peripheral neuropathy, patients reported that neuropathic pain interfered with daily life and expressed frustration, depression and loss of purpose.37
Undermanagement
Despite the presence of cancer pain guidelines, such as those from the WHo, cancer pain is often undertreated. A large-scale study on patients with recurrent or metastatic cancer revealed that 42% of patients suffering from pain received inadequate analgesia.38 This may be because of inadequate knowledge of pain management, poor pain assessment, reluctance to use analgesics, and restrictive analgesic regulations.4,38 Adherence to the WHO analgesic ladder is associated with some shortcomings in clinical practice. Twenty-five percent of patients treated with basic analgesics actually had moderate to severe pain that should have been treated with more potent analgesics. 4 Other authors suggested that since certain analgesics may be more useful for particular pain conditions, a more mechanistic approach may have a role in drug selection, especially in pain that involves multiple mechanisms or is poorly responsive to conventional therapies, such as neuropathic pain. 5,20 However, as described above, neuropathic cancer pain can be relieved by multimodal treatment following the WHO analgesic ladder in the majority of patients.29
Figure. Management of cancer pain.

Cancer pain
Physiotherapy Heat and cold therapy (eg, compress) Massage Exercise Acupuncture Psychological therapy Cognitivebehavioural therapy Moderate to severe pain
Mild to moderate pain
Associated neuropathic pain
Non-opioid analgesics
+ Anticonvulsant and/or tricyclic antidepressant
For direct tumour involvement Oncological management, eg, radiotherapy For acute spinal cord compression, consider highdose corticosteroid immediately Consider bisphosphonates for metastatic bone pain
Weak opioid + non-opioid analgesics
+ Anticonvulsant and antidepressant
Strong opioid non-opioid analgesics
+ Other agents (eg, systemic ketamine or lidocaine)
Interventional therapy Neuraxial drug administration Spinal cord stimulation Neural blockade Neurolysis
Declaration of Interests
TheMultidisciplinaryPanelonNeuropathicPainissupported byanunrestrictededucationalgrantfromPfizerCorporation Hong Kong ltd.
adapted from references 4, 10, 11, 1620, 26, 30.
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Appendix. Evidence-based management of neuropathic cancer pain

Pharmacotherapy
I. opioids
lower global pain scores (4.6 vs 5.4; P = 0.025), and less dysaesthesia (4.3 vs 5.2; P = 0.0077) when measured on a 010 numerical scale. More recently, studies have demonstrated that gabapentin provides additional pain relief as an adjuvant analgesic in neuropathic cancer pain whencombinedwithopioids.55,56inanotherstudy,low-dosegabapentin (200 to 400 mg/day) combined with the antidepressant imipramine (20 mg/day) in patients with neuropathic cancer pain significantly decreasedtotalpainscoreanddailyparoxysmalepisodescomparedwith either drug alone.57 While effective in a number of neuropathic pain conditions,24,58,59 there are few studies yet on pregabalin in neuropathic cancer pain. A case report in a patient with pancreatic cancer and oxaliplatin-induced hyperexcitability syndrome revealed that pregabalin reduced the symptoms of this syndrome.60 A study in 39 patients with continuous epiduralanalgesiaforchroniccancerpaindemonstratedthatpregabalin lowered the visual analog scale (Vas) score from 5.3 0.4 to 2.9 0.2 (P < 0.01) and improved quality of life significantly (P < 0.05) after just 2 days of treatment.61 older anticonvulsants, such as phenytoin and carbamazepine, have alsobeenusedtraditionallyforanalgesia.62 However,theiradverseeffect profiles are less favourable than gabapentin,21 and evidence supporting their efficacy in neuropathic cancer pain is lacking. Topiramate may provide benefit as a second- or third-line treatment.63
Anticonvulsants for Post-treatment Neuropathic Pain
Evidence supports the role of opioids for other neuropathies such as postherpetic neuralgia39,40 and central or peripheral neuropathic pain.41 However, the effectiveness of opioids for neuropathic pain is controversial. While some literature suggests that the response of neuropathic pain to opioids is suboptimal, this may be relative and not duetoreducedopioidsensitivity.4,5,10,42,42instead,theremaybefailureto deliver a sufficiently high concentration of systemic opioid to the spinal cord without causing adverse effects.5 despite the reliance on opioids, adherence to the WHo guidelines provides equally effective analgesia regardless of the pain mechanism.26,44 Owing to mixed pain mechanisms in many cancer patients, one review suggested that patients may require both opioids and nsaids, in addition to specific neuropathic pain agents, to achieve acceptable pain relief.10 Transdermal buprenorphine is a further option for neuropathic cancer pain. A recent expert panel consensus statement indicated that transdermalbuprenorphinewasavaluabletreatmentforchroniccancer pain, including neuropathic cancer pain.45 It has good efficacy and an acceptable safety and tolerability profile, including a low risk of respiratory depression, a lack of immunosuppression and a lack of accumulation in patients with impaired renal function. Tramadol may also be an effective therapeutic option for neuropathic cancerpain.inadouble-blind,placebo-controlledstudy(n=36),patients receivingtramadolhadmajorimprovementsinpainintensity(P < 0.001), improved sleep quality by day 45 (P < 0.05), improved activities of daily living (P < 0.05) and reduced use of analgesics (P < 0.05) compared with placebo.46 However, the tramadol group was associated with more adverse events (P < 0.05), most commonly nausea, vomiting and constipation. in addition, care must be taken when using tramadol in combination with selective serotonin reuptake inhibitors, such as venlafaxineandduloxetine,andselectiveserotoninandnorepinephrine reuptake inhibitors, as this may increase the risk of serotonin syndrome; tramadol may also increase the risk of seizure.47There is some evidence that methadone may be effective for neuropathic cancer pain.48
II. Anticonvulsants
Gabapentinmayalsorelieveneuropathicpainduetoanticancertherapy. An open-label exploratory non-controlled study involving cancer outpatients without active disease and with chronic, treatment-related pain (n = 23) demonstrated that gabapentin reduced pain intensity (P < 0.01) and increased pain relief from 8.3% to 66.6% (P < 0.01).49
III. Antidepressants
Antidepressantsarerecommendedforthemanagementofmanytypesof neuropathicpain.24,47Antidepressantsarealsocommonlyrecommended as adjunctive therapy for neuropathic cancer pain, especially for patients with continuous dysaesthesia.3,4,16,17,20These agents provide analgesia, potentiatetheeffectofopioids,andreducedepressionandinsomnia.18,64 although commonly used in practice, there is limited evidence from controlled trials evaluating the analgesic efficacy of tricyclic antidepressants in cancer patients.24 one randomized, double-blind, placebo-controlled, crossover trial (n = 16) showed that short-term amitriptyline as add-on therapy to morphine therapy for cancer patients with moderate neuropathic pain did not significantly improve global pain intensity and quality-of-life scores, and failed to reduce opioid requirements; there was a significant difference in worst pain (P < 0.035).65 However,thisstudywaslimitedbylowpatientnumbersand a relatively short washout period (2 weeks).
Antidepressants for Post-treatment Neuropathic Pain
While opioids are the usual first-line treatments for moderate to severe cancer pain in general,16 neuropathic cancer pain responds less reliably than other pain types.21 Anticonvulsants may be used as adjunctive therapy for neuropathic cancer pain, especially for patients with lancinatingpainorthosepoorlyresponsivetoopioidtherapy.3,4,11,16,17,20,22 anticonvulsantusemaydecreaseopioiddoseand,hence,associatedside effects.4 Gabapentin has established efficacy in a variety of neuropathic pain syndromes, including neuropathic cancer pain.4957 a multicentre, randomized, double-blind, placebo-controlled trial demonstrated that gabapentin was effective in treating neuropathic cancer pain.54 compared with placebo, gabapentin-treated patients had significantly
Antidepressants may be effective for neuropathic pain due to anticancer treatment. one randomized, controlled trial (n = 15) demonstrated that amitriptylineeffectivelyreducedneuropathicpainfollowingtreatmentof breast cancer, but adverse effects hindered its regular use.66 in contrast,
PAIN MANAGEMENT
another randomized controlled trial in patients with chemotherapyinduced neuropathic pain (n = 44) reported that low-dose amitriptyline (1050 mg/day) showed a trendforan improvementin neuropathicpain symptoms, but the authors felt that statistical significance was likely not reached owing to small patient numbers.67 another study (n = 13) showed that maximum pain intensity was lower inpatientstreatedwithvenlafaxinecomparedwithplacebo,andadverse effects from venlafaxine were similar to placebo.68
Pre-emptive Analgesia
V. nSAIDs and Corticosteroids
Although current cancer pain guidelines recommend the use of nsaids, there is little evidence supporting their role in treating the neuropathiccomponentofcancerpain.similarly,evidencesupportingthe use of corticosteroids for neuropathic cancer pain is lacking. However, corticosteroids are recommended for patients with acute nerve or spinal cord compression.10,18
VI. topical Agents
a randomized, double-blind, trial (n = 114) on the efficacy of amitriptyline versus placebo in preventing chemotherapy-induced neuropathic symptoms found no difference between the groups.69 Following surgery for breast cancer, some patients develop postmastectomypainsyndrome,aneuropathicpainsyndrome.adouble-blind, randomizedstudycomparedtheefficacyofperioperativeadministration ofvenlafaxine(37.5mg/day),gabapentin(300mg/day)orplacebogiven for 10 days starting the night before surgery on the development of pain during the 6 months postoperatively.70 Both drugs reduced analgesic requirementsfollowingsurgery,andat6monthsvenlafaxinesignificantly reduced the incidence of post-mastectomy pain syndrome; gabapentin had no effect on chronic pain except for decreasing the incidence of burning pain.
IV. Anaesthetics, Anti-arrhythmic Agents and n-methyl-d-aspartate Receptor Antagonists
Theprimaryroleofcapsaicininneuropathiccancerpainisinpost-surgical neuropathic pain. A study involving cancer patients with post-surgical neuropathic pain (n = 99) showed that capsaicin 0.075% cream given for 8 weeks, four times daily, reduced pain by 53%, compared with a 17% reduction with placebo (P = 0.01).27 after the study period, significantly morepatientsindicatedthatcapsaicinwasthemorebeneficialtreatment (60% vs 18% for placebo; P = 0.001). Lidocainepatchesarerecommendedforthetreatmentofsometypesof neuropathicpain,mostnotablypostherpeticneuralgia.24,47Aretrospective audit of lidocaine 5% patch within a comprehensive cancer centre found that the data supported the trials of lidocaine 5% patch for cancer patients with neuropathic pain syndromes associated with allodynia.28 However,incancerpatientswithpost-surgicalincisionalneuropathicpain, a double-blind, randomized, cross-over study found that lidocaine 5% patchesdidnotsignificantlyreducepainintensityratingscomparedwith placebo, but did improve some secondary outcomes including general activity (P = 0.02).78 Non-pharmacological Treatments Most non-drug treatments for neuropathic cancer pain involve interventionaltherapy,asdescribedbelow.Whilethereislittledataonthe roleofcomplementarytherapyinthemanagementofneuropathiccancer pain, a recent review article described that such treatments as massage, acupuncture, and psychological and behavioural approaches may be of use in the management of neuropathic cancer pain.79 Interventional Therapy
I. neuraxial Drug Administration
Anaesthetics may be used as primary therapy for treatment of cancerassociatedneuropathicpaininsomecentres,whereasothersusethemas second-lineagents.4,10However,thereislimitedevidencesupportingtheir use for cancer pain.There are a few reports that subcutaneous infusion of lidocaine 10% improved pain refractory to systemic and spinal opiates in patientswithterminalmalignancy.71Whileasystematicreviewreported thatalthoughintravenouslidocainewaseffectivefornon-cancer-related neuropathic pain, it had no effect on cancer-related pain.72 in contrast, a recentlypublishedcasereportconcludedthatintravenouslidocainemay havearoleforseverecancer-relatedneuropathicpainattheend-of-life.73 Oral mexiletine showed some efficacy in pain due to peripheral nerve damage, but not for central pain.72 in a systematic review, lidocaine and oral analogues were better than placebo and were as effective as other analgesics in the treatment of neuropathic pain.74 Ketamine, an N-methyl-d-aspartate (nMda) antagonist, may reduce hypersensitivity in the dorsal horn, alleviate nMda-related neuropathic pain, and has a synergistic effect with opioids in cancer pain patients that are unresponsive to high-dose morphine.5,75 However, because of itsadverseeffects,ketaminetherapyshouldbeinstitutedbyexperienced teams.26 A recent case report described the use of low-dose intravenous ketamine in an inpatient setting followed by the use of oral memantine forlong-termoutpatientmanagementinanopioid-refractoryoncology patient.76 Flupirtine, a non-opioid analgesic that acts as a functional nMda receptorantagonist,showedsomebenefitinpalliativecarepatientswith neuropathic pain due to cancer.77 It may be useful in the treatment of neuropathic pain as an adjuvant to opioids.
Spinal analgesia effectively relieves refractory cancer pain and should be considered for patients with pain that is poorly responsive to administration of drugs via conventional routes, and those with poor tolerancetosystemicmedications.10,80,81Intrathecaladministrationmay minimizesystemicabsorptionandrelatedsideeffectsafteradministration of higher doses, which may be required for opioid-resistant pain such as neuropathic cancer pain.81 Studies have shown that intrathecal opioids andintraspinalclonidinemaybeeffectiveinneuropathiccancerpain.31,32 Spinal administration of other anaesthetics may be effective as an adjunct to intrathecal opioids, but efficacy in neuropathic cancer pain is anecdotal.82,83
II. Radiofrequency treatment and neurostimulation
Percutaneous electrical nerve stimulation has been useful for a small subset of cancer patients, such as those with opioid-resistant pain due to bony metastasis.84 However, evidence to support its use in neuropathic cancer pain is lacking.
10
PAIN MANAGEMENT
spinal cord stimulation (scs) may be effective in a variety of neuropathicpainsyndromes.85,86 Asystematicliteraturereviewshowed that although SCS is beneficial in vasculopathic and postherpetic neuralgia, it has no clinical usefulness in cancer pain.87 However, a recent publication has demonstrated that SCS provided pain relief in patients with cancer-related chest wall pain (n = 14).33 Radiofrequency treatment combined with glucocorticoid in patients withrefractoryneuropathicpainfollowingbreastcancersurgeryrelieved painandimprovedqualityoflife34;however,furtherstudiesarenecessary toevaluatetheeffectivenessofradiofrequencytreatmentinneuropathic cancer pain.
III. neural Blockade
reports or by small sample sizes, probably because of the specificity of indicationsfortheseprocedures.35,36Thismayindicatearoleinneuropathic pain control but highlights the need for careful patient assessment and selection to optimize outcomes.
IV. neurolysis
The literature on neural blockade via anaesthetic infusion to control neuropathic cancer pain shows favourable effects but is limited to case
some cancer patients may benefit from neurolytic procedures, such as patients with severe, intractable pain that is responsive to diagnostic neural blockade but uncontrolled by less aggressive procedures owing to poor response or tolerance.30 A clinical review concluded that neurolytic sympathetic procedures for pancreatic and pelvic cancer may be useful for reducingpainwhenmultiplepainmechanismsareinvolved.88However,the literature on the use of neurolysis specifically for neuropathic cancer pain is scarce and suggests a limited role, with one review stating that peripheral neurolytic blocks may be helpful in some cancer patients with peripheral neuropathies.89
23.BennettMI.Effectivenessofantiepilepticorantidepressantdrugswhenaddedtoopioidsforcancerpain:systematic review. Palliat Med 2011;25:553559. 24.attaln,cruccug,Baronr,etal. eFnsguidelinesonthe pharmacologicaltreatmentofneuropathicpain:2010revision. eur J neurol 2010;17:11131188. 25. Berger a, dukes e, Mercadante s, oster g. use of antiepilepticsandtricyclicantidepressantsincancerpatients withneuropathicpain.eurJcancercare2006;15:138145. 26.Mercadantes.WorldHealthorganizationguidelines: Problemareasincancerpainmanagement.CancerControl 1999;6:191197. 27. ellison n, loprinzi cl, Kugler J, et al. Phase iii placebocontrolled trial of capsaicin cream in the management of surgical neuropathic pain in cancer patients. J Clin Oncol 1997;15:29742980. 28.FlemingJa, oconnorBd. useoflidocainepatchesfor neuropathicpaininacomprehensivecancercentre.PainRes Manage 2009;14:381388. 29. Mishra s, Bhatnagar s, gupta d, et al. Management of neuropathiccancerpainfollowingWHOanalgesicladder:a prospectivestudy.amJHospPalliatcare2009;25:447450. 30.MiguelR.Interventionaltreatmentofcancerpain:the fourthstepintheWorldHealthOrganizationanalgesicladder? cancer control 2000;7:149156. 31.Beckerr,Jakobd,uhleei,etal.Thesignificanceofintrathecalopioidtherapyforthetreatmentofneuropathiccancer painconditions.stereotactFunctneurosurg2000;75:1626. 32.eisenachJc,duPens,duboisM,etal.epiduralclonidine analgesiaforintractablecancerpain.TheEpiduralClonidine study group. Pain 1995;61:391399. 33.yakovlevae,reschBe,Karasevsa.Treatmentofcancerrelatedchestwallpainusingspinalcordstimulation.AmJ Hosp Palliat care 2010;27:552556.
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34. uchida Ki. radiofrequency treatment of the thoracic paravertebralnervecombinedwithglucocorticoidforrefractoryneuropathicpainfollowingbreastcancersurgery.Pain Physician 2009;12:e277e283. 35. Vranken JH, Van der Vegt MH, ubags lH, et al. continuous sacral nerve root block in the management of neuropathiccancerpain.anesthanalg2002;95:17241725. 36. Vranken JH, van der Vegt MH, Zuurmond WW, et al. Continuousbrachialplexusblockatthecervicallevelusing aposteriorapproachinthemanagementofneuropathic cancer pain. reg anesth Pain Med 2001;26:572575. 37.TofthagenC.Patientperceptionsassociatedwithchemotherapy-inducedperipheralneuropathy.ClinJOncolNurs 2010;14:e22e28. 38. cleeland cs, gonin r, Hatfield aK, et al. Pain and its treatment in outpatients with metastatic cancer. N Engl J Med 1994;330:592596. 39.WatsoncP,Babuln.efficacyofoxycodoneinneuropathic pain:arandomizedtrialinpostherpeticneuralgia.Neurology 1998;50:18371841. 40. raja sn, Haythornthwaite Ja, Pappagallo M, et al. Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial. neurology 2002;59:10151021. 41.rowbothamMc,Twillingl,daviesPs,etal.oralopioid therapyforchronicperipheralandcentralneuropathicpain. n engl J Med 2003;348:12231232. 42.yoshioka H,Tsuneto s, KashiwagiT. Pain control with morphineforvertebralmetastasesandsciaticainadvanced cancer patients. J Palliat care 1994;10:1013. 43.BallantyneJc,MaoJ.opioidtherapyforchronicpain.n engl J Med 2003;349:19431953. 44. grond s, radbruch l, MeuserT, et al. assessment and treatmentofneuropathiccancerpainfollowingWHOguidelines. Pain 1999;79:1520. 45. Pergolizzi JV Jr, Mercadante s, echaburu aV, et al. The role of transdermal buprenorphine in the treatment of cancer pain: an expert consensus. Curr Med Res Opin 2009;25:15171528. 46. arbaiza d, Vidal o.Tramadol in the treatment of neuropathiccancerpainadouble-blind,placebo-controlled study. clin drug invest 2007;27:7583. 47.dworkinrH,o'connoraB,audetteJ,etal.recommendationsforthepharmacologicalmanagementofneuropathic pain: an overview and literature update. Mayo Clin Proc 2010;85(3 suppl):s3s14. 48. gagnon B, almahrezi a, schreier g. Methadone in the treatment of neuropathic pain. Pain Res Manag 2003;8:149154. 49.Bosnjaks,Jelics,susnjars,etal.gabapentinforreliefof neuropathicpainrelatedtoanticancertreatment:aprelimi-
nary study. J chemother 2002;14:214219. 50.BackonjaM,Beydouna,edwardsKr,etal.gabapentin forthesymptomatictreatmentofpainfuldiabeticneuropathy inpatientswithdiabetesmellitus:arandomizedcontrolled trial. JaMa 1998;280:18311836. 51. rowbotham M, Harden n, stacey B, et al. gabapentin forthetreatmentofpostherpeticneuralgia:arandomized controlled trial. JaMa 1998;280:18371842. 52.Van deVusse ac, stomp-van den Berg sg, Kessels aH, etal.RandomisedcontrolledtrialofgabapentininComplex regional Pain syndrome type 1. BMc neurol 2004;4:13. 53.caracenia,Zeccae,Martinic,deconnoF.gabapentin asanadjuvanttoopioidanalgesiaforneuropathiccancer pain. J Pain symptom Manage 1999;17:441445. 54. caraceni a, Zecca e, Bonezzi c, et al. gabapentin for neuropathiccancerpain:arandomizedcontrolledtrialfrom the Gabapentin Cancer Pain Study Group. J Clin Oncol 2004;22:29092917. 55.TakahasiH,shimoyaman.aprospectiveopen-labeltrial of gabapentin as an adjuvant analgesic with opioids for Japanesepatientswithneuropathiccancerpain.IntJClin oncol 2010;15:4651. 56. Keskinboro K, Pekel aF, aydinli i. gabapentin and an opioidcombinationversusopioidaloneforthemanagement ofneuropathiccancerpain:Arandomizedopentrial.JPain symptom Manage 2007;34:183189. 57. araiycP,TamsubaraT, shimo K, et al. low-dose gabapentinasusefuladjuvanttoopioidsforneuropathiccancer painwhencombinedwithlow-doseimipramine.JAnaesth 2010;24:407410. 58. rosenstock J, Tuchman M, laMoreaux l, et al. Pregabalin for the treatment of painful diabetic peripheral neuropathy:adouble-blind,placebo-controlledtrial.Pain 2004;110:628638. 59. dworkin rH, corbin ae, young JP Jr, et al. Pregabalin forthetreatmentofpostherpeticneuralgia:arandomized, placebo-controlledtrial.neurology2003;60:12741283. 60.saifMW,Hashmis.successfulameliorationofoxaliplatin-inducedhyperexcitabilitysyndromewithantiepileptic pregabalin in a patient with pancreatic cancer. Cancer chemother Pharmacol 2008;61:349354. 61. Pourzitaki c, logotheti H, sardeli c, et al. Pregabalincombinedwithepiduralanalgesiainchroniccancer painpatients.revclinPharmacolPharmacokinet(inted) 2008;22:308309. 62.BackonjaMM.anticonvulsants(antineuropathics)for neuropathic pain syndromes. clin J Pain 2000;16(suppl 2):s67s72. 63.Bendalyea,Jordanca,staehlerss,rushingda.Topiramateinthetreatmentofneuropathicpaininpatientswith cancer. support cancer Ther 2007;4:241246.
64.Paneraiae,BianchiM,sacerdoteP,etal.antidepressants in cancer pain. J Palliat care 1991;7:4244. 65. Mercadante s, arcuri e,TirelliW, et al. amitriptyline in neuropathiccancerpaininpatientsonmorphinetherapy: arandomizedplacebo-controlled,double-blindcrossover study. Tumori 2002;88:239242. 66.Kalsoe,TasmuthT,neuvonenPJ.amitriptylineeffectively relievesneuropathicpainfollowingtreatmentofbreastcancer. Pain 1996;64:293302. 67.Kautioal,HaanpM,saartoT,Kalsoe.amitriptylinein thetreatmentofchemotherapy-inducedneuropathicsymptoms. J Pain symptom Manage 2008;35:3139. 68.TasmuthT,HartelB,Kalsoe.Venlafaxineinneuropathic pain following treatment of breast cancer. Eur J Pain 2002;6:1724. 69. Kautio al, Haanp M, leminen a, et al. amitriptyline inthepreventionofchemotherapy-inducedneuropathic symptoms. anticancer res 2009;29:26012606. 70. amr yM, yousef aaaM. evaluation of efficacy of the
A complete list of references can be obtained upon request from the editor.
About the Authors dr chen is consultant and chief of service, department of anaesthesiology and operating services, Alice Ho Miu Ling Nethersole Hospital and North district Hospital, and adjunct associate Professor, The chinese university of Hong Kong, Hong Kong sar. dr ip is associate Professor and chief, division of Hand and Foot surgery, department of orthopaedicsurgery,TheuniversityofHongKong, Queen Mary Hospital, Hong Kong sar. dr lam is an Honorary Consultant and Honorary Clinical associate Professor, division of neurosurgery, departmentofsurgery,ThechineseuniversityofHong Kong, Prince of Wales Hospital, Hong Kong sar. dr Mok is Associate Professor and Honorary Associate consultant, division of neurology, department of Medicine and Therapeutics, The chinese university of Hong Kong, Prince of Wales Hospital, Hong Kong sar. dr Tsoi is a neurologist and consultant Physician, department of Medicine, Pamelayoude nethersole eastern Hospital, Hong Kong sar. dr cP Wong is chief, integrated Medical services, and consultant and Head, department of geriatrics, ruttonjee andTang shiu Kin Hospitals, Hong Kong SAR.DrSWongisConsultantAnaesthesiologistand Head of the Pain Management Team, department ofanaesthesiologyandoperatingTheatreservices, Queen elizabeth Hospital, Hong Kong sar.
12
in Focus
urology
Reviews achieving effective Management of the Overactive Bladder The Patient With a urinary calculus: What to Do Next Management of lower urinary Tract Symptoms and Bladder Outlet Obstruction
How much do you know about urology? General practitioners can play a role in the investigation of common urological problems, including the overactive bladder, urinary calculus and lower urinary tract symptoms.
True 1. referral of patients with overactive bladder (oaB) to a specialist is recommended for those who are refractory to treatment or in whom the diagnosis of OAB is unclear. 2. Approximately 80% of urinary stones are calcium stones. 3. Most patients who form stones are unlikely to benefit from dietary changes. 4. lower urinary tract symptoms (luTs) have a variety of systemic, neurological, drug-related or urological causes. False
5. First-line treatment of luTs in men with mild or moderate luTs should be conservative, followed by medical therapy.
See page 32 for answers
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Peer Reviewed
Achieving Effective Management of the Overactive Bladder

