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June 2012 VOL. 4 NO. 6

Global Summaries

Clinical Review

Recommendations on the Management of Neuropathic

GP Pointer

Tocotrienols: Their Role in the Prevention and Treatment of CVD and Met Syn

CME

Non-Pharmacological Treatment for Low Back Pain

From the Publishers of

CIMS, IDR, and the

Today Group of Journals

Medical Progress May 2012 i


181-182 Global Summaries

181 Cardiology

181 Diabetes

181 Gastroenteroloy

182 General Medicine

182 Oncology

183-190 Clinical Review

183 PAIN MANAGEMENT Recommendations on the Management of Neuropathic

The Multidisciplinary Panel on Neuropathic Pain

Chen Phoon Pirg, Josephine WY Ip, Vincent Mok, Tsoi Tak Hong,

Wong Chun Por, Wong Ho Shan Steven

191-207 In Focus: Gout

192 Crystal Arthropathies

Spencer Ellis, G Koduri

199 Addressing Problems in Gout and Hyperuricaemia

Peter A simkin

CONTENTS

EDITORIAL BOARD

Dermatology

Dr S SacchidanandRajiv Gandhi University of Health Sciences, BangaloreGastroenterology

Dr Rakesh TandonPushpawati Singhania Research Institute, New DelhiGeriatric Medicine

Dr OP SharmaGeriatric Society of India

INDIAN EDITORIAL BOARDMedicine

Prof Dinesh Kumar DhanwalMAMC, Associated Lok Nayak and GB Pant Hospital, New Delhi

Prof Randeep GuleriaAll India Institute of Medical Sciences, New DelhiNeurology

Dr (Maj Gen) S VenkataramanMata Chanan Devi Hospital, New Delhi

Anaesthesia & Intensive Care Medicine

Prof Gavin JOYNTThe Chinese University of Hong Kong, HKSAR, ChinaAndrology

Prof Wimpie PANGKAHILAUdayana University, IndonesiaCardiology

Emeritus Prof Ramon F ABARQUEZUniversity of the Philippines, Philippines

Prof Boon-Lock CHIANational University of Singapore, Singapore

Dr Anna Maria CHOYNinewells Hospital and Medical School, UK

Prof Harmani KALIMUniversity of Indonesia, Indonesia

Dr Anwar SANTOSOUdayana University, IndonesiaClinical Pharmacology

Prof Bernard CHEUNGUniversity of Birmingham, UK

Prof Chay-Hoon TANNational University of Singapore, SingaporeDermatology

Dr Adrian YP FUNGPrivate Practice, HKSAR, China

Dr Yoke Chin GIAMNational Skin Centre, SingaporeEndocrinology

Dr Norman CHANPrivate Practice, HKSAR, China

Prof Siew-Pheng CHANUniversity of Malaya, Malaysia

Dr Ma Teresa P QUEPhilippine Diabetes Association, Philippines

Prof Sidartawan SOEGONDOUniversity of Indonesia, IndonesiaFamily Medicine

Prof Cindy LK LAMThe University of Hong Kong, HKSAR, ChinaGastroenterology & Hepatology

Prof Khean-Lee GOHUniversity of Malaya, Malaysia

Prof George KK LAUThe University of Hong Kong, HKSAR, China

Prof HA Aziz RaniUniversity of Indonesia, Indonesia

Prof Benjamin CY WONGThe University of Hong Kong, HKSAR, ChinaGeriatric Medicine

Dr Leung-Wing CHU The University of Hong Kong, HKSAR, ChinaHaematology & Oncology

Prof Raymond LIANGThe University of Hong Kong, HKSAR, China

Dr Raymond WONGPrince of Wales Hospital, HKSAR, ChinaInfectious Disease

Dr Christopher LEEHospital Sungai Buluh, Malaysia

Prof Amorn LEELARASAMEESiriraj Hospital, Thailand

Nephrology

Prof Philip KT LI Prince of Wales Hospital, HKSAR, China

Prof Wiguno PRODJOSUDJADIThe University of Indonesia, IndonesiaNeurology

Prof Raymond TF CHEUNG The University of Hong Kong, HKSAR, China

Dr Gardian CY FONG The University of Hong Kong, HKSAR, China

Dr Chen-Ya HUANGThe University of Hong Kong, HKSAR, China

Dr Venketasubramanian RAMANINational Neuroscience Institute, Singapore

Prof Hasan SJAHRIRUniversitas Sumatera Utara, Indonesia

Prof Lawrence KS WONG The Chinese University of Hong Kong, HKSAR, ChinaOccupation Medicine & Public Health

Prof David KOHNational University of Singapore, Singapore

Dr Judy SNGNational University of Singapore, SingaporeOphthalmology

Dr Michael SH LAWPrivate Practice, MalaysiaOrthopaedics & Orthopaedic Surgery

Prof David SK CHOONUniversity of Malaya, Malaysia

Dr Daniel KH YIPPrivate Practice, HKSAR, ChinaOtorhinolaryngology

Prof Dato’ Balwant Singh GENDEHThe National University Hospital Malaysia, Malaysia

Prof William I WEI Queen Mary Hospital, HKSAR, ChinaPharmacy

Prof Vincent HL LEEThe Chinese University of Hong Kong, HKSAR, ChinaPsychiatry

Dr Eric YH CHENThe University of Hong Kong, HKSAR, China

Prof M Parameshvara DEVASSB Hospital, BruneiRespiratory & Critical Care Medicine

Prof Menaldi RASMINUniversity of Indonesia, Indonesia

Dr Dessmon YH TAITan Tock Seng Hospital, Singapore

Dr Kenneth WT TSANGPrivate Practice, HKSAR, ChinaRheumatolzogy & Immunology

Prof Handono KALIMBrawijaya University, Indonesia

Dr Swan-Sim YEAPPrivate Practice, Malaysia

Director:

Dr Gerald KOH, National University of Singapore, Singapore

Deputy Director:

Dr Adrian WU, Private Practice, HKSAR, China

183181

Medical Progress May 2012 ii


CONTENTS

ChinaTeo Wai ChooTel: (86 21) 5228 9503Email: [email protected]

Hong KongKristina Lo-Kurtz, Pagon Lo, Miranda WongTel: (852) 2559 5888Email: [email protected]

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PhilippinesPhilip Katipunan, Sennie Tolentino,Grace Aquino, Margie Malacas-Sabio,Owen Puno, Mei PadillaTel: (63 2) 886 0333Email: [email protected]

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INTERNATIONAL PUBLISHING TEAM

208-212 GP Pointer

208 Tocotrienols: Their Role in the Prevention and

Treatment of CVD and Met Syn

Sneh A Gehlot, N Trehan

213-214 In Practice213 Case Report : Case of Hemoglobin Sickle/D Punjab

Deepak Sharma, Madhulata Agarwal, Vishal Batra,

Dinesh Kothari, Sneha Ambwani

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CONTENTS

215-221 Continuing Medical Education

215 Non-Pharmacological Treatment for Low Back Pain

Steven J Atlas

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Medical Progress contains articles under license from UBM Healthcare Media LLC. The article appearing on pages192-198 is from Elsevier.

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Colorectal Cancer

� CME �Sports Injuries in Weekend Warriors: 20 Clinical Pearls

Medical Progress June 2012 181

Global Summaries Synopses of major trials from leading international journals

CARDIOLOGY

Vorapaxar in acute coronary syndromesVorapaxar is an oral drug that inhibits thrombin-induced platelet aggregation by acting as an antagonist of protease-

activated receptor 1, an activator of such platelet aggregation. It has been compared with placebo in patients with acute non-ST-segment-elevation coronary syndromes in a multinational trial.

A total of 12,944 patients with a non-ST-segment-elevation acute coronary syndrome were randomized at 818 sites in 37 countries to vorapaxar (40 mg loading dose, then 2.5 mg daily) or placebo, in addition to standard therapy. The trial was stopped early after a safety review. After an average follow-up of 502 days, the rate of the primary end point (cardiovascular death, myocardial infarction, stroke, rehospitali-zation for recurrent ischaemia, or urgent coronary revascularization) was 1,031/6,473 (16%) in the vorapaxar group and 1,102/6,471 (17%) in the placebo group, with Kaplan–Meier 2-year rates of 18.5% vs 19.9%, a non-significant difference. The composite outcome of cardiovascular death, myocardial infarction, or stroke occurred in 14.7% vs 16.4%, a significant 11% reduction in the vorapaxar group. There was a highly significant increase of 35% in moderate or severe bleeding in the vorapaxar group compared with the placebo group. There was a 3.4-fold increase in risk of intracranial haemorrhage in the vorapaxar group.

The addition of vorapaxar to standard

therapy increased the risk of major bleeding and did not reduce the rate of the primary end point significantly.

Tricoci P et al. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. NEJM 2012; 366: 20–33.

DIABETES

Diabetes risk models and scoresA systematic review has assessed risk models and scores for the prediction of risk of type 2 diabetes.

The review included 43 papers with details of the development and/or validation of 145 models and scores, of which 94 were assessed in detail. They had been based on data from almost 7 million people with follow-up for up to 28 years. Meta-analysis was not possible because of the hetero-geneity of the data. The mean number of components per score was 8 (3–14), and some, but not all, models and scores were statistically robust and had been externally validated on a different population. Seven risk scores were chosen as having a high potential for use in practice, and ten mechanisms were outlined whereby the assessment of risk of type 2 diabetes might lead to improvement in outcomes.

There are many risk scores for the development of type 2 diabetes, but few are used routinely. Seven risk scores were considered to be highly suitable for clinical use.

Noble D et al. Risk models and scores for type 2 diabetes: systematic review. BMJ 2011; 343: 1243

(d7163).

GASTROENTEROLOGY

New drugs for chronicHCV genotype 1Treatment of chronic hepatitis C virus (HCV) infection with pegylated interferon (peginterferon) alpha and ribavirin for 48 weeks achieves a sustained virological response at 24 weeks after stopping treatment in 40–50% of patients. Adding

a protease inhibitor to treatment for non-responders after 12 weeks of treatment produces a sustained virological response in 14–33%. Now, a multicentre phase II study in the USA has shown that the use of two new antiviral agents may improve results. Daclatasvir is an HCVNS5A replication complex inhibitor and asunaprevir is an HCV NS3 protease inhibitor.

The trial included 21 patients with chronic HCV genotype 1 infection unre-sponsive to treatment with peginterferon and ribavirin for 12 weeks. Randomization was to daclatasvir plus asunaprevir with (DAPR) or without (DA) peginterferon plus ribavirin. In the DA group, four of 11 patients achieved a sustained virological response at 12 and 24 weeks after treatment. In the DAPR group, all 10 patients had a sustained virological response at 12 weeks and nine at 24 weeks. In the DA group, six patients had viral break-through on treatment, and in all six cases there were resistance mutations to both daclatasvir and asunaprevir. Diarrhoea was common in both groups, and six patients had transient rises in alanine aminotrans-ferase levels.

Adding daclatasvir and asunaprevir to peginterferon and ribavirin achieved sustained virological response in patients who had not responded initially to peginter-feron and ribavirin alone.

Lok AS et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. NEJM 2012; 366: 216–224; Chung RT. A watershed moment in the treatment of

hepatitis C. Ibid: 273–275 (editorial).

182 Medical Progress June 2012

Global Summaries

GENERAL MEDICINE

Gene therapy for haemophilia BHaemophilia B (Christmas disease) results from a mutation in the gene for coagulation factor IX (FIX). In severe haemophilia B, functional FIX levels are < 1% of normal. Current therapy with FIX protein concentrate is not curative, and it is associated with inhibitor formation as well as being expensive. Gene therapy offers the prospect of a cure. Researchers in the UK and the USA have assessed a new gene therapy—a serotype-8-pseudotyped, self-complementary adenovirus-associated virus (AAV) vector expressing a codon-optimized human factor IX (FIX) transgene (sc AAV2/8-LP1-hFIXco) given intravenously.

Six patients with severe haemophilia B received a single gene therapy dose via a peripheral vein: two given a high dose, two an intermediate dose, and two a low dose. Follow-up was for 6–16 months. All patients benefitted: the two given the low dose were able to increase the intervals between injections of FIX and the other four were able to stop FIX prophylaxis and remained free of spontaneous bleeding. One patient who received the high dose had a transient asymptomatic increase in serum aminotransferase levels with detection of AAV8-capsid-specific T cells in peripheral blood. The other high-dose patient had a transient increase in aminotransferase. Both had normal aminotransferase levels after a course of steroids. Their FIX levels were 3–11% of normal values.

This gene therapy at intermediate or high dosage was successful in raising FIX levels sufficiently to stop spontaneous bleeding without prophylactic FIX. The investigators express concern about immune-mediated clearance of AAV-transduced hepatocytes but point out that the process can be controlled with a short course of steroid without loss of transgene expression.

Nathwani AC et al. Adenovirus-associated virus vector-mediated gene transfer in haemophilia B. NEJM 2011; 365: 2357–2365; Ponder KP. Merry Christmas for patients with haemophilia B. Ibid: 2424–2425

Catheter-directed thrombolysis for acute ileofemoral DVTThe incidence of acute deep vein thrombosis (DVT) in the legs is about 1 in 1,000 people per year. Anticoagulant therapy prevents extension of the thrombus, recurrence and pulmonary embolism, and reduces mortality. It does not, however, dissolve the clot, and patients may develop post-thrombotic syndrome (PTS) with pain, swelling, a feeling of heaviness, oedema, skin pigmentation, and, in severe cases, venous ulcers. In most cases of symptomatic DVT, the thrombus is in the popliteal and more proximal veins. The risk of PTS can be halved by daily use of compression stockings, but more effective initial treatment is needed. Systemic thrombolysis is effective but associated with a high risk of bleeding. A multicentre trial in Norway has shown that local delivery of the throm-bolytic agent into the clot via a catheter is effective with less risk.

At 20 hospitals in southeast Norway, a total of 209 patients aged 18–75 with a first iliofemoral DVT were randomized within 21 days of symptom onset to conventional treatment with or without catheter-directed thrombolysis (CDT). Data were analysed from 189 patients. At 24 months, PTS had occurred in 41% (CDT) vs 56% (controls), a significant difference with an absolute reduction in risk of PTS of 14% and a number-needed-to-treat of seven. After 6 months, the rate of iliofemoral patency was 66% vs 47%. Among the 90 patients in the CDT group, there were 20 bleeding compli-cations related to the CDT, with three major and five clinically relevant bleeds.

These researchers conclude that additional CDT should be considered in patients with a high proximal DVT and low risk of bleeding.

