Gut, 1986, 27, 444-449

Case reports

Dextropropoxyphene induced hepatotoxicitymimicking biliary tract diseaseM F BASSENDINE, K W WOODHOUSE, M BENNETT, AND 0 F W JAMES

From the Departments of Medicine and Pathology, Freeman Hospital and the Department of Medicine(Geriatrics), Royal Victoria Infirmary, Newcastle upon Tyne.

SUMMARY Three patients are described with recurrent jaundice, upper abdominal pain -andrigors attributable to dextropropoxyphene hepatotoxicity. The diagnosis was established in eachpatient by rechallenge; post challenge hepatic histology is reported in two. Twelve previouspatients with probable dextropropoxyphene hepatic toxicity have been described and arereviewed. In 10 of the 15 patients, a clinical diagnosis of gall stone disease was made. Liverfunction tests are usually hepatitic shortly after challenge, but more cholestatic after a few days.No fatalities have been described, but as dextropropoxyphene is widely available in manydifferent analgesic preparations possible toxicity should be considered in patients with relapsingjaundice mimicking biliary disease, in whom gall stones have been excluded.

Dextropropoxyphene is widely used as an analgesicboth alone and in combination with other drugs.Although several reports have suggested that it mayrarely cause liver damage,-9 a causal relationshiphas only been firmly established by rechallenge in atotal of six patients and in only two was hepatichistology available after the rechallenge. We reportthree patients in whom dextropropoxyphene wasresponsible for hepatotoxicity.

Case histories

PATIENT 1A 52 year old woman had two episodes of un-explained jaundice in 1981 and 1982. On eachoccasion jaundice lasted about two weeks and wasaccompanied by pruritus, nausea, and intolerance offatty foods. No investigations were carried out. Thepatient had osteoarthritis of the right knee for whichshe took various analgesics, usually Benorylate (anaspirin-paracetamol ester). She had a known allergyto penicillin. The patient was admitted to hospitalwith a history of sudden onset of jaundice for a thirdtime three weeks previously, the jaundice had beenpreceded by epigastric pain for a few hours and was

Address for correspondence: Dr 0 F W James, Medical Unit No 1, FreemanHospital, Newcastle upon Tync, NE7 7DN.

Received for publication 2 August 1985.

accompanied by dark urine, pale stools, malaise, andpruritus. Investigations: bilirubin 76 imol/l, alkalinephosphatase 121 IU/l (normal

Dextropropoxyphene induced hepatotoxicity mimicking biliary tract disease

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Fig. 1 (Case 1) Liverfunction tests after oral Xwith 32-5 mg dextropropoxyphene at time 0 in c1, 2and3.

again showed centrilobular cholestasis. Cportal tracts contained numerous eosincfew mononuclear cells. The eosinophilinfrequently situated around bile ducts (occasionally were seen passing throug}ment membrane. Ultrastructurally dicanaliculi with loss of microvilli wasmarked in the centrilobular areas.concretions had a granular appearancethe cytosol, mitochondria showed eloncurling of the cristae (Fig. 3). After tijaundice she had pruritus and malaise, liPtests were still abnormal after 24 days (Ealkaline phosphatase 96, AST 102) but hto normal after five weeks.

PATIENT 2A 65 year old woman with a long histopain reported three episodes of jaundicemonths before hospital referral. On ea(she developed upper abdominal pain,

jaundice starting about 12 hours after taking Distal-gesic tablets (she normally took paracetamol alone).

;el"o""o On each occasion jaundice lasted a few days and was;e2 .--. accompanied by dark urine and pale stools. The;ej3A following investigations had been carried out: bili-

rubin 40 IU/l, AST 270, alkaline phosphatase 22KAU (N cytes was present in most portal tracts (Fig. 4). Nopolymorphs, significant oedema or bile ductule

aim//////// proliferation were seen. Liver function tests had16 24 34 returned to normal after 16 days except for a raised

alkaline phosphatase of 138. She remained quitewell with normal liver function tests after sevenweeks.