Mariolyn d raj, MBBs; audrey Wang, MBBs(syd), Fracs(urol)
appropriate diagnosis and management of overactive bladder (oaB) by gPs is essential in reducing its negative impact on an individuals quality of life. Successful communitybased treatment of oaB involves behavioural therapy, often in conjunction with anticholinergic medications.
urinary urgency is the hallmark of overactive bladder.
veractive bladder (oaB) is a common condition in Australia and is characterized by urinary urgency with or without urge incontinence. usually, it is also associated with urinary frequency and nocturia, in the absence of a urinary tract infection. For diagnostic purposes, urinary frequency up to eight times a day and nocturia up to once per night in a 24-hour period is considered normal. urinary urgency is the hallmark symptom of oaB and is defined as a sudden compelling desire to pass urine that is difficult to defer.1 About 3050% of these patients also experience urge urinary incontinence, which refers to involuntary urine leakage accompanied by or immediately preceded by urgency.2 These patients are referred
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to as having OAB wet. The remaining patients who are referred to as having oaB dry, and their condition can progress to OAB wet if not properly treated. Patients with OAB should be thoroughly assessed to exclude a concomitant urinary tract infection. This article discusses the investigation and management of overactive bladder in a general practice setting in men and women.
Demographics and Impact on Quality of Life

it is estimated that up to 16% of the population over the age of 40 years may experience OAB syndrome and that the incidence most likely increases with advancing age.3,4 Patients with OAB often report embarrassment, social isolation and lowered self-esteem associated with the constant anxiety and fear of wetting themselves. They often feel debilitated by their symptoms, which have a negative impact on their overall quality of life. in women over 65 years of age with oaB, there is also a higher rate of falls and resultant
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fractures, with the associated increase in morbidity and mortality. Sur veys carried out on the Australian population report that urinar y incontinence costs our economy approximately a$1 billion annually and this cost is rising.4,5 For the individual, the financial burden due to the need for continence pads, laundry care and medications can also be significant. Many patients with OAB delay reporting their symptoms to their GP because of feeling embarrassed or their incorrect belief that this is a natural part of ageing. It is therefore worthwhile for GPs to screen patients for OAB symptoms as part of their annual physical assessment.
Lower urinary tract symptoms (International Continence Society terminology, 2002)1

Storage symptoms daytime frequency (normal = eight or fewer voids/day) urgency incontinence nocturia (normal = up to one void/night) Voiding symptoms slow stream splitting or spraying of stream intermittent stream Hesitancy straining to void Terminal dribble Post-micturition symptoms Feeling of incomplete emptying Post-micturition dribble
Conditions that can cause overactive bladder symptoms

Metabolic diabetes mellitus Neurological Parkinsons disease Multiple sclerosis cerebrovascular disease spinal cord injury Bladder outlet obstruction Prostatic enlargement Pelvic organ prolapse in females Bladder irritants urinary tract infection Bladder calculi carcinoma in situ Bladder cancer
Clinical Assessment
Most patients with an initial complaint of OAB without any associated complex features can receive successful first-line treatment via their GP. Initial assessment and treatment of OAB relies on an accurate history and targeted physical examination. Some of these patients will require further assessment and management by a urologist or urogynaecologist.
History
History should include information regarding the patients age, lower urinary tract symptoms (see the box on this page), previous urinary tract infections or urinary calculi, presence of constipation and daily fluid intake, especially caffeine and alcohol consumption. The symptoms of OAB can occur in the setting of other disorders. Patients should therefore be screened for neurological conditions such as Parkinsons disease or cerebrovascular disease, and for metabolic conditions such as diabetes that can produce
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symptoms including polyuria and polydipsia, which can mimic oaB (see the box on this page). Prior urogynaecological surgery in women or prostate surgery in men is also relevant. use of medications such as diuretics, anticholinergics or alpha blockers should also be noted. These drugs can contribute to incontinence by increasing urine output (as in the case of diuretics) or by producing stress urinary incontinence (which may occur with alpha blockers in women).
investigate for an enlarged prostate. Prostatic enlargement can produce OAB symptoms by obstructing the flow of urine at the level of the bladder neck. in women, a vaginal examination is recommended to assess for pelvic organ prolapse or atrophy. Cystoceles can cause urethral kinking, thereby increasing bladder outlet resistance and hence obstructing urine flow. A focused neurological examination to identify any underlying neurological disease is also helpful.
Investigations
Mandatory investigations include a midstream urine analysis to rule out urinary infection and haematuria. A bladder scan or dedicated urinary tract ultrasound is needed to assess post-void residual urine volume and exclude urinary retention. in our practice, we consider a post-void residual urine volume of more than 100 mL to be clinMedical Progress January 2012
Examination
An examination of the abdomen and pelvis for masses, including a palpable bladder, is important as it may indicate urinary retention. in men, a rectal examination of the prostate should be performed to
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ically significant and likely to indicate poor bladder emptying. However, there is currently no international consensus on the volume of residual urine in the bladder that constitutes a diagnosis of urinary retention based on a post-void residual measurement alone. All patients being investigated for OAB should be asked to keep a 3-day bladder diary. This should include information such as oral fluid intake, number of voids per day, volume of urine passed on each occasion, incontinence episodes, and use of pads. The information provided enables the GP to determine the maximum voided volume (largest volume of urine voided in a single micturition), the interval between episodes of voiding, timing and type of fluid intake, and the presence of nocturnal polyuria (increased proportion of the 24-hour output occurs at night). A GP can use this information to counsel the patient about behaviour modifications that may help to alleviate symptoms. For example, in patients with nocturia, this symptom may be improved by avoiding fluid intake prior to bedtime or developing a pattern of voiding before bedtime if this is not already occurring based on a review of the patients voiding diary. Blood tests, such as serum creatinine and fasting blood glucose, and prostate-specific antigen in age-appropriate men may be helpful. In patients in whom the information gained from history taking, examination and their bladder diary is inconclusive, further investigations are often warranted. This often necessitates referral of patients to a urologist or urogynaecologist. A multichannel urodynamics study can confirm the diagnosis of detrusor overactivity in patients with OAB and can indicate the relative contributions of coexistent stress
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incontinence or outflow obstruction if present. This study involves the passage of small catheters into the bladder and rectum, the infusion of water or contrast into the bladder and the recording of pressure readings. It provides an assessment of the storage and voiding function of the bladder. In oaB, the presence of unstable bladder muscle (detrusor) contractions, their magnitude and any associated urine leakage can be demonstrated. It is particularly useful in patients presenting with neurological bladder dysfunction, mixed incontinence or possible bladder outlet obstruction. A cystoscopy is necessary in patients with OAB and coexisting symptoms of haematuria or recurrent bacterial cystitis. Cystoscopy enables visualization of the bladder lumen to rule out causes such as bladder stones, neoplasms or inflammation.
and micturition deferment. Pelvic floor exercise is also considered an important part of behavioural modification therapy. The bladder training strategy should be individualized for each patient in consultation with the continence advisor and/or pelvic floor physiotherapist, and different bladder training strategies may be used during various periods of treatment. Fluid Management To achieve better fluid management, patients should be advised to drink evenly throughout the day, and to reduce their fluid intake in the evenings to avoid the likelihood of nocturia. Caffeine and alcohol consumption should be limited because of their diuretic effects. Patients should be encouraged to maintain a high-fibre diet to reduce the occurrence of constipation.5 Bladder Training Bladder drill involves educating patients with an intact nervous system to relearn to inhibit a detrusor contraction or a sensation of urgency. It involves timed voiding, so that patients develop a voiding pattern according to a schedule that incorporates incremental increase in the voiding interval. This may be achieved by voiding according to a clock or timer alarm at an interval that has been negotiated with patients after review of their bladder diary. A voiding schedule, which promotes regular bladder emptying, aims to reduce the occurrence of urinary urgency by avoiding over-distension of the bladder. Micturition deferment is a bladder training technique in which patients are taught strategies to suppress the urge to urinate, which is often triggered by involuntary contraction of the bladder muscle in OAB. Through use of a graded programme, patients
Management
Most patients with OAB can initially be conservatively managed in the community. This often requires multidisciplinary team care, including the patient, the gP, a continence advisor and/or a pelvic floor physiotherapist. Management of OAB includes educating the patient about normal lower urinary tract structure and function, behavioural modification via fluid scheduling, restriction of caffeine and alcohol intake, bladder retraining and pelvic floor exercise, and use of anticholinergic medications. use of diuretics should be avoided if possible in these patients.
Behavioural Modification techniques