Enden T et al. Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVen T study): a randomised controlled trial. Lancet 2012; 379: 31–38; The Lancet; ibid: 1 (editorial); Hofmann LV, Kuo WT. Catheter-directed thrombolysis for acute DVT. Ibid: 3–4 (comment).

ONCOLOGY

Gene changes and resistance of colorectal cancer to chemotherapy

Gene alterations, both genomic and epigenetic, are common in human cancers, and some of them may affect response to chemotherapy. Researchers in Germany have concentrated on the gene encoding transcription factor AP-2 epsilon (TFAP2E) and its potential downstream target, DKK4, the gene encoding Dickkopf homologue 4 protein. Tumour samples were obtained from 74 patients treated for colorectal cancer and, later, another four cohorts (total, 220 patients) undergoing chemo-therapy with or without radiotherapy. The expression, methylation, and function of TFAP2E was analysed in colorectal cancer cell lines in vitro and in patients with colorectal cancer. The gene was hypermeth-ylated in 38 of the initial 74 samples, and this was associated with decreased gene expression. Cancer cell lines with overex-pression of DKK4 had increased resistance to fluorouracil but not to irinotecan or oxaliplatin. In the four later cohorts, hyper-methylation of TFAP2E was significantly associated with resistance to chemo-therapy. Hypomethylation was associated with a sixfold increase in likelihood of chemotherapy responsiveness. Epigenetic alterations in TFAP2E were independent of key regulatory cancer gene mutations, microsatellite instability, and other genes affecting fluorouracil metabolism.

Hypermethylation of TFAP2E is associated with chemotherapy resistance in patients with colorectal cancer, and this resistance is mediated through DKK4. Targeting of DKK4 could potentially reverse this resistance.

Ebert MPA et al. TFAP2E-DKK4 and chemoresistance in colorectal cancer. NEJM 2012; 366: 44–53.


PAIN MANAGEMENT

Recommendations on the Management of Neuropathic Cancer PainThe Multidisciplinary Panel on Neuropathic Pain

Chen Phoon Ping, MBBS, FHKAM (Anaes), FANZCA, FFPMANZCA, Dip Pain Mgt (HKCA); Josephine WY 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); Tsoi Tak 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)

Pain is prevalent in cancer patients and is often difficult to treat, especially neuro-pathic cancer pain. Neuropathic cancer pain often responds poorly to opioids;

hence, the use of adjuvant medications is necessary. Patients who do not experience suf-ficient pain relief with pharmacological therapy may benefit from interventional therapies. These recommendations, which are an update of those first published by the Multidisciplinary

This is an update of the recommendations on neuropathic cancer pain management

written by members of the Hong Kong–based Multidisciplinary Panel on Neuropathic

Pain.

Panel on Neuropathic Pain in 2006,1 aim to provide a logical approach to effectively manage cancer pain, with a particular focus on neuro-pathic 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 mech-anisms.2 Cancer pain may be chronic or acute, and patients with chronic pain commonly experience acute flares of pain. One-half to two-thirds 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

The use of adjuvant medications is necessary in neuropathic cancer pain.


PAIN MANAGEMENT

or compression of adjacent local structures, such 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 rec-ognizing these syndromes can help identify pain aetiology and the need for additional evaluation, and target therapy more appropriately.

Types of PainSomatic 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 com-pression of visceral structures and supporting connective tissues.3 Visceral pain is often diffuse and sometimes referred to other non-visceral structures, making the source of pain difficult to localize.

Neuropathic pain is charac-terized by aching, burning, stabbing or lancinating pain,3,6 and may also present as paraesthesia, dysaesthesia, hyperalgesia or allodynia. It occurs in approximately 30–55% 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 sym-pathetic activity also plays a role in spontaneous neuropathic pain.3 In addition, most post-treatment pain syndromes (eg, post-surgical, post-radiotherapy or post-chemotherapy pain) are neuropathic.3 Relative to somatic and visceral pain, neuropathic pain responds poorly to systemic

opioids; hence, other treatments are often utilized.5,10,11

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 neuro-pathic cancer pain may be challenging; currently no single method is available to reliably diagnose cancer-related neu-ropathic 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 Neuro-pathic Pain Questionnaire (NPQ), Leeds Assessment of Neuropathic Signs and Symptoms (LANSS) and Neuro-pathic Pain Symptom Inventory (NPSI) may also help to identify neuropathic pain in cancer patients.14

• If a patient has neuropathic 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 estab-lished.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.

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, par-ticularly for patients with bone metastasis.10,16 • Pain caused by soft-tissue infil-tration, visceral distention and increased intracranial pressure may be treated initially with corticosteroids.18 Acute spinal cord compression should be treated with intravenous dexa-methasone 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 anal-gesics in a stepwise manner according to response (Figure).11,16 However, pain

”Currently no single method is available to

reliably diagnose cancer-related

neuropathic pain“


PAIN MANAGEMENT

that is moderate to severe at the outset should be treated with higher-potency opioids or with higher doses.17 • Adjunctive therapies may be used with or without conventional anal-gesics 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, benefit-risk analysis, anticipated duration of hospitalization and likely duration of survival).4,16 • Physiotherapy may reduce the need for analgesics.4 However, while phys-iotherapy 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 immo-bility. 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 multidisci-plinary. Patients with terminal cancer often have significant emotional and mood disturbances, or other psy-chosocial 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 neu-ropathic 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.

Table. Indications for adjunctive therapy5,11,16–19

Indication Adjunctive therapy

Neuropathic pain Anticonvulsants (eg, gabapentin, pregabalin)

Antidepressants (eg, amitriptyline, venlafaxine)

Other agents (eg, ketamine, mexiletine, lidocaine)

Metastatic bone pain Bisphosphonates (eg, pamidronate)

Anxiety symptoms Hydroxyzine

Emesis Hydroxyzine

Poor analgesic response Corticosteroids

Increased intracranial pressure Corticosteroids

Spinal cord compression Corticosteroids

Perineural oedema and nerve compression Corticosteroids

Nausea Corticosteroids

Anorexia and poor appetite Corticosteroids

Cachexia Corticosteroids

Physiotherapy should be introduced early to treat generalized weakness, deconditioning, and pain associated

with inactivity and immobility.


PAIN MANAGEMENT

• Anticonvulsants (eg, gabapentin, pregabalin) and antidepressants (eg, amitriptyline, venlafaxine) are rec-ommended adjuvant analgesics for cancer-related neuropathic pain (Figure).9,21,22 A recent systematic review revealed that the use of anti-epileptic 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 gaba-pentin.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

• 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

UndermanagementDespite the presence of cancer pain guidelines, such as those from the WHO, cancer pain is often under- treated. 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

Declaration of InterestsThe Multidisciplinary Panel on Neuropathic Pain is supported

by an unrestricted educational grant from Pfizer Corporation

Hong Kong Ltd.Adapted from references 4, 10, 11, 16–20, 26, 30.

Figure. Management of cancer pain.

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, dexa-methasone.29 • Interventional therapy may also be effective for neuropathic cancer pain.30–36 However, certain interven-tional techniques for neuropathic pain should only be considered when phar-macological interventions have failed, are poorly tolerated, or are inappro-priate.17


PAIN MANAGEMENT

Pharmacotherapy

I. Opioids

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 due to reduced opioid sensitivity.4,5,10,42,42 Instead, there may be failure to 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 transdermal buprenorphine was a valuable treatment for chronic cancer 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 cancer pain. In a double-blind, placebo-controlled study (n = 36), patients receiving tramadol had major improvements in pain intensity (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 venlafaxine and duloxetine, and selective serotonin and norepinephrine reuptake inhibitors, as this may increase the risk of serotonin syndrome; tramadol may also increase the risk of seizure.47 There is some evidence that methadone may be effective for neuropathic cancer pain.48

II. Anticonvulsants

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 lancinating pain or those poorly responsive to opioid therapy.3,4,11,16,17,20,22 Anticonvulsant use may decrease opioid dose and, hence, associated side effects.4

Gabapentin has established efficacy in a variety of neuropathic pain syndromes, including neuropathic cancer pain.49–57 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

Appendix. Evidence-based management of neuropathic cancer pain

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 0–10 numerical scale.

More recently, studies have demonstrated that gabapentin provides additional pain relief as an adjuvant analgesic in neuropathic cancer pain when combined with opioids.55,56 In another study, low-dose gabapentin (200 to 400 mg/day) combined with the antidepressant imipramine (20 mg/day) in patients with neuropathic cancer pain significantly decreased total pain score and daily paroxysmal episodes compared with 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 epidural analgesia for chronic cancer pain demonstrated that pregabalin 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 also been used traditionally for analgesia.62 However, their adverse effect 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

Gabapentin may also relieve neuropathic pain due to anticancer therapy. 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

Antidepressants are recommended for the management of many types of neuropathic pain.24,47 Antidepressants are also commonly recommended as adjunctive therapy for neuropathic cancer pain, especially for patients with continuous dysaesthesia.3,4,16,17,20 These agents provide analgesia, potentiate the effect of opioids, and reduce depression and insomnia.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, this study was limited by low patient numbers and a relatively short washout period (2 weeks).

Antidepressants for Post-treatment Neuropathic Pain

Antidepressants may be effective for neuropathic pain due to anticancer treatment. One randomized, controlled trial (n = 15) demonstrated that amitriptyline effectively reduced neuropathic pain following treatment of breast cancer, but adverse effects hindered its regular use.66 In contrast,


PAIN MANAGEMENT

another randomized controlled trial in patients with chemotherapy-induced neuropathic pain (n = 44) reported that low-dose amitriptyline (10–50 mg/day) showed a trend for an improvement in neuropathic pain 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 in patients treated with venlafaxine compared with placebo, and adverse effects from venlafaxine were similar to placebo.68

Pre-emptive Analgesia

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 post-mastectomy pain syndrome, a neuropathic pain syndrome. A double-blind, randomized study compared the efficacy of perioperative administration of venlafaxine (37.5 mg/day), gabapentin (300 mg/day) or placebo given for 10 days starting the night before surgery on the development of pain during the 6 months postoperatively.70 Both drugs reduced analgesic requirements following surgery, and at 6 months venlafaxine significantly 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

Anaesthetics may be used as primary therapy for treatment of cancer-associated neuropathic pain in some centres, whereas others use them as second-line agents.4,10 However, there is limited evidence supporting their use for cancer pain. There are a few reports that subcutaneous infusion of lidocaine 10% improved pain refractory to systemic and spinal opiates in patients with terminal malignancy.71 While a systematic review reported that although intravenous lidocaine was effective for non-cancer-related neuropathic pain, it had no effect on cancer-related pain.72 In contrast, a recently published case report concluded that intravenous lidocaine may have a role for severe cancer-related neuropathic pain at the end-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 its adverse effects, ketamine therapy should be instituted by experienced 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 for long-term outpatient management in an opioid-refractory oncology patient.76

Flupirtine, a non-opioid analgesic that acts as a functional NMDA receptor antagonist, showed some benefit in palliative care patients with neuropathic pain due to cancer.77 It may be useful in the treatment of neuropathic pain as an adjuvant to opioids.

V. NSAIDs and Corticosteroids

Although current cancer pain guidelines recommend the use of NSAIDs, there is little evidence supporting their role in treating the neuropathic component of cancer pain. Similarly, evidence supporting the 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

The primary role of capsaicin in neuropathic cancer pain is in post-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 more patients indicated that capsaicin was the more beneficial treatment (60% vs 18% for placebo; P = 0.001).

Lidocaine patches are recommended for the treatment of some types of neuropathic pain, most notably postherpetic neuralgia.24,47 A retrospective 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, in cancer patients with post-surgical incisional neuropathic pain, a double-blind, randomized, cross-over study found that lidocaine 5% patches did not significantly reduce pain intensity ratings compared with 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 interventional therapy, as described below. While there is little data on the role of complementary therapy in the management of neuropathic cancer 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

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 tolerance to systemic medications.10,80,81 Intrathecal administration may minimize systemic absorption and related side effects after administration of higher doses, which may be required for opioid-resistant pain such as neuropathic cancer pain.81 Studies have shown that intrathecal opioids and intraspinal clonidine may be effective in neuropathic cancer pain.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.


PAIN MANAGEMENT

Spinal cord stimulation (SCS) may be effective in a variety of neuropathic pain syndromes.85,86 A systematic literature review showed 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 with refractory neuropathic pain following breast cancer surgery relieved pain and improved quality of life34; however, further studies are necessary to evaluate the effectiveness of radiofrequency treatment in neuropathic cancer pain.

III. Neural Blockade

The literature on neural blockade via anaesthetic infusion to control neuropathic cancer pain shows favourable effects but is limited to case

reports or by small sample sizes, probably because of the specificity of indications for these procedures.35,36 This may indicate a role in neuropathic pain control but highlights the need for careful patient assessment and selection to optimize outcomes.

IV. Neurolysis

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 reducing pain when multiple pain mechanisms are involved.88 However, 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

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About the AuthorsDr Chen is Consultant and Chief of Service, Depart-ment 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 Orthopaedic Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR. Dr Lam is an Honorary Consultant and Honorary Clinical Associate Professor, Division of Neurosurgery, De-partment of Surgery, The Chinese University of Hong 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 Universi-ty of Hong Kong, Prince of Wales Hospital, Hong Kong SAR. Dr Tsoi is a Neurologist and Consultant Physician, Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong SAR. Dr CP Wong is Chief, Integrated Medical Services, and Consultant and Head, Department of Geriatrics, Ruttonjee and Tang Shiu Kin Hospitals, Hong Kong SAR. Dr S Wong is Consultant Anaesthesiologist and Head of the Pain Management Team, Department of Anaesthesiology and Operating Theatre Services, Queen Elizabeth Hospital, Hong Kong SAR.

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A complete list of references can be obtained upon request from the editor.


Gout is the most common type

of crystal-induced arthritis and

is a painful and debilitating

condition. Gout needs to be

correctly diagnosed before it can

be managed by controlling the

underlying hyperuricaemia, and

treating and preventing gouty

attacks.

How How much do you know about gout?

True False 1. Gout is usually monoarticular and commonly affects the first metatarsophalangeal joint.

2. Modest hyperuricaemia (eg, a level below 8 mg/dL) may respond to lifestyle

modification (eg, reducing calories and alcohol intake, and avoiding high-fructose- content fast foods).

