Vol. 37 No. 3 March 2009 Journal of Pain and Symptom Management e1

Letters

Anti-Inflammatories and HeartFailuredIdentifying Patientsat Risk

To the Editor:Nonsteroidalanti-inflammatorydrugs(NSAIDs)

are commonly used in the management of can-cer pain. In patients with a known history ofheart failure, there is an association betweenNSAID use and heart failure relapse. Patientswithout a known history of heart failure, butwith cardiovascular morbidity, are also at riskof developing heart failure. We describe a caseto illustrate the phenomenon and provide prac-tical prescribing advice for this group of pallia-tive care patients.

Case

A 64-year-old man developed weight loss andright hip discomfort, and was subsequentlyfound to have a chondrosarcoma of the righthemipelvis extending into the bladder and rec-tum. Multiple bilateral lung metastases werealso evident at diagnosis, and definitive surgi-cal treatment was, therefore, not possible.Palliative radiotherapy was given to treat themain symptom of hip pain.

His past medical history included hyperten-sion and atrial fibrillation, for which he wastaking atenolol, doxazosin, lisinopril, andbendrofluazide. His World Health Organiza-tion performance status was 0. He had no car-diac or respiratory symptoms (despite the lungmetastases), and had been discharged fromregular cardiology follow-up for over a year.His renal function was normal.

In addition to palliative radiotherapy, hispain was initially managed with co-codamol.He was subsequently treated with morphine

� 2009 U.S. Cancer Pain Relief CommitteePublished by Elsevier Inc. All rights reserved.

sulfate tablets. His pain had a significant neu-ropathic element, which did not appear to beparticularly opioid sensitive, and gabapentinwas added.

Finally, diclofenac was introduced, with goodresponse. Over the following three months, thepatient was regularly reviewed. His pain wascontrolled, and his main problems were consti-pation and lymphedema of his right leg.

He then developed exertional breathless-ness, orthopnea, paroxysmal nocturnal dysp-nea, and clinical signs of heart failure. Hisdiuretic was increased, spironolactone wasadded, and the diclofenac was stopped. A com-puted tomography (which had been prear-ranged for repeat staging) showed dilatationof the cardiac chambers, a shallow right pleu-ral effusion and shallow ascites, but no changein the appearance of the known lung metasta-ses (Fig. 1). An echo at subsequent cardiologyreview some weeks later showed left ventricularhypertrophy, an ejection fraction of 74%, bi-atrial dilatation, and moderate tricuspid regur-gitation. The cardiologist attributed the heartfailure to diclofenac. We postulate that anepisode of dehydration in addition to diclofe-nac had unbalanced this patient’s cardiovascu-lar homeostasis.

Comment

Current prescribing guidelines state that allNSAIDs are contraindicated in patients whoare known to have ‘‘severe’’ heart failure andthat selective inhibitors of cyclo-oxygenase-2should be used cautiously in patients with a his-tory of heart failure, left ventricular dysfunc-tion and hypertension.1 The mechanism ofNSAID-induced heart failure is not direct myo-cardial damage, but rather, inhibition of theenzyme cyclo-oxygenase, which leads to a de-crease in prostaglandin synthesis.2e6 Under

0885-3924/09/$esee front matter

Fig. 1. Computed tomography image of dilatedcardiac chambers, right pleural effusion, and multi-ple bilateral lung metastases.

e2 Vol. 37 No. 3 March 2009Letters

normal circumstances, prostaglandins playa negligible role both in maintaining renalblood flow and preserving sodium/waterretention.7 However, in susceptible individ-uals, prostaglandin synthesis inhibition byNSAIDs can reduce renal perfusion and in-crease peripheral systemic vascular resistance.The resulting fluid retention may adverselyaffect cardiovascular homeostasis in patientswith a propensity for congestive cardiacfailure, and interfere with the cardiovasculareffects of angiotensin-converting enzymeinhibitors and diuretics.2e5

Several case-controlled and cohort studies,which included patients without a preexistinghistory of heart failure, have explored the rela-tionship between NSAIDs and heart failure. Inpatients not known to have heart failure, thoseparticularly at risk of developing heart failureon introduction of an NSAID are patients withhypertension, atrial fibrillation, diabetes, renalfailure, or a history of myocardial infarction(relative risk of 2e3).2,5,7,8 The risk is highestin (but not exclusive to) the first month ofNSAID use, and falls rapidly once stopped.2,7

NSAIDs with a longer half-life (naproxen, pir-oxicam, and tenoxicam) have a higher riskthan those with short half-lives, such as ibupro-fen or diclofenac (one study found a relativerisk of 2.01 with naproxen compared with1.08 for diclofenac).5,7 The risk appears to be

dose-dependent, regardless of the NSAID,5,7,8

and is distinct from other potential toxicities,including gastrointestinal effects (e.g., pepticulceration) and cardiovascular events (particu-larly thrombotic events, such as myocardial in-farction and stroke).

Ibuprofen, as an NSAID with a short half-life,may be preferred when risk factors for heart fail-ure exist. Ibuprofen also has a low risk of gastro-intestinal toxicity and has not been associatedwith an increased risk of myocardial infarctionat low doses (1.2 g daily or less).1 It shouldperhaps be the initial NSAID selected, particu-larly as differences in anti-inflammatory activitybetween NSAIDs are small.