Behavioural modification involves fluid management and bladder training. Numerous bladder training strategies are available, including bladder drill
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learn to suppress the urge to void for longer and longer periods of time. Pelvic Floor Exercise Pelvic floor exercise is an important part of behavioural therapy. The aim of these exercises is to inhibit detrusor muscle contraction by voluntary contraction of the pelvic floor muscle when the patient experiences urgency and to counteract the urethral relaxation that accompanies an involuntary detrusor contraction. A physiotherapist or continence nurse advisor will tailor an exercise programme for the individual patient. Patients are advised to perform pelvic floor exercises daily for strengthening and to use short maximal contractions when they experience urgency symptoms.
It is important to encourage patients to continue their medication for at least 1 month, because the maximal benefit is not evident until then. in the elderly, a lower starting dose of anticholinergic medication (eg, oxybutynin hydrochloride 2.5 mg twice daily) should be considered. Vaginal Oestrogen Supplementation Local vaginal oestrogen supplementation is useful in postmenopausal women with symptomatic vaginal atrophy and OAB. There are no data currently to support the use of systemic hormone replacement for this indication. Imipramine imipramine, a tricyclic antidepressant with anticholinergic effects, is often
used in patients with oaB, especially for the treatment of nocturia. Imipramine functions by promoting detrusor muscle relaxation. Side effects include sedation and skin photosensitivity.
other treatment options

For patients with symptoms refractory to behavioural therapy and anticholinergic medications, second-line management options include off-label use of botulinum toxin and sacral or peripheral neuromodulation. Botulinum toxin inhibits the release of acetylcholine into the synaptic cleft of the motor nerve and thus causes potent relaxation of smooth and skeletal muscle. Injection of botulinum toxin at multiple sites within the bladder under cystoscopic
Medications
Anticholinergic Medications Pharmacotherapy with anticholinergic medications (antimuscarinics) is used in conjunction with behavioural therapy for the treatment of OAB (Table).6 Physiological bladder contractions are triggered by acetylcholine-induced stimulation of postganglionic parasympathetic muscarinic receptors on the detrusor muscle. The anticholinergic agents compete with acetylcholine on the muscarinic receptors and therefore depress normal bladder contractions and any involuntary contractions. They can also cause effects on muscarinic receptors at sites other than the bladder, because they have variable receptor selectivity. Potential side effects of anticholinergic medications include dry mouth, dry eyes, constipation, blurred vision, cardiac arrhythmias and drowsiness. These medications are contraindicated in patients with untreated narrow angle glaucoma and urinary or intestinal obstruction.
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Table. Anticholinergic medications available in Australia

Generic name Darifenacin hydrobromide PBS information Not currently PBS-listed Dose 7.5 to 15 mg daily Action SelectivemuscarinicM3 receptor antagonist; less lipophilic and theoretical advantage of minimal CNS side effects Mixed action: anticholinergic, musculotropicrelaxant, local anaesthetic activity Mixed action
Oxybutynin hydrochloride
PBS-listed for detrusoroveractivity
Maximum 5 mg four times daily in adults
Oxybutynin hydrochloride
PBS-listed for detrusoroveractivity in a patient who cannot tolerate oral oxybutynin, or who cannot swallow oral oxybutynin Not currently PBSlisted Not currently PBSlisted
One patch twice weekly
Solifenacin succinate Tolterodine tartrate
5 to 10 mg daily 1 to 2 mg twice daily
Competitivemuscarinic receptor antagonist Competitivemuscarinic receptor antagonist
PBs = Pharmaceutical Benefits scheme; cns = central nervous system.
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guidance has been reported to reduce urinary urgency and urge incontinence by inhibiting detrusor contractions. Since the effect of botulinum toxin usually wears off 6 to 9 months after injection, repeat treatments are often necessary. urinary retention is a possible complication of treatment and may limit its use in patients who cannot or are unwilling to perform self-catheterization. The techniques of sacral nerve neuromodulation and peripheral nerve neuromodulation are other options for patients who are refractory to pharmacological treatment. Sacral neuromodulation involves using mild electrical pulses to stimulate the sacral nerve root at s3, and has been shown to reduce urge incontinence and symptoms of urgency frequency. It is approved for use in Australia and there may be an increased use of this technique. Complex reconstructive surgical alternatives available include bladder augmentation (ileal enterocystoplasty) and urinary diversion; however, these are infrequently performed.
Recommendations for referral of patients with overactive bladder

Presence of haematuria suspicion of underlying bladder or prostate neoplasm (elevated prostate specific antigen level, abnormal digital rectal examination) High post-void residual urine volume (more than 100 ml) atypical symptoms (eg, pelvic pain, recurrent urinary tract infections) Worsening symptoms or symptoms refractory to treatment with behavioural therapy and anticholinergic medications Previous genitourinary surgery Previous genitourinary trauma
Key points
overactive bladder (oaB) is characterized by urinary urgency with or without urinary incontinence, generally in the presence of frequency and nocturia. oaB is a common condition and the prevalence increases with age. Without treatment, oaB may produce a significant negative impact on an individuals quality of life. diagnosis involves history and physical examination, urinalysis, measurement of post-void residual urine volume and assessment of a bladder diary. oaB can be successfully treated in the general practice setting via behavioural modifications(eg,fluidscheduling,bladder retraining,micturitiondeferment)anduseof anticholinergic medications. referral of patients to a urologist or urogynaecologistisindicatedforthosewho are refractory to treatment or in whom the diagnosis of OAB is unclear.
Conclusion
OAB is a common condition in Australia and its prevalence is expected to increase as our population ages. Effective management of OAB in men and women is achievable in a general practice setting. This involves careful assessment via directed history and physical examination, as well as baseline investigations, including a urine test, assessment of post-void residual urine volume and use of a bladder diary. Treatment involves behavioural therapy in conjunction with anticholinergic medications. Referral to a specialist is warranted in patients with atypical symptoms or who are refractory to treatment.
2003;326:841844. 3. Milsom i, abrams P, cardozo l, roberts rg, Thuroff J, WeinAJ.Howwidespreadarethesymptomsofanoveractive bladderandhowaretheymanaged?Apopulation-based prevalence study. BJu int 2001;87:760766. 4.Millardr,MooreK.urinaryincontinence:thecinderella subject. Med J aust 1996;165:124125. 5.ContinenceFoundationofAustralia.2010.Availableonline at: www.continence.org.au (accessed June 2011). 6.KuteesaW,MooreK.anticholinergicdrugsforoveractive bladder. aust Prescr 2006;29:2224.
When Should I Refer?

The symptoms attributed to OAB can also occur in the setting of other disorders and therefore clinicians should maintain a high degree of suspicion if patients report atypical symptoms or fail to respond to conventional therapy. Patients who report symptoms of haematuria, pain, urinary retention or likely prostatic enlargement should also seek specialist advice. The box on this page lists situations in which referral of patients with OAB to a specialist is recommended.
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Declaration of Interest
None. 2011 Medicine Today Pty ltd. initially published in Medicine Today July 2011;12(7):5156. reprinted with permission. About the Authors dr raj is an advanced Trainee in urology at Westmead Hospital, sydney. dr Wang is a consultant urologist atWestmead Hospital, sydney, nsW, Australia.
References
1. abrams P, cardozo l, Fall M, et al.The standardisation of terminologyoflowerurinarytractfunction:reportfromthe StandardisationSub-committeeoftheInternationalContinence society. neurourol urodyn 2002;21:167178. 2.HerbisonP,Hay-smithJ,ellisg,MooreK.effectivenessof anticholinergicdrugscomparedwithplacebointhetreatment of overactive bladder: systematic review. Br Med J
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Peer Reviewed
The Patient With a urinary Calculus: What to Do Next

duncan cooke, MBBs(Hons), FracP; stephen Mcdonald, MBBs, Phd, FracP; christopher s Pokorny, MBBs, FracPseries editor
Authoritative advice for GPs on the investigation of the patient with a urinary calculus is presented in this article.
rinary stones are a common problem. They are frequently symptomatic and costly in terms of hospital presentations, investigations and treatment. in the usa, the yearly cost of urinary stones has been estimated at us$1.23 billion per year.1 Furthermore, medical stone prevention has been shown to save approximately us$2,000 per patient.2 The purpose of investigating the patient with urinary stones is primarily to prevent recurrence. In the case of asymptomatic stones, the aim is to prevent these stones from becoming symptomatic.
Why Do Patients Form Stones?

The propensity to form urinary stones relates to the physicochemical derangement of urine composition whereby solutes are deposited in crystalline form rather than remaining in solution.3 There are a number of basic steps in stone formation, which are outlined in the box on page 18. A number of opportunities exist for clinical intervention in the process of urinary stone
urinary stone formation is the final common pathway of a very complex physicochemical system.
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Basic steps in urinary stone formation

Supersaturation Supersaturationofasolutionexistswhentheamountofdissolvedmaterialexceedsthemaximum that can usually be dissolved in a given solvent. There is a net drive toward crystallization in a solution in this state. Crystal formation Crystal formation occurs when solutes come together to form a nucleus in a process known as nucleation. although the supersaturated state favours crystal formation, it still requires the presence of promoters of nucleation. urine contains both promoters and inhibitors of nucleation. Membrane fragments, pre-existing calcium phosphate, sodium urate and uric acid stones are all examples of nucleation promoters, whereas urinary citrate, magnesium and some macromolecules are examples of nucleation inhibitors. Crystal growth crystalluria is very common, but stone formation is much less frequent. Both supersaturation and crystallization must be followed by retention and growth of the crystal for a stone to form. This is akin to dropping a salt crystal into different solutions. if the solution is a concentrated salt solution, the original crystal will grow; however, if the solution is water only, the crystal will itself dissolve.
formation. Crystal growth and supersaturation can be altered by changing the urine volume and the amount of filtered solute. Nucleation can be prevented by introducing inhibitors or reducing the concentration of promoters in the urine and existing stones can be dissolved. urinary stone formation is the final common pathway of a very complex physicochemical system. Intervention focusing on one single variable is unlikely to be effective, because stone formation is multifactorial. A more holistic approach is therefore needed.
Initial General Investigations

All patients with suspected and proven urinary stones should have radiological imaging of their urinary tracts. in addition to making the diagnosis, imaging may demonstrate other asymptomatic stones and complications of urinary stone disease such as ureteric obstruction (see the flowchart on this page). Patients with multiple stones are by definition recurrent stone formers. The imaging test of choice for urinary stones is a non-contrast helical computed tomography (cT ) scan. An ultrasound is an alternative for patients in whom it is necessary to avoid radiation (ie, in women who are pregnant). However, an ultrasound is less sensitive than a cT scan, especially for ureteric stones. An evidence-based concise set of guidelines with suggestions for the clinical care of patients with urinary stones is available on the Caring for Australasians with Renal Impairment (cari) website.4 Simple metabolic tests on urine and blood should be undertaken in all patients who present with stones. These tests include: measurement of serum calcium levels
Investigating patients with urinary stones

A patient presents with a suspected urinary stone Take patient history and assess renal function by carrying out simple metabolic tests
Patient has a history of stones and/or abnormal renal function
Patient has no previous history of stones and has a normal renal function and normal urinary tract
Perform a non-contrast abdominal CT scan
Perform a non-contrast abdominal CT scan
Stone visualized but no ureteric obstruction
Ureteric obstruction
No ureteric obstruction
Multiple stones
Single stone
Non-urgent urology referral and specific metabolic evaluation
Urgent urology referral (complicated nephrolithiasis) and specific metabolic evaluation
Non-urgent urology referral and specific metabolic evaluation
Symptomatic treatment. No further investigation needed
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measurement of serum urea and creatinine levels measurement of serum bicarbonate and potassium levels as a screen for renal tubular acidosis measurement of urine pH urine culture. Complete metabolic investigation is not necessarily required after a patient presents with their first stone. However, complete investigation should be undertaken if there are recurrent episodes. Investigations for the most common types of stones (ie, calcium and uric acid stones) should be included in this group of patients. Details of these investigations are described in the relevant sections below and in Table 1. i f p a s s e d o r ex t ra c te d, a l l stones should be sent for composition analysis unless this has been established with previous calculi. Knowledge of the composition of stones formed in a particular patient is the best guide to effective prophylaxis. In the setting of an acute episode of nephrolithiasis, straining of the urine for 48 hours after the onset of pain should be routinely undertaken.
Table 1. Metabolic evaluation in patients with recurrent or complicated stones

Calcium stones serum calcium levels 24-hour calcium excretion serum creatinine levels serum bicarbonate levels 24-hour citrate excretion urine pH 24-hour urinary urate excretion uric acid stones 24-hour urinary urate excretion serum urate levels urine pH Cystine stones 24-hour urinary cystine excretion Struvite stones urine pH urine culture Stones of unknown composition All the above investigations should be carriedout;however,24-hoururinarycystine excretion should only be measured if the patient has a strong family history of cystine stones.
and vegetables. This diet can lead to hypercalciuria, hyperoxaluria, hyperuricosuria and hypocitraturia. All of these have been shown to be powerfully predictive of urinary stone disease. Most patients who form stones are therefore likely to benefit from dietary changes to remedy these problems.
Specific Investigation and Treatment of Different Stone Types

Patients who require more specific investigations and treatment include: those who are recurrent stone formers (including those found to have multiple stones at presentation) those with complications of their stone disease those who are first stone formers with: pre-existing renal impairment a single functioning kidney abnormal urinary tracts a strong family histor y of recurrent urinary stones. Table 1 lists the specific metabolic investigations, depending on stone type, recommended in patients with recurrent or complicated stones. O f patients presenting with their first stone, 515% will develop another symptomatic stone within 1 year, suggesting that some form of prophylaxis should be considered.7 There are a number of interventions that have proven benefit in all patients who form stones. More specific intervention depends on the underlying cause and the type of stone being formed. Patients who form stones can be broadly divided into four groups: calcium stone formers, uric acid stone formers, cystine stone formers and struvite stones formers. clearly, knowledge of the biochemical composition is extremely helpful. Major risk
General Treatment Measures

in many cases, the stone composition will not be known. These patients should be treated with general treatment measures, as described below, to prevent stone recurrence and limit growth of existing calculi. The aim of treatment should be to increase urine output to at least 2 L per day. Fluid intake should be spaced evenly during the day. Increasing fluid intake just before going to bed can be especially helpful but will result in some degree of nocturia. Some patients find this an unacceptable imposition on lifestyle.
Fluid Intake
All patients who form stones benefit from increased fluid intake. 5,6 assuming the same excretion of solute, increased fluid intake will reduce the supersaturation of urine. In addition to dilution, increased urine flow will reduce the contact time available for crystal growth.
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Dietetic Intervention
urinary stone disease appears to be largely a disease of wealthy developed countries. It has been linked to a diet containing excessive amounts of refined carbohydrates, animal proteins and salt in association with a low intake of fruit
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factors for forming the different types of stones are outlined in Table 2.
Calcium Stones
About 80% of urinary stones are calcium-containing, with most consisting of calcium oxalate (Figure).
Table 2. Major risk factors for urinary stone formation

Calcium stones
Urinary
low urinary volume High urinary calcium levels High oxalate levels (specific for calcium oxalate stones) low urinary citrate levels High urine pH (specific for calcium phosphate stones)
Anatomical
Medullary sponge kidney Horseshoe kidney