3. Allopurinol for gouty arthritis should be stopped whenever the arthritis flares.

4. The crystal associated with the inflammation of pseudogout is monosodium urate.

5. Acute crystal-induced arthritis of a single joint, whether due to calcium

pyrophosphate dihydrate or urate crystals, is not usually associated with fever.

GoutReviews

• Crystal Arthropathies

• Addressing Problems In Gout & Hyperuricaemia

IN FOCUS

see page 207 for answers


IN FOCUS

Crystal ArthropathiesSpencer Ellis, FRCP; G Koduri, MBBS, MRCP

Crystal arthropathies are a diverse group of disorders characterized by deposition of

various minerals in joints and soft tissues leading to inflammation. The patterns of

presentation for different types of crystal arthritis are often characteristic enough to

differentiate them from each other and from other types of inflammatory arthropathies,

but mistakes can be made, leading to delayed or incorrect management. Gout is the

most common of all the crystal arthropathies, and its prevalence and clinical complexity

appear to be increasing. In addition to gout, which is caused by monosodium urate

crystal precipitation, two other main crystal types can be associated with inflammatory

symptoms because of their deposition in and around joints. These are calcium

pyrophosphate dihydrate, which causes pseudogout, and basic calcium phosphate (BCP)

(hydroxyapatite). The most accurate way of diagnosing the common forms of crystal-

associated arthritis is through the identification of specific crystal types in synovial

fluid, although this is less reliable for BCP. Crystal arthritis can cause severe pain, and

management generally revolves around the control of acute flares, followed by

prevention of recurrent episodes, where possible.

Gout

Gout is an ancient and fascinating medical disorder dating as far back as 5th century, when Hippocrates described it as podagra. The term

gout covers a spectrum of clinical presentations, ranging from acute joint inflammation to chronic erosive arthritis, but also including tenosynovitis, bursitis, and subcutaneous urate deposits which are responsible for the appearance of classical tophi. In addition, it encompasses nephrolithiasis, urolithiasis, and resultant chronic renal disease.

Epidemiology of GoutThe prevalence of gout in the UK is about 1–2%,1,2 increasing with age to a peak incidence

Gout is the most common of all the crystal arthropathies.

IN FOCUS


between the ages of 30 and 50 years. Acute gouty arthritis is five times more common in men than in women and seldom occurs in females before the menopause. The prevalence of gout has been reported to have risen threefold in the UK over 20 years of follow-up. This increase is largely the result of factors such as an ageing population, hyper-tension, metabolic syndrome, and hyperlipidaemia.3,4 Obesity, end-stage renal disease and diuretic use are also associated with hyperuricaemia and gout.5

PathogenesisGout is a disorder of purine metabolism characterized by acute, recurrent attacks of arthritis. The precise mechanisms by which monosodium urate (MSU) crystals gain entry into the leukocyte and how leukocytes respond to these crystals are still unclear. Phagocytosis of crystals in the joint initially occurs in synovial lining cells, stimulating a brisk, neutrophil-mediated inflam-matory response. MSU crystals activate caspase-1 and stimulate monocytes and macrophages to produce IL-1 , which has a central role in the patho-genesis of acute gout, setting in motion an inflammatory cascade that involves a variety of other proinflammatory molecules.

Recently, a gene for the transporter

of uric acid in renal proximal tubular cells has been identified, potentially providing a future therapeutic target.

Clinical Presentation and Progression of GoutThe diagnosis of gout is usually based on the clinical presentation, with sudden onset of intense pain, redness, and swelling in a joint. The erythema can be diffuse, often leading to a mis-diagnosis of cellulitis (Table 1), and if inflammation is severe, desquamation of overlying skin can ensue.

Gout is usually monoarticular and the first metatarsophalangeal joint is classically affected in about 75% of cases, causing patients to complain of pain on weight-bearing and impaired mobility. Other typical sites affected, in order of decreasing frequency, are ankle, knee, wrist, elbow, and small joints of the hands and feet. The attacks can be accompanied by fever and, in the elderly, may present with non-specific symptoms including confusion. The duration of an acute attack ranges from a few days to weeks.

It is important to remember that gout can coexist with septic arthritis, highlighting the need for joint aspi-ration when the diagnosis is unclear.

There are three clinical stages of gout: acute gouty arthritis, intercritical gout, and chronic tophaceous gout (Figure 1). The latter can be confused with nodular rheumatoid arthritis or nodal osteoarthritis.

The majority of untreated patients will experience further acute attacks within 2 years, but intervals between the attacks are of very variable duration.

Table 1. Differential diagnosis of crystal arthritis

Figure 1. Picture of tophi.

"It is important to remember that gout can

coexist with septic arthritis"


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InvestigationsBlood Tests

common.

elevated during acute attacks.

normal or raised during a flare.

Synovial Aspiration

on identifying MSU crystals in fluid aspirated from an acutely affected joint.

negatively birefringent when examined under polarized light microscopy.

Microbiology

joint fluid, cultures of joint aspirate and blood are indicated if any sign of systemic toxicity is present.

Figure 2. Radiology of erosive tophaceous gout

Radiology

can be normal or reveal only soft-tissue swelling. Long-standing gout can lead to erosions, typically described as ‘punched out’ lesions (Figure 2).

ManagementThe treatment of gout has two main objectives: immediate relief of the attack and prophylaxis for prevention of recurrences. Prophylactic treatment is usually recommended in patients who have more than two or three gouty attacks per year and in those with tophi or renal stones, and it should be regarded as being lifelong. Traditional therapies aim to reduce the serum urate either by promoting renal excretion or by decreasing urate synthesis. Antihy-peruricaemic therapy should only be commenced once the acute inflam-matory attack has fully resolved.

Asymptomatic hyperuricaemia generally does not require treatment, but attempts should be made to find an association (eg, diuretics) and address co-morbidities. Advising a low-purine diet is prudent.

How Should We Treat Acute Gout?

drugs (NSAIDs) should be commenced immediately and continued for 1–2 weeks if there are no contraindications. Indomethacin 75 mg twice daily and etoricoxib 90–120 mg once daily are both effective agents for acute attacks, but other NSAIDs can be used at their maximum recommended dose. The dosage should be reduced after 48 hours where possible. Gastro-pro-tective cover should be considered, particularly when using high-potency NSAIDs such as indomethacin, as there is a greater risk of gastrointestinal toxicity compared with newer cyclo-oxygenase-2 inhibitors.

gouty arthritis, but previously recom-mended higher doses are often poorly tolerated owing to diarrhoea. A dose of 500 µg twice daily will frequently suffice for both acute and maintenance therapy. The duration of use will vary depending on the clinical situation; it can be continued for up to 6 months, although longer-term use can be asso-ciated with toxicity. Colchicine must be used with caution in patients with

"Antihyperuricaemic therapy should only be

commenced once the acute inflammatory attack has

fully resolved"

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renal and liver disease or patients undergoing dialysis.

are highly effective in monoarticular disease where infection has been excluded, at a dose of between 40 and 80 mg of methylprednisolone acetate.

-costeroids are useful in polyarticular disease and where patients are intolerant to NSAIDs or refractory to other treatments. An oral dose of pred-nisolone 10–15 mg daily for 5–7 days, or 80–120 mg methylprednisolone acetate as an intramuscular injection can be used.

Non-pharmacological Treatment and Lifestyle Modification

mass index > 35, the risk of gout is increased. Reduction to ideal body weight should be encouraged.

rich foods, such as offal, red meat, shellfish and yeast extracts, should be avoided. Such dietary restriction alone is, however, seldom adequate in controlling gout and should generally complement the use of antihyperuri-caemic drugs.

encouraged to drink 2 litres of water or

Table 2. What to say to patients with gout

binge drinking

considered as lifelong

particularly during an acute attack

colchicine available at home to begin immediately at the onset of an attack

where possible

more per day.

be avoided or significantly reduced as regular daily use may potentially double the risk of attacks. Moderate wine intake does not appear to increase the risk of gout (Table 2).

Treating Chronic and Recurrent GoutThe aim is to prevent joint destruction and disability. Recommendations from the European League Against Rheumatism state that reducing and maintaining SUA below 360 µmol/L (6 mg/dL) will achieve this most effec-tively,6 although other guidelines have set an even lower target, of below 300 µmol/L.7

Indications for Urate-lowering Therapy

chronic gouty arthritis.

subchondral bone.

nephrolithiasis.Allopurinol: the current drug of

choice to prevent gout is allopurinol,

Patients with gout should be encouraged to attain an ideal body weight.


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tolerated, corticosteroids intramus-cularly or even orally can prove useful.

Uricosuric agents: indicated in patients who are under-excretors of uric acid or intolerant of allopurinol. They promote renal clearance of uric acid, but drugs such as probenecid have limited suitability in renal impairment. Sulphinpyrazone or benzbromarone are suitable alternatives in patients with mild renal insufficiency.

Newer TherapiesFebuxostat is a thiazolecarboxylic acid derivative and is an effective alternative to allopurinol. Research has shown that subjects who failed to respond to allopurinol were successfully treated with febuxostat. It is better tolerated in

a xanthine oxidase inhibitor that inac-tivates the enzyme both directly and via its active metabolite, oxypurinol. As a result, urate production falls. The starting dose should be 50–100 mg/d, with increments of 50–100 mg every few weeks or until SUA is below 360 mmol/L. The standard maintenance dose is 300 mg daily, but higher doses can be required while lower doses of 100–200 mg daily are preferable in renal failure. Adverse effects include rash, cytopenias, diarrhoea, fever, gas-trointestinal upset and, less commonly, vasculitis and interstitial nephritis. Allopurinol hypersensitivity syndrome is a rare but potentially fatal reaction in less than 0.1% of patients. It is more likely to occur in those with renal insuf-ficiency and manifests as erythematous rash, fever, hepatitis, eosinophilia, and acute renal failure.

Allopurinol is recognized to pre-cipitate acute gout on initiation of therapy. Co-prescription of NSAIDs or colchicine 500 µg 12-hourly, should be commenced 1–2 weeks before starting allopurinol and continued for between 2 and 6 months, dependent on the response and adverse effects. Where these drugs are contraindicated or not

What’s new?

Inst itute for Health and Clinical

where allopurinol is contraindicated or not tolerated

form and has potential value in refracto-ry gout; however, current infusion prepa-rations have clinical limitations

active gout that is difficult to control with other drugs

mild-to-moderate renal insufficiency and appears to have superior efficacy as urate-lowering therapy.8

The discovery that MSU crystals induce IL-1 release within the joint, which may have a key role in the inflammatory cascade, has led to trials of newer biological agents. Anakinra, an interleukin-1 receptor antagonist, is currently of particular interest.

Uricase, an enzyme that converts urate to the more soluble allantoin, is being studied as a potential treatment for refractory gout. The enzyme is absent in humans and has led to the development of recombinant uricases. The value of current preparations may be limited by the need for frequent infusions, but there is a role in tumour lysis syndrome.9

Follow-upSerum urate should be measured 3-monthly in the first year after the start of treatment with urate-lowering therapy, then annually.

The single most important risk factor for developing recurrence is a raised SUA. Evidence shows that the 5-year cumulative risk of developing gout is 30.5% in men with an SUA >

"Febuxostat is . . . an effective alternative to

allopurinol"

The single most important risk factor for developing recurrence of gout is elevated serum uric acid levels.

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which in itself is not associated with acute inflammation. The arthritis of pseudogout occurs because of crystal shedding from the cartilage into the synovial cavity. Mediators for the inflammatory reaction have not been well studied but could be similar to gout.

Epidemiology of PseudogoutThe prevalence of pseudogout increases with age from about 15% in those aged 65–74 years, rising to around 45% in patients older than 85 years. It is slightly more common in females. The annual incidence of acute attacks of arthritic pain and swelling is about 1.3 per 1,000 adults, despite nearly half of adults developing radiographic

changes typical of CPPD by age 80 years.

Clinical Presentation of PseudogoutThe attacks are abrupt in onset and similar to gout but less dramatic. Commonly affected joints are the wrists, shoulders, and ankles. Attacks are self-limiting, lasting a few days to weeks, and are usually superimposed on degenerative osteoarthritis. Elderly patients can present with confusion, fevers, and constitutional symptoms. CPPD crystals are iden-tified as weakly positively birefringent and rhomboid-shaped. Patients who have an initial attack of arthritis with CPPD crystals should have a targeted work-up including a chemistry screen,

590 µmol/L and only 0.6% in those with an SUA < 420 µmol/L.

Pseudogout

PathogenesisThe aetiology of calcium pyro-phosphate dihydrate (CPPD) deposition and pseudogout is multi-factorial. Invariably, no clear cause is found, but it can be associated with metabolic disorders, surgery or trauma. Underlying disorders should always be considered, particularly in younger patients.

CPPD crystal deposition in fibrocartilage is commonly seen in degenerative joints. It can result in cal-cification known as chondrocalcinosis,

The attacks in pseudogout are similar but less dramatic than in gout, and pseudogout commonly affects the joints in the wrists, shoulders, and ankles.


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About the AuthorsSpencer Ellis is a Consultant Rheumatologist and General Physician at the Lister Hospital, Stevenage, UK. G Koduri is currently a Clinical Research Fellow at West Hertfordshire NHS Trust, UK.

© 2010 Elsevier Ltd. Initially published in Medicine

2010;38(3):146–150.

Practice points

attack of gout

be very helpful in terminating acute episodes of crystal arthritis

initiating allopurinol

always be considered where infection

magnesium, calcium, iron, and thyroid function tests (Table 3).

Management of PseudogoutAcute attacks can be managed similarly to gout, but no prophylactic regimen for patients with idiopathic pseu-dogout is known. Episodes usually subside within 10 days, and prognosis for resolution is excellent.

If an underlying metabolic problem is found, the arthritis may resolve when the disorder is addressed.

for an acute attack, usually continued for 1–2 weeks.

corticosteroid are effective in monoar-thritis or intolerance to NSAIDs.

evidence-based.

oral corticosteroids can be helpful when NSAIDs are contraindicated and symptoms are severe.

Basic Calcium PhosphateThe origin of basic calcium phosphate (BCP) (hydroxyapatite) crystals is not fully understood, but hydroxyapatite crystals are associated with severe osteoarthritis and destructive arthrop-athies. Milwaukee shoulder is a rare arthropathy that affects mainly elderly

women and is characterized by intra-articular or periarticular hydroxyapatite crystals, leading to rapid destruction of the rotator cuff and the glenohumeral joint.

BCP crystals are difficult to identify by light microscopy and can easily be mistaken for artefact or debris.

