MORFINA SUBCUTANEA

8/7/2019 MORFINA SUBCUTANEA

1/8


2/8

capital costs of pumps and recurring cost ofdisposables needed for the pumps are majorbarriers to their use.Hence cost-effective meth-ods of continuous delivery of parenteralopioidsfor palliative care purposes were explored.

This study was undertaken to determine themost cost-effective method of parenteral mor-phine administration for cancer pain manage-ment in a resource-constrained health caresystem. The study compared the alternate subcu-taneous(SC)routetotheIVrouteforcontinuousadministration of morphine. Morphine wasstudied because it is inexpensive and readilyavailable for use in rural and resource-scarcesettings. Thisstrong opioid iswell studiedanditcanbeusedsafelyinawidevarietyofsettings.

PATIENTS AND METHODS

This study was conducted on the Pain andPalliative Care ward of a regional cancercentersituated in southern India. Thirty terminally illcancer patientswho presentedconsecutively tothePainClinicattheRegionalCancerCentreinTrivandrum, Kerala, India, with severe pain(numerical pain intensity rating on a numeri-cally-anchored visual analogue score [VAS]greater thaneight out of 10, with zero being nopain and 10 being pain as bad as the patientcould imagine) were included. Informed con-sent was obtained and the patients were allo-cated randomized into two groups using a ran-domnumbertable.PatientsinGroup I receivedIV continuous morphine infusion. Patients inGroupII received SC continuous morphine in-fusion.Patients with generalized edema,coag-ulation disorders and erythema were excludedfrom the study. Further stratification in eachgroup was as follows: (i) opioid-nave group Ipatients were given 20 mg morphine IV; groupIIpatientsreceived30mgmorphineSCover24hrs, (ii) patients who were previously taking

oral morphine but were presentlyexperiencingpain due to inability to take the medicationorally were given morphine equivalent to theirprevious 24 hours oral intake in both groups Iand II, (iii) patients who had pain in spite ofregularly-scheduledoral morphine doses weregiven morphine in a dose equivalent to 1.5times the dose received in previous 24 hoursthrough the respective route.

The calculations for morphine dosage instrata (ii) and (iii) were as follows:

Step (a): Totaloraldoseofmorphinerequiredto control pain was calculated as

described above,Step (b): Equivalentdosages forIV(group I)and SC(groupII) routes were cal-culated (oral: SC: IVthe dosageconversion ratio for morphine was3:2:1). Thus group I patients re-ceived 33% and group II patientsreceived50%ofthecalculatedoraldose of morphine over 24 hoursthrough the IV and SC routes, re-spectively.

The dose of morphine was diluted in 0.9%

normal saline to a total volume of 60 mL in ameasured volume chamber with micro drip fa-cility.ThiswashungfromanIVpoleataheightof1 meterfromthe patientsbed andconnectedto an 18 gauge small vein (butterfly) needleplaced subcutaneouslywith bevel facingdown-wards, in the right infraclavicular region ingroup II patients, and to an indwelling venouscannulaingroupIpatients.Thesolutionwasal-lowedtodrip from themeasuredvolumecham-ber and the rate of was flow adjusted manually(Figure1). Inboth groups, flowwas adjustedtoa rate of 20 micro drops per minute in the first

hour, 10 micro drops per minute in the secondhour, and thereafter 5 micro drops per minute.At any time that pain was not controlled, infu-sion rates were further increased by 5 microdrops per minute.

The baseline parameterspain intensity mea-sured on the visual analogue scale (VAS),pulserate (PR), blood pressure (BP), and respiratoryrate (RR) were noted prior to drug administra-tion. After initiating each infusion, theseparam-eters as well as sedationscore, pruritus, nausea,and vomiting were noted at fixed intervals, i.e.,1, 2, 3, 4, 8, 12, 16, 20 and 24 hours. Break-

throughpainwasmanagedwitha rescueanalge-sic dose of intramuscular tramadol 50 mg.