Diet
low fluid intake low calcium intake High oxalate intake low potassium intake High animal protein intake High sodium intake
other medical conditions
Investigation Patients with normal urinary tracts presenting with their first calcium stone do not need extensive investigation. Measurement of serum creatinine, urea, calcium, bicarbonate and urate levels, in addition to renal imaging preferably with noncontrast cT, are sufficient investigations in these patients. The identification of significant abnormalities suggests underlying pathology, an extensive discussion of which is outside the scope of this article. Patients with calcium phosphate stones are specific cases, because their stones are critically dependant on urine pH. Given the role of the kidney in excreting endogenous and exogenous acid, the urine pH is usually acidic. Calcium phosphate stones therefore suggest either impaired urinary acidification, such as distal renal tubular acidosis, or high oral intake of alkali. Morning urine pH greater than 6 or recurrent pH never less than 5.8 is highly suggestive. Measurement of serum bicarbonate
levels will distinguish renal tubular acidosis from a high intake of alkali. If the calcium stone is recurrent or there are other high-risk features as described previously, more extensive investigation is indicated. This includes the following: measurements of 24-hour urinary calcium, oxalate, citrate and urate excretions measurement of parathyroid hormone levels. Treatment Dietetic intervention should be seen as an extension of the usual advice given for healthy eating. The aspects relevant to urinary stones are a reduction in animal protein (reduced purine metabolism and oxalate excretion) and reduced salt intake. Foods such as spinach, rhubarb and black tea are particularly high in oxalate and should be limited in patients who form calcium stones. counter intuitively, strategies involving restriction of dietary calcium
Figure. Multiple calcium oxalate urinary stones (scale in centimetres).
Primary hyperparathyroidism gout obesity diabetes mellitus uric acid stones High urinary urate excretion High serum urate levels Cystine stones cystinuria Struvite stones urinary infection
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to treat patients with calcium stones are not effective, even in those with hypercalciuria, and may cause a number of adverse effects. 810 Both primary and secondary prevention studies have shown that calcium restriction is ineffective in the prevention of calcium stones. A number of agents have been shown to reduce urinary calcium excretion, including thiazide diuretics, indapamide, sodium or potassium phosphate and bisphosphonates. Of these drugs, only thiazide diuretics and indapamide have been shown to reduce the occurrence of stones. Patients treated with these agents need to be monitored for adverse effects, including hypotension, hypokalaemia, hyperglycaemia and hypercholesterolaemia. Addition of potassium citrate may be useful to supplement potassium and replenish citrate when using these agents for stone prevention. (Citrate supplementation will be discussed in more detail below.) Increased oxalate excretion usually occurs as a result of dietary intake and is best treated with dietary modification. Two additional conditions, described below, can also cause hyperoxaluria. Primary hyperoxaluria. This rare autosomal recessive disorder results from one of a number of mutations in genes involved in the metabolism of glycoxalate. The excess glycoxalate is metabolized to oxalate instead of the more soluble glycine or glycolate. Affected individuals present with urinary stones or nephrocalcinosis, usually during childhood. Very high 24-hour urinary oxalate excretion confirms the diagnosis. However, the disease spectrum is wide and some patients present with urinary stones during adulthood. The definitive treatment is liver transplantation, which replaces the deficient enzymes.
23
Foods such as spinach, rhubarb and black tea are particularly high in oxalate and should be limited in patients who form calcium stones
Liver transplantation is most often required for patients who present during childhood. Adult patients with milder forms of the disease may be managed medically. Enteric hyperoxaluria. This occurs following surgery such as small bowel resection and intestinal diversion, which can cause fat malabsorption. The excess fatty acids in the gut form complexes with intestinal calcium, freeing oxalate for absorption. The result is excessive oxalate absorption.11 Pharmacological treatment of patients with hyperoxaluria has a limited effect, regardless of the cause. Cholestyramine has been shown to decrease oxalate absorption, but no controlled trials have been undertaken to demonstrate an effect on stone formation. Pyridoxine (vitamin B 6 ) induces enzymes involved in oxalate metabolism, thereby lowering oxalate levels. Observational studies have shown an inverse relationship between stone formation and high pyridoxine intake. Given the lack of toxicity associated with pyridoxine, its use
is not unreasonable in patients with hyperoxaluria. Decreased concentrations of urinary citrate are a major risk factor for stone formation. Citrate has an important physiological role in keeping solutes in solution. It effectively forms soluble complexes with urinary calcium preventing crystallisation. Plasma citrate is derived from dietary intake and metabolism of oxaloacetate in the citric acid cycle and is freely filtered at the glomerulus. The urinary concentration of citrate depends both on the filtered load and the amount reabsorbed. The western diet, which is high in animal protein, causes a reduction in urinary citrate probably via the acid load. Increased acid excretion in the urine increases the proportion of the divalent form of citrate, which is preferentially taken up by tubular cells. Although all urinary alkalinizers will, therefore, increase citrate levels, potassium citrate is the preferred urinary alkalinizer for use in patients with calcium stones. sodium-containing alkalinizers, such as sodium bicarbonate and sodium citrate, are not recommended, as the sodium load tends to increase urinary calcium excretion.12 Finally, although low urinar y magnesium levels are a risk factor for calcium stones, there is no evidence that magnesium supplementation prevents stones. However, if low serum magnesium levels are detected, then it may be reasonable to consider supplements.
Uric Acid Stones

Investigation Patients with uric acid stones require only measurement of serum urate levels and 24-hour urinary urate excretion. These tests are useful to monitor treatment but are not relevant to the
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diagnosis if the presence of uric acid stones has been established by stone analysis. Treatment Treatment of uric acid stones includes the use of allopurinol to reduce uric acid formation and uricosuria. Some patients with calcium oxalate stones also have hyperuricosuria in the absence of any other metabolic abnormality. They may or may not have hyperuricaemia. Hyperuricosuria is associated with the formation of calcium oxalate stones; however, it has been difficult to show a reduction in stone formation with allopurinol. nonetheless, it is reasonable to treat patients who have hyperuricosuria and recurrent calcium stones with allopurinol, providing it is well tolerated. The only word of caution is in patients with significant overproduction of uric acid (ie, those with myeloproliferative disorders and haemolytic anaemia). Blockade of xanthine oxidase with allopurinol can cause build up of the urate precursor xanthine, which itself can form stones when excreted in the urine. These stones, similar to pure uric acid stones, are radiolucent and difficult to detect radiographically.
All patients who form stones benefit from increased fluid intake.
other amino acids and, at high concentrations, forms crystals and stones in the urine. Patients with cystinuria frequently form mixed stones of cystine and calcium oxalate. Investigation Diagnosis of cystinuria is made by measuring 24-hour urinary cystine excretion and should be considered under the following circumstances: presence of urinary stones containing cystine urinary stones presenting during childhood frequent recurrences and formation of staghorn calculi a strong family history of urinary stones. Treatment Treatment of patients with cystine stones includes increased fluid intake, dietary modification, urinary alkalinization and pharmacological chelation of cystine.
Cystine Stones
Cystinuria is a genetic disorder and patients with this condition can present with recurrent urinary stones, mostly during childhood. Cystinuria results from mutations in genes producing amino acid transporters in the proximal nephron. in the normal individual, a number of amino acids are filtered into the urine and then reabsorbed in the proximal nephron. In patients with cystinuria, the reabsorption does not occur, resulting in aminoaciduria (including cystine). Cystine is less soluble than the
24
Increasing fluid intake is effective in reducing recurrent cystine stones; however, urine output needs to be increased to over 3 L per day. Night-time fluid needs to be increased to limit the high concentration of cystine in the urinary system overnight. The urinary excretion of cystine in these patients is related to endogenous production or conversion, as their intestinal cystine transporters are also defective. Limiting cystine intake is not an effective treatment for cystine stones. However, avoiding excessive protein intake is effective. Sodium intake increases cystine excretion; therefore, these patients should be commenced on a low-sodium diet. urinary alkalinization increases cystine solubility and, again, potassium citrate is the agent of choice. Cystine chelation therapy is available for patients not responding to the measures described above. d -Penicillamine is the only drug licensed in Australia and available
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When to Repeat Investigations

In summary
urinary stones are a common problem. They are frequently symptomatic and costly in terms of hospital presentations, investigations and treatment. approximately 80% of urinary stones are calcium stones. non-contrast cT scanning is the best imaging modality for urinary stones. stones should be retrieved for composition analysis. extensive metabolic assessment is only required for patients who are recurrent stone formers. all patients should be encouraged to drink more than 3 L of water daily. Most patients who form stones are also likely to benefit from dietary changes.
formation.endocrinolMetabclinnortham2002;31:855 867. 4.chronicKidneydiseaseguidelines:kidneystones.cari guidelines.sydney:cariguidelines;2007.availableonline at:www.cari.org.au/guidelines.php(accessedapril2010). 5.Tayloren,stampferMJ,curhangc.dietaryfactorsandthe riskofincidentkidneystonesinmen:newinsightsafter14 yearsoffollow-up.Jamsocnephrol2004;15:32253232. 6.curhangc,WillettWc,rimmeB,spiegelmand,stampfer MJ.Prospectivestudyofbeverageuseandtheriskofkidney stones. am J epidemiol 1996;143:240247. 7.JohnsoncM,WilsondM,oFallonWM,Malekrs,Kurland lT.renalstoneepidemiology:a25-yearstudyinrochester, Minnesota. Kidney int 1979;16:624631. 8. curhan gc, Willett Wc, rimm eB, stampfer MJ. a prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. N Engl J Med 1993;328:833838. 9. Borghi l, schianchiT, MeschiT, et al. comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. n engl J Med 2002;346:7784. 10.curhangc,WillettWc,Knightel,stampferMJ.dietary factors and the risk of incident kidney stones in younger women. arch intern Med 2004;164:885891. 11.AsplinJR.Hyperoxaluriccalciumnephrolithiasis.Endocrinol Metab clin north am 2002;31:927929. 12.Hammll,Hering-smithKs.Pathophysiologyofhypocitraturicnephrolithiasis.EndocrinolMetabClinNorthAm 2002;31:885893. 13.shekarrizB,stollerMl.cystinuriaandothernoncalcareouscalculi.endocrinolMetabclinnortham2002;31:951 977.
If the stone composition is unknown and no specific predisposing factors are identified, continued attempts to retrieve stones for analysis is the only ongoing investigation required. These patients should be treated with all the general measures described above. If a specific predisposing factor is identified and treatment instituted, repeat testing to assess the efficacy of treatment should be undertaken. For example, if a patient is commenced on a thiazide diuretic to treat increased urine calcium excretion, repeat urine calcium measurements should be performed after stabilization on the drug.
on the Pharmaceutical Benefits Scheme for patients with cystinuria. unfortunately, its use is associated with many side effects, and it should not be commenced without consultation with a specialist.
Conclusion
urinary stones are common and place a significant cost burden on the health system. Specific investigations are indicated in patients with recurrent or complicated stones and should commence with stone collection and composition analysis. All stone formers should be advised to increase fluid intake to greater than 3 L per day. Dietary calcium restriction is not recommended regardless of stone type and metabolic abnormality. Treatment recommendations are based on the type of stones formed and the specific metabolic derangement detected.
Struvite Stones
Discussion of struvite stones is included in this article for completeness. They form as a result of infection with urease-producing bacteria. This produces alkaline urine, causing formation of crystals containing magnesium, ammonium and phosphate mixed with carbonate. The most common organism involved is Proteus mirabilis. Stagnation of urine is also a major risk factor, occurring in patients with spinal cord injuries and neurogenic bladder. Treatment is eradication of the infection, which may also involve removal of foreign bodies such as catheters and stents, or correction of anatomic abnormalities or improvement of drainage of the urinary tract.13
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2010 Medicine Today Pty ltd. initially published in Medicine Today May 2010;11(5):1422. reprinted with permission.
None.
References
1.clarkJy,ThompsoniM,optenbergsa.economicimpact of urolithiasis in the united states. J urol 1995;154:2020 2024. 2. Parks JH, coe Fl. The financial effects of kidney stone prevention. Kidney int 1996;50:17061712. 3.KokdJ.clinicalimplicationsofphysicochemistryofstone
About the Authors Dr Cooke is a Consultant Nephrologist at the launcestongeneralHospital,Hobart,Tas,australia. Associate Professor McDonald is a Senior Staff specialist, central northern adelaide renal and Transplant service,and associateProfessor, school of Medicine, university of adelaide, sa, australia. Dr Pokorny is a member of the Board of Continuing education,royalaustralasiancollegeofPhysicians, andagastroenterologistinprivatepractice,sydney, nsW, australia.
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Peer Reviewed
Management of lower urinary Tract Symptoms and Bladder Outlet Obstruction

surayne segaran, MBBs, Mrcs; Mark J speakman, Ms, Frcs
lower urinary tract symptoms (luTs) affect more than 60% of men and women aged over 40. symptoms may be classed as storage, voiding or post-micturition and have a variety of systemic, neurological, drug-related or urological causes. Many patients with luTs will require no treatment. if indicated, first-line treatment of luTs should be conservative, followed by medical therapy.
Introduction and Terminology

significant number of men and women over the age of 40 suffer from bothersome urinary symptoms (62.5% men, 66.6% women).1 in the past, it was common to refer to these symptoms in men as prostatism, making the assumption that they were directly related to the prostate. in addition, many men were labelled with the presumptive histological diagnosis of benign prostatic hyperplasia and treated as such. It is now recognized that causes for these symptoms are multifactorial and include systemic illnesses, detrusor overactivity, infection, abnormal bladder sensation and sphincteric weakness, as well as benign prostatic enlargement (BPe).2 The term lower urinary tract symptoms (luTs) is therefore preferred, as it does not presume a diagnosis. luTs can be subdivided further into storage, voiding and post-micturition symptoms.3 The voiding symptoms were previously called the obstructive symptoms, and
Irritative storage symptoms are bothersome, particularly the symptoms of urinary urgency and nocturia.
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whilst these are more common they are less frequently complained about. The irritative storage symptoms are considerably more bothersome, particularly the symptoms of urinary urgency and nocturia. Although a significant number of men will have bladder outlet obstruction (Boo), principally due to BPe, there are many other causes such as stricture formation and prostate cancer.
Figure 1. Types of urinary symptoms.
types of Urinary Symptoms (table 1)

It is rare for patients to present with one group of symptoms in isolation; the majority will have mixed symptoms.4 The epiluTs study was an investigation of over 14,000 men, of whom 71% complained of luTs (Figure 1).
evaluating luTs
GPs or other health-care professionals can perform initial assessment, with referral to urologists for specific tests, for complicated cases or after failed medical treatment.5 A thorough medical history and physical examination are the first steps in establishing the cause of luTs it is important to rule out the various systemic causes of luTs as well as to exclude conditions such as meatal stenosis and phimosis.
Investigating LUtS (table 2)

The following should be carried out for men presenting with bothersome luTs: a targeted medical history and physical examination, including digital rectal examination (dre) a urine dipstick test to check for the presence of blood, glucose, protein, leucocytes and nitrites completion of a validated symptom score (eg, the international prostate symptom score [iPss]) a urinary frequency/volume chart. Whereas the 2010 NICE guideline5
27
suggested that prostate-specific antigen (Psa) testing should be carried out only in men who have luTs suggestive of BPe (ie, with a predominance of voiding over storage symptoms), men with an abnormal prostate on DRE or those who are particularly concerned about prostate cancer, there is evidence that PSA can also be a good indicator for risk of progression. Marberger et al demonstrated that in men with luTs, a Psa above 1.4 ng/ml was associated with a ninefold increase in risk of acute urinary retention (aur).6
Adequate patient information and counselling before PSA testing are essential. Renal function tests (serum creatinine and estimated glomerular filtration rate) are indicated only where there is a clinical suspicion of renal impairment, for instance, in patients with nocturnal enuresis, a palpable bladder, recurrent urinary tract infections or a history of renal tract calculi. 5 Flow rates, post-void residual volume (PVr) measurement, upper tract imaging or cystoscopy is
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Table 1. Types of urinary symptoms

Storage symptoms Frequency nocturia urgency incontinence altered bladder sensation Voiding symptoms slow stream intermittent stream Hesitancy straining splitting or spraying of stream Terminal dribbling Post-micturition symptoms incomplete emptying Post-micturition dribble
not recommended in the initial evaluation of uncomplicated luTs.5 The IPSS is a validated and widely used tool for the assessment of luTs (Figure 2). it is not a diagnostic questionnaire but allows stratification of symptom severity into mild (17), moderate (819) and severe (20+) symptom categories. There are four questions for voiding symptoms and three for storage symptoms. It is particularly valuable if used again after treatment to measure the treatment effect. Quality of life is usually assessed in addition to iPss, and this question is the most valuable and sensitive to change with treatment. Frequency/volume (F/V ) charts are increasingly used in the firstline evaluation of luTs and are useful for formulating a diagnosis as well as for monitoring response to treatment (Figure 3). They are particularly helpful in identifying nocturnal polyuria and polyuria due to excess fluid intake. However, F/V
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charts are not standardized and may not routinely include measurement of fluid intake. There is no clear evidence to suggest a particular duration for recording F/V charts, but the current consensus is to record them for at least 3 complete days. one-day charts, while convenient, are not sufficiently accurate for diagnosis or treatment monitoring. Fl ow- rate te s t i n g, P V r a n d urodynamic testing: flow-rate measurements can give a rough probability of obstruction but cannot discriminate between poor detrusor function and BOO. They are recommended in specialist assessment of luTs together with PVr measurement, which also has a poor correlation with obstruction. 7,8 The shape of the flow curve can often provide more information than the absolute numeric value, particularly for identifying obstruction secondary to urethral stricture. More detailed specialized assessment of obstruction is carried out with urodynamics (pressure flow testing). This is the only accurate way to discriminate among Boo, detrusor overactivity and reduced detrusor contractility. urodynamics should be considered in the significantly older (and younger) patient, those with coexisting neurological disease, patients who have failed previous surgical therapies, and patients with unusual symptom combinations.
Table 2. Causes of urinary symptoms in men

Neurological diseases Parkinsons dementia diabetic neuropathy Multiple sclerosis Other systemic diseases diabetes mellitus diabetes insipidus cardiac failure Metabolic syndrome Drugs opioids antimuscarinics (including tricyclic antidepressants, ipratropium bromide) diuretics alcohol caffeine Benzodiazepines lithium antipsychotics Other causes Prolapse Pelvic mass urological causes Benign prostatic enlargement urethral strictures calculi Bladder and prostate cancer urinary tract infections Phimosis Meatal stenosis interstitial cystitis
Treatment
Several factors drive the decision to treat. These include the severity of the symptoms and their impact on a patients quality of life, the risk of disease progression, the patients other co-morbidities and any other complications of the disease, such as renal dysfunction or bladder stone. luTs in association with certain red-flag symptoms should trigger referral to a urologist: dre suggestive of prostate cancer renal dysfunction haematuria bladder pain recurrent infection palpable or percussible bladder
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Figure 2. The international Prostate symptom score (iPss)

name: Date:
Not at all
Less than 1 time in 5
Less than half the time
About half the time
More than half the time
Almost always
your score
Incomplete emptying
over the past month, how often have you had a sensation of not emptying your bladder completely after you finish urinating?
Frequency
over the past month, how often have you had to urinate again less than two hours after you finished urinating?
Intermittency
over the past month, how often have you found you stopped and started again several times when you urinated?
Urgency
over the last month, how difficult have you found it to postpone urination?
Weak stream
over the past month, how often have you had a weak urinary stream?
Straining
over the past month, how often have you had to push or strain to begin urination?
None
nocturia
1 time
2 times
3 times
4 times
5 times or more
your score
over the past month, many times did you most typically get up to urinate from the time you went to bed until the time you got up in the morning? Total IPSS score Quality of life due to urinary symptoms If you were to spend the rest of your life with your urinary condition the way it is now, how would you feel about that?
Delighted
Pleased
Mostly satisfied 2
Mixed about equallysatisfied and dissatisfied 3
Mostly dissatisfied 4
unhappy
Terrible
Total score: 07 Mildly symptomatic; 819 moderately symptomatic; 2035 severely symptomatic.
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Figure 3. urine frequency / volume / leaks chart