It is not clear whether BCP crystals are a cause or consequence of osteo-arthritis, but it is known that their concentration increases with the severity of the osteoarthritis. The treatment is similar to that for pseu-dogout.

References1. Mikuls TR, Farrar JT, Bilker WB, Fernandez S, Schumacher

HR Jr, Saag KG. Gout epidemiology: results from the UK Gen-

eral Practice Research Database, 1990–1999. Ann Rheum

Dis 2005;64:267–272.

2. Annemans L, Spaepen E, Gaskin M, et al. Gout in the

UK and Germany: prevalence, comorbidities and manage-

ment in general practice 2000–2005. Ann Rheum Dis

2008;67:960–966.

3. Emmerson B. Hyperlipidemia in hyperuricaemia and gout.

Ann Rheum Dis 1998;57:509.

4. Becker MA, Jolly M. Clinical gout and pathogenesis of

hyperuricemia. In: Koopman WJ, Moreland LW, eds. Arthritis

and allied conditions. 15th ed. Phildelphia: Lippincott, Wil-

liams and Wilkins; 2005:2303.

5. Choi HK, Atkinson K, Karlson EW, Curham G. Obesity,

weight change, hypertension, diuretic use, and risk of gout

in men: the health professionals follow up study. Arch Intern

Table 3. Screening for underlying disorders in pseudogout

CPPD in other metabolic conditions Basic recommended tests

Hyperparathyroidism Ca, phosphate, ALP, PTH

Hypothyroidism TFT, thyroid antibodies

Haemachromatosis Ferritin

Hypophosphatasia ALP, genetics

Hypomagnesaemia Mg, Ca, K+, creatinine

Wilson’s disease LFT, serum/urine copper caeruloplasmin

Ochronosis HGA in urine and blood

Amyloidosis Amyloid protein, biopsy

= parathyroid hormone; TFT = thyroid function test.

Med 2005;165:742.

6. Zhang W, Doherty M, Bardin T, et al. EULAR evidence

based recommendations for gout – Part II Management:

report of a task force of the EULAR Standing Committee

for International Clinical Studies Including Therapeutics

(ESCISIT). Ann Rheum Dis 2006;65:1312–1324.

7. Jordan KM, Cameron JS, Snaith M, et al. British Society

for Rheumatology and British Health Professionals in Rheu-

matology Standards, Guidelines and Audit Working Group

(SGAWG). British Society for Rheumatologyand British Health

Professionals in Rheumatology guideline for the manage-

ment of gout. Rheumatology 2007;46:1372–1374.

8. Schumacher HR, Becker MA, Wortman RL, et al. Effects of

febuxostat versus allopurinol and placebo in reducing serum

urate in subjects with hyperuricemia and gout: a 28-week,

phase III, randomized, double-blind, parallel group trial.

Arthritis Rheum 2008;15:1535–1537.

9. Sundy JS, Ganson NJ, Kelly SJ, et al. Pharmacokinetics and

pharmacodynamics of intravenous PEGylated recombinant

mammalian urate oxidase in patients with refractory gout.

Arthritis Rheum 2007;56:1021.

Declaration of InterestNone.

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Addressing Problems in Gout and HyperuricaemiaPeter A Simkin, MD

In the management of gout, problems regularly arise and treatment results often

are inconsistent and disappointing. Some recurring concerns in its management and

principles that may help lead physicians to more effective disease control are highlighted

in this article.

Gout would seem to be the exemplar of what rheumatologists should aspire to in their understanding and man-agement of rheumatologic disease.

The cause—precipitation of sodium urate crystals—is known, and a diagnostic test—rec-

ognition of those crystals—is pathognomonic. The metabolic pathways of urate production are well understood, and remarkable progress has been made in acquiring knowledge of the transport processes that are involved in renal elimination. Effective therapeutic agents

Gout is a chronic, progressive disease that is managed most effectively when the patient’s serum urate level is reduced to lower than 6 mg/dL by early therapeutic intervention.


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enable physicians to manipulate both the metabolic and the transport sides of urate balance, to reduce tissue urate concentration and, as a result, to eliminate the supersaturation that leads to crystal formation. The classic recurring episodes of disabling pain usually may be avoided or controlled with use of effective anti-inflammatory agents.1–3

Despite this solid theoretical foun-dation, problems regularly arise and treatment results often are inconsistent and disappointing. In this article, I consider some recurring concerns in gout management and suggest prin-ciples that may help lead physicians to more effective disease control (Table).

Complacency

Gout is one of the most painful afflictions of human joints and can be one of the most destructive. However, many patients and physicians consider it a minor inconvenience or even a wry joke. The gouty toe, like the stubbed toe, is seen as a nuisance to be endured with the certainty that a full recovery is not far off. That is not the case.

Gout is a chronic, progressive disease, although the rate of progression varies widely. So long as hyperuri-caemia persists, the crystals that once may have fired an acute, polymorph-mediated arthritic ‘flare’ will remain in the joint, where they then may feed a more subtle, but far more destructive, macrophage-mediated invasion.4 Then, the effects of these crystals will be amplified silently as they recruit addi-tional crystals, ultimately forming a ‘urate icing’ over articular structures and tophi in juxta-articular tissues. By the time that tophi become apparent on examination or detectable with imaging, far more extensive micro-scopic deposition is almost certain to have long been in progress.5 This is

the process that destroys joints, may lead to major renal impairment, and greatly complicates subsequent efforts to control the hyperuricaemia.

Currently, however, there is no method that permits detection of these subtle deposits and gauging of their rate of progression. That rate may be glacially slow at the onset, when recurrent attacks are rare or not apparent. Frequent episodes (2 or 3 in a 1-year period) almost certainly signify progression.

Knowing the baseline serum urate level helps. Modest hyperuricaemia (eg, a level below 8 mg/dL) usually

reflects a gouty course that moves slowly and may respond to ‘lifestyle’ interventions (eg, reducing calories and alcohol intake and avoiding high-fructose-content fast foods).6,7 Conversely, when acute arthritis occurs in the presence of severe hyperuri-caemia (eg, a serum urate level above 10 mg/dL), gout almost certainly is progressing.

Assessment of progression is fun-damental to the commitment to long-term hypouricaemic therapy. A patient who has experienced repeated episodes or has a high urate concen-tration or both must understand his or her risk and, with disease progression, the decreasing chances of satisfactory control.

A trial of febuxostat studied 760 patients with hyperuricaemia and gout.8 Their average serum urate level was 9.8 mg/dL, and the average disease duration was 12 years. One-third of the study patients had renal disease, and many other candidates were rejected because they had serum creatine values greater than 1.5 mg/dL. Tophi were rec-ognized in one-fourth of the patients,

Table. Goals in gout management

Consider the conservative course: Well-taught, motivated patients may control their hyperuricaemia and, therefore, their early disease with a modified diet and altered medication regimens.

Confirm the crystals: Classic gout may be unmistakable, but the disease also may be subtle, insidious, and confused with other forms of arthritis. Demonstration of crystals removes all doubt.

Dissolve deposits:7 mg/dL. Aim for a level lower than 6 mg/dL.

Prepare for the flare: Effective (and desirable) dissolution of urate deposits carries a

contingency plans for attacks that break through this shield.

Conserve the kidneys: Progressive renal impairment happens often and limits therapeutic options. Consider evidence of such progression an indication for control of hyperuricaemia.

Persevere: Gout can be controlled, but it rarely is cured. Patients need regular surveillance to

“Gout is one of the most painful afflictions

of human joints and can be one of the most

destructive”

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and many others had experienced kidney stones.

Each patient who meets these criteria represents a failure of the current standard of care. The major problems that the patients expe-rienced when effective hypouricaemic therapy caused repeated gouty flares document the difficulties of delayed intervention. Earlier, more aggressive treatment of hyperuricaemic patients with gout should go far to prevent younger patients from reaching this state. Evidence of worsening renal function in these patients also should weigh heavily in therapeutic decision making.

Lack of Crystal Confirmation

Despite the pathognomonic value of urate crystal recognition, many patients never experience a diagnostic arthro-centesis. In part, this reflects arthritis at sites, such as the midfoot, where aspi-

ration is difficult. More often, however, the omission results from physician reluctance to exacerbate patient suffering with an ‘unnecessary’ ordeal.

Aspiration of the acutely painful gouty joint provides the most immediate relief that any physician can offer. The procedure decompresses the distended joint capsule, and the decompression is sustained through the venting needle path.

Knowledge of this pain relief steels physician resolve and patient acceptance. In addition, the procedure permits use of stains and cultures for identifying possible infectious agents and polarizing microscopy for con-firming the presence of crystals in the aspirate. Then, the procedure estab-lishes an unequivocal diagnosis before the patient and his physician embark on a therapeutic journey that carries risk in itself and, usually, is lifelong.

There is room for judgment. It remains reasonable to proceed on the

basis of the clinical diagnosis alone when the pain is not severe, the patient is known to be hyperuricaemic, and identical episodes have come and gone before. When a panel of experts charac-terized a series of consecutive patients who had gout, about 50% of their new diagnoses were based on recognition of aspirated crystals.9 That percentage seems about right.

The value of crystal identification does not diminish as the disease pro-gresses. Crystal examination is essential in sorting out patients whose gouty arthritis has been misdiagnosed as another rheumatologic disease (eg, long-standing polyarticular gout often is mistaken for rheumatoid arthritis and tophi are interpreted as rheumatoid nodules). Whenever ‘rheu-matoid’ disease is atypical (eg, there is little or no rheumatoid factor, joint involvement is asymmetrical, or the patient is unresponsive to metho-trexate), the basic diagnosis should be

out patients whose gouty arthritis has been misdiagnosed as another rheumatologic disease.


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reconsidered. A diagnostic aspiration with a crystal examination becomes a fundamental part of that process.

Bear in mind that osteoarthritis confers an increased risk of gout in any peripheral joint. Therefore, bunions of the great toes and Heberden nodes of the distal interphalangeal joints of the hands indicate sites of special risk of gout. Consideration of possible gouty arthritis is warranted by flaring, episodic inflammation of these sites, or the acute arrival of a painful effusion in a knee that is known to have chronic degenerative disease. Osteoar-thritis rarely is a reasonable alternative diagnosis, but often it is a helpful sup-porting finding in the search for gouty joints. Again, a simple diagnostic aspi-ration may provide confirmation.

Starting Allopurinol for Gouty Arthritis

To many physicians, a simple train of logic continues to make sense: (1) Allopurinol is the most effective drug for gout; (2) My patient has gout; and (3) I had better start my patient on allopurinol. What could be wrong with that?

The answer is that allopurinol manages hyperuricaemia but initially is bad for gouty arthritis. When any drug lowers the serum urate level below 6 mg/dL, the extant deposits of urate crystals begin to be mobilized. As it is freed, the crystal that was relatively inert in its tophus appears to shed its pro-tective coating of plasma proteins10,11; then, it regains its full potential to promote inflammation. When mobi-lization of additional crystals occurs in the presence of active, crystal-driven arthritis, it simply adds fuel to the fire.

Therefore, the most appealing strategy is to put out the fire by using whichever anti-inflammatory agents are needed, then establish ongoing prophylaxis and, finally, control the hyperuricaemia under that prophy-lactic protection. This way, the fuel can be removed without igniting another fire.12 The task is fraught with danger and it does not always succeed, but it remains the best available plan.

Stopping Allopurinol for Gouty Arthritis

If effective doses of allopurinol release crystals and those crystals then drive

arthritis, should the drug be stopped whenever the arthritis flares? Doing so makes sense in theory. In practice, however, many patients with chronic disease go through frequent flares—some less severe than others—and there never seems to be a perfect time.

In this situation, it has seemed most appropriate to begin with a small dose and build gradually to a consistent, effective level while avoiding the yo-yo effect of frequent on-and-off periods. All too often, the drug is stopped for a flare, the physician and patient both conclude that the flare means that allopurinol was not a good choice, and the drug is not resumed. That patient’s disease will progress, and any future hypouricaemic agent will cause the same complication.

Therefore, a programme that emphasizes consistency best serves the long-term interests of most patients. This means staying with the estab-lished dose of allopurinol even though that dose has demonstrated its effec-tiveness by mobilizing enough crystals to induce a flare.

Allopurinol Dosage Fixed at 300 mg/d

The proper dosage of allopurinol is not 300 mg/d but rather the amount needed to control hyperuricaemia. In most patients, this means a target serum concentration of less than 6 mg/dL, although many rheumatol-ogists aim for less than 5 mg/dL when extensive crystalline deposits need to be mobilized. I usually start the dosage at 100 mg/d and increase it by monthly increments of 100 mg/d while moni-toring the serum urate level until the necessary dosage has been established. With renal disease or massive tophi (Figure), using 50 mg as both the starting dosage and the amount of each increment may be the wisest.

Allopurinol manages hyperuricaemia but initially is bad for gouty arthritis.

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Figure. Even the largest tophi may be dissolved with use of appropriate medication and with sufficient perseverance. The hands of a patient with gout who required both allopurinol and probenecid to maintain his serum urate level at 4 mg/dL are seen (a) before and (b) after 7 years of treatment.

a

b


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Unless the patient pushes for more rapid control, there is no reason to hurry. Essentially, every patient with gout has been hyperuricaemic for many years and no regimen will change his situation overnight. This unhurried approach is taken in the belief that (with concurrent colchicine prophylaxis) it lessens the probability of arthritic flares. That hypothesis has not been confirmed experimentally, however, and it may be found that a more aggressive hypouricaemic course (as may become possible with pegylated uricase preparations) may lead to less overall morbidity.13

In practice, the eventual allopurinol dosage often turns out to be 400 mg/d or more.14 Higher baseline levels and long-standing disease usually imply a higher ultimate dosage; modest hyper-uricaemia of recent onset is easier to control.

The need to normalize serum urate concentrations applies to patients who have impaired renal function as well as to those whose kidneys are normal. The rare but rightly feared complication of severe hypersensitivity occurs more often when the kidneys are impaired; this complication almost certainly is the result of the renal retention of oxypurinol, the major metabolite of allopurinol.15 Oxypurinol also is the effective agent, however, and renal retention may mean that less drug is required. Often, 200 mg handles the problem well; no patient should receive more than he needs. Also, in theory, no patient should receive less than the needed amount.

