© U.S. Cancer Pain Relief Committee, 1999 0885-3924/99/$–see front matterPublished by Elsevier, New York, New York PII S0885-3924(99)00051-2

Vol. 18 No. 2 August 1999 Journal of Pain and Symptom Management 111

Original Article

A Comparison of Subcutaneous Morphine and Fentanyl in Hospice Cancer Patients

Roger Hunt, BMBS, GDPH, Belinda Fazekas, DipAppSc, BN ,David Thorne, MBBS, and Mary Brooksbank, MBBS, FRACS

Southern Community Hospice Programme (R.H.), Daw House Hospice, Daw Park, SA, Australia; Flinders University of South Australia (B.F.), Bedford Park, SA, Australia; Western and Northern Palliative Care Service (D.T.), Queen Elizabeth Hospital, Woodville, SA, Australia; and Central and Eastern Adelaide Palliative Care Service (M.B.), Royal Adelaide Hospital, Adelaide, Australia

Abstract

This study compares subcutaneous (sc) morphine and fentanyl with respect to pain control and side effects using a 6-day randomized, double-blind, cross-over design. Results were obtained from 23 patients (12 males and 11 females: mean age of 70.5 years) who could tolerate morphine. Thirteen patients were randomized to receive morphine for the first 3 days followed by fentanyl; 10 received fentanyl first followed by morphine. There were no significant differences in the scores for pain between the two drugs, suggesting that fentanyl is equally efficacious and the conversion ratio of morphine 10 mg: fentanyl 150

m

g is appropriate. Patients had more frequent bowel movements during days 4–6 while on the fentanyl arm [

t

-test, df (22),

P

5

0.015]. Other measures for nausea, delirium, and cognitive function showed no differences between the two drugs. This study highlights the need to further assess the role of various opioids in hospice patients, and emphasizes the requirement for sensitive and simple cognitive tests in this population.

J Pain Symptom Manage 1999;18:111–119.

© U.S. Cancer Pain Relief Committee, 1999.

Key Words

Cancer pain, morphine, fentanyl, subcutaneous infusion, adverse effects,

palliative treatment, constipation

Introduction

Opioids are the mainstay for the relief ofpain in palliative care. When the oral route be-comes difficult or ineffective, a subcutaneous(sc) infusion of opioid produces a constantplasma level of drug for pain relief.

1–3

Mor-phine is generally considered to be the drug of

choice for cancer pain,

4

but it can cause unac-ceptable adverse effects in some patients, withhallucinations, confusion, nausea, constipationand sedation being particularly troublesome.

2–6

In these circumstances, change to another opi-oid may relieve the adverse effect.

7

Oxy-codone, for example, compared favorably withmorphine in studies of both postoperative andpalliative care patients, causing less nausea andpsychotomimetic effects.

8–10

There are, how-ever, very few reports in the literature concern-ing the neuropsychological effects of long-term opioid administration.

11

Address reprint requests to:

Roger Hunt, BMBS, South-ern Community Hospice Programme, Daw HouseHospice, Daw Park, SA, 5041, Australia.

Accepted for publication: October 13, 1998.

112 Hunt et al. Vol. 18 No. 2 August 1999

Fentanyl, a synthetic opioid commonly usedduring anesthesia, is also now being used to re-lieve pain in terminally ill patients.

2

Fentanyl is li-pophilic, rapidly penetrating the central nervoussystem, and has high potency as an analgesic. Ithas a terminal elimination half-life of approxi-mately 6.0 hours, and its metabolites, includingnorfentanyl, are thought to be pharmacologi-cally inactive.

12

Fentanyl quickly reaches a steadystate when administered by continuous intrave-nous infusion.

13

Studies of the plasma concen-trations following the intravenous (IV) andtransdermal administration of fentanyl havebeen published previously.

14–17

There are no es-tablished data on the pharmacokinetics of fenta-nyl administered by continuous sc infusion.

Studies have recently appeared in the litera-ture which suggest that fentanyl may producefewer and less severe side effects than mor-phine, and is preferred by some patients. Onestudy described 11 patients with cancer painwho experienced unacceptable morphine sideeffects which improved when switched to a scinfusion of fentanyl.

18

Studies comparing sus-tained-release oral morphine and transdermalfentanyl indicate equivalent analgesia, but lessconstipation, sedation, and nausea with trans-dermal fentanyl.

