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influenza-like symptoms. Because of this shechanged to a combination of micro-currentelectrotherapy and tramadol drops, 25 mg threetimes daily, with moderate success. For severalmonths, this therapy was satisfactory. Later, themicro-current therapy was discontinued andshe switched to a combination of paracetamol(325 mg) and tramadol (37.5 mg) tablets threetimes daily. This medication was moderatelyeffective. However, several weeks later she no-ticed fever (especially in the evening, occasion-ally up to 39.8�C) and generalized malaisewith headache and occasional chills. She con-tinued this treatment for three months but feltprogressively sick. She was admitted to hospitalfor a thorough check-up. Investigations didnot reveal any abnormality. No skin rash wasobserved. Extensive blood tests, including im-munoglobulins, antinuclear antibodies andcomplement, were all normal.

On her mother’s initiative, analgesic therapywas discontinued. The next day, fever and mal-aise disappeared, and the pain became moreintensive. Two months later, the patient waschallenged with a paracetamol tablet 500 mg.Her temperature increased from 37.2�C atbaseline to 38.5�C two hours after administra-tion. She was complaining of malaise, chills,and headache. The next day, her body tempera-ture returned to 36.7�C and the malaisedisappeared.

CommentParacetamol-induced fever has not been re-

ported earlier in isolation. A single case of drug-induced fever was reported after diclofenac.5

As both paracetamol and NSAIDs are frequentlyused to control fever, especially in young chil-dren, it is possible that their fever-inducing po-tential remains unseen. In our patient, feverafter diclofenac, naproxen and paracetamol,lack of abnormalities in blood tests, and ab-sence of skin rash, points directly to the toxiceffect on the thermoregulatory centers. Itshould be borne in mind that, in rare situations,even drugs which are used to control feveroccasionally also induce fever.

Zbigniew Zylicz, MD, PhDComprehensive Cancer CenterNijmegen, The NetherlandsCollegium Medicum, Torun,The Nicolans Copernicus UniversityBydgoszcz, Poland

Małgorzata Krajnik, MDCollegium Medicum, Torun,The Nicolaus Copernicus UniversityBydgoszcz, Poland

doi:10.1016/j.jpainsymman.2005.03.003

References1. Nakajima M, Yoshida K, Miyashita N, et al.Acetaminophen-induced pneumonitis. Nihon Koky-uki Gakkai Zasshi 1998;36(11):973–977.

2. Akashi S, Tominaga M, Naitou K, et al. Two casesof acetaminophen-induced pneumonitis. NihonKyobu Shikkan Gakkai Zasshi 1997;35(9):974–979.

3. Halevi A, Ben-Amitai D, Garty BZ. Toxic epi-dermal necrolysis associated with acetaminopheningestion. Ann Pharmacother 2000;34(1):32–34.

4. Thabet F, Durand P, Chevret L, et al. SevereReye’s syndrome: report of 14 cases managed in apediatric intensive care unit over 11 years. ArchPediatr 2002;9(6):581–586.

5. Enrique E, Cistero-Bahima A, Alonso R, et al.Diclofenac-induced fever. Allergy 2000;55(4):413–414.

The Use of Long-Term, Low-DoseErythromycin in Treating PersistentGastric Stasis

To the Editor:We would like to describe a case in which the

use of low-dose erythromycin provided long-term benefit for gastric stasis.

Case ReportA 59-year-old man with moderate learning

disability had good comprehension but noformal speech. He communicated with vocali-zations, facial expressions, eye contact (oravoiding eye contact if he did not want to com-municate), and hand gestures, such as ‘thumbsup.’ His mobility was minimal and he required24-hour nursing care. In 1992, he began to haveincreasing dysphagia and assessment by a swal-lowing therapist suggested a neurologicalcause, with poor coordination of swallowing.Because oral hydration and feeding carried anever-increasing risk of aspiration, he had a per-cutaneous endoscopic gastrostomy (PEG) in-serted. This was well tolerated initially, but the