A problem occurs when the dosage is increased (occasionally to as much as 800 mg/d) and hyper-uricaemia persists. This situation may reflect patient non-compliance, which may be tested by measuring the blood oxypurinol level. If no oxypurinol is present, the allopurinol is not being

taken. If the oxypurinol concentration is high (eg, greater than 150 µmol/L), the allopurinol is being taken and there is no present solution, although the addition of probenecid may help control hyperuricaemia in patients with normal renal function. When the kidneys are damaged, however, such patients and their physicians now wait in hope that a new agent, such as febuxostat, ultimately will control their hyperuricaemia.8

Misuse of Colchicine (Acute)

Darwin might have predicted that over centuries of use, regimens for colchicine would have evolved to a comfortable consensus programme that affords maximal benefits with minimal toxicity. That does not seem to have happened. Instead, this valuable but noxious agent has been overused (in the traditional regimen of hourly doses to the point of gastrointestinal [GI] toxicity), compounding the misery of acute gouty arthritis. At the same time, colchicine prophylaxis for gouty flares has been underused and withheld by clinicians who are overly concerned about marrow suppression.

After GI absorption, colchicine moves rapidly into cells, as dem-onstrated by a 2 L/kg volume of

distribution. Because of this intra-cellular localization, plasma half-lives and concentrations are of little interest to clinicians. Within polymorpho-nuclear leukocytes, colchicine fights inflammation by inhibiting white cell recruitment to sites of crystallization.16

Conversely, intracellular concentration of colchicine in the marrow, nerves, and muscle presumably is responsible for potential toxicity in those organs. Ultimately, both the liver and the kidney participate in elimination of colchicine. Disease in either organ can potentiate its positive and negative properties; therefore, disease in either organ is a reason for caution.17

A useful regimen of colchicine for acute gouty arthritis is an initial 1.2-mg dose followed by another 1.2 mg after 3 to 4 hours and a final 0.6-mg dose at bedtime. Either or both of the latter doses may be lowered or withheld in the event of GI distress or liver disease, or if the patient is unusually small. This regimen (adapted from that used widely in France18) is effective when it is used early, although many clinicians prefer to start with non-steroidal anti-inflammatory drugs (NSAIDs) (if renal function is normal) or corti-costeroids (when the kidneys cause concern). Intra-articular corticosteroid suspensions are the agent of choice for monarticular gouty arthritis in an accessible joint; this is particularly true when the attack is well estab-lished (2 or more days), the evolving cascade of inflammation has filled the articular cavity with a ‘cytokine soup’, and no oral option is likely to result in dramatic improvement.

Misuse of Colchicine (Chronic)

The second widely endorsed appli-cation of colchicine is its use as prophylaxis against repeated attacks.12 Experience with both allopurinol and

“The proper dosage of allopurinol is not

300 mg/d but rather the amount needed to

control hyperuricaemia”

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febuxostat shows that as little as 0.6 mg/d dramatically reduces this com-plication of effective hypouricaemic therapy.8,19 Higher doses have not been studied as carefully, but they are used frequently, especially in some of the very large men who have gout.

Toxicity may occur in the form of more frequent stools (a feature often welcomed by constipated patients), neuromyopathy, and myelosup-pression. Because both the liver and the kidney participate in the clearance of colchicine, concurrent disease in either organ increases the risk of toxicity. These risks also are enhanced by cyclo-sporine therapy in gouty recipients of transplants.17

All patients should be aware that their physician wants to know about new paraesthesias or weakness. Blood cell counts (especially the white blood cell count) should be monitored peri-odically. However, rheumatologists are experienced in managing drug-induced myelosuppression; perhaps they should consider the example of familial Mediterranean fever, in which colchicine routinely is recommended more aggressively for maximal thera-peutic benefit (even in patients who have renal impairment).20

One major concern about colchicine prophylaxis stems from its effectiveness. When the classic attacks of acute gouty arthritis are ‘swept under the rug’ by colchicine suppression, chronic crystal precipitation may progress out of sight and beyond the reach of the exam-iner’s hand. This subtle process may lead to tophi, articular damage, and nephropathy, making treatment far more difficult. Without the warning of sentinel attacks, irremediable injury then takes place while the patient and his physician assume that the problem is under control. Therefore, daily pro-phylaxis is best reserved for control of drug-induced arthritic flares in

patients whose hyperuricaemia is being managed with effective hypouricaemic therapy.

Disease Flares During Hypouricaemic Therapy

When probenecid was introduced, it rapidly became apparent that lowering the patient’s serum urate concentration leads directly to increasing episodes of gouty arthritis.21 This seeming paradox has been confirmed with the use of each subsequent effective agent, including allopurinol, febuxostat, and

pegylated uricase.8,13,19 Such flares are provoked by the decreasing urate con-centration and not by the drug itself. Therefore, the many patients with gout who have stopped effective therapy in the hope that some new hypouri-caemic agent will avoid this problem almost certainly are destined to wait in vain.

Since the early observations of van Leeuwenhoek, it has been known that gouty tophi are masses of crystals. However, these aggregates rarely cause inflammation. Therefore, it came as a surprise when McCarty and Hollander22

Progressive renal impairment often occurs in patients with gout, so one of the goals in gout management is to conserve the kidney through control of hyperuricaemia.


IN FOCUS

incontrovertibly established that these same crystals of monosodium urate monohydrate induce the dramatic inflammation of classic gouty arthritis.

Subsequent studies from the laboratories of Terkeltaub et al and of Ortiz-Bravo et al explained this dichotomy by showing that the bio-logically inert crystals of a tophus are coated with an insulating layer of plasma proteins that largely prevents them from activating those cells involved in the acute inflammatory response.10,11 As those crystals begin to dissolve in response to a reduced urate concentration, the protective coating appears to be lost and the mobilized crystals regain their phlo-gistic potential. It is this ‘strip mining’ of existing crystals, not formation of new ones, that leads to the therapy-induced flare.

Each physician who prescribes ther-apeutic agents must be aware of this risk and do his utmost to prepare each patient for the real possibility that his gouty arthritis may become tran-siently worse. Part of this preparation is co-prescription of colchicine as a prophylactic agent. The patient also should know that flares may still break through this prophylaxis and, therefore, have a contingency plan, keeping in his mind and in his medicine cabinet the NSAID (with good kidneys) or the corticosteroid that he will use at flare outset. Gouty arthritis becomes less responsive by the hour; patients should not have to wait until they see their physician before they start therapy.

A few patients who have gout—virtually always those with extensive tophi—refuse effective therapy because of recurrent or continuous arthritis or both. Such patients accept progressive, destructive disease because—alone or in combination—the current anti-inflammatory tools of colchicine, NSAIDs, and corticosteroids do not

provide adequate control of flares. The existence of these patients should mandate aggressive investigations of new strategies for relief of intractable gouty arthritis. At present, the most promising candidates would seem to be the biologic agents that have now become standard weapons in the armamentarium of every practicing rheumatologist.

Disrespect for Uricosuric Therapy

Although many patients with gout may attain and maintain target serum urate levels with probenecid,21 this drug rarely is used in the United States. In large part, this reflects an effort to use the simplest possible regimen (once-daily allopurinol rather than twice-daily probenecid) and, therefore, optimize long-term compliance.

In addition, many patients with gout have renal impairment that precludes effective uricosuric therapy. The apparent reason is that probenecid (as well as sulfinpyrazone, benz-bromarone, and losartan) is highly protein-bound and therefore bypasses

glomerular filtration.23 The drug then must be secreted into the renal tubule before it can begin to inhibit the URAT1 transporter responsible for urate reab-sorption. This secretory process is compromised disproportionally by renal impairment; therefore, the uri-cosuric agent is not effective because it does not reach its intratubular target.24,25

However, some patients—often those who are already taking medications several times a day for concurrent problems—can adhere faithfully to a twice-daily regimen. When such patients have adequate renal function (particularly when they fear the rare problem of severe allo-purinol hypersensitivity), use of a dose of probenecid sufficient to keep the serum urate level below 6 mg/dL is perfectly appropriate.

Uricosuric therapy is appropriate for early, intermittent gout. However, allopurinol remains a better choice for patients who have tophaceous gout, renal stones, or a high rate of urinary uric acid excretion.

Disregard for Renal Problems

Renal impairment continues to figure prominently in the illness of at least half of patients with gout; kidney failure was cited as the cause of death in 20% of patients.26 However, little work has been done in progressive urate nephropathy, and little is known about it. Hypertension and diabetes mellitus both contribute to this complex and multifactorial problem, but neither factor accounts for the medullary crystals of urate that remain demonstrable when autopsy specimens are obtained and preserved in absolute alcohol.27,28 These precipitates are associated with infiltrates of inflam-matory cells and seem likely to lead to a significant loss of nephrons.29

“Each physician who prescribes therapeutic agents must . . . do his utmost to prepare each

patient for the real possibility that his gouty

arthritis may become transiently worse”

IN FOCUS


About the AuthorDr Simkin is emeritus professor of medicine in the division of rheumatology at the University of Washington in Seattle, USA. This article, based on a presentation he gave at the Hospital for Special Surgery in New York City, was first published in 2006 in The Journal of Musculoskeletal Medicine.

Such attrition of nephrons has been recognized increasingly as a cause of hypertension as well as of chronic renal failure.30

Intriguing animal work and epi-demiological analysis suggest that additional injury may ensue from hyperuricaemia.31 Therefore, both the crystalline solid and the solute in solution may contribute to renal injury. Currently, whether effective control of hyperuricaemia will stay or reverse the course of this complication is not known definitively.

Past renal concerns have focused on the recognition and reversal of uric acid overexcretion. With each passing decade, it became more apparent that the true overexcretor is rare. Fewer than 5% of all persons with gout truly overexcrete uric acid, but those who do should be identified to permit proactive handling of their renal risk and to allow for effective genetic counselling and surveillance for family members who may share that risk.

The simplest way to screen for this problem is to measure the rate of uric acid excretion per unit of glo-merular filtration rate in a spot urine sample. This useful measurement can be determined by calculating the product of urinary uric acid level and the plasma creatinine level divided by the urinary creatinine level.

References1. Terkeltaub RA. Clinical practice: gout. N Engl J Med

2003;349:1647–1655.

2. Choi HK, Mount DB, Reginato AM, et al. Pathogenesis of

gout. Ann Intern Med 2005;143:499–516.

3. Schlesinger N. Management of acute and chronic gouty

arthritis: present state-of-the-art. Drugs 2004;64:2399–

2416.

4. Pascual E, Batlle-Gualda E, Martinez A, et al. Synovial fluid

analysis for diagnosis of intercritical gout. Ann Intern Med

1999;131:756–759.

5. Weinberger A, Schumacher HR, Agudelo CA. Urate crystals

in asymptomatic metatarsophalangeal joints. Ann Intern Med

1979;91:56–57.

6. Nakagawa T, Hu H, Zharikov S, et al. A causal role for uric

acid in fructose-induced metabolic syndrome. Am J Physiol

Renal Physiol 2006;290:F625–F631.

7. Dessein PH, Shipton EA, Stanwix AE, et al. Beneficial

effects of weight loss associated with moderate calorie/

carbohydrate restriction, and increased proportional intake

of protein and unsaturated fat on serum urate and lipo-

protein levels in gout: a pilot study. Ann Rheum Dis

2000;59:539–543.

8. Becker MA, Schumacher HR Jr, Wortmann RL, et al.

Febuxostat compared with allopurinol in patients with hyper-

uricemia and gout. N Engl J Med 2005;353:2450–2461.

9. Wallace SL, Robinson H, Masi AT, et al. Preliminary criteria

for the classification of the acute arthritis of primary gout.

Arthritis Rheum 1977;20:895–900.

10. Terkeltaub RA, Dyer CA, Martin J, Curtiss LK. Apolipopro-

tein (apo) E inhibits the capacity of monosodium urate crys-

tals to stimulate neutrophils: characterization of intraarticular

apo E and demonstration of apo E binding to urate crystals in

vivo. J Clin Invest 1991;87:20–26.

11. Ortiz-Bravo E, Sieck MS, Schumacher HR Jr. Changes

in the proteins coating monosodium urate crystals during

active and subsiding inflammation: immunogold studies of

synovial fluid from patients with gout and of fluid obtained

using the rat subcutaneous air pouch model. Arthritis Rheum

1993;36:1274–1285.

12. Wortmann RL. Effective management of gout: an anal-

ogy. Am J Med 1998;105:513–514.

13. Ganson NJ, Kelly SJ, Scarlett E, et al. Control of hyper-

uricemia in subjects with refractory gout, and induction of

antibody against poly(ethylene glycol) (PEG), in a phase I

trial of subcutaneous PEGylated urate oxidase. Arthritis Res

Ther 2006;8:R12.

14. Perez-Ruiz F, Alonso-Ruiz A, Calabozo M, et al. Efficacy of

allopurinol and benzbromarone for the control of hyperuri-

caemia: a pathogenic approach to the treatment of primary

chronic gout. Ann Rheum Dis 1998;57:545–549.

15. Hande KR, Noone RM, Stone WJ. Severe allopurinol toxic-

ity: description and guidelines for prevention in patients with

renal insufficiency. Am J Med 1984;76:47–56.

16. Levy M, Spino M, Read SE. Colchicine: a state-of-the-art

review. Pharmacotherapy 1991;11:196–211.

17. Simkin PA, Gardner GC. Colchicine use in cyclosporine

treated transplant recipients: how little is too much? J Rheu-

matol 2000;27:1334–1337.

18. Rozenberg S, Lang T, Laatar A, et al. Diversity of opinions

on the management of gout in France: a survey of 750 rheu-

matologists. Rev Rhum Engl Ed 1996;63:255–261.

19. Borstad GC, Bryant LR, Abel MP, et al. Colchicine for pro-

phylaxis of acute flares when initiating allopurinol for chronic

gouty arthritis. J Rheumatol 2004;31:2429–2432.

20. Onen F. Familial Mediterranean fever. Rheumatol Int

2006;26:489–496.

21. Mason RM. Studies on the effect of probenecid (ben-

emid) in gout. Ann Rheum Dis 1954;13:120–130.

22. McCarty DJ, Hollander JL. Identification of urate crystals

in gouty synovial fluid. Ann Intern Med 1961;54:452–460.

23. Fanelli GM Jr. Uricosuric agents. Arthritis Rheum

1975;18:853–858.

24. Guerrini VH, Filippich LJ, English PB, et al. Pharma-

cokinetics of cefotaxime and probenecid in sheep with

normal and reduced renal function. J Vet Pharmacol Ther

1984;7:283–291.

25. Kamilli I, Gresser U, Pellkofer T, et al. Uricosuric effect of

irtemazole in hyperuricemic patients without and with renal

insufficiency. Z Rheumatol 1989;48:307–312.