19,20

Patients in these studiesexpressed a preference for fentanyl. It is possi-ble these differences are due to different prop-erties of the two opioids and the differentroutes of administration.

Our aim was to compare morphine and fen-tanyl for pain relief and adverse effects whenboth drugs were administered by the sc routein a group of hospice patients with cancer. Adouble-blind cross-over design was chosen,with patients randomized to receive either 3days of sc morphine followed by 3 days of scfentanyl or vice versa. The pharmacokineticdata obtained during this study will be the sub-ject of a separate report.

Methods and Measures

Method

Patients were enrolled from three Adelaidehospices: Daw House Hospice, Mary PotterHospice, and Philip Kennedy Centre Hospice.In these hospices, the average length of stayand proportion of admissions resulting indeath are 13 days with 53% deaths, 16.6 dayswith 90% deaths, and 12 days with 80% deaths,

respectively. Hospice in-patients were eligibleto participate if they were taking opioids forpain relief, were able to give informed consent,and were likely to complete the 6-day study.Patients were excluded if hematology and bio-chemistry results were known to be grosslyabnormal, the patient was likely to die or bedischarged within the 6 days of the study, or if,for some other reason, staff felt that the patientwould be unable to comply with the protocol.For example, patients were excluded if therewas a clear history of morphine intolerance.

Randomization was carried out by the phar-macy at the Repatriation General Hospital andsyringes for sc infusion were prepared andcoded by the respective pharmacies at the par-ticipating institutions. A conversion factor ofmorphine sulfate 10 mg:fentanyl citrate 150

m

gsc was used. The syringes were labeled with thenames of both drugs and equivalence doses.To ensure “blinding,” the volume of fluid inthe syringes was kept constant for each patientover the 6 days. After 72 hours, the patientswere changed to an equivalent dose of the al-ternative opioid.

Because of the difficulties of “blinding” break-through medication, meperidine was orderedfor breakthrough pain, using a dose of one-sixthof the 24-hour sc infusion dose and a conversionfactor of morphine sulfate 10 mg sc:meperidine100 mg sc. Two or more doses of breakthroughmedication in a 24-hour period resulted in a30% increase in the sc infusion dose for the fol-lowing day.

Measures

A standard protocol form was completed foreach patient recording, age, gender, diagnosis,drug therapy (particularly the analgesics, coanal-gesics, antiemetics, laxatives, tranquilizers, andthe use of ketamine, octreotide, or lidocaine),liver and renal function tests, complete bloodcount and calcium level, a pain history includ-ing pain score, previous exposure to opioids,and side effects. The routine administration ofnonopioid medications continued throughoutthe 6 days of the study.

At the end of the morning and afternoonnursing shifts, patients were asked three ques-tions to quantify their pain levels. These were:“On a scale of 0–10, 0 being no pain and 10 be-ing the worst pain imaginable, what numberwould you give your pain right now?” “Overall,

Vol. 18 No. 2 August 1999 Comparison of SC Morphine and Fentanyl 113

over the shift I have been caring for you, whatnumber would you put on your pain?” “Hasyour pain been controlled for 50% of the shift(Y/N)?”. Pain levels and nausea score (0–10, 0being no nausea and 10 being worst imagin-able nausea) were recorded by nurses on adaily observation sheet. The Saskatoon Delir-ium Checklist, chosen to measure mental sta-tus, was also completed at these times. Thischecklist has been shown to detect mild ortransient impairment in the early phases ofdrug toxicity with the numerical ratings corre-sponding to the criteria for delirium describedin the

Diagnostic and Statistical Manual

, 3rd edi-tion.

21

A record of medication administeredover the 6 days and a record of bowel activity,including the number of bowel movementswere maintained for the 6 days. Other side ef-fects, including itching, myoclonus, and hallu-cinations, were asked about and recorded ifpresent.

At the end of the third day, trail making andsemantic fluency tests were applied to assesscognitive function.

22,23

Parallel versions wereadministered at the end of day 6. The trail mak-ing test assesses planning ability, visuomotorspeed, and concentration. The semantic flu-ency test is a verbal analogue to the trail makingtest. The semantic fluency results were scoredas the number of correct words generated, thenumber of rule breaking errors, the number ofperseverative errors, and the total number ofwords generated. Both tests were implementedby the research assistant trained and supervisedby a registered clinical psychologist. Overallpreference for the first or the second opioidwas recorded at the end of the sixth day.