Vol. 29 No. 5 May 2005 431Letters

following year he started to have occasionalproblems with nausea and vomiting. By 1999,this problem was still present despite consecu-tively trying cisapride 20 mg every 8 hours,domperidone 60 mg as a suppository, metoclo-pramide 60 mg/24 hours as a continuous subcu-taneous (SC) infusion, and a combination ofcisapride and metoclopramide. A jejunal exten-sion was fitted to the PEG tube and this allowedhim to tolerate continuously infused feeds. By2000, the jejunal extension had become dis-placed on several occasions, but he tolerated feedboluses through the gastrostomy. Unfortunately,by early 2003, he was having problems with vom-iting again. His tolerated daily intake volume andfeed rate had reduced and he had developed anaspiration pneumonia (see Table 1). He wasswitched from domperidone to erythromycin 250mg every 12 hours. He tolerated an increase inhis daily intake volume and it was possible toincrease his feed rate. Both reduced again onswitching back to domperidone. Switching backto erythromycin restored the tolerated dailyintake volume and feed rate, and his episodes ofvomiting stopped (see Table 1). Five monthsafter starting erythromycin, he needed hospitaladmission for a pneumonia, but this resolvedwith antibiotics. His improvement in vomiting,nausea, feed rates, and daily intake volume hascontinued for 12 months on erythromycin with-out any evidence of tolerance to its proki-netic effects.

CommentErythromycin was first isolated in 1952 and

is a widely used antibiotic with a broad spectrumof activity against many common pathogens. Its

gastrointestinal adverse effects of nausea, vom-iting, and cramping abdominal pain have beenwidely reported. These adverse effects canoccur in at least half of patients with intravenousadministration,1 but the incidence of nauseacan be as low as 5% with oral administration,2

especially if erythromycin ethylsuccinate isused.3 Research carried out in the mid 1980sindicated that erythromycin has a direct effecton gastrointestinal motility by its action on thesmooth muscle cell via the motilin receptor.4

The endogenous hormone motilin is a 22amino acid peptide, which has the action ofincreasing gastric emptying and small bowelcontraction.5 Its molecular structure is very dif-ferent than erythromycin, yet it has been postu-lated that their spatial configuration and chargedistribution must be similar in order to acti-vate the same receptor.4

The prokinetic effect of erythromycin can beused in clinical situations where gastrointestinalsmooth muscle function is impaired. Many trialshave been undertaken in patients with diabe-tes mellitus, as up to 50% of diabetic patientshave some element of delayed gastric empty-ing.6 Janssens et al. carried out a study in 1992of erythromycin versus placebo in a double-blind, crossover trial of 10 patients withsevere diabetic gastroparesis who had failed torespond to other treatments.7 Gastric emptyingwas measured after administering 200 mg ofintravenous erythromycin or placebo and theningesting isotope-labeled solids and liquids.Erythromycin was shown to markedly improvegastric emptying compared with placebo. Anadditional study, again measuring gastric emp-tying using isotope-labeled food, compared

Table 1Details of Symptoms and Feed Volumes Over Observation Period

Symptoms Related Feed plus Fluid Average Feed plus Fluid AverageWeeks Prokinetic to Dysphagia Rate in mL/hr Volume in mL/day

1 none Vomiting on 2 days 70 18852 domperidone Aspiration pneumonia 50 19673 erythromycin Vomiting on 2 days 68 2290

Coughing on 1 day4–5 domperidone Vomiting on 2 days 50 1880

Coughing on 2 days6 none Vomiting on 2 days 50 20657–11 erythromycin Vomited once 65 208812–15 erythromycin Nausea once 65 2109

Coughing on 1 day16–52 erythromycin Nausea once 65 2124

Coughing once

432 Vol. 29 No. 5 May 2005Letters

three-week treatments with metoclopramidefollowed by erythromycin after a washoutperiod.8

This study demonstrated that both drugswere equally effective at improving gastric emp-tying. Further metanalyses have suggested thaterythromycin may have the strongest effect ongastric emptying when compared with metoclo-pramide, domperidone, and cisapride.9

The effects of erythromycin on the symp-toms of gastric stasis (nausea, vomiting, earlysatiety, and bloating) have been less well dem-onstrated. A systematic review of 35 trials oferythromycin in gastric stasis10 found that only5 trials assessed symptom relief; of these trials,48% of patients reported symptomatic benefit.All the trials had small sample sizes andtreatment duration was less than 4 weeks. Im-provement in gastric emptying does not seem tobe well correlated with improvement in symp-toms and there are many patients with demon-strable delayed gastric emptying who arecompletely asymptomatic.