PATIENT 3

16 24 34 51 A 22 year old nurse was admitted to hospital withsciatica. She was treated with pelvic traction and

challenge analgesics (paracetamol, pentazocine, codeineeases phosphate). She was subsequently given aspirin and

Distalgesic. She then developed severe epigastricpain, nausea, and vomiting followed by rigors and

)edematous sweating. A few days later she became mildly icteric)phils and a with pruritus and pale stools. Her sciatica had easedIs were not so all analgesics were stopped. Investigations were(Fig. 2) and as follows: bilirubin 46, AST 149, alkaline phos-h the base- phatase 290, amylase 125 IU/I (normal

Bassendine, Woodhouse, Bennett, and Jamess'l

Fig. 2 (Case 1) Near the central veins, cholestasis was indicated by bile thrombi (arrow) (original magnification X1280).Oedematous portal tracts contain both eosinophils and lymphocytes (original magnification x512).

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Dextropropoxyphene induiced hepatotoxicity mimicking biliary tract disease

Fig. 4 Portal tract shows an increase in lymphocytes with an occasional eosinophil. Kupffer cells are hypertrophied withinthe adjacent sinusoids (original magnification X320).

Table Details ofpatients

Reference Age Sex Cliniical features Challenge Histology

1. Klein and Magida 39 M Fever, anorexia, malaise Mixed/hepatitic Intrahepatic cholestasis periportal1971 LFFs infiltrate, round cells,

polymorphs and cosinophils2. Daikos and Kosmidis 47 M Upper abdominal pain then dark Mixed LFTs

1975 urine, pale stools3. Lee and Rees 1977 56 M Relapsing jaundice, upper Mixed LFTs Mild portal fibrosis (before

abdominal pain followed by jaundice challenge)66 F Malaise and tiredness found to Pyrexia, mildly

have abnormal LFTs abnormal LFTs4. Ford et al. 1977 54 F Rigors, jaundice, pruritus Intrahepatic cholestasis, portal

A gall stones-laparotomy tracts infiltrated with plasmacells, lymphocytes, eosinophils

32 F Recurrent epigastric pain,nausea, dairk urine, pale stools

45 F Pruritus, pale stools and dark Intrahepatic cholestasisurine then jaundice. A gallstones-laparotomy

5. Pramming aind 62 F Abdominal pain '? gall stones Mixed LFTs Cholestasis, intrahepatic oedemaPeterson 1978

6. Van Brcnkilen and 72 F Fever, abdominal pain, Hepatitic LFTsSchrijver 1978 jaundice-'3 gall stoncs

7. Adverse Drug 56 F Nausea and rclapsing jaundiceCommittee Australia mixed LFTs1979

8. Lindholm 1979 77 F Fever and jaundiceCholcstattic LFTs

9. Kerst and Strik 46 F Recurrent cholestasis Intrahepatic cholestasis1979

LFTs= livcr function tests.

447

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448 Bassendine, Woodhouse, Bennett, and James

analgesic both alone and, more commonly, incombination with other drugs. Indeed Distalgesic isthe second most commonly prescribed analgesic inthe United Kingdom.'( Dextropropoxyphene ispresent in many preparations (currently at leasteight are listed in the British National Formulary)and has been in use for more than 15 years. Hepatictoxicity reliably attributable to dextropropoxypheneis rare - only 12 cases have hitherto been reported inthe literature.1-9 The first report was in 1971. Liverbiopsies have been carried out in only six patientsand rechallenge with dextropropoxyphene alone hasbeen carried out in only five patients (in two ofwhom a liver biopsy was also available). Thepreviously reported cases are summarised in theTable. The present three patients are important fora number of reasons.

CLINICAL HISTORYIn each case the history was of epigastric pain,nausea and vomiting and the symptoms wereaccompanied by fever and/or rigors followed byjaundice, pale stools and dark urine. In all threepatients a clinical diagnosis of biliary tract diseasewas made. The symptoms described have been afeature of over half of the previously documentedcases and this was sufficiently convincing to lead tolaparotomy for cholecystectomy in two. In all threeof our patients different analgesics had been takenover a variable period thus the incrimination ofdextropropoxyphene was difficult and only provenby rechallenge.

RECHALLENGEIn each instance symptoms of severe malaise andabdominal pain began within 24 hours after re-challenge with a low dose of dextropropoxyphenehydrochloride (32.5 mg) - equivalent to thecontents of only 1 tablet of the majority of com-pound preparations or half a tablet of the noncompound preparation. In patients 1 and 2 liverfunction tests became abnormal within 24 hours andwere predominantly hepatitic initially. This wasfollowed by a more prolonged cholestatic phase;three weeks postchallenge patient 1 still had a raisedserum bilirubin and patient 2 a raised alkalinephosphatase. The marked abnormality of liverfunction tests after challenge ultimately returnedcompletely to normal. Each patient felt unwell forabout two weeks. In patient 3 where rechallengefollowed only one dose liver function tests wereslower to become abnormal, were less deranged andreturned to normal more quickly. This patient'speriod of ill health was short.