Venous blood samples for plasma concentra-tions of the drugs were taken at the end ofeach 72-hour period of drug administration.The samples were centrifuged and frozen,then stored until analysis. The results of theanalysis will be reported in another paper.

Results

Fifty patients met the entry criteria and wereasked to participate. Patients who were askedbut declined to participate gave the reasonsoutlined in Table 1. Thirty patients partici-pated, with 23 patients completing the study.There were 13 males (52.2%) and 10 females

(47.8%), with a mean age of 70.5 years (range48–89 years). Thirteen (56.5%) participantswere taking controlled-release morphine (MSContin, Bard Pharmaceuticals, England) priorto commencement of the infusion; four(17.4%) were receiving sc morphine; four(17.4%) were taking morphine syrup or sus-tained-release morphine (Kapanol, FauldingPharmaceuticals, Salisbury, Australia). Onlytwo patients (8.6%) were not taking morphine;both were taking oxycodone.

Thirteen patients (56.5%) were randomizedto start the study with sc morphine and 10(43.5%) with fentanyl. Profiles of the partici-pants are shown in Table 2. There were no sig-nificant differences between the two groupswith respect to age, gender, biochemistry, andhematological results, or previous opioid useand reports of side effects. As expected in hos-pice patients, biochemical and hematologicalabnormalities were common. Only one patienthad a hemoglobin level in the normal range,only two patients had normal albumin levels,and 20 patients had elevated liver functiontests. Five patients had mild renal impairment,with the highest creatinine level being 0.17mmol/L (patient number 13). Three patients(numbers 2, 9, and 22) had elevated calciumlevels (uncorrected) of 2.65, 2.96, and 2.75mmol/L, respectively.

Withdrawals

Seven patients withdrew during the study(Table 3). Six of these had been taking con-trolled-release morphine prior to the start ofthe study. Six patients withdrew prior to cross-over and one patient withdrew after cross-over.Six patients withdrew while on the fentanylarm, and one patient withdrew on the mor-phine arm. The reasons for withdrawal varied:

Table 1

Reasons for Nonparticipation

Number of patients Reason

9 Satisfied with present medication5 Too worried or upset to consider study2 Hoping for discharge1 “Too old” (patient comment)1 Too tired1 Too nauseated on morphine1 Consented, died prior to start

114 Hunt et al. Vol. 18 No. 2 August 1999

two were due to the onset of confusion, andone each due to hallucinations, deterioratingphysical condition, uncontrolled pain, and ex-ceeding the 500 mg meperidine limit (which

also caused confusion). One patient withdrewwith the request to remain on the current infu-sion drug (morphine). One patient (number20) had an exceptionally high white cell count,

Table 2

Participants

Patient number Gender Age Cancer diagnosis Opioid prior to study 24-hour dose

b

Drug schedule (infusion drug given first)

1

a

M 75 mesothelioma oxycodone 13.3 morphine3 F 49 ca endometrium MS Contin 266.6 morphine5 M 84 ca lung sc morphine 10 morphine8 F 56 ca ovary sc morphine 30 morphine

10 F 73 adeno ca colon sc fentanyl 13.3 morphine11 M 88 adeno ca lung MS Contin 80 morphine13 M 69 ca kidney MS Contin 6.6 morphine17 F 66 unknown MS Contin 40 morphine19

a

F 80 n h lymphoma MS Contin 16.6 morphine21 M 71 ca prostate sc morphine 20 morphine24 M 69 ca prostate MS Contin 10 morphine27 M 75 ca prostate Kapanol 70 morphine28 M 77 unknown MS Contin 6.6 morphine29 F 73 chondrosarcoma sc morphine 7.5 morphine

2 M 48 ca caecum sc morphine/Kapanol 40 fentanyl4 M 81 myeloma Kapanol 6.6 fentanyl6 F 74 ca breast sc morphine 95 fentanyl7

a

F 81 tcc bladder sc morphine 200 fentanyl9 F 63 renal cell ca sc morphine 180 fentanyl