This form is to: 1) record the times you pass urine. 2) record the amount of urine you pass on each occasion. 3) record the times you leak urine (are incontinent). so... Please tick (to the nearest hour) each time you go to the toilet to pass urine. if your doctor or nurse asks, when possible, also record the amount (volume) of urine you pass each time.you can use a household measuring jug to do this. If you are away from home and it is inconvenient to measure the amount then just record the time with a tick. if you leak urine unintentionally, record the times it happens (to the nearest hour). Put one, two or three + signs in the box. + = damp. ++ = wet. +++ = soaking. Time Date: Tick when go to toilet 12 mn 1 am 2 am 3 am 4 am 5 am 6 am 7 am 8 am 9 am 10 am 11 am 12 noon 1 pm 2 pm 3 pm 4 pm 5 pm 6 pm 7 pm 8 pm 9 pm 10 pm 11 pm Volume of urine passed (if known) Leaks Day 1 Date: Tick when go to toilet Volume of urine passed (if known) Leaks Day 2
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very severe symptoms. conversely, many patients can be reassured and/or treated conservatively with lifestyle modifications, such as avoidance of caffeinated drinks and excessive alcohol, or limitation of fluid intake. Some patients are not unduly bothered by their luTs and are reassured once baseline investigations have been carried out.
Identification of High-risk Patients

Only a percentage of patients will need surgery or develop aur. The following features have been identified as baseline risk factors for progression of luTs, as detailed for their risk of developing aur: age (eight times increase in risk in those aged 7079 compared with those aged 4049) severity of luTs at baseline (three times the risk if symptoms are moderate/severe rather than mild) prostate volume (three times the risk if prostate volume > 30 ml) Psa concentration (nine times the risk if Psa > 1.4) Q max (four times the risk if < 12 ml/s) PVr (three times the risk if > 50 ml) prostatic inflammation. Three dynamic variables have also been shown to predict progression of luTs: recurrent episodes of retention increase in PVr over time increasing inconvenience or deterioration of symptoms while receiving treatment. Risk stratification in patients with luTs can aid in planning management. Patients with a low risk of progression may find symptomatic relief sufficient, while those at higher risk may require treatments aimed at
31
preventing or reducing disease progression and complications. A common end-point used to define progression is aur, characterized by the sudden, painful inability to void, with a bladder volume usually < 1 L. This is a fairly straightforward clinical diagnosis and usually triggers urgent intervention with catheterization, with or without specialist referral. A more insidious and difficult diagnosis is that of chronic retention, when a patient persistently retains a substantial amount of urine in the bladder after voiding (usually defined as at least 300 ml, but sometimes as much as 3 l). Patients with chronic retention may be asymptomatic, or may present with nocturnal enuresis, low-volume micturition, increased frequency or difficulty initiating and maintaining micturition. Some of these patients will have highly compliant bladders with low detrusor pressure at the beginning of micturition; this is known as low-pressure chronic retention. Many with Boo, though, will have high-pressure chronic retention, with a high voiding detrusor pressure and high end-void pressures. The constantly raised bladder pressure results in back pressure on the upper tracts, hydronephrosis and, ultimately, renal failure.
link between metabolic syndrome and luTs has also been suggested. The precise nature of this link remains unknown, but two possible mechanisms have been suggested. Insulin may directly induce prostate growth because of its structural similarity to insulin-like growth factor (igF), as well as by increasing the bioavailability of IGF through reduction of IGF-binding protein 1.10 also, insulin resistance has been linked to sympathetic activation, which may increase tone in bladder muscle,11 as well as smooth muscle in the prostate.
Medical Treatment of luTs

First-line treatment of luTs in men with mild or moderate luTs who are bothered by their symptoms should be conservative, followed by medical therapy. Several classes of drugs are widely used, and the particular choice of drug or combination depends largely on the type of symptoms experienced by the patient and their risk of progression. Selective -blockers (aBs), such as tamsulosin, doxazosin and alfuzosin, act on 1 receptors in the bladder neck and prostatic urethra, causing smooth muscle relaxation and improved urinary flow. They are relatively quick to act (within days) and are particularly effective in treating voiding symptoms, but can cause postural hypotension in some patients, as well as retrograde ejaculation in a few. They are recommended for first-line treatment of moderate to severe luTs. 5- reductase inhibitors (5aris), such as dutasteride and finasteride, block the conversion of testosterone into the more potent androgen, dihydrotestosterone, in the testes, thereby reducing prostate size and improving voiding symptoms. They can take 6 months to be fully effective. Recent
Metabolic syndrome and luTs

An increasing problem in the last few years has been the presentation of luTs in patients with significant obesity. The metabolic syndrome is defined by the presence of central obesity and two of the following: raised triglycerides, reduced high-density lipoprotein cholesterol, hypertension and raised fasting plasma glucose.9 While it is accepted as a strong predictor of cardiovascular disease and overall mortality, a
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studies, such as the reduce trial, have suggested that this class of drugs can reduce the risk of developing prostate cancer as well as slow the progression of luTs.12 as anti-androgens, these drugs can cause decreased libido, erectile dysfunction and gynaecomastia. They are recommended for use in men with a high risk of disease progression, or with a large prostate (> 30 g) or Psa more than 1.4, or in the older patient or those with additional risk factors. Patients with bothersome symptoms as well as risk of progression merit combination therapy with an AB and a 5ARI. antimuscarinics, such as oxyb u t y n i n , s o l i fe n a c i n , t ro s p i u m , tolterodine and fesoterodine, are useful in the treatment of predominantly storage symptoms. They act on muscarinic receptors in the detrusor muscle and inhibit involuntary contraction, and also increase bladder storage capacity. Some patients find it difficult to tolerate their adverse effects, such as dry eyes, dry mouth and gastrointestinal disturbances. They can be used effectively in patients with mixed storage and voiding symptoms, in combination with ABs. Phosphodiesterase -5 (Pde5) inhibitors, such as sildenafil, tadalafil and vardenafil, are widely used to treat erectile dysfunction, but there is growing evidence that they can also be used in the treatment of luTs. Several mechanisms of action have been proposed, particularly changes in prostate tone medicated by nitric oxide, but the precise way in which these drugs improve luTs is not yet clearly understood. PDE5 inhibitors can improve IPSS scores as much as monotherapy with selective aBs, but they do not improve flow rates. 13 as luTs and erectile dysfunction commonly coexist and the severity of luTs has been shown to correlate with
32
the severity of erectile and ejaculatory dysfunction, significant improvements in overall quality of life can be achieved using PDE5 inhibitors to treat both conditions simultaneously. However, further research is needed before this becomes the preferred treatment.14 Some patients will benefit from combination therapy with two of the above-mentioned drugs. Patients who continue to suffer from storage symptoms after treatment with an AB may benefit from the addition of an antimuscarinic. Data from the MTOPS and CombAT trials demonstrated that using ABs and 5ARIs together reduces the risk of progression of luTs, aur and need for surgery, and improves quality of life significantly more than monotherapy.15,16 The combination of PDE5 inhibitors and ABs has also been shown to improve luTs more effectively than either agent alone, with the added benefit of improved sexual function.
as predictors of acute urinary retention: combined experience from three large multinational placebocontrolled trials. eur urol 2000;38:563568. 7. speakman MJ, Kirby rs, Joyce a, abrams P, Pocock r. Guidelinefortheprimarycaremanagementofmalelower urinary tract symptoms. BJu int 2004;93:985990. 8.abramsPH,griffithsdJ.assessmentofprostaticobstruction from urodynamic measurements and from residual urine. Br J urol 1979;51:129134. 9. alberti Kg, Zimmet P, shaw J. Metabolic syndrome a new world-wide definition. a consensus statement from the International Diabetes Federation.DiabetMed 2006;23:469480. 10. roberts ro, Jacobson dJ, girman cJ, et al. insulin-like growthfactori,insulin-likegrowthfactorbindingprotein3, andurologicmeasuresofbenignprostatichyperplasia.AmJ epidemiol 2003;157:784791. 11. Michel Mc, Mehlburgerl, schumacher H, Bressel Hu, GoepelM.Effectofdiabetesonlowerurinarytractsymptomsinpatientswithbenignprostatichyperplasia.J urol 2000;163:17251729. 12. andriole gl, Bostwick dg, Brawley oW, et al. effect of dutasteride on the risk of prostate cancer. N Engl J Med 2010;362:13. 13.WongP,lawrentschukn,BoltondM.Phosphodiesterase 5inhibitorsinthemanagementofbenignprostatichyperplasiaanderectiledysfunction:thebestofbothworlds.Curr opin urol 2009;19:712. 14.speakmanMJ.Pde5inhibitorsinthetreatmentofluTs. curr Pharm des 2009;15:35023505. 15. Mcconnell Jd, roehrborn cg, Bautista oM, et al.The long-termeffectofdoxazosin,finasteride,andcombination therapyontheclinicalprogressionofbenignprostatichyperplasia. n engl J Med 2003;349:23872398. 16. roehrborn cg, siami P, Barkin J, et al. The effects of combinationtherapywithdutasterideandtamsulosinon clinicaloutcomesinmenwithsymptomaticbenignprostatic hyperplasia:4-yearresultsfromthecombaTstudy.eururol 2010;57:123131. epub 2009 sep 19. 2011 elsevier ltd. initially published in Medicine 2011;39(7):378383.
Declaration of Interests
None.
References
1. irwin de, Milsom i, Hunskaar s, et al. Population-based surveyofurinaryincontinence,overactivebladder,andother lowerurinarytractsymptomsinfivecountries:resultsofthe ePic study. eur urol 2006;50:13061315. 2. Abrams P. New words for old: lower urinary tract symptoms for prostatism. Br Med J 1994;308:929. 3.abramsP,chapplec,Khourys,roehrbornc,delarosette J.Evaluationandtreatmentoflowerurinarytractsymptoms in older men. J urol 2009;181:17791787. 4. sexton cc, coyne Ks, Kopp Zs, et al.The overlap of storage,voidingandpostmicturitionsymptomsandimplications fortreatmentseekingintheusa,uKandsweden:epiluTs. BJu int 2009;103(suppl 3):1223. 5. The management of lower urinary tract symptoms in men.niceclinicalguideline97,http://guidance.nice.org. uk/cg97; 2010. 6. Marberger MJ, andersen JT, nickel Jc, et al. Prostate volume and serum prostate-specific antigen
About the Authors dr segaran is a research Fellow in urology at Taunton and somerset nHs Trust, england, uK. dr speakman is a consultant urologist atTaunton and somerset nHs Trust, england, uK.
answers to questions on page 13: 1. T, 2. T, 3. F, 4. T, 5. T
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Peer Reviewed
A Broken Heart: The Health Consequences of Spouse Bereavement

roger Bartrop, MBBs, Md, FracP, FranZcP; Tom Buckley, rn, Bsc(Hons), Mn, Phd
loss of a spouse or partner can cause heart break, both in symbolic terms and expressed as physical symptoms. recognition of a spouse's or partners loss and provision of appropriate services can help adaptation and prevent major health problems. Although grief reactions are expected, symptoms suggestive of cardiac disease should be investigated immediately.
Substantialevidencerevealsincreased mortality during the first 6 months of griefamongsurvivingspousesofboth genders, especially in the late middle age and retired age bands.
he death of a loved one or life partner is recognized as one of lifes greatest stressors requiring significant adjustment, sometimes lasting several weeks to years and, for some patients, leading to severe and chronic psychological distress. Substantial evidence from the past decade reveals increased mortality during the first 6 months of grief among surviving spouses of both genders, especially in the late middle age and retired age bands.1,2 It is difficult to separate the influence of companionship from other common factors (such as the genome, diet, exercise and nicotine) that affect heart function. We continue to use the phrase heartbroken when no such diagnosis appears on death certificates.3 Could lack of companionship exert a toxic influence on our cardiac health?
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Reasons why the baby boomer generation are more vulnerable to complicated bereavement5
aspirations to high self-efficacy comfortable material well-being greater flexibility to pursue own pursuits self-fulfilment expectations while working aspirations of many to work into eighth decade Visceral reaction to getting old longer lifespan Possibility of shorter relationships: seek choice
A New Generation Moves Into Retirement

A significant majority of single people of future decades will be the baby boomers (born in the two decades after World War 2) who have become divorced or bereaved. There are several reasons why they might be more vulnerable than their antecedent generation, including their higher expectations of health and material wellbeing (see the box on this page). in addition, their sadness and loneliness could be accentuated by the reduced incidence of smaller and fewer traditional families, resulting in potential loss of support during the early decades of retirement.4 Baby boomers are the first large group to move into retirement with significantly different family circumstances to previous cohorts. A recent survey identified that this group are three times more worried about illness, their ability to pay for health care and winding up in a nursing home rather than dying.5 The Census of Population and Housing in 2006 revealed that 937,000 adults were registered as
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widowed in australia, with the great majority being over the age of 55 years. 6 Short-term morbidity has been studied at intervals since the 1950s. These reports have generally listed non-specific complaints such as headaches, dizziness, indigestion, chest pain, vegetative symptoms (eg, poor sleep and appetite), dysphoric mood and pain syndromes. Other symptoms such as yearning, restless behaviour and perceptual phenomena (seemingly tangible presence or mood-laden memory of the deceased) were more likely to be identified as uniquely grief-related. 1 However, there have been major limitations in much of the research because of lack of homogeneity in small sample sizes, lack of a theory of hypothesized illness complicating such severe distress, absence of established health outcomes, and retrospectivity in design.7 Although there are some shortterm studies on health outcomes after bereavement, no long-term studies appear to have been reported. This is surprising, as the association between bereavement and increased health risk has been the subject of much discussion over the past 50 years.
the bereaved, both 2 weeks and 6 months after the loss of the partner, with those disturbed more likely to be of lower socioeconomic status and to have a prior history of psychological disturbance.9 in addition, immunological function in a matched cohort of 26 bereaved subjects showed significant depression of T-cell responsiveness to mitogenic stimulation in the first 8 weeks after bereavement. 8 These immunological findings have been replicated in other studies, 10,11 and evidence of significant mood disturbance also highlighted frequently in the international literature.2
Long-term effects
In a longer-term follow-up study on 176 subjects (bereaved and their controls) who had taken part in the original study in the mid-1970s,8 mental health morbidity increased over a 10-year follow-up period among bereaved relatives compared with controls, ranging from a 61% increase (according to self-reports) to a 92% rise (among medical record reports).7 similar ly, circulator y system disorders (ischaemic heart disease and hypertension) were more frequent in bereaved subjects, being described in 66% of those subjects by medical record reports compared with 100% by self-reports. There was no evidence of an elevation in illnesses with a principal immunological component, nor a significant difference in mortality rates in this small cohort.7
Risks for Mental Health and Cardiac Morbidity

Short-term effects
In a study of the short-term effects of bereavement conducted in several Sydney metropolitan hospitals from 1975 to 1977, 89 spouses were followed up over a 12-month period following the death of their partner. They were matched for age, sex and race with a cohort of non-bereaved controls.8 There was an elevation in dysphoric mood (depression, anxiety and grief-related symptoms) among
CARBeR Study
The Cardiovascular Health in Bereavement (carBer) study commenced in 2005 at the Northern Sydney and Central Coast Area Health Service with the aim of identifying psychological, behavioural and physiological changes in acute bereavement
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that may contribute to cardiovascular risk. To our knowledge, this is the first such prospective study in the first 2 weeks of bereavement to focus on factors previously associated with cardiovascular risk. Eighty bereaved spouses and parents were recruited within the first 2 weeks of bereavement and compared with a non-bereaved cohort of 80 family members of discharged patients.1,12,13 The CARBER study s findings repor ted so far include significantly higher levels of depression, anxiety and anger symptoms in the bereaved during the early grief phase compared with the non-bereaved, and also higher scores on the depression questionnaire associated with being unprepared for the death, decreased sleep duration and younger age. 1 additionally, decreased satisfaction with social support was associated with reduced sleep time in the early phase of bereavement. Increased morning cortisol levels in the bereaved were reported in this study over the initial 6 months of bereavement, suggesting that a hypothalamicpituitaryadrenal axis stress reaction may contribute to the known increased health risk, as increased cortisol levels have been previously associated with effects on body mass, blood pressure, coronary stenosis and reduced quality of life.2 indeed, there was significant elevation in blood pressure and heart rate in the bereaved sample compared with non-bereaved subjects and, although the heart rate lowered at 6 months, blood pressure remained elevated. Cortisol levels responded similarly.13
suggest that bereavement results in an array of complex physiological responses, as noted above, but also including changes to prothrombotic factor levels and heart rate variability, all of which are associated with increased cardiovascular risk.14 Although these findings do not establish causality, they are consistent with evidence for psychosocial triggering of cardiovascular events and suggest the need for further investigation of the potential for acute risk prevention.15
Vulnerability factors for the bereaved16