26. Rosenberg A. Bones, joints and soft tissue tumors. In:

Kumar V, Abbas A, Fausto N, eds. Pathologic Basis of Disease.

7th ed. Philadelphia: Elsevier; 2005:1311–1314.

27. Talbott JH, Terplan KL. The kidney in gout. Medicine

(Baltimore) 1960;39:405–467.

28. Simkin PA, Bassett JE, Lee QP. Not water, but formalin,

dissolves urate crystals in tophaceous tissue samples. J Rheu-

matol 1994;21:2320–2321.

29. Sokoloff L. The pathology of gout. Metabolism

1957;6:230–243.

30. Zandi-Nejad K, Brenner BM. Primary and second-

ary prevention of chronic kidney disease. J Hypertens

2005;23:1771–1776.

31. Mazzali M, Hughes J, Kim Y, et al. Elevated uric acid

increases blood pressure in the rat by a novel crystal-inde-

pendent mechanism. Hypertension 2001;38:1101–1106.

© 2011 UBM Medica LLC. Initially published in The

January

2011;28(1):23–33.

Answers to questions on page 191: 1. F, 2. T, 3. T

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Role of Tocotrienols in CVD and Role of Tocotrienols in CVD and Metabolic SyndromeMetabolic SyndromeAnusuya Gehlot, Nita Trehan

Abstract

We are currently facing a "slow motion disaster" which is silently affecting people in

the prime of their working lives. The risk of heart attacks cannot be reversed. It's not just genetics, but lifestyle factors that are responsible for this increase in the incidences. For nearly a decade, tocotrienols have gained importance in the prevention of car-diovascular disease (CVD) due to their powerful anti-atherogenic, oxidative stress reducing, anti inflammatory and cholesterol lowering properties. Toco-trienols are also finding a place in the prophylaxis of metabolic syndrome (MetSyn). Tocotrienols belong to the class of vitamin E family. Vitamins have been used in the prevention of CVD. Vitamins like Folic acid, B6 and B12 are being used for the reduction in CVD risk by reducing hyperhomo-cysteinemia. Tocotrienols delay the progression of atherosclerosis, offer vasculoprotection and are beneficial in prevention and treatment of CVD. This article reviews the role of tocotrienols in atheroprotection and in the pre-vention of CVD and MetSyn.

IntroductionCVD refers to several diseases that

affect heart and blood vessels which majorly include coronary heart diseases (CHD), stroke, myocardial infarction and hypertension. CVD prevalence in India has risen four fold in the last four decades and already causes 29% of deaths in the country. According to the World Health Organization (WHO) Report, CVD will be the largest cause of death and disability in India by 2020. It is estimated that the overall prevalence of diabetes, hypertension, ischaemic heart diseases (IHD) and stroke is 62.47, 159.46, 37.00 and 1.54 respectively per 1,000 population of India. The incidence of atherosclerosis and CVD is now increasingly seen even in the younger age groups.1 Risk of heart disease can be lowered by addressing the risk factors. Reducing oxidative stress and the role of antihy-perlipidaemic agents is important in the prevention of CVD as they delay the progression of atherosclerosis and thereby provide a therapeutic option in the prevention and amelioration of CVD.

Prophylax i s thus becomes important to prevent CVD. Many such prophylactic agents are available like coenzyme Q10, resveratrol and other vitamins. Vitamins are high flying among natural or endogenous compounds, beneficial to human health and have proven to be effective

in reducing CVD. Vitamins like folic acid, B6 and B12 are being used for the reduction in CVD risk by reducing hyperhomocysteinemia. Tocotrienols are found to be effective in decreasing mortality due to CVD. Tocotrienols, are thus considered to be important therapeutic agents for the prevention and treatment of CVD and MetSyn.

Tocotrienols

Initially discovered in 1938 as a "fertility factor," vitamin E now refers to 8 different isoforms that belong to 2 categories, 4 saturated analogues (alpha, beta, gamma, and delta) called tocopherols and 4 unsaturated analogues (alpha, beta, gamma, and delta) referred to as tocotrienols (Fig. 1).2 Palm oil (Elaeis guineensis) is the largest natural source of tocotrienols (Fig. 2). The other good sources are rice bran oil and coconut oil. The other food sources include cereal grains such as barley, oats and rye.

Role of Tocotrienols in the Prevention of CVD

Tocotrienols have several cardiopro-tective effects; including ability to prevent oxidative stress, preventing the oxidation of low density lipoproteins, inhibiting HMG-CoA reductase (a


rate limiting enzyme in cholesterol biosynthesis), anti-atherosclerotic, suppressing inflammation, inhibiting platelet aggregation and monocyte adhesion and preventing smooth muscle proliferation.3 Tocotrienols play an important role in prophylaxis of MetSyn by lowering triglycerides, lipoprotein a increasing HDL-C and decreasing plaque progression.

Inhibition of Adhesion Molecules by Tocotrienols

In vitro study using human umbilical vein endothelial cells (HUVEC) as the model system has shown that tocot-rienols markedly inhibit the expression of all 3 adhesion molecules (ICAM-1, VCAM-1 and E selectin). NF-kB is a redox sensitive transcription factor known to regulate several molecules involved in atherosclerosis, including ICAM and VCAM. Tocotrienols inhibit expression of adhesion molecule by blocking activation of NF-kB. Due to these multifactorial mechanisms, tocotrienols not only inhibit the pro-gression, but also cause regression of atherosclerosis.

Tocotrienols Delay Atheroprogression

ICAM and VCAM play an important role in the progression of athero-sclerosis by attracting more and more monocytes and T cells into the endo-thelium. By inhibiting the expression of adhesion molecules, progression of atherosclerosis can be halted. In vitro model have proved that inhi-bition of ICAM, VCAM and E selectin by tocotrienols reduce the migration of monocytes and T cells into the intima. These sequential effects inhibit formation of foam cells and thereby the progression of atherosclerosis.

As shown in Fig. 3 tocotrienols

CH3

CH3

O

O

CH3

HOAlpha

Tocotrienols

Delta

H3C

H3C

CH3 CH3 CH3

CH3

CH3

CH3

CH3

HO

H

CH3 CH3 CH3

CH3

O

Gamma

Beta

CH3

CH3

CH3

HO CH3 CH3

CH3

O

CH3

CH3

CH3

HO

H

CH3 CH3 CH3

CH3

Figure 1 : Chemical Structure of Tocotrienols

Fig 2 : Palm Richest source of Tocotrienols

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delay the progression of athero-sclerosis and stand as atheroprotective agents in improving vascular health of the patient by acting on multiple sites in the process of atherosclerosis.12

Tocotrienols Reduce Cholesterol : Inhibit HMG-CoA Reductase

The molecular mechanism for this unique inhibition was ascribed to the ability of tocotrienols prenylated side chain, which induces prenyl pyrophosphate pyrophosphatase that catalyse the dephosphorylation of farnesyl with a concomitant increase in cellular farnesol. Farnesol is a meva-lonate derived product, which signals the proteolytic degradation of HMG- CoA (Fig.4) Conclusively, tocotrienols influence the mevalonate pathway in mammalian cells; by post-transcrip-tional suppression of HMG-CoA reductase (HMGR).

Tocotrienols in Hyperlipidaemic Patients

Combination of citrus flavonoids (270 mg) and tocotrienols (30 mg) for 12 weeks in hyperlipidaemic patients significantly causes reduction in total cholesterol (30%), LDL-C (27%), apo-lipoproteins (21%) and triglycerides (34%). Combination of fruit extracts including tocotrienols is a safe and efficacious option for promoting car-diovascular wellness. Tocotrienols when given to patients with diabetic dyslipidaemia are known to be ben-eficial as they decrease the total cholesterol and LDL-C.

Tocotrienols in Type 2 Diabetic Patients with Hyperlipidaemia

In Type 2 diabetics, the progression of atherosclerosis is more rapid than the general population and 80% of these patients will die of an atherosclerotic

Circulating LDL

Adhesion molecules

Tocotrienol

Intimal LDL Monocyte/Macrophage

Endothelial cells

BloodvesselwallUptake of

Oxidised LDL

Foam CellMacrophageOxidised LDL

1

2

3

Circulating monocyte

Figure 3 : Tocotrienols reduce oxidative stress and foam cells formation by inhibiting oxidation of

LDL-C and by inhibiting expression of adhesion molecules12

+

––

Acetyl CoA

β-Hydroxy-β-methylglutaryl-CoA (HMG-CoA)

HMG-CoA reducatase(HMGR)

Mevalonate

Farnesyl

Squalene

Cholesterol

Tocotrienol

Post-transcriptional

Tra

nsc

rip

tio

nal

Farnesol

Fig. 4 : Mechanism of cholesterol inhibition by Tocotrienols4

45


events. Daily intake of tocotrienols by Type 2 diabetics will be useful in the prevention and treatment of hyperhpi-daemia and atherogenesis.

Lipoprotein A as a Cardiovascular Risk Factor in Indians

Elevated lipoprotein levels can poten-tially increase the risk of CVD • Via prothrombotic/anti-fibri-

nolytic effects as apolipoprotein(a) possesses structural homology with plasminogen and plasmin but has no fibrinolytic activity

• Via accelerated atherogenesis as a result of intimal deposition of lipo-protein cholesterol, or both

Meta analysis has already proven a clear association between elevated lipo-protein levels and increased risk of CVD. Individuals with levels above 50 mg/dL have 2-3 fold risk of myocardial infarction. Therapeutically lowering of apoB in CAD patients has resulted in regression of atherosclerosis. Treatment with tocotrienol can reduce atherogenic apoB 10-15% and can prevent pro-gression of atherosclerosis.

The other treatments for ath-erogenic dyslipidaemia include

fibrates, nicotinic acid, and omega 3 fatty acids.

MetSyn as a Forerunner for CVD

MetSyn is a group of risk factors that occur together and increase the risk of CVD. International Diabetes Fed-eration (IDF) defines MetSyn for Asian Indians as high waist circumference plus any two of the following:• Increased triglycerides• Decrease in HDL-C• Increase in blood pressure and

increase in fasting plasma glucose Recent trial estimates MetSyn preva-

lent in 31.6% of Indian urban popula-tion. The other components of the MetSyn include; systemic inflamma-tion, prothrombotic state, increased oxidative stress, increased circulating levels of inflammatory and other pro-inflammatory cytokines and increased levels of plasminogen activator inhibi-tor 1 (PAI 1). In patients with MetSyn, the risk of atherosclerotic heart diseases increases 2-3 times, the risk of stroke increases 4 times and there is 5 fold increase in diabetes.

Treatment with tocotrienols can reduce atherogenic apoB by 10-15%,

1000

100

10

Veg. oil

5

35

60

1048 1059

Vitamin E EssentialOils

1EGCG/

CatechinsTocotrienols

L-O

RA

C U

nit

s/G

ram

Fig.5 : Oxidative stress reducing agents and their ORAC values

lipoprotein by 171% and triglyc-erides by 34%. Studies have proved that the treatment with tocotrienols rich fraction (TRF) 160 mg/day for 6 months significantly elevates HDL-C by 13% tocotrienols therefore find a place in the treatment of metabolic syndrome by improving lipid profile of the patients.

Plaque Progression

MetSyn accelerates the course of ath-erosclerotic plaque. Tocotrienols are known for their effects on the inhibition of plaque progression. Tocotrienols inhibit plaque pro-gression by inhibiting the expression of adhesion molecules (ICAM and VCAM), monocyte attachment, LDL oxidation as well as smooth muscle proliferation. Therefore, adminis-tration of tocotrienols can be effective in the inhibition of plaque progression in patient with MetSyn.

Tocotrienols Reduce Oxidative Stress

Oxidative stress reducing property of tocotrienols resides mainly with its "chain breaking" property which neu-tralises peroxyl and alkoxyl radicals generated during lipid peroxidation. The oxidative stress reducing values of foods listedare expressed in 'oxygen radical absorbance capacity' (ORAC) units, a unit of measurement for anti-oxidants; developed by the National Institute on Aging in the National Institutes of Health (NIH). Tocot-rienols have ORAC value 1059, which is higher than vegetable oils, vitamin E, essential oil, and epigallocatechin-gallate (EGCG) (Fig.5).

Lastly, lipid peroxidation (LPO) is a marker of oxidative stress. Peroxidation of membrane lipids; modify and inactivate cellular com-ponents which can have damaging

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About the AuthorsDr. Anusuya Gehlot is Associate Professor, Depart-ment of Pharmacology, Dr Nita Trehan is Senior Demonstrator Department of Pharmacology at Dr. S N Medical College, Jodhpur (Rajasthan) India

effects on crucial cellular factors leading to diseases. Treatments with Tocotrienols have shown reduction in LPO. Tocotrienols are also helpful in preventing and possibly reversing of carotid atherosclerosis.

Conclusion

Tocotrienols effectively inhibit cho-lesterol synthesis by reversibly inhibiting HMG-CoA reductase enzyme. Tocotrienols are known to reduce oxidative stress. Tocotrienols effectively inhibit synthesis as well as oxidative modification of LDL-C which is one of the key initial steps in the onset of atherosclerosis. Tocotrienols possess a strong penetration power in cell membranes. Tocotrienols; inhibit expression of adhesion molecules (ICAM 1, VCAM 1 and E selectin) thereby prevents entry of monocytes in arterial intima. By decreasing plasma levels of LDL-C, apoB and lipoprotein. Tocotrienols inhibit massive deposition

in atherogenic lesion. Tocotrienols reduce plasma levels of triglycerides and elevate good HDL-C. All these unique mechanisms of tocotrienols prevent initiation and progression of atherosclerosis. In clinical studies Toco-trienols in the range of 100-200 mg are found to be effective in regression of atherosclerosis. Therefore, Tocotrienols prove to be an effective agent in main-taining vascular health which is most important in CVD patients. In combi-nation 'with statins, Tocotrienols, can be helpful in improving efficacy of statins which was found to be low (25-35%) in prevention of CVD. Toco-trienols effectively address atherogenic dyslipidaemia and plaque progression, hence are effectively used in the pro-phylaxis of the MetSyn. Due to their efficacy and unique mechanisms; Tocotrienols delay progression of ath-erosclerosis, maintain good vascular health and stand as an effective natural agent in prevention and treatment of CVD and MetSyn.

References1. The Times of India. September 28, 2011.

2. Tocotrienols, the vitamin E of the 21st Century : its potential

against cancer and other chronic diseases. Biochem Pharmacol.

2010;80(11): 1613-31.