12 M 76 ca kidney sc morphine 40 fentanyl14 M 76 ca lung sc morphine 40 fentanyl15

a

M 75 ca pancreas MS Contin 20 fentanyl16 M 56 glioma MS Contin 50 fentanyl18 F 89 tcc bladder sc morphine 5 fentanyl20

a

M 65 ca esophagus rectal oxycodone 30 fentanyl22

a

F 83 unknown MS Contin 20 fentanyl23 F 63 pseudo myxoma sc morphine 15 fentanyl25

a

M 69 ca lung MS Contin 13.3 fentanyl26 M 69 ca lung MS Contin 20 fentanyl30 F 77 rectal melanoma MS Contin 3.3 fentanyl

a

Denotes withdrawal from the study.

b

Equivalent subcutaneous morphine dose (mg) in the 24 hours prior to commencing the study.nh

5

non-Hodgkins lymphomatcc

5

transitional cell carcinoma

Table 3

Withdrawn Patient Characteristics

No. Age Sex OpioidAbnormal

results

a

Infusion dose

Withdrawal reason Day

Drug on withdrawal

Recommenced on

Subsequent condition

1 75 M MS ALP 26.58 Confusion 5 fentanyl sc morphine Improved but drowsy

7 81 F MS K 200 Meperidine 2 fentanyl sc morphine Confusion resolved

15 75 M MS K, UREA, ALP, ALT, WCC

20 Confusion 1 fentanyl prn morphine Less confused

19 80 F MS K, UREA, ALP 16.6 Comfortable 3 morphine sc morphine Remained comfortable

20 65 M RO WCC 24.38 Hallucinating 1 fentanyl sc morphine Resolved22 83 F MS ALP, WCC, CA

b

19.2 Deterioration 2 fentanyl sc morphine Died 3 days later

25 69 M MS ALP, WCC, PLATELETS

13 Uncontrolledpain

3 fentanyl MS Contin Unknown? continued

Abbreviations:

ALP

5

Alkaline phosphatase; ALT

5

Alocnine amino transferese; Ca

5

calcium; K

5

potassium; MS

5

MS Contin; RO

5

rectal oxy-codone; WCC

5

white cell count

a

Results are above the normal range.

b

Indicates the result being grossly abnormal (ca 2.75) (corrected prior to study commencement).

Vol. 18 No. 2 August 1999 Comparison of SC Morphine and Fentanyl 115

and when this patient was excluded from theanalysis, there were no significant differencesbetween patients who withdrew and those whocompleted the study.

Treatment Preferences

At the completion of the 6 days, patientswere asked to indicate which of the periods ofdrug administration they preferred. Data wasnot available for 4 patients, and 9 patients saidthey had no preference for one drug or theother. Ten patients expressed a preference; 4preferred morphine, and 6 preferred fentanyl(Pearson’s chi-square

P

5

0.269).

Pain

Using Pearson’s chi-square analysis, therewas no significant difference in the pain scoresbetween the drugs overall. However, on a shift-by-shift analysis, the patients receiving fentanylon the second shift of day 2 reported morepain than those patients receiving morphineon the same shift [

t

-test, df (20),

P

5

0.032].An insignificant but continued trend was seenon the first shift of day 3. Differences in the

pain scores between the drugs were not ob-served on any of the other shifts.

Opioid Dose

Figure 1 displays the total opioid dose (mor-phine equivalents) administered over the 6 daysfor both groups. Fisher’s exact test (

P

5

0.067)suggests a period effect with increasing dosesover the 6 days. Overall, the morphine-firstgroup had a lower dose of opioid throughoutthe study than those patients who receivedfentanyl first. The number of meperidinedoses in the fentanyl-first group was signifi-cantly greater on days 2 and 3 than the mor-phine-first group (Fisher’s exact test

P

5

0.025and

P

5

0.032, respectively). This correspondsto the higher pain scores on these days for thefentanyl-first group.

Nausea

There was a large number of zero nauseascores throughout the study indicating thatnausea was generally well-controlled. The nu-meric nausea scores were recoded as nauseabeing present or absent, and were analyzedwith Pearson’s chi square. There was no signifi-

Fig. 1. Total opioid dose per day by drug schedule, displaying mean, interquartile range, and range. Open circleindicates outlier values. Asterisk indicates extreme values.

116 Hunt et al. Vol. 18 No. 2 August 1999

cant difference in nausea prevalence betweenthe two drugs.

Saskatoon Delirium Scores

Total scores for delirium for each shift overthe 6 days were examined and revealed nosignificant differences between the two drugs.