STATISTICAL ANALYSIS

The between-groupcomparison of quantita-tive data: respiratory rate,pulse rate, andbloodpressure was analyzed using the students t

28 JOURNAL OF PAIN & PALLIATIVE CARE PHARMACOTHERAPY


3/8

test.Qualitativedatacomparisonbetweengroupswas done by chi-square test for sex. VAS wastested by paired t test and paired correlationand sedation tested with ANOVA.

DISCUSSION

Cancer is a major problemworldwide. Pres-ent estimates indicate that every year, ten mil-lion new cancer patients are diagnosed, ofwhomsixmillion die.5 Theincidenceof canceris estimated to be increasing each year. Two-thirds of cancer patients are from developingcountries where eighty percent of cancers aretoo far advanced tobe curable at the timeof di-agnosis. Yet, developing countries have accesstoonly five percent of theworlds resources for

cancer control.6 The Indian scenario typicallydepicts this picture with one million new can-cer cases detected yearly of whom eighty per-cent have disease beyond the scope of cure.7,8

This situation necessitates pain relief and pal-liative care for the vast majority of Indian can-cer patients at the time they are diagnosed.

Cancerpatients presentingfor reliefof acute,severe pain are common in oncology practice.

Uncontrolled pain in these patients may be dueto advancing malignancies or inadequate anal-gesia.9 Pain; upper obstructive gastrointestinallesions; and nausea and vomiting induced byradiation, chemotherapy,anddisease mayalso

limit oral intake of analgesics.10,11

Parenteralanalgesia with strong opioids often is neededfor these patients.

Among the various parenteral routes formorphineadministration,wewereinterestedinthe IV and SC routes, practiced commonly inour center. The IV routewas useful in those pa-tients with an intravenous cannula, while theSCrouteproved tobeusefulevenin terminallyillpatientswithpoorvenousaccess.Incompar-ison to intermittent boluses, continuous infu-sionscould provideconstantbloodlevelsof thedrug. Although the drug could be diluted in

larger volumes of infusion solution, we usedlowvolumesforboth routes toensureeffectivecomparison. We planned to use tramadol forbreakthrough pain because it was easily avail-able in our center and is recommended as anadjuvant for managing severe cancer pain.

We used the gravity-dependant drip methodtoprovide morphine infusions in ourstudy. Thecost incurred in the use of various infusiontech-niques is high and the problems associated aremany (Table 1). The use of measured volumedrip set and small (scalp) vein needle set wasconsideredbecausein outlyinghealthcenters indevelopingcountries thisequipment isavailableandpersonneltrainedtomanageinfusionpumpsoften are absent. Another advantage of simplegravity drip administration was that the rate ofdrug flow could be adjusted according to pa-tients response.Thetechnique issimple,easytoadminister, does not need trained personnel andis cost effective. This can be safely providedeven forpatientsreceivinghomecare.However,the titration of drug has to be judiciously fol-lowed at the end of first and second hours. Oth-erwisedrugoverdoseresultinginrespiratoryde-pression and sedation may occur.

Our study demonstrated that morphine ad-

ministered by the IV and SC routes producedsimilar favorable effects on vital parameters.The stability noticed among the groups inpulse rate and respiratory rate along with asteady, slight reduction inblood pressure overtime reflects the reduction in endogenouscatcholamine response resulting from relief ofpainandhencegoodanalgesia(Tables2 through5). The pain relief achieved with morphine in-

Koshy et al. 29

FIGURE1. TheGravityDrip AdministrationMethod


4/8

TABLE 1. Comparison of costs incurred with various techniques adopted for continuous morphine infu-sions and associated problems (1 US dollar = 44 Indian rupees [Rs])

Equipment Capital costCost of

disposablesAvailability ofdisposables

Ease of handling by nursing staff

Graseby syringe driver Rs 35,000 Rs 130 Freely available HighBraun Perfusor Rs 35,000 Rs 20 Freely available Technical expertise required

IVAC PcA Machine Rs 150,000 Rs 85 Freely available Technical expertise required

Spring fusor Rs 2,000 Rs 150 Not freely available Difficult to handle

Nippin Rs 1,500 Rs 10 Device not freelyavailable

Difficult to fit

Measured volume drip set Rs 35 Rs 10 Widely available Easy to handle


TABLE 2. Demographic data: Comparison of baseline parameters, Group I: received morphine intrave-nously, Group II: received morphine subcutaneously (n = 15 in each group)