High degree of dependency spirit of ambivalence about the lost relationship unexpected or traumatic death absence of inadequate social support, or perception of it Multiple stressors at time of bereavement Previous losses in childhood Poorly resolved past losses socioeconomic disadvantage Housing difficulties Poor functioning of the family system (internal disharmony) inflexibility of roles and ineffective sharing in conjugal bonding
Management Issues
The health professional should approach grief, when possible, as a natural process of loss of a loved one. GPs who are counselling even the most secure individual, in what appears to be a normal grief process, should use their experience and communication skills as best they can. Grief can be complicated because of cer tain individual qualities, lack of ongoing family or professional suppor t, or coexistent stressors. unresolved grief may then become obvious in the first 12 months, possibly by enduring sadness, worsening irritability and other symptoms of grief sometimes leading to major depression or anxiety disorders, or by awareness of the deceased individuals poor integration into activities of daily living. Patients should be encouraged to act on cardiac symptoms by seeking immediate medical advice. Any chest pain, palpitations or dyspnoea may need to trigger a review by a cardiologist with some urgency, rather than be considered simply an atypical bereavement response. It is important for GPs to take note of vulnerability factors for the bereaved (see the box on this page)16 Important factors to consider in inter-
actions with the bereaved and the family are listed in the box on page 36.17
Key Communication Skills

The first step is to establish a relationship with the bereaved person or family. GPs can help their patients communicate freely by carrying out the following16: listening to the patients you are supporting and the problems or concerns they have acknowledging their concerns (feedback); this may simply involve your recognizing that they are having some difficulty telling them what you are able to do and whether you will be seeking further specialist opinion; give them options so they can be partners in the coping process encouraging them with a positive comment, or reassuring them about possible emotional and natural reactions to grief and its management.
Additional Physiological effects

other findings, presented at a cardiac society of australia and new Zealand meeting in 2009 and the American Heart association meeting in 2010,
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Conclusion
Important points for GPs to consider when interacting with the bereaved17
explore the loss with the patient: its circumstances, the psychological trauma associated with it review the lost relationship with the patient: the gradual undoing of the bonds to the lost person, how the relationship started, plus its course, its vicissitudes, and its rewarding and painful aspects assess the background of the bereaved: losses of an acute or chronic nature, family and cultural issues Provide support to the patient to encouragesocialinteraction(eg,community and sporting clubs, hobbies, university of the Third age activities), which will encourageresolutionofmourningandassist the bereaved in dealing with any feelings of dependency and redundancy Plan for help for the family through the mediation of social work or psychology services evaluate the process during the course of counselling and at its completion Prescription of medication is rarely needed except for brief periods of respite. Depressive symptoms (especially melancholia)areanothermatter:psychiatric assistance may be needed
Resources on bereavement for practitioners

Book Anexcellentresourceforhealthpractitioners is the book by diane and Mal McKissock calledBereavementCounselling:Guidelines for Practitioners, published by the Bereavement CARE Centre.18 Online resources Bereavement care centre www. bereavementcare.com.au The national centre for childhood grief www.childhoodgrief.org.au sids and Kids www.sidsandkids.org cancercouncilwww.cancercouncil.com.au lifeline www.lifeline.org.au
Although the focus before bereavement is naturally directed to the ill or dying person, the health and welfare of bereaved survivors should be of great concern to health care professionals, family and friends. If GPs suspect a risk of self-harm, an assessment via the Mental Health Help line, the local community health centre or the emergency department of the local hospital could be indicated. The key message, however, is one of hope for a satisfactory passage through what is, after all, a natural process and one that we will all have to navigate.
None.
difficult to achieve efficacious outcomes for the bereaved, several important skilled practitioners and community groups are available as resources. Such recommended resources for health practitioners are listed in the box on this page.18
References
1.BuckleyT,Bartropr,Mckinleys,etal.aprospectivestudy ofearlybereavementonpsychologicalandbehaviouralcardiac risk factors. intern Med J 2009;39:370378. 2.BuckleyT,Mckinleys,Toflerg,Bartropr.cardiovascular riskinearlybereavement:aliteraturereviewandproposed mechanisms. int J nurs stud 2010;47:229238. 3.LynchJJ.Lifeandtheheart.In:LynchJJ.TheBrokenHeart: TheMedicalConsequencesofLoneliness.Sydney:Harper& row; 1979:314. 4. salt B. Beyond the white picket fence 2026: a vision
Psychological Support
collateral information, such as how close a bereaved man or woman was to his or her spouse or partner, and what percentage of time was spent exclusively in each others company, will be crucial to fully understanding the impact of spouse bereavement. Some patients may be at risk of psychiatric ill health and possibly of other medical illness when left alone and, potentially, lonely. If there is evidence of inhibition of feelings, impairment in adjustment and lack of reintegration into activities of daily living, then the assistance of an experienced psychologist under the Medicare-funded scheme, or even intervention by a psychiatrist, may be necessary. Goals may be achieved in as few as one or two sessions, or up to 10 or more sessions.
A complete list of references can be obtained from the editor upon request.
Some possible issues for GP to raise when talking to bereaved patients are listed in the box on this page. The period of 6 to 8 weeks after the death is frequently a critical time in social terms. ideally, patients recovery will feature the following phases in the period after bereavement: resolution of the symptoms of loss (6 to 12 months) satisfactory adjustment and reintegration into life (6 to 12 months) new and satisfying attachments (1 to 2 years) exploration of relaxing and creative pursuits (1 to 2 years). If counselling seems to be proving
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2011 Medicine Today Pty ltd. initially published in Medicine Today May 2011;12(5):5558. reprinted with permission.
About the Authors Dr Bartrop is Emeritus Associate Professor in the discipline of Psychiatry at the university of sydney, northern clinical school, royal north shore Hospital,sydney;ProfessorofMentalHealth,school of Medicine at the university of Western sydney, Blacktown-Mt druitt clinical school, sydney. dr Buckley is senior lecturer (acute/critical care) at the sydney nursing school, university of sydney; royalnorthshoreHospital, sydney,nsW,australia.
Continuing Medical Education
Take the challenge, test your knowledge Take the challenge, Test your knowledge

reme Mountifield, MBBs, FracP; Jane M andrews, MBBs, FracP, Phd, agaF
Irritable bowel syndrome is a functional disorder of the bowel affecting nearly 17% of adults in Australia and accounting for 2550% of all referrals to gastroenterologists. successful management encompasses an appreciation of its multifactorial aetiology and a biopsychosocial approach to treatment.
Table 1. Functional bowel disorders

irritable bowel syndrome Functional bloating Functional constipation Functional diarrhoea
irritable bowel syndrome (iBs) can be a frustrating disorder for both physicians and patients, because it is lifelong and impairs patients quality of life and social functioning. 1,2 Its complex aetiology, involving both biological and psychological factors, remains incompletely understood. IBS affects both genders and all ages but has a 2:1 female predominance3 and most commonly presents in those aged 2544 years. iBs affects nearly 17% of adults in Australia4 and accounts for 2550% of all referrals to gastroenterologists. IBS is second only to the common cold in accounting for work absenteeism.5 Previously, iBs was regarded as a diagnosis of exclusion, but its current definition emphasizes identification of a positive symptom complex involving abdominal pain associated with changes in bowel habit and stool characteristics. Physicians are encouraged to use the Rome III criteria to make a positive diagnosis and to communicate this clearly to patients. A clinical diagnosis of IBS in the absence
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of alarm features is highly secure (ie, it is not likely to be wrong or to be changed to an alternative organic diagnosis in the medium-term future) and should allay anxiety on the part of both the doctor and the patient. IBS is probably the best recognized of the functional gastrointestinal disorders. However, many patients who are given a clinical label of IBS do not actually have IBS when strict criteria (eg, rome iii diagnostic criteria) are applied, but another func tional bowel disorder such as functional bloating, functional diarrhoea or functional constipation. This is probably of little direct clinical relevance, but it is useful to be aware of as newer literature appears with different and more restrictive terminology. in future, it may become more useful to refer to this constellation of conditions as functional bowel disorders (FBds), not simply iBs (Table 1). When making a diagnosis of a FBd, it is important to seek specific gastrointestinal diagnostic features
unspecified functional bowel disorder
Irritable bowel syndrome affects both genders and all ages but has a 2:1 female predominance.
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such as bloating and faecal urgency to help manage patients. However, it may be equally important to be aware of coexistent anxiety and depressive symptoms. Exhaustive investigation of the young, otherwise well patient is now considered unnecessary, with most clinically suspected cases of FBD/IBS confirmed using brief, targeted investigation unless alarm features suggesting organic pathology are present. interestingly, patients who seek help for IBS have increased rates of anxiety, depression, phobias and s o m at i z at i o n , w h e re a s p at i e nt s with IBS who do not seek medical attention are psychologically similar to healthy controls. 6 This implies that psychological distress affects the experience of IBS but does not cause symptoms alone. Recognizing anxiety and depression in patients with FBd/iBs is important, because management of these conditions may improve bowel as well as emotional symptoms, and these conditions are common in patients with iBs; 13% of general practice consultations for IBS in Australia involve management of psychological problems also.7 The aetiology of IBS remains unclear, with twin studies suggesting that environmental factors are more impor tant than genetics. 8 O ther theories propose a role for altered neuroimmune responses to past enteric infections, colonic motility disorders, visceral hypersensitivity, abnormal serotonin pathways and psychological dysfunction (Table 2).
can be elicited by taking a history and examining the patient (Table 3). Clinical diagnostic criteria have been established and have evolved over time, because no biological marker of the disease has been identified.9 Rome III is the current research criteria most widely used (see the box on page 40). The rome iii criteria focuses on episodic abdominal pain or discomfort as the hallmark of the disorder, accompanied by changes in stool frequency and consistency, or relief of pain/discomfort with defaecation. However, in clinical practice, doctors frequently label any FBD as iBs. at a clinical level, this is not of great relevance as these disorders behave similarly, and symptomtargeted therapy is used regardless of the precise label.
have symptom flares that can last for days, whereas others have daily but briefer symptoms.
Altered Bowel Habit

As a relationship between abdominal pain and stool passage is a necessary feature for a diagnosis of iBs, a careful stool history is required. Moreover, a careful stool history may assist with targeting therapy. It is important to remember that a wide range of normal bowel habit exists, with stool frequency varying from three per day to three per week in most people without iBs. Therefore,
Table 2. Proposed pathogenic mechanisms for irritable bowel syndrome

Altered colonic and small bowel motility Visceral afferent hypersensitivity Microscopic inflammation altered faecal microflora Psychosocial dysfunction
Pain/Discomfort
IBS-related abdominal pain is usually colicky in nature and often located in the left iliac fossa, although location and severity are highly variable. Emotional stress and eating often exacerbate discomfort, whereas defaecation relieves pain. Some patients
Table 3. Suggested approach to diagnosing irritable bowel syndrome

History Perform an open-ended and non-judgemental history elicit positive features as per rome iii criteria (see the box on page 40) seek psychological symptoms reason for current presentation look for stressors look for dietary factors exacerbating symptoms exclude effects of medications for example, sorbitol, antacids (diarrhoea), calcium channel blockers, anticholinergics (constipation) ensure no alarm features are present (see Table 4) check time course symptoms should have been present for at least 6 months examination examine patient for normal or mild generalized abdominal tenderness the presence of an abdominal mass or abdominal wall pain suggests organic pathology
clinical Features of iBs Making the Diagnosis

Patients with IBS can present with a broad range of gastrointestinal and non-gastrointestinal symptoms that
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changes in bowel habit are often of greater importance than the actual stool form or frequency itself.
having prolonged fever with gastroenteritis, and pre-existing anxiety and depression.11
Subtypes
The variation in clinical phenotype of IBS based on the Rome criteria has given rise to several subtypes, the identification of which helps to direct therapy. A substantial proportion of patients switch subtypes over time. These subtypes are described below. Constipation-predominant. This occurs in one-third of patients with IBS. Hard stools occur more than 25% of the time and loose stools less than 25% of the time. characteristically, stools are hard and pellet-shaped and there is a sense of incomplete evacuation. Diarrhoea-predominant. This occurs in one-third of patients with IBS. Loose stools occur more than 25% of the time and hard stools less than 25% of the time. The diarrhoea aspect of IBS usually involves frequent small volume loose stools with mucus, often in the morning or after meals, and is heralded by urgency and followed by a sense of incomplete evacuation. large volume diarrhoea, blood in stools, nocturnal diarrhoea or fatty stools should prompt investigation for other causes such as malabsorption (fat and carbohydrate) and inflammatory bowel disease. Mixed type IBS. This occurs in one-third of patients with IBS. Both hard and loose stools occur more than 25% of the time. IBS-unspecified. Post-infectious IBS. This is a distinct subtype describing the 1030% patients with previous bacterial gastroenteritis who develop iBs, usually the diarrhoeal subtype. 10 Risk factors for post-infectious IBS include being female, being young,
time Frame
a diagnosis of iBs requires at least 6 months of symptoms with the patient having had 3 days of symptoms monthly for the past 3 months.
Table 4. Alarm features for irritable bowel syndrome warranting further investigation
age over 40 years at symptom onset Family history of inflammatory bowel disease, coeliac disease or colorectal cancer significant weight loss anaemia or iron deficiency Malnutrition gastrointestinal blood loss nocturnal symptoms severe, large volume diarrhoea, (especially if faecal incontinence) short history of symptoms or significant change in symptoms Fever steatorrhoea severe pain Perianal disease abnormality on physical examination (eg, abdominal mass, abdominal wall pain)
Supportive Symptoms
several supportive symptoms, such as defaecation straining, urgency, a feeling of incomplete evacuation, mucus passage and bloating, are recognized as characteristic of IBS but are not included in the diagnostic criteria. Other gastrointestinal symptoms such as reflux, dysphagia, dyspepsia, early satiety and nausea,12 plus non-gastrointestinal problems such as lethargy, headache, backache, urinary symptoms, dyspareunia, 13 fibromyalgia, chronic fatigue syndrome, temporomandibular joint disorder and chronic pelvic pain13 are more frequent in patients with IBS.
Psychological Symptoms
Psychological distress is very common, with 50% of patients who seek medical care for IBS being depressed or anxious. 14 Screening questions for these disorders often reveal the current psychological stressors of patients affecting the timing of presentation for their IBS symptoms. This may be important for therapy.
coeliac disease can be beneficial in selected patients.
Investigations
The major challenge for clinicians is to undertake cost-effective and limited investigation in most patients with symptoms consistent with IBS/ FBd, while recognizing those with alarm features who may have organic pathology and warrant specialist referral (Table 4). This parsimonious approach is to be recommended, because patients with IBS/FBD are reported to have a high rate of unnecessary investigations and surgeries, i n c l u d i n g c h o l e c ys te c to my a n d hysterectomy.16 Breath testing is simple and safe but hampered by methodological limitations and lack of availability in some
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Dietary Factors
The relationship between certain foods and symptoms is individualized in patients with IBS. A food and symptom diary can aid in identifying troublesome foods for an individual p a t i e n t . M a ny p a t i e n t s r e p o r t lactose,15 wheat, fat and fruits as being poorly tolerated, thus screening for
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areas. Breath testing may be appropriate for patients reporting dietary symptoms suggestive of lactose intolerance, or in whom bacterial overgrowth is suspected, although sugar malabsorption has not been shown to be more common in patients with IBS. Routine breath testing of patients with iBs for lactose, fructose and sorbitol as well as for small bowel bacterial overgrowth was not recommended at the recent Rome Consensus Conference. The commentary below is generally directed towards the initial presentation of patients with IBS/FBD.
clinical history reveals alarm features (Table 4).
mucosal biopsies is appropriate only in patients with severe or large volume diarrhoea to look for colitis.
Constipation-predominant IBS
at initial presentation, patients with suspected constipation-predominant IBS should undergo investigation to exclude hypothyroidism, hypercalcaemia, depression, dehydration and drug effects (eg, opioids, calcium channel blockers, anticholinergics) before a diagnosis of IBS/FBD is made. It is important to remember that patients aged over 50 years with new onset altered bowel habit warrant colonoscopy to exclude neoplasia.
Abdominal Pain
Although pain and/or discomfort associated with disturbed bowel function is the hallmark of iBs, certain pain characteristics are atypical and may dictate further investigation. Constant pain with radiation to the back and biliary type right upper quadrant pain should usually lead to imaging with either ultrasound or computed tomography scan.
Suspected IBS and no Alarm Features

In patients with clinically suspected IBS/FBD with no alarm features and normal physical examination (the overwhelming majority consulting in primar y care), the american Gastroenterology Association g u i d e l i n e s re c o m m e n d a g a i n s t routine use of flexible sigmoidoscopy, barium enema, colonoscopy and faecal occult blood testing. 17 A full blood count is recommended and is normal in patients with IBS/FBD. Limited fur ther investigation should be deter mined by age, duration of iBs/FBd symptoms, presence of alarm features and IBS subtype, and should be led by suspicions based on the clinical history. use of the investigative approach described results in less than 5% of patients with organic disease being wrongly diagnosed with IBS. 18 Patients with known IBS/FBD should not generally be reinvestigated each time they re-present with the same symptoms, as chronic, relapsing symptoms are expected from the natural histor y of the disorder. Reassurance and targeted therapy (if needed) are recommended and a review of the triggers, unless the
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Diarrhoea-predominant IBS
at initial presentation, patients with the diarrhoea-predominant subtype may warrant investigation to exclude i n f l a m m a to r y o r m a l a b s o r p t i ve disease, starting with a full blood count, erythrocyte sedimentation rate/C-reactive protein and serological tests for coeliac disease, especially if symptoms are of recent onset. A loose stool specimen should be sent for microscopy and culture, as well as examining for cysts, ova and parasites. If malabsorption or osmotic/secretory diarrhoea is suspected based on history, a 24-hour stool specimen is useful as stool weight should be less than 300 g a day in patients with IBS and stools should not have increased faecal fat. Fl ex ib le s i gm oi d os co py wi t h
Treatment
The aim of IBS/FBD management is to optimize fun c tion a l s t at us and minimize reliance on health care input, while recognizing and treating associated psychological or psychiatric comorbidity. Effective management is based on a sound therapeutic relationship between doctors and patients, because patients with positive physician interactions have fewer follow-up visits for IBS. 19 Education about IBS/FBD should be nonjudgemental, promote realistic expectations and involve patients in treatment decisions. 20 Reassurance that a normal life span is usual and that IBS does not lead to other gastrointestinal illnesses is important, along with the provision of written
Rome III diagnostic criteria for irritable bowel syndrome*