Semantic Fluency

A Mann-Whitney U-test was applied to eachparameter for the four tests. There were no sig-nificant differences detected between thedrugs with respect to the words generated orthe error rate.

Trail Making

A large number of patients were unable tobe scored for both testing phases of trail mak-ing, either because they were unable to attemptthe test, or were unable to complete it withinthe specified time limit. Consequently there wasa small number of patients who achieved a scorefor both testing phases. Pearson’s chi-squareanalysis on these scores revealed no significantdifference between the drugs for this test.

Bowel Movements

This variable revealed a large number ofdays with no bowel movements, suggestingconstipation was common. A

t

-test was appliedto the total number of bowel actions for days1–3 and days 4–6. There was a significant dif-ference [df (22),

P

5

0.015] between the drugsduring days 4–6 (Fig. 2). The patients receivingfentanyl as the second drug demonstrated sig-nificantly more bowel movements than the pa-tients receiving morphine as the second drug.There was no significant difference betweenthe drugs during the first arm of the study.

Discussion

Morphine and fentanyl administered by thesc route have not previously been compared. Pa-tients, staff, and researchers were blinded towhich drug was being administered. Previousopen studies have compared these two drugs ad-ministered by different routes.

19,20

This studywas designed to detect differences in pain reliefand adverse effects due to the intrinsic pharma-cological properties of the different opioids

Fig. 2. Number of bowel movements, displaying mean, interquartile range, and range. Open circle indicates out-lier values. Asterisk indicates extreme values.

Vol. 18 No. 2 August 1999 Comparison of SC Morphine and Fentanyl 117

rather than to the different routes of adminis-tration.

The results indicate that fentanyl is an effec-tive analgesic in this population of hospice can-cer patients. Fentanyl was significantly less con-stipating than morphine. When the inhibitoryeffect of morphine on bowel peristalsis was re-moved, a return of bowel function was foundwithin the 3-day period. It is acknowledged thatthe small period of observations may have re-duced the opportunity to observe changes and alonger period may have produced greater dif-ferences. Other side effects were not signifi-cantly different to those observed with mor-phine. Only 6 patients were able to indicate apreference for fentanyl and 4 for morphine.

The study did not confirm the range of ben-efits with fentanyl suggested by other studies.In the retrospective case series described byPaix et al., patients were switched from mor-phine because they experienced profound ad-verse effects and improved markedly with fen-tanyl.

18

The benefits of a change to fentanylfrom morphine would be expected to be mostmarked in those patients experiencing toxicityfrom morphine. In contrast, patients in ourstudy were mainly stable and tolerating mor-phine. Patients who had a known sensitivity tomorphine, and those with marked renal im-pairment who could accumulate active mor-phine metabolites, were not asked to partici-pate and were excluded from our study. Anumber of patients who were stable on fenta-nyl declined to enter our study because of pre-vious adverse experience with morphine.

To determine the relative therapeutic ratioof morphine and fentanyl with respect to effi-cacy and side effects would require further in-vestigation not only in morphine-tolerant pa-tients but also in an opioid-naive population.Our selection of patients who were toleratingmorphine would have reduced the ability todetect differences between (and preferencesfor) morphine and fentanyl. Enrolling opioid-naive patients in a study would eliminate selec-tion bias, and a cross-over design could thenbetter help determine the therapeutic profileof pain relief versus adverse effects for each drug.

Previous comparisons of oral, controlled-release morphine and transdermal fentanylfound that fentanyl produced less sedation,constipation, and nausea, and improved qual-ity of life. Significantly more patients indicated

a preference for fentanyl.

19,20

The much smallernumber of patients in our study reduced theability to demonstrate such differences. Themarked preference for transdermal fentanylcould be due to a stigma associated with mor-phine, whereas in our study the “blinding” ofpatients and observers eliminated any negativebias associated with morphine. The differentroutes of administration are also relevant. Oralmorphine is absorbed and metabolized in itsfirst pass through the liver to produce levels ofactive metabolites which are higher than whenadministered via the subcutaneous route, andit has been suggested that morphine metabo-lites contribute to adverse effects.

24

Further-more, oral morphine may have direct adverseeffects on the gastrointestinal tract whichwould be less when administered subcutane-ously. Nevertheless, we found significantly lessconstipation with sc fentanyl compared with scmorphine, suggesting fentanyl is intrinsicallyless inhibiting of intestinal motility than equi-analgesic doses of morphine.

