Comment

Levomepromazine, also known as methotri-meprazine, is an antipsychotic drug. In addi-tion to this use, it has a role in palliative carefor the alleviation of nausea. It also has beenused to manage terminal restlessness, al-though it can cause restlessness and akathisia.

Drug-induced lupus is a condition thatresembles a mild form of idiopathic systemic lu-pus erythematosus and is associated with drugssuch as procainamide, hydralazine, minocy-cline, quinidine, chlorpromazine, isoniazide,and methyldopa.1,2 It is a reversible condition,with the symptoms often resolving within daysof stopping the offending medication.1,3,4

Symptoms may develop up to one year afterthe drug is commenced. It is diagnosed whena patient has one or more symptoms of systemiclupus erythematosus, with positive ANA titerand no symptoms of lupus before starting thesuspected drug. Table 1 shows the features thatcan be associated with drug-induced lupus.5

Although there is no published literaturedirectly pertaining to lupus secondary to levome-promazine, this drug has pharmacological activ-ity similar to that of chlorpromazine, for whicha published association with the onset of lupus-type symptoms exists.6 The combination ofraised homogeneous ANA levels, features of lu-pus (Table 1), symptoms starting after monthsof treatment with levomepromazine and resolv-ing within days of discontinuing it, all supportthe possibility of drug-induced lupus secondaryto levomepromazine.

Antihistone antibodies are raised in approx-imately 90% of cases of drug-induced lupusand would have certainly supported the

diagnosis. However, a negative result does notexclude it as a possibility. The ANA levels werenot rechecked, as they can remain elevated forseveral months to years even after an offendingdrug is discontinued.

This case demonstrates the general impor-tance of reviewing medications when there isa change or deterioration in symptoms, as sim-ply discontinuing an offending drug can pre-vent escalating doses of potential toxic drugsor the commencement of additional drugs tomanage these symptoms. In addition, levome-promazine is increasingly used in the palliativecare setting because of its broad actions on themechanisms leading to nausea. Therefore, it isimportant to be aware of its side-effect profile.

Andrew J. Fletcher, MBBS, MRCPRoyal Bolton HospitalBolton, Greater ManchesterUnited Kingdom

doi:10.1016/j.jpainsymman.2008.12.001

References1. Price EJ, Venables PJ. Drug-induced lupus. DrugSaf 1995;12(4):283e290.

2. Skaer TL. Medication-induced systemic lupuserythematosus. Clin Ther 1992;14(4):496e506.

3. Brogan BL, Olsen NJ. Drug-induced rheumatic syn-dromes. Curr Opin Rheumatol 2003;15(1):76e80.

4. Borchers AT, Keen CL, Gershwin ME. Drug-inducedlupus. Ann N Y Acad Sci 2007;1108(5):166e182.

5. Parent-Stevens L. Systemic lupus erythematosusand drug-induced lupus. Available from. Universityof Illinois at Chicago Courses Online, 1998.http://www.uic.edu/classes/pmpr/pmpr652/Final/stevens/sle.html. Accessed November 2007.

6. Canoso RT, Sise HS. Chlorpromazine-inducedlupus anticoagulant and associated immunologicabnormalities. Am J Hematol 1982;13(2):121e129.

Table 1Features of Drug-Induced Lupus5

Antinuclear antibodiesa

AnemiaArthralgia/arthritisa

Discoid rashFatigue/malaiseFeverHepatosplenomegalyLymphadenopathyMalar rashMouth ulcersMyalgiaa

Raynaud’s phenomenonRenal and neurological involvement (rare)Serositis (pleuritis/pericarditis)

aFeatures present in this case.

e2 Vol. 37 No. 6 June 2009Letters

Opioid-Induced RespiratoryDepression Resulting fromTransdermal Fentanyl-Clarithromycin Drug Interactionin a Patient with Advanced COPD

To the Editor:Concomitant administration of transdermal

fentanyl and potent inhibitors of cytochrome

Vol. 37 No. 6 June 2009 e3Letters

P450 has the potential to result in significantrespiratory depression and death because ofpharmacokinetic drug interaction. A recentcase involving near fatal respiratory depressionin a patient with chronic obstructive pulmo-nary disease (COPD) is reported.

Case

The patient, a frail 81-year-old man withdementia and advanced COPD requiringhome oxygen, had suffered from cervical spon-dylosis and spinal stenosis for several years. Formore than a year, his chronic neck pain wastreated with a transdermal fentanyl patch(Duragesic�) at a dosage of 200 ug/hourchanged every 48 hours.

He was admitted to a tertiary hospital witha five-day history of increased shortness ofbreath, purulent sputum, unilateral inflamma-tion of his parotid gland, worsening confusionand disorientation. The initial workup revealedleukocytosis and iron deficiency anemia, andhe was diagnosed with an acute exacerbationof COPD and parotitis. He was treated withaerosolized salbutamol and ipratropium, oralprednisone and levofloxacin, as well as a 10-day course of intravenous vancomycin anda transfusion of two units of packed cells. Hewas also continued on his previous dose of fen-tanyl and oxygen.

By hospital Day 12, he had returned to base-line and was being prepared for discharge. Inthe meanwhile, his Helicobacter pylori serologyreturned and was positive. He was presumedto have a possible H. pylori gastritis and an asso-ciated upper gastrointestinal bleed causing hisanemia, and was started on an H. pylori eradica-tion regimen of clarithromycin 500 mg twicea day and metronidazole 250 mg four timesdaily.

Thirty-six hours after receiving the initialdose of clarithromycin, he was found to be un-responsive to verbal or tactile stimuli. He hadpinpoint pupils, hypoventilation, profoundhypoxemia, and a respiratory rate of twobreaths per minute. He was administered0.4 mg intravenous naloxone and promptlyrecovered consciousness. His respiratory rateincreased to 30 breaths per minute, with asso-ciated tachycardia, agitation, and respiratorydistress. The fentanyl patch was discontinuedand his opioid withdrawal symptoms were

managed with supplemental doses of subcuta-neous morphine. By the following morning,he was alert and conversive, with normal respi-ratory rate and oxygen saturation. He deniedpain and did not exhibit signs or symptomsof opioid withdrawal. Clarithromycin was dis-continued and he subsequently resumed trans-dermal fentanyl at 50% of his preadmissiondose, which was tolerated without significantincrease in pain or further evidence of opioidtoxicity. He was ultimately discharged withoutfurther incident.

Comment

This case serves as a warning about a knownbut often underappreciated serious interac-tion between two widely prescribed drugs: fen-tanyl and clarithromycin. Adverse outcomesand deaths related to the prescription of trans-dermal fentanyl in opioid-naı̈ve patients andmisuse of fentanyl under other circumstancesare well documented.1,2 The aforementionedcase outlines the unforeseen development ofopioid-induced respiratory depression in a pa-tient on a chronic stable dose of transdermalfentanyl.

The development of respiratory depression inan opioid-tolerant patient within 48 hours of theinitiation of clarithromycin suggests that themost probable cause was a pharmacokineticinteraction between the potent cytochromeP450 inhibitor clarithromycin and fentanyl. Thisis further supported by the prior recognition anddocumentation of this interaction,3e5 theprompt resolution of symptoms with the admin-istration of an opioid antagonist, the absence ofother suspect conditions or medications, andthe successful reintroduction of fentanyl afterclarithromycin was withdrawn. Given these fac-tors, our confidence in this causality, based onaccepted criteria,6 is greater than 95%.

Transdermal fentanyl has been available formore than a decade and is widely used forthe treatment of both cancer pain and chronicnonmalignant pain. IMS HEALTH data indi-cate that more than half a million prescrip-tions were dispensed from Canadian retailpharmacies in 2007. Prescriptions for clari-thromycin, a potent inhibitor of the cyto-chrome P450 system, topped over 2.1 millionfor the same time period.

e4 Vol. 37 No. 6 June 2009Letters

Table 1Transdermal Fentanyl: Factors Increasing the Potential for Serious or Life-Threatening Hypoventilation

� Concomitant use with potent cytochrome P450 3A4 inhibitors, such as ritonavir, ketoconazole, itraconazole, troleandomy-cin, clarithromycin, nelfinavir, and nefazodone.� Use in combination with CNS depressants (including other opioids, sedatives or hypnotics, general anesthetics, phenothi-azines, tranquilizers), skeletal muscle relaxants, sedating antihistamines, and alcoholic beverages. Additive depressant effectsmay result.� Fever: fentanyl concentrations could theoretically increase by approximately one-third for patients with a body temperatureof 40 �C (104 �F) because of temperature-dependent increases in fentanyl release from the system and increased skinpermeability.� Exposure of the application site to direct external heat sources. All patients should be advised to avoid external heat sources,such as heating pads, electric blankets, heated water beds, heat lamps, hot water bottles, saunas and hot whirlpool spa baths,intensive sunbathing, and so on.

CNS¼ central nervous system.Source: Health Canada Endorsed Important Safety Information on Duragesic (fentanyl transdermal system): http://www.hc-sc.gc.ca/dhpmps/medeff/advisories-avis/prof/2005/duragesic_hpc-cps_e.html

In 2005, Janssen, the manufacturer of Dura-gesic�, in cooperation with the United StatesFood and Drug Administration (FDA) andHealth Canada, issued an important drugwarning, including a statement that ‘‘concom-itant use of transdermal fentanyl with potentcytochrome P450 3A4 inhibitors may cause po-tentially fatal respiratory depression.’’4 As withmany relatively rare postmarketing adverseeffects, the exact incidence of this seriousadverse event is not known and rates are diffi-cult to determine because of several factors,including a general underreporting of adverseevents by health professionals. Additionalcautions and potential pitfalls are outlined inTable 1.

Lack of physician knowledge regardingpharmacokinetic properties of this prepara-tion has been previously reported.7 Despitethe 2005 warning, significant adverse eventsand fatalities associated with the use of trans-dermal fentanyl continue to be reported,prompting the FDA to issue an updated warn-ing in December 2007.8

Fentanyl is metabolized in the liver by thecytochrome P450 system, mainly undergoingdealkylation to inactive metabolites by cyto-chrome P450 3A4.9 Case reports of opioidtoxicity from drug-drug interactions becauseof coadministration of fentanyl and cyto-chrome P450 inhibitors have been publishedelsewhere.3,5

Several strategies might have been used inthis case that could have prevented the adverseoutcome. These include, but are not limitedto: 1) fentanyl dose reduction with close mon-itoring for increase in pain or symptoms ofopioid toxicity; 2) rotation to alternate opioid

not undergoing P450 metabolism; 3) an alter-nate H. pylori eradication regimen that didnot include clarithromycin; and 4) forgoingempiric H. pylori eradication in a patient withmultiple comorbidities who might be unlikelyto benefit.

This case report serves as a cautionary tale.The use of transdermal fentanyl in patientswith multiple comorbidities without apprecia-tion of the drug’s pharmacokinetic profileand potential for serious drug interactionswith commonly used drugs may place patientsat increased risk for serious complications.

Robert Horton, MD, CCFPClaire Barber, MDDalhousie UniversityQE II Health Science CenterHalifax, Nova ScotiaCanada

doi:10.1016/j.jpainsymman.2009.02.230

References1. Martin TL, Woodall KL, McLellan BA.Fentanyl-related deaths in Ontario, Canada:toxicological findings and circumstances of deathin 112 cases (2002-2004). J Anal Toxicol 2006;30(8):603e610.

2. Raymond B, Morawiecka I. Transdermal fentanyl(Duragesic): respiratory arrest in adolescents. CMAJ2004;171(8):991e992.

3. Hallberg P, Marten L, Wadelius M. Possible fluco-nazole-fentanyl interactionda case report. Eur JClin Pharmacol 2006;62(6):491e492.

4. U.S. Food and Drug Administration. Alert forhealthcare professionals: fentanyl transdermal sys-tem (marketed as Duragesic). Available from. http://www.fda.gov/medwatch/SAFETY/2005/duragesic_ddl.pdf 2005;. Accessed January 3, 2008.

radiologically. Despite evidence of widespreadbony disease progression, the patient main-tained a good performance status and active lifeuntil shortly before admission to his local hospi-tal. At the time of transfer, the patient reporteda one-week history of lower lumbar bony andneuropathic pain, which was quickly controlledwith an increase in the dose of a transdermalfentanyl patch (to 50 mcg/hour) and the addi-tion of nortriptyline (10 mg three times a day).Additionally, on a background of intermittentconstipation for the previous three months,the patient reported nine days of constipation,for which the referring hospital had com-menced polyethylene glycol and phosphateenemas. At this stage and throughout the admis-sion, his plasma electrolytes were unremark-

Vol. 37 No. 6 June 2009 e5Letters

5. Mercadante S, Villari P, Ferrera P. Itraconazole--fentanyl interaction in a cancer patient. J PainSymptom Manage 2002;24(3):284e286.

6. Cobert B, Biron P. Practical drug safety from A toZ. Boston: Jones and Bartlett, 2008.

7. Welsh J, Reid A, Graham J, et al. Physicians’knowledge of transdermal fentanyl. Palliat Med2005;19(1):9e16.

8. U.S. Food and Drug Administration. FDA issuessecond safety warning on fentanyl skin patch. Avail-able from. http://www.fda.gov/bbs/topics/NEWS/2007/NEW01762.html 2007. Accessed January 3,2008.

9. Tateishi T, Krivoruk Y, Ueng YF, et al. Identifica-tion of human liver cytochrome P-450 3A4 as theenzyme responsible for fentanyl and sufentanilN-dealkylation. Anesth Analg 1996;82(1):167e172.

An Unusual Case of SevereConstipation Due to MetastaticPheochromocytoma

To the Editor:Pheochromocytomas are rare tumors of the

endocrine system. We report a case of severeconstipation in the setting of metastatic pheo-chromocytoma requiring interdisciplinarymanagement and an infrequently used ap-proach to management.

Case

A 42-year-old man with a history of metastaticextra-adrenal pheochromocytoma originatingin the para-aortic region and involving multiplebony sites was transferred from a local hospitalto a tertiary referral center for management ofcatecholamine excess symptoms and bone pain.

The diagnosis was established four years pre-viously on the basis of raised urinary catechol-amines. Shortly after diagnosis, the patientunderwent cytoreductive surgery on the pri-mary tumor site, cervical lymph node metasta-ses, and L3 metastasis (with concurrentvertebral stabilization). Surgery was precededby MIBG (I131 meta-iodobenzylguanidine) ther-apy, which was also given in the adjuvant settingon three further occasions over the next threeyears. The tumor was initially responsive to thistreatment, but after the third MIBG treatment,it became refractory both biochemically and

able. Symptoms of catecholamine excess atthis time included intermittent flushing, sweat-ing, and tinnitus; however, blood pressure wasmaintained within normal limits using regulardoxazocin.

Clinical examination revealed nontenderabdominal distension and quiet bowel sounds;abdominal radiograph revealed severe fecalloading. Over the following week, intravenoushydration was commenced and laxatives werechanged to high-dose danthron and poloxamerplus phosphate enemas, but with no effect. A‘‘decompaction’’ regimen using the polyethyl-ene glycol was put to trial, also without effect; itwas poorly tolerated because of vomiting. A sub-cutaneous syringe driver with metoclopramidewas added for both antiemetic and prokinetic ef-fect, and the polyethylene glycol was changed toa formulation of sodium picosulfate, magnesiumoxide, and citric acid. The latter drug, which hada smaller volume, was well tolerated for severaldays, but when defecation was not achieved, dailyarachis oil enemas were added to the phosphateenemas.

Repeat abdominal imaging (computed to-mography) with gastrograffin and multidisci-plinary discussion suggested a transitionpoint at the splenic flexure. Therefore, stimu-lant laxatives were temporarily stopped untilfurther investigation could be performed.Flexible sigmoidoscopy confirmed no mechan-ical obstruction. During this time, the patientdeveloped uncontrolled hypertension andwas treated with phenoxybenzamine and an in-creased dose of doxazocin. After a surgicalconsultation, large volume-retention enemas