Variable Mean standard deviation F value/t Chi square value P value

Group I Group II

Age 56.8 14.74 58.87 11.46 0.43 0.671

Sex (M:F) 10:5 8:7 0.556 0.456

Pulse rate 85.4 14.5 86.4 8.02 0.055 0.817

Respiratory rate 22.27 4.4 21.07 4.65 0.527 0.474

Systolic blood pressure 116.67 9.76 118.8 36.39 0.048 0.828

Visual analogue score 8.4 1.12 8.4 1.12 0.0001 1.000

P value significant (P < 0.05). This table shows both Group I and Group II were comparable in the various parameters noted.

TABLE 3. Pulse rate (PR) measured at fixed intervals in Group I (received intravenous morphine) andGroup II (received subcutaneous morphine). In each group n = 15

Pulse ratemeasured

during infusion(per minute)

Group I Group II

Inter group t value P valueMean Standarddeviation

Mean Standarddeviation

Baseline 85.4 14.50 86.4 8.02 0.055 0.817

1 hour 84.93 16.64 83.93 9.99 0.04 0.843

2 hours 86.07 15.07 82.87 7.38 0.545 0.466

3 hours 85.20 13.15 81.20 8.87 0.954 0.337

4 hours 86.07 15.43 81.73 9.74 0.846 0.365

8 hours 85.87 12.39 83.67 8.55 0.321 0.576

12 hours 81.73 10.08 81.73 9.95 0.000 1.000

16 hours 83.07 9.07 80.53 10.23 0.515 0.479

20 hours 82.67 10.65 82.20 10.42 0.015 0.904

24 hours 82.13 11.02 80.00 10.79 0.001 0.974

* P < 0.05 Significant. No statistically or clinically significant difference was noted in pulse rate in either group.This indicates that both Groupswere comparable and had effective pain relief maintaining this vital sign in normal limits.


5/8

fusions by both routes was similar and effec-tive, irrespective of the initial pain scorethroughoutinfusion(Table6).Theonlysideef-fect noticed in both groups was mild sedation(Tables 7 and 8). This was acceptable, ratherclinically useful and there was not a need for

close supervision of the patient during medica-tion. Vomiting, nausea, and pruritus wereabsent in these patients. The absence of break-through pain in both groups could be the resultof constant blood levels of morphine duringmedication. Thus, the SC route of administra-

Koshy et al. 31

TABLE 4. Respiratory rate (RR) measured at fixed intervals in Group I (who received intravenous mor-phine) and Group II (who received subcutaneous morphine). In each Group n = 15

Respiratory ratenoted during

infusion(per minute)

Group I Group II

Inter group t value P valueMean Standard

deviation

Mean Standard

deviation

Baseline 22.27 4.40 21.07 4.65 0.527 0.474

1 hour 21.07 3.53 18.8 5.0 2.054 0.163

2 hours 21.73 3.20 19.13 4.91 2.953 0.097

3 hours 20.67 5.89 19.33 4.51 0.484 0.492

4 hours 21.47 3.42 19.53 5.69 1.271 0.269

8 hours 21.87 2.56 18.67 5.0 4.875 0.036*

12 hours 21.33 3.18 18.67 4.76 3.256 0.082

16 hours 21.6 2.41 19.07 4.46 3.738 0.063

20 hours 22.00 3.46 19.60 5.03 2.319 0.139

24 hours 21.73 2.71 18.87 4.32 4.732 0.038*

* P< 0.05 significant. No clinically significant difference was noted in the respiratory rates during infusion among both groups although statisti-callysignificantdifferencewas noted at8 and24 hours.Thisshows that both Groupshad similar andcomparableeffectson respiratory rate.