3. Vasanthi HR, Parameshwari RP, DAS DK. Tocotrienols and its

role in cardiovascular health- a lead for drug design. Curr Pharm

Des 2011;17(21):2170-75.

4. Chin SF, et al. Tocotrienol rich fraction supplementation

improved lipid profile and oxidative status in healthy older

adults: A randomized controlled study. Nutr Metab (Lond) 2011;

24;8(1):42.

In Practice


Case of Haemoglobin Sickle/D-Punjab Disease

Deepak Sharma, Madhulata Agarwal, Vishal Batra, Dinesh Kothari, Sneha AmbwaniCase Report

Case Report

A 23 year old, female patient, presented with history of 8 months of amenorrhoea,

yellowing of eyes and urine since 15-20 days with no history of fever, past trans-fusions or jaundice or pain abdomen. Her elder sister died of anaemia and repeated blood transfusions 6 months back. On examination her vitals were stable, she was pallor and have jaundice with 32 weeks gestation with mild hep-atosplenomegaly.

Blood investigations showed: Hb–7.7gm/dl, TLC–6500/cmm, DLC–N60, L36, M2, B2, and normal platelet count with PBF showing microcytic hypochromic RBC’s, aniso-poikilocytosis with some macrocytes, occasional target cells and some sickle cells, with many polychromatic RBC’s. Sickle test was positive. LDH: 628, total bilirubin: 5.99, with rest of the LFT being normal. Hence she was initially diagnosed as sickle cell anaemia but later Hb electro-phoresis by HPLC revealed HbS–40%, HbD–44%, HbF–9.4% with low HbA and HbA2. Ultrasound revealed single live and intra-uterine gestation of 31 weeks and 5 days with mild hepatosplenomegaly.

Introduction

Haemoglobin D is the 4th most common Hb variant which in itself is non-pathological and silent but depending on the other inherited

variant, it manifests with clinical features. One such variant is compound heterozygosity for HbS/D disease that manifests similar to sickle cell anaemia. Here is an unusual case of HbS/D, with 8 months of amen-orrhoea and mild haemolytic anaemia with hepatosplenomegaly. She was initially diagnosed as sickle cell anaemia and later found to be HbS/D disease.

Haemoglobinopathy is a genetic defect that results in abnormal structure of 1 globin chain of Hb molecule.1 These are single gene disorders in most cases, inherited as autosomal co-dominant trait.2 Most common is sickle cell anaemia. HbD–Punjab is most commonly found in approximately 3% of population in Punjab region of India and Pakistan, but it is also common in people of English, Irish, or Scottish descent.3 Characterised by GAA→CAA mutation at codon 121 of β-globin gene where glutamic acid is replaced by glutamine and has eletrophoretic mobility in alkaline pH similar to HbS.4 Described in both homozygous4 and hetero-zygous states and also with HbS5 and β-thalassemia.4 Heterozygotes, homo-zygotes of HbD, and those with HbD with β-thalassemia trait are asymp-tomatic4 but those with HbS/D disease have variable features.5 There are two types of HbD trait, Punjab and Non-Punjab; patients with HbD–Punjab with HbS presented as sickle cell anaemia and those with HbD–non-

Punjab HbS were asymptomatic.6 This is an unusual case of HbD with HbS who was mildly symptomatic.

Discussion

HbD was discovered in 1951 by Ibano.7 HbD–Punjab also known as HbD–Los Angeles, HbD–North Carolene, HbD–Portugal, HbD–Oak Ridge etc.8 It has several variants, one being Ibadan, where lysine is sub-stituted for threonine at codon 7 in β-globin chain.9 Quantity of HbD in heterozygotes is approximately 40% and can be seen in combination with HbS, HbC, HbE, β-thal and α-thal.10 When one partner has HbD trait and other has sickle cell anaemia there is 25% chances of the child to have HbD disease or SD disease in each pregnancy which usually presents as chronic haemolytic anaemia and features similar to sickle cell anaemia.11

HbS and HbD are one of the most common encountered variants worldwide.12 In India HbS gene prev-alence varies from 0-34%13 and that of HbD is 0.86%, with 3.6% in Punjab (highest frequency), 3.3% in J&K and 2.3% in UP.14 Various earlier studies4,5 have shown HbSD to present as severe haemolytic anaemia as in sickle cell disease but reports from India show14,15 variable manifestations of HbSD.

HbD has decreased oxygen affinity and decreased osmotic fragility and itself doesn’t take part in sickling process, as homozygotes for HbD do

In Practice

Medical Progress June 2012 214Medical Progress June 2012 214

In Practice

About the AuthorsDr Deepak Sharma is Resident Dept of Medicine, Dr

Madhulata Agarwal is Resident Dept of Medicine,

Dr Vishal Batra is Resident Dept of Medicine,

Dr Dinesh Kothari is Professor and Head, Dept of

Medicine, Dr Sneha Ambwani is Professor Dept of

Pharmacology at Dr. S. N. Medical College, Jodhpur,

Rajasthan

not manifest sickling. Some studies have shown that it facilitates poly-merisation of HbS, thus increasing the disease severity.16 At the same time, the coinheritence of increased HbF levels has negative effect on manifes-tations of sickle cell disease,13 as seen in the case report who was only mildly symptomatic. Such patients further require screening of family members, PCR to determine the mutation and haplotyping.

Conclusion

This case report disputes the usual presentation of HbSD as seen in various studies conducted worldwide (Pakistan, Mexico, UAE) and shows that in Indian scenario manifestation of HbSD is variable due to various unknown factors yet being researched.

References1. Haemoglobinopathy at Dorland’s Medical Dic-

tionary.

2. Weather all DJ, Clogg JB. Inherited haemoglo-

bin disorders: an increasing Global health problem

Bull World Health Organ. 2001:79(8):704-172.

3. Zago MA, Costa FF, HbD–Los Angeles in

Brazil: Simple Heterozygotes and Associations

with β-thalassemia dn with Hb S. Haemoglobin.

12(4):399-403(1988).

4. A dekile AD et al. Co-inheritance of Hb D- Pun-

jab codon 121: GAA á (AA) and B0- Thalassemia

(IVS-II-1:GáA) Journal of Peadiatrics Haematology/

Oncology 18(2):151-153(1996).

5. Perea F J et al. Hb D- Los Angeles Associated

with Hb S or β-thalassemia in Four Mexican Mestizo

Families. Haemoglobin 23(3): 231-237.

6. Brent Sickle cell and Thalassemia centre- The

North West London Hospitals NHS Trust.

7. Babin D R Jones R T and Schroeder. W.A.(1964).

Haemoglobin D Los Angeles: a2A, 62, 121 Glu

NH2, Biochemica et Biophysica Acta, 86, 136-143.

8. Higgs D R, Vickers M A, Wilkie A U, Pretorius

I M, Jarman A P, Weatherall D J (May 1989). “A

review of the molecular genetics of the human

alpha- globin gene cluster.” Blood 73(5):10 81-104.

9. Collin F S, Weissman SM (1985). “ The Molecu-

lar Genetics of Human Hemoglobin.” Prog. Nucleic

Acid Res. Mol. Biol. 31:315-462.

10. Kelleher J F, Park J K, Life Threatening Compli-

cations In A Child With Hemoglobin SD- Los Ange-

les disease. Haemoglobin : 8(3):203-213 (1984).

11. Newborn Screening Of Sickle Cell Disease :

4 years of experience from California’s newborn

screening programme. Journal of Peadiatric Hema-

tology Oncology.18(1):36-41 (1996).

12. Winter WP. Hemoglobin variants in human

populations. CRC Pves, Boca Raton, Vol 1 and 2,

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13. Mohanty D, Mukherjee M B. Sickle Cell Disease

in India. Curr Opin Hematol 2002:9:117-22.

14. Tyagi S, Marwaha N, Parmar V, Basu S. Sickle

cell haemoglobin D- Punjab disease (compound

heterozygous state). Ind J Hematol Blood Transf

2000:18:31-2.

15. Panigrahi I, Agarwal S, Singhal P. Hb D- Punjab

associated with Hb S: A report of two cases from

India. Ind J Hematol Blood Transf. 2000:18:86-7.

16. Winford C W, John N L. Wintrobe’s Clinical

Hematolgy, 11th Edition. Philadelphia; 2004 pp.

1347-81.


Non-pharmacological Treatment for

Low Back PainSteven J Atlas, MD, MPH

A serious underlying condition rarely is present in patients with low

back pain (LBP), but the pain can be intense and can severely limit

home and work activities. For most patients with LBP, the cause is a

non-specific mechanical process; for those with acute symptoms, the

course is self-limited. Initial treatments include activity modification,

non-narcotic analgesic agents, and patient education. For patients

whose symptoms are not improving, referral for physical treatments

is appropriate. For patients with subacute and chronic LBP,

behavioural treatments, exercise programmes, spinal manipulation,

and multidisciplinary rehabilitation can help. For patients with

chronic LBP, a variety of other therapeutic options (eg, acupuncture)

also are effective. Primary care physicians may help patients by

providing unbiased information and redirecting care for those who

are not improving.

Low back pain (LBP)—pain expe-rienced in the lumbosacral spinal and paraspinal regions, including the buttocks and upper thigh—is a common patient complaint. Although rarely the result of a serious condition, LBP can create significant limitations in home and work activities, and it is a major cause of disability. Most patients with acute pain, who are seen in a primary care setting, improve within a month.1 However, persistent low-grade symptoms and recurrence are common.2 Although chronic symptoms develop in only 6% to 10% of patients, the high incidence of LBP

makes the societal burden great.2,3

When evaluating patients who have LBP, the clinician’s goal is to classify the symptoms into broad categories4:• Back pain potentially associated with radiculopathy (radiating leg pain typically posteriorly localized to the knee or below) or neurogenic clau-dication (pain encompassing the buttock, groin, and anterior thigh that can radiate into the lower leg)• Back pain potentially associated with another specific cause• Non-specific LBP.

Primary care physicians most often give patients a diagnosis of

non-specific mechanical LBP, because reliably identifying the exact structure that gives rise to the local pain is difficult.5 Even when LBP is associated with specific imaging findings, such as degenerative disk disease or spon-dylolisthesis (anterior displacement, most often of the L5 vertebra over the S1), determining whether the patient’s symptoms are caused by the finding can be challenging. A precise cause is more likely to be identified in patients who have radicular leg symptoms or non-mechanical disorders, such as cancer or infection. The duration of symptoms (acute, less than 4 weeks; sub acute, 4 to 12 weeks; and chronic, more than 12 weeks) is a key deter-minant that influences the initial management of LBP.

A wide variety of therapies provided by various health care profes-sionals are available for patients with LBP (Table 1). Given the abundance of available options and limited infor-mation about their relative benefits, primary care physicians may feel uncomfortable in devising a treatment plan tailored to a patient’s situation. Many patients turn to other care providers, such as complementary and alternative medicine (CAM) practi-tioners, often without informing their physician; a lack of satisfaction with ’traditional‘ medical approaches may be a reason why.6 Diversity among back pain care providers is reflected in wide variations in the nature and frequency of testing, treatments, and


Continuing Medical Education

referrals.7 As a result, large differences in costs are seen that appear to have little relationship with symptomatic and functional improvements.7,8

For most patients who have acute non-specific LBP, initial treatment should focus on self-care with activity modification, use of medi-cations or local heat for pain relief, and avoidance of factors that worsen symptoms (Figure 1).4,9 For patients who do not improve after 2 to 3 weeks, adding physical treatments often is recommended. For patients who have subacute or chronic LBP but no known cause that would guide treatment, physical treatments should include exercise.10

In this article, I highlight key management points that can guide primary care physicians in conservative treatment or referral of patients who have LBP. I focus on patients who have non-specific LBP and who have had symptoms for more than a few weeks.

Patients Need to Know What to Expect

A key role of the primary care physician is to educate patients about reasonable expectations, starting at the first visit (Table 2). Reassure patients who have acute symptoms that the cause of their pain rarely is serious (so-called hurt does not mean harm); recommend treatments that control symptoms while healing takes place or accelerate healing. For patients who have subacute or chronic symptoms, emphasize that decreasing pain and allowing for return to work and usual activities require hard work from the patient and help from a health care professional (patient perceptions about receiving treatments passively should be discouraged).

Points to focus on include uncer-tainty in determining the precise cause of the pain and why it does not negatively influence initial treatment; in most patients, the natural history of gradual pain resolution over a

few weeks; why testing usually is not needed at first and how it can cause confusion by identifying problems that may not be related to the patient’s symptoms; what physical treatments are available and when to obtain them; and when to check in with the primary care physician for an update. Given the time constraints of most office visits, written material should be used to help reinforce verbal communication.

If the patient is being referred to a CAM provider, especially if it is at the patient’s request, inform the patient that this provider may have different views about the cause of pain, certainty of the diagnosis, and the specific benefits of his or her treatment. Because many treatments probably are effective for a number of different causes and identifying which treatments are more effective in which patients is difficult, downplay these different perspectives and instead focus on identifying what helps the pain.

Ask About Previous Episodes of Care and Treatment Preferences

If a patient currently has LBP that is similar in nature and intensity to past episodes, use past treatment expe-rience when devising a management plan because it may help identify treatments that are more or less likely to be effective this time around.11 Even if the current episode differs from past ones, ask what treatment made the condition better or worse. Whether earlier treatment actually relieved pain or simply was given while pain relief was taking place, that treatment may be more likely to be effective again than treatments that have not been effective previously or have not been tried.

A growing consensus suggests that a range of acute and subacute LBP

Table 1. Managing low back pain: non-pharmacological conservative measures

Physical measures Stimulation techniques

Activity modification Bed restExercise Range of motion Strengthening AerobicLocal heat Superficial (hot packs) Deep (ultrasonography or diathermy)Local coldManual therapies Spinal manipulation Massage Mobilization techniques Other soft tissue techniques

AcupunctureTranscutaneous electrical nerve stimulationPercutaneous electrical nerve stimulation

(electroacupuncture)Psychological interventionsBiofeedbackBehavioural therapyMultidisciplinary rehabilitationBack schoolFunctional restoration

Other

YogaLumbar supportsTraction


Figure 1. Clinical guideline for the management of acute low back paina

Risk factors for cancer,infection, fracture?

Symptoms or signs suggesting radiculopathy?

Cauda equina syndrome or severe, progressive motor deficit?

Persistent radiculopathy with disk herniation or bony entrapment?