Recurrent abdominal pain or discomfort for at least 3 days per month in the last 3 months associated with two or more of the following: improvement in pain/discomfort with defaecation onset associated with a change in frequency of stool onset associated with a change in form (appearance) of stool.
*criteria fulfilled for the past 3 months with symptom onset at least 6 months before diagnosis.
Medical Progress
information. 19 Exploration of current emotional stressors often explains the timing of presentation with IBS/ FBd symptoms, and often identifies specific patient fears such as that of bowel cancer, which can then be put into perspective. The heterogenous nature of FBDs as a group of disorders means that treatment must be individualized; it frequently involves trials of different modalities until an optimal management plan is recognized for each patient. Evidence exists for dietary modification, psychological treatments, medications and some alternative therapies (see the box on this page for an approach to IBS management based on symptom severity).
Diet
Dietary management is best individualized using a food diary to identify relationships between bowel symptoms and certain dietary components. All patients may benefit from dietitian referral to assist in this process. A dietary history is impor tant and should focus on meal patterns and fluid intake as well as intake of dairy, fruit, wheat, fat, fibre, alcohol, caffeine and gas-producing foods, which are often associated with symptoms (Table 5). some patients benefit from trialling a lactose-free and wheat-free diet, or a low fructose diet in cases of fructose intolerance.21 Recent Australian data suggest that in patients with IBS and an intolerance to fructose, restriction of dietary fructans and fructose and other foods high in fermentable o l i g o s a cc h a r i d e s, d i s a cc h a r i d e s, monosaccharides and polyols (FodMaPs) results in significant symptomatic improvement. 22,23 The mechanism of such improvement is thought to be a reduction in fer41
mentable gas content and therefore reduced luminal distension, which often correlates with symptoms of IBS. Foods high in FodMaPs include fruits, honey, some corn syrup, wheat and onions.22,23 The aim of dietary modification in IBS is to substitute nutritious alternatives for foods associated with symptoms, ideally under dietetic supervision. Extensive elimination diets have not been demonstrated to be of benefit and should be avoided. A trial of fibre supplementation is worthwhile in all patients except those with bloating who may benefit from non-fermentable fibre. Although many patients report improvement with fibre supplementation, a significant proportion note worsening, and supplements should be stopped in this group.
disorders is important and should prompt medical treatment and/or psychiatric referral. Patients with more subtle psychological symptoms and stressors should be considered for relaxation training, c o g n i t i ve b e h a v i o u r a l t h e r a p y, interpersonal psychotherapy and hypnotherapy. These modalities are appropriate for motivated patients in whom a temporal relationship exists between emotional stressors and bowel symptoms, rather than those with overt psychiatric disease.
Drugs
Few patients require treatment beyond explanation, reassurance and dietary modification. Randomized IBS
Psychological and Psychiatric Intervention

The identification of axis 1 disorders such as major depressive and anxiety
An approach to irritable bowel syndrome management based on symptom severity

Mild no psychological problems and infrequent symptoms reassurance, education and consider dietary modification, with or without fibre supplementation. Moderate disrupted normal daily activities due to symptoms, with or without psychological disturbance Food and mood diary to identify precipitating foods (such as lactose, fructose and caffeine) or specific stressors. Diet change and psychotherapy may help. Short-term targeted medication may be appropriate if symptoms are not controlled with simple measures. Severe intractable symptoms, functional impairment with frequent presentations and underlying psychological disturbance Behavioural modification and psychoactive drugs are often required in the longer term in this group of patients.
Table 5. Dietary recommendations for patients with irritable bowel syndrome

Keep a food diary to identify individual dietary and lifestyle symptom triggers Trial fibre supplementation restrict dietary fructans and fructose and other foods high in fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FodMaPs). These foods include lactose, wheat, fruits, onions, honey, corn starch, some vegetables, sorbitol and other artificial sweeteners23 avoid caffeine and alcohol Trial a low-fat diet consider dietitian review
Medical Progress
trials suggest the gain over placebo is only about 1015% for most agents, whereas the placebo response is high at 4050%, 24 supporting the greater power of the therapeutic relationship compared with discrete pharmacological interventions. As no medication is known to alter the course of IBS and adverse effects are recognized with all commonly used agents, drugs for iBs/FBd should be used on a when needed basis for the shortest period possible, targeting the main symptom and be individualized. Medications should be trialled for 3 to 6 weeks; in the presence of progressive or changing symptoms, an IBS/FBD diagnosis should be reconsidered and further investigation contemplated. If IBS/FBD remains the most likely diagnosis and medication is ineffective at a reasonable dose, switching to a different agent should be tried. Once symptoms are well controlled, medical treatment should be ceased if possible. Treating Abdominal Pain The most commonly used agents for treating abdominal pain are antispasmodics, which promote smooth muscle relaxation. These include: hyoscine butylbromide 20 mg orally four times daily when needed mebeverine 135 mg orally three times daily when needed pepper mint oil, one to t wo capsules orally, three times daily (should be taken 30 minutes before a meal otherwise this may worsen gastro-oesophageal reflux). Low-dose tricyclic antidepressants (Tca) can be used as some evidence supports improved pain perception in patients with iBs, independent of antidepressant effect. Lower doses are used than that for the treatment of depression. TCAs should be avoided in patients with constipation.
Limited evidence also supports the use of selective serotonin reuptake inhibitors for IBS-related pain. At least 4 weeks of treatment is required b e fo re a s s e s s m e nt o f e f f i c a c y. Common agents include amitriptyline 1050 mg orally at night or fluoxetine 20 mg orally daily (both off-label uses). Treating Diarrhoea Exacerbations of IBS-related diarrhoea in adults can be managed by short-term use of the least toxic antidiarrhoeal agents. These include: loperamide 2 mg orally, once to three times daily as required or after each loose motion up to a maximum of eight tablets daily cholestyramine 48 g orally, once or twice daily. Treating Constipation Simple measures such as increasing dietary fibre, fluid intake and physical exercise should be initiated in patients with constipation. Laxatives may then be added in non-responders, avoiding the use of stimulant laxatives where possible and long-term use of any agent, although chronic therapy is preferable to faecal loading. Bulking agents should be first line for example, psyllium powder one to two teaspoons one to three times daily taken orally although some patients with prominent bloating may tolerate non-fermentable fibre better (eg, sterculia). This can be followed by osmotic laxatives if constipation can be objectively confirmed. Osmotic laxatives include: lactulose syrup 1530 ml one to two times daily orally sorbitol 20 ml one to three times daily orally macrogol 3,350 with electrolytes, one to two sachets dissolved in water once daily
sodium picosulfate preparations (eg, sodium picosulfate powder, one sachet dissolved in 120 ml water; adults to drink 60120 ml of the solution as a once-off dose). Stool softeners such as docusate 120 mg twice daily orally can also be used in patients with constipation.
Alternative therapies
Alternative therapies are reviewed in detail elsewhere. 25 Summar y comments only are included below. Probiotics Probiotics may be beneficial in patients reporting bloating and flatulence as predominant symptoms. However, further studies are needed before particular preparations and dosages can be recommended. Herbal Preparations Many herbal agents are marketed towards IBS. Some improve IBS symptoms and overall well-being but the active ingredients responsible fo r s u c h i m p r o v e m e n t r e m a i n undefined.26 Acupuncture Although acupuncture has been used to treat iBs, there are no convincing data to support this practice.
When to Refer for Specialist Review

The presence of alarm symptoms, uncertainty about the diagnosis of iBs/FBd, or patient concerns that persist after GP consultation are indications for specialist referral (Table 6).
Conclusion
IBS and other FBDs are very common in our community, although only a proportion of people with these
Medical Progress
42
Table 6. When to refer patients for specialist review

alarm features (see Table 4) diagnostic uncertainty Persistent patient concerns despite GP consultation
Table 7. Behavioural features helpful in identifying patients with irritable bowel syndrome in general practice26
symptoms for more than 6 months Frequent consultations for nongastrointestinal symptoms or minor illness Multiple somatic complaints Previous medically unexplained symptoms abnormal behaviour in response to stress
family is a unique therapeutic environment, allowing the gP to have a heightened awareness of a patients social context. This places GPs in an excellent position to manage functional gastrointestinal disorders. The challenging and complex nature of FBD/IBS means that planning longer consultations (30 minutes) for patients with these conditions is likely to be beneficial in improving patient satisfaction and reducing re-presentation rates.
Declaration of Interest Associate Professor Andrews has been involved in conducting partially supported studies for Ardeypharm, steigerwald, nycomed and astraZeneca, all of whom have products that are used in functional gastrointestinal disorders. She has given paid educational lectures for Nycomed
and
astraZeneca,
received
travel
support
from them and been involved in consultancies. Dr Mountifield: None. References 1. andrews eB, eaton sc, Hollis Ka, et al. Prevalence and demographics of irritable bowel syndrome: results from a large web-based survey. Aliment Pharmacol Ther 2005;22:935942. 2. longstreth gF, Bolus r, naliboff B, et al. impact of irritable bowel syndrome on patients lives: development and psychometric documentation of a disease-specific measure for use in clinical trials. Eur J Gastroenterol Hepatol 2005;17:411420. 3. Hungin aP, chang l, locke gr, dennis eH, Barghout V. irritable bowel syndrome in the united states: prevalence, symptom patterns and impact. aliment Pharmacol Ther 2005;21:13651375. 4. Boyce P, Koloski n, Talley n. irritable bowel syndrome according to varying criteria: are the new Rome 2 criteria unnecessarily restrictive for research and practice? am J gastroenterol 2000;95:31763183. 5. Schuster M. Diagnostic evaluation of the irritable bowel syndrome. Gastroenterol Clin North Am 1991;20:269. 6. Kassinen a, Krogius-Kurikka l, Makivuokko H, et al. The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects. gastroenterology 2007;133:2433. 7. charles J, Harrison c. irritable bowel syndrome in Australian general practice. Aust Fam Physician 2006;35:840841. A complete list of references can be obtained upon request from the editor. 2010 Medicine Today Pty ltd. initially published in Medicine Today Februar y 2010;11(2):3240. Reprinted with permission.
Summary
irritable bowel syndrome (iBs) is a common, lifelong functional gastrointestinal disorder in which the hallmarks are abdominal pain associated with changes in bowel habit (stool form and/or frequency). a positive diagnosis of iBs is made clinically by identifying the typical symptom complex. a diagnosis of iBs requires at least 6 months of symptoms, with the patient having had 3 days of symptoms monthly for the past 3 months. organic pathology can usually be simply excluded by the recognition of alarm features. of those patients with iBs, 50% have coexistent depression/anxiety symptoms that should be sought and addressed. Management of iBs should be biopsychosocial and individualized, with options ranging from reassurance, education, dietary modifications and psychological
conditions ever present for management. 27,28 Patients presenting with de novo probable FBD/IBS need careful psychological as well as medical assessment to uncover emotional stressors determining the timing of presentation (Table 7).26 A careful clinical history and wellvalidated criteria allow a positive diagnosis to be made in most patients with a minimum of investigations. Once a diagnosis is established and relevant organic pathology excluded (if necessary), therapeutic options include reassurance, education, dietary modification, medications and psychological approaches, depending on the patients unique symptom profile. The long-term relationship that a GP has with a patient and his or her
interventions to a variety of medications aimed at controlling exacerbating symptoms.
About the Author Dr Mountifield is a Gastroenterologist at the Department of Gastroenterology and Hepatology, Flinders Medical centre and a Phd student at Flinders university, Adelaide. Clinical Associate Professor An d re ws i s a G a s t ro e nte ro l o gi s t a n d Head of The Inflammatory Bowel Disease Service & Education at the Department of gastroenterology and Hepatology, royal adelaide Hospital, adelaide, sa, australia
43
Medical Progress
CMe Questions
CME 1 POINT
This continuing medical education service is brought to you by the Medical Progress institute, an institute dedicated to cMe learning, in partnership with the Malaysian Medical association. Read the article Managing Irritable Bowel Syndrome and answer the following questions for 1 CME Point.
Instructions:
1. Please use the ANSWER FORM for submission. 2. alternatively, you may submit your answers online at www.asia.cmpmedica.com/cmpmedica_my. 3. your answers should reach the Malaysian Medical association by 30 June 2012.
One CME point will be awarded only to registered candidates for each module according to Category 5 of the MMC-CME Grading System.
CME Article: Managing Irritable Bowel Syndrome Please indicate on your answer sheet whether the following statements are True or False.
1. Genetics appear to be more important than environmental factors in the aetiology of irritable bowel syndrome (iBs). 2. Epidemiological data suggest that twice as many women suffer from IBS than men. 3. rome iii diagnostic criteria for iBs focus on recurrent abdominal pain or discomfort, as well as changes in stool frequency/consistency or relief of pain/discomfort with defaecation. 4. There is little variation between patients when it comes to IBS symptoms. 5. a patient is diagnosed with iBs if, at least 6 months after symptom onset, he or she has experienced at least 3 days of symptoms a month for the previous 3 months. 6. anxiety and depression are quite common in patients with iBs and managing these psychological symptoms may also help to improve bowel symptoms. 7. young, otherwise healthy patients with clinically suspected iBs or functional bowel disorder should undergo exhaustive investigations to confirm diagnosis. 8. Most patients with iBs can be adequately managed through education, reassurance and dietary modification. 9. drugs for iBs, while having a therapeutic effect, do not alter the course of iBs and should only be administered as required for the shortest time possible, targeting the main symptom. 10. There is unequivocal evidence to support the use of acupuncture for the treatment of IBS.
44
Take the challenge, test your knowledge
Peer-Reviewed
Diagnosis and Evaluation of Irondeficiency Anaemia

stephen Jn Tattersall, MBBs, Bsc, FracP; christopher s Pokorny, MBBs, FracP, FrcP, Facg
This article presents authoritative advice on the investigation of a common clinical problemiron-deficiency anaemia.
Figure 3. Endoscopic view of caecal cancer.
Iron- deficienc y anaemia is a commonly encountered clinical problem usually diagnosed by the finding of microcytic, hypochromic red blood cells in association with characteristic abnormalities of iron studies (low levels of serum ferritin and serum iron, high levels of transferrin and low transferrin saturation). diagnosis of iron-deficiency anaemia can be more difficult in patients with acute or chronic inflammatory conditions, because ferritin is an acute-phase reactant.
Causes of iron deficiency include: blood loss (eg, gastrointestinal [gi] bleeding, which may be overt or occult [Figures 1 to 5], menorrhagia or repeated venesection) reduced absorption of iron (eg, coeliac disease [Figure 6]) increased metabolic requirements inadequate dietary intake (Table 1). GI blood loss should be considered in all patients with iron-deficiency anaemia and is the most common cause in men and postmenopausal women. Colorectal cancer is a clinically
Figure 1. Endoscopic view of severe ulcerative oesophagitis in a patient with irondeficiency anaemia.
Figure 2. Endoscopic view of a small bowel angiodysplastic lesion.
important cause of gi blood loss, and in most patients with iron-deficiency anaemia the diagnostic workup should include colonoscopy to exclude this possibility. The diagnostic evaluation of patients with iron-deficiency anaemia should be guided by a thorough history and physical examination. GI blood loss should be the presumed diagnosis in all patients unless there is a clear history of significant menorrhagia or other obvious cause such as regular blood donation. in most patients, initial evaluation of the GI tract includes gastroscopy with small bowel biopsy and colonoscopy. Further investigations may be warranted depending on the clinical setting. Obscure GI bleeding (typically from the small bowel) after normal gastroscopy and colonoscopy results can now be investigated with capsule endoscopy. New endoscopic
45
Diagnosis of Iron Deficiency