TABLE 5. Systolic blood pressure (SBP) measured at fixed intervals in Group I (who received intrave-nous morphine) and Group II (who received subcutaneous morphine). In each group n = 15

Systolic bloodpressuremeasured

during infusion(in mms of Hg)

Group I Group II

Inter group t value P valueMean Standarddeviation

Mean Standarddeviation

Baseline 116.67 9.76 118.80 36.39 0.048 0.828

1 hour 114.67 9.15 120.40 12.05 2.153 0.153

2 hours 114.00 8.28 122.00 17.40 2.585 0.119

3 hours 114.80 10.16 118.27 15.75 0.513 0.480

4 hours 113.27 13.52 115.33 11.25 0.207 0.653

8 hours 109.33 12.23 114.93 11.18 1.713 0.201

12 hours 106.00 11.83 115.87 10.51 5.828 0.023*

16 hours 107.20 9.59 117.00 9.60 7.828 0.009*

20 hours 108.67 12.89 115.87 8.23 3.326 0.079

24 hours 108 10.82 115.67 6.23 5.653 0.024*

* P< 0.05 significant. Systolic blood pressure showed a decreasing trend over time in both Groups although not clinically significant. Both

groups showed a statisticallysignificant difference in SBPat 12, 16 and 24 hours. The mildfall in blood pressure couldbe the result of effectiveanalgesia and hence reduced catecholamine release in these patients.


6/8


TABLE 6. Paired sample t test showing comparison of VAS scale at different time intervals

Group MeanStandarddeviation

Standarderror

(mean)

95% confidencelimits t

valueP

valueUpper Lower

Group I Pair 1 V0 & V1 2.33 1.59 0.41 3.21 1.45 5.688 0.0001 *Group I Pair 2 V0 & V2 3.73 2.25 0.58 4.98 2.49 6.424 0.0001 *

Group I Pair 3 V0 & V3 4.87 1.73 0.45 5.82 3.91 10.917 0.0001 *

Group I Pair 4 V0 & V4 5.20 1.93 0.50 6.27 4.13 10.410 0.0001 *

Group I Pair 5 V0 & V5 5.80 1.86 0.48 6.83 4.77 12.081 0.0001 *

Group I Pair 6 V0 & V6 6.47 1.64 0.42 7.38 5.56 15.256 0.0001 *

Group I Pair 7 V0 & V7 6.73 1.53 0.40 7.58 5.88 17.003 0.0001 *

Group I Pair 8 V0 & V8 6.73 1.71 0.44 7.68 5.79 15.251 0.0001 *

Group I Pair 9 V0 & V9 7.13 1.41 0.36 7.91 6.35 19.629 0.0001 *

Group II Pair 1 V0 & V1 2.40 2.06 0.53 3.54 1.26 4.505 0.0001 *

Group II Pair 2 V0 & V2 3.87 1.77 0.46 4.85 2.89 8.473 0.0001 *

Group II Pair 3 V0 & V3 4.60 2.23 0.58 5.83 3.37 7.990 0.0001 *

Group II Pair 4 V0 & V4 5.33 1.76 0.45 6.31 4.36 11.741 0.0001 *

Group II Pair 5 V0 & V5 5.73 1.79 0.46 6.73 4.74 12.395 0.0001 *

Group II Pair 6 V0 & V6 6.27 1.67 0.43 7.19 5.34 14.554 0.0001 *

Group II Pair 7 V0 & V7 6.60 1.96 0.51 7.68 5.52 13.064 0.0001 *

Group II Pair 8 V0 & V8 7.20 1.66 0.43 8.12 6.28 16.837 0.0001 *

Group II Pair 9 V0 & V9 7.60 1.30 0.34 8.32 6.88 22.671 0.0001 *

* P < 0.05 significant. Statistically significant pain relief was achieved in both groups throughout the period of infusion.

TABLE 7. Between-group comparison of sedationscore at fixed time intervals tested by ANOVA (n =15 in each group). Group I received intravenousmorphine and Group II received morphine subcu-taneously

Timeintervals

PairsF value P value

Group I Group II

1 hour S1 S1 0.2732 0.6054

2 hours S2 S2 3.0624 0.0915

3 hours S3 S3 0.2342 0.6323

4 hours S4 S4 0.2996 0.5886

8 hours S5 S5 0.2024 0.6564

12 hours S6 S6 1.0065 0.3246

16 hours S7 S7 2.2400 0.1457

20 hours S8 S8 0.1489 0.7025

24 hours S9 S9 0.1273 0.7240

P < 0.05significant. S1, 2,3, 4,5, 6,7, 8,9 standsforsedationat 1,2,3, 4, 8, 12, 16, 20 and 24 hours, respectively.