Prevention(follow-up visit)

Conservative treatment ( 3 weeks)• Education, activity modification• Gradual return to usual activities• Low-stress aerobic exercise• NSAIDs, acetaminophen• If severe symptoms, opioids or

muscle relaxants

Consider adding physical treatments (in weeks 4–12)

• Exercise, heat/cold, massage• Spinal manipulation (if no radiculopathy)

Consider stimulation or behavioural therapyFollow-up evaluation, including

spine imaging

Urgent surgical evaluation MRI or CTElectromyography (if confirmation of

radiculopathy needed)

MRI or CTConsider corticosteroid injection

Consider physical treatmentsFollow-up evaluation

Improved?

Improved?

Surgical evaluation Multidisciplinary rehabilitation (> 12 weeks)If other spinal pathology, consider surgical

evaluation

Plain radiography of lumbosacral spineOther imaging (CT, MRI, bone scanning)

Other—ESR, CBC count, urinalysis

ESR, erythrocyte sedimentation rate; CBC, complete blood cell.

a Times listed are meant to serve as a guide rather than a rule.

Adapted from Atlas SJ, Nardin RA. Muscle Nerve 2003.9

No, with radiculopathy No, without radiculopathy

NOYES

YES

YES

YES

YES

YES

NO

NO

NO

NO



treatments are associated with similar outcomes.12,13 Therefore, patient pref-erences should be solicited when a plan is being devised.

When to Refer for Physical Treatments

The optimal timing of referral for physical treatments, as well as their frequency and duration, is unknown. In most patients with acute LBP, symptoms resolve within 2 to 4 weeks and higher costs and similar long-term outcomes

are associated with various physical treatments. Therefore, treatments should be reserved for patients who do not respond adequately to initial conservative treatment, generally after 2 to 3 weeks, or sooner if symptoms are incapacitating.14 If a visit cannot be scheduled for a week or two, earlier referral may be considered so that the patient is seen in an appropriate time frame (3 to 4 weeks of symptoms).

Some patients who have risk factors for delayed recovery may

benefit from earlier referral, but there is little evidence to indi cate that doing so improves outcomes.15 Risk factors for persistent symptoms include previous LBP that required time off from work or resulted in disability, an expectation that passive treatments are effective, a belief that back pain is harmful or disabling, fear avoidance behaviour (such as incapacitating fear that any movement will increase pain), reduced activity out of proportion to symp toms, and depression or anxiety symptoms.

Which Physical Treatments?

Providers of physical treatments include chiropractors, osteopathic physicians, physical therapists, and massage ther-apists. Common therapies include a variety of back exercises; local heat therapies; manual treatments, such as spinal manipulation, massage, and other tissue mobilization techniques; and other modalities, such as back supports and traction. Manual therapy for LBP is the most common reason why patients seek care from CAM providers.6 Because therapeutic plans sometimes involve more than one physical treatment, it is often difficult to know their relative impact.

When LBP is acute and severe, spec i f i c back s t re tching and strengthening therapies generally do not help and can worsen symptoms. Therefore, early referral for physical treatments often focuses on passive therapies performed by the provider. For patients with subacute or chronic symptoms, however, there is good evidence to suggest that physical measures that actively involve the patient are more effective.12 How manual and other passive therapies may add to an active exercise programme for persons with chronic pain is still unclear. However, primary

Table 2. Patient education: Key points in managing non-specific low back pain

Content domain Acute or subacute symptoms Chronic symptoms

Initial management

Cause Likely cause is non-specific musculoligamentous strain

Typically, cause is unknown or non-specific

Natural history Gradual improvement over a few weeks Persistence of symptoms

Evaluation Clinical evaluation usually sufficient, testing rarely helpful initially

Confirm previous appropriate evaluation to exclude rare causes

Treatment recommendations

Perform usual activities, avoid bed rest, use non-narcotic analgesics; if resolution is slow, obtain physical treatments

Goals: manage pain, improve physical function, develop coping skills

Work issues Recommendations focus on job accommodation and avoiding heavy lifting and prolonged sitting

Assess work/disability status

Follow-up When to contact health care professional; if high risk of persistent symptoms, a scheduled visit

Scheduled follow-up

Referrals Typically, if symptoms persist, refer for physical treatments

Appropriate referral based on evaluation and treatment

Long-term issues

Natural history Recurrence common Persistent symptoms likely

Prevention ’Back-friendly‘ cardiovascular exercise (eg, swimming, stationary bicycling, walking)

Work issues If work is physically demanding or pain is recurrent, discuss career plans

When possible, job retraining or modification

Adapted from Atlas SJ, Nardin RA. Muscle Nerve 2003.9


care physicians should inform patients who are interested in trying manual therapies that active exercise should be an integral part of any management plan.

Recommend Activity and Discourage Bed Rest

From the 1950s through the 1980s, bed rest was a cornerstone of treatment for LBP, largely because of expert opinion and physiological studies that showed lower disk pressure when a person is supine. Since then, studies have shown that continuation of usual activity with no recommendation for a defined period of bed rest results in better outcomes, even in those patients who have leg pain resulting from radiculopathy.4

When pain is severe and inca-pacitating, limited periods of bed rest are reasonable; early ambulation should be encouraged, but activities that provoke severe pain should be avoided. The latter include prolonged sitting and standing—patients should be instructed to walk and move their backs at regular intervals. Patients who have severe pain should also avoid strenuous activity, such as heavy lifting, climbing, or jogging, until symptoms diminish.

The Role of Physical Therapy

Physical therapy exercises for treatment of LBP include specific back stretching and strengthening therapies (eg, Williams flexion exercises or McKenzie extension exercises) in various com-binations, as well as aerobic exercises. Various physical therapy exercises have been shown to speed recovery, but the relative benefit of specific pro-grammes remains uncertain. Although back exercises may worsen symptoms when the pain is acute and severe, per-

formance of low-stress aerobic activities early in the course, especially walking, is superior to bed rest or inactivity.4

When a patient is referred to a physical therapist early on, treatment should involve patient instruction about self-care and positioning, although this has not been shown to be associated with better outcomes.4 Hot or cold packs applied locally to the skin and heat applied with ultra-sonography or diathermy often are used for LBP. Local heat may provide short-term relief of acute LBP.4 However, whether these treatments have a meaningful impact on improving recovery is unclear, partly because thermal therapies rarely are applied as the sole treatment but are included with other treatments, such as exercise or manual therapy.16

Although specific back exercises may not help during the acute phase, exercise is useful in preventing future episodes and improving symptoms in those patients who have per-sistent LBP.12,16 Ideally, a regular exercise routine should combine stretching and strength-building with endurance training. Physical therapy referral is common for patients who have radicular leg pain, but whether exercise therapy speeds recovery is unclear.16

Consider Spinal Manipulation Therapy

Spinal manipulation most often is associated with chiropractic care, but it also is provided by others, including osteopathic physicians and some physical therapists. Chiropractors are the most frequent providers of CAM care for persons with LBP. Often, patient satisfaction with care obtained from CAM providers is higher than satisfaction with physician-directed

care.7,8 Regardless of whether referral for spinal manipulation is patient- or provider-initiated, primary care phy-sicians should communicate to patients information about what they should expect in timing of improvement and treatment duration.

Spinal manipulation is thought to hasten symptom recovery modestly compared with placebo treatments, but outcomes are similar to those of other active treatments. Therefore, primary care physicians can include spinal manipulation as a reasonable treatment option for acute LBP not controlled with self-care options, espe-cially if the patient asks about such treatments and they are covered by the patient’s health insurance or he has other means to cover the costs.

Spinal manipulation and other manual therapies often are provided for patients who have chronic LBP; they have been shown to have moderate but short-term benefits.12 There is no evidence to indicate that spinal manipulation or other manual therapies offer long-term benefit for chronic pain or prevent acute recurrences.17,18 Although spinal manipulation and other manual therapies may be offered as a ‘preventive’ treatment, primary care physicians should advise patients that exercise works better. Because spinal manipulation has not been shown to help patients with radicular leg symptoms, generally it should not be recommended.

The Role of Massage and Other Soft Tissue Treatments

There are many forms of massage and other soft tissue and mobi lization tech-niques. Whether certain techniques provide better outcomes than others do remains to be proved.



Although patients generally associate massage with CAM providers, physical therapists often use massage. Non-spinal manipulation therapies have been evaluated in fewer studies, especially therapies for patients with acute symptoms.12 For patients with chronic LBP, massage shows results similar to those for spinal manipu-lation and acupuncture.12,18–20 The long-term benefit of massage for chronic LBP is unclear.

Are Other Physical Modalities Effective?

Yoga can be considered an exercise-based therapy, but it also includes other components, such as relaxation techniques. Some forms of yoga may be helpful for patients with chronic LBP,21 but no systematic reviews are yet available.12 Lumbar supports, such as braces and corsets, sometimes are used to prevent or manage LBP. Evidence does not support their use in pre-venting LBP, and it is unclear whether they help patients with LBP.12,22 Spinal traction has not been shown to be effective for acute LBP with or without radicular leg pain,12,23 and there is no evidence of benefit in patients with chronic pain.

Acupuncture and Other Stimulation Techniques

Acupuncture has been shown to provide moderate, short-term benefit for those with chronic LBP.12 However, some studies that compared acupuncture with sham acupuncture have shown similar results.12,18,24 Few studies have evaluated acupuncture in patients who have acute symptoms with or without radiculopathy.12,18

Transcutaneous electrical nerve stimulation (TENS) generally has not

been shown to be effective in patients who have chronic LBP.12,25 The benefit of percutaneous electrical nerve stim-ulation, which combines features of TENS and electroacupuncture, is uncertain for LBP.26

Managing Patients Who Are Not Improving

For patients who are not improving after a course of physical therapy, the primary care physician should review the course of the symptoms, the treatments received, and the patient’s reported response. Specific questions should address activity limitation, work issues, and what improves or worsens the pain. The primary care physician should reinforce the key educational points previously described.

Patients who have subacute or chronic pain should be asked about personal treatment goals, both short- and long-term, that go beyond pain relief, especially because a ’cure‘ cannot be guaranteed. If the patient is not working because of his symptoms, does he want to go back to work? To the same job? What activities cannot be performed that he wants to perform? How active does he want to be in finding alternatives that meet his goals? Referrals for further evaluation and treatment should be based on the patient’s stated goals and pref-erences using shared decision-making techniques.27

Psychological Treatment of Chronic Pain

A variety of psychological therapies have been used to treat patients who have LBP, typically those with chronic symptoms.12 Biofeedback involves giving ex ternal feedback to translate the physiological activity of muscular

response (often using electromy-ography) into visual or auditory signals that help patients reduce their muscle tension and pain. However, the results of studies have been mixed and bio-feedback generally is not considered to be effective in patients who have chronic LBP.28

A va r i e ty o f behav ioura l approaches are used to reduce impairment by decreasing mal-adaptive pain thoughts, feelings, and beliefs. These include operant condi-tioning (using positive re inforcement of healthy behaviour and time-con-tingent pain management), cognitive therapy (using cognitive restruc-turing methods, such as imagery and attention diversion), and respondent techniques (using relaxation to modify physiological responses). The cog-nitive-behavioural therapy technique has been shown to be moderately effective for chronic LBP and demon-strates better evidence than progressive relaxation.12,28

Depression and anxiety symptoms are common in patients who have chronic LBP. Regardless of whether such symptoms precede or are a result of the back problem, antidepressant therapy is appropriate for patients who have depressive symptoms and chronic pain.29 Serotonergic-noradrener gic agents, such as tricyclic anti-depressants, may have more consistent effects than serotonergic agents.13

Multidisciplinary Rehabilitation Programmes

These programmes combine psycho-logical, behavioural, and educational interventions with physical rehabili-tation. Multidisciplinary components often are found in functional res-toration programmes that often are work-based but may be confused with ’back schools‘, which generally


provide only a structured educational programme in a group setting. Results of educational programmes alone have been modest at best.

For patients who have occupational or chronic LBP, intensive multidisci-plinary rehabilitations reduce pain and improve function compared with alternative treatments.12,30 However, work-related outcomes have been mixed.

When to Consider an Aggressive Rehabilitation Programme

Although exercise has been shown to improve outcomes in patients who have chronic LBP, many physical treatments are passive in nature. Combined with recommendations to avoid activities that worsen symptoms, such treatments may lead to less active patients, not more active ones.

An alternative concept of care focuses on programmes of aggressive physical therapy—a ’no pain, no gain‘ perspective that emphasizes active rather than passive therapies. These exercise-based programmes provide intensive, graded physical activity during longer sessions that occur two or three times a week for 1 or 2 months, generally under the supervision of a physical medicine physician.31

Unlike comprehensive pro-grammes that generally combine multiple standard treatments into one programme, aggressive rehabilitation focuses on physical activity. Mental preparation and coping, key aspects of managing pain associated with such exertion, are incorporated into the exercise regimen rather than taught in group-learning sessions. There is little evidence to compare these programmes with other treatment modalities or programmes.4 Success

requires highly motivated patients who can cope with increased pain that often occurs early on.

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A complete list of references can be obtained upon request from the editor.

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Journal article:1. Ben-Sholmo Y, White I, McKeigue PM. Prediction of general practice workload from census based social depri-vation scores. J Epidemiol Community Health 1992;46:532-536.

Book:2. Armitage P, Berry G. Statistical methods in medical research. 1st ed. Oxford: Blackwell Scientific Publications; 1987:194-216.3. Wisniewski HM, Sturman JA. Neurotoxicity of alumin-ium. In: Gielmad IIJ, ed. Aluminium and health: a critical review. New York: Marcel Decker; 1989:125-126.

Website:4. Tsai TF. Japanese Encephalitis Vac-cines. CDC Wonder Home website. Available at http://aepo-xdv-www.epo.cdc.gov/wonder/prevguid/p0000008/p0000008.asp. Accessed 9 Septem-ber 2002.

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PUBLICATION PERIODICITY 1 YR 2 YRS 3 YRS 5 YRS OVERSEAS

(1 YR)

CIMS Quarterly Rs. 660 — — — —

IDR Triple i Bimonthly Rs. 840 Rs. 1510 Rs. 2140 Rs. 3150 Rs. 5040

Medical Progress Monthly Rs. 2040 Rs. 3670 Rs. 5200 Rs. 7650 —

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Cardiology Today Bimonthly Rs. 720 Rs. 1300 Rs. 1840 Rs.2700 Rs. 10800

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Clinical Assist Annual Rs. 399

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Documents

From the Publishers of CIMS, IDR, and the Today Group of ...enews.mims.com/landingpages/mp/pdf/Medical_Progress_June2012_IN.pdfF ABARQUEZ University of the Philippines, ... vs 19.9%,