techniques are also expanding the therapeutic options. This review considers only anaemia due to occult bleeding. Patients with overt GI bleeding (eg, haematemesis, melaena or haematochezia) should be evaluated differently. contained within circulating red blood cells. The remainder is stored in the liver, spleen and bone marrow (0.81 g), found in proteins elsewhere in the body such as myoglobin (0.4 g) and bound to circulating transferrin (0.0030.007 g). Small amounts of iron are absorbed from dietary intake. Iron absorption occurs in the proximal small bowel and requires adequate gastric acid secretion to liberate iron from food. The typical western diet contains about 15 mg per day of elemental iron. Iron from vegetables (non-haem iron) is poorly absorbed by the body (less than 10% of intake), whereas haem iron from meat is absorbed much more efficiently (about 30% of intake). it is important to note, however, that the iron content of fish and poultry is small compared with that in red meat. There is no physiological excretion pathway for iron, although small amounts are lost during menstruation and in the faeces due to the shedding of enteral cells. The gold standard diagnostic test for iron deficiency is a bone marrow aspirate with Prussian blue staining to assess bone marrow iron stores. However, in most patients, the diagnosis of iron deficiency can be made from less invasive tests such as a blood film and iron studies. A low mean cellular haemoglobin (McH) value (hypochromia) is more specific for iron deficiency than a low mean cellular volume (McV; microcytosis). additional features of iron deficiency found on a blood film include anisocytosis (variable size of red cells) and poikilocytosis (abnormally shaped red cells); however, these are not specific to iron deficiency. The differential diagnoses of hypochromic, microcytic anaemia include thalassaemia, sideroblastic anaemia and anaemia of chronic disease. Iron studies are the most useful test in differentiating these conditions (Table 2). Thalassaemia is an inherited disorder of haemoglobin synthesis. The diagnosis may be suspected on the grounds of disproportionately reduced MCV compared with MCH or on the basis of family history or heritage. Diagnosis is confirmed by haemoglobin electrophoresis. Sideroblastic anaemia is a hereditary or an acquired disorder of haem protein synthesis. Iron studies provide clues to the diagnosis of sideroblastic anaemia, but a definite diagnosis usually requires a bone marrow biopsy. Anaemia of chronic disease can be difficult to distinguish from irondeficiency anaemia on the basis of iron studies alone, and the two conditions can occur concurrently. In these circumstances, a bone marrow aspirate may be required to confirm the presence of iron deficiency.
Iron Metabolism
under physiological conditions, total body iron stores amount to between 3 and 4 g, with more than half (2 g)
Figure 4. Endoscopic view of an inflamed terminal ileum of a patient with Crohns disease.
Figure 6. small bowel histology of a patient with coeliac disease demonstrating subtotal villous atrophy. Figure 5. Endoscopic view of a large colonic polyp.
46
The most commonly used iron studies are ferritin, serum iron, transferrin (also reported as total iron binding capacity) and transferrin saturation. A low ferritin level is the most specific marker of iron deficiency (specificity of 99% for ferritin levels less than 15 ng/ mL and 98% for ferritin levels less than 40 ng/ml). a normal or high ferritin level does not exclude the diagnosis of irondeficiency anaemia because levels can be elevated (but rarely by more than a factor of three) in the presence of acute or chronic inflammation, malignancy or liver disease. Concurrent measurement of C-reactive protein levels and liver function tests are useful in this regard. generally, the serum iron level is reduced and the transferrin level is raised in patients with iron deficiency. The transferrin saturation is calculated from these indices (100 [serum iron/transferrin]) and is usually reduced in patients with iron-deficiency anaemia. The presence of low transferrin saturation with a low-normal serum ferritin level is also suggestive of iron deficiency. However, pregnancy and use of the oral contraceptive pill will raise serum transferrin levels and therefore lower transferrin saturation in the absence of iron deficiency. Soluble transferrin receptor is a newer test available in some laboratories to diagnose patients with iron deficiency. It is a marker of erythropoietic activity and is increased in patients with iron deficiency. unfortunately, it has not proven to be as useful a test as initially thought and in head-to-head trials measurement of serum ferritin levels has superior sensitivity and specificity. If doubt remains about the diagnosis of iron-deficiency anaemia after iron studies have been
Table 1. Causes of iron-deficiency anaemia

Cause Occult gastrointestinal bleeding underlying condition Colonic polyps or cancer NSAID or aspirin use angiodysplasia (small bowel or colonic) Gastric antral vascular ectasia gastric, oesophageal or small bowel tumours ulcerative colitis or crohns disease chronic liver disease (portal hypertensive gastropathy) Oesophagitis Hiatus hernia (large) with camerons ulcers Haemorrhoids Peptic ulcer disease Gastric or duodenal polyps Erosive gastritis Hookworm infestation Hereditary haemorrhagic telangiectasia Iron malabsorption Coeliac disease gastric atrophy (including pernicious anaemia) gastrectomy (complete or partial) Proximal small bowel resection or bypass Small bowel bacterial overgrowth achlorhydria for other reasons (vagotomy) Increased iron utilization Pregnancy Breastfeeding Inadequate dietary intake Extraintestinal blood loss Vegetarian diet or poor intake of red meat Menorrhagia Repeated phlebotomy or blood donation intravascular haemolysis including mechanical heart valves urinary blood loss (renal cell cancer) Recurrent epistaxis Paroxysmal nocturnal haemoglobinuria
Table 2. results of iron studies for differential diagnoses of microcytic, hypochromic anaemia
Differential diagnosis Ferritin Iron deficiency Anaemia of chronic disease Thalassaemia Sideroblastic anaemia Low Normal or high Normal Normal or high Normal Normal or high Normal Normal or high Normal Normal or high Normal Normal or high (sideroblasts seen) Serum iron Low Low High Normal or low Transferrin Transferrin saturation Low Normal or low Low Normal or high Bone marrow iron Iron studies
47
performed, a bone marrow biopsy is the test of choice. When the patient or clinician wish to avoid a bone marrow biopsy, an alternative diagnostic test is a therapeutic trial of iron supplementation. The diagnosis is confirmed by a resolution of the anaemia and improvement in the red cell indices. Reticulocytosis may be seen after 5 to 7 days and the patients haemoglobin level should increase by 200400 mg/l every 3 to 4 weeks. A lack of response to iron supplementation is not helpful diagnostically and should lead to reconsideration of a bone marrow biopsy. If the diagnosis of iron-deficiency anaemia is confirmed then the usual diagnostic pathways should be followed to determine the cause.
helpful in establishing the cause of irondeficiency anaemia include urinalysis for haematuria, because 1% of patients with iron-deficiency anaemia have renal tract malignancy. A substantial proportion of these patients will have
Table 3. Clinical evaluation of iron deficiency

History reflux odynophagia dyspepsia dysphagia abdominal pain altered bowel habit (constipation or diarrhoea) rectal bleeding steatorrhoea Menorrhagia Haematuria Blood donation epistaxis aspirin or nsaid use dietary history Previous gastric surgery Weight loss Family history of malignancy Physical examination
Clinical and Endoscopic Evaluation

Evaluation of the patient with iron-deficiency anaemia should be guided by a thorough history and physical examination aimed at identifying potential causes of bleeding in the GI tract or other causes of the anaemia (Table 3). For medically fit men and postmenopausal women, the initial diagnostic workup should include a gastroscopy with small bowel biopsy and a colonoscopy. Gastroscopy will identify the cause of iron-deficiency anaemia in about one-third of patients, colonoscopy will identify the cause in one-third of patients, and one-eighth of patients will have dual pathology. All patients should have small bowel biopsies taken to exclude the presence of coeliac disease. The strongest predictors of malignancy are age and haemoglobin levels less than 800 g/L. In patients with iron deficiency who are not anaemic, the diagnostic yield of endoscopic investigations is much lower (less than 1%). Additional simple tests that may be
48
Features of iron deficiency

glossitis angular stomatitis Koilonychia
Physical findings suggesting cause

abdominal mass or organomegaly Mass on digital rectal examination lymphadenopathy oral or facial telangiectasia signs of chronic liver disease abdominal scar signs of malnutrition Mouth ulcers
overt haematuria. Faecal occult blood testing (FoBT) is a useful screening test for colorectal cancer in asymptomatic, low-risk patients. However, in the setting of iron-deficiency anaemia, it plays a small part because it is not sufficiently sensitive to exclude colon cancer and a negative FOBT should not preclude endoscopic evaluation. Coeliac serology is useful in screening for coeliac disease in those patients with mild upper-gut symptoms. Anti-tissue-transglutaminase immunoglobulin IgA and IgG is the test of choice. Simultaneous measurement of serum iga is important, because IgA deficiency is not uncommon and serology may be negative in these cases. However, in patients with irondeficiency anaemia, serology is not sufficiently sensitive to exclude the diagnosis and therefore is of questionable use in the evaluation of these patients. Premenopausal women are a difficult group to diagnose, because iron deficiency is commonly due to menstrual loss or the increased demands of pregnancy and breastfeeding. Fur thermore, malignant tumours are relatively uncommon and dietary iron intake may be lower in this population. Those with GI symptoms or risk factors for malignancy (such as a family history) should proceed to endoscopic evaluation. For patients under the age of 50 years who have no symptoms and no risk factors, a therapeutic trial of iron supplements may be appropriate after addressing other potential causes of iron deficiency such as menorrhagia and dietary intake. If the iron deficiency recurs or does not respond to iron therapy, then endoscopic evaluation should be undertaken. There may be some role for FOBT and
coeliac serology in the evaluation of iron-deficiency anaemia in this group.
Obscure Gastrointestinal Bleeding

For patients with no cause found for their iron deficiency after initial endoscopic evaluation, a number of approaches are reasonable but the clinician should be guided by the clinical context and specialist advice. For patients with mild iron-deficiency anaemia who are otherwise considered unlikely to have sinister gi pathology, a therapeutic trial of iron supplements may be reasonable with close follow up. alternatively, evaluation for small bowel causes of iron-deficiency anaemia may be undertaken, including small bowel series, computed tomographic (cT) enterography, enteroscopy or capsule endoscopy (Figure 7). Small bowel series have been largely replaced by cT enterography, which has the advantage of being able to detect both intestinal and extraintestinal GI causes of iron-deficiency anaemia (eg, renal tract malignancies). However, in common with small bowel series, intestinal mucosal vascular abnormalities such as angiodysplasia
Small bowel series has the advantage of being able to detect both intestinal and extraintestinal GI causes of iron-deficiency anaemia.
Figure 7. Small bowel vascular lesion as seen by capsule endoscopy
(the most common cause of obscure, small bowel bleeding) cannot be diagnosed with CT enterography. Push enteroscopy allows detection of vascular lesions and also permits therapy but is invasive and rarely able to access the entire small bowel mucosa. Newer techniques such as balloon enteroscopy are most useful as therapeutic rather than diagnostic procedures. These techniques remain relatively invasive, are time consuming and their availability is geographically limited. since 2005, capsule endoscopy has been reimbursed under the australia's Pharmaceutical Benefits scheme (PBs) for the investigation of patients with
iron-deficiency anaemia. To qualify for the rebate for capsule endoscopy, the patient must have anaemia from recurrent or persistent bleeding or have active bleeding. The patient must also have had both a gastroscopy and colonoscopy performed within the preceding 6 months. capsule endoscopy is relatively non-invasive, well tolerated and has a higher yield for small bowel causes of iron-deficiency anaemia than other investigations (radiological or endoscopic). The procedure will also identify lesions missed at gastroscopy in a significant proportion of patients. The disadvantage of capsule endoscopy is that it does not permit
49
biopsy or therapy for identified lesions.
oral iron supplements are simple to use, inexpensive and generally well tolerated.
Correction of Iron Deficiency

After identification and treatment of the causative factor of iron-deficiency anaemia, correction of the iron deficiency should be undertaken. Although improved dietary iron intake is advisable, it is rarely sufficient to replenish significantly depleted iron stores within a reasonable time frame. Oral iron supplements (usually ferrous sulfate preparations) are simple to use, inexpensive and generally well tolerated. An adequate dose of oral iron is more than 150 mg of elemental iron per day (two to three tablets of a ferrous sulfate preparation; each tablet usually contains between 55 and 105 mg of elemental iron). The concurrent use of vitamin C supplements will improve absorption, and folate supplementation can improve the haematological response to oral iron. Preparations of iron combined with vitamin C or folate are available. Oral iron supplements should not be taken with food because food will reduce their absorption. Dose-dependent constipation or nausea will be experienced by 1020% of patients taking orally administered iron and they should be warned about this possibility. In these circumstances, the dose may be reduced to improve tolerability. Supplementation should continue until the anaemia is resolved (usually 3 to 6 months) and a further 6 months of therapy should be undertaken to ensure adequate replenishment of body stores. Failure to respond to iron supplementation may be due to noncompliance, malabsorption, incorrect diagnosis, intercurrent disease (such as renal
50
Conclusion
failure) or ongoing gi loss. all patients should be monitored for recurrence of anaemia or iron deficiency. Parenterally administered iron is more invasive, more expensive and has a risk of significant side effects. However, it can provide a much larger quantity of iron more quickly and may be appropriate for some patients (such as those with cancer, inflammatory bowel disease or renal failure, particularly those on dialysis). it may also be used in those who do not tolerate oral iron supplementation. Intramuscular delivery is slow, unreliable and often painful. Furthermore, the quantity of elemental iron provided is not significantly greater than that absorbed from an adequate dose of oral iron. Intravenously administered iron (iron infusion) is available as a hospital day procedure. There are reports of serious adverse reactions including death (although rare and more common with the older, higher molecular weight preparations no longer routinely used), and administration of intravenous iron should not be undertaken without consideration of these risks.
Iron-deficiency anaemia is common and usually diagnosed by characteristic abnormalities of iron studies. Its diagnosis should initiate careful evaluation for the cause as well as the correction of the iron deficiency. GI bleeding is the most common cause of iron-deficiency anaemia in men and postmenopausal women, and all medically fit patients should be evaluated for a GI cause. young women with an obvious reason for the anaemia such as menorrhagia or regular blood donation and no GI symptoms or abnormal physical findings represent a special case in which a therapeutic trial of iron supplementation with close observation and follow-up may be appropriate.
None.
References
1. goddard Fa, James MW, Mcintyre as, scott BB on behalf of the British Society of Gastroenterology. Guidelines for the management of iron deficiency anaemia. May 2005. Available online at: http://www. bsg.org.uk/pdf_word_docs/iron_def.pdf (accessed august 2010). 2. rockey dc, cello JP. evaluation of the gastrointestinal
In summary
iron-deficiency anaemia is a common condition that is usually identified by the presence of microcytic, hypochromic red cells and characteristic abnormalities of iron studies. a low serum ferritin level is the most specific serological marker of iron deficiency, but it may be elevated in patients with inflammation, liver disease or malignancy. Faecal occult blood testing is a useful screening test for colon cancer in asymptomatic patients but is rarely useful in the setting of iron-deficiency anaemia. initial endoscopic evaluation of patients with iron-deficiency anaemia includes gastroscopy with small bowel biopsy and colonoscopy. in one-third of patients no cause for iron-deficiency anaemia is found on gastroscopy or colonoscopy, and for these patients capsule endoscopy is available on the australia's Pharmaceutical Benefits scheme within 6 months of these negative tests. iron deficiency in the absence of anaemia is less likely to have a sinister gastrointestinal cause. oral iron supplementation is generally well tolerated by patients, and absorption and haematological response are improved by concurrent administration of vitamin c and folate, respectively.
tract in patients with iron-deficiency anaemia. N Engl J Med 1993; 329: 16911695. 3. rockey ds, green BT. gastrointestinal endoscopic evaluation in premenopausal women with iron deficiency anaemia. J clin gastroenterol 2004; 38: 104109. 2010 Medicine Today Pty ltd. initially published in Medicine Today september 2010;11(9):5159. Reprinted with permission.
About the Authors Dr Tattersall is a Senior Clinical Fellow at the John radcliffe Hospital, oxford, uK. associate Professor Pokorny is Conjoint Associate Professor of Medicine, university of new south Wales; and Visiting gastroenterologist, sydney and liverpool Hospitals, sydney, nsW, australia.
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CMe Questions
CME 1 POINT
This continuing medical education service is brought to you by the Medical Progress institute, an institute dedicated to cMe learning, in partnership with the Malaysian Medical association. Read the article Diagnosis and Evaluation of Iron-deficiency Anaemia and answer the following questions for 1 CME Point.
Instructions:
1. Please use the ANSWER FORM for submission. 2. alternatively, you may submit your answers online at www.asia.cmpmedica.com/cmpmedica_my. 3. your answers should reach the Malaysian Medical association by 30 June 2012.
One CME point will be awarded only to registered candidates for each module according to Category 5 of the MMC-CME Grading System.
CME Article: Diagnosis and Evaluation of Iron-deficiency Anaemia Please indicate on your answer sheet whether the following statements are True or False.
1. iron-deficiency anaemia is a common condition, diagnosed by microcytic, hypochromic red blood cells, as well as low levels of serum ferritin and serum iron, high levels of transferrin and low transferrin saturation. 2. causes of iron deficiency include blood loss, reduced iron absorption, increased metabolic requirements, and inadequate dietary iron intake. 3. More than half (2 g) of the 34 g total body iron stores are found within circulating red blood cells. 4. Thalassaemia is an infectious disorder of haemoglobin synthesis. 5. a low ferritin level is the most specific marker of iron deficiency, but ferritin levels may be normal or high in patients with inflammation, malignancy or liver disease. 6. only a gastroscopy is required for the initial diagnostic workup to determine iron-deficiency anaemia. 7. Faecal occult blood testing is useful to screen for colon cancer in asymptomatic patients, even for those with iron-deficiency anaemia. 8. special attention should be paid when diagnosing premenopausal women because menstrual loss, pregnancy and breastfeeding can cause iron deficiency. 9. Vitamin C and folate have no effect on oral iron supplement absorption or haematological response. 10. Iron supplements for anaemia should continue until the condition is resolved but is not necessary after that time.
52
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Peer-reviewed CME Journal

January 2012 VOL. 39 NO. 1

Global Summaries Clinical Review

Management of Neuropathic Cancer Pain The Health Consequences of Spouse Bereavement

Managing Irritable Bowel Syndrome

Diagnosis and Evaluation of Iron-deficiency Anaemia

assoc Prof gerald KoH, national university of singapore, singapore

dr adrian Wu, Private Practice, HKsar, china

Prof gavin JoynT

January 2012 VOL. 39 NO. 1

Prof Wiguno ProdJosudJadi

Prof Wimpie PangKaHila

Prof raymond TF cHeung

Emeritus Prof Ramon F aBarQueZ

Prof Boon-Lock CHIA

dr anna Maria cHoy

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Prof lawrence Ks Wong

Prof Bernard cHeung

Prof Chay-Hoon TAN

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Prof Benjamin cy Wong

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assoc Prof dessmon yH Tai

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Prof Amorn LEELARASAMEE

Prof Ron HH NELWAN