Erythromycin also has been used in otherconditions that have gastroparesis as a problem.Studies have been published describing its useafter surgery (such as vagotomy and esophagec-tomy11), as well as in myotonic dystrophy12 andsystemic sclerosis. Another use has been in criti-cally ill patients who have been intolerant ofnasogastric feeding. Chapman et al. published astudy of 20 ventilated patients who had impairedtolerance to gastric feeding.13 They were giveneither 200 mg of intravenous erythromycin orplacebo and the residual gastric volume mea-sured. It was demonstrated that the patientswho received erythromycin had improved vol-umes of gastric emptying compared with pla-cebo. The effect was still present at 12 hoursbut disappeared at 24 hours, suggesting once-or twice-daily dosage may be sufficient. A similarstudy in 68 trauma patients fed by nasogastrictube used 250 mg of erythromycin intrave-nously (or placebo) and demonstrated an im-provement in the amount of feed tolerated.14

Most studies have had follow-up periods ofless than four weeks, but a recent study followedsome patients for up to 18 months and sug-gested that tolerance may develop over time.15

A major concern that has been raised aboutusing erythromycin in this way is that resistanceof pathogens, such as S. pneumoniae, may in-crease. Although the doses of erythromycin

used are smaller doses than those typically usedin treating bacterial infections, they may pro-vide almost ideal conditions for the inductionof bacterial mutation, and selection and resis-tance to erythromycin is well recognized.16,17

The answer may be the development of com-pounds that, like erythromycin, can activate themotilin receptor but do not have antimicrobialproperties.4 In the meantime, erythromycin isa useful third-line prokinetic in palliative carethat can be used for several months without lossof efficacy.

Alice Hunter, MRCPSt. Oswald’s HospiceNewcastle-upon-Tyne, United Kingdom

Claud Regnard, BMSc, FRCPSt. Oswald’s Hospice, and Newcastle City HospitalsNewcastle-upon-Tyne, United KingdomNHS Trust and Northgate & Prudhoe NHS TrustNorthumberland, United Kingdom

Christine Armstrong, RNMHMedical Center, Northgate, and Prudhoe HospitalMorpeth, United Kingdom

doi:10.1016/j.jpainsymman.2005.03.004

References1. Anastasio GD, Robinson MD, Little LM Jr., et al.

A comparison of the gastrointestinal side effects oftwo forms of erythromycin. J Fam Pract 1992;35(5):517–523.

2. Bowler WA, Hostettler C, Samuelson D, et al.Gastrointestinal side effects of intravenous erythro-mycin: incidence and reduction with prolongedinfusion time and glycopyrrolate pretreatment. AmJ Med 1992;92(3):249–253.

3. Shanson DC,Tidbury P, McNabb WR,Tadayon M.The pharmacokinetics and tolerance of oral erythro-mycin stearate compared with erythromycin ethylsuc-cinate: implications for preventing endocarditis.J Antimicrobial Chemother 1984;14(2):157–163.

4. Catnach SM, Fairclough PD. Erythromycin andgut. Gut 1992;33:397–401.

5. Kumar P, Clark M. Clinical medicine, 3rd ed.London: Bailliere Tindal, 1994:204.

6. Smith DS, Ferris CD. Current concepts in dia-betic gastroparesis. Drugs 2003;63(13):1339–1358.

7. Janssens J, Peeters TL, Vantrappen G, et al.Improvement of gastric emptying in diabetic gas-troparesis by erythromycin. Preliminary studies.N Engl J Med 1990;332:1028–1031.

Vol. 29 No. 5 May 2005 433Letters

fear of adverse effects. One of the possible linksin the chain limiting the appropriate and timelyuse of opioids is represented by pharmacies andthe availability of opioids.2 We conducted asurvey to explore the difficulties patients mayhave in obtaining opioids after being dis-charged from an acute pain relief and palliativecare unit with a prescription of strong opioidsfor cancer pain management.