The use of meperidine for breakthroughpain possibly acted to obscure differences be-tween the morphine and fentanyl arms. Anumber of patients (including one who with-drew) were dissatisfied with meperidine. Somestated that meperidine caused a feeling of diz-ziness, detachment, or confusion, and most pa-tients commented that the sc meperidine break-through injections were painful. Meperidinewas chosen as the breakthrough medicationdue to its availability at all participating sites,and because morphine or fentanyl for break-through pain would have been logistically diffi-cult to administer in a blinded way. The studyprotocol would have been more complex forstaff, thereby increasing the chance of protocolviolations. The use of a blinded breakthroughdrug identical to the infusion drug should beconsidered in subsequent studies through theuse of infusion devices capable of deliveringmeasured doses as boluses.

A number of patients in the fentanyl-firstgroup experienced pain on days 2 and 3, andrequired more breakthrough meperidine. Thismay be related to an inadequate ratio for con-verting oral morphine to sc fentanyl, or it maybe that the steady state of sc fentanyl was notreached before oral morphine levels dimin-ished. Pharmacokinetic data may clarify thesepossibilities. It is notable that none of the pa-

118 Hunt et al. Vol. 18 No. 2 August 1999

tients in this study experienced an obviouswithdrawal syndrome when switching fromoral or sc morphine to sc fentanyl.

25–27

The tests of cognitive function we used wereinappropriate to show subtle changes in thispopulation of patients. In accordance with therecommended test guidelines for trail making,patients were asked to stop the test at 5 min-utes. Those who were unable to complete thetest within that time were scored as “attemptedbut incomplete.” The results for those patientswho completed the test were scored in thenumber of seconds taken. Many patients weretoo weak and frail to complete one or bothparts of the test in either or both phases. Thesmall number of patients completing this test,together with the large variability in scoresfrom 1 to 300 seconds, made analysis problem-atic. The semantic fluency test also appeared tobe too taxing for the patients. Many were tootired or not able to concentrate enough tothink of words. One patient commented on hislack of education and could not think of wordswithin one category. A more sensitive and lessdemanding test is required to assess cognitivefunction in this population.

Morphine in ampules is relatively cheap, aboutone-third the cost of an equivalent amount offentanyl for parenteral administration. Sustained-release oral morphine is also about three timesthe cost of parenteral morphine. The fentanylskin patch is more expensive again. In weighingthe cost–benefit of each opioid preparation, it isimportant to consider the professional time ittakes to set up a syringe driver each day, the costof treating adverse effects (laxatives, antiemetics,hospitalization, etc.), and the patient’s quality oflife. The question of who bears the cost will alsoinfluence prescribing. A full cost analysis is be-yond the scope of this paper.

In conclusion, sc fentanyl is an effective anal-gesic in hospice patients with cancer and it ap-pears to be less constipating than morphine.We did not find the range of other differencesreported in previous studies. We suggest thatthis is because patients who participated in ourstudy were tolerating morphine. Patients whowere sensitive to morphine and possibly morelikely to demonstrate an improvement whenchanged to another drug were excluded. Weconfirmed the conversion ratio of sc morphinesulfate 10 mg:sc fentanyl citrate 150

m

g, butsuggest clinicians should be prepared to ad-

minister additional breakthrough doses in thedays following a substitution of oral morphinewith sc fentanyl. A great deal of pharmacoki-netic and basic scientific work is required tofurther elucidate the properties and roles ofthese opioids in palliative care.

Acknowledgment

Appreciation is extended to StatewideProjects (South Australian Health Commission)and the Janssen-Cilag Company for fundingthis study. Recognition is extended to themany medical and nursing staff in the hospicesinvolved for their time and dedication in car-ing for the patients participating in this study,and who, by carefully completing the datasheets, enabled this study to proceed. Thankyou also to the pharmacists involved in prepar-ing the syringes, Lynne Giles for her statisticalexpertise, and Anna McLure for preparing,storing, and collating the blood samples. Spe-cial gratitude to the patients and their relativeswho participated knowing that they may not re-ceive any benefit from doing so, but were pre-pared to change medications and undergo test-ing anyway. The assistance of the SouthAustralian Palliative Care Research Group isgratefully acknowledged.

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