TABLE 8. Paired sample t test showing comparisonof sedation score at different time intervals (S1 = 1hour,S2 = 2 hours,S3 = 3 hours, S4 = 4 hours, S5 =8 hours, S6 = 12 hours, S7 = 16 hours, S8 = 20hours and S9 = 24 hours)

Group t value P value

Group I Pair 1 S1 & S2 0.713 0.004 *

Group I Pair 2 S1 & S3 0.548 0.043 *

Group I Pair 3 S1 & S4 0.228 0.433

Group I Pair 4 S1 & S5 0.228 0.433

Group I Pair 5 S1 & S6 0.175 0.549

Group I Pair 6 S1 & S7 0.000 1.000

Group I Pair 7 S1 & S8 0.300 0.297

Group I Pair 8 S1 & S9 0.411 0.145

Group II Pair 1 S1 & S2 0.535 0.040 *

Group II Pair 2 S1 & S3 0.431 0.108Group II Pair 3 S1 & S4 0.200 0.474

Group II Pair 4 S1 & S5 0.559 0.030 *

Group II Pair 5 S1 & S6 0.354 0.196

Group II Pair 6 S1 & S7 0.302 0.275

Group II Pair 7 S1 & S8 0.354 0.196

Group II Pair 8 S1 & S9 0.134 0.635

*P < 0.05significant.Statistically significant sedation wasnoticedat 1hour and 8 hours of onset of infusion in Group II and at 1st and 2ndhours in Group.


7/8

tion for morphine was as effective as the IVroute for continuous administration. Either ofthese routes could be used to provide good an-algesia in emergencies.

In conclusion, the SC route may be an excel-

lent alternative to IV administration for mor-phine.Continuousinfusionsprovidedgoodpainrelief throughout the duration of the morphineadministration byboth the SCandIVroutes.Thegravity-dependant drip method of continuousdrug delivery is a cost-effective, simple tech-niqueeffectiveinensuringadequateanalgesia.

REFERENCES

1. Rowlingson JC, Murphy TM. Chronic Pain. InMiller RD, ed. Anesthesia. Fifth edition. Volume V.

Churchill Livingstone, 2000; 2351-76.2. Zachrisson U, Furst CJ. Drug infusors in pallia-tive medicine: a Swedish inquiry. J Pain Symptom Man-age 1998; 75:299-304.

3. Herndon CM, Fike DS. Continuous subcutane-ous infusion practices of United States Hospices. J PainSymptom Manage 2001; 22:1027-34.

4. ODoherty CA,Hall EJ, Schofield L, et al.Drugsand syringe drivers: a survey of adult specialist pallia-tive care practice in the United Kingdom and Eire.Palliat Med 2001; 15:149-54.

5. MurrayCJL, Lopez A. Global and regional causeof death of patients in 1990. Bulletin of the WHO 1994;

72:447-80.6. WHO Cancer Pain Relief, Geneva, WHO 1986.7. Koli SP. Palliative care and pain relief. National

Cancer Control Programme, India 1995;100-01.8. Rao DN, Ganesh B. Estimate of cancer incidence

in India in1991. Indian J Cancer 1998;35:8-10.9. Collin E, Poulain P, Guavain-Piquard A: Is dis-

ease progression the major factor in morphine toler-ance in cancer treatment? Pain 1993;5:319.

10. Thornsen AB, Yung NS, Leung AC, et al. Ad-ministration of drugs by infusion pumps in palliativemedicine. Ann Acad Med Singapore 1994; 23:209-11.

11. Poniatowski L. Continuous subcutaneous infu-sions for pain control. J Intraven Nurs 1991;14:30-5.

RECEIVED: 05/15/04REVISED: 06/20/04

ACCEPTED: 07/07/04

Koshy et al. 33


8/8

Documents

MORFINA SUBCUTANEA