Our case suggests the following guidelineswhen considering NSAID therapy for patientswith a history of hypertension, atrial fibrillation,diabetes, renal failure, or previous myocardialinfarction: 1) use caution when introducingNSAIDs; 2) monitor closely during the firstmonth of treatment and withdraw the NSAIDif symptoms or signs of heart failure develop;3) use NSAIDs with a short half-life (e.g., ibupro-fen); and 4) initiate the NSAID at the lowest rec-ommended therapeutic dose.

Dylan Harris, MBBCh(Hons), MRCP DipPallMedNikki Pease, BSc(Hons), MBBCh, MRCGP, MSc

Department of Palliative MedicineVelindre HospitalCardiff, Wales, United Kingdom

doi:10.1016/j.jpainsymman.2008.10.004

References1. In: British National Formulary, Vol. 55. London:BMJ Group and RPS Publishing, 2008.

2. Feenstra J, Heerdink ER, Grobbee DE, StrickerBHC. Association of nonsteroidal anti-inflamma-

tory drugs with first occurrence of heart failureand with relapsing heart failure. The RotterdamStudy. Arch Intern Med 2002;162:265e270.

3. Feenstra JF, Grobbee DE, Remme WJ,Stricker BHC. Drug-induced heart failure. J Am CollCardiol 1999;33:1152e1162.

4. Heerdink ER, Leufkens HG, Herings RMC, et al.NSAIDs associated with increased risk of congestiveheart failure in elderly patients taking diuretics.Arch Intern Med 1998;158:1108e1112.

5. Page J, Henry D. Consumption of NSAIDs and thedevelopment of congestive heart failure in elderlypatients. Arch Intern Med 2000;(160):777e784.

Vol. 37 No. 3 March 2009 e3Letters

6. Dzau VJ, Packer M, Lilly LS, Swartz SL,Hollenberg NK, Williams GH. Prostaglandins in se-vere congestive heart failure: relation to activationof the renin-angiotensin system and hyponatremia.N Engl J Med 1984;310:347e352.

7. Rodriguez LAG, Hernandez-Diaz S. Nonsteroidalanti-inflammatory drugs as a trigger of clinical heartfailure. Epidemiology 2003;14:240e246.

8. Huerta C, varas-Lorenzo C, Castellsague J,Rodriguez LAG. Non-steroidal anti-inflammatorydrugs and risk of first hospital admission for heartfailure in the general population. Heart 2006;92:1610e1615.

Topical Analgesic Combinationsfor Bortezomib Neuropathy

To the Editor:A 62-year-old man was found to have mono-

clonal gammopathy. Work-up revealed plasma-cytosis, with 50% plasma cells in his bonemarrow, as well as circulating plasma cells. Cy-togenetic evaluation revealed a nonhyperdi-ploid variant with chromosome 13 deletion.His performance status was 0, and on the basisof cytogenetic analysis, the patient was startedon a trial of cyclophosphamide, bortezomib,and dexamethasone. He had no evidence ofpre-existing neuropathy.

After two cycles of chemotherapy, he hada complete hematologic response. At the sametime, however, symmetric leg cramping andpain developed, starting in the calves and ex-tending downward. The patient described sen-sations of electrical shock and gnawing. Takinga shower or putting on socks provoked associ-ated edema, allodynia, and hyperesthesia. Dis-appearance of his monoclonal protein andmarrow abnormality led to discontinuation ofchemotherapy. Continued symptoms of neu-ropathy had a profound impact on his qualityof life. Pain scores averaged 8/10.

The patient began to have difficulty in walk-ing and found it difficult to work. He initiallyreceived pregabalin and morphine. Switchingto methadone (briefly) and gabapentin af-forded no relief. Attempts to escalate the mor-phine dosage were associated with severeconstipation despite an oral bowel regimen.Depression led to a psychiatric referral. Maxi-mizing the gabapentin dose and adding

lidocaine patches to his feet had minimal ef-fect on his pain scores.

Treatment with a gel containing ketamine5%, clonidine 0.5%, and gabapentin 6% wasinitiated by the Pain Service and applied belowthe ankles three times a day. Pain ratings im-proved immediately, with scores averaging 5/10. The percentage of ketamine in the gelwas increased to 10%, with a further decreasein pain scores to 3/10. There was marked im-provement in symptoms of tingling andallodynia.

The patient has been maintained on the ket-amine 10% as part of the combination gel. Allopioids and agents for neuropathic pain havebeen stopped. He has been able to return towork and has experienced no adverse effectsfrom the topical combination.

Comment

Bortezomib (formerly PS-341) is a newly de-veloped chemotherapeutic drug that showspromising antineoplastic effects against vari-ous lymphoid disorders, most notably multiplemyeloma, for which previously no treatmenthas been satisfactory.1 Pain due to peripheralneuropathy is now also emerging as a majordose-limiting adverse effect of this chemother-apeutic drug, with the overall incidence rang-ing between 30% and 47%;2 the incidence ofsevere neuropathy (Grade 3e4) is approxi-mately 15%.2 Patients report sensory symp-toms in a stocking-and-glove distribution,similar to that experienced by patients whohave chemotherapy-induced neuropathy pro-duced by other cancer therapy drugs, includ-ing paclitaxel, vincristine, and cisplatin.3

Bortezomib neuropathy causes severe pain infingertips and toes.3 Bortezomib has beenshown to affect sharpness detection and in-creases touch and warm detection thresholds,as well as heat and cold pain thresholds.3

These sensory effects suggest that bortezomibaffects all major sensory fibers; major symp-toms occur in glabrous skin and much less soin hairy skin.3 Previous exposure to thalido-mide had little effect and even produceda modest amelioration of bortezomib-evokedsensory deficits.3

Current management of bortezomib neu-ropathy includes dose reduction and