LIVER HISTOLOGYIn both of the present patients where postchallengebiopsies are available the portal tract infiltrate ofeosinophils and lymphocytes is suggestive of a drughypersensitivity reaction. Although not very fullydocumented only one previous histological reporthas shown a portal infiltrate of plasma cells,lymphocytes and eosinophils. Other previous liverbiopsies have only described cholestasis. In patient 1where liver biopsy was carried out six days post-challenge during the more cholestatic phase of the'illness', centrilobular cholestasis was a feature. Theultrastructural changes with biliary concretions aresimilar to those found in chlorpromazine jaundice.

POSSIBLE MECHANISM OF HEPATOTOXICITYThe rarity of hepatic toxicity from dextropropoxy-phene, the clinical features of fever and rigorsshortly after exposure, the marked hepatic toxicityafter a small challenge dose and the histologicalfeatures all point to the probability of a hyper-sensitivity or immune mechanism. In this connectionit is of interest that 1 patient had a history ofhypersensitivity to other drugs (penicillins). Thehypersensitivity could be to dextropropoxypheneitself or to a normal or abnormal metabolite. Thesame dose of dextropropoxyphene in differentindividuals gives rise to a wide variation in plasmaconcentrations that result from differences inabsorption and biotransformation.11 All three of ourpatients were women, as were nine of 12 of theprevious cases. Men and women have been shown tohave different propoxyphene kinetic profiles after asingle dose, women exhibiting more extensive firstpass biotransformation to nor-propoxyphene. 12Elimination of nor-propoxyphene may be influencedby the rate of conjugation so plasma concentrationsof dextropropoxyphene and nor-propoxyphenedepend on rates of absorption, metabolism -predominantly N-demethylation - and conjugation.However the 'normal' half-life of propoxypheneafter a single dose is three hours and nor-propoxyphene is 16-8 hours so that peak concentra-tions of dextropropoxyphene metabolite(s) couldaccount for the time scale of the drug's hepato-toxicity. The mechanism of this rare hepatotoxicreaction requires further investigation.

We thank Dr R Lendrum for permission to publishdetails of case 3 and also Mrs A Asch who preparedthe manuscript.

References

1 Klein NC, Magida MG. Propoxyphene (Darvon)hepatotoxicity. Am J Dig Dis 1971; 16: 467-9.

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Dextropropoxyphene induced hepatotoxicity mimicking biliary tract disease 449

2 Daikos GK, Kosmidis JC. Propoxyphene jaundice.JAMA 1975; 232: 835.

3 Lee TH, Rees PJ. Hepatotoxicity of dextropropoxy-phene. Br Med J 1977; II: 296-7.

4 Ford MJ, Kellett RJ, Busuttil A, Finlayson NDC.Dextropropoxyphene and jaundice. Br Med J 1977; II:674.

5 Pramming S, Petersen HO. Dextropropoxifene andliver involvement. Ugeskr Laeg 1978; 140: 2249.

6 Breukelen FJM van, Shrijver H. Icterus during treat-ment with D-propoxyphene (Depronal). Ned T Geneesk1978; 122: 870-2.

7 Adverse Drug Reactions Advisory Committee.Dextropropoxyphene. Med J Aust 1979; 2: 494.

8 Lindholm L. Fever, skin and liver reactions in a patienttreated with Paraflex comp. Lakartidningen 1979; 76:2795-6.

9 Kerst AJFA, Strik HPM. Bijwerkingen van Genees-middelen. Ned Tidschr Geneeskd 1979; 123: 1570-2.

10 A new look at Distalgesic. [Editorial]. Drug Ther Bull1978; 16: 71-2.

11 Verebely K, Inturrisi CE. Disposition of propoxypheneand norpropoxyphene in man after a single dose. ClinPharmacol Ther 1974; 15: 302-9.

12 Inturnsi CE, Colburn WA, Verebey K, Dayton HE,Woody GE, O'Brien CP. Propoxyphene and nor-propoxyphene kinetics after single and repeated dosesof propoxyphene. Clin Pharmacol Ther 1982; 31:157-67.

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