One hundred twenty-six consecutive patientswho were prescribed strong opioids for cancerpain and discharged home were surveyed by atelephone interview. Drugs were collected atpharmacies by the patient’s son/daughter in 47cases, husband/wife in 47 cases, brother/sisterin 10 cases, father/mother in 3 cases, brother-in-law in 3 cases, nephew in 3 cases, patient him/herself in 11 cases, and others in 2 cases. Tenpharmacies were in villages (less than 10,000inhabitants), 27 in small centers (10,000–50,000 inhabitants), 7 in medium centers(50,000–100,000 inhabitants), and 82 in bigcenters (�100,000 inhabitants). Ninety-eightpharmacists delivered the drugs prescribedwithout creating problems, 13 did not deliveropioids (unclear reasons), 9 of them did nothave opioids in stock, one did not have metha-done, 3 did not have free morphine formu-lation, and two considered the prescriptionirregular. No differences were found betweenpharmacies located in different size centers(Pearson chi-square, P � 0.976).

General practitioners correctly followed theindications suggested and prescribed opioidsfor 108 patients. Nine physicians did not have

8. Erbas T, Varoglu E, Erbas B, et al. Comparisonof metoclopramide and erythromycin in the treat-ment of diabetic gastroparesis. Diabetes Care 1993;16:1511–1514.

9. Sturm A, Holtmann G, Goebell H, et al. Proki-netics in patients with gastroparesis: a systematicanalysis. Digestion 1999;60:422–427.

10. Maganti K, Onyemere K, Jones MP. Oral erythro-mycin and symptomatic relief of gastroparesis: a sys-tematic review. Am J Gastroenerol 2003;98:259–263.

11. Nakabayashi T, Mochiki E, Garcia M, et al. Gas-tropyloric motor activity and the effects of erythromy-cin given orally after esophagectomy. Am J Surg2002;183:317–323.

12. Ronblom A, Andersson S, Hellstrom PM, et al.Gastric emptying in myotonic dystrophy. Eur J ClinInvest 2002;32:570–574.

13. Chapman M, Fraser RJ, Kluger MT, et al. Eryth-romycin improves gastric emptying in critically illpatients intolerant of nasogastric feeding. Crit CareMed 2000;28:2334–2337.

14. Berne JD, Norwood SH, McAuley CE, et al.Erythromycin reduces delayed gastric emptying incritically ill trauma patients: a randomized controlledtrial. J Trauma Injury Infection Crit Care 2002;53:422–425.

15. Dhir R, Richter JE. Erythromycin in the short-and long-term control of dyspepsia symptoms inpatients with gastroparesis. J Clin Gastroenterol2004;38(3):237–242.

16. Hyde TB, Gay K, Stephens DS, et al. Activebacterial core surveillance/emerging infectionsprogram network. Macrolide resistance amonginvasive streptococcus pneumoniae isolates. JAMA 2001;286(15):1857–1862.

17. Guerin JM, Leibinger F. Letter. Chest 2002;121:301.

Problematic Discharge from Hospitalfor Patients Prescribed Opioids forCancer Pain

To the Editor:Opioid consumption in Italy remains one of

the lowest in Europe, despite recent changesin legislation favoring opioid prescription byphysicians.1 Different reasons have been re-ported to explain this phenomenon, includingopiophobia associated with the previous restric-tive legislation, poor education and knowledgeof principles of cancer pain management, and

the prescription books for opioids, one physi-cian changed the prescription, and 5 of themdid not know how to prescribe opioids. No dif-ferences were found between physicians livingin different size centers (Pearson chi-square,P � 0.702). These problems resulted in somedelay (1–2 days) in obtaining the drugs in 26patients.

According to these results, despite optimiza-tion of opioid therapy in hospital and clearindications for continuing opioid therapy, 15–20% of patients may discontinue or delay thetreatment. Thus, even in conditions where painis adequately treated, patients continue tosuffer due to practical problems. As a conse-quence, patients are currently provided with atwo-day supply of